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Targeting tumor metabolism to augment CD8+ T cell anti-tumor immunity
Huan Liu, Wenyong Yang, Jingwen Jiang
, Available online  , doi: 10.1016/j.jpha.2024.101150
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CD8+ T cell-based immune-therapeutics, including immune checkpoint inhibitors and adoptive cell therapies (TILs, TCR-T, CAR-T), have achieved significant successes and prolonged patient survival to varying extents and even achieved cure in some cases. However, immunotherapy resistance and tumor insusceptibility frequently occur, leading to treatment failure. Recent evidences have highlighted the ponderance of tumor cells metabolic reprogramming in establishing an immunosuppressive milieu through the secretion of harmful metabolites, immune-inhibitory cytokines, and alteration of gene expression, which suppress the activity of immune cells, particularly CD8+ T cells to evade immune surveillance. Therefore, targeting tumor cell metabolic adaptations to reshape the immune microenvironment holds promise as an immunomodulatory strategy to facilitate immunotherapy. Here, we summarize recent advances in the crosstalk between immunotherapy and tumor reprogramming, focusing on the regulatory mechanisms underlying tumor cell glucose metabolism, amino acid metabolism, and lipid metabolism in influencing CD8+ T cells to provide promising metabolic targets or combinational strategies for immunotherapy.
Rapid enrichment and SERS differentiation of various bacteria in skin interstitial fluid by 4-MPBA-AuNPs-functionalized hydrogel microneedles
Ying Yang, Xingyu Wang, Yexin Hu, Zhongyao Liu, Xiao Ma, Feng Feng, Feng Zheng, Xinlin Guo, Wenyuan Liu, Wenting Liao, Lingfei Han
, Available online  , doi: 10.1016/j.jpha.2024.101152
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Bacterial infection is a major threat to global public health, and can cause serious diseases such as bacterial skin infection and foodborne diseases. It is essential to develop a new method to rapidly diagnose clinical multiple bacterial infections and monitor food microbial contamination in production sites in real-time. In this work, we developed a 4-mercaptophenylboronic acid gold nanoparticles (4-MPBA-AuNPs)-functionalized hydrogel microneedle (MPBA-MN) for bacteria detection in skin interstitial fluid. MPBA-MN could conveniently capture and enrich a variety of bacteria within 5 min. Surface enhanced Raman spectroscopy (SERS) detection was then performed and combined with machine learning technology to distinguish and identify a variety of bacteria. Overall, the capture efficiency of this method exceeded 50%. In the concentration range of 1×107 to 1×1010 colony-forming units/mL (CFU/mL), the corresponding SERS intensity showed a certain linear relationship with the bacterial concentration. Using rank forest-based machine learning, bacteria were effectively distinguished with an accuracy of 97.87%. In addition, the harmless disposal of used microneedles by photothermal ablation was convenient, environmentally friendly and inexpensive. This technique provided a potential method for rapid and real-time diagnosis of multiple clinical bacterial infections and for monitoring microbial contamination of food in production sites.
Hypothalamic lipidomics reveals that AMPK-FA metabolism mediates the energy-balancing effect of the four typical ‘hot’ herbs on hypothyroidism
Yangyang Wang, Yizhou Rong, Liangce Chen, Qi Cui, Haixue Kuang, Bo Yang
, Available online  , doi: 10.1016/j.jpha.2024.101151
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Natural products for the treatment of age-related macular degeneration: new insights focusing on mitochondrial quality control and cGAS/STING pathway
Xuelu Xie, Shan Lian, Wenyong Yang, Sheng He, Jingqiu He, Yuke Wang, Yan Zeng, Fang Lu, Jingwen Jiang
, Available online  , doi: 10.1016/j.jpha.2024.101145
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Age-related macular degeneration (AMD) is a disease that affects the vision of elderly individuals worldwide. Although current therapeutics have shown effectiveness against AMD, some patients may remain unresponsive and continue to experience disease progression. Therefore, in-depth knowledge of the mechanism underlying AMD pathogenesis is urgently required to identify potential drug targets for AMD treatment. Recently, studies have suggested that dysfunction of mitochondria can lead to the aggregation of reactive oxygen species (ROS) and activation of the cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) innate immunity pathways, ultimately resulting in sterile inflammation and cell death in various cells, such as cardiomyocytes and macrophages. Therefore, combining strategies targeting mitochondrial dysfunction and inflammatory mediators may hold great potential in facilitating AMD management. Notably, emerging evidence indicates that natural products targeting mitochondrial quality control (MQC) and the cGAS/STING innate immunity pathways exhibit promise in treating AMD. Here, we summarize phytochemicals that could directly or indirectly influence the MQC and the cGAS/STING innate immunity pathways, as well as their interconnected mediators, which have the potential to mitigate oxidative stress and suppress excessive inflammatory responses, thereby hoping to offer new insights into therapeutic interventions for AMD treatment.
Polyphyllin VII promotes hepatic stellate cell ferroptosis via the HIC1/CX3CL1/GPX4 axis
Feng Jiang, Xinmiao Li, Mengyuan Li, Weizhi Zhang, Yifei Li, Lifan Lin, Lufan He, Jianjian Zheng
, Available online  , doi: 10.1016/j.jpha.2024.101147
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Ferroptosis has been shown to mediate the development of fibrosis. Polyphyllin VII (PP7), a bioactive component of Paris polyphylla, exhibits potent anti-inflammatory activity and can significantly alleviate liver fibrosis. In this study, treatment with PP7 significantly inhibited the proliferation and activation of hepatic stellate cells (HSCs), which could be suppressed by a ferroptosis inhibitor. In addition, it promoted HSC ferroptosis by suppressing glutathione peroxidase 4 (GPX4) and enhanced the expression of CX3C chemokine ligand 1 (CX3CL1). Depletion of CX3CL1 attenuated the effects of PP7 on the activation and ferroptosis of HSCs and the expression of GPX4. Notably, CX3CL1 directly interacted with GPX4, triggering HSC ferroptosis. The transcription factor hypermethylated in cancer 1 (HIC1), which binds to the CX3CL1 promoter, increased the expression of CX3CL1. Its absence resulted in downregulation of CX3CL1, suppressing the GPX4-dependent ferroptosis of PP7-treated HSCs and promoting their activation. HIC1 was found to directly interact with PP7 at the GLY164 site. Co-culture experiments showed that PP7-induced HSC ferroptosis attenuated macrophage recruitment by regulating inflammation-related genes. HSC-specific inhibition of HIC1 counteracted PP7-induced collagen depletion and HSC ferroptosis in vivo. These findings suggest that PP7 induces HSC ferroptosis through the HIC1/CX3CL1/GPX4 axis.
Depression of CaV1.2 activation and expression in mast cells ameliorates allergic inflammation diseases
Yongjing Zhang, Yingnan Zeng, Haoyun Bai, Wen Zhang, Zhuoyin Xue, Shiling Hu, Shemin Lu, Nan Wang
, Available online  , doi: 10.1016/j.jpha.2024.101149
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Allergic inflammation is closely related to the activation of mast cells (MCs), which is regulated by its intracellular Ca2+ level, but the intake and effects of the intracellular Ca2+ remain unclear. The Ca2+ influx is controlled by members of Ca2+ channels, among which calcium voltage-gated channel subunit alpha1 C (CaV1.2) is the most robust. This study aimed to reveal the role and underlying mechanism of MC CaV1.2 in allergic inflammation. We found that Cav1.2 participated in MC activation and allergic inflammation. Nimodipine (Nim), as a strong CaV1.2-specific antagonist, ameliorated allergic inflammation in mice. Further, CaV1.2 activation in MC was triggered by phosphatizing at its Ser1928 through protein kinase C (PKC), which calcium–calmodulin-dependent protein kinase II (CaMKII) catalyzed. Overexpression or knockdown of MC CaV1.2 influenced MC activation. Importantly, CaV1.2 expression in MC had detrimental effects, while its deficiency ameliorated allergic pulmonary inflammation. Results provide novel insights into Cav1.2 function and a potential drug target for controlling allergic inflammation.
Exploring the potential protective role of anthocyanins in mitigating micro/nanoplastic-induced reproductive toxicity: A steroid receptor perspective
Jiaojiao Zhang, Wenyi Liu, Fuqiang Cui, Marjukka Kolehmainen, Jing Chen, Lei Zhang, Iman Zarei
, Available online  , doi: 10.1016/j.jpha.2024.101148
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Microplastics and nanoplastics (MPs/NPs) are ubiquitous environmental pollutants that act as endocrine-disrupting chemicals, raising significant concerns about their impact on human health. Research highlights the hazardous effects of MPs/NPs on both male and female reproductive systems, influencing germ cells, embryo development, and progeny. Additionally, studies show that MPs/NPs affect the gene expression of anabolic steroid hormones in vitro and in vivo, inducing reproductive toxicity through mechanisms such as oxidative stress and inflammation. Considering these adverse effects, identifying natural compounds that can mitigate the toxicity of MPs/NPs is increasingly important. Plants offer a wealth of antioxidants and anti-inflammatory compounds that can counteract these harmful effects. Among these, anthocyanins, natural colorants responsible for the vibrant hues of fruits and flowers, exhibit a wide range of biological activities, including antioxidant, anti-inflammatory, and antineoplastic properties. Moreover, anthocyanins can modulate sex hormone levels and alleviate reproductive toxicity. Cyanidin-3-glucoside (C3G), one of the most extensively studied anthocyanins, shows promise in reducing reproductive toxicity, particularly in females, and in protecting male reproductive organs, including the testis and epididymis. This protective effect is believed to result from its interaction with steroid receptors, specifically the androgen and estrogen receptors. These findings highlight the need to explore the mechanisms by which anthocyanins mitigate the reproductive toxicity caused by MPs/NPs. This review provides novel insights into how natural compounds can be leveraged to lessen the impact of environmental contaminants on human health, especially concerning reproductive health.
Mitochondrial quality control disorder in neurodegenerative disorders: potential and advantages of traditional Chinese medicines
Lei Xu, Tao Zhang, Baojie Zhu, Honglin Tao, Yue Liu, Xianfeng Liu, Yi Zhang, Xianli Meng
, Available online  , doi: 10.1016/j.jpha.2024.101146
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Mitochondrial quality control disorder in neurodegenerative disorders: Potential and advantages of traditional Chinese medicines Abstract Neurodegenerative disorders (NDDs) are prevalent chronic conditions characterized by progressive synaptic loss and pathological protein alterations. Increasing evidence suggested that mitochondrial quality control (MQC) serves as the key cellular process responsible for clearing misfolded proteins and impaired mitochondria. Herein, we provided a comprehensive analysis of the mechanisms through which MQC mediates the onset and progression of NDDs, emphasizing mitochondrial dynamic stability, the clearance of damaged mitochondria, and the generation of new mitochondria. In addition, traditional Chinese medicines (TCMs) and their active monomers targeting MQC in NDD treatment have been demonstrated. Consequently, we compiled the TCMs that show great potential in the treatment of NDDs by targeting MQC, aiming to offer novel insights and a scientific foundation for the use of MQC stabilizers in NDD prevention and treatment.
Elucidating the role of artificial intelligence in drug development from the perspective of drug-target interactions
Boyang Wang, Tingyu Zhang, Qingyuan Liu, Chayanis Sutcharitchan, Ziyi Zhou, Dingfan Zhang, Shao Li
, Available online  , doi: 10.1016/j.jpha.2024.101144
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Drug development remains a critical issue in the field of biomedicine. With the rapid advancement of information technologies such as artificial intelligence (AI) and the advent of the big data era, AI-assisted drug development has become a new trend, particularly in predicting drug-target associations. To address the challenge of drugtarget prediction, AI-driven models have emerged as powerful tools, offering innovative solutions by effectively extracting features from complex biological data; accurately modeling molecular interactions; and precisely predicting potential drug-target outcomes. Traditional machine learning, network-based, and advanced deep learning architectures such as convolutional neural networks (CNNs), graph convolutional networks (GCNs), and transformers each play a pivotal role. This review systematically compiles and evaluates AI algorithms for drug- and drug combination-target predictions, highlighting their theoretical frameworks, strengths, and limitations. CNNs effectively identify spatial patterns and molecular features critical for drug-target interactions. GCNs provide deep insights into molecular interactions via relational data, whereas transformers increase prediction accuracy by capturing complex dependencies within biological sequences. Network-based models offer a systematic perspective by integrating diverse data sources, and traditional machine learning efficiently handles large datasets to improve overall predictive accuracy. Collectively, these AI-driven methods are transforming drug-target predictions and advancing the development of personalized therapy. This review summarizes the application of AI in drug development, particularly in drug-target prediction, and offers recommendations on models and algorithms for researchers engaged in biomedical research. It also provides typical cases to better illustrate how AI can further accelerate development in the fields of biomedicine and drug discovery.
Probing the Biological Efficacy and Mechanistic Pathways of Natural Compounds in Breast Cancer Therapy via the Hedgehog Signaling Route
Yining Cheng, Wenfeng Zhang, Qi Sun, Xue Wang, Qihang Shang, Jingyang Liu, Yubao Zhang, Ruijuan Liu, Changgang Sun
, Available online  , doi: 10.1016/j.jpha.2024.101143
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Breast cancer (BC) is one of the most prevalent malignant tumors affecting women worldwide, with its incidence rate continuously increasing. As a result, treatment strategies for this disease have received considerable attention. Research has highlighted the crucial role of the Hedgehog (Hh) signaling pathway in the initiation and progression of BC, particularly in promoting tumor growth and metastasis. Therefore, molecular targets within this pathway represent promising opportunities for the development of novel BC therapies. This study aims to elucidate the therapeutic mechanisms by which natural compounds modulate the Hh signaling pathway in BC. By conducting a comprehensive review of various natural compounds—including polyphenols, terpenes, and alkaloids—we reveal both common and unique regulatory mechanisms that influence this pathway. This investigation represents the first comprehensive analysis of five distinct mechanisms through which natural compounds modulate key molecules within the Hh pathway and their impact on the aggressive behaviors of BC. Furthermore, by exploring the structure-activity relationships between these compounds and their molecular targets, we shed light on the specific structural features that enable natural compounds to interact with various components of the Hh pathway. These novel insights contribute to advancing the development and clinical application of natural compound-based therapeutics. Our thorough review not only lays the groundwork for exploring innovative BC treatments but also opens new avenues for leveraging natural compounds in cancer therapy.
Ginsenoside Rb1 inhibits cardiomyocyte apoptosis and rescues ischemic myocardium by targeting Caspase-3
Chenhui Zhong, Liyuan Ke, Fen Hu, Zuan Lin, Shuming Ye, Ziyao Zheng, Shengnan Han, Zan Lin, Yuying Zhan, Yan Hu, Peiying Shi, Lei Wen, Hong Yao
, Available online  , doi: 10.1016/j.jpha.2024.101142
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Inhibiting Neddylation: A New Strategy for Tumor Therapy
Jian Sun, Cui Liu, Changhui Lang, Jing Wang, Qingxiang Li, Chang Peng, Zuochen Du, Yan Chen, Pei Huang
, Available online  , doi: 10.1016/j.jpha.2024.101140
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Neddylation is a crucial posttranslational modification that involves the attachment of neural precursor cellexpressed developmentally downregulated protein 8 (NEDD8) to a lysine residue in the substrate via the sequential actions of the E1 NEDD8-activating enzyme (NAE), E2 NEDD8-conjugating enzyme (E2), and E3 NEDD8-ligase (E3). The most extensively studied substrates of neddylation are members of the cullin family, which act as scaffold components for cullin ring E3 ubiquitin ligases (CRLs). Since cullin neddylation activates CRLs, which are frequently overactive in tumors, inhibiting neddylation has emerged as a promising strategy for developing novel antitumor therapies. This review explores the antitumor effects of inhibiting neddylation that leads to the inactivation of CRLs and provides a summary of known inhibitors that target protein-protein interactions (PPIs) within the neddylation enzymatic cascade.
The role of mitochondria transfer in cancer biological behavior, the immune system and therapeutic resistance
Xintong Lyu, Yangyang Yu, Yuanjun Jiang, Zhiyuan Li, Qiao Qiao
, Available online  , doi: 10.1016/j.jpha.2024.101141
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Mitochondria play a crucial role as organelles, managing several physiological processes such as redox balance, cell metabolism, and energy synthesis. Initially, the assumption was that mitochondria primarily resided in the host cells and could exclusively transmit from oocytes to offspring by a mechanism known as vertical inheritance of mitochondria.
Recent scholarly works, however, suggest that certain cell types transmit their mitochondria to other developmental cell types via a mechanism referred to as intercellular or horizontal mitochondrial transfer.
This review details the process of which mitochondria are transferred across cells and explains the impact of mitochondrial transfer between cells on the efficacy and functionality of cancer cells in various cancer forms. Specifically, we review the role of mitochondria transfer in regulating cellular metabolism restoration, excess reactive oxygen species (ROS) generation, proliferation, invasion, metastasis, mitophagy activation, mitochondrial DNA (mtDNA) inheritance, immune system modulation and therapeutic resistance in cancer. Additionally, we highlight the possibility of using intercellular mitochondria transfer as a therapeutic approach to treat cancer and enhance the efficacy of cancer treatments.
Huangqin decoction inhibits colorectal inflammatory cancer transformation by improving gut microbiome-mediated metabolic dysfunction
Lu Lu, Yuan Li, Hang Su, Sisi Ren, Yujing Liu, Gaoxuan Shao, Weiwei Liu, Guang Ji, Hanchen Xu
, Available online  , doi: 10.1016/j.jpha.2024.101138
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Colorectal inflammatory cancer transformation poses a major risk to patients with colitis. Patients with chronic intestinal inflammation have an approximately 2- 3fold increased risk of developing colorectal cancer (CRC). Unfortunately, there is currently no effective intervention available. Huangqin decoction (HQD), a wellknown traditional Chinese medicine (TCM) formula, is frequently clinically prescribed for treating patients with colitis, and its active ingredients have effective antitumour efficacy. Nonetheless, the mechanism of HQD-mediated prevention of colorectal inflammatory cancer transformation remains unclear. A strategy integrating metagenomic, lipidomic, and messenger RNA (mRNA) sequencing analysis was used to investigate the regulatory effects of HQD on the gut microbiome, metabolism and potential mechanisms involved in colorectal inflammatory cancer transformation. Our study revealed that HQD suppressed colorectal inflammatory cancer transformation, which was associated with enhanced intestinal barrier function, decreased the inflammatory response, and regulation of the gut microbiome. Notably, cohousing experiments revealed that the transfer of the gut microbiome from HQD-treated mice largely inhibited the pathological transformation of colitis. Moreover, gut microbiome transfer from HQD-treated mice primarily resulted in the altered regulation of fatty acid metabolism, especially the remodeling of arachidonic acid metabolism, which was associated with the amelioration of pathological transformation. Arachidonic acid metabolism and the key metabolic enzyme arachidonic acid 12-lipoxygenase (ALOX12) were affected by HQD treatment, and no obvious protective effect of HQD was observed in ALOX12-/- mice, which revealed that ALOX12 was a critical mediator of HQD protection against colorectal inflammatory cancer transformation. In summary, multiple omics analyses were applied to produce valuable data and theoretical support for the application of HQD as a promising intervention for the transformation of inflammatory colorectal cancer.
Diffusion-based generative drug-like molecular editing with chemical natural language
Jianmin Wang, Peng Zhou, Zixu Wang, Wei Long, Yangyang Chen, Kyoung Tai No, Dongsheng Ouyang, Jiashun Mao, Xiangxiang Zeng
, Available online  , doi: 10.1016/j.jpha.2024.101137
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Recently, diffusion models have emerged as a promising paradigm for molecular design and optimization. However, most diffusion-based molecular generative models focus on modeling 2D graphs or 3D geometries, with limited research on molecular sequence diffusion models. The International Union of Pure and Applied Chemistry (IUPAC) names are more akin to chemical natural language than the Simplified Molecular Input Line Entry System (SMILES) for organic compounds. In this work, we apply an IUPAC-guided conditional diffusion model to facilitate molecular editing from chemical natural language to chemical language (SMILES) and explore whether the pre-trained generative performance of diffusion models can be transferred to chemical natural language. We propose DiffIUPAC, a controllable molecular editing diffusion model that converts IUPAC names to SMILES strings. Evaluation results demonstrate that our model outperforms existing methods and successfully captures the semantic rules of both chemical languages. Chemical space and scaffold analysis show that the model can generate similar compounds with diverse scaffolds within the specified constraints. Additionally, to illustrate the model's applicability in drug design, we conducted case studies in functional group editing, analogue design and linker design.
Raman Analysis of Lipids in Cells: Current Applications and Future Prospects
Yixuan Zhou, Yuelin Xu, Xiaoli Hou, Daozong Xia
, Available online  , doi: 10.1016/j.jpha.2024.101136
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Lipids play an important role in the regulation of cell life processes. Although there are various lipid detection methods, Raman spectroscopy, a non-invasive technique, provides the detailed chemical composition of lipid profiles without a complex sample preparation procedure and possesses greater potential in basic biology, clinical diagnosis and disease therapy. In this review, we summarized the characteristics and advantages of Raman-based techniques and their primary contribution to illustrating cellular lipid metabolism.
Gold nanorod-based engineered nanogels for cascade-amplifying photothermoenzymatic synergistic therapy
Ling Ding, Xiaoshan Wang, Qing Wu, Xia Wang, Qigang Wang
, Available online  , doi: 10.1016/j.jpha.2024.101139
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Reactive oxygen species (ROS)-mediated anticancer modalities, which disturb the redox balance of cancer cells through multi-pathway simulations, hold great promise for effective cancer management. Among these, cooperative physical and biochemical activation strategies have attracted increasing attention because of their spatiotemporal controllability, low toxicity, and high therapeutic efficacy. Herein, we demonstrate a nanogel complex as a multilevel ROS-producing system by integrating chloroperoxidase (CPO) into gold nanorod-based nanogels (ANGs) for cascadeamplifying photothermal-enzymatic synergistic tumor therapy. Benefiting from photothermal-induced hyperthermia upon near-infrared laser exposure, the exogenous ROS (including H2O2) were boosted by the AuNR nanogel owing to the intercellular stress response. This ultimately promoted the efficient enzyme-catalyzed reaction of loaded CPO combined with the rich endogenous H2O2 in tumor cells to significantly elevate intracellular ROS levels above the threshold for improved therapeutic outcomes. Both in vitro and in vivo studies have verified the cascade-amplifying ROSmediated antitumor effects, providing feasible multimodal synergistic tactics for tumor treatment.
Open flow microperfusion to assess local drug concentrations in the buccal mucosa
Laura Wiltschko, Paula Fischer, Simon Schwingenschuh, Reingard Raml, Georg Raber, Thomas Birngruber, Eva Roblegg
, Available online  , doi: 10.1016/j.jpha.2024.101135
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Multi-Scale Information Fusion and Decoupled Representation Learning for Robust Microbe-Disease Interaction Prediction
Wentao Wang, Qiaoying Yan, Qingquan Liao, Xinyuan Jin, Yinyin Gong, Linlin Zhuo, Xiangzheng Fu, Dongsheng Cao
, Available online  , doi: 10.1016/j.jpha.2024.101134
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Research indicates that microbe activity within the human body significantly influences health by being closely linked to various diseases. Accurately predicting microbe-disease interactions (MDIs) offers critical insights for disease intervention and pharmaceutical research. Current advanced AI-based technologies automatically generate robust representations of microbes and diseases, enabling effective MDI predictions. However, these models continue to face significant challenges. A major issue is their reliance on complex feature extractors and classifiers, which substantially diminishes the models’ generalizability. To address this, we introduce a novel graph autoencoder framework that utilizes decoupled representation learning and multi-scale information fusion strategies to efficiently infer potential MDIs. Initially, we randomly mask portions of the input microbe-disease graph based on Bernoulli distribution to boost self-supervised training and minimize noise-related performance degradation. Secondly, we employ decoupled representation learning technology, compelling the graph neural network (GNN) to independently learn the weights for each feature subspace, thus enhancing its expressive power. Finally, we implement multi-scale information fusion technology to amalgamate the multi-layer outputs of GNN, reducing information loss due to occlusion. Extensive experiments on public datasets demonstrate that our model significantly surpasses existing top MDI prediction models. This indicates that our model can accurately predict unknown MDIs and is likely to aid in disease discovery and precision pharmaceutical research.
Hemodynamic Disturbance and mTORC1 Activation: Unveiling the Biomechanical Pathogenesis of Thoracic Aortic Aneurysms in Marfan Syndrome
MingYuan Liu, Meili Wang, JunjunLiu, AnQiang Sun, ChangShun He, Xin Cong, Wei Kong, Wei Li
, Available online  , doi: 10.1016/j.jpha.2024.101120
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Thoracic aortic aneurysm (TAA) significantly endangers the lives of individuals with Marfan syndrome (MFS), yet the intricacies of their biomechanical origins remain elusive. Our investigation delves into the pivotal role of hemodynamic disturbance in the pathogenesis of TAA, with a particular emphasis on the mechanistic contributions of the mammalian target of rapamycin (mTOR) signaling cascade. We uncovered that activation of the mTOR complex 1 (mTORC1) within smooth muscle cells, instigated by the oscillatory wall shear stress (OSS) that stems from disturbed flow (DF), is a catalyst for TAA progression. This revelation was corroborated through both an MFS mouse model (Fbn1+/C1039G) and clinical MFS specimens. Crucially, our research demonstrates a direct linkage between the activation of the mTORC1 pathway and the intensity in OSS. Therapeutic administration of rapamycin suppresses mTORC1 activity, leading to the attenuation of aberrant SMC behavior, reduced inflammatory infiltration, and restoration of extracellular matrix integrity—collectively decelerating TAA advancement in our mouse model. These insights posit the mTORC1 axis as a strategic target for intervention, offering a novel approach to manage TAAs in MFS and potentially pave insights for current treatment paradigms.
The biological roles of exosome-encapsulated traditional Chinese medicine monomers in neuronal disorders
Chen Pang, Jie Zhang, Yujin Gu, Qili Zhang, Yanfang Zhao
, Available online  , doi: 10.1016/j.jpha.2024.101131
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A traditional Chinese medicine (TCM) monomer is a bioactive compound extracted from Chinese herbal medicines possessing determined biological activity and pharmacological effects, that has gained much attention for treating neuronal diseases. However, the application of TCM monomers is limited by their low solubility and poor ability to cross the blood-brain barrier (BBB). Exosomes are small extracellular vesicles ranging in size from 30– 150 nm in diameter and can be used as drug delivery carriers that directly target cells or tissues with unique advantages, including low toxicity, low immunogenicity, high stability in blood, and the ability to cross the BBB. This review discusses the biogenesis, components, stability, surface modification, isolation technology, advantages, and disadvantages of exosomes as drug carriers and compares exosomes and other similar drug delivery systems. Furthermore, exosome-encapsulated TCM monomers exert neuroprotective roles, such as anti-inflammation, anti-apoptosis, anti-mitophagy, and anti-oxidation, in various neuronal diseases, including Alzheimer's disease (AD), Parkinson’s disease (PD), multiple sclerosis (MS), and cerebral ischemia and reperfusion injury (CI/R), as well as anti-drug resistance, anti-tumorigenesis, anti-angiogenesis, and promotion of apoptosis in brain tumors, providing more inspiration to promote the development of an exosome-based delivery tool in targeted therapy for neuronal diseases.
Lycium Barbarum's Diabetes Secrets: A Comprehensive Review of Cellular, Molecular, and Epigenetic Targets with Immune Modulation and Microbiome Influence
Zeshan Ali, Aqsa Ayub, Ya wen Lin, Sonam Anis, Ishrat Khan, Shoaib Younas, Rana Adnan Tahir, Shulin Wang, Jianrong Li
, Available online  , doi: 10.1016/j.jpha.2024.101130
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Diabetes, a metabolic disease stemming from impaired or defective insulin secretion, ranks among the most severe chronic illnesses globally. While several approved drugs exist for its treatment, they often come with multiple side effects. Therefore, there is a pressing need for safe and effective anti-diabetic medications. Traditional Chinese medicine has recognized Lycium barbarum (LB, goji berry) plant, commonly known as "wolfberry fruit" in China, for over 2,000 years. Natural compounds derived from LB show promise in reducing diabetes levels. Although research on the impact of LB on diabetes is still limited, our review aims to explore the potential of LB in reducing the risk of diabetes and examine the underlying mechanisms involved. LB can modulate diabetes through various pathways, such as inhibiting α-amylase and α-glucosidase activities, promoting β-cell proliferation, stimulating insulin secretion, inhibiting glucagon secretion, improving insulin resistance and glucose tolerance, and enhancing antioxidant and anti-inflammatory activities. Additionally, LB improves gut flora and immunomodulation, further aiding diabetes management. These findings highlight the potential clinical utility of LB in managing diabetes and its complications within the framework of evidence-based modern medicine.
Advanced treatment strategies for high-altitude pulmonary hypertension employing natural medicines: A review
Zahra Batool, Mohammad Amjad Kamal, Bairong Shen
, Available online  , doi: 10.1016/j.jpha.2024.101129
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High-altitude pulmonary hypertension (HAPH) occurs when blood pressure in the pulmonary arteries rises due to exposure to high altitudes above 2,500 m. At these elevations, reduced atmospheric pressure leads to lower oxygen levels, triggering a series of physiological responses, including pulmonary artery constriction, which elevates blood pressure. This review explored the complex pathophysiological mechanisms of HAPH and reviewed current pharmaceutical interventions for its management. Meanwhile, particularly emphasized on the emerging research concerning Chinese medicinal plants as potential treatments for HAPH. Traditional Chinese medicines are rich in diverse natural ingredients that show significant promise in alleviating HAPH symptoms. We reviewed both in vitro and in vivo studies to assess the efficacy, safety, and mechanisms of these natural medicines, along with their potential adverse effects. Additionally, this review highlighted new alternative natural remedies, underscoring the need for ongoing research to expand available treatment options for HAPH.
Discovery of E0199: A novel compound targeting both peripheral NaV and KV7 channels to alleviate neuropathic pain
Boxuan Zhang, Xiaoxing Shi, Xingang Liu, Yan Liu, Xuedong Li, Qi Wang, Dongyang Huang, Weidong Zhao, Junru Cui, Yawen Cao, Xu Chai, Jiahao Wang, Yang Zhang, Xiangyu Wang, Qingzhong Jia
, Available online  , doi: 10.1016/j.jpha.2024.101132
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This research study focuses on addressing the limitations of current neuropathic pain (NP) treatments by developing a novel dual-target modulator, E0199, targeting both NaV1.7, NaV1.8, and NaV1.9 and KV7 channels, a crucial regulator in controlling NP symptoms. The objective of the study was to synthesize a compound capable of modulating these channels to alleviate NP. Through an experimental design involving both in vitro and in vivo methods, E0199 was tested for its efficacy on ion channels and its therapeutic potential in a chronic constriction injury (CCI) mouse model. The results demonstrated that E0199 significantly inhibited NaV1.7, NaV1.8, and NaV1.9 channels with a particularly low half maximal inhibitory concentration (IC50) for NaV1.9 by promoting sodium channel inactivation, and also effectively increased KV7.2/7.3, KV7.2, and KV7.5 channels, excluding KV7.1 by promoting potassium channel activation. This dual action significantly reduced the excitability of dorsal root ganglion neurons and alleviated pain hypersensitivity in mice at low doses, indicating a potent analgesic effect without affecting heart and skeletal muscle ion channels critically. The safety of E0199 was supported by neurobehavioral evaluations. Conclusively, E0199 represents a ground-breaking approach in NP treatment, showcasing the potential of dual-target small-molecule compounds in providing a more effective and safe therapeutic option for NP. This study introduces a promising direction for the future development of NP therapeutics.
Research and application of thermosensitive Pickering emulsion with X-ray and ultrasound dual-modal imaging functions for intra-arterial embolization treatment
Ling Li, Anran Guo, Haixia Sun, Yanbing Zhao, Qing Yao, Ling Zhang, Peng Shi, Hongan Tian, Min Zheng
, Available online  , doi: 10.1016/j.jpha.2024.101133
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Transcatheter arterial embolization (TAE) is the mainstay for treating advanced hepatocellular carcinoma (HCC), and the performance of the embolization material is crucial in TAE. With the development of medical imaging and the birth of “X-ray-free” technologies, we designed a new dual-mode imaging material of dimethoxy tetraphenyl ethylene (DMTPE) via emulsification by mixing poly (N-isopropylacrylamide-co-acrylic acid) (PNA) with lipiodol and fluorocarbons, which was evaluated for temperature sensitivity, stability, and dual-mode visualization in vitro. Additionally, blood vessel casting embolization and renal artery imaging were assessed in healthy rabbits. In a rabbit model with a VX2 tumor, the effectiveness of transarterial embolization (TAE) for treating HCC was examined, with an emphasis on evaluating long-term outcomes of embolization and its effects on tumor growth, necrosis, and proliferation through imaging techniques. In vitro experiments confirmed that the temperature-sensitive dual-oil-phase Pickering emulsion had good flow, stable contrast, and embolism when the oil-to-oil ratio and water-to-oil ratio were both 7:3 (V/V) and stabilized with 8% PNA. Similarly, in vivo, arterial embolization confirmed the excellent properties of DMTPE prepared at the abovementioned ratios. It was observed that DMTPE not only has an antitumor effect but can also achieve dual imaging using X-rays and ultrasound, making it a promising excellent vascular embolization material for TAE in tumor treatment.
A disentangled generative model for improved drug response prediction in patients via sample synthesis
Kunshi Li, Bihan Shen, Fangyoumin Feng, Xueliang Li, Yue Wang, Na Feng, Zhixuan Tang, Liangxiao Ma, Hong Li
, Available online  , doi: 10.1016/j.jpha.2024.101128
Abstract(21) HTML Full Text PDF(1)
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Thalidomide mitigates Crohn's disease colitis by modulating gut microbiota, metabolites, and regulatory T cell immunity
Chao-Tao Tang, Yonghui Wu, Qing Tao, Chun-Yan Zeng, You-Xiang Chen
, Available online  , doi: 10.1016/j.jpha.2024.101121
Abstract(19) HTML Full Text PDF(1)
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Thalidomide (THA) is renowned for its potent anti-inflammatory properties. This study aimed to elucidate its underlying mechanisms in the context of Crohn’s disease (CD) development. Mouse colitis models were established by dextran sulfate sodium (DSS) treatment. Fecal microbiota and metabolites were analyzed by metagenomic sequencing and mass spectrometry, respectively. Antibiotic- treated mice served as models for microbiota depletion and transplantation. The expression of Forkhead box P3+ (FOXP3+) Regulatory T cells (Tregs) was measured by flow cytometry and immunohistochemical assay in colitis model and patient cohort. THA inhibited colitis in DSS–treated mice by altering the gut microbiota profile, with an increased abundance of probiotics Bacteroides fragilis (Bf), while pathogenic bacteria were depleted. In addition, THA increased beneficial metabolites bile acids and significantly restored gut barrier function. Transcriptomic profiling revealed that THA inhibited interleukin-17 (IL17), IL1β and cell cycle signaling. Fecal microbiota transplantation from THA-treated mice to microbiota-depleted mice partly recapitulated the effects of THA. Specifically, increased level of gut commensal Bf was observed, correlated with elevated levels of the microbial metabolite 7-Ketolithocholic acid (7-KA) following THA treatment. This microbial metabolite may stable FOXP3 expression by targeting the bile acid receptor farnesol X receptor 1(FXR1) to inhibit autophagy. An interaction between FOXP3 and FXR1 was identified, with binding regions localized to the FOXP3 domain (aa 238-335) and the FXR1 domain (aa 82-222), respectively. Conclusively, THA modulates the gut microbiota and metabolite profiles towards a more beneficial composition, enhances gut barrier function, promotes the differentiation of FOXP3+ Tregs and curbs pro-inflammatory pathways.
Advances in lysosomal escape mechanisms for gynecological cancer nanotherapeutics
Heng Wei, Yingying Hao, Jin Zhang, Yue Qi, Chong Feng, Chen Zhang
, Available online  , doi: 10.1016/j.jpha.2024.101119
Abstract(53) HTML Full Text PDF(0)
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Gynecological cancers present significant treatment challenges due to drug resistance and adverse side effects. This review explores advancements in lysosomal escape mechanisms, essential for enhancing nano-therapeutic efficacy. Strategies such as pHsensitive linkers and membrane fusion are examined, showcasing their potential to improve therapeutic outcomes in ovarian, cervical, and uterine cancers. We delve into novel materials and strategies developed to bypass the lysosomal barrier, including pHsensitive linkers, fusogenic lipids, and nanoparticles (NPs) engineered for endosomal disruption. Mechanisms such as the proton sponge effect, where NPs induce osmotic swelling and rupture of the lysosomal membrane, and membrane fusion, which facilitates the release of therapeutic agents directly into the cytoplasm, are explored in detail. These innovations not only promise to improve therapeutic outcomes but also minimize side effects, marking a significant step forward in the treatment of ovarian, cervical, and uterine cancers. By providing a comprehensive analysis of current advancements and their implications for clinical applications, this review sheds light on the potential of lysosomal escape strategies to revolutionize gynecological cancer treatment, setting the stage for future research and development in this vital area.
Advances and mechanisms of traditional Chinese medicine and its active ingredients against antibiotic-resistant Escherichia coli infections
Shuo Yang, Ping Su, Lu Li, Shuang Liu, Yi Wang
, Available online  , doi: 10.1016/j.jpha.2024.101117
Abstract(109) HTML Full Text PDF(10)
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In clinical practice, antibiotics have historically been utilized for the treatment of pathogenic bacteria. However, the gradual emergence of antibiotic resistance among bacterial strains has posed a significant challenge to this approach. In 2022, Escherichia coli, a Gram-negative bacterium renowned for its widespread pathogenicity and high virulence, emerged as the predominant pathogenic bacterium in China. The rapid emergence of antibiotic-resistant E. coli strains has rendered antibiotics insufficient to fight E. coli infections. Traditional Chinese medicine (TCM) has made remarkable contributions to the health of Chinese people for thousands of years, and its significant therapeutic effects have been proven in clinical practice. In this paper, we provide a comprehensive review of the advances and mechanisms of TCM and its active ingredients against antibiotic-resistant E. coli infections. First of all, this review introduces the classification, antibiotic resistance characteristics and mechanisms of E. coli. Then, the TCM formulas and extracts are listed along with their active ingredients against E. coli, including extraction solution, minimum inhibitory concentration (MIC) and the antibacterial mechanisms. In addition, there is growing evidence supporting the synergistic therapeutic strategy of combining TCM with antibiotics for the treatment of antibiotic-resistant E. coli infections, and we provide a summary of this evidence and its underlying mechanisms. In conclusion, we present a comprehensive review of TCM and highlight its potential and advantages in the prevention and treatment of E. coli infections. We hold the opinion that TCM will play an important role in global health, pharmaceutical development and livestock farming in the future.
Elemene as a binding stabilizer of microRNA-145-5p suppresses the growth of non-small cell lung cancer
Meirong Zhou, Jiayue Wang, Yulin Peng, Xiangge Tian, Wen Zhang, Junlin Chen, Yue Wang, Yu Wang, Youjian Yang, Yongwei Zhang, Xiaokui Huo, Yuzhuo Wu, Zhenlong Yu, Tian Xie, Xiaochi Ma
, Available online  , doi: 10.1016/j.jpha.2024.101118
Abstract(67) HTML Full Text PDF(9)
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Elemene is widely recognized as an effective anti-cancer compound and is routinely administered in Chinese clinical settings for the management of several solid tumors, including non-small cell lung cancer (NSCLC). However, its detailed molecular mechanism has not been adequately demonstrated. In this research, it was demonstrated that elemene effectively curtailed NSCLC growth in the patient-derived xenograft (PDX) model. Mechanistically, employing high-throughput screening techniques and subsequent biochemical validations such as microscale thermophoresis (MST), microRNA-145-5p (miR-145-5p) was pinpointed as a critical target through which elemene exerts its anti-tumor effects. Interestingly, elemene serves as a binding stabilizer for miR-145-5p, demonstrating a strong binding affinity (KD = 0.39 ±0.17 μg/mL) and preventing its degradation both in vitro and in vivo, while not interfering with the synthesis of the primary microRNA transcripts (pri-miRNAs) and precursor miRNAs (pre-miRNAs). The stabilization of miR-145-5p by elemene resulted in an increased level of this miRNA, subsequently suppressing NSCLC progression through the miR-145-5p/mitogen-activated protein kinase kinase kinase 3 (MAP3K3)/nuclear factor kappaB (NF-κB) pathway. Our findings provide a new perspective on revealing the interaction patterns between clinical anti-tumor drugs and miRNAs.
Integration of deep neutral network modeling and LC-MS-based pseudo-targeted metabolomics to discriminate easily confused ginseng species
Meiting Jiang, Yuyang Sha, Yadan Zou, Xiaoyan Xu, Mengxiang Ding, Xu Lian, Hongda Wang, Qilong Wang, Kefeng Li, De-an Guo, Wenzhi Yang
, Available online  , doi: 10.1016/j.jpha.2024.101116
Abstract(71) HTML Full Text PDF(4)
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Metabolomics covers a wide range of applications in life sciences, biomedicine, and phytology. Data acquisition (to achieve high coverage and efficiency) and analysis (to pursue good classification) are two key segments involved in metabolomics workflows. Various chemometric approaches utilizing either pattern recognition or machine learning have been employed to separate different groups. However, insufficient feature extraction, inappropriate feature selection, overfitting, or underfitting lead to an insufficient capacity to discriminate plants that are often easily confused. Using two ginseng varieties, namely Panax japonicus and P. japonicus var. major, containing the similar ginsenosides, we integrated pseudo-targeted metabolomics and deep neural network (DNN) modeling to achieve accurate species differentiation. A pseudo-targeted metabolomics approach was optimized through data acquisition mode, ion pairs generation, comparison between multiple reaction monitoring (MRM) and scheduled MRM, and chromatographic elution gradient. In total, 1980 ion pairs were monitored within 23 min, allowing for the most comprehensive ginseng metabolome analysis. The established DNN model demonstrated excellent classification performance (in terms of accuracy, precision, recall, F1 score, area under the curve, and receiver operating characteristic) using the entire metabolome data and feature-selection dataset, exhibiting superior advantages over random forest (RF), support vector machine (SVM), extreme gradient boosting (XGBoost), and multilayer perceptron (MLP). Moreover, DNNs were advantageous for automated feature learning, nonlinear modeling, adaptability, and generalization. This study confirmed practicality of the established strategy for efficient metabolomics data analysis and reliable classification performance even when using small-volume samples. This established approach holds promise for plant metabolomics and is not limited to ginseng.
Photoaffinity probe-enabled discovery of sennoside A reductase in Bifidobacterium pseudocatenulatum
Yang Xu, Shujing Lv, Xiang Li, Chuanjia Zhai, Yulian Shi, Xuejiao Li, Zhiyang Feng, Gan Luo, Ying Wang, Xiaoyan Gao
, Available online  , doi: 10.1016/j.jpha.2024.101108
Abstract(47) HTML Full Text PDF(5)
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Sennoside A (SA), a typical prodrug, exerts its laxative effect only after its transformation into rheinanthrone catalyzed by gut microbial hydrolases and reductases. Hydrolases have been identified, but reductases remain unknown. By linking a photoreactive group to the SA scaffold, we synthesized a photoaffinity probe to covalently label SA reductases and identified SA reductases using activity-based protein profiling. From lysates of an active strain, Bifidobacterium pseudocatenulatum (B. pseudocatenulatum), 397 proteins were enriched and subsequently identified using mass spectrometry. Among these proteins, chromate reductase/nicotinamide adenine dinucleotide phosphate (NADPH)-dependent flavin mononucleotide (FMN) reductase/oxygen-insensitive NADPH nitroreductase (nfrA) was identified as a potent SA reductase through further bioinformatic analysis and Uniprot database screening. We also determined that recombinant nfrA could reduce SA. Our study contributes to further illuminating mechanisms of SA transformation to rheinanthrone and simultaneously offers an effective method to identify gut bacterial reductases.
Radiosynthesis and preclinical evaluation of [18F]AlF-labeled HBED-CC-FAPI derivatives for imaging of cancer-associated fibroblasts
Haiyan Hong, Yan Zhang, Jinping Qiao, Wensheng Zhang, Lin Zhu, Jiehua Xu
, Available online  , doi: 10.1016/j.jpha.2024.101107
Abstract(39) HTML Full Text PDF(2)
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Altered serum metabolic profile in patients with autoimmune gastritis compared to other chronic gastritis
Jihua Shi, Yang Zhang, Yiran Wang, Yuxi Huang, Zhe Chen, Xue Xu, Wenbin Li, Dan Chen, Hao Luo, Qingfeng Luo, Ruiyue Yang, Xue Qiao
, Available online  , doi: 10.1016/j.jpha.2024.101104
Abstract(29) HTML Full Text PDF(3)
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Integrating transcriptomics, metabolomics, and network pharmacology to investigate multi-target effects of Sporoderm-broken spores of Ganoderma lucidum on improving HFD-induced diabetic nephropathy rats
Lidan Hu, Lili Yu, Zhongkai Cao, Yue Wang, Caifeng Zhu, Yayu Li, Jiazhen Yin, Zhichao Ma, Xuelin He, Ying Zhang, Wunan Huang, Yuelin Guan, Yue Chen, Xue Li, Xiangjun Chen
, Available online  , doi: 10.1016/j.jpha.2024.101105
Abstract(77) HTML Full Text PDF(5)
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Diabetes mellitus (DM) is a major metabolic disease endangering global health, with diabetic nephropathy (DN) as a primary complication lacking curative therapy. Sporoderm-broken spores of Ganoderma lucidum (GLP), an herbal medicine, has been used for the treatment of metabolic disorders. In this study, DN was induced in Sprague-Dawley rats using streptozotocin (STZ) and a high-fat diet (HFD), and the protective mechanisms of GLP were investigated through transcriptomic, metabolomic, and network pharmacology analyses. Our results demonstrated that GLP intervention ameliorated renal damage and inflammation levels in DN rats. Integrative metabolomic and transcriptomic analysis revealed that GLP treatment modulated glucose and cellular energy metabolisms by regulating relevant genes. GLP significantly suppressed the inflammations by impacting glucose and energy metabolism- related gene expression (Igfbp1 and Angptl4) and enhanced metabolic biomarkers of 4- Aminocatechol. In addition, network pharmacology analysis further indicated that GLP may efficiently alleviate DN via immune-related pathways. In conclusion, this study provides supportive evidence of the anti-inflammatory effects of GLP supplements, highlighting their potential for promising clinical applications in treating diabetic nephropathy.
Targeting ceramide-induced microglial pyroptosis: Icariin is a promising therapeutic therapy for Alzheimer's disease
Hongli Li, Qiao Xiao, Lemei Zhu, Jin Kang, Qiong Zhan, Weijun Peng
, Available online  , doi: 10.1016/j.jpha.2024.101106
Abstract(105) HTML Full Text PDF(22)
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Alzheimer’s disease (AD), a progressive dementia, is one of the most common neurodegenerative diseases. Clinical trial results of amyloid-β (Aβ) and tau regulators based on the pretext of straightforward amyloid and tau immunotherapy were disappointing. There are currently no effective strategies for slowing the progression of AD. Herein, we spotlight the dysregulation of lipid metabolism, particularly the elevation of ceramides (Cers), as a critical yet underexplored facet of AD pathogenesis. Our study delineates the role of Cers in promoting microglial pyroptosis, a form of programmed cell death distinct from apoptosis and necroptosis, characterized by cellular swelling, and membrane rupture mediated by the NLRP3 inflammasome pathway. Utilizing both in vivo experiments with APP/PS1 transgenic mice and in vitro assays with BV-2 microglial cells, we investigate the activation of microglial pyroptosis by Cers and its inhibition by Icariin (ICA), a flavonoid with known antioxidant and anti-inflammatory properties. Our findings reveal a significant increase in Cers levels and pyroptosis markers (NLRP3, apoptosis-associated speck-like protein containing a caspase recruitment domain, caspase-1, gasdermin D, and interleukin-18) in the brains of AD model mice, indicating a direct involvement of Cers in AD pathology through the induction of microglial pyroptosis. Conversely, ICA treatment effectively reduces these pyroptotic markers and Cer levels, thereby attenuating microglial pyroptosis and suggesting a novel therapeutic mechanism of action against AD. This study not only advances our understanding of the pathogenic role of Cers in AD but also introduces ICA as a promising candidate for AD therapy, capable of mitigating neuroinflammation and pyroptosis through the COX2-NLRP3 inflammasome-GSDMD axis. Our results pave the way for further exploration of Cer metabolism disorders in neurodegenerative diseases and highlight the therapeutic potential of targeting microglial pyroptosis in AD.
Natural Product Virtual-Interact-Phenotypic Target Characterization: A Novel Approach Demonstrated with Salvia Miltiorrhiza Extract
Rui Xu, Hengyuan Yu, Yichen Wang, Boyu Li, Yong Chen, Xuesong Liu, Tengfei Xu
, Available online  , doi: 10.1016/j.jpha.2024.101101
Abstract(232) HTML Full Text PDF(70)
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Natural products (NPs) have historically been a fundamental source for drug discovery. Yet the complex nature of NPs presents substantial challenges in pinpointing bioactive constituents, and corresponding targets. In the present study, an innovative Natural Product Virtual screening-Interaction-Phenotype (NP-VIP) strategy that integrates virtual screening, chemical proteomics, and metabolomics to identify and validate the bioactive targets of NPs. This approach reduces false positive results and enhances the efficiency of target identification. Salvia miltiorrhiza (SM), a herb with recognized therapeutic potential against ischemic stroke (IS), was used to illustrate the workflow. Utilizing virtual screening, chemical proteomics, and metabolomics, potential therapeutic targets for SM in the IS treatment were identified, totaling 29, 100, and 78, respectively. Further analysis via the NP-VIP strategy highlighted five high- confidence targets, including Poly [ADP-ribose] polymerase 1 (PARP1), signal transducer and activator of transcription 3 (STAT3), amyloid precursor protein (APP), glutamate-ammonia ligase (GLUL), and glutamate decarboxylase 67 (GAD67). These targets were subsequently validated and found to play critical roles in the neuroprotective effects of SM. The study not only underscores the importance of SM in treating IS but also sets a precedent for NP research, proposing a comprehensive approach that could be adapted for broader pharmacological explorations.
The application of spectroscopic technology with machine learning in Chinese herbs from seeds to medicinal materials: The case of genus Paris
Yangna Feng, Xinyan Zhu, Yuanzhong Wang
, Available online  , doi: 10.1016/j.jpha.2024.101103
Abstract(23) HTML Full Text PDF(3)
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To ensure the safety and efficacy of Chinese herbs, it is of great significance to conduct rapid quality detection of Chinese herbs at every link of their supply chain. Spectroscopic technology can reflect the overall chemical composition and structural characteristics of Chinese herbs, with the multi-component and multitarget characteristics of Chinese herbs. This review took the genus Paris as an example, and applications of spectroscopic technology with machine learning in supply chain of the genus Paris from seeds to medicinal materials were introduced. The specific contents included the confirmation of germplasm resources, identification of growth years, cultivar, geographical origin, and original processing and processing methods. The potential application of spectroscopic technology in genus Paris was pointed out, and the prospects of combining spectroscopic technology with blockchain were proposed. The summary and prospects presented in this paper will be beneficial to the quality control of the genus Paris in all links of its supply chain, so as to rationally use the genus Paris resources and ensure the safety and efficacy of medication.
A promising strategy of brain targeted delivery for the treatment of Parkinson’s disease: Cyclodextrin supramolecular inclusion complex based thermosensitive gel
Yan-Qiu Wang, Li-Ming Wang, Li-Feng Han, Yi-Bing Chen, Yuan-Lu Cui
, Available online  , doi: 10.1016/j.jpha.2024.101102
Abstract(85) HTML Full Text PDF(2)
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Synergistic approach to combating triple-negative breast cancer: ddr1-targeted antibody-drug conjugate combined with pembrolizumab
Shoubing Zhou, Wenyu Li, Dan Zhao, Qiujun Zhang, Hu Liu, Tengchuan Jin, Yueyin Pan
, Available online  , doi: 10.1016/j.jpha.2024.101100
Abstract(27) HTML Full Text PDF(1)
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Discoidin domain receptor 1 (DDR1) is overexpressed in various tumors, such as triple-negative breast cancer (TNBC), and is rarely expressed in normal tissues. These characteristics make DDR1 a preferable target candidate for the construction of an antibody‒drug conjugate (ADC) for targeted therapy. Here, we investigated the preparation and preclinical efficacy of DDR1-DX8951, an ADC that includes an antiDDR1 monoclonal antibody conjugated to DX8951 by a cleavable GGFG linker. The anti-DDR1 monoclonal antibody was coupled to DX8951, producing the targeted therapy ADC, DDR1-DX8951. The antitumor activities of DDR1-DX8951 monotherapy or DDR1-DX8951 plus pembrolizumab were assessed in TNBC mouse models. DDR1-DX8951 can specifically target DDR1, be quickly internalized by TNBC cells, and reduce the viability of TNBC cells in vitro. The potent antitumor activity of DDR1-DX8951 was revealed in TNBC xenograft models. Importantly, our investigation demonstrated that DDR1-DX8951 plus pembrolizumab not only revealed the inhibitory efficacy on tumor growth and metastasis but also played an important role in improving the immunosuppressive tumor microenvironment of TNBC. Taken together, this investigation provides justification for large-sample studies to further assess the safety and efficacy of DDR1-DX8951 plus pembrolizumab for TNBC clinical trials.
Therapeutic strategies targeting CD47-SIRPα signaling pathway in gastrointestinal cancers treatment
Zhengping Che, Wei Wang, Lin Zhang, Zhenghong Lin
, Available online  , doi: 10.1016/j.jpha.2024.101099
Abstract(61) HTML Full Text PDF(7)
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Gastrointestinal (GI) cancers are prevalent globally, with leading incidence and mortality rates among malignant tumors. Despite notable advancements in surgical resection, radiotherapy, and chemotherapy, the overall survival rates remain low. Hence, it is imperative to explore alternative approaches that enhance patient outcomes. Cluster of differentiation 47 (CD47), serving as an early diagnostic marker, is predominantly overexpressed in GI cancers and associated with poor prognosis. Targeting the CD47-signal regulatory protein alpha (SIRPα) signaling pathway may provide a novel strategy for GI cancers treatment. This study summarizes current knowledge of the structure and function of CD47 and SIRPα, their roles in signaling pathways, the prognostic significance of CD47, therapeutic strategies targeting the CD47-SIRPα signaling pathway in GI cancer, and highlights key issues for future investigations.
Unlocking the dual role of autophagy: A new strategy for treating lung cancer
Fei Tang, Jing-Nan Zhang, Xiao-Lan Zhao, Li-Yue Xu, Hui Ao, Cheng Peng
, Available online  , doi: 10.1016/j.jpha.2024.101098
Abstract(69) HTML Full Text PDF(16)
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Lung cancer exhibits the highest incidence and mortality rates among cancers globally, with a five-year overall survival rate alarmingly below 20%. Targeting autophagy, though a controversial therapeutic strategy, is extensively employed in clinical practice. Current research is actively pursuing various therapeutic strategies using small molecules to exploit the dual function of autophagy. Nevertheless, the pivotal question of enhancing or inhibiting autophagy in cancer therapy merits further attention. This review aims to provide a comprehensive overview of the mechanisms of autophagy in lung cancer. It also explores recent advances in targeting cytotoxic autophagy and inhibiting protective autophagy with small molecules to induce cell death in lung cancer cells. Notably, most autophagy-targeting drugs, primarily natural small molecules, have demonstrated that activating cytotoxic autophagy effectively induces cell death in lung cancer, as opposed to inhibiting protective autophagy. These insights contribute to identifying druggable targets and drug candidates for potential autophagy-related lung cancer therapies, offering promising approaches to combat this disease.
Luteolin and its antidepressant properties: From mechanism of action to potential therapeutic application
Jiayu Zhou, Ziyi Wu, Ping Zhao
, Available online  , doi: 10.1016/j.jpha.2024.101097
Abstract(40) HTML Full Text PDF(0)
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Luteolin is a natural flavonoid compound exists in various fruits and vegetables. Recent studies have indicated that luteolin has variety pharmacological effects, including a wide range of antidepressant properties. Here, we systematically review the preclinical studies and limited clinical evidence on the antidepressant and neuroprotective effects of luteolin to fully explore its antidepressant power. Network pharmacology and molecular docking analyses contribute to a better understanding of the preclinical models of depression and antidepressant properties of luteolin. Seventeen preclinical studies were included that combined network pharmacology and molecular docking analyses to clarify the antidepressant mechanism of luteolin and its antidepressant targets. The antidepressant effects of luteolin may involve promoting intracellular noradrenaline (NE) uptake; inhibiting 5-hydroxytryptamine (5-HT) reuptake; upregulating the expression of synaptophysin, postsynaptic density protein 95, brain- derived neurotrophic factor, B cell lymphoma protein-2, superoxide dismutase, and glutathione S-transferase; and decreasing the expression of malondialdehyde, caspase- 3, and amyloid-beta peptides. The antidepressant effects of luteolin are mediated by various mechanisms, including anti-oxidative stress, anti-apoptosis, anti-inflammation, anti-endoplasmic reticulum stress, dopamine transport, synaptic protection, hypothalamic-pituitary-adrenal axis regulation, and 5-HT metabolism. Additionally, we identified insulin-like growth factor 1 receptor (IGF1R), AKT serine/threonine kinase 1 (AKT1), prostaglandin-endoperoxide synthase 2 (PTGS2), estrogen receptor alpha (ESR1), and epidermal growth factor receptor (EGFR) as potential targets, luteolin has an ideal affinity for these targets, suggesting that it may play a positive role in depression through multiple targets, mechanisms, and pathways. However, the clinical efficacy of luteolin and its potential direct targets must be confirmed in further multicenter clinical case-control and molecular targeting studies.
Detection of multiple specific adventitious viruses in viral gene therapy products using multiplex PCR coupled with capillary electrophoresis
Guangyu Wang, Lingli Xu, Lei Yu, Xinchang Shi, Xi Qin, Yong Zhou
, Available online  , doi: 10.1016/j.jpha.2024.101096
Abstract(72) HTML Full Text PDF(12)
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Permeable polydimethylsiloxane microneedles for the delivery of traditional Chinese medicine elemene
Qingchang Tian, Mengmeng Liu, Yiqiu Wang, Zhaoming Li, Daizhou Zhang, Tian Xie, Shuling Wang
, Available online  , doi: 10.1016/j.jpha.2024.101094
Abstract(66) HTML Full Text PDF(4)
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Urease-powered micro/nanomotors: Current progress and challenges
Wen-Wen Li, Zi-Li Yu, Jun Jia
, Available online  , doi: 10.1016/j.jpha.2024.101095
Abstract(66) HTML Full Text PDF(3)
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Enzyme-powered micro/nanomotors (EMNMs) use natural enzymes to facilitate the decomposition of fuels, including hydrogen peroxide (H2O2), glucose, triglycerides, and urea to provide power. EMNMs can achieve self-propulsion through the in situ utilization of biofuels without additional fuels, exhibiting excellent biocompatibility and significant potential for application in the biomedical field. Compared with H2O2, which may cause oxidative damage to the body, urea exhibits superior biosafety characteristics. Presently, urease-powered MNMs (UMNMs) have made notable progress in their applications in the biomedical field and have garnered considerable attention from researchers. In this review, we present the latest advancements in the biomedical field of UMNMs, primarily focusing on: 1) diverse materials used for constructing the fundamental framework of motors; 2) control of motor movement through the regulation of enzymatic reaction rates; and 3) research directions for the clinical application of motors including in vivo imaging, biomarker detection, cancer treatment, optical therapy, overcoming biological barriers, antibacterial interventions, antithrombotic strategies, and gastric disease management. Despite showing immense potential in biomedical applications, there are still several challenges impeding its practical implementation, such as maintaining activity in the in vivo environment while accurately targeting specific sites to achieve the desired clinical therapeutic effects.
Application of Lipidomics in the Study of Traditional Chinese Medicine
Yang Yang, Guangyi Yangc, Wenpeng Zhang, Lingyi Xin, Jing Zhu, HangtianWang, Baodong Feng, Renyan Liu, Shuya Zhang, Yuanwu Cui, Qinhua Chen, Dean Guo
, Available online  , doi: 10.1016/j.jpha.2024.101083
Abstract(60) HTML Full Text PDF(5)
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Lipidomics is an emerging discipline that systematically studies the various types, functions, and metabolic pathways of lipids within living organisms. This field compares changes in diseases or drug impact, identifying biomarkers and molecular mechanisms present in lipid metabolic networks across different physiological or pathological states. Through employing analytical chemistry within the realm of lipidomics, researchers analyze traditional Chinese medicine (TCM). This analysis aids in uncovering potential mechanisms for treating diverse physiopathological conditions, assessing drug efficacy, understanding mechanisms of action and toxicity, and generating innovative ideas for disease prevention and treatment. This manuscript assesses recent literature, summarizing existing lipidomics technologies and their applications in TCM research. It delineates the efficacy, mechanisms, and toxicity research related to lipidomics in Chinese medicine. Additionally, it explores the utilization of lipidomics in quality control research for Chinese medicine, aiming to expand the application of lipidomics within this field. Ultimately, this initiative seeks to foster the integration of traditional medicine theory with modern science and technology, promoting an organic fusion between the two domains.
A review of transformers in drug discovery and beyond
Jian Jiang, Long Chen, Lu Ke, Bozheng Dou, Chunhuan Zhang, Hongsong Feng, Yueying Zhu, Huahai Qiu, Bengong Zhang, Guowei Wei
, Available online  , doi: 10.1016/j.jpha.2024.101081
Abstract(59) HTML Full Text PDF(8)
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Transformer models have emerged as pivotal tools within the realm of drug discovery, distinguished by their unique architectural features and exceptional performance in managing intricate data landscapes. Leveraging the innate capabilities of transformer architectures to comprehend intricate hierarchical dependencies inherent in sequential data, these models showcase remarkable efficacy across various tasks, including new drug design and drug target identification. The adaptability of pre-trained transformer-based models renders them indispensable assets for driving data-centric advancements in drug discovery, chemistry, and biology, furnishing a robust framework that expedites innovation and discovery within these domains. Beyond their technical prowess, the success of transformer-based models in drug discovery, chemistry, and biology extends to their interdisciplinary potential, seamlessly combining biological, physical, chemical, and pharmacological insights to bridge gaps across diverse disciplines. This integrative approach not only enhances the depth and breadth of research endeavors but also fosters synergistic collaborations and exchange of ideas among disparate fields. In our review, we elucidate the myriad applications of transformers in drug discovery, as well as chemistry and biology, spanning from protein design and protein engineering, to molecular dynamics, drug target identification, transformer-enabled drug virtual screening, drug lead optimization, drug addiction, small data set challenges, chemical and biological image analysis, chemical language understanding, and single cell data. Finally, we conclude the survey by deliberating on promising trends in transformer models within the context of drug discovery and other sciences.
Screen of FDA-approved drug library identifies Vitamin K as anti-ferroptotic drug for osteoarthritis therapy through Gas6
Yifeng Shi, Sunlong Li, Shuhao Zhang, Caiyu Yu, Jiansen Miao, Shu Yang, Yan Chen, Yuxuan Zhu, Xiaoxiao Huang, Chencheng Zhou, Hongwei Ouyang, Xiaolei Zhang, Xiangyang Wang
, Available online  , doi: 10.1016/j.jpha.2024.101092
Abstract(67) HTML Full Text PDF(11)
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Ferroptosis of chondrocytes is a significant contributor to osteoarthritis (OA), for which there is still a lack of safe and effective therapeutic drugs targeting ferroptosis. Here, we screen for anti-ferroptotic drugs in Food and Drug Administration (FDA)-approved drug library via a high-throughput manner in chondrocytes. We identified a group of FDA-approved anti- ferroptotic drugs, among which vitamin K showed the most powerful protective effect. Further study demonstrated that vitamin K effectively inhibited ferroptosis and alleviated the extracellular matrix (ECM) degradation in chondrocytes. Intra-articular injection of vitamin K inhibited ferroptosis and alleviated OA phenotype in destabilization of the medial meniscus (DMM) mouse model. Mechanistically, transcriptome sequencing and knockdown experiments revealed that the anti-ferroptotic effects of vitamin K depended on growth arrest–specific 6 (Gas6). Furthermore, exogenous expression of Gas6 was found to inhibit ferroptosis through the AXL/PI3K/AKT axis. Together, we demonstrate that vitamin K inhibits ferroptosis and alleviates OA progression via enhancing Gas6 expression and its downstream pathway of AXL/PI3K/AKT axis, indicating vitamin K as well as Gas6 to serve as a potential therapeutic target for OA and other ferroptosis-related diseases.
Liquiritin improves macrophage degradation of engulfed tumor cells by promoting the formation of phagolysosomes via NOX2/gp91phox
Caiyi Yang, Kehan Chen, Yunliang Chen, Xuting Xie, Pengcheng Li, Meng Zhao, Junjie Liang, Xueqian Xie, Xiaoyun Chen, Yanping Cai, Bo Xu, Qing Wang, Lian Zhou, Xia Luo
, Available online  , doi: 10.1016/j.jpha.2024.101093
Abstract(29) HTML Full Text PDF(1)
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The incomplete degradation of tumour cells by macrophages (Mφ) is a contributing factor to tumour progression and metastasis, and the degradation function of Mφ is mediated through phagosomes and lysosomes. In our preliminary experiments, we found that overactivation of NADPH oxidase 2 (NOX2) reduced the ability of Mφ to degrade engulfed tumour cells. Above this, we screened out liquiritin from Glycyrrhiza uralensis Fisch, which can significantly inhibit NOX2 activity and inhibit tumours, to elucidate that suppressing NOX2 can enhance the ability of Mφ to degrade tumour cells. We found that the tumour environment could activate the NOX2 activity in Mφ phagosomes, causing Mφ to produce excessive reactive oxygen species (ROS), thus prohibiting the formation of phagolysosomes before degradation. Conversely, inhibiting NOX2 in Mφ by liquiritin can reduce ROS and promote phagosome-lysosome fusion, therefore improving the enzymatic degradation of tumour cells after phagocytosis, and subsequently promote T cell activity by presenting antigens. We further confirmed that liquiritin down-regulated the expression of the NOX2 specific membrane component protein gp91 phox, blocking its binding to the NOX2 cytoplasmic component proteins p67 phox and p47 phox, thereby inhibiting the activity of NOX2. This study elucidates the specific mechanism by which Mφ cannot degrade tumour cells after phagocytosis, and indicates that liquiritin can promote the ability of Mφ to degrade tumour cells by suppressing NOX2.
Coupling of an Au@AgPt nanozyme array with an micrococcal nuclease-specific responsiveness strategy for colorimetric/SERS sensing of Staphylococcus aureus in patients with sepsis
Xueqin Huang, Yingqi Yang, Hanlin Zhou, Liping Hu, Annan Yang, Hua Jin, Biying Zheng, Jiang Pi, Jun Xu, Pinghua Sun, Huai-Hong Cai, Xujing Liang, Bin Pan, Junxia Zheng, Haibo Zhou
, Available online  , doi: 10.1016/j.jpha.2024.101085
Abstract(42) HTML Full Text PDF(0)
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Rapid and ultrasensitive detection of pathogen-associated biomarkers is vital for the early diagnosis and therapy of bacterial infections. Herein, we developed a close-packed and ordered Au@AgPt array coupled with a cascade triggering strategy for surface-enhanced Raman scattering (SERS) and colorimetric identification of the Staphylococcus aureus (S. aureus) biomarker micrococcal nuclease (MNase) in serum samples. The trimetallic Au@AgPt nanozymes can catalyze the oxidation of 3,3’,5,5’-tetramethylbenzidine (TMB) molecules to SERS-enhanced oxidized TMB (oxTMB), accompanied by the color change from colorless to blue. In the presence of S. aureus, the secreted MNase preferentially cut the nucleobase AT-rich regions of DNA sequences on magnetic beads (MBs) to release alkaline phosphatase (ALP), which subsequently mediated the oxTMB reduction for inducing the colorimetric/SERS signal fade away. Using this “on-to-off” triggering strategy, the target S. aureus can be recorded in a wide linear range with a limit of detection of 38 CFU/mL in the colorimetric mode and 6 CFU/mL in the SERS mode. Meanwhile, the MNase-mediated strategy characterized by high specificity and sensitivity successfully discriminated between patients with sepsis (n=7) and healthy participants (n=3), as well as monitored the prognostic progression of the disease (n=2). Overall, benefiting from highly active and dense “hot spot” substrate, MNase-mediated cascade response strategy, and colorimetric/SERS dual-signal output, this methodology will offer a promising avenue for the early diagnosis of S. aureus infection.
Exploration of innovative drug repurposing strategies for combating human protozoan diseases: Advances, challenges, and opportunities
ShanShan Hu, Zahra Batool, Xin Zheng, Yin Yang, Amin Ullah, Bairong Shen
, Available online  , doi: 10.1016/j.jpha.2024.101084
Abstract(78) HTML Full Text PDF(1)
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Protozoan infections (e.g., malaria, trypanosomiasis, and toxoplasmosis) pose a considerable global burden on public health and socioeconomic problems, leading to high rates of morbidity and mortality. Due to the limited arsenal of effective drugs for these diseases, which are associated with devastating side effects and escalating drug resistance, there is an urgent need for innovative antiprotozoal drugs. The emergence of drug repurposing offers a low-cost approach to discovering new therapies for protozoan diseases. In this review, we summarize recent advances in drug repurposing for various human protozoan diseases and explore cost-effective strategies to identify viable new treatments. We highlight the cross-applicability of repurposed drugs across diverse diseases and harness common chemical motifs to provide new insights into drug design, facilitating the discovery of new antiprotozoal drugs. Challenges and opportunities in the field are discussed, delineating novel directions for ongoing and future research.
Peptide-based immuno-PET/CT monitoring of dynamic PD-L1 expression during glioblastoma radiotherapy
Yong Wang, Kewen He, Yang Zhang, Yunhao Chen, Shijie Wang, Kunlong Zhao, Zhiguo Liu, Man Hu
, Available online  , doi: 10.1016/j.jpha.2024.101082
Abstract(76) HTML Full Text PDF(4)
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Real-time, noninvasive programmed death-ligand 1 (PD-L1) testing using molecular imaging has enhanced our understanding of the immune environments of neoplasms and has served as a guide for immunotherapy. However, the utilization of radiotracers in the imaging of human brain tumors using positron emission tomography/computed tomography (PET/CT) remains limited. This investigation involved the synthesis of [18F]AlF-NOTA-PCP2, which is a novel peptide-based radiolabeled tracer that targets PD-L1, and evaluated its imaging capabilities in orthotopic glioblastoma (GBM) models. Using this tracer, we could noninvasively monitor radiation-induced PD-L1 changes in GBM. [18F]AlF-NOTA-PCP2 exhibited high radiochemical purity (>95%) and stability up to 4 hours after synthesis. It demonstrated specific, high-affinity binding to PD-L1 in vitro and in vivo, with a dissociation constant of 0.24 nM. PET/CT imaging, integrated with contrast- enhanced magnetic resonance imaging, revealed significant accumulation of [18F]AlF-NOTA-PCP2 in orthotopic tumors, correlating with blood–brain barrier disruption. After radiotherapy (15 Gy), [18F]AlF-NOTA-PCP2 uptake in tumors increased from 9.51% ± 0.73% to 12.04% ± 1.43%, indicating enhanced PD-L1 expression consistent with immunohistochemistry findings. Fractionated radiation (5 Gy × 3) further amplified PD-L1 upregulation (13.9% ± 1.54% ID/cc) compared with a single dose (11.48% ± 1.05% ID/cc). Taken together, [18F]AlF-NOTA-PCP2 may be a valuable tool for noninvasively monitoring PD-L1 expression in brain tumors after radiotherapy.
Distribution of pamiparib, a novel inhibitor of poly(ADP-ribose)-polymerase (PARP), in tumor tissue analyzed by multimodal imaging
Lavinia Morosi, Sara Timo, Rosy Amodeo, Monica Lupi, Marina Meroni, Ezia Bello, Roberta Frapolli, Giuseppe Martano, Maurizio D'Incalci
, Available online  , doi: 10.1016/j.jpha.2024.101079
Abstract(51) HTML Full Text PDF(5)
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New uses of halofuginone to treat cancer
Runan Zuo, Xinyi Guo, Xinhao Song, Xiuge Gao, Junren Zhang, Shanxiang Jiang, Vojtech Adam, Kamil Kuca, Wenda Wu, Dawei Guo
, Available online  , doi: 10.1016/j.jpha.2024.101080
Abstract(39) HTML Full Text PDF(0)
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The small-molecule alkaloid halofuginone (HF) is obtained from febrifugine. Recent studies on HF have aroused widespread attention owing to its universal range of noteworthy biological activities and therapeutic functions, which range from protozoan infections and fibrosis to autoimmune diseases. In particular, HF is believed to play an excellent anticancer role by suppressing the proliferation, adhesion, metastasis, and invasion of cancers. This review supports the goal of demonstrating various anticancer effects and molecular mechanisms of HF. In the studies covered in this review, the anticancer molecular mechanisms of HF mainly included Transforming growth factor-β (TGF-β)/Smad-3/ Nuclear factor erythroid 2-related factor 2 (Nrf2), Serine/Threonine Kinase Proteins (Akt)/mechanistic target of rapamycin complex A1(mTORCA1)/ Wingless/Integrated (Wnt)/β-catenin, the exosomal MicroRNA-31 (miR-31)/ Histone Deacetylase 2 (HDAC2) signaling pathway, and the interaction of the extracellular matrix (ECM) and immune cells. Notably, HF, as a novel type of adenosine triphosphate (ATP)-dependent inhibitor that is often combined with Prolyl transfer RNA synthetase (ProRS) and amino acid starvation therapy (AAS) to suppress the formation of ribosome, further exerts a significant effect on the tumor microenvironment (TME). Additionally, the combination of HF with other drugs or therapies obtained universal attention. Our results showed that HF has significant potential for clinical cancer treatment.
Identifying purgative targets of Sennoside A via in situ biotransformation of prodrugbased probes
Zhen Liu, Xinyue Geng, Xinyue Liu, Mengru Li, Xiang Li, Zhixin Zhang, Gan Luo, Ying Wang, Xiaoyan Gao
, Available online  , doi: 10.1016/j.jpha.2024.101078
Abstract(57) HTML Full Text PDF(11)
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Ursodeoxycholic acid inhibits the uptake of cystine through SLC7A11 and impairs de novo synthesis of glutathione
Fu'an Xie, Yujia Niu, Xiaobing Chen, Xu Kong, Guangting Yan, Aobo Zhuang, Xi Li, Lanlan Lian, Dongmei Qin, Quan Zhang, Ruyi Zhang, Kunrong Yang, Xiaogang Xia, Kun Chen, Mengmeng Xiao, Chunkang Yang, Ting Wu, Ye Shen, Chundong Yu, Chenghua Luo, Shu-Hai Lin, Wengang Li
, Available online  , doi: 10.1016/j.jpha.2024.101068
Abstract(78) HTML Full Text PDF(12)
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Ursodeoxycholic acid (UDCA) is a naturally occurring, low-toxicity, and hydrophilic bile acid (BA) in the human body that is converted by intestinal flora using primary BA. Solute carrier family 7 member 11 (SLC7A11) functions to uptake extracellular cystine in exchange for glutamate, and is highly expressed in a variety of human cancers. Retroperitoneal liposarcoma (RLPS) refers to liposarcoma originating from the retroperitoneal area. Lipidomics analysis revealed that UDCA was one of the most significantly downregulated metabolites in sera of RLPS patients compared with healthy subjects. The augmentation of UDCA concentration (≥25 μg/mL) demonstrated a suppressive effect on the proliferation of liposarcoma cells. [15N2]-cystine and [13C5]-glutamine isotope tracing revealed that UDCA impairs cystine uptake and glutathione (GSH) synthesis. Mechanistically, UDCA binds to the cystine transporter SLC7A11 to inhibit cystine uptake and impair GSH de novo synthesis, leading to reactive oxygen species (ROS) accumulation and mitochondrial oxidative damage. Furthermore, UDCA can promote the anticancer effects of ferroptosis inducers (Erastin, RSL3), the murine double minute 2 (MDM2) inhibitors (Nutlin 3a, RG7112), cyclin dependent kinase 4 (CDK4) inhibitor (Abemaciclib), and glutaminase inhibitor (CB839). Together, UDCA functions as a cystine exchange factor that binds to SLC7A11 for antitumor activity, and SLC7A11 is not only a new transporter for BA but also a clinically applicable target for UDCA. More importantly, in combination with other antitumor chemotherapy or physiotherapy treatments, UDCA may provide effective and promising treatment strategies for RLPS or other types of tumors in a ROS-dependent manner.
Natural Products Based on Correa's Cascade for the Treatment of Gastric Cancer Trilogy: Current Status and Future Perspective
Wenhao Liao, Jing Wang, Yuchen Li
, Available online  , doi: 10.1016/j.jpha.2024.101075
Abstract(55) HTML Full Text PDF(3)
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Gastric carcinoma (GC) is a malignancy with multifactorial involvement, multicellular regulation, and multistage evolution. The classic Correa's cascade of intestinal GC specifies a trilogy of malignant transformation of the gastric mucosa, in which normal gastric mucosa gradually progresses from inactive or chronic active gastritis (Phase I) to gastric precancerous lesions (Phase II) and finally to GC (Phase III). Correa's cascade highlights the evolutionary pattern of GC and the importance of early intervention to prevent malignant transformation of the gastric mucosa. Intervening in early gastric mucosal lesions, i.e., Phase I and II, will be the key strategy to prevent and treat GC. Natural products (NPs) have been an important source for drug development due to abundant sources, tremendous safety, and multiple pharmacodynamic mechanisms. This review is the first to investigate and summarize the multi-step effects and regulatory mechanisms of NPs on the Correa's cascade in gastric carcinogenesis. In phase I, NPs modulate Helicobacter pylori (H. pylori) urease activity, motility, adhesion, virulence factors, and drug resistance, thereby inhibiting H. pylori-induced gastric mucosal inflammation and oxidative stress, and facilitating ulcer healing. In Phase II, NPs modulate multiple pathways and mediators regulating gastric mucosal cell cycle, apoptosis, autophagy, and angiogenesis to reverse gastric precancerous lesions. In Phase III, NPs suppress cell proliferation, migration, invasion, angiogenesis, and cancer stem cells, induce apoptosis and autophagy, and enhance chemotherapeutic drug sensitivity for the treatment of GC. In contrast to existing work, we hope to uncover NPs with sequential therapeutic effects on multiple phases of GC development, providing new ideas for gastric cancer prevention, treatment, and drug development.
Exploring the Impact of the Liver-Intestine-Brain Axis on Brain Function in Non-Alcoholic Fatty Liver Disease
Jingting Zhang, Keyan Chen, Fu Chen
, Available online  , doi: 10.1016/j.jpha.2024.101077
Abstract(129) HTML Full Text PDF(10)
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This study investigates the molecular complexities of Non-alcoholic Fatty Liver Disease (NAFLD)-induced brain dysfunction, with a focus on the liver-intestine-brain axis and potential therapeutic interventions. The main objectives include understanding critical microbiota shifts in NAFLD, exploring altered metabolites, and identifying key regulatory molecules influencing brain function. The methods employed encompassed 16S rRNA sequencing to scrutinize stool microbiota in NAFLD patients and healthy individuals, non-targeted metabolomics using LC-MS to uncover elevated levels of deoxycholic acid (DCA) in NAFLD mice, and single-cell RNA sequencing to pinpoint the pivotal gene Hpgd in microglial cells and its downstream janus kinase 2/signal transducer and activator of transcription 3 (Jak2/Stat3) signaling pathway. Behavioral changes and brain function were assessed in NAFLD mice with and without Fecal Microbiota Transplantation (FMT) treatment, utilizing various assays and analyses. The results revealed significant differences in microbiota composition, with increased levels of Bacteroides in NAFLD patients. Additionally, elevated DCA levels were observed in NAFLD mice, and FMT treatment demonstrated efficacy in ameliorating liver function and brain dysfunction. Hpgd inhibition by DCA activated the Jak2/Stat3 pathway in microglial cells, leading to inflammatory activation, inhibition of mitochondrial autophagy, induction of neuronal apoptosis, and reduction in neuronal action potentials. This study elucidates the intricate molecular mechanisms underlying the liver-gut-brain axis in NAFLD, and the identification of increased DCA and the impact of Jak2/Stat3 signaling on microglial cells highlight potential therapeutic targets for addressing NAFLD-induced brain dysfunction.
An economical and flexible chip using surface-enhanced infrared absorption spectroscopy for pharmaceutical detection: Combining qualitative analysis and quantitative detection
Jikai Wang, Pengfei Zeng, Haitao Xie, Suisui He, Xilin Xiao, Cuiyun Yu
, Available online  , doi: 10.1016/j.jpha.2024.101076
Abstract(112) HTML Full Text PDF(5)
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New applications of Clioquinol in the treatment of inflammation disease by directly targeting arginine 335 of NLRP3
Peipei Chen, Yunshu Wang, Huaiping Tang, Chao Zhou, Zhuo Liu, Shenghan Gao, Tingting Wang, Yun Xu, Sen-Lin Ji
, Available online  , doi: 10.1016/j.jpha.2024.101069
Abstract(40) HTML Full Text PDF(2)
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The NOD-like receptor protein 3 (NLRP3) inflammasome is essential in innate immune- mediated inflammation, with its overactivation implicated in various autoinflammatory, metabolic, and neurodegenerative diseases. Pharmacological inhibition of NLRP3 offers a promising treatment strategy for inflammatory conditions, although no medications targeting the NLRP3 inflammasome are currently available. This study demonstrates that clioquinol (CQ), a clinical drug with chelating properties, effectively inhibits NLRP3 activation, resulting in reduced cytokine secretion and cell pyroptosis in both human and mouse macrophages, with a half maximal inhibitory concentration (IC50) of 0.478 µM. Additionally, CQ mitigates experimental acute peritonitis, gouty arthritis, sepsis, and colitis by lowering serum levels of interleukin-1β (IL-1β), IL-6, and tumour necrosis factor-α (TNF-α). Mechanistically, CQ covalently binds to Arginine 335 (R335) in the NACHT domain, inhibiting NLRP3 inflammasome assembly and blocking the interaction between NLRP3 and its component protein. Collectively, this study identifies CQ as an effective natural NLRP3 inhibitor and a potential therapeutic agent for NLRP3-driven diseases.
An improved reporter gene assay for evaluating the biological activity of recombinant human growth hormone
Xiaoming Zhang, Heyang Li, Ying Huang, Ping Lv, Lvyin Wang, Kezheng Xu, Yi Li, Xinyue Hu, Yue Sun, Cheng-gang Liang, Jing Li
, Available online  , doi: 10.1016/j.jpha.2024.101073
Abstract(37) HTML Full Text PDF(1)
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Pharmacological modulation of mitochondrial function as novel strategies for treating intestinal inflammatory diseases and colorectal cancer
Boya Wang, Xinrui Guo, Lanhui Qin, Liheng He, Jingnan Li, Xudong Jin, Dapeng Chen, Guangbo Ge
, Available online  , doi: 10.1016/j.jpha.2024.101074
Abstract(148) HTML Full Text PDF(5)
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Inflammatory bowel disease (IBD) is a chronic and recurrent intestinal disease, and has become a major global health issue. Individuals with IBD face an elevated risk of developing colorectal cancer (CRC), and recent studies have indicated that mitochondrial dysfunction plays a pivotal role in the pathogenesis of both IBD and CRC. This review covers the pathogenesis of IBD and CRC, focusing on mitochondrial dysfunction, and explores pharmacological targets and strategies for addressing both conditions by modulating mitochondrial function. Additionally, recent advancements in the pharmacological modulation of mitochondrial dysfunction for treating IBD and CRC, encompassing mitochondrial damage, release of mitochondrial DNA (mtDNA) and impairment of mitophagy are thoroughly summarized. The review also provides a comprehensive overview of various natural compounds (such as flavonoids, alkaloids, and diterpenoids), Chinese medicines, and intestinal microbiota which can alleviate IBD and retarding the progression of CRC by modulating mitochondrial function. In the future, it will be imperative to develop more practical methodologies for real-time monitoring and accurate detection of mitochondrial function, which will greatly aid scientists in identifying more effective agents for treating IBD and CRC through modulation of mitochondrial function.
Advanced bioanalytic techniques for pharmacokinetic studies of nanocarrier drug delivery systems
Xiangjun Meng, Jiayi Yao, Jingkai Gu
, Available online  , doi: 10.1016/j.jpha.2024.101070
Abstract(57) HTML Full Text PDF(5)
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Significant investment in nanocarrier drug delivery systems (Nano-DDSs) has yielded only a limited number of successfully marketed nanomedicines, highlighting a low rate of clinical translation. A primary contributing factor is the lack of foundational understanding of in vivo processes. Comprehensive knowledge of the pharmacokinetics of Nano-DDSs is essential for developing more efficacious nanomedicines and accurately evaluating their safety and associated risks. However, the complexity of Nano-DDSs has impeded thorough and systematic pharmacokinetic studies. Key components of pharmacokinetic investigations on Nano-DDSs include the analysis of the released drug, the encapsulated drug, and the nanomaterial, which present a higher level of complexity compared to traditional small-molecule drugs. Establishing an appropriate approach for monitoring the pharmacokinetics of Nano-DDSs is crucial for facilitating the clinical translation of nanomedicines. This review provides an overview of advanced bioanalytical methodologies employed in studying the pharmacokinetics of anticancer organic Nano-DDSs over the past five years. We hope that this review will enhance the understanding of the pharmacokinetics of Nano-DDSs and support the advancement of nanomedicines.
Targeted screening and profiling of massive components of colistimethate sodium by two-dimensional-liquid chromatography-mass spectrometry based on self-constructed compound database
Xuan Li, Minwen Huang, Yue-Mei Zhao, Wenxin Liu, Nan Hu, Jie Zhou, Zi-Yi Wang, Sheng Tang, Jian-Bin Pan, Hian Kee Lee, Yao-zuo Yuan, Taijun Hang, Hai-Wei Shi, Hongyuan Chen
, Available online  , doi: 10.1016/j.jpha.2024.101072
Abstract(62) HTML Full Text PDF(2)
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In-depth study of the components of polymyxins is the key to controlling the quality of this class of antibiotics. Similarities and variations of components present significant analytical challenges. A two-dimensional (2D) liquid chromatography-mass spectrometric (LC-MS) method was established for screening and comprehensive profiling of compositions of the antibiotic colistimethate sodium (CMS). A high concentration of phosphate buffer mobile phase was used in the first-dimensional LC system to get the components well separated. For efficient and high-accuracy screening of CMS, a targeted method based on a self-constructed high resolution mass spectrum database of CMS components was established. The database was built based on the commercial MassHunter Personal Compound Database and Library (PCDL) software and its accuracy of the compound matching result was verified with 6 known components before being applied to genuine sample screening. On this basis, the unknown peaks in the CMS chromatograms were deduced and assigned. The molecular formula, group composition and origins of a total of 99 compounds, of which the combined area percentage accounted for more than 95% of CMS components, were deduced by this 2D-LC-MS method combined with the MassHunter PCDL. This profiling method was highly efficient and could distinguish hundreds of components within 3 h, providing reliable results for quality control of this kind of complex drugs.
Blocking the adverse outcome pathway of skin sensitization through a N-acetyl cysteine and lysine-loaded hydrogel
Gonçalo S. Brites, Isabel Ferreira, Ana I. Sebastião, Cátia Sousa, Ana Silva, Mylene Carrascal, Rui C. Oliveira, Margarida Gonçalo, Carla Vitorino, Bruno M. Neves, Maria T. Cruz
, Available online  , doi: 10.1016/j.jpha.2024.101071
Abstract(42) HTML Full Text PDF(0)
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Exosomal circRNAs: Deciphering the novel drug resistance roles in cancer therapy
Xi Li, Hanzhe Liu, Peixu Xing, Tian Li, Yi Fang, Shuang Chen, Siyuan Dong
, Available online  , doi: 10.1016/j.jpha.2024.101067
Abstract(85) HTML Full Text PDF(6)
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Exosomal circRNAs are pivotal in cancer biology, and tumor pathophysiology. These stable, non-coding RNAs encapsulated in exosomes participated in cancer progression, tumor growth, metastasis, drug sensitivity and the tumor microenvironment (TME). Their presence in bodily fluids positions them as potential non-invasive biomarkers, revealing the molecular dynamics of cancers. Research in exosomal circRNAs is reshaping our understanding of neoplastic intercellular communication. Exploiting the natural properties of exosomes for targeted drug delivery and disrupting circRNA-mediated pro-tumorigenic signaling can develop new treatment modalities. Therefore, ongoing exploration of exosomal circRNAs in cancer research is poised to revolutionize clinical management of cancer. This emerging field offers hope for significant breakthroughs in cancer care. This review underscores the critical role of exosomal circRNAs in cancer biology and drug resistance, highlighting their potential as non-invasive biomarkers and therapeutic targets that could transform the clinical management of cancer.
A tailored database combining reference compound-derived metabolite, metabolism platform and chemical characteristic of Chinese herb followed by activity screening: Application to Magnoliae Officinalis Cortex
Zhenzhen Xue, Yudong Shang, Lan Yang, Tao Li, Bin Yang
, Available online  , doi: 10.1016/j.jpha.2024.101066
Abstract(57) HTML Full Text PDF(4)
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A strategy combining a tailored database and high-throughput activity screening that discover bioactive metabolites derived from Magnoliae Officinalis Cortex (MOC) was developed and implemented to rapidly profile and discover bioactive metabolites in vivo derived from traditional Chinese medicine (TCM). The strategy possessed four characteristics: 1) The tailored database consisted of metabolites derived from big data-originated reference compound, metabolites predicted in silico, and MOC chemical profile-based pseudomolecular ions. 2) When profiling MOC-derived metabolites in vivo, attentions were paid not only on prototypes of MOC compounds and metabolites directly derived from MOC compounds, as reported by most papers, but also on isomerized metabolites and the degradation products of MOC compounds as well as their derived metabolites. 3) Metabolite traceability was performed, especially to distinguish isomeric prototypes-derived metabolites, and prototypes of MOC compounds as well as phase I metabolites derived from other MOC compounds. 4) Molecular docking was utilized for high-throughput activity screening and molecular dynamic simulation as well as zebrafish model were used for verification. Using this strategy, 134 metabolites were swiftly characterized after the oral administration of MOC to rats, and several metabolites were reported for the first time. Furthermore, 17 potential active metabolites were discovered by targeting the motilin, dopamine D2, and the serotonin type 4 (5-HT4) receptors, and their bioactivities were verified using molecular dynamic simulation and a zebrafish constipation model. This study extends the application of mass spectrometry (MS) to rapidly profile TCM-derived metabolites in vivo, which will help pharmacologists rapidly discover potent metabolites from a complex matrix.
SnoRNAs: the promising targets for anti-tumor therapy
Xiaoyun Hu, Wanlin Cui, Min Liu, Fangxiao Zhang, Yingqi Zhao, Mingrong Zhang, Yuhang Yin, Yalun Li, Ying Che, Xianglong Zhu, Yuxuan Fan, Xiaolan Deng, Minjie Wei, Huizhe Wu
, Available online  , doi: 10.1016/j.jpha.2024.101064
Abstract(63) HTML Full Text PDF(3)
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Recently, snoRNAs have transcended the genomic "noise" to emerge as pivotal molecular markers due to their essential roles in tumor progression. Substantial evidence indicates a strong association between snoRNAs and critical clinical features such as tumor pathology and drug resistance. Historically, snoRNA research has concentrated on two classical mechanisms: 2'-O-ribose methylation and pseudouridylation. This review specifically summarizes the novel regulatory mechanisms and functional patterns of snoRNAs in tumors, encompassing transcriptional, post-transcriptional, and post-translational regulation. We further discuss the synergistic effect between snoRNA host genes (SNHGs) and snoRNAs in tumor progression. More importantly, snoRNAs extensively contribute to the development of tumor cell resistance as oncogenes or tumor suppressor genes. Accordingly, we provide a comprehensive review of the clinical diagnosis and treatment associated with snoRNAs and explore their significant potential as novel drug targets.
Targeting AMPK related signaling pathways: A feasible approach for natural herbal medicines to intervene nonalcoholic fatty liver disease
Yongqing Cai, Lu Fang, Fei Chen, Peiling Zhong, Xiangru Zheng, Haiyan Xing, Rongrong Fan, Lie Yuan, Wei Peng, Xiaoli Li
, Available online  , doi: 10.1016/j.jpha.2024.101052
Abstract(66) HTML Full Text PDF(4)
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Non-alcoholic fatty liver disease (NAFLD) is a metabolic disease characterized by abnormal deposition of lipid in hepatocytes. If not intervened in time, NAFLD may develop into liver fibrosis or liver cancer, and ultimately threatening life. NAFLD has complicated etiology and pathogenesis, and there are no effective therapeutic means and specific drugs. Currently, insulin sensitizers, lipid-lowering agents and hepatoprotective agents are often used for clinical intervention, but these drugs have obvious side effects, and their effectiveness and safety need to be further confirmed. AMP-activated protein kinase (AMPK) plays a central role in maintaining energy homeostasis. Activated AMPK can enhanace lipid degradation, alleviate insulin resistance, suppress oxidative stress and inflammatory response, and regulate autophagy, thereby alleviating NAFLD. Natural herbal medicines have received extensive attention recently because of their regulatory effects on AMPK and low side effects. In this article, we reviewed the biologically active natural herbal medicines (such as natural herbal medicine formulas, extracts, polysaccharides, and monomers) that reported in recent years to treat NAFLD via regulating AMPK, which can serve as a foundation for subsequent development of candidate drugs for NAFLD.
Nose to brain strategy coupled to nano vesicular system for natural products delivery: Focus on synaptic plasticity in Alzheimer’s disease
Nunzia Maisto, Dalila Mango
, Available online  , doi: 10.1016/j.jpha.2024.101057
Abstract(57) HTML Full Text PDF(4)
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A wide number of natural molecules demonstrated neuroprotective effects on synaptic plasticity defects induced by amyloid-β (Aβ) in ex vivo and in vivo Alzheimer’s disease (AD) models, suggesting a possible use in the treatment of this neurodegenerative disorder. However, several compounds, administered parenterally and orally, are unable to reach the brain due to the presence of the blood-brain barrier (BBB) which prevents the passage of external substances, such as proteins, peptides, or phytocompounds, representing a limit to the development of treatment for neurodegenerative diseases, such as AD. The combination of nano vesicular systems, as colloidal systems, and nose to brain (NtB) delivery depicts a new nanotechnological strategy to overtake this limit and to develop new treatment approaches for brain diseases, including the use of natural molecules in combination therapy for AD. Herein, we will provide an updated overview, examining the literature of the last 20 years and using specific keywords that provide evidence on natural products with the ability to restore synaptic plasticity alterations in AD models, and the possible application using safe and non-invasive strategies focusing on nano vesicular systems for NtB delivery.
A gene set enrichment analysis for the cancer hallmarks
Otília Menyhart, William Jayasekara Kothalawala, Balázs Győrffy
, Available online  , doi: 10.1016/j.jpha.2024.101065
Abstract(102) HTML Full Text PDF(6)
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The "hallmarks of cancer" concept provides a valuable framework for understanding fundamental organizing principles common to various cancers. However, without a consensus gene set for cancer hallmarks, data comparison and integration result in diverse biological interpretations across studies. Therefore, we aimed to form a consensus cancer hallmark gene set by merging data from available mapping resources and establishing a framework for mining these gene sets. By consolidating data from seven projects, 6,763 genes associated with ten cancer hallmarks were identified. A cancer hallmarks enrichment analysis was performed for prognostic genes associated with overall survival across twelve types of solid tumors. "Tissue invasion and metastasis" was most prominent in cancers of the stomach (P = 2.2×10-11), pancreas (P = 4.2×10-9), bladder (P = 3.3×10-8), and ovaries (P = 0.0007), aligning with their heightened potential to spread. "Sustained angiogenesis" was most prominent in squamous cell carcinomas of the lung (P = 2.5×10-7), while "genome instability" showed strong enrichment in lung adenocarcinomas (P = 1.5×10-8) and cancers of the liver (P = 5.5×10-10), pancreas (P = 2.1×10-5), and kidney (P = 0.018). Pancreatic cancers displayed the highest enrichment of hallmarks, emphasizing the disease's complexity, while in melanomas, and cancers of the liver, prostate, and kidney, a single hallmark was enriched among the prognostic markers of survival. Additionally, an online tool (www.cancerhallmarks.com) that allows the identification of cancer-associated hallmarks from new gene sets was established. In summary, our aim of establishing a consensus list of cancer hallmark genes was achieved. Furthermore, the analysis of survival-associated genes revealed a unique pattern of hallmark enrichment with potential pharmacological implications in different tumor types.
Supramolecular prodrug inspiring from Rhizoma Coptidis-Fructus Mume herbal pair alleviated inflammatory diseases by inhibiting pyroptosis
Wenhui Qian, Bei Zhang, Ming Gao, Yuting Wang, Jiachen Shen, Dongbing Liang, Chao Wang, Wei Wei, Xing Pan, Qiuying Yan, Dongdong Sun, Dong Zhu, Haibo Cheng
, Available online  , doi: 10.1016/j.jpha.2024.101056
Abstract(62) HTML Full Text PDF(0)
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Sustained inflammatory responses are closely related to various severe diseases, and inhibiting the excessive activation of inflammasomes and pyroptosis has significant implications for clinical treatment. Natural products have garnered considerable concern for the treatment of inflammation. Huanglian-Wumei decoction (HLWMD) is a classic prescription used for treating inflammatory diseases, but the necessity of their combination and the exact underlying anti-inflammatory mechanism have not yet been elucidated. Inspired by the supramolecular self-assembly strategy and natural drug compatibility theory, we successfully obtained berberine (BBR)-chlorogenic acid (CGA) supramolecular (BCS), which is an herbal pair from HLWMD. Using a series of characterization methods, we confirmed the self-assembly mechanism of BCS. BBR and CGA were self-assembled and stacked into amphiphilic spherical supramolecules in a 2:1 ratio, driven by electrostatic interactions, hydrophobic interactions and π-π stacking; the hydrophilic fragments of CGA were outside, and the hydrophobic fragments of BBR were inside. This stacking pattern significantly improved the anti-inflammatory performance of BCS compared with that of single free molecules. Compared with free molecules, BCS significantly attenuated the release of multiple inflammatory mediators and Lipopolysaccharide (LPS)-induced pyroptosis. Its anti-inflammatory mechanism is closely related to the inhibition of intracellular nuclear factor-kappaB (NF-κB) p65 phosphorylation and the noncanonical pyroptosis signalling pathway mediated by caspase11.
Identification of the fruit of Brucea javanica as an anti-liver fibrosis agent working via SMAD2/SMAD3 and JAK1/STAT3 signaling pathways
Di Yan, Liansheng Qiao, Wenting Huang, Xiaoling Zhang, Chengmei Ma, Quansheng Feng, Jing Cheng, Lan Xie
, Available online  , doi: 10.1016/j.jpha.2024.101047
Abstract(61) HTML Full Text PDF(7)
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The molecular and metabolic landscape of ferroptosis in respiratory diseases: Pharmacological aspects
Tong Wu, Miaorong Ji, Tian Li, Lianxiang Luo
, Available online  , doi: 10.1016/j.jpha.2024.101050
Abstract(44) HTML Full Text PDF(1)
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Ferroptosis is a form of cell death that occurs when there is an excess of reactive oxygen species (ROS), lipid peroxidation, and iron accumulation. The precise regulation of metabolic pathways, including iron, lipid, and amino acid metabolism, is crucial for cell survival. This type of cell death, which is associated with oxidative stress, is controlled by a complex network of signaling molecules and pathways. It is also implicated in various respiratory diseases such as asthma, chronic obstructive pulmonary disease (COPD), Acute lung injury (ALI), lung cancer, pulmonary fibrosis, and the coronavirus disease of 2019 (COVID-19). To combat drug resistance, it is important to identify appropriate biological markers and treatment targets, as well as intervene in respiratory disorders to either induce or prevent ferroptosis. The focus is on the role of ferroptosis in the development of respiratory diseases and the potential of targeting ferroptosis for prevention and treatment. The review also explores the interaction between immune cell ferroptosis and inflammatory mediators in respiratory diseases, aiming to provide more effective strategies for managing cellular ferroptosis and respiratory disorders.
Intrinsic Gallium-68 Labeling of Nanoclays for In vivo Tracking
Nian Liu, Tingting Wang, Jian Li, Xinhui Su
, Available online  , doi: 10.1016/j.jpha.2024.101055
Abstract(56) HTML Full Text PDF(1)
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Ginger protects against vein graft remodeling by precisely modulating ferroptotic stress in vascular smooth muscle cell dedifferentiation
Xiaoyu Yu, Weiwei Wu, Jingjun Hao, Yuxin Zhou, Deyang Yu, Wei Ding, Xuejuan Zhang, Gaoli Liu, Jianxun Wang
, Available online  , doi: 10.1016/j.jpha.2024.101053
Abstract(119) HTML Full Text PDF(18)
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Vein graft failure (VGF) is associated with vein graft (VG) intimal hyperplasia, which is characterized by abnormal accumulation of vascular smooth muscle cells (VSMCs). Most neointimal VSMCs are derived from pre-existing VSMCs via a process of VSMC phenotypic transition, also known as dedifferentiation. There is increasing evidence to suggest that ginger or its bioactive ingredients may block VSMC dedifferentiation, exerting vasoprotective functions; however, the precise mechanisms have not been fully characterized. Therefore, we investigated the effect of ginger on VSMC phenotypic transition in VG remodeling after transplantation. Ginger significantly inhibited neointimal hyperplasia and promoted lumen opening in a 3-month VG, which was primarily achieved by reducing ferroptotic stress. Ferroptotic stress is a pro-ferroptotic state. Contractile VSMCs did not die but instead gained a proliferative capacity and switched to the secretory type, forming neointima after vein transplantation. Ginger and its two main vasoprotective ingredients (6-gingerol and 6-shogaol) inhibit VSMC dedifferentiation by reducing ferroptotic stress. Network pharmacology analysis revealed that 6-gingerol inhibits ferroptotic stress by targeting P53 while 6-shogaol inhibits ferroptotic stress by targeting 5-lipoxygenase (Alox5), both promoting ferroptosis. Furthermore, both ingredients co-target peroxisome proliferator-activated receptor gamma (PPARγ), decreasing PPARγ mediated nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 1 (Nox1) expression. Nox1 promotes intracellular reactive oxygen species (ROS) production and directly induces VSMC dedifferentiation. In addition, Nox1 is a ferroptosis-promoting gene that encourages ferroptotic stress production, indirectly leading to VSMC dedifferentiation. Ginger, a natural multi-targeted ferroptotic stress inhibitor, finely and effectively prevents VSMC phenotypic transition and protects against venous injury remodeling.
Recent Advances in Bacterial Outer Membrane Vesicles: Effects on the Immune System, Mechanisms and their Usage for Tumor Treatment
Shuo Xiang, Arshad Khan, Qiufang Yao, Dong Wang
, Available online  , doi: 10.1016/j.jpha.2024.101049
Abstract(82) HTML Full Text PDF(2)
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Tumor treatment remains a significant medical challenge, with many traditional therapies causing notable side effects. Recent research has led to the development of immunotherapy, which offers numerous advantages. Bacteria inherently possess motility, allowing them to preferentially colonize tumors and modulate the tumor immune microenvironment, thus influencing the efficacy of immunotherapy. Bacterial outer membrane vesicles (OMVs) secreted by gram-negative bacteria, are nanoscale lipid bilayer structures rich in bacterial antigens, pathogenassociated molecular patterns (PAMPs), various proteins, and vesicle structures. These features allow OMVs to stimulate immune system activation, generate immune responses, and serve as efficient drug delivery vehicles. This dual capability enhances the effectiveness of immunotherapy combined with chemotherapy or phototherapy, thereby improving anticancer drug efficacy. Current research has concentrated on engineering OMVs to enhance production yield, minimize cytotoxicity, and improve the safety and efficacy of treatments. Consequently, OMVs hold great promise for applications in tumor immunotherapy, tumor vaccine development, and drug delivery. This article provides an overview of the structural composition and immune mechanisms of OMVs, details various OMVs modification strategies, and reviews the progress in using OMVs for tumor treatment and their anti-tumor mechanisms. Additionally, it discusses the challenges faced in translating OMV-based anti-tumor therapies into clinical practice, aiming to provide a comprehensive understanding of OMVs' potential for in-depth research and clinical application.
Mitochondria and myocardial ischemia/reperfusion injury: Effects of Chinese herbal medicine and the underlying mechanisms
Chuxin Zhang, Xing Chang, Dandan Zhao, Yu He, Guangtong Dong, Lin Gao
, Available online  , doi: 10.1016/j.jpha.2024.101051
Abstract(106) HTML Full Text PDF(12)
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Ischemic heart disease is associated with high morbidity and mortality rates. Reperfusion therapy is the best treatment option for this condition. However, reperfusion can aggravate myocardial damage through a phenomenon known as myocardial ischemia/reperfusion (I/R) injury, which has recently gained the attention of researchers. Several studies have shown that Chinese herbal medicines and their natural monomeric components exert therapeutic effects against I/R injury. This review outlines the current knowledge on the pathological mechanisms through which mitochondria participate in I/R injury, focusing on the issues related to energy metabolism, mitochondrial quality control disorders, oxidative stress, and calcium. The mechanisms by which mitochondria mediate cell death have also been discussed. To develop a resource for the prevention and management of clinical myocardial I/R damage, we compiled the most recent research on the effects of Chinese herbal remedies and their monomer components.
Oxymatrine, a novel TLR2 agonist, promotes megakaryopoiesis and thrombopoiesis through the STING/NF-ĸB pathway
Chengyang Ni, Ling Zhou, Shuo Yang, Mei Ran, Jiesi Luo, Kui Cheng, Feihong Huang, Xiaoqin Tang, Xiang Xie, Dalian Qin, Qibing Mei, Long Wang, Juan Xiao, Jianming Wu
, Available online  , doi: 10.1016/j.jpha.2024.101054
Abstract(40) HTML Full Text PDF(6)
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Radiation-induced thrombocytopenia (RIT) faces a perplexing challenge in the clinical treatment of cancer patients, and current therapeutic approaches are inadequate in the clinical settings. In this researsh, oxymatrine, a new molecule capable of healing RIT was screened out, and the underlying regulatory mechanism associated with magakaryocyte (MK) differentiation and thrombopoiesis was demonstrated. The capacity of oxymatrine to induce MK differentiation was verified in K-562 and Meg-01 cells in vitro. The ability to induce thrombopoiesis was subsequently demonstrated in Tg (cd41:eGFP) zebrafish and RIT model mice. In addition, we carried out network pharmacological prediction, drug affinity responsive target stability assay (DARTS) and cellular thermal shift assay (CETSA) analyses to explore the potential targets of oxymatrine. Moreover, the pathway underlying the effects of oxymatrine was determined by Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses, Western blot, and immunofluorescence. Oxymatrine markedly promoted MK differentiation and maturation in vitro. Moreover, oxymatrine induced thrombopoiesis in Tg (cd41:eGFP) zebrafish and accelerated thrombopoiesis and platelet function recovery in RIT model mice. Mechanistically, oxymatrine directly binds to toll-like receptor 2 (TLR2) and further regulates the downstream pathway stimulator of interferon genes (STING)/nuclear factor-kappaB (NF-κB), which can be blocked by C29 and C-176, which are specific inhibitors of TLR2 and STING, respectively. Taken together, we demonstrated that oxymatrine, a novel TLR2 agonist, plays a critical role in accelerating MK differentiation and thrombopoiesis via the STING/NF-κB axis, suggesting that oxymatrine is a promising candidate for RIT therapy.
Discovery of toad-derived peptide analogue targeting ARF6 to induce immunogenic cell death for immunotherapy of hepatocellular carcinoma
Dihui Xu, Xiang Lv, Meng Yu, Ao Tan, Jiaojiao Wang, Xinyi Tang, Mengyuan Li, Wenyuan Wu, Yuyu Zhu, Jing Zhou, Hongyue Ma
, Available online  , doi: 10.1016/j.jpha.2024.101038
Abstract(73) HTML Full Text PDF(2)
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Coral calcium hydride promotes peripheral mitochondrial division and reduces AT-II cells damage in ARDS via activation of the Trx2/Myo19/Drp1 pathway
Qian Li, Yang Ang, Qingqing Zhou, Min Shi, Wei Chen, Yujie Wang, Pan Yu, Bing Wan, Wanyou Yu, Liping Jiang, Yadan Shi, Zhao Lin, Shaozheng Song, Manlin Duan, Yun Long, Qi Wang, WenTao Liu, Hongguang Bao
, Available online  , doi: 10.1016/j.jpha.2024.101039
Abstract(74) HTML Full Text PDF(6)
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Acute respiratory distress syndrome (ARDS) is a common respiratory emergency, but current clinical treatment remains at the level of symptomatic support and there is a lack of effective targeted treatment measures. Our previous study confirmed that inhalation of hydrogen gas can reduce the acute lung injury of ARDS, but the application of hydrogen has flammable and explosive safety concerns. Drinking hydrogen-rich liquid or inhaling hydrogen gas has been shown to play an important role in scavenging reactive oxygen species and maintaining mitochondrial quality control balance, thus improving ARDS in patients and animal models. Coral calcium hydrogenation (CCH) is a new solid molecular hydrogen carrier prepared from coral calcium (CC). Whether and how CCH affects acute lung injury in ARDS remains unstudied. In this study, we observed the therapeutic effect of CCH on lipopolysaccharide (LPS) induced acute lung injury in ARDS mice. The survival rate of mice treated with CCH and hydrogen inhalation was found to be comparable, demonstrating a significant improvement compared to the untreated ARDS model group. CCH treatment significantly reduced pulmonary hemorrhage and edema, and improved pulmonary function and local microcirculation in ARDS mice. CCH promoted mitochondrial peripheral division in the early course of ARDS by activating mitochondrial thioredoxin 2(Trx2), improved lung mitochondrial dysfunction induced by LPS, and reduced oxidative stress damage. The results indicate that CCH is a highly efficient hydrogen-rich agent that can attenuate acute lung injury of ARDS by improving the mitochondrial function through Trx2 activation.
A review on the screening methods for the discovery of natural antimicrobial peptides
Bin Yang, Hongyan Yang, Jianlong Liang, Jiarou Chen, Chunhua Wang, Yuanyuan Wang, Jincai Wang, Wenhui Luo, Tao Deng, Jialiang Guo
, Available online  , doi: 10.1016/j.jpha.2024.101046
Abstract(77) HTML Full Text PDF(3)
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Natural antimicrobial peptides (AMPs) are promising candidates for the development of a new generation of antimicrobials to combat antibiotic-resistant pathogens. They have found extensive applications in the fields of medicine, food, and agriculture. However, efficiently screening AMPs from natural sources poses several challenges, including low efficiency and high antibiotic resistance. This review focuses on the action mechanisms of AMPs, both through membrane and non-membrane routes. We thoroughly examine various highly efficient AMP screening methods, including wholebacterial adsorption binding, cell membrane chromatography, phospholipid membrane chromatography binding, membrane-mediated capillary electrophoresis, colorimetric assays, thin layer chromatography, fluorescence-based screening, genetic sequencingbased analysis, computational mining of AMP databases, and virtual screening methods. Additionally, we discuss potential developmental applications for enhancing the efficiency of AMP discovery. This review provides a comprehensive framework for identifying AMPs within complex natural product systems.
Isovalerylspiramycin I alleviates liver injury and liver fibrosis by targeting the nucleotide-binding protein 2 (NUBP2)-vascular non-inflammatory molecule-1 (VNN1) pathway
Na Zhang, Weixiao Niu, Weiping Niu, Yiming Li, Simin Guo, Yang Li, Weiqing He, Hongwei He
, Available online  , doi: 10.1016/j.jpha.2024.101048
Abstract(69) HTML Full Text PDF(2)
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Liver fibrosis is a vital cause of morbidity in patients with liver diseases and developing novel anti-fibrotic drugs is imperative. Isovalerylspiramycin I (ISP I) as a major component of carrimycin applied to upper respiratory infections, was first found to possess anti-fibrotic potential. The present study aims to evaluate the functions and mechanisms of ISP I in protecting against liver fibrosis. According to our results, ISP I not only reduced the expressions of fibrogenic markers in LX-2 cells but also appeared great protective effects on liver injury and liver fibrosis in bile duct ligation (BDL) rats and carbon tetrachloride (CCl4) mice. We proved that nucleotide-binding protein 2 (NUBP2) was the direct target of ISP I. ISP I through targeting NUBP2, increased the amount of vascular non-inflammatory molecule-1 (VNN1) on the cell membrane, which will inhibit oxidative stress and fibrosis. Simultaneously, the original carrimycin’s protective effect on liver damage and fibrosis was verified. Therefore, our study provides potential agents for patients with liver fibrosis-related diseases, and the clear mechanism supports wide application in the clinic.
Strategy for Cysteine-Targeting Covalent Inhibitors Screening using In-house Database based LC-MS/MS and Drug Repurposing
Xiaolan Hu, Jian-Lin Wu, Quan He, Zhi-Qi Xiong, Na Li
, Available online  , doi: 10.1016/j.jpha.2024.101045
Abstract(45) HTML Full Text PDF(3)
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Targeted covalent inhibitors, primarily targeting cysteine residues, have attracted great attention as potential drug candidates due to good potency and prolonged duration of action. However, their discovery is challenging. In this research, a database-assisted liquid chromatography-tandem mass spectrometry (LC-MS/MS) strategy was developed to quickly discover potential cysteine-targeting compounds. First, compounds with potential reactive groups were selected and incubated with N-acetyl-cysteine in microsomes. And the precursor ions of possible cysteine-adducts were predicted based on covalent binding mechanisms to establish in-house database. Second, substrate-independent product ions produced from N-acetyl-cysteine moiety were selected. Third, multiple reaction monitoring scan was conducted to achieve sensitive screening for cysteine-targeting compounds. This strategy showed broad applicability, and covalent compounds with diverse structures were screened out, offering structural resources for covalent inhibitors development. Moreover, the screened compounds, norketamine and hydroxynorketamine, could modify synaptic transmission-related proteins in vivo, indicating their potential as covalent inhibitors. This experimental-based screening strategy provides a quick and reliable guidance for the design and discovery of covalent inhibitors.
Pterostilbene: A natural neuroprotective stilbene with anti-Alzheimer’s disease properties
Songlan Gao, Honglei Zhang, Na Li, Lijuan Zhang, Zhe Zhu, Changlu Xu
, Available online  , doi: 10.1016/j.jpha.2024.101043
Abstract(43) HTML Full Text PDF(1)
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Alzheimer's disease (AD) is the leading cause of dementia, and no effective treatment has been developed for it thus far. Recently, the use of natural compounds in the treatment of neurodegenerative diseases has garnered significant attention owing to their minimal adverse reactions. Accordingly, the potential therapeutic effect of pterostilbene (PTS) on AD has been demonstrated in multiple in vivo and in vitro experiments. In this study, we systematically reviewed and summarized the results of these studies investigating the use of PTS for treating AD. Analysis of the literature revealed that PTS may play a role in AD treatment through various mechanisms, including anti-oxidative damage, anti-neuroinflammation, anti-apoptosis, cholinesterase activity inhibition, attenuation of β-amyloid deposition, and tau protein hyperphosphorylation. Moreover, PTS interferes with the progression of AD by regulating the activities of peroxisome proliferator-activated receptor alpha, monoamine oxidase B, Sirtuin-1, and phosphodiesterase 4A. Furthermore, to further elucidate the potential therapeutic mechanisms of PTS in AD, we employed network pharmacology and molecular docking technology to perform molecular docking of related proteins, and the obtained binding energies ranged from −2.83 kJ/mol to −5.14 kJ/mol, indicating that these proteins exhibit good binding ability with PTS. Network pharmacology analysis revealed multiple potential mechanisms of action for PTS in AD. In summary, by systematically collating and summarizing the relevant studies on the role of PTS in treatment of AD, it is anticipated that this will serve as a reference for the precise targeted prevention and treatment of AD, either using PTS or other developed drug interventions.
A high-throughput measurement of critical micelle concentrations based on absolute aggregation-caused quenching probes
Xin Ji, Aun Raza, Jianping Qi, Yi Lu, Haisheng He, Wei Wu
, Available online  , doi: 10.1016/j.jpha.2024.101044
Abstract(64) HTML Full Text PDF(8)
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Phillygenin ameliorates tight junction proteins reduction, fibrosis, and apoptosis in mice with chronic colitis via TGR5-mediated PERK-eIF2α-Ca2+ pathway
Huanhuan Xue, Peijie Li, Jing Guo, Tinggui Chen, Shifei Li, Liwei Zhang
, Available online  , doi: 10.1016/j.jpha.2024.101042
Abstract(62) HTML Full Text PDF(3)
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Ulcerative colitis (UC) is an idiopathic, relapsing, and etiologically complicated chronic inflammatory bowel disease. Despite substantial progress in the management of UC, the outcomes of mucosal barrier repair are unsatisfactory. In this study, phillygenin (PHI) treatment alleviated the symptoms of chronic colitis in mice, including body weight loss, severe disease activity index scores, colon shortening, splenomegaly, oxidative stress, and inflammatory response. In particular, PHI treatment ameliorated the tight junction proteins (TJs) reduction, fibrosis, apoptosis, and intestinal stem cell activity, indicating that PHI exerted beneficial effects on the intestinal mucosal barrier in mice with chronic colitis. In the NCM460 cells damage model, dextran sulfate sodium triggered the sequential induction of TJs reduction, fibrosis, and apoptosis. Takeda G protein-coupled receptor-5 (TGR5) dysfunction mediated NCM460 cell injury. Moreover, PHI treatment enhanced TJs and suppressed fibrosis and apoptosis to maintain NCM460 cell function, depending on TGR5 activation. PHI promoted TGR5 activation and elevated intracellular cyclic adenosine monophosphate levels in HEK 293T cells transfected with TGR5 expression plasmids. Cellular thermal shift assay and molecular docking studies confirmed that PHI directly binds to TGR5, indicating that PHI is an agonist of TGR5. The process of PERK-eIF2α pathway-mediated endoplasmic reticulum Ca2+ release was involved in NCM460 cell injury as well, which was associated with TGR5 dysfunction. When NCM460 cells were pretreated with PHI, the PERK-eIF2α pathway and elevated Ca2+ levels were blocked. In conclusion, our study demonstrated a novel mechanism that PHI inhibited the PERK-eIF2α-Ca2+ pathway through TGR5 activation to against DSS-induced TJs reduction, fibrosis, and apoptosis.
Development of a Smartphone-Integrated Handheld Automated Biochemical Analyzer for Point-of-Care Testing of Urinary Albumin
Ze Wu, Peng Zhang, Wei Xiao, Qian Chen, Wangrun Lin, Peipei Chen, Kangwei Chen, Qiangqiang Fu, Zhijian Wang, Lei Zheng
, Available online  , doi: 10.1016/j.jpha.2024.101041
Abstract(77) HTML Full Text PDF(4)
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The level of urinary albumin is a critical indicator for the early diagnosis and management of chronic kidney disease (CKD). However, existing methods for detecting albumin are not conducive to point-of-care testing due to the complexity of reagent addition and incubation processes. This study presents a smartphone-integrated handheld automated biochemical analyzer (sHABA) designed for point-of-care testing of urinary albumin. The sHABA features a pre-loaded, disposable reagent cassette with reagents for the albumin assay arranged in the order of their addition within a hose. The smartphone-integrated analyzer can drive the reagents following a preset program, to enable automatic sequential addition. The sHABA has a detection limit for albumin of 5.9 mg/L and a linear detection range from 7 to 450 mg/L. The consistency of albumin level detection in 931 urine samples using sHABA with clinical tests indicates good sensitivity (95.78%) and specificity (90.16%). This research advances the field by providing an automated detection method for albumin in a portable device, allowing even untrained individuals to monitor CKD in real time at the patient's bedside. In the context of promoting tiered diagnosis and treatment, the sHABA has the potential to become an essential tool for the early diagnosis and comprehensive management of CKD and other chronic conditions.
Fluvoxamine: First comprehensive insights into its molecular characteristics and inclusion complexation with β-cyclodextrin
Thammarat Aree
, Available online  , doi: 10.1016/j.jpha.2024.101040
Abstract(84) HTML Full Text PDF(3)
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Fluvoxamine (FXM) is a well-known selective serotonin reuptake inhibitor (SSRI) for treating depression and has recently been repurposed for efficacious treatment of coronavirus disease 2019. Although cyclodextrin (CD) encapsulation effectively improves the physicochemical properties of structurally diverse SSRIs, the molecular understanding of their associations is deficient. This comprehensive study used single-crystal X-ray diffraction integrated with density functional theory (DFT) calculation to provide deep insights into the conformationally flexible FXM and its inclusion complexation with β-CD. X-ray analysis revealed the first crystallographic evidence of the uncomplexed 3FXM-H+·3maleate- (1). Three FXM-H+ ions are counter-balanced by three planar maleate- ions to form a thin layer stabilized by infinite fused H-bond rings R44(12) and R64(16) and the interplay of π…π, CF…π and F…F interactions. For 2β-CD·2FXM-H+·maleate2-·23.2H2O (2), the tail-to-tail β-CD dimer encapsulates two FXM-H+ 4-(trifluoromethyl)phenyl moieties, which are charge- balanced by the rare non-planar maleate2- and stabilized by N/OH…O H-bonds and F…F interactions. This is a host-guest recognition pattern uniquely observed for all β-CD complexes with halogen (X)-bearing SSRIs, indicating the essence of X…X interactions and the shielding of X-containing moieties in the wall of the β-CD dimer. DFT calculations unveiled that the monomeric and dimeric β-CD-FXM complexes and FXM isomers are energetically stable, which alleviates the numbness and bitterness of the orally administered drug as previously patented. Additionally, an insightful conformational analysis of FXM emphasizes the importance of drug structural adaptation in pharmacological functions.
Single-cell RNA sequencing reveals the changes of the pulmonary immune environment in rat after Siegesbeckia orientalis L. treatment
Fan Zhang, Shu Gan, Jingjing Liao, Ting Jiang, Zhiqiang Shi, Xueying Fan, Hiu-Yee Kwan, Zhongqiu Liu, Tao Su
, Available online  , doi: 10.1016/j.jpha.2024.101035
Abstract(91) HTML Full Text PDF(9)
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Potential of natural drug modulation of endoplasmic reticulum stress in the treatment of myocardial injury
Kai Yang, Ping Zhang, Jixin Li, Genming Zhang, Xing Chang
, Available online  , doi: 10.1016/j.jpha.2024.101034
Abstract(139) HTML Full Text PDF(11)
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Myocardial injury （MI） is a common occurrence in clinical practice caused by various factors such as ischemia, hypoxia, infection, metabolic abnormalities, and inflammation. Such damages are characterized by a reduction in myocardial function and cardiomyocyte death that can result in dangerous outcomes such as cardiac failure and arrhythmias. An endoplasmic reticulum stress （ERS） -induced unfolded protein response is triggered by several stressors, and its intricate signaling networks are instrumental in both cell survival and death. Cardiac damage frequently triggers ERS in response to different types of injuries and stress. High levels of ERS can exacerbate myocardial damage by inducing necrosis and apoptosis.
To target ERS in MI prevention and treatment, current medical research is focused on identifying effective therapy approaches. Traditional Chinese medicine (TCM) is frequently used because of its vast range of applications and low risk of adverse effects. Various studies have demonstrated that active components of Chinese medicines, including polyphenols, saponins, and alkaloids, can reduce myocardial cell death, inflammation, and modify the ERS pathway, thus preventing and mitigating cardiac injury.
Thus, this paper aims to provide a new direction and scientific basis for targeting ERS in MI prevention and treatment. We specifically summarize recent research progress on the regulation mechanism of ERS in MI by active ingredients of TCM.
Spatial metabolomics reveal metabolic alternations in the injured mice kidneys induced by triclocarban treatment
Peisi Xie, Jing Chen, Yongjun Xia, Zian Lin, Yu He, Zongwei Cai
, Available online  , doi: 10.1016/j.jpha.2024.101024
Abstract(109) HTML Full Text PDF(8)
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Triclocarban (TCC) is a common antimicrobial agent that has been widely used in medical care. Given the close association between TCC treatment and metabolic disorders, we assessed whether long-term treatment to TCC at a human-relevant concentration could induce nephrotoxicity by disrupting the metabolic levels in a mouse model. Matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) was applied to investigate the alterations in the spatial distributions and abundances of TCC, endogenous and exogenous metabolites in the kidney after TCC treatment. The results showed that TCC treatment induced the changes in the organ weight, organ coefficient and histopathology of the mouse kidney. MSI data reveled that TCC accumulated in the all regions of the kidney, while its five metabolites mainly distributed in the cortex regions. The abundances of 79 biomolecules associated with pathways of leukotriene E4 metabolism, biosythesis and degradation of glycerophospholipids and glycerolipids, ceramide-to-sphingomyelin signaling were significantly altered in the kidney after TCC treatment. These biomolecules showed distinctive distributions in the kidney and displayed a favorable spatial correlation with the pathological damage. This work offers new insights into the related mechanisms of TCC-induced nephrotocicity and exhibits the potential of MALDI-MSI-based spatial metabolomics as a promising approach for the risk assessment of agents in medical care.
A novel strategy based on the dielectric barrier discharge plasma for rapid eliminating the carryover associated with μPESI-MS/MS system
Qian Liu, Simin Zhang, Xiangyang Qu, Yunhui Xing, Zhenwei Xiao, Shicheng Fan, Janshon Zhu, Min Huang, Huichang Bi
, Available online  , doi: 10.1016/j.jpha.2024.101017
Abstract(156) HTML Full Text PDF(17)
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In mass spectrometry (MS) analysis, carryover is a common and unavoidable problem. It causes over-estimation of analyte levels, which significantly influences accuracy and precision. Therefore, there are strict limits on carryover in MS-based assays. The conventional capillary-based electrospray ionization (ESI) restricts the use of MS for real-time monitoring, where a prompt response is crucial. Recently, we have developed a micro probe electrospray ionization (μPESI) coupled with MS (μPESI-MS) technology, enabling MS analysis within 40 seconds without a chromatographic column [1]. However, the challenge of carryover arises when trying to make the micro probe reusable for resource-saving purposes. Considering that dielectric barrier discharge (DBD) plasma is effective in degrading contaminants in water and gas [2], we hypothesized the eventual use of the DBD plasma to “wash” the micro probe. Then, a DBD plasma wash tube (DBD-WT) was introduced for rapid carryover elimination in μPESI-MS analysis.
A holistic visualization for quality of Chinese materia medica: Structural and metabolic visualization by magnetic resonance imaging
Jing Wu, Kai Zhong, Hongyi Yang, Peiliang Zhang, Nianjun Yu, Weidong Chen, Na Zhang, Shuangying Gui, Lan Han, Daiyin Peng
, Available online  , doi: 10.1016/j.jpha.2024.101019
Abstract(111) HTML Full Text PDF(13)
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The quality of Chinese materia medica (CMM) is a challenging and focused topic in the modernization of traditional Chinese medicine. A profound comprehension of the morphology, structure, active constituents, and dynamic changes during the whole process of CMM growth is essential, which needs highly precise contemporary techniques for in-depth elucidation. Magnetic resonance imaging (MRI) is a cutting- edge tool integrating the benefits of both nuclear magnetic resonance spectroscopy and imaging technology. With real-time, non-destructive, and in situ detection capabilities, MRI has been previously used for monitoring internal and external structures of plants alongside compounds during physiological processes in vivo. Here, factors involved in the holistic quality evaluation of CMMs were investigated. Given the applications of MRI in various plants, several representative CMMs were used as examples to demonstrate a methodology of quality visualization by MRI, embodying holistically monitoring the real-time macroscopic morphology, mesoscopic structure, and microscopic metabolites non-destructively in situ. Taken together, the review not only presents a pioneering application mode for utilizing MRI for CMM quality visualization but also holds promise for advancing the quality control and evaluation of CMMs.
Wheel-shaped polyoxometalates as nanozymes for autophagyaugmented and phototherapy-involved cancer nanotherapy
Jun Miao, Xiaofeng Fan, Yining Shao, Yalei Zhang, Cailing Chen, Hongrui Tian, Shujun Li, Zhiping Zheng, Xiaoqian Xu
, Available online  , doi: 10.1016/j.jpha.2024.101018
Abstract(167) HTML Full Text PDF(20)
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Optimizing lipopeptide bioactivity: The impact of non-ionic surfactant dressing
Ágnes Ábrahám, Gergő Gyulai, Judith Mihály, Andrea Horváth, Orsolya Dobay, Zoltán Varga, Éva Kiss, Kata Horváti
, Available online  , doi: 10.1016/j.jpha.2024.101020
Abstract(81) HTML Full Text PDF(2)
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The aim of the research is to increase the applicability of lipopeptides as drugs. To this end, non-ionic triblock copolymers, namely poloxamers, were applied. The physicochemical properties of poloxamers vary depending on the length of the blocks, so different types were experimented with. Systems containing different additives were systematically investigated, and the change in the critical micelle concentration of the poloxamers at 25 and 37 ℃ in different media was assessed. In addition, the cytotoxicity of the different poloxamer micelles on three different cell lines was evaluated, and based on the results, Plur104, Plur123, and Plur127 were selected. Fatty acid elongated derivatives of a short antibacterial peptide (pL1), a medium-sized anticancer peptide (pCM15), and a branched-chain vaccine antigen (pATIPC) were used as lipopeptide models, and their formulations with the selected poloxamers were investigated. The solubility and homogeneity of the lipopeptides were significantly increased, and dynamic light scattering (DLS) measurements showed the formation of small particles of around 20 nm, which were well reproducible and storable. Similar homogenous micelle formation was observed after freeze-drying and reconstitution. The pL1 lipopeptide, formulated with the selected poloxamers, exhibited enhanced antibacterial activity with significantly reduced haemolytic side effects. The pCM15 peptide, when incorporated into poloxamer micelles, showed significantly enhanced cytotoxicity against tumor cells. Additionally, the internalization rate of pATIPC peptide formulated with poloxamers by antigen-presenting model cells exceeded that of the unformulated peptide. Our results demonstrate the potential of poloxamers as promising tools for the formulation of lipopeptides and for the optimization of their selectivity.
Comparative study of trastuzumab modification analysis using mono/multi-epitope affinity technology with LC-QTOF-MS
Chengyi Zuo, Jingwei Zhou, Sumin Bian, Qing Zhang, Yutian Lei, Yuan Shen, Zhiwei Chen, Peijun Ye, Leying Shi, Mao Mu, Jia-Huan Qu, Zhengjin Jiang, Qiqin Wang
, Available online  , doi: 10.1016/j.jpha.2024.101015
Abstract(122) HTML Full Text PDF(7)
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Dynamic tracking analysis of monoclonal antibodies (mAbs) biotransformation in vivo is crucial, as certain modifications could inactivate the protein and reduce drug efficacy. However, a particular challenge (i.e. immune recognition deficiencies) in biotransformation studies may arise when modifications occur at the paratope recognized by the antigen. To address this limitation, a multi-epitope affinity technology utilizing the MOF@Au@peptide@aptamer composite material was proposed and developed by simultaneously immobilizing complementarity determining region (CDR) mimotope peptide (HH24) and non-CDR mimotope aptamer (CH1S-6T) onto the surface of MOF@Au nanocomposite. Comparative studies demonstrated that MOF@Au@peptide@aptamer exhibited significantly enhanced enrichment capabilities for trastuzumab variants in comparison to mono-epitope affinity technology. Moreover, the higher deamidation ratio for LC-Asn-30 and isomerization ratio for HC-Asn-55 can only be monitored by the novel bioanalytical platform based on MOF@Au@peptide@aptamer and LC-QTOF-MS. Therefore, multi-epitope affinity technology could effectively overcome the biases of traditional affinity materials for key sites modification analysis of mAb. Particularly, the novel bioanalytical platform can be successfully used for the tracking analysis of trastuzumab modifications in different biological fluids. Compared to the spiked PB model, faster modification trends were monitored in the spiked serum and patients’ sera due to the catalytic effect of plasma proteins and relevant proteases. Differences in peptide modification levels of trastuzumab in patients’ sera were also monitored. In summary, the novel bioanalytical platform based on the multi-epitope affinity technology holds great potentials for in vivo biotransformation analysis of mAb, contributing to improved understanding and paving the way for future research and clinical applications.
Formulation, Characterization, and Evaluation of CurcuminLoaded Ginger-Derived Nanovesicles for Anti-Colitis Activity
Shengjie Huang, Min Zhang, Xiaoge Li, Jierong Pei, Zhirong Zhou, Peng Lei, Meng Wang, Peng Zhang, Heshui Yu, Guanwei Fan, Lifeng Han, Haiyang Yu, Yuefei Wang, Miaomiao Jiang
, Available online  , doi: 10.1016/j.jpha.2024.101014
Abstract(74) HTML Full Text PDF(6)
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Plant-derived nanovesicles have gained attention given their similarity to mammalian exosomes and advantages such as low cost, sustainability, and tissue targeting. Thus, they hold promise for disease treatment and drug delivery. In this study, we proposed a time-efficient method, PEG 8000 combined with sucrose density gradient centrifugation to prepare ginger-derived nanovesicles (GDNVs). Subsequently, curcumin (CUR) was loaded onto GDNV by ultrasonic incubation. The optimum conditions for ginger-derived nanovesicles loaded with curcumin (CG) were ultrasound time of 3 min, a carrier-to-drug ratio (GDNV:CUR) of 1:1. The study achieved a high loading capacity (94.027 ± 0.0944%) and encapsulation efficiency (89.300 ± 0.3437% ). Finally, the drugs' in vivo distribution and anti-colitis activity were investigated in mice. CG was primarily distributed in the colon after oral administration. Compared to CUR and GDNV, CG was superior in improving disease activity, colon length, liver and spleen coefficients, myeloperoxidase activity, and biochemical factor levels in ulcerative colitis (UC) mice. In addition, CG plays a protective role against UC by modulating serum metabolite levels and gut flora. In summary, our study demonstrated that GDNV can be used for CUR delivery with enhanced therapeutic potential.
Green analytical chemistry metrics for evaluating the greenness of analytical procedures
Lei Yin, Luyao Yu, Yingxia Guo, Chuya Wang, Yuncheng Ge, Xinyue Zheng, Ning Zhang, Jiansong You, Yong Zhang, Meiyun Shi
, Available online  , doi: 10.1016/j.jpha.2024.101013
Abstract(311) HTML Full Text PDF(28)
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Green analytical chemistry (GAC) focuses on mitigating the adverse effects of analytical activities on human safety, human health and environment. In addition to the 12 principles of GAC, proper GAC tools should be developed and employed to assess the greenness of different analytical assays. 15 widely used GAC metrics, i.e., national environmental methods index (NEMI), advanced NEMI, assessment of green profile (AGP), chloroform-oriented toxicity estimation scale (ChlorTox Scale), Analytical Eco-Scale, Green Certificate Modified Eco-Scale, analytical method greenness score (AMGS), green analytical procedure index (GAPI), ComplexGAPI, red-green-blue (RGB) additive color model, red-green-blue (RGB) 12 algorithm, analytical greenness calculator (AGREE), AGREE preparation (AGREEprep), Hexagon, and blue applicability grade index (BAGI), are selected as the typical tools. This article comprehensively presents and elucidates the principles, characteristics, merits, and demerits of 15 widely used GAC tools. This review is helpful for researchers to use the current GAC metrics to assess the environmental sustainability of analytical assays.
Characterization of extracellular vesicles by capillary zone electrophoresis: A novel concept for characterization of a next-generation drug delivery platform
Aleksandra Steć, Andrea Heinz, Szymon Dziomba
, Available online  , doi: 10.1016/j.jpha.2024.101004
Abstract(134) HTML Full Text PDF(3)
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Extracellular vesicles (EVs) are a part of a cell-to-cell communication system of prokaryotic and eukaryotic organisms. Their ability to penetrate biological barriers and to transfer molecules between cells shows their potential as a novel class of drug delivery platform. However, because of the great heterogeneity of EVs and the complexity of biological matrices from which they are typically isolated, reliable quality control procedures need to be established to ensure their safety for medical use. According to current recommendations, quantification of EVs, confirmation of their identity, and purity assessment require the use of several analytical techniques, including particle-size distribution analysis, proteomics, and electron microscopy, making the characterization process demanding. Capillary electrophoresis (CE) has recently emerged as an alternative tool for EV characterization. In this study, the available literature on this novel concept for EV characterization was reviewed. Its performance was critically evaluated and compared with currently used methods. The utility of CE in the quality control of EV-based medicines was discussed.
Tumor microenvironment-responsive hyperbranched polymers for controlled drug delivery
Yuqiong Guo, Xinni He, Gareth R. Williams, Yue Zhou, Xinying Liao, Ziyi Xiao, Cuiyun Yu, Yang Liu
, Available online  , doi: 10.1016/j.jpha.2024.101003
Abstract(127) HTML Full Text PDF(2)
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Hyperbranched polymers (HBPs) have drawn great interest in the biomedical field on account of their special morphology, low viscosity, self-regulation and facile preparation methods. Moreover, their large intramolecular cavities, high biocompatibility, biodegradability, and targeting properties render them very suitable for anti-tumor drug delivery. Recently, exploiting the specific characteristics of the tumor microenvironment, a range of multifunctional HBPs responsive to the tumor microenvironment have emerged. By further introducing various types of drugs through physical embedding or chemical coupling, the resulting HBPs based delivery systems have played a crucial part in improving drug stability, increasing effective drug concentration, decreasing drug toxicity and side effects, and enhancing anti-tumor effect. Here, based on different types of tumor microenvironment stimulation signals such as pH, redox, temperature, etc., we systematically review the preparation and response mechanism of HBPs, summarize the latest advances in drug delivery applications, and analyze the challenges and future research directions for such nanomaterials in biomedical clinical applications.
Clinically and orally compatible formulation-manufactured DDX5 (p68)-targeting molecular glue FL118 products exhibit low toxicity but high efficacy against human cancer
Xiang Ling, Wenjie Wu, Li Yan, Leslie Curtin, Melanie M. Farrauto, Sandra Sexton, Anmbreen Jamroze, Changjun Yu, Christos Fountzilas, Dean G. Tang, Fengzhi Li
, Available online  , doi: 10.1016/j.jpha.2024.101001
Abstract(166) HTML Full Text PDF(12)
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Investigation of oligomeric proanthocyanidins extracted from Rhodiolae Crenulatae Radix et Rhizomes using deep eutectic solvents and identified via data-dependentacquisition mass-spectroscopy
Li Jia, Liming Wang, Xiaoxiao Zhang, Qingrui Zhang, Peng Lei, Yanxu Chang, Lifeng Han, Xin Chai, Wenzhi Yang, Yuefei Wang, Miaomiao Jiang
, Available online  , doi: 10.1016/j.jpha.2024.101002
Abstract(119) HTML Full Text PDF(16)
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In this study, 34 deep eutectic solvents were successfully prepared for the extraction of proanthocyanidin from Rhodiolae Crenulatae Radix et Rhizomes. The extraction process was optimized using single factor exploration and Box-Behnken design- response surface analysis. The extraction rate was significantly improved when the molar ratio of choline chloride to 1,3-propanediol was 1:3.5 and the water content was 30% (V/V) in deep eutectic solvents. AB-8 macroporous resin and ethyl acetate were used for separation and refining, and the oligomer-rich proanthocyanidin components were eventually obtained. The ultraviolet (UV) and infrared spectrometer (IR) spectra showed that the proanthocyanidins were mainly composed of catechin and epicatechin. To further clarify the chemical composition of proanthocyanidin, an ion scan list containing 156 proanthocyanidins precursors was obtained by constructing a proanthocyanidins structural library and mass defect filtering algorithm, combined with the Full mass spectrometry (MS)/dd-MS2 scan mode that turns on the “if idle pick others” function. By using Ultra high performance liquid chromatography & High-resolution mass spectrometer (UHPLC/Orbitrap MS), the analysis used both targeted and non- targeted methods to detect proanthocyanidins. Finally, 50 oligomeric proanthocyanidin compounds were identified, including 7 monomers, 22 dimers, 20 trimers, and 1 tetramer, most of which were procyanidins of proanthocyanidins (84%), and a small amount of prodelphinidin (14%) and other types of proanthocyanidins (2%), which enabled the systematic characterization of proanthocyanidin components from Rhodiolae Crenulatae Radix et Rhizomes. Meanwhile, the comparison with the grape seeds oligomeric proanthocyanidins standard (United States Pharmacopoeia) revealed that the proanthocyanidins in Rhodiolae Crenulatae Radix et Rhizomes were more abundant, suggesting that the proanthocyanidins in Rhodiolae Crenulatae Radix et Rhizomes has promising applications.
Circulating Memory T Cells and TCF1+ T Cells Aid in Diagnosis and Monitor Disease Activity in Vitiligo
Xinju Wang, Jianru Chen, Wei Wu, Jinrong Fan, Luling Huang, Weiwei Sun, Kaiqiao He, Shuli Li, Chunying Li
, Available online  , doi: 10.1016/j.jpha.2024.100998
Abstract(64) HTML Full Text PDF(6)
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Vitiligo is an immune memory skin disease. T-cell factor 1 (TCF1) is essential for maintaining the maintenance of the memory T-cell pool. There is an urgent need to investigate the characteristics of peripheral memory T-cell profile and TCF1+ T-cell frequencies in patients with vitiligo patients. In this study, 31 patients with active vitiligo (AV), 22 with stable vitiligo (SV), and 30 healthy controls (HCs) were included. We measured circulating memory and TCF1+ T-cell frequencies using by flow cytometry. The Spearman’s rank test was used to evaluate the correlation correlations between cell frequencies and disease characteristics. Receiver operating characteristic curves (ROC) were constructed to investigate the discriminative power of the cell subpopulations. Circulating CD4+ and CD8+ terminally differentiated effector memory T-cell (TEMRA) frequencies were significantly higher in the AV group than in compared to HCs (P < 0.05). TCF1+ T-cell subpopulations were widespread increased in patients with vitiligo patients (P < 0.05). After adjusting adjustment for potential confounders, CD8+ and CD4+ central memory (TCM) cells, and CD8+ TEMRA were correlated with disease activity (P < 0.05). The combined diagnostic value of the four (naïve naive, effector memory, TCM, and TEMRA) CD8+TCF1+ T-cell subsets was relatively high (area under the ROC curve [AUC]AUC = 0.804, sensitivity = 71.70%, specificity = 83.34%), and the CD8+ T-cell subsets combination performed well in discriminating disease activity (AUC = 0.849, sensitivity = 70.97%, specificity = 90.91%). We demonstrated an altered circulating memory T-cell profile and increased TCF1+ T-cell percentage percentages in patients with vitiligo patients. T-cell subpopulations had a strong value values for vitiligo diagnosis and activity evaluation. This evidence presents a potential new pharmacological target for inhibiting to inhibit the autoimmunity that leads leading to vitiligo disease activity.
Machine learning-driven optimization of mRNA-lipid nanoparticle vaccine quality with XGBoost/Bayesian method and ensemble model approaches
Ravi Maharjan, Ki Hyun Kim, Kyeong Lee, Hyo-Kyung Han, Seong Hoon Jeong
, Available online  , doi: 10.1016/j.jpha.2024.100996
Abstract(41) HTML Full Text PDF(6)
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To enhance the efficiency of vaccine manufacturing, this study focuses on optimizing the microfluidic conditions and lipid mix ratios of messenger RNA - lipid nanoparticles (mRNA-LNP). Different mRNA - LNP formulations (n = 24) were developed using an I - optimal design, where machine learning tools (XGBoost/Bayesian optimization and self - validated ensemble (SVEM)) were used to optimize the process and predict lipid mix ratio. The investigation included material attributes, their respective ratios, and process attributes. The critical responses like particle size (PS), polydispersity index (PDI), Zeta potential, pKa, heat trend cycle, encapsulation efficiency (EE), recovery ratio, and encapsulated mRNA were evaluated. Overall prediction of SVEM (> 97%) was comparably better than that of XGBoost/Bayesian optimization (> 94%). Moreover, in actual experimental outcomes, SVEM prediction is close to the actual data as confirmed by the experimental PS (94∼96 nm) is close to the predicted one (95~97 nm). The other parameters including PDI and EE were also close to the actual experimental data.
Dual-targeted halofuginone hydrobromide nanocomplexes for promotion of macrophage repolarization and apoptosis of rheumatoid arthritis fibroblast-like synoviocytes in adjuvant-induced arthritis in rats
Junping Zhu, Ye Lin, Gejing Li, Yini He, Zhaoli Su, Yuanyuan Tang, Ye Zhang, Qian Xu, Zhongliu Yao, Hua Zhou, Bin Liu, Xiong Cai
, Available online  , doi: 10.1016/j.jpha.2024.100981
Abstract(160) HTML Full Text PDF(15)
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Rheumatoid arthritis (RA) is a prevalent autoimmune disease characterized by chronic inflammation and excessive proliferation of the synovium. Currently, treatment options focus on either reducing inflammation or inhibiting synovial hyperplasia. However, these modalities are unsatisfactory in achieving the desired therapeutic outcomes. Halofuginone hydrobromide (HF), an herbal active ingredient, has demonstrated pharmacological effects of both anti-inflammation and inhibition of synovial hyperplasia proliferation. However, HF's medical efficacy is limited due to its poor water solubility, short half-life, and non-target toxicity. In the current study, by using the advantages of nanotechnology, we presented a novel dual-targeted nanocomplex, termed HA-M@P@HF NPs, which consisted of a hyaluronic acid (HA)-modified hybrid membrane (M)-camouflaged poly lactic-co-glycolic acid (PLGA) nanosystem for HF delivery. These nanocomplexes not only overcame the limitations of HF but also achieved simultaneous targeting of inflammatory macrophages and human fibroblast-like synoviocytes-rheumatoid arthritis (HFLS-RA). In vivo experiments demonstrated that these nanocomplexes effectively suppressed immune-mediated inflammation and synovial hyperplasia, safeguarding against bone destruction in rats with adjuvant-induced arthritis (AIA). Remarkable anti-arthritic effects of these nanocomplexes were accomplished through promoting repolarization of M1-to-M2 macrophages and apoptosis of HFLS-RA, thereby offering a promising therapeutic strategy for RA.
Radiotracer labelled thymohydroquinyl gallate capped gold nanoparticles as theranostic radiopharmaceutical for targeted antineoplastic and bioimaging
Munaza Batool, Batool Fatima, Dilshad Hussain, Rubaida Mahmood, Muhammad Imran, Saeed Akhter, Muhammad Saqib Khan, Saadat Majeed, Muhammad Najam-ul-Haq
, Available online  , doi: 10.1016/j.jpha.2024.100965
Abstract(123) HTML Full Text PDF(2)
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Thymoquinone (Tq) and gallic acid (GA) are known for counter-tumorigenic characteristics. GA inhibits cancer cell proliferation by interfering with many apoptotic signaling pathways, producing more reactive oxygen species (ROS), focusing on the cell cycle, and suppressing the expression of oncogenes and matrix metalloproteinases (MMPs). In this study, thymoquinone (after reducing to thymohydroquinone) and gallic acid are esterified to form thymohydroquinyl gallate (a prodrug). Thymohydroquinyl gallate (THQG) possesses enhanced antineoplastic efficacy and targeted delivery potential. The chemical and spectroscopic analysis confirms ester synthesis. Gold nanoparticles (AuNPs) are employed as nanocarriers due to their physicochemical and optical characteristics, biocompatibility, and low toxicity. As an efficient drug transporter, gold nanoparticles (AuNPs) shield conjugated drugs from enzymatic digestion. The prodrug acts as a reducing agent for Au metal atoms and is loaded onto it after reduction. The nano drug is radiolabeled with 99mTc and 131I to monitor the drug biodistribution in animals using a gamma camera and single-photon emission computerized tomography (SPECT). 131I is an antineoplastic that helps enhance the drug's efficiency. Chromatographic results reveal promising radiolabeling percentages. In vitro, drug release shows sustained release at pH 5.8. In vitro 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT) cytotoxicity assay reveals drug potency on CAL 27 and MCF 7 cell lines.
Progress and application of intelligent nanomedicine in urinary system tumors
YingmingXiao, Lei Zhong, Jinpeng Liu, Li Chen, Yi Wu, Ge Li
, Available online  , doi: 10.1016/j.jpha.2024.100964
Abstract(234) HTML Full Text PDF(14)
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Urinary system tumors include malignancies of the bladder, kidney, and prostate, and present considerable challenges in diagnosis and treatment. The conventional therapeutic approaches against urinary tumors are limited by the lack of targeted drug delivery and significant adverse effects, thereby necessitating novel solutions. Intelligent nanomedicine has emerged as a promising therapeutic alternative for cancer in recent years, and uses nanoscale materials to overcome the inherent biological barriers of tumors, and enhance diagnostic and therapeutic accuracy. In this review, we have explored the recent advances and applications of intelligent nanomedicine for the diagnosis, imaging, and treatment of urinary tumors. The principles of nanomedicine design pertaining to drug encapsulation, targeting and controlled release have been discussed, with emphasis on the strategies for overcoming renal clearance and tumor heterogeneity. Furthermore, the therapeutic applications of intelligent nanomedicine, its advantages over traditional chemotherapy, and the challenges currently facing clinical translation of nanomedicine, such as safety, regulation and scalability, have also been reviewed. Finally, we have assessed the potential of intelligent nanomedicine in the management of urinary system tumors, emphasizing emerging trends such as personalized nanomedicine and combination therapies. This comprehensive review underscores the substantial contributions of nanomedicine to the field of oncology and offers a promising outlook for more effective and precise treatment strategies for urinary system tumors.
Recent Trends and Impact of Localized Surface Plasmon Resonance (LSPR) and Surface-Enhanced Raman Spectroscopy (SERS) in Modern Analysis
Bibhu Prasad Nanda, Priyanka Rani, Priyanka Paul, Aman, Subrahmanya S Ganti, Rohit Bhatia
, Available online  , doi: 10.1016/j.jpha.2024.02.013
Abstract(148) HTML Full Text PDF(5)
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An optical biosensor is a specialized analytical device that utilizes the principles of optics and light bimolecular processes. Localized surface plasmon resonance (LSPR) is a phenomenon in the realm of nanophotonics that arises when metallic nanoparticles (NPs) or nanostructures interact with incident light. On the other hand, surface-enhanced Raman spectroscopy (SERS) is an influential analytical technique rooted in Raman scattering, wherein it amplifies the Raman signals of molecules when they are situated near specific and specially designed nanostructures. A detailed exploration of the recent groundbreaking developments in optical biosensors employing LSPR and SERS technologies has been exhaustively discussed along with their underlying principle and the working mechanism. A biosensor chip has been created, featuring a high-density deposition of gold nanoparticles under varying ligand concentration and reaction duration on the substrate. An ordinary description, along with a visual illustration, has been thoroughly provided for concepts such as a sensogram, refractive index shift, surface plasmon resonance (SPR), and the evanescent field, Rayleigh scattering, Raman scattering as well as the electromagnetic enhancement & chemical enhancement. LSPR and SERS both have their advantages and disadvantages but widely used SERS has some advantages over LSPR like chemical specificity, high sensitivity, multiplexing, and versatility in different fields. This review confirms and elucidates the significance of different disease biomarker identification. LSPR, and SERS both play a vital role in the detection of various types of cancer like cervical cancer, ovarian cancer, endometrial cancer, prostate cancer, colorectal cancer, and brain tumors. This proposed optical biosensor provides potential application for early diagnosis and monitoring of viral disease, bacterial infectious diseases, fungal diseases, diabetes, and cardiac disease biosensing. LSPR and SERS provide a new direction for environmental monitoring, food safety, refining of impurities from water samples, and detection of lead. The understanding of these biosensors is still limited and challenging.
β-glucan-modified nanoparticles with different particle sizes exhibit different lymphatic targeting efficiencies and adjuvant effects
Wen Guo, Xinyue Zhang, Long Wan, Zhiqi Wang, Meiqi Han, Ziwei Yan, Jia Li, Ruizhu Deng, Shenglong Li, Yuling Mao, Siling Wang
, Available online  , doi: 10.1016/j.jpha.2024.02.007
Abstract(207) HTML Full Text PDF(14)
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Particle size and surface properties are crucial for lymphatic drainage (LN), dendritic cell (DC) uptake, DC maturation, and antigen cross-presentation induced by nanovaccine injection, which lead to an effective cell-mediated immune response. However, the manner in which the particle size and surface properties of vaccine carriers such as mesoporous silica nanoparticles (MSNs) affect this immune response is unknown. We prepared 50, 100, and 200 nm of MSNs that adsorbed ovalbumin antigen (OVA) while modifying β-glucan to enhance immunogenicity. The results revealed that these MSNs with different particle sizes were just as efficient in vitro, and MSNs with β-glucan modification demonstrated higher efficacy. However, the in vivo results indicated that MSNs with smaller particle sizes have stronger lymphatic targeting efficiency and a greater ability to promote the maturation of DCs. The results also indicate that β-glucan-modified MSN, with a particle size of ~100 nm, has a great potential as a vaccine delivery vehicle and immune adjuvant and offers a novel approach for the delivery of multiple therapeutic agents that target other lymphmediated diseases.
PEG-PLGA nanoparticles deposited in Pseudomonas aeruginosa and Burkolderia cenocepacia
Tinatini Tchatchiashvilli, Helena Duering, , Lisa Mueller-Boetticher, Christian Grune, Dagmar Fischer, Mathias W. Pletz, Oliwia Makarewicz
, Available online  , doi: 10.1016/j.jpha.2024.01.007
Abstract(187) HTML Full Text PDF(8)
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In our prior research, polymer nanoparticles containing tobramycin displayed robust antibacterial efficacy against biofilm-embedded Pseudomonas aeruginosa and Burkholderia cenocepacia cells, critical pathogens in cystic fibrosis. In the current study, we investigated the deposition of a nanoparticulate carrier composed of poly(D,Llactic-co-glycolic acid) (PLGA) and poly(ethylene glycol)-block-PLGA (PEG-PLGA) that was either covalently bonded with cyanine-5-amine or noncovalently bound with freely embedded cationic rhodamine B, which served as a drug surrogate. After exposing these nanoparticles to bacteria, we performed cell fractionation and fluorescence analysis, which highlighted the accumulation of cyanine-5-amine in the outer membranes and the accumulation of rhodamine B in the cytoplasm of cells. The results indicated that these organic nanoparticles are effective vehicles for targeted antibiotic delivery in bacterial cells, explaining the observed increase in the efficacy of encapsulated tobramycin against biofilms. This work emphasizes the potential of PEGPLGA-based formulations for advanced drug delivery strategies.
Platelet membrane biomimetic nanomedicine induces dual glutathione consumption for enhancing cancer radioimmunotherapy
Xiaopeng Li, Yang Zhong, Pengyuan Qi, Daoming Zhu, Chenglong Sun, Nan Wei, Yang Zhang, Zhanggui Wang
, Available online  , doi: 10.1016/j.jpha.2024.01.003
Abstract(187) HTML Full Text PDF(10)
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Radiotherapy (RT) is one of the most common treatments for cancer. However, intracellular glutathione (GSH) plays a key role in protecting cancer from radiation damage. Herein, we have developed a platelet membrane biomimetic nanomedicine (PMD) that induces double GSH consumption to enhance tumor radioimmunotherapy. This biomimetic nanomedicine consists of an external platelet membrane and internal organic mesoporous silica nanoparticles (MON) loaded with 2-deoxy-D-glucose (2-DG). Thanks to the tumor-targeting ability of the platelet membranes, PMD can target and aggregate to the tumor site, which is internalized by tumor cells. Within tumor cells overexpressing GSH, MON reacts with GSH to degrade and release 2-DG. This step initially depletes the intracellular GSH content. The subsequent release of 2-DG inhibits glycolysis and adenosine triphosphate (ATP) production, ultimately leading to secondary GSH consumption. This nanodrug combines dual GSH depletion, starvation therapy, and RT to promote immunogenic cell death and stimulate the systemic immune response. In the bilateral tumor model in vivo, distal tumor growth was also well suppressed. The proportion of mature dendritic cells (DC) and CD8+T cells in the mice was increased. This indicates that PMD can promote anti-tumor radioimmunotherapy and has good prospects for clinical application.
Lentinan-Functionalized PBAE-G-nanodiamonds as an adjuvant to induce cGAS-STING Pathway-mediated macrophage activation and immune enhancement
Zhiqiang Zhang, Li Wang, Xia Ma, Hui Wang
, Available online  , doi: 10.1016/j.jpha.2023.12.012
Abstract(131) HTML Full Text PDF(16)
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A series of biodegradable nanoparticle-based drug delivery systems have been designed utilizing poly(β-amino ester)-guanidine-phenylboronic acid (PBAE-G) polymers. In this study, a novel Lentinan-Functionalized PBAE-G-nanodiamond system was developed to carry ovalbumin (LNT-PBAE-G-ND@OVA). The impact of this drug delivery system on the activation and maturation of macrophages was then assessed . Furthermore, LNT-PBAE-G-ND@OVA induced potent antibody response and showed no obvious toxicity ` and in vivo. Moreover, treatment with LNT-PBAE-G-ND@OVA was sufficient to alter the expression of genes associated with the cGAS-STING pathway, and the LNT-PBAE-G-ND@OVA induced upregulation of costimulatory molecules. LNT-PBAE-G-ND@OVA treatment was sufficient to induce macrophage activation through a complex mechanism in which cGAS-STING signaling plays an integral role.
3D-Printed Constructs Deliver Bioactive Cargos to Expedite Cartilage Regeneration
Rong Jiao, Xia Lin, Jingchao Wang, Chunyan Zhu, Jiang Hu, Huali Gao, Kun Zhang
, Available online  , doi: 10.1016/j.jpha.2023.12.015
Abstract(349) HTML Full Text PDF(24)
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Cartilage is solid connective tissue that recovers slowly from injury, and pain and dysfunction from cartilage damage affect many people. The treatment of cartilage injury is clinically challenging and there is no optimal solution, which is a hot research topic at present. With the rapid development of 3D printing technology in recent years, 3D bioprinting can better mimic the complex microstructure of cartilage tissue and thus enabling the anatomy and functional regeneration of damaged cartilage. This article reviews the methods of 3D printing used to mimic cartilage structures, the selection of cells and biological factors, and the development of bioinks and advances in scaffold structures, with an emphasis on how 3D printing structure provides bioactive cargos in each stage to enhance the effect. Finally, clinical applications and future development of simulated cartilage printing are introduced, which are expected to provide new insights into this field and guide other researchers who are engaged in cartilage repair.
Targeted protein degradation: A promising approach for cancer treatment
Muhammad Zafar Irshad Khan, Adila Nazli, Iffat Naz, Dildar Khan, Ihsan-ul Haq, Jian-Zhong Chen
, Available online  , doi: 10.1016/j.jpha.2023.09.004
Abstract(578) HTML Full Text PDF(10)
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Targeted protein degradation (TPD) is a promising approach that has the ability to address disease-causing proteins. Compared to traditional inhibition, proteolysis targeting chimera (PROTAC) technology offers various benefits, including the potential to target mutant and overexpressed proteins along with characteristics to target undruggable proteomes. A significant obstacle to the ongoing effective treatment of malignancies is cancer drug resistance, which is developed frequently by mutated or overexpressed protein targets and causes current remedies to continuously lose their effectiveness. The effective use of PROTACs to degrade targets that have undergone mutations and conferred resistance to first-line cancer therapies has attracted much research attention. To find novel/effective treatments, we analyzed the advancements in PROTACs aimed at cancer resistance and targets. This review provides a description of how PROTAC-based anticancer drugs are currently being developed and how to counter resistance if developed to PROTAC technology. Moreover, modern technologies related to protein degradation, including autophagy-targeting chimeras (AUTAC), lysosome-targeting chimeras (LYTAC), antibody-based PROTAC (AbTAC), Glue-body chimeras (GlueTAC), transcription-factor-targeting chimeras (TRAFTAC), RNA-PROTAC, aptamer-PROTAC, Photo-PROTAC, folate-PROTAC, and in-cell click-formed proteolysis targeting chimeras (CLIPTACs), have been discussed along with their mechanisms of action.
Caenorhabditis elegansdeep lipidome profiling by using integrative mass spectrometry acquisitions reveals significantly altered lipid networks
Nguyen Hoang Anh, Young Cheol Yoon, Young Jin Min, Nguyen Phuoc Long, Cheol Woon Jung, Sun Jo Kim, Suk Won Kim, Eun Goo Lee, Daijie Wang, Xiao Wang, Sung Won Kwon
, Available online  , doi: https://doi.org/10.1016/j.jpha.2022.06.006
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Abstract:
Lipidomics coverage improvement is essential for functional lipid and pathway construction. powerful approach to discovering organism lipidome is to combine various data acquisitions, uch as full scan (full MS), data-dependent acquisition (DDA), and data-independent acquisition DIA). Caenorhabditis elegans(C. elegans) is a useful model for discovering toxic-induced etabolism, high-throughput drug screening, and a variety of human disease pathways. To etermine the lipidome of C. elegans and investigate lipid disruption from the molecular to the ystem biology level, we used integrative data acquisition. The methyl-tert-butyl ether method was sed to extract L4 stage C. elegans after exposure to triclosan (TCS), perfluorooctanoic acid, and nanopolystyrene (nPS). Full MS, DDA, and DIA integrations were performed to comprehensively profile the C. elegans lipidome by Q-Exactive Plus mass spectrometry. All annotated lipids were then analyzed using lipid ontology and pathway analysis. We annotated up to 940 lipids from 20 lipid classes involved in various functions and pathways. The biological investigations revealed that when C. elegans were exposed to nPS, lipid droplets were disrupted, whereas plasma membrane-functionalized lipids were likely changed in the TCS treatment group. The nPS treatment caused a significant disruption in lipid storage. Triacylglycerol, glycerophospholipid, and ether class lipids were those primarily hindered by toxicants. Finally, toxicant exposure frequently involves numerous lipid-related pathways, including the PI3K/AKT pathway. In conclusion, an integrative data acquisition strategy was used to characterize the C. elegans lipidome, providing valuable biological insights needed for hypothesis generation and validation.

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