Life sciences最新文献

{"title":"Targeted inhibition of JMJD2C/MALAT1 axis compensates for the deficiency of metformin in reversing ovarian cancer platinum resistance","authors":"Linlin Li ,&nbsp;Jialin Zhang ,&nbsp;Huiqing Li ,&nbsp;Liying Qin ,&nbsp;Han Wu ,&nbsp;Zijiao Li ,&nbsp;Lei Cai ,&nbsp;Di Chen ,&nbsp;Jianping Yang ,&nbsp;Yibing Chen ,&nbsp;Ya Xie","doi":"10.1016/j.lfs.2025.123663","DOIUrl":"10.1016/j.lfs.2025.123663","url":null,"abstract":"<div><h3>Aims</h3><div>We explored JMJD2C’s role in platinum resistance in ovarian cancer and its modulation by metformin to propose strategies for overcoming treatment limitations.</div></div><div><h3>Materials and methods</h3><div>JMJD2C and MALAT1 expression was assessed via RT-qPCR, western blotting, and immunohistochemical assays using OC cell lines, tissue from OC patients, and xenograft treatment with or without metformin. CCK-8 assays, flow cytometry, inductively coupled plasma mass spectrometry, luciferase reporter assays, and ChIP assays were employed to evaluate the impact of JMJD2C/MALAT1 on PR and the effects of metformin on JMJD2C. The effects of metformin in combination with JMJD2C knockdown were assessed in vitro and in vivo.</div></div><div><h3>Key findings</h3><div>JMJD2C and MALAT1 expression was higher in tissue samples from platinum-resistant phase compared to those from paired platinum-sensitive phase. JMJD2C upregulated MALAT1 in platinum-resistant ovarian cancer (PROC) cells by demethylating its promoter at sites H3K9m3 and H3K36m3. Overexpression of JMJD2C or MALAT1 promoted PR by activating NF-κB/P-gp and P38 MAPK/ERCC1 signaling pathways, with their knockdown produced the opposite effect. Metformin increased JMJD2C expression in tumor tissue, cell lines, and a xenograft model of OC; however, elevated JMJD2C expression attenuated the PR-reversal efficacy of low-concentration metformin. Low-dose metformin combined with JMJD2C-knockdown effectively reversed PR both in in vitro and in vivo, achieving better results than either treatment alone.</div></div><div><h3>Significance</h3><div>JMJD2C drives PR in OC by demethylating the MALAT1 promoter. Metformin upregulated JMJD2C expression, thus necessitating a higher effective dosage of metformin. Targeted inhibition of JMJD2C synergistically enhanced the efficacy of low-dose metformin in overcoming PR, thus providing a promising approach for addressing PR.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"373 ","pages":"Article 123663"},"PeriodicalIF":5.2,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143899042","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Excessive mitochondrial fission and associated extracellular mitochondria mediate cardiac dysfunction in obesity cardiomyopathy","authors":"Sin-Jin Li ,&nbsp;Laura H. Tetri ,&nbsp;Vijith Vijayan ,&nbsp;Aly Elezaby ,&nbsp;Chun-Hsien Chiang ,&nbsp;Ivan Lopez ,&nbsp;Nicolai P. Ostberg ,&nbsp;Timothy T. Cornell ,&nbsp;Ching-Yi Chen ,&nbsp;Bereketeab Haileselassie","doi":"10.1016/j.lfs.2025.123658","DOIUrl":"10.1016/j.lfs.2025.123658","url":null,"abstract":"<div><h3>Aims</h3><div>Obesity cardiomyopathy (OCM) is associated with mitochondrial dysfunction caused by altered mitochondrial dynamics. Extracellular mitochondria (exMito) are released following tissue injury under various conditions. While the excessive mitochondrial fission-mediated release of exMito as a mechanism for mitochondrial quality control in several inflammatory disorders, its role in OCM remains unclear. The present work aimed to determine if excessive mitochondrial fission and associated exMito mediate the chronic inflammatory response and cardiac remodeling in OCM.</div></div><div><h3>Materials and methods</h3><div>H9c2 cardiomyoblasts were treated with 200 μM palmitate (PA) to induce lipotoxicity. C57BL/6J mice were fed a high-fat diet (HFD) for 12 weeks to induce OCM. P110, a peptide inhibitor of Drp1/Fis1 interaction, was used to evaluate the impact of excessive mitochondrial fission on cardiac mitochondrial function, quality, and quantity of exMito, systemic inflammatory response, and cardiac contractile function in both models of OCM.</div></div><div><h3>Key findings</h3><div>PA induced excessive mitochondrial fission, increased oxidative stress, decreased ATP level, and damaged exMito release <em>in vitro</em>. Exposure of naïve cardiomyoblasts to exMito isolated from PA treated cells resulted in mitochondrial dysfunction and a pro-inflammatory response. <em>In vivo</em>, HFD induced cardiac mitochondrial and contractile dysfunction, exMito release, and a pro-inflammatory response. Inhibition of Drp1/Fis1 interaction with P110 attenuated the observed effects both <em>in vitro</em> and <em>in vivo</em>.</div></div><div><h3>Significance</h3><div>P110 limited lipid-induced mitochondrial dysfunction and decreased exMito release, subsequently improving the inflammatory state and contractile function in our OCM model. Drp1/Fis1 dependent fission and associated exMito release might serve as a therapeutic target for obesity induced cardiomyopathy.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"373 ","pages":"Article 123658"},"PeriodicalIF":5.2,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143892188","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The role of bioactive compounds in the management of metabolic and alcohol-related liver disease","authors":"Chang Ma ,&nbsp;Xi Cheng ,&nbsp;Min Hu ,&nbsp;Wanyu Wang ,&nbsp;Wei Guo ,&nbsp;Sha Li","doi":"10.1016/j.lfs.2025.123660","DOIUrl":"10.1016/j.lfs.2025.123660","url":null,"abstract":"<div><div>Metabolic and alcohol-related liver disease (MetALD) is a newly defined category within the spectrum of steatotic liver diseases, designed to capture the interplay between metabolic dysfunction and alcohol consumption more effectively. Bioactive compounds, celebrated for their potent antioxidant, anti-inflammatory, and hepatoprotective properties, have emerged as promising therapeutic agents for the management of MetALD. This review comprehensively examines the underlying mechanisms by which these compounds exert their effects, including the modulation of oxidative stress pathways, the enhancement of lipid metabolism, and the promotion of liver regeneration. Specific bioactive constituents, such as polyphenols, flavonoids, and omega-3 fatty acids, have demonstrated potential in ameliorating hepatic steatosis and fibrosis associated with MetALD. Incorporating these natural compounds into treatment regimens presents a novel strategy for managing MetALD, with significant implications for both lifestyle modifications and pharmacological interventions. Future research should prioritize clinical trials, improvements in bioavailability, and investigations into the synergistic effects of multi-compound formulations to establish effective and sustainable treatment strategies for MetALD.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"373 ","pages":"Article 123660"},"PeriodicalIF":5.2,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143892297","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A review of the human microRNA and the Mycobacterium tuberculosis epigenetic effects on the emergence drug resistance","authors":"Yashna Sukdeo,&nbsp;Nozibusiso Pearl Shozi,&nbsp;Nonsikelelo Ndimande,&nbsp;Kingsley Chimaeze Mbara,&nbsp;Peter M.O. Owira","doi":"10.1016/j.lfs.2025.123637","DOIUrl":"10.1016/j.lfs.2025.123637","url":null,"abstract":"<div><h3>Aims</h3><div><em>Mycobacterium tuberculosis</em> (MTB) uses epigenetics to avoid the hostile host immune defence systems and also mount resistance to chemotherapy when exposed to antibiotic stress. MTB's epigenetic survival tool-kit includes genomic DNA histone acetylation/deacetylation, methylation, phosphorylation, ubiquitylation, etc. The non-coding host microRNAs (miRNAs) as genomic products of epigenetic control of drug extrusion processes, drug permeability barrier formation or metabolism, and target alteration are hijacked by MTB to mount multi-drug resistance. The miRNAs involved and the mechanisms used are not yet completely understood. The role of MTB genome-derived miRNA are currently indeterminate as the current studies are only focused on the host miRNA biogenesis in MTB pathogenesis. However, the contribution of host miRNA to drug resistance in MTB chemotherapy is largely unknown.</div></div><div><h3>Materials and methods</h3><div>We have comprehensively searched online databases for medical, health, and nanotechnology for articles published in English between 2020 and 2024 using search words “MTB”, “Epigenetics”, “microRNA”, “TB Chemotherapy” to compile this narrative review.</div></div><div><h3>Key findings</h3><div>MTB epigenetic tool-kit of DNA methylation, histone acetylation/deacetylation, cell membrane impermeability, drug metabolism and target mimicry are mediated by the hijacked host cell microRNAs in the development of drug resistance. Antisense oligomers or mimetics can therefore, be used as miRNA antagonists/silencers or agomirs, respectively, depending on the pattern of miRNA expression, to combat resistance to MTB chemotherapy.</div></div><div><h3>Conclusions</h3><div>This review discusses microRNAs as epigenetic agents in the emergence of Multi-Drug Resistance TB (MDR-TB) and their potential role in chemotherapeutics.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"374 ","pages":"Article 123637"},"PeriodicalIF":5.2,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143929071","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Gender disparities in myotonic dystrophy 1","authors":"Dipti Chakraborty,&nbsp;Shreya Borthakur,&nbsp;Ritu Sarkar,&nbsp;Mayanglambam Dhruba Singh","doi":"10.1016/j.lfs.2025.123659","DOIUrl":"10.1016/j.lfs.2025.123659","url":null,"abstract":"<div><div>Myotonic Dystrophy Type 1 (DM1) is a complex, inherited disorder characterized by significant clinical heterogeneity, affecting multiple organ systems with varying severity and age of onset. It is a multisystemic disorder with a wide range of clinical presentations that lead to symptoms and complications associated with various body systems. Predicting the overall phenotype and prognosis is challenging due to the lack of a single determining factor, complicating medical management and clinical trials. While extensive research has explored the genetic and molecular mechanisms of DM1, the influence of gender on disease manifestations, progression, and outcomes remains elusive. Emerging evidence suggests that male patients often experience greater morbidity and mortality with severe muscular, cardiac, central nervous system, and respiratory impairments, while females are more prone to ophthalmological, gastrointestinal, and endocrine complications. Potential gender-based differences in inheritance patterns also require further investigation. Despite these disparities, gender-specific considerations are largely absent in clinical management and research, limiting the development of targeted therapeutic strategies. This review provides a comprehensive analysis of gender-related differences in DM1, emphasizing their implications for disease prognosis, diagnosis, and treatment. Recognizing gender as a crucial factor in DM1 research and clinical practice could improve patient outcomes and more personalized therapeutic approaches.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"373 ","pages":"Article 123659"},"PeriodicalIF":5.2,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143864054","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Chemerin facilitates placental trophoblast invasion and spiral artery remodeling through the pentose phosphate pathway","authors":"Jiaxuan Cai ,&nbsp;Xinyue Han ,&nbsp;Suohao Peng ,&nbsp;Jie Chen ,&nbsp;Jian V. Zhang ,&nbsp;Chen Huang","doi":"10.1016/j.lfs.2025.123645","DOIUrl":"10.1016/j.lfs.2025.123645","url":null,"abstract":"<div><h3>Aims</h3><div>The invasion of trophoblasts and remodeling of spiral arteries are the requisite processes for successful placentation. A defect of trophoblast invasion is closely associated with pregnancy complications, including miscarriage and preeclampsia. In this study, we investigated the function of chemerin in trophoblast invasion and artery remodeling and explored the underlying mechanism in this process.</div></div><div><h3>Main methods</h3><div>Immunostaining was performed to examine chemerin expression in different days of mouse placenta and early stage of human placenta. Chemerin KO and LPS-treated mice, with exogenous chemerin peptide, were used to evaluate trophoblast giant cells (TGC) invasion, artery remodeling, and NK cell infiltration. Chemerin KO and LPS-treated decidua on E8.5 were conducted in metabolites file and measured related enzymes' expression. Chemerin’s function was further examined by human trophoblast HTR-8 cell migration and the enzymes expression in the pentose phosphate pathway.</div></div><div><h3>Key findings</h3><div>Chemerin has high expression in mouse-invasive TGC and human extra-villous trophoblast cells. Deficiency of chemerin and LPS treatment in pregnant mice impaired placental TGC invasion, spiral artery remodeling, and NK cell infiltration in decidua, which mainly attributed to the downregulation of metabolites and G6PD and RPIA expression in pentose phosphate pathway (PPP). Chemerin activated the PPP to accelerate HTR-8 cell migration. Exogenous chemerin administration remarkably attenuated the defect of TGC invading and artery remodeling in LPS-treated mice, and promoted NK infiltration and maternal blood perfusion.</div></div><div><h3>Significance</h3><div>This study described the indispensable role of chemerin in trophoblast invasion and arterial remodeling, and suggested its potential application in pregnancy complications miscarriage and preeclampsia.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"373 ","pages":"Article 123645"},"PeriodicalIF":5.2,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143882541","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Toxicological profiling and diuretic potential of arbutin via aldosterone synthase gene inhibition","authors":"Maria Nazeer MS ,&nbsp;Nabi Shah PhD ,&nbsp;Saif Ullah MS ,&nbsp;Muhammad Ikram PhD ,&nbsp;Muhammad Imran Amirzada PhD ,&nbsp;Abdulmohsin J. Alamoudi PhD ,&nbsp;Meshal Alshamrani PhD ,&nbsp;Abdul Jabbar Shah PhD","doi":"10.1016/j.lfs.2025.123661","DOIUrl":"10.1016/j.lfs.2025.123661","url":null,"abstract":"<div><h3>Aims</h3><div>Arbutin (ARB), a natural polyphenol isolated from the bearberry plant <em>Arctostaphylos uva-ursi</em>, has been studied for its diverse pharmacological activities including anti-diabetic, cardioprotective and anti-inflammatory effects. This study aimed to evaluate arbutin’s diuretic activity, focusing on its impact on aldosterone synthase gene expression and its toxicity profile.</div></div><div><h3>Material and methods</h3><div>Acute toxicity was assessed using single doses ranging from 500 to 9000 mg/kg and sub-acute toxicity with doses of 375 and 750 mg/kg over 14 days. To evaluate acute diuretic activity, ARB was administered in three doses (25, 50 and 75 mg/kg i.p) alongside standard groups, furosemide (FUR) 10 mg/kg i.p and Spironolactone (SPIR) 25 mg/kg i.p. In sub-acute diuretic study, treatment was administered for seven days, followed by blood collection and adrenal dissection for gene expression analysis.</div></div><div><h3>Key findings</h3><div>Acute toxicity studies revealed that ARB is well-tolerated up to 7000 mg/kg with no significant changes in organ and body weight. However, sub-acute studies showed minor changes in leukocyte count, alkaline phosphatase (ALP), alanine aminotransferase (ALT) and triglycerides (TGs) at high doses while histopathological evaluations revealed no severe organ damage. The diuretic index and electrolyte analysis confirmed the potential of ARB as diuretic and saluretic with reduced risk of hyperuricemia and hyperkalemia. Gene expression studies showed non-selective downregulation of aldosterone synthase gene (CYP11B2) and 11β-hydroxylase (CYP11B1). While the effects on 17α-hydroxylase (CYP17A1) were less pronounced than SPIR, indicating fewer possible anti-androgenic effects.</div></div><div><h3>Significance</h3><div>Our findings suggest that ARB is a promising diuretic agent with a favorable safety profile.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"373 ","pages":"Article 123661"},"PeriodicalIF":5.2,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143873907","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Co-therapy with S1P and heparan sulfate derivatives to restore endothelial glycocalyx and combat pro-atherosclerotic endothelial dysfunction.","authors":"Ronodeep Mitra, Kaleigh Pentland, Svilen Kolev, Matthew Eden, Erel Levine, Jessica M Oakes, Eno E Ebong","doi":"10.1016/j.lfs.2025.123662","DOIUrl":"https://doi.org/10.1016/j.lfs.2025.123662","url":null,"abstract":"<p><strong>Aims: </strong>Endothelial cell (EC) glycocalyx (GCX) shedding from disturbed blood flow and chemical factors leads to low-density lipoprotein infiltration, reduced nitric oxide synthesis, vascular dysfunction and atherosclerosis. This study evaluates a therapy combining sphingosine-1-phosphate (S1P) and heparin (heparan sulfate derivative). We hypothesized that heparin/S1P co-treatment repairs mechanically damaged EC GCX in disturbed flow (DF) regions and restores anti-atherosclerotic mechanotransduction to treat cardiovascular disease.</p><p><strong>Materials and methods: </strong>We used a parallel-plate flow chamber to simulate flow conditions in vitro and a partial carotid ligation mouse model to mimic DF in vivo. Heparin and albumin-bound S1P were administered to assess their reparative effects on the endothelial GCX. Fluorescent staining, confocal microscopy, and ultrasound evaluated endothelial cell function and endothelial-dependent vascular function. Barrier functionality was assessed via macrophage uptake. Heparin/S1P mechanism-of-action insights were gained through fluid dynamics simulations and staining of GCX synthesis enzyme and S1P receptor. Statistical analyses validated the results.</p><p><strong>Key findings: </strong>The in vitro data showed that heparin/S1P therapy improves DF-conditioned ECs by restoring GCX and elevating vasodilator eNOS (endothelial-type nitric oxide synthase) expression. In vivo studies confirmed GCX degradation, vessel inflammation, hyperpermeability, and wall thickening in the mouse model's partially ligated left carotid artery. Heparin/S1P treatment restored GCX thickness and coverage, reduced inflammation and hyperpermeability, and inhibited vessel wall thickening.</p><p><strong>Significance: </strong>This work introduces a new approach to regenerating the EC GCX and restoring its function in ECs under DF conditions, offering a groundbreaking solution for preventing cardiovascular diseases like atherosclerosis.</p>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":" ","pages":"123662"},"PeriodicalIF":5.2,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144001180","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A signpost to guide the key therapeutic components of Aralia continentalis Kitag roots in treating T2DM-derived heart attack, and diabetic nephropathy via systems biology concept","authors":"Ki-Kwang Oh ,&nbsp;Seol Hee Song,&nbsp;Jeong Ha Park ,&nbsp;Min Ju Kim,&nbsp;Dong Joon Kim,&nbsp;Ki-Tae Suk","doi":"10.1016/j.lfs.2025.123635","DOIUrl":"10.1016/j.lfs.2025.123635","url":null,"abstract":"<div><h3>Aims</h3><div><em>Aralia continentalis</em> Kitag roots (ACKRs) have been regarded as a nutritional natural resource for treating different diseases, including type 2 diabetes mellitus (T2DM), and its complications (heart attack; HA, diabetic nephropathy; DN). Nonetheless, an extensive investigation of T2DM-derived complications has yet to be performed.</div></div><div><h3>Main methods</h3><div>Accordingly, we adopted gas chromatography–mass spectrometry (GC–MS) to identify the molecules of ACKRs, followed by the use of cheminformatics (Similarity Ensemble Approach; SEA, SwissTargetPrediction; STP), bioinformatics (STRING, DisGeNET, and OMIM), and computer screening tools to investigate its corresponding targets, in T2DM diseases and its complications.</div></div><div><h3>Key findings</h3><div>The primary targets (PPARG, and IL6) were confirmed via a protein–protein interaction (PPI) network, suggesting that IL6- Andrographolide, PPARA-Germacrene D, PPARD- Kaurenoic acid, PPARG- Kaurenoic acid, NR1H3- 1-Naphthalenepropanol, α-ethenyldecahydro-5-(hydroxymethyl)-α,2,5,5,8a-pentamethyl-, and FABP4- Kaurenoic acid conformers on PPAR signaling pathway might exert agonistic mode.</div></div><div><h3>Significance</h3><div>These findings underline that ACKRs' bioactives filtered by the devised platform could prevent T2DM-derived complications through multiple-target.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"372 ","pages":"Article 123635"},"PeriodicalIF":5.2,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143864954","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"N6-methyladenosine-modified circQKI inhibits prostate cancer docetaxel-sensitivity via miR-188-3p/Beclin-1 pathway","authors":"Tong Zhao ,&nbsp;Kai Li ,&nbsp;Yetao Zhang ,&nbsp;Yuxiang Dong ,&nbsp;Yongshan Li ,&nbsp;Mingyang Pang ,&nbsp;Yong Wei ,&nbsp;Bing Yao ,&nbsp;Qingyi Zhu","doi":"10.1016/j.lfs.2025.123646","DOIUrl":"10.1016/j.lfs.2025.123646","url":null,"abstract":"<div><h3>Background</h3><div>Docetaxel (DTX) is used in the first-line chemotherapy for advanced castration-resistant prostate cancer (CRPC), but resistance remains a major clinical challenge. Circular RNAs (circRNAs) play critical roles in DTX resistance. This study aimed to investigate the mechanism of a novel circRNA, circQKI, in DTX resistance and its regulatory network in CRPC.</div></div><div><h3>Methods</h3><div>DTX-resistant cell lines (PC3/DR and 22RV1/DR) were established, and circQKI's circular structure was validated by Sanger sequencing. CircQKI expression was modulated via siRNA knockdown and overexpression plasmids. Cell viability, apoptosis, and colony formation were assessed by CCK-8, flow cytometry, and clonogenic assays. The interaction between circQKI and miR-188-3p was verified by dual-luciferase reporter, RIP, and RNA pull-down. Autophagy activation was analyzed via Western blot and TEM. Subcutaneous xenograft models evaluated in vivo drug resistance. M6A modification was investigated through m6A RIP-PCR, METTL3/IGF2BP2 knockdown, and stability assays.</div></div><div><h3>Results</h3><div>CircQKI was significantly upregulated in resistant cells and promoted DTX resistance by sponging miR-188-3p, thereby enhancing Beclin-1 expression and autophagy activation. Inhibiting Beclin-1 or co-treatment with chloroquine (CQ) partially restored DTX sensitivity. Mechanistically, METTL3-mediated m6A modification stabilized circQKI via IGF2BP2 recognition, leading to its accumulation in resistant cells. In vivo studies confirmed that circQKI overexpression reduced tumor sensitivity to DTX by enhancing autophagy.</div></div><div><h3>Conclusion</h3><div>circQKI drives DTX resistance via the miR-188-3p/Beclin-1 axis and autophagy activation, with its expression regulated by METTL3-dependent m6A modification and IGF2BP2. Targeting circQKI or autophagy pathways may offer novel therapeutic strategies to overcome DTX resistance in prostate cancer.</div></div>","PeriodicalId":18122,"journal":{"name":"Life sciences","volume":"372 ","pages":"Article 123646"},"PeriodicalIF":5.2,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143844014","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}