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Ginger protects against vein graft remodeling by precisely modulating ferroptotic stress in vascular smooth muscle cell dedifferentiation
Xiaoyu Yu, Weiwei Wu, Jingjun Hao, Yuxin Zhou, Deyang Yu, Wei Ding, Xuejuan Zhang, Gaoli Liu, Jianxun Wang
, Available online  , doi: 10.1016/j.jpha.2024.101053
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Vein graft failure (VGF) is associated with vein graft (VG) intimal hyperplasia, which is characterized by abnormal accumulation of vascular smooth muscle cells (VSMCs). Most neointimal VSMCs are derived from pre-existing VSMCs via a process of VSMC phenotypic transition, also known as dedifferentiation. There is increasing evidence to suggest that ginger or its bioactive ingredients may block VSMC dedifferentiation, exerting vasoprotective functions; however, the precise mechanisms have not been fully characterized. Therefore, we investigated the effect of ginger on VSMC phenotypic transition in VG remodeling after transplantation. Ginger significantly inhibited neointimal hyperplasia and promoted lumen opening in a 3-month VG, which was primarily achieved by reducing ferroptotic stress. Ferroptotic stress is a pro-ferroptotic state. Contractile VSMCs did not die but instead gained a proliferative capacity and switched to the secretory type, forming neointima after vein transplantation. Ginger and its two main vasoprotective ingredients (6-gingerol and 6-shogaol) inhibit VSMC dedifferentiation by reducing ferroptotic stress. Network pharmacology analysis revealed that 6-gingerol inhibits ferroptotic stress by targeting P53 while 6-shogaol inhibits ferroptotic stress by targeting 5-lipoxygenase (Alox5), both promoting ferroptosis. Furthermore, both ingredients co-target peroxisome proliferator-activated receptor gamma (PPARγ), decreasing PPARγ mediated nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 1 (Nox1) expression. Nox1 promotes intracellular reactive oxygen species (ROS) production and directly induces VSMC dedifferentiation. In addition, Nox1 is a ferroptosis-promoting gene that encourages ferroptotic stress production, indirectly leading to VSMC dedifferentiation. Ginger, a natural multi-targeted ferroptotic stress inhibitor, finely and effectively prevents VSMC phenotypic transition and protects against venous injury remodeling.
Recent Advances in Bacterial Outer Membrane Vesicles: Effects on the Immune System, Mechanisms and their Usage for Tumor Treatment
Shuo Xiang, Arshad Khan, Qiufang Yao, Dong Wang
, Available online  , doi: 10.1016/j.jpha.2024.101049
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Tumor treatment remains a significant medical challenge, with many traditional therapies causing notable side effects. Recent research has led to the development of immunotherapy, which offers numerous advantages. Bacteria inherently possess motility, allowing them to preferentially colonize tumors and modulate the tumor immune microenvironment, thus influencing the efficacy of immunotherapy. Bacterial outer membrane vesicles (OMVs) secreted by gram-negative bacteria, are nanoscale lipid bilayer structures rich in bacterial antigens, pathogenassociated molecular patterns (PAMPs), various proteins, and vesicle structures. These features allow OMVs to stimulate immune system activation, generate immune responses, and serve as efficient drug delivery vehicles. This dual capability enhances the effectiveness of immunotherapy combined with chemotherapy or phototherapy, thereby improving anticancer drug efficacy. Current research has concentrated on engineering OMVs to enhance production yield, minimize cytotoxicity, and improve the safety and efficacy of treatments. Consequently, OMVs hold great promise for applications in tumor immunotherapy, tumor vaccine development, and drug delivery. This article provides an overview of the structural composition and immune mechanisms of OMVs, details various OMVs modification strategies, and reviews the progress in using OMVs for tumor treatment and their anti-tumor mechanisms. Additionally, it discusses the challenges faced in translating OMV-based anti-tumor therapies into clinical practice, aiming to provide a comprehensive understanding of OMVs' potential for in-depth research and clinical application.
Mitochondria and myocardial ischemia/reperfusion injury: Effects of Chinese herbal medicine and the underlying mechanisms
Chuxin Zhang, Xing Chang, Dandan Zhao, Yu He, Guangtong Dong, Lin Gao
, Available online  , doi: 10.1016/j.jpha.2024.101051
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Ischemic heart disease is associated with high morbidity and mortality rates. Reperfusion therapy is the best treatment option for this condition. However, reperfusion can aggravate myocardial damage through a phenomenon known as myocardial ischemia/reperfusion (I/R) injury, which has recently gained the attention of researchers. Several studies have shown that Chinese herbal medicines and their natural monomeric components exert therapeutic effects against I/R injury. This review outlines the current knowledge on the pathological mechanisms through which mitochondria participate in I/R injury, focusing on the issues related to energy metabolism, mitochondrial quality control disorders, oxidative stress, and calcium. The mechanisms by which mitochondria mediate cell death have also been discussed. To develop a resource for the prevention and management of clinical myocardial I/R damage, we compiled the most recent research on the effects of Chinese herbal remedies and their monomer components.
Oxymatrine, a novel TLR2 agonist, promotes megakaryopoiesis and thrombopoiesis through the STING/NF-ĸB pathway
Chengyang Ni, Ling Zhou, Shuo Yang, Mei Ran, Jiesi Luo, Kui Cheng, Feihong Huang, Xiaoqin Tang, Xiang Xie, Dalian Qin, Qibing Mei, Long Wang, Juan Xiao, Jianming Wu
, Available online  , doi: 10.1016/j.jpha.2024.101054
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Radiation-induced thrombocytopenia (RIT) faces a perplexing challenge in the clinical treatment of cancer patients, and current therapeutic approaches are inadequate in the clinical settings. In this researsh, oxymatrine, a new molecule capable of healing RIT was screened out, and the underlying regulatory mechanism associated with magakaryocyte (MK) differentiation and thrombopoiesis was demonstrated. The capacity of oxymatrine to induce MK differentiation was verified in K-562 and Meg-01 cells in vitro. The ability to induce thrombopoiesis was subsequently demonstrated in Tg (cd41:eGFP) zebrafish and RIT model mice. In addition, we carried out network pharmacological prediction, drug affinity responsive target stability assay (DARTS) and cellular thermal shift assay (CETSA) analyses to explore the potential targets of oxymatrine. Moreover, the pathway underlying the effects of oxymatrine was determined by Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses, Western blot, and immunofluorescence. Oxymatrine markedly promoted MK differentiation and maturation in vitro. Moreover, oxymatrine induced thrombopoiesis in Tg (cd41:eGFP) zebrafish and accelerated thrombopoiesis and platelet function recovery in RIT model mice. Mechanistically, oxymatrine directly binds to toll-like receptor 2 (TLR2) and further regulates the downstream pathway stimulator of interferon genes (STING)/nuclear factor-kappaB (NF-κB), which can be blocked by C29 and C-176, which are specific inhibitors of TLR2 and STING, respectively. Taken together, we demonstrated that oxymatrine, a novel TLR2 agonist, plays a critical role in accelerating MK differentiation and thrombopoiesis via the STING/NF-κB axis, suggesting that oxymatrine is a promising candidate for RIT therapy.
Discovery of toad-derived peptide analogue targeting ARF6 to induce immunogenic cell death for immunotherapy of hepatocellular carcinoma
Dihui Xu, Xiang Lv, Meng Yu, Ao Tan, Jiaojiao Wang, Xinyi Tang, Mengyuan Li, Wenyuan Wu, Yuyu Zhu, Jing Zhou, Hongyue Ma
, Available online  , doi: 10.1016/j.jpha.2024.101038
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Coral calcium hydride promotes peripheral mitochondrial division and reduces AT-II cells damage in ARDS via activation of the Trx2/Myo19/Drp1 pathway
Qian Li, Yang Ang, Qingqing Zhou, Min Shi, Wei Chen, Yujie Wang, Pan Yu, Bing Wan, Wanyou Yu, Liping Jiang, Yadan Shi, Zhao Lin, Shaozheng Song, Manlin Duan, Yun Long, Qi Wang, WenTao Liu, Hongguang Bao
, Available online  , doi: 10.1016/j.jpha.2024.101039
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Acute respiratory distress syndrome (ARDS) is a common respiratory emergency, but current clinical treatment remains at the level of symptomatic support and there is a lack of effective targeted treatment measures. Our previous study confirmed that inhalation of hydrogen gas can reduce the acute lung injury of ARDS, but the application of hydrogen has flammable and explosive safety concerns. Drinking hydrogen-rich liquid or inhaling hydrogen gas has been shown to play an important role in scavenging reactive oxygen species and maintaining mitochondrial quality control balance, thus improving ARDS in patients and animal models. Coral calcium hydrogenation (CCH) is a new solid molecular hydrogen carrier prepared from coral calcium (CC). Whether and how CCH affects acute lung injury in ARDS remains unstudied. In this study, we observed the therapeutic effect of CCH on lipopolysaccharide (LPS) induced acute lung injury in ARDS mice. The survival rate of mice treated with CCH and hydrogen inhalation was found to be comparable, demonstrating a significant improvement compared to the untreated ARDS model group. CCH treatment significantly reduced pulmonary hemorrhage and edema, and improved pulmonary function and local microcirculation in ARDS mice. CCH promoted mitochondrial peripheral division in the early course of ARDS by activating mitochondrial thioredoxin 2(Trx2), improved lung mitochondrial dysfunction induced by LPS, and reduced oxidative stress damage. The results indicate that CCH is a highly efficient hydrogen-rich agent that can attenuate acute lung injury of ARDS by improving the mitochondrial function through Trx2 activation.
A review on the screening methods for the discovery of natural antimicrobial peptides
Bin Yang, Hongyan Yang, Jianlong Liang, Jiarou Chen, Chunhua Wang, Yuanyuan Wang, Jincai Wang, Wenhui Luo, Tao Deng, Jialiang Guo
, Available online  , doi: 10.1016/j.jpha.2024.101046
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Natural antimicrobial peptides (AMPs) are promising candidates for the development of a new generation of antimicrobials to combat antibiotic-resistant pathogens. They have found extensive applications in the fields of medicine, food, and agriculture. However, efficiently screening AMPs from natural sources poses several challenges, including low efficiency and high antibiotic resistance. This review focuses on the action mechanisms of AMPs, both through membrane and non-membrane routes. We thoroughly examine various highly efficient AMP screening methods, including wholebacterial adsorption binding, cell membrane chromatography, phospholipid membrane chromatography binding, membrane-mediated capillary electrophoresis, colorimetric assays, thin layer chromatography, fluorescence-based screening, genetic sequencingbased analysis, computational mining of AMP databases, and virtual screening methods. Additionally, we discuss potential developmental applications for enhancing the efficiency of AMP discovery. This review provides a comprehensive framework for identifying AMPs within complex natural product systems.
Isovalerylspiramycin I alleviates liver injury and liver fibrosis by targeting the nucleotide-binding protein 2 (NUBP2)-vascular non-inflammatory molecule-1 (VNN1) pathway
Na Zhang, Weixiao Niu, Weiping Niu, Yiming Li, Simin Guo, Yang Li, Weiqing He, Hongwei He
, Available online  , doi: 10.1016/j.jpha.2024.101048
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Liver fibrosis is a vital cause of morbidity in patients with liver diseases and developing novel anti-fibrotic drugs is imperative. Isovalerylspiramycin I (ISP I) as a major component of carrimycin applied to upper respiratory infections, was first found to possess anti-fibrotic potential. The present study aims to evaluate the functions and mechanisms of ISP I in protecting against liver fibrosis. According to our results, ISP I not only reduced the expressions of fibrogenic markers in LX-2 cells but also appeared great protective effects on liver injury and liver fibrosis in bile duct ligation (BDL) rats and carbon tetrachloride (CCl4) mice. We proved that nucleotide-binding protein 2 (NUBP2) was the direct target of ISP I. ISP I through targeting NUBP2, increased the amount of vascular non-inflammatory molecule-1 (VNN1) on the cell membrane, which will inhibit oxidative stress and fibrosis. Simultaneously, the original carrimycin’s protective effect on liver damage and fibrosis was verified. Therefore, our study provides potential agents for patients with liver fibrosis-related diseases, and the clear mechanism supports wide application in the clinic.
Strategy for Cysteine-Targeting Covalent Inhibitors Screening using In-house Database based LC-MS/MS and Drug Repurposing
Xiaolan Hu, Jian-Lin Wu, Quan He, Zhi-Qi Xiong, Na Li
, Available online  , doi: 10.1016/j.jpha.2024.101045
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Targeted covalent inhibitors, primarily targeting cysteine residues, have attracted great attention as potential drug candidates due to good potency and prolonged duration of action. However, their discovery is challenging. In this research, a database-assisted liquid chromatography-tandem mass spectrometry (LC-MS/MS) strategy was developed to quickly discover potential cysteine-targeting compounds. First, compounds with potential reactive groups were selected and incubated with N-acetyl-cysteine in microsomes. And the precursor ions of possible cysteine-adducts were predicted based on covalent binding mechanisms to establish in-house database. Second, substrate-independent product ions produced from N-acetyl-cysteine moiety were selected. Third, multiple reaction monitoring scan was conducted to achieve sensitive screening for cysteine-targeting compounds. This strategy showed broad applicability, and covalent compounds with diverse structures were screened out, offering structural resources for covalent inhibitors development. Moreover, the screened compounds, norketamine and hydroxynorketamine, could modify synaptic transmission-related proteins in vivo, indicating their potential as covalent inhibitors. This experimental-based screening strategy provides a quick and reliable guidance for the design and discovery of covalent inhibitors.
Pterostilbene: A natural neuroprotective stilbene with anti-Alzheimer’s disease properties
Songlan Gao, Honglei Zhang, Na Li, Lijuan Zhang, Zhe Zhu, Changlu Xu
, Available online  , doi: 10.1016/j.jpha.2024.101043
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Alzheimer's disease (AD) is the leading cause of dementia, and no effective treatment has been developed for it thus far. Recently, the use of natural compounds in the treatment of neurodegenerative diseases has garnered significant attention owing to their minimal adverse reactions. Accordingly, the potential therapeutic effect of pterostilbene (PTS) on AD has been demonstrated in multiple in vivo and in vitro experiments. In this study, we systematically reviewed and summarized the results of these studies investigating the use of PTS for treating AD. Analysis of the literature revealed that PTS may play a role in AD treatment through various mechanisms, including anti-oxidative damage, anti-neuroinflammation, anti-apoptosis, cholinesterase activity inhibition, attenuation of β-amyloid deposition, and tau protein hyperphosphorylation. Moreover, PTS interferes with the progression of AD by regulating the activities of peroxisome proliferator-activated receptor alpha, monoamine oxidase B, Sirtuin-1, and phosphodiesterase 4A. Furthermore, to further elucidate the potential therapeutic mechanisms of PTS in AD, we employed network pharmacology and molecular docking technology to perform molecular docking of related proteins, and the obtained binding energies ranged from −2.83 kJ/mol to −5.14 kJ/mol, indicating that these proteins exhibit good binding ability with PTS. Network pharmacology analysis revealed multiple potential mechanisms of action for PTS in AD. In summary, by systematically collating and summarizing the relevant studies on the role of PTS in treatment of AD, it is anticipated that this will serve as a reference for the precise targeted prevention and treatment of AD, either using PTS or other developed drug interventions.
A high-throughput measurement of critical micelle concentrations based on absolute aggregation-caused quenching probes
Xin Ji, Aun Raza, Jianping Qi, Yi Lu, Haisheng He, Wei Wu
, Available online  , doi: 10.1016/j.jpha.2024.101044
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Phillygenin ameliorates tight junction proteins reduction, fibrosis, and apoptosis in mice with chronic colitis via TGR5-mediated PERK-eIF2α-Ca2+ pathway
Huanhuan Xue, Peijie Li, Jing Guo, Tinggui Chen, Shifei Li, Liwei Zhang
, Available online  , doi: 10.1016/j.jpha.2024.101042
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Ulcerative colitis (UC) is an idiopathic, relapsing, and etiologically complicated chronic inflammatory bowel disease. Despite substantial progress in the management of UC, the outcomes of mucosal barrier repair are unsatisfactory. In this study, phillygenin (PHI) treatment alleviated the symptoms of chronic colitis in mice, including body weight loss, severe disease activity index scores, colon shortening, splenomegaly, oxidative stress, and inflammatory response. In particular, PHI treatment ameliorated the tight junction proteins (TJs) reduction, fibrosis, apoptosis, and intestinal stem cell activity, indicating that PHI exerted beneficial effects on the intestinal mucosal barrier in mice with chronic colitis. In the NCM460 cells damage model, dextran sulfate sodium triggered the sequential induction of TJs reduction, fibrosis, and apoptosis. Takeda G protein-coupled receptor-5 (TGR5) dysfunction mediated NCM460 cell injury. Moreover, PHI treatment enhanced TJs and suppressed fibrosis and apoptosis to maintain NCM460 cell function, depending on TGR5 activation. PHI promoted TGR5 activation and elevated intracellular cyclic adenosine monophosphate levels in HEK 293T cells transfected with TGR5 expression plasmids. Cellular thermal shift assay and molecular docking studies confirmed that PHI directly binds to TGR5, indicating that PHI is an agonist of TGR5. The process of PERK-eIF2α pathway-mediated endoplasmic reticulum Ca2+ release was involved in NCM460 cell injury as well, which was associated with TGR5 dysfunction. When NCM460 cells were pretreated with PHI, the PERK-eIF2α pathway and elevated Ca2+ levels were blocked. In conclusion, our study demonstrated a novel mechanism that PHI inhibited the PERK-eIF2α-Ca2+ pathway through TGR5 activation to against DSS-induced TJs reduction, fibrosis, and apoptosis.
Development of a Smartphone-Integrated Handheld Automated Biochemical Analyzer for Point-of-Care Testing of Urinary Albumin
Ze Wu, Peng Zhang, Wei Xiao, Qian Chen, Wangrun Lin, Peipei Chen, Kangwei Chen, Qiangqiang Fu, Zhijian Wang, Lei Zheng
, Available online  , doi: 10.1016/j.jpha.2024.101041
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The level of urinary albumin is a critical indicator for the early diagnosis and management of chronic kidney disease (CKD). However, existing methods for detecting albumin are not conducive to point-of-care testing due to the complexity of reagent addition and incubation processes. This study presents a smartphone-integrated handheld automated biochemical analyzer (sHABA) designed for point-of-care testing of urinary albumin. The sHABA features a pre-loaded, disposable reagent cassette with reagents for the albumin assay arranged in the order of their addition within a hose. The smartphone-integrated analyzer can drive the reagents following a preset program, to enable automatic sequential addition. The sHABA has a detection limit for albumin of 5.9 mg/L and a linear detection range from 7 to 450 mg/L. The consistency of albumin level detection in 931 urine samples using sHABA with clinical tests indicates good sensitivity (95.78%) and specificity (90.16%). This research advances the field by providing an automated detection method for albumin in a portable device, allowing even untrained individuals to monitor CKD in real time at the patient's bedside. In the context of promoting tiered diagnosis and treatment, the sHABA has the potential to become an essential tool for the early diagnosis and comprehensive management of CKD and other chronic conditions.
Fluvoxamine: First comprehensive insights into its molecular characteristics and inclusion complexation with β-cyclodextrin
Thammarat Aree
, Available online  , doi: 10.1016/j.jpha.2024.101040
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Fluvoxamine (FXM) is a well-known selective serotonin reuptake inhibitor (SSRI) for treating depression and has recently been repurposed for efficacious treatment of coronavirus disease 2019. Although cyclodextrin (CD) encapsulation effectively improves the physicochemical properties of structurally diverse SSRIs, the molecular understanding of their associations is deficient. This comprehensive study used single-crystal X-ray diffraction integrated with density functional theory (DFT) calculation to provide deep insights into the conformationally flexible FXM and its inclusion complexation with β-CD. X-ray analysis revealed the first crystallographic evidence of the uncomplexed 3FXM-H+·3maleate- (1). Three FXM-H+ ions are counter-balanced by three planar maleate- ions to form a thin layer stabilized by infinite fused H-bond rings R44(12) and R64(16) and the interplay of π…π, CF…π and F…F interactions. For 2β-CD·2FXM-H+·maleate2-·23.2H2O (2), the tail-to-tail β-CD dimer encapsulates two FXM-H+ 4-(trifluoromethyl)phenyl moieties, which are charge- balanced by the rare non-planar maleate2- and stabilized by N/OH…O H-bonds and F…F interactions. This is a host-guest recognition pattern uniquely observed for all β-CD complexes with halogen (X)-bearing SSRIs, indicating the essence of X…X interactions and the shielding of X-containing moieties in the wall of the β-CD dimer. DFT calculations unveiled that the monomeric and dimeric β-CD-FXM complexes and FXM isomers are energetically stable, which alleviates the numbness and bitterness of the orally administered drug as previously patented. Additionally, an insightful conformational analysis of FXM emphasizes the importance of drug structural adaptation in pharmacological functions.
Tetrandrine Targeting SIRT5 Exerts Anti-melanoma Properties via Inducing ROS, ER Stress, and Blocked Autophagy
Yacong Ji, Chongyang Li, Sicheng Wan, Zhen Dong, Chaolong Liu, Leiyang Guo, Shaomin Shi, Mingxin Ci, Minghao Xu, Qian Li, Huanrong Hu, Hongjuan Cui, Yaling Liu
, Available online  , doi: 10.1016/j.jpha.2024.101036
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Tetrandrine (TET), a natural bisbenzyl isoquinoline alkaloid extracted from Stephania tetrandra Moore, has diverse pharmacological effects. However, its effects on melanoma remain unclear. Cellular proliferation assays, multi-omics analyses, and xenograft models were used to determine the effect of TET on melanoma. The direct target of TET was identified using biotin-TET pull-down LC/MS, cellular thermal shift assays, and isothermal titration calorimetry (ITC) analysis. Our findings revealed that TET treatment induced robust cellular autophagy dependent on ATF6-mediated endoplasmic reticulum (ER) stress. Simultaneously, it hindered autophagic flux by inducing cytoskeletal protein depolymerization in melanoma cells. TET treatment resulted in excessive accumulation of reactive oxygen species (ROS) and simultaneously triggered mitophagy. Sirtuin 5 (SIRT5) was ultimately found to be a direct target of TET. Mechanistically, TET led to the degradation of SIRT5 via the ubiquitin-26s proteasome system. SIRT5 knockdown induced ROS accumulation, whereas SIRT5 overexpression attenuated the TET-induced ROS accumulation and autophagy. Importantly, TET exhibited anti-cancer effects in xenograft models that relied on SIRT5 expression. This study highlights the potential of TET as an antimelanoma agent that targets SIRT5. These findings provide a promising avenue for the use of TET in melanoma treatment and underscore its potential as a therapeutic candidate.
Determination of related substances in disulfide-rich peptide ziconotide by establishing tandem mass spectrometry methods
Yuya Cheng, Peize Wu, Peng Xiao, Ming Li
, Available online  , doi: 10.1016/j.jpha.2024.101037
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Single-cell RNA sequencing reveals the changes of the pulmonary immune environment in rat after Siegesbeckia orientalis L. treatment
Fan Zhang, Shu Gan, Jingjing Liao, Ting Jiang, Zhiqiang Shi, Xueying Fan, Hiu-Yee Kwan, Zhongqiu Liu, Tao Su
, Available online  , doi: 10.1016/j.jpha.2024.101035
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Potential of natural drug modulation of endoplasmic reticulum stress in the treatment of myocardial injury
Kai Yang, Ping Zhang, Jixin Li, Genming Zhang, Xing Chang
, Available online  , doi: 10.1016/j.jpha.2024.101034
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Myocardial injury （MI） is a common occurrence in clinical practice caused by various factors such as ischemia, hypoxia, infection, metabolic abnormalities, and inflammation. Such damages are characterized by a reduction in myocardial function and cardiomyocyte death that can result in dangerous outcomes such as cardiac failure and arrhythmias. An endoplasmic reticulum stress （ERS） -induced unfolded protein response is triggered by several stressors, and its intricate signaling networks are instrumental in both cell survival and death. Cardiac damage frequently triggers ERS in response to different types of injuries and stress. High levels of ERS can exacerbate myocardial damage by inducing necrosis and apoptosis.
To target ERS in MI prevention and treatment, current medical research is focused on identifying effective therapy approaches. Traditional Chinese medicine (TCM) is frequently used because of its vast range of applications and low risk of adverse effects. Various studies have demonstrated that active components of Chinese medicines, including polyphenols, saponins, and alkaloids, can reduce myocardial cell death, inflammation, and modify the ERS pathway, thus preventing and mitigating cardiac injury.
Thus, this paper aims to provide a new direction and scientific basis for targeting ERS in MI prevention and treatment. We specifically summarize recent research progress on the regulation mechanism of ERS in MI by active ingredients of TCM.
Spatial metabolomics reveal metabolic alternations in the injured mice kidneys induced by triclocarban treatment
Peisi Xie, Jing Chen, Yongjun Xia, Zian Lin, Yu He, Zongwei Cai
, Available online  , doi: 10.1016/j.jpha.2024.101024
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Triclocarban (TCC) is a common antimicrobial agent that has been widely used in medical care. Given the close association between TCC treatment and metabolic disorders, we assessed whether long-term treatment to TCC at a human-relevant concentration could induce nephrotoxicity by disrupting the metabolic levels in a mouse model. Matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) was applied to investigate the alterations in the spatial distributions and abundances of TCC, endogenous and exogenous metabolites in the kidney after TCC treatment. The results showed that TCC treatment induced the changes in the organ weight, organ coefficient and histopathology of the mouse kidney. MSI data reveled that TCC accumulated in the all regions of the kidney, while its five metabolites mainly distributed in the cortex regions. The abundances of 79 biomolecules associated with pathways of leukotriene E4 metabolism, biosythesis and degradation of glycerophospholipids and glycerolipids, ceramide-to-sphingomyelin signaling were significantly altered in the kidney after TCC treatment. These biomolecules showed distinctive distributions in the kidney and displayed a favorable spatial correlation with the pathological damage. This work offers new insights into the related mechanisms of TCC-induced nephrotocicity and exhibits the potential of MALDI-MSI-based spatial metabolomics as a promising approach for the risk assessment of agents in medical care.
CeFe nanofibrous carbon nanozyme integrated with smartphone for the point-of-care testing of norfloxacin in water
Yue Liu, Taimei Cai, Sen Chen, Tao Wen, Hailong Peng
, Available online  , doi: 10.1016/j.jpha.2024.101023
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The overuse of antibiotics has led to the severe contamination of water bodies, posing a considerable hazard to human health. Therefore, the development of an accurate and rapid point-of-care testing (POCT) platform for the quantitative detection of antibiotics is necessary. In this study, Cerium oxide (CeO2) and Ferrosoferric oxide (Fe3O4) nanoparticles were simultaneously encapsulated into N-doped nanofibrous carbon microspheres to form of a novel nanozyme (CeFe-NCMzyme) with a porous structure, high surface area, and N-doped carbon material properties, leading to a considerable enhancement of the peroxidase (POD)-like activity compared with that of the CeO2 or Fe3O4 nanoparticles alone. The POD-like activity of CeFe-NCMzyme can be quenched using L-Cysteine (Cys) and subsequently restored by the addition of a quinolone antibiotic (norfloxacin, NOR). Therefore, CeFe-NCMzyme was used as a colorimetric sensor to detect NOR via an “On-Off” model of POD-like activity. The sensor possessed a wide linear range of 0.05-20.0 μM (R2 = 0.9910) with a detection limit of 35.70 nM. Furthermore, a smartphone-assisted POCT platform with CeFe-NCMzyme was fabricated for quantitative detection of NOR based on RGB analysis. With the use of the POCT platform, a linear range of 0.1-20.0 μM and a detection limit of 54.10 nM were obtained. The spiked recoveries in the water samples were ranged from 97.73% to 102.01%, and the sensor exhibited good accuracy and acceptable reliability. This study provides a portable POCT platform for the on-site and quantitative monitoring of quinolone antibiotics in real samples, particularly in resource-constrained settings.
Terpene extract from the stem of Celastrus orbiculatus inhibits actin cytoskeleton remodelling in gastric cancer cells by regulating the protein interaction between PTBP1 and ACTN4
Zewen Chu, Miao Zhu, Yuanyuan Luo, Yaqi Hu, Xinyi Feng, Jiacheng Shen, Haibo Wang, Masataka Sunagawa, Yanqing Liu
, Available online  , doi: 10.1016/j.jpha.2024.101021
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Adjuvant chemoradiotherapy, molecular targeted therapy, and immunotherapy are frequently employed to extend the survival of patients with advanced gastric cancer (GC). However, most of these treatments have toxic side effects, drug resistance, and limited improvements in survival and quality of life. Therefore, it is crucial to discover and develop new medications targeting GC that are highly effective and have minimal toxicity. In previous studies, the total terpene extract from the stem of Celastrus orbiculatus demonstrated anti-GC activity; however, the specific mechanism was unclear. Our research utilising co-immunoprecipitation-mass spectrometry (CoIP-MS), polypyrimidine domain-binding protein 1 (ptbp1) clustered regularly interspaced short palindromic repeat-associated protein 9 (Cas9)-knockout (KO) mouse model, tissue microarray, and functional experiments suggests that alpha actinin-4 (ACTN4) could be a significant biomarker of GC. PTBP1 influences actin cytoskeleton restructuring in GC cells by interacting with ACTN4. Celastrus orbiculatus stem extract (COE) may directly target ACTN4 and affect the interaction between PTBP1 and ACTN4, thereby exerting anti-GC effects.
Deep learning-based drug screening for the discovery of potential therapeutic agents for Alzheimer's disease
Tong Wu, Ruimei Lin, Pengdi Cui, Jie Yong, Heshui Yu, Zheng Li
, Available online  , doi: 10.1016/j.jpha.2024.101022
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Alzheimer’s disease (AD) is gradually increasing in prevalence and the complexity of its pathogenesis has led to a lengthy process of developing therapeutic drugs with limited success. Faced with this challenge, we proposed using a state-of-the-art drug screening algorithm to identify potential therapeutic compounds for AD from traditional Chinese medicine formulas with strong empirical support. We developed four deep neural network models for AD drugs screening at the disease and target levels. The AD model was trained with compounds labeled for AD activity to predict active compounds at the disease level, while the acetylcholinesterase (AChE), monoamine oxidase-A (MAO-A), and 5-hydroxytryptamine receptor 6 models were trained for specific AD targets. All four models performed excellently and were used to identify potential AD agents in the Kaixinsan formula. High-scoring compounds underwent experimental validation at the enzyme, cellular, and animal levels. Compounds like 2,4- di-tert-butylphenol and elemicin showed significant binding and inhibitory effects on AChE and MAO-A. Additionally, 13 compounds, including α-asarone, penetrated the blood-brain barrier, indicating potential brain target binding, and eight compounds enhanced microglial β-amyloid phagocytosis, aiding in clearing AD pathological substances. Our results demonstrate the effectiveness of deep learning models in developing AD therapies and provide a strong platform for AD drug discovery.
A novel strategy based on the dielectric barrier discharge plasma for rapid eliminating the carryover associated with μPESI-MS/MS system
Qian Liu, Simin Zhang, Xiangyang Qu, Yunhui Xing, Zhenwei Xiao, Shicheng Fan, Janshon Zhu, Min Huang, Huichang Bi
, Available online  , doi: 10.1016/j.jpha.2024.101017
Abstract(94) HTML Full Text PDF(7)
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In mass spectrometry (MS) analysis, carryover is a common and unavoidable problem. It causes over-estimation of analyte levels, which significantly influences accuracy and precision. Therefore, there are strict limits on carryover in MS-based assays. The conventional capillary-based electrospray ionization (ESI) restricts the use of MS for real-time monitoring, where a prompt response is crucial. Recently, we have developed a micro probe electrospray ionization (μPESI) coupled with MS (μPESI-MS) technology, enabling MS analysis within 40 seconds without a chromatographic column [1]. However, the challenge of carryover arises when trying to make the micro probe reusable for resource-saving purposes. Considering that dielectric barrier discharge (DBD) plasma is effective in degrading contaminants in water and gas [2], we hypothesized the eventual use of the DBD plasma to “wash” the micro probe. Then, a DBD plasma wash tube (DBD-WT) was introduced for rapid carryover elimination in μPESI-MS analysis.
A holistic visualization for quality of Chinese materia medica: Structural and metabolic visualization by magnetic resonance imaging
Jing Wu, Kai Zhong, Hongyi Yang, Peiliang Zhang, Nianjun Yu, Weidong Chen, Na Zhang, Shuangying Gui, Lan Han, Daiyin Peng
, Available online  , doi: 10.1016/j.jpha.2024.101019
Abstract(69) HTML Full Text PDF(12)
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The quality of Chinese materia medica (CMM) is a challenging and focused topic in the modernization of traditional Chinese medicine. A profound comprehension of the morphology, structure, active constituents, and dynamic changes during the whole process of CMM growth is essential, which needs highly precise contemporary techniques for in-depth elucidation. Magnetic resonance imaging (MRI) is a cutting- edge tool integrating the benefits of both nuclear magnetic resonance spectroscopy and imaging technology. With real-time, non-destructive, and in situ detection capabilities, MRI has been previously used for monitoring internal and external structures of plants alongside compounds during physiological processes in vivo. Here, factors involved in the holistic quality evaluation of CMMs were investigated. Given the applications of MRI in various plants, several representative CMMs were used as examples to demonstrate a methodology of quality visualization by MRI, embodying holistically monitoring the real-time macroscopic morphology, mesoscopic structure, and microscopic metabolites non-destructively in situ. Taken together, the review not only presents a pioneering application mode for utilizing MRI for CMM quality visualization but also holds promise for advancing the quality control and evaluation of CMMs.
Wheel-shaped polyoxometalates as nanozymes for autophagyaugmented and phototherapy-involved cancer nanotherapy
Jun Miao, Xiaofeng Fan, Yining Shao, Yalei Zhang, Cailing Chen, Hongrui Tian, Shujun Li, Zhiping Zheng, Xiaoqian Xu
, Available online  , doi: 10.1016/j.jpha.2024.101018
Abstract(79) HTML Full Text PDF(9)
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Optimizing lipopeptide bioactivity: The impact of non-ionic surfactant dressing
Ágnes Ábrahám, Gergő Gyulai, Judith Mihály, Andrea Horváth, Orsolya Dobay, Zoltán Varga, Éva Kiss, Kata Horváti
, Available online  , doi: 10.1016/j.jpha.2024.101020
Abstract(39) HTML Full Text PDF(2)
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The aim of the research is to increase the applicability of lipopeptides as drugs. To this end, non-ionic triblock copolymers, namely poloxamers, were applied. The physicochemical properties of poloxamers vary depending on the length of the blocks, so different types were experimented with. Systems containing different additives were systematically investigated, and the change in the critical micelle concentration of the poloxamers at 25 and 37 ℃ in different media was assessed. In addition, the cytotoxicity of the different poloxamer micelles on three different cell lines was evaluated, and based on the results, Plur104, Plur123, and Plur127 were selected. Fatty acid elongated derivatives of a short antibacterial peptide (pL1), a medium-sized anticancer peptide (pCM15), and a branched-chain vaccine antigen (pATIPC) were used as lipopeptide models, and their formulations with the selected poloxamers were investigated. The solubility and homogeneity of the lipopeptides were significantly increased, and dynamic light scattering (DLS) measurements showed the formation of small particles of around 20 nm, which were well reproducible and storable. Similar homogenous micelle formation was observed after freeze-drying and reconstitution. The pL1 lipopeptide, formulated with the selected poloxamers, exhibited enhanced antibacterial activity with significantly reduced haemolytic side effects. The pCM15 peptide, when incorporated into poloxamer micelles, showed significantly enhanced cytotoxicity against tumor cells. Additionally, the internalization rate of pATIPC peptide formulated with poloxamers by antigen-presenting model cells exceeded that of the unformulated peptide. Our results demonstrate the potential of poloxamers as promising tools for the formulation of lipopeptides and for the optimization of their selectivity.
Rapid Toxicity Characterization of Aconitum Herbal Medicines using Perfusion Nano-electrospray Ionization Mass Spectrometry
Chaofa Wei, Liping Kang, Yaqiu Zhao, Li Zhou, Xiang Li, Shuanglong Wang, Luqi Huang, Zidong Qiu
, Available online  , doi: 10.1016/j.jpha.2024.101016
Abstract(59) HTML Full Text PDF(9)
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Comparative study of trastuzumab modification analysis using mono/multi-epitope affinity technology with LC-QTOF-MS
Chengyi Zuo, Jingwei Zhou, Sumin Bian, Qing Zhang, Yutian Lei, Yuan Shen, Zhiwei Chen, Peijun Ye, Leying Shi, Mao Mu, Jia-Huan Qu, Zhengjin Jiang, Qiqin Wang
, Available online  , doi: 10.1016/j.jpha.2024.101015
Abstract(71) HTML Full Text PDF(6)
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Dynamic tracking analysis of monoclonal antibodies (mAbs) biotransformation in vivo is crucial, as certain modifications could inactivate the protein and reduce drug efficacy. However, a particular challenge (i.e. immune recognition deficiencies) in biotransformation studies may arise when modifications occur at the paratope recognized by the antigen. To address this limitation, a multi-epitope affinity technology utilizing the MOF@Au@peptide@aptamer composite material was proposed and developed by simultaneously immobilizing complementarity determining region (CDR) mimotope peptide (HH24) and non-CDR mimotope aptamer (CH1S-6T) onto the surface of MOF@Au nanocomposite. Comparative studies demonstrated that MOF@Au@peptide@aptamer exhibited significantly enhanced enrichment capabilities for trastuzumab variants in comparison to mono-epitope affinity technology. Moreover, the higher deamidation ratio for LC-Asn-30 and isomerization ratio for HC-Asn-55 can only be monitored by the novel bioanalytical platform based on MOF@Au@peptide@aptamer and LC-QTOF-MS. Therefore, multi-epitope affinity technology could effectively overcome the biases of traditional affinity materials for key sites modification analysis of mAb. Particularly, the novel bioanalytical platform can be successfully used for the tracking analysis of trastuzumab modifications in different biological fluids. Compared to the spiked PB model, faster modification trends were monitored in the spiked serum and patients’ sera due to the catalytic effect of plasma proteins and relevant proteases. Differences in peptide modification levels of trastuzumab in patients’ sera were also monitored. In summary, the novel bioanalytical platform based on the multi-epitope affinity technology holds great potentials for in vivo biotransformation analysis of mAb, contributing to improved understanding and paving the way for future research and clinical applications.
Formulation, Characterization, and Evaluation of CurcuminLoaded Ginger-Derived Nanovesicles for Anti-Colitis Activity
Shengjie Huang, Min Zhang, Xiaoge Li, Jierong Pei, Zhirong Zhou, Peng Lei, Meng Wang, Peng Zhang, Heshui Yu, Guanwei Fan, Lifeng Han, Haiyang Yu, Yuefei Wang, Miaomiao Jiang
, Available online  , doi: 10.1016/j.jpha.2024.101014
Abstract(36) HTML Full Text PDF(5)
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Plant-derived nanovesicles have gained attention given their similarity to mammalian exosomes and advantages such as low cost, sustainability, and tissue targeting. Thus, they hold promise for disease treatment and drug delivery. In this study, we proposed a time-efficient method, PEG 8000 combined with sucrose density gradient centrifugation to prepare ginger-derived nanovesicles (GDNVs). Subsequently, curcumin (CUR) was loaded onto GDNV by ultrasonic incubation. The optimum conditions for ginger-derived nanovesicles loaded with curcumin (CG) were ultrasound time of 3 min, a carrier-to-drug ratio (GDNV:CUR) of 1:1. The study achieved a high loading capacity (94.027 ± 0.0944%) and encapsulation efficiency (89.300 ± 0.3437% ). Finally, the drugs' in vivo distribution and anti-colitis activity were investigated in mice. CG was primarily distributed in the colon after oral administration. Compared to CUR and GDNV, CG was superior in improving disease activity, colon length, liver and spleen coefficients, myeloperoxidase activity, and biochemical factor levels in ulcerative colitis (UC) mice. In addition, CG plays a protective role against UC by modulating serum metabolite levels and gut flora. In summary, our study demonstrated that GDNV can be used for CUR delivery with enhanced therapeutic potential.
Epigenetic regulation of targeted ferroptosis: a new strategy for drug development
Shengli Ouyang, Zeyao Zeng, Jieyi He, Lianxiang Luo
, Available online  , doi: 10.1016/j.jpha.2024.101012
Abstract(64) HTML Full Text PDF(8)
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Ferroptosis is a newly discovered form of cell death that is influenced by iron levels and is triggered by cellular metabolism and excessive lipid peroxidation. Epigenetic regulation plays a crucial role in the development and progression of diseases, making it essential to understand these mechanisms in order to identify potential targets for drug development and clinical treatment. The intersection of ferroptosis and epigenetics has opened up new avenues for research in drug development, offering innovative strategies for combating diseases. Recent studies have shown that epigenetic modifications can impact pathways related to ferroptosis, potentially leading to organ dysfunction. Despite the increasing focus on this relationship, the role of epigenetic regulation in drug development remains largely unexplored. This article explores current research on the interplay between epigenetic regulation and ferroptosis, delving into their regulatory mechanisms and discussing the effects of existing epigenetic modification regulators on diseases. Additionally, we highlight ongoing research on epigenetic factors involved in targeting ferroptosis in cancer, providing new insights for the development of cancer treatments.
Green analytical chemistry metrics for evaluating the greenness of analytical procedures
Lei Yin, Luyao Yu, Yingxia Guo, Chuya Wang, Yuncheng Ge, Xinyue Zheng, Ning Zhang, Jiansong You, Yong Zhang, Meiyun Shi
, Available online  , doi: 10.1016/j.jpha.2024.101013
Abstract(100) HTML Full Text PDF(11)
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Green analytical chemistry (GAC) focuses on mitigating the adverse effects of analytical activities on human safety, human health and environment. In addition to the 12 principles of GAC, proper GAC tools should be developed and employed to assess the greenness of different analytical assays. 15 widely used GAC metrics, i.e., national environmental methods index (NEMI), advanced NEMI, assessment of green profile (AGP), chloroform-oriented toxicity estimation scale (ChlorTox Scale), Analytical Eco-Scale, Green Certificate Modified Eco-Scale, analytical method greenness score (AMGS), green analytical procedure index (GAPI), ComplexGAPI, red-green-blue (RGB) additive color model, red-green-blue (RGB) 12 algorithm, analytical greenness calculator (AGREE), AGREE preparation (AGREEprep), Hexagon, and blue applicability grade index (BAGI), are selected as the typical tools. This article comprehensively presents and elucidates the principles, characteristics, merits, and demerits of 15 widely used GAC tools. This review is helpful for researchers to use the current GAC metrics to assess the environmental sustainability of analytical assays.
Cirsium japonicum mitigates allergic nasal inflammation by regulating NRF2-mediated mucin production: systematic transcriptome and molecular docking analyses
Bo-Jeong Pyun, Su-Jin Baek, Kyuhyung Jo, Ik Soo Lee, Musun Park, Hye Jin Kim, Joo Young Lee, Susanna Choi, Yun Hee Kim, Taesoo Kim
, Available online  , doi: 10.1016/j.jpha.2024.101000
Abstract(132) HTML Full Text PDF(14)
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Characterization of extracellular vesicles by capillary zone electrophoresis: A novel concept for characterization of a next-generation drug delivery platform
Aleksandra Steć, Andrea Heinz, Szymon Dziomba
, Available online  , doi: 10.1016/j.jpha.2024.101004
Abstract(81) HTML Full Text PDF(2)
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Extracellular vesicles (EVs) are a part of a cell-to-cell communication system of prokaryotic and eukaryotic organisms. Their ability to penetrate biological barriers and to transfer molecules between cells shows their potential as a novel class of drug delivery platform. However, because of the great heterogeneity of EVs and the complexity of biological matrices from which they are typically isolated, reliable quality control procedures need to be established to ensure their safety for medical use. According to current recommendations, quantification of EVs, confirmation of their identity, and purity assessment require the use of several analytical techniques, including particle-size distribution analysis, proteomics, and electron microscopy, making the characterization process demanding. Capillary electrophoresis (CE) has recently emerged as an alternative tool for EV characterization. In this study, the available literature on this novel concept for EV characterization was reviewed. Its performance was critically evaluated and compared with currently used methods. The utility of CE in the quality control of EV-based medicines was discussed.
Tumor microenvironment-responsive hyperbranched polymers for controlled drug delivery
Yuqiong Guo, Xinni He, Gareth R. Williams, Yue Zhou, Xinying Liao, Ziyi Xiao, Cuiyun Yu, Yang Liu
, Available online  , doi: 10.1016/j.jpha.2024.101003
Abstract(64) HTML Full Text PDF(2)
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Hyperbranched polymers (HBPs) have drawn great interest in the biomedical field on account of their special morphology, low viscosity, self-regulation and facile preparation methods. Moreover, their large intramolecular cavities, high biocompatibility, biodegradability, and targeting properties render them very suitable for anti-tumor drug delivery. Recently, exploiting the specific characteristics of the tumor microenvironment, a range of multifunctional HBPs responsive to the tumor microenvironment have emerged. By further introducing various types of drugs through physical embedding or chemical coupling, the resulting HBPs based delivery systems have played a crucial part in improving drug stability, increasing effective drug concentration, decreasing drug toxicity and side effects, and enhancing anti-tumor effect. Here, based on different types of tumor microenvironment stimulation signals such as pH, redox, temperature, etc., we systematically review the preparation and response mechanism of HBPs, summarize the latest advances in drug delivery applications, and analyze the challenges and future research directions for such nanomaterials in biomedical clinical applications.
Clinically and orally compatible formulation-manufactured DDX5 (p68)-targeting molecular glue FL118 products exhibit low toxicity but high efficacy against human cancer
Xiang Ling, Wenjie Wu, Li Yan, Leslie Curtin, Melanie M. Farrauto, Sandra Sexton, Anmbreen Jamroze, Changjun Yu, Christos Fountzilas, Dean G. Tang, Fengzhi Li
, Available online  , doi: 10.1016/j.jpha.2024.101001
Abstract(83) HTML Full Text PDF(9)
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Investigation of oligomeric proanthocyanidins extracted from Rhodiolae Crenulatae Radix et Rhizomes using deep eutectic solvents and identified via data-dependentacquisition mass-spectroscopy
Li Jia, Liming Wang, Xiaoxiao Zhang, Qingrui Zhang, Peng Lei, Yanxu Chang, Lifeng Han, Xin Chai, Wenzhi Yang, Yuefei Wang, Miaomiao Jiang
, Available online  , doi: 10.1016/j.jpha.2024.101002
Abstract(64) HTML Full Text PDF(14)
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In this study, 34 deep eutectic solvents were successfully prepared for the extraction of proanthocyanidin from Rhodiolae Crenulatae Radix et Rhizomes. The extraction process was optimized using single factor exploration and Box-Behnken design- response surface analysis. The extraction rate was significantly improved when the molar ratio of choline chloride to 1,3-propanediol was 1:3.5 and the water content was 30% (V/V) in deep eutectic solvents. AB-8 macroporous resin and ethyl acetate were used for separation and refining, and the oligomer-rich proanthocyanidin components were eventually obtained. The ultraviolet (UV) and infrared spectrometer (IR) spectra showed that the proanthocyanidins were mainly composed of catechin and epicatechin. To further clarify the chemical composition of proanthocyanidin, an ion scan list containing 156 proanthocyanidins precursors was obtained by constructing a proanthocyanidins structural library and mass defect filtering algorithm, combined with the Full mass spectrometry (MS)/dd-MS2 scan mode that turns on the “if idle pick others” function. By using Ultra high performance liquid chromatography & High-resolution mass spectrometer (UHPLC/Orbitrap MS), the analysis used both targeted and non- targeted methods to detect proanthocyanidins. Finally, 50 oligomeric proanthocyanidin compounds were identified, including 7 monomers, 22 dimers, 20 trimers, and 1 tetramer, most of which were procyanidins of proanthocyanidins (84%), and a small amount of prodelphinidin (14%) and other types of proanthocyanidins (2%), which enabled the systematic characterization of proanthocyanidin components from Rhodiolae Crenulatae Radix et Rhizomes. Meanwhile, the comparison with the grape seeds oligomeric proanthocyanidins standard (United States Pharmacopoeia) revealed that the proanthocyanidins in Rhodiolae Crenulatae Radix et Rhizomes were more abundant, suggesting that the proanthocyanidins in Rhodiolae Crenulatae Radix et Rhizomes has promising applications.
Circulating Memory T Cells and TCF1+ T Cells Aid in Diagnosis and Monitor Disease Activity in Vitiligo
Xinju Wang, Jianru Chen, Wei Wu, Jinrong Fan, Luling Huang, Weiwei Sun, Kaiqiao He, Shuli Li, Chunying Li
, Available online  , doi: 10.1016/j.jpha.2024.100998
Abstract(38) HTML Full Text PDF(6)
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Vitiligo is an immune memory skin disease. T-cell factor 1 (TCF1) is essential for maintaining the maintenance of the memory T-cell pool. There is an urgent need to investigate the characteristics of peripheral memory T-cell profile and TCF1+ T-cell frequencies in patients with vitiligo patients. In this study, 31 patients with active vitiligo (AV), 22 with stable vitiligo (SV), and 30 healthy controls (HCs) were included. We measured circulating memory and TCF1+ T-cell frequencies using by flow cytometry. The Spearman’s rank test was used to evaluate the correlation correlations between cell frequencies and disease characteristics. Receiver operating characteristic curves (ROC) were constructed to investigate the discriminative power of the cell subpopulations. Circulating CD4+ and CD8+ terminally differentiated effector memory T-cell (TEMRA) frequencies were significantly higher in the AV group than in compared to HCs (P < 0.05). TCF1+ T-cell subpopulations were widespread increased in patients with vitiligo patients (P < 0.05). After adjusting adjustment for potential confounders, CD8+ and CD4+ central memory (TCM) cells, and CD8+ TEMRA were correlated with disease activity (P < 0.05). The combined diagnostic value of the four (naïve naive, effector memory, TCM, and TEMRA) CD8+TCF1+ T-cell subsets was relatively high (area under the ROC curve [AUC]AUC = 0.804, sensitivity = 71.70%, specificity = 83.34%), and the CD8+ T-cell subsets combination performed well in discriminating disease activity (AUC = 0.849, sensitivity = 70.97%, specificity = 90.91%). We demonstrated an altered circulating memory T-cell profile and increased TCF1+ T-cell percentage percentages in patients with vitiligo patients. T-cell subpopulations had a strong value values for vitiligo diagnosis and activity evaluation. This evidence presents a potential new pharmacological target for inhibiting to inhibit the autoimmunity that leads leading to vitiligo disease activity.
Multidimensional screening of Astragalus membranaceus small molecules to mitigate carbon ion radiation-induced bystander effects
Liying Zhang, Yiming Zhang, Yangyang Li, Qiyang Li, Shangzu Zhang, Zhiming Miao, Jinpeng He, Ting Zhou, Gengqiang Yang, Xin Wang, Jufang Wang, Yongqi Liu
, Available online  , doi: 10.1016/j.jpha.2024.100999
Abstract(40) HTML Full Text PDF(11)
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Optical biosensing of monkeypox virus using novel recombinant silica-binding proteins for site-directed antibody immobilization
Xixi Song, Ying Tao, Sumin Bian, Mohamad Sawan
, Available online  , doi: 10.1016/j.jpha.2024.100995
Abstract(55) HTML Full Text PDF(7)
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The efficient immobilization of capture antibodies is crucial for timely pathogen detection during global pandemic outbreaks. Therefore, we proposed a silica-binding protein featuring core functional domains (cSP). It comprises a peptide with a silica-binding tag designed to adhere to silica surfaces and tandem protein G fragments for effective antibody capture. This innovation facilitates precise site-directed immobilization of antibodies onto silica surfaces. We applied cSP to silica-coated optical fibers, creating a fiber-optic biolayer interferometer (FO-BLI) biosensor capable of monitoring the Monkeypox Virus (MPXV) Protein A29L in spiked clinical samples to rapidly detect the MPXV. The cSP-based FO-BLI biosensor for MPXV demonstrated a limit of detection (LOD) of 0.62 ng/mL in buffer, comparable to the 0.52 ng/mL LOD achieved using a conventional streptavidin-based FO-BLI biosensor. Furthermore, it achieved LODs of 0.77 ng/mL in spiked serum and 0.80 ng/mL in spiked saliva, exhibiting no cross-reactivity with other viral antigens. The MPXV detection process was completed within 14 min. We further proposed a cSP-based multi-virus biosensor strategy capable of detecting various pandemic strains, such as MPXV, the latest coronavirus disease (COVID) variants, and influenza A protein, to extend its versatility. The proposed cSP-modified FO-BLI biosensor has a high potential for rapidly and accurately detecting MPXV antigens, making valuable contributions to epidemiological studies.
miR-135b: an emerging player in cardio-cerebrovascular diseases
Yingchun Shao, Jiazhen Xu, Wujun Chen, Minglu Hao, Xinlin Liu, Renshuai Zhang, Yanhong Wang, Yinying Dong
, Available online  , doi: 10.1016/j.jpha.2024.100997
Abstract(73) HTML Full Text PDF(3)
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miR-135 is a highly conserved miRNA in mammals and includes miR-135a and miR-135b. Recent studies have shown that miR-135b is a key regulatory factor in cardio-cerebrovascular diseases. It is involved in regulating the pathological process of myocardial infarction, myocardial ischemia/reperfusion injury, cardiac hypertrophy, atrial fibrillation, diabetic cardiomyopathy, atherosclerosis, pulmonary hypertension, cerebral ischemia/reperfusion injury, Parkinson's disease, and Alzheimer's disease. Obviously, miR-135b is an emerging player in cardio-cerebrovascular diseases and is expected to be an important target for the treatment of cardio-cerebrovascular diseases. However, the crucial role of miR-135b in cardio-cerebrovascular diseases and its underlying mechanism of action has not been reviewed. Therefore, in this review, we aimed to comprehensively summarize the role of miR-135b and the signaling pathway mediated by miR-135b in cardio-cerebrovascular diseases. Drugs targeting miR-135b for the treatment of diseases and related patents, highlighting the importance of this target and its utility as a therapeutic target for cardio-cerebrovascular diseases, have been discussed.
Machine learning-driven optimization of mRNA-lipid nanoparticle vaccine quality with XGBoost/Bayesian method and ensemble model approaches
Ravi Maharjan, Ki Hyun Kim, Kyeong Lee, Hyo-Kyung Han, Seong Hoon Jeong
, Available online  , doi: 10.1016/j.jpha.2024.100996
Abstract(14) HTML Full Text PDF(4)
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To enhance the efficiency of vaccine manufacturing, this study focuses on optimizing the microfluidic conditions and lipid mix ratios of messenger RNA - lipid nanoparticles (mRNA-LNP). Different mRNA - LNP formulations (n = 24) were developed using an I - optimal design, where machine learning tools (XGBoost/Bayesian optimization and self - validated ensemble (SVEM)) were used to optimize the process and predict lipid mix ratio. The investigation included material attributes, their respective ratios, and process attributes. The critical responses like particle size (PS), polydispersity index (PDI), Zeta potential, pKa, heat trend cycle, encapsulation efficiency (EE), recovery ratio, and encapsulated mRNA were evaluated. Overall prediction of SVEM (> 97%) was comparably better than that of XGBoost/Bayesian optimization (> 94%). Moreover, in actual experimental outcomes, SVEM prediction is close to the actual data as confirmed by the experimental PS (94∼96 nm) is close to the predicted one (95~97 nm). The other parameters including PDI and EE were also close to the actual experimental data.
Software-aided efficient identification of the components of compound formulae and their metabolites in rats by UHPLC/IM-QTOF-MS and an in-house high-definition MS2 library: Sishen Formula as a case
Lili Hong, Wei Wang, Shiyu Wang, Wandi Hu, Yuyang Sha, Xiaoyan Xu, Xiaoying Wang, Kefeng Li, Hongda Wang, Xiumei Gao, Dean Guo, Wenzhi Yang
, Available online  , doi: 10.1016/j.jpha.2024.100994
Abstract(39) HTML Full Text PDF(4)
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Identifying the compound formulae-related xenobiotics in bio-samples is full of challenges. Conventional strategies always exhibit the insufficiencies in overall coverage, analytical efficiency, and degree of automation, and the results highly rely on the personal knowledge and experience. The goal of this work was to establish a software-aided approach, by integrating ultra-high performance liquid chromatography/ion-mobility quadrupole time-of-flight mass spectrometry and in-house high-definition MS2 library, to enhance the identification of prototypes and metabolites of the compound formulae in vivo, taking Sishen formula (SSF) as a template. Seven different MS2 acquisition methods were compared, which demonstrated the potency of a hybrid scan approach (namely HDDIDDA) in the identification precision, MS1 coverage, and MS2 spectra quality. The HDDIDDA data for 55 reference compounds, four component drugs, and SSF, together with the rat bio-samples (e.g., plasma, urine, feces, liver, and kidney), were acquired. Based on the UNIFITM platform (Waters), the efficient data processing workflows were established by combining mass defect filtering (MDF)-induced classification, diagnostic product ions (DPIs), and neutral loss filtering (NLF)-dominated structural confirmation. The high-definition MS2 spectral libraries, dubbed in vitro-SSF and in vivo-SSF, were elaborated, enabling the efficient and automatic identification of SSF-associated xenobiotics in diverse rat bio-samples. Consequently, 118 prototypes and 206 metabolites of SSF were identified, with the identification rate reaching 80.51% and 79.61%, respectively. The metabolic pathways mainly involved the oxidation, reduction, hydrolysis, sulfation, methylation, demethylation, acetylation, glucuronidation, and the combined reactions. Conclusively, the proposed strategy can drive the identification of compound formulae-related xenobiotics in vivo in an intelligent manner.
“Small is beautiful”-examining reliable determination of low-abundant therapeutic antibody glycovariants
Katharina Böttinger, Christof Regl, Veronika Schäpertöns, Erdmann Rapp, Therese Wohlschlager, Christian G. Huber
, Available online  , doi: 10.1016/j.jpha.2024.100982
Abstract(51) HTML Full Text PDF(4)
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Glycans associated with biopharmaceutical drugs play crucial roles in drug safety and efficacy, and therefore, their reliable detection and quantification is essential. Our study introduces a multi-level quantification approach for glycosylation analysis in monoclonal antibodies, focusing on minor abundant glycovariants. Mass spectrometric data is evaluated mainly employing open-source software tools. Released N-glycan and glycopeptide data form the basis for integrating information across different structural levels up to intact glycoproteins. Comprehensive comparison showed that indeed, variations across structural levels were observed especially for minor abundant species. Utilizing MoFi (short for modification finder), a tool for annotating mass spectra of intact proteins, we quantify isobaric glycosylation variants at the intact protein level. Our workflow's utility is demonstrated on NISTmAb, rituximab and adalimumab, profiling their minor abundant variants for the first time across diverse structural levels. This study enhances understanding and accessibility in glycosylation analysis, spotlighting minor abundant glycovariants in therapeutic antibodies.
Increasing the tumour targeting of antitumour drugs through anlotinib-mediated modulation of the extracellular matrix and the RhoA/ROCK signalling pathway
Xuedan Han, Jialei Liu, Yidong Zhang, Eric Tse, Qiyi Yu, Yu Lu, Yi Ma, Lufeng Zheng
, Available online  , doi: 10.1016/j.jpha.2024.100984
Abstract(91) HTML Full Text PDF(14)
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Anlotinib has strong antiangiogenic effects and leads to vessel normalization. However, the "window period" characteristic in regulating vessel normalization by anlotinib cannot fully explain the long-term survival benefits achieved through combining it with other drugs. In this study, through RNA sequencing and label-free quantitative proteomics analysis, we discovered that anlotinib regulated the expression of components of the extracellular matrix (ECM), leading to a significant reduction in ECM stiffness. Our bioinformatic analysis revealed a potential positive relationship between the ECM pathway and gefitinib resistance, poor treatment outcomes for programmed death 1 (PD-1) targeting, and unfavourable prognosis following chemotherapy in lung cancer patients. We administered anlotinib in combination with these antitumour drugs and visualized their distribution using fluorescent labelling in various tumour types. Notably, our results demonstrated that anlotinib prolonged the retention time and distribution of antitumour drugs at the tumour site. Moreover, the combination therapy induced notable loosening of the tumour tissue structure. This reduction was associated with decreased interstitial fluid pressure and tumour solid pressure. Additionally, we observed that anlotinib effectively suppressed the RhoA/ROCK signalling pathway. These findings suggest that, in addition to its antiangiogenic and vessel normalization effects, anlotinib can increase the distribution and retention of antitumour drugs in tumours by modulating ECM expression and physical properties through the RhoA/ROCK signalling pathway. These valuable insights contribute to the development of combination therapies aimed at improving tumour targeting in cancer treatment.
Advances in surface plasmon resonance for analyzing active components in traditional Chinese medicine
XIE Jing, LI Xian-deng, LI Mi, ZHU Hong-yan, CAO Yan, ZHANG Jian, XU A-jing
, Available online  , doi: 10.1016/j.jpha.2024.100983
Abstract(89) HTML Full Text PDF(7)
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The surface plasmon resonance (SPR) biosensor technology is a novel optical analysis method for studying intermolecular interactions. Owing to in-depth research on Traditional Chinese Medicine (TCM) in recent years, comprehensive and specific identification of components and target interactions have become key yet difficult tasks. SPR has gradually been used to analyze the active components of TCM owing to its high sensitivity, strong exclusivity, large flux, and real-time monitoring capabilities. This review sought to briefly introduce the active components of TCM and the principle of SPR, and provide historical and new insights into the application of SPR in the analysis of the active components of TCM.
Dual-targeted halofuginone hydrobromide nanocomplexes for promotion of macrophage repolarization and apoptosis of rheumatoid arthritis fibroblast-like synoviocytes in adjuvant-induced arthritis in rats
Junping Zhu, Ye Lin, Gejing Li, Yini He, Zhaoli Su, Yuanyuan Tang, Ye Zhang, Qian Xu, Zhongliu Yao, Hua Zhou, Bin Liu, Xiong Cai
, Available online  , doi: 10.1016/j.jpha.2024.100981
Abstract(98) HTML Full Text PDF(12)
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Rheumatoid arthritis (RA) is a prevalent autoimmune disease characterized by chronic inflammation and excessive proliferation of the synovium. Currently, treatment options focus on either reducing inflammation or inhibiting synovial hyperplasia. However, these modalities are unsatisfactory in achieving the desired therapeutic outcomes. Halofuginone hydrobromide (HF), an herbal active ingredient, has demonstrated pharmacological effects of both anti-inflammation and inhibition of synovial hyperplasia proliferation. However, HF's medical efficacy is limited due to its poor water solubility, short half-life, and non-target toxicity. In the current study, by using the advantages of nanotechnology, we presented a novel dual-targeted nanocomplex, termed HA-M@P@HF NPs, which consisted of a hyaluronic acid (HA)-modified hybrid membrane (M)-camouflaged poly lactic-co-glycolic acid (PLGA) nanosystem for HF delivery. These nanocomplexes not only overcame the limitations of HF but also achieved simultaneous targeting of inflammatory macrophages and human fibroblast-like synoviocytes-rheumatoid arthritis (HFLS-RA). In vivo experiments demonstrated that these nanocomplexes effectively suppressed immune-mediated inflammation and synovial hyperplasia, safeguarding against bone destruction in rats with adjuvant-induced arthritis (AIA). Remarkable anti-arthritic effects of these nanocomplexes were accomplished through promoting repolarization of M1-to-M2 macrophages and apoptosis of HFLS-RA, thereby offering a promising therapeutic strategy for RA.
Targeting NTCP for liver disease treatment: A promising strategy
Xin Tan, , Yu Xiang, Jianyou Shi, Lu Chen, Dongke Yu
, Available online  , doi: 10.1016/j.jpha.2024.100979
Abstract(60) HTML Full Text PDF(4)
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The sodium taurocholate co-transporting polypeptide (NTCP), a bile acids transporter, has been identified as a new therapeutic target for the treatment of liver disease. This paper thoroughly investigates the function of NTCP for regulating bile acid regulation, its correlation with hepatitis B and D infections, and its association with various liver diseases. Additionally, in this review we examine recent breakthroughs in creating NTCP inhibitors and their prospective applications in liver disease treatment. While this review emphasizes the promising potential of targeting NTCP, it concurrently underscores the need for broader and more detailed research to fully understand the long-term implications and potential side effects associated with NTCP inhibition.
Emerging role of Jumonji domain-containing protein D3 (JMJD3) in inflammatory diseases
Xiang Li, Ru-Yi Chen, Jin-Jin Shi, Chang-Yun Li, Yan-Jun Liu, Chang Gao, Ming-Rong Gao, Shun Zhang, Jian-Fei Lu, Jia-Feng Cao, Guan-Jun Yang, Jiong Chen
, Available online  , doi: 10.1016/j.jpha.2024.100978
Abstract(84) HTML Full Text PDF(2)
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Jumonji domain-containing protein D3 (JMJD3) is a 2-oxoglutarate-dependent dioxygenase that specifically removes transcriptional repression marks di- and tri- 6 methylated groups from lysine 27 on histone (H3K27me2/3). The erasure of these 7 marks leads to the activation of some associated genes, thereby influencing various biological processes, such as development, differentiation, and immune response. However, comprehensive descriptions regarding the relationship between JMJD3 and inflammation are lacking. Here, we provide a comprehensive overview of JMJD3, including its structure, functions, and involvement in inflammatory pathways. In addition, we summarize the evidence supporting JMJD3’s role in several inflammatory diseases, as well as the potential therapeutic applications of JMJD3 inhibitors. Additionally, we also discuss the challenges and opportunities associated with investigating the functions of JMJD3 and developing targeted inhibitors and propose feasible solutions to provide valuable insights into the functional exploration and discovery of potential drugs targeting JMJD3 for inflammatory diseases.
Xianling Lianxia formula improves the efficacy of trastuzumab by enhancing NK cell-mediated ADCC in HER2-positive BC
Feifei Li, Youyang Shi, Mei Ma, Xiaojuan Yang, Xiaosong Chen, Ying Xie, Sheng Liu
, Available online  , doi: 10.1016/j.jpha.2024.100977
Abstract(937) HTML Full Text PDF(17)
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Trastuzumab has improved survival rates in human epidermal growth factor receptor 2 (HER2)-positive breast cancer (BC), but drug resistance leads to treatment failure. Natural killer (NK) cell-mediated antibody-dependent cell cytotoxicity (ADCC) represents an essential antitumor immune mechanism of trastuzumab. Traditional Chinese medicine (TCM) has been used for centuries to treat diseases because of its capacity to improve immune responses. Xianling Lianxia formula (XLLXF), based on the principle of “strengthening body and eliminating toxin”, exhibits a synergistic effect in the trastuzumab treatment of patients with HER2-positive BC. Notably, this synergistic effect of XLLXF was executed by enhancing NK cells and ADCC, as demonstrated through in vitro co-culture of NK cells and BC cells and in vivo intervention experiments. Mechanistically, the augmented impact of XLLXF on NK cells is linked to a decrease in cytokine inducible SH2 containing protein (CISH) expression, which in turn activates the Janus kinase 1 (JAK1)/signal transducer and activator of transcription 5 (STAT5) pathway. Collectively, these findings suggested that XLLXF holds promise for enhancing NK cell function and sensitizing patients with HER2-positive BC to trastuzumab.
Hepatic PPP1R3G alleviates obesity and liver steatosis by affecting gut microbiota and bile acid metabolism
Chu Zhang a, Gui Wang, Xin Yin, Lingshan Gou, Mengyuan Guo, Feng Suo, Tao Zhuang, Zhenya Yuan, Yanan Liu, Maosheng Gu, Ruiqin Yao
, Available online  , doi: 10.1016/j.jpha.2024.100976
Abstract(108) HTML Full Text PDF(3)
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Intestinal dysbiosis and disrupted bile acid (BA) homeostasis are associated with obesity, but the precise mechanisms remain insufficiently explored. Hepatic protein phosphatase 1 regulatory subunit 3G (PPP1R3G) plays a pivotal role in regulating glycolipid metabolism; nevertheless, its obesity-combatting potency remains unclear. In this study, a substantial reduction was observed in serum PPP1R3G levels in highbody mass index and high-fat diet (HFD)-exposed mice, establishing a positive correlation between PPP1R3G and non-12α-hydroxylated (non-12-OH) BA content. Additionally, hepatocyte-specific overexpression of Ppp1r3g (PPP1R3G HOE) mitigated HFD-induced obesity as evidenced by reduced weight and fat mass, and an improved serum lipid profile; hepatic steatosis alleviation was confirmed by normalized liver enzymes and histology. PPP1R3G HOE considerably impacted systemic BA homeostasis, which notably increased the non-12-OH BAs ratio, particularly lithocholate (LCA). 16S ribosomal DNA (16S rDNA) sequencing assay indicated that PPP1R3G HOE reversed HFD-induced gut dysbiosis by reducing the Firmicutes/Bacteroidetes ratio and Lactobacillus population, and elevating the relative abundance of Blautia, which exhibited a positive correlation with serum LCA levels. A fecal microbiome transplantation test confirmed that the anti-obesity effect of hepatic PPP1R3G was gut microbiota-dependent. Mechanistically, PPP1R3G HOE markedly suppressed hepatic cholesterol 7α-hydroxylase and sterol-12α-hydroxylase, and concurrently upregulated oxysterol 7-α hydroxylase and Takeda G protein-coupled receptor 5 expression under HFD conditions. Furthermore, LCA administration significantly mitigated the HFD-induced obesity phenotype and elevated non-12-OH BA levels. These findings emphasize the significance of hepatic PPP1R3G in ameliorating diet-induced adiposity and hepatic steatosis through the gut microbiotaBA axis, which may serve as potential therapeutic targets for obesity-related disorders.
Dissection of triple-negative breast cancer microenvironment and identification of potential therapeutic drugs using single-cell RNA sequencing analysis
Weilun Cheng, Wanqi Mi, Shiyuan Wang, Xinran Wang, Hui Jiang, Jing Chen, Kaiyue Yang, Wenqi Jiang, Jun Ye, Baoliang Guo, Yunpeng Zhang
, Available online  , doi: 10.1016/j.jpha.2024.100975
Abstract(127) HTML Full Text PDF(2)
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Breast cancer remains a leading cause of mortality in women worldwide. Triplenegative breast cancer (TNBC) is a particularly aggressive subtype characterized by rapid progression, poor prognosis, and lack of clear therapeutic targets. In the clinic, delineation of tumor heterogeneity and development of effective drugs continue to pose considerable challenges. Within the scope of our study, high heterogeneity inherent to breast cancer was uncovered based on the landscape constructed from both tumor and healthy breast tissue samples. Notably, TNBC exhibited significant specificity regarding cell proliferation, differentiation, and disease progression. Significant associations between tumor grade, prognosis, and TNBC oncogenes were established via pseudotime trajectory analysis. Consequently, we further performed comprehensive characterization of the TNBC microenvironment. A crucial epithelial subcluster, E8, was identified as highly malignant and strongly associated with tumor cell proliferation in TNBC. Additionally, epithelial-mesenchymal transition-associated fibroblast and M2 macrophage subclusters exerted an influence on E8 through cellular interactions, contributing to tumor growth. Characteristic genes in these three cluster cells could therefore serve as potential therapeutic targets for TNBC. The collective findings provided valuable insights that assisted in the screening of a series of therapeutic drugs, such as pelitinib. We further confirmed the anti-cancer effect of pelitinib in an orthotopic 4T1 tumor-bearing mouse model. Overall, our study sheds light on the unique characteristics of TNBC at single-cell resolution and the crucial cell types associated with tumor cell proliferation that may serve as potent tools in the development of effective anti-cancer drugs.
Advancing drug safety and mitigating health concerns: High-resolution mass spectrometry in the levothyroxine case study
Hana Chmelařová, Maria Carmen Catapano, Jean-Christophe Garrigues, František Švec, Lucie Nováková
, Available online  , doi: 10.1016/j.jpha.2024.100970
Abstract(96) HTML Full Text PDF(3)
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Levothyroxine is a drug with a narrow therapeutic index. Changing the drug formulation composition or switching between pharmaceutical brands can alter the bioavailability, which can result in major health problems. However, the increased adverse drug reactions have not been fully explained scientifically yet and a thorough investigation of the formulations is needed.In this study, we used a non-targeted analytical approach to examine the various levothyroxine formulas in detail and to reveal possible chemical changes. Ultra-high-performance liquid chromatography coupled with a data-independent acquisition high-resolution mass spectrometry (UHPLC-DIA-HRMS) was employed.UHPLC-DIA-HRMS allowed aside the detection of levothyroxine degradation products also the presence of non-expected components in the formulations. Among these, we identified compounds resulting from reactions between mannitol and other excipients, such as citric acid, stearate, and palmitate, or from reactions between an excipient and an active pharmaceutical ingredient, such as levothyroxine-lactose adduct. In addition to these compounds, undeclared phospholipids were also found in three formulations. This non-targeted approach is not common in pharmaceutical quality control analysis. Revealing the presence of unexpected compounds in drug formulations proved that the current control mechanisms do not have to cover the full complexity of pharmaceutical formulations necessarily.
Spatially resolved metabolomics visualizes heterogeneous distribution of metabolites in lung tissue and the anti-pulmonary fibrosis effect of Prismatomeris connate extract
Haiyan Jiang, Bowen Zheng, Guang Hu, Lian Kuang, Tianyu Zhou, Sizheng Li, Xinyi Chen, Chuangjun Li, Dongming Zhang, Jinlan Zhang, Zengyan Yang, Jiuming He, Hongtao Jin
, Available online  , doi: 10.1016/j.jpha.2024.100971
Abstract(106) HTML Full Text PDF(24)
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Pulmonary fibrosis (PF) is a chronic progressive end-stage lung disease. However, the mechanisms underlying the progression of this disease remain elusive. Presently, clinically employed drugs are scarce for the treatment of pulmonary fibrosis. Hence, there is an urgent need for developing novel drugs to address such diseases. properties. Our study found for the first time that a natural source of Prismatomeris connate ethyl acetate extract (HG-2) had a significant anti-pulmonary fibrosis effect by inhibiting the expression of the transforming growth factor beta 1/suppressor of mothers against decapentaplegic (TGF-β1/Smad) pathway. Network pharmacological analysis suggested that HG-2 had effects on tyrosine kinase phosphorylation, cellular response to reactive oxygen species, and extracellular matrix disassembly. Moreover, mass spectrometry imaging (MSI) was used to visualize the heterogeneous distribution of endogenous metabolites in lung tissue and reveal the anti-pulmonary fibrosis metabolic mechanism of HG-2, which was related to arginine synthesis, alanine, aspartic acid and glutamate metabolism, the down-regulation of arachidonic acid metabolism, and the up-regulation of glycerophospholipid metabolism. In conclusion, we elaborated on the relationship between metabolite distribution and the progression of PF, constructed the regulatory metabolic network of HG-2, and discovered the multi-target therapeutic effect of HG-2, which might be conducive to the development of new drugs for PF.
Pharmacometabolomics and Mass Spectrometry Imaging Approach to Reveal the Neurochemical Mechanisms of Polygala tenuifolia
Qian Li, Jinpeng Bai, Yuxue Ma, Yu Sun, Wenbin Zhou, Zhaoying Wang, Zhi Zhou, Zhonghua Wang, Yanhua Chen, Zeper Abliz
, Available online  , doi: 10.1016/j.jpha.2024.100973
Abstract(139) HTML Full Text PDF(7)
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Structural characterization and mechanisms of macrophage immunomodulatory activity of a novel polysaccharide with a galactose backbone from the processed Polygonati Rhizoma
Hongna Su, Lili He, Xina Yu, Yue Wang, Li Yang, Xiaorui Wang, Xiaojun Yao, Pei Luo, Zhifeng Zhang
, Available online  , doi: 10.1016/j.jpha.2024.100974
Abstract(148) HTML Full Text PDF(5)
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A purified polysaccharide with a galactose backbone (SPR-1, Mw 3,622 Da) was isolated from processed Polygonati Rhizoma with black beans (PRWB) and characterized its chemical properties. The backbone of SPR-1 consisted of [(4)-β-D-Galp-(1]9→4,6)-β-D-Galp-(1→4)-α-D-GalpA-(1→4)-α-D-GalpA-(1→4)-α-D-Glcp-(1→4,6)-α-D-Glcp-(1→4)-α/β-D-Glcp, with a branch chain of R1: β-D-Galp-(1→3)-β-D-Galp-(1→ connected to the →4,6)-β-D-Galp-(1→ via O-6, and a branch chain of R2: α-D-Glcp-(1→6)-α-D-Glcp-(1→ connected to the →4,6)-α-D-Glcp-(1→ via O-6. Immunomodulatory assays showed that the SPR-1 significantly activated macrophages, and increased secretion of NO and cytokines (i.e., IL-1β and TNF-α), as well as promoted the phagocytic activities of cells. Furthermore, isothermal titration calorimetry (ITC) analysis and molecular docking results indicated high-affinity binding between SPR-1 and MD2 with the equilibrium dissociation constant (K) of 18.8 μM. It was suggested that SPR-1 activated the immune response through Toll-like receptor 4 (TLR4) signaling and downstream responses. Our research demonstrated that the SPR-1 has a promising candidate from PRWB for the TLR4 agonist to induce immune response, and also provided an easily accessible way that can be used for PR deep processing.
Baicalein: a potential GLP-1R agonist improves cognitive disorder of diabetes through mitophagy enhancement
Na Liu, Xin Cui, Wenhui Yan, Tingli Guo, Zhuanzhuan Wang, Xiaotong Wei, Yuzhuo Sun, Jieyun Liu, Cheng Xian, Weina Ma, Lina Chen
, Available online  , doi: 10.1016/j.jpha.2024.100968
Abstract(152) HTML Full Text PDF(20)
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There is increasing evidence that the activation of glucagon-like peptide-1 receptor (GLP-1R) can be used as a therapeutic intervention for cognitive disorders. Here, we have screened GLP-1R targeted compounds from Scutellaria baicalensis, which revealed baicalein is a potential GLP-1R small-molecule agonist. Mitophagy, a selective autophagy pathway for mitochondrial quality control, plays a neuroprotective role in multiple cognitive impairment diseases. We noticed that Glp1r knock-out (KO) mice present cognitive impairment symptoms and appear worse in spatial learning memory and learning capacity in Morris water maze (MWM) test than their wide-type (WT) counterparts. Our mechanistic studies revealed that mitophagy is impaired in hippocampus tissue of diabetic mice and Glp1r KO mice. Finally, we verified that the cognitive improvement effects of baicalein on diabetic cognitive dysfunction occur through the enhancement of mitophagy in a GLP-1R-dependent manner. Our findings shed light on the importance of GLP-1R for cognitive function maintenance, and revealed the vital significance of GLP-1R for maintaining mitochondrial homeostasis. Furthermore, we identified the therapeutic potential of baicalein in the treatment of cognitive disorder associated with diabetes.
Mapping conformational changes on bispecific antigen-binding biotherapeutic by covalent labeling and mass spectrometry
Arnik Shah, Dipanwita Batabyal, Dayong Qiu, Weidong Cui, John Harrahy, Alexander R. Ivanov
, Available online  , doi: 10.1016/j.jpha.2024.100966
Abstract(65) HTML Full Text PDF(10)
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Biotherapeutic’s higher order structure (HOS) is a critical determinant of its functional properties and conformational relevance. Here, we evaluated two covalent labeling methods: diethylpyrocarbonate (DEPC)-labeling and fast photooxidation of proteins (FPOP), in conjunction with mass spectrometry (MS), to investigate structural modifications for the new class of immuno-oncological therapy known as bispecific antigen-binding biotherapeutics (BABB). The evaluated techniques unveiled subtle structural changes occurring at the amino acid residue level within the antigen-binding domain under both native and thermal stress conditions, which cannot be detected by conventional biophysical techniques, e.g., near-ultraviolet circular dichroism (NUV-CD). The determined variations in labeling uptake under native and stress conditions, corroborated by binding assays, shed light on the binding effect, and highlighted the potential of covalent-labeling methods to effectively monitor conformational changes that ultimately influence the product quality. Our study provides a foundation for implementing the developed techniques in elucidating the inherent structural characteristics of novel therapeutics and their conformational stability.
Radiotracer labelled thymohydroquinyl gallate capped gold nanoparticles as theranostic radiopharmaceutical for targeted antineoplastic and bioimaging
Munaza Batool, Batool Fatima, Dilshad Hussain, Rubaida Mahmood, Muhammad Imran, Saeed Akhter, Muhammad Saqib Khan, Saadat Majeed, Muhammad Najam-ul-Haq
, Available online  , doi: 10.1016/j.jpha.2024.100965
Abstract(80) HTML Full Text PDF(2)
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Thymoquinone (Tq) and gallic acid (GA) are known for counter-tumorigenic characteristics. GA inhibits cancer cell proliferation by interfering with many apoptotic signaling pathways, producing more reactive oxygen species (ROS), focusing on the cell cycle, and suppressing the expression of oncogenes and matrix metalloproteinases (MMPs). In this study, thymoquinone (after reducing to thymohydroquinone) and gallic acid are esterified to form thymohydroquinyl gallate (a prodrug). Thymohydroquinyl gallate (THQG) possesses enhanced antineoplastic efficacy and targeted delivery potential. The chemical and spectroscopic analysis confirms ester synthesis. Gold nanoparticles (AuNPs) are employed as nanocarriers due to their physicochemical and optical characteristics, biocompatibility, and low toxicity. As an efficient drug transporter, gold nanoparticles (AuNPs) shield conjugated drugs from enzymatic digestion. The prodrug acts as a reducing agent for Au metal atoms and is loaded onto it after reduction. The nano drug is radiolabeled with 99mTc and 131I to monitor the drug biodistribution in animals using a gamma camera and single-photon emission computerized tomography (SPECT). 131I is an antineoplastic that helps enhance the drug's efficiency. Chromatographic results reveal promising radiolabeling percentages. In vitro, drug release shows sustained release at pH 5.8. In vitro 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT) cytotoxicity assay reveals drug potency on CAL 27 and MCF 7 cell lines.
17β-estradiol, through activating G protein-coupled estrogen receptor, exacerbated the complication of benign prostate hyperplasia in type 2 diabetes mellitus by inducing prostatic proliferation
Tingting Yang, Zhen Qiu, Jiaming Shen, Yutian He, Longxiang Yin, Li Chen, Jiayu Yuan, Junjie Liu, Tao Wang, Zhenzhou Jiang, Changjiang Ying, Sitong Qian, Jinfang Song, Xiaoxing Yin, Qian Lu
, Available online  , doi: 10.1016/j.jpha.2024.03.003
Abstract(76) HTML Full Text PDF(7)
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Benign prostate hyperplasia (BPH) is one of the major chronic complications of type 2 diabetes mellitus (T2DM), and sex steroid hormones are common risk factors for the occurrence of T2DM and BPH. The profiles of sex steroid hormones are simultaneously quantified by LC-MS/MS in the clinical serum of patients, including simple BPH patients, newly diagnosed T2DM patients, T2DM complicated with BPH patients and matched healthy individuals. The G protein-coupled estrogen receptor (GPER) inhibitor G15, GPER knockdown lentivirus, the YAP1 inhibitor verteporfin, YAP1 knockdown/overexpression lentivirus, targeted metabolomics analysis, and Co-IP assays are used to investigate the molecular mechanisms of the disrupted sex steroid hormones homeostasis in the pathological process of T2DM complicated with BPH. The homeostasis of sex steroid hormone is disrupted in the serum of patients, accompanying with the proliferated prostatic epithelial cells (PECs). The sex steroid hormone metabolic profiles of T2DM patients complicated with BPH have the greatest degrees of separation from those of healthy individuals. Elevated 17β-estradiol (E2) is the key contributor to the disrupted sex steroid hormone homeostasis, and is significantly positively related to the clinical characteristics of T2DM patients complicated with BPH. Activating GPER by E2 via Hippo-YAP1 signaling exacerbates high glucose (HG)-induced PECs proliferation through the formation of the YAP1-TEAD4 heterodimer. Knockdown or inhibition of GPER-mediated Hippo-YAP1 signaling suppresses PECs proliferation in HG and E2 co-treated BPH-1 cells. The anti-proliferative effects of verteporfin, an inhibitor of YAP1, are blocked by YAP1 overexpression in HG and E2 co-treated BPH-1 cells. Inactivating E2/GPER/Hippo/YAP1 signaling may be effective at delaying the progression of T2DM complicated with BPH by inhibiting PECs proliferation.
Progress and application of intelligent nanomedicine in urinary system tumors
YingmingXiao, Lei Zhong, Jinpeng Liu, Li Chen, Yi Wu, Ge Li
, Available online  , doi: 10.1016/j.jpha.2024.100964
Abstract(133) HTML Full Text PDF(3)
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Urinary system tumors include malignancies of the bladder, kidney, and prostate, and present considerable challenges in diagnosis and treatment. The conventional therapeutic approaches against urinary tumors are limited by the lack of targeted drug delivery and significant adverse effects, thereby necessitating novel solutions. Intelligent nanomedicine has emerged as a promising therapeutic alternative for cancer in recent years, and uses nanoscale materials to overcome the inherent biological barriers of tumors, and enhance diagnostic and therapeutic accuracy. In this review, we have explored the recent advances and applications of intelligent nanomedicine for the diagnosis, imaging, and treatment of urinary tumors. The principles of nanomedicine design pertaining to drug encapsulation, targeting and controlled release have been discussed, with emphasis on the strategies for overcoming renal clearance and tumor heterogeneity. Furthermore, the therapeutic applications of intelligent nanomedicine, its advantages over traditional chemotherapy, and the challenges currently facing clinical translation of nanomedicine, such as safety, regulation and scalability, have also been reviewed. Finally, we have assessed the potential of intelligent nanomedicine in the management of urinary system tumors, emphasizing emerging trends such as personalized nanomedicine and combination therapies. This comprehensive review underscores the substantial contributions of nanomedicine to the field of oncology and offers a promising outlook for more effective and precise treatment strategies for urinary system tumors.
Mechanisms and therapeutic targets of ferroptosis: Implications for nanomedicine design
Meihong Zhang, Mengqin Guo, Yue Gao, Chuanbin Wu, Xin Pan, Zhengwei Huang
, Available online  , doi: 10.1016/j.jpha.2024.03.001
Abstract(114) HTML Full Text PDF(1)
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Ferroptosis is a nonapoptotic form of cell death and differs considerably from the well- known forms of cell death in terms of cell morphology, genetics, and biochemistry. The three primary pathways for cell ferroptosis are system Xc-/glutathione peroxidase 4, lipid metabolism, and ferric metabolism. Since the discovery of ferroptosis, mounting evidence has revealed its critical regulatory role in several diseases, especially as a novel potential target for cancer therapy, thereby attracting increasing attention in the fields of tumor biology and anti-tumor therapy. Accordingly, broad prospects exist for identifying ferroptosis as a potential therapeutic target. In this review, we aimed to systematically summarize the activation and defense mechanisms of ferroptosis, highlight the therapeutic targets, and discuss the design of nanomedicines for ferroptosis regulation. In addition, we opted to present the advantages and disadvantages of current ferroptosis research and provide an optimistic vision of future directions in related fields. Overall, we aim to provide new ideas for further ferroptosis research and inspire new strategies for disease diagnosis and treatment.
β-elemene promotes miR-127-3p maturation, induces NSCLCs autophagy, and enhances macrophage M1 polarization through exosomal communication
Xiahui Wu, Jie Wu, Tingting Dai, Qiangcheng Wang, Shengjie Cai, Xuehan Wei, Jing Chen, Ziyu Jiang
, Available online  , doi: 10.1016/j.jpha.2024.03.002
Abstract(213) HTML Full Text PDF(26)
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β-elemene has been observed to exert inhibitory effects on a multitude of tumors, primarily through multiple pathways such as the inhibition of cancer cell proliferation and the induction of apoptosis. The present study is designed to elucidate the role and underlying mechanisms of β-elemene in the therapeutic intervention of non-small cell lung cancer (NSCLC). Both in vitro and in vivo experimental models corroborate the inhibitory potency of β-elemene on NSCLCs. Our findings indicate that β-elemene facilitates the maturation of miR-127-3p by inhibiting CBX8. Functioning as an upstream regulator of MAPK4, miR-127-3p deactivates the Akt/mTOR/p70S6K pathway by targeting MAPK4, thereby inducing autophagy in NSCLCs. Additionally, β-elemene augments the packaging of miR-127-3p into exosomes via SYNCRIP. Exosomal miR-127-3p further stimulates M1 polarization of macrophages by suppressing ZC3H4. Taken together, the detailed understanding of the mechanisms through which β-elemene induces autophagy in NSCLCs and facilitates M1 polarization of macrophages provides compelling scientific evidence supporting its potential utility in NSCLC treatment.
Recent Trends and Impact of Localized Surface Plasmon Resonance (LSPR) and Surface-Enhanced Raman Spectroscopy (SERS) in Modern Analysis
Bibhu Prasad Nanda, Priyanka Rani, Priyanka Paul, Aman, Subrahmanya S Ganti, Rohit Bhatia
, Available online  , doi: 10.1016/j.jpha.2024.02.013
Abstract(77) HTML Full Text PDF(1)
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An optical biosensor is a specialized analytical device that utilizes the principles of optics and light bimolecular processes. Localized surface plasmon resonance (LSPR) is a phenomenon in the realm of nanophotonics that arises when metallic nanoparticles (NPs) or nanostructures interact with incident light. On the other hand, surface-enhanced Raman spectroscopy (SERS) is an influential analytical technique rooted in Raman scattering, wherein it amplifies the Raman signals of molecules when they are situated near specific and specially designed nanostructures. A detailed exploration of the recent groundbreaking developments in optical biosensors employing LSPR and SERS technologies has been exhaustively discussed along with their underlying principle and the working mechanism. A biosensor chip has been created, featuring a high-density deposition of gold nanoparticles under varying ligand concentration and reaction duration on the substrate. An ordinary description, along with a visual illustration, has been thoroughly provided for concepts such as a sensogram, refractive index shift, surface plasmon resonance (SPR), and the evanescent field, Rayleigh scattering, Raman scattering as well as the electromagnetic enhancement & chemical enhancement. LSPR and SERS both have their advantages and disadvantages but widely used SERS has some advantages over LSPR like chemical specificity, high sensitivity, multiplexing, and versatility in different fields. This review confirms and elucidates the significance of different disease biomarker identification. LSPR, and SERS both play a vital role in the detection of various types of cancer like cervical cancer, ovarian cancer, endometrial cancer, prostate cancer, colorectal cancer, and brain tumors. This proposed optical biosensor provides potential application for early diagnosis and monitoring of viral disease, bacterial infectious diseases, fungal diseases, diabetes, and cardiac disease biosensing. LSPR and SERS provide a new direction for environmental monitoring, food safety, refining of impurities from water samples, and detection of lead. The understanding of these biosensors is still limited and challenging.
An Fe-Cu bimetallic organic framework as a microwave sensitizer for treating tumors using combined microwave thermotherapy and chemodynamic therapy
Xinyang Zhu, Chao He, Longfei Tan, Xun Qi, Meng Niu, Xianwei Meng, Hongshan Zhong
, Available online  , doi: 10.1016/j.jpha.2024.02.006
Abstract(87) HTML Full Text PDF(5)
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Microwave thermotherapy (MWTT), as a treatment for tumors, lacks specificity and requires sensitizers. Most reported microwave sensitizers are single-metal organic frameworks (MOFs), which must be loaded with ionic liquids to enhance the performance in MWTT. Meanwhile, MWTT is rarely combined with other treatment modalities. Here, we synthesized a novel Fe-Cu bimetallic organic framework FeCuMOF (FCM) by applying a hydrothermal method and further modified it with methyl polyethylene glycol (mPEG). The obtained FeCuMOF@PEG (FCMP) showed remarkable heating performance under low-power microwave irradiation; it also acted as a novel nanoparticle enzyme to catalyze hydrogen peroxide decomposition, producing abundant reactive oxygen species (ROS) to deplete glutathione and prevent ROS clearance from tumor cells during chemodynamic treatment. The FCMP was biodegradable and demonstrated excellent biocompatibility, allowing it to be readily metabolized without causing toxic effects. Finally, it was shown to act as a suitable agent for T2 magnetic resonance imaging (MRI) in vitro and in vivo. This new bimetallic nanostructure could successfully realize two tumor treatment modalities (MWTT and chemodynamic therapy) and dual imaging modes (MRI and microwave thermal imaging). Our findings represent a breakthrough for integrating the diagnosis and treatment of tumors and provides a reference for developing new microwave sensitizers.
Signal interference between drugs and metabolites in LC-ESI-MS quantitative analysis and its evaluation strategy
Fulin Jiang, Jingyu Liu, Yagang Li, Zihan Lu, Qian Liu, Yunhui Xing, Janshon Zhu, Min Huang, Guoping Zhong
, Available online  , doi: 10.1016/j.jpha.2024.02.008
Abstract(99) HTML Full Text PDF(3)
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Liquid chromatography-electrospray ionization tandem mass spectrometry (LC-ESI-MS) is a widely utilized technique for in vivo pharmaceutical analysis. Ionization interference within electrospray ion source, occurring between drugs and metabolites, can lead to signal variations, potentially compromising quantitative accuracy. Currently, method validation often overlooks this type of signal interference, which may result in systematic errors in quantitative results without matrix-matched calibration. In this study, we conducted an investigation using ten different groups of drugs and their corresponding metabolites across three LC-ESI-MS systems to assess the prevalence of signal interference. Such interferences can potentially cause or enhance nonlinearity in the calibration curves of drugs and metabolites, thereby altering the relationship between analyte response and concentration for quantification. Finally, we established an evaluation scheme through a step-by-step dilution assay and employed three resolution methods: chromatographic separation, dilution, and stable labeled isotope internal standards correction. The above strategies were integrated into the method establishment process to improve quantitative accuracy.
Multiple roles of arsenic compounds in phase separation and membraneless organelles formation determine their therapeutic efficacy in tumors
Meiyu Qu, Qiangqiang He, , Hangyang Bao, Xing Ji, Tingyu Shen, Muhammad Qasim Barkat, Ximei Wu, Ling-Hui Zeng
, Available online  , doi: 10.1016/j.jpha.2024.02.011
Abstract(98) HTML Full Text PDF(11)
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Arsenic compounds are widely used for the therapeutic intervention of multiple diseases. Ancient pharmacologists discovered the medicinal utility of such highly toxic substances, and modern pharmacologists have further recognized the specific active ingredients in human diseases. In particular, Arsenic trioxide (ATO), as a main component, has therapeutic effects on various tumors (including leukemia, hepatocellular carcinoma, lung cancer, etc.). However, its toxicity limits its efficacy, and how to control its toxicity has been an important issue. Interestingly, recently emerging evidence has pointed out the pivotal roles of arsenic compounds in phase separation and membraneless organelles formation, which may decide their toxicity and therapeutic efficacy. Here, we summarized the arsenic compounds-regulating phase separation and membraneless organelles formation. We further hypothesize their potential involvement in the therapy and toxicity of arsenic compounds, highlighting potential mechanisms underlying the clinical application of arsenic compounds.
β-glucan-modified nanoparticles with different particle sizes exhibit different lymphatic targeting efficiencies and adjuvant effects
Wen Guo, Xinyue Zhang, Long Wan, Zhiqi Wang, Meiqi Han, Ziwei Yan, Jia Li, Ruizhu Deng, Shenglong Li, Yuling Mao, Siling Wang
, Available online  , doi: 10.1016/j.jpha.2024.02.007
Abstract(142) HTML Full Text PDF(11)
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Particle size and surface properties are crucial for lymphatic drainage (LN), dendritic cell (DC) uptake, DC maturation, and antigen cross-presentation induced by nanovaccine injection, which lead to an effective cell-mediated immune response. However, the manner in which the particle size and surface properties of vaccine carriers such as mesoporous silica nanoparticles (MSNs) affect this immune response is unknown. We prepared 50, 100, and 200 nm of MSNs that adsorbed ovalbumin antigen (OVA) while modifying β-glucan to enhance immunogenicity. The results revealed that these MSNs with different particle sizes were just as efficient in vitro, and MSNs with β-glucan modification demonstrated higher efficacy. However, the in vivo results indicated that MSNs with smaller particle sizes have stronger lymphatic targeting efficiency and a greater ability to promote the maturation of DCs. The results also indicate that β-glucan-modified MSN, with a particle size of ~100 nm, has a great potential as a vaccine delivery vehicle and immune adjuvant and offers a novel approach for the delivery of multiple therapeutic agents that target other lymphmediated diseases.
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
Abstract(88) HTML Full Text PDF(2)
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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.
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
Abstract(149) HTML Full Text PDF(10)
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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.
Automated and integrated ultrahigh throughput industrial strain screening enabled by acoustic-droplet-ejection mass spectrometry
Zhidan Zhang, Chao Zhang, Xu Zhang, Jiuzhou Chen, Ningyun Cai, Shasha Zhong, Zhibo Han, Yan Zhu, Ping Zheng, Jibin Sun, Changxiao Liu
, Available online  , doi: 10.1016/j.jpha.2024.02.003
Abstract(267) HTML Full Text PDF(31)
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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
Abstract(52) HTML Full Text PDF(3)
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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
Abstract(94) HTML Full Text PDF(7)
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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.
A novel fluorescent labeling compound for GluN2A containing N-methyl-D-aspartate receptors identified by Autodisplay-based screening
Alexander DOMBOVSKI, Ruben STEIGERWALD, Nadine RITTER, Paul DISSE, Gunnar GOERGES, Jana OSTHUES, Isabel AYMANNS, Carina DILKAUTE, Julian SCHREIBER, Martina DÜFER, Guiscard SEEBOHM, Bernhard WÜNSCH, Joachim JOSE
, Available online  , doi: 10.1016/j.jpha.2024.01.013
Abstract(133) HTML Full Text PDF(9)
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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
Abstract(64) HTML Full Text PDF(9)
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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
Abstract(159) HTML Full Text PDF(8)
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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
Abstract(89) HTML Full Text PDF(7)
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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.
PEG-PLGA nanoparticles deposited in Pseudomonas aeruginosa and Burkolderia cenocepacia
Tinatini Tchatchiashvilli, Helena Duering, , Lisa Mueller-Boetticher, Christian Grune, Dagmar Fischer, Mathias W. Pletz, Oliwia Makarewicz
, Available online  , doi: 10.1016/j.jpha.2024.01.007
Abstract(153) HTML Full Text PDF(8)
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In our prior research, polymer nanoparticles containing tobramycin displayed robust antibacterial efficacy against biofilm-embedded Pseudomonas aeruginosa and Burkholderia cenocepacia cells, critical pathogens in cystic fibrosis. In the current study, we investigated the deposition of a nanoparticulate carrier composed of poly(D,Llactic-co-glycolic acid) (PLGA) and poly(ethylene glycol)-block-PLGA (PEG-PLGA) that was either covalently bonded with cyanine-5-amine or noncovalently bound with freely embedded cationic rhodamine B, which served as a drug surrogate. After exposing these nanoparticles to bacteria, we performed cell fractionation and fluorescence analysis, which highlighted the accumulation of cyanine-5-amine in the outer membranes and the accumulation of rhodamine B in the cytoplasm of cells. The results indicated that these organic nanoparticles are effective vehicles for targeted antibiotic delivery in bacterial cells, explaining the observed increase in the efficacy of encapsulated tobramycin against biofilms. This work emphasizes the potential of PEGPLGA-based formulations for advanced drug delivery strategies.
Discovery of potent anti-MRSA components from Dalbergia odorifera through UPLC-Q-TOF-MS and targeting PBP2a protein through in-depth transcriptomic, in vitro, and in-silico studies
Jiajia Wu, Syed Shams ul Hassan, Xue Zhang, Tao Li, Abdur Rehman, Shikai Yan, Huizi Jin
, Available online  , doi: 10.1016/j.jpha.2024.01.006
Abstract(202) HTML Full Text PDF(33)
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Platelet membrane biomimetic nanomedicine induces dual glutathione consumption for enhancing cancer radioimmunotherapy
Xiaopeng Li, Yang Zhong, Pengyuan Qi, Daoming Zhu, Chenglong Sun, Nan Wei, Yang Zhang, Zhanggui Wang
, Available online  , doi: 10.1016/j.jpha.2024.01.003
Abstract(145) HTML Full Text PDF(10)
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Radiotherapy (RT) is one of the most common treatments for cancer. However, intracellular glutathione (GSH) plays a key role in protecting cancer from radiation damage. Herein, we have developed a platelet membrane biomimetic nanomedicine (PMD) that induces double GSH consumption to enhance tumor radioimmunotherapy. This biomimetic nanomedicine consists of an external platelet membrane and internal organic mesoporous silica nanoparticles (MON) loaded with 2-deoxy-D-glucose (2-DG). Thanks to the tumor-targeting ability of the platelet membranes, PMD can target and aggregate to the tumor site, which is internalized by tumor cells. Within tumor cells overexpressing GSH, MON reacts with GSH to degrade and release 2-DG. This step initially depletes the intracellular GSH content. The subsequent release of 2-DG inhibits glycolysis and adenosine triphosphate (ATP) production, ultimately leading to secondary GSH consumption. This nanodrug combines dual GSH depletion, starvation therapy, and RT to promote immunogenic cell death and stimulate the systemic immune response. In the bilateral tumor model in vivo, distal tumor growth was also well suppressed. The proportion of mature dendritic cells (DC) and CD8+T cells in the mice was increased. This indicates that PMD can promote anti-tumor radioimmunotherapy and has good prospects for clinical application.
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
Abstract(273) HTML Full Text PDF(30)
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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.
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
Abstract(284) HTML Full Text PDF(36)
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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.
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
Abstract(126) HTML Full Text PDF(8)
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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.
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
Abstract(127) HTML Full Text PDF(9)
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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.
Lentinan-Functionalized PBAE-G-nanodiamonds as an adjuvant to induce cGAS-STING Pathway-mediated macrophage activation and immune enhancement
Zhiqiang Zhang, Li Wang, Xia Ma, Hui Wang
, Available online  , doi: 10.1016/j.jpha.2023.12.012
Abstract(100) HTML Full Text PDF(11)
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A series of biodegradable nanoparticle-based drug delivery systems have been designed utilizing poly(β-amino ester)-guanidine-phenylboronic acid (PBAE-G) polymers. In this study, a novel Lentinan-Functionalized PBAE-G-nanodiamond system was developed to carry ovalbumin (LNT-PBAE-G-ND@OVA). The impact of this drug delivery system on the activation and maturation of macrophages was then assessed . Furthermore, LNT-PBAE-G-ND@OVA induced potent antibody response and showed no obvious toxicity ` and in vivo. Moreover, treatment with LNT-PBAE-G-ND@OVA was sufficient to alter the expression of genes associated with the cGAS-STING pathway, and the LNT-PBAE-G-ND@OVA induced upregulation of costimulatory molecules. LNT-PBAE-G-ND@OVA treatment was sufficient to induce macrophage activation through a complex mechanism in which cGAS-STING signaling plays an integral role.
3D-Printed Constructs Deliver Bioactive Cargos to Expedite Cartilage Regeneration
Rong Jiao, Xia Lin, Jingchao Wang, Chunyan Zhu, Jiang Hu, Huali Gao, Kun Zhang
, Available online  , doi: 10.1016/j.jpha.2023.12.015
Abstract(258) HTML Full Text PDF(22)
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Cartilage is solid connective tissue that recovers slowly from injury, and pain and dysfunction from cartilage damage affect many people. The treatment of cartilage injury is clinically challenging and there is no optimal solution, which is a hot research topic at present. With the rapid development of 3D printing technology in recent years, 3D bioprinting can better mimic the complex microstructure of cartilage tissue and thus enabling the anatomy and functional regeneration of damaged cartilage. This article reviews the methods of 3D printing used to mimic cartilage structures, the selection of cells and biological factors, and the development of bioinks and advances in scaffold structures, with an emphasis on how 3D printing structure provides bioactive cargos in each stage to enhance the effect. Finally, clinical applications and future development of simulated cartilage printing are introduced, which are expected to provide new insights into this field and guide other researchers who are engaged in cartilage repair.
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
Abstract(100) HTML Full Text PDF(9)
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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.
MEOX2 promotes glioma growth and temozolomide chemoresistance
Tengfei Li, Kaijun Sun, Wanchun Yang, Meiling Zhang, Wentao Feng, Siliang Chen, Mingrong Zuo, Qiuyun Yuan, Yanhui Liu, Mina Chen
, Available online  , doi: 10.1016/j.jpha.2023.12.002
Abstract(58) HTML Full Text PDF(9)
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Targeted protein degradation: A promising approach for cancer treatment
Muhammad Zafar Irshad Khan, Adila Nazli, Iffat Naz, Dildar Khan, Ihsan-ul Haq, Jian-Zhong Chen
, Available online  , doi: 10.1016/j.jpha.2023.09.004
Abstract(365) HTML Full Text PDF(8)
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Targeted protein degradation (TPD) is a promising approach that has the ability to address disease-causing proteins. Compared to traditional inhibition, proteolysis targeting chimera (PROTAC) technology offers various benefits, including the potential to target mutant and overexpressed proteins along with characteristics to target undruggable proteomes. A significant obstacle to the ongoing effective treatment of malignancies is cancer drug resistance, which is developed frequently by mutated or overexpressed protein targets and causes current remedies to continuously lose their effectiveness. The effective use of PROTACs to degrade targets that have undergone mutations and conferred resistance to first-line cancer therapies has attracted much research attention. To find novel/effective treatments, we analyzed the advancements in PROTACs aimed at cancer resistance and targets. This review provides a description of how PROTAC-based anticancer drugs are currently being developed and how to counter resistance if developed to PROTAC technology. Moreover, modern technologies related to protein degradation, including autophagy-targeting chimeras (AUTAC), lysosome-targeting chimeras (LYTAC), antibody-based PROTAC (AbTAC), Glue-body chimeras (GlueTAC), transcription-factor-targeting chimeras (TRAFTAC), RNA-PROTAC, aptamer-PROTAC, Photo-PROTAC, folate-PROTAC, and in-cell click-formed proteolysis targeting chimeras (CLIPTACs), have been discussed along with their mechanisms of action.
Caenorhabditis elegansdeep lipidome profiling by using integrative mass spectrometry acquisitions reveals significantly altered lipid networks
Nguyen Hoang Anh, Young Cheol Yoon, Young Jin Min, Nguyen Phuoc Long, Cheol Woon Jung, Sun Jo Kim, Suk Won Kim, Eun Goo Lee, Daijie Wang, Xiao Wang, Sung Won Kwon
, Available online  , doi: https://doi.org/10.1016/j.jpha.2022.06.006
Abstract(0) HTML Full Text PDF(17)
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Lipidomics coverage improvement is essential for functional lipid and pathway construction. powerful approach to discovering organism lipidome is to combine various data acquisitions, uch as full scan (full MS), data-dependent acquisition (DDA), and data-independent acquisition DIA). Caenorhabditis elegans(C. elegans) is a useful model for discovering toxic-induced etabolism, high-throughput drug screening, and a variety of human disease pathways. To etermine the lipidome of C. elegans and investigate lipid disruption from the molecular to the ystem biology level, we used integrative data acquisition. The methyl-tert-butyl ether method was sed to extract L4 stage C. elegans after exposure to triclosan (TCS), perfluorooctanoic acid, and nanopolystyrene (nPS). Full MS, DDA, and DIA integrations were performed to comprehensively profile the C. elegans lipidome by Q-Exactive Plus mass spectrometry. All annotated lipids were then analyzed using lipid ontology and pathway analysis. We annotated up to 940 lipids from 20 lipid classes involved in various functions and pathways. The biological investigations revealed that when C. elegans were exposed to nPS, lipid droplets were disrupted, whereas plasma membrane-functionalized lipids were likely changed in the TCS treatment group. The nPS treatment caused a significant disruption in lipid storage. Triacylglycerol, glycerophospholipid, and ether class lipids were those primarily hindered by toxicants. Finally, toxicant exposure frequently involves numerous lipid-related pathways, including the PI3K/AKT pathway. In conclusion, an integrative data acquisition strategy was used to characterize the C. elegans lipidome, providing valuable biological insights needed for hypothesis generation and validation.

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