Current medicinal chemistry最新文献

{"title":"Therapeutic Effects of WIN55,212-2 on Temporomandibular Joint Osteoarthritis in a Rat Model and Primary Temporomandibular Joint Condylar Chondrocytes.","authors":"Yiman Guo, Xincheng Zhang, Shen Zhao, Ce Bian, Mengyao Zhu, Chengjun Su, Yuqing Zhang, Miao Liu, Lin-Hai Kurahara, Ning Zhang","doi":"10.2174/0109298673521071260901095016","DOIUrl":"https://doi.org/10.2174/0109298673521071260901095016","url":null,"abstract":"<p><strong>Introduction/objective: </strong>This study investigates the therapeutic potential of the synthetic cannabinoid WIN55,212-2 (WIN55) in temporomandibular joint osteoarthritis (TMJOA), focusing on its capacity to attenuate cartilage degradation and modulate inflammatory pathways, thereby providing preclinical evidence to support future clinical translation.</p><p><strong>Methods: </strong>A monosodium iodoacetate (MIA)-induced TMJOA model was established in rats, followed by WIN55 treatment. Cartilage integrity and subchondral bone structure were evaluated using histological and imaging techniques. Primary condylar chondrocytes were treated with IL-1β and WIN55 to elucidate the underlying inflammatory and molecular mechanisms through transcriptomic and protein-level analyses.</p><p><strong>Results: </strong>WIN55 significantly alleviated cartilage degradation in TMJOA, as evidenced by improved histological scores, preserved proteoglycan content, and maintained subchondral bone architecture. in vitro, WIN55 suppressed IL-1β-induced pro-inflammatory cytokines (e.g., Il-6, Tnf-α) and chemokines (e.g., Ccl2, Ccl5, Cxcl1). Transcriptomic analysis revealed that WIN55 reversed key inflammatory pathways, including TNF and IL-17 signaling, and downregulated IL-1β-induced colony-stimulating factors (Csf1, Csf2, Csf3). Additionally, WIN55 modulated the expression profiles of lncRNAs and circRNAs.</p><p><strong>Discussion: </strong>These findings provide the first comprehensive evidence that WIN55 exerts multi-target anti-inflammatory and chondroprotective effects in the TMJ context. By suppressing chemokine networks, CSF family members, and matrix-degrading enzymes while preserving extracellular matrix homeostasis, WIN55 addresses both inflammatory and degradative processes central to TMJOA pathogenesis. Modulation of non-coding RNAs suggests additional regulatory layers that may be exploited in future therapeutic strategies.</p><p><strong>Conclusion: </strong>WIN55 demonstrates significant therapeutic potential for TMJOA by mitigating cartilage degradation and modulating inflammatory responses. These findings highlight the promise of cannabinoid-based therapies for TMJOA and establish a foundation for subsequent clinical investigation.</p>","PeriodicalId":10984,"journal":{"name":"Current medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":3.2,"publicationDate":"2026-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149015954","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":"Type 2 Diabetes Mellitus: Interplay Among Biological, Environmental, and Socioeconomic Determinants in Disease Progression and Management.","authors":"Ilderbayeva Gulzhan, Tatayeva Rosa, Tazhibayeva Damira, Zharmakhanova Gulmira, Ilderbayev Oralbek, Zeliha Selamoglu, Esra Küpeli Akkol, Eduardo Sobarzo-Sánchez","doi":"10.2174/0109298673464017260902100238","DOIUrl":"https://doi.org/10.2174/0109298673464017260902100238","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Type 2 Diabetes Mellitus (T2DM) is a complex metabolic disorder characterized by insulin resistance and progressive β-cell dysfunction, although these mechanisms alone do not account for the considerable variability observed in disease presentation and clinical evolution. During the last decade, epidemiological and mechanistic studies have shown that metabolic dysfunction develops within a broader framework in which biological susceptibility is continuously shaped by environmental exposures, occupational conditions, lifestyle-related behaviors, psychosocial influences, and socioeconomic circumstances. Rather than acting independently, these factors appear to modify metabolic regulation through interconnected biological pathways that contribute to differences in disease susceptibility, progression, and long-term outcomes across populations. This perspective supports a more integrated interpretation of T2DM pathophysiology, in which biological, environmental, and socioeconomic influences jointly determine disease expression. Accordingly, this review critically evaluates current evidence regarding the contribution of these interacting determinants to the onset, progression, and clinical manifestations of T2DM.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;This narrative review was based on publications retrieved from PubMed, Scopus, and Web of Science addressing biological, environmental, behavioral, occupational, and socioeconomic factors relevant to T2DM. Epidemiological, clinical, and experimental studies were selected to provide complementary evidence on the mechanisms through which these variables contribute to metabolic dysfunction, disease progression, and diabetes-related complications. Particular attention was given to investigations examining the interplay among these factors rather than considering them as isolated contributors to disease development.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;The literature examined indicates that T2DM arises through the convergence of multiple pathogenic processes rather than from a single metabolic abnormality. Obesity, insulin resistance, sedentary lifestyles, and dietary imbalance remain central contributors to disease development, while increasing evidence also points to a relevant contribution from environmental exposures and socioeconomic conditions. Pollutants, adverse occupational settings, chronic psychosocial stress, and inequalities in healthcare access have all been associated with disturbances in metabolic regulation and less favorable clinical outcomes. Delayed diagnosis, limited preventive strategies, and insufficient diabetes education further compromise long-term disease management and may contribute to the persistence of chronic complications.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Discussion: &lt;/strong&gt;T2DM arises from metabolic alterations driven by environmental and socioeconomic factors that can modify disease susceptibility and clinical evolution. Differences in disease burden observed across popula","PeriodicalId":10984,"journal":{"name":"Current medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":3.2,"publicationDate":"2026-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149015975","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":"Integrative Perspectives on COX-2 Signaling and Selective Inhibitors in Central Nervous System Disorders: A Narrative Review.","authors":"Hanieh Maleksabet, Mahsa Azami Movahed, Afshin Zarghi","doi":"10.2174/0109298673496586260831110156","DOIUrl":"https://doi.org/10.2174/0109298673496586260831110156","url":null,"abstract":"<p><strong>Introduction: </strong>Central nervous system disorders include various neurodegenerative and psychiatric conditions characterized by progressive neuronal damage, synaptic dysfunction, and chronic neuroinflammation, affecting millions worldwide. This group includes Alzheimer's Disease (AD), Parkinson's Disease (PD), Amyotrophic Lateral Sclerosis (ALS), schizophrenia, Multiple Sclerosis (MS), Major Depressive Disorder (MDD), and epilepsy, among others. Recent studies have emphasized the significant role of Cyclooxygenase-2 (COX-2), an inducible enzyme in the arachidonic acid pathway, in maintaining neuroinflammatory cascades that worsen these conditions.</p><p><strong>Methods: </strong>For this review, we gathered and carefully analyzed published literature related to COX-2 signaling in CNS disorders. We reviewed preclinical studies, animal models, and clinical trials to understand how COX-2 contributes to disease mechanisms and whether selective inhibitors show real therapeutic promise.</p><p><strong>Results: </strong>Inflammatory cytokines or excitotoxic insults upregulate COX-2 and promote the formation of prostaglandins, including PGE2. These mediators subsequently trigger the activation of microglia and astrocytes, cytokine release, oxidative stress, disruption of the blood-brain barrier, and neuronal apoptosis. Despite variations in disease-specific features, the mechanisms dependent on COX-2 are generally consistent across these disorders.</p><p><strong>Discussion: </strong>The consistent involvement of COX-2-driven neuroinflammation across multiple CNS disorders suggests it could be a promising therapeutic target. However, failures in some clinical trials highlight the complexity of translating preclinical findings into patient care. This may be due to the stage-dependent expression of COX-2, the multifunctional roles of the enzyme in normal brain function, and the cardiovascular risks associated with long-term COX-2 inhibition. These factors must be carefully considered in future research and drug development.</p><p><strong>Conclusion: </strong>COX-2 plays a central role in driving neuroinflammation and disease progression in AD, PD, ALS, schizophrenia, MS, MDD, and epilepsy. Selective COX-2 inhibitors show promising neuroprotective potential, especially in early stages or in combination therapies, but inconsistent efficacy and cardiovascular risks necessitate safer next- generation inhibitors.</p>","PeriodicalId":10984,"journal":{"name":"Current medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":3.2,"publicationDate":"2026-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149016008","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":"Sult2b1 Modulates NLRP3/BCL-2 Signaling and Pro-Inflammatory Microglial/Macrophage Polarization After Traumatic Brain Injury.","authors":"Hao Zhang, Zhenhong Pan, Hua Chen, Yinxing Huang, Shousen Wang","doi":"10.2174/0109298673532074260901055730","DOIUrl":"https://doi.org/10.2174/0109298673532074260901055730","url":null,"abstract":"<p><strong>Introduction: </strong>Traumatic Brain Injury (TBI) causes prolonged neurological impairment through primary mechanical damage and secondary cascades including neuroinflammation and apoptosis. This study investigated whether Sult2b1, a cholesterol sulfation enzyme, protects against secondary injury after TBI.</p><p><strong>Methods: </strong>A Controlled Cortical Impact (CCI) mouse model was used. Sult2b1 expression was assessed by RT-qPCR and western blotting. AAV-mediated delivery restored Sult2b1, and its effects were evaluated via histology, immunofluorescence, imaging, ELISA, and behavioral tests.</p><p><strong>Results: </strong>Sult2b1 was markedly downregulated after TBI. Overexpression improved cerebral blood flow, preserved neurons, reduced apoptosis, decreased TNF-α and IL-1β, and increased IL-4. Mechanistically, it modulated NLRP3/BCL-2 and suppressed M1-like microglial/macrophage polarization. Functionally, it enhanced sensorimotor and cognitive performance and reduced lesion volume and chronic tissue loss.</p><p><strong>Discussion: </strong>Our findings identify Sult2b1 as an endogenous protective factor that limits neuroinflammation and promotes neuronal survival via NLRP3/BCL-2 and microglial polarization modulation, suggesting therapeutic potential.</p><p><strong>Conclusion: </strong>Sult2b1 confers neuroprotection after TBI and may serve as a potential target for reducing secondary brain injury.</p>","PeriodicalId":10984,"journal":{"name":"Current medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":3.2,"publicationDate":"2026-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149015989","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 in the Discovery of Bioactive Natural Products.","authors":"Atta-Ur Rahman, Asia","doi":"10.2174/0109298673528346260907070035","DOIUrl":"https://doi.org/10.2174/0109298673528346260907070035","url":null,"abstract":"<p><p>Artificial intelligence (AI) is transforming natural products discovery by integrating genome mining, metabolomics, bioactivity prediction, and virtual screening into unified computational ecosystems. This review provides a comprehensive overview of AIdriven approaches for the discovery of bioactive natural products, covering AI-ready databases, machine learning tools for biosynthetic gene cluster (BGC) prediction, metabolomics platforms, NMR and MS spectral interpretation, and translational development. The convergence of AI with multi-omics technologies, synthetic biology, and automated experimentation is accelerating the identification and prioritization of novel therapeutic leads. Key challenges, including data quality, reproducibility, interpretability, and ethical considerations, are critically examined. The review concludes that AI functions most effectively as an integrative decision-support framework that augments rather than replaces experimental chemistry and pharmacology expertise.</p>","PeriodicalId":10984,"journal":{"name":"Current medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":3.2,"publicationDate":"2026-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149012134","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":"Comprehensive Spectroscopic, Computational, and Pharmacokinetic Characterization of the Cardiovascular Drug- Bisoprolol.","authors":"Mohd Amin Mir, Noushi Zaidi","doi":"10.2174/0109298673441134260213093319","DOIUrl":"https://doi.org/10.2174/0109298673441134260213093319","url":null,"abstract":"<p><strong>Introduction: </strong>The introduction outlines the bisoprolol study aimed at elucidating its molecular structure, physicochemical properties, and biological activity using several combined analytical techniques, including spectroscopy, computational modeling, and pharmacokinetics.</p><p><strong>Methods: </strong>Structural features were determined via FT-IR, Raman, and NMR spectroscopy. Optimized geometry, molecular stability, and frontier molecular orbital (FMO) properties were determined using density functional theory (DFT). Molecular docking studies and ADME analysis were conducted with the hydrolase enzyme (4W71) and an IgG-like protein (4PR5), following Lipinski's rules for drug-like properties.</p><p><strong>Results: </strong>In spectroscopy, the presence of hydroxyl, amine, aromatic, and carbonyl groups was confirmed. In DFT, intramolecular hydrogen bonding, with appropriate bond parameters, was observed, with a HOMO-LUMO gap (6.32 eV) indicating potential π-π* and n-π* transitions. The interactions observed during docking showed stable binding with the hydrolase (-7.21 kcal/mol) and immune-related protein targets (-5.64 kcal/mol). ADME characteristics were also reviewed for compliance with Lipinski's Rule of Five.</p><p><strong>Discussion: </strong>Overall, the spectroscopic, computational modeling, and pharmacokinetic data are consistent with one another and provide insight into the structural integrity, electronic properties, and biological activity of bisoprolol.</p><p><strong>Conclusion: </strong>Based on the in silico molecular docking investigations and ADME predictions, it is reasonable to conclude that the metabolic pathways of bisoprolol and its interactions with biological systems are highly likely to be consistent with the available literature.</p>","PeriodicalId":10984,"journal":{"name":"Current medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":3.2,"publicationDate":"2026-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149012143","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":"Unveiling the Mechanism of Cibotium barometz in the Treatment of Rheumatoid Arthritis: A Study Based on Network Pharmacology and Experimental Validation.","authors":"Qing-Rui Li, Yu-Xin Han, Yu-Ting Bian, Mei-Qi Lan, Guang-Yao Chen","doi":"10.2174/0109298673485645260902110718","DOIUrl":"https://doi.org/10.2174/0109298673485645260902110718","url":null,"abstract":"<p><strong>Objective: </strong>Cibotium barometz, a perennial arborescent fern of the family Cibotiaceae widely distributed in tropical and subtropical mountainous regions of China, exhibits significant therapeutic efficacy against Rheumatoid Arthritis (RA). This study aims to reveal the key molecular mechanisms underlying Cibotium barometz in the treatment of RA through an integrated approach combining network pharmacology and experimental validation.</p><p><strong>Methods: </strong>Active components and targets of Cibotium barometz were identified using Herb and TCMSP databases, and RA-related targets from GeneCards. A compound-target network was constructed, followed by PPI and KEGG analyses. Aqueous Extract of Cibotium barometz (AECB) was prepared and analyzed by LC-MS. RA-derived Fibroblast- like Synoviocytes (RA-FLS) were isolated and treated with AECB for in vitro validation.</p><p><strong>Results: </strong>Network pharmacology identified 7 active components and 104 RA-related targets. LC-MS confirmed the presence of all 7 components in AECB. PPI highlighted IL-6 as a key target, and KEGG pointed to inflammation-related pathways. TNF-α stimulation enhanced IL-6 expression and activated NF-κB, p38 MAPK, and AKT signaling in RA-FLS, whereas AECB dose-dependently suppressed these responses.</p><p><strong>Discussion: </strong>This study predicted the molecular mechanisms of Cibotium barometz in treating RA through network pharmacology and identified its key bioactive components and core hub targets. Experimental results showed that AECB can effectively downregulate the expression of pro-inflammatory cytokines by modulating inflammation-related pathways.</p><p><strong>Conclusion: </strong>Network pharmacology and experimental validation demonstrate that the therapeutic effect of Cibotium barometz on RA is closely associated with inhibition of inflammatory pathways and cytokine release.</p>","PeriodicalId":10984,"journal":{"name":"Current medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":3.2,"publicationDate":"2026-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149012148","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":"Ameliorative Effect of Rosinidin Against an Ethanol-induced Ulcer: Molecular Docking and Implication of PGE2/ IL-6/IL-1β/TNF-α and NF-κB Pathways.","authors":"Asma B Omer, Muhammad Afzal, Shahnaz Haque, Misbahuddin Rafeeq, Hussam Aly Sayed Murad, Sami I Alzarea, Nadeem Sayyed, Imran Kazmi","doi":"10.2174/0109298673491931260824110242","DOIUrl":"https://doi.org/10.2174/0109298673491931260824110242","url":null,"abstract":"<p><strong>Introduction/objective: </strong>In this study, we assessed the antiulcer property of rosinidin on the Ethanol (EtOH)-induced ulcer.</p><p><strong>Methods: </strong>EtOH was administered orally to induce ulcers in rats. The potency of rosinidin 10 and 20 (mg/kg) was evaluated under trial with EtOH-induced gastric ulcer (EtOH 1.5 ml/animal). After induction of the ulcer, rats were decapitated, and gastric contents were subjected to various biochemical estimations and histopathological examination. Furthermore, molecular docking was performed.</p><p><strong>Results: </strong>Rosinidin restored gastric ulcer alterations and attenuated ulcer scores. Rosinidin modulated gastric pH and restored levels of MDA, CAT, SOD, GSH, urea, creatinine, AST, ALT, NO, PGE2, and pro-inflammatory markers. A histopathology study revealed healing and a protective effect on the stomach wall. The rosinidin showed the best binding energies at -6.061 (IL-6) and -6.275 (NF-κB) kcal/mol.</p><p><strong>Discussion: </strong>Rosinidin also exhibited significant gastroprotection against alcohol-induced ulcers with oxidative stress and inflammation reduction. It has replenished antioxidant levels, reduced proinflammatory cytokines, and regulated NF-κB activity, as corroborated by positive docking outcomes. These results indicate that it can be used as a therapeutic agent for the management of gastric ulcers.</p><p><strong>Conclusion: </strong>Rosinidin has antiulcer properties attributed to normalizing TNF-α, PGE2, and NF-κB levels. The study suggested that rosinidin possessed favorable outcomes on EtOH-induced gastric ulcers in rats.</p>","PeriodicalId":10984,"journal":{"name":"Current medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":3.2,"publicationDate":"2026-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149012050","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":"Daphnetin Alleviates Sepsis-Associated Acute Kidney Injury by Promoting Autophagy and Suppressing Non-canonical NF-κB Signaling.","authors":"Zigang Zhao, Chen Zhang, Xiaoqiong Zhang, Ling Wang, Yuan Ou, Huagang Jian, Pan Yang","doi":"10.2174/0109298673472716260820103609","DOIUrl":"https://doi.org/10.2174/0109298673472716260820103609","url":null,"abstract":"<p><strong>Background: </strong>Sepsis-Associated Acute Kidney Injury (SA-AKI) is a lifethreatening complication with high mortality and limited treatment options. Daphnetin (DAP), a coumarin derivative with anti-inflammatory activity, has shown promise in several inflammatory disorders, but its role in SA-AKI remains unclear.</p><p><strong>Methods: </strong>We induced SA-AKI in mice using the Cecal Ligation and Puncture (CLP) model and established an in vitro injury model by stimulating HK-2 cells with Lipopolysaccharide (LPS). The effects of DAP were evaluated in both models. RNA sequencing was performed to identify the mechanisms underlying DAP-mediated protective effects, and the results were further validated by immunoblotting and related assays.</p><p><strong>Results: </strong>DAP treatment markedly reduced renal injury, lowered serum creatinine and blood urea nitrogen levels, preserved renal histological architecture, and attenuated tubular cell apoptosis. It also reduced the production of pro-inflammatory cytokines and enhanced autophagic activity. Transcriptomic analysis together with biochemical validation implicated non-canonical nuclear factor kappa-B (NF-κB) signaling as a potential mediator of the anti-inflammatory effects of DAP. In addition, DAP reduced pro-inflammatory M1 macrophage infiltration in the kidney.</p><p><strong>Discussion: </strong>These findings expand current understanding of the mechanisms underlying DAP-mediated renoprotection by demonstrating enhanced autophagic activity in experimental SA-AKI. The observation that pharmacological inhibition of NF-κB-inducing kinase (NIK) also enhances autophagic activity suggests that suppression of non-canonical NF-κB signaling contributes to autophagy regulation. Together with its anti-inflammatory effects, these findings support a multifaceted mechanism underlying the renoprotective actions of DAP.</p><p><strong>Conclusion: </strong>DAP attenuates inflammation and kidney injury in SA-AKI, accompanied by inhibition of non-canonical NF-κB signaling and enhanced autophagic activity. These findings suggest that DAP may represent a promising therapeutic candidate for SAAKI.</p>","PeriodicalId":10984,"journal":{"name":"Current medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":3.2,"publicationDate":"2026-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149012101","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":"Fibroblast-Derived LIF Suppresses Osteogenesis Through LIFR/ STAT3 Signalling in Fracture Nonunion.","authors":"Tianchao Lu, Dong Wang, Maoqi Gong, Ziyi Li, Hanzhou Wang, Junlin Zhou","doi":"10.2174/0109298673535044260831072605","DOIUrl":"https://doi.org/10.2174/0109298673535044260831072605","url":null,"abstract":"<p><strong>Introduction: </strong>Fracture nonunion represents a biologically dysregulated repair state rather than a purely mechanical failure. This study investigated whether fibroblast- derived Leukemia Inhibitory Factor (LIF) contributes to nonunion by suppressing osteogenesis via canonical LIFR-containing STAT3 signalling.</p><p><strong>Materials and methods: </strong>We profiled clinical fracture-healing tissues using single-cell RNA sequencing, integrating three normally healed control specimens and three nonunion specimens after quality control. Mechanistic validation was performed using a Transwell coculture of mouse L-929 fibroblasts and MC3T3-E1 osteoblast-lineage cells, followed by pharmacological rescue and evaluation in a rat tibial nonunion model.</p><p><strong>Results: </strong>Computational analyses prioritised fibroblast-to-osteoblast signalling and identified the enhanced LIF-(LIFR+IL6ST) interaction as a candidate signal in nonunion. Human tissue immunofluorescence supported increased fibroblast-associated LIF localisation in nonunion lesions. In Transwell cocultures of L-929 fibroblasts and MC3T3-E1 osteoblast- lineage cells, LIF knockdown reduced STAT3 phosphorylation and enhanced osteogenic gene expression, alkaline phosphatase activity and mineralisation, whereas LIF overexpression produced opposite effects. Pharmacological inhibition of LIFR (EC359) or STAT3 (Stattic) partially rescued the anti-osteogenic effects of LIF overexpression. In a rat tibial nonunion model, EC359 improved callus continuity and increased BV/TV and Tb.N at both 2 and 4 weeks, with additional trabecular improvements at 4 weeks; histomorphometry confirmed significantly increased Callus/ROI and Blue/Callus ratios at 4 weeks.</p><p><strong>Discussion: </strong>The convergent findings support fibroblast-associated LIF as a biologically plausible inhibitory signal in nonunion. The human, cellular, and animal models provide complementary rather than directly interchangeable evidence, and direct clinical generalisation remains limited.</p><p><strong>Conclusion: </strong>Together, these results nominate fibroblast-associated LIF as a niche-related inhibitory signal in nonunion, with effects that are most compatible with canonical LIFR/IL6ST-mediated STAT3 signalling.</p>","PeriodicalId":10984,"journal":{"name":"Current medicinal chemistry","volume":" ","pages":""},"PeriodicalIF":3.2,"publicationDate":"2026-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149012137","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}