Pub Date : 2024-10-18DOI: 10.1016/j.bcp.2024.116580
Chen Xiubing , Li Huazhen , Wei Xueyan , Ning Jing , Li Qing , Jiang Haixing , Qin Shanyu , Lu Jiefu
Serpin peptidase inhibitor clade A member 1 (SERPINA1) is highly expressed in a variety of solid tumors. However, its role in pancreatic ductal adenocarcinoma (PDAC) remains unclear. Here, we report evidence that SERPINA1 acts as a potent oncogene to drive its extremely malignant character. We found that elevated SERPINA1 expression in primary tumors was associated with lymph node metastasis and shorter survival in PDAC patients. Mechanistic investigations revealed that overexpression of SERPINA1 induced nuclear translocation and phosphorylation of the p65 subunit through the PI3K/Akt/NF-κB pathway, thereby promoting the invasion, metastasis and proliferation of PDAC cells in vitro and in vivo. Conversely, the knockdown of SERPINA1 attenuated this signaling pathway and restored the phenotype of PDAC cells overexpressing SERPINA1. Overall, our study reveals that SERPINA1 affects the properties of PDAC through the PI3K/Akt/NF-κB pathway, and its activation confers the clinical features of epithelial-mesenchymal transition and proliferation in the disease.
{"title":"SERPINA1 promotes the invasion, metastasis, and proliferation of pancreatic ductal adenocarcinoma via the PI3K/Akt/NF-κB pathway","authors":"Chen Xiubing , Li Huazhen , Wei Xueyan , Ning Jing , Li Qing , Jiang Haixing , Qin Shanyu , Lu Jiefu","doi":"10.1016/j.bcp.2024.116580","DOIUrl":"10.1016/j.bcp.2024.116580","url":null,"abstract":"<div><div>Serpin peptidase inhibitor clade A member 1 (SERPINA1) is highly expressed in a variety of solid tumors. However, its role in pancreatic ductal adenocarcinoma (PDAC) remains unclear. Here, we report evidence that SERPINA1 acts as a potent oncogene to drive its extremely malignant character. We found that elevated SERPINA1 expression in primary tumors was associated with lymph node metastasis and shorter survival in PDAC patients. Mechanistic investigations revealed that overexpression of SERPINA1 induced nuclear translocation and phosphorylation of the p65 subunit through the PI3K/Akt/NF-κB pathway, thereby promoting the invasion, metastasis and proliferation of PDAC cells <em>in vitro</em> and <em>in vivo</em>. Conversely, the knockdown of SERPINA1 attenuated this signaling pathway and restored the phenotype of PDAC cells overexpressing SERPINA1. Overall, our study reveals that SERPINA1 affects the properties of PDAC through the PI3K/Akt/NF-κB pathway, and its activation confers the clinical features of epithelial-mesenchymal transition and proliferation in the disease.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"230 ","pages":"Article 116580"},"PeriodicalIF":5.3,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142457057","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}
Pub Date : 2024-10-16DOI: 10.1016/j.bcp.2024.116571
Sandra Moraña-Fernández , Xocas Vázquez-Abuín , Alana Aragón-Herrera , Laura Anido-Varela , Javier García-Seara , Óscar Otero-García , Diego Rodríguez-Penas , Manuel Campos-Toimil , Manuel Otero-Santiago , Alexandre Rodrigues , Alexandre Gonçalves , Juliana Pereira Morais , Inês N. Alves , Cláudia Sousa-Mendes , Inês Falcão-Pires , José Ramón González-Juanatey , Sandra Feijóo-Bandín , Francisca Lago
The promising results obtained in the PARADIGM-HF trial prompted the approval of sacubitril/valsartan (SAC/VAL) as a first-in-class treatment for heart failure with reduced ejection fraction (HFrEF) patients. The effect of SAC/VAL treatment was also studied in patients with heart failure with preserved ejection fraction (HFpEF) and, although improvements in New York Heart Association (NYHA) class, HF hospitalizations, and cardiovascular deaths were observed, these results were not so promising. However, the demand for HFpEF therapies led to the approval of SAC/VAL as an alternative treatment, although further studies are needed. We aimed to elucidate the effects of a 9-week SAC/VAL treatment in cardiac function and metabolism using a preclinical model of HFpEF, the Zucker Fatty and Spontaneously Hypertensive (ZSF1) rats. We found that SAC/VAL significantly improved diastolic function parameters and modulated respiratory quotient during exercise. Ex-vivo studies showed that SAC/VAL treatment significantly decreased heart, liver, spleen, and visceral fat weights; cardiac hypertrophy and percentage of fibrosis; lipid infiltration in liver and circulating levels of cholesterol and sodium. Moreover, SAC/VAL reduced glycerophospholipids, cholesterol, and cholesteryl esters while increasing triglyceride levels in cardiac tissue. In conclusion, SAC/VAL treatment improved diastolic and hepatic function, respiratory metabolism, reduced hypercholesterolemia and cardiac fibrosis and hypertrophy, and was able to modulate cardiac metabolic profile. Our findings might provide further insight into the therapeutic benefits of SAC/VAL treatment in obese patients with HFpEF.
{"title":"Cardiometabolic effects of sacubitril/valsartan in a rat model of heart failure with preserved ejection fraction","authors":"Sandra Moraña-Fernández , Xocas Vázquez-Abuín , Alana Aragón-Herrera , Laura Anido-Varela , Javier García-Seara , Óscar Otero-García , Diego Rodríguez-Penas , Manuel Campos-Toimil , Manuel Otero-Santiago , Alexandre Rodrigues , Alexandre Gonçalves , Juliana Pereira Morais , Inês N. Alves , Cláudia Sousa-Mendes , Inês Falcão-Pires , José Ramón González-Juanatey , Sandra Feijóo-Bandín , Francisca Lago","doi":"10.1016/j.bcp.2024.116571","DOIUrl":"10.1016/j.bcp.2024.116571","url":null,"abstract":"<div><div>The promising results obtained in the PARADIGM-HF trial prompted the approval of sacubitril/valsartan (SAC/VAL) as a first-in-class treatment for heart failure with reduced ejection fraction (HFrEF) patients. The effect of SAC/VAL treatment was also studied in patients with heart failure with preserved ejection fraction (HFpEF) and, although improvements in New York Heart Association (NYHA) class, HF hospitalizations, and cardiovascular deaths were observed, these results were not so promising. However, the demand for HFpEF therapies led to the approval of SAC/VAL as an alternative treatment, although further studies are needed. We aimed to elucidate the effects of a 9-week SAC/VAL treatment in cardiac function and metabolism using a preclinical model of HFpEF, the Zucker Fatty and Spontaneously Hypertensive (ZSF1) rats. We found that SAC/VAL significantly improved diastolic function parameters and modulated respiratory quotient during exercise. <em>Ex-vivo</em> studies showed that SAC/VAL treatment significantly decreased heart, liver, spleen, and visceral fat weights; cardiac hypertrophy and percentage of fibrosis; lipid infiltration in liver and circulating levels of cholesterol and sodium. Moreover, SAC/VAL reduced glycerophospholipids, cholesterol, and cholesteryl esters while increasing triglyceride levels in cardiac tissue. In conclusion, SAC/VAL treatment improved diastolic and hepatic function, respiratory metabolism, reduced hypercholesterolemia and cardiac fibrosis and hypertrophy, and was able to modulate cardiac metabolic profile. Our findings might provide further insight into the therapeutic benefits of SAC/VAL treatment in obese patients with HFpEF.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"230 ","pages":"Article 116571"},"PeriodicalIF":5.3,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142457059","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 : 2024-10-16DOI: 10.1016/j.bcp.2024.116576
Lili Song , Huimin Liu , Weiyu Yang , Hongqing Yin , Jiayi Wang , Maojuan Guo , Zhen Yang
N6-methyladenosine (m6A) is a prevalent mRNA modification in eukaryotic cells, characterized by its reversible nature. YTH structural domain family protein 2 (YTHDF2), a key reader of m6A, plays a crucial role in identifying and binding m6A-containing RNAs, thereby influencing RNA metabolism through various functional mechanisms. The upstream and downstream targets of YTHDF2 are critical in the pathogenesis of various central nervous system (CNS) diseases, affecting disease development by regulating signaling pathways and gene expression. This paper provides an overview of current research on the role of YTHDF2 in CNS diseases and investigates the regulatory mechanisms by which YTHDF2 influences the development of these conditions. This exploration aims to improve understanding of disease pathogenesis and offer novel insights for the targeted prevention and treatment of neurological disorders.
{"title":"Biological functions of the m6A reader YTHDF2 and its role in central nervous system disorders","authors":"Lili Song , Huimin Liu , Weiyu Yang , Hongqing Yin , Jiayi Wang , Maojuan Guo , Zhen Yang","doi":"10.1016/j.bcp.2024.116576","DOIUrl":"10.1016/j.bcp.2024.116576","url":null,"abstract":"<div><div>N6-methyladenosine (m6A) is a prevalent mRNA modification in eukaryotic cells, characterized by its reversible nature. YTH structural domain family protein 2 (YTHDF2), a key reader of m6A, plays a crucial role in identifying and binding m6A-containing RNAs, thereby influencing RNA metabolism through various functional mechanisms. The upstream and downstream targets of YTHDF2 are critical in the pathogenesis of various central nervous system (CNS) diseases, affecting disease development by regulating signaling pathways and gene expression. This paper provides an overview of current research on the role of YTHDF2 in CNS diseases and investigates the regulatory mechanisms by which YTHDF2 influences the development of these conditions. This exploration aims to improve understanding of disease pathogenesis and offer novel insights for the targeted prevention and treatment of neurological disorders.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"230 ","pages":"Article 116576"},"PeriodicalIF":5.3,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142457058","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 : 2024-10-12DOI: 10.1016/j.bcp.2024.116570
Wei-Yu Lin , Yu-Hsuan Cheng , Pei-Yu Liu , Shih-Ping Hsu , San-Chi Lin , Chiang-Ting Chien
Glomerulonephritis (GN) is one of the main causes of end stage renal disease and requires an effective treatment for inhibiting GN. Renal nerves through efferent (RENA) and afferent (RANA) innervation to glomeruli regulate the glomerular function. We delineated the role of RENA and RANA on anti-Thy1.1-induced GN. Female Wistar rats were divided into Control, Thy1.1 plus anti-Thy1.1, bilaterally renal nerve denervation (DNX) plus anti-Thy1.1, and topical capsaicin to bilateral renal nerves for selective ablation of RANA (DNAX) plus anti-Thy1.1. We examined RANA and RENA response to anti-Thy1.1 and compared the effect of DNX or DNAX on urinary oxidative stress, renal gp91, tyrosine hydroxylase (TH), calcitonin gene-related peptide (CGRP), apoptosis, autophagy, ferroptosis, antioxidant enzymes, endoplasmic reticulum (ER) stress and inflammation by western blot. Anti-Thy1.1 significantly enhanced RENA, but did not affect RANA. DNX significantly decreased TH and CGRP expression, whereas DNAX only reduced CGRP expression. Anti-Thy1.1 significantly increased glomerulosclerosis injury, urinary protein, electron paramagnetic resonance signals of alpha-(4-pyridyl-N-oxide)-N-tert-butylnitrone adducts, 8-isoprostane and nitrotyrosine levels, NADPH oxidase gp91phox (gp91), macrophage/monocyte (ED-1), GRP-78, Beclin-1/LC3-II, Bax/caspase-3/poly(ADP-ribose) polymerase expression, inflammatory cytokines levels and decreased renal Copper/Zinc superoxide dismutase, Cystine/glutamate transporter (xCT) and Glutathione peroxidase 4 (GPX4) expression vs. Control. The enhanced oxidative parameters or reduced antioxidant defense by anti-Thy1.1 were significantly attenuated by DNX but not DNAX. Additionally, oral ß1-adrenoceptor antagonist-Carvedilol at an early stage reduced anti-Thy1.1 increased proteinuria level and oxidative parameters. Our data suggest that DNX and ß1-adrenoceptor antagonist-Carvedilol efficiently attenuate oxidative stress, inflammation, ER stress, autophagy, ferroptosis and apoptosis in GN.
{"title":"Carvedilol through ß1-Adrenoceptor blockade ameliorates glomerulonephritis via inhibition of oxidative stress, apoptosis, autophagy, ferroptosis, endoplasmic reticulum stress and inflammation","authors":"Wei-Yu Lin , Yu-Hsuan Cheng , Pei-Yu Liu , Shih-Ping Hsu , San-Chi Lin , Chiang-Ting Chien","doi":"10.1016/j.bcp.2024.116570","DOIUrl":"10.1016/j.bcp.2024.116570","url":null,"abstract":"<div><div>Glomerulonephritis (GN) is one of the main causes of end stage renal disease and requires an effective treatment for inhibiting GN. Renal nerves through efferent (RENA) and afferent (RANA) innervation to glomeruli regulate the glomerular function. We delineated the role of RENA and RANA on anti-Thy1.1-induced GN. Female Wistar rats were divided into Control, Thy1.1 plus anti-Thy1.1, bilaterally renal nerve denervation (DNX) plus anti-Thy1.1, and topical capsaicin to bilateral renal nerves for selective ablation of RANA (DNAX) plus anti-Thy1.1. We examined RANA and RENA response to anti-Thy1.1 and compared the effect of DNX or DNAX on urinary oxidative stress, renal gp91, tyrosine hydroxylase (TH), calcitonin gene-related peptide (CGRP), apoptosis, autophagy, ferroptosis, antioxidant enzymes, endoplasmic reticulum (ER) stress and inflammation by western blot. Anti-Thy1.1 significantly enhanced RENA, but did not affect RANA. DNX significantly decreased TH and CGRP expression, whereas DNAX only reduced CGRP expression. Anti-Thy1.1 significantly increased glomerulosclerosis injury, urinary protein, electron paramagnetic resonance signals of alpha-(4-pyridyl-N-oxide)-N-<em>tert</em>-butylnitrone adducts, 8-isoprostane and nitrotyrosine levels, NADPH oxidase gp91phox (gp91), macrophage/monocyte (ED-1), GRP-78, Beclin-1/LC3-II, Bax/caspase-3/poly(ADP-ribose) polymerase expression, inflammatory cytokines levels and decreased renal Copper/Zinc superoxide dismutase, Cystine/glutamate transporter (xCT) and Glutathione peroxidase 4 (GPX4) expression vs. Control. The enhanced oxidative parameters or reduced antioxidant defense by anti-Thy1.1 were significantly attenuated by DNX but not DNAX. Additionally, oral ß1-adrenoceptor antagonist-Carvedilol at an early stage reduced anti-Thy1.1 increased proteinuria level and oxidative parameters. Our data suggest that DNX and ß1-adrenoceptor antagonist-Carvedilol efficiently attenuate oxidative stress, inflammation, ER stress, autophagy, ferroptosis and apoptosis in GN.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"230 ","pages":"Article 116570"},"PeriodicalIF":5.3,"publicationDate":"2024-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142457054","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 : 2024-10-11DOI: 10.1016/j.bcp.2024.116574
Xudong He , Jinye Shi , Lina Bu , Shuting Zhou , Kaixuan Wu , Gui Liang , Xiaotao Xu , Aizhong Wang
Acute lung injury (ALI) caused by fat embolism syndrome (FES) is a disease with high mortality. This study aimed to explore the roles of ursodeoxycholic acid (UDCA) in FES-induced ALI and its underlying mechanisms. An ALI mouse model was established by allografting mouse perinephric fat. For in vitro experiments, human pulmonary microvascular endothelial cells (HPMEC) were treated with FFAs. The effects of UDCA on the expression of farnesoid X receptor (FXR) and the inflammatory response in endothelial cells were investigated. UDCA significantly inhibited the inflammatory response and the expression of proinflammatory markers during FES-induced ALI. UDCA markedly decreased TNF-α and IL-1β expression in vitro. UDCA administration markedly upregulated FXR expression and significantly reduced the phosphorylation of p38 MAPK and NF-κB p65. Knock down FXR expression decreased the effect of UDCA in vivo. Furthermore, knock down FXR expression and overexpressing FXR increased and decreased the inflammatory response, respectively, in vitro. Moreover, administration of a p38 MAPK activator reversed the anti-inflammatory effect of FXR overexpression. UDCA ameliorated inflammation during FES-induced ALI by suppressing p38 MAPK/NF-κB signalling and activating FXR. These findings provide new evidence for the potential of UDCA for FES-induced ALI treatment.
{"title":"Ursodeoxycholic acid alleviates fat embolism syndrome-induced acute lung injury by inhibiting the p38 MAPK/NF-κB signalling pathway through FXR","authors":"Xudong He , Jinye Shi , Lina Bu , Shuting Zhou , Kaixuan Wu , Gui Liang , Xiaotao Xu , Aizhong Wang","doi":"10.1016/j.bcp.2024.116574","DOIUrl":"10.1016/j.bcp.2024.116574","url":null,"abstract":"<div><div>Acute lung injury (ALI) caused by fat embolism syndrome (FES) is a disease with high mortality. This study aimed to explore the roles of ursodeoxycholic acid (UDCA) in FES-induced ALI and its underlying mechanisms. An ALI mouse model was established by allografting mouse perinephric fat. For in vitro experiments, human pulmonary microvascular endothelial cells (HPMEC) were treated with FFAs. The effects of UDCA on the expression of farnesoid X receptor (FXR) and the inflammatory response in endothelial cells were investigated. UDCA significantly inhibited the inflammatory response and the expression of proinflammatory markers during FES-induced ALI. UDCA markedly decreased TNF-α and IL-1β expression in vitro. UDCA administration markedly upregulated FXR expression and significantly reduced the phosphorylation of p38 MAPK and NF-κB p65. Knock down FXR expression decreased the effect of UDCA in vivo. Furthermore, knock down FXR expression and overexpressing FXR increased and decreased the inflammatory response, respectively, in vitro. Moreover, administration of a p38 MAPK activator reversed the anti-inflammatory effect of FXR overexpression. UDCA ameliorated inflammation during FES-induced ALI by suppressing p38 MAPK/NF-κB signalling and activating FXR. These findings provide new evidence for the potential of UDCA for FES-induced ALI treatment.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"230 ","pages":"Article 116574"},"PeriodicalIF":5.3,"publicationDate":"2024-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142457061","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 : 2024-10-11DOI: 10.1016/j.bcp.2024.116573
Nhung Thi Hong Van , Joo Hyun Nam
The KCa3.1 channel (also known as the KCNN4, IK1, or SK4 channel) is an intermediate-conductance calcium-activated potassium channel that regulates the membrane potential and maintains calcium homeostasis. Recently, KCa3.1 channels have attracted increasing attention because of their diverse roles in various types of cancers. In cancer cells, KCa3.1 channels regulate key processes, including cell proliferation, cell cycle, migration, invasion, tumor microenvironments, and therapy resistance. In addition, abnormal KCa3.1 expression in cancers is utilized to distinguish between tumor and normal tissues, classify cancer stages, and predict patient survival outcomes. This review comprehensively examines the current understanding of the contribution of KCa3.1 channels to tumor formation, metastasis, and its mechanisms. We evaluated the potential of KCa3.1 as a biomarker for cancer diagnosis and prognosis. Finally, we discuss the advances and challenges of applying KCa3.1 modulators in cancer treatment and propose approaches to overcome these obstacles. In summary, this review highlights the importance of this ion channel as a potent therapeutic target and prognostic biomarker of cancer.
{"title":"Intermediate conductance calcium-activated potassium channel (KCa3.1) in cancer: Emerging roles and therapeutic potentials","authors":"Nhung Thi Hong Van , Joo Hyun Nam","doi":"10.1016/j.bcp.2024.116573","DOIUrl":"10.1016/j.bcp.2024.116573","url":null,"abstract":"<div><div>The KCa3.1 channel (also known as the KCNN4, IK1, or SK4 channel) is an intermediate-conductance calcium-activated potassium channel that regulates the membrane potential and maintains calcium homeostasis. Recently, KCa3.1 channels have attracted increasing attention because of their diverse roles in various types of cancers. In cancer cells, KCa3.1 channels regulate key processes, including cell proliferation, cell cycle, migration, invasion, tumor microenvironments, and therapy resistance. In addition, abnormal KCa3.1 expression in cancers is utilized to distinguish between tumor and normal tissues, classify cancer stages, and predict patient survival outcomes. This review comprehensively examines the current understanding of the contribution of KCa3.1 channels to tumor formation, metastasis, and its mechanisms. We evaluated the potential of KCa3.1 as a biomarker for cancer diagnosis and prognosis. Finally, we discuss the advances and challenges of applying KCa3.1 modulators in cancer treatment and propose approaches to overcome these obstacles. In summary, this review highlights the importance of this ion channel as a potent therapeutic target and prognostic biomarker of cancer.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"230 ","pages":"Article 116573"},"PeriodicalIF":5.3,"publicationDate":"2024-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142438351","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 : 2024-10-11DOI: 10.1016/j.bcp.2024.116575
Zhi Yang , Hao Li , Hong-yan Wu, Yi Zhou, Jing-xue Du, Zhang-xue Hu
Hyperuricemic nephropathy (HN) is characterized by increased serum uric acid levels that incite renal inflammation. While omega-3 polyunsaturated fatty acids (PUFAs) are known for their anti-inflammatory properties, their impact on HN remains unclear. This study explored the effects of omega-3 PUFAs, specifically docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), on HN. Using a mouse model induced by adenine and potassium oxonate, we treated HN mice with DHA, EPA, or both for four weeks. The results showed that omega-3 PUFAs significantly reduced serum uric acid levels and improved kidney function, with DHA, EPA, and their combination showing similar efficacy. Transcriptome sequencing and further analysis revealed that these fatty acids alleviate renal pyroptosis by reducing key markers such as NOD-like receptor pyrin containing 3 (NLRP3), cleaved gasdermin-D, caspase-1, and interleukin-1β. To further investigate the underlying mechanism, we focused on G-protein coupled receptor 120 (GPR120), a receptor activated by DHA. The use of a GPR120 antagonist (AH7614) partially blocked DHA’s effects, while the agonist (TUG891) mimicked its anti-pyroptotic actions. Co-immunoprecipitation assays showed that DHA activates GPR120, leading to its internalization and interaction with β-arrestin2, ultimately inhibiting NLRP3 inflammasome formation and reducing inflammation. Overall, omega-3 PUFAs, particularly through GPR120 activation, appear to protect against renal inflammation in HN by modulating the NLRP3/caspase-1/GSDMD pathway.
{"title":"Omega-3 polyunsaturated fatty acids alleviate hyperuricemic nephropathy by inhibiting renal pyroptosis through GPR120","authors":"Zhi Yang , Hao Li , Hong-yan Wu, Yi Zhou, Jing-xue Du, Zhang-xue Hu","doi":"10.1016/j.bcp.2024.116575","DOIUrl":"10.1016/j.bcp.2024.116575","url":null,"abstract":"<div><div>Hyperuricemic nephropathy (HN) is characterized by increased serum uric acid levels that incite renal inflammation. While omega-3 polyunsaturated fatty acids (PUFAs) are known for their anti-inflammatory properties, their impact on HN remains unclear. This study explored the effects of omega-3 PUFAs, specifically docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), on HN. Using a mouse model induced by adenine and potassium oxonate, we treated HN mice with DHA, EPA, or both for four weeks. The results showed that omega-3 PUFAs significantly reduced serum uric acid levels and improved kidney function, with DHA, EPA, and their combination showing similar efficacy. Transcriptome sequencing and further analysis revealed that these fatty acids alleviate renal pyroptosis by reducing key markers such as NOD-like receptor pyrin containing 3 (NLRP3), cleaved gasdermin-D, caspase-1, and interleukin-1β. To further investigate the underlying mechanism, we focused on G-protein coupled receptor 120 (GPR120), a receptor activated by DHA. The use of a GPR120 antagonist (AH7614) partially blocked DHA’s effects, while the agonist (TUG891) mimicked its anti-pyroptotic actions. Co-immunoprecipitation assays showed that DHA activates GPR120, leading to its internalization and interaction with β-arrestin2, ultimately inhibiting NLRP3 inflammasome formation and reducing inflammation. Overall, omega-3 PUFAs, particularly through GPR120 activation, appear to protect against renal inflammation in HN by modulating the NLRP3/caspase-1/GSDMD pathway.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"230 ","pages":"Article 116575"},"PeriodicalIF":5.3,"publicationDate":"2024-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142438352","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 : 2024-10-11DOI: 10.1016/j.bcp.2024.116572
Hanwen Chen , Shujun Xie , Yichen Zhou , Lin Chen , Jian Xu , Jianting Cai
Inflammasomes are cytosolic supramolecular complexes that play a key role in the innate immune response. Overactivation of NLR family pyrin domain containing 3 (NLRP3) inflammasome leads to multiple diseases. Post-translational modifications (PTMs) are essential modulators of inflammasomes especially in activation phase. Here we found that MEK1/2 kinase activity was indispensable in NLRP3 inflammasome activation both in vitro and in vivo. Inhibition of MEK1/2 resulted in reactive oxygen species (ROS) scavenging and ubiquitination of NLRP3, which further blocked NLRP3 inflammasome activation. These effects were independent of ERK1/2, which were classic downstream of MEK1/2. These investigations proposed a mechanism that MEK1/2 regulated inflammation via non-transcriptional regulation of NLRP3 inflammasome and might help better understanding the effects and side-effects of MEK inhibitors in clinical use.
{"title":"MEK1/2 promote ROS production and deubiquitinate NLRP3 independent of ERK1/2 during NLRP3 inflammasome activation","authors":"Hanwen Chen , Shujun Xie , Yichen Zhou , Lin Chen , Jian Xu , Jianting Cai","doi":"10.1016/j.bcp.2024.116572","DOIUrl":"10.1016/j.bcp.2024.116572","url":null,"abstract":"<div><div>Inflammasomes are cytosolic supramolecular complexes that play a key role in the innate immune response. Overactivation of NLR family pyrin domain containing 3 (NLRP3) inflammasome leads to multiple diseases. Post-translational modifications (PTMs) are essential modulators of inflammasomes especially in activation phase. Here we found that MEK1/2 kinase activity was indispensable in NLRP3 inflammasome activation both <em>in vitro</em> and <em>in vivo</em>. Inhibition of MEK1/2 resulted in reactive oxygen species (ROS) scavenging and ubiquitination of NLRP3, which further blocked NLRP3 inflammasome activation. These effects were independent of ERK1/2, which were classic downstream of MEK1/2. These investigations proposed a mechanism that MEK1/2 regulated inflammation via non-transcriptional regulation of NLRP3 inflammasome and might help better understanding the effects and side-effects of MEK inhibitors in clinical use.</div></div>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"230 ","pages":"Article 116572"},"PeriodicalIF":5.3,"publicationDate":"2024-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142441651","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 : 2024-10-10DOI: 10.1016/j.bcp.2024.116569
Kannapiran Ponraj , Kari A. Gaither , Dilip Kumar Singh , Nadezhda Davydova , Mengqi Zhao , Shaman Luo , Phillip Lazarus , Bhagwat Prasad , Dmitri R. Davydov
To explore functional interconnections between multiple P450 enzymes and their manifestation in alcohol-induced changes in drug metabolism, we implemented a high-throughput study of correlations between the composition of the P450 pool and the substrate saturation profiles (SSP) of amitriptyline and ketamine demethylation in a series of 23 individual human liver microsomes preparations from donors with a known history of alcohol consumption. The SSPs were approximated with linear combinations of three Michaelis-Menten equations with globally optimized KM (substrate affinity) values. This analysis revealed a strong correlation between the rate of ketamine metabolism and alcohol exposure. For both substrates, alcohol consumption caused a significant increase in the role of the low-affinity enzymes. The amplitudes of the kinetic components and the total rate were further analyzed for correlations with the abundance of 11 major P450 enzymes assessed by global proteomics. The maximal rate of metabolism of both substrates correlated with the abundance of CYP3A4, their predicted principal metabolizer. However, except for CYP2D6 and CYP2E1, responsible for the low-affinity metabolism of ketamine and amitriptyline, respectively, none of the other potent metabolizers of the drugs revealed a positive correlation. Instead, in the case of ketamine, we observed negative correlations with the abundances of CYP1A2, CYP2C9, and CYP3A5. For amitriptyline, the data suggest inhibitory effects of CYP1A2 and CYP2A6. Our results demonstrate the importance of functional interactions between multiple P450 species and their decisive role in the effects of alcohol exposure on drug metabolism.
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