Pub Date : 2024-09-05DOI: 10.1016/j.cellsig.2024.111382
Oxidative stress causes damage to cancer cells and plays an important role in cancer therapy. Antagonizing oxidative stress is crucial for cancer cells to survive during the oxidation-based therapy. In this study, we defined the role of nuclear receptor co-activator 7 (NCOA7) in anti-oxidation in lung cancer cells and found that NCOA7 protects lung cancer A549 cells from the oxidative damage caused by hydrogen peroxide. Knockdown of NCOA7 in A549 cells significantly enhanced the hydrogen peroxide-caused inhibition of cell proliferation and migration, and markedly increased the damage effect of hydrogen peroxide on F-actin and focal adhesion structure, suggesting that NCOA7 protects F-actin and focal adhesion structure, thus the cell proliferation and migration, from oxidation-caused damage. Mechanistically, the anti-oxidation effect of NCOA7 is mediated by its nuclear receptor binding domain, the ERbd domain, suggesting that the anti-oxidation function of NCOA7 is dependent on its nuclear receptor co-activator activity. Our studies identified NCOA7 as an anti-oxidative protein through its nuclear receptor co-activator function and revealed the mechanism underlying the anti-oxidative effect of NCOA7 on cancer cell proliferation and migration.
{"title":"Nuclear receptor coactivator 7 (NCOA7) protects cancer cells from oxidative damage through its ERbd domain","authors":"","doi":"10.1016/j.cellsig.2024.111382","DOIUrl":"10.1016/j.cellsig.2024.111382","url":null,"abstract":"<div><p>Oxidative stress causes damage to cancer cells and plays an important role in cancer therapy. Antagonizing oxidative stress is crucial for cancer cells to survive during the oxidation-based therapy. In this study, we defined the role of nuclear receptor co-activator 7 (NCOA7) in anti-oxidation in lung cancer cells and found that NCOA7 protects lung cancer A549 cells from the oxidative damage caused by hydrogen peroxide. Knockdown of NCOA7 in A549 cells significantly enhanced the hydrogen peroxide-caused inhibition of cell proliferation and migration, and markedly increased the damage effect of hydrogen peroxide on F-actin and focal adhesion structure, suggesting that NCOA7 protects F-actin and focal adhesion structure, thus the cell proliferation and migration, from oxidation-caused damage. Mechanistically, the anti-oxidation effect of NCOA7 is mediated by its nuclear receptor binding domain, the ERbd domain, suggesting that the anti-oxidation function of NCOA7 is dependent on its nuclear receptor co-activator activity. Our studies identified NCOA7 as an anti-oxidative protein through its nuclear receptor co-activator function and revealed the mechanism underlying the anti-oxidative effect of NCOA7 on cancer cell proliferation and migration.</p></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":null,"pages":null},"PeriodicalIF":4.4,"publicationDate":"2024-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142145228","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}
Pub Date : 2024-09-05DOI: 10.1016/j.cellsig.2024.111384
This study aimed to investigate the effects of hepatic microRNA-122 (miR-122) on Sortilin-mediated apolipoprotein B100 (apoB-100) secretion, and on aortic lipid deposition and atherosclerosis (AS) lesions and to clarify the antiatherosclerotic mechanism of 6-methylcoumarin (6-MC) via the modulation of miR-122. Bioinformatics analysis revealed that miR-122 was putatively overexpressed in a liver-specific manner and was downregulated in steatotic livers. miR-122 was shown to suppress the expression of Sortilin by complementarily pairing to the 3′-untranslated region (3’-UTR) of Sortilin mRNA via bioinformatics and dual-luciferase reporter assays, impeding Sortilin-mediated apoB-100 secretion from HepG2 cells. Administration of 6-MC significantly upregulated hepatocellular miR-122 levels, reducing Sortilin expression and apoB-100 secretion in HepG2 cells. The miR-122 mimic vigorously enhanced 6-MC-depressed Sortilin expression, while miR-122 inhibitor repealed the inhibitory effect of 6-MC on Sortilin expression to some extent in HepG2 cells. After internal intervention with the miR-122 precursor, and 6-MC supplementation alone or in combination with the miR-122 sponge led to the reduction in blood triglyceride (TG) levels, low-density lipoprotein-cholesterol (LDL-C) and apoB-100 and a reduction in aortic lipid deposition and AS lesions in apolipoprotein E-deficient (ApoE−/−) mice fed a high fat diet (HFD). The hepatic levels of Sortilin and apoB-100 expression were also decreased in these treated mice. In conclusion, miR-122 suppresses Sortilin expression and Sortilin-mediated apoB-100 secretion to resist circulating LDL production and aortic AS development, which is enhanced by 6-MC-upregulated miR-122 in the liver.
{"title":"6-methylcoumarin/miR-122 suppresses hepatic Sortilin-mediated ApoB-100 secretion to attenuate aortic atherosclerosis","authors":"","doi":"10.1016/j.cellsig.2024.111384","DOIUrl":"10.1016/j.cellsig.2024.111384","url":null,"abstract":"<div><p>This study aimed to investigate the effects of hepatic microRNA-122 (miR-122) on Sortilin-mediated apolipoprotein B100 (apoB-100) secretion, and on aortic lipid deposition and atherosclerosis (AS) lesions and to clarify the antiatherosclerotic mechanism of 6-methylcoumarin (6-MC) via the modulation of miR-122. Bioinformatics analysis revealed that miR-122 was putatively overexpressed in a liver-specific manner and was downregulated in steatotic livers. miR-122 was shown to suppress the expression of Sortilin by complementarily pairing to the 3′-untranslated region (3’-UTR) of Sortilin mRNA via bioinformatics and dual-luciferase reporter assays, impeding Sortilin-mediated apoB-100 secretion from HepG2 cells. Administration of 6-MC significantly upregulated hepatocellular miR-122 levels, reducing Sortilin expression and apoB-100 secretion in HepG2 cells. The miR-122 mimic vigorously enhanced 6-MC-depressed Sortilin expression, while miR-122 inhibitor repealed the inhibitory effect of 6-MC on Sortilin expression to some extent in HepG2 cells. After internal intervention with the miR-122 precursor, and 6-MC supplementation alone or in combination with the miR-122 sponge led to the reduction in blood triglyceride (TG) levels, low-density lipoprotein-cholesterol (LDL-C) and apoB-100 and a reduction in aortic lipid deposition and AS lesions in apolipoprotein <em>E</em>-deficient (ApoE<sup>−/−</sup>) mice fed a high fat diet (HFD). The hepatic levels of Sortilin and apoB-100 expression were also decreased in these treated mice. In conclusion, miR-122 suppresses Sortilin expression and Sortilin-mediated apoB-100 secretion to resist circulating LDL production and aortic AS development, which is enhanced by 6-MC-upregulated miR-122 in the liver.</p></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":null,"pages":null},"PeriodicalIF":4.4,"publicationDate":"2024-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142145225","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}
Pub Date : 2024-09-05DOI: 10.1016/j.cellsig.2024.111383
Background
High expression of low-density lipoprotein receptor related protein 11 (LRP11) has been associated with unfavorable prognosis of breast cancer (BC). This study explores the exact roles of LRP11 in BC progression and investigates the associated mechanism.
Methods
LRP11 expression in BC tissues and cells was determined by immunohistochemistry or RT-qPCR. LRP11 upregulation was induced in two human BC cell lines to investigate its impact on cell proliferation, migration, and invasion. Its regulation on immune activity was assessed by detecting PD-L1 protein levels and generating a co-culture system of cancer cells and CD8+ T cells. Mouse allograft tumor models were generated to analyze the function of LRP11 in tumorigenesis and immune activity in vivo. Gain-of-function assays of SRY-box transcription factor 13 (SOX13) were performed to investigate its function in development and immunosuppression of BC.
Results
LRP11 was found to be highly expressed in BC tissues and cells, presenting an association with unfavorable prognosis of patients. Artificial upregulation of LRP11 in BC cells triggered malignant properties of cells, enhancing β-catenin-mediated transcriptional activation of PD-L1, thus decreasing immune activity of the co-cultured CD8+ T cells. Consistently, LRP11 upregulation in mouse 4 T1 cells and promoted tumorigenesis and immune evasion in mice. SOX13 was found to bind the LRP11 promoter for transcriptional activation. Upregulation of SOX13 similarly promoted growth of BC cells and immunosuppression, with its oncogenic effects blocked by the additional LRP11 knockdown.
Conclusion
This study demonstrates that SOX13 is responsible for LRP11 transcription activation, leading to increased malignant phenotype of BC cells and diminished activity CD8+ T cells. This evidence highlights SOX13 and LRP11 as promising novel therapeutic targets to reduce malignant phenotype of BC cells and overcome immunosuppression.
背景:低密度脂蛋白受体相关蛋白11(LRP11)的高表达与乳腺癌(BC)的不良预后有关。本研究探讨了 LRP11 在乳腺癌进展中的确切作用,并研究了相关机制:方法:通过免疫组化或 RT-qPCR 检测 LRP11 在 BC 组织和细胞中的表达。在两种人类 BC 细胞系中诱导 LRP11 上调,研究其对细胞增殖、迁移和侵袭的影响。通过检测 PD-L1 蛋白水平和生成癌细胞与 CD8+ T 细胞的共培养系统,评估了 LRP11 对免疫活性的调节作用。为了分析 LRP11 在体内肿瘤发生和免疫活动中的功能,我们制作了小鼠异种移植肿瘤模型。对SRY-box转录因子13(SOX13)进行了功能增益分析,以研究其在BC的发育和免疫抑制中的功能:结果:研究发现 LRP11 在 BC 组织和细胞中高表达,与患者的不良预后有关。LRP11在BC细胞中的人为上调会激发细胞的恶性特性,增强β-catenin介导的PD-L1转录激活,从而降低共培养CD8+ T细胞的免疫活性。同样,LRP11 在小鼠 4 T1 细胞中上调,促进了小鼠的肿瘤发生和免疫逃避。研究发现,SOX13 可与 LRP11 启动子结合以激活转录。SOX13的上调同样促进了BC细胞的生长和免疫抑制,其致癌作用被额外的LRP11敲除所阻断:这项研究表明,SOX13是LRP11转录激活的原因,导致BC细胞恶性表型增加和CD8+ T细胞活性降低。这些证据表明,SOX13和LRP11是降低BC细胞恶性表型和克服免疫抑制的有希望的新型治疗靶点。
{"title":"SOX13-mediated transcription of LRP11 enhances malignant properties of tumor cells and CD8+ T cell inactivation in breast cancer through the β-catenin/PD-L1 axis","authors":"","doi":"10.1016/j.cellsig.2024.111383","DOIUrl":"10.1016/j.cellsig.2024.111383","url":null,"abstract":"<div><h3>Background</h3><p>High expression of low-density lipoprotein receptor related protein 11 (LRP11) has been associated with unfavorable prognosis of breast cancer (BC). This study explores the exact roles of LRP11 in BC progression and investigates the associated mechanism.</p></div><div><h3>Methods</h3><p>LRP11 expression in BC tissues and cells was determined by immunohistochemistry or RT-qPCR. LRP11 upregulation was induced in two human BC cell lines to investigate its impact on cell proliferation, migration, and invasion. Its regulation on immune activity was assessed by detecting PD-L1 protein levels and generating a co-culture system of cancer cells and CD8<sup>+</sup> T cells. Mouse allograft tumor models were generated to analyze the function of LRP11 in tumorigenesis and immune activity in vivo. Gain-of-function assays of SRY-box transcription factor 13 (SOX13) were performed to investigate its function in development and immunosuppression of BC.</p></div><div><h3>Results</h3><p>LRP11 was found to be highly expressed in BC tissues and cells, presenting an association with unfavorable prognosis of patients. Artificial upregulation of LRP11 in BC cells triggered malignant properties of cells, enhancing β-catenin-mediated transcriptional activation of PD-L1, thus decreasing immune activity of the co-cultured CD8<sup>+</sup> T cells. Consistently, LRP11 upregulation in mouse 4 T1 cells and promoted tumorigenesis and immune evasion in mice. SOX13 was found to bind the LRP11 promoter for transcriptional activation. Upregulation of SOX13 similarly promoted growth of BC cells and immunosuppression, with its oncogenic effects blocked by the additional LRP11 knockdown.</p></div><div><h3>Conclusion</h3><p>This study demonstrates that SOX13 is responsible for LRP11 transcription activation, leading to increased malignant phenotype of BC cells and diminished activity CD8<sup>+</sup> T cells. This evidence highlights SOX13 and LRP11 as promising novel therapeutic targets to reduce malignant phenotype of BC cells and overcome immunosuppression.</p></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":null,"pages":null},"PeriodicalIF":4.4,"publicationDate":"2024-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142145230","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}
Pub Date : 2024-09-04DOI: 10.1016/j.cellsig.2024.111378
Crosstalk between cancer-associated fibroblasts (CAFs) and tumour cells plays a critical role in multiple cancers, including hepatocellular carcinoma (HCC). CAFs contribute to tumorigenesis by secreting growth factors, modifying the extracellular matrix, supporting angiogenesis, and suppressing antitumor immune responses. However, effect and mechanism of CAF-mediated promotion of hepatocellular carcinoma cells are still unclear. In study, we demonstrated CAFs promoted the proliferation and inhibited the apoptosis of HCC cells by secreting interleukin-6 (IL-6), which induced autocrine insulin-like growth factor-1 (IGF-1) in HCC. IGF-1 promoted the progression and chemoresistance of HCC. IGF-1 receptor (IGF-1R) inhibitor NT157 abrogated the effect of CAF-derived IL-6 and autocrine IGF-1 on HCC. Mechanistic studies revealed that NT157 decreased IL-6-induced IGF-1 expression by inhibiting STAT3 phosphorylation and led to IRS-1 degradation, which mediated the proliferation of tumour by activating AKT signalling in ERK-dependent manner. Inhibition of IGF-1R also enhanced the therapeutic effect of sorafenib on HCC, especially chemoresistant tumours.
Statement of significance
Our study showed IL-6-IGF-1 axis played crucial roles in the crosstalk between HCC and CAFs, providing NT157 inhibited of STAT3 and IGF-1R as a new targeted therapy in combination with sorafenib.
{"title":"Cancer-associated fibroblasts promote the progression and chemoresistance of HCC by inducing IGF-1","authors":"","doi":"10.1016/j.cellsig.2024.111378","DOIUrl":"10.1016/j.cellsig.2024.111378","url":null,"abstract":"<div><p>Crosstalk between cancer-associated fibroblasts (CAFs) and tumour cells plays a critical role in multiple cancers, including hepatocellular carcinoma (HCC). CAFs contribute to tumorigenesis by secreting growth factors, modifying the extracellular matrix, supporting angiogenesis, and suppressing antitumor immune responses. However, effect and mechanism of CAF-mediated promotion of hepatocellular carcinoma cells are still unclear. In study, we demonstrated CAFs promoted the proliferation and inhibited the apoptosis of HCC cells by secreting interleukin-6 (IL-6), which induced autocrine insulin-like growth factor-1 (IGF-1) in HCC. IGF-1 promoted the progression and chemoresistance of HCC. IGF-1 receptor (IGF-1R) inhibitor NT157 abrogated the effect of CAF-derived IL-6 and autocrine IGF-1 on HCC. Mechanistic studies revealed that NT157 decreased IL-6-induced IGF-1 expression by inhibiting STAT3 phosphorylation and led to IRS-1 degradation, which mediated the proliferation of tumour by activating AKT signalling in ERK-dependent manner. Inhibition of IGF-1R also enhanced the therapeutic effect of sorafenib on HCC, especially chemoresistant tumours.</p></div><div><h3>Statement of significance</h3><p>Our study showed IL-6-IGF-1 axis played crucial roles in the crosstalk between HCC and CAFs, providing NT157 inhibited of STAT3 and IGF-1R as a new targeted therapy in combination with sorafenib.</p></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":null,"pages":null},"PeriodicalIF":4.4,"publicationDate":"2024-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0898656824003462/pdfft?md5=ab8891a0c1f626bdf68c3ffe002f68ac&pid=1-s2.0-S0898656824003462-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142145226","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}
Pub Date : 2024-09-03DOI: 10.1016/j.cellsig.2024.111376
While certain members of ubiquitin-coupled enzymes (E2s) have garnered attention as potential therapeutic targets across diverse diseases, research progress on Ubiquitin-Conjugating Enzyme 5 (UBC5)—a pivotal member of the E2s family involved in crucial cellular processes such as apoptosis, DNA repair, and signal transduction—has been relatively sluggish. Previous findings suggest that UBC5 plays a vital role in the ubiquitination of various target proteins implicated in diseases and homeostasis, particularly in various cancer types. This review comprehensively introduces the structure and biological functions of UBC5, with a specific focus on its contributions to the onset and advancement of diverse diseases. It suggests that targeting UBC5 holds promise as a therapeutic approach for disease therapy. Recent discoveries highlighting the high homology between UBC5, UBC1, and UBC4 have provided insight into the mechanism of UBC5 in protein degradation and the regulation of cellular functions. As our comprehension of the structural distinctions among UBC5 and its homologues, namely UBC1 and UBC4, advances, our understanding of UBC5's functional significance also expands.
{"title":"Unraveling the role of ubiquitin-conjugating enzyme 5 (UBC5) in disease pathogenesis: A comprehensive review","authors":"","doi":"10.1016/j.cellsig.2024.111376","DOIUrl":"10.1016/j.cellsig.2024.111376","url":null,"abstract":"<div><p>While certain members of ubiquitin-coupled enzymes (E2s) have garnered attention as potential therapeutic targets across diverse diseases, research progress on Ubiquitin-Conjugating Enzyme 5 (UBC5)—a pivotal member of the E2s family involved in crucial cellular processes such as apoptosis, DNA repair, and signal transduction—has been relatively sluggish. Previous findings suggest that UBC5 plays a vital role in the ubiquitination of various target proteins implicated in diseases and homeostasis, particularly in various cancer types. This review comprehensively introduces the structure and biological functions of UBC5, with a specific focus on its contributions to the onset and advancement of diverse diseases. It suggests that targeting UBC5 holds promise as a therapeutic approach for disease therapy. Recent discoveries highlighting the high homology between UBC5, UBC1, and UBC4 have provided insight into the mechanism of UBC5 in protein degradation and the regulation of cellular functions. As our comprehension of the structural distinctions among UBC5 and its homologues, namely UBC1 and UBC4, advances, our understanding of UBC5's functional significance also expands.</p></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":null,"pages":null},"PeriodicalIF":4.4,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142139458","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}
Pub Date : 2024-09-03DOI: 10.1016/j.cellsig.2024.111380
Gliomas, the most prevalent malignant brain tumors in the central nervous system, are marked by rapid growth, high recurrence rates, and poor prognosis. Glioblastoma (GBM) stands out as the most aggressive subtype, characterized by significant heterogeneity. The etiology of gliomas remains elusive. RNA modifications, particularly reversible methylation, play a crucial role in regulating transcription and translation throughout the RNA lifecycle. Increasing evidence highlights the prevalence of RNA methylation in primary central nervous system malignancies, underscoring its pivotal role in glioma pathogenesis. This review focuses on recent findings regarding changes in RNA methylation expression and their effects on glioma development and progression, including N6-methyladenosine (m6A), 5-methylcytosine (m5C), N1-methyladenosine (m1A), and N7-methylguanosine (m7G). Given the extensive roles of RNA methylation in gliomas, the potential of RNA methylation-related regulators as prognostic markers and therapeutic targets was also explored, aiming to enhance clinical management and improve patient outcomes.
{"title":"Unveiling the role of RNA methylation in glioma: Mechanisms, prognostic biomarkers, and therapeutic targets","authors":"","doi":"10.1016/j.cellsig.2024.111380","DOIUrl":"10.1016/j.cellsig.2024.111380","url":null,"abstract":"<div><p>Gliomas, the most prevalent malignant brain tumors in the central nervous system, are marked by rapid growth, high recurrence rates, and poor prognosis. Glioblastoma (GBM) stands out as the most aggressive subtype, characterized by significant heterogeneity. The etiology of gliomas remains elusive. RNA modifications, particularly reversible methylation, play a crucial role in regulating transcription and translation throughout the RNA lifecycle. Increasing evidence highlights the prevalence of RNA methylation in primary central nervous system malignancies, underscoring its pivotal role in glioma pathogenesis. This review focuses on recent findings regarding changes in RNA methylation expression and their effects on glioma development and progression, including N6-methyladenosine (m6A), 5-methylcytosine (m5C), N1-methyladenosine (m1A), and N7-methylguanosine (m7G). Given the extensive roles of RNA methylation in gliomas, the potential of RNA methylation-related regulators as prognostic markers and therapeutic targets was also explored, aiming to enhance clinical management and improve patient outcomes.</p></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":null,"pages":null},"PeriodicalIF":4.4,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142139459","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}
Pub Date : 2024-09-02DOI: 10.1016/j.cellsig.2024.111379
Background and aims
Acetaminophen (APAP) is the main cause of acute liver injury (ALI) in the Western. Our previous study has shown that fenofibrate activated hepatic expression of fibroblast growth factor 21 (FGF21) can protect the liver form APAP injuries by promoting autophagy. However, the underlying mechanism involved in FGF21-mediated autophagy remains unsolved.
Methods
The ALI mice model was established by intraperitoneal injection of APAP. To investigate the influence of FGF21 on autophagy and Sirt1 expression in APAP-induced ALI, FGF21 knockout (FGF21KO) mice and exogenously supplemented mouse recombinant FGF21 protein were used. In addition, primary isolated hepatocytes and the Sirt1 inhibitor EX527 were used to observe whether FGF21 activated autophagy in APAP injury is regulated by Sirt1 at the cellular level.
Results
FGF21, Sirt1, and autophagy levels increased in mice with acute liver injury (ALI) and in primary cultured hepatocytes. Deletion of the FGF21 gene exacerbated APAP-induced liver necrosis and oxidative stress, and decreased mitochondrial potential. It also reduced the mRNA and protein levels of autophagy-related proteins such as Sirt1, LC3-II, and p62, as well as the number of autophagosomes. Replenishment of FGF21 reversed these processes. In addition, EX527 partially counteracted the protective effect of FGF21 by worsening oxidative damage, mitochondrial damage, and reducing autophagy in primary liver cells treated with APAP.
Conclusion
FGF21 increases autophagy by upregulating Sirt1 to alleviate APAP-induced injuries.
{"title":"Fibroblast growth factor 21 alleviates acetaminophen induced acute liver injury by activating Sirt1 mediated autophagy","authors":"","doi":"10.1016/j.cellsig.2024.111379","DOIUrl":"10.1016/j.cellsig.2024.111379","url":null,"abstract":"<div><h3>Background and aims</h3><p>Acetaminophen (APAP) is the main cause of acute liver injury (ALI) in the Western. Our previous study has shown that fenofibrate activated hepatic expression of fibroblast growth factor 21 (FGF21) can protect the liver form APAP injuries by promoting autophagy. However, the underlying mechanism involved in FGF21-mediated autophagy remains unsolved.</p></div><div><h3>Methods</h3><p>The ALI mice model was established by intraperitoneal injection of APAP. To investigate the influence of FGF21 on autophagy and Sirt1 expression in APAP-induced ALI, FGF21 knockout (FGF21KO) mice and exogenously supplemented mouse recombinant FGF21 protein were used. In addition, primary isolated hepatocytes and the Sirt1 inhibitor EX527 were used to observe whether FGF21 activated autophagy in APAP injury is regulated by Sirt1 at the cellular level.</p></div><div><h3>Results</h3><p>FGF21, Sirt1, and autophagy levels increased in mice with acute liver injury (ALI) and in primary cultured hepatocytes. Deletion of the FGF21 gene exacerbated APAP-induced liver necrosis and oxidative stress, and decreased mitochondrial potential. It also reduced the mRNA and protein levels of autophagy-related proteins such as Sirt1, LC3-II, and p62, as well as the number of autophagosomes. Replenishment of FGF21 reversed these processes. In addition, EX527 partially counteracted the protective effect of FGF21 by worsening oxidative damage, mitochondrial damage, and reducing autophagy in primary liver cells treated with APAP.</p></div><div><h3>Conclusion</h3><p>FGF21 increases autophagy by upregulating Sirt1 to alleviate APAP-induced injuries.</p></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":null,"pages":null},"PeriodicalIF":4.4,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142131981","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}
Pub Date : 2024-09-01DOI: 10.1016/j.cellsig.2024.111377
Background
Nitric oxide and Reactive Nitrogen Species are known to effect tumorigenicity. GSNO is one of the main NO carrying signalling moiety in cell. In the current study, we tried to delve into the effect of GSNO induced nitrosative stress in three different myelogenous leukemic K562, U937 and THP-1 cell lines.
Method
WST-8 assay was performed to investigate cell viability. RT-PCR and western-blot analysis were done to investigate mRNA and protein expression. Spectrophotometric and fluorimetric assays were done to investigate enzyme activities.
Result
We found that GSNO exposure led to reduced cell viability and the mode of cell death in K562 was non apoptotic in nature. GSNO promoted impaired autophagic flux and necroptosis. GSNO treatment heightened phosphorylation of AMPK and TSC2 and inhibited mTOR pathway. We observed increase in NAD+/ NADH ratio following GSNO treatment. Increase in both SIRT1 m-RNA and protein expression was observed. While total SIRT activity remained unaltered. GSNO increased tumor suppressor TAp73/ oncogenic ∆Np73 ratio in K562 cells which was correlated with cell mortality. Surprisingly, GSNO did not alter cellular redox status or redox associated protein expression. However, steep increase in total SNO and PSNO content was observed. Furthermore, inhibition of autophagy, AMPK phosphorylation or SIRT1 exacerbated the effect of GSNO. Altogether our work gives insights into GSNO mediated necroptotic event in K562 cells which can be excavated to develop NO based anticancer therapeutics.
Conclusion
Our data suggests that GSNO could induce necroptotic cell death in K562 through mitochondrial dysfunctionality and PTM of different cellular proteins.
{"title":"S-nitrosoglutathione (GSNO) induces necroptotic cell death in K562 cells: Involvement of p73, TSC2 and SIRT1","authors":"","doi":"10.1016/j.cellsig.2024.111377","DOIUrl":"10.1016/j.cellsig.2024.111377","url":null,"abstract":"<div><h3>Background</h3><p>Nitric oxide and Reactive Nitrogen Species are known to effect tumorigenicity. GSNO is one of the main NO carrying signalling moiety in cell. In the current study, we tried to delve into the effect of GSNO induced nitrosative stress in three different myelogenous leukemic K562, U937 and THP-1 cell lines.</p></div><div><h3>Method</h3><p>WST-8 assay was performed to investigate cell viability. RT-PCR and western-blot analysis were done to investigate mRNA and protein expression. Spectrophotometric and fluorimetric assays were done to investigate enzyme activities.</p></div><div><h3>Result</h3><p>We found that GSNO exposure led to reduced cell viability and the mode of cell death in K562 was non apoptotic in nature. GSNO promoted impaired autophagic flux and necroptosis. GSNO treatment heightened phosphorylation of AMPK and TSC2 and inhibited mTOR pathway. We observed increase in NAD<sup>+</sup>/ NADH ratio following GSNO treatment. Increase in both SIRT1 m-RNA and protein expression was observed. While total SIRT activity remained unaltered. GSNO increased tumor suppressor TAp73/ oncogenic ∆Np73 ratio in K562 cells which was correlated with cell mortality. Surprisingly, GSNO did not alter cellular redox status or redox associated protein expression. However, steep increase in total SNO and PSNO content was observed. Furthermore, inhibition of autophagy, AMPK phosphorylation or SIRT1 exacerbated the effect of GSNO. Altogether our work gives insights into GSNO mediated necroptotic event in K562 cells which can be excavated to develop NO based anticancer therapeutics.</p></div><div><h3>Conclusion</h3><p>Our data suggests that GSNO could induce necroptotic cell death in K562 through mitochondrial dysfunctionality and PTM of different cellular proteins.</p></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":null,"pages":null},"PeriodicalIF":4.4,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142119120","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}
Pub Date : 2024-08-30DOI: 10.1016/j.cellsig.2024.111370
Acute myocardial infarction (AMI) is the leading cause of death worldwide, and reperfusion therapy is a critical therapeutic approach to reduce myocardial ischemic injury and minimize infarct size. However, ischemia/reperfusion (I/R) itself also causes myocardial injury, and inflammation is an essential mechanism by which it leads to myocardial injury, with macrophages as crucial immune cells in this process. Macrophages are innate immune cells that maintain tissue homeostasis, host defence during pathogen infection, and repair during tissue injury. During the acute phase of I/R, M1-type macrophages generate a pro-inflammatory milieu, clear necrotic myocardial tissue, and further recruit mononuclear (CCR2+) macrophages. Over time, the reparative (M2 type) macrophages gradually became dominant. In recent years, metabolic studies have shown a clear correlation between the metabolic profile of macrophages and their phenotype and function. M1-type macrophages are mainly characterized by glycolytic energy supply, and their tricarboxylic acid (TCA) cycle and mitochondrial oxidative phosphorylation (OXPHOS) processes are impaired. In contrast, M2 macrophages rely primarily on OXPHOS for energy. Changing the metabolic profile of macrophages can alter the macrophage phenotype. Altered energy pathways are also present in macrophages during I/R, and intervention in this process contributes to earlier and greater M2 macrophage infiltration, which may be a potential target for the treatment of myocardial I/R injury. Therefore, this paper mainly reviews the characteristics of macrophage energy metabolism alteration and phenotypic transition during I/R and its mechanism of mediating myocardial injury to provide a basis for further research in this field.
{"title":"Advances in macrophage metabolic reprogramming in myocardial ischemia-reperfusion","authors":"","doi":"10.1016/j.cellsig.2024.111370","DOIUrl":"10.1016/j.cellsig.2024.111370","url":null,"abstract":"<div><p>Acute myocardial infarction (AMI) is the leading cause of death worldwide, and reperfusion therapy is a critical therapeutic approach to reduce myocardial ischemic injury and minimize infarct size. However, ischemia/reperfusion (I/R) itself also causes myocardial injury, and inflammation is an essential mechanism by which it leads to myocardial injury, with macrophages as crucial immune cells in this process. Macrophages are innate immune cells that maintain tissue homeostasis, host defence during pathogen infection, and repair during tissue injury. During the acute phase of I/R, M1-type macrophages generate a pro-inflammatory milieu, clear necrotic myocardial tissue, and further recruit mononuclear (CCR2<sup>+</sup>) macrophages. Over time, the reparative (M2 type) macrophages gradually became dominant. In recent years, metabolic studies have shown a clear correlation between the metabolic profile of macrophages and their phenotype and function. M1-type macrophages are mainly characterized by glycolytic energy supply, and their tricarboxylic acid (TCA) cycle and mitochondrial oxidative phosphorylation (OXPHOS) processes are impaired. In contrast, M2 macrophages rely primarily on OXPHOS for energy. Changing the metabolic profile of macrophages can alter the macrophage phenotype. Altered energy pathways are also present in macrophages during I/R, and intervention in this process contributes to earlier and greater M2 macrophage infiltration, which may be a potential target for the treatment of myocardial I/R injury. Therefore, this paper mainly reviews the characteristics of macrophage energy metabolism alteration and phenotypic transition during I/R and its mechanism of mediating myocardial injury to provide a basis for further research in this field.</p></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":null,"pages":null},"PeriodicalIF":4.4,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142097520","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}
Pub Date : 2024-08-30DOI: 10.1016/j.cellsig.2024.111374
Sepsis is a systemic inflammatory disease that can cause multiple organ damage. Septic patients with cardiac dysfunction have a significantly higher mortality. Based on the results of bioinformatics analysis, weighted gene co-expression network analysis (WGCNA), we found that Erbin is vital in cardiomyocyte. However, the function of Erbin in sepsis-induced cardiomyopathy (SIC) has not been explicitly studied. We discussed the role of Erbin in SIC by employing the Erbin−/− mice and HL-1 cardiomyocyte. An in vitro model of inflammation in HL-1 was used to confirm stimulation with lipopolysaccharide (LPS) and a mouse model of cecal ligation and puncture (CLP) to study the molecular mechanisms under SIC. Transmission electron microscopy (TEM) was used to characterize the morphological characteristics at the ultrastructural level. The expressions of Erbin, p-RIPK1, RIPK1, p-RIPK3, RIPK3, p-MLKL, MLKL, p-PKA, PKA, p-CREB and CREB were detected by western blot. qPCR analysis was applied to detect TNF-α, IL-1β, IL-6, RIPK1 and MLKL mRNA expression. Cell survival was detected by CCK-8 assay and the levels of c TnI concentration were detected by ELISA kit. Our study revealed that necroptosis and inflammation were activated in cardiomyocytes during sepsis and deficiency of Erbin aggravated them. Furthermore, deficiency of Erbin exacerbated systolic dysfunction including the decline of LVEF and LVFS induced by CLP. Overexpression of Erbin alleviated necroptosis and inflammation by activating PKA/CREB pathway. Our research elucidates a noval mechanism whereby Erbin participates in SIC, providing a promising therapeutic target for myocardial dysfunction during sepsis.
败血症是一种全身性炎症疾病,可造成多器官损伤。有心脏功能障碍的败血症患者死亡率明显较高。根据生物信息学分析、加权基因共表达网络分析(WGCNA)的结果,我们发现 Erbin 在心肌细胞中至关重要。然而,Erbin在败血症诱发的心肌病(SIC)中的功能尚未得到明确研究。我们利用 Erbin-/- 小鼠和 HL-1 心肌细胞探讨了 Erbin 在 SIC 中的作用。我们利用 HL-1 的体外炎症模型来确认脂多糖(LPS)的刺激,并利用小鼠盲肠结扎和穿刺(CLP)模型来研究 SIC 的分子机制。透射电子显微镜(TEM)用于描述超微结构层面的形态特征。用 western blot 检测 Erbin、p-RIPK1、RIPK、p-RIPK3、RIPK3、p-MLKL、MLKL p-PKA、PKA、p-CREB、CREB 的表达。细胞存活率通过 CCK-8 法检测,cTnI 浓度水平通过 ELISA 试剂盒检测。我们的研究表明,脓毒症期间心肌细胞坏死和炎症被激活,而 Erbin 的缺乏会加重这种情况。过表达Erbin可通过激活PKA/CREB通路缓解坏死和炎症反应。
{"title":"Erbin alleviates sepsis-induced cardiomyopathy by inhibiting RIPK1-dependent necroptosis through activating PKA/CREB pathway","authors":"","doi":"10.1016/j.cellsig.2024.111374","DOIUrl":"10.1016/j.cellsig.2024.111374","url":null,"abstract":"<div><p>Sepsis is a systemic inflammatory disease that can cause multiple organ damage. Septic patients with cardiac dysfunction have a significantly higher mortality. Based on the results of bioinformatics analysis, weighted gene co-expression network analysis (WGCNA), we found that Erbin is vital in cardiomyocyte. However, the function of Erbin in sepsis-induced cardiomyopathy (SIC) has not been explicitly studied. We discussed the role of Erbin in SIC by employing the Erbin<sup>−/−</sup> mice and HL-1 cardiomyocyte. An in vitro model of inflammation in HL-1 was used to confirm stimulation with lipopolysaccharide (LPS) and a mouse model of cecal ligation and puncture (CLP) to study the molecular mechanisms under SIC. Transmission electron microscopy (TEM) was used to characterize the morphological characteristics at the ultrastructural level. The expressions of Erbin, p-RIPK1, RIPK1, p-RIPK3, RIPK3, p-MLKL, MLKL, p-PKA, PKA, p-CREB and CREB were detected by western blot. qPCR analysis was applied to detect TNF-α, IL-1β, IL-6, RIPK1 and MLKL mRNA expression. Cell survival was detected by CCK-8 assay and the levels of c TnI concentration were detected by ELISA kit. Our study revealed that necroptosis and inflammation were activated in cardiomyocytes during sepsis and deficiency of Erbin aggravated them. Furthermore, deficiency of Erbin exacerbated systolic dysfunction including the decline of LVEF and LVFS induced by CLP. Overexpression of Erbin alleviated necroptosis and inflammation by activating PKA/CREB pathway. Our research elucidates a noval mechanism whereby Erbin participates in SIC, providing a promising therapeutic target for myocardial dysfunction during sepsis.</p></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":null,"pages":null},"PeriodicalIF":4.4,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142104802","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}