Biochemical pharmacology最新文献

{"title":"Exploring the potential of soluble guanylyl cyclase stimulators and activators in heart failure","authors":"Olga Gawrys ,&nbsp;Petr Kala ,&nbsp;Michal Šnorek ,&nbsp;Vojtěch Melenovský ,&nbsp;Stefano Corda ,&nbsp;Peter Sandner","doi":"10.1016/j.bcp.2025.117363","DOIUrl":"10.1016/j.bcp.2025.117363","url":null,"abstract":"<div><div>Heart failure (HF) is a life-threatening disease characterized by substantial morbidity and mortality. Yet despite recent advances, prognosis remains poor. Cyclic guanosine 3′,5′-monophosphate (cGMP) mediates a wide range of physiological processes in various cell types. Its deficiency has been implicated in numerous pathological cardiovascular diseases, including HF, pulmonary hypertension (PH), and kidney disease. Therefore, restoring and enhancing the nitric oxide (NO)–soluble guanylyl cyclase (sGC)–cGMP signalling pathway appears to have far-reaching therapeutic potential.</div><div>The discovery of sGC stimulators and activators marked a milestone in the field of NO–sGC–cGMP pharmacology, enabling NO-independent and long-acting enhancement of cGMP signalling without the formation of NO-derived radicals. Over a decade ago, the sGC stimulator riociguat was approved for the treatment of pulmonary arterial hypertension (PAH) and chronic thromboembolic PH (CTEPH). More recently, the sGC stimulator vericiguat was approved for symptomatic chronic HF. A number of sGC activators are currently being investigated for the treatment of chronic kidney diseases.</div><div>This review summarizes the evidence for NO–sGC–cGMP signalling in the regulation of cardiovascular and cardiac function, focusing on preclinical and clinical evidence for sGC stimulators and sGC activators in HF subtypes. Promising results have been observed in clinical trials of HF with reduced ejection fraction (HFrEF), but not in clinical trials of HF with preserved ejection fraction (HFpEF). Further studies are needed to determine the precise mechanisms of action of sGC agonists in HF and associated cardiorenal diseases to fully leverage their therapeutic potential and address the challenges of implementing these agents in routine clinical practice.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"242 ","pages":"Article 117363"},"PeriodicalIF":5.6,"publicationDate":"2025-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145130007","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Chemoproteomics-based profiling reveals the targeting molecular mechanism of reversal of cisplatin resistance by baicalin in head and neck squamous cell carcinoma","authors":"Nan Wu ,&nbsp;Shuang Yu ,&nbsp;Shuyan Du ,&nbsp;Xiaoqi Wei ,&nbsp;Linyuan Wang ,&nbsp;Haomeng Xu ,&nbsp;Xiaowen Zhang","doi":"10.1016/j.bcp.2025.117360","DOIUrl":"10.1016/j.bcp.2025.117360","url":null,"abstract":"<div><div>Cisplatin resistance is a major cause of chemotherapy failure and poor prognosis in patients with head and neck squamous cell carcinoma (HNSCC). The combination of natural compounds and platinum-based agents can overcome cisplatin resistance. Here, we demonstrate that baicalin, one of the major active flavonoids extracted from the root of the medicinal herb <em>Scutellaria baicalensis Georgi</em>, reverses cisplatin resistance in HNSCC <em>in vitro</em> and <em>in vivo</em>. Mechanistically, glutathione S-transferase (GST)-π subtype, also known as GSTP1, was identified as a direct target of baicalin, and the cysteine 47 (cys47) of GSTP1 is modified by baicalin, which is mediated by the Michael reaction. Moreover, baicalin increased the accumulation of cisplatin and activated the c-Jun N-terminal kinase (JNK) pathway in wild-type cisplatin-resistant HNSCC cells, but its effects were lost in cys47-mutated cisplatin-resistant HNSCC cells. Meanwhile, cys47 mutation of GSTP1 abrogated baicalin-induced reversal of cisplatin resistance in HNSCC cells. In conclusion, we demonstrate a novel mechanism for the reversal of cisplatin resistance by baicalin, confirming that baicalin can inhibit GSTP1 activity by interacting with the Cys47 residue of GSTP1, thereby enhancing intracellular accumulation of cisplatin or activation of the JNK pathway. This study lays the foundation for the use of baicalin to overcome cisplatin resistance in HNSCC.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"242 ","pages":"Article 117360"},"PeriodicalIF":5.6,"publicationDate":"2025-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145130046","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Butyrolactone I from Aspergillus fungi blocks neutrophil FPR1 to alleviate acute respiratory distress syndrome","authors":"Chun-Yu Chen ,&nbsp;Yu-Ting Kuo ,&nbsp;Chih-Chuang Liaw ,&nbsp;Yi-Hsuan Wang ,&nbsp;Shih-Hsin Chang ,&nbsp;Yung-Fong Tsai ,&nbsp;Kai-Cheng Hsu ,&nbsp;Tony Eight Lin ,&nbsp;Tsong-Long Hwang","doi":"10.1016/j.bcp.2025.117348","DOIUrl":"10.1016/j.bcp.2025.117348","url":null,"abstract":"<div><div>Formyl peptide receptor 1 (FPR1), activated by <em>N</em>-formyl peptides, significantly contributes to neutrophil activation and the development of acute respiratory distress syndrome (ARDS). This study showed that butyrolactone I (BLI), a secondary metabolite of <em>Aspergillus terreus</em>, effectively blocks FPR1 and reduces the severity of ARDS. BLI selectively inhibited superoxide anion production, elastase release, cluster of differentiation molecule 11b (CD11b) expression, and chemotaxis in human neutrophils activated by <em>N</em>-formyl peptides derived from bacteria and mitochondria. The FPR1 receptor-binding and molecular docking assays confirmed that BLI acted as an FPR1 inhibitor. Pharmacological experiments demonstrated that BLI selectively inhibited FPR1 downstream signals in human neutrophils, including calcium mobilization and phosphorylation of protein kinase B (Akt), c-Jun N-terminal kinases (JNK), extracellular regulated protein kinases (ERK), and p38 mitogen-activated protein kinases (p38). In a mouse model of ARDS, treatment with BLI reduced neutrophil infiltration, oxidative damage, and levels of elastase and interleukin-1 beta (IL-1β) in the lungs. The fungal compound BLI could serve as a potential treatment for ARDS by blocking FPR1 and reducing neutrophil-induced injury.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"242 ","pages":"Article 117348"},"PeriodicalIF":5.6,"publicationDate":"2025-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145130020","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dual targeting of Phosphoinositide 3-Kinase (PI3K) and histone deacetylase 6 (HDAC6) in cancer","authors":"Sami Hamdoun ,&nbsp;Nafees Ahemad ,&nbsp;Sharifah Aminah Syed Mohamad","doi":"10.1016/j.bcp.2025.117361","DOIUrl":"10.1016/j.bcp.2025.117361","url":null,"abstract":"<div><div>Phosphoinositide 3-kinases (PI3Ks) and histone deacetylase 6 (HDAC6) have been widely studied as promising therapeutic targets in cancer. Both play key roles in maintaining cellular homeostasis, and their dysregulation is closely linked to oncogenesis. Consequently, several dual PI3K/HDAC6 inhibitors have been developed as potential anticancer agents. This review explores the cellular and molecular functions of PI3K and HDAC6, their involvement in cancer progression, and the structural and pharmacological properties of dual-targeting inhibitors. Additionally, we discuss future perspectives for designing clinically effective dual PI3K/HDAC6 inhibitors.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"242 ","pages":"Article 117361"},"PeriodicalIF":5.6,"publicationDate":"2025-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145130041","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ETV5 transcriptionally inhibits KIF23 to repress pyroptosis in aged mice with perioperative neurocognitive disorders","authors":"Shaoqun Tang ,&nbsp;Xueshan Bu ,&nbsp;Xi Yu,&nbsp;Wenqin Song,&nbsp;Lei Zhang,&nbsp;Wei Wang","doi":"10.1016/j.bcp.2025.117352","DOIUrl":"10.1016/j.bcp.2025.117352","url":null,"abstract":"<div><div>Caspase-3/gasdermin E (GSDME)-dependent pyroptosis activation has emerged as a potential mechanism contributing to perioperative neurocognitive disorders (PND). Public transcriptome profiling identified the diminution of the transcription factor E-twenty-six variant 5 (ETV5) in the hippocampus of aged PND mice. This study intended to investigate the role of ETV5 and its target genes in the pathogenesis of PND. Bioinformatics analysis identified kinesin family member 23 (KIF23) as a putative target gene of ETV5. The PND mouse model was established via laparotomy under isoflurane anesthesia after treatment with recombinant adeno-associated virus 9 (AAV9) to overexpress ETV5 and/or KIF23. HT22 neurons were transfected with either pcDNA3.1-ETV5 or siETV5, followed by treatment with isoflurane and lipopolysaccharide (Iso + LPS). Cognitive behavior, TUNEL staining, and pyroptosis-associated indicators were assessed. ETV5 mRNA and protein levels were significantly reduced in the mouse hippocampus following anesthesia and surgery. ETV5 overexpression attenuated cognitive impairment, enhanced antioxidant capacity, and hampered caspase-3/GSDME-mediated pyroptosis, which was neutralized by AAV9-KIF23. Under Iso + LPS conditions, ETV5 overexpression enhanced HT22 neuronal viability and antioxidant defense, suppressed the cleavage of caspase-3 and GSDME, and diminished the release of IL-1β, IL-18, and LDH. Contrarily, its silencing had inverse effects on oxidative stress and pyroptosis, which was abrogated by KIF23 knockdown. Mechanistically, ETV5 directly bound to the sequence spanning from 1 to 700 bp upstream of the KIF23 gene transcription initiation site and repressed its transcription. Our findings suggest that ETV5/KIF23 may represent a promising therapeutic target for PND.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"242 ","pages":"Article 117352"},"PeriodicalIF":5.6,"publicationDate":"2025-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145124108","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"HIF-1α/A2BAR signalling pathway alleviates kidney fibrosis after ischemia–reperfusion injury by preventing macrophage-to-myofibroblast transition","authors":"Yanyan Yang ,&nbsp;Tao Tao ,&nbsp;Jingrong Huang ,&nbsp;Xue Sun ,&nbsp;Shaozheng Ai ,&nbsp;Pengli Luo","doi":"10.1016/j.bcp.2025.117358","DOIUrl":"10.1016/j.bcp.2025.117358","url":null,"abstract":"<div><div>The activation of hypoxia-inducible factor-1α (HIF-1α) under hypoxic or ischemic conditions plays a crucial in the progression from acute kidney injury (AKI) to chronic kidney disease (CKD). Inflammatory macrophages are potentially involved in kidney fibrosis, and the macrophage-to-myofibroblast transition (MMT) is a significant contributor to renal fibrosis. This study investigates the role of HIF-1α in modulating MMT during renal fibrosis development post-ischemia–reperfusion injury (IRI). Using a model of AKI-to-CKD transition in wild-type (WT) and HIF-1α- knockdown mice, we evaluated kidney fibrosis, macrophage infiltration, and MMT. The influence of the HIF-1α/A2BAR signalling pathway on MMT was assessed by modulating adenosine A2B receptor (A2BAR) activity. In WT mice, IRI-induced renal fibrosis was associated with increased macrophage infiltration and MMT marker co-expression (F4/80⁺–α-SMA⁺), alongside activation of the HIF-1α and A2BAR pathways. Following HIF-1α knockdown, macrophage infiltration and MMT increased significantly, accompanied by a marked aggravation of renal fibrosis. Inhibition of A2BAR signalling with the antagonist MRS1754 in HIF-1α-knockdown mice further increased macrophage infiltration and MMT, aggravating renal fibrosis post-IRI. In contrast, activation of A2BAR signalling with the agonist BAY60-6583 markedly decreased macrophage infiltration and MMT, effectively mitigating renal fibrosis. This study underscores the critical role of MMT in renal fibrosis after IRI and suggests that the HIF-1α/A2BAR signalling pathway mitigates fibrosis by modulating macrophage infiltration and MMT, providing new insights into the mechanisms underlying the AKI-to-CKD progression.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"242 ","pages":"Article 117358"},"PeriodicalIF":5.6,"publicationDate":"2025-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145117819","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"High-throughput screening reveals paeoniflorin’s efficacy against Apoc2-deficient hypertriglyceridemia via HNF4A/PPARA/LDLR","authors":"Qingquan Li ,&nbsp;Kun Qi ,&nbsp;Shang Wu ,&nbsp;Aling Shen ,&nbsp;Lu Zhao","doi":"10.1016/j.bcp.2025.117351","DOIUrl":"10.1016/j.bcp.2025.117351","url":null,"abstract":"<div><div>Hypertriglyceridemia (HTG) is a significant risk factor for cardiovascular disease, fatty liver, and acute pancreatitis, yet remains a therapeutic challenge due to limitations of current treatment options. To address this unmet clinical need, we screened a natural small-molecule library at an initial concentration of 100 μM to identify effective HTG therapeutic candidates using a CRISPR/Cas9-generated apolipoprotein C2 (<em>apoc2</em>) knockout zebrafish model that resembles human lipid metabolism disorders. Phenotype-based screening identified paeoniflorin (PAE) from 351 compounds as a potent triglyceride-lowering agent. Lipidomics analysis revealed PAE promoted triglyceride lipolysis by β-oxidation and lipophagy. Mechanistic studies demonstrated PAE upregulates peroxisome proliferator-activated receptor α (<em>ppara</em>) and lipoprotein receptor (<em>ldlr</em>) in <em>apoc2</em> mutants. In oleic acid-induced Huh7 human hepatocytes, PAE reduces intracellular lipid droplet accumulation and significantly upregulated PPARA and LDLR expression, indicating enhanced hepatocellular uptake and oxidative catabolism of triglyceride-rich lipoproteins. Further investigation revealed that PAE upregulates the expression of hepatocyte nuclear factor 4 α (HNF4A), a key upstream transcription factor of PPARA. The HNF4A inhibitor BI-6015 completely abolished PAE’s triglyceride-lowering effects, suggesting mediation through the HNF4A-PPARA-LDLR axis. These findings establish PAE as a promising therapeutic candidate for HTG through a novel mechanism targeting the HNF4A-PPARA-LDLR pathway. Our work not only identifies a potential lead compound for HTG treatment but also supports the zebrafish model as an effective platform for discovering drugs targeting hepatic lipid metabolic pathways.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"242 ","pages":"Article 117351"},"PeriodicalIF":5.6,"publicationDate":"2025-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145117820","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Evaluation of the functional impact of rare CYP2C19 missense variants identified in understudied Populations: An Integrated in silico and in vitro analysis","authors":"Reema Saleous ,&nbsp;Eiji Hishinuma ,&nbsp;Zeina N. Al-Mahayri ,&nbsp;Akiko Ueda ,&nbsp;Yuma Suzuki ,&nbsp;Mohammad A. Ghattas ,&nbsp;Radwa E. Mahgoub ,&nbsp;Masahiro Hiratsuka ,&nbsp;Bassam R. Ali","doi":"10.1016/j.bcp.2025.117350","DOIUrl":"10.1016/j.bcp.2025.117350","url":null,"abstract":"<div><div>Cytochrome P450 enzymes, particularly CYP2D6 and CYP2C19, play a crucial role in metabolizing various prescribed medications. While common <em>CYP2C19</em> variants, such as <em>*2</em> and <em>*3</em> alleles, are well-studied, rare and novel variants remain less understood, especially in understudied populations. This study investigated the functional impact of seven rare or novel <em>CYP2C19</em> missense variants (p.T55S, p.E92D, p.V113I, p.D262N, p.F267L, p.P337S, and p.I387V) identified in the Emirati population, some of which have also been reported in other populations. In silico prediction programs and molecular modeling have been used to evaluate and predict the expected impacts of these variants. In addition, we employed site-directed mutagenesis to generate these variants in <em>CYP2C19</em> cDNA, which was cloned into a mammalian expression vector, and evaluated their functional consequences using in vitro enzymatic assays. Our findings revealed that five of the seven variants (p.T55S, p.V113I, p.D262N, p.F267L, and p.P337S) significantly reduced CYP2C19 4′-hydroxylation catalytic activity towards (<em>S</em>)-mephenytoin, suggesting detrimental effects on drug metabolism. These results underscore the clinical importance of considering the impact of rare variants and, consequently, the need for their detailed functional analysis to integrate them into the implementation of pharmacogenomics and personalized medicine. This research contributes to the growing understanding of population-specific genetic variations in <em>CYP2C19</em> and their potential implications for the response and safety of a significant number of medications metabolized by this enzyme.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"242 ","pages":"Article 117350"},"PeriodicalIF":5.6,"publicationDate":"2025-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145117818","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"UHRF1 ameliorates liver cirrhosis through suppressing macrophage M1 polarization by catalyzing HMGA2 promoter methylation","authors":"Ruixi Li ,&nbsp;Qiang Tao ,&nbsp;Jiandong Zha ,&nbsp;Shikai Wang ,&nbsp;Xiaozhun Huang ,&nbsp;Jicai Wang ,&nbsp;Hang Zhai ,&nbsp;Shengjie Hong ,&nbsp;Guangquan Zhang","doi":"10.1016/j.bcp.2025.117357","DOIUrl":"10.1016/j.bcp.2025.117357","url":null,"abstract":"<div><div>Currently, suppressing macrophage M1 polarization and HSC activation are recognized as potential therapeutic strategies for liver cirrhosis. Ubiquitin-like with PHD and RING Finger Domains 1 (UHRF1) is a crucial epigenetic modulator implicated in maintaining DNA methylation and chromatin structure. Knockdown of high mobility group A protein 2 (HMGA2) was reported to ameliorate hepatic inflammation and fibrosis in nonalcoholic fatty liver disease. Here, the elaborate effect of UHRF1-mediated HMGA2 promoter methylation was investigated during the progression of liver cirrhosis. Transcriptomic sequencing of liver tissues of cirrhotic patients was carried out and a mouse model with liver cirrhosis was established by intraperitoneal injection of carbon tetrachloride (CCl₄) twice weekly for four consecutive weeks. Lipopolysaccharide (LPS)-induced RAW264.7 were transduced with overexpressed UHRF1 adenovirus and cell supernatant was applied as the conditional medium to cultivate hepatic stellate cells (HSCs). Notably, in vivo experiments, enhanced UHRF1 expression alleviated fibrosis and inflammation of mouse livers. In vitro experiments, upregulated UHRF1 suppressed CCl₄-stimulated macrophage M1 polarization and HSC activation. Moreover, MSP assay revealed that methylation was enhanced on HMGA2 promoter at −599/2−450 site after UHRF1 overexpression. More intriguingly, ChIP and Co-IP results clarified that UHRF1 interacted with DNA methyltransferase 1 (DNMT1), thereby bound to HMGA2 promoter and facilitated its methylation. Furthermore, increased HMGA2 level abolished the inhibitory effects of UHRF1 upregulation on the mRNA expression of pro-inflammatory genes of macrophages and genes encoding collagen of HSCs. Collectively, UHRF1 weakened HMGA2 expression by catalyzing its promoter methylation, thereby blocked macrophage M1 polarization and mitigated liver cirrhosis.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"242 ","pages":"Article 117357"},"PeriodicalIF":5.6,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145111479","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tanshinone IIA suppresses endoplasmic reticulum stress-mediated IRE1α/TXNIP/NLRP3 pathway to mitigate pyroptosis in type 2 diabetic osteoporosis","authors":"Zhuojun Jiang ,&nbsp;Jiancao Zuo ,&nbsp;Hailan Luo ,&nbsp;Yan Tang ,&nbsp;Zhuoting Tan ,&nbsp;Meining An ,&nbsp;Yuxuan Feng ,&nbsp;Shunxin Shi ,&nbsp;Jianfei Sun ,&nbsp;Ning Wu","doi":"10.1016/j.bcp.2025.117356","DOIUrl":"10.1016/j.bcp.2025.117356","url":null,"abstract":"<div><div>Type 2 diabetic osteoporosis (T2DOP) is a chronic skeletal disorder affecting bone structure and strength. Research has shown that endoplasmic reticulum stress (ERS) activates the NLRP3 inflammasome and osteoblast pyroptosis through inositol-requiring enzyme 1 alpha (IRE1α) and its interaction with thioredoxin-interacting protein (TXNIP). Tanshinone IIA (Tan IIA), a naturally occurring lipophilic diterpene derived from Salvia miltiorrhiza, inhibits the activation of IRE1α. This study explored Tan IIA’s therapeutic effects on T2DOP. MC3T3-E1 cells were cultured in a high-glucose medium to replicate conditions characteristic of the diabetic environment. Additionally, a T2DOP mouse model was developed through the intraperitoneal injection of streptozotocin in conjunction with a 60 %kacl high fat diet. Tan IIA was administered at different concentrations. Cell viability, differentiation and mineralization was assessed via CCK-8 assays, alkaline phosphatase staining, and Alizarin Red S staining. Serum biochemical markers were quantified using ELISA kits, while bone quality was evaluated using micro-CT and histological analysis. The mechanism was confirmed by Western blot, immunohistochemistry, RT-qPCR, molecular docking, and Cellular Thermal Shift Assay. Results showed Tan IIA improved insulin resistance, reduced inflammation and oxidative stress, and restored bone mass in T2DOP mice. Mechanistically, Tan IIA inhibited the IRE1α/TXNIP/NLRP3 pathway in vivo and in vitro, and ERS inducer tunicamycin attenuated its beneficial effects. The data establish Tan IIA as a promising candidate for treating T2DOP by alleviating osteoblast dysfunction and bone loss via the ERS-mediated IRE1α/TXNIP/NLRP3 pathway and pyroptosis.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"242 ","pages":"Article 117356"},"PeriodicalIF":5.6,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145111871","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}