Current medicinal chemistry最新文献

{"title":"The Association of Serum Calcium Levels with the Risk of Metabolic Syndrome: A Meta-Analysis of Observational Studies.","authors":"Mi Tian, Jingjie Luan, Xue Li, Yingsheng Pei, Li Lu, Sijie Gu, Airefate Tusunkali, Zhiyi Li, Jia He","doi":"10.2174/0109298673474975260804093837","DOIUrl":"https://doi.org/10.2174/0109298673474975260804093837","url":null,"abstract":"<p><strong>Introduction: </strong>Although some studies have examined the relationship between serum calcium levels and Metabolic Syndrome (MetS), results remain inconsistent, and a quantitative synthesis is lacking. This meta-analysis aims to consolidate existing evidence and clarify the association between serum calcium levels and MetS risk.</p><p><strong>Methods: </strong>We systematically searched seven databases up to May 1, 2025, for observational studies comparing serum calcium in MetS versus non-MetS groups. A random-effects model was applied to pool Odds Ratios (ORs) and Weighted Mean Differences (WMDs) with 95% Confidence Intervals (CIs). Subgroup analyses, sensitivity analyses, and publication bias assessments were also performed.</p><p><strong>Results: </strong>Twenty-three studies (n=67,148) showed a positive association in categorical data analysis (OR=1.79, 95% CI: 1.37-2.34, P<0.0001, I2=82.3%), whereas continuous data did not reveal a significant difference (WMD=0.0107 mmol/L, 95% CI: -0.0078-0.0291, P=0.258, I2=89.4%). Subgroup analysis tentatively suggested a higher MetS risk in elderly (65 years old or older) populations (OR=2.44, 95% CI: 1.70-3.51), though this finding was based on a limited number of studies. Substantial heterogeneity was observed in both analyses.</p><p><strong>Discussion: </strong>These findings suggest a potential association between elevated serum calcium and increased MetS risk, which may follow a nonlinear, threshold-like pattern. The observed age-related difference, while notable, should be interpreted with caution given the small number of studies in the elderly subgroup. The inconsistency between categorical and continuous results underscores the need for standardized protocols and further prospective investigations to clarify the nature of this relationship.</p><p><strong>Conclusion: </strong>Elevated serum calcium may be associated with an increased risk of MetS, with a possibly more pronounced effect suggested in older adults. However, these preliminary observations require validation in well-designed prospective studies with agespecific analyses.</p>","PeriodicalId":10984,"journal":{"name":"Current medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":3.2,"publicationDate":"2026-08-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148886577","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 Inhibitory Impacts of Anamorelin on Colorectal Cancer Proliferation via Regulation of Transketolase.","authors":"Zhenkai Fu, Saiying Wang, Fei Li, Wenna Liu, Yujia Zhao, Dan Wu, An Liu, Ying Liang","doi":"10.2174/0109298673450549260810115103","DOIUrl":"https://doi.org/10.2174/0109298673450549260810115103","url":null,"abstract":"<p><strong>Background/objectives: </strong>Colorectal cancer (CRC) is a major cause of cancer- related deaths worldwide and poses a significant global health challenge. Metabolic reprogramming, including transketolase (TKT) upregulation in the pentose phosphate pathway, is a hallmark of CRC. Drugs targeting TKT have shown promise in cancer treatments; however, their mechanisms are poorly understood.</p><p><strong>Methods: </strong>In this study, by integrating bioinformatics analysis of 494 cases from the TCGA database, we identified that transketolase (TKT) may be a potential key target for colorectal cancer. Furthermore, we systematically screened the Natural Product Library for HTS (L6000) TargetMol using molecular docking technology.</p><p><strong>Results: </strong>Anamorelin was identified, which exhibited optimal spatial matching with the ligand in the target protein crystal structure. As a selective growth hormone secretagogue receptor (GHS-R) agonist, anamorelin has been clinically demonstrated to significantly improve appetite and increase lean body mass in patients with CRC by activating the GHS-R signaling pathway and is currently used for treating cancer cachexia in patients with advanced CRC. However, existing research has primarily focused on its metabolic benefits, and its direct effects on tumor cell proliferation, migration, and related molecular mechanisms remain unclear. This study elucidated the regulatory relationship between anamorelin and TKT in CRC, thereby addressing a critical knowledge gap in this field (Fig. 1).</p><p><strong>Discussion: </strong>These findings reveal a previously unrecognized antitumor mechanism of anamorelin through TKT inhibition. These findings provide preliminary evidence of a TKT-associated mechanism of anamorelin in CRC, offering dual benefits in cachexia management and tumor suppression, and warrant further validation in advanced preclinical models. Further preclinical and clinical validation is warranted to translate these insights into practice.</p><p><strong>Conclusion: </strong>By integrating bioinformatics analysis with in vitro cellular experiments, we systematically validated the molecular mechanism whereby anamorelin inhibited tumor cell proliferation and migration via the targeted suppression of TKT. These findings provide a theoretical foundation for the development of novel metabolism-based therapeutic strategies for CRC, ultimately contributing to improved clinical outcomes.</p>","PeriodicalId":10984,"journal":{"name":"Current medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":3.2,"publicationDate":"2026-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148886516","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":"CDC20B Dysregulation: Links to Tumor Prognosis and Immunity.","authors":"Hongrong Wu, Liangli Hong","doi":"10.2174/0109298673463433260729044815","DOIUrl":"https://doi.org/10.2174/0109298673463433260729044815","url":null,"abstract":"<p><strong>Objective: </strong>This study aimed to clarify the pan-cancer expression pattern, upstream regulatory mechanisms, prognostic relevance, and immune associations of CDC20B.</p><p><strong>Method: </strong>Using public databases (GTEx, GEO, and TCGA), we examined CDC20B expression and its associations with prognosis and tumor immunity across multiple cancers. Immunohistochemistry (IHC) on an independent clinical cohort was performed to validate CDC20B upregulation in tumor tissues. Promoter methylation, genetic alterations, and immune infiltration were analyzed using bioinformatics tools (cBioPortal, UALCAN, TIMER2.0, ESTIMATE). Functional enrichment was assessed by GSEA and single-cell state analysis (CancerSEA).</p><p><strong>Results: </strong>CDC20B was markedly upregulated in most tumor types (p < 0.001), with strong diagnostic efficiency (AUC > 0.7 in 15 cancers) and potential regulation by promoter hypomethylation. IHC confirmed its overexpression in clinical tumor tissues. However, the prognostic impact of CDC20B was cancer-type-specific: high expression correlated with poor overall survival in UCS, LGG, KIRC, and OV, but with favorable survival in BRCA, LUAD, and PAAD. CDC20B expression was associated with immune infiltration patterns, showing negative correlations with ImmuneScore in most cancers but positive correlations with CD8+ T cells in PAAD. Functional analyses indicated involvement in EMT, KRAS/NF-κB signaling, and DNA damage response pathways.</p><p><strong>Discussion: </strong>The dual prognostic role of CDC20B suggests context-dependent functions, likely influenced by tumor microenvironment composition and underlying oncogenic programs. Promoter hypomethylation emerges as a potential epigenetic driver of overexpression. The associations with immune modulation and genomic instability suggest that CDC20B is a candidate biomarker, though causal relationships require experimental validation.</p><p><strong>Conclusion: </strong>CDC20B may contribute to tumor progression in a context-dependent manner, with its prognostic impact varying across cancer types. Its role in tumor immunity and oncogenic pathways warrants further investigation, particularly in stratified patient populations.</p>","PeriodicalId":10984,"journal":{"name":"Current medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":3.2,"publicationDate":"2026-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148886462","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":"Applications of Graphene in Biomedical Fields and Advances in Its Antitumor Research.","authors":"Huifang Zang, Yan Gao, Lu Liu, Yifei Wang, Jing Lyu, Bonian Zhao","doi":"10.2174/0109298673450850260804060949","DOIUrl":"https://doi.org/10.2174/0109298673450850260804060949","url":null,"abstract":"<p><p>Graphene is a two-dimensional crystal formed by carbon atoms through sp2 hybridization, exhibiting exceptional physicochemical properties such as ultra-high strength, high specific surface area, and outstanding chemical stability. It has garnered extensive attention across multiple fields and emerged as a core focus in interdisciplinary research. This paper systematically reviews the fundamental information and key physicochemical properties of graphene and its derivatives, elucidating their differences in structure, performance, and functionality. It analyzes the research progress of graphene-based materials over the past decade, focusing on the latest achievements in the biomedical field. Based on graphene heating films, this study delves into the mechanism of far-infrared radiation. This study systematically addresses core issues in biomedical applications. It focuses particularly on variations in biocompatibility and safety, as well as potential influencing factors. Existing biomedical applications of graphene and its derivatives are enumerated, elucidating the biological activity of graphene's far-infrared radiation. Its antitumor mechanisms are analyzed at both in vitro and in vivo levels, though relevant clinical research data remains scarce. This underscores the immense application potential and translational value of graphene-based materials in biomedicine. Finally, it analyzes existing barriers in the graphene industry from three aspects: standard establishment, safety assessment, and mechanism clarification. It identifies priority development directions for graphene materials: improving the quality standards system, optimizing safety and biocompatibility, supplementing clinical data, and deepening research on therapeutic mechanisms. These are key prerequisites for graphene-based materials to break through laboratory research limitations and advance toward clinical application, which is crucial for accelerating their industrialization in the biomedical field.</p>","PeriodicalId":10984,"journal":{"name":"Current medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":3.2,"publicationDate":"2026-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148886413","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":"Apigenin Protects Against Ischemic Stroke Through Anti- Inflammatory Mechanisms: A Study Combining Comprehensive Network Analysis, Mendelian Randomization and Animal Experiments for Validation.","authors":"Jinwen Yao, Xu Wang, Dexi Zhao","doi":"10.2174/0109298673468784260728054736","DOIUrl":"https://doi.org/10.2174/0109298673468784260728054736","url":null,"abstract":"<p><strong>Background and objective: </strong>There is a well-established link between inflammation and Ischemic Stroke (IS) pathology. A natural compound, Apigenin (APG), has a neuroprotective effect. However, the specific mechanisms underlying the anti-inflammatory effects of APG and its protective effects on the blood-brain barrier following IS are unclear. This study aimed to explore the mechanisms behind the anti-inflammatory effect of APG in IS.</p><p><strong>Methods: </strong>Male Sprague-Dawley rats were used to establish a model of unilateral middle cerebral artery occlusion (MCAO) and were administered APG by oral gavage at doses of 30, 60, or 120 mg/kg for 7 days. On the following day, brain tissues were collected after MCAO. Brain injury was evaluated by measuring brain water content, hematoxylin and eosin (H&E) staining, and Evans blue extravasation. To investigate potential proteins associated with inflammation, methods such as molecular docking, molecular dynamics simulations, Mendelian randomization analysis, immunohistochemistry, and Western blotting were employed.</p><p><strong>Results: </strong>APG therapy has improved neurological deficiencies, lowered brain edema, and improved blood-brain barrier integrity. It has also resulted in decreased levels of inflammatory proteins TLR4, MyD88, NFκB, IL1β, MMP9, and iNOS after IS. Furthermore, IL1R2 was identified as a potential predictive target for IS.</p><p><strong>Discussion: </strong>APG can repair nerve damage post-IS, with its protective effects mediated by anti-inflammatory mechanisms. The TLR4/myD88/NF-kB signaling pathway is a protective pathway of the body. APG may exert a protective effect on the blood-brain barrier after IS through the TLR4/MyD88/NF-kB signaling pathway.</p><p><strong>Conclusion: </strong>APG can protect against IS by inhibiting the inflammatory response, providing a theoretical basis for clinical translation and further experimental research of APG.</p>","PeriodicalId":10984,"journal":{"name":"Current medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":3.2,"publicationDate":"2026-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148863872","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":"Integrated Transcriptomic Analysis and Molecular Modeling Identify ENO1 and Naftopidil as Candidates for Chronic Myelomonocytic Leukemia.","authors":"Minming Li, Suxia Geng, Lingji Zeng, Jianyu Weng, Xin Huang, Chengxin Deng, Xin Du","doi":"10.2174/0109298673521243260810063309","DOIUrl":"https://doi.org/10.2174/0109298673521243260810063309","url":null,"abstract":"<p><strong>Introduction: </strong>In-depth analysis of the biological status of Hematopoietic Stem Cells (HSCs) may reveal the intrinsic pathological mechanism of Chronic Myelomonocytic Leukemia (CMML).</p><p><strong>Materials and methods: </strong>Single-cell dataset GSE211033 and bulk transcriptomic dataset GSE102312 were analyzed. Single-cell preprocessing was performed using the Seurat package, cell-cell communication was analyzed with CellChat, and HSC-associated co-- expression modules were identified via hdWGCNA. Pathway and candidate-compound analyses were conducted using Enrichr with the DSigDB database. Molecular docking and a 100 ns molecular dynamics simulation were performed with GROMACS 2025, and the function of ENO1 was preliminarily assessed in myeloid leukemia cell lines.</p><p><strong>Results: </strong>Ten major cell populations were identified, among which HSCs comprised 14,729 cells. Seven HSC co-expression modules were classified. Among 25 genes represented in the M1 hub-gene network, ENO1 was the only evaluated candidate that showed a distinct difference between CMML samples and healthy controls. ENO1 knockdown reduced the viability of HL-60 and MV-4-11 cells in a time-dependent manner. High ENO1 expression was associated with enrichment of cell-cycle, DNA damage- response, and energy-metabolism pathways. Naftopidil ranked first among the significant HL-60-associated candidates screened from the DSigDB. Molecular docking and 100 ns molecular dynamics simulation revealed that the ligand dynamically interacted with ENO1 following conformational rearrangement, although direct binding remains to be experimentally validated.</p><p><strong>Discussion: </strong>ENO1 emerged as an HSC-associated candidate gene with a potential role in supporting the metabolic and proliferative state of CMML-related hematopoietic cells. Naftopidil was computationally predicted as a candidate ENO1-binding compound, but its direct binding and therapeutic activity require experimental validation.</p><p><strong>Conclusion: </strong>These findings provide a hypothesis-generating basis for further investigation of ENO1 and naftopidil in CMML-specific models, primary samples, and in vivo studies.</p>","PeriodicalId":10984,"journal":{"name":"Current medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":3.2,"publicationDate":"2026-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148863866","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":"Artepillin C as a Potential Anticancer Phytochemical: Chemistry, Bioavailability and Preclinical Insights.","authors":"Wesam Nofal, Abdulaziz A Aloliqi, Md Ali Mujtaba, Sorabh Lakhanpal, Shivani Sharma, Meenakshi Verma, Pratibha Pandey, Fahad Khan","doi":"10.2174/0109298673493386260711092835","DOIUrl":"https://doi.org/10.2174/0109298673493386260711092835","url":null,"abstract":"<p><p>Numerous plants are significant sources of bioactive chemicals with diverse therapeutic efficacy against numerous cancer types. Since ancient times, numerous plant types and their phytochemicals have been used for traditional and contemporary medicinal applications. Artepillin C (AC) is a biologically active phenolic component and prenylated derivative of p-coumaric acid of Brazilian green propolis (BGP), which is derived from Baccharis dracunculifolia (native to central and southeastern regions of Brazil). AC, the primary chemical marker of green propolis, is a key factor in its therapeutic efficacy. Several studies have substantiated its pharmacological activities, including neuroprotective, anti-inflammatory, antidiabetic, antitumor, gastroprotective, antioxidant, antimicrobial, and immunomodulatory effects. This review not only explains its anticancer potential but also explains its chemical properties, bioavailability, and production. Thus, we selected this compound for a thorough overview of its anticancer effects. A limited number of studies on this compound from the last 15 years have been synthesized from Science Direct, Medline, PubMed, Scopus, and Google Scholar search engines. Therefore, this review consolidates widespread research from 2010 to 2025 related to the pharmacological and anticancer efficacy of AC, which may potentiate its candidature as a potent anticancer drug for future research and therapeutic applications.</p>","PeriodicalId":10984,"journal":{"name":"Current medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":3.2,"publicationDate":"2026-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148863953","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":"T Cell-associated Co-expression Module Genes as Prognostic Biomarkers and Predictors of Immunotherapy Response in Head and Neck Squamous Cell Carcinoma.","authors":"Qingmiao Shi, Zhenzhen Qi, Bingyang Shang, Xiaonan Geng, Zhibo Zhang, Di Huang, Xinjun Hu","doi":"10.2174/0109298673513005260806080704","DOIUrl":"https://doi.org/10.2174/0109298673513005260806080704","url":null,"abstract":"<p><strong>Introduction: </strong>The important roles of T cells in tumor progression support the development of a T cell-associated prognostic model for Head and Neck Squamous Cell Carcinoma (HNSCC).</p><p><strong>Methods: </strong>The single-cell RNA-seq (scRNS-seq) data from GSE181919 were processed via the Seurat package for quality control and cell annotation. hdWGCNA was used to identify T cell-associated co-expression modules. Key genes were screened by univariate and LASSO Cox regression in TCGA to build a RiskScore model, followed by validation in the GSE41613 and GSE117973 datasets. The correlations of the RiskScore with the immune microenvironment, predicted immunotherapy response, and drug sensitivity were analyzed, and preliminary in vitro assays were conducted to explore PIM2 function in HNSCC cells.</p><p><strong>Results: </strong>Ten cell populations were identified in HNSCC tissues, with T cells representing one of the major cell populations. An eight-gene RiskScore model (TNFRSF4, TNFRSF18, PIM2, CORO1B, CUL9, SOD1, ZC3H12D, and TUBA1B) was established, showing moderate but significant prognostic value. High-risk patients exhibited significantly poorer survival. A nomogram integrating the RiskScore and clinical features was further constructed. Additional analyses supported the prognostic value of the model in HPV-negative patients and showed that the RiskScore was independently associated with overall survival after adjustment for tumor purity. C-index comparisons further revealed higher and relatively consistent prognostic discrimination compared with two previously published HNSCC models. The high-risk group exhibited lower ImmuneScore, StromalScore, ESTIMATEScore, higher TIDE scores, and reduced immune infiltration. The RiskScore was significantly correlated with 11 candidate compounds, and preliminary in vitro assays showed that PIM2 knockdown suppressed malignant phenotypes of HNSCC cells.</p><p><strong>Discussion: </strong>The scRNS-seq and hdWGCNA analyses identified eight T cell-associated module genes related to HNSCC prognosis. High- and low-risk patients stratified by the RiskScore exhibited distinct immune infiltration and angiogenesis in their Tumor Microenvironment (TME). Drug sensitivity analysis predicted candidate compounds for HNSCC treatment, but further experimental and clinical validation is required.</p><p><strong>Conclusion: </strong>The T cell-associated prognostic model was associated with immune microenvironment features and predicted treatment response and may help predict HNSCC prognosis, providing candidate biomarkers for further investigation.</p>","PeriodicalId":10984,"journal":{"name":"Current medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":3.2,"publicationDate":"2026-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148808369","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":"Blocking the RhoA/ROCK/cofilin/F-actin Pathway via Y27632 Protects Against MERTK-deficient Retinal Degeneration and Visual Function Impairment.","authors":"Lujia Feng, Ting Zhang, Yong Du, Yingyan Qin, Linbin Zhou, Bingyu Bai, Manjuan Peng, Lu Chen, Jin Ma, Shaochong Zhang","doi":"10.2174/0109298673436432260728094713","DOIUrl":"https://doi.org/10.2174/0109298673436432260728094713","url":null,"abstract":"<p><strong>Introduction: </strong>Retinitis pigmentosa (RP) is the most common inherited neurodegenerative retinal disease. Mer receptor tyrosine kinase (MERTK) mutations are associated with severe RP and dysfunction of the RPE. Previous studies have shown that MERTK and the Rho-associated coiled-coil-containing kinases (ROCK) pathway are involved in phagocytosis. However, the specific role of the ROCK pathway in the context of MERTK-associated RP needs to be revealed.</p><p><strong>Methods: </strong>We established an in vitro RP cellular model via MERTK depletion in human primary retinal pigment epithelium (HsRPE) cells by siRNAs, and RCS rats with spontaneous Mertk mutations were used as RP experimental animal models. Cell viability, apoptosis, phagocytosis, and visual function were measured by MTT, TUNEL and Annexin V/propidium iodide staining, phagocytosis assays and transmission electron microscopy, and electroretinography, respectively. The expression of RhoA, ROCK, Factin, and cofilin was determined by quantitative real-time PCR, western blotting, or immunofluorescence staining.</p><p><strong>Results: </strong>MERTK knockdown substantially impaired cell survival, promoted apoptosis, and suppressed phagocytosis in HsRPE cells. In RCS rats, Mertk mutations impaired phagocytosis, promoted apoptosis of the RPE, and damaged visual functions. Silencing MERTK upregulated the phosphorylation of RhoA, ROCK2, and cofilin and decreased F-actin expression in HsRPE cells. Blocking the RhoA/ROCK axis by a selective ROCK inhibitor, Y27632, rescued the MERTK depletion-induced phagocytic dysfunction and apoptosis of HsRPE cells and rat RPE.</p><p><strong>Discussion: </strong>Our results collectively indicate that MERTK maintains RPE survival and phagocytosis via regulating the RhoA/ROCK/cofilin/F-actin axis.</p><p><strong>Conclusion: </strong>This study demonstrates that MERTK deficiency impairs RPE phagocytosis and promotes cell apoptosis, leading to retinal degeneration and visual dysfunction. These findings provide new insight into RP pathogenesis and thereby offer valuable references for future drug development.</p>","PeriodicalId":10984,"journal":{"name":"Current medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":3.2,"publicationDate":"2026-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148808001","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":"Design and Evaluation of Naphthoxy and Phenoxy amide as Potential PARP 1 inhibitors: Molecular Docking and In Vitro Analysis.","authors":"Hardha Balachandran, Subhajit Majumder, Gowramma Byran, Kalirajan Rajagopal, Vishnu Kumar Malakar, Kaviarasan Lakshmanan","doi":"10.2174/0109298673424861260602102534","DOIUrl":"https://doi.org/10.2174/0109298673424861260602102534","url":null,"abstract":"<p><strong>Introduction: </strong>The objective was to design, synthesize, and evaluate novel naphthoxy and phenoxy amide derivatives as potential poly(ADP-ribose) polymerase-1 (PARP1) inhibitors, aiming to identify compounds with improved binding affinity, favorable pharmacokinetic properties, and enhanced anticancer activity compared with existing PARP1 inhibitors.</p><p><strong>Methods: </strong>A series of naphthoxy and phenoxy amide derivatives (A1-A9 and B1-B9) were evaluated using combined computational and experimental approaches. Molecular docking against PARP1 (PDB ID: 4ZZZ) was performed using Glide to assess binding affinity. ADMET and drug-likeness properties were predicted via SWISS-ADME, and binding free energies were refined using Prime MM-GB/SA. The lead compound B2 underwent a 50-ns molecular dynamics simulation using Desmond. In vitro cytotoxicity was assessed against MCF-7 human breast cancer cell lines.</p><p><strong>Results: </strong>Compounds B2 and B3 exhibited strong docking scores comparable to the reference PARP1 inhibitor and demonstrated favourable ADMET profiles. MM-GB/SA analysis supported their high binding affinity toward PARP1. Molecular dynamics simulations revealed that compound B2 formed a stable complex within the PARP1 active site. In vitro assays showed enhanced cytotoxic activity of B2 against MCF-7 cells.</p><p><strong>Discussion: </strong>The findings highlight the effectiveness of combining computational and biological approaches to identify promising PARP1 inhibitors, with B2 showing strong binding, stability, and cytotoxicity, despite lacking in vivo validation.</p><p><strong>Conclusion: </strong>Overall, compound B2 emerged as a promising PARP1 inhibitor with strong binding affinity, structural stability, and significant in vitro anticancer activity, warranting further optimization and preclinical investigation.</p>","PeriodicalId":10984,"journal":{"name":"Current medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":3.2,"publicationDate":"2026-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148808248","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}