Current medicinal chemistry最新文献

{"title":"Investigating the Mechanisms of Pazopanib-induced Hepatotoxicity: Insights from Network Toxicology, Microarray Analysis, and Machine Learning.","authors":"Yidong Zhu, Jun Liu, Fei Wang","doi":"10.2174/0109298673367311250508082747","DOIUrl":"https://doi.org/10.2174/0109298673367311250508082747","url":null,"abstract":"<p><strong>Background: </strong>Pazopanib is an oral multi-kinase inhibitor that is effective in treating various tumors. However, it is commonly associated with hepatotoxicity, which can interrupt treatments and cause delays, thereby increasing the risk of tumor progression. The mechanisms underlying pazopanib-induced hepatotoxicity remain unclear and limit the development of effective preventive strategies. This study aimed to identify the core gene products and investigate the mechanisms associated with pazopanib-induced hepatotoxicity by integrating network toxicology, microarray analysis, and machinelearning.</p><p><strong>Methods: </strong>Potential pazopanib targets were identified from multiple databases. Differential expression analysis was conducted using microarray data from hepatocyte-like cells treated with pazopanib and from matched control samples. Genes that overlapped between pazopanib targets and differentially expressed genes (DEGs) were considered potential pathogenic targets for hepatotoxicity. Multiple machine learning algorithms were employed for gene selection to improve accuracy and predictive capability. Molecular docking was used to evaluate the binding affinity of pazopanib to core proteins. Functional enrichment analysis was conducted to elucidate the potential toxic mechanisms.</p><p><strong>Results: </strong>Our analysis identified 162 target genes for pazopanib and 291 DEGs, revealing seven shared genes as potential pathogenic targets for pazopanib-induced hepatotoxicity. Using machine learning, we further detected four core target proteins: CYP1A1, DDR2, FGF1, and PLK4. Molecular docking confirmed that pazopanib stably bound to these core proteins. Functional enrichment analysis indicated that the hepatotoxicity associated with pazopanib may involve p53 signaling, impaired cell cycle, and immune modulation.</p><p><strong>Conclusion: </strong>This study enhances our understanding of the molecular mechanisms underlying pazopanib-induced hepatotoxicity, which is essential for developing protective strategies and therapeutic interventions. By integrating network toxicology, microarray analysis, and machine learning, this study provides a comprehensive framework for investigating the complex toxicological processes of specific compounds and offers insights that could improve the clinical applications and regulatory safety of targeted therapies.</p>","PeriodicalId":10984,"journal":{"name":"Current medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144141618","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of Hub Genes and Prediction of Interacting Chemicals in Parkinson's Disease Using Bioinformatics.","authors":"Lianping Gu, Xu Wang, Yaohua Liu, Hongyu Tang, Jingyan Gu, Wei Wang, Xiaowen Lu, Meiqing Lou","doi":"10.2174/0109298673338465241228021705","DOIUrl":"https://doi.org/10.2174/0109298673338465241228021705","url":null,"abstract":"<p><strong>Background: </strong>Parkinson's disease (PD) ranks as the second most prevalent neurodegenerative disorder globally, with its etiology intricately linked to a complex interplay of genetic predispositions and environmental factors.</p><p><strong>Methods: </strong>A comprehensive comparative analysis of the substantia nigra transcriptome between patients with PD and controls, utilizing data from the Gene Expression Omnibus (GEO) repository, enabled the identification and validation of key hub genes associated with PD. This analysis was further substantiated at the single-cell level. The study identified four candidate chemicals potentially interacting with the proteins encoded by these hub genes, followed by molecular docking to evaluate binding affinities.</p><p><strong>Results: </strong>DDC, KCNJ6, SLC18A2, and SLC6A3 were identified as central to PD pathology, with Benzo(a)pyrene, bisphenol A, Valproic Acid, and Fulvestrant as corresponding chemical agents. Molecular docking demonstrated Benzo(a)pyrene's highest binding affinity, with SLC6A3 emerging as the most vulnerable target among the hub genes.</p><p><strong>Conclusions: </strong>These findings underscore the roles of DDC, KCNJ6, SLC18A2, and SLC6A3 in PD's molecular mechanisms, potentially modulated by the identified chemicals, with Benzo(a)pyrene highlighted as a significant environmental toxin. This study offers novel insights into the genetic and environmental determinants of PD, advancing our understanding of its etiology.</p>","PeriodicalId":10984,"journal":{"name":"Current medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144141615","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Advancements in Structure-based Drug Design Using Geometric Deep Learning.","authors":"Tomojit Bhattacharjee, Rohit Bhatia","doi":"10.2174/0109298673388739250516071228","DOIUrl":"https://doi.org/10.2174/0109298673388739250516071228","url":null,"abstract":"","PeriodicalId":10984,"journal":{"name":"Current medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144141555","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Capsid Assembly Modulators: A Promising Curative Regimen for Chronic Hepatitis B.","authors":"Chunhua Ma, Xiaoyan Zhang, Junbiao Chang, Bin Yu","doi":"10.2174/0109298673388370250512095841","DOIUrl":"https://doi.org/10.2174/0109298673388370250512095841","url":null,"abstract":"","PeriodicalId":10984,"journal":{"name":"Current medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144141606","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Betanin, a Natural Product from Red Beets, Improves Endothelial Dysfunction through Activation of Autophagy.","authors":"Junpei Li, Luyan Xu, Duoduo Zha, Yixiong Zhan, Yijia Wu, Xianxian Mao, Li Zuo, Xinyan Bai, Linsiqi Wang, Kunhua Chen, Jinghua Luo, Yisong Qian","doi":"10.2174/0109298673244974250507034834","DOIUrl":"https://doi.org/10.2174/0109298673244974250507034834","url":null,"abstract":"<p><strong>Objective: </strong>Endothelial dysfunction is the altered pathological ability of endothelial cells to modulate the passage of cells and solutes across vessels, which underlies the development of inflammatory diseases. Betanin (betanidin-5-O-β-glucoside), a natural product rich in red beets, is a water-soluble nitrogen-containing pigment, and its potential protective effects on cardiovascular disease have been reported. In this study, we investigated the protective role of betanin in vascular endothelial dysfunction induced by TNFα and explored potential mechanisms.</p><p><strong>Methods: </strong>We modelled endothelial dysfunction through TNFα stimulation in human umbilical vein endothelial cells (HUVECs) and examined the role of betanin and its possible mechanism of action by MTT assay, western blotting, and immunofluorescence staining. A systemic inflammation model of mice was built through LPS to investigate the protective roles of betanin.</p><p><strong>Results: </strong>Betanin pre-treatment increased cell viability, inhibited the expression of intercellular cell adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM- 1), and improved endothelial tight junction by upregulating the expression of occludin and zonula occludens-1 (ZO-1) after TNFα stimulation in HUVECs. In terms of endothelial-mesenchymal transition, betanin up-regulated the expression of endothelial phenotypes VE-cadherin and CD31, whereas it inhibited the expression of mesenchymal phenotype N-cadherin, indicating that betanin reduced endothelial-mesenchymal transition in TNFα-stimulated HUVECs. In addition, betanin increased the expression of LC3 and decreased the expression of p62, two central proteins in autophagy. Betanin also reversed the abnormal autophagic flux after TNFα exposure. However, the specific autophagy inhibitor, 3-methyladenine, blocked the protective effect of betanin. Finally, betanin was found to greatly decrease ICAM-1 and VCAM-1 expression, and upregulate occludin and ZO-1 levels in a systemic inflammation model of mice.</p><p><strong>Conclusions: </strong>The above results collectively suggested that betanin may improve endothelial dysfunction by promoting autophagy, thus exerting beneficial effects on cardiovascular health.</p>","PeriodicalId":10984,"journal":{"name":"Current medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144141560","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploring New Frontiers in Pharmacological Treatment of Depression: A Review on Recent Advances.","authors":"Muthukumaran Thulasingam, Chitra Vellapandian","doi":"10.2174/0109298673342524250109181220","DOIUrl":"https://doi.org/10.2174/0109298673342524250109181220","url":null,"abstract":"<p><p>The current treatment strategy is still subpar, especially for severe mental problems, despite tremendous progress in the understanding of the central nervous system. Improving healthcare usually entails two main approaches: investigating new treatment approaches and improving current ones. New pharmacological options include enhanced monoaminergic pharmaceuticals, old treatments reassessed with a better knowledge of the biology of mental disease, and medications that target new therapeutic pathways. One major clinical challenge in the treatment of depression is resistance to antidepressant drugs. It appears promising to switch to monotherapy using new multifunctional antidepressants and add new atypical antipsychotics, such as brexpiprazole and aripiprazole. Current efforts are concentrated on unraveling depression's origins and pinpointing fresh targets for pharmacological intervention. This review explores encouraging novel pharmacological avenues for major depressive disorder treatment. These include targeting receptors, such as N-methyl-D-aspartate and metabotropic glutamate receptors, and employing glutamatergic modulators and various augmentation strategies, all of which hold the potential for reversal of depressant effects. Combining innovative concepts with enhancements of existing discoveries may propel antidepressant research forward, offering hope for developing compounds that are effective and rapid in their action, even among patients who have found limited success with other therapies.</p>","PeriodicalId":10984,"journal":{"name":"Current medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144141612","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Construction of PANoptosis-related LncRNA Prognostic Signature and Functional Analysis of AC034229.4 in Hepatocellular Carcinoma.","authors":"Rui He, Ningning Wang, Xiujuan Zheng, Baiming Jin, Xuying Li, Mingqi Li, Shijing Nian, Kewei Wang","doi":"10.2174/0109298673358065250421072252","DOIUrl":"https://doi.org/10.2174/0109298673358065250421072252","url":null,"abstract":"<p><strong>Aims: </strong>This study aimed to establish a PANoptosis related prognostic signature and identify potential prognostic markers and therapeutic targets for HCC.</p><p><strong>Background: </strong>Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide. The survival rate of patients with HCC remains relatively low. PANoptosis can be mediated by lncRNA to involve the pathophysiology of HCC, but the mechanism is still unclear.</p><p><strong>Objective: </strong>TCGA and GEO hepatocellular carcinoma databases and previous research results were used to construct the PANoptosis related risk model.</p><p><strong>Method: </strong>Based on the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) database, this study identified long non-coding RNAs (lncRNAs) associated with PANoptosis in HCC. Univariate, LASSO-Cox, and multivariate COX analyses were employed to gradually screen prognostic lncRNAs and construct prognostic models. Further analysis was conducted on the core lncRNA-AC034229.4.</p><p><strong>Result: </strong>A total of 8 differentially expressed lncRNAs closely correlated with HCC prognosis were discovered. A prognostic model comprising 6 lncRNAs (AC090192.2, LINC01703, AC034229.4, AC073352.1, AC004816.1, and AL136162.1) was established demonstrating good predictive ability for prognosis. Moreover, this prognostic model exhibited close associations with tumor immune microenvironment and immune checkpoints. Subsequent investigations revealed that AC034229.4 independently influenced HCC prognosis by regulating cell cycle progression and inhibiting the immune microenvironment response. Drug sensitivity analysis indicated that AC034229 .4 displayed sensitivity to various anticancer drugs as well. In addition, inhibition of AC034229 .4 expression suppressed HCC migration and invasion abilities.</p><p><strong>Conclusion: </strong>This study generated a novel and efficient prognostic signature model while identifying AC034229 .4 as a promising diagnostic and prognostic biomarker in HCC.</p>","PeriodicalId":10984,"journal":{"name":"Current medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144141608","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cholesteatoma: An Updated Review of Molecular Pathogenesis and Potential Therapeutic Directions.","authors":"Bingwen Xing, Yalong Dang, Kai Xi","doi":"10.2174/0109298673404489250515074316","DOIUrl":"https://doi.org/10.2174/0109298673404489250515074316","url":null,"abstract":"<p><p>Cholesteatoma, an abnormal accumulation of keratinized squamous epithelium in the middle ear, occurs as a locally invasive but histologically benign lesion. Its capacity for bone erosion leads to significant complications, including hearing loss, facial nerve paralysis, and intracranial infections. Chronic inflammation is central to its pathogenesis, with proinflammatory mediators like TNF-α, IL-1β, and IL-6 activating signaling pathways, such as NF-κB, JAK/STAT, and MAPK. These pathways contribute to epithelial hyperproliferation and extracellular matrix degradation mediated by Matrix Metalloproteinases (MMPs). Dysregulation of epithelial cell behavior, involving altered keratinocyte function and reduced E-cadherin-mediated adhesion, may facilitate lesion formation and expansion. Furthermore, aberrant signaling involving growth factors (e.g., EGF, TGF-β) and dysregulation of osteoclast activity via the RANKL pathway contribute to enhanced bone erosion and tissue invasion. Emerging research highlights potential roles of the c-MYC proto-oncogene, microRNAs, and Sonic hedgehog signaling in disease progression, offering deeper insights into the pathogenesis. Current management primarily involves surgical excision, yet high recurrence rates emphasize the need for adjunctive therapeutic strategies. Potential future directions include modulating key pathways, such as NF-κB, MMP activity, and RANKL signaling, as well as exploring interventions related to growth factors and cell adhesion. Integrating molecular insights with clinical research is essential for developing strategies to reduce recurrence and improve patient outcomes.</p>","PeriodicalId":10984,"journal":{"name":"Current medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144110038","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Relationship between 21 Medications and Negative Emotions: A Mendelian Randomization Analysis in Asian Populations.","authors":"Xiaotong Wang, Yuhan Wei, Xi Nie, Yuchuan Zhang, Lan Yang, Weiting Zeng, Kexin Shi, Haixiong Lin","doi":"10.2174/0109298673359046250502104101","DOIUrl":"https://doi.org/10.2174/0109298673359046250502104101","url":null,"abstract":"<p><strong>Objective: </strong>Negative emotional states, such as nervousness, anxiety, depression, and tension, exert profound detrimental effects on an individual's quality of life and overall health. Although certain widely prescribed medications have been observed to modulate these emotional states, the existing body of research in this domain remains insufficient. To address this gap, Mendelian randomization (MR) methodologies, leveraging large-scale datasets, were employed to investigate the causal relationships between 21 commonly utilized medications and the manifestation of negative emotions.</p><p><strong>Methods: </strong>The inverse variance weighting (IVW) method was employed as the primary analytical strategy to analyze causal relationships. MR-Egger, weighted mode, and weighted median approaches were utilized to enhance the robustness of the results. Sensitivity analyses were conducted to assess the stability of the data.</p><p><strong>Results: </strong>Agents acting on the renin-angiotensin system, β-blocking agents, antithrombotic agents, and salicylic acid and derivatives could reduce the risk of nervousness, anxiety, tension, or depression (OR = 0.61, 95% CI 0.37 to 0.99, p = 0.047; OR = 0.59, 95% CI 0.36 to 0.98, p = 0.041; OR = 0.55, 95% CI 0.34 to 0.88, p = 0.013; OR = 0.61, 95% CI 0.40 to 0.95, p = 0.030), with no heterogeneity, horizontal pleiotropy, or reverse causation (p > 0.05).</p><p><strong>Conclusion: </strong>This study revealed four medications to be associated with a reduced risk of negative emotions, providing clinicians with a scientific basis for medication selection to better assist patients in alleviating psychological issues and improving their quality of life.</p>","PeriodicalId":10984,"journal":{"name":"Current medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144110040","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Emerging New Treatments for Colon Cancer.","authors":"Sheu Ibrahim Adedayo, Eva Riethmacher","doi":"10.2174/0109298673372776250505155945","DOIUrl":"https://doi.org/10.2174/0109298673372776250505155945","url":null,"abstract":"<p><p>Colorectal cancer includes cancer of the rectum and colon. It is the primary cause of cancer-related deaths among men under 50 years of age. In 2022, over 1.9 million cases of CRC were reported, resulting in approximately 904,000 deaths worldwide. Factors like smoking, alcohol consumption, obesity, familial history, and inflammation significantly contribute to the risk of CRC development. Additionally, bacterial infections from organisms like Bacteroides fragilis, Fusobacterium nucleatum, and Helicobacter pylori also play a role in increasing this risk. Conventional treatment methods for CRC typically involve surgery/polypectomy, chemotherapy, and radiotherapy. Because of limitations like lack of target specificity, the risk of tumor relapse, and the potential for tumor resistance, there is a growing necessity for more individually tailored treatment strategies to improve the outcomes of patients with CRC. As such, emerging treatments like cancer vaccine, (CAR) T-cells, CAR-NK cells, macrophages, and stem cell engineering (particularly mesenchymal stem cells), dendritic vaccine, siRNA, and miRNA, hold significant promise in enhancing outcomes for CRC patients. Moreover, specific gut microbiomes like Bacteroides fragilis, Streptococcus gallolyticus, Enterococcus faecalis, and Escherichia coli, linked to CRC development, have been identified. Hence, modulating the gut microbiome to potentially enhance responses to CRC in high- -risk populations could be a new line of treatment. This modulation can be accomplished through dietary interventions, prebiotics, probiotics, postbiotics, antibiotics, and fecal microbiota transplantation (FMT). This review summarizes the most promising new emerging treatments in the fight against colon cancer.</p>","PeriodicalId":10984,"journal":{"name":"Current medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":3.5,"publicationDate":"2025-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144101594","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}