Cellular signalling最新文献_第3页

Dichloroacetate: A metabolic game-changer in alleviating macrophage inflammation and enhancing recovery after myocardial infarction

IF 4.4 2区生物学 Q2 CELL BIOLOGY

Cellular signalling

Pub Date : 2025-01-23 DOI: 10.1016/j.cellsig.2025.111618

Fuyou Lv , Ning Qi , Chang Liu , Lili Wang , Tianning Dai , Hai Tian

Background

Dichloroacetate (DCA) has shown potential in modulating cellular metabolism and inflammation, particularly in cardiac conditions. This study investigates DCA's protective effects in a mouse model of myocardial infarction (MI), focusing on its ability to enhance cardiac function, reduce inflammation, and shift macrophage polarization from the pro-inflammatory M1 to the anti-inflammatory M2 phenotype.

Methods

An acute MI model was created using left anterior descending coronary artery ligation. Mice were assigned to four groups: normal control, MI control, MI + 50 mM DCA, and MI + 100 mM DCA. Cardiac fibrosis and injury were assessed through H&E staining. Cardiac function was evaluated via echocardiography, and serum levels of creatine kinase-MB (CK-MB) and lactate dehydrogenase (LDH) were measured. Inflammation and apoptosis were analyzed through immunohistochemistry, ELISA, western blotting, and flow cytometry in heart tissue and RAW264.7 cells. Additionally, macrophage polarization and relevant signaling pathways were examined.

Results

DCA significantly improved cardiac function in MI mice, evidenced by reduced myocardial injury and lower CK-MB and LDH levels. It also decreased inflammatory cytokines (TNF-α, IL-6 and IL-1β) and facilitated macrophage polarization from M1 to M2. Western blotting revealed that DCA inhibited iNOS and COX2 while enhancing Arg1 expression, alongside improved mitochondrial function and reduced apoptosis. Additionally, by injecting AAV-PDHK4 (pyruvate dehydrogenase kinase) into MI mice, we found that DCA effectively inhibited the progression of MI through the suppression of PDHK4.

Conclusion

DCA protects against myocardial infarction by enhancing cardiac function, reducing inflammation, and promoting macrophage polarization, likely through inhibition of PDHK4 and NF-κB pathways, positioning it as a potential therapeutic strategy for cardiac repair post-MI.

{"title":"Dichloroacetate: A metabolic game-changer in alleviating macrophage inflammation and enhancing recovery after myocardial infarction","authors":"Fuyou Lv , Ning Qi , Chang Liu , Lili Wang , Tianning Dai , Hai Tian","doi":"10.1016/j.cellsig.2025.111618","DOIUrl":"10.1016/j.cellsig.2025.111618","url":null,"abstract":"<div><h3>Background</h3><div>Dichloroacetate (DCA) has shown potential in modulating cellular metabolism and inflammation, particularly in cardiac conditions. This study investigates DCA's protective effects in a mouse model of myocardial infarction (MI), focusing on its ability to enhance cardiac function, reduce inflammation, and shift macrophage polarization from the pro-inflammatory M1 to the anti-inflammatory M2 phenotype.</div></div><div><h3>Methods</h3><div>An acute MI model was created using left anterior descending coronary artery ligation. Mice were assigned to four groups: normal control, MI control, MI + 50 mM DCA, and MI + 100 mM DCA. Cardiac fibrosis and injury were assessed through H&E staining. Cardiac function was evaluated via echocardiography, and serum levels of creatine kinase-MB (CK-MB) and lactate dehydrogenase (LDH) were measured. Inflammation and apoptosis were analyzed through immunohistochemistry, ELISA, western blotting, and flow cytometry in heart tissue and RAW264.7 cells. Additionally, macrophage polarization and relevant signaling pathways were examined.</div></div><div><h3>Results</h3><div>DCA significantly improved cardiac function in MI mice, evidenced by reduced myocardial injury and lower CK-MB and LDH levels. It also decreased inflammatory cytokines (TNF-α, IL-6 and IL-1β) and facilitated macrophage polarization from M1 to M2. Western blotting revealed that DCA inhibited iNOS and COX2 while enhancing Arg1 expression, alongside improved mitochondrial function and reduced apoptosis. Additionally, by injecting AAV-PDHK4 (pyruvate dehydrogenase kinase) into MI mice, we found that DCA effectively inhibited the progression of MI through the suppression of PDHK4.</div></div><div><h3>Conclusion</h3><div>DCA protects against myocardial infarction by enhancing cardiac function, reducing inflammation, and promoting macrophage polarization, likely through inhibition of PDHK4 and NF-κB pathways, positioning it as a potential therapeutic strategy for cardiac repair post-MI.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"127 ","pages":"Article 111618"},"PeriodicalIF":4.4,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143037360","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

METTL14-mediated depression of NEIL1 aggravates oxidative damage and mitochondrial dysfunction of lens epithelial cells through regulating KEAP1/NRF2 pathways

IF 4.4 2区生物学 Q2 CELL BIOLOGY

Cellular signalling

Pub Date : 2025-01-22 DOI: 10.1016/j.cellsig.2025.111623

Lihua Kang , Sijie Bao , Pengfei Li , Guowei Zhang , Xi Zhu, Min Ji, Huaijin Guan

Abnormal base excision repair (BER) pathway and N6-methyladenosine (m6A) of RNA have been proved to be significantly related to age-related cataract (ARC) pathogenesis. However, the relationship between the Nei Endonuclease VIII-Like1 (NEIL1) gene (a representative DNA glycosylase of BER pathway) and its m6A modification remains unclear. Here, we showed that the expression of NEIL1 was decreased in the ARC anterior lens capsules and H₂O₂-stimulated SRA01/04 cells. Our findings demonstrated that ectopic expression of NEIL1 alleviated DNA oxidative damage, apoptosis and mitochondrial dysfunction through disturbing KEAP1/NRF2 interaction. Furthermore, silencing NEIL1 aggravated H₂O₂-induced lens opacity, whereas ML334 could mitigate lens cloudy ex vitro in rat lenses. Besides, intravitreal injection of AAV2-NEIL1 alleviated lens opacity in Emory mice in vivo. Mechanistically, the N(6)-Methyladenosine (m6A) methyltransferase-like 14 (METTL14) was identified as a factor in promoting m6A modification of NEIL1, which resulted in the recruitment of YTHDF2 to recognize and impair NEIL1 RNA stability. Collectively, these findings highlight the critical role of the m6A modification in NEIL1 on regulating oxidative stress and mitochondrial homeostasis through KEAP1/NRF2 pathways, providing a new way to explore the pathogenesis of ARC.

{"title":"METTL14-mediated depression of NEIL1 aggravates oxidative damage and mitochondrial dysfunction of lens epithelial cells through regulating KEAP1/NRF2 pathways","authors":"Lihua Kang , Sijie Bao , Pengfei Li , Guowei Zhang , Xi Zhu, Min Ji, Huaijin Guan","doi":"10.1016/j.cellsig.2025.111623","DOIUrl":"10.1016/j.cellsig.2025.111623","url":null,"abstract":"<div><div>Abnormal base excision repair (BER) pathway and N6-methyladenosine (m6A) of RNA have been proved to be significantly related to age-related cataract (ARC) pathogenesis. However, the relationship between the Nei Endonuclease VIII-Like1 (NEIL1) gene (a representative DNA glycosylase of BER pathway) and its m6A modification remains unclear. Here, we showed that the expression of NEIL1 was decreased in the ARC anterior lens capsules and H<sub>2</sub>O<sub>2</sub>-stimulated SRA01/04 cells. Our findings demonstrated that ectopic expression of NEIL1 alleviated DNA oxidative damage, apoptosis and mitochondrial dysfunction through disturbing KEAP1/NRF2 interaction. Furthermore, silencing NEIL1 aggravated H<sub>2</sub>O<sub>2</sub>-induced lens opacity, whereas ML334 could mitigate lens cloudy ex vitro in rat lenses. Besides, intravitreal injection of AAV2-NEIL1 alleviated lens opacity in Emory mice in vivo. Mechanistically, the N(6)-Methyladenosine (m6A) methyltransferase-like 14 (METTL14) was identified as a factor in promoting m6A modification of NEIL1, which resulted in the recruitment of YTHDF2 to recognize and impair NEIL1 RNA stability. Collectively, these findings highlight the critical role of the m6A modification in NEIL1 on regulating oxidative stress and mitochondrial homeostasis through KEAP1/NRF2 pathways, providing a new way to explore the pathogenesis of ARC.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"127 ","pages":"Article 111623"},"PeriodicalIF":4.4,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143037361","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

D-Ala2-GIP (1−30) promotes angiogenesis by facilitating endothelial cell migration via the Epac/Rap1/Cdc42 signaling pathway

IF 4.4 2区生物学 Q2 CELL BIOLOGY

Cellular signalling

Pub Date : 2025-01-22 DOI: 10.1016/j.cellsig.2025.111615

Tuchen Guan , Wenxue Zhang , Mingxuan Li , Qing Wang , Longyu Guo , Beibei Guo , Xiaoqian Luo , Zhen Li , Muxing Lu , Zhangji Dong , Man Xu , Mei Liu , Yan Liu , Jian Feng

Angiogenesis, a meticulously regulated process essential for both normal development and pathological conditions, necessitates a comprehensive understanding of the endothelial mechanisms governing its progression. Leveraging the zebrafish model and NgAgo knockdown system to identify target genes influencing angiogenesis, our study highlights the significant role of gastric inhibitory polypeptide (GIP) and its receptor (GIPR) in this process. While GIP has been extensively studied for its insulinotropic and glucagonotropic effects, its role in angiogenesis remains unexplored. This study demonstrated that GIPR knockdown induced developmental delays, morphological abnormalities, and pronounced angiogenic impairments in zebrafish embryos. Conversely, exogenous D-Ala2-GIP administration enhanced blood vessel formation in the yolk sac membrane of chick embryos. Consistent with these findings, D-Ala2-GIP treatment promoted microvessel formation in the tube formation assays and rat aortic ring models. Further investigation revealed that D-Ala2-GIP facilitated human umbilical vein endothelial cell (HUVEC) migration, a key step in angiogenesis, through the cyclic adenosine monophosphate (cAMP)-mediated activation of the Epac/Rap1/Cdc42 signaling pathway. This study provides novel insights into the angiogenic functions of GIP and its potential implications for cardiovascular biology.

{"title":"D-Ala2-GIP (1−30) promotes angiogenesis by facilitating endothelial cell migration via the Epac/Rap1/Cdc42 signaling pathway","authors":"Tuchen Guan , Wenxue Zhang , Mingxuan Li , Qing Wang , Longyu Guo , Beibei Guo , Xiaoqian Luo , Zhen Li , Muxing Lu , Zhangji Dong , Man Xu , Mei Liu , Yan Liu , Jian Feng","doi":"10.1016/j.cellsig.2025.111615","DOIUrl":"10.1016/j.cellsig.2025.111615","url":null,"abstract":"<div><div>Angiogenesis, a meticulously regulated process essential for both normal development and pathological conditions, necessitates a comprehensive understanding of the endothelial mechanisms governing its progression. Leveraging the zebrafish model and NgAgo knockdown system to identify target genes influencing angiogenesis, our study highlights the significant role of gastric inhibitory polypeptide (GIP) and its receptor (GIPR) in this process. While GIP has been extensively studied for its insulinotropic and glucagonotropic effects, its role in angiogenesis remains unexplored. This study demonstrated that GIPR knockdown induced developmental delays, morphological abnormalities, and pronounced angiogenic impairments in zebrafish embryos. Conversely, exogenous D-Ala2-GIP administration enhanced blood vessel formation in the yolk sac membrane of chick embryos. Consistent with these findings, D-Ala2-GIP treatment promoted microvessel formation in the tube formation assays and rat aortic ring models. Further investigation revealed that D-Ala2-GIP facilitated human umbilical vein endothelial cell (HUVEC) migration, a key step in angiogenesis, through the cyclic adenosine monophosphate (cAMP)-mediated activation of the Epac/Rap1/Cdc42 signaling pathway. This study provides novel insights into the angiogenic functions of GIP and its potential implications for cardiovascular biology.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"127 ","pages":"Article 111615"},"PeriodicalIF":4.4,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143037359","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

KGF impedes TRIM21-enhanced stabilization of keratin 10 mediating differentiation in hypopharyngeal cancer

IF 4.4 2区生物学 Q2 CELL BIOLOGY

Cellular signalling

Pub Date : 2025-01-21 DOI: 10.1016/j.cellsig.2025.111614

Fangyu Chai , Guangyi Wang , Yibang Shen , Yanfang Niu , Yichuan Huang , Tao Fu , Tao Yang , Yan Jiang , Jisheng Zhang

KGF, also known as FGF7, is a member of the fibroblast growth factor (FGF) family that binds with high affinity to the FGF receptor 2b (FGFR2b) and regulates various cellular processes, including cell proliferation and differentiation in a variety of tumors. However, its potential role in hypopharyngeal cancer (HPC) remains largely unknown. In our study, we observed increased expression of FGFR2b in HPC. KGF treatment inhibited the expression of the differentiation marker keratin 10 (K10) protein at the post-transcriptional level in FaDu cells. Furthermore, treatment with the proteasome inhibitor MG132 was found to attenuate KGF-induced K10 reduction, suggesting the involvement of the ubiquitin-proteasome system. Using mass spectrometry and immunoprecipitation analysis, we identified the E3 ubiquitin ligase TRIM21 as a K10-interacting protein. Unexpectedly, instead of causing degradation, TRIM21 enhanced K10 protein stability through K6-linked ubiquitination of K10 at lysine 163 (K163) in the context of KGF exposure. Meanwhile, KGF treatment decreased TRIM21 protein levels, which were regulated by the p38 MAPK pathway, leading to K48-linked ubiquitination-mediated degradation of TRIM21. Notably, TRIM21 knockdown significantly promoted proliferation, inhibited differentiation and migration of FaDu cells, whereas TRIM21 overexpression had opposite effects in vitro and suppressed xenograft tumor growth in vivo. Our study demonstrates that TRIM21 may act as a tumor suppressor in HPC. However, TRIM21 overexpression decreased the sensitivity of FaDu cells to 5-fluorouracil, whereas TRIM21 knockdown or KGF administration significantly increased 5-fluorouracil sensitivity. Taken together, these findings highlight the intricate balance between protein stabilization and degradation orchestrated by KGF. This ubiquitination-mediated non-degradation mechanism of TRIM21 may provide novel therapeutic strategies for HPC and other cancers.

{"title":"KGF impedes TRIM21-enhanced stabilization of keratin 10 mediating differentiation in hypopharyngeal cancer","authors":"Fangyu Chai , Guangyi Wang , Yibang Shen , Yanfang Niu , Yichuan Huang , Tao Fu , Tao Yang , Yan Jiang , Jisheng Zhang","doi":"10.1016/j.cellsig.2025.111614","DOIUrl":"10.1016/j.cellsig.2025.111614","url":null,"abstract":"<div><div>KGF, also known as FGF7, is a member of the fibroblast growth factor (FGF) family that binds with high affinity to the FGF receptor 2b (FGFR2b) and regulates various cellular processes, including cell proliferation and differentiation in a variety of tumors. However, its potential role in hypopharyngeal cancer (HPC) remains largely unknown. In our study, we observed increased expression of FGFR2b in HPC. KGF treatment inhibited the expression of the differentiation marker keratin 10 (K10) protein at the post-transcriptional level in FaDu cells. Furthermore, treatment with the proteasome inhibitor MG132 was found to attenuate KGF-induced K10 reduction, suggesting the involvement of the ubiquitin-proteasome system. Using mass spectrometry and immunoprecipitation analysis, we identified the E3 ubiquitin ligase TRIM21 as a K10-interacting protein. Unexpectedly, instead of causing degradation, TRIM21 enhanced K10 protein stability through K6-linked ubiquitination of K10 at lysine 163 (K163) in the context of KGF exposure. Meanwhile, KGF treatment decreased TRIM21 protein levels, which were regulated by the p38 MAPK pathway, leading to K48-linked ubiquitination-mediated degradation of TRIM21. Notably, TRIM21 knockdown significantly promoted proliferation, inhibited differentiation and migration of FaDu cells, whereas TRIM21 overexpression had opposite effects in vitro and suppressed xenograft tumor growth in vivo. Our study demonstrates that TRIM21 may act as a tumor suppressor in HPC. However, TRIM21 overexpression decreased the sensitivity of FaDu cells to 5-fluorouracil, whereas TRIM21 knockdown or KGF administration significantly increased 5-fluorouracil sensitivity. Taken together, these findings highlight the intricate balance between protein stabilization and degradation orchestrated by KGF. This ubiquitination-mediated non-degradation mechanism of TRIM21 may provide novel therapeutic strategies for HPC and other cancers.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"127 ","pages":"Article 111614"},"PeriodicalIF":4.4,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143028061","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

SRF and CBP jointly regulate integrin β6 overexpression in head and neck squamous cell carcinomas

IF 4.4 2区生物学 Q2 CELL BIOLOGY

Cellular signalling

Pub Date : 2025-01-21 DOI: 10.1016/j.cellsig.2025.111621

Mingyan Xu , Gongwei Luo , Yixin Xiao , Feixiang Zhu , Hongfa Yao , Haohao Zhu , Fan Liu , Songlin Shi , Xiaoling Deng

Overexpression of integrin β6 (ITGB6) is crucially linked to the invasion and metastasis of head and neck squamous cell carcinoma (HNSCC). The molecular mechanisms driving ITGB6 upregulation in HNSCC are not well understood. Our study comprehensively analyzed the transcriptional regulation and epigenetic modification mechanisms affecting ITGB6 transcription. We retrospectively evaluated ITGB6 expression using immunohistochemistry on a tissue microarray. Elevated ITGB6 expression in HNSCC specimens correlates with poor clinical prognosis. Using a luciferase reporter assay, site-directed mutagenesis, RNA interference, chromatin immunoprecipitation assay, and a 4-nitroquinoline 1-oxide (4NQO)-induced murine HNSCC model, we have demonstrated that the transcription factor Serum Response Factor (SRF) upregulates ITGB6 transcription. Our results further demonstrated that the histone acetyltransferase (HAT) CBP mediates the hyperacetylation of histones H3 and H4, facilitating their recruitment to the ITGB6 promoter. This recruitment strengthens SRF binding to the ITGB6 promoter. These findings suggest that SRF and CBP-mediated histone hyperacetylation are crucial for ITGB6 overexpression in HNSCC. Epigenetic mechanisms play a critical role in the active transcriptional expression of ITGB6 in HNSCC cells.

{"title":"SRF and CBP jointly regulate integrin β6 overexpression in head and neck squamous cell carcinomas","authors":"Mingyan Xu , Gongwei Luo , Yixin Xiao , Feixiang Zhu , Hongfa Yao , Haohao Zhu , Fan Liu , Songlin Shi , Xiaoling Deng","doi":"10.1016/j.cellsig.2025.111621","DOIUrl":"10.1016/j.cellsig.2025.111621","url":null,"abstract":"<div><div>Overexpression of integrin β6 (ITGB6) is crucially linked to the invasion and metastasis of head and neck squamous cell carcinoma (HNSCC). The molecular mechanisms driving <em>ITGB6</em> upregulation in HNSCC are not well understood. Our study comprehensively analyzed the transcriptional regulation and epigenetic modification mechanisms affecting <em>ITGB6</em> transcription. We retrospectively evaluated ITGB6 expression using immunohistochemistry on a tissue microarray. Elevated ITGB6 expression in HNSCC specimens correlates with poor clinical prognosis. Using a luciferase reporter assay, site-directed mutagenesis, RNA interference, chromatin immunoprecipitation assay, and a 4-nitroquinoline 1-oxide (4NQO)-induced murine HNSCC model, we have demonstrated that the transcription factor Serum Response Factor (SRF) upregulates <em>ITGB6</em> transcription. Our results further demonstrated that the histone acetyltransferase (HAT) CBP mediates the hyperacetylation of histones H3 and H4, facilitating their recruitment to the <em>ITGB6</em> promoter. This recruitment strengthens SRF binding to the <em>ITGB6</em> promoter. These findings suggest that SRF and CBP-mediated histone hyperacetylation are crucial for ITGB6 overexpression in HNSCC. Epigenetic mechanisms play a critical role in the active transcriptional expression of <em>ITGB6</em> in HNSCC cells.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"127 ","pages":"Article 111621"},"PeriodicalIF":4.4,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143028062","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

HMGB1 secretion by resveratrol in NSCLC: A pathway to ferroptosis-mediated platelet activation suppression

IF 4.4 2区生物学 Q2 CELL BIOLOGY

Cellular signalling

Pub Date : 2025-01-21 DOI: 10.1016/j.cellsig.2025.111607

Yifan Zhang , Shihao Bao , Jingtong Zeng , Jingyu Liu , Xianjie Li , Bo Zhang , Hanqing Wang , Yuan Cheng , Hao Zhang , Wei Xia , Lingling Zu , Xiaohong Xu , Song Xu , Zuoqing Song

Background

Cancer-associated venous thromboembolism (CAT) is a frequent and serious complication in cancer patients. Resveratrol, a natural compound with reported anti-tumor effects, is not fully understood in its role regarding CAT in lung cancer. This study aims to explore resveratrol's potential to diminish platelet activation induced by lung adenocarcinoma cells and uncover the underlying mechanisms.

Methods

Clinical data on coagulation function in non-small cell lung cancer (NSCLC) patients were gathered. A549 human lung cancer cells and Lewis mouse lung cancer cells were employed to assess tumor-induced platelet activation and the impact of resveratrol on this process. Western blotting analyzed protein expression, electron microscopy examined extracellular vesicle (EV) morphology, flow cytometry measured platelet activation, reactive oxygen species (ROS), and exocrine protein expression, while ELISA quantified secretory proteins. Tumor control and platelet function were studied in tumor-bearing mice.

Results

We identified that hematological profiles of NSCLC patients frequently manifest a hypercoagulable state relative to healthy controls and lung cancer cells could instigate platelet activation, yet resveratrol could attenuate this phenomenon induced by lung cancer. Resveratrol stimulates lung cancer cells to release HMGB1-enriched EVs, promoting platelet ferroptosis and inhibiting platelet activation through increased ROS, lipid peroxidation, and disrupted cystine transporters. In vivo studies confirm that resveratrol inhibits lung cancer cell growth and suppresses tumor-induced platelet activation in mice.

Conclusion

Our studies revealed that resveratrol alleviated lung cancer-induced ferroptosis associated platelet activation. This suggests a potential pharmacological approach for preventing and treating both lung cancer and CAT.

{"title":"HMGB1 secretion by resveratrol in NSCLC: A pathway to ferroptosis-mediated platelet activation suppression","authors":"Yifan Zhang , Shihao Bao , Jingtong Zeng , Jingyu Liu , Xianjie Li , Bo Zhang , Hanqing Wang , Yuan Cheng , Hao Zhang , Wei Xia , Lingling Zu , Xiaohong Xu , Song Xu , Zuoqing Song","doi":"10.1016/j.cellsig.2025.111607","DOIUrl":"10.1016/j.cellsig.2025.111607","url":null,"abstract":"<div><h3>Background</h3><div>Cancer-associated venous thromboembolism (CAT) is a frequent and serious complication in cancer patients. Resveratrol, a natural compound with reported anti-tumor effects, is not fully understood in its role regarding CAT in lung cancer. This study aims to explore resveratrol's potential to diminish platelet activation induced by lung adenocarcinoma cells and uncover the underlying mechanisms.</div></div><div><h3>Methods</h3><div>Clinical data on coagulation function in non-small cell lung cancer (NSCLC) patients were gathered. A549 human lung cancer cells and Lewis mouse lung cancer cells were employed to assess tumor-induced platelet activation and the impact of resveratrol on this process. Western blotting analyzed protein expression, electron microscopy examined extracellular vesicle (EV) morphology, flow cytometry measured platelet activation, reactive oxygen species (ROS), and exocrine protein expression, while ELISA quantified secretory proteins. Tumor control and platelet function were studied in tumor-bearing mice.</div></div><div><h3>Results</h3><div>We identified that hematological profiles of NSCLC patients frequently manifest a hypercoagulable state relative to healthy controls and lung cancer cells could instigate platelet activation, yet resveratrol could attenuate this phenomenon induced by lung cancer. Resveratrol stimulates lung cancer cells to release HMGB1-enriched EVs, promoting platelet ferroptosis and inhibiting platelet activation through increased ROS, lipid peroxidation, and disrupted cystine transporters. In vivo studies confirm that resveratrol inhibits lung cancer cell growth and suppresses tumor-induced platelet activation in mice.</div></div><div><h3>Conclusion</h3><div>Our studies revealed that resveratrol alleviated lung cancer-induced ferroptosis associated platelet activation. This suggests a potential pharmacological approach for preventing and treating both lung cancer and CAT.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"127 ","pages":"Article 111607"},"PeriodicalIF":4.4,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143022380","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Ribosomal protein L6 suppresses hepatocellular carcinoma by modulating FBXO22-mediated p53 degradation

IF 4.4 2区生物学 Q2 CELL BIOLOGY

Cellular signalling

Pub Date : 2025-01-21 DOI: 10.1016/j.cellsig.2025.111612

Zhen Lei , Yiming Luo , Qinggang Fu , Junli Lu , Chao Wang , Long Zhang , Zhiwei Zhang

The ribosomal protein L6 (RPL6) is significant in the progression of different cancer types. However, its precise role in hepatocellular carcinoma (HCC) remains unclear. This research demonstrated that the expression levels of RPL6 are notably decreased in HCC tissues. The decreased expression of RPL6 is strongly linked to tumor size, the presence of vascular invasion, and a worse prognosis. Functional experiments revealed that the expression of RPL6 impedes the proliferation of HCC cells and the advancement of xenograft tumors. Mechanistically, we found that RPL6 binds to and is degraded by the E3 ubiquitin ligase FBXO22, thereby inhibiting the polyubiquitination and subsequent degradation of p53 by FBXO22. The enhanced activity of p53 further contributes to cell growth inhibition. In contrast, the levels of p53 decreased significantly following RPL6 depletion, indicating that RPL6 is essential for the stabilization of p53. In summary, RPL6 inhibits the proliferation of HCC cells via the FBXO22/p53 signaling pathway, suggesting its potential as a biomarker and a therapeutic target for HCC.

{"title":"Ribosomal protein L6 suppresses hepatocellular carcinoma by modulating FBXO22-mediated p53 degradation","authors":"Zhen Lei , Yiming Luo , Qinggang Fu , Junli Lu , Chao Wang , Long Zhang , Zhiwei Zhang","doi":"10.1016/j.cellsig.2025.111612","DOIUrl":"10.1016/j.cellsig.2025.111612","url":null,"abstract":"<div><div>The ribosomal protein L6 (RPL6) is significant in the progression of different cancer types. However, its precise role in hepatocellular carcinoma (HCC) remains unclear. This research demonstrated that the expression levels of RPL6 are notably decreased in HCC tissues. The decreased expression of RPL6 is strongly linked to tumor size, the presence of vascular invasion, and a worse prognosis. Functional experiments revealed that the expression of RPL6 impedes the proliferation of HCC cells and the advancement of xenograft tumors. Mechanistically, we found that RPL6 binds to and is degraded by the E3 ubiquitin ligase FBXO22, thereby inhibiting the polyubiquitination and subsequent degradation of p53 by FBXO22. The enhanced activity of p53 further contributes to cell growth inhibition. In contrast, the levels of p53 decreased significantly following RPL6 depletion, indicating that RPL6 is essential for the stabilization of p53. In summary, RPL6 inhibits the proliferation of HCC cells via the FBXO22/p53 signaling pathway, suggesting its potential as a biomarker and a therapeutic target for HCC.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"127 ","pages":"Article 111612"},"PeriodicalIF":4.4,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143022395","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

AP2A1 modulates cell states between senescence and rejuvenation

IF 4.4 2区生物学 Q2 CELL BIOLOGY

Cellular signalling

Pub Date : 2025-01-21 DOI: 10.1016/j.cellsig.2025.111616

Pirawan Chantachotikul , Shiyou Liu , Kana Furukawa , Shinji Deguchi

Aging proceeds with the accumulation of senescent cells in multiple organs. These cells exhibit increased size compared to young cells, which promotes further senescence and age-related diseases. Currently, the molecular mechanism behind the maintenance of such huge cell architecture undergoing senescence remains poorly understood. Here we focus on the reorganization of actin stress fibers induced upon replicative senescence in human fibroblasts, widely used as a senescent cell model. We identified, together with our previous proteomic study, that AP2A1 (alpha 1 adaptin subunit of the adaptor protein 2) is upregulated in senescent cells along the length of enlarged stress fibers. Knockdown of AP2A1 reversed senescence-associated phenotypes, exhibiting features of cellular rejuvenation, while its overexpression in young cells advanced senescence phenotypes. Similar functions of AP2A1 were identified in UV- or drug-induced senescence and were observed in epithelial cells as well. Furthermore, we found that AP2A1 is colocalized with integrin β1, and both proteins move linearly along stress fibers. With the observations that focal adhesions are enlarged in senescent cells and that this coincides with strengthened cell adhesion to the substrate, these results suggest that senescent cells maintain their large size by reinforcing their effective anchorage through integrin β1 translocation along stress fibers. This mechanism may work efficiently in senescent cells, compared with a case relying on random diffusion of integrin β1, given the enlarged cell size and resulting increase in travel time and distance for endocytosed vesicle transportation.

{"title":"AP2A1 modulates cell states between senescence and rejuvenation","authors":"Pirawan Chantachotikul , Shiyou Liu , Kana Furukawa , Shinji Deguchi","doi":"10.1016/j.cellsig.2025.111616","DOIUrl":"10.1016/j.cellsig.2025.111616","url":null,"abstract":"<div><div>Aging proceeds with the accumulation of senescent cells in multiple organs. These cells exhibit increased size compared to young cells, which promotes further senescence and age-related diseases. Currently, the molecular mechanism behind the maintenance of such huge cell architecture undergoing senescence remains poorly understood. Here we focus on the reorganization of actin stress fibers induced upon replicative senescence in human fibroblasts, widely used as a senescent cell model. We identified, together with our previous proteomic study, that AP2A1 (alpha 1 adaptin subunit of the adaptor protein 2) is upregulated in senescent cells along the length of enlarged stress fibers. Knockdown of AP2A1 reversed senescence-associated phenotypes, exhibiting features of cellular rejuvenation, while its overexpression in young cells advanced senescence phenotypes. Similar functions of AP2A1 were identified in UV- or drug-induced senescence and were observed in epithelial cells as well. Furthermore, we found that AP2A1 is colocalized with integrin β1, and both proteins move linearly along stress fibers. With the observations that focal adhesions are enlarged in senescent cells and that this coincides with strengthened cell adhesion to the substrate, these results suggest that senescent cells maintain their large size by reinforcing their effective anchorage through integrin β1 translocation along stress fibers. This mechanism may work efficiently in senescent cells, compared with a case relying on random diffusion of integrin β1, given the enlarged cell size and resulting increase in travel time and distance for endocytosed vesicle transportation.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"127 ","pages":"Article 111616"},"PeriodicalIF":4.4,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143028060","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Non-coding RNAs as mediators of epithelial to mesenchymal transition in metastatic colorectal cancers

IF 4.4 2区生物学 Q2 CELL BIOLOGY

Cellular signalling

Pub Date : 2025-01-20 DOI: 10.1016/j.cellsig.2025.111605

Aisha Shigna Nadukkandy , Britny Blaize , Chethana D Kumar , Giulia Mori , Marco Cordani , Lekha Dinesh Kumar

Colorectal cancer (CRC) remains a leading cause of cancer-related mortality globally, necessitating the development of innovative treatment strategies. Recent research has underscored the significant role of non-coding RNAs (ncRNAs) in CRC pathogenesis, offering new avenues for diagnosis and therapy. In this review, we delve into the intricate roles of various ncRNAs, including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), in CRC progression, epithelial-mesenchymal transition (EMT), metastasis, and drug resistance. We highlight the interaction of these ncRNAs with and regulation of key signaling pathways, such as Wnt/β-catenin, Notch, JAK-STAT, EGFR, and TGF-β, and the functional relevance of these interactions in CRC progression. Additionally, the review highlights the emerging applications of nanotechnology in enhancing the delivery and efficacy of ncRNA-based therapeutics, which could address existing challenges related to specificity and side effects. Future research directions, including advanced diagnostic tools, targeted therapeutics, strategies to overcome drug resistance, and the integration of personalized medicine approaches are discussed. Integrating nanotechnology with a deeper understanding of CRC biology offers the potential for more effective, targeted, and personalized strategies, though further research is essential to validate these approaches.

{"title":"Non-coding RNAs as mediators of epithelial to mesenchymal transition in metastatic colorectal cancers","authors":"Aisha Shigna Nadukkandy , Britny Blaize , Chethana D Kumar , Giulia Mori , Marco Cordani , Lekha Dinesh Kumar","doi":"10.1016/j.cellsig.2025.111605","DOIUrl":"10.1016/j.cellsig.2025.111605","url":null,"abstract":"<div><div>Colorectal cancer (CRC) remains a leading cause of cancer-related mortality globally, necessitating the development of innovative treatment strategies. Recent research has underscored the significant role of non-coding RNAs (ncRNAs) in CRC pathogenesis, offering new avenues for diagnosis and therapy. In this review, we delve into the intricate roles of various ncRNAs, including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), in CRC progression, epithelial-mesenchymal transition (EMT), metastasis, and drug resistance. We highlight the interaction of these ncRNAs with and regulation of key signaling pathways, such as Wnt/β-catenin, Notch, JAK-STAT, EGFR, and TGF-β, and the functional relevance of these interactions in CRC progression. Additionally, the review highlights the emerging applications of nanotechnology in enhancing the delivery and efficacy of ncRNA-based therapeutics, which could address existing challenges related to specificity and side effects. Future research directions, including advanced diagnostic tools, targeted therapeutics, strategies to overcome drug resistance, and the integration of personalized medicine approaches are discussed. Integrating nanotechnology with a deeper understanding of CRC biology offers the potential for more effective, targeted, and personalized strategies, though further research is essential to validate these approaches.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"127 ","pages":"Article 111605"},"PeriodicalIF":4.4,"publicationDate":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143022392","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

CircMRP4 orchestrates podocytes injury via the miR-499-5p/RRAGB/mTORC1 axis in diabetic kidney disease

IF 4.4 2区生物学 Q2 CELL BIOLOGY

Cellular signalling

Pub Date : 2025-01-20 DOI: 10.1016/j.cellsig.2025.111611

Shujun Deng , Lingzhi Huang , Yawen Shao , Yongsheng Xie , Siming Yuan , Liqin Tang

Diabetic kidney disease² (DKD) is a chronic complication of diabetes characterized by kidney damage due to persistent hyperglycemia. A growing number of evidence indicated that circular RNAs³ (circRNAs) play a crucial role in diabetes and associated complications. However, the function and mechanism of circRNAs in DKD remain unclear. Herein, we investigated the expression profiles of circRNAs in DKD mice compared to non-diabetic mice using RNA-seq analysis. A novel circRNA, circMRP4, derived from the circularization of Multidrug resistance-associated protein 4⁴ (MRP4) was identified. The expression of circMRP4 was significantly increased in both kidney tissues of DKD and mouse podocytes exposed to high glucose⁵ (HG). In addition, knockdown of circMRP4 alleviated podocytes apoptosis and inflammation induced by HG, while circMRP4 overexpression resulted in the opposite impact. Dual-luciferase reporter, RNA immunoprecipitation and RNA pull-down assay demonstrated that circMRP4 could directly target miR-499-5p which was closely associated with podocytes apoptosis and inflammation. Furthermore, circMRP4 was found to act as a sponge for miR-499-5p, leading to the upregulation of its target RRAGB, thereby activating the mTORC1/P70S6K signaling. In summary, our findings suggested that circMRP4 mediated podocytes apoptosis and inflammation in DKD by modulating the miR-499-5p/RRAGB/mTORC1/P70S6K axis, highlighting circMRP4 as a potential therapeutic target for DKD.

{"title":"CircMRP4 orchestrates podocytes injury via the miR-499-5p/RRAGB/mTORC1 axis in diabetic kidney disease","authors":"Shujun Deng , Lingzhi Huang , Yawen Shao , Yongsheng Xie , Siming Yuan , Liqin Tang","doi":"10.1016/j.cellsig.2025.111611","DOIUrl":"10.1016/j.cellsig.2025.111611","url":null,"abstract":"<div><div>Diabetic kidney disease<span><span><sup>2</sup></span></span> (DKD) is a chronic complication of diabetes characterized by kidney damage due to persistent hyperglycemia. A growing number of evidence indicated that circular RNAs<span><span><sup>3</sup></span></span> (circRNAs) play a crucial role in diabetes and associated complications. However, the function and mechanism of circRNAs in DKD remain unclear. Herein, we investigated the expression profiles of circRNAs in DKD mice compared to non-diabetic mice using RNA-seq analysis. A novel circRNA, circMRP4, derived from the circularization of Multidrug resistance-associated protein 4<span><span><sup>4</sup></span></span> (MRP4) was identified. The expression of circMRP4 was significantly increased in both kidney tissues of DKD and mouse podocytes exposed to high glucose<span><span><sup>5</sup></span></span> (HG). In addition, knockdown of circMRP4 alleviated podocytes apoptosis and inflammation induced by HG, while circMRP4 overexpression resulted in the opposite impact. Dual-luciferase reporter, RNA immunoprecipitation and RNA pull-down assay demonstrated that circMRP4 could directly target miR-499-5p which was closely associated with podocytes apoptosis and inflammation. Furthermore, circMRP4 was found to act as a sponge for miR-499-5p, leading to the upregulation of its target RRAGB, thereby activating the mTORC1/P70S6K signaling. In summary, our findings suggested that circMRP4 mediated podocytes apoptosis and inflammation in DKD by modulating the miR-499-5p/RRAGB/mTORC1/P70S6K axis, highlighting circMRP4 as a potential therapeutic target for DKD.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"127 ","pages":"Article 111611"},"PeriodicalIF":4.4,"publicationDate":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143022378","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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