Biochimica et biophysica acta. Molecular basis of disease最新文献

{"title":"Isorhapontigenin alleviates acetaminophen-induced liver injury by promoting fatty acid oxidation","authors":"Huiyan Zha ,&nbsp;Shuying Lv ,&nbsp;Yuming Hu ,&nbsp;Yaochen Xie ,&nbsp;Lingkun Wang ,&nbsp;Chen Yang ,&nbsp;Guilin Li ,&nbsp;Shuchen Gong ,&nbsp;Li Ping ,&nbsp;Difeng Zhu ,&nbsp;Jiajia Wang ,&nbsp;Qinjie Weng ,&nbsp;Qiaojun He ,&nbsp;Jincheng Wang","doi":"10.1016/j.bbadis.2024.167575","DOIUrl":"10.1016/j.bbadis.2024.167575","url":null,"abstract":"<div><div>Acetaminophen (APAP) is a widely used analgesic and antipyretic medicine. It is frequently employed to alleviate pain and mitigate fever-related symptoms, but it can cause liver injury or even liver failure when overdosed. Isorhapontigenin, a compound derived from Chinese herbs and grapes, has been demonstrated to exhibit antioxidant and anti-inflammatory effects. This study focused on evaluating the effect of isorhapontigenin in alleviating APAP-induced liver injury. In the study, a single intraperitoneal administration of APAP was employed to induce liver injury, and isorhapontigenin was given orally 3 days before or 1 h after APAP administration. The results revealed that isorhapontigenin significantly mitigated liver injury by effectively inhibiting APAP-induced apoptosis, oxidative stress, and inflammation. Furthermore, transcriptomic RNA sequencing of liver tissues indicated that isorhapontigenin probably protected against APAP-induced liver injury by promoting fatty acid oxidation. Pharmacological experiments also demonstrated that isorhapontigenin treatment led to a significant reduction in triglyceride accumulation, increased ATP levels and direct fatty acid oxidation activity, as well as enhanced expression of proteins associated with fatty acid oxidation, including PPAR-α, PGC-1α, and CPT-1A. Moreover, the protective effects of isorhapontigenin against APAP-induced liver injury were abolished by a CPT-1A inhibitor, etomoxir. Notably, we found that combining isorhapontigenin with NAC (<em>N</em>-acetyl-L-cysteine) resulted in a more significant alleviation of APAP-induced liver injury compared to NAC alone. In conclusion, our study indicates that isorhapontigenin is a potential therapeutic strategy that works by regulating fatty acid oxidation to alleviate APAP-induced liver injury.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 2","pages":"Article 167575"},"PeriodicalIF":4.2,"publicationDate":"2024-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142693820","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":"The role of suppressor of cytokine signaling 3 in inflammatory bowel disease and its associated colorectal cancer","authors":"Pengfei Zhang ,&nbsp;Bing Pei ,&nbsp;Chengxue Yi ,&nbsp;Francis Atim Akanyibah ,&nbsp;Fei Mao","doi":"10.1016/j.bbadis.2024.167578","DOIUrl":"10.1016/j.bbadis.2024.167578","url":null,"abstract":"<div><div>Inflammatory bowel disease (IBD) and colorectal cancer (CRC), as two of the major human intestinal diseases, provide challenges for the medical field. Suppressor of cytokine signaling 3 (SOCS3), a protein molecule that negatively regulates cytokine signaling through multiple pathways, is involved in the regulation of various inflammatory diseases and tumors. In IBD, SOCS3 acts on a variety of cells to repair mucosal damage and balance the immune response, including epithelial cells, macrophages, dendritic cells, neutrophils, and T cells. In CRC, SOCS3 is inextricably linked to tumor cell proliferation, invasion, metastasis, and drug resistance. Therefore, it is crucial to systematically investigate the pathogenic involvement of SOCS3 in IBD and CRC. This article reviews the mechanisms and pathways by which SOCS3 is involved in the inhibition of IBD and the mitigation of CRC, and details the therapeutic options for targeting SOCS3.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 2","pages":"Article 167578"},"PeriodicalIF":4.2,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142689979","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":"Zdhhc1 deficiency mitigates foam cell formation and atherosclerosis by inhibiting PI3K-Akt-mTOR signaling pathway through facilitating the nuclear translocation of p110α","authors":"Binhui Zhou ,&nbsp;Yang Liu ,&nbsp;Haoyuan Ma ,&nbsp;Bowen Zhang ,&nbsp;Beijia Lu ,&nbsp;Sainan Li ,&nbsp;Tingting Liu ,&nbsp;Yingcheng Qi ,&nbsp;Ying Wang ,&nbsp;Mengjie Zhang ,&nbsp;Juanjuan Qiu ,&nbsp;Rui Fu ,&nbsp;Wushan Li ,&nbsp;Liaoxun Lu ,&nbsp;Shuanghua Tian ,&nbsp;Qiaoli Liu ,&nbsp;Yanrong Gu ,&nbsp;Rong Huang ,&nbsp;Toby Lawrence ,&nbsp;Eryan Kong ,&nbsp;Yinming Liang","doi":"10.1016/j.bbadis.2024.167577","DOIUrl":"10.1016/j.bbadis.2024.167577","url":null,"abstract":"<div><div>Monocyte-to-macrophage differentiation and subsequent foam cell formation are key processes that contribute to plaque build-up during the progression of atherosclerotic lesions. Palmitoylation enzymes are known to play pivotal roles in the development and progression of inflammatory diseases. However, their specific impact on atherosclerosis development remains unclear. In this study, we discovered that the knockout of zDHHC1 in THP-1 cells, as well as Zdhhc1 in mice, markedly reduces the uptake of oxidized low-density lipoprotein (ox-LDL) by macrophages, thereby inhibiting foam cell formation. Moreover, the absence of Zdhhc1 in ApoE^−/− mice significantly suppresses atherosclerotic plaque formation. Mass spectrometry coupled with bioinformatic analysis revealed an enrichment of the PI3K-Akt-mTOR signaling pathway. Consistent with this, we observed that knockout of zDHHC1 significantly decreases the palmitoylation levels of p110α, a crucial subunit of PI3K. Notably, the deletion of Zdhhc1 facilitates the nuclear translocation of p110α in macrophages, leading to a significant reduction in the downstream phosphorylation of Akt at Ser473 and mTOR at Ser2448. This cascade results in a decreased number of macrophages within plaques and ultimately mitigates the severity of atherosclerosis. These findings unveil a novel role for zDHHC1 in regulating foam cell formation and the progression of atherosclerosis, suggesting it as a promising target for clinical intervention in atherosclerosis therapy.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 2","pages":"Article 167577"},"PeriodicalIF":4.2,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142683857","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":"Sanguinarine chloride hydrate mitigates colitis symptoms in mice through the regulation of the intestinal microbiome and metabolism of short-chain fatty acids","authors":"Jige Xin ,&nbsp;Lin He ,&nbsp;Yanlin Li ,&nbsp;Qiqi Pu ,&nbsp;Xuan Du ,&nbsp;Fuze Ban ,&nbsp;Diangang Han","doi":"10.1016/j.bbadis.2024.167579","DOIUrl":"10.1016/j.bbadis.2024.167579","url":null,"abstract":"<div><div>Sanguinarine constitutes the main components of <em>Macleaya cordata</em>, and exhibits diverse biological and pharmacological activities. This study investigated the effects of sanguinarine chloride hydrate (SGCH) on dextran sulfate sodium (DSS)-induced ulcerative colitis (UC) mice. Five groups were designed to investigate the effects of SGCH on the pathological symptoms, the mRNA expression levels of inflammatory cytokines, colonic mucosal barrier damage, microbiota composition, and SCFAs metabolism in UC mice. The administration of SGCH in DSS-induced UC mice resulted in the amelioration of pathological symptoms, as evidenced by an increase in body weight, a decrease in disease activity index score, elongation of colon length, reduction in spleen index, and improvement in colon injury. SGCH can regulate the expression of inflammatory cytokines (IL-6, TNF-α, IL-1β and IL-10) and tight junction proteins (ZO-1 and Occludin) associated with UC. SGCH exhibited a significant decrease in NF-κB P65 mRNA expression levels, accompanied by a significantly reduced protein level of NF-κB P-P65/P65. Further studies revealed SGCH effectively reversed the decrease in intestinal microbiota diversity induced by UC, thereby promoting the growth of beneficial bacteria such as <em>Akkermansia</em>, <em>Alistipes</em>, and <em>norank_o_Clostridia_UCG-014.</em> Correlation analysis demonstrated a positive association between butanoic acid, propanoic acid, isobutyric acid, isovaleric acid, valeric acid, hexanoic acid with <em>Colidextribacter</em>, while <em>Coriobacteriaceae_UCG-002</em> exhibited a negative correlation with butanoic acid, acetic acid and propanoic acid. In conclusion, the administration of SGCH can ameliorate clinical symptoms in UC mice, regulate the expression of inflammatory cytokines and tight junction proteins, modulate intestinal microbiota metabolism and SCFAs production.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 2","pages":"Article 167579"},"PeriodicalIF":4.2,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142678120","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":"Uncovering the protective role of lipid droplet accumulation against acid-induced oxidative stress and cell death in osteosarcoma","authors":"Cortini Margherita ,&nbsp;Ilieva Elizabeta ,&nbsp;Massari Stefania ,&nbsp;Bettini Giuliano ,&nbsp;Avnet Sofia ,&nbsp;Baldini Nicola","doi":"10.1016/j.bbadis.2024.167576","DOIUrl":"10.1016/j.bbadis.2024.167576","url":null,"abstract":"<div><div>Extracellular acidosis stemming from altered tumor metabolism promotes cancer progression by enabling tumor cell adaptation to the hostile microenvironment. In osteosarcoma, we have previously shown that acidosis increases tumor cell survival alongside substantial lipid droplet accumulation. In this study, we explored the role of lipid droplet formation in mitigating cellular stress induced by extracellular acidosis in osteosarcoma cells, thereby enhancing tumor survival during progression. Specifically, we examined how lipid droplets shield against reactive oxygen species induced by extracellular acidosis. We demonstrated that lipid droplet biogenesis is critical for acid-exposed tumor cell survival, as it starts shortly after acid exposure (24 h) and inversely correlates with ROS levels (DCFH-DA assay), lipid peroxidation (Bodipy assay), and the antioxidant response, as also revealed by NRF2 transcript. Additionally, extracellular metabolites, such as lactate, and interaction with mesenchymal stromal cells within the tumor microenvironment intensify lipid droplet build-up in osteosarcoma cells. Critically, upon targeting two key proteins implicated in LD formation - PLIN2 and DGAT1 - cell viability significantly declined while ROS production escalated. In summary, our findings underscore the vital reliance of acid-exposed tumor cells on lipid droplet formation to scavenge oxidative stress. We conclude that the rewiring of lipid metabolism driven by microenvironmental cues is of paramount importance for the survival of metabolically altered osteosarcoma cells in acidic condition. Overall, we suggest that targeting key members of lipid droplet biogenesis may eradicate more aggressive and resistant tumor cells, uncovering potential new treatment strategies for osteosarcoma.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 2","pages":"Article 167576"},"PeriodicalIF":4.2,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142678121","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":"CD36 inhibition corrects lipid-FetuinA mediated insulin secretory defects by preventing intracellular lipid accumulation and inflammation in the pancreatic beta cells","authors":"Samanwita Mandal ,&nbsp;Snehasish Nag ,&nbsp;Oindrila Mukherjee ,&nbsp;Nandita Das ,&nbsp;Priyajit Banerjee ,&nbsp;Tanmay Majumdar ,&nbsp;Satinath Mukhopadhyay ,&nbsp;Kathrin Maedler ,&nbsp;Rakesh Kundu","doi":"10.1016/j.bbadis.2024.167580","DOIUrl":"10.1016/j.bbadis.2024.167580","url":null,"abstract":"<div><div>CD36 is a multifunctional protein involved in long chain fatty acid uptake and immune modulation in different cells. Recently it was reported that increased expression of CD36 is evident in the islets of diabetic obese individuals. In this present study we investigated the role of CD36 in regulating intracellular lipid accumulation and inflammation in beta cells and its implication on secretory dysfunction. Additionally, we have elucidated the potential role of fetuinA, a circulatory glycoprotein and an endogenous ligand of TLR4, for aggravating lipid accumulation and insulin secretory defects in beta cells. MIN6 mouse insulinoma cells when incubated with palmitate and fetuinA together showed activation of TLR4-NFkB inflammatory cascade and increased uptake of palmitate, which was rescued by CD36 functional inhibition or knockdown. Moreover, glucose stimulated insulin secretion was restored with consequent downregulation of IL-1β secretion. TLR4 inhibition also decreased intracellular lipid content with a reduction of CD36, suggesting functional crosstalk between them. At physiological level, excess fetuinA in the islet milieu of HFD fed C57BL/6J mice or exogenous fetuinA administration (i.p.) promoted lipid accumulation in the islets resulting in decreased insulin secretion with increased CD36 expression. Interestingly, CD36 inhibition in HFD mice with a pharmacological inhibitor Salvianolic acid B attenuated inflammation, reduced intracellular lipid accumulation in beta cells and restored insulin secretory function. Therefore, our results suggest that inhibition of CD36 protects beta cells from the derogatory effects of lipid and fetuinA and restores secretory function and can be considered as a therapeutic target for obesity mediated beta cell dysfunction.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 2","pages":"Article 167580"},"PeriodicalIF":4.2,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142678118","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":"Molecular mechanisms restoring olaparib efficacy through ATR/CHK1 pathway inhibition in olaparib-resistant BRCA1/2MUT ovarian cancer models","authors":"Łukasz Biegała ,&nbsp;Małgorzata Statkiewicz ,&nbsp;Arkadiusz Gajek ,&nbsp;Izabela Szymczak-Pajor ,&nbsp;Natalia Rusetska ,&nbsp;Agnieszka Śliwińska ,&nbsp;Agnieszka Marczak ,&nbsp;Michał Mikula ,&nbsp;Aneta Rogalska","doi":"10.1016/j.bbadis.2024.167574","DOIUrl":"10.1016/j.bbadis.2024.167574","url":null,"abstract":"<div><div>Resistance to olaparib inevitably develops in ovarian cancer (OC) patients, highlighting the necessity for effective strategies to improve its efficacy. Here, we established a novel olaparib-resistant patient-derived xenograft model of high-grade serous OC with <em>BRCA1/2</em> mutations and examined the molecular characteristics of acquired resistance and resensitization to olaparib in treatment-naïve tumors <em>in vivo</em>. Olaparib-resistant xenografts were treated with olaparib, ATR inhibitor (ATRi, ceralasertib), CHK1 inhibitor (CHK1i, MK-8776) or their combinations. Proliferation, apoptosis, ATR/CHK1 activity, PARP signaling, DNA damage response (DDR), epithelial-to-mesenchymal transition (EMT), and MDR1 expression, were examined <em>via</em> RT-qPCR, western blot, and immunohistochemistry. Resistant tumors exhibited defects in PARP and ATR/CHK1 signaling, accompanied by altered expression of proteins involved in DDR and EMT. Olaparib rechallenge combined with ATR/CHK1 inhibitors showed promising synergistic effects on tumor growth inhibition. Mechanistically, combined treatments suppressed tumor proliferation without increasing apoptosis or necrosis, while inducing tumor cell vacuolization indicative of cell death. ATRi combined with olaparib induced or augmented downregulation of ATR, CHK1, PARP1, PARG, BRCA1, γH2AX, and PARylated protein expression, while reversing olaparib-induced upregulation of vimentin, BRCA2, and 53BP1. Our collective findings indicate that ATR/CHK1 pathway inhibition restores the olaparib efficacy in resistant <em>BRCA1/2</em>^MUT high-grade serous OC, highlighting promising approach for olaparib rechallenge of non-responsive patients. Uncovered mechanisms might improve our understanding of acquisition and overcoming resistance to olaparib in ovarian cancer.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 2","pages":"Article 167574"},"PeriodicalIF":4.2,"publicationDate":"2024-11-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142670088","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":"CRISPR-Cas9 mediated knockout of NDUFS4 in human iPSCs: A model for mitochondrial complex I deficiency","authors":"Shivani Goolab ,&nbsp;Karin Terburgh ,&nbsp;Charl du Plessis ,&nbsp;Janine Scholefield ,&nbsp;Roan Louw","doi":"10.1016/j.bbadis.2024.167569","DOIUrl":"10.1016/j.bbadis.2024.167569","url":null,"abstract":"<div><div>Mitochondrial diseases, often caused by defects in complex I (CI) of the oxidative phosphorylation system, currently lack curative treatments. Human-relevant, high-throughput drug screening platforms are crucial for the discovery of effective therapeutics, with induced pluripotent stem cells (iPSCs) emerging as a valuable technology for this purpose. Here, we present a novel iPSC model of <em>NDUFS4</em>-related CI deficiency that displays a strong metabolic phenotype in the pluripotent state. Human iPSCs were edited using CRISPR-Cas9 to target the <em>NDUFS4</em> gene, generating isogenic <em>NDUFS4</em> knockout (KO) cell lines. Sanger sequencing detected heterozygous biallelic deletions, whereas no indel mutations were found in isogenic control cells. Western blotting confirmed the absence of NDUFS4 protein in KO iPSCs and CI enzyme kinetics showed a ~56 % reduction in activity compared to isogenic controls. Comprehensive metabolomic profiling revealed a distinct metabolic phenotype in <em>NDUFS4</em> KO iPSCs, predominantly associated with an elevated NADH/NAD⁺ ratio, consistent with alterations observed in other models of mitochondrial dysfunction. Additionally, β-lapachone, a recognized NAD⁺ modulator, alleviated reductive stress in KO iPSCs by modifying the redox state in both the cytosol and mitochondria. Although undifferentiated iPSCs cannot fully replicate the complex cellular dynamics of the disease seen <em>in vivo</em>, these findings highlight the utility of iPSCs in providing a relevant metabolic milieu that can facilitate early-stage, high-throughput exploration of therapeutic strategies for mitochondrial dysfunction.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 2","pages":"Article 167569"},"PeriodicalIF":4.2,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142640423","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":"A novel Cdc42-YAP-fibronectin signaling axis regulates ameloblast differentiation during early enamel formation","authors":"Jiayi Zhang ,&nbsp;Jingyi Gao ,&nbsp;Xiangliang Zeng ,&nbsp;Zijie Wang ,&nbsp;Chuying Chen ,&nbsp;Chao Rong ,&nbsp;Shaowei Li ,&nbsp;Lingxuan Cai ,&nbsp;Luchen Wang ,&nbsp;Lin Zhang ,&nbsp;Zhihui Tian","doi":"10.1016/j.bbadis.2024.167570","DOIUrl":"10.1016/j.bbadis.2024.167570","url":null,"abstract":"<div><div>Enamel formation is a developmental event governed by intricate molecular signal pathways. Cdc42 is proven to regulate enamel development yet its underlying role and molecular mechanism in early amelogenesis remain elusive. The extracellular matrix of tooth germ basement membrane is critical for the regulation of ameloblast differentiation. Present study investigated whether Cdc42 influences amelogenesis by affecting ECM synthesis and how Cdc42 regulates ameloblasts differentiation. Epithelial-specific knockout of Cdc42 (Cdc42-cKO) mice model was employed to study the ECM expression including Fibronectin (Fn) and amelogenesis markers. Cdc42-cKO mice results in retarded ameloblast differentiation and enamel matrix decrease. Fn synthesis in the enamel organ and basal membrane was totally diminished along with Cdc42 knockdown. YAP acting as the Cdc42 downstream transcription factor, its distribution in ameloblasts was synchronously attenuated by Cdc42 knockdown and nuclear localization progressively decreased with tooth germ development. Cdc42 unidirectionally controls the Fn synthesis via YAP regulation. Overall, ameloblast differentiation inhibition by silencing of Cdc42 was successfully rescued by YAP activation. We demonstrated that Cdc42 as an initiator, mediated downstream pathway through transcriptional activator YAP, thereby affecting ameloblast differentiation by controlling Fn synthesis. The Cdc42-YAP-Fn signaling axis are elucidated to act critical role during the early amelogenesis.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 2","pages":"Article 167570"},"PeriodicalIF":4.2,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142640422","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":"Physiological activation of liver X receptor provides protection against ocular inflammation in uveitic glaucoma","authors":"Hyun Hee Ju ,&nbsp;Jiyoung Lee ,&nbsp;Seon-Kyu Kim ,&nbsp;Seon-Young Kim ,&nbsp;Jin-Hyun Ahn ,&nbsp;Nikolai P. Skiba ,&nbsp;Ponugoti V. Rao ,&nbsp;Jin A. Choi","doi":"10.1016/j.bbadis.2024.167573","DOIUrl":"10.1016/j.bbadis.2024.167573","url":null,"abstract":"<div><div>Virus-induced trabeculitis is considered a significant cause of uveitic glaucoma, being marked by a sudden increase in intraocular pressure and relatively mild inflammation in the anterior chamber of the eye. In previous proteome analyses of aqueous humor (AH) derived from Cytomegalovirus (CMV) uveitic glaucoma patients, we observed the liver X receptor (LXR) pathway to be among the most prominently activated canonical pathways. In the present study, we explored the role of the LXR pathway in the etiology of glaucoma in association with ocular inflammation. LXRα/β and ABCA1, the downstream targets of LXR, were distributed throughout the conventional AH outflow pathway of the human eye, and their increased levels in human trabecular meshwork cells in response to CMV infection and -lipopolysaccharide (LPS) treatment. Treatment with an LXR agonist (T091317) suppressed LPS-induced inflammation and this response was reversed under the deficiency of <em>LXRα</em>/<em>LXRβ</em>. Furthermore, in the rat endotoxin uveitis model, the LXR agonist significantly reduced infiltrating cells and expression of proinflammatory cytokines in the iris and retina. These results reveal upregulation of LXR-ABCA1 under inflammatory insult in the conventional AH outflow pathway, and activation of LXR exhibiting an anti-inflammatory effect, implying its essential physiological protective role in glaucoma associated with ocular inflammation.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 1","pages":"Article 167573"},"PeriodicalIF":4.2,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142640426","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}