Biochemical pharmacology最新文献_第8页

Corrigendum to “4-octyl itaconate protects against oxidative stress-induced liver injury by activating the Nrf2/Sirt3 pathway through AKT and ERK1/2 phosphorylation” [Biochem. Pharmacol. 220 (2024) 115992]

IF 5.3 2区医学

Biochemical pharmacology Pub Date : 2025-03-14 DOI: 10.1016/j.bcp.2025.116853

Ziyun Hu , Di Xu , Huihui Meng, Wenya Liu, Qi Zheng, Junsong Wang

引用次数: 0

Unveiling ODP4: A breakthrough in PCOS treatment via BAT transplantation 揭开 ODP4 的面纱：通过 BAT 移植治疗多囊卵巢综合症的突破。

IF 5.3 2区医学

Biochemical pharmacology Pub Date : 2025-03-14 DOI: 10.1016/j.bcp.2025.116871

Fangfang Di , Yan Yan , Lihua Yao, Zhongxiao Zhang, Liwen Song, Jin Qiu, Runjie Zhang

{"title":"Unveiling ODP4: A breakthrough in PCOS treatment via BAT transplantation","authors":"Fangfang Di , Yan Yan , Lihua Yao, Zhongxiao Zhang, Liwen Song, Jin Qiu, Runjie Zhang","doi":"10.1016/j.bcp.2025.116871","DOIUrl":"10.1016/j.bcp.2025.116871","url":null,"abstract":"<div><div>Women with polycystic ovary syndrome (PCOS) often face infertility due to endocrine disorders affecting their reproductive, metabolic, and endocrine systems. Although brown adipose tissue (BAT) transplantation has been established to treat polycystic ovaries and hyperandrogenism in PCOS rats, the underlying mechanism is still largely unclear owing to lacking effective clinical treatment. Peptides are believed to significantly contribute to PCOS pathogenesis, however, the specific effects of active peptides released by BAT on PCOS remain largely unexplored. This study sought to identify active peptides secreted in the recipient’s BAT and investigate their potential biological functions in PCOS. We validated the impact of BAT transplantation and found that an overexpressed ovary derived peptide 4 (ODP4) in BAT transplantation rats could potentiate the inhibitory effect of dehydroepiandrosterone (DHEA) on granulosa cell (GC) development, yield a stimulatory effect on cell apoptosis and regulate ovulation genes and hormone synthesis. In DHEA-induced PCOS rats, ODP4 restored the estrous cycle and reduced cystic follicles, indicating its potential in PCOS treatment. Furthermore, transcriptomic analysis of KGN cells treated with ODP4 and DHEA showed changes in genes related to mitochondrial activity and oxidative damage. The mechanism results showed that ODP4 enhanced mitochondrial functionality, elevated ATP production, and decreased oxidative damage in KGN cells treatment with DHEA, suggesting its preventive role in mitochondrial malfunction and oxidative damage. These findings reveal unrecognized roles of ODP4 in PCOS pathogenesis. Our study substantiates that the connection between BAT transplantation and PCOS is related to peptidomics. Additionally, ODP4 has prospects for clinical application as an innovative therapeutic PCOS target.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"236 ","pages":"Article 116871"},"PeriodicalIF":5.3,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143639515","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Downregulation of DDIT4 levels with borneol attenuates hepatotoxicity induced by gilteritinib

IF 5.3 2区医学

Biochemical pharmacology Pub Date : 2025-03-12 DOI: 10.1016/j.bcp.2025.116869

Yiming Yin , Yashi Cao , Yourong Zhou , Zhifei Xu , Peihua Luo , Bo Yang , Qiaojun He , Hao Yan , Xiaochun Yang

{"title":"Downregulation of DDIT4 levels with borneol attenuates hepatotoxicity induced by gilteritinib","authors":"Yiming Yin , Yashi Cao , Yourong Zhou , Zhifei Xu , Peihua Luo , Bo Yang , Qiaojun He , Hao Yan , Xiaochun Yang","doi":"10.1016/j.bcp.2025.116869","DOIUrl":"10.1016/j.bcp.2025.116869","url":null,"abstract":"<div><div>Gilteritinib, a multi-target kinase inhibitor, is currently used as standard therapy for acute myeloid leukemia. However, approximately half of the patients encounter liver-related adverse effects during the treatment with gilteritinib, which limiting its clinical applications. The underlying mechanisms of gilteritinib-induced hepatotoxicity and the development of strategies to prevent this toxicity are not well-reported. In our study, we utilized JC-1 dye, and MitoSOX to demonstrate that gilteritinib treatment leads to hepatocytes undergoing p53-mediated mitochondrial apoptosis. Furthermore, qRT-PCR analysis revealed that DNA damage-inducible transcript 4 (DDIT4), a downstream target of p53, was upregulated following gilteritinib administration and was identified as a key factor in gilteritinib-induced hepatotoxicity. After drug screening and western blot analysis, borneol, a bicyclic monoterpenoid, was found to decrease the protein level of DDIT4. This is the first compound found to downregulate DDIT4 levels and ameliorate hepatic injury caused by gilteritinib. Our findings suggest that high levels of DDIT4 are the primary driver behind gilteritinib-induced liver injury, and that borneol could potentially be a clinically safe and feasible therapeutic strategy by inhibiting DDIT4 levels.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"236 ","pages":"Article 116869"},"PeriodicalIF":5.3,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143620603","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Irisin alleviates steroid-induced vascular dysfunction by regulating the αVβ5-c-Abl-Caveolin-1 signaling pathway

IF 5.3 2区医学

Biochemical pharmacology Pub Date : 2025-03-12 DOI: 10.1016/j.bcp.2025.116870

Lijun Fang , Wenqiang Li , Hua Zhao , Wei Wang , Hongmei Gao , Pengqi Wang , Xinzhi Zhang , Ruijuan Lv , Feng Xu , Jiazheng Chen , Linmao Lyu , Yuguo Chen

{"title":"Irisin alleviates steroid-induced vascular dysfunction by regulating the αVβ5-c-Abl-Caveolin-1 signaling pathway","authors":"Lijun Fang , Wenqiang Li , Hua Zhao , Wei Wang , Hongmei Gao , Pengqi Wang , Xinzhi Zhang , Ruijuan Lv , Feng Xu , Jiazheng Chen , Linmao Lyu , Yuguo Chen","doi":"10.1016/j.bcp.2025.116870","DOIUrl":"10.1016/j.bcp.2025.116870","url":null,"abstract":"<div><div>Steroid-induced avascular necrosis of the femoral head (SANFH) is a progressive degenerative disease of the hip, primarily due to glucocorticoid (GC)-induced endothelial cell (EC) injury and compromised blood supply. Irisin is an EC-protective mytokine whose receptor is the integrin αVβ5. Caveolin-1 (CAV-1)， a major component of caveolae, causes endothelial dysfunction when phosphorylated. However, the role of irisin and CAV-1 in SANFH remains unclear. In our study, irisin levels decreased but CAV-1 phosphorylation increased in human and mouse SANFH samples. Intraperitoneal irisin injection (250 μg/kg daily) notably reduced GC-induced osteonecrosis, vascular abnormalities, and CAV-1 phosphorylation in SANFH mice. In cultured ECs, GC induced CAV-1 phosphorylation by activating c-Abl via the glucocorticoid receptor, and irisin inhibited GC-induced phosphorylation of c-Abl and CAV-1 via the integrin αVβ5. Inhibition of integrin αVβ5 also abolished the protective effects of irisin on ERK and eNOS signalling, viability, angiogenesis, and migration in ECs. Therefore, our findings indicate that irisin has a protective role against vascular dysfunction in SANFH, possibly mediated by the inhibition of GC-triggered c-Abl-CAV-1 phosphorylation through integrin αVβ5. These findings provide insights into the potential therapeutic applications of irisin in SANFH.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"236 ","pages":"Article 116870"},"PeriodicalIF":5.3,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143629393","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}

引用次数: 0

Leptin impairs the therapeutic efficacy of adipose-derived mesenchymal stem cells by inducing apoptosis through NLRP3 inflammasomes activation

IF 5.3 2区医学

Biochemical pharmacology Pub Date : 2025-03-11 DOI: 10.1016/j.bcp.2025.116868

Thi-Kem Nguyen , Duc-Vinh Pham , Pil-Hoon Park

{"title":"Leptin impairs the therapeutic efficacy of adipose-derived mesenchymal stem cells by inducing apoptosis through NLRP3 inflammasomes activation","authors":"Thi-Kem Nguyen , Duc-Vinh Pham , Pil-Hoon Park","doi":"10.1016/j.bcp.2025.116868","DOIUrl":"10.1016/j.bcp.2025.116868","url":null,"abstract":"<div><div>Mesenchymal stem cells (MSC) have been widely applied for regenerative medicine and the treatment of immune-disorders due to their multilineage differentiation and potent immunomodulatory properties. The therapeutic application of MSC post transplantation are influenced by various endogenous modulators. Leptin, a hormone primarily derived from adipose tissue, exerts a variety of physiological functions, in addition to the metabolic effects. In this study, we examined the effects of leptin on the viability of adipose-derived mesenchymal stem cells (ADSC) and its underlying molecular mechanisms with a particular focus on NLRP3 inflammasomes, which serve as signaling platform of the innate immune system. Leptin significantly decreased the viability of ADSC and induced apoptosis. Mechanistically, NLRP3 inflammasomes signaling critically contributes to leptin-induced apoptosis of ADSC by upregulating p53 and Puma. In addition, NLRP3 inflammasomes activation by leptin is mediated via ER stress induction and ROS accumulation. Finally, suppression of ADSC therapeutic efficacy by leptin and the critical role of NLRP3 inflammasomes in this phenomenon were confirmed in DSS-induced colitis model. Pre-conditioning with leptin before transplantation impaired the therapeutic efficacy and immunomodulatory function of ADSC, which were restored by treatment with a pharmacological inhibitor of NLRP3 inflammasomes. Taken together, the results suggest that leptin induces apoptotic cell death in ADSC and impairs the therapeutic effectiveness of ADSC by activating NLRP3 inflammasomes.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"236 ","pages":"Article 116868"},"PeriodicalIF":5.3,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143623285","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}

引用次数: 0

Therapeutic opportunities in polycystic kidney and liver disease through extracellular matrix dynamics 通过细胞外基质动力学研究多囊肾和肝病的治疗机会。

IF 5.3 2区医学

Biochemical pharmacology Pub Date : 2025-03-11 DOI: 10.1016/j.bcp.2025.116858

Adrian Cordido , Laura Nuñez-González , Olaya Lamas-González , Marta Vizoso-González , Susana Bravo , Candido Díaz , Jesus M Banales , Miguel A. García-González

{"title":"Therapeutic opportunities in polycystic kidney and liver disease through extracellular matrix dynamics","authors":"Adrian Cordido , Laura Nuñez-González , Olaya Lamas-González , Marta Vizoso-González , Susana Bravo , Candido Díaz , Jesus M Banales , Miguel A. García-González","doi":"10.1016/j.bcp.2025.116858","DOIUrl":"10.1016/j.bcp.2025.116858","url":null,"abstract":"<div><div>Autosomal Dominant and Autosomal Recessive Polycystic Kidney Disease (ADPKD and ARPKD) are, respectively, common and rare forms of polycystic disorders, characterized by the formation and progressive growth of cysts from tubules in the kidneys and bile ducts in the liver. Alterations in the extracellular matrix (ECM) and in the activity of matrix metalloproteases (MMPs), both associated with fibrosis, have been shown to be important factors in cystic growth and progression of these diseases. We used tandem mass spectrometry (LC-MS/MS) to identify the most enriched proteins and pathways in an orthologous rapidly progressive mouse model of ADPKD: <em>Pkd1<sup>flox/flox</sup>TamCre.</em> This information was used to discover and validate novel therapeutic targets in orthologous models of ADPKD (<em>Pkd1<sup>flox/flox</sup>TamCre</em>) and ARPKD (<em>Pkdh1<sup>del3-4/del3-4</sup></em>). ECM related pathways and expression levels of MMPs were among the most dysregulated cellular processes in polycystic kidney and liver. Selective inhibition of MMPs by marimastat (MTT) altered the ECM response and resulted in inhibition of collecting duct-derived cyst growth, delay of global kidney cyst progression and rescue of liver phenotype by normalized MMPs expression and significant reduction in fibrosis. This phenotypic improvement was further enhanced by treatment of MTT and tolvaptan, indicating an additive benefit to targeting the fibrotic and growth pathways in cysts.</div><div>As conclusion, targeting of MMPs are important in ECM dysregulation and offers a new potential therapeutic strategy for both kidney and bile duct derived fibrocystic disease in ADPKD and ARPKD. Such approaches can have additive benefits with other treatment approaches, such as tolvaptan.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"236 ","pages":"Article 116858"},"PeriodicalIF":5.3,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143623289","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}

引用次数: 0

Inhibition of METTL3 promotes mesangial cell mitophagy and attenuates glomerular damage by alleviating FOSL1 m6A modifications via IGF2BP2-dependent mechanisms 抑制 METTL3 可促进系膜细胞有丝分裂，并通过 IGF2BP2 依赖性机制减轻 FOSL1 m6A 修饰，从而减轻肾小球损伤。

IF 5.3 2区医学

Biochemical pharmacology Pub Date : 2025-03-11 DOI: 10.1016/j.bcp.2025.116867

Tao Liu , Xing Xing Zhuang , Xiao Li Zhu , Xi Wu , Xiu Juan Qin , Liang Bing Wei , Ya Chen Gao , Jia Rong Gao

{"title":"Inhibition of METTL3 promotes mesangial cell mitophagy and attenuates glomerular damage by alleviating FOSL1 m6A modifications via IGF2BP2-dependent mechanisms","authors":"Tao Liu , Xing Xing Zhuang , Xiao Li Zhu , Xi Wu , Xiu Juan Qin , Liang Bing Wei , Ya Chen Gao , Jia Rong Gao","doi":"10.1016/j.bcp.2025.116867","DOIUrl":"10.1016/j.bcp.2025.116867","url":null,"abstract":"<div><div>Epigenetic changes are involved in many physiological and pathological processes. Mitophagy plays a critical role in chronic kidney disease (CKD); however, the role of N6-methyladenosine (m6A) modification in renal mitophagy remains unclear. In this research, we aim to elucidate the role of RNA methylation in modulating mitophagy and its involvement in the pathophysiology of chronic glomerulonephritis (CGN). We found that Methyltransferase-like 3 (METTL3) was significantly upregulated in biopsies from CKD patients, as well as in CGN mice and cultured mouse mesangial cells (MMCs), and was inversely correlated with glomerular filtration rate. Adeno-associated virus serotype 9 (AAV9)-mediated METTL3 silencing from mouse kidneys attenuated adenine-induced glomerular damage, and promoted renal mitophagy. METTL3 knockdown significantly reduced the oxidative stress and inflammation levels and promoted mitophagy in lipopolysaccharide (LPS)-stimulated MMCs, while its overexpression significantly aggravated these responses in vitro. Moreover, FOSL1 (Fos-like antigen 1) was identified as a target of METTL3 and the stability of FOSL1 was increased through binding of IGF2BP2 (Insulin-like Growth Factor 2 mRNA-binding Protein 2) to its m6A-modified regions. The mitophagy regulatory effects of FOSL1 were then explored both in vitro and in vivo. Mechanistically, METTL3 modulated AMPK (AMP-activated Protein Kinase)/mTOR (Mechanistic Target of Rapamycin) signaling via the m6A modification of FOSL1 in an IGF2BP2-dependent manner and exerted a mitophagy inhibitory effect. In summary, this study suggested that METTL3-mediated m6A modification is an important mechanism of mesangial cell (MCs) injury in CGN. Targeting m6A through the writer enzyme METTL3 is a potential approach for the treatment of CGN.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"236 ","pages":"Article 116867"},"PeriodicalIF":5.3,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143623283","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}

引用次数: 0

Ifosfamide alleviates autoimmune toxicity and enhances antitumor efficacy in melanoma immunotherapy

IF 5.3 2区医学

Biochemical pharmacology Pub Date : 2025-03-11 DOI: 10.1016/j.bcp.2025.116851

Yuehan Gao , Xiuxing Liu , Jianjie Lv , Chenyang Gu , Tianyu Tao , Chun Zhang , Danping Huang , Renbing Jia , Xinping Yu , Wenru Su

{"title":"Ifosfamide alleviates autoimmune toxicity and enhances antitumor efficacy in melanoma immunotherapy","authors":"Yuehan Gao , Xiuxing Liu , Jianjie Lv , Chenyang Gu , Tianyu Tao , Chun Zhang , Danping Huang , Renbing Jia , Xinping Yu , Wenru Su","doi":"10.1016/j.bcp.2025.116851","DOIUrl":"10.1016/j.bcp.2025.116851","url":null,"abstract":"<div><div>Autoimmune toxicity affects up to 60 % of patients receiving immune checkpoint inhibitor (ICI) therapy for cancer, presenting a notable clinical obstacle that constrains its wider application. Hence, there is an imperative demand to develop novel strategies to manage immune-related adverse events (irAEs). Ifosfamide (IFO) shares structural and functional resemblances with cyclophosphamide (CPA). Despite the acknowledged dual anti-tumor and immunomodulatory effects of CPA, the specific effect of IFO on autoimmune conditions remains elusive. Here, we evaluated the efficacy of IFO on experimental autoimmune uveitis (EAU) mouse models and explored the cell-specific effects of IFO under autoimmune conditions using single-cell RNA sequencing. Our data indicated that IFO effectively alleviated inflammatory infiltration and reversed pathological alterations of EAU. Subsequent single-cell data analysis and <em>in vivo</em> experiments suggested IFO exerted broad suppressive effects on autoimmune responses, concurrently restoring the balance between Th17 and Treg populations. In addition, we observed that IFO enhanced CD8<sup>+</sup> T cell activation and its cytotoxic immune responses, highlighting the cell-type-specific immunomodulatory effects of IFO. Moreover, we constructed EAU models on tumor-bearing mice under ICI treatment, and found that ICI exacerbated EAU symptoms. IFO not only possessed anti-tumor effects as monotherapy, but also augmented ICI efficacy by promoting CD8<sup>+</sup> T cell-mediated immunity. Furthermore, we found that IFO alleviated EAU symptoms exacerbated by ICI treatment and effectively restored Th17/Treg balance. Our results elucidated the immunomodulatory effects of IFO treatment, providing evidence for the application of IFO in managing autoimmune conditions and irAEs.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"236 ","pages":"Article 116851"},"PeriodicalIF":5.3,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143623280","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}

引用次数: 0

A high affinity Sybody blocks Cofilin-1 binding to F-actin in vitro and in cancer cells

IF 5.3 2区医学

Biochemical pharmacology Pub Date : 2025-03-09 DOI: 10.1016/j.bcp.2025.116866

Themistoklis Paraschiakos , Jing Li , Jonas Scholz , Soo-Ji Han , Marcus Deckers , Vivian Pogenberg , Jan Faix , Sabine Windhorst

{"title":"A high affinity Sybody blocks Cofilin-1 binding to F-actin in vitro and in cancer cells","authors":"Themistoklis Paraschiakos , Jing Li , Jonas Scholz , Soo-Ji Han , Marcus Deckers , Vivian Pogenberg , Jan Faix , Sabine Windhorst","doi":"10.1016/j.bcp.2025.116866","DOIUrl":"10.1016/j.bcp.2025.116866","url":null,"abstract":"<div><div>Upregulation of the actin-severing protein Cofilin-1 is implicated in enhancing malignancy of various cancer types by promoting actin turnover and increasing cellular motility. Despite the importance of targeting Cofilin-1, currently there is a lack of inhibitors specifically targeting its actin-severing activity. To address this issue, we generated synthetic anti-Cofilin-1 nanobodies (Sybodies) that interfere with human Cofilin-1 binding to filamentous actin. We identified four high affinity Sybodies against human Cofilin-1 with dissociation constants (K<sub>D</sub>) in the nanomolar range that inhibited G-actin sequestration, and actin-severing activity of Cofilin-1 <em>in vitro</em>. Notably, Sybody B12, with the lowest K<sub>D</sub> of approximately 27 nM, competitively blocked actin binding to Cofilin-1, and also inhibited G-actin sequestration of murine Cofilin-1. The crystal structure of the Sybody-B12-Cofilin-1 complex, resolved at 1.8 Å, revealed that Sybody B12 binds to the G-actin binding site of Cofilin-1, showing that Sybody B12 engages the same binding site on Cofilin-1 as actin. Consistently, transient expression of mPlum-tagged Sybody B12 in human H1299 lung cancer cells inhibited the formation of enhanced green fluorescent protein (EGFP)-Cofilin-actin rods. Notably, stable expression of Sybody B12 did not affect viability of H1299 cells, and no compensatory up-regulation of Cofilin-2 or actin-depolymerization factor (ADF) mRNA were detectable in Sybody B12 expressing H1299 cells. Together, these findings suggest that Sybody B12 exhibits a strong potential as tool for inhibiting the interaction of Cofilin-1 with actin. In addition, it could serve as a promising lead structure for designing Cofilin-1 inhibitors <em>in silico</em>.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"236 ","pages":"Article 116866"},"PeriodicalIF":5.3,"publicationDate":"2025-03-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143596201","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The SGLT2 inhibitor dapagliflozin suppresses endothelial cell pyroptosis mediated by the NF-κB/NLRP3 pathway through downregulation of CTSB

IF 5.3 2区医学

Biochemical pharmacology Pub Date : 2025-03-07 DOI: 10.1016/j.bcp.2025.116857

Quanwei Zhao , Hui Li , Danan Liu , Bo Zhou , Caiwei Gong , Long Chen , Fujun Liao

{"title":"The SGLT2 inhibitor dapagliflozin suppresses endothelial cell pyroptosis mediated by the NF-κB/NLRP3 pathway through downregulation of CTSB","authors":"Quanwei Zhao , Hui Li , Danan Liu , Bo Zhou , Caiwei Gong , Long Chen , Fujun Liao","doi":"10.1016/j.bcp.2025.116857","DOIUrl":"10.1016/j.bcp.2025.116857","url":null,"abstract":"<div><div>Atherosclerosis (AS) is a chronic inflammatory disease, and pyroptosis—a recently discovered pro-inflammatory programmed cell death process—can exacerbate these inflammatory responses. Vascular endothelial cell pyroptosis contributes to AS progression. Cathepsin B (CTSB) is a crucial member of the cysteine protease family found in lysosomes. However, its exact role in vascular endothelial cell pyroptosis remains unclear. Dapagliflozin (DAPA), a sodium–glucose cotransporter-2 (SGLT2) inhibitor, inhibits pyroptosis and alleviates AS independent of its hypoglycemic effect. This study utilized oxidized low-density lipoprotein (ox-LDL) to induce pyroptosis in human umbilical vein endothelial cells (HUVECs) and investigated the effect of this process. The study revealed that ox-LDL induced HUVEC pyroptosis in a concentration-dependent manner, resulting in Na<sup>+</sup> and Ca<sup>2+</sup> overload, lysosomal damage, and increased CTSB release into the cytosol. Lentiviral vectors were used to overexpress or silence CTSB; subsequent analysis revealed that CTSB promotes NLRP3-mediated pyroptosis through nuclear factor κB (NF-κB) activation. Finally, we found that DAPA attenuated HUVEC pyroptosis by inhibiting the NF-κB/NLRP3 pathway and decreasing the expression of CTSB. This effect may be attributed to its ability to alleviate lysosomal damage caused by Na<sup>+</sup>–Ca<sup>2+</sup> overload, thereby reducing CTSB release into the cytosol.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"236 ","pages":"Article 116857"},"PeriodicalIF":5.3,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143576978","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}

引用次数: 0