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

{"title":"The IP3R inhibitor desmethylxestospongin B reduces tumor cell migration, invasion and metastasis by impairing lysosome acidification and β1-integrin recycling","authors":"Galdo Bustos ,&nbsp;Ulises Ahumada-Castro ,&nbsp;Eduardo Silva-Pavez ,&nbsp;Hernán Huerta ,&nbsp;Andrea Puebla ,&nbsp;Camila Quezada ,&nbsp;Pablo Morgado-Cáceres ,&nbsp;César Casanova-Canelo ,&nbsp;Natalia Smith-Cortinez ,&nbsp;Maša Podunavac ,&nbsp;Cesar Oyarce ,&nbsp;Alvaro Lladser ,&nbsp;Paula Farias ,&nbsp;Alenka Lovy ,&nbsp;Jordi Molgó ,&nbsp;Vicente A. Torres ,&nbsp;Armen Zakarian ,&nbsp;J. César Cárdenas","doi":"10.1016/j.bbadis.2024.167557","DOIUrl":"10.1016/j.bbadis.2024.167557","url":null,"abstract":"<div><div>Cancer is the second leading cause of death worldwide. &gt;90 % of cancer-related deaths are due to metastasis, a process that depends on the ability of cancer cells to leave the primary tumor, migrate, and colonize different tissues. Inositol 1,4,5-trisphosphate receptor (IP₃R)-mediated Ca²⁺ signaling plays an essential role in maintaining the homeostasis of cancer cells and the sustained proliferation. Desmethylxestospongin B (dmXeB) is a specific inhibitor of the IP₃R that selectively arrests cell proliferation and promotes cancer cell death at high concentrations. However, whether migration, invasion and metastasis can be affected by this drug is unknown. Here, by using the highly metastatic triple negative breast cancer (TNBC) cell line MDA-MB-231, we demonstrate that a prolonged inhibition of IP₃R-mediated Ca²⁺ signals with dmXeB significantly reduces cell migration and invasion <em>in vitro</em> and metastasis <em>in vivo</em>. We found that this phenomenon was independent of the bioenergetic control of IP₃R over the mitochondria and AMPK activation. Furthermore, employing a tandem LC3-GFP-mcherry assay, we found that prolonged inhibition of IP₃R with dmXeB leads to diminished autophagic flux. This reduction can be attributed to impaired lysosomal acidification, as evidenced by assessments using DQ-BSA and pHrodo. Since cell migration requires appropriate assembly and disassembly of focal adhesions, along with the internalization and recycling of integrins <em>via</em> autophagy, we explored the dependency of integrin recycling from autophagosomes, finding that IP₃R inhibition with dmXeB impaired the recycling of β1-integrins, which accumulated within autophagosomes. Our findings reveal an unexpected effect of IP₃R inhibition with dmXeB in cancer cells that could represent a novel therapeutic strategy for the treatment of cancer metastasis.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 1","pages":"Article 167557"},"PeriodicalIF":4.2,"publicationDate":"2024-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142565165","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":"BCAR1 facilitates the survival of lung adenocarcinoma cells by augmenting the unfolded protein response, autophagy, and the formation of vasculogenic mimicry","authors":"Chengyi Mao ,&nbsp;Jingge Zhang ,&nbsp;Chuan Yang ,&nbsp;Longyong Mei ,&nbsp;Yonggeng Feng ,&nbsp;Fuqiang Dai ,&nbsp;Yi Huang ,&nbsp;Hualiang Xiao ,&nbsp;Bo Deng","doi":"10.1016/j.bbadis.2024.167558","DOIUrl":"10.1016/j.bbadis.2024.167558","url":null,"abstract":"<div><h3>Background</h3><div>Our objective was to elucidate the pivotal roles of BCAR1 in unfolded protein response (UPR), autophagy and vasculogenic mimicry (VM) formation, processes that essential for the metastasis of lung adenocarcinoma (LUAD) cells.</div></div><div><h3>Methods</h3><div>The morphological assessment of endoplasmic reticulum (ER) status and autolysosomes in H1975 and H1299 LUAD cells following BCAR1 knockout (KO) was conducted using transmission electron microscope. The expression of markers and cellular functions related to the UPR, autophagy, and VM formation were examined in LUAD cells tissues. Additionally, proteomic analysis of LUAD cells was performed via mass spectrometry, and the pertinent signaling pathways were analyzed using bioinformatics tools.</div></div><div><h3>Results</h3><div>BCAR1-KO inhibited autophagy and UPR induced triggered starvation in LUAD cells. Cleaved-ATF6a-mediated UPR and subsequent autophagy, enhanced by BCAR1, were confirmed using the UPR stimulator and blocker. High BCAR1 expression, along with elevated UPR and autophagy, predicts poor prognosis in LUAD patients. BCAR1-KO reduced tube formation and VM markers expressions in LUAD cells. Additionally, BCAR1 expression positively correlated with VM formation in BALB/c-nu mice xenografts and LUAD patient tissues.</div></div><div><h3>Conclusion</h3><div>BCAR1 promotes LUAD metastasis by enhancing cancer cell survival in nutrient-poor environments through ATF6-mediated UPR activation and autophagy. As BCAR1 induces VM formation, metastatic lesions eventually colonize. Thus, BCAR1 is a promising anti-metastasis target.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 1","pages":"Article 167558"},"PeriodicalIF":4.2,"publicationDate":"2024-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142565142","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":"Overexpression of FBP1 enhances dendritic cell activation and maturation by inhibiting glycolysis and promoting the secretion of IL33 in lung adenocarcinoma","authors":"Chunwei Li ,&nbsp;Lili Zhu ,&nbsp;Yaqi Yang ,&nbsp;Tengfei Zhang ,&nbsp;Chengxin Chen ,&nbsp;Yixing Zhang ,&nbsp;Wenxuan Ji ,&nbsp;Xiaoran Duan ,&nbsp;Wenhua Xue ,&nbsp;Lifeng Li ,&nbsp;Jie Zhao","doi":"10.1016/j.bbadis.2024.167559","DOIUrl":"10.1016/j.bbadis.2024.167559","url":null,"abstract":"<div><div>Fructose 1,6-diphosphatase 1 (FBP1) is an enzyme involved in gluconeogenesis and glycolysis inhibition. Dendritic cells (DCs) are antigen-presenting cells, and antigens presented to T cells activate the immune response. FBP1 inhibits the development of several tumors, and high FBP1 expression inhibits the proliferation, migration, and invasion of lung cancer cells. However, the mechanism through which FBP1 mediates the tumor immune microenvironment is unclear. This study mainly analyzed the role of FBP1 in regulating the function of DCs through metabolic reprogramming and immune microenvironment using in vitro and in vivo experiments. The positive association of FBP1 with DCs was found by bioinformatic analysis. The in vitro experiments revealed that the extracellular acidification rate and lactate level were lower in the FBP1 overexpression cells than in the control cells and that the lower lactate level reduced the inhibition of DC function. In addition, high FBP1 expression promoted the secretion of IL33 by activating the cGAS/STING/NF-κB/IL33 pathway, which was identified and verified via high-throughput sequencing and in vitro experiments. FBP1 activated the cGAS/STING pathway by increasing the degree of DNA damage, as revealed by the level of γH2AX and comet assay. IL33 enhanced the expression of the DC costimulatory molecules CD86 and HLA-DR as well as that of the functional factor IL-1β. The results demonstrated that FBP1 promoted the activation and maturation of DCs by inhibiting glycolysis and promoting the secretion of IL33 as well as by further activating the function of CD8⁺T cells. Finally, the humanized immune system mouse models confirmed the above role of FBP1. Thus, FBP1 may serve as a new target to cure lung adenocarcinoma, and IL33 may improve the efficiency of immune therapy in lung adenocarcinoma.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 1","pages":"Article 167559"},"PeriodicalIF":4.2,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142565239","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":"Canine Mammary Tumours (CMTs) exploit mitochondrial cholesterol for aggressive reprogramming","authors":"Liana Hardy ,&nbsp;Brindha Kannan ,&nbsp;Manuel Rigon ,&nbsp;Genevieve Benton-Hawthorn ,&nbsp;Renato L. Previdelli ,&nbsp;Iris M. Reichler ,&nbsp;Franco Guscetti ,&nbsp;Mariusz P. Kowalewski ,&nbsp;Michelangelo Campanella","doi":"10.1016/j.bbadis.2024.167546","DOIUrl":"10.1016/j.bbadis.2024.167546","url":null,"abstract":"<div><div>In human breast cancer the mitochondrial translocator protein (TSPO) aids pro-survival cellular response by facilitating the formation of mitochondrial contact sites with the nucleus termed Nucleus Associated Mitochondria (NAM). Here, we show that TSPO positively associates with the aggressiveness of tissues and cells isolated from Canine Mammary Tumours (CMTs).</div><div>TSPO is also readily upregulated in reprogrammed mammary tumour cells following long-term deprivation of oestrogen or exposure to the endocrine chemotherapeutic (ET) agent Tamoxifen. The latter triggers mitochondrial handling of cholesterol which is facilitated by TSPO whose upregulation reduces susceptibility to Tamoxifen. TSPO binding ligands boost, on the other hand, the efficacy of Tamoxifen and Chemotherapy agents. In aggressive canine mammary tumour cells, TSPO repression impairs the NF-kB pattern thus confirming the pro-survival role of the NAM uncovered in the human counterpart.</div><div>Mitochondrial cholesterol handling via TSPO emerges therefore as a signature in the aggressive reprogramming of CMTs thus advancing our understanding of the molecular mechanisms underpinning this pathology. A novel target mechanism to improve bio-marking and therapeutic protocols is here proposed.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 2","pages":"Article 167546"},"PeriodicalIF":4.2,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142565145","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 of transmitted endoplasmic reticulum stress mediating immune escape of gastric cancer via PVR overexpression in TAMs","authors":"Xuxian Zhong ,&nbsp;Youqin Xu ,&nbsp;Shengnan Yang ,&nbsp;Jiaqi Liao ,&nbsp;Ziyang Hong ,&nbsp;Xingyu Zhang ,&nbsp;Ziqing Wu ,&nbsp;Chengshu Tu ,&nbsp;Qiang Zuo","doi":"10.1016/j.bbadis.2024.167560","DOIUrl":"10.1016/j.bbadis.2024.167560","url":null,"abstract":"<div><div>Gastric cancer (GC) is the fourth leading cause of cancer death worldwide. Due to the complex tumor microenvironment (TME), the efficacy of immunotherapy in GC has not met expectations. Malignant changes in the TME induce endoplasmic reticulum stress (ERS). ERS can be transmitted between tumor cells and tumor-associated macrophages (TAMs), promoting tumor immune escape, but the specific mechanism in GC remains unclear. We established a TAM model of transmitted ERS (TERS), and iTRAQ proteomic analysis identified overexpressed proteins. The overexpression of poliovirus receptor (PVR) was screened while flow cytometry and ELISA showed that PVR mediated the immunosuppressive function of TAMs by downregulating the proliferative activity and cytotoxicity of cocultured CD8+ T lymphocytes. With EMSA and dual-luciferase reporter assays, we confirmed that erythropoietin-producing hepatocellular receptor A2 (EphA2) affected PVR expression by increasing the transcriptional activity of activator protein-1 (AP-1). MFC cells were mixed with EphA2 knockdown or control RAW264.7 cells to establish subcutaneous tumor models with or without tunicamycin treatment in vivo. The vivo experiments revealed that ERS promoted subcutaneous xenograft growth, which was reversed by EphA2 knockdown. Clinically, GC patients with high expression of PVR and EphA2 tended to have an immunosuppressive TME, which were determined by immunohistochemical and immunofluorescence analyses. In conclusion, the transcriptional activity of AP-1 is upregulated in ERS-transmitted TAMs through EphA2 to increase PVR expression, which promotes immune escape in GC. Our study provides a new perspective on the role of ERS in tumor immunity.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 1","pages":"Article 167560"},"PeriodicalIF":4.2,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142565224","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":"PTPN2 dephosphorylates STAT3 to ameliorate anesthesia-induced cognitive decline in aged rats by altering the microglial phenotype and inhibiting inflammation","authors":"Xiaochun Zhao ,&nbsp;Xueting Wang ,&nbsp;Ziyang Xu ,&nbsp;Xiaohan Chang ,&nbsp;Yue Tian","doi":"10.1016/j.bbadis.2024.167545","DOIUrl":"10.1016/j.bbadis.2024.167545","url":null,"abstract":"<div><div>Perioperative neurocognitive disorders (PNDs) are common neurological complications after anesthesia in the elderly. Protein tyrosine phosphatase non-receptor type 2 (PTPN2) regulates signal transducer and activator of transcription protein 3 (STAT3) signaling to control inflammation in certain organs, but its role in PNDs remains unknown. Herein, we constructed a PND model in 18-month-old rats by treating them with sevoflurane. PND rats developed neuroinflammation, along with a significant decrease in PTPN2 expression and a rise in STAT3 phosphorylation in the hippocampus. <em>Ptpn2</em> overexpression alleviated the behavioral disorders of PND rats, ameliorated neuronal injury, inhibited neuroinflammation, inflammasome activation, microglial activation, and microglial phenotype switching. Similar results were observed in sevoflurane-treated HMC3 microglia with PTPN2 overexpression, while PTPN2 silencing showed the opposite results. Additionally, PTPN2 seems to be a target of T-box transcription factor 2 (TBX2). These results contribute to the evidence supporting the idea that PTPN2 is a regulatory factor in PND progression.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 1","pages":"Article 167545"},"PeriodicalIF":4.2,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142559724","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":"EZH2 contributes to sepsis-induced acute lung injury through regulating macrophage polarization","authors":"Ziyi Wang ,&nbsp;Zhe Guo ,&nbsp;Xuesong Wang ,&nbsp;Yan Chai ,&nbsp;Ziwen Wang ,&nbsp;Haiyan Liao ,&nbsp;Feng Chen ,&nbsp;Yuxiang Xia ,&nbsp;Xinrui Wang ,&nbsp;Zhong Wang","doi":"10.1016/j.bbadis.2024.167554","DOIUrl":"10.1016/j.bbadis.2024.167554","url":null,"abstract":"<div><h3>Background</h3><div>Zeste enhancer homolog 2 (EZH2) is a pivotal regulator of gene dynamics implicated in the progression of sepsis-induced acute lung injury (SALI). EZH2 regulates aberrant inflammatory and immune responses in macrophages via unconventional biochemical interactions. However, the mechanisms driving atypical behavior of EZH2 during sepsis remain elusive, and therapeutic strategies targeting EZH2 are currently underutilized.</div></div><div><h3>Purpose</h3><div>This study aimed to investigate how EZH2 regulates macrophage polarization through the AKT pathway to improve SALI and to explore therapeutic drugs targeting EZH2.</div></div><div><h3>Methods</h3><div>We used Western blotting, hematoxylin-eosin stainin, immunofluorescence, flow cytometry, qRT-PCR, RNA sequencing, and chromatin immunoprecipitation sequencing methods to investigate regulation of macrophage immune response by EZH2 and explored its specific mechanism. These methods were also used to examine the protective effects of MS177 against SALI.</div></div><div><h3>Results</h3><div>Specific deletion of EZH2 in macrophages reduced the level of AKTIP, downregulated the M1 macrophage markers CD86 and cytotoxic T cell marker CD8+, upregulated the M2 macrophage marker CD206 and regulatory T cell marker FOXP3+, decreased the levels of pro-inflammatory cytokines IL-6, TNF-α, and IL-β, and increased the level of anti-inflammatory cytokine IL-10. This ultimately improved lung injury and mortality in SALI mice. EZH2 promoted the M1 polarization of macrophages by activating AKT2 via direct binding to the promoter region of AKTIP in a SALI mouse model. Furthermore, MS177 alleviated SALI by degrading EZH2 both in vitro and in vivo.</div></div><div><h3>Conclusion</h3><div>EZH2 regulates macrophage polarization via the AKTIP-AKT2 pathway. Our findings suggest that MS177 is a promising therapeutic agent for EZH2-dependent SALI.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 1","pages":"Article 167554"},"PeriodicalIF":4.2,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142549516","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":"TMEM106B knockdown exhibits a neuroprotective effect in Parkinson's disease models via regulating autophagy-lysosome pathway","authors":"Yumei Liu,&nbsp;Kunpeng Qin,&nbsp;Kaixin Dou,&nbsp;Jiwen Ren,&nbsp;Binghui Hou,&nbsp;Anmu Xie","doi":"10.1016/j.bbadis.2024.167553","DOIUrl":"10.1016/j.bbadis.2024.167553","url":null,"abstract":"<div><h3>Background</h3><div>TMEM106B, a lysosomal transmembrane protein, has been reported to be associated with Parkinson's disease (PD). However, the precise physiopathologic mechanism of TMEM106B in PD remains unclear.</div></div><div><h3>Objective</h3><div>This study aimed to explore the influence of TMEM106B on the autophagy-lysosome pathway (ALP) in PD.</div></div><div><h3>Methods</h3><div>55 patients with PD and 40 healthy controls were enrolled. RT-qPCR and ELISA were employed to assess the levels of TMEM106B. In vitro and in vivo models of PD, Lentivirus-shTMEM106B and AAV-shTMEM106B were used to knockdown the expression of TMEM106B. Behavioral experiments, western blot, immunofluorescence, and immunohistochemistry were used to detect the effect of TMEM106B on the ALP process.</div></div><div><h3>Results</h3><div>We found that the levels of TMEM106B were increased in the PD patients and PD models. TMEM106B knockdown markedly improved the motor deficits and tyrosine hydroxylase (TH) expression of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned mice. TMEM106B knockdown promoted α-syn clearance by regulating the ALP process in MPP⁺-induced SH-SY5Y cells and MPTP-treated mice. Further studies revealed that TMEM106B knockdown might activate ALP through activating AMPK-mTOR-TFEB axis. Furthermore, TMEM106B may play a vital role in the ALP by mediating the expression of TDP43. <strong>Conclusions</strong>: Taken together, our study suggests that TMEM106B knockdown mediates the ALP pathway, leading to a decrease in α-syn, providing a new direction and perspective for the regulation of autophagy in PD.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 1","pages":"Article 167553"},"PeriodicalIF":4.2,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142555557","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":"The relevance of the heme oxygenase system in alleviating diabetes-related hormonal and metabolic disorders","authors":"Tomasz Szkudelski,&nbsp;Katarzyna Szkudelska","doi":"10.1016/j.bbadis.2024.167552","DOIUrl":"10.1016/j.bbadis.2024.167552","url":null,"abstract":"<div><div>Heme oxygenase (HO) is an enzyme that catalyzes heme degradation. HO dysfunction is linked to various pathological conditions, including diabetes. Results of animal studies indicate that HO expression and activity are downregulated in experimentally induced diabetes. This is associated with severe hormonal and metabolic disturbances. However, these pathological changes have been shown to be reversed by therapy with HO activators. In animals with experimentally induced diabetes, HO was upregulated by genetic manipulation or by pharmacological activators such as hemin and cobalt protoporphyrin. Induction of HO alleviated elevated blood glucose levels and improved insulin action, among other effects. This effect resulted from beneficial changes in the main insulin-sensitive tissues, i.e., the skeletal muscle, the liver, and the adipose tissue. The action of HO activators was due to positive alterations in pivotal signaling molecules and regulatory enzymes. Furthermore, diabetes-related oxidative and inflammatory stress was reduced due to HO induction. HO upregulation was effective in various animal models of type 1 and type 2 diabetes. These data suggest the possibility of testing HO activators as a potential tool for alleviating hormonal and metabolic disorders in people with diabetes.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 1","pages":"Article 167552"},"PeriodicalIF":4.2,"publicationDate":"2024-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142555558","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":"Thioredoxin-1 protein interactions in neuronal survival and neurodegeneration","authors":"Md Imamul Islam ,&nbsp;Shakila Sultana ,&nbsp;Nirmala Padmanabhan ,&nbsp;Mahamud-Ur Rashid ,&nbsp;Tabrez J. Siddiqui ,&nbsp;Kevin M. Coombs ,&nbsp;Peter F. Vitiello ,&nbsp;Soheila Karimi-Abdolrezaee ,&nbsp;Eftekhar Eftekharpour","doi":"10.1016/j.bbadis.2024.167548","DOIUrl":"10.1016/j.bbadis.2024.167548","url":null,"abstract":"<div><div>Neuronal cell death remains the principal pathophysiologic hallmark of neurodegenerative diseases and the main challenge for treatment strategies. Thioredoxin1 (Trx1) is a major cytoplasmic thiol oxidoreductase protein involved in redox signaling, hence a crucial player in maintaining neuronal health. Trx1 levels are notably reduced in neurodegenerative diseases including Alzheimer's and Parkinson's diseases, however, the impact of this decrease on neuronal physiology remains largely unexplored. This is mainly due to the nature of Trx1 redox regulatory role which is afforded by a rapid electron transfer to its oxidized protein substrates. During this reaction, Trx1 forms a transient bond with the oxidized disulfide bond in the substrate. This is a highly fast reaction which makes the identification of Trx1 substrates a technically challenging task. In this project, we utilized a transgenic mouse model expressing a Flag-tagged mutant form of Trx1 that can form stable disulfide bonds with its substrates, hence allowing identification of the Trx1 target proteins. Autophagy is a vital housekeeping process in neurons that is critical for degradation of damaged proteins under oxidative stress conditions and is interrupted in neurodegenerative diseases. Given Trx1's suggested involvement in autophagy, we aimed to identify potential Trx1 substrates following pharmacologic induction of autophagy in primary cortical neurons. Treatment with rapamycin, an autophagy inducer, significantly reduced neurite outgrowth and caused cytoskeletal alterations. Using immunoprecipitation and mass spectrometry, we have identified 77 Trx1 target proteins associated with a wide range of cellular functions including cytoskeletal organization and neurodegenerative diseases. Focusing on neuronal cytoskeleton organization, we identified a novel interaction between Trx1 and RhoB which was confirmed in genetic models of Trx1 downregulation in primary neuronal cultures and HT22 mouse immortalized hippocampal neurons. The applicability of these findings was also tested against the publicly available proteomic data from Alzheimer's patients. Our study uncovers a novel role for Trx1 in regulating neuronal cytoskeleton organization and provides a mechanistic explanation for its multifaceted role in the physiology and pathology of the nervous system, offering new insights into the molecular mechanisms underlying neurodegeneration.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 1","pages":"Article 167548"},"PeriodicalIF":4.2,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142514563","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}