Pub Date : 2024-10-10DOI: 10.1016/j.cellsig.2024.111462
Zedong Li , Panping Liang , Zhengwen Chen , Zehua Chen , Tao Jin , Fengjun He , Xiaolong Chen , Kun Yang
In gastric cancer treatment, cancer-associated fibroblasts (CAF) may significantly influence the efficacy of immune checkpoint inhibitors by modulating PD-L1 expression. However, the precise mechanisms remain unclear. This study aims to explore the relationship between CAF and PD-L1 expression, providing new insights for improving PD-L1-targeted therapies.
Using primary fibroblasts, transcriptome sequencing, ChIP-qPCR, and a lung metastasis model, we discovered that CAF secrete lysyl oxidase (LOX), which activates the TGFβ signaling pathway in gastric cancer cells, thereby promoting insulin-like growth factor 1(IGF1) expression. Upregulation of IGF1 enhances gastric cancer cell migration, epithelial-mesenchymal transition (EMT), and glycolysis. Additionally, we found that lactate accumulation leads to lysine 18 lactylation on histone H3 (H3K18la), which enriches at the PD-L1 promoter region, thus promoting PD-L1 transcription. These findings suggest that CAF may diminish the effectiveness of PD-1/PD-L1 blockade immunotherapy through LOX-induced glycolysis and lactate accumulation. Consequently, we have constructed a model of the interactions among CAF, lactate, and PD-L1 in gastric cancer progression, providing new experimental evidence for PD-L1-based immunotherapy.
{"title":"CAF-secreted LOX promotes PD-L1 expression via histone Lactylation and regulates tumor EMT through TGFβ/IGF1 signaling in gastric Cancer","authors":"Zedong Li , Panping Liang , Zhengwen Chen , Zehua Chen , Tao Jin , Fengjun He , Xiaolong Chen , Kun Yang","doi":"10.1016/j.cellsig.2024.111462","DOIUrl":"10.1016/j.cellsig.2024.111462","url":null,"abstract":"<div><div>In gastric cancer treatment, cancer-associated fibroblasts (CAF) may significantly influence the efficacy of immune checkpoint inhibitors by modulating PD-L1 expression. However, the precise mechanisms remain unclear. This study aims to explore the relationship between CAF and PD-L1 expression, providing new insights for improving PD-L1-targeted therapies.</div><div>Using primary fibroblasts, transcriptome sequencing, ChIP-qPCR, and a lung metastasis model, we discovered that CAF secrete lysyl oxidase (LOX), which activates the TGFβ signaling pathway in gastric cancer cells, thereby promoting insulin-like growth factor 1(IGF1) expression. Upregulation of IGF1 enhances gastric cancer cell migration, epithelial-mesenchymal transition (EMT), and glycolysis. Additionally, we found that lactate accumulation leads to lysine 18 lactylation on histone H3 (H3K18la), which enriches at the PD-L1 promoter region, thus promoting PD-L1 transcription. These findings suggest that CAF may diminish the effectiveness of PD-1/PD-L1 blockade immunotherapy through LOX-induced glycolysis and lactate accumulation. Consequently, we have constructed a model of the interactions among CAF, lactate, and PD-L1 in gastric cancer progression, providing new experimental evidence for PD-L1-based immunotherapy.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"124 ","pages":"Article 111462"},"PeriodicalIF":4.4,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142445315","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 : 2024-10-09DOI: 10.1016/j.cellsig.2024.111461
Pitchai Balakumar , Khalid M. Orayj , Noohu Abdulla Khan , Kumaran Shanmugam , Gowraganahalli Jagadeesh
Perivascular adipose tissue (PVAT) is found locally around blood vessels. It has the ability to release vasoactive chemicals, such as factors that relax and contract blood vessels. PVAT is now recognized as an endocrine organ with metabolic activity and as a “protagonist” for maintaining vascular homeostasis. Angiotensin II, a powerful vasoconstrictor of the renin–angiotensin system (RAS) that can increase blood pressure and vascular tone, is produced locally by PVAT. To mitigate the multiple vascular effects of angiotensin II, PVAT also generates molecules such as angiotensin (1–7), adiponectin, and nitric oxide. Reactive oxygen species and proinflammatory cytokines are produced in greater amounts when PVAT-mediated angiotensin II is present, resulting in endothelial dysfunction, inflammation, atherosclerosis, and other vascular disorders. The anticontractile and procontractile nature of PVAT is frequently disrupted in obese individuals, which increases the production of angiotensin II and decreases the production of anti-inflammatory and vasodilatory factors. These changes in turn exacerbate vascular inflammation, hypertension, and atherosclerosis. PVAT, which is crucial for maintaining vascular homeostasis, loses its anticontractile effect in obesity due to adipocyte hypertrophy, inflammation, and oxidative stress, exacerbating endothelial dysfunction. Overactive RAS in PVAT facilitates the migration and proliferation of vascular smooth muscle cells and atherosclerotic plaques, both of which accelerate the development of atherosclerosis. Targeting PVAT and the local RAS can offer therapeutic benefits in treating hypertension, atherosclerosis, and other vascular diseases. This review highlights the scientific underpinnings of the function of PVAT in regulating the autocrine and paracrine activities of vascular RAS constituents.
血管周围脂肪组织（PVAT）位于血管周围。它能够释放具有血管活性的化学物质，如放松和收缩血管的因子。目前，人们已认识到血管周围脂肪组织是一个具有新陈代谢活性的内分泌器官，也是维持血管平衡的 "主角"。血管紧张素 II 是肾素-血管紧张素系统（RAS）的一种强效血管收缩剂，可升高血压和血管张力，由 PVAT 在局部产生。为了减轻血管紧张素 II 对血管的多重影响，PVAT 还会产生血管紧张素 (1-7)、脂联素和一氧化氮等分子。当 PVAT 介导的血管紧张素 II 存在时，会产生更多的活性氧和促炎细胞因子，导致内皮功能障碍、炎症、动脉粥样硬化和其他血管疾病。肥胖者的 PVAT 的抗收缩和促收缩特性经常受到破坏，这增加了血管紧张素 II 的产生，减少了抗炎因子和血管舒张因子的产生。这些变化反过来又加剧了血管炎症、高血压和动脉粥样硬化。肥胖症患者的脂肪细胞肥大、炎症和氧化应激使对维持血管平衡至关重要的 PVAT 失去了抗收缩作用，从而加剧了内皮功能障碍。PVAT 中过度活跃的 RAS 会促进血管平滑肌细胞和动脉粥样硬化斑块的迁移和增殖，这两者都会加速动脉粥样硬化的发展。以 PVAT 和局部 RAS 为靶点可为治疗高血压、动脉粥样硬化和其他血管疾病带来疗效。本综述重点介绍了 PVAT 在调节血管 RAS 成分的自分泌和旁分泌活动方面的功能的科学依据。
{"title":"Impact of the local renin–angiotensin system in perivascular adipose tissue on vascular health and disease","authors":"Pitchai Balakumar , Khalid M. Orayj , Noohu Abdulla Khan , Kumaran Shanmugam , Gowraganahalli Jagadeesh","doi":"10.1016/j.cellsig.2024.111461","DOIUrl":"10.1016/j.cellsig.2024.111461","url":null,"abstract":"<div><div>Perivascular adipose tissue (PVAT) is found locally around blood vessels. It has the ability to release vasoactive chemicals, such as factors that relax and contract blood vessels. PVAT is now recognized as an endocrine organ with metabolic activity and as a “protagonist” for maintaining vascular homeostasis. Angiotensin II, a powerful vasoconstrictor of the renin–angiotensin system (RAS) that can increase blood pressure and vascular tone, is produced locally by PVAT. To mitigate the multiple vascular effects of angiotensin II, PVAT also generates molecules such as angiotensin (1–7), adiponectin, and nitric oxide. Reactive oxygen species and proinflammatory cytokines are produced in greater amounts when PVAT-mediated angiotensin II is present, resulting in endothelial dysfunction, inflammation, atherosclerosis, and other vascular disorders. The anticontractile and procontractile nature of PVAT is frequently disrupted in obese individuals, which increases the production of angiotensin II and decreases the production of anti-inflammatory and vasodilatory factors. These changes in turn exacerbate vascular inflammation, hypertension, and atherosclerosis. PVAT, which is crucial for maintaining vascular homeostasis, loses its anticontractile effect in obesity due to adipocyte hypertrophy, inflammation, and oxidative stress, exacerbating endothelial dysfunction. Overactive RAS in PVAT facilitates the migration and proliferation of vascular smooth muscle cells and atherosclerotic plaques, both of which accelerate the development of atherosclerosis. Targeting PVAT and the local RAS can offer therapeutic benefits in treating hypertension, atherosclerosis, and other vascular diseases. This review highlights the scientific underpinnings of the function of PVAT in regulating the autocrine and paracrine activities of vascular RAS constituents.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"124 ","pages":"Article 111461"},"PeriodicalIF":4.4,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142399552","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 : 2024-10-09DOI: 10.1016/j.cellsig.2024.111454
Dolly Ann Padovani-Claudio , Monica S. Morales , Taylor E. Smith , Cayla D. Ontko , Neeraj S. Namburu , Samuel A. Palmer , Marvarakumari G. Jhala , Carla J. Ramos , Megan E. Capozzi , Gary W. McCollum , John S. Penn
Ocular levels of IL-1β, TNFα, IL-8, and IL-6 correlate with progression of diabetic retinopathy (DR). Müller cells (MC), which are crucial to maintaining retinal homeostasis, are targets and sources of these cytokines. We explored the relative capacities of these four DR-associated cytokines to amplify inflammatory signal expression both in and between human MC (hMC) and retinal microvascular endothelial cells (hRMEC) and in the mouse retina. Of the four cytokines, IL-1β was the most potent stimulus of transcriptomic alterations in hMC and hRMEC in vitro, as well as in the mouse retina after intravitreal injection in vivo. Stimulation with IL-1β significantly induced expression of all four transcripts in hMC and hRMEC. TNFα significantly induced expression of some, but not all, of the four transcripts in each cell, while neither IL-8 nor IL-6 showed significant induction in either cell. Similarly, conditioned media (CM) derived from hMC or hRMEC treated with IL-1β, but not TNFα, upregulated inflammatory cytokine transcripts in the reciprocal cell type. hRMEC responses to hMC-derived CM were dependent on IL-1R activation. In addition, we observed a correlation between cytokine expression changes following direct and CM stimulation and NFκB-p65 nuclear translocation in both hMC and hRMEC. Finally, in mice, intravitreal injections of IL-1β, but not TNFα, induced retinal expression of Il1b and CXCL8 homologues Cxcl1, Cxcl2, Cxcl3, and Cxcl5, encoding pro-angiogenic chemokines. Our results suggest that expression of IL-1β, TNFα, IL-8, and IL-6 may be initiated, propagated, and sustained by autocrine and paracrine signals in hRMEC and hMC through a process involving IL-1β and NFκB. Targeting these signals may help thwart inflammatory amplification, preventing progression to vision-threatening stages and preserving sight.
{"title":"Induction, amplification, and propagation of diabetic retinopathy-associated inflammatory cytokines between human retinal microvascular endothelial and Müller cells and in the mouse retina","authors":"Dolly Ann Padovani-Claudio , Monica S. Morales , Taylor E. Smith , Cayla D. Ontko , Neeraj S. Namburu , Samuel A. Palmer , Marvarakumari G. Jhala , Carla J. Ramos , Megan E. Capozzi , Gary W. McCollum , John S. Penn","doi":"10.1016/j.cellsig.2024.111454","DOIUrl":"10.1016/j.cellsig.2024.111454","url":null,"abstract":"<div><div>Ocular levels of IL-1β, TNFα, IL-8, and IL-6 correlate with progression of diabetic retinopathy (<strong>DR</strong>). Müller cells (<strong>MC)</strong>, which are crucial to maintaining retinal homeostasis, are targets and sources of these cytokines. We explored the relative capacities of these four DR-associated cytokines to amplify inflammatory signal expression both in and between human MC (<strong>hMC</strong>) and retinal microvascular endothelial cells (<strong>hRMEC</strong>) and in the mouse retina. Of the four cytokines, IL-1β was the most potent stimulus of transcriptomic alterations in hMC and hRMEC in vitro, as well as in the mouse retina after intravitreal injection in vivo. Stimulation with IL-1β significantly induced expression of <em>all four</em> transcripts in hMC <em>and</em> hRMEC. TNFα significantly induced expression of some, but not all, of the four transcripts in each cell, while neither IL-8 nor IL-6 showed significant induction in either cell. Similarly, conditioned media (<strong>CM</strong>) derived from hMC or hRMEC treated with IL-1β, but not TNFα, upregulated inflammatory cytokine transcripts in the reciprocal cell type. hRMEC responses to hMC-derived CM were dependent on IL-1R activation. In addition, we observed a correlation between cytokine expression changes following direct and CM stimulation and NFκB-p65 nuclear translocation in both hMC and hRMEC. Finally, in mice, intravitreal injections of IL-1β, but not TNFα, induced retinal expression of <em>Il1b</em> and <em>CXCL8</em> homologues <em>Cxcl1</em>, <em>Cxcl2</em>, <em>Cxcl3</em>, and <em>Cxcl5,</em> encoding pro-angiogenic chemokines. Our results suggest that expression of IL-1β, TNFα, IL-8, and IL-6 may be initiated, propagated, and sustained by autocrine and paracrine signals in hRMEC and hMC through a process involving IL-1β and NFκB. Targeting these signals may help thwart inflammatory amplification, preventing progression to vision-threatening stages and preserving sight.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"124 ","pages":"Article 111454"},"PeriodicalIF":4.4,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142388442","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}
Leptin, a hormone mainly secreted by adipocytes, has attracted significant attention since its discovery in 1994. Initially known for its role in appetite suppression and energy regulation, leptin is now recognized for its influence on various physiological processes, including immune response, bone formation, and reproduction. It exerts its effects by binding to receptors and initiating an intracellular signaling cascade. Heparan sulfate (HS) is known to regulate the intracellular signaling of various ligands. HS is present as the glycan portion of HSPGs on cell surfaces and in intercellular spaces, with diverse structures due to extensive sulfation and epimerization. Although HS chains on HSPGs are involved in many physiological processes, the detailed effects of HS chains on leptin signaling are not well understood.
This study examined the role of HS chains on HSPGs in leptin signaling using Neuro2A cells expressing the full-length leptin receptor (LepR). We showed that cell surface HS was essential for efficient leptin signaling. Enzymatic degradation of HS significantly reduced leptin-induced phosphorylation of downstream molecules, such as signal transducer and activator of transcription 3 and p44/p42 Mitogen-activated protein kinase. In addition, HS regulated LepR expression and internalization, as treatment with HS-degrading enzymes decreased cell surface LepR. HS was also found to exhibit a weak interaction with LepR. Enzymatic removal of HS enhanced the interaction between LepR and low-density lipoprotein receptor-related protein 1, suggesting that HS negatively regulates this interaction. In conclusion, HS plays a significant role in modulating LepR availability on the cell surface, thereby influencing leptin signaling. These findings provide new insights into the complex regulation of leptin signaling and highlight potential therapeutic targets for metabolic disorders and obesity.
{"title":"Regulatory role of Heparan sulfate in leptin signaling","authors":"Naoko Nagai, Tatsumasa Shioiri, Sonoko Hatano, Nobuo Sugiura, Hideto Watanabe","doi":"10.1016/j.cellsig.2024.111456","DOIUrl":"10.1016/j.cellsig.2024.111456","url":null,"abstract":"<div><div>Leptin, a hormone mainly secreted by adipocytes, has attracted significant attention since its discovery in 1994. Initially known for its role in appetite suppression and energy regulation, leptin is now recognized for its influence on various physiological processes, including immune response, bone formation, and reproduction. It exerts its effects by binding to receptors and initiating an intracellular signaling cascade. Heparan sulfate (HS) is known to regulate the intracellular signaling of various ligands. HS is present as the glycan portion of HSPGs on cell surfaces and in intercellular spaces, with diverse structures due to extensive sulfation and epimerization. Although HS chains on HSPGs are involved in many physiological processes, the detailed effects of HS chains on leptin signaling are not well understood.</div><div>This study examined the role of HS chains on HSPGs in leptin signaling using Neuro2A cells expressing the full-length leptin receptor (LepR). We showed that cell surface HS was essential for efficient leptin signaling. Enzymatic degradation of HS significantly reduced leptin-induced phosphorylation of downstream molecules, such as signal transducer and activator of transcription 3 and p44/p42 Mitogen-activated protein kinase. In addition, HS regulated LepR expression and internalization, as treatment with HS-degrading enzymes decreased cell surface LepR. HS was also found to exhibit a weak interaction with LepR. Enzymatic removal of HS enhanced the interaction between LepR and low-density lipoprotein receptor-related protein 1, suggesting that HS negatively regulates this interaction. In conclusion, HS plays a significant role in modulating LepR availability on the cell surface, thereby influencing leptin signaling. These findings provide new insights into the complex regulation of leptin signaling and highlight potential therapeutic targets for metabolic disorders and obesity.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"124 ","pages":"Article 111456"},"PeriodicalIF":4.4,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142388444","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 : 2024-10-09DOI: 10.1016/j.cellsig.2024.111459
Pitchai Balakumar, Gowraganahalli Jagadeesh
Novel perspectives on the role of the renin-angiotensin-aldosterone system (RAAS) offer a groundbreaking understanding of the system's role in health and illness. Our understanding of the role of the RAAS in several diseases, such as heart failure, hypertension, metabolic disorders, and chronic renal disease, has been broadened by recent studies. Specific variations in RAAS pathways can affect the course of disease and response to treatment, as shown by genetic and molecular research. The dynamic and fast-evolving nature of RAAS research described in this special issue might transform our approach to managing renal, neurological, and cardiovascular health, among other disease conditions, including cancer.
{"title":"Game-changing breakthroughs to redefine the landscape of the renin-angiotensin-aldosterone system in health and disease.","authors":"Pitchai Balakumar, Gowraganahalli Jagadeesh","doi":"10.1016/j.cellsig.2024.111459","DOIUrl":"10.1016/j.cellsig.2024.111459","url":null,"abstract":"<p><p>Novel perspectives on the role of the renin-angiotensin-aldosterone system (RAAS) offer a groundbreaking understanding of the system's role in health and illness. Our understanding of the role of the RAAS in several diseases, such as heart failure, hypertension, metabolic disorders, and chronic renal disease, has been broadened by recent studies. Specific variations in RAAS pathways can affect the course of disease and response to treatment, as shown by genetic and molecular research. The dynamic and fast-evolving nature of RAAS research described in this special issue might transform our approach to managing renal, neurological, and cardiovascular health, among other disease conditions, including cancer.</p>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":" ","pages":"111459"},"PeriodicalIF":4.4,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142399550","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 : 2024-10-09DOI: 10.1016/j.cellsig.2024.111451
Qingmiao Lu , Xiao Hu , Qing Hou , Long Yu , Kai Cao , Dafa Ding , Yibing Lu , Chunsun Dai
Podocyte senescence can cause persistent podocyte injury and albuminuria in diabetic kidney disease (DKD), but the mechanism remains obscure. In this study, podocyte senescence was confirmed by immunohistochemical staining in podocytes from patients and mice with DKD. Rheb1 knockout in podocytes aggravated podocyte senescence and injury in diabetic mice, but mitigated podocyte injury in mice with podocyte-specific mTORC1 activation induced by Tsc1 deletion. In cultured podocytes, Rheb1 knockdown remarkably accelerated podocyte senescence, independent of mTORC1. Mechanistically, PDH phosphorylation in podocyte was correlated with podocyte senescence in DKD patients. Rheb1 deficiency decreased ATP, mitochondrial membrane potential and partial components of respiratory chain complex, and enhanced ROS production and PDH phosphorylation, which indicates mitochondrial dysfunction, both in vitro and in vivo. Furthermore, Rheb1 interacted with Atp5f1c, and regulated its acetylation under a high-glucose condition. Together, Rheb1 deficiency elicits mitochondrial dysfunction and accelerates podocyte senescence through promoting Atp5f1c acetylation, in an mTORC1-independent manner, which provides experimental basis for the treatment of DKD.
{"title":"Rheb1 deficiency elicits mitochondrial dysfunction and accelerates podocyte senescence through promoting Atp5f1c acetylation","authors":"Qingmiao Lu , Xiao Hu , Qing Hou , Long Yu , Kai Cao , Dafa Ding , Yibing Lu , Chunsun Dai","doi":"10.1016/j.cellsig.2024.111451","DOIUrl":"10.1016/j.cellsig.2024.111451","url":null,"abstract":"<div><div>Podocyte senescence can cause persistent podocyte injury and albuminuria in diabetic kidney disease (DKD), but the mechanism remains obscure. In this study, podocyte senescence was confirmed by immunohistochemical staining in podocytes from patients and mice with DKD. Rheb1 knockout in podocytes aggravated podocyte senescence and injury in diabetic mice, but mitigated podocyte injury in mice with podocyte-specific mTORC1 activation induced by Tsc1 deletion. In cultured podocytes, Rheb1 knockdown remarkably accelerated podocyte senescence, independent of mTORC1. Mechanistically, PDH phosphorylation in podocyte was correlated with podocyte senescence in DKD patients. Rheb1 deficiency decreased ATP, mitochondrial membrane potential and partial components of respiratory chain complex, and enhanced ROS production and PDH phosphorylation, which indicates mitochondrial dysfunction, both in vitro and in vivo. Furthermore, Rheb1 interacted with Atp5f1c, and regulated its acetylation under a high-glucose condition. Together, Rheb1 deficiency elicits mitochondrial dysfunction and accelerates podocyte senescence through promoting Atp5f1c acetylation, in an mTORC1-independent manner, which provides experimental basis for the treatment of DKD.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"124 ","pages":"Article 111451"},"PeriodicalIF":4.4,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142399553","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 : 2024-10-09DOI: 10.1016/j.cellsig.2024.111458
Xin Chen , Liming Yu , Shan Meng , Jikai Zhao , Xinyi Huang , Zhishang Wang , Zijun Zhou , Yuting Huang , Tao Hong , Jinfeng Duan , Tong Su , Zijun Cao , Yanbang Chi , Tao Huang , Huishan Wang
Inflammation and infiltration of immune cells are intricately linked to the pathogenesis of atrial fibrillation (AF). Triggering receptor expressed on myeloid cells-1 (TREM-1), an enhancer of inflammation, is implicated in various cardiovascular disorders. However, the precise role and potential mechanisms of TREM-1 in the development of AF remain ambiguous. Atrial samples from patients with AF were used to assess the expression levels of TREM-1. An angiotensin II (Ang II)-induced AF mouse model was established to assess the functionality of TREM-1. Cardiac function and AF inducibility were assessed through echocardiography, programmed transvenous cardiac pacing, and atrial electrophysiological mapping. Peripheral blood and atrial inflammatory cells were assessed using flow cytometry. Using histology, bulk RNA sequencing, biochemical analyses, and cell cultures, the mechanistic role of TREM-1 in AF was elucidated. TREM-1 expression was upregulated and co-localized with macrophages in the atria of patients with AF. Pharmacological inhibition of TREM-1 decreased Ang II-induced atrial enlargement and electrical remodeling. TREM-1 inhibition also ameliorated Ang II-induced NLRP3 inflammasome activation, inflammatory factor release, atrial fibrosis, and macrophage infiltration. Transcriptomic analysis revealed that TREM-1 modulates Ang II-induced inflammation through the PI3K/AKT/FoxO3a signaling pathway. In vitro studies further supported these findings, demonstrating that TREM-1 activation exacerbates Ang II-induced inflammation, while overexpression of FoxO3a counteracts this effect. This study discovered the critical role of TREM-1 in the pathogenesis of AF and its underlying molecular mechanisms. Inhibition of TREM-1 provides a new therapeutic strategy for the treatment of AF.
炎症和免疫细胞浸润与心房颤动（房颤）的发病机制密切相关。髓系细胞上表达的触发受体-1（TREM-1）是一种炎症增强因子，与多种心血管疾病有关。然而，TREM-1在心房颤动发病过程中的确切作用和潜在机制仍不明确。研究人员使用房颤患者的心房样本来评估 TREM-1 的表达水平。建立了血管紧张素II（Ang II）诱导的房颤小鼠模型，以评估TREM-1的功能。通过超声心动图、程序化经静脉心脏起搏和心房电生理图评估心脏功能和房颤诱导性。使用流式细胞术评估了外周血和心房炎症细胞。通过组织学、大量 RNA 测序、生化分析和细胞培养，阐明了 TREM-1 在房颤中的机制作用。在心房颤动患者的心房中，TREM-1表达上调并与巨噬细胞共定位。药物抑制 TREM-1 可减少 Ang II 诱导的心房扩大和电重塑。抑制 TREM-1 还能改善 Ang II 诱导的 NLRP3 炎症小体激活、炎症因子释放、心房纤维化和巨噬细胞浸润。转录组分析表明，TREM-1 通过 PI3K/AKT/FoxO3a 信号通路调节 Ang II 诱导的炎症。体外研究进一步证实了这些发现，表明TREM-1的激活会加剧Ang II诱导的炎症，而过量表达FoxO3a则会抵消这种效应。这项研究发现了 TREM-1 在心房颤动发病机制中的关键作用及其潜在的分子机制。抑制 TREM-1 为治疗心房颤动提供了一种新的治疗策略。
{"title":"Inhibition of TREM-1 ameliorates angiotensin II-induced atrial fibrillation by attenuating macrophage infiltration and inflammation through the PI3K/AKT/FoxO3a signaling pathway","authors":"Xin Chen , Liming Yu , Shan Meng , Jikai Zhao , Xinyi Huang , Zhishang Wang , Zijun Zhou , Yuting Huang , Tao Hong , Jinfeng Duan , Tong Su , Zijun Cao , Yanbang Chi , Tao Huang , Huishan Wang","doi":"10.1016/j.cellsig.2024.111458","DOIUrl":"10.1016/j.cellsig.2024.111458","url":null,"abstract":"<div><div>Inflammation and infiltration of immune cells are intricately linked to the pathogenesis of atrial fibrillation (AF). Triggering receptor expressed on myeloid cells-1 (TREM-1), an enhancer of inflammation, is implicated in various cardiovascular disorders. However, the precise role and potential mechanisms of TREM-1 in the development of AF remain ambiguous. Atrial samples from patients with AF were used to assess the expression levels of TREM-1. An angiotensin II (Ang II)-induced AF mouse model was established to assess the functionality of TREM-1. Cardiac function and AF inducibility were assessed through echocardiography, programmed transvenous cardiac pacing, and atrial electrophysiological mapping. Peripheral blood and atrial inflammatory cells were assessed using flow cytometry. Using histology, bulk RNA sequencing, biochemical analyses, and cell cultures, the mechanistic role of TREM-1 in AF was elucidated. TREM-1 expression was upregulated and co-localized with macrophages in the atria of patients with AF. Pharmacological inhibition of TREM-1 decreased Ang II-induced atrial enlargement and electrical remodeling. TREM-1 inhibition also ameliorated Ang II-induced NLRP3 inflammasome activation, inflammatory factor release, atrial fibrosis, and macrophage infiltration. Transcriptomic analysis revealed that TREM-1 modulates Ang II-induced inflammation through the PI3K/AKT/FoxO3a signaling pathway. In vitro studies further supported these findings, demonstrating that TREM-1 activation exacerbates Ang II-induced inflammation, while overexpression of FoxO3a counteracts this effect. This study discovered the critical role of TREM-1 in the pathogenesis of AF and its underlying molecular mechanisms. Inhibition of TREM-1 provides a new therapeutic strategy for the treatment of AF.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"124 ","pages":"Article 111458"},"PeriodicalIF":4.4,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142388443","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 : 2024-10-09DOI: 10.1016/j.cellsig.2024.111457
Xinyu Gao, Zhongwei Zhang, Qinyi Li, Guokai Tai, ZhiDong Wang
Distant metastasis is a prevalent cause of mortality in gastric cancer (GC) patients. Anoikis, a process that induces cell death when cells get detached from the extracellular matrix (ECM), acts as a barrier to tumor metastasis. To survive in the circulatory system and metastasize, tumor cells must acquire anoikis resistance. It is crucial to identify the molecular processes that cause resistance to anoikis in GC since this might lead to the discovery of novel treatment targets and improve the long-term survival of GC patients. In this study, we employed quantitative proteomics to identify growth differentiation factor 15 (GDF15) as a key factor in GC anoikis resistance. We found that GDF15 enhances protective autophagy, thereby promoting anoikis resistance in GC cells. Furthermore, through DNA pull down assay, activating transcription factor 2 (ATF2) was found to be a critical regulator of GDF15 expression, acting as a transcriptional activator of GDF15. Collectively, these discoveries indicate that ATF2 and GDF15 have great potential as target candidates for developing therapeutic strategies to address the metastasis of GC.
{"title":"GDF15 enhances anoikis resistance and metastasis of gastric cancer through protective autophagy","authors":"Xinyu Gao, Zhongwei Zhang, Qinyi Li, Guokai Tai, ZhiDong Wang","doi":"10.1016/j.cellsig.2024.111457","DOIUrl":"10.1016/j.cellsig.2024.111457","url":null,"abstract":"<div><div>Distant metastasis is a prevalent cause of mortality in gastric cancer (GC) patients. Anoikis, a process that induces cell death when cells get detached from the extracellular matrix (ECM), acts as a barrier to tumor metastasis. To survive in the circulatory system and metastasize, tumor cells must acquire anoikis resistance. It is crucial to identify the molecular processes that cause resistance to anoikis in GC since this might lead to the discovery of novel treatment targets and improve the long-term survival of GC patients. In this study, we employed quantitative proteomics to identify growth differentiation factor 15 (GDF15) as a key factor in GC anoikis resistance. We found that GDF15 enhances protective autophagy, thereby promoting anoikis resistance in GC cells. Furthermore, through DNA pull down assay, activating transcription factor 2 (ATF2) was found to be a critical regulator of GDF15 expression, acting as a transcriptional activator of GDF15. Collectively, these discoveries indicate that ATF2 and GDF15 have great potential as target candidates for developing therapeutic strategies to address the metastasis of GC.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"124 ","pages":"Article 111457"},"PeriodicalIF":4.4,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142399551","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}
Cerebral ischemic injury is characterized by reduced blood flow to the brain, remains a significant cause of morbidity and mortality worldwide. Despite improvements in therapeutic approaches, there is an urgent need to identify new targets to lessen the effects of ischemic stroke. Aquaporins, a family of water channel proteins, have recently come to light as promising candidates for therapeutic intervention in cerebral ischemic injury. There are 13 aquaporins identified, and AQP4 has been thoroughly involved with cerebral ischemia as it has been reported that modulation of AQP4 activity can offers a possible pathway for therapeutic intervention along with their role in pH, osmosis, ions, and the blood-brain barrier (BBB) as possible therapeutic targets for cerebral ischemia injury. The molecular pathways which can interacts with particular cellular pathways, participation in neuroinflammation, and possible interaction with additional proteins thought to be involved in the etiology of a stroke. Understanding these pathways offers crucial information on the diverse role of AQPs in cerebral ischemia, paving the door for the development of focused/targeted therapeutics.
{"title":"Aquaporin proteins: A promising frontier for therapeutic intervention in cerebral ischemic injury","authors":"Ashi Mannan , Maneesh Mohan , Anshika Gulati , Sonia Dhiman , Thakur Gurjeet Singh","doi":"10.1016/j.cellsig.2024.111452","DOIUrl":"10.1016/j.cellsig.2024.111452","url":null,"abstract":"<div><div>Cerebral ischemic injury is characterized by reduced blood flow to the brain, remains a significant cause of morbidity and mortality worldwide. Despite improvements in therapeutic approaches, there is an urgent need to identify new targets to lessen the effects of ischemic stroke. Aquaporins, a family of water channel proteins, have recently come to light as promising candidates for therapeutic intervention in cerebral ischemic injury. There are 13 aquaporins identified, and AQP4 has been thoroughly involved with cerebral ischemia as it has been reported that modulation of AQP4 activity can offers a possible pathway for therapeutic intervention along with their role in pH, osmosis, ions, and the blood-brain barrier (BBB) as possible therapeutic targets for cerebral ischemia injury. The molecular pathways which can interacts with particular cellular pathways, participation in neuroinflammation, and possible interaction with additional proteins thought to be involved in the etiology of a stroke. Understanding these pathways offers crucial information on the diverse role of AQPs in cerebral ischemia, paving the door for the development of focused/targeted therapeutics.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"124 ","pages":"Article 111452"},"PeriodicalIF":4.4,"publicationDate":"2024-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142380150","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}
Growth hormone (GH) is a crucial regulator of growth, cell reproduction, and regeneration; and it is controlled by growth hormone-releasing hormone (GHRH) and somatostatin. Lipopolysaccharides (LPS) can compromise endothelial function, leading to increased inflammation and vascular leak. Octreotide (OCT) is an FDA-approved synthetic somatostatin analog (SSA) used to treat acromegaly and neuroendocrine tumors. The present study investigates the effects of OCT on LPS-induced injury in bovine and human lung endothelial cells, as well as in mouse lungs. Our in vitro observations suggest that OCT effectively counteracts LPS-induced endothelial leak, inflammation, and reactive oxygen species (ROS) generation. Furthermore, OCT reduces bronchoalveolar lavage fluid (BALF) protein concentration in an experimental model of Acute Lung Injury (ALI). Our study suggests that OCT mitigates LPS-induced endothelial cell and lung injury, suggesting that it may represent an exciting therapeutic possibility in diseases related to barrier dysfunction.
生长激素（GH）是生长、细胞繁殖和再生的重要调节剂，受生长激素释放激素（GHRH）和体生长激素控制。脂多糖（LPS）会损害内皮功能，导致炎症和血管渗漏增加。奥曲肽 (OCT) 是一种经 FDA 批准的合成体生长抑素类似物 (SSA)，用于治疗肢端肥大症和神经内分泌肿瘤。本研究调查了 OCT 对牛和人肺内皮细胞以及小鼠肺内 LPS 诱导损伤的影响。我们的体外观察结果表明，OCT 能有效对抗 LPS 诱导的内皮渗漏、炎症和活性氧（ROS）生成。此外，OCT 还能降低急性肺损伤（ALI）实验模型中支气管肺泡灌洗液（BALF）的蛋白质浓度。我们的研究表明，OCT 可减轻 LPS 诱导的内皮细胞和肺损伤，这表明它可能是治疗与屏障功能障碍有关的疾病的一种令人兴奋的方法。
{"title":"Octreotide protects against LPS-induced endothelial cell and lung injury","authors":"Saikat Fakir, Khadeja-Tul Kubra, Nektarios Barabutis","doi":"10.1016/j.cellsig.2024.111455","DOIUrl":"10.1016/j.cellsig.2024.111455","url":null,"abstract":"<div><div>Growth hormone (GH) is a crucial regulator of growth, cell reproduction, and regeneration; and it is controlled by growth hormone-releasing hormone (GHRH) and somatostatin. Lipopolysaccharides (LPS) can compromise endothelial function, leading to increased inflammation and vascular leak. Octreotide (OCT) is an FDA-approved synthetic somatostatin analog (SSA) used to treat acromegaly and neuroendocrine tumors. The present study investigates the effects of OCT on LPS-induced injury in bovine and human lung endothelial cells, as well as in mouse lungs. Our in vitro observations suggest that OCT effectively counteracts LPS-induced endothelial leak, inflammation, and reactive oxygen species (ROS) generation. Furthermore, OCT reduces bronchoalveolar lavage fluid (BALF) protein concentration in an experimental model of Acute Lung Injury (ALI). Our study suggests that OCT mitigates LPS-induced endothelial cell and lung injury, suggesting that it may represent an exciting therapeutic possibility in diseases related to barrier dysfunction.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"124 ","pages":"Article 111455"},"PeriodicalIF":4.4,"publicationDate":"2024-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142388445","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}
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