EXCLI Journal最新文献

{"title":"Bridging pathologies: Mechanistic insights into the diabetes-Alzheimer's nexus.","authors":"Aniket Kakkar, Harpreet Singh, Yash Jasoria, Arvind Kumar, Shivani Chopra, Hitesh Chopra, Arun Kumar Mishra","doi":"10.17179/excli2025-9165","DOIUrl":"10.17179/excli2025-9165","url":null,"abstract":"<p><p>Type 2 diabetes mellitus (T2DM) is increasingly recognized as a major risk factor for Alzheimer's disease (AD), with mounting evidence highlighting shared pathophysiological mechanisms. This review explores the intricate biological and molecular links between these two chronic disorders. Key overlapping pathways include impaired insulin signaling, chronic inflammation, oxidative stress, mitochondrial dysfunction, amyloid-beta (Aβ) accumulation, tau hyperphosphorylation, and the formation of advanced glycation end-products (AGEs). Disruption of insulin signaling in the brain contributes to synaptic loss and neurodegeneration, while systemic metabolic disturbances aggravate blood-brain barrier dysfunction and neurovascular damage. Emerging studies also underscore the role of antidiabetic treatments, especially newer agents targeting the gut-brain axis, in modulating AD progression. The review further examines preclinical models, clinical observations, and the development of biomarkers to improve early detection and intervention. Despite growing insights, challenges remain in translating mechanistic knowledge into effective therapies. A multidisciplinary approach integrating metabolic control and neuroprotective strategies is essential for addressing the comorbid burden of T2DM and AD. See also the graphical abstract(Fig. 1).</p>","PeriodicalId":12247,"journal":{"name":"EXCLI Journal","volume":"25 ","pages":"261-289"},"PeriodicalIF":6.2,"publicationDate":"2026-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12982873/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147462932","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Epigenetic regulation of PANoptosis: DNA methylation, histone modifications and non-coding RNAs.","authors":"Yogendra Singh, Muhammad Afzal, M Arockia Babu, Surya Nath Pandey, Arcot Rekha, Gaurav Gupta, Imran Kazmi, Sami I Alzarea, Omar Awad Alsaidan, Waleed Hassan Almalki, Salem Salman Almujri","doi":"10.17179/excli2025-9099","DOIUrl":"10.17179/excli2025-9099","url":null,"abstract":"<p><p>PANoptosome (Programmed Necrosis-Apoptosis Optosome) multiprotein complexes mediate the convergence of apoptosis, pyroptosis, and necroptosis. The ability of cells to undergo programmed inflammatory cell death is regulated by the epigenetic control of PANoptotic sensors, adaptors, and effectors, and has pivotal implications for their use in cancer therapies. DNA methylation suppresses the main PANoptotic pathways, such as RIPK3 (Receptor-Interacting Serine/Threonine-Protein Kinase 3), GSDME (Gasdermin E), and CASP8 (Caspase-8) that promote chemoresistance; hypomethylating DNA silencers resume PANoptotic sensitivity. BRD4 (Bromodomain-Containing Protein 4)/p300 (E1A-Associated Protein p300 - Histone Acetyltransferase) -mediated histone acetylation in enhancers (H3K27ac) stimulates ZBP1 (Z-DNA Binding Protein 1), NLRP3 (NOD-Like Receptor Family Pyrin Domain Containing 3), and caspase-8 transcription but inhibits the formation of inflammasomes by HDAC (Histone Deacetylase). PANoptotic regulatory regions become accessible in response to inflammatory signals through the dynamic regulation of accessibility through the SWI/SNF (Switch/Sucrose Non-Fermentable Chromatin Remodeling Complex) and NuRD (Nucleosome Remodeling Complex) and NuRD (Nucleosome Remodeling and Deacetylase Complex) chromatin remodelling complexes. Post-transcriptional regulation is mediated by ncRNAs (ncRNAs) such as miR-223-3p (MicroRNA-223-3p) and lncRNA NEAT1 (Long Non-Coding RNA - Nuclear Enriched Abundant Transcript 1) which converge to regulate the expression of NLRP3, RIPK3, and Gasdermin D (GSDMD). The interaction of DNA methylation, histone modification, and ncRNAs creates quantitative epigenetic thresholds that regulate PANoptotic sensitivity. The rational next step to overcome tumor immunoresistance is epigenetic biomarker stratification in combination with DNA methyltransferase inhibitors (DNMTi), histone deacetylase modulators (HDACi), and PANoptosis agonists, which could help reduce collateral tissue toxicity. See also the graphical abstract(Fig. 1).</p>","PeriodicalId":12247,"journal":{"name":"EXCLI Journal","volume":"25 ","pages":"238-260"},"PeriodicalIF":6.2,"publicationDate":"2026-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12982872/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147462943","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Eugenol: A promising therapeutic terpenoid against ischemia-reperfusion injury.","authors":"Puneet Kaur Randhawa, Deepti Gupta, Mohd Hanifa, Bivek Bajgai, Sorabh Sehajpal, Sarbeshwar Jaggi, Anjana Bali","doi":"10.17179/excli2025-9036","DOIUrl":"10.17179/excli2025-9036","url":null,"abstract":"<p><p>Ischemic disorders are one of the prime causes of mortality and disability among various individuals across the globe. Although drug treatment/percutaneous coronary interventions may recanalize the obstructed blood vessels, yet reperfusion therapy may aggravate tissue damage and result in ischemia-reperfusion injury. Eugenol, a phenolic monoterpenoid (4-allyl-2-methoxyphenol), has been used extensively in various preclinical studies as an antioxidant compound that ameliorates ischemia-reperfusion injury in several organs, including the heart, brain, kidney, and intestine. This protective effect of eugenol is attributed to its ability to influence various several key signaling pathways. These include the AMPK-mTOR-P70S6K (AMP-activated protein kinase-mammalian target of rapamycin-p70 ribosomal S6 kinase) pathway, AMPK/GSK3β (Glycogen synthase kinase-3 beta) axis, PI3K/Akt (phoshatidylinositol-3 kinase/ protein kinase B) signaling, which help to mitigate oxidative damage and inflammation. It also modulates the activity of the Nrf2 transcription factor, ACE, and the apoptotic pathway, affects histone acetylation, and alters the expression of HMGN1, PPP2Ca, and CD151 genes, demonstrating its wide-ranging therapeutic effects. In this review, we will discuss the preclinical evidences and potential mechanisms of action of eugenol-dependent protective benefits against ischemia-reperfusion injury. See also the graphical abstract(Fig. 1).</p>","PeriodicalId":12247,"journal":{"name":"EXCLI Journal","volume":"25 ","pages":"222-237"},"PeriodicalIF":6.2,"publicationDate":"2026-01-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12982868/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147462964","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Candesartan cilexetil as a repurposed therapeutic candidate for nasopharyngeal carcinoma: Integrated in vitro and in silico analyses.","authors":"Chawalit Ngernsombat, Utid Suriya, Somsiri Udompaisarn, Natta Panomchoeng, Tavan Janvilisri","doi":"10.17179/excli2025-9094","DOIUrl":"10.17179/excli2025-9094","url":null,"abstract":"<p><p>Nasopharyngeal carcinoma (NPC) is prevalent in East and Southeast Asia and is often diagnosed at advanced stages, where current treatment options are limited and associated with high relapse rates and toxicity. Repurposing clinically approved drugs provides a rapid, cost-effective strategy to identify new therapeutic interventions. Here, we investigated candesartan cilexetil (CC), an angiotensin II type 1 receptor (AT1R) blocker widely used for hypertension (13), for its potential anti-cancer effects in NPC. <i>In vitro</i> assays were performed to assess cell viability, proliferation, clonogenic survival, migration, cell-cycle distribution, and epithelial-mesenchymal transition (EMT) marker expression. Molecular mechanisms were examined via immunoblotting of AT1R and downstream MAPK and PI3K-AKT pathways. <i>In silico</i> molecular dynamics (MD) simulations were conducted to characterize CC-AT1R binding. We found that CC significantly decreased NPC cell viability and proliferation in a concentration-dependent manner, while exhibiting lower cytotoxicity toward immortalized nasopharyngeal epithelial cells. CC inhibited colony formation, induced G0/G1 cell-cycle arrest, and suppressed migration. EMT markers were differentially regulated, with consistent downregulation of vimentin and Slug but paradoxical cadherin changes, indicating context-dependent EMT modulation. Mechanistically, CC downregulated AT1R expression, reduced phosphorylation of p38 MAPK, and enhanced AKT phosphorylation, suggesting compensatory survival signaling. MD simulations confirmed stable CC-AT1R binding, identifying key residues critical for ligand stabilization. Therefore, CC exerts multi-faceted inhibitory effects on NPC cells through AT1R blockade and downstream modulation of oncogenic pathways. The integration of <i>in vitro</i> and <i>in silico</i> analyses highlights CC as a promising repurposed therapeutic candidate for NPC and supports further preclinical evaluation. See also the graphical abstract(Fig. 1).</p>","PeriodicalId":12247,"journal":{"name":"EXCLI Journal","volume":"25 ","pages":"204-221"},"PeriodicalIF":6.2,"publicationDate":"2026-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12946440/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147325182","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Real-world data of tirzepatide in obesity management: a multicenter study by the Italian Society of Obesity - Campania Region.","authors":"Luigi Barrea, Ludovica Verde, Martina Galasso, Renato Patrone, Lucia Digitale, Alessandro Limardi, Marcello Orio, Giovanni Ragozzino, Luigi Digitale, Vittorio Salvatore, Antonella Savoia, Silvia Savastano, Annamaria Colao, Giovanna Muscogiuri","doi":"10.17179/excli2025-9067","DOIUrl":"10.17179/excli2025-9067","url":null,"abstract":"<p><p>Obesity is a growing public health concern, closely linked to metabolic and cardiovascular complications. Tirzepatide, a dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist, has shown substantial weight loss effects in clinical trials; however, real-world data, especially at lower doses, remain limited. This study aimed to evaluate the short-term effects of tirzepatide 2.5 mg and 5.0 mg on weight, metabolic parameters, and tolerability in adults with obesity in a real-world outpatient setting. This retrospective multicenter study included 70 adults with obesity but without type 2 diabetes, treated with tirzepatide between January and June 2025 in the Campania Region, Italy. Anthropometric and biochemical parameters were assessed at baseline. Follow-up data were collected at dose transitions: from 2.5 mg to 5.0 mg, and from 5.0 mg to 7.5 mg, allowing assessment of the effects of the 2.5 mg and 5.0 mg doses. Seventy participants were included (mean age 50.7 ± 10.2 years; 60 % female; BMI 37.5 ± 6.8 kg/m2). Treatment led to dose-dependent reductions in body weight, BMI, and waist circumference (p < 0.001 for all vs baseline and between doses). Significant improvements were observed in total cholesterol (p = 0.006 between doses), LDL cholesterol (p = 0.001), triglycerides (p < 0.001), prediabetes prevalence (p < 0.001 vs baseline; p = 0.002 between doses), fasting plasma glucose (p < 0.001 vs baseline; p < 0.001 between doses), insulin (p < 0.001 vs baseline; p < 0.001 between doses), HoMA-IR (p < 0.001 vs baseline; p < 0.001 between doses), AST (p = 0.012 vs baseline; p = 0.006 between doses), and ALT (p < 0.001 vs baseline; p = 0.007 between doses). Amylase increased significantly only at 5.0 mg (p = 0.016), while lipase remained unchanged. Renal function (eGFR) improved at both doses (p = 0.025 for 2.5 mg; p = 0.005 for 5.0 mg). Gastrointestinal adverse events were mild and similar between doses. In this real-world cohort, tirzepatide at 2.5 mg and 5.0 mg led to substantial improvements in weight and metabolic health, with good tolerability. These findings support its use in routine obesity care and justify further longitudinal research. See also the graphical abstract(Fig. 1).</p>","PeriodicalId":12247,"journal":{"name":"EXCLI Journal","volume":"25 ","pages":"191-203"},"PeriodicalIF":6.2,"publicationDate":"2026-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12946444/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147325232","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"On the prenatal origins of the myeloproliferative neoplasms.","authors":"Stephen E Langabeer","doi":"10.17179/excli2025-9181","DOIUrl":"10.17179/excli2025-9181","url":null,"abstract":"","PeriodicalId":12247,"journal":{"name":"EXCLI Journal","volume":"25 ","pages":"189-190"},"PeriodicalIF":6.2,"publicationDate":"2026-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12946437/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147325219","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ethnicity matters: The case for regional reference intervals in polycystic ovary syndrome (PCOS) diagnostics.","authors":"Pallav Sengupta, Sulagna Dutta","doi":"10.17179/excli2025-9011","DOIUrl":"10.17179/excli2025-9011","url":null,"abstract":"","PeriodicalId":12247,"journal":{"name":"EXCLI Journal","volume":"25 ","pages":"186-188"},"PeriodicalIF":4.9,"publicationDate":"2026-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12901958/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146200618","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Redefining the role of exercise: beyond medicine and polypill.","authors":"Kayvan Khoramipour, Susana López-Ortiz, Alejandro Santos-Lozano","doi":"10.17179/excli2025-9114","DOIUrl":"10.17179/excli2025-9114","url":null,"abstract":"","PeriodicalId":12247,"journal":{"name":"EXCLI Journal","volume":"25 ","pages":"170-173"},"PeriodicalIF":6.2,"publicationDate":"2026-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12946443/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147325198","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Semaglutide and tirzepatide: Oral cavity effects of weight-loss therapies.","authors":"Maria Eduarda Bernardo, Felipe Gomes Dallepiane, Mario Escobar, Ariadne Cristiane Cabral Cruz, Cesar Augusto Magalhães Benfatti","doi":"10.17179/excli2025-9065","DOIUrl":"10.17179/excli2025-9065","url":null,"abstract":"","PeriodicalId":12247,"journal":{"name":"EXCLI Journal","volume":"25 ","pages":"167-169"},"PeriodicalIF":6.2,"publicationDate":"2026-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12946442/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147325253","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A cross-sectional exploratory study of rat sarcoma (Ras) activation in non-obese women with and without polycystic ovary syndrome.","authors":"Sara Anjum Niinuma, Haniya Habib, Ashleigh Suzu-Nishio Takemoto, Thozhukat Sathyapalan, Stephen L Atkin, Alexandra E Butler","doi":"10.17179/excli2025-9005","DOIUrl":"10.17179/excli2025-9005","url":null,"abstract":"<p><p>Studies in obese polycystic ovary syndrome (PCOS) have shown growth factors that activate rat sarcoma (Ras) proteins, which regulate intracellular signaling pathways, differ in PCOS; however, it is difficult to account for obesity, insulin resistance, and systemic inflammation that are linked to many of the features found in PCOS. This study explores Ras signaling proteins and related growth factors in non-obese women with and without PCOS. Somascan proteomic analysis of circulating KRas, Ras GTPase-activating protein-1 (RASA1), and 45 growth factor-related proteins that signal through Ras was undertaken in a non-obese population of women with (n=44) and without (n=78) PCOS, groups matched for age and body mass index (BMI), without insulin resistance (HOMA-IR) or systemic inflammation (normal CRP; C-reactive protein). There was an increase in the free androgen index (FAI, p<0.0001) and anti-Müllerian hormone (AMH, p<0.0001) in PCOS. Cohen's <i>d</i> showed a moderate effect size for 3 proteins, of which Vascular endothelial growth factor-A (VEGFA) and EGFR were increased and EGFR1 was decreased in PCOS (all FDR p<0.05). EGFR and VEGF pathways interact closely and when EGFR signaling decreases, VEGFA may increase to maintain angiogenic balance, suggesting that in non-obese PCOS there may be a signal for compensatory angiogenesis in a dysfunctional endothelial environment. See also the graphical abstract(Fig. 1).</p>","PeriodicalId":12247,"journal":{"name":"EXCLI Journal","volume":"25 ","pages":"174-185"},"PeriodicalIF":4.9,"publicationDate":"2026-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12901957/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146200611","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}