Biochemical pharmacology最新文献_第5页

N6-methyladenosine-modified RNF220 induces cisplatin resistance and immune escape via regulating PDE10A K48-linked ubiquitination in bladder cancer

IF 5.3 2区医学

Biochemical pharmacology Pub Date : 2025-03-28 DOI: 10.1016/j.bcp.2025.116903

Kai Li , Yongshan Li , Yetao Zhang , Jiancheng Lv , Tong Zhao , Yuxiang Dong , Fuyang Liu , Jun Wang , Yong Wei , Qingyi Zhu

{"title":"N6-methyladenosine-modified RNF220 induces cisplatin resistance and immune escape via regulating PDE10A K48-linked ubiquitination in bladder cancer","authors":"Kai Li , Yongshan Li , Yetao Zhang , Jiancheng Lv , Tong Zhao , Yuxiang Dong , Fuyang Liu , Jun Wang , Yong Wei , Qingyi Zhu","doi":"10.1016/j.bcp.2025.116903","DOIUrl":"10.1016/j.bcp.2025.116903","url":null,"abstract":"<div><div>Bladder cancer (BCa) remains one of the most prevalent malignancies worldwide, with cisplatin-based combination chemotherapy as the cornerstone of adjuvant treatment. However, cisplatin resistance frequently arises in advanced BCa, limiting therapeutic efficacy. Comparative proteomic analysis of cisplatin-sensitive and -resistant BCa cells identified phosphodiesterase 10A (PDE10A) as significantly downregulated at the protein level in resistant cells, despite unchanged mRNA levels, indicating post-transcriptional regulation. Functional assays demonstrated that PDE10A enhanced cisplatin sensitivity by promoting apoptosis. Mechanistically, the E3 ubiquitin ligase RNF220 directly interacted with PDE10A, facilitating its ubiquitination and degradation under cisplatin-resistant conditions. RNF220 overexpression markedly reinforced cisplatin resistance <em>in vitro</em> and <em>in vivo</em>. Furthermore, N6-methyladenosine (m6A) modification mediated by METTL3 stabilized RNF220 mRNA in an IGF2BP2-dependent manner. Additionally, RNF220 promoted PD-L1 expression by destabilizing PDE10A, thereby facilitating immune evasion in BCa. These findings establish RNF220 as a pivotal ubiquitinase that drives both cisplatin resistance and immune escape through PDE10A destabilization, highlighting its potential as a therapeutic target to enhance chemotherapy and immunotherapy efficacy in advanced BCa.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"236 ","pages":"Article 116903"},"PeriodicalIF":5.3,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143724921","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

Effect of PAI-1 inhibitor on pancreatic islet function and hepatic insulin resistance in db/db mice

IF 5.3 2区医学

Biochemical pharmacology Pub Date : 2025-03-28 DOI: 10.1016/j.bcp.2025.116906

Menghua Lin , Lijing Wang , Binbin Guan , Shuzhi Tang , Lu Lin , Kejun Wu , Qintao Huang , Guanlian He , Zhouyangyang Zhang , Ruonan Gao , Xiaoying Liu , XiaoHong Liu , Zhuo Chen , Libin Liu

{"title":"Effect of PAI-1 inhibitor on pancreatic islet function and hepatic insulin resistance in db/db mice","authors":"Menghua Lin , Lijing Wang , Binbin Guan , Shuzhi Tang , Lu Lin , Kejun Wu , Qintao Huang , Guanlian He , Zhouyangyang Zhang , Ruonan Gao , Xiaoying Liu , XiaoHong Liu , Zhuo Chen , Libin Liu","doi":"10.1016/j.bcp.2025.116906","DOIUrl":"10.1016/j.bcp.2025.116906","url":null,"abstract":"<div><div>Type 2 diabetes mellitus (T2DM) is a global health challenge, necessitating innovative antidiabetic treatments. Levels of plasminogen activator inhibitor-1 (PAI-1) are elevated in patients with T2DM and may be an important but underappreciated risk factor for diabetes. However, its relationship with T2DM remains unclear. To this end, we developed a potent and highly specific PAI-1 inhibitor named PAItrap3. We aimed to elucidate the metabolic effects of PAItrap3 using a preclinical <em>db/db</em> mouse model. PAItrap3 was administered to mice intravenously, followed by an assessment of biochemical markers, histopathological examination of the liver and pancreas, and evaluation of the expression of hepatic proteins integral to insulin signaling. PAItrap3 demonstrated potent efficacy in alleviating hyperglycemia and enhancing glycemic control. This therapeutic action was supported by its ability to enhance β-cell function, consequently mitigating β-cell apoptosis and preserving their integrity. Furthermore, PAItrap3 alleviated hepatic insulin resistance through the regulation of lipid and glucose metabolism, thereby maintaining the delicate homeostasis of systemic lipid and glucose metabolism. These findings suggest that PAItrap3 is a promising therapeutic candidate for T2DM. The multifaceted benefits of PAItrap3 highlight its potential to vastly improve the effectiveness and specificity of T2DM treatment paradigms.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"237 ","pages":"Article 116906"},"PeriodicalIF":5.3,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143750938","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

Suppression of global protein synthesis and hepatocellular carcinoma cell growth by Benzimidazoisoquinoline, 4,11-Dichloro-BBQ

IF 5.3 2区医学

Biochemical pharmacology Pub Date : 2025-03-27 DOI: 10.1016/j.bcp.2025.116896

Lo-Wei Lin , Hyo Sang Jang , Zifeng Song , Arpa Ebrahimi , Jun Yang , Bach D. Nguyen , Edmond F. O’Donnell , David A. Hendrix , Claudia S. Maier , Siva K. Kolluri

{"title":"Suppression of global protein synthesis and hepatocellular carcinoma cell growth by Benzimidazoisoquinoline, 4,11-Dichloro-BBQ","authors":"Lo-Wei Lin , Hyo Sang Jang , Zifeng Song , Arpa Ebrahimi , Jun Yang , Bach D. Nguyen , Edmond F. O’Donnell , David A. Hendrix , Claudia S. Maier , Siva K. Kolluri","doi":"10.1016/j.bcp.2025.116896","DOIUrl":"10.1016/j.bcp.2025.116896","url":null,"abstract":"<div><div>The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor best known for mediating biological responses to a wide range of xenobiotics, such as dioxins and polycyclic aromatic hydrocarbons. Recently, AhR has emerged as an important player in cancer biology, with the potential for therapeutic applications through targeted modulation of its activity in specific cancer types. In this study, we report that 4,11-dichloro-BBQ (DiCl-BBQ), a benzimidazoisoquinoline, exhibits AhR-mediated antiproliferative activity in HepG2 hepatocellular carcinoma cells. DiCl-BBQ was found to decrease cell growth at nanomolar concentrations, and this antiproliferative effect persisted even after the compound’s removal. Using inducible shRNA expression system, we demonstrated that the inhibitory effect of DiCl-BBQ was significantly reduced following AhR knockdown. Flow cytometric analysis revealed that DiCl-BBQ halted cell division and induced G1 cell cycle arrest in an AhR-dependent manner. Proteomic profiling identified the top four enriched pathways following DiCl-BBQ exposure: metabolism of RNA, translation, ribonucleoprotein complex biogenesis, and carboxylic acid metabolic processes. Notably, DiCl-BBQ caused a dramatic downregulation of translation-associated proteins, with this response diminished in AhR-depleted cells. Consistently, global protein synthesis was significantly repressed in DiCl-BBQ-treated cells. Together, these results indicate that DiCl-BBQ effectively inhibits HepG2 cells growth by inducing G1 cell cycle arrest and downregulating the protein translation machinery in an AhR-dependent manner.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"236 ","pages":"Article 116896"},"PeriodicalIF":5.3,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143742096","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

Understanding the peroxisome proliferator-activated receptor gamma (PPAR-γ) role in periodontitis and diabetes mellitus: A molecular perspective

IF 5.3 2区医学

Biochemical pharmacology Pub Date : 2025-03-27 DOI: 10.1016/j.bcp.2025.116908

Ingra Gagno Nicchio , Thamiris Cirelli , Lucas César da Costa Quil , Angelo Constantino Camilli , Raquel Mantuaneli Scarel-Caminaga , Fabio Renato Manzolli Leite

{"title":"Understanding the peroxisome proliferator-activated receptor gamma (PPAR-γ) role in periodontitis and diabetes mellitus: A molecular perspective","authors":"Ingra Gagno Nicchio , Thamiris Cirelli , Lucas César da Costa Quil , Angelo Constantino Camilli , Raquel Mantuaneli Scarel-Caminaga , Fabio Renato Manzolli Leite","doi":"10.1016/j.bcp.2025.116908","DOIUrl":"10.1016/j.bcp.2025.116908","url":null,"abstract":"<div><div>Periodontitis and Type 2 Diabetes Mellitus (T2DM) are chronic conditions with dysregulated immune responses. Periodontitis involves immune dysfunction and dysbiotic biofilms, leading to tissue destruction. T2DM is marked by insulin resistance and systemic inflammation, driving metabolic and tissue damage. Both conditions share activation of key pathways, including Nuclear Factor Kappa B (NF-κB), Activator Protein-1 (AP-1), and Signal Transducer and Activator of Transcription (STAT) proteins, reinforcing an inflammatory feedback loop. This review highlights the role of Peroxisome Proliferator-Activated Receptor Gamma (PPAR-γ), a transcription factor central to lipid and glucose metabolism, adipogenesis, and immune regulation. PPAR-γ activation has been shown to suppress inflammatory mediators such as Tumor Necrosis Factor Alpha (TNF-α) and Interleukin 6 (IL-6) through the inhibition of NF-κB, AP-1, and STAT pathways, thereby potentially disrupting the inflammatory-metabolic cycle that drives both diseases. PPAR-γ agonists, including thiazolidinediones (TZDs) and endogenous ligands such as 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2), show promise in reducing inflammation and improving insulin sensitivity, but they are limited by adverse effects. Therapies, including Selective Peroxisome Proliferator-Activated Receptor Modulators (SPPARMs), have been developed to offer a more targeted approach, allowing for selective modulation of PPAR-γ activity to retain its anti-inflammatory benefits while minimizing their side effects. By integrating insights into PPAR-γ’s molecular mechanisms, this review underscores its therapeutic potential in mitigating inflammation and enhancing metabolic control.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"237 ","pages":"Article 116908"},"PeriodicalIF":5.3,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143742097","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

Nanotechnology-Assisted mesenchymal stem cells treatment for improved cartilage regeneration: A review of current practices

IF 5.3 2区医学

Biochemical pharmacology Pub Date : 2025-03-26 DOI: 10.1016/j.bcp.2025.116895

Hongming Lin , Chao Zhou , Qingping Li , Qiong Xie , Linying Xia , Lu Liu , Wenwen Bao , Xiaochun Xiong , Hao Zhang , Zeping Zheng , Jiayi Zhao , Wenqing Liang

{"title":"Nanotechnology-Assisted mesenchymal stem cells treatment for improved cartilage regeneration: A review of current practices","authors":"Hongming Lin , Chao Zhou , Qingping Li , Qiong Xie , Linying Xia , Lu Liu , Wenwen Bao , Xiaochun Xiong , Hao Zhang , Zeping Zheng , Jiayi Zhao , Wenqing Liang","doi":"10.1016/j.bcp.2025.116895","DOIUrl":"10.1016/j.bcp.2025.116895","url":null,"abstract":"<div><div>Cartilage tissue does not promptly elicit an inflammatory response upon injury, hence constraining its capacity for healing and self-regeneration. Mesenchymal Stem Cells (MSC) therapy, enhanced by nanotechnology, offers promising advancements in cartilage repair. Injuries to cartilage often cause chronic pain, where current treatments are inadequate. As MSCs can readily differentiate into chondrocytes and secrete soluble factors, they are essential components in tissue engineering of cartilage repair. Although, like other stem cell applications, clinical applications are restricted by poor post implantation survival and differentiation. Recent studies show that nanoparticles (NPs) can further improve MSC outcomes by promoting cell adhesion, and chondrogenic differentiation allowing for sustained growth factor release. In addition, nanomaterials can improve the biological activity of MSCs, by also facilitating the composition of a conducive microenvironment for cartilage repair. In this review, the application of nanofibrous scaffolds, hydrogels and nanoscale particulate matter to improve mechanical properties in cartilage tissue engineering, are discussed. Moreover, the MSCs and nanotechnology synergistic effects present hope of overcoming the limitations of conventional treatments. Nanotechnology greatly enhances the MSC based cartilage regeneration strategies and could provide better treatment for cartilage related diseases in the future. Future research should be aimed at standardizing MSC harvesting and culturing protocols and contrasting their long–term efficacy.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"237 ","pages":"Article 116895"},"PeriodicalIF":5.3,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143742095","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

Exploration of functional cytochrome P450 4F enzymes in liver, intestine, and kidney from dogs, cats, pigs, and tree shrews and comparison of their metabolic capacities with human P450 4F2 and 4F12

IF 5.3 2区医学

Biochemical pharmacology Pub Date : 2025-03-26 DOI: 10.1016/j.bcp.2025.116894

Yasuhiro Uno , Izumi Kawabata , Genki Ushirozako , Kyoko Tsukiyama-Kohara , Mayumi Ishizuka , Hazuki Mizukawa , Norie Murayama , Hiroshi Yamazaki

{"title":"Exploration of functional cytochrome P450 4F enzymes in liver, intestine, and kidney from dogs, cats, pigs, and tree shrews and comparison of their metabolic capacities with human P450 4F2 and 4F12","authors":"Yasuhiro Uno , Izumi Kawabata , Genki Ushirozako , Kyoko Tsukiyama-Kohara , Mayumi Ishizuka , Hazuki Mizukawa , Norie Murayama , Hiroshi Yamazaki","doi":"10.1016/j.bcp.2025.116894","DOIUrl":"10.1016/j.bcp.2025.116894","url":null,"abstract":"<div><div>Pigs are often used in drug metabolism studies because of their evolutionary proximity to humans, including similarities in their cytochromes P450 (P450s or CYPs). In the current study, the following cDNAs of novel CYP4Fs were isolated and characterized: dog CYP4F22 and CYP4F140; cat CYP4F22 and CYP4F140; pig CYP4F22, CYP4F52, CYP4F53, CYP4F54, CYP4F56, and CYP4F176; and tree shrew CYP4F22. Previously identified pig CYP4F55 cDNA was also isolated. These CYP4F cDNAs contained open reading frames of 522–531 amino acids and shared high sequence identities (60–92 %) with human CYP4Fs. Dog CYP4F3a and CYP4F3b cDNAs were also identified but lacked the 3′ end of the coding region. Phylogenetic analysis of amino acid sequences showed that these CYP4Fs were clustered in a species-dependent manner, except for CYP4F3, CYP4F22, and CYP4F140, which were clustered in an isoform-dependent manner. All <em>CYP4F</em> genes, containing 12 coding exons, formed a gene cluster at the corresponding location of the genome in each species. Among the tissue samples analyzed, dog and cat CYP4F140 mRNAs were more abundantly expressed in liver/testis and kidney, respectively. Preferential expression of pig CYP4F mRNAs were found in liver, small intestine, and/or kidney, where the most abundant were CYP4F56, CYP4F52, and CYP4F176 mRNAs, respectively. Enzyme assays using recombinant proteins revealed that all these CYP4Fs oxidized the human CYP4F substrate arachidonic acid at the ω-position, indicating that they are functional enzymes. These findings suggest that dog, cat, pig, and tree shrew CYP4Fs have similar functional characteristics to human CYP4Fs.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"236 ","pages":"Article 116894"},"PeriodicalIF":5.3,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143742094","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

Characterization of the first antimicrobial peptide from Sea Seal with potent therapeutic effect in septic mice

IF 5.3 2区医学

Biochemical pharmacology Pub Date : 2025-03-25 DOI: 10.1016/j.bcp.2025.116891

Jiali Li , Weichen Xiong , Jianxi Yang , Weifei Liao , Yihan Gao , Jinwei Chai , Jiena Wu , Shuwen Liu , Xueqing Xu

{"title":"Characterization of the first antimicrobial peptide from Sea Seal with potent therapeutic effect in septic mice","authors":"Jiali Li , Weichen Xiong , Jianxi Yang , Weifei Liao , Yihan Gao , Jinwei Chai , Jiena Wu , Shuwen Liu , Xueqing Xu","doi":"10.1016/j.bcp.2025.116891","DOIUrl":"10.1016/j.bcp.2025.116891","url":null,"abstract":"<div><div>Marine organisms are a valuable source of natural bioactive substances, and an increasing number of marine antimicrobial peptides as the potential alternative to antibiotics are being developed. Nonetheless, antimicrobial peptides from Antarctic mammals have not been reported heretofore. In this context, we identified a Cathelicidin antimicrobial peptide, Cath-LW (RLRDLIRRGRQKIGRRINRLGRRIQDILKNLQPGKVS), from the whole-genome database of <em>Leptonychotes weddellii</em>, an Antarctic mammal. Cath-LW was characterized to exhibit a typical α-helix structure and broad-spectrum antimicrobial activity. Furthermore, Cath-LW was found to exert its antibacterial effect by destroying cytomembrane, binding to bacterial genome, and inhibiting DNA function. Additionally, Cath-LW could neutralize lipopolysaccharide (LPS) and inhibit LPS-induced inflammatory responses. Interestingly, Cath-LW also showed anticoagulant activity and suppressed FeCl<sub>3</sub>-induced carotid thrombosis in mice. Finally, in septic mice, Cath-LW was demonstrated to improve the survival rate by effectively alleviating organ inflammation and damage, as well as thrombus formation. These findings not only deepen our understanding of the survival strategies of <em>L. weddellii</em> against microbial infections but also provide a crucial template for developing a novel multifunctional anti-sepsis drug.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"236 ","pages":"Article 116891"},"PeriodicalIF":5.3,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143715359","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

Dual blockade of GSTK1 and CD47 improves macrophage-mediated phagocytosis on cancer cells

IF 5.3 2区医学

Biochemical pharmacology Pub Date : 2025-03-25 DOI: 10.1016/j.bcp.2025.116898

Wei-Bang Yu , Zi-Han Ye , Jia-Jie Shi , Wei-Qing Deng , Jun Chen , Jin-Jian Lu

{"title":"Dual blockade of GSTK1 and CD47 improves macrophage-mediated phagocytosis on cancer cells","authors":"Wei-Bang Yu , Zi-Han Ye , Jia-Jie Shi , Wei-Qing Deng , Jun Chen , Jin-Jian Lu","doi":"10.1016/j.bcp.2025.116898","DOIUrl":"10.1016/j.bcp.2025.116898","url":null,"abstract":"<div><div>CD47 is a crucial anti-phagocytic signal in regulating macrophage responses and its manipulation offers the therapeutic potential in cancer treatment. However, in many cases, blockade of CD47 by itself is insufficient to activate macrophage effectively, indicating other unidentified phagocytosis-regulating factors to resist the macrophage activity. In this study, a genome-wide human CRISPR-Cas9 library was developed for comprehensive screening of phagocytosis-regulating factors in the context of CD47 blockade. The screening results identified GSTK1 as a potential anti-phagocytic signal counteracting the efficacy of CD47-based phagocytosis. The disruption of GSTK1 significantly increased the phagocytosis rate of cancer cells by macrophages in combination with anti-CD47 antibody. Further mechanism investigation unveiled that GSTK1 blockade increased the membrane exposure of calreticulin in different cancer cells, which might be the primary mechanism driving enhanced macrophage-mediated phagocytosis. To this end, si<em>GSTK1</em>-loaded nanoparticles (si<em>GSTK1</em>-LNPs) were designed to suppress the GSTK1 expression efficiently. The comparable phagocytosis efficacy was also observed when combining si<em>GSTK1</em>-LNPs with anti-CD47 antibody. Above all, GSTK1 blockade was identified as a promising and feasible stimulus for enhancing the effectiveness of anti-CD47 antibody, introducing a novel and effective combination approach in cancer immunotherapy.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"236 ","pages":"Article 116898"},"PeriodicalIF":5.3,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143715360","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

xCT/Slc7a11 promotes pulmonary arterial hypertension by disrupting AMPKα suppression of mTOR activation

IF 5.3 2区医学

Biochemical pharmacology Pub Date : 2025-03-25 DOI: 10.1016/j.bcp.2025.116897

Yan Meng , Cuiting Zheng , Xiyu Zhang , Zhenqiang Gao , Hongyu Chen , Xianmei Qi , Kai Li , Fangming Liu , Weiwei Deng , Yuting Wu , Jie Liu , Chen Chen , Chen Wang , Heng Zhao , Hongbing Zhang

{"title":"xCT/Slc7a11 promotes pulmonary arterial hypertension by disrupting AMPKα suppression of mTOR activation","authors":"Yan Meng , Cuiting Zheng , Xiyu Zhang , Zhenqiang Gao , Hongyu Chen , Xianmei Qi , Kai Li , Fangming Liu , Weiwei Deng , Yuting Wu , Jie Liu , Chen Chen , Chen Wang , Heng Zhao , Hongbing Zhang","doi":"10.1016/j.bcp.2025.116897","DOIUrl":"10.1016/j.bcp.2025.116897","url":null,"abstract":"<div><div>While mTOR plays a key role in the development of pulmonary arterial hypertension (PAH), its suppressor, AMPKα, acts as an inhibitor. Although mTOR-driven transcriptional upregulation of the plasma membrane exchanger and amino acid transporter xCT, encoded by the <em>Slc7a11</em> gene, is critical for cell proliferation and tumorigenesis, the involvement of xCT in PAH remains unexplored. In this study, we found that xCT expression was elevated in hypoxia-treated human pulmonary arterial endothelial cells (HPAECs) and the lungs of hypoxia-exposed mice and Sugen5416/hypoxia (SuHx)-induced PAH mice. Knockout of xCT prevented the development of PAH and right heart failure in SuHx-conditioned mice. The xCT inhibitor sulfasalazine prevented and reversed SuHx-induced PAH in mice. Deleting and inhibiting xCT activated AMPKα and inactivated mTOR in mouse lungs with PAH and in HPAECs. Sulfasalazine suppressed mTOR through activation of AMPKα in HPAECs. The mTOR inhibitor rapamycin reduced xCT expression, activated AMPKα, and suppressed mTOR in HPAECs. These findings suggest that xCT promotes the development of PAH, likely through suppression of AMPKα and activation of mTOR. Blockage of xCT and mTOR or activation of AMPKα by existing drugs such as sulfasalazine, sirolimus, and metformin may offer readily therapeutic strategies for PAH.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"236 ","pages":"Article 116897"},"PeriodicalIF":5.3,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143724922","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

Mitomycin induced the senescence of alveolar epithelial cells by targeting peroxiredoxin I 丝裂霉素通过靶向过氧化物酶I诱导肺泡上皮细胞衰老

IF 5.3 2区医学

Biochemical pharmacology Pub Date : 2025-03-24 DOI: 10.1016/j.bcp.2025.116890

Xionghua Sun , Xuelei Wan , Li Chen, Yadong Cui, Xihua Chen, Jian Zhang, Xiaogang Jiang

{"title":"Mitomycin induced the senescence of alveolar epithelial cells by targeting peroxiredoxin I","authors":"Xionghua Sun , Xuelei Wan , Li Chen, Yadong Cui, Xihua Chen, Jian Zhang, Xiaogang Jiang","doi":"10.1016/j.bcp.2025.116890","DOIUrl":"10.1016/j.bcp.2025.116890","url":null,"abstract":"<div><div>The senescence of alveolar epithelial cells is one of the characteristics of mitomycin pulmonary toxicity, but the direct target of mitomycin-induced alveolar epithelial cell senescence remains unclear. In this study, a method of small-molecule ligand–protein interaction by pulldown/mass spectrometry identified peroxiredoxin I (Prdx I) as the target of mitomycin-induced alveolar epithelial cell senescence, and mitomycin was shown to significantly inhibit the peroxidase activity of Prdx I. Consequently, the levels of cellular reactive oxygen species (ROS) increased, leading to the activation of mitogen-activated protein kinase kinase 1/2 (MEK1/2)-extracellular signal-regulated protein kinases 1/2 (ERK 1/2) and, accordingly, to the increased expression of p53. Both a Prdx I activator and Prdx I overexpression alleviated mitomycin-induced alveolar cell senescence. A ROS scavenger inhibited MEK1/2-ERK1/2-p53 activation and then attenuated the senescence of alveolar epithelial cells triggered by mitomycin. Thus, Prdx I can serve as the first target of mitomycin-induced alveolar epithelial cell senescence, which might represent a promising approach to reduce mitomycin-induced lung toxicity.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"236 ","pages":"Article 116890"},"PeriodicalIF":5.3,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143705035","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