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

{"title":"Suppression of intestinal Ticam1 ameliorated MASH via Akkermansia muciniphila QAA37749.1 mediated betaine transformation","authors":"Zhonglin Li ,&nbsp;Wenkang Gao ,&nbsp;Hang Yuan ,&nbsp;Xiaoli Pan ,&nbsp;Ruiqing Yuan ,&nbsp;Weijun Wang ,&nbsp;Lei Guan ,&nbsp;Lilin Hu ,&nbsp;Yue Chen ,&nbsp;Zilu Cheng ,&nbsp;Ruohang He ,&nbsp;Lei Zhang ,&nbsp;Bowen Yang ,&nbsp;Qingjing Zhu ,&nbsp;Minglu Liang ,&nbsp;Ekihiro Seki ,&nbsp;Rong Lin ,&nbsp;Huikuan Chu ,&nbsp;Ling Yang","doi":"10.1016/j.bbadis.2024.167571","DOIUrl":"10.1016/j.bbadis.2024.167571","url":null,"abstract":"<div><h3>Background &amp; aims</h3><div>Gut inflammation caused by diets could damage the intestinal barrier, which increases the liver exposition to pathogenic substances. Toll-IL-1 receptor (TIR) domain-containing adaptor molecule-1 (Ticam1) is a key molecule in the Toll-like receptors (TLRs) pathway, which is important for the immune defense against pathogens such as bacteria or viruses. In this study, mouse intestinal epithelial cell (IEC) Ticam1 was knocked out to suppress the intestinal inflammation response in metabolic dysfunction-associated steatohepatitis (MASH) to investigate its influence on the development of MASH.</div></div><div><h3>Methods</h3><div>The IEC-specific Ticam1 knockout (<em>Ticam1</em>^{<em>ΔIEC</em>}) mice and the control (<em>Ticam1</em>^{<em>fl/fl</em>}) mice were fed with high-fat high-fructose diet (HFD) for 22 weeks to evaluate the gut alteration and the MASH-associated disorders. The intestinal secreted immunoglobulin A (sIgA) and IgA-secreting immune cells were detected. Shotgun metagenomic sequencing was used to find the gut microbiome shift in different groups. Liquid chromatography mass spectrometry was also performed to evaluate the change of serum metabolites caused by the gut microbiome alteration.</div></div><div><h3>Results</h3><div>The gut inflammation and gut barrier dysfunction were both alleviated in HFD-fed <em>Ticam1</em>^{<em>ΔIEC</em>} mice, which had improved MASH disorders compared with <em>Ticam1</em>^{<em>fl/fl</em>}. Additionally, HFD-fed <em>Ticam1</em>^{<em>ΔIEC</em>} mice had increased sIgA and intestinal IgA-secreting immune cells. It showed a significantly higher content of <em>Akkermansia muciniphila</em>. We proved that <em>Akkermansia muciniphila</em> encoded a protein named QAA37749.1 that could promote the conversion of choline to betaine, through which the development of MASH was inhibited in HFD-<em>Ticam1</em>^{<em>ΔIEC</em>} mice.</div></div><div><h3>Conclusion</h3><div>Deletion of IEC Ticam1 alleviated MASH disorder and gut dysfunction in mice. It enhanced the level of intestinal sIgA and the growth of <em>Akkermansia muciniphila</em>, which supported the betaine transformation by QAA37749.1. Suppressing IEC Ticam1 might be a promising strategy for MASH disorder.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 1","pages":"Article 167571"},"PeriodicalIF":4.2,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142634248","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":"OTUD7B inhibited hepatic injury from NAFLD by inhibiting K48-linked ubiquitination and degradation of β-catenin","authors":"Jing Sun,&nbsp;Xiuli Jin,&nbsp;Yiling Li","doi":"10.1016/j.bbadis.2024.167555","DOIUrl":"10.1016/j.bbadis.2024.167555","url":null,"abstract":"<div><div>Non-alcoholic fatty liver disease (NAFLD) is the prevalent liver disease. Ovarian tumor domain-containing 7B (OTUD7B) is a deubiquitinating enzyme and its role in NAFLD remains unclear. In high-fat diet (HFD)-induced NAFLD mouse model and palmitic acid (PA)-treated HepG2 cells, OTUD7B expression was decreased. Adenoviral overexpression of OTUD7B in mice resulted in reduced body weight and liver injury, with decreased serum aminotransferase (ALT) and aspartate aminotransferase (AST) levels. OTUD7B overexpression attenuated hepatic lipid deposition (serum TG, TC, LDL-C, HDL<img>C, and FFA levels), which might be through the suppression of lipogenesis and β-oxidation-related genes. The contents of hepatic inflammatory factors (TNF-α, IL-6, and IL-1β) were decreased following OTUD7B overexpression in NAFLD mice. A mechanism study indicated that the protective effect of OTUD7B overexpression might be associated with β-catenin signal activation. OTUD7B overexpression promoted PA-induced β-catenin activity in TopFlash assay, and increased total β-catenin and c-myc levels in cells. The increase in β-catenin levels was contributed to the stabilization via inhibiting K48-linked ubiquitination and proteasomal degradation by OTUD7B. NR4A2 role in NASH has been proved. NR4A2 ChIP-seq and RNA-seq data excluded transcriptional regulation of NR4A2 to OTUD7B, and it was experimentally evidenced that NR4A2 bound to OTUD7B promoter region and positively transcriptionally regulate OTUD7B expression. In summary, OTUD7B overexpression ameliorated hepatic inflammation and steatosis in NAFLD. The possible mechanism of OTUD7B might be through the inhibition of β-catenin degradation by removing K48-linked ubiquitination, which might be regulated by NR4A2.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 1","pages":"Article 167555"},"PeriodicalIF":4.2,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142634256","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":"Functional brain changes in Mexican women with fibromyalgia","authors":"Odelia Elkana ,&nbsp;Iman Beheshti","doi":"10.1016/j.bbadis.2024.167564","DOIUrl":"10.1016/j.bbadis.2024.167564","url":null,"abstract":"<div><div>Fibromyalgia (FM) is a chronic condition marked by widespread pain, fatigue, sleep problems, cognitive decline, and other symptoms. Despite extensive research, the pathophysiology of FM remains poorly understood, complicating diagnosis and treatment, which often relies on self-report questionnaires. This study explored structural and functional brain changes in women with FM, identified potential biomarkers, and examined their relationship with FM severity. MRI data from 33 female FM patients and 33 matched healthy controls were utilized, focusing on T1-weighted MRI and resting-state fMRI scans. Functional connectivity (FC) analysis was performed using a machine learning framework to differentiate FM patients from healthy controls and predict FM symptom severity. No significant differences were found in brain structural features, such as gray matter volume, white matter volume, deformation-based morphometry, and cortical thickness. However, significant differences in FC were observed between FM patients and healthy controls, particularly in the default mode network (DMN), somatomotor network (SMN), visual network (VIS), and dorsal attention network (DAN). The FC metrics were significantly associated with FM severity. Our prediction model differentiated FM patients from healthy controls with an area under the curve of 0.65. FC measures accurately estimated FM symptom severities with a significant correlation (<em>r</em> = 0.45, <em>p</em> = 0.007). Functional connections in the DMN, VIS, and DAN were crucial in determining FM severity. These findings suggest that integrating brain FC measurements could serve as valuable biomarkers for identifying FM patients from healthy individuals and predicting FM symptom severity, improving diagnostic accuracy and facilitating the development of targeted therapeutic strategies.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 1","pages":"Article 167564"},"PeriodicalIF":4.2,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142634230","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":"Dysfunctional RNA binding protein induced neurodegeneration is attenuated by inhibition of the integrated stress response","authors":"Joseph-Patrick W.E. Clarke ,&nbsp;Miranda L. Messmer ,&nbsp;Jacob Pilon ,&nbsp;Jenna Reding ,&nbsp;Patricia A. Thibault ,&nbsp;Hannah E. Salapa ,&nbsp;Michael C. Levin","doi":"10.1016/j.bbadis.2024.167562","DOIUrl":"10.1016/j.bbadis.2024.167562","url":null,"abstract":"<div><div>Dysfunction of the RNA binding protein heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) contributes to neurodegeneration, the primary cause of permanent disability in multiple sclerosis (MS). To better understand the role of hnRNP A1 dysfunction in the pathogenesis of neurodegeneration, we utilized optogenetics-driven hnRNP A1 clustering to model its dysfunction in neuron-like differentiated Neuro-2A cells. hnRNP A1 clustering activates the integrated stress response (ISR) and results in a neurodegenerative phenotype marked by decreased neuronal protein translation and neurite loss. Small molecule inhibition of the ISR with either PERKi (GSK2606414) or ISRIB (<u>i</u>ntegrated <u>s</u>tress <u>r</u>esponse <u>i</u>nhi<u>b</u>itor) attenuated both the decrease in neuronal translation and neurite loss, without affecting hnRNP A1 clustering. We then confirmed a strong association between hnRNP A1 clustering and ISR activation in neurons from MS brains. These data illustrate that hnRNP A1 dysfunction promotes neurodegeneration by activation of the ISR <em>in vitro</em> and <em>in vivo</em>, thus revealing a novel therapeutic target to reduce neurodegeneration and subsequent disability in MS.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 1","pages":"Article 167562"},"PeriodicalIF":4.2,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142634255","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":"Linking COVID-19 and cancer: Underlying mechanism","authors":"Sourabh Tyagi ,&nbsp;Nipanshi Tyagi ,&nbsp;Anu Singh ,&nbsp;Akanksha Gautam ,&nbsp;Awantika Singh ,&nbsp;Shelja Jindal ,&nbsp;Rana P. Singh ,&nbsp;Rupesh Chaturvedi ,&nbsp;Hemant Ritturaj Kushwaha","doi":"10.1016/j.bbadis.2024.167563","DOIUrl":"10.1016/j.bbadis.2024.167563","url":null,"abstract":"<div><div>COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), lead to a global health crisis with a spectrum of clinical manifestations. A potentially vulnerable category for SARS-CoV-2 infection was identified in patients with other medical conditions. Intriguingly, parallels exist between COVID-19 and cancer at the pathophysiological level, suggesting a possible connection between them. This review discusses all possible associations between COVID-19 and cancer. Expression of receptors like angiotensin-converting enzyme 2 (ACE2) and transmembrane protease serine 2 (TMPRSS2) increases COVID-19 susceptibility. SARS-CoV-2 infection might increase cancer susceptibility and accelerate cancer progression through mechanisms involving cytokine storm, tissue hypoxia, impaired T-cell responses, autophagy, neutrophil activation, and oxidative stress. These mechanisms collectively contribute to immune suppression, hindered apoptosis, and altered cellular signaling in the tumor microenvironment, creating conditions favorable for tumor growth, metastasis, and recurrence. Approved vaccines and their impact on cancer patients along-with new clinical trials are also described.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 1","pages":"Article 167563"},"PeriodicalIF":4.2,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142607213","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":"Depression and obesity: Focus on factors and mechanistic links","authors":"Ashley Selman ,&nbsp;Jean Dai ,&nbsp;Jackson Driskill ,&nbsp;Arubala P. Reddy ,&nbsp;P. Hemachandra Reddy","doi":"10.1016/j.bbadis.2024.167561","DOIUrl":"10.1016/j.bbadis.2024.167561","url":null,"abstract":"<div><div>Major depressive disorder (MDD) is defined as mood disorder causing a persistent loss of interest and despair for two weeks or greater, with related symptoms. Depression can interfere with daily life and can cause those affected to not work, study, eat, sleep, and enjoy previously enjoyed hobbies and life events as they did previously. If untreated, it can become a serious health condition. Depression is multifactorial with a variety of factors influencing the condition. These factors include: (1) poor diet and exercise, (2) socioeconomic status, (3) gender, (4) biological clocks, (5) genetics and epigenetics, and (6) personal stressors. Treatment of depressive disorders is thus also multifactorial and utilizes the following therapies: (1) diet and exercise, (2) bright light therapy, (3) cognitive behavioral therapy, and (4) pharmaceutical therapy. Obesity is defined as body mass index over 30 and above, is believed to be causally linked to MDD through both psychological and molecular means. Atypical depression, a common form of MDD, is most strongly correlated with a high proclivity for obesity. Obesity and depression have a bidirectional relationship, a patient experiencing either condition singularly is more likely to develop the other due to the neural links between the two, including emotional lability, physical health of the brain, hormones, cytokine secretion, appetite, diet and feeding habits, inflammatory state. In individuals consuming a high fat diet (HFD) commonly ingested by those with obesity, the gut-microbiome is altered leading to systemic inflammation and the dysregulation of mood and the HPA axis impacting their neural health. The purpose of this paper is to examine the interplay of potential molecular, psychological, societal, and environmental causal factors of depressive disorders and how obesity perpetuates depression. A secondary aim of this paper is to examine current interventions that may help improve those affected by both conditions.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 1","pages":"Article 167561"},"PeriodicalIF":4.2,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142592383","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":"Mitochondrial respiratory complex II is altered in renal carcinoma","authors":"Sona Miklovicova ,&nbsp;Luca Volpini ,&nbsp;Ondrej Sanovec ,&nbsp;Federica Monaco ,&nbsp;Katerina Hadrava Vanova ,&nbsp;Jaromir Novak ,&nbsp;Stepana Boukalova ,&nbsp;Renata Zobalova ,&nbsp;Petr Klezl ,&nbsp;Marco Tomasetti ,&nbsp;Vladimir Bobek ,&nbsp;Vojtech Fiala ,&nbsp;Josef Vcelak ,&nbsp;Lory Santarelli ,&nbsp;Zuzana Bielcikova ,&nbsp;Katerina Komrskova ,&nbsp;Katarina Kolostova ,&nbsp;Karel Pacak ,&nbsp;Sarka Dvorakova ,&nbsp;Jiri Neuzil","doi":"10.1016/j.bbadis.2024.167556","DOIUrl":"10.1016/j.bbadis.2024.167556","url":null,"abstract":"<div><h3>Background</h3><div>Renal cell carcinoma (RCC) is a disease typified by anomalies in cell metabolism. The function of mitochondria, including subunits of mitochondrial respiratory complex II (CII), in particular SDHB, are often affected. Here we investigated the state and function of CII in RCC patients.</div></div><div><h3>Methods</h3><div>We evaluated tumour tissue as well as the adjacent healthy kidney tissue of 78 patients with RCC of different histotypes, focusing on their mitochondrial function. As clear cell RCC (ccRCC) is by far the most frequent histotype of RCC, we focused on these patients, which were grouped based on the pathological WHO/ISUP grading system to low- and high-grade patients, indicative of prognosis. We also evaluated mitochondrial function in organoids derived from tumour tissue of 7 patients.</div></div><div><h3>Results</h3><div>ccRCC tumours were characterized by mutated von Hippel-Lindau gene and high expression of carbonic anhydrase IX. We found low levels of mitochondrial DNA, protein and function, together with CII function in ccRCC tumour tissue, but not in other RCC types and non-tumour tissues. Mitochondrial content increased in high-grade tumours, while the function of CII remained low. Tumour organoids from ccRCC patients recapitulated molecular characteristics of RCC tissue.</div></div><div><h3>Conclusions</h3><div>Our findings suggest that the state of CII, epitomized by its assembly and SDHB levels, deteriorates with the progressive severity of ccRCC. These observations hold the potential for stratification of patients with worse prognosis and may guide the exploration of targeted therapeutic interventions.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 1","pages":"Article 167556"},"PeriodicalIF":4.2,"publicationDate":"2024-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142565212","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 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}