Pub Date : 2026-05-01Epub Date: 2026-02-10DOI: 10.1016/j.bcp.2026.117783
Dantong Sun , Jun Wang , Xue Yang , Han Shu , Yongfeng Cheng , Ying Chen , Qingqing Xia , Facai Wang , Siwei Deng , Jun Li , Xiao-Feng Li , Biao Song
The central role in the pathogenesis of rheumatoid arthritis (RA) is played by fibroblast-like synoviocytes (FLS), which drive disease progression through aberrant proliferation, recruitment of inflammatory cells, and subsequent degradation of cartilage and bone. Cullin 4A (CUL4A) is an important member of the Cullin family, which is a scaffolding protein for the E3 ubiquitin ligase complex. In this study, we investigated the functional significance and molecular mechanisms of CUL4A in the pathogenesis of RA. We identified elevated CUL4A expression in synovial tissues, TNFα-stimulated FLS, and peripheral blood mononuclear cells from RA patients. Furthermore, CUL4A mRNA expression levels showed a positive correlation with both clinical disease activity and inflammatory markers in RA. Knockdown of CUL4A led to a marked suppression of both cytokine production and glycolytic metabolism in FLS in vitro. RNA sequencing analysis and validation revealed the PI3K/AKT pathway as a key mediator in this process, with a significant functional interaction between CUL4A and fibroblast growth factor 2 (FGF2). Furthermore, knocking down FGF2 significantly inhibited synovial inflammation in RA FLS. In vivo experiments, knocking down CUL4A significantly reduced synovial inflammation in K/BxN serum transfer-induced arthritis (STA) mice and inhibited glycolytic metabolism. In conclusion, our findings reveal that CUL4A, via FGF2 binding, initiates PI3K/AKT pathway signaling, fostering the glycolysis process and synovial inflammation. Consequently, CUL4A holds significant promise as a target for early intervention against this pathogenic cascade.
{"title":"CUL4A promotes glycolytic metabolism of fibroblast-like synoviocytes by targeting FGF2 in rheumatoid arthritis","authors":"Dantong Sun , Jun Wang , Xue Yang , Han Shu , Yongfeng Cheng , Ying Chen , Qingqing Xia , Facai Wang , Siwei Deng , Jun Li , Xiao-Feng Li , Biao Song","doi":"10.1016/j.bcp.2026.117783","DOIUrl":"10.1016/j.bcp.2026.117783","url":null,"abstract":"<div><div>The central role in the pathogenesis of rheumatoid arthritis (RA) is played by fibroblast-like synoviocytes (FLS), which drive disease progression through aberrant proliferation, recruitment of inflammatory cells, and subsequent degradation of cartilage and bone. Cullin 4A (CUL4A) is an important member of the Cullin family, which is a scaffolding protein for the E3 ubiquitin ligase complex. In this study, we investigated the functional significance and molecular mechanisms of CUL4A in the pathogenesis of RA. We identified elevated CUL4A expression in synovial tissues, TNFα-stimulated FLS, and peripheral blood mononuclear cells from RA patients. Furthermore, <em>CUL4A</em> mRNA expression levels showed a positive correlation with both clinical disease activity and inflammatory markers in RA. Knockdown of CUL4A led to a marked suppression of both cytokine production and glycolytic metabolism in FLS <em>in vitro.</em> RNA sequencing analysis and validation revealed the PI3K/AKT pathway as a key mediator in this process, with a significant functional interaction between CUL4A and fibroblast growth factor 2 (FGF2). Furthermore, knocking down FGF2 significantly inhibited synovial inflammation in RA FLS. <em>In vivo</em> experiments, knocking down CUL4A significantly reduced synovial inflammation in K/BxN serum transfer-induced arthritis (STA) mice and inhibited glycolytic metabolism. In conclusion, our findings reveal that CUL4A, via FGF2 binding, initiates PI3K/AKT pathway signaling, fostering the glycolysis process and synovial inflammation. Consequently, CUL4A holds significant promise as a target for early intervention against this pathogenic cascade.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"247 ","pages":"Article 117783"},"PeriodicalIF":5.6,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146171751","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}
Pub Date : 2026-05-01Epub Date: 2026-01-27DOI: 10.1016/j.bcp.2026.117760
Jun Yan , Long Cheng , Qing-qing Ma , Qiao-xuan Zhang , Shu Gan , Hai-biao Lin , Li-qiao Han , Peng-wei Zhang , Fen Ouyang , Pei-feng Ke , Xian-zhang Huang
Prostate cancer (PCa) remains a major threat to male health. Due to the inevitable progression of incurable castration-resistant prostate cancer (CRPC) after androgen deprivation therapy (ADT), it is an urgent need to seek out new therapeutic strategies that not dependent on androgen receptor (AR) signaling pathway. Through high-throughput screening of our in-house compound library, compound CD-15, a chalcone derivative, demonstrated remarkable anti-proliferative activity on AR-negative PCa cells at subnanomolar concentrations and completely blocked tumor growth in both cell line-derived xenograft (CDX) mice model and a zebrafish patient-derived xenograft (zPDX) model. Notably, CD-15 displayed a more favorable safety profile than the clinically widely-used drug docetaxel. Leveraging drug affinity responsive target stability (DARTS) technology and virtual target screening, thioredoxin reductase (TrxR) was identified as the direct target of CD-15. Our study also found TrxR was over-expressed in the serum and tissues in PCa patients and TrxR1 knockdown partially attenuated the suppressive effect of CD-15 in vitro and in vivo. Moreover, several means including BIAM assay, molecular docking, LC-MS/MS and DARTS analysis confirmed that CD-15 covalently modified selenocysteine 498 (U) residues within the redox-active site of TrxR, leading to the enzyme inhibition. Mechanistically, CD-15 exerted a dual anti-PCa mechanism, which was capable of inducing ferroptosis in a TrxR-dependent manner. Altogether, CD-15 emerges as a promising candidate for the treatment of PCa and deserves further investigation.
{"title":"Identification of a novel chalcone derivative as ferroptosis inducer through targeting TrxR in prostate cancer","authors":"Jun Yan , Long Cheng , Qing-qing Ma , Qiao-xuan Zhang , Shu Gan , Hai-biao Lin , Li-qiao Han , Peng-wei Zhang , Fen Ouyang , Pei-feng Ke , Xian-zhang Huang","doi":"10.1016/j.bcp.2026.117760","DOIUrl":"10.1016/j.bcp.2026.117760","url":null,"abstract":"<div><div>Prostate cancer (PCa) remains a major threat to male health. Due to the inevitable progression of incurable castration-resistant prostate cancer (CRPC) after androgen deprivation therapy (ADT), it is an urgent need to seek out new therapeutic strategies that not dependent on androgen receptor (AR) signaling pathway. Through high-throughput screening of our in-house compound library, compound <strong>CD-15</strong>, a chalcone derivative, demonstrated remarkable anti-proliferative activity on AR-negative PCa cells at subnanomolar concentrations and completely blocked tumor growth in both cell line-derived xenograft (CDX) mice model and a zebrafish patient-derived xenograft (zPDX) model. Notably, <strong>CD-15</strong> displayed a more favorable safety profile than the clinically widely-used drug docetaxel. Leveraging drug affinity responsive target stability (DARTS) technology and virtual target screening, thioredoxin reductase (TrxR) was identified as the direct target of <strong>CD-15</strong>. Our study also found TrxR was over-expressed in the serum and tissues in PCa patients and TrxR1 knockdown partially attenuated the suppressive effect of <strong>CD-15</strong> in vitro and in vivo. Moreover, several means including BIAM assay, molecular docking, LC-MS/MS and DARTS analysis confirmed that <strong>CD-15</strong> covalently modified selenocysteine 498 (U) residues within the redox-active site of TrxR, leading to the enzyme inhibition. Mechanistically, <strong>CD-15</strong> exerted a dual anti-PCa mechanism, which was capable of inducing ferroptosis in a TrxR-dependent manner. Altogether, <strong>CD-15</strong> emerges as a promising candidate for the treatment of PCa and deserves further investigation.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"247 ","pages":"Article 117760"},"PeriodicalIF":5.6,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146083552","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}
Pub Date : 2026-05-01Epub Date: 2026-02-10DOI: 10.1016/j.bcp.2026.117788
Xiaoling Cheng , Shuangshuang Ma , Wenli Hao , Xi Zhao , Yaping Guo , Jin Zhang , Le Zhou , Zhendan He , Dahong Yao
Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype associated with a poor prognosis and limited treatment options. Current clinical management relies primarily on surgical resection and adjuvant chemotherapy, underscoring the urgent need for novel therapeutic strategies. Through systematic pharmacological screening, we reveal that fenticonazole, a widely used imidazole antifungal, functions as a potent suppressor of TNBC cell growth. Mechanistic studies revealed that fenticonazole directly binds to NF-κB p105, impairing its processing into p50. Consequently, the formation of the p50–p65 heterodimer is suppressed, accompanied by enhanced p65 activation and inhibition of NRF2 transcription. These molecular alterations drive the accumulation of mitochondrial reactive oxygen species (ROS), resulting in endoplasmic reticulum (ER) stress and ultimately apoptosis in TNBC cells. Our results not only elucidate a previously unrecognized antitumor mechanism of fenticonazole but also provide a compelling rationale for its drug repurposing as a promising therapeutic option for TNBC.
{"title":"Fenticonazole targets NF-κB p105/p50 to suppress triple-negative breast cancer via ROS-mediated ER stress and apoptosis","authors":"Xiaoling Cheng , Shuangshuang Ma , Wenli Hao , Xi Zhao , Yaping Guo , Jin Zhang , Le Zhou , Zhendan He , Dahong Yao","doi":"10.1016/j.bcp.2026.117788","DOIUrl":"10.1016/j.bcp.2026.117788","url":null,"abstract":"<div><div>Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype associated with a poor prognosis and limited treatment options. Current clinical management relies primarily on surgical resection and adjuvant chemotherapy, underscoring the urgent need for novel therapeutic strategies. Through systematic pharmacological screening, we reveal that fenticonazole, a widely used imidazole antifungal, functions as a potent suppressor of TNBC cell growth. Mechanistic studies revealed that fenticonazole directly binds to NF-κB p105, impairing its processing into p50. Consequently, the formation of the p50–p65 heterodimer is suppressed, accompanied by enhanced p65 activation and inhibition of NRF2 transcription. These molecular alterations drive the accumulation of mitochondrial reactive oxygen species (ROS), resulting in endoplasmic reticulum (ER) stress and ultimately apoptosis in TNBC cells. Our results not only elucidate a previously unrecognized antitumor mechanism of fenticonazole but also provide a compelling rationale for its drug repurposing as a promising therapeutic option for TNBC.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"247 ","pages":"Article 117788"},"PeriodicalIF":5.6,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146177636","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}
Pub Date : 2026-05-01Epub Date: 2026-02-04DOI: 10.1016/j.bcp.2026.117771
Jun Liu , Shunfei Liu , Qiannan Ma , Yilin Xie , Xinyue Zeng , Chunyang Zhang , Panhui Guo , Zhiwei Gao , Xiangpeng Hu
Ulcerative colitis (UC) is a recurrent inflammatory bowel disease characterized by mucosal inflammation. Recently, the incidence rate of UC increases year by year, and patients diagnosed with UC usually have the poor quality of life. The search for effective treatments of UC remains a crucial research priority. Since traditional Chinese medicine (TCM) is an important treatment for UC, the components of these TCMs were analyzed. Our data indicated that Mairin was the common core component of TCMs with UC therapeutic effects, including Licorice, Paeoniae Radix Alba and Aucklandiae Radix. Recently, only one study reported that the hydroxamate of Mairin prevented colonic inflammation and fibrosis, and the function and mechanism of Mairin on UC were still obscure. Dextran sulfate sodium (DSS)-induced UC mice were alleviated after Mairin treatment. Mechanistically, RNA sequencing data indicated that Mairin treatment increased the levels of Irf4 and Cd5l. Molecular docking, drug affinity responsive target stability (DARTS) and immunofluorescence experiments were used to verify that Mairin interacted with EGFR and SRC, promoted IRF4 nuclear import in macrophages. ChIP analysis was verified that IRF4, as a transcription factor, interacted with Cd5l promoter, and Mairin treatment increased the mRNA and protein levels of CD5L. CD5L+ macrophages exhibited the high level of M2 phenotype markers, and M2-phenotype macrophages alleviated UC. That was to say, Mairin activated IRF4-CD5L pathway, polarized macrophages into M2-phenotype, and alleviated UC. Our study contributes to the exploration the therapeutic mechanism of Mairin and it also may provide insights for new therapeutic medicine of UC.
{"title":"Mairin polarizes Macrophages into M2-phenotype and alleviates Ulcerative colitis through activating IRF4-CD5L pathway","authors":"Jun Liu , Shunfei Liu , Qiannan Ma , Yilin Xie , Xinyue Zeng , Chunyang Zhang , Panhui Guo , Zhiwei Gao , Xiangpeng Hu","doi":"10.1016/j.bcp.2026.117771","DOIUrl":"10.1016/j.bcp.2026.117771","url":null,"abstract":"<div><div>Ulcerative colitis (UC) is a recurrent inflammatory bowel disease characterized by mucosal inflammation. Recently, the incidence rate of UC increases year by year, and patients diagnosed with UC usually have the poor quality of life. The search for effective treatments of UC remains a crucial research priority. Since traditional Chinese medicine (TCM) is an important treatment for UC, the components of these TCMs were analyzed. Our data indicated that Mairin was the common core component of TCMs with UC therapeutic effects, including <em>Licorice</em>, <em>Paeoniae Radix Alba</em> and <em>Aucklandiae Radix</em>. Recently, only one study reported that the hydroxamate of Mairin prevented colonic inflammation and fibrosis, and the function and mechanism of Mairin on UC were still obscure. Dextran sulfate sodium (DSS)-induced UC mice were alleviated after Mairin treatment. Mechanistically, RNA sequencing data indicated that Mairin treatment increased the levels of <em>Irf4</em> and <em>Cd5l</em>. Molecular docking, drug affinity responsive target stability (DARTS) and immunofluorescence experiments were used to verify that Mairin interacted with EGFR and SRC, promoted IRF4 nuclear import in macrophages. ChIP analysis was verified that IRF4, as a transcription factor, interacted with <em>Cd5l</em> promoter, and Mairin treatment increased the mRNA and protein levels of CD5L. CD5L<sup>+</sup> macrophages exhibited the high level of M2 phenotype markers, and M2-phenotype macrophages alleviated UC. That was to say, Mairin activated IRF4-CD5L pathway, polarized macrophages into M2-phenotype, and alleviated UC. Our study contributes to the exploration the therapeutic mechanism of Mairin and it also may provide insights for new therapeutic medicine of UC.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"247 ","pages":"Article 117771"},"PeriodicalIF":5.6,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146131138","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}
ADP-ribosylation is a versatile post-translational modification that governs fundamental processes, including DNA repair, transcription, and stress adaptation. Its homeostasis relies on the dynamic interplay between poly(ADP-ribose) polymerases (PARPs), which assemble mono- or poly-ADP-ribose (PAR) chains on target macromolecules, and ADP-ribosyl hydrolases, which dismantle them. Disruption of this balance leads to the accumulation of toxic PAR and cell death, revealing vulnerabilities that can be therapeutically exploited. PARP inhibitors (PARPis) have revolutionised the treatment of homologous recombination-deficient cancers via synthetic lethality. Yet, emerging resistance limits their long-term efficacy, underscoring the need for novel targets within ADP-ribose signalling. The poly(ADP-ribose) glycohydrolase (PARG), the principal enzyme involved in hydrolysing PAR, has emerged as a compelling candidate: its inhibition amplifies replication stress, drives mitotic catastrophe, and selectively kills cancer cells, particularly those reliant on PAR turnover for survival. Elevated PARG expression correlates with aggressive tumours and poor prognosis, positioning it as both a prognostic biomarker and therapeutic target. This review integrates recent structural and biochemical insights into PARG, highlighting the mechanisms of PAR reversal, regulatory control, and potential synthetic lethal interactions. We also discuss the discovery and development of selective PARG inhibitors, which promise to expand the therapeutic landscape, overcome PARPis resistance, and exploit vulnerabilities in replication-stressed cancers. By bridging mechanistic understanding with translational potential, targeting PARG represents a frontier in precision cancer therapy.
{"title":"The PARG frontier: mechanisms of PAR turnover and opportunities in precision oncology","authors":"Giuliana Catara , Gaetano Gerace , Raffaella Lauro , Luca Palazzo","doi":"10.1016/j.bcp.2026.117770","DOIUrl":"10.1016/j.bcp.2026.117770","url":null,"abstract":"<div><div>ADP-ribosylation is a versatile post-translational modification that governs fundamental processes, including DNA repair, transcription, and stress adaptation. Its homeostasis relies on the dynamic interplay between poly(ADP-ribose) polymerases (PARPs), which assemble mono- or poly-ADP-ribose (PAR) chains on target macromolecules, and ADP-ribosyl hydrolases, which dismantle them. Disruption of this balance leads to the accumulation of toxic PAR and cell death, revealing vulnerabilities that can be therapeutically exploited. PARP inhibitors (PARPis) have revolutionised the treatment of homologous recombination-deficient cancers via synthetic lethality. Yet, emerging resistance limits their long-term efficacy, underscoring the need for novel targets within ADP-ribose signalling. The poly(ADP-ribose) glycohydrolase (PARG), the principal enzyme involved in hydrolysing PAR, has emerged as a compelling candidate: its inhibition amplifies replication stress, drives mitotic catastrophe, and selectively kills cancer cells, particularly those reliant on PAR turnover for survival. Elevated PARG expression correlates with aggressive tumours and poor prognosis, positioning it as both a prognostic biomarker and therapeutic target. This review integrates recent structural and biochemical insights into PARG, highlighting the mechanisms of PAR reversal, regulatory control, and potential synthetic lethal interactions. We also discuss the discovery and development of selective PARG inhibitors, which promise to expand the therapeutic landscape, overcome PARPis resistance, and exploit vulnerabilities in replication-stressed cancers. By bridging mechanistic understanding with translational potential, targeting PARG represents a frontier in precision cancer therapy.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"247 ","pages":"Article 117770"},"PeriodicalIF":5.6,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146131127","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}
Pub Date : 2026-05-01Epub Date: 2026-02-11DOI: 10.1016/j.bcp.2026.117800
Bailun Wang , Ziyi Zhou , Chang Sun , Angran Gu , Jiahan Wang , Hongqian Wang , Dong Wang , Yizheng Yang , Xinyue Li , Yuelan Wang , Changping Gu
Acute lung injury (ALI) represents the most frequent complication of sepsis; however, effective drug-based interventions are still unavailable. β-sitosterol (BS) has demonstrated anti-inflammatory effects and protective properties on alveolar epithelial barriers. This study investigated the mechanism by which BS targets alveolar macrophages to attenuate sepsis-associated acute lung injury (SALI) via in vivo and in vitro experiments. Sepsis was induced in mice through cecal ligation and puncture (CLP), and BS was administered orally. An in vitro model of lipopolysaccharide (LPS)-induced MH-S cell infection validated the proposed mechanism. Macrophage polarization and mitochondrial function were assessed using flow cytometry, electron microscopy, and Western blot analysis. Results showed that BS suppressed reactive oxygen species (ROS) production and M1 macrophage polarization in LPS-stimulated MH-S cells. Mechanistically, BS promoted lysosomal degradation of dynamin-related protein 1 (DRP1) via SUMO2/3-mediated SUMOylation, preserving mitochondrial integrity and function. Transfection of MH-S cells with DRP1 plasmid abolished the BS-mediated mitochondrial protection mechanism, reducing inhibition of oxidative stress and M1 polarization. In summary, BS inhibits M1 polarization of alveolar macrophages by promoting DRP1 SUMOylation, effectively alleviating SALI in mice. These findings support BS as a potential therapeutic agent for SALI, providing a theoretical basis for clinical application.
{"title":"β − sitosterol promotes the SUMOylation of DRP1 in alveolar macrophages and alleviates sepsis-associated acute lung injury","authors":"Bailun Wang , Ziyi Zhou , Chang Sun , Angran Gu , Jiahan Wang , Hongqian Wang , Dong Wang , Yizheng Yang , Xinyue Li , Yuelan Wang , Changping Gu","doi":"10.1016/j.bcp.2026.117800","DOIUrl":"10.1016/j.bcp.2026.117800","url":null,"abstract":"<div><div>Acute lung injury (ALI) represents the most frequent complication of sepsis; however, effective drug-based interventions are still unavailable. β-sitosterol (BS) has demonstrated anti-inflammatory effects and protective properties on alveolar epithelial barriers. This study investigated the mechanism by which BS targets alveolar macrophages to attenuate sepsis-associated acute lung injury (SALI) via <em>in vivo</em> and in vitro experiments. Sepsis was induced in mice through cecal ligation and puncture (CLP), and BS was administered orally. An in vitro model of lipopolysaccharide (LPS)-induced MH-S cell infection validated the proposed mechanism. Macrophage polarization and mitochondrial function were assessed using flow cytometry, electron microscopy, and Western blot analysis. Results showed that BS suppressed reactive oxygen species (ROS) production and M1 macrophage polarization in LPS-stimulated MH-S cells. Mechanistically, BS promoted lysosomal degradation of dynamin-related protein 1 (DRP1) via SUMO2/3-mediated SUMOylation, preserving mitochondrial integrity and function. Transfection of MH-S cells with DRP1 plasmid abolished the BS-mediated mitochondrial protection mechanism, reducing inhibition of oxidative stress and M1 polarization. In summary, BS inhibits M1 polarization of alveolar macrophages by promoting DRP1 SUMOylation, effectively alleviating SALI in mice. These findings support BS as a potential therapeutic agent for SALI, providing a theoretical basis for clinical application.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"247 ","pages":"Article 117800"},"PeriodicalIF":5.6,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146193759","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}
Pub Date : 2026-05-01Epub Date: 2026-02-11DOI: 10.1016/j.bcp.2026.117798
Weichu Liu, Fengwen Yang, Jie Yu
Myocardial fibrosis (MF) is a central feature in the terminal stages of many cardiovascular diseases. Findings from a previous study that we conducted show that when exposed to perinatal nonylphenol (NP), adult male rats developed MF. However, the underlying pathogenic mechanisms that drive its development have not been well established. This study aims to determine whether exposure to NP during the pregnancy and lactation periods causes MF in adult male offspring rats, and also to investigate the role of the TGF-β1/Smads signaling pathway in NP-induced fibrosis in cardiac fibroblasts (CFs). On postnatal day 21 (PND21), we observed a dose-dependent increase in NP levels in both the hearts and serum of the offspring rats. In comparison to the blank group, the fiber structure in the NP group was notably disorganized, and there was an occurrence of collagen deposition. Furthermore, expression levels of Collagen I/III, α-SMA, TGF-β1, MMP2, and MMP9 also increased in a dose-dependent manner in the NP group and were positively correlated with the levels of NP in the heart. In comparison to the blank control group, the levels of myocardial enzyme indicators (CK, CK-MB, LDH, and α-HBDH) as well as the levels of hydroxyproline (HYP) in both the NP and model groups showed an increase at postnatal day 90 (PND90). Furthermore, there were significant variations in the homeostasis of the outer matrix and functions related to TGF-β and Smads genes. Expression levels of Collagen I/III, TGF-β1, Smad2/3/4, α-SMA, CTGF, and MMP1 were significantly upregulated, while expression levels of Smad7 and TIMP1 were significantly downregulated. In vitro, exposure to NP significantly inhibited the activity of CFs in a dose-dependent manner and promoted abnormal expression of fibrosis-related factors and proteins related to the TGF-β1/Smads signaling pathway. TGF-β receptor type I/II inhibitors (LY2109761) reversed increased levels of NP-induced HYP and partially inhibited the expression of the TGF-β1/Smads signaling pathway and its downstream factors. This study demonstrates that exposure to NP during the pregnancy and lactation periods activates the TGF-β1/Smads signaling pathway and its downstream factors, thereby initiating the development of MF in their offspring. Moreover, the TGF-β1/Smads signaling pathway was determined to be involved in NP-induced CFs fibrosis, highlighting TGF-β1 as a critical target of NP-induced MF.
{"title":"Exploring the mechanism of nonylphenol-induced myocardial fibrosis based on TGF-β1/Smads signaling pathway","authors":"Weichu Liu, Fengwen Yang, Jie Yu","doi":"10.1016/j.bcp.2026.117798","DOIUrl":"10.1016/j.bcp.2026.117798","url":null,"abstract":"<div><div>Myocardial fibrosis (MF) is a central feature in the terminal stages of many cardiovascular diseases. Findings from a previous study that we conducted show that when exposed to perinatal nonylphenol (NP), adult male rats developed MF. However, the underlying pathogenic mechanisms that drive its development have not been well established. This study aims to determine whether exposure to NP during the pregnancy and lactation periods causes MF in adult male offspring rats, and also to investigate the role of the TGF-β1/Smads signaling pathway in NP-induced fibrosis in cardiac fibroblasts (CFs). On postnatal day 21 (PND21), we observed a dose-dependent increase in NP levels in both the hearts and serum of the offspring rats. In comparison to the blank group, the fiber structure in the NP group was notably disorganized, and there was an occurrence of collagen deposition. Furthermore, expression levels of Collagen I/III, α-SMA, TGF-β1, MMP2, and MMP9 also increased in a dose-dependent manner in the NP group and were positively correlated with the levels of NP in the heart. In comparison to the blank control group, the levels of myocardial enzyme indicators (CK, CK-MB, LDH, and α-HBDH) as well as the levels of hydroxyproline (HYP) in both the NP and model groups showed an increase at postnatal day 90 (PND90). Furthermore, there were significant variations in the homeostasis of the outer matrix and functions related to TGF-β and Smads genes. Expression levels of Collagen I/III, TGF-β1, Smad2/3/4, α-SMA, CTGF, and MMP1 were significantly upregulated, while expression levels of Smad7 and TIMP1 were significantly downregulated. In vitro, exposure to NP significantly inhibited the activity of CFs in a dose-dependent manner and promoted abnormal expression of fibrosis-related factors and proteins related to the TGF-β1/Smads signaling pathway. TGF-β receptor type I/II inhibitors (LY2109761) reversed increased levels of NP-induced HYP and partially inhibited the expression of the TGF-β1/Smads signaling pathway and its downstream factors. This study demonstrates that exposure to NP during the pregnancy and lactation periods activates the TGF-β1/Smads signaling pathway and its downstream factors, thereby initiating the development of MF in their offspring. Moreover, the TGF-β1/Smads signaling pathway was determined to be involved in NP-induced CFs fibrosis, highlighting TGF-β1 as a critical target of NP-induced MF.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"247 ","pages":"Article 117798"},"PeriodicalIF":5.6,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146193766","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}
Pub Date : 2026-05-01Epub Date: 2026-02-12DOI: 10.1016/j.bcp.2026.117799
Abdeslam Chagraoui , Paulina Kazmierska-Grebowska , Olivia Byache , Alejandro Abraham , Deborah Rudin , Bartosz Caban , Tomasz Kowalczyk , Matthias E. Liechti , Daniel Wacker , Chloé Aman , Philippe De Deurwaerdère , Hugo R. Arias
The antiseizure properties of ibogalogs, including ibogaminalog (DM506), ibogainalog (IBG), and nor-IBG, were assessed in rodents using the pentylenetetrazol (PTZ)-induced seizure test. The behavioral findings indicated that ibogalogs exhibited mild acute antiseizure effects in mice, with endpoint- and time window-dependent differences between the compounds. The antiseizure effect was suppressed by volinanserin and SB242084, consistent with the involvement of 5-HT2A and 5-HT2C receptors. The antiseizure activity after repeated administration (7 and 14 days) of subthreshold doses of nor-IBG (3 mg/kg) or DM506 (5 mg/kg) was higher than that after acute treatment, indicating augmented efficacy. Subthreshold doses of DM506 and nor-IBG restored the impact of PTZ on monoamine levels in hippocampal tissue following repeated administration, but not after a single dose. Additionally, the influence of ibogalogs was evaluated on epileptiform discharges induced by kainic acid (KA) in the CA3 region of the hippocampus. The results showed that nor-IBG and DM506 decreased epileptiform discharges in a concentration-dependent manner. Nor-IBG activity was inhibited by volinanserin, supporting a role for the 5-HT2AR. Functional studies have shown that ibogalogs are more potent agonists at 5-HT2A/2CRs than at 5-HT1A/1BRs, supporting the role of 5-HT2AR. In conclusion, repetitive treatment with ibogalogs induced antiseizure activity in mice through 5-HT2A/2CR activation, accompanied by normalization of PTZ-induced alterations in hippocampal monoamines. In the hippocampal CA3 subfield, ibogalogs reduced KA-induced epileptiform discharges, where nor-IBG activity was mediated by 5-HT2AR activation.
{"title":"Ibogalogs induce antiseizure activity in rodents by a mechanism involving 5-HT2A/2C receptor activation with a major role of 5-HT2A receptors in the hippocampal CA3 subfield","authors":"Abdeslam Chagraoui , Paulina Kazmierska-Grebowska , Olivia Byache , Alejandro Abraham , Deborah Rudin , Bartosz Caban , Tomasz Kowalczyk , Matthias E. Liechti , Daniel Wacker , Chloé Aman , Philippe De Deurwaerdère , Hugo R. Arias","doi":"10.1016/j.bcp.2026.117799","DOIUrl":"10.1016/j.bcp.2026.117799","url":null,"abstract":"<div><div>The antiseizure properties of ibogalogs, including ibogaminalog (DM506), ibogainalog (IBG), and nor-IBG, were assessed in rodents using the pentylenetetrazol (PTZ)-induced seizure test. The behavioral findings indicated that ibogalogs exhibited mild acute antiseizure effects in mice, with endpoint- and time window-dependent differences between the compounds. The antiseizure effect was suppressed by volinanserin and SB242084, consistent with the involvement of 5-HT<sub>2A</sub> and 5-HT<sub>2C</sub> receptors. The antiseizure activity after repeated administration (7 and 14 days) of subthreshold doses of nor-IBG (3 mg/kg) or DM506 (5 mg/kg) was higher than that after acute treatment, indicating augmented efficacy. Subthreshold doses of DM506 and nor-IBG restored the impact of PTZ on monoamine levels in hippocampal tissue following repeated administration, but not after a single dose. Additionally, the influence of ibogalogs was evaluated on epileptiform discharges induced by kainic acid (KA) in the CA3 region of the hippocampus. The results showed that nor-IBG and DM506 decreased epileptiform discharges in a concentration-dependent manner. Nor-IBG activity was inhibited by volinanserin, supporting a role for the 5-HT<sub>2A</sub>R. Functional studies have shown that ibogalogs are more potent agonists at 5-HT<sub>2A/2C</sub>Rs than at 5-HT<sub>1A/1B</sub>Rs, supporting the role of 5-HT<sub>2A</sub>R. In conclusion, repetitive treatment with ibogalogs induced antiseizure activity in mice through 5-HT<sub>2A/2C</sub>R activation, accompanied by normalization of PTZ-induced alterations in hippocampal monoamines. In the hippocampal CA3 subfield, ibogalogs reduced KA-induced epileptiform discharges, where nor-IBG activity was mediated by 5-HT<sub>2A</sub>R activation.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"247 ","pages":"Article 117799"},"PeriodicalIF":5.6,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146197404","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}
Pub Date : 2026-05-01Epub Date: 2026-02-13DOI: 10.1016/j.bcp.2026.117815
Jenna Thibodeau , Jianlei Zhao , Holly Edwards , Lisa Polin , Juiwanna Kushner , Sijana H Dzinic , Kathryn White , Kian Hershberger , Yongwei Su , Tasnim Arroum , Lucynda Pham , Lauren Pavelich , Raina Awdish , Jacob LaValley , Austin C. Boucher , Wei Chen , Jing Li , Xun Bao , Maik Hüttemann , Jessica B. Back , Yubin Ge
Myeloid leukemia associated with Down syndrome (ML-DS), as classified by WHO 2016, includes acute myeloid leukemia (AML) and myelodysplasia in children with DS. While ML-DS patients show high sensitivity to cytarabine (Ara-C)-based chemotherapy with better overall survival than non-DS AML patients, relapsed/refractory cases have dismal outcomes. This underscores the need to understand Ara-C-resistance mechanisms and develop effective therapies. The chromosome 21 gene, cystathionine-β-synthase (CBS), is significantly overexpressed in ML-DS cells. Overexpression of CBS leads to increased hydrogen sulfide (H2S) production, which reduces complex IV activity and oxidative phosphorylation (OXPHOS). OXPHOS has been shown to play an important role in Ara-C resistance in non-DS AML. Thus, in this study, we investigated the role of CBS as a regulator of OXPHOS and Ara-C response. We found that Ara-C-resistant ML-DS cells have lower CBS activity. Overexpression of CBS in an Ara-C-resistant ML-DS cell line resulted in increased H2S and Ara-C sensitivity and decreased both complex IV activity and OXPHOS. Knockdown of CBS in an Ara-C-sensitive ML-DS cell line increased OXPHOS and Ara-C resistance. However, complex IV activity decreased and H2S production was unchanged, indicating that CBS regulates OXPHOS through both a H2S-dependent and −independent mechanism. We further demonstrate that targeting both OXPHOS, using ONC213, and apoptosis, using venetoclax, results in synergistic induction of cell death in Ara-C-resistant ML-DS cells. This study identifies CBS as a regulator of OXPHOS and Ara-C response, while the combination of ONC213 and venetoclax offers a promising therapeutic approach for relapsed/refractory ML-DS, addressing key vulnerabilities to improve patient outcomes.
{"title":"Loss of cystathionine-β-synthase contributes to elevated OXPHOS, a vulnerability in Ara-C-resistant Myeloid Leukemia in Down syndrome","authors":"Jenna Thibodeau , Jianlei Zhao , Holly Edwards , Lisa Polin , Juiwanna Kushner , Sijana H Dzinic , Kathryn White , Kian Hershberger , Yongwei Su , Tasnim Arroum , Lucynda Pham , Lauren Pavelich , Raina Awdish , Jacob LaValley , Austin C. Boucher , Wei Chen , Jing Li , Xun Bao , Maik Hüttemann , Jessica B. Back , Yubin Ge","doi":"10.1016/j.bcp.2026.117815","DOIUrl":"10.1016/j.bcp.2026.117815","url":null,"abstract":"<div><div>Myeloid leukemia associated with Down syndrome (ML-DS), as classified by WHO 2016, includes acute myeloid leukemia (AML) and myelodysplasia in children with DS. While ML-DS patients show high sensitivity to cytarabine (Ara-C)-based chemotherapy with better overall survival than non-DS AML patients, relapsed/refractory cases have dismal outcomes. This underscores the need to understand Ara-C-resistance mechanisms and develop effective therapies. The chromosome 21 gene, <em>cystathionine-β-synthase</em> (<em>CBS</em>), is significantly overexpressed in ML-DS cells. Overexpression of CBS leads to increased hydrogen sulfide (H<sub>2</sub>S) production, which reduces complex IV activity and oxidative phosphorylation (OXPHOS). OXPHOS has been shown to play an important role in Ara-C resistance in non-DS AML. Thus, in this study, we investigated the role of CBS as a regulator of OXPHOS and Ara-C response. We found that Ara-C-resistant ML-DS cells have lower CBS activity. Overexpression of CBS in an Ara-C-resistant ML-DS cell line resulted in increased H<sub>2</sub>S and Ara-C sensitivity and decreased both complex IV activity and OXPHOS. Knockdown of CBS in an Ara-C-sensitive ML-DS cell line increased OXPHOS and Ara-C resistance. However, complex IV activity decreased and H<sub>2</sub>S production was unchanged, indicating that CBS regulates OXPHOS through both a H<sub>2</sub>S-dependent and −independent mechanism. We further demonstrate that targeting both OXPHOS, using ONC213, and apoptosis, using venetoclax, results in synergistic induction of cell death in Ara-C-resistant ML-DS cells. This study identifies CBS as a regulator of OXPHOS and Ara-C response, while the combination of ONC213 and venetoclax offers a promising therapeutic approach for relapsed/refractory ML-DS, addressing key vulnerabilities to improve patient outcomes.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"247 ","pages":"Article 117815"},"PeriodicalIF":5.6,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146199596","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}
Pub Date : 2026-05-01Epub Date: 2026-02-10DOI: 10.1016/j.bcp.2026.117789
Qinxin Shu , Yuxin Lin , Wenqi Su , Hui Peng, Xing Wang
Age-related macular degeneration (AMD) is a leading cause of visual impairment in elderly individuals and is influenced by various factors, such as age, genetics, and environmental conditions. While research into therapies for dry AMD is rapidly advancing, effective interventions are still lacking, underscoring the urgent need for new drug development. Recent studies have highlighted the multifaceted pharmacological activities of Exendin-4 (EX-4), including its anti-inflammatory, antioxidant, and antiapoptotic properties, along with its role in maintaining calcium homeostasis. The precise effects of EX-4 on AMD and its immediate target remain unclear. In this study, we investigated whether EX-4 could protect against Aβ1-40-induced AMD and explored the underlying mechanism. Our findings indicated that pretreatment with EX-4 alleviated apoptosis and restored calcium homeostasis both in vivo and in vitro. To identify the target of EX-4, we employed proteome microarrays and pulldown LC‒MS/MS analyses. Our results revealed that EX-4 bound to Calcineurin-like EF-hand protein 1(CHP1), reducing CHP1 protein expression in a concentration-dependent manner. This interaction led to a subsequent reduction in apoptosis and the normalization of intracellular Ca2+ levels through the CHP1/NHE1 complex. Furthermore, we demonstrated that the inhibitory effects of EX-4 on apoptosis and calcium signaling were reversed by knocking down or overexpressing CHP1 in vitro. Finally, in AMD mice with CHP1-deficient retinas, the beneficial effects of EX-4 on apoptosis and calcium signaling were partially attenuated. In summary, our results suggest that the interaction of EX-4 with CHP1 has therapeutic potential for AMD, likely through alleviating apoptosis and restoring calcium homeostasis.
{"title":"Exendin-4 alleviates Aβ1-40-induced apoptosis and calcium dysregulation in RPE cells through the CHP1/NHE1 complex","authors":"Qinxin Shu , Yuxin Lin , Wenqi Su , Hui Peng, Xing Wang","doi":"10.1016/j.bcp.2026.117789","DOIUrl":"10.1016/j.bcp.2026.117789","url":null,"abstract":"<div><div>Age-related macular degeneration (AMD) is a leading cause of visual impairment in elderly individuals and is influenced by various factors, such as age, genetics, and environmental conditions. While research into therapies for dry AMD is rapidly advancing, effective interventions are still lacking, underscoring the urgent need for new drug development. Recent studies have highlighted the multifaceted pharmacological activities of Exendin-4 (EX-4), including its anti-inflammatory, antioxidant, and antiapoptotic properties, along with its role in maintaining calcium homeostasis. The precise effects of EX-4 on AMD and its immediate target remain unclear. In this study, we investigated whether EX-4 could protect against Aβ1-40-induced AMD and explored the underlying mechanism. Our findings indicated that pretreatment with EX-4 alleviated apoptosis and restored calcium homeostasis both in vivo and in vitro. To identify the target of EX-4, we employed proteome microarrays and pulldown LC‒MS/MS analyses. Our results revealed that EX-4 bound to Calcineurin-like EF-hand protein 1(CHP1), reducing CHP1 protein expression in a concentration-dependent manner. This interaction led to a subsequent reduction in apoptosis and the normalization of intracellular Ca<sup>2+</sup> levels through the CHP1/NHE1 complex. Furthermore, we demonstrated that the inhibitory effects of EX-4 on apoptosis and calcium signaling were reversed by knocking down or overexpressing CHP1 in vitro. Finally, in AMD mice with CHP1-deficient retinas, the beneficial effects of EX-4 on apoptosis and calcium signaling were partially attenuated. In summary, our results suggest that the interaction of EX-4 with CHP1 has therapeutic potential for AMD, likely through alleviating apoptosis and restoring calcium homeostasis.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"247 ","pages":"Article 117789"},"PeriodicalIF":5.6,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146171738","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}
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