Pub Date : 2025-04-21DOI: 10.1016/j.bcp.2025.116951
Yan-wei Ji , Xin-yu Wen , He-peng Tang , Wa-ting Su, Zhong-yuan Xia, Shao-qing Lei
Due to changes in dietary structures, population aging, and the exacerbation of metabolic risk factors, the incidence of cardiovascular disease continues to rise annually, posing a significant health burden worldwide. Cell death plays a crucial role in the onset and progression of cardiovascular diseases. As a regulated endpoint encountered by cells under adverse stress conditions, the execution of necroptosis is regulated by classicalpathways, the calmodulin-dependent protein kinases (CaMK) pathway, and mitochondria-dependent pathways, and implicated in various cardiovascular diseases, including atherosclerosis, myocardial infarction, myocardial ischemia–reperfusion injury (IRI), heart failure, diabetic cardiomyopathy, dilated cardiomyopathy, hypertrophic cardiomyopathy, chemotherapy drug-induced cardiomyopathy, and abdominal aortic aneurysm (AAA). To further investigate potential therapeutic targets for cardiovascular diseases, we also analyzed the main molecules and their inhibitors involved in necroptosis in an effort to uncover insights for treatment.
{"title":"Necroptosis: a significant and promising target for intervention of cardiovascular disease","authors":"Yan-wei Ji , Xin-yu Wen , He-peng Tang , Wa-ting Su, Zhong-yuan Xia, Shao-qing Lei","doi":"10.1016/j.bcp.2025.116951","DOIUrl":"10.1016/j.bcp.2025.116951","url":null,"abstract":"<div><div>Due to changes in dietary structures, population aging, and the exacerbation of metabolic risk factors, the incidence of cardiovascular disease continues to rise annually, posing a significant health burden worldwide. Cell death plays a crucial role in the onset and progression of cardiovascular diseases. As a regulated endpoint encountered by cells under adverse stress conditions, the execution of necroptosis is regulated by classicalpathways, the calmodulin-dependent protein kinases (CaMK) pathway, and mitochondria-dependent pathways, and implicated in various cardiovascular diseases, including atherosclerosis, myocardial infarction, myocardial ischemia–reperfusion injury (IRI), heart failure, diabetic cardiomyopathy, dilated cardiomyopathy, hypertrophic cardiomyopathy, chemotherapy drug-induced cardiomyopathy, and abdominal aortic aneurysm (AAA). To further investigate potential therapeutic targets for cardiovascular diseases, we also analyzed the main molecules and their inhibitors involved in necroptosis in an effort to uncover insights for treatment.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"237 ","pages":"Article 116951"},"PeriodicalIF":5.3,"publicationDate":"2025-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143865058","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 : 2025-04-19DOI: 10.1016/j.bcp.2025.116954
Danlei Weng , Wei Shi , Yue Hu , Yanqian Su , Andong Li , Shuxing Wei , Shubin Guo
Septic myocardial injury, a severe sepsis complication linked to high morbidity and mortality, remains a major global clinical challenge. Interleukin-33 (IL-33), a damage-associated pro-inflammatory factor, has been implicated in regulating immune responses and inflammation, but its specific role in septic myocardial injury has not been fully elucidated. This study examined IL-33’s role in septic myocardial injury using Gene Expression Omnibus (GEO) database datasets, alongside in vitro and in vivo experiments. Our results indicated a significant upregulation of IL-33 in septic myocardial injury, as demonstrated in both clinical and experimental settings. Blocking IL-33 significantly enhanced cardiac function and alleviated cardiomyocyte damage. Mechanistic investigations revealed that neutralizing IL-33 mitigates inflammation, oxidative stress, and apoptosis in cardiomyocytes by regulating the nuclear factor kappa B (NF-κB)/signal transducer and activator of transcription 3 (STAT3)/suppressors of cytokine signaling 3 (SOCS3) signaling pathway. Peritoneal macrophages are recognized as a potential origin of IL-33, and targeting IL-33 derived from these cells further reduced cardiomyocyte injury. The study underscores IL-33’s crucial involvement in septic myocardial injury pathogenesis, indicating that IL-33 may serve as a promising therapeutic target.
{"title":"Neutralization of IL-33 ameliorates septic myocardial injury through anti-inflammatory, anti-oxidative, and anti-apoptotic by regulating the NF-κB/STAT3/SOCS3 signaling pathway","authors":"Danlei Weng , Wei Shi , Yue Hu , Yanqian Su , Andong Li , Shuxing Wei , Shubin Guo","doi":"10.1016/j.bcp.2025.116954","DOIUrl":"10.1016/j.bcp.2025.116954","url":null,"abstract":"<div><div>Septic myocardial injury, a severe sepsis complication linked to high morbidity and mortality, remains a major global clinical challenge. Interleukin-33 (IL-33), a damage-associated pro-inflammatory factor, has been implicated in regulating immune responses and inflammation, but its specific role in septic myocardial injury has not been fully elucidated. This study examined IL-33’s role in septic myocardial injury using Gene Expression Omnibus (GEO) database datasets, alongside in vitro and in vivo experiments. Our results indicated a significant upregulation of IL-33 in septic myocardial injury, as demonstrated in both clinical and experimental settings. Blocking IL-33 significantly enhanced cardiac function and alleviated cardiomyocyte damage. Mechanistic investigations revealed that neutralizing IL-33 mitigates inflammation, oxidative stress, and apoptosis in cardiomyocytes by regulating the nuclear factor kappa B (NF-κB)/signal transducer and activator of transcription 3 (STAT3)/suppressors of cytokine signaling 3 (SOCS3) signaling pathway. Peritoneal macrophages are recognized as a potential origin of IL-33, and targeting IL-33 derived from these cells further reduced cardiomyocyte injury. The study underscores IL-33’s crucial involvement in septic myocardial injury pathogenesis, indicating that IL-33 may serve as a promising therapeutic target.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"237 ","pages":"Article 116954"},"PeriodicalIF":5.3,"publicationDate":"2025-04-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143865060","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 : 2025-04-16DOI: 10.1016/j.bcp.2025.116953
Qihang Guo , Yue Mao , Jiyu Zhang , Yangyang Zhou , Yue Zhao , Ying Li , Jinglong Lv , Huiyu Yang , Bingrong Liu
Esophageal cancer, a malignant neoplasm originating from the epithelial cells of the esophagus, predominantly manifests as esophageal squamous cell carcinoma (ESCC) in approximately 90% of cases in China. Cisplatin-based chemotherapy regimens remain the first-line therapeutic option for ESCC, however, the five-year overall survival rate of patients is disappointingly low. Oridonin, a bioactive diterpenoid extracted from the traditional Chinese medicine herb Donglingcao, has demonstrated inhibitory effects against various malignancies. Currently, research on the combination of oridonin and cisplatin for the treatment of ESCC is limited. This study aims to elucidate the potential synergistic anti-cancer effects of oridonin in combination with cisplatin on ESCC, along with the underlying synergistic molecular mechanisms. In vitro experiments revealed that the combination of oridonin and cisplatin could synergistically inhibit ESCC cell proliferation, migration, invasion. The synergistic effect also induced cell cycle arrest and promoted apoptosis via the mitochondrial pathway by augmenting NOXA transcriptional activity and activating the NOXA-BCL2 axis. In vivo experiments corroborated these findings, showing a marked reduction in the growth of subcutaneous xenograft tumors in mice treated with the combination, without exacerbating the cisplatin-associated side effects such as weight loss or hepatic and renal toxicity. In conclusion, the combination of oridonin and cisplatin can synergistically inhibit the development of ESCC through the activation of the NOXA-BCL2 axis signaling pathway. This treatment is both safe and effective, presenting a promising prospect for combined therapeutic application in ESCC management.
{"title":"Oridonin combined with cisplatin synergistically induces apoptosis by activating the NOXA-BCL2 axis in esophageal squamous cell carcinoma","authors":"Qihang Guo , Yue Mao , Jiyu Zhang , Yangyang Zhou , Yue Zhao , Ying Li , Jinglong Lv , Huiyu Yang , Bingrong Liu","doi":"10.1016/j.bcp.2025.116953","DOIUrl":"10.1016/j.bcp.2025.116953","url":null,"abstract":"<div><div>Esophageal cancer, a malignant neoplasm originating from the epithelial cells of the esophagus, predominantly manifests as esophageal squamous cell carcinoma (ESCC) in approximately 90% of cases in China. Cisplatin-based chemotherapy regimens remain the first-line therapeutic option for ESCC, however, the five-year overall survival rate of patients is disappointingly low. Oridonin, a bioactive diterpenoid extracted from the traditional Chinese medicine herb Donglingcao, has demonstrated inhibitory effects against various malignancies. Currently, research on the combination of oridonin and cisplatin for the treatment of ESCC is limited. This study aims to elucidate the potential synergistic anti-cancer effects of oridonin in combination with cisplatin on ESCC, along with the underlying synergistic molecular mechanisms. In vitro experiments revealed that the combination of oridonin and cisplatin could synergistically inhibit ESCC cell proliferation, migration, invasion. The synergistic effect also induced cell cycle arrest and promoted apoptosis via the mitochondrial pathway by augmenting <em>NOXA</em> transcriptional activity and activating the <em>NOXA-BCL2</em> axis. In vivo experiments corroborated these findings, showing a marked reduction in the growth of subcutaneous xenograft tumors in mice treated with the combination, without exacerbating the cisplatin-associated side effects such as weight loss or hepatic and renal toxicity. In conclusion, the combination of oridonin and cisplatin can synergistically inhibit the development of ESCC through the activation of the <em>NOXA-BCL2</em> axis signaling pathway. This treatment is both safe and effective,<!--> <!-->presenting a promising prospect for combined therapeutic application in ESCC management.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"237 ","pages":"Article 116953"},"PeriodicalIF":5.3,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143865059","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 : 2025-04-12DOI: 10.1016/j.bcp.2025.116942
Wan-Lin Tan , Xiong Yu , Jing Jia , Rong-Yu Chen , Xiao-Xiao Xu , Lu-Qun Liang , Yuan-Yuan Ruan , Fang-Fang Wang , Yu-Ting Chen , Yu-Lin Peng , Jin Peng , Mingjun Shi , Lei Tang , Bing Guo , Yuan-Yuan Wang
Acute kidney injury (AKI) is a critical condition marked by a sudden decline in kidney function, frequently resulting in high morbidity and mortality. Renal ischemia–reperfusion injury (IRI) is a leading cause of AKI, characterized by reactive oxygen species (ROS) release, cell death, and inflammation. Alpha-lipoamide (ALM), a neutral derivative of lipoic acid, is recognized for its antioxidant and organ-protective properties. Prior research indicates that ALM mitigates diabetic nephropathy by decreasing ROS. This study examines ALM’s protective role in a mouse model of IRI-induced AKI and its mechanisms using mouse renal tubular epithelial cells (mRTECs). Mice were subjected to IRI by renal artery occlusion for 30 min, followed by reperfusion, and treated with ALM (100 or 200 mg/kg) for three days before surgery. In vitro, mRTECs were exposed to hypoxia/reoxygenation injury, with ALM (200 μM) applied to assess oxidative stress. ALM significantly decreased serum creatinine levels, neutrophil gelatinase-associated lipocalin (NGAL), and kidney injury marker-1 (KIM-1), mitigated kidney injury, and reduced both ROS and Malondialdehyde(MDA) content. ALM increased glutathione (GSH) levels and upregulated SIRT1 expression. This resulted in the deacetylation of the NF-κB p65 subunit, facilitating its nuclear export, suppressing NF-κB signaling, and reducing the expression of the inflammatory marker NLRP3. ALM decreased the levels of pyroptosis-related proteins (Caspase-1, GSDMD, and IL-1β), which in turn suppressed IL-6 secretion and macrophage infiltration. These findings suggest that ALM reduces inflammation and pyroptosis-associated proteins by promoting the upregulation of SIRT1, ultimately preventing IRI-mediated renal tubular epithelial cell damage and inflammation.
{"title":"Alpha-lipoamide prevents acute kidney injury in mouse by inhibiting renal tubular epithelial cell pyroptosis","authors":"Wan-Lin Tan , Xiong Yu , Jing Jia , Rong-Yu Chen , Xiao-Xiao Xu , Lu-Qun Liang , Yuan-Yuan Ruan , Fang-Fang Wang , Yu-Ting Chen , Yu-Lin Peng , Jin Peng , Mingjun Shi , Lei Tang , Bing Guo , Yuan-Yuan Wang","doi":"10.1016/j.bcp.2025.116942","DOIUrl":"10.1016/j.bcp.2025.116942","url":null,"abstract":"<div><div>Acute kidney injury (AKI) is a critical condition marked by a sudden decline in kidney function, frequently resulting in high morbidity and mortality. Renal ischemia–reperfusion injury (IRI) is a leading cause of AKI, characterized by reactive oxygen species (ROS) release, cell death, and inflammation. Alpha-lipoamide (ALM), a neutral derivative of lipoic acid, is recognized for its antioxidant and organ-protective properties. Prior research indicates that ALM mitigates diabetic nephropathy by decreasing ROS. This study examines ALM’s protective role in a mouse model of IRI-induced AKI and its mechanisms using mouse renal tubular epithelial cells (mRTECs). Mice were subjected to IRI by renal artery occlusion for 30 min, followed by reperfusion, and treated with ALM (100 or 200 mg/kg) for three days before surgery. <em>In vitro</em>, mRTECs were exposed to hypoxia/reoxygenation injury, with ALM (200 μM) applied to assess oxidative stress. ALM significantly decreased serum creatinine levels, neutrophil gelatinase-associated lipocalin (NGAL), and kidney injury marker-1 (KIM-1), mitigated kidney injury, and reduced both ROS and Malondialdehyde(MDA) content. ALM increased glutathione (GSH) levels and upregulated SIRT1 expression. This resulted in the deacetylation of the NF-κB p65 subunit, facilitating its nuclear export, suppressing NF-κB signaling, and reducing the expression of the inflammatory marker NLRP3. ALM decreased the levels of pyroptosis-related proteins (Caspase-1, GSDMD, and IL-1β), which in turn suppressed IL-6 secretion and macrophage infiltration. These findings suggest that ALM reduces inflammation and pyroptosis-associated proteins by promoting the upregulation of SIRT1, ultimately preventing IRI-mediated renal tubular epithelial cell damage and inflammation.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"237 ","pages":"Article 116942"},"PeriodicalIF":5.3,"publicationDate":"2025-04-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143843353","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 : 2025-04-12DOI: 10.1016/j.bcp.2025.116943
Li Wang , Xia-Juan Huan , Shan-Shan Song , Xu-Bin Bao , Chang-Qing Tian , Ze-Hong Miao , Ying-Qing Wang
Ubiquitination factor E4B (UBE4B) is crucial to the high mortality rate and poor prognosis associated with hepatocellular carcinoma (HCC). Evidence suggests that aberrant epigenetic modifications significantly contribute to HCC carcinogenesis, making epigenetic mechanisms a promising area for therapeutic intervention. However, the precise role of UBE4B in the epigenetic dysregulation observed in HCC remains elusive. In this study, we silenced UBE4B in HCC cells and exposed them to a panel of epigenetic compounds. Notably, only bromodomain and extraterminal inhibitors (BETis) exhibited resistance to UBE4B silencing, while restoring UBE4B expression partially reversed this resistance. Furthermore, UBE4B deletion led to decreased growth rates and impaired proliferation, resulting in cell cycle arrest and diminished tumorigenicity. However, this deletion did not affect the cell cycle arrest induced by BETi. Interestingly, KLHL22, a ubiquitin substrate of UBE4B, accumulated in UBE4B-deleted cells. Knockdown of KLHL22 restored sensitivity to BETi, accompanied by downregulation of JAK2 and upregulation of its negative regulator, LNK. Additionally, UBE4B deletion resulted in decreased LNK expression, and LNK knockdown increased JAK2 expression and mediated resistance to BETi. Increased JAK2 subsequently targeted PIM1, further reducing the inhibitory effect of BETi. Directly silencing PIM1 in UBE4B-deleted cells restored BETi sensitivity. Overall, our findings provide novel insights into the relationship between UBE4B expression and BETi sensitivity, which is mediated through the KLHL22-JAK2-PIM1 regulatory axis. These findings not only deepen our understanding of the mechanisms underlying HCC progression but also suggest that targeting this axis may present a promising therapeutic strategy for enhancing the treatment outcomes of HCC.
{"title":"UBE4B modulates BET inhibitor sensitivity via KLHL22-JAK2-PIM1 axis in hepatocellular carcinoma","authors":"Li Wang , Xia-Juan Huan , Shan-Shan Song , Xu-Bin Bao , Chang-Qing Tian , Ze-Hong Miao , Ying-Qing Wang","doi":"10.1016/j.bcp.2025.116943","DOIUrl":"10.1016/j.bcp.2025.116943","url":null,"abstract":"<div><div>Ubiquitination factor E4B (UBE4B) is crucial to the high mortality rate and poor prognosis associated with hepatocellular carcinoma (HCC). Evidence suggests that aberrant epigenetic modifications significantly contribute to HCC carcinogenesis, making epigenetic mechanisms a promising area for therapeutic intervention. However, the precise role of UBE4B in the epigenetic dysregulation observed in HCC remains elusive. In this study, we silenced UBE4B in HCC cells and exposed them to a panel of epigenetic compounds. Notably, only bromodomain and extraterminal inhibitors (BETis) exhibited resistance to UBE4B silencing, while restoring UBE4B expression partially reversed this resistance. Furthermore, UBE4B deletion led to decreased growth rates and impaired proliferation, resulting in cell cycle arrest and diminished tumorigenicity. However, this deletion did not affect the cell cycle arrest induced by BETi. Interestingly, KLHL22, a ubiquitin substrate of UBE4B, accumulated in UBE4B-deleted cells. Knockdown of KLHL22 restored sensitivity to BETi, accompanied by downregulation of JAK2 and upregulation of its negative regulator, LNK. Additionally, UBE4B deletion resulted in decreased LNK expression, and LNK knockdown increased JAK2 expression and mediated resistance to BETi. Increased JAK2 subsequently targeted PIM1, further reducing the inhibitory effect of BETi. Directly silencing PIM1 in UBE4B-deleted cells restored BETi sensitivity. Overall, our findings provide novel insights into the relationship between UBE4B expression and BETi sensitivity, which is mediated through the KLHL22-JAK2-PIM1 regulatory axis. These findings not only deepen our understanding of the mechanisms underlying HCC progression but also suggest that targeting this axis may present a promising therapeutic strategy for enhancing the treatment outcomes of HCC.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"237 ","pages":"Article 116943"},"PeriodicalIF":5.3,"publicationDate":"2025-04-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143847737","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 : 2025-04-12DOI: 10.1016/j.bcp.2025.116949
Shen-nan Shi , Qiuyang Xu , Xiaofei Jiao , Yuanjia Wen , Yijie Wu , Jiahao Liu , Ding Ma , Bingbing Zhao , Qinglei Gao , Yong Fang
Necroptosis induced by DNA damage during chemotherapy is a significant and effective treatment strategy for malignant tumors. Ataxia telangiectasia and rad3-related protein (ATR), a key kinase in DNA damage checkpoints, initiates repair by transmitting damage signals to effectors. However, persistent DNA damage may result in cell death. The mechanisms by which ATR regulates necroptosis remain incompletely understood. In this study, we demonstrated that ATR binds to receptor-interacting serine/threonine-protein kinase 1 (RIPK1) and inhibits its activation, thereby suppressing RIPK1-dependent necroptosis triggered by DNA damage. Mechanistically, ATR directly inhibited RIPK1 and downstream necrosome formation through Ser335 phosphorylation following DNA damage, thereby attenuating RIPK1-dependent necroptosis. In the case of the S335A mutation, RIPK1 repression was relieved, leading to enhanced downstream necroptosis. Furthermore, RIPK1 knockout with complementation of wild-type or S335A mutation in ovarian cancer cell lines revealed that ATR phosphorylation of RIPK1 at S335 promoted chemoresistance, while the S335A mutation significantly increased chemosensitivity. This was characterized by heightened necroptosis activation, reduced cell viability, and increased cell death. These findings expand our understanding of the interaction between DNA damage and cell death regulation and may aid in developing therapeutic drugs to enhance DNA damage-induced tumor necroptosis and improve chemosensitivity.
{"title":"ATR-mediated phosphorylation of RIPK1 inhibits DNA damage-induced necroptosis","authors":"Shen-nan Shi , Qiuyang Xu , Xiaofei Jiao , Yuanjia Wen , Yijie Wu , Jiahao Liu , Ding Ma , Bingbing Zhao , Qinglei Gao , Yong Fang","doi":"10.1016/j.bcp.2025.116949","DOIUrl":"10.1016/j.bcp.2025.116949","url":null,"abstract":"<div><div>Necroptosis induced by DNA damage during chemotherapy is a significant and effective treatment strategy for malignant tumors. Ataxia telangiectasia and rad3-related protein (ATR), a key kinase in DNA damage checkpoints, initiates repair by transmitting damage signals to effectors. However, persistent DNA damage may result in cell death. The mechanisms by which ATR regulates necroptosis remain incompletely understood. In this study, we demonstrated that ATR binds to receptor-interacting serine/threonine-protein kinase 1 (RIPK1) and inhibits its activation, thereby suppressing RIPK1-dependent necroptosis triggered by DNA damage. Mechanistically, ATR directly inhibited RIPK1 and downstream necrosome formation through Ser335 phosphorylation following DNA damage, thereby attenuating RIPK1-dependent necroptosis. In the case of the S335A mutation, RIPK1 repression was relieved, leading to enhanced downstream necroptosis. Furthermore, RIPK1 knockout with complementation of wild-type or S335A mutation in ovarian cancer cell lines revealed that ATR phosphorylation of RIPK1 at S335 promoted chemoresistance, while the S335A mutation significantly increased chemosensitivity. This was characterized by heightened necroptosis activation, reduced cell viability, and increased cell death. These findings expand our understanding of the interaction between DNA damage and cell death regulation and may aid in developing therapeutic drugs to enhance DNA damage-induced tumor necroptosis and improve chemosensitivity.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"237 ","pages":"Article 116949"},"PeriodicalIF":5.3,"publicationDate":"2025-04-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143847735","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 : 2025-04-12DOI: 10.1016/j.bcp.2025.116947
Huina Liu , Weitao Chen , Meiyuan He , Linlin Nie , Yaru Pan , Danni Guan , Yongyi Li , Ting Wan , Lining Duan , Cong Yang , Weirong Li , Qi wang , Lixing Zhuang , Yifan Zhang
Microglial neuroinflammation is considered to be a vital injury factor aggravating ischemia–reperfusion (I/R) injury on the progression of cerebral ischemic stroke. Mounting evidences have verified the effect of pyroptosis mediated by NLRP3 inflammasome on modulating microglial phenotype, and maintaining the microglial M1/M2 phenotype balance could be a novel target to ameliorate cerebral I/R injury. Herein, we focused on the anti-neuroinflammatory effect of methyl isoeugenol, a bioactive compound isolated from Acorus tatarinowii Schott, on nuclear factor erythroid 2-related factor 2 (Nrf2)-mediated NLRP3 inflammasome in vivo or in vitro. The results showed that methyl isoeugenol reduced cerebral infarct volume, modulated microglia M1/M2 phenotypes, and protected against NLRP3 inflammasome-primed pyroptosis. Mechanistically, methyl isoeugenol increased the nuclear translocation of Nrf2 and decreased that of NF-κB, and consequently, upregulated cellular antioxidants (HO-1 and NQO1), with the increased expression of antioxidant enzymes SOD and the decreased expression of lipid peroxidation MDA. These findings suggest that Nrf2 may serve as a vital target for the protective effect of methyl isoeugenol, making methyl isoeugenol as a promising anti-neuroinflammatory agent for NLRP3 inflammasome mediated microglial neuroinflammation in I/R injury.
{"title":"Methyl isoeugenol suppresses NLRP3 inflammasome-mediated pyroptosis via activation of Nrf2/NQO1/HO-1 signaling in cerebral ischemia–reperfusion injury","authors":"Huina Liu , Weitao Chen , Meiyuan He , Linlin Nie , Yaru Pan , Danni Guan , Yongyi Li , Ting Wan , Lining Duan , Cong Yang , Weirong Li , Qi wang , Lixing Zhuang , Yifan Zhang","doi":"10.1016/j.bcp.2025.116947","DOIUrl":"10.1016/j.bcp.2025.116947","url":null,"abstract":"<div><div>Microglial neuroinflammation is considered to be a vital injury factor aggravating ischemia–reperfusion (I/R) injury on the progression of cerebral ischemic stroke. Mounting evidences have verified the effect of pyroptosis mediated by NLRP3 inflammasome on modulating microglial phenotype, and maintaining the microglial M1/M2 phenotype balance could be a novel target to ameliorate cerebral I/R injury. Herein, we focused on the anti-neuroinflammatory effect of methyl isoeugenol, a bioactive compound isolated from <em>Acorus tatarinowii Schott</em>, on nuclear factor erythroid 2-related factor 2 (Nrf2)-mediated NLRP3 inflammasome <em>in vivo</em> or <em>in vitro</em>. The results showed that methyl isoeugenol reduced cerebral infarct volume, modulated microglia M1/M2 phenotypes, and protected against NLRP3 inflammasome-primed pyroptosis. Mechanistically, methyl isoeugenol increased the nuclear translocation of Nrf2 and decreased that of NF-κB, and consequently, upregulated cellular antioxidants (HO-1 and NQO1), with the increased expression of antioxidant enzymes SOD and the decreased expression of lipid peroxidation MDA. These findings suggest that Nrf2 may serve as a vital target for the protective effect of methyl isoeugenol, making methyl isoeugenol as a promising anti-neuroinflammatory agent for NLRP3 inflammasome mediated microglial neuroinflammation in I/R injury.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"237 ","pages":"Article 116947"},"PeriodicalIF":5.3,"publicationDate":"2025-04-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143847736","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 : 2025-04-12DOI: 10.1016/j.bcp.2025.116946
Lu Zhou , Mengke Cui , Jian Yu , Yujie Liu , Feiyue Zeng , Yingzi Liu
Ovarian cancer is the most lethal malignancy affecting the female reproductive system, with its progression and metastasis being significant contributors to patient mortality. Our previous study identified the zinc finger protein ZNF587B as a potential tumor suppressor that inhibited the proliferation, migration and invasion of ovarian cancer cells, although the underlying mechanism remains elusive. In this study, ZNF587B was demonstrated to bind directly to the promoter region of Versican (VCAN), a high molecular weight chondroitin sulfate glycoprotein, and repress its transcription using Chromatin immunoprecipitation-qPCR (ChIP-qPCR), luciferase reporter assays, and immunofluorescence (IF). Moreover, in vivo and in vitro assays revealed that the effect of ZNF587B knockdown on ovarian cancer proliferation may be mediated through VCAN. Not only that, patients with reduced expression of ZNF587B and increased expression of VCAN exhibit a poorer prognosis. The potential mechanism behind this may involve its impact on the phosphorylation process of AKT.
{"title":"Identification of Versican as a target gene of the transcription Factor ZNF587B in ovarian cancer","authors":"Lu Zhou , Mengke Cui , Jian Yu , Yujie Liu , Feiyue Zeng , Yingzi Liu","doi":"10.1016/j.bcp.2025.116946","DOIUrl":"10.1016/j.bcp.2025.116946","url":null,"abstract":"<div><div>Ovarian cancer is the most lethal malignancy affecting the female reproductive system, with its progression and metastasis being significant contributors to patient mortality. Our previous study identified the zinc finger protein ZNF587B as a potential tumor suppressor that inhibited the proliferation, migration and invasion of ovarian cancer cells, although the underlying mechanism remains elusive. In this study, ZNF587B was demonstrated to bind directly to the promoter region of Versican (VCAN), a high molecular weight chondroitin sulfate glycoprotein, and repress its transcription using Chromatin immunoprecipitation-qPCR (ChIP-qPCR), luciferase reporter assays, and immunofluorescence (IF). Moreover, in vivo and <em>in vitro</em> assays revealed that the effect of ZNF587B knockdown on ovarian cancer proliferation may be mediated through VCAN. Not only that, patients with reduced expression of ZNF587B and increased expression of VCAN exhibit a poorer prognosis. The potential mechanism behind this may involve its impact on the phosphorylation process of AKT.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"237 ","pages":"Article 116946"},"PeriodicalIF":5.3,"publicationDate":"2025-04-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143838570","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 : 2025-04-12DOI: 10.1016/j.bcp.2025.116945
Sichen Zhao , Dongting Wu , Yao Lu , Lei Zhu , Shuihuan Wang , Zhaohuai Li , Xuening Peng , He Li , Xiaofang Xu , Wenru Su
Autoimmune uveitis (AU) is a sight-threatening eye disease, marked by a complex pathogenesis and limited treatment options. Herein, we conducted single-cell RNA sequencing (scRNA-seq) on the spleen and cervical draining lymph nodes (CDLNs) of both normal and experimental autoimmune uveitis (EAU) mice and found common alterations in celluar composition and transcriptional regulation occurred throughout the EAU process. Moreover, we identified activator protein-1 (AP-1) as a pivotal disease-related molecule in the pathogenesis of EAU. Inhibiting AP-1 alleviated symptoms of EAU and reduced the retina infiltration of T helper 17 cells (Th17) and Th1 cells. Additionally, following treatment with the AP-1 inhibitor, both the spleen and CDLNs showed decreased Th17 and Th1 cell proportions. Meanwhile, in vitro studies revealed that treatment with AP-1 inhibitor reduced the level of granulocyte–macrophage colony-stimulating factor (GM-CSF) and interleukin-23 (IL-23), two pivotal molecules implicated in the Th17 cell pathogenicity, during EAU. The adoptive transfer experiment also showed that inhibiting AP-1 in CD4+ T cells suppressed their ability to elicit EAU. Altogether, our study demonstrates that AP-1 might involved in EAU pathogenesis by supporting Th17 cell pathogenicity via the GM-CSF/IL-23 feedback loop. Thus, AP-1 inhibition might be a novel treatment strategy for uveitis.
{"title":"Single-cell RNA sequencing indicates AP-1 as a potential therapeutic target for autoimmune uveitis","authors":"Sichen Zhao , Dongting Wu , Yao Lu , Lei Zhu , Shuihuan Wang , Zhaohuai Li , Xuening Peng , He Li , Xiaofang Xu , Wenru Su","doi":"10.1016/j.bcp.2025.116945","DOIUrl":"10.1016/j.bcp.2025.116945","url":null,"abstract":"<div><div>Autoimmune uveitis (AU) is a sight-threatening eye disease, marked by a complex pathogenesis and limited treatment options. Herein, we conducted single-cell RNA sequencing (scRNA-seq) on the spleen and cervical draining lymph nodes (CDLNs) of both normal and experimental autoimmune uveitis (EAU) mice and found common alterations in celluar composition and transcriptional regulation occurred throughout the EAU process. Moreover, we identified activator protein-1 (AP-1) as a pivotal disease-related molecule in the pathogenesis of EAU. Inhibiting AP-1 alleviated symptoms of EAU and reduced the retina infiltration of T helper 17 cells (Th17) and Th1 cells. Additionally, following treatment with the AP-1 inhibitor, both the spleen and CDLNs showed decreased Th17 and Th1 cell proportions. Meanwhile, in vitro studies revealed that treatment with AP-1 inhibitor reduced the level of granulocyte–macrophage colony-stimulating factor (GM-CSF) and interleukin-23 (IL-23), two pivotal molecules implicated in the Th17 cell pathogenicity, during EAU. The adoptive transfer experiment also showed that inhibiting AP-1 in CD4+ T cells suppressed their ability to elicit EAU. Altogether, our study demonstrates that AP-1 might involved in EAU pathogenesis by supporting Th17 cell pathogenicity via the GM-CSF/IL-23 feedback loop. Thus, AP-1 inhibition might be a novel treatment strategy for uveitis.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"237 ","pages":"Article 116945"},"PeriodicalIF":5.3,"publicationDate":"2025-04-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143843351","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 : 2025-04-12DOI: 10.1016/j.bcp.2025.116944
Rongchen Sun , Xue Yang , Shang Liu , Ting Wang , Pei Du , Youyou Yang , Zhen Hua , Zhengqi Zha , Mingtao Fan , Meijia Yang , Hongping Yin
Follicle-stimulating hormone (FSH) plays an indispensable role in fertility. Although Recombinant human FSH (rh-FSH) and long-acting FSH analogs, such as FSH-CTP (Elonva), have been used to treat infertility for many years. The need for multiple injections remains inconvenient and uncomfortable. Therefore, long-acting FSH with optimized metabolic properties and bioactivity is urgently required. In this study, we designed a new long-acting FSH by fusing mucin domain II of CD164 to the β-subunit of FSH, which was then combined with the α-subunit, generating FSH164. SDS-PAGE and a series of liquid chromatography analyses showed the changed physicochemical properties, in which the MW of FSH164 was 2-fold greater than that of rh-FSH, and exceeded the MW of Elonva. Glycosylation analysis via ultra-performance liquid chromatography (UPLC) demonstrated an abundance of O-glycans and N-glycans, with sialic acid in the extremities. In vitro experiments suggested that FSH164 improved efficacy in addressing the attenuation of downstream signaling activation associated with sustained-action FSH modifications compared with Elonva. Pharmacokinetic results suggested that, compared with Elonva, FSH164 had a 1.5-fold longer half-life in rats. Furthermore, increased activities in terms of ovary weight gain and superovulations were verified in rats and mice. In conclusion, the designed hyperglycosylated FSH164 exhibits a prolonged metabolic duration, with a single dose of FSH164 possessing bioactivity comparable to that of multiple rh-FSH injections, suggesting that it has great potential as a therapy for infertility.
{"title":"A novel long-acting recombinant follicle-stimulating hormone with hyperglycosylation exhibits improved pharmacokinetic and bioactivity on promoting follicle growth","authors":"Rongchen Sun , Xue Yang , Shang Liu , Ting Wang , Pei Du , Youyou Yang , Zhen Hua , Zhengqi Zha , Mingtao Fan , Meijia Yang , Hongping Yin","doi":"10.1016/j.bcp.2025.116944","DOIUrl":"10.1016/j.bcp.2025.116944","url":null,"abstract":"<div><div>Follicle-stimulating hormone (FSH) plays an indispensable role in fertility. Although Recombinant human FSH (rh-FSH) and long-acting FSH analogs, such as FSH-CTP (Elonva), have been used to treat infertility for many years. The need for multiple injections remains inconvenient and uncomfortable. Therefore, long-acting FSH with optimized metabolic properties and bioactivity is urgently required. In this study, we designed a new long-acting FSH by fusing mucin domain II of CD164 to the β-subunit of FSH, which was then combined with the α-subunit, generating FSH164. SDS-PAGE and a series of liquid chromatography analyses showed the changed physicochemical properties, in which the MW of FSH164 was 2-fold greater than that of rh-FSH, and exceeded the MW of Elonva. Glycosylation analysis via ultra-performance liquid chromatography (UPLC) demonstrated an abundance of O-glycans and N-glycans, with sialic acid in the extremities. In vitro experiments suggested that FSH164 improved efficacy in addressing the attenuation of downstream signaling activation associated with sustained-action FSH modifications compared with Elonva. Pharmacokinetic results suggested that, compared with Elonva, FSH164 had a 1.5-fold longer half-life in rats. Furthermore, increased activities in terms of ovary weight gain and superovulations were verified in rats and mice. In conclusion, the designed hyperglycosylated FSH164 exhibits a prolonged metabolic duration, with a single dose of FSH164 possessing bioactivity comparable to that of multiple rh-FSH injections, suggesting that it has great potential as a therapy for infertility.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"237 ","pages":"Article 116944"},"PeriodicalIF":5.3,"publicationDate":"2025-04-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143838572","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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