Biochemical pharmacology最新文献_第5页

Targeting GPX4 alleviates ferroptosis and retards abdominal aortic aneurysm formation

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2025-02-12 DOI: 10.1016/j.bcp.2025.116800

Yu Shi , Yi Zhao , Si-Jia Sun , Xiu-Ting Lan , Wen-Bin Wu , Zhen Zhang , Yu-Xin Chen , Yu-Ying Yan , Yu-Ping Xu , Dong-Jie Li , Hui Fu , Fu-Ming Shen

Abdominal aortic aneurysm (AAA) is a potentially fatal cardiovascular disease, closely related to inflammation and loss of vascular smooth muscle cells (VSMCs). Ferroptosis is an iron-dependent cell death associated with peroxidation of lipids. However, the direct role of glutathione peroxidase 4 (GPX4) itself determined ferroptosis in the course of AAA pathogenesis remains unknown. Here, we reported that ferroptosis was triggered in human AAA, elastase- and angiotensin II (Ang II)-induced mouse AAA, and Ang II-incubated VSMCs. Inhibition of ferroptosis via global genetic overexpression of GPX4, a critical anti-ferroptosis molecule, markedly prevented both vascular remodeling and inflammatory response. Mechanistically, GPX4 changed the migration and activation of macrophages/monocytes in AAA tissues in mice. Experiments in vitro demonstrated that overexpression of GPX4 prevented the JAK1/STAT3 signaling activation in VSMCs induced by IL-6, production of pro-inflammatory macrophages. Finally, the role of ferroptosis was confirmed on an Ang II-induced mice AAA model. These results emphasized the significance of ferroptosis in AAA, and provided novel insights that therapy focusing on GPX4 might be a promising strategy for treatment of AAA in the clinic.

{"title":"Targeting GPX4 alleviates ferroptosis and retards abdominal aortic aneurysm formation","authors":"Yu Shi , Yi Zhao , Si-Jia Sun , Xiu-Ting Lan , Wen-Bin Wu , Zhen Zhang , Yu-Xin Chen , Yu-Ying Yan , Yu-Ping Xu , Dong-Jie Li , Hui Fu , Fu-Ming Shen","doi":"10.1016/j.bcp.2025.116800","DOIUrl":"10.1016/j.bcp.2025.116800","url":null,"abstract":"<div><div>Abdominal aortic aneurysm (AAA) is a potentially fatal cardiovascular disease, closely related to inflammation and loss of vascular smooth muscle cells (VSMCs). Ferroptosis is an iron-dependent cell death associated with peroxidation of lipids. However, the direct role of glutathione peroxidase 4 (GPX4) itself determined ferroptosis in the course of AAA pathogenesis remains unknown. Here, we reported that ferroptosis was triggered in human AAA, elastase- and angiotensin II (Ang II)-induced mouse AAA, and Ang II-incubated VSMCs. Inhibition of ferroptosis via global genetic overexpression of GPX4, a critical anti-ferroptosis molecule, markedly prevented both vascular remodeling and inflammatory response. Mechanistically, GPX4 changed the migration and activation of macrophages/monocytes in AAA tissues in mice. Experiments <em>in vitro</em> demonstrated that overexpression of GPX4 prevented the JAK1/STAT3 signaling activation in VSMCs induced by IL-6, production of pro-inflammatory macrophages. Finally, the role of ferroptosis was confirmed on an Ang II-induced mice AAA model. These results emphasized the significance of ferroptosis in AAA, and provided novel insights that therapy focusing on GPX4 might be a promising strategy for treatment of AAA in the clinic.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"234 ","pages":"Article 116800"},"PeriodicalIF":5.3,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143419894","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

Tamibarotene directly targets the NACHT domain of NLRP3 to alleviate acute myocardial infarction

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2025-02-12 DOI: 10.1016/j.bcp.2025.116801

Xiuhui Chen , Yunjing Wang , Junjun Huang , Huaqian Dou , Zhe Zhang , Yutong Zheng , Rui Long , Xiaofeng Zhang , Fengdan Xu , Weijun Ye , Qing Xiao

The aberrant activation of the nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing protein 3 (NLRP3) inflammasome has been implicated in the exacerbation of myocardial damage and the subsequent development of heart failure following myocardial infarction (MI). Inhibiting NLRP3 inflammasome activation offers a promising therapeutic strategy for mitigating MI-related injury, although no NLRP3 inhibitors have received Food and Drug administration (FDA) approval to date. To identify novel NLRP3 inflammasome inhibitors through the repurposing of FDA-approved drugs, Tamibarotene emerged as a potent inhibitor with a favorable safety profile. Mechanistically, Tamibarotene inhibits NLRP3 inflammasome activation independently of retinoic acid receptor activation, binding to Phe410 and Ile417 within the nucleotide-binding and oligomerization (NACHT) domain in an ATPase activity-dependent manner. This interaction further inhibits the assembly of the NLRP3 inflammasome. In a murine model of MI, Tamibarotene significantly reduced myocardial damage and improved cardiac function by inhibiting NLRP3 inflammasome activation. In summary, NLRP3 has been identified as a direct target of Tamibarotene for myocardial repair following MI, indicating that Tamibarotene could serve as a potential precursor for the development of innovative NLRP3 inhibitors.

{"title":"Tamibarotene directly targets the NACHT domain of NLRP3 to alleviate acute myocardial infarction","authors":"Xiuhui Chen , Yunjing Wang , Junjun Huang , Huaqian Dou , Zhe Zhang , Yutong Zheng , Rui Long , Xiaofeng Zhang , Fengdan Xu , Weijun Ye , Qing Xiao","doi":"10.1016/j.bcp.2025.116801","DOIUrl":"10.1016/j.bcp.2025.116801","url":null,"abstract":"<div><div>The aberrant activation of the nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing protein 3 (NLRP3) inflammasome has been implicated in the exacerbation of myocardial damage and the subsequent development of heart failure following myocardial infarction (MI). Inhibiting NLRP3 inflammasome activation offers a promising therapeutic strategy for mitigating MI-related injury, although no NLRP3 inhibitors have received Food and Drug administration (FDA) approval to date. To identify novel NLRP3 inflammasome inhibitors through the repurposing of FDA-approved drugs, Tamibarotene emerged as a potent inhibitor with a favorable safety profile. Mechanistically, Tamibarotene inhibits NLRP3 inflammasome activation independently of retinoic acid receptor activation, binding to Phe410 and Ile417 within the nucleotide-binding and oligomerization (NACHT) domain in an ATPase activity-dependent manner. This interaction further inhibits the assembly of the NLRP3 inflammasome. In a murine model of MI, Tamibarotene significantly reduced myocardial damage and improved cardiac function by inhibiting NLRP3 inflammasome activation. In summary, NLRP3 has been identified as a direct target of Tamibarotene for myocardial repair following MI, indicating that Tamibarotene could serve as a potential precursor for the development of innovative NLRP3 inhibitors.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"234 ","pages":"Article 116801"},"PeriodicalIF":5.3,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143419895","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

Endoplasmic reticulum stress and unfolded protein response: Roles in skeletal muscle atrophy

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2025-02-12 DOI: 10.1016/j.bcp.2025.116799

Yanan Ji , Quan Jiang , Bingqian Chen , Xin Chen , Aihong Li , Dingding Shen , Yuntian Shen , Hua Liu , Xiaowei Qian , Xinlei Yao , Hualin Sun

Skeletal muscle atrophy is commonly present in various pathological states, posing a huge burden on society and patients. Increased protein hydrolysis, decreased protein synthesis, inflammatory response, oxidative stress, mitochondrial dysfunction, endoplasmic reticulum stress (ERS) and unfolded protein response (UPR) are all important molecular mechanisms involved in the occurrence and development of skeletal muscle atrophy. The potential mechanisms of ERS and UPR in skeletal muscle atrophy are extremely complex and have not yet been fully elucidated. This article elucidates the molecular mechanisms of ERS and UPR, and discusses their effects on different types of muscle atrophy (muscle atrophy caused by disuse, cachexia, chronic kidney disease (CKD), diabetes mellitus (DM), amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), spinal and bulbar muscular atrophy (SBMA), aging, sarcopenia, obesity, and starvation), and explores the preventive and therapeutic strategies targeting ERS and UPR in skeletal muscle atrophy, including inhibitor therapy and drug therapy. This review aims to emphasize the importance of endoplasmic reticulum (ER) in maintaining skeletal muscle homeostasis, which helps us further understand the molecular mechanisms of skeletal muscle atrophy and provides new ideas and insights for the development of effective therapeutic drugs and preventive measures for skeletal muscle atrophy.

{"title":"Endoplasmic reticulum stress and unfolded protein response: Roles in skeletal muscle atrophy","authors":"Yanan Ji , Quan Jiang , Bingqian Chen , Xin Chen , Aihong Li , Dingding Shen , Yuntian Shen , Hua Liu , Xiaowei Qian , Xinlei Yao , Hualin Sun","doi":"10.1016/j.bcp.2025.116799","DOIUrl":"10.1016/j.bcp.2025.116799","url":null,"abstract":"<div><div>Skeletal muscle atrophy is commonly present in various pathological states, posing a huge burden on society and patients. Increased protein hydrolysis, decreased protein synthesis, inflammatory response, oxidative stress, mitochondrial dysfunction, endoplasmic reticulum stress (ERS) and unfolded protein response (UPR) are all important molecular mechanisms involved in the occurrence and development of skeletal muscle atrophy. The potential mechanisms of ERS and UPR in skeletal muscle atrophy are extremely complex and have not yet been fully elucidated. This article elucidates the molecular mechanisms of ERS and UPR, and discusses their effects on different types of muscle atrophy (muscle atrophy caused by disuse, cachexia, chronic kidney disease (CKD), diabetes mellitus (DM), amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), spinal and bulbar muscular atrophy (SBMA), aging, sarcopenia, obesity, and starvation), and explores the preventive and therapeutic strategies targeting ERS and UPR in skeletal muscle atrophy, including inhibitor therapy and drug therapy. This review aims to emphasize the importance of endoplasmic reticulum (ER) in maintaining skeletal muscle homeostasis, which helps us further understand the molecular mechanisms of skeletal muscle atrophy and provides new ideas and insights for the development of effective therapeutic drugs and preventive measures for skeletal muscle atrophy.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"234 ","pages":"Article 116799"},"PeriodicalIF":5.3,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143424923","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

Small-molecule inhibitor BAY synergizes with gemcitabine through AHR inhibition in pancreatic cancer cells

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2025-02-11 DOI: 10.1016/j.bcp.2025.116798

Darius Stukas , Inga Zievyte , Sandra Ivanauskiene , Gabriele Karvelyte , Aldona Jasukaitiene , Arenida Bartkeviciene , Jason Matthews , Toivo Maimets , Indrek Teino , Kristaps Jaudzems , Antanas Gulbinas , Zilvinas Dambrauskas

Pancreatic cancer (PC) presents a significant challenge in treatment efficacy due to late-stage diagnosis and chemoresistance. The effects of the combination of a selective small-molecule AHR inhibitor and gemcitabine treatment effectiveness in PC cells has been a focus of research. This study utilized the PC cell lines BxPC-3 and Su.86.86 to investigate the impact of AHR activity modulation on gene and protein expression related to the gemcitabine response. Assays including viability measurement, combinational index calculation, qRT–PCR, Western blot analysis, immunocytofluorescence, and clonogenic assays, were employed. Additionally, patient tissue samples were analysed for AHR, ELAVL1, and DCK levels. The results show that AHR activity modulation influenced ELAVL1 localization, DCK expression, and gemcitabine response. Inhibition of AHR activity caused synergistic effects with gemcitabine, whereas activation had an antagonistic effect. Regarding colony formation, inhibition of AHR increased gemcitabine effectiveness by 30–41%, whereas activation decreased the response by 11–28%. Patient tissue analysis revealed correlations between AHR, ELAVL1, and DCK mRNA levels and showed increased levels of AHR protein (2.2-fold) and decreased DCK protein levels (36% decrease) in tumor tissue compared to next-to-cancer tissue. These findings demonstrate the potential of AHR modulation to improve gemcitabine treatment outcomes. This study highlights the significance of AHR modulation in influencing the gemcitabine response in PC cells. By inhibiting AHR activity, cells exhibited improved gemcitabine response, offering a promising avenue for enhancing treatment efficacy. These findings suggest that AHR could serve as a target for optimizing gemcitabine treatment and potentially reducing cancer aggressiveness.

{"title":"Small-molecule inhibitor BAY synergizes with gemcitabine through AHR inhibition in pancreatic cancer cells","authors":"Darius Stukas , Inga Zievyte , Sandra Ivanauskiene , Gabriele Karvelyte , Aldona Jasukaitiene , Arenida Bartkeviciene , Jason Matthews , Toivo Maimets , Indrek Teino , Kristaps Jaudzems , Antanas Gulbinas , Zilvinas Dambrauskas","doi":"10.1016/j.bcp.2025.116798","DOIUrl":"10.1016/j.bcp.2025.116798","url":null,"abstract":"<div><div>Pancreatic cancer (PC) presents a significant challenge in treatment efficacy due to late-stage diagnosis and chemoresistance. The effects of the combination of a selective small-molecule AHR inhibitor and gemcitabine treatmenteffectiveness in PC cells has been a focus of research. This study utilized the PC cell lines BxPC-3 and Su.86.86 to investigate the impact of AHR activity modulation on gene and protein expression related to the gemcitabine response. Assays including viability measurement, combinational index calculation, qRT–PCR, Western blot analysis, immunocytofluorescence, and clonogenic assays, were employed. Additionally, patient tissue samples were analysed for AHR, ELAVL1, and DCK levels. The results show that AHR activity modulation influenced ELAVL1 localization, DCK expression, and gemcitabine response. Inhibition of AHR activity caused synergistic effects with gemcitabine, whereas activation had an antagonistic effect. Regarding colony formation, inhibition of AHR increased gemcitabine effectiveness by 30–41%, whereas activation decreased the response by 11–28%. Patient tissue analysis revealed correlations between AHR, ELAVL1, and DCK mRNA levels and showed increased levels of AHR protein (2.2-fold) and decreased DCK protein levels (36% decrease) in tumor tissue compared to next-to-cancer tissue. These findings demonstrate the potential of AHR modulation to improve gemcitabine treatment outcomes. This study highlights the significance of AHR modulation in influencing the gemcitabine response in PC cells. By inhibiting AHR activity, cells exhibited improved gemcitabine response, offering a promising avenue for enhancing treatment efficacy. These findings suggest that AHR could serve as a target for optimizing gemcitabine treatment and potentially reducing cancer aggressiveness.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"233 ","pages":"Article 116798"},"PeriodicalIF":5.3,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143394616","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Sulforaphane: An emerging star in neuroprotection and neurological disease prevention

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2025-02-08 DOI: 10.1016/j.bcp.2025.116797

Na Wu , Zepeng Luo , Renfu Deng , Zhijing Zhang , Jichun Zhang , Songlin Liu , Zhongping Luo , Qi Qi

Neurological diseases, including both acute injuries and chronic neurodegenerative disorders, represent major contributors to morbidity and mortality worldwide. Chronic neurodegenerative diseases, such as Alzheimer’s disease (AD) and Parkinson’s disease (PD), which require long-term management, present significant challenges in the search for neuroprotective agents with reduced adverse effects and enhanced therapeutic efficacy. Sulforaphane (SFN), a bioactive compound found in cruciferous vegetables like broccoli and cauliflower, has garnered considerable attention for its potent neuroprotective properties and overall health benefits. Marketed primarily as a dietary supplement, SFN has shown a variety of biological activities and therapeutic potential in neurological diseases. Recent surging studies including ours have highlighted its ability to impede the progression of AD, PD, and cerebral ischemia by fostering neurogenesis and inhibiting apoptosis, oxidative stress, and neuroinflammation. This review aims to summarize the latest research on SFN, exploring its advanced therapeutic potential and underlying mechanisms in various neurological diseases, offering a comprehensive overview for researchers focused on neurological pathogenesis and drug development in neuroprotection.

{"title":"Sulforaphane: An emerging star in neuroprotection and neurological disease prevention","authors":"Na Wu , Zepeng Luo , Renfu Deng , Zhijing Zhang , Jichun Zhang , Songlin Liu , Zhongping Luo , Qi Qi","doi":"10.1016/j.bcp.2025.116797","DOIUrl":"10.1016/j.bcp.2025.116797","url":null,"abstract":"<div><div>Neurological diseases, including both acute injuries and chronic neurodegenerative disorders, represent major contributors to morbidity and mortality worldwide. Chronic neurodegenerative diseases, such as Alzheimer’s disease (AD) and Parkinson’s disease (PD), which require long-term management, present significant challenges in the search for neuroprotective agents with reduced adverse effects and enhanced therapeutic efficacy. Sulforaphane (SFN), a bioactive compound found in cruciferous vegetables like broccoli and cauliflower, has garnered considerable attention for its potent neuroprotective properties and overall health benefits. Marketed primarily as a dietary supplement, SFN has shown a variety of biological activities and therapeutic potential in neurological diseases. Recent surging studies including ours have highlighted its ability to impede the progression of AD, PD, and cerebral ischemia by fostering neurogenesis and inhibiting apoptosis, oxidative stress, and neuroinflammation. This review aims to summarize the latest research on SFN, exploring its advanced therapeutic potential and underlying mechanisms in various neurological diseases, offering a comprehensive overview for researchers focused on neurological pathogenesis and drug development in neuroprotection.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"233 ","pages":"Article 116797"},"PeriodicalIF":5.3,"publicationDate":"2025-02-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143390026","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

Glutamine transporter inhibitor enhances the sensitivity of NSCLC to trametinib through GSDME-dependent pyroptosis

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2025-02-07 DOI: 10.1016/j.bcp.2025.116796

Qingxia Liu , Jinxia Hu , Xinzhen Li , Haiwang Gao , Dexin Kong , Meihua Jin

Trametinib, an inhibitor of mitogen-activated extracellular signal-regulated kinases 1/2 (MEK1/2), is used to treat BRAF^V600E/K melanoma and non-small-cell lung cancer (NSCLC). Mutant Kirsten rat sarcoma viral oncogene homolog (KRAS) promotes glutamine utilization, therefore, in the present study we investigated the anti-cancer effects of trametinib in combination with V-9302, a glutamine transporter inhibitor, in NSCLC with KRAS mutations. Trametinib in combination with V-9302 exhibited a potent synergistic antitumor effect, inducing cell cycle arrest and pyroptosis. Mechanistically, combination treatment triggered caspase-3 activation and gasdermin E (GSDME) cleavage, as well as elevated lactate dehydrogenase (LDH) and IL-1β levels. Meanwhile, combination treatment reduced cyclin D1 and p-Rb levels and increased p27 expression. Moreover, this combination increased forkhead box class O3a (FOXO3a) levels and decreased forkhead box M1 (FOXM1) expression by regulating the phosphorylation of ERK, Akt, AMPK, and c-Jun N-terminal kinase (JNK). Trametinib in combination with V-9302 increased reactive oxygen species (ROS) generation and reduced glutathione (GSH) synthesis and ATP levels. Furthermore, V-9302 in combination with trametinib inhibited the trametinib-induced autophagy, thereby enhancing pyroptosis in cancer cells. In vivo, the co-administration of trametinib and V-9302 remarkably inhibited tumor growth in a xenograft mouse model compared to each drug alone. Taken together, the combination of trametinib and V-9302 resulted in increased pyroptosis and cell cycle arrest compared to each single agent through regulation of the FOXO3a/FOXM1 axis and autophagy and significantly enhanced antitumor efficacy in vivo. Our results suggest a potential new therapeutic strategy for KRAS-mutant NSCLC using trametinib in combination with glutamine restriction.

{"title":"Glutamine transporter inhibitor enhances the sensitivity of NSCLC to trametinib through GSDME-dependent pyroptosis","authors":"Qingxia Liu , Jinxia Hu , Xinzhen Li , Haiwang Gao , Dexin Kong , Meihua Jin","doi":"10.1016/j.bcp.2025.116796","DOIUrl":"10.1016/j.bcp.2025.116796","url":null,"abstract":"<div><div>Trametinib, an inhibitor of mitogen-activated extracellular signal-regulated kinases 1/2 (MEK1/2), is used to treat <em>BRAF</em><sup>V600E/K</sup> melanoma and non-small-cell lung cancer (NSCLC). Mutant <em>Kirsten rat sarcoma viral oncogene homolog</em> (KRAS) promotes glutamine utilization, therefore, in the present study we investigated the anti-cancer effects of trametinib in combination with V-9302, a glutamine transporter inhibitor, in NSCLC with <em>KRAS</em> mutations. Trametinib in combination with V-9302 exhibited a potent synergistic antitumor effect, inducing cell cycle arrest and pyroptosis. Mechanistically, combination treatment triggered caspase-3 activation and gasdermin E (GSDME) cleavage, as well as elevated lactate dehydrogenase (LDH) and IL-1β levels. Meanwhile, combination treatment reduced cyclin D1 and p-Rb levels and increased p27 expression. Moreover, this combination increased forkhead box class O3a (FOXO3a) levels and decreased forkhead box M1 (FOXM1) expression by regulating the phosphorylation of ERK, Akt, AMPK, and c-Jun N-terminal kinase (JNK). Trametinib in combination with V-9302 increased reactive oxygen species (ROS) generation and reduced glutathione (GSH) synthesis and ATP levels. Furthermore, V-9302 in combination with trametinib inhibited the trametinib-induced autophagy, thereby enhancing pyroptosis in cancer cells. <em>In vivo</em>, the co-administration of trametinib and V-9302 remarkably inhibited tumor growth in a xenograft mouse model compared to each drug alone. Taken together, the combination of trametinib and V-9302 resulted in increased pyroptosis and cell cycle arrest compared to each single agent through regulation of the FOXO3a/FOXM1 axis and autophagy and significantly enhanced antitumor efficacy <em>in vivo</em>. Our results suggest a potential new therapeutic strategy for <em>KRAS</em>-mutant NSCLC using trametinib in combination with glutamine restriction.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"233 ","pages":"Article 116796"},"PeriodicalIF":5.3,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143381575","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

Linoleic acid metabolism is implicated in the anti-obesity effects of actein in C57BL/6 mice

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2025-02-06 DOI: 10.1016/j.bcp.2025.116793

Juan Chen , Jing-jing Yuan , Li-na Huang , Qiang-qiang Shi , Xian Zhang , Ming-hua Qiu , Jian Liu

Natural products are known to be a rich source of potential compounds for metabolic diseases. In this study, we aim to identify the lead compounds with anti-adipogenic and anti-obesity effects in Cimicifuga foetida L. (CF). Five high-content chemicals from ethyl acetate extract of CF (ECF) were isolated to investigate their effects on adipogenesis in 3T3-L1 preadipocytes. Actein is identified to possess substantial anti-adipogenic activity in 3T3-L1 adipocytes, which exerts its anti-adipogenic effect throughout the entire adipocyte differentiation stages. Dietary actein ameliorates diet-induced obesity, improves the disturbed serum lipid levels, and enhances white fat browning in diet-induced obese mice. Metabolomic analysis using urine and serum samples from mice revealed that actein treatment reverses the dysregulation of γ-linolenic acid and lecithin in obese mice, thus ameliorating the disturbance of linoleic acid metabolism induced by high-fat diet, suggesting that actein can be used as a lead compound with the potential to develop new therapies for obesity and related metabolic disorders.

{"title":"Linoleic acid metabolism is implicated in the anti-obesity effects of actein in C57BL/6 mice","authors":"Juan Chen , Jing-jing Yuan , Li-na Huang , Qiang-qiang Shi , Xian Zhang , Ming-hua Qiu , Jian Liu","doi":"10.1016/j.bcp.2025.116793","DOIUrl":"10.1016/j.bcp.2025.116793","url":null,"abstract":"<div><div>Natural products are known to be a rich source of potential compounds for metabolic diseases. In this study, we aim to identify the lead compounds with anti-adipogenic and anti-obesity effects in <em>Cimicifuga foetida</em> L. (CF). Five high-content chemicals from ethyl acetate extract of CF (ECF) were isolated to investigate their effects on adipogenesis in 3T3-L1 preadipocytes. Actein is identified to possess substantial anti-adipogenic activity in 3T3-L1 adipocytes, which exerts its anti-adipogenic effect throughout the entire adipocyte differentiation stages. Dietary actein ameliorates diet-induced obesity, improves the disturbed serum lipid levels, and enhances white fat browning in diet-induced obese mice. Metabolomic analysis using urine and serum samples from mice revealed that actein treatment reverses the dysregulation of γ-linolenic acid and lecithin in obese mice, thus ameliorating the disturbance of linoleic acid metabolism induced by high-fat diet, suggesting that actein can be used as a lead compound with the potential to develop new therapies for obesity and related metabolic disorders.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"233 ","pages":"Article 116793"},"PeriodicalIF":5.3,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143373472","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

Investigation of the role and mechanism of dapagliflozin in mitigating renal injury in rats afflicted with diabetic kidney disease

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2025-02-06 DOI: 10.1016/j.bcp.2025.116795

Hao Wang , Xiuli Zhao , Xiao Wang , Yi Gong , Songping Li , Yanting Gu , Bosai He , Jiahong Wang

The etiology of diabetic kidney disease (DKD) is multifaceted, with hyperglycemia, inflammation, oxidative stress, and fibrosis recognized as key contributors to renal damage in individuals with DKD. Clinical evidence suggests that dapagliflozin not only reduces blood glucose levels but also demonstrates superior efficacy in ameliorating pancreatic islet cell injury while preserving cardiac and renal function. However, the precise underlying mechanism has been poorly elucidated in the current literature. In this study, a DKD rat model was established by administering a single intraperitoneal injection of streptozotocin (STZ) to investigate the renoprotective properties of dapagliflozin and its underlying mechanisms. The findings of this study indicate that dapagliflozin enhanced pancreatic islet cell function, lowered blood glucose levels, and significantly reduced biochemical markers and renal pathological damage in DKD rats. Dapagliflozin also exerted anti-inflammatory, antioxidant, and antifibrotic effects by inhibiting the activation of the p38 MAPK/NF-κB pathway, enhancing the activity of the SIRT1/Akt/GSK-3β/Nrf2/HO-1 signaling pathway, and inhibiting the over-activation of the TGF-β1/Smad2/3 signaling pathway. These effects led to a reduction in renal injury and improved renal function in DKD rats.

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引用次数: 0

Role of OX/OXR cascade in insomnia and sleep deprivation link Alzheimer’s disease and Parkinson’s disease: Therapeutic avenue of Dual OXR Antagonist (DORA)

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2025-02-05 DOI: 10.1016/j.bcp.2025.116794

Siva Prasad Panda , Suman Sinha , Adarsh Kesharwani , Sanjesh Kumar , Mansi Singh , Gana Manjusha Kondepudi , Abhishek Samuel , Ashwani Kumar Sanghi , Shailendra Thapliyal , Kundan Kumar Chaubey , Ajay Guru

Sleep plays a role in the elimination of neurotoxic metabolites that are accumulated in the waking brain as a result of neuronal activity. Long-term insomnia and sleep deprivation are associated with oxidative stress, neuroinflammation, amyloid beta (Aβ) deposition, and Lewy body formation, which are known to increase the risk of mild cognitive impairment (MCI) and dementia. Orexin A (OXA) and orexin B (OXB), two neuropeptides produced in the lateral hypothalamus, are known to influence the sleep-wake cycle and the stress responses through their interactions with OX receptor 1 (OX1R) and OX receptor 2 (OX2R), respectively. OX/OXR cascade demonstrates intricate neuroprotective and anti-inflammatory effects by inhibiting nuclear factor-kappa B (NF-kB) and PLC/Ca²⁺ pathway activation. OX1R binds OXA more strongly than OXB by one-order ratio, whereas OX2R binds both OXA and OXB with equal strengths. Overexpression of OXs in individuals experiences sleep deprivation, circadian rhythm disturbances, insomnia-associated MCI, Parkinson’s disease (PD), and Alzheimer’s disease (AD). Many dual OXR antagonists (DORAs) have been effective in their clinical studies, with suvorexant and daridorexant receiving FDA clearance for insomnia therapy in 2014 and 2022 respectively. The results of clinical studies suggested that there is a new pharmaceutical option for treating insomnia and the sleep deprivation-AD/PD relationship by targeting the OXR system. DORAs treatment reduces Aβ deposition in the brain and improves synaptic plasticity and circadian expression. This review indicates the link between sleep disorders and MCI, DORAs are an appropriate medication category for treating insomnia, and sleep deprivation links AD and PD.

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引用次数: 0

Cordycepin alleviates metabolic dysfunction-associated liver disease by restoring mitochondrial homeostasis and reducing oxidative stress via Parkin-mediated mitophagy 虫草素通过恢复线粒体稳态和通过帕金森介导的线粒体自噬减少氧化应激来减轻代谢功能障碍相关的肝脏疾病。

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology

Pub Date : 2025-02-01 DOI: 10.1016/j.bcp.2025.116750

Hai-Ying Tian , Dao-Jiang Yu , Teng Xie , Meng-Xia Xu , Yu-Hao Wang , Xi-Lu Sun , Xin-Meng Zhou , Ying-Xuan Han , Qing-Qing Liao , Yu-Jie Zhao , Juan Liao , Mohamed El-Kassas , Xiao-Dong Sun , Yuan-Yuan Zhang

The prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) keeps rising with only a few drugs available. The present study aims to investigate the effects and mechanisms of cordycepin on MASLD. Male C57BL/6 mice were induced with a 90-day high-fat diet (HFD) and intraperitoneal administration with streptozotocin to establish MASLD murine model. Then they were randomly divided into the HFD and cordycepin groups (15, 30, 45 mg/kg). Cordycepin was orally given for 30 days. Serum total cholesterol (TC), triacylglyceride (TG), and aspartate aminotransferase (AST) levels were measured. L02 cells were induced by oleate acid (OA) or lipopolysaccharides (LPS), and treated with cordycepin or combined with inhibitors including chloroquine, 3-Methyladenine, and compound C. Atg7 and Parkin were knocked down in L02 cells using siRNA. Oil Red O and Nile Red staining for measuring lipid deposition. Mitochondria were visualized by transfection with mCherry-TOMM20-N10. Quantitative real-time PCR, Western blotting, and immunofluorescence staining were used to determine expressions of key molecules in inflammation, lipid metabolism, mitochondria homeostasis, and oxidative stress. Cordycepin significantly mitigated lipid deposition and ballooning in the livers of MASLD mice. Serum TC, TG, and AST levels were decreased by cordycepin. Cordycepin alleviated OA-induced lipid deposition and LPS-induced inflammation in L02 cells, attenuated oxidative stress, promoted autophagy, and maintained the autophagic flux by activating AMP-activated protein kinase (AMPK). Cordycepin reduced the accumulation of impaired mitochondria by enhancing Parkin-dependent mitophagy and promoting mitochondrial biogenesis. Cordycepin alleviates MASLD by restoring mitochondrial homeostasis and reducing oxidative stress via activating the Parkin-mediated mitophagy.

代谢功能障碍相关脂肪变性肝病（MASLD）的患病率持续上升，只有少数药物可用。本研究旨在探讨虫草素对MASLD的作用及其机制。采用高脂饮食（HFD）和腹腔注射链脲佐菌素诱导雄性C57BL/6小鼠建立MASLD小鼠模型。然后随机分为HFD组和虫草素组（15、30、45 mg/kg）。口服虫草素30 d。测定血清总胆固醇（TC）、甘油三酯（TG）、天冬氨酸转氨酶（AST）水平。用油酸（OA）或脂多糖（LPS）诱导L02细胞，并用虫草素或与氯喹、3-甲基腺嘌呤和化合物c等抑制剂联合处理。油红O和尼罗河红染色测定脂质沉积。转染mCherry-TOMM20-N10后，线粒体可见。采用实时荧光定量PCR、Western blotting和免疫荧光染色检测炎症、脂质代谢、线粒体稳态和氧化应激中关键分子的表达。冬虫夏草素可显著减轻MASLD小鼠肝脏中的脂质沉积和水肿。虫草素降低血清TC、TG和AST水平。冬虫夏草素可减轻oa诱导的脂质沉积和lps诱导的L02细胞炎症，减轻氧化应激，促进自噬，并通过激活amp活化蛋白激酶（AMPK）维持自噬通量。虫草素通过增强帕金森依赖性线粒体自噬和促进线粒体生物发生来减少受损线粒体的积累。虫草素通过激活帕金森介导的线粒体自噬来恢复线粒体稳态和减少氧化应激，从而减轻MASLD。

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引用次数: 0