Cellular signalling最新文献

{"title":"PRKAA2-mediated mitophagy regulates oxygen consumption in yak renal tubular epithelial cells under chronic hypoxia","authors":"Xuefeng Bai ,&nbsp;Hongqin Lu ,&nbsp;Yan Cui ,&nbsp;Sijiu Yu ,&nbsp;Rui Ma ,&nbsp;Shanshan Yang ,&nbsp;Junfeng He","doi":"10.1016/j.cellsig.2024.111450","DOIUrl":"10.1016/j.cellsig.2024.111450","url":null,"abstract":"<div><div>Hypoxic environments are significant factors in the induction of various kidney diseases and are closely associated with high oxygen consumption in the kidneys. Yaks live at high altitude for a long time, exhibit a unique ability to regulate kidney oxygen consumption, protecting them from hypoxia-induced damage. However, the mechanisms underlying the regulation of oxygen consumption in yak kidneys under hypoxic conditions remain unclear. To explore this hypoxia adaptation mechanism in yak kidneys, this study analyzed the oxygen consumption rate (OCR) of renal tubular epithelial cells (RTECs) under hypoxia. We found that the OCR and apoptosis rates of RTECs under chronic hypoxia (&gt; 24 h) were lower than those under acute hypoxia (≤ 24 h). However, when oxygen consumption was promoted under chronic hypoxia, the apoptosis rate increased, indicating that reducing the cellular OCR is crucial for maintaining RTECs activity under hypoxia. High-throughput sequencing results showed that the mitophagy pathway is likely a key mechanism for inhibiting OCR of yak RTECs, with protein kinase AMP-activated catalytic subunit alpha 2 (PRKAA2) playing a significant role in this process. Further studies demonstrated that chronic hypoxia activates the mitophagy pathway, which inhibits oxidative phosphorylation (OXPHOS) while increasing glycolytic flux in yak RTECs. Conversely, when the mitophagy pathway was inhibited, there was an increase in the activity of OXPHOS enzymes and OCR. To further explore the role of PRKAA2 in the mitophagy pathway, we inhibited PRKAA2 expression under chronic hypoxia. Results showed that the downregulation of PRKAA2 decreased the expression of mitophagy-related proteins, such as p-FUNDC1/FUNDC1, LC3-II/LC3-I, BNIP3 and ULK1 while upregulating P62 expression. Additionally, there was an increase in the enzyme activities of Complex II, Complex IV, PDH, and SDH, which further promoted oxygen consumption in RTECs. These findings suggest that PRKAA2 mediated mitophagy under chronic hypoxia is crucial mechanism for reducing oxygen consumption in yak RTECs.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"124 ","pages":"Article 111450"},"PeriodicalIF":4.4,"publicationDate":"2024-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142445316","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}

{"title":"Enriched environment enhances angiogenesis in ischemic stroke through SDF-1/CXCR4/AKT/mTOR pathway","authors":"Yonggang Zhang ,&nbsp;Sheng Qiu ,&nbsp;Yi Pang ,&nbsp;Zhongzhou Su ,&nbsp;Lifang Zheng ,&nbsp;Binghao Wang ,&nbsp;Hongbo Zhang ,&nbsp;Pingping Niu ,&nbsp;Shehong Zhang ,&nbsp;Yuntao Li","doi":"10.1016/j.cellsig.2024.111464","DOIUrl":"10.1016/j.cellsig.2024.111464","url":null,"abstract":"<div><div>Environmental-gene interactions significantly influence various bodily functions. Enriched environment (EE), a non-pharmacological treatment method, enhances angiogenesis in ischemic stroke (IS). However, underlying the role of EE in angiogenesis in aged mice post-IS remain unclear. This study aimed to determine the potential mechanism by which EE mediates angiogenesis in 12-month-old IS mice and oxygen-glucose deprivation/reperfusion (OGD/R)-induced bEnd.3 cells. <em>In vivo</em>, EE treatment alleviated the neurological deficits, enhanced angiogenesis, upregulated SDF-1, VEGFA, and the AKT/mTOR pathway. In addition, exogenous SDF-1 treatment had a protective effect similar to that of EE treatment in aged mice with IS. However, SDF-1 neutralizing antibody, AMD3100 (CXCR4 inhibitor), ARQ092 (AKT inhibitor), and rapamycin (mTOR inhibitor) treatment blocked the neuroprotective effect of EE treatment and inhibited angiogenesis in IS mice. <em>In vitro</em>, exogenous SDF-1 promoted migration of OGD/R-induced bEnd.3 cells and activated the AKT/mTOR pathway. AMD3100, ARQ092, and rapamycin inhibited SDF-1-induced cell migration. Collectively, these findings demonstrate that EE enhances angiogenesis and improves the IS outcomes through SDF-1/CXCR4/AKT/mTOR pathway.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"124 ","pages":"Article 111464"},"PeriodicalIF":4.4,"publicationDate":"2024-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142459266","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}

{"title":"Forkhead box C1 promotes the pathology of osteoarthritis in subchondral bone osteoblasts via the Piezo1/YAP axis","authors":"Zhengyuan Li ,&nbsp;Lin Hao ,&nbsp;Shenghong Chen ,&nbsp;Wenhan Fu ,&nbsp;Hui Zhang ,&nbsp;Zongsheng Yin ,&nbsp;Yin Wang ,&nbsp;Jun Wang","doi":"10.1016/j.cellsig.2024.111463","DOIUrl":"10.1016/j.cellsig.2024.111463","url":null,"abstract":"<div><div>Subchondral bone sclerosis is a key characteristic of osteoarthritis (OA). Prior research has shown that Forkhead box C1 (FoxC1) plays a role in the synovial inflammation of OA, but its specific role in the subchondral bone of OA has not been explored. Our research revealed elevated expression levels of FoxC1 and Piezo1 in OA subchondral bone tissues. Further experiments on OA subchondral bone osteoblasts with FoxC1 or Piezo1 overexpression showed increased cell proliferation activity, expression of Yes-associated Protein 1 (YAP) and osteogenic markers, and secretion of proinflammatory factors. Mechanistically, the overexpression of FoxC1 through Piezo1 activation, in combination with downstream YAP signaling, led to increased levels of alkaline phosphatase (ALP), collagen type 1 (COL1) A1, RUNX2, Osteocalcin, matrix metalloproteinase (MMP) 3, and MMP9 expression. Notably, inhibition of Piezo1 reversed the regulatory function of FoxC1. The binding of FoxC1 to the targeted area (ATATTTATTTA, residues +612 to +622) and the activation of Piezo1 transcription were verified by the dual luciferase assays. Additionally, Reduced subchondral osteosclerosis and microangiogenesis were observed in knee joints from FoxC1-conditional knockout (CKO) and Piezo1-CKO mice, indicating reduced lesions. Collectively, our study reveals the significant involvement of FoxC1 in the pathologic process of OA subchondral bone via the Piezo1/YAP signaling pathway, potentially establishing a novel therapeutic target.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"124 ","pages":"Article 111463"},"PeriodicalIF":4.4,"publicationDate":"2024-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142445317","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}

{"title":"Histone H4K12 lactylation promotes malignancy progression in triple-negative breast cancer through SLFN5 downregulation","authors":"Jingyi Li ,&nbsp;Ziyu Chen ,&nbsp;Mingming Jin ,&nbsp;Xuefeng Gu ,&nbsp;Yuhan Wang ,&nbsp;Gang Huang ,&nbsp;Weiming Zhao ,&nbsp;Changlian Lu","doi":"10.1016/j.cellsig.2024.111468","DOIUrl":"10.1016/j.cellsig.2024.111468","url":null,"abstract":"<div><div>Lactylation, a newly identified post-translational modification, is uncertain in its implication in triple-negative breast cancer (TNBC). In this study, we analyzed 60 TNBC samples using immunohistochemical staining and revealed elevated levels of pan-lactylated proteins and specific histone H4K12 lactylation in tumor tissues, correlating with TNBC progression. Lactate exposure in TNBC cell lines significantly induced lysine lactylation at the H4K12 site, leading to alterations in gene profiles and reduced apoptosis. These effects were attenuated by DCA or sodium Oxamate, inhibitors of endogenous lactate production. Gene sequencing showed an increase in Schlafen 5 (SLFN5) expression in TNBC cells treated with Oxamate, contrasting with the effects of lactate exposure. Analysis of TNBC tissues showed a negative correlation between H4K12 lactylation and SLFN5 protein levels. Overexpression of SLFN5 countered the effects of lactate on apoptosis and tumor growth, highlighting its pivotal role in TNBC malignancy. CUT&amp;Tag sequencing indicated that lactylated H4K12 potentially binds to the SLFN5 promoter region. Luciferase reporter assays further verified that lactate-induced suppression of SLFN5 promoter activity is mediated by wild-type H4K12, but not by its R or A mutants, verified by both in vitro and in vivo apoptosis detection in response to lactate and Oxamate stimulation. These results establish that H4K12 lactylation, induced by lactate in TNBC cells, specifically suppresses SLFN5 expression, contributing to TNBC malignancy. Our findings illuminate a critical histone lactylation-dependent carcinogenic pathway in TNBC.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"124 ","pages":"Article 111468"},"PeriodicalIF":4.4,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142459268","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}

{"title":"Effects of pomegranate exocarp extract on H. pylori-induced pancreatic EMT: Molecular mechanisms and therapeutic potential","authors":"Mariam A. Abo-Saif ,&nbsp;Ghada M. Al-Ashmawy ,&nbsp;Amany E. Ragab ,&nbsp;Lamiaa A. Al-Madboly ,&nbsp;Ahmed B.M. Mehany ,&nbsp;Sherin R. El-Afify","doi":"10.1016/j.cellsig.2024.111465","DOIUrl":"10.1016/j.cellsig.2024.111465","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Background&lt;/h3&gt;&lt;div&gt;Previous studies have linked &lt;em&gt;Helicobacter pylori&lt;/em&gt; infection with pancreatic diseases, including cancer.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Purpose&lt;/h3&gt;&lt;div&gt;To explore the influence of pomegranate exocarp extract (PEE) on epithelial-mesenchymal transition (EMT) in &lt;em&gt;H. pylori&lt;/em&gt;-induced pancreatic rat tissue and to uncover the underlying molecular mechanisms.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Study design&lt;/h3&gt;&lt;div&gt;Twenty-eight rats were divided into six groups: group 1 (negative control), group 2 (&lt;em&gt;H. pylori-&lt;/em&gt;infected), group 3 (infected + PEE pretreatment), group 4 (infected + PEE treatment), group 5 (infected + metronidazole treatment), and group 6 (infected + metronidazole/PEE co-treatment).&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods and results&lt;/h3&gt;&lt;div&gt;This study aimed to assess the effectiveness of pomegranate exocarp extract (PEE) in treating &lt;em&gt;Helicobacter pylori&lt;/em&gt; infection and its associated pancreatic tissue changes in Wistar rats. The study involved Forty-eight male rats divided into six groups: &lt;em&gt;H. pylori&lt;/em&gt;-infected control, PEE-preventive, PEE treatment, metronidazole treatment, PEE combined with metronidazole treatment, and negative control. The results showed a significant reduction in &lt;em&gt;H. pylori&lt;/em&gt; concentration in the antrum in the PEE-treated groups (27.08 %) compared to that in the positive control group (&lt;em&gt;p&lt;/em&gt; &lt; 0.05). The group receiving the combined treatment exhibited the highest reduction (55.8 %) in &lt;em&gt;H. pylori&lt;/em&gt; concentration (&lt;em&gt;p&lt;/em&gt; &lt; 0.005), with no significant difference observed between the PEE-preventive and metronidazole-treated groups. The ELISA results showed that the groups treated with PEE, PEE-preventive, and PEE combined with metronidazole experienced a significant increase in pancreatic E-cadherin levels by 47.7 %, 73.8 %, and 118.06 % respectively, and a substantial decrease in vimentin levels by 16.6 %, 31.6 %, and 43.5 % respectively, compared to the positive control group (&lt;em&gt;p&lt;/em&gt; &lt; 0.05). The results of the RT-qPCR analysis showed that the PEE treatment group, as well as the PEE preventive and PEE combined with metronidazole treatment groups, displayed significant downregulation of vimentin, sirtuin1, and lncRNA MALAT-1, and upregulation of E-cadherin compared to the positive control group. However, there was no significant difference between the PEE-preventive and metronidazole-treated groups (&lt;em&gt;p&lt;/em&gt; &lt; 0.05). Histopathological analysis showed considerable improvement in pancreatic tissue morphology in the PEE-treated groups. The inflammation score was significantly lower in these groups (&lt;em&gt;p&lt;/em&gt; &lt; 0.05), and the combined treatment group exhibited minimal signs of metaplasia and mononuclear cell infiltration. A computational study identified 54 human target genes of bioactive compounds in PEE. These findings shed light on the crucial interactions and pathways in treating pancreatic tumors. Additionally, GO enrichment and KEGG pathway analyses re","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"124 ","pages":"Article 111465"},"PeriodicalIF":4.4,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142459265","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}

{"title":"Corrigendum to “Recent progress of protein kinase inhibitors derived from marine peptides for developing anticancer gents” [Cellular Signalling 124 (2024) 111411]","authors":"Lanhong Zheng ,&nbsp;Ning Wei ,&nbsp;Ammad Ahmad Farooqi ,&nbsp;Yan Zhang ,&nbsp;Renald Blundell ,&nbsp;Xiujun Liu ,&nbsp;Yixin Xu ,&nbsp;Xiukun Lin","doi":"10.1016/j.cellsig.2024.111449","DOIUrl":"10.1016/j.cellsig.2024.111449","url":null,"abstract":"","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"124 ","pages":"Article 111449"},"PeriodicalIF":4.4,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142399549","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}

{"title":"Fangchinoline inhibits metastasis and reduces inflammation-induced epithelial-mesenchymal transition by targeting the FOXM1-ADAM17 axis in hepatocellular carcinoma","authors":"Liyun Zheng ,&nbsp;Vinothkumar Rajamanickam ,&nbsp;Mengyuan Wang ,&nbsp;Huajun Zhang ,&nbsp;Shiji Fang ,&nbsp;Michael Linnebacher ,&nbsp;A.M. Abd El-Aty ,&nbsp;Xinbin Zhang ,&nbsp;Yeyu Zhang ,&nbsp;Jianbo Wang ,&nbsp;Minjiang Chen ,&nbsp;Zhongwei Zhao ,&nbsp;Jiansong Ji","doi":"10.1016/j.cellsig.2024.111467","DOIUrl":"10.1016/j.cellsig.2024.111467","url":null,"abstract":"<div><div>Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide. Efforts have been focused on developing new anti-HCC agents and understanding their pharmacology. However, few agents have been able to effectively combat tumor growth and invasiveness due to the rapid progression of HCC. In this study, we discovered that fangchinoline (FAN), a bisbenzylisoquinoline alkaloid derived from Stephania tetrandra S. Moore, effectively inhibited the migration, invasion, and epithelial-mesenchymal transition (EMT) of HCC cells. FAN treatment also led to the suppression of IL6 and IL1β release, as well as the expression of inflammation-related proteins such as COX-2 and iNOS, and the activation of the NF-κB pathway, thereby reducing inflammation-related EMT. Additionally, FAN directly bound to forkhead box protein M1 (FOXM1), resulting in decreased levels of FOXM1 proteins and disruption of the FOXM1-ADAM17 axis. Our <em>in vivo</em> findings confirmed that FAN effectively hindered the growth and lung metastasis of HCCLM3-xenograft tumors. Importantly, the upregulation of FOXM1 in HCC tissue suggested that targeting FOXM1 inhibition with FAN or its inhibitors could be a promising therapeutic approach for HCC. Overall, this study elucidated the anti-tumor effects and potential pharmacological mechanisms of FAN, and proposed that targeting FOXM1 inhibition may be an effective therapeutic strategy for HCC with potential clinical applications.</div></div>","PeriodicalId":9902,"journal":{"name":"Cellular signalling","volume":"124 ","pages":"Article 111467"},"PeriodicalIF":4.4,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142406186","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}

{"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 ,&nbsp;Panping Liang ,&nbsp;Zhengwen Chen ,&nbsp;Zehua Chen ,&nbsp;Tao Jin ,&nbsp;Fengjun He ,&nbsp;Xiaolong Chen ,&nbsp;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}

{"title":"Impact of the local renin–angiotensin system in perivascular adipose tissue on vascular health and disease","authors":"Pitchai Balakumar ,&nbsp;Khalid M. Orayj ,&nbsp;Noohu Abdulla Khan ,&nbsp;Kumaran Shanmugam ,&nbsp;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}

{"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 ,&nbsp;Monica S. Morales ,&nbsp;Taylor E. Smith ,&nbsp;Cayla D. Ontko ,&nbsp;Neeraj S. Namburu ,&nbsp;Samuel A. Palmer ,&nbsp;Marvarakumari G. Jhala ,&nbsp;Carla J. Ramos ,&nbsp;Megan E. Capozzi ,&nbsp;Gary W. McCollum ,&nbsp;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}