Current medicinal chemistry最新文献

{"title":"Endoplasmic Reticulum Stress Drives Carotid Atherosclerotic Plaque Instability: Integrative Insights into Biomarkers and Therapeutic Targets.","authors":"Haifeng Zhou, Zhiwei Zhang, Jianhuang Huang, Zhanghui Ding","doi":"10.2174/0109298673431652260305070957","DOIUrl":"https://doi.org/10.2174/0109298673431652260305070957","url":null,"abstract":"<p><strong>Objective: </strong>Carotid atherosclerosis is a leading cause of stroke, with plaque rupture closely linked to endoplasmic reticulum stress (ERS). However, the precise mechanisms of ERS in plaque instability remain incompletely understood. This study aims to investigate the role of ERS in carotid plaque instability, identify potential biomarkers, and screen candidate therapeutic drugs.</p><p><strong>Methods: </strong>Transcriptomic data from the Gene Expression Omnibus (GEO) database (GSE43292 and GSE163154) were analyzed using differential expression analysis, weighted gene co-expression network analysis (WGCNA), and machine learning approaches (Elastic Net, RFE-SVM, GBM) to identify ERS-related differentially expressed genes (ERS-DEGs). The expression, apoptosis, and inflammatory responses of ERS marker genes were validated using qRT-PCR, flow cytometry, and ELISA. CIBERSORT was employed to assess immune cell infiltration, and the Enrichr database was used for drug prediction.</p><p><strong>Results: </strong>Four ERS marker genes (TFRC, APOE, NLRP3, NOD2) were identified, showing significantly higher expression in the unstable plaque model (ox-LDL+TNF-α) compared to the stable model (p<0.01), with NLRP3 upregulation being particularly pronounced. Knockdown of these genes significantly reduced apoptosis rates and IL-1β/IL-6 secretion in HUVECs and THP-1-derived macrophages in the unstable model (p<0.01). Immune cell infiltration analysis revealed increased M0 macrophage abundance and decreased CD8+ T cell presence in unstable plaques. Drug prediction identified Bupropion and Triamcinolone as candidate drugs with potential therapeutic value.</p><p><strong>Discussion: </strong>ERS drives carotid plaque instability by regulating inflammation and apoptosis. The identified marker genes serve as potential biomarkers, offering novel targets for the diagnosis and treatment of atherosclerosis. The candidate drugs provide directions for future clinical interventions.</p><p><strong>Conclusion: </strong>This study suggests that ERS contributes to carotid plaque instability and identifies TFRC, APOE, NLRP3, and NOD2 as genes of interest with potential diagnostic value. Bupropion and triamcinolone emerged as in silico predicted compounds warranting further investigation. These findings provide exploratory insights into ERS in human carotid atherosclerosis and highlight directions for future studies.</p>","PeriodicalId":10984,"journal":{"name":"Current medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":3.2,"publicationDate":"2026-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149179962","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":"Melatonin and Diabetic Nephropathy: From Mechanistic Pathways to Translational Opportunities in Clinical Management.","authors":"Mohammad Saleh Chapani, Kosar Ostadmohammadi, Mohammad Moulaei-Arani, Mohadese Sattari-Arani, Ghodratollah Panahi, Seyed Masoud Moeini Taba, Mahboobe Sattari-Arani","doi":"10.2174/0109298673480116260915111102","DOIUrl":"https://doi.org/10.2174/0109298673480116260915111102","url":null,"abstract":"<p><strong>Introduction/objective: </strong>Diabetic Nephropathy (DN) remains a leading cause of end-stage renal disease worldwide, characterized by a complex interplay of oxidative stress, chronic inflammation, and circadian rhythm disruption. Despite standard-of-care treatments like RAS inhibitors and newer agents like SGLT2 inhibitors and GLP-1 receptor agonists, a significant residual risk for renal progression persists. Melatonin, a pleiotropic pineal hormone, has emerged as a potential adjunctive therapy due to its potent antioxidant and anti-inflammatory properties. This article is a narrative review, incorporating elements of a systematic literature-search strategy, and aims to synthesize the molecular mechanisms of melatonin in DN, evaluate the current preclinical and clinical evidence for its efficacy, and discuss its potential integration into precision-based treatment protocols.</p><p><strong>Methods: </strong>A comprehensive search of electronic databases (PubMed, Scopus, Web of Science) was conducted to identify relevant preclinical and clinical studies published through mid-2025 focusing on melatonin's role in DN and its interaction with standard therapies.</p><p><strong>Results: </strong>Preclinical evidence robustly demonstrates that melatonin mitigates renal injury by inhibiting NF-κB-mediated inflammation, activating Nrf2-driven antioxidant defenses, and restoring SIRT1-mediated mitophagy to preserve mitochondrial function. Emerging clinical data suggest that melatonin may improve markers of insulin resistance and oxidative stress; however, its metabolic effects are context-dependent and influenced by genetic variants. Furthermore, melatonin shows potential synergistic effects when combined with SGLT2 inhibitors and GLP-1 receptor agonists in animal models.</p><p><strong>Discussion: </strong>The available findings support the potential of melatonin as an adjunctive approach in DN by targeting interconnected oxidative, inflammatory, mitochondrial, and circadian mechanisms. However, the current evidence base remains predominantly preclinical, and clinical evidence is still limited.</p><p><strong>Conclusion: </strong>Melatonin represents a promising adjunctive agent for DN. However, translating its experimental success to clinical practice requires well-powered, multicenter trials. Future research should prioritize precision trial designs using molecular biomarkers and chronotherapeutic dosing to optimize therapeutic outcomes and long-term safety.</p>","PeriodicalId":10984,"journal":{"name":"Current medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":3.2,"publicationDate":"2026-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149079766","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":"Synthetic Approach and Antibacterial Potential of 1,3,4-Oxadiazole: A Comprehensive Review.","authors":"Swati Srivastava, Alok Kumar Srivastava, Chandra Prakash Singh, Davendra Pratap Rao","doi":"10.2174/0109298673472439260803062349","DOIUrl":"https://doi.org/10.2174/0109298673472439260803062349","url":null,"abstract":"<p><p>Presently, antimicrobial resistance (AMR) is a major global problem, aggravated by the mismanagement of available antibiotics. This not only makes the treatment of patients difficult but also leads to longer hospital stays and increased mortality. Many available antibiotics have lost their efficacy due to excessive and uncontrolled use on plants and animals. Therefore, it is desirable to develop a new generation of antibiotic drugs that can effectively cure diseases and provide rapid relief to patients. The 1,3,4- oxadiazole moiety, which exhibits various biological activities, including antifungal, antibacterial, anticancer, anti-inflammatory, and analgesic, has attracted the attention of medicinal chemists for developing novel drugs to address AMR. This review paper aims to provide a valuable resource for investigators interested in this area of research and is divided into two sections based on the medicinal features of 1,3,4-oxadiazole. The first section covers various synthetic procedures for preparing derivatives of heterocyclic compounds containing a 1,3,4-oxadiazole core, and the second section focuses on the antibacterial activity of the synthesized compounds.</p>","PeriodicalId":10984,"journal":{"name":"Current medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":3.2,"publicationDate":"2026-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149036812","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":"Phenotypic Plasticity of Tumor-Associated Neutrophils in the Solid Tumor Microenvironment and Emerging Interventions.","authors":"Dan Wei, Ruixue Lu, Donglin Li, Hongjia Dou, Junling Han, Tianyu Cao","doi":"10.2174/0109298673469435260908062541","DOIUrl":"https://doi.org/10.2174/0109298673469435260908062541","url":null,"abstract":"<p><p>Tumor-associated neutrophils (TANs) are a highly dynamic and key component of the tumor microenvironment (TME) in solid tumors and are characterized by an exceptional degree of phenotypic plasticity and functional heterogeneity. TANs play an important role in the control of tumor evolution, metastasis, immune suppression, and therapeutic resistance. The heterogeneity of TANs is reflected in their protumor (TAN2) or antitumor (TAN1) behaviors, which depend on the signals provided by the TME, such as cytokines, metabolism, and epigenetic changes. New developments in single cell RNA sequencing and spatial transcriptomics have also revealed a range of TAN subpopulations in addition to the original TAN1/TAN2 dichotomization. Protumor TANs aid in angiogenesis, metastasis, extracellular matrix remodeling, and immunosuppression, and anti-tumor TANs play a role in cytotoxicity, antibody-dependent cellular cytotoxicity (ADCC), antigen presentation, and the promotion of adaptive immunity. This review provides a summary of the phenotypic plasticity of TANs, their dual function in solid tumors, and the underlying mechanisms. In addition, this review explains the therapeutic approaches using TANs in cancer therapy, such as blocking pro-tumor actions, reconfiguring TANs to an antitumor phenotype, restructuring the immune microenvironment, and creating novel advanced nanomedicines. This article highlights the importance of focusing on neutrophils and improving the management of solid tumors by combining their biological properties with a discussion of the possible mechanisms and limitations connected to neutrophil heterogeneity and plasticity. In addition, a fresh perspective for interpreting basic neutrophil studies in clinical practice is provided.</p>","PeriodicalId":10984,"journal":{"name":"Current medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":3.2,"publicationDate":"2026-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149036765","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":"Primary Aldosteronism: Reassessing Underdiagnosis, Overdiagnosis, and Clinical Decision-Making.","authors":"Gamze Akkus, Aslı Boz, Tamer Tetiker","doi":"10.2174/0109298673475866260914114648","DOIUrl":"10.2174/0109298673475866260914114648","url":null,"abstract":"<p><p>Primary Aldosteronism (PA) is postulated to represent one of the most prevalent and significant etiologies of secondary hypertension. A majority of investigations have indicated that the incidence of PA has been escalating, particularly within the cohort of normokalemic individuals. PA generally constitutes an adrenal pathology characterized by excessive production of aldosterone, which may occur bilaterally or unilaterally. The evaluation for Primary Aldosteronism (PA) is alarmingly inadequate, frequently postponed until a substantial duration after the identification of hypertension, generally occurring after the onset of significant adverse health outcomes. This situation may, in part, stem from prevalent misconceptions that PA exists solely in conjunction with hypokalemia, adrenal macro-nodules, markedly elevated levels of aldosterone, or severely elevated blood pressure. Despite the effective methods for diagnosing and treating PA, it remains markedly underdiagnosed and undertreated. The screening and diagnosis of Primary Aldosteronism represent a critical advancement for the timely management of the condition; however, it can occasionally pose significant challenges for healthcare professionals. As a screening methodology, the plasma aldosterone concentration to renin ratio continues to serve as a pragmatic and dependable indicator, acknowledging that aldosterone levels are affected by numerous confounding variables, including ethnicity, gender, pharmacological agents, and the timing of measurements. This review aimed to highlight the optimal conditions for measuring plasma aldosterone levels and discuss who should undergo PA screening and when. It also aims to critically reassess clinical outcomes, diagnostic methodologies, and treatment strategies related to Primary Aldosteronism through the presentation of a detailed case report. Furthermore, this review emphasizes the diagnostic methodologies that should be prioritized in clinical practice by elucidating a specific case.</p>","PeriodicalId":10984,"journal":{"name":"Current medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":3.2,"publicationDate":"2026-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149036782","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":"Comparative Evaluation of Five Obesity Indices for Cardiovascular and All-Cause Mortality Prediction in Prediabetes and Diabetes Population: A Prospective Cohort.","authors":"Dexiang Xia, Rui Li, Chang Shu, Lei Zhang, Xin Li","doi":"10.2174/0109298673481562260914095259","DOIUrl":"https://doi.org/10.2174/0109298673481562260914095259","url":null,"abstract":"<p><strong>Background: </strong>In the US population, the association and predictive performance of obesity indices -- Body Mass Index (BMI), Body Shape Index (ABSI), Body Roundness Index (BRI), Waist Circumference (WC), and Waist-to-Height Ratio (WHtR) with mortality outcomes Cardiovascular Mortality (CVM) and All-Cause Mortality (ACM)) in prediabetes and diabetes (DM) populations have not been systematically evaluated.</p><p><strong>Methods: </strong>Utilizing NHANES data (prediabetes: n = 10,988, DM: n = 5,868), we evaluated these associations and predictive ability using Kaplan-Meier curves, multivariable Cox proportional hazards models, Restricted Cubic Splines (RCS), and time-dependent ROC analysis, and performed subgroup analyses to assess heterogeneity.</p><p><strong>Results: </strong>BMI/BRI/WC/WHtR generally displayed patterns consistent with the \"obesity paradox\", while ABSI did not clearly conform to this paradox. In two-piecewise Cox models, ABSI was not associated with CVM but demonstrated a significant, non-paradox association with ACM in DM at higher ABSI levels. RCS revealed nonlinear associations for BMI/BRI/WC/WHtR, while ABSI showed a nonlinear association only with ACM (inflection point: prediabetes = 0.82, DM = 0.77). In unadjusted ROC analyses, ABSI generally showed higher discriminative ability for mortality outcomes; however, after full adjustment, AUC values became similar across indicators. Subgroup analyses further indicated that the predictive performance of these indicators varied across different smoking statuses, race, and sex.</p><p><strong>Discussion: </strong>The \"obesity paradox\" observed in BMI/BRI/WC/WHtR likely reflects their inability to distinguish fat from muscle. ABSI, which primarily captures central adiposity, did not clearly conform to this paradox; however, its incremental predictive value diminished after adjustment, suggesting substantial overlap with conventional risk factors.</p><p><strong>Conclusion: </strong>Unlike BMI, BRI, WC, and WHtR, ABSI did not display a clear \"obesity paradox\" pattern and showed higher unadjusted discrimination for mortality outcomes, although this advantage was attenuated after full adjustment, suggesting it may provide complementary risk information.</p>","PeriodicalId":10984,"journal":{"name":"Current medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":3.2,"publicationDate":"2026-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149036754","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":"Artificial Intelligence-Driven Strategies for Predicting, Personalizing, and Optimizing Therapeutic Targets in Inflammatory Bowel Disease.","authors":"Priyanka Paul, Ankush Kumar, Rajwinder Kaur, Rohit Bhatia, Rajesh K Singh","doi":"10.2174/0109298673466687260709050745","DOIUrl":"https://doi.org/10.2174/0109298673466687260709050745","url":null,"abstract":"<p><p>Inflammatory bowel diseases (IBD), including Crohn's disease and ulcerative colitis, represent chronic relapsing inflammatory disorders characterized by complex interactions among genetic, microbiome-related, immunological, and environmental factors. Although advances in biologics and small-molecule inhibitors have expanded therapeutic options, substantial variability in treatment response, drug resistance, and unpredictable disease progression remain major clinical challenges. Recent breakthroughs in artificial intelligence (AI), particularly machine learning and deep learning, have reshaped current approaches to understanding IBD pathogenesis, identifying druggable molecular targets, and optimizing patient-specific treatment strategies. AI-based models have demonstrated strong potential in predicting disease trajectories, stratifying patients, detecting therapeutic biomarkers, and accelerating target identification in drug discovery pipelines. Moreover, integrative AI frameworks combining multi-omics data, endoscopic imaging, and electronic health records enable real-time, personalized decision-making and improved evaluation of therapeutic response. This review summarizes emerging AI-driven methodologies for drug target discovery, personalized therapy optimization, and clinical outcome prediction in IBD. Additionally, we outline current limitations, translational challenges, and future directions for incorporating AI into precision medicine frameworks aimed at reducing chronic inflammation and improving long-term disease management.</p>","PeriodicalId":10984,"journal":{"name":"Current medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":3.2,"publicationDate":"2026-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149036797","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":"Research on the Role and Mechanism of Rehmannioside D in Regulating Fracture Healing.","authors":"Ying Li, Xibin Wang, Xipeng Yue, Wanyue Li, Jiahuan Gao, Xiguo Cai, Yang Yang, Chang Wang, Weisheng Zhuang","doi":"10.2174/0109298673463194260907075910","DOIUrl":"https://doi.org/10.2174/0109298673463194260907075910","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Introduction: &lt;/strong&gt;Rehmannioside D (RD), a characteristic iridoid glycoside from Rehmannia glutinosa, possesses antioxidant and bone metabolism-regulating activity. Existing studies have confirmed its protective effects on cartilage injury, but its specific molecular mechanism in fracture repair remains unclear. This study aimed to explore the regulatory function and underlying signaling pathway of RD on bone marrow mesenchymal stem cell (BMSC) osteogenic differentiation and mouse femoral fracture healing.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;This study combined network pharmacology prediction with in vitro cell experiments and in vivo mouse fracture model validation. First, potential targets of RD and fracture-related disease were retrieved from the PubChem, GeneCards, and OMIM databases; PPI networks and KEGG enrichment analyses were performed to identify core signaling pathways. in vitro, CCK-8, Alizarin Red S (ARS) staining, immunofluorescence, and Western blot were used to detect the proliferation and osteogenic differentiation of C57BL/6J mouse BMSCs treated with gradient concentrations of RD (0-160 μg/mL). in vivo, a stable mouse femoral transverse fracture model was established; mice were divided into the model group, low-dose RD (0.05 mg/kg/d), and high-dose RD (0.1 mg/kg/d) groups via intragastric administration for 3 weeks. Micro-CT, HE/Safranin O-Fast Green staining, and immunohistochemistry (IHC) were applied to evaluate callus remodeling and the expression of osteogenic markers RUNX2, BMP2, OPG, and OPN. PI3K inhibitor Alpelisib was used for reverse verification of core pathways.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;In vitro assays showed that RD (0-160 μg/mL) exhibited no cytotoxicity to BMSCs; 40 μg/mL and 80 μg/mL RD significantly enhanced mineralized nodule formation (P &lt; 0.05). Western blot and immunofluorescence verified that RD dose-dependently upregulated phosphorylated PI3K and AKT protein expression. After PI3K inhibition, the osteogenic promotion effect of RD was markedly abolished. in vivo Micro-CT results demonstrated that RD significantly reduced BV/TV and Tb.N of fracture callus (P &lt; 0.05), accelerating callus remodeling. Histological staining revealed that RD facilitated endochondral ossification, reduced residual immature chondrocytes, and promoted mature bone formation. uIHC results confirmed that RD was significantly elevated at the fracture site, with increased expression of BMP2, OPN, OPG, and RUNX2 (P &lt; 0.05). Network pharmacology predicted PI3K/AKT as the core pathway mediating RD's bone-protective effects.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Discussion: &lt;/strong&gt;RD exerts dual regulatory effects on fracture repair by facilitating BMSC osteogenic differentiation and accelerating callus remodeling. Mechanistically, RD activates the PI3K/AKT signaling cascade to upregulate key osteogenic transcription factors and matrix proteins, thereby boosting endochondral ossification during fracture healing. The present study complements th","PeriodicalId":10984,"journal":{"name":"Current medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":3.2,"publicationDate":"2026-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149036809","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 Computational Evaluation of Isatin Derivatives as Dual MAO-A/IDO1 Inhibitors: Molecular Docking and Molecular Dynamics Insights.","authors":"Muthukumaran Thulasingam, Chitra Vellapandian","doi":"10.2174/0109298673499805260828051316","DOIUrl":"https://doi.org/10.2174/0109298673499805260828051316","url":null,"abstract":"<p><strong>Background: </strong>Monoamine oxidase-A (MAO-A) and indoleamine 2,3- dioxygenase-1 (IDO1) contribute to major depressive disorder via monoamine depletion and activation of the kynurenine pathway. Dual inhibition of these enzymes represents a rational multitarget therapeutic strategy.</p><p><strong>Objective: </strong>To identify potent dual MAO-A/IDO1 inhibitors from a focused library of isatin derivatives using an integrated computational approach.</p><p><strong>Methods: </strong>A total of 140 isatin derivatives were screened against MAO-A (PDB ID: 2BXR) and IDO1 (PDB ID: 6E35) using AutoDock 4.2. Top-ranked candidates were subjected to 100 ns molecular dynamics simulations using the Desmond module. Complex stability was evaluated through root mean square deviation (RMSD), root mean square fluctuation (RMSF), radius of gyration (rGyr), and solvent-accessible surface area (SASA) analyses to assess the structural stability and dynamic behavior of the protein- ligand complexes throughout the 100 ns molecular dynamics simulations. Moclobemide was used as the reference inhibitor.</p><p><strong>Results: </strong>Several derivatives demonstrated improved docking scores and favorable interactions within the catalytic pockets of both targets. SDI-107 and SDI-113 maintained stable binding conformations during 100 ns simulations, with protein backbone deviations within 2.0 to 2.5 Å, limited active-site residue fluctuations, sustained hydrogen bonding, and favorable binding free energy profiles compared with moclobemide.</p><p><strong>Discussion: </strong>The combined docking and molecular dynamics analyses indicate that structural stability and persistent intermolecular interactions underpin the dual inhibitory potential of SDI-107 and SDI-113. The isatin scaffold appears well suited for simultaneous engagement of the catalytic environments of MAO-A and IDO1, supporting its potential as a multitarget pharmacophore for antidepressant drug discovery.</p><p><strong>Conclusion: </strong>SDI-107 and SDI-113 emerged as promising dual MAO-A/IDO1 inhibitors, demonstrating favorable binding affinity, stable protein-ligand interactions, and encouraging binding free energy profiles. These findings support further experimental validation and structural optimization toward the development of multitarget-directed antidepressant agents.</p>","PeriodicalId":10984,"journal":{"name":"Current medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":3.2,"publicationDate":"2026-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149036744","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":"Nanoengineered Metformin Delivery System Targeting the AMPK/ PI3K/Akt/mTOR Pathway: A Potential Therapeutic Strategy Against Cisplatin-Induced Nephrotoxicity.","authors":"Shereen H Noshi, Sherine M Ibrahim, Omnia F Hassan, Mervat Shafik Ibrahim","doi":"10.2174/0109298673478182260904132549","DOIUrl":"https://doi.org/10.2174/0109298673478182260904132549","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Cisplatin, an effective antitumor drug, is clinically limited by its dose-dependent nephrotoxicity. Rational nanocarrier design offers a strategy to improve drug delivery and minimize off-target effects. In this work, we developed a metformin-loaded mesoporous silica nanoparticle (MSNP) system, which was further coated with chitosan (CTS) and tailored into distinct sizes and geometries (elliptical vs. rounded) to enhance bioactivity, kidney targeting, and biocompatibility.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;Thirty-five rats were divided into seven groups after nephrotoxicity induction with cisplatin (2 mg/kg, intraperitoneally, once weekly for 4 weeks). Groups were treated orally with metformin, uncoated MET-MSNPs, or CTS-coated MET-MSNPs (elliptical and rounded; 40 mg/kg orally daily for 4 weeks. Biochemical markers, histology, and immunohistochemistry were performed to evaluate renal function and tissue remodeling.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;Cisplatin exposure induced oxidative stress, elevated TGF-β1, TNF-α, IL-1β, and caspase- 3 levels, and caused renal dysfunction with marked histopathological damage. Both MET and CTS-MET-MSNPs mitigated these changes, with geometry- and coating-dependent improvements in renal biomarkers and tissue recovery. qPCR analysis showed that CTS-MET-MSNPs significantly downregulated cisplatin-induced AMPK/PI3K/Akt and restored mTOR expression. CTS-coated carriers showed superior anti-inflammatory, antioxidant, and anti-apoptotic effects compared with free MET.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Discussion: &lt;/strong&gt;In light of the available evidence, the design of our carrier system was guided by key parameters known to enhance kidney targeting. Rounded nanoparticles were selected since their geometry has been reported to promote efficient circulation, facilitate passage through the glomerular filtration barrier, and improve interaction with renal tissues. In addition, surface functionalization with chitosan was introduced to confer a positive charge, which is expected to favor electrostatic interactions with the negatively charged renal cell membranes. Accordingly, for our formulation strategy, rounded particles with a CH coating were deliberately chosen to maximize kidney selectivity. The morphological assessment of CTS-MET-MSNPs by TEM showed the successful formulation of the rounded nanoparticles with a defined mesoporous structure.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusion: &lt;/strong&gt;This study demonstrated that the CTS-MET-MSNPs offer a superior strategy for mitigating cisplatin-induced acute kidney injury compared to free metformin. By optimizing the vehicle's architecture using rounded geometry to promote favorable glomerular filtration kinetics and applying a positively charged chitosan coating to exploit electrostatic binding with negatively charged renal membranes. We achieved highly site-specific kidney targeting. Morphological evaluation via TEM confirmed the successful fabrication of these rounded nanoparti","PeriodicalId":10984,"journal":{"name":"Current medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":3.2,"publicationDate":"2026-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149036759","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}