Science Signaling最新文献_第10页

Blocking lipid synthesis induces DNA damage in prostate cancer and increases cell death caused by PARP inhibition 阻止脂质合成会诱发前列腺癌的 DNA 损伤，并增加 PARP 抑制造成的细胞死亡

IF 7.3 1区生物学

Science Signaling Pub Date : 2024-04-09 DOI: 10.1126/scisignal.adh1922

Caroline Fidalgo Ribeiro, Silvia Rodrigues, Debora Campanella Bastos, Giuseppe Nicolò Fanelli, Hubert Pakula, Marco Foiani, Giorgia Zadra, Massimo Loda

{"title":"Blocking lipid synthesis induces DNA damage in prostate cancer and increases cell death caused by PARP inhibition","authors":"Caroline Fidalgo Ribeiro, Silvia Rodrigues, Debora Campanella Bastos, Giuseppe Nicolò Fanelli, Hubert Pakula, Marco Foiani, Giorgia Zadra, Massimo Loda","doi":"10.1126/scisignal.adh1922","DOIUrl":"10.1126/scisignal.adh1922","url":null,"abstract":"<div >Androgen deprivation therapy (ADT) is the primary treatment for prostate cancer; however, resistance to ADT invariably develops, leading to castration-resistant prostate cancer (CRPC). Prostate cancer progression is marked by increased de novo synthesis of fatty acids due to overexpression of fatty acid synthase (FASN), making this enzyme a therapeutic target for prostate cancer. Inhibition of FASN results in increased intracellular amounts of ceramides and sphingomyelin, leading to DNA damage through the formation of DNA double-strand breaks and cell death. We found that combining a FASNi with the poly-ADP ribose polymerase (PARP) inhibitor olaparib, which induces cell death by blocking DNA damage repair, resulted in a more pronounced reduction in cell growth than that caused by either drug alone. Human CRPC organoids treated with a combination of PARP and FASNi were smaller, had decreased cell proliferation, and showed increased apoptosis and necrosis. Together, these data indicate that targeting FASN increases the therapeutic efficacy of PARP inhibitors by impairing DNA damage repair, suggesting that combination therapies should be explored for CRPC.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"17 831","pages":""},"PeriodicalIF":7.3,"publicationDate":"2024-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/scisignal.adh1922","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140541212","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The heavy subunit of ferritin stimulates NLRP3 inflammasomes in hepatic stellate cells through ICAM-1 to drive hepatic inflammation 铁蛋白重亚基通过 ICAM-1 刺激肝星状细胞中的 NLRP3 炎症小体，从而驱动肝脏炎症

IF 7.3 1区生物学

Science Signaling Pub Date : 2024-04-02 DOI: 10.1126/scisignal.ade4335

Manuel A. Fernandez-Rojo, Michael A. Pearen, Anita G. Burgess, Maria P. Ikonomopoulou, Diem Hoang-Le, Berit Genz, Silvia L. Saggiomo, Sujeevi S. K. Nawaratna, Maura Poli, Regina Reissmann, Geoffrey N. Gobert, Urban Deutsch, Britta Engelhardt, Andrew J. Brooks, Alun Jones, Paolo Arosio, Grant A. Ramm

{"title":"The heavy subunit of ferritin stimulates NLRP3 inflammasomes in hepatic stellate cells through ICAM-1 to drive hepatic inflammation","authors":"Manuel A. Fernandez-Rojo, Michael A. Pearen, Anita G. Burgess, Maria P. Ikonomopoulou, Diem Hoang-Le, Berit Genz, Silvia L. Saggiomo, Sujeevi S. K. Nawaratna, Maura Poli, Regina Reissmann, Geoffrey N. Gobert, Urban Deutsch, Britta Engelhardt, Andrew J. Brooks, Alun Jones, Paolo Arosio, Grant A. Ramm","doi":"10.1126/scisignal.ade4335","DOIUrl":"10.1126/scisignal.ade4335","url":null,"abstract":"<div >Serum ferritin concentrations increase during hepatic inflammation and correlate with the severity of chronic liver disease. Here, we report a molecular mechanism whereby the heavy subunit of ferritin (FTH) contributes to hepatic inflammation. We found that FTH induced activation of the NLRP3 inflammasome and secretion of the proinflammatory cytokine interleukin-1β (IL-1β) in primary rat hepatic stellate cells (HSCs) through intercellular adhesion molecule–1 (ICAM-1). FTH–ICAM-1 stimulated the expression of <i>Il1b</i>, NLRP3 inflammasome activation, and the processing and secretion of IL-1β in a manner that depended on plasma membrane remodeling, clathrin-mediated endocytosis, and lysosomal destabilization. FTH–ICAM-1 signaling at early endosomes stimulated <i>Il1b</i> expression, implying that this endosomal signaling primed inflammasome activation in HSCs. In contrast, lysosomal destabilization was required for FTH-induced IL-1β secretion, suggesting that lysosomal damage activated inflammasomes. FTH induced IL-1β production in liver slices from wild-type mice but not in those from <i>Icam1<sup>−/−</sup></i> or <i>Nlrp3<sup>−/−</sup></i> mice. Thus, FTH signals through its receptor ICAM-1 on HSCs to activate the NLRP3 inflammasome. We speculate that this pathway contributes to hepatic inflammation, a key process that stimulates hepatic fibrogenesis associated with chronic liver disease.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"17 830","pages":""},"PeriodicalIF":7.3,"publicationDate":"2024-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140343125","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The heavy subunit of ferritin stimulates NLRP3 inflammasomes in hepatic stellate cells through ICAM-1 to drive hepatic inflammation 铁蛋白重亚基通过 ICAM-1 刺激肝星状细胞中的 NLRP3 炎症小体，从而驱动肝脏炎症

IF 7.3 1区生物学

Science Signaling Pub Date : 2024-04-02 DOI: https://www.science.org/doi/10.1126/scisignal.ade4335

Manuel A. Fernandez-Rojo, Michael A. Pearen, Anita G. Burgess, Maria P. Ikonomopoulou, Diem Hoang-Le, Berit Genz, Silvia L. Saggiomo, Sujeevi S. K. Nawaratna, Maura Poli, Regina Reissmann, Geoffrey N. Gobert, Urban Deutsch, Britta Engelhardt, Andrew J. Brooks, Alun Jones, Paolo Arosio, Grant A. Ramm

{"title":"The heavy subunit of ferritin stimulates NLRP3 inflammasomes in hepatic stellate cells through ICAM-1 to drive hepatic inflammation","authors":"Manuel A. Fernandez-Rojo, Michael A. Pearen, Anita G. Burgess, Maria P. Ikonomopoulou, Diem Hoang-Le, Berit Genz, Silvia L. Saggiomo, Sujeevi S. K. Nawaratna, Maura Poli, Regina Reissmann, Geoffrey N. Gobert, Urban Deutsch, Britta Engelhardt, Andrew J. Brooks, Alun Jones, Paolo Arosio, Grant A. Ramm","doi":"https://www.science.org/doi/10.1126/scisignal.ade4335","DOIUrl":"https://doi.org/https://www.science.org/doi/10.1126/scisignal.ade4335","url":null,"abstract":"Serum ferritin concentrations increase during hepatic inflammation and correlate with the severity of chronic liver disease. Here, we report a molecular mechanism whereby the heavy subunit of ferritin (FTH) contributes to hepatic inflammation. We found that FTH induced activation of the NLRP3 inflammasome and secretion of the proinflammatory cytokine interleukin-1β (IL-1β) in primary rat hepatic stellate cells (HSCs) through intercellular adhesion molecule–1 (ICAM-1). FTH–ICAM-1 stimulated the expression of <i>Il1b</i>, NLRP3 inflammasome activation, and the processing and secretion of IL-1β in a manner that depended on plasma membrane remodeling, clathrin-mediated endocytosis, and lysosomal destabilization. FTH–ICAM-1 signaling at early endosomes stimulated <i>Il1b</i> expression, implying that this endosomal signaling primed inflammasome activation in HSCs. In contrast, lysosomal destabilization was required for FTH-induced IL-1β secretion, suggesting that lysosomal damage activated inflammasomes. FTH induced IL-1β production in liver slices from wild-type mice but not in those from <i>Icam1<sup>−/−</sup></i> or <i>Nlrp3<sup>−/−</sup></i> mice. Thus, FTH signals through its receptor ICAM-1 on HSCs to activate the NLRP3 inflammasome. We speculate that this pathway contributes to hepatic inflammation, a key process that stimulates hepatic fibrogenesis associated with chronic liver disease.","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"298 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2024-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140586807","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Lipid drops in on Alzheimer’s disease 脂质对老年痴呆症的影响

IF 7.3 1区生物学

Science Signaling Pub Date : 2024-04-02 DOI: 10.1126/scisignal.adp4951

Amy E. Baek

引用次数: 0

Biasing microglia to help, not hurt 让小胶质细胞助人而非伤人

IF 7.3 1区生物学

Science Signaling Pub Date : 2024-03-26 DOI: 10.1126/scisignal.adp3241

Leslie K. Ferrarelli

引用次数: 0

Glucosylceramide accumulation in microglia triggers STING-dependent neuroinflammation and neurodegeneration in mice 小胶质细胞中的葡萄糖酰胺积累会引发 STING 依赖性神经炎症和小鼠神经退行性变

IF 7.3 1区生物学

Science Signaling Pub Date : 2024-03-26 DOI: https://www.science.org/doi/10.1126/scisignal.adk8249

Rui Wang, Hongyang Sun, Yifan Cao, Zhixiong Zhang, Yajing Chen, Xiying Wang, Lele Liu, Jin Wu, Hao Xu, Dan Wu, Chenchen Mu, Zongbing Hao, Song Qin, Haigang Ren, Junhai Han, Ming Fang, Guanghui Wang

{"title":"Glucosylceramide accumulation in microglia triggers STING-dependent neuroinflammation and neurodegeneration in mice","authors":"Rui Wang, Hongyang Sun, Yifan Cao, Zhixiong Zhang, Yajing Chen, Xiying Wang, Lele Liu, Jin Wu, Hao Xu, Dan Wu, Chenchen Mu, Zongbing Hao, Song Qin, Haigang Ren, Junhai Han, Ming Fang, Guanghui Wang","doi":"https://www.science.org/doi/10.1126/scisignal.adk8249","DOIUrl":"https://doi.org/https://www.science.org/doi/10.1126/scisignal.adk8249","url":null,"abstract":"Mutations in the gene encoding the lysosomal enzyme glucocerebrosidase (GCase) are responsible for Gaucher disease (GD) and are considered the strongest genetic risk factor for Parkinson’s disease (PD) and Lewy body dementia (LBD). GCase deficiency leads to extensive accumulation of glucosylceramides (GCs) in cells and contributes to the neuropathology of GD, PD, and LBD by triggering chronic neuroinflammation. Here, we investigated the mechanisms by which GC accumulation induces neuroinflammation. We found that GC accumulation within microglia induced by pharmacological inhibition of GCase triggered STING-dependent inflammation, which contributed to neuronal loss both in vitro and in vivo. GC accumulation in microglia induced mitochondrial DNA (mtDNA) leakage to the cytosol to trigger STING-dependent inflammation. Rapamycin, a compound that promotes lysosomal activity, improved mitochondrial function, thereby decreasing STING signaling. Furthermore, lysosomal damage caused by GC accumulation led to defects in the degradation of activated STING, further exacerbating inflammation mediated by microglia. Thus, limiting STING activity may be a strategy to suppress neuroinflammation caused by GCase deficiency.","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"298 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2024-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140586901","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Glucosylceramide accumulation in microglia triggers STING-dependent neuroinflammation and neurodegeneration in mice 小胶质细胞中的葡萄糖甘油酰胺积累会引发 STING 依赖性神经炎症和小鼠神经退行性变。

IF 7.3 1区生物学

Science Signaling Pub Date : 2024-03-26 DOI: 10.1126/scisignal.adk8249

Rui Wang, Hongyang Sun, Yifan Cao, Zhixiong Zhang, Yajing Chen, Xiying Wang, Lele Liu, Jin Wu, Hao Xu, Dan Wu, Chenchen Mu, Zongbing Hao, Song Qin, Haigang Ren, Junhai Han, Ming Fang, Guanghui Wang

{"title":"Glucosylceramide accumulation in microglia triggers STING-dependent neuroinflammation and neurodegeneration in mice","authors":"Rui Wang, Hongyang Sun, Yifan Cao, Zhixiong Zhang, Yajing Chen, Xiying Wang, Lele Liu, Jin Wu, Hao Xu, Dan Wu, Chenchen Mu, Zongbing Hao, Song Qin, Haigang Ren, Junhai Han, Ming Fang, Guanghui Wang","doi":"10.1126/scisignal.adk8249","DOIUrl":"10.1126/scisignal.adk8249","url":null,"abstract":"<div >Mutations in the gene encoding the lysosomal enzyme glucocerebrosidase (GCase) are responsible for Gaucher disease (GD) and are considered the strongest genetic risk factor for Parkinson’s disease (PD) and Lewy body dementia (LBD). GCase deficiency leads to extensive accumulation of glucosylceramides (GCs) in cells and contributes to the neuropathology of GD, PD, and LBD by triggering chronic neuroinflammation. Here, we investigated the mechanisms by which GC accumulation induces neuroinflammation. We found that GC accumulation within microglia induced by pharmacological inhibition of GCase triggered STING-dependent inflammation, which contributed to neuronal loss both in vitro and in vivo. GC accumulation in microglia induced mitochondrial DNA (mtDNA) leakage to the cytosol to trigger STING-dependent inflammation. Rapamycin, a compound that promotes lysosomal activity, improved mitochondrial function, thereby decreasing STING signaling. Furthermore, lysosomal damage caused by GC accumulation led to defects in the degradation of activated STING, further exacerbating inflammation mediated by microglia. Thus, limiting STING activity may be a strategy to suppress neuroinflammation caused by GCase deficiency.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"17 829","pages":""},"PeriodicalIF":7.3,"publicationDate":"2024-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140295105","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Polarizing itch 极化之痒

IF 7.3 1区生物学

Science Signaling Pub Date : 2024-03-19 DOI: 10.1126/scisignal.adp2197

John F. Foley

引用次数: 0

Exercise-induced BDNF promotes PPARδ-dependent reprogramming of lipid metabolism in skeletal muscle during exercise recovery 运动诱导的 BDNF 可促进运动恢复期骨骼肌脂质代谢的 PPARδ 依赖性重编程

IF 7.3 1区生物学

Science Signaling Pub Date : 2024-03-19 DOI: https://www.science.org/doi/10.1126/scisignal.adh2783

Wing Suen Chan, Chun Fai Ng, Brian Pak Shing Pang, Miaojia Hang, Margaret Chui Ling Tse, Elsie Chit Yu Iu, Xin Ci Ooi, Xiuying Yang, Jason K. Kim, Chi Wai Lee, Chi Bun Chan

{"title":"Exercise-induced BDNF promotes PPARδ-dependent reprogramming of lipid metabolism in skeletal muscle during exercise recovery","authors":"Wing Suen Chan, Chun Fai Ng, Brian Pak Shing Pang, Miaojia Hang, Margaret Chui Ling Tse, Elsie Chit Yu Iu, Xin Ci Ooi, Xiuying Yang, Jason K. Kim, Chi Wai Lee, Chi Bun Chan","doi":"https://www.science.org/doi/10.1126/scisignal.adh2783","DOIUrl":"https://doi.org/https://www.science.org/doi/10.1126/scisignal.adh2783","url":null,"abstract":"Post-exercise recovery is essential to resolve metabolic perturbations and promote long-term cellular remodeling in response to exercise. Here, we report that muscle-generated brain-derived neurotrophic factor (BDNF) elicits post-exercise recovery and metabolic reprogramming in skeletal muscle. BDNF increased the post-exercise expression of the gene encoding PPARδ (peroxisome proliferator–activated receptor δ), a transcription factor that is a master regulator of lipid metabolism. After exercise, mice with muscle-specific <i>Bdnf</i> knockout (<i>MBKO</i>) exhibited impairments in PPARδ-regulated metabolic gene expression, decreased intramuscular lipid content, reduced β-oxidation, and dysregulated mitochondrial dynamics. Moreover, <i>MBKO</i> mice required a longer period to recover from a bout of exercise and did not show increases in exercise-induced endurance capacity. Feeding naïve mice with the bioavailable BDNF mimetic 7,8-dihydroxyflavone resulted in effects that mimicked exercise-induced adaptations, including improved exercise capacity. Together, our findings reveal that BDNF is an essential myokine for exercise-induced metabolic recovery and remodeling in skeletal muscle.","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"26 1","pages":""},"PeriodicalIF":7.3,"publicationDate":"2024-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140203273","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Exercise-induced BDNF promotes PPARδ-dependent reprogramming of lipid metabolism in skeletal muscle during exercise recovery 运动诱导的 BDNF 可促进运动恢复期骨骼肌脂质代谢的 PPARδ 依赖性重编程

IF 7.3 1区生物学

Science Signaling Pub Date : 2024-03-19 DOI: 10.1126/scisignal.adh2783

Wing Suen Chan, Chun Fai Ng, Brian Pak Shing Pang, Miaojia Hang, Margaret Chui Ling Tse, Elsie Chit Yu Iu, Xin Ci Ooi, Xiuying Yang, Jason K. Kim, Chi Wai Lee, Chi Bun Chan

{"title":"Exercise-induced BDNF promotes PPARδ-dependent reprogramming of lipid metabolism in skeletal muscle during exercise recovery","authors":"Wing Suen Chan, Chun Fai Ng, Brian Pak Shing Pang, Miaojia Hang, Margaret Chui Ling Tse, Elsie Chit Yu Iu, Xin Ci Ooi, Xiuying Yang, Jason K. Kim, Chi Wai Lee, Chi Bun Chan","doi":"10.1126/scisignal.adh2783","DOIUrl":"10.1126/scisignal.adh2783","url":null,"abstract":"<div >Post-exercise recovery is essential to resolve metabolic perturbations and promote long-term cellular remodeling in response to exercise. Here, we report that muscle-generated brain-derived neurotrophic factor (BDNF) elicits post-exercise recovery and metabolic reprogramming in skeletal muscle. BDNF increased the post-exercise expression of the gene encoding PPARδ (peroxisome proliferator–activated receptor δ), a transcription factor that is a master regulator of lipid metabolism. After exercise, mice with muscle-specific <i>Bdnf</i> knockout (<i>MBKO</i>) exhibited impairments in PPARδ-regulated metabolic gene expression, decreased intramuscular lipid content, reduced β-oxidation, and dysregulated mitochondrial dynamics. Moreover, <i>MBKO</i> mice required a longer period to recover from a bout of exercise and did not show increases in exercise-induced endurance capacity. Feeding naïve mice with the bioavailable BDNF mimetic 7,8-dihydroxyflavone resulted in effects that mimicked exercise-induced adaptations, including improved exercise capacity. Together, our findings reveal that BDNF is an essential myokine for exercise-induced metabolic recovery and remodeling in skeletal muscle.</div>","PeriodicalId":21658,"journal":{"name":"Science Signaling","volume":"17 828","pages":""},"PeriodicalIF":7.3,"publicationDate":"2024-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140164519","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0