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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
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.
IR-EcoSpectra: Exploring sustainable ex situ and in situ FTIR applications for green chemical and pharmaceutical analysis
Alina Cherniienko, Roman Lesyk, Lucjusz Zaprutko, Anna Pawełczyk
, Available online  , doi: 10.1016/j.jpha.2024.02.005
In various industries, particularly the chemical and pharmaceutical fields, Fourier transform infrared spectroscopy (FTIR) spectroscopy provides a unique capacity to detect and characterise complex chemicals while minimising environmental damage by minimal waste generation and reducing the need for extensive sample preparation or use of harmful reagents. This review showcases the versatility of ex situ and in situ FTIR applications for substance identification, analysis, and dynamic monitoring. Ex situ FTIR spectroscopy’s accuracy in identifying impurities, monitoring crystallisation processes, and regulating medication release patterns improves product quality, safety, and efficacy. Furthermore, its quantification capabilities enable more effective drug development, dosage procedures, and quality control practices, all of which are consistent with green analytical principles. On the other hand, in situ FTIR spectroscopy appears to be a novel tool for the real-time investigation of molecular changes during reactions and processes, allowing for the monitoring of drug release kinetics, crystallisation dynamics, and surface contacts, as well as providing vital insights into material behaviour. The combination of ex situ FTIR precision and in situ FTIR dynamic capabilities gives a comprehensive analytical framework for developing green practices, quality control, and innovation in the chemical and pharmaceutical industries. This review presents the wide range of ex situ and in situ FTIR spectroscopy applications in chemical, pharmaceutical and medical fields as an analytical green chemistry tool. However, further study is required to fully realise FTIR’s potential and develop new applications that improve sustainability in these areas.
MGMT activated by Wnt pathway promotes cisplatin tolerance through inducing slow-cycling cells and nonhomologous end joining in colorectal cancer
Haowei Zhang, Qixin Li, Xiaolong Guo, Hong Wu, Chenhao Hu, Gaixia Liu, Tianyu Yu, Xiake Hu, Quanpeng Qiu, Gang Guo, Junjun She, Yinnan Chen
, Available online  , doi: 10.1016/j.jpha.2024.02.004
Chemotherapy resistance plays a pivotal role in the prognosis and therapeutic failure of patients with colorectal cancer (CRC). Cisplatin-resistant cells exhibit an inherent ability to evade the toxic chemotherapeutic drug effects which are characterized by the activation of slow-cycle programs and DNA repair. Among the elements that lead to cisplatin resistance, O6-methylguanine (O6-MG)-DNA-methyltransferase (MGMT), a DNA-repair enzyme, performs a quintessential role. In this study, we clarify the significant involvement of MGMT in conferring cisplatin resistance in CRC, elucidating the underlying mechanism of the regulatory actions of MGMT. A notable upregulation of MGMT in cisplatin-resistant cancer cells was found in our study, and MGMT repression amplifies the sensitivity of these cells to cisplatin treatment in vitro and in vivo. Conversely, in cancer cells, MGMT overexpression abolishes their sensitivity to cisplatin treatment. Mechanistically, the interaction between MGMT and CDK1 inducing slow-cycling cells is attainted via the promotion of ubiquitination degradation of CDK1. Meanwhile, to achieve nonhomologous end joining, MGMT interacts with XRCC6 to resist chemotherapy drugs. Our transcriptome data from samples of 88 patients with CRC suggest that MGMT expression is co-related with the Wnt signaling pathway activation, and several Wnt inhibitors can repress drug-resistant cells. In summary, our results point out that MGMT is a potential therapeutic target and predictive marker of chemoresistance in CRC.
Global hotspots and future directions for drugs to improve the skin flap survival: A bibliometric and visualized review
Shuangmeng Jia, Jieshen Huang, Wuyan Lu, Yongen Miao, Kehua Huang, Chenchang Shi, Shuaijun Li, Jiefeng Huang
, Available online  , doi: 10.1016/j.jpha.2024.02.002
Skin flaps are frequently employed in plastic and reconstructive surgery to address tissue defects. However, their low survival rates remain a challenge, attributed to vascular crisis and necrosis. Despite numerous studies investigating drugs to alleviate flap necrosis, a comprehensive analysis of the research trend in this critical area is lacking. To gain a deeper understanding of the current status, research focal points, and future trends in drugs aimed at enhancing flap survival, a thorough retrospective analysis is imperative. This study aims to employ bibliometric methods to scrutinize the evolution, mechanisms, and forthcoming trends of drugs targeting flap survival improvement. Using VOSviewer software, we quantitatively and visually depict 1) annual temporal trends in the number of documents and citations; 2) national/regional publications and their collaborations; 3) institutional and authors’ contribution; 4) journal contribution and relevance; and 5) analysis of research hotspots and directions derived from keywords. Ultimately, we discussed the prospects and challenges of future advances and clinical translation of drugs designed to enhance skin flap survival. In conclusion, the field of pharmacology dedicated to improving skin flap survival is expanding, and this study aims to offer a fresh perspective to promote the advancement and clinical application of such drugs.
Natural compounds improve diabetic nephropathy by regulating the TLR4 signaling pathway
Jiabin Wu, Ke Li, Muge Zhou, Haoyang Gao, Wenhong Wang, Weihua Xiao
, Available online  , doi: 10.1016/j.jpha.2024.01.014
Diabetic nephropathy (DN), a severe complication of diabetes, is widely recognized as a primary contributor to end-stage renal disease. Recent studies indicate that the inflammation triggered by Toll-like receptor 4 (TLR4) is of paramount importance in the onset and progression of DN. TLR4 can bind to various ligands, including exogenous ligands such as proteins and polysaccharides from bacteria or viruses, as well as endogenous ligands such as biglycan, fibrinogen, and hyaluronan. In DN, the expression or release of TLR4-related ligands is significantly elevated, resulting in excessive TLR4 activation and increased production of proinflammatory cytokines through downstream signaling pathways. This process is closely associated with the progression of DN. Natural compounds are biologically active products derived from natural sources that have advantages in the treatment of certain diseases. Various types of natural compounds, including alkaloids, flavonoids, polyphenols, terpenoids, glycosides, and polysaccharides, have demonstrated their ability to improve DN by affecting the TLR4 signaling pathway. In this review, we summarize the mechanism of action of TLR4 in DN and the natural compounds that can ameliorate DN by modulating the TLR4 signaling pathway. We specifically highlight the potential of compounds such as curcumin, paclitaxel, berberine, and ursolic acid to inhibit the TLR4 signaling pathway, which provides an important direction of research for the treatment of DN.
Non-coding RNAs as therapeutic targets in cancer and its clinical application
Xuejiao Leng, Mengyuan Zhang, Yujing Xu, Jingjing Wang, Ning Ding, Yancheng Yu, Shanliang Sun, Weichen Dai, Xin Xue, Nianguang Li, Ye Yang, Zhihao Shi
, Available online  , doi: 10.1016/j.jpha.2024.02.001
Cancer genomics has led to the discovery of numerous oncogenes and tumor suppressor genes that play critical roles in cancer development and progression. Oncogenes promote cell growth and proliferation, whereas tumor suppressor genes inhibit cell growth and division. The dysregulation of these genes can lead to the development of cancer. Recent studies have focused on non-coding RNAs (ncRNAs), including circular RNA (circRNA), long non-coding RNA (lncRNA), and microRNA (miRNA), as therapeutic targets for cancer. In this article, we discuss the oncogenes and tumor suppressor genes of ncRNAs associated with different types of cancer and their potential as therapeutic targets. Here, we highlight the mechanisms of action of these genes and their clinical applications in cancer treatment. Understanding the molecular mechanisms underlying cancer development and identifying specific therapeutic targets are essential steps towards the development of effective cancer treatments.
Bio-soft matter derived from traditional Chinese medicine: characterizations of hierarchical structure, assembly mechanism, and beyond
Guiya Yang, Yue Liu, Yuying Hu, Yue Yuan, Yunan Qin, Quan Li, Shuangcheng Ma
, Available online  , doi: 10.1016/j.jpha.2024.01.011
Structural and functional explorations on bio-soft matter such as micelles, vesicles, nanoparticles, aggregates or polymers derived from traditional Chinese medicine (TCM) has emerged as a new topic in the field of TCM. The discovery of such cross-scaled bio-soft matter may provide a unique perspective for unraveling the new effective material basis of TCM as well as developing innovative medicine and biomaterials. Despite the rapid rise of TCM-derived bio-soft matter, their hierarchical structure and assembly mechanism must be unambiguously probed for a further in-depth understanding of their pharmacological activity. In this review, the current emerged TCM-derived bio-soft matter assembled from either small molecules or macromolecules will be introduced, and particularly the unambiguous elucidation of their hierarchical structure and assembly mechanism with combined electron microscopic and spectroscopic techniques will be depicted. The pros and cons of each technique are also discussed. The future challenges and perspective of TCM-derived bio-soft matter are outlined, particularly the requirement for their precise in situ structural determination is highlighted.
Melatonin enhances the efficacy of anti-PD-L1 by improving hypoxia in residual tumors after insufficient radiofrequency ablation
Yanqiao Ren, Licheng Zhu, Yusheng Guo, Jinqiang Ma, Lian Yang, Chuansheng Zheng, Xiangjun Dong
, Available online  , doi: 10.1016/j.jpha.2024.01.010
The hypoxic microenvironment and inflammatory state of residual tumors caused by insufficient radiofrequency ablation (iRFA) are major reasons for rapid tumor progression and pose challenges for immunotherapy. We retrospectively analyzed the clinical data of patients with hepatocellular carcinoma (HCC) treated with RFA and observed that iRFA was associated with poor survival outcomes and progression-free survival. Using an orthotopic HCC mouse model and a colorectal liver metastasis model, we observed that treatment with melatonin after iRFA reduced tumor growth and metastasis and achieved the best outcomes when combined with anti-programmed death-ligand 1 (anti-PD-L1) therapy. In mechanism, melatonin inhibited the expression of epithelial–mesenchymal transitions, hypoxia-inducible factor-1α and PD-L1 in tumor cells after iRFA. Flow cytometry revealed that melatonin reduced the proportion of myeloid-derived suppressor cells and increased the proportion of CD8+ T cells. Transcriptomic analysis revealed an upregulation of immune-activated function-related genes in residual tumors. These findings demonstrated that melatonin can reverse hypoxia and iRFA-induced inflammation, thereby overcoming the immunosuppressive tumor microenvironment, and enhancing the efficacy of immunotherapy.
In situ repolarization of Tumor-Associated Macrophages with synergic nanoformulation to reverse immunosuppressive TME in mouse breast cancer for cancer therapy
Ruhua Luo, Zhongyu Yue, Qian Yang, Honghua Zhang, Tian Xie, Shuling Wang, Qingchang Tian
, Available online  , doi: 10.1016/j.jpha.2024.01.009
The conversion of tumor-associated macrophages (TAMs) from M2 phenotype to M1 phenotype could reverse the immunosuppression associated with the tumor microenvironment. Here, we constructed M2 phenotype macrophage-targeted Lipo@CpG-FA by encapsulating CpG ODNs. The combination of Lipo@CpG-FA with FA-Lipo@Ele-AS1411 caused regression and inhibition of 4T1 breast cancers by reversing the M2-TAMs mediated immunosuppression and efficiently inducing effector T cell activation in the tumor microenvironment. In addition to antitumor effects, Elemene (Ele) could inhibit the effect M2 macrophage proliferation by enhancing the therapeutic effects. The application of this strategy may be potentially expanded for cancer therapy in combination with other therapeutics.
Dual mass spectrometry imaging and spatial metabolomics to investigate the metabolism and nephrotoxicity of nitidine chloride
Shu Yang, Zhonghua Wang, Yanhua Liu, Xin Zhang, Hang Zhang, Zhaoying Wang, Zhi Zhou, Zeper Abliz
, Available online  , doi: 10.1016/j.jpha.2024.01.012
Evaluating toxicity and decoding the underlying mechanisms of active compounds are crucial for drug development. In this study, we present an innovative, integrated approach that combines air flow-assisted desorption electrospray ionization mass spectrometry imaging (AFADESI-MSI), time-of-flight secondary ion mass spectrometry (ToF-SIMS), and spatial metabolomics to comprehensively investigate the nephrotoxicity and underlying mechanisms of nitidine chloride (NC), a promising anti-tumor drug candidate. Our quantitive AFADESI-MSI analysis unveiled the region specific of accumulation of NC in the kidney, particularly within the inner cortex (IC) region, following single and repeated dose of NC. High spatial resolution ToF-SIMS analysis further allowed us to precisely map the localization of NC within the renal tubule. Employing spatial metabolomics based on AFADESI-MSI, we identified over 70 discriminating endogenous metabolites associated with chronic NC exposure. These findings suggest the renal tubule as the primary target of NC toxicity and implicate renal transporters (organic cation transporters, multidrug and toxin extrusion, organic cation transporter 2), metabolic enzymes (protein arginine N-methyltransferase, nitric oxide synthase), mitochondria, oxidative stress, and inflammation in NC-induced nephrotoxicity. This study offers novel insights into NC-induced renal damage, representing a crucial step towards devising strategies to mitigate renal damage caused by this compound.
Paeoniflorin ameliorates chronic colitis via the DR3 signaling pathway in group 3 innate lymphoid cells
Shaowei Huang, Xueqian Xie, Bo Xu, Zengfeng Pan, Junjie Liang, Meiling Zhang, Simin Pan, Xiaojing Wang, Meng Zhao, Qing Wang, Jinyan Chen, Yanyang Li, Lian Zhou, Xia Luo
, Available online  , doi: 10.1016/j.jpha.2024.01.008
Inhibiting the death receptor 3 (DR3) signaling pathway in group 3 innate lymphoid cells (ILC3s) presents a promising approach for promoting mucosal repair in individuals with ulcerative colitis (UC). Paeoniflorin, a prominent component of Paeonia lactiflora Pall., has demonstrated the ability to restore barrier function in UC mice, but the precise mechanism remains unclear. In this study, we aimed to delve into whether paeoniflorin may promote intestinal mucosal repair in chronic colitis by inhibiting DR3 signaling in ILC3s. C57BL/6 mice were subjected to random allocation into 7 distinct groups, namely the control group, the 2% dextran sodium sulfate (DSS) group, the paeoniflorin groups (25, 50, and 100 mg/kg), the anti- tumor necrosis factor- like ligand 1A (anti-TL1A) antibody group, and the IgG group. We detected the expression of DR3 signaling pathway proteins and the proportion of ILC3s in the mouse colon using western blot and flow cytometry, respectively. Meanwhile, DR3- overexpressing MNK-3 cells and 2% DSS-induced Rag1-/- mice were used for verification. The results showed that paeoniflorin alleviated DSS-induced chronic colitis and repaired the intestinal mucosal barrier. Simultaneously, paeoniflorin inhibited the DR3 signaling pathway in ILC3s and regulated the content of cytokines (Interleukin-17A, Granulocyte-macrophage colony stimulating factor, and Interleukin- 22). Alternatively, paeoniflorin directly inhibited the DR3 signaling pathway in ILC3s to repair mucosal damage independently of the adaptive immune system. We additionally confirmed that paeoniflorin-conditioned medium (CM) restored the expression of tight junctions in Caco-2 cells via coculture. In conclusion, paeoniflorin ameliorates chronic colitis by enhancing the intestinal barrier in an ILC3-dependent manner, and its mechanism is associated with the inhibition of the DR3 signaling pathway.
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
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
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.
Analysis of GC × GC fingerprints from medicinal materials using a novel contour detection algorithm: A case of Curcuma wenyujin
Xinyue Yang, Yingyu Sima, Xuhuai Luo, Yaping Li, Min He
, Available online  , doi: 10.1016/j.jpha.2024.01.004
This study introduces an innovative contour detection algorithm, PeakCET, designed for rapid and efficient analysis of natural product image fingerprints using comprehensive two-dimensional gas chromatogram (GC × GC). This method innovatively combines contour edge tracking with affinity propagation (AP) clustering for peak detection in GC × GC fingerprints, a first in this field. Contour edge tracking significantly reduces false positives caused by "burr" signals, while AP clustering enhances detection accuracy in the face of false negatives. The efficacy of this approach is demonstrated using three medicinal products derived from Curcuma wenyujin. PeakCET not only performs contour detection but also employs inter-group peak matching and peak-volume percentage calculations to assess the compositional similarities and differences among various samples. Furthermore, this algorithm compares the GC × GC fingerprints of Radix/Rhizoma Curcumae Wenyujin with those of products from different botanical origins. The findings reveal that genetic and geographical factors influence the accumulation of secondary metabolites in various plant tissues. Each sample exhibits unique characteristic components alongside common ones, and variations in content may influence their therapeutic effectiveness. This research establishes a foundational data-set for the quality assessment of Curcuma products and paves the way for the application of computer vision techniques in twodimensional (2D) fingerprint analysis of GC × GC data.
Targeted delivery of rosuvastatin enhances treatment of HHcy-induced atherosclerosis using macrophage membrane-coated nanoparticles
Dayue Liu, Anning Yang, Yulin Li, Zhenxian Li, Peidong You, Hongwen Zhang, Shangkun Quan, Yue Sun, Yaling Zeng, Shengchao Ma, Jiantuan Xiong, Yinju Hao, Guizhong Li, Bin Liu, Huiping Zhang, Yideng Jiang
, Available online  , doi: 10.1016/j.jpha.2024.01.005
Rosuvastatin (RVS) is an excellent drug with anti-inflammatory and lipidlowering properties in the academic and medical fields. However, this drug faces a series of challenges when used to treat atherosclerosis caused by hyperhomocysteinemia (HHcy), including high oral dosage, poor targeting, and longterm toxic side effects. In this study, we applied nanotechnology to construct a biomimetic nano-delivery system, macrophage membrane (Møm)-coated RVS-loaded Prussian blue (PB) nanoparticles (MPR NPs), for improving the bioavailability and targeting capacity of RVS, specifically to the plaque lesions associated with HHcyinduced atherosclerosis. In vitro assays demonstrated that MPR NPs effectively inhibited the Toll-like receptor 4 (TLR4)/hypoxia-inducible factor-1α (HIF-1α/nucleotide-binding and oligomerization domain (NOD)-like receptor thermal protein domain associated protein 3 (NLRP3) signaling pathways, reducing pyroptosis and inflammatory response in macrophages. Additionally, MPR NPs reversed the abnormal distribution of ABCA1/ABCG1 caused by HIF-1α, promoting cholesterol efflux and reducing lipid deposition. In vivo studies using apolipoprotein E knockout (ApoE-/-) mice confirmed the strong efficacy of MPR NPs in treating atherosclerosis with favorable biosecurity, the mechanism behind this efficacy is believed to involve the regulation of serum metabolism and the remodeling of gut microbes. These findings suggest that the synthesis of Møm-coated RVS-loaded PB NPs provides a promising nanosystem for the targeted therapy of HHcy-induced atherosclerosis.
In situ visualization of the cellular uptake and sub-cellular distribution of mussel oligosaccharides
Zhenjie Yu, Huarong Shao, Xintian Shao, Linyan Yu, Yanan Gao, Youxiao Ren, Fei Liu, Caicai Meng, Peixue Ling, Qixin Chen
, Available online  , doi: 10.1016/j.jpha.2023.12.022
Unlike chemosynthetic drugs designed for specific molecular and disease targets, active small-molecule natural products typically have a wide range of bioactivities and multiple targets, necessitating extensive screening and development. To address this issue, we propose a strategy for the direct in situ microdynamic examination of potential drug candidates to rapidly identify their effects and mechanisms of action. As a proofof-concept, we investigated the behavior of mussel oligosaccharide (MOS-1) by tracking the subcellular dynamics of fluorescently labeled MOS-1 in cultured cells. We recorded the entire dynamic process of the localization of fluorescein isothiocyanate (FITC)-mussel oligosaccharide (MOS-1) to the lysosomes and visualized the distribution of the drug within the cell. Remarkably, lysosomes containing FITC-MOS- 1 actively recruited lipid droplets, leading to fusion events and increased cellular lipid consumption. These drug behaviors confirmed MOS-1 is a candidate for the treatment of lipid-related diseases. Furthermore, in a high-fat HepG2 cell model and in high-fat diet-fed ApoE−/− mice, MOS-1 significantly promoted triglyceride degradation, reduced lipid droplet accumulation, lowered serum triglyceride levels, and mitigated liver damage and steatosis. Overall, our work supports the prioritization of in situ visual monitoring of drug location and distribution in subcellular compartments during the drug development phase as this methodology contributes to the rapid identification of drug indications. Collectively, this methodology is significant for the screening and development of selective small-molecule drugs, and is expected to expedite the identification of candidate molecules with medicinal effects.
Baicalin alleviates chronic stress-induced breast cancer metastasis via directly targeting β2-adrenergic receptor
Qi Jia, Yinyin Zhou, Li Song, Ximeng Shi, Xuan Jiang, Ruizhi Tao, Aiyun Wang, Yuanyuan Wu, Zhonghong Wei, Yinan Zhang, Xiaoman Li, Yin Lu
, Available online  , doi: 10.1016/j.jpha.2024.01.002
Recent studies have shown that stress can substantially facilitate breast cancer metastasis, which can be ameliorated by nonselective β1/β2-adrenergic receptor (β1/β2- AR) blocker. However, several side effects were identified. Thus, it is extremely warranted to explore more effective and better-tolerated β2-AR blocker. Currently, we demonstrated that baicalin (BA), a major bioactive component of Scutellaria baicalensis Georgi, could significantly attenuate stress hormones especially epinephrine (Epi)-induced breast cancer cell migration and invasion in vitro. Mechanistically, we identified that β2-AR was a direct target of BA via the drug affinity responsive target stability (DARTS) combined with mass spectrum assay, and BA photoaffinity probe with pull-down assay, which was further confirmed by a couple of biophysical and biochemical assays. Furthermore, we demonstrated that BA could directly bind to the Phe-193 and Phe-289 of β2-AR, subsequently inhibit cAMP-PKA- FAK pathway, and thus impede epithelial-mesenchymal transition (EMT), thereby hindering the metastatic progression of the chronic stress coupled with syngeneic and xenograft in vivo orthotopic and tail vein mouse model. These findings firstly identify BA as a potential β2-AR inhibitor in the treatment of stress-induced breast cancer metastasis.
New perspectives on the therapeutic potential of quercetin in non-communicable diseases: Targeting Nrf2 to counteract oxidative stress and inflammation
Li Zhang, Li Yue Xu, Fei Tang, Dong Liu, Xiao Lan Zhao, Jing Nan Zhang, Jia Xia, Jiao Jiao Wu, Yu Yang, Cheng Peng, Hui Ao
, Available online  , doi: 10.1016/j.jpha.2023.12.020
Non-communicable diseases (NCDs), including cardiovascular diseases, cancer, metabolic diseases, and skeletal diseases, pose significant challenges to public health worldwide. The complex pathogenesis of these diseases is closely linked to oxidative stress and inflammatory damage. Nuclear factor erythroid 2-related factor 2 (Nrf2), a critical transcription factor, plays an important role in regulating antioxidant and antiinflammatory responses to protect the cells from oxidative damage and inflammationmediated injury. Therefore, Nrf2-targeting therapies hold promise for preventing and treating NCDs. Quercetin (Que) is a widely available flavonoid that has significant antioxidant and anti-inflammatory properties. It modulates the Nrf2 signaling pathway to ameliorate oxidative stress and inflammation. Que modulates mitochondrial function, apoptosis, autophagy, and cell damage biomarkers to regulate oxidative stress and inflammation, highlighting its efficacy as a therapeutic agent against NCDs. Here, we discussed, for the first time, the close association between NCD pathogenesis and the Nrf2 signaling pathway, involved in neurodegenerative diseases, cardiovascular disease, cancers, organ damage, and bone damage. Furthermore, we reviewed the availability, pharmacokinetics, pharmaceutics, and therapeutic applications of Que in treating NCDs. In addition, we focused on the challenges and prospects for its clinical use. Que represents a promising candidate for the treatment of NCDs due to its Nrf2-targeting properties.
Renal tubular epithelial cell quality control mechanisms as therapeutic targets in renal fibrosis
Yini Bao, Qiyuan Shan, Keda Lu, Qiao Yang, Ying Liang, Haodan Kuang, Lu Wang, Min Hao, Mengyun Peng, Shuosheng Zhang, Gang Cao
, Available online  , doi: 10.1016/j.jpha.2024.01.001
Renal fibrosis is a devastating consequence of progressive chronic kidney disease, representing a major public health challenge worldwide. The underlying mechanisms in the pathogenesis of renal fibrosis remain unclear, and effective treatments are still lacking. Renal tubular epithelial cells (RTECs) maintain kidney function, and their dysfunction has emerged as a critical contributor to renal fibrosis. Cellular quality control comprises several components, including telomere homeostasis, ubiquitin-proteasome system, autophagy, mitochondrial homeostasis (mitophagy and mitochondrial metabolism), endoplasmic reticulum (unfolded protein response), and lysosomes. Failures in the cellular quality control of RTECs, including deoxyribonucleic acid (DNA), protein, and organelle damage, exert profibrotic functions by leading to senescence, defective autophagy, endoplasmic reticulum stress, mitochondrial and lysosomal dysfunction, apoptosis, fibroblast activation, and immune cell recruitment. In this review, we summarize recent advances in understanding the role of quality control components and intercellular crosstalk networks in RTECs, within the context of renal fibrosis.
Discrimination of Polysorbate 20 by High-Performance Liquid Chromatography-Charged Aerosol Detection and Characterization for Components by Expanding Compound Database and Library
Shi-Qi Wang, Xun Zhao, Li-Jun Zhang, Yue-Mei Zhao, Lei Chen, Jin-Lin Zhang, Bao-Cheng Wang, Sheng Tang, Tom Yuan, Yaozuo Yuan, Mei Zhang, Hian Kee Lee, Hai-Wei Shi
, Available online  , doi: 10.1016/j.jpha.2023.12.019
Analyzing polysorbate 20 (PS20) composition and the impact of each component on stability and safety is crucial due to formulation variations and individual tolerance. The similar structures and polarities of PS20 components make accurate separation, identification, and quantification challenging. In this work, a high-resolution quantitative method was developed using single-dimensional high-performance liquid chromatography (HPLC) with charged aerosol detection (CAD) to separate 18 key components with multiple esters. The separated components were characterized by ultra-high-performance LC-quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOF-MS) with an identical gradient as the HPLC-CAD analysis. The polysorbate compound database and library were expanded over 7-time compared to the commercial database. The method investigated differences in PS20 samples from various origins and grades for different dosage forms to evaluate the composition-process relationship. UHPLC-Q-TOF-MS identified 1329 to 1511 compounds in 4 batches of PS20 from different sources. The method observed the impact of 4 degradation conditions on peak components, identifying stable components and their tendencies to change. HPLC-CAD and UHPLC-Q-TOF-MS results provided insights into fingerprint differences, distinguishing quasi products.
Dynamic gut microbiome-metabolome in c-BSA induced experimental immune-complex glomerulonephritis and effect of losartan and MMF on microbiota modulation
Wenying Shi, Zhaojun Li, Weida Wang, Xikun Liu, Haijie Wu, Xiaoguang Chen, Xunrong Zhou, Sen Zhang
, Available online  , doi: 10.1016/j.jpha.2023.12.021
Dynamic changes in gut dysbiosis and metabolomic dysregulation are associated with immune-complex glomerulonephritis (ICGN). However, an in-depth study on this topic is currently lacking. Herein, we report an ICGN model to address this gap. ICGN was induced via the intravenous injection of cationized bovine serum albumin into Sprague-Dawley rats for two weeks, after which mycophenolate mofetil (MMF) and losartan were administered orally. Two and six weeks after ICGN establishment, fecal samples were collected and 16S ribosomal DNA (rDNA) sequencing and untargeted metabolomic were conducted. Fecal microbiota transplantation (FMT) was conducted to determine whether gut normalization caused by MMF and losartan contributed to their renal protective effects. A gradual decline in microbial diversity and richness was accompanied by a loss of renal function. Approximately 18 genera were found to have significantly different relative abundances between the early and later stages, and Marvinbryantia and Allobaculum were markedly upregulated in both stages. Untargeted metabolomics indicated that the tryptophan metabolism was enhanced in ICGN, characterized by the overproduction of indole and kynurenic acid, while the serotonin pathway was reduced. Administration of losartan and MMF ameliorated microbial dysbiosis and reduced the accumulation of indoxyl conjugates in feces. FMT using feces from animals administered MMF and losartan improved gut dysbiosis by decreasing the Firmicutes/Bacteroidetes ratio but did not improve renal function. These findings indicate that ICGN induces serous gut dysbiosis, wherein an altered tryptophan metabolism may contribute to its progression. MMF and losartan significantly reversed the gut microbial and metabolomic dysbiosis, which partially contributed to their renoprotective effects.
Design of a Nanozyme−Based Magnetic Nanoplatform to Enhance Photodynamic Therapy and Immunotherapy
Chen Bai, Jiajing Liu, Luyao Bai, Dapeng Yao, Xiaofeng Li, Haoran Zhang, Dong Guo
, Available online  , doi: 10.1016/j.jpha.2023.12.018
The tumor microenvironment, particularly the hypoxic property and glutathione (GSH) overexpression, substantially inhibits the efficacy of cancer therapy. In this article, we present the design of a magnetic nanoplatform (MNPT) comprised of a photosensitizer (Ce6) and an iron oxide (Fe3O4)/manganese oxide (MnO2) composite nanozyme. Reactive oxygen species (ROS), such as singlet oxygen (1O2) radicals produced by light irradiation and hydroxyl radicals (·OH) produced by catalysis, are therapeutic species. These therapeutic substances stimulate cell apoptosis by increasing oxidative stress. This apoptosis then triggers the immunological response, which combines photodynamic therapy and T−cell−mediated immunotherapy to treat cancer. Furthermore, MNPT can be utilized as a contrast agent in magnetic resonance and fluorescence dual−modality imaging to give real−time tracking and feedback on treatment.
Secondary metabolites of mulberry leaves exert anti-lung cancer activity through regulating the PD-L1/PD-1 signaling pathway
Guiqin Ye, Xin Sun, Jiuzhou Li, Yuanyuan Mai, Ruilan Gao, Jianbin Zhang
, Available online  , doi: 10.1016/j.jpha.2023.12.016
Lung cancer ranks the top of malignancies that cause cancer-related deaths worldwide. The leaves of Morus alba L are traditional Chinese medicine widely applied in respiratory diseases. Our previous work has demonstrated the anti-lung cancer effect of secondary metabolites of mulberry leaf. But their mechanism of action has still not fully elucidated. We synthesized Moracin N (MAN) probe conjugated with alkyne to label lung cancer cells and identified protein targets by chemical proteomic analysis. MAN and its probe exerted similar growth-inhibitory effect on human lung cancer cells. Chemical proteomic results showed that MAN targeted the programmed death ligand 1 (PD-L1) checkpoint pathway and T cell receptor (TCR) signaling pathway, indicating its immune-regulatory function. Cell-free surface plasmon resonance (SPR) results showed the direct interaction of MAN with PD-L1 protein. Molecular docking analysis demonstrated that MAN bound to E158 residue of PD-L1 protein. MAN downregulated the expression levels of PD-L1 in a time- and dose-dependent manner and disrupted the PD-L1/programmed death 1 (PD-1) binding, including other secondary metabolites of mulberry leaves Guangsangon E (GSE) and Chalcomoracin (CMR). Human peripheral blood mononuclear cells (PBMCs) co-cultured with MAN-treated A549 cells, resulting in the increase of cluster of differentiation (CD)8+ Granzyme B (GZMB)+ T cells and the decrease of CD8+PD-1+ T cells. It suggested that MAN exerts anti-cancer effect through blocking the PD-L1/PD-1 signaling. In vivo, MAN combined with anti-PD-1 antibody significantly inhibited lung cancer development and metastasis, indicating their synergistic effect. Taken together, secondary metabolites of mulberry leaves target the PD-L1/PD-1 signaling, enhance T cell-mediated immunity and inhibit the tumorigenesis of lung cancer. Their modulatory effect on tumor microenvironment makes them able to enhance the therapeutic efficacy of immune checkpoint inhibitors in lung cancer.
Rapid discovery of a novel “green” and natural GST inhibitor for sensitizing hepatocellular carcinoma to Cisplatin by visual screening strategy
Linxi Mao, Yan Qin, Jialong Fan, Wei Yang, Bin Li, Liang Cao, Liqin Yuan, Mengyun Wang, Bin Liu, Wei Wang
, Available online  , doi: 10.1016/j.jpha.2023.12.013
Over-expression of glutathione S-transferase (GST) can promote Cisplatin resistance in hepatocellular carcinoma (HCC) treatment. Hence, inhibiting GST is an attractive strategy to improve Cisplatin sensitivity in HCC therapy. Although several synthesized GST inhibitors have been developed, the side effects and narrow spectrum for anticancer seriously limit their clinical application. Considering the abundance of natural compounds with anticancer activity, this study developed a rapid fluorescence technique to screen “green” natural GST inhibitors with high specificity. The fluorescence assay demonstrated that schisanlactone B (hereafter abbreviated as C1) isolated from Xue tong significantly down-regulated GST levels in Cisplatin-resistant HCC cells in vitro and in vivo. Importantly, C1 can selectively kill HCC cells from normal liver cells, effectively improving the therapeutic effect of Cisplatin on HCC mice by down-regulating GST expression. Considering the high GST levels in HCC patients, this compound demonstrated the high potential for sensitizing HCC therapy in clinical practice by down-regulating GST levels.
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
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
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.
Cornus officinalis with high pressure wine steaming enhanced anti-hepatic fibrosis: Possible through SIRT3-AMPK axis
Xin Han, Yan Ning, Xinyue Dou, Yiwen Wang, Qiyuan Shan, Kao Shi, Zeping Wang, Chuan Ding, Min Hao, Kuilong Wang, Mengyun Peng, Haodan Kuang, Qiao Yang, Xianan Sang, Gang Cao
, Available online  , doi: 10.1016/j.jpha.2023.12.017
Cornus officinalis, a medicinal and edible plant known for its liver-nourishing properties, has shown promise in inhibiting the activation of hepatic stellate cells (HSCs), crucial indicators of hepatic fibrosis, especially when processed by high pressure wine steaming (HPWS). Herein, this study aims to investigate the regulatory effects of cornus officinalis, both in its raw and HPWS forms, on inflammation and apoptosis in liver fibrosis and their underlying mechanisms. In vivo liver fibrosis models were established by subcutaneous injection of CCl4, while in vitro HSCs were exposed to transforming growth factor-β (TGF-β). These findings demonstrated that cornus officinalis with HPWS conspicuously ameliorated histopathological injury, reduced the release of proinflammatory factors, and decreased collagen deposition in CCl4-induced rats compared to its raw form. Utilizing ultra-high-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometer (UHPLC-QTOF-MS) combined with network analysis, we identified that the pharmacological effects of the changed components of cornus officinalis before and after HPWS, primarily centered on the adenosine phosphate (AMP)-activated protein kinase (AMPK) pathway. Of note, cornus officinalis activated AMPK and Sirtuin 3 (SIRT3), promoting the apoptosis of activated HSCs through the caspase cascade by regulating caspase3, caspase6 and caspase9. siRNA experiments showed that cornus officinalis could regulate AMPK activity and its mediated-apoptosis through SIRT3. In conclusion, cornus officinalis exhibited the ability to reduce inflammation and apoptosis, with the SIRT3-AMPK signaling pathway identified as a potential mechanism underlying the synergistic effect of cornus officinalis with HPWS on anti-liver fibrosis.
Measurement of very low-molecular weight metabolites by traveling wave ion mobility and its use in human urine samples
Alongkorn Kurilung, Suphitcha Limjiasahapong, Khwanta Kaewnarin, Pattipong Wisanpitayakorn, Narumol Jariyasopit, Kwanjeera Wanichthanarak, Sitanan Sartyoungkul, Stephen Choong Chee Wong, Nuankanya Sathirapongsasuti, Chagriya Kitiyakara, Yongyut Sirivatanauksorn, Sakda Khoomrung
, Available online  , doi: 10.1016/j.jpha.2023.12.011
The collision cross-sections (CCS) measurement using ion mobility spectrometry (IMS) in combination with mass spectrometry (MS) offers a great opportunity to increase confidence in metabolite identification. However, owing to the lack of sensitivity and resolution, IMS has an analytical challenge in studying the CCS values of very low-molecular-weight metabolites (VLMs ≤ 250 Da). Here, we describe an analytical method using ultrahigh-performance liquid chromatography coupled to a traveling wave ion mobility-quadrupole-time-of-flight mass spectrometer optimized for the measurement of VLMs in human urine samples. The experimental CCS values, along with mass spectral properties were reported for the 174 metabolites. The experimental data included the mass-to-charge ratio (m/z), retention time (RT), tandem MS (MS/MS) spectra, and CCS values. Among the studied metabolites, 263 traveling wave ion mobility spectrometry (TWIMS)-derived CCS values (TWCCSN2) were reported for the first time, and more than 70% of these were CCS values of VLMs. The TWCCSN2 values were highly repeatable, with inter-day variations of < 1% RSD. The developed method revealed excellent TWCCSN2 accuracy with a CCS difference (ΔCCS) within ±2% of the reported drift tube IMS (DTIMS) and TWIMS CCS values. The complexity of the urine matrix did not affect the precision of the method, as evidenced by ΔCCS within ±1.92%. According to the Metabolomics Standards Initiative, 55 urinary metabolites were identified with a confidence level of 1. Among these 55 metabolites, 53 (96%) were VLMs. The larger number of confirmed compounds found in this study was a result of the addition of TWCCSN2 values, which clearly increased metabolite identification confidence.
Extracellular Vesicles in Anti-tumor Drug Resistance: Mechanisms and Therapeutic Prospects
Hao-Yang Cheng, Guang-Liang Su, Yu-Xuan Wu, Gang Chen, Zi-Li Yu
, Available online  , doi: 10.1016/j.jpha.2023.12.010
Drug resistance presents a significant challenge to achieving positive clinical outcomes in anti-tumor therapy. Prior research has illuminated reasons behind drug resistance, including increased drug reflux, alterations in drug targets, and abnormal activation of oncogenic pathways. However, there's a need for deeper investigation into the impact of drug-resistant tumor cells on parental tumor cells and intricate crosstalk between tumor cells and the malignant tumor microenvironment (TME). Recent studies on extracellular vesicles (EVs) have provided valuable insights. EVs are membrane-bound particles secreted by all cells, mediating cell-to-cell communication. They contain functional cargoes like DNA, RNA, lipids, proteins, and metabolites from mother cells, delivered to other cells. Notably, EVs are increasingly recognized as regulators in the resistance to anti-cancer drugs. This review aims to summarize the mechanisms of EVmediated anti-tumor drug resistance, covering therapeutic approaches like chemotherapy, targeted therapy, immunotherapy and even radiotherapy. Detecting EVbased biomarkers to predict drug resistance assists in bypassing anti-tumor drug resistance. Additionally, targeted inhibition of EV biogenesis and secretion emerges as a promising approach to counter drug resistance. We highlight the importance of conducting in-depth mechanistic research on EVs, their cargoes, and functional approaches specifically focusing on EV subpopulations. These efforts will significantly advance the development of strategies to overcome drug resistance in anti-tumor therapy.
Nitrosamines crisis in pharmaceuticals - insights on toxicological implications, root causes and risk assessment: A systematic review
Hemanth P.R. Vikram, Tegginamath Pramod Kumar, Gunjan Kumar, Narasimha M. Beeraka, Rajashree Deka, Sheik Mohammed Suhail, Sandeep Jat, Namitha Bannimath, Gayatiri Padmanabhan, Ravandur S. Chandan, Pramod Kumar, Bannimath Gurupadayya
, Available online  , doi: 10.1016/j.jpha.2023.12.009
The presence of N-nitroso compounds, particularly N-nitrosamines, in pharmaceutical products has raised global safety concerns due to their significant genotoxic and mutagenic effects. This systematic review investigates their toxicity in active pharmaceutical ingredients, drug products, and pharmaceutical excipients, along with novel analytical strategies for detection, root cause analysis, reformulation strategies, and regulatory guidelines for nitrosamines. This review emphasizes the molecular toxicity of N-nitroso compounds, focusing on genotoxic, mutagenic, carcinogenic, and other physiological effects. Additionally, it addresses the ongoing nitrosamine crisis, the development of nitrosamine-free products, and the importance of sensitive detection methods and precise risk evaluation. This comprehensive overview will aid molecular biologists, analytical scientists, and formulation scientists in research and development sector, and researchers involved in management of nitrosamine-induced toxicity and promoting safer pharmaceutical products.
Perspective on in vivo SPME for human applications: starting from monitoring doxorubicin during lung chemo-perfusion
Wei Zhou, Runshan Will Jiang, Barbara Bojko, Janusz Pawliszyn
, Available online  , doi: 10.1016/j.jpha.2023.12.008
In vivo solid-phase microextraction (SPME) is a non-destructive and minimally invasive sampling technique for living systems that facilitates the acquisition of representative metabolome profiles while offering detection of low abundance, short-lived, and unstable species that not easily captured by traditional methods. Recently, following over 10 years of adventure in ex vivo and in vivo animal studies, SPME was successfully applied for in vivo analysis of human tissue. The proposed in vivo SPME method was coupled to LC-MS for monitoring of doxorubicin during in vivo lung perfusion (IVLP) with temporal and spatial information. In view of this breakthrough and considering the already comprehensive body of research on animal models in the literature, we provide here future perspectives on in vivo SPME from three different aspects: optimization and development of SPME features, direct coupling with MS for real-time monitoring, and future applications.
New Advances of adiponectin in regulating obesity and related metabolic syndromes
Yanqi Han, Qianwen Sun, Wei Chen, Yue Gao, Jun Ye, Yanmin Chen, Tingting Wang, Lili Gao, Yuling Liu, Yanfang Yang
, Available online  , doi: 10.1016/j.jpha.2023.12.003
Obesity and related metabolic syndromes have been recognized as important disease risks, in which the role of adipokines cannot be ignored. Adiponectin (ADP) is one of the key adipokines with various beneficial effects, including improving glucose and lipid metabolism, enhancing insulin sensitivity, reducing oxidative stress and inflammation, promoting ceramides degradation, and stimulating adipose tissue vascularity. Based on those, it can serve as a positive regulator in many metabolic syndromes, such as type 2 diabetes (T2D), cardiovascular diseases, non-alcoholic fatty liver disease (NAFLD), sarcopenia, neurodegenerative diseases, and certain cancers. Therefore, a promising therapeutic approach for treating various metabolic diseases may involve elevating ADP levels or activating ADP receptors. The modulation of ADP genes, multimerization, and secretion covers the main processes of ADP generation, providing a comprehensive orientation for the development of more appropriate therapeutic strategies. In order to have a deeper understanding of ADP, this paper will provide an all-encompassing review of ADP.
GLP-1 receptor agonists and myocardial metabolism in atrial fibrillation
Jiani Zhong, Hang Chen, Qiming Liu, Shenghua Zhou, Zhenguo Liu, Yichao Xiao
, Available online  , doi: 10.1016/j.jpha.2023.12.007
Atrial fibrillation (AF) is the most common cardiac arrhythmia. Many medical conditions, including hypertension, diabetes, obesity, sleep apnea, and heart failure, increase the risk for AF. Cardiomyocytes have unique metabolic characteristics to maintain adenosine triphosphate production. Significant changes occur in myocardial metabolism in AF. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have been used to control blood glucose fluctuations and weight in the treatment of type 2 diabetes and obesity. GLP-1RAs have also been shown to reduce oxidative stress, inflammation, autonomic nervous system modulation, and mitochondrial function. This article reviews the changes in metabolic characteristics in cardiomyocytes in AF. Although the clinical trial outcomes are unsatisfactory, the findings demonstrate that GLP-1 RAs can improve myocardial metabolism in the presence of various risk factors, lowering the incidence of AF.
Model informed Precision Medicine of Chinese Herbal Medicines Formulas- A Multi-scale Mechanistic Intelligent Model
Yuanyuan Qian, Xiting Wang, Lulu Cai, Jiangxue Han, Zhu Huang, Yahui Lou, Bingyue Zhang, Yanjie Wang, Xiaoning Sun, Yan Zhang, Aisong Zhu
, Available online  , doi: 10.1016/j.jpha.2023.12.004
Recent trends suggest that Chinese herbal medicine formulas (CHM formulas) are promising treatments for complex diseases. To characterize the precise syndromes, precise diseases and precise targets of the precise targets between complex diseases and CHM formulas, we developed an artificial intelligence-based quantitative predictive algorithm (DeepTCM). DeepTCM has gone through multilevel model calibration and validation against a comprehensive set of herb and disease data so that it accurately captures the complex cellular signaling, molecular and theoretical levels of traditional Chinese medicine (TCM). As an example, our model simulated the optimal CHM formulas for the treatment of coronary heart disease (CHD) with depression, and through model sensitivity analysis, we calculated the balanced scoring of the formulas. Furthermore, we constructed a biological knowledge graph representing interactions by associating herb-target and gene-disease interactions. Finally, we experimentally confirmed the therapeutic effect and pharmacological mechanism of a novel model-predicted intervention in humans and mice. This novel multiscale model opened up a new avenue to combine “disease syndrome” and "macro micro" system modeling to facilitate translational research in CHM formulas.
Traditional Chinese Medicine Pien-Tze-Huang ameliorates LPS-induced sepsis through bile acid-mediated activation of TGR5-STAT3-A20 signaling
Bei Li, Yong Zhang, Xinyuan Liu, Ziyang Zhang, Shuqing Zhuang, Xiaoli Zhong, WenBo Chen, Yilin Hong, Pingli Mo, Shuhai Lin, Shicong Wang, Chundong Yu
, Available online  , doi: 10.1016/j.jpha.2023.12.005
Pien Tze Huang (PZH), a Class I nationally protected Traditional Chinese Medicine (TCM), has been used to treat liver diseases such as hepatitis; however, the effect of PZH on the progression of sepsis is unknown. Here, we reported that PZH attenuated lipopolysaccharide (LPS)-induced sepsis in mice and reduced LPS-induced production of proinflammatory cytokines in macrophages by inhibiting the activation of mitogen-activated protein kinase (MAPK) and nuclear factor-kappa B (NF-κB) signalling. Mechanistically, PZH stimulated signal transducer and activator of transcription 3 (STAT3) phosphorylation to induce the expression of A20, which could inhibit the activation of NF-κB and MAPK signalling. Knockdown of the bile acid (BA) receptor G protein-coupled bile acid receptor 1 (TGR5) in macrophages abolished the effects of PZH on STAT3 phosphorylation and A20 induction, as well as the LPS-induced inflammatory response, suggesting that BAs in PZH may mediate its anti-inflammatory effects by activating TGR5. Consistently, deprivation of BAs in PZH by cholestyramine resin reduced the effects of PZH on the expression of phosphorylated-STAT3 and A20, the activation of NF-κB and MAPK signalling, and the production of proinflammatory cytokines, whereas the addition of BAs to cholestyramine resin-treated PZH partially restored the inhibitory effects on the production of proinflammatory cytokines. Overall, our study identifies BAs as the effective components in PZH that activate TGR5-STAT3-A20 signalling to ameliorate LPS-induced sepsis.
Basic Regulatory Science Behind Drug Substance and Drug Product Specifications of Monoclonal Antibodies and Other Protein Therapeutics
Patanachai K. Limpikirati, Sorrayut Mongkoltipparat, Thinnaphat Denchaipradit, Nathathai Siwasophonpong, Wudthipong Pornnopparat, Parawan Ramanandana, Phumrapee Pianpakt, Songsak Tongchusak, Maoxin Tim Tian, Trairak Pisitkun
, Available online  , doi: 10.1016/j.jpha.2023.12.006
In this review, we focus on providing basics and examples for each component of the protein therapeutic specifications to interested pharmacists and biopharmaceutical scientists with a goal to strengthen understanding in regulatory science and compliance. Pharmaceutical specifications comprise a list of important quality attributes for testing, references to use for test procedures, and appropriate acceptance criteria for the tests, and they are set up to ensure that when a drug product is administered to a patient, its intended therapeutic benefits and safety can be rendered appropriately. Conformance of drug substance or drug product to the specifications is achieved by testing an article according to the listed tests and analytical methods and obtaining test results that meet the acceptance criteria. Quality attributes are chosen to be tested based on their quality risk, and consideration should be given to the merit of the analytical methods which are associated with the acceptance criteria of the specifications. Acceptance criteria are set forth primarily based on efficacy and safety profiles, with an increasing attention noted for patient-centric specifications. Discussed in this work are related guidelines that support the biopharmaceutical specification setting, how to set the acceptance criteria, and examples of the quality attributes and the analytical methods from 60 articles and 23 pharmacopeial monographs. Outlooks are also explored on process analytical technologies and other orthogonal tools which are on-trend in biopharmaceutical characterization and quality control.
Alginate oligosaccharide-mediated butyrate-HIF-1α axis improves skin aging in mice
Ting Gao, Yixuan Li, Xiaoyu Wang, Fazheng Ren
, Available online  , doi: 10.1016/j.jpha.2023.12.001
The “gut-skin” axis has been proved and is considered as a novel therapy for the prevention of skin aging. The antioxidant efficacy of oligomannonic acid (MAOS), make it an intriguing target for use to improve skin aging. The present study further explored whereby MAOS-mediated gut-skin axis balance prevented skin aging in mice. The data indicated there was a skin aging phenotypes, oxidative stress, skin mitochondrial dysfunction and intestinal dysbiosis (especially the butyrate and HIF-1α levels decreased) in aging mice. Similarly, fecal microbiota transplantation (FMT) from aging mice rebuild the aging-like phenotypes. Further, we demonstrated MAOS-mediated colonic butyrate-HIF-1α axis homeostasis promoted the entry of butyrate into the skin, up-regulated mitophagy level and ultimately improving skin aging via HDAC3/PHD/HIF-1α/mitophagy loop in skin of mice. Overall, our study offered a better insights of the effectiveness of AOS, promised to become a personalized targeted therapeutic agents, on gut-skin axis disorder inducing skin aging.
Sonodynamic therapy for the treatment of atherosclerosis
Yan Zhang, Ying Yang, Yudi Feng, Xueyan Gao, Liping Pei, Xiaopan Li, Bingxin Gao, Lin Liu, Chengzeng Wang, Shuochen Gao
, Available online  , doi: 10.1016/j.jpha.2023.11.016
Atherosclerosis (AS) is a chronic inflammatory disease of large and medium-sized arteries that leads to ischemic heart disease, stroke, and peripheral vascular disease. Despite the current treatments, mortality and disability still remain high. Sonodynamic therapy (SDT), as a non-invasive and local methodology, has been developed as a promising new treatment for inhibiting atherosclerotic progression and stabilizing plaques. Promising progress has been made through cell and animal assays, as well as clinical trials. For example, the effect of SDT on apoptosis and autophagy of cells in AS, especially macrophages, and the concept of non-lethal SDT has also been proposed. In this review, we summarize the ultrasonic parameters and known sonosensitizers utilized in SDT for AS; we elaborate on SDT’s therapeutic effects and mechanisms in terms of macrophages, T lymphocytes, neovascularization, smooth muscle cells, lipid, extracellular matrix and efferocytosis within plaques; additionally, we discuss the safety of SDT. A comprehensive summary of the confirmed effects of SDT on AS is conducted to establish a framework for future researchers.
Apatinib and gamabufotalin co-loaded lipid/prussian blue nanoparticles for synergistic therapy to gastric cancer with metastasis
Binlong Chen, Yanzhong Zhao, Zichang Lin, Jiahao Liang, Jialong Fan, Yanyan Huang, Leye He, Bin Liu
, Available online  , doi: 10.1016/j.jpha.2023.11.011
Due to the non-targeted release and low solubility of anti-gastric cancer agent, apatinib (Apa), a first-line drug with long-term usage in a high dosage often induces multi-drug resistance and causes serious side effects, as well. In order to avoid these drawbacks, lipid-film-coated Prussian blue nanoparticles (PB NPs) with hyaluronan (HA) modification was used for Apa loading to improve its solubility and targeting ability. Furthermore, anti-tumor compound of gamabufotalin (CS-6) was selected as a partner of Apa with reducing dosage for combinational gastric therapy. Thus, HA-Apa-Lip@PB-CS-6 NPs were constructed to synchronously transport the two drugs into tumor tissue. In vitro assay indicated that HA-Apa-Lip@PB-CS-6 NPs can synergistically inhibit proliferation and invasion/metastasis of BGC-823 cells via downregulating VEGFR and MMP-9. In vivo assay demonstrated strongest anti-tumor growth and liver metastasis of HA-Apa-Lip@PB-CS-6 NPs administration in BGC-823 cells-bearing mice compared with other groups due to the excellent penetration in tumor tissues and outstanding synergistic effects. In summary, we have successfully developed a new nanocomplexes for synchronous Apa/CS-6 delivery and synergistic gastric cancer (GC) therapy.
Targeting the chromatin structural changes of antitumor immunity
Nian-nian Li, Deng-xing Lun, Ningning Gong, Gang Meng, Xin-ying Du, He Wang, Xiangxiang Bao, Xin-yang Li, Ji-wu Song, Kewei Hu, Lala Li, Si-ying Li, Wenbo Liu, Wanping Zhu, Yunlong Zhang, Jikai Li, Ting Yao, Leming Mou, Xiaoqing Han, Furong Hao, Lei Wang, Yongcheng Hu, Lin Liu, Hongguang Zhu, Yuyun Wu, Bin Liu
, Available online  , doi: 10.1016/j.jpha.2023.11.012
Epigenomic imbalance drives abnormal transcriptional processes, promoting the onset and progression of cancer. Although defective gene regulation generally affects carcinogenesis and tumor suppression networks, tumor immunogenicity and immune cells involved in antitumor responses may also be affected by epigenomic changes, which may have significant implications for the development and application of epigenetic therapy, cancer immunotherapy, and their combinations. Herein, we focus on the impact of epigenetic regulation on tumor immune cell function and the role of key abnormal epigenetic processes, DNA methylation, histone post-translational modification, and chromatin structure in tumor immunogenicity, and introduce these epigenetic research methods. We emphasize the value of small-molecule inhibitors of epigenetic modulators in enhancing antitumor immune responses and discuss the challenges of developing treatment plans that combine epigenetic therapy and immunotherapy through the complex interaction between cancer epigenetics and cancer immunology.
Ginsenoside Rb1 induces hepatic stellate cell ferroptosis to alleviate liver fibrosis via the BECN1/SLC7A11 axis
Lifan Lin, Xinmiao Li, Yifei Li, Zhichao Lang, Yeping Li, Jianjian Zheng
, Available online  , doi: 10.1016/j.jpha.2023.11.009
Liver fibrosis is primarily driven by the activation of hepatic stellate cells (HSCs), a process associated with ferroptosis. Ginsenoside Rb1 (GRb1), a major active component extracted from Panax ginseng, inhibits HSC activation. However, the potential role of GRb1 in mediating HSC ferroptosis remains unclear. This study examined the effect of GRb1 on liver fibrosis both in vivo and in vitro, using CCl4-induced liver fibrosis mouse model and primary HSCs, LX-2 cells. The findings revealed that GRb1 effectively inactivated HSCs in vitro, reducing alpha-smooth muscle actin and Type I collagen levels. Moreover, GRb1 significantly alleviated CCl4-induced liver fibrosis in vivo. From a mechanistic standpoint, the ferroptosis pathway appeared to be central to the antifibrotic effects of GRb1. Specifically, GRb1 promoted HSC ferroptosis both in vivo and in vitro, characterized by increased glutathione depletion, malondialdehyde production, iron overload, and accumulation of reactive oxygen species. Intriguingly, GRb1 increased Beclin 1 (BECN1) levels and decreased the System Xc-key subunit SLC7A11. Further experiments showed that BECN1 silencing inhibited GRb1-induced effects on HSC ferroptosis and mitigated the reduction of SLC7A11 caused by GRb1. Moreover, BECN1 could directly interact with SLC7A11, initiating HSC ferroptosis. In conclusion, the suppression of BECN1 counteracted the effects of GRb1 on HSC inactivation both in vivo and in vitro. Overall, this study highlights the novel role of GRb1 in inducing HSC ferroptosis and promoting HSC inactivation, at least partly through its modulation of BECN1 and SLC7A11.
Integrated Spatial Metabolomics and Transcriptomics Decipher the Hepatoprotection Mechanisms of Wedelolactone and Demethylwedelolactone on Non-alcoholic Fatty Liver Disease
Panpan Chen, Zihan Zhu, Haoyuan Geng, Xiaoqing Cui, Yuhao Han, Lei Wang, Yaqi Zhang, Heng Lu, Xiao Wang, Yun Zhang, Chenglong Sun
, Available online  , doi: 10.1016/j.jpha.2023.11.017
Eclipta prostrata L. has been used in traditional medicine and known for its liver-protective properties for centuries. Wedelolactone (WEL) and demethylwedelolactone (DWEL) are the major coumarins found in Eclipta prostrata L.. However, the comprehensive characterization of these two compounds on non-alcoholic fatty liver disease (NAFLD) still remains to be explored. Utilizing a well-established zebrafish model of thioacetamide (TAA)-induced liver injury, the present study sought to investigate the impacts and mechanisms of WEL and DWEL on NAFLD through integrative spatial metabolomics with liver-specific transcriptomics analysis. Our results showed that WEL and DWEL significantly improved liver function and reduced the accumulation of fat in the liver. The biodistributions and metabolism of these two compounds in whole-body zebrafish were successfully mapped, and the discriminatory endogenous metabolites reversely regulated by WEL and DWEL treatments were also characterized. Based on spatial metabolomics and transcriptomics, we identified that steroid biosynthesis and fatty acid metabolism are mainly involved in the hepatoprotective effects of WEL instead of DWEL. Our study unveils the distinct mechanism of WEL and DWEL in ameliorating NAFLD, and presents a ''multi-omics'' platform of spatial metabolomics and liver-specific transcriptomics to develop highly effective compounds for further improved therapy.
Contemporary strategies and approaches for characterizing composition and enhancing biofilm penetration targeting bacterial extracellular polymeric substances
Lan Lu, Yuting Zhao, Mingxing Li, Xiaobo Wang, Jie Zhu, Li Liao, Jingya Wang
, Available online  , doi: 10.1016/j.jpha.2023.11.013
Extracellular polymeric substances (EPS) constitutes crucial elements within bacterial biofilms, facilitating accelerated antimicrobial resistance and conferring defense against the host's immune cells. Developing precise and effective antibiofilm approaches and strategies, tailored to the specific characteristics of EPS composition, can offer valuable insights for the creation of novel antimicrobial drugs. This, in turn, holds the potential to mitigate the alarming issue of bacterial drug resistance. Current analysis of EPS compositions relies heavily on colorimetric approaches with a significant bias, which is likely due to the selection of a standard compound and the cross-interference of various EPS compounds. Considering the pivotal role of EPS in biofilm functionality, it is imperative for EPS research to delve deeper into the analysis of intricate compositions, moving beyond the current focus on polymeric materials. This necessitates a shift from heavy reliance on colorimetric analytic methods to more comprehensive and nuanced analytical approaches. In this study, we have provided a comprehensive summary of existing analytical methods utilized in the characterization of EPS compositions. Additionally, novel strategies aimed at targeting EPS to enhance biofilm penetration were explored, with a specific focus on highlighting the limitations associated with colorimetric methods. Furthermore, we have outlined the challenges faced in identifying additional components of EPS and propose a prospective research plan to address these challenges. This review has the potential to guide future researchers in the search for novel compounds capable of suppressing EPS, thereby inhibiting biofilm formation. This insight opens up a new avenue for exploration within this research domain.
An Enviromentally Sensitive Zinc-Selective Two-Photon NIR Fluorescent Turn-on probe And Zinc sensing In Stroke
Junfeng Wang, Qibing Liu, Yingbo Li, Yi Pang
, Available online  , doi: 10.1016/j.jpha.2023.11.010
A two-photon near infrared (NIR) fluorescence turn-on sensor with high selectivity and sensitivity for Zn2+ detection has been developed. This sensor exhibits a large Stokes' shift (∼300 nm) and can be excited from 900 to 1000 nm, with an emission wavelength of ∼785 nm, making it ideal for imaging in biological tissues. The sensor's high selectivity for Zn2+ over other structurally similar cations, such as Cd2+, makes it a promising tool for monitoring zinc ion levels in biological systems. Given the high concentration of zinc in thrombi, this sensor could provide a useful tool for in vivo thrombus imaging.
YTE-17 inhibits colonic carcinogenesis by resetting antitumor immune response via Wnt5a/JNK mediated metabolic signaling
Hua Sui, Wanli Deng, Qiong Chai, Bing Han, Yuli Zhang, Zhenzhen Wei, Zan Li, Ting Wang, Jiling Feng, Man Yuan, Qingfeng Tang, Hongxi Xu
, Available online  , doi: 10.1016/j.jpha.2023.11.008
The density and composition of lymphocytes infiltrating colon tumors serve as predictive factors for the clinical outcome of colon cancer. Our previous studies highlighted the potent anti-cancer properties of the principal compounds found in Garcinia yunnanensis (YTE-17), attributing these effects to the regulation of multiple signaling pathways. However, knowledge regarding the mechanism and effect of YTE-17 in the prevention of colorectal cancer is limited. In this study, we conducted isobaric tags for relative and absolute quantification (iTRAQ) analysis on intestinal epithelial cells (IECs) exposed YTE-17, both in vitro and vivo, revealing a significant inhibition of the Wnt5a (Wnt family member 5a)/c-Jun N-terminal kinase (JNK) signaling pathway. Subsequently, we elucidated the influence and mechanism of YTE-17 on the tumor microenvironment (TME), specifically focusing on macrophage-mediated T helper 17 (Th17) cell induction in a colitis-associated cancer (CAC) model with Wnt5a deletion. Additionally, we performed the single-cell RNA sequencing on the colonic tissue from the Wnt5a-deleted CAC model to characterize the composition, lineage, and functional status of immune mesenchymal cells during different stages of Colorectal Cancer (CRC) progression. Remarkably, our findings demonstrate a significant reduction in M2 macrophage polarization and Th17 phenotype upon treatment with YTE-17, leading to the restoration of regulatory T (Treg)/Th17 balance in azoxymethane (AOM)/dextran sodium sulfate (DSS) model. Furthermore, we also confirmed that YTE-17 effectively inhibited the glycolysis of Th17 cells in both direct and indirect co-culture systems with M2 macrophages. Notably, our study shed light on potential mechanisms linking the non-canonical Wnt5a/JNK signaling pathway and well-established canonical β-catenin oncogenic pathway in vivo. Specifically, we proposed that Wnt5a/JNK signaling activity in IECs promotes the development of cancer stem cells with β-catenin activity within the tumor microenvironment, involving macrophages and T cells. In summary, our study undergoes the potential of YTE-17 as a preventive strategy against CRC development by addressing the imbalance with the immune microenvironment, thereby mitigating the risk of malignancies.
Pretreatment and analysis techniques development of TKIs in biological samples for pharmacokinetic studies and therapeutic drug monitoring
Lan Chen, Yuan Zhang, Yi-Xin Zhang, Wei-Lai Wang, De-Mei Sun, Peng-Yun Li, Xue-Song Feng, Yue Tan
, Available online  , doi: 10.1016/j.jpha.2023.11.006
Tyrosine kinase inhibitors (TKIs) have emerged as the first-line small molecule drugs in many cancer therapies, exerting their effects by impeding aberrant cell growth and proliferation through the modulation of tyrosine kinase-mediated signaling pathways. However, there exists a substantial inter-individual variability in the concentrations of certain TKIs and their metabolites, which may render patients with compromised immune function susceptible to diverse infections despite receiving theoretically efficacious anticancer treatments, alongside other potential side effects or adverse reactions. Therefore, an urgent need exists for an up-to-date review concerning the biological matrices relevant to bioanalysis and the sampling methods, clinical pharmacokinetics, and therapeutic drug monitoring of different TKIs. This paper provides a comprehensive overview of the advancements in pretreatment methods, such as protein precipitation (PPT), liquid-liquid extraction (LLE), solid-phase extraction (SPE), micro-solid phase extraction (μ-SPE), magnetic solid‑phase extraction (MSPE), and vortex-assisted dispersive solid-phase extraction (VA-DSPE) achieved since 2017. It also highlights the latest analysis techniques such as newly developed highperformance liquid chromatography (HPLC) and high-resolution mass spectrometry (HRMS) methods, capillary electrophoresis (CE), gas chromatography (GC), supercritical fluid chromatography (SFC) procedures, surface plasmon resonance (SPR) assays as well as novel nanoprobes-based biosensing techniques. In addition, a comparison is made between the advantages and disadvantages of different approaches while presenting critical challenges and prospects in pharmacokinetic studies and therapeutic drug monitoring.
Modern approaches for detection of volatile organic compounds in metabolic studies focusing on pathogenic bacteria: Current state of the art
Karolina Żuchowska, Wojciech Filipiak
, Available online  , doi: 10.1016/j.jpha.2023.11.005
Pathogenic microorganisms produce numerous metabolites, including volatile organic compounds (VOCs). Monitoring these metabolites in biological matrices (e.g., urine, blood, or breath) can reveal the presence of specific microorganisms, enabling the early diagnosis of infections and the timely implementation of targeted therapy. However, complex matrices only contain trace levels of VOCs, and their constituent components can hinder determination of these compounds. Therefore, modern analytical techniques enabling the non-invasive identification and precise quantification of microbial VOCs are needed. In this paper, we discuss bacterial VOC analysis under in vitro conditions, in animal models and disease diagnosis in humans, including techniques for offline and online analysis in clinical settings. We also consider the advantages and limitations of novel microextraction techniques used to prepare biological samples for VOC analysis, in addition to reviewing current clinical studies on bacterial volatilomes that address inter-species interactions, the kinetics of VOC metabolism, and species- and drug-resistance specificity.
Antibody-platinum (IV) prodrugs conjugates for targeted treatment of cutaneous squamous cell carcinoma
Xiangye Yin, Yingjie Zhuang, Haiqin Song, Yujian Xu, Fan Zhang, Jianxin Cui, Lei Zhao, Yingjie Yu, Qixu Zhang, Jun Ye, Youbai Chen, Yan Han
, Available online  , doi: 10.1016/j.jpha.2023.11.002
Antibody-drug conjugates (ADCs) are a new type of targeting antibodies that conjugate with highly toxic anticancer drugs via chemical linkers to exert high specificity and efficient killing of tumor cells, thereby attracting considerable attention in precise oncology therapy. Cetuximab (Cet) is a typical antibody that offers the benefits of good targeting and safety for individuals with advanced and inoperable cutaneous squamous cell carcinoma (cSCC); however, its anti-tumor activity is limited to a single use. Cisplatin (CisPt) shows good curative effects; however, its adverse effects and nontumor-targeting ability are major drawbacks. In this study, we designed and developed a new ADC based on a new cytotoxic platinum (IV) prodrug (C8Pt(IV)) and Cet. The so-called antibody-platinum (IV) prodrugs conjugates, named Cet-C8Pt(IV), showed excellent tumor targeting in cSCC. Specifically, it accurately delivered C8Pt(IV) into tumor cells to exert the combined anti-tumor effect of Cet and CisPt. Herein, metabolomic analysis showed that Cet-C8Pt(IV) promoted cellular apoptosis and increased DNA damage in cSCC cells by affecting the vitamin B6 metabolic pathway in tumor cells, thereby further enhancing the tumor-killing ability and providing a new strategy for clinical cancer treatment using antibody-platinum (IV) prodrugs conjugates.
Altered synaptic currents, mitophagy, mitochondrial dynamics in Alzheimer's disease models and therapeutic potential of Dengzhan Shengmai Capsules intervention
Binbin Zhao, Dongfeng Wei, Qinghua Long, Qingjie Chen, Fushun Wang, Linlin Chen, Zefei Li, Tong Li, Tao Ma, Wei Liu, Linshuang Wang, Caishui Yang, Xiaxia Zhang, Ping Wang, Zhanjun Zhang
, Available online  , doi: 10.1016/j.jpha.2023.10.006
Emerging research suggests a potential association of progression of Alzheimer's disease (AD) with alterations in synaptic currents and mitochondrial dynamics. However, the specific associations between these pathological changes remain unclear. In this study, we utilized Aβ42-induced AD rats and primary neural cells as in vivo and in vitro models. The investigations included behavioural tests, brain magnetic resonance imaging (MRI), liquid chromatography-tandem mass spectrometry(UPLC-MS/MS) analysis, Nissl staining, thioflavin-S staining, enzyme-linked immunosorbent assay, Golgi-Cox staining, transmission electron microscopy (TEM), immunofluorescence staining, proteomics, adenosine triphosphate (ATP) detection, mitochondrial membrane potential (MMP) and reactive oxygen species (ROS) assessment, mitochondrial morphology analysis, electrophysiological studies, western blotting, and molecular docking. The results revealed changes in synaptic currents, mitophagy, and mitochondrial dynamics in the AD models. Remarkably, intervention with Dengzhan Shengmai (DZSM) capsules emerged as a pivotal element in this investigation. Aβ42-induced synaptic dysfunction was significantly mitigated by DZSM intervention, which notably amplified the frequency and amplitude of synaptic transmission. The cognitive impairment observed in AD rats was ameliorated and accompanied by robust protection against structural damage in key brain regions, including the hippocampal CA3, primary cingular cortex, prelimbic system, and dysgranular insular cortex. DZSM intervention led to increased IDE levels, augmented LTP amplitude, and enhanced dendritic spine density and length. Moreover, DZSM intervention led to favourable changes in mitochondrial parameters, including ROS expression, MMP and ATP contents, and mitochondrial morphology. In conclusion, our findings delved into the realm of altered synaptic currents, mitophagy, and mitochondrial dynamics in AD, concurrently highlighting the therapeutic potential of DZSM intervention.
The “depict” strategy for discovering new compounds in complex matrice: Lycibarbarspermidines as a case
Chen Han, Zhixin Zhang, Zhiyang Feng, Chuanjia Zhai, Xuejiao Li, Yulian Shi, Xiang Li, Miao Li, Ying Wang, Gan Luo, Xiaoyan Gao
, Available online  , doi: 10.1016/j.jpha.2023.10.007
The comprehensive detection and identification of active ingredients in complex matrices is a crucial challenge. Liquid chromatography coupled with high-resolution mass spectrometry (LC-HRMS) is the most prominent analytical platform for the exploration of novel active compounds from complex matrices. However, the LC-HRMS-based analysis workflow suffers from several bottleneck issues, such as trace content of target compounds, limited acquisition for fragment information, and uncertainty in interpreting relevant MS2 spectra. Lycibarbarspermidines are vital antioxidant active ingredients in Lycii Fructus, while the reported structures are merely focused on dicaffeoylspermidines due to their low content. To comprehensively detect the new structures of lycibarbarspermidine derivatives, a “depict” strategy was developed in this study. First, potential new lycibarbarspermidine derivatives were designed according to the biosynthetic pathway, and a comprehensive database was established, which enlarged the coverage of lycibarbarspermidine derivatives. Second, the polarity-oriented sample preparation of potential new compounds increased the concentration of the target compounds. Third, the construction of the molecular network based on the fragmentation pathway of lycibarbarspermidine derivatives broadened the comprehensiveness of identification. Finally, the weak response signals were captured by data-dependent scanning (DDA) followed by parallel reaction monitoring (PRM), and the efficiency of acquiring MS2 fragment ions of target compounds was significantly improved. Based on the integrated strategy above, 210 lycibarbarspermidine derivatives were detected and identified from Lycii Fructus, and in particular, 170 potential new compounds were structurally characterized. The integrated strategy improved the sensitivity of detection and the coverage of low-response components, and it is expected to be a promising pipeline for discovering new compound
Potentials of ribosomopathy gene as pharmaceutical targets for cancer treatment
Mengxin Wang, Stephen Vulcano, Changlu Xu, Renjian Xie, Weijie Peng, Jie Wang, Qiaojun Liu, Lee Jia, Zhi Li, Yumei Li
, Available online  , doi: 10.1016/j.jpha.2023.10.001
Ribosomopathies encompass a spectrum of disorders arising from impaired ribosome biogenesis and reduced functionality. Mutation or dysexpression of the genes that disturb any finely regulated steps of ribosome biogenesis can result in different types of ribosomopathies in clinic, collectively known as ribosomopathy genes. Emerging data suggest that ribosomopathy patients exhibit a significantly heightened susceptibility to cancer. Abnormal ribosome biogenesis and dysregulation of some ribosomopathy genes have also been found to be intimately associated with cancer development. The correlation between ribosome biogenesis or ribosomopathy and the development of malignancies has been well established. This work aims to review the recent advances in the research of ribosomopathy genes among human cancers and meanwhile, to excavate the potential role of these genes, which have not or rarely been reported in cancer, in the disease development across cancers. We plan to establish a theoretical framework between the ribosomopathy gene and cancer development, to further facilitate the potential of these genes as diagnostic biomarker as well as pharmaceutical targets for cancer treatment.
The potential of herbal drugs to treat heart failure: The roles of Sirt1/AMPK
Tao Zhang, Lei Xu, Xiaowei Guo, Honglin Tao, Yue Liu, Xianfeng Liu, Yi Zhang, Xianli Meng
, Available online  , doi: 10.1016/j.jpha.2023.09.001
Heart failure (HF) is a highly morbid syndrome that seriously affects the physical and mental health of patients and generates an enormous socio-economic burden. In addition to cardiac myocyte oxidative stress and apoptosis, which are considered mechanisms for the development of HF, alterations in cardiac energy metabolism and pathological autophagy also contribute to cardiac abnormalities and ultimately HF. Silent information regulator 1 (Sirt1) and adenosine monophosphate-activated protein kinase (AMPK) are nicotinamide adenine dinucleotide (NAD+)-dependent deacetylases and phosphorylated kinases, respectively. They play similar roles in regulating some pathological processes of the heart through regulating targets such as peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), protein 38 mitogen-activated protein kinase (p38 MAPK), peroxisome proliferator-activated receptors (PPARs), and mammalian target of rapamycin (mTOR). We summarized the synergistic effects of Sirt1 and AMPK in the heart, and listed the traditional Chinese medicines (TCM) that exhibit cardioprotective properties by modulating the Sirt1/AMPK pathway, to provide a basis for the development of Sirt1/AMPK activators or inhibitors for the treatment of HF and other cardiovascular diseases (CVDs).
Tanshinone II ameliorates energy metabolism dysfunction of pulmonary fibrosis using 13C metabolic flux analysis
Baixi Shan, Haoyan Zhou, Congying Guo, Xiaolu Liu, Mingyu Wu, Rao Zhai, Jun Chen
, Available online  , doi: 10.1016/j.jpha.2023.09.008
Evidence indicates that metabolic reprogramming characterized by the changes in cellular metabolic patterns contributes to the pathogenesis of pulmonary fibrosis (PF). It is considered as a promising therapeutic target anti-PF. The well-documented against PF properties of Tanshinone IIA (Tan IIA) have been primarily attributed to its antioxidant and anti-inflammatory potency. Emerging evidence suggests that Tan IIA may target energy metabolism pathways, including glycolysis and tricarboxylic acid (TCA) cycle. However, the detailed and advanced mechanisms underlying the anti-PF activities remain obscure. In this study, we applied [U-13C]-glucose metabolic flux analysis (MFA) to examine metabolism flux disruption and modulation nodes of Tan IIA in PF. We identified that Tan IIA inhibited the glycolysis and TCA flux, thereby suppressing the production of TGF-β1- dependent extracellular matrix and the differentiation and proliferation of myofibroblasts in vitro. We further revealed that Tan IIA inhibited the expression of key metabolic enzyme hexokinase 2 (HK2) by inhibiting phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR)/hypoxia-inducible factor 1α (HIF-1α) pathway activities, which decreased the accumulation of abnormal metabolites. Notably, we demonstrated that Tan IIA inhibited ATP citrate lyase (ACLY) activity, which reduced the collagen synthesis pathway caused by cytosol citrate consumption. Further, these results were validated in a mouse model of bleomycin-induced PF. This study was novel in exploring the mechanism of the occurrence and development of Tan ⅡA in treating PF using 13C-MFA technology. It provided a novel understanding of the mechanism of Tan IIA against PF from the perspective of metabolic reprogramming.
Targeted metabolomics reveals the aberrant energy status in diabetic peripheral neuropathy and the neuroprotective mechanism of traditional Chinese medicine JinMaiTong
Bingjia Zhao, Qian Zhang, Yiqian He, Weifang Cao, Wei Song, Xiaochun Liang
, Available online  , doi: 10.1016/j.jpha.2023.09.007
Diabetic peripheral neuropathy (DPN) is a common and devastating complication of diabetes, for which effective therapies are currently lacking. Disturbed energy status plays a crucial role in DPN pathogenesis. However, the integrated profile of energy metabolism, especially the central carbohydrate metabolism, remains unclear in DPN. Here, we developed a metabolomics approach by targeting 56 metabolites using highperformance ion chromatography-tandem mass spectrometry to illustrate the integrative characteristics of central carbohydrate metabolism in patients with DPN and streptozotocin-induced DPN rats. Furthermore, JinMaiTong (JMT), a traditional Chinese medicine (TCM) formula, was found to be effective for DPN, improving the peripheral neurological function and alleviating the neuropathology of DPN rats even after demyelination and axonal degeneration. JMT ameliorated DPN by regulating the aberrant energy balance and mitochondrial functions, including excessive glycolysis restoration, tricarboxylic acid cycle improvement, and increased adenosine triphosphate (ATP) generation. Bioenergetic profile was aberrant in cultured rat Schwann cells under high-glucose conditions, which was remarkably corrected by JMT treatment. In vivo and in vitro studies revealed that these effects of JMT were mainly attributed to the activation of AMP-activated protein kinase and downstream peroxisome proliferator-activated receptor gamma coactivator 1-alpha. Our results expand the therapeutic framework for DPN and suggest the integrative modulation of energy metabolism using TCMs, such as JMT, as an effective strategy for its treatment.
Hapln1 promotes dedifferentiation and proliferation of iPSC-derived cardiomyocytes via promoting versican-based GDF11 trapping
Ding-Jun Hao, Yue Qin, Shi-Jie Zhou, Bu-Huai Dong, Jun-Song Yang, Peng Zou, Li-Ping Wang, Yuan-Ting Zhao
, Available online  , doi: 10.1016/j.jpha.2023.09.013
Hyaluronan and proteoglycan link protein 1 (Hapln1) supports active cardiomyogenesis in zebrafish hearts, but its regulation in mammal cardiomyocytes is unclear. This study aimed to explore the potential regulation of Hapln1 in the dedifferentiation and proliferation of cardiomyocytes and its therapeutic value in myocardial infarction with human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes (CMs) and an adult mouse model of myocardial infarction. hiPSCCMs and adult mice with myocardial infarction were used as in vitro and in vivo models, respectively. Previous single-cell RNA sequencing data were retrieved for bioinformatic exploration. The results showed that recombinant human Hapln1 (rhHapln1) promotes the proliferation of hiPSC-CMs in a dose-dependent manner. As a physical binding protein of Hapln1, Versican interacted with Nodal growth differentiation factor (NODAL) and growth differentiation factor 11 (GDF11). GDF11, but not NODAL, was expressed by hiPSC-CMs. GDF11 expression was unaffected by rhHapln1 treatment. However, this molecule was required for rhHapln1-mediated activation of the transforming growth factor (TGF)-β/Drosophila mothers against decapentaplegic protein (SMAD)2/3 signaling in hiPSC-CMs, which stimulates cell dedifferentiation and proliferation. Recombinant mouse Hapln1 (rmHapln1) could induce cardiac regeneration in the adult mouse model of myocardial infarction. In addition, rmHapln1 induced human iPSC-CM proliferation. In conclusion, Hapln1 can stimulate the dedifferentiation and proliferation of iPSC-derived cardiomyocytes by promoting versican-based GDF11 trapping and subsequent activation of the TGF- β/SMAD2/3 signaling pathway. Hapln1 might be an effective hiPSC-CM dedifferentiation and proliferation agent and a potential reagent for repairing damaged hearts. Journal Pre-proof
Enhancing metformin-induced tumor metabolism destruction by glucose oxidase for triple-combination therapy
Rangrang Fan, Linrui Cai, Hao Liu, Hongxu Chen, Caili Chen, Gang Guo, Jianguo Xu
, Available online  , doi: 10.1016/j.jpha.2023.09.015
Despite decades of laboratory and clinical trials, breast cancer remains the main cause of cancer-related disease burden in women. Considering the metabolism destruction effect of metformin (Met) and cancer cell starvation induced by glucose oxidase (GOx), after their efficient delivery to tumor sites, GOx and Met may consume a large amount of glucose and produce sufficient hydrogen peroxide in situ. Herein, a pH-responsive epigallocatechin gallate (EGCG)-conjugated low-molecular-weight chitosan (LC-EGCG, LE) nanoplatform (Met-GOx/Fe@LE NPs) was constructed. The coordination between iron ions (Fe3+) and EGCG in this nanoplatform can enhance the efficacy of chemodynamic therapy via the Fenton reaction. Met-GOx/Fe@LE NPs allow GOx to retain its enzymatic activity while simultaneously improving its stability. Moreover, this pH-responsive nanoplatform presents controllable drug release behavior. An in vivo biodistribution study showed that the intracranial accumulation of GOx delivered by this nanoplatform was 3.6-fold higher than that of the free drug. The in vivo anticancer results indicated that this metabolism destruction/starvation/chemodynamic triple-combination therapy could induce increased apoptosis/death of tumor cells and reduce their proliferation. This triplecombination therapy approach is promising for efficient and targeted cancer treatment.
On-site rapid detection of multiple pesticide residues in tea leaves by lateral flow immunoassay
Junxia Gao, Tianyi Zhang, Yihua Fang, Ying Zhao, Mei Yang, Li Zhao, Ye Li, Jun Huang, Guonian Zhu, Yirong Guo
, Available online  , doi: 10.1016/j.jpha.2023.09.011
The application of pesticides (mostly insecticides and fungicides) during the teaplanting process will undoubtedly increase the dietary risk associated with drinking tea. Thus, it is necessary to ascertain whether pesticide residues in tea products exceed the maximum residue limits. However, the complex matrices present in tea samples comprise a major challenge in the analytical detection of pesticide residues. In this study, 9 types of lateral flow immunochromatographic strips (LFICSs) were developed to detect the pesticides of interest (fenpropathrin, chlorpyrifos, imidacloprid, thiamethoxam, acetamiprid, carbendazim, chlorothalonil, pyraclostrobin, and iprodione). To reduce the interference of tea substrates on the assay sensitivity, the pretreatment conditions for tea samples, including the extraction solvent, extraction time, and purification agent, were optimized for the simultaneous detection of these pesticides. The entire testing procedure (including pretreatment and detection) could be completed within 30 min. The detected results of authentic tea samples were confirmed by ultra-performance liquid chromatography-tandem mass spectrometry, which suggest that the LFICS coupled with sample rapid pretreatment can be used for on-site rapid screening of the target pesticide in tea products prior to their market release.
Ginsenoside Rk3 modulates gut microbiota and regulates immune response of group 3 innate lymphoid cells to against colorectal tumorigenesis
Xue Bai, Rongzhan Fu, Yannan Liu, Jianjun Deng, Qiang Fei, Zhiguang Duan, Chenhui Zhu, Daidi Fan
, Available online  , doi: 10.1016/j.jpha.2023.09.010
The gut microbiota plays a pivotal role in the immunomodulatory and protumorigenic microenvironment of colorectal cancer (CRC). However, the effect of ginsenoside Rk3 (Rk3) on CRC and gut microbiota remains unclear. Therefore, the purpose of this study is to explore the potential effect of Rk3 on CRC from the perspective of gut microbiota and immune regulation. Our results reveal that treatment with Rk3 significantly suppresses the formation of colon tumors, repairs intestinal barrier damage, and regulates the gut microbiota imbalance caused by CRC, including enrichment of probiotics such as Akkermansia muciniphila and Barnesiella intestinihominis, and clearance of pathogenic Desulfovibrio. Subsequent metabolomics data demonstrate that Rk3 can modulate the metabolism of amino acids and bile acids, particularly by upregulating glutamine, which has the potential to regulate the immune response. Furthermore, we elucidate the regulatory effects of Rk3 on chemokines and inflammatory factors associated with group 3 innate lymphoid cells (ILC3s) and T helper 17 (Th17) signaling pathways, and inhibits the hyperactivation of the Janus kinase-signal transducer and activator of transcription 3 (JAK-STAT3) signaling pathway. These results indicate that Rk3 modulates gut microbiota, regulates ILC3s immune response, and inhibits the JAK-STAT3 signaling pathway to suppress the development of colon tumors. More importantly, the results of fecal microbiota transplantation suggest that the inhibitory effect of Rk3 on colon tumors and its regulation of ILC3 immune responses are mediated by the gut microbiota. In summary, these findings emphasize that Rk3 can be utilized as a regulator of the gut microbiota for the prevention and treatment of CRC.
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
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.
Mapping the metabolic responses to oxaliplatin-based chemotherapy with in vivo spatiotemporal metabolomics
Mariola Olkowicz, Khaled Ramadan, Hernando Rosales-Solano, Miao Yu, Aizhou Wang, Marcelo Cypel, Janusz Pawliszyn
, Available online  , doi: 10.1016/j.jpha.2023.08.001
Adjuvant chemotherapy improves the survival outlook for patients undergoing operations for lung metastases caused by colorectal cancer (CRC). However, a multidisciplinary approach that evaluates several factors related to patient and tumour characteristics is necessary for managing chemotherapy treatment in metastatic CRC patients with lung disease, as such factors dictate the timing and drug regimen, which may affect treatment response and prognosis. In this paper, we explore the potential of spatial metabolomics for evaluating metabolic phenotypes and therapy outcomes during the local delivery of the anticancer drug, oxaliplatin, to the lung. 12 male Yorkshire pigs underwent a 3-h left lung in vivo lung perfusion (IVLP) with various doses of oxaliplatin (7.5, 10, 20, 40 and 80 mg/L), which were administered to the perfusion circuit reservoir as a bolus. Biocompatible solid-phase microextraction (SPME) microprobes were combined with global metabolite profiling to obtain spatiotemporal information about the activity of the drug, determine toxic doses that exceed therapeutic efficacy, and conduct a mechanistic exploration of associated lung injury. Mild and subclinical lung injury was observed at 40 mg/L of oxaliplatin, and significant compromise of the hemodynamic lung function was found at 80 mg/L. This result was associated with massive alterations in metabolic patterns of lung tissue and perfusate, resulting in a total of 139 discriminant compounds. Uncontrolled inflammatory response, abnormalities in energy metabolism, and mitochondrial dysfunction next to accelerated kynurenine and aldosterone production were recognized as distinct features of dysregulated metabolipidome. Spatial pharmacometabolomics may be a promising tool for identifying pathological responses to chemotherapy.
Small molecule deoxynyboquinone triggers alkylation and ubiquitination of Keap1 at Cys489 on Kelch domain for Nrf2 activation and inflammatory therapy
Ke-Gang Linghu, Tian Zhang, Guang-Tao Zhang, Peng Lv, Wen-Jun Zhang, Guan-Ding Zhao, Shi-Hang Xiong, Qiu-Shuo Ma, Ming-Ming Zhao, Meiwan Chen, Yuan-Jia Hu, Chang-Sheng Zhang, Hua Yu
, Available online  , doi: 10.1016/j.jpha.2023.07.009
Activation of Nrf2 by Keap1 alkylation plays a central role in anti-inflammatory therapy. However, activators of Nrf2 through alkylation of Keap1-Kelch domain have not been identified. Deoxynyboquinone (DNQ) is a natural small molecule discovered from marine actinomycetes. The current study was designed to investigate the anti- inflammatory effects and molecular mechanisms of DNQ via alkylation of Keap1. DNQ exhibited significant anti-inflammatory properties both in vitro and in vivo. The pharmacophore responsible for the anti-inflammatory properties of DNQ was determined to be the α, β-unsaturated amides moieties by a chemical reaction between DNQ and N-acetylcysteine. DNQ exerted anti-inflammatory effects through activation of Nrf2/ARE pathway. Keap1 was demonstrated to be the direct target of DNQ and bound with DNQ through conjugate addition reaction involving alkylation. The specific alkylation site of DNQ on Keap1 for Nrf2 activation was elucidated with a synthesized probe in conjunction with liquid chromatography-tandem mass spectrometry. DNQ triggered the ubiquitination and subsequent degradation of Keap1 by alkylation of the cysteine residue 489 (Cys489) on Keap1-Kelch domain, ultimately enabling the activation of Nrf2. Our findings revealed that DNQ exhibited potent anti-inflammatory capacity through α, β-unsaturated amides moieties active group which specifically activated Nrf2 signal pathway via alkylation/ubiquitination of Keap1-Kelch domain, suggesting the potential values of targeting Cys489 on Keap1-Kelch domain by DNQ- like small molecules in inflammatory therapies.
Chemical derivatization strategies for enhancing the HPLC analytical performance of natural active triterpenoids
Xiao-Feng Huang, Ying Xue, Li Yong, Tian-Tian Wang, Pei Luo, Lin-Sen Qing
, Available online  , doi: 10.1016/j.jpha.2023.07.004
Triterpenoids widely exist in nature, displaying a variety of pharmacological activities. Determining triterpenoids in different matrices, especially in biological samples holds great significance. HPLC has become the predominant method for triterpenoids analysis due to its exceptional analytical performance. However, due to the structural similarities among botanical samples, achieving effective separation of each triterpenoid proves challenging, necessitating significant improvements in analytical methods. Additionally, triterpenoids are characterized by a lack of UV absorption groups and chromophores, along with low ionization efficiency in mass spectrometry. Consequently, routine HPLC analysis suffers from poor sensitivity. Chemical derivatization emerges as an indispensable technique in HPLC analysis to enhance its performance. Considering the structural characteristics of triterpenoids, various derivatization reagents such as acid chlorides, rhodamines, isocyanates, sulfonic esters, and amines have been employed for the derivatization analysis of triterpenoids. This review comprehensively summarized the research progress made in derivatization strategies for HPLC detection of triterpenoids. Moreover, the limitations and challenges encountered in previous studies are discussed, and future research directions are proposed to develop more effective derivatization methods.
Pyrimethamine upregulates BNIP3 to interfere SNARE-mediated autophagosomelysosomal fusion in hepatocellular carcinoma
Jingjing Wang, Qi Su, Kun Chen, Qing Wu, Jiayan Ren, Wenjuan Tang, Yu Hu, Zeren Zhu, Cheng Cheng, Kaihui Tu, Huaizhen He, Yanmin Zhang
, Available online  , doi: 10.1016/j.jpha.2023.05.014
Hepatocellular carcinoma (HCC) is one of the most common tumor types and remains a major clinical challenge. Increasing evidence has revealed that mitophagy inhibitors can enhance the effect of chemotherapy on HCC. However, few mitophagy inhibitors have been approved for clinical use in humans. Pyrimethamine (Pyr) is used to treat infections caused by protozoan parasites. Recent studies have reported that Pyr may be beneficial in the treatment of various tumors. However, its mechanism of action is still not clearly defined. Here, we found that blocking mitophagy sensitized cells to Pyr-induced apoptosis. Mechanistically, Pyr potently induced the accumulation of autophagosomes by inhibiting autophagosome-lysosome fusion in human HCC cells. In vitro and in vivo studies revealed that Pyr blocked autophagosome-lysosome fusion by upregulating BNIP3 to inhibit SNAP29-VAMP8 interaction. Moreover, Pyr acted synergistically with sorafenib (Sora) to induce apoptosis and inhibit HCC proliferation in vitro and in vivo. Pyr enhances the sensitivity of HCC cells to Sora, a common chemotherapeutic, by inhibiting mitophagy. Thus, these results provide new insights into the mechanism of action of Pyr and imply that Pyr could potentially be further developed as a novel mitophagy inhibitor. Notably, Pyr and Sora combination therapy could be a promising treatment for malignant HCC.
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:
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.