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

{"title":"PI3K/Akt inhibition promotes AR activity and prostate cancer cell proliferation through p35-CDK5 modulation","authors":"Wei-Hsiang Kao ,&nbsp;Kun-Yuan Chiu ,&nbsp;Stella Chin-Shaw Tsai ,&nbsp;Chieh-Lin Jerry Teng ,&nbsp;Muhammet Oner ,&nbsp;Chih-Ho Lai ,&nbsp;Jer-Tsong Hsieh ,&nbsp;Chi-Chien Lin ,&nbsp;Hsin-Yi Wang ,&nbsp;Mei-Chih Chen ,&nbsp;Ho Lin","doi":"10.1016/j.bbadis.2024.167568","DOIUrl":"10.1016/j.bbadis.2024.167568","url":null,"abstract":"<div><div>Aberrant PI3K/Akt activation is linked to prostate cancer (PCa) malignancy, while androgen receptor (AR) is critical in early-stage PCa development. Investigating the interaction between these pathways is crucial for PCa malignancy. Our previous study demonstrated that p35-CDK5 mediates post-translational modifications of AR, STAT3, and p21^CIP1, eventually promoting PCa cell growth. This study revealed the role of p35-CDK5 in between PI3K/Akt and AR by utilizing LNCaP and 22Rv1 cells. Through the TCGA database analysis, we observed a positive correlation between PTEN and p35 expression, implying a potential negative correlation between PI3K/Akt activation and p35-CDK5. Inhibiting PI3K/Akt with LY294002, Capivasertib (AZD5363), or using an inactive Akt mutant significantly increased p35 expression and subsequently enhanced AR stability and activation in PCa cells. On the other hand, CDK5-knockdown reversed these effects. The involvement of the β-catenin/Egr1-axis was observed in regulating PI3K/Akt inhibition and p35-CDK5 activation, implying a possible mechanistic connection. Importantly, CDK5 knockdown further reduced PI3K/Akt-inhibition-induced AR and cell viability maintenance, suggesting a compensatory role for CDK5-AR in maintaining cell viability under Akt inhibition. In conclusion, PI3K/Akt inhibition could trigger p35-CDK5-dependent AR activation and cell viability, highlighting p35-CDK5 as a critical link connecting PI3K/Akt inhibition to AR activation and pivotal in PCa cell resistance to PI3K/Akt blockade.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 2","pages":"Article 167568"},"PeriodicalIF":4.2,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142634235","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":"Chemogenetic activation of hepatic G12 signaling ameliorates hepatic steatosis and obesity","authors":"Kaito Arai ,&nbsp;Yuki Ono ,&nbsp;Natsumi Hirai ,&nbsp;Yuki Sugiura ,&nbsp;Keizo Kaneko ,&nbsp;Shigeru Matsuda ,&nbsp;Keita Iio ,&nbsp;Keita Kajino ,&nbsp;Tsuyoshi Saitoh ,&nbsp;Fan-Yan Wei ,&nbsp;Hideki Katagiri ,&nbsp;Asuka Inoue","doi":"10.1016/j.bbadis.2024.167566","DOIUrl":"10.1016/j.bbadis.2024.167566","url":null,"abstract":"<div><h3>Objective</h3><div>Hepatic steatosis, the early stage of nonalcoholic fatty liver disease (NAFLD), currently lacks targeted pharmacological treatments. G protein-coupled receptors (GPCRs) in hepatocytes differentially regulate lipid metabolism depending on their coupling profile of G protein subtypes. Unlike G_s, G_i, and G_q signaling, the role of G₁₂ signaling in hepatic steatosis remains elusive. The objective of this study was to investigate the effect of G₁₂ signaling on hepatic steatosis and obesity and its mechanisms.</div></div><div><h3>Methods</h3><div>We generated mice expressing a G₁₂-coupled designer GPCR in a liver-specific manner. We performed phenotypic analysis in the mice under the condition of fasting (acute hepatic steatosis model) or high-fat diet feeding (chronic hepatic steatosis model).</div></div><div><h3>Results</h3><div>In acute and chronic hepatic steatosis models, chemogenetic activation of hepatic G₁₂ signaling suppressed the progression of hepatic steatosis. The treatment led to an increased triglyceride secretion with little effect on mitochondrial respiratory activity, fatty acid oxidation, de novo lipogenesis, and fatty acid uptake. Furthermore, in a high-fat-diet-induced obesity model, activation of the G₁₂-coupled designer GPCR exerted anti-obesity effects with increased whole-body energy expenditure and fat oxidation. Anti-FGF21 antibody treatment showed that the anti-obesity effects of the hepatic G₁₂D activation relied in part on the hepatokine FGF21.</div></div><div><h3>Conclusions</h3><div>Our findings indicate that the activation of G₁₂ signaling in the liver has the potential to prevent hepatic steatosis and obesity. This discovery provides a strong rationale for the development of drugs targeting G₁₂-coupled GPCRs expressed in the liver.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 2","pages":"Article 167566"},"PeriodicalIF":4.2,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142634227","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":"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":"GPR68 supports AML cells through the calcium/calcineurin pro-survival pathway and confers chemoresistance by mediating glucose metabolic symbiosis","authors":"Xiaofei He ,&nbsp;Caleb Hawkins ,&nbsp;Lauren Lawley ,&nbsp;Tra Mi Phan ,&nbsp;Isaac Park ,&nbsp;Nicole Joven ,&nbsp;Jiajia Zhang ,&nbsp;Mark Wunderlich ,&nbsp;Benjamin Mizukawa ,&nbsp;Shanshan Pei ,&nbsp;Amisha Patel ,&nbsp;Jennifer VanOudenhove ,&nbsp;Stephanie Halene ,&nbsp;Jing Fang","doi":"10.1016/j.bbadis.2024.167565","DOIUrl":"10.1016/j.bbadis.2024.167565","url":null,"abstract":"<div><div>Accumulating evidence demonstrates that the “Warburg effect” that glycolysis is enhanced even in the presence of oxygen existed in hematopoietic malignancies, contributing to extracellular acidosis. G-protein coupled receptor 68 (GPR68), as a proton sensing GPCR responding to extracellular acidosis, is expected to play a critical role in hematopoietic malignancies. In the present study, we found that GPR68 was overexpressed in acute myeloid leukemia (AML) cells, and GPR68 deficiency impaired AML cell survival <em>in vitro</em> and cell engraftment <em>in vivo</em>. Mechanistic studies revealed that unlike GPR68 regulates Calpain1 in myelodysplastic syndromes (MDS) cells, GPR68 deficiency reduced cytosolic Ca²⁺ levels and calcineurin (CaN) activity in AML cells through an NFAT-independent mechanism. Moreover, the decreased Ca²⁺ levels disturbed cellular respiration (<em>i.e.</em>, oxidative phosphorylation, OxPhos) by inhibiting isocitrate dehydrogenase (IDH) activity; this was more pronounced when BCL2 was inhibited simultaneously. Interestingly, GPR68 inhibition also decreased aerobic glycolysis in AML cells in a Ca²⁺-independent manner, suggesting that GPR68 mediated glucose metabolic symbiosis. As glucose metabolic symbiosis and the heterogeneous dependencies on aerobic glycolysis and cellular respiration tremendously impact chemosensitivity, the inhibition of GPR68 potentiated the tumoricidal effect of first-line chemotherapeutic agents, including BCL-2 inhibitors targeting OxPhos and cytarabine (Ara-C) targeting glycolysis. Consistent with these <em>in vitro</em> observations, higher levels of GPR68 were associated with inferior clinical outcomes in AML patients who received chemotherapies. In short, GPR68 drives the Ca²⁺/CaN pro-survival pathway and mediates glucose metabolic pathways in AML cells. Targeting GPR68 eradicates AML cells and alleviates chemoresistance, which could be exploited as a therapeutic target.</div></div>","PeriodicalId":8821,"journal":{"name":"Biochimica et biophysica acta. Molecular basis of disease","volume":"1871 1","pages":"Article 167565"},"PeriodicalIF":4.2,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142634234","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}