Biomolecules最新文献

{"title":"Silymarin and Zinc Oxide Nanoparticles Attenuate Experimental Colon Cancer in Rats Through Crosstalk of miR-192 and β-Catenin Pathways.","authors":"Eman H Yousef, Aya Megahed, Alaa Samy, Amgad E Salem, Jawaher Abdullah Alamoudi, Ahmed Abbas, Eman M Embaby","doi":"10.3390/biom16091374","DOIUrl":"10.3390/biom16091374","url":null,"abstract":"<p><p>Colon cancer (CC) is a leading cause of cancer-related mortality globally. Although chemotherapy remains the primary treatment, its toxicity and drug resistance highlight the need for alternative therapeutic strategies. Silymarin (Sily), a natural compound, and zinc oxide nanoparticles (ZnO-NPs) have shown potential antitumor activity. This study evaluated Sily and/or ZnO-NPs against DMH-induced CC in rats. Thirty male Sprague-Dawley rats were divided into five groups (<i>n</i> = 6): control, CC (DMH 20 mg/kg/16-week S.C.), and three groups receiving Sily (40 mg/kg orally), ZnO-NPs (10 mg/kg IP), or their combination daily for 4 weeks. In comparison to the CC group, Sily or ZnO-NPs significantly decreased CEA levels, restored mucin synthesis, and improved colonic histology, with the combination treatment producing the most pronounced antitumor effects. Treatments attenuated oxidative stress, with Sily restoring SOD and GSH levels, whereas ZnO-NPs primarily reduced lipid peroxidation, as reflected by decreased MDA levels. Mechanistically, the combined therapy decreased inhibitory GSK-3β phosphorylation and β-catenin expression, consistent with restoration of GSK-3β-mediated suppression of β-catenin. The combination also restored PKCα and miR-192 expression and reduced the expression of the proliferation- and metastasis-associated markers MMP-9, c-Myc, and Cyclin-D1. CD133 expression was significantly reduced, suggesting an effect on the cancer stem cell-associated phenotype. Sily and ZnO-NPs demonstrated therapeutic effects against CC, particularly when administered in combination. Their antitumor effects were associated with modulation of miR-192/PKCα and GSK-3β/β-catenin signaling, supporting further investigation of their combined multitargeted potential in CC.</p>","PeriodicalId":8943,"journal":{"name":"Biomolecules","volume":"16 9","pages":""},"PeriodicalIF":5.6,"publicationDate":"2026-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13604585/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149058408","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":"Metabolic Vulnerability and Regenerative Failure of the External Urethral Sphincter: A Ferroptosis-Associated Framework for Stress Urinary Incontinence.","authors":"Shuo Sun, Jialiang Liu, Xiaoying Pan, Yong Yang, Zhitao Wei","doi":"10.3390/biom16091376","DOIUrl":"10.3390/biom16091376","url":null,"abstract":"<p><p>Stress urinary incontinence (SUI) has long been understood as a structural failure of pelvic floor support. While this view explains acute anatomical damage, it offers little insight into why functionally similar injuries produce markedly different long-term outcomes, or why sphincteric deterioration often progresses years after the initial insult. In this review, we examine the possibility that progressive external urethral sphincter (EUS) degeneration reflects an underlying metabolic vulnerability. The EUS is a striated muscle of unusual metabolic demand, sustaining continuous basal tone through oxidative phosphorylation while retaining rapid contractile capacity. Its membranes are enriched in polyunsaturated fatty acids and subjected to recurrent ischemia-reperfusion, features that are hypothesized to limit redox buffering capacity. We discuss how parturition trauma, aging, obesity, and neurogenic injury may converge to disrupt iron homeostasis, impair the GSH/GPX4 antioxidant axis, and exhaust satellite cell-mediated repair. Crucially, direct evidence for ferroptosis in the EUS remains limited. We therefore integrate EUS-specific findings with evidence from skeletal muscle and other tissues to propose a hypothesis-generating framework. Rather than treating ferroptosis-associated stress as an isolated cell death pathway, we consider it a candidate biochemical nexus linking metabolic stress to fibro-adipogenic niche remodeling. By shifting focus from mechanical injury to eroding tissue resilience, this framework generates testable hypotheses regarding biomarker development and potential therapies aimed at restoring the adaptive capacity of the EUS.</p>","PeriodicalId":8943,"journal":{"name":"Biomolecules","volume":"16 9","pages":""},"PeriodicalIF":5.6,"publicationDate":"2026-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13604672/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149058205","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":"TH1177, Clemastine, and Benzhydryl Derivatives Act as Novel Extracellular Blockers of ORAI Channels.","authors":"Pengyun Li, Hussein N Rubaiy, Thomas Hallett, Yi Liang, Gui-Lan Chen, Bo Zeng, Pingping Zheng, Nawel Zaibi, Dong-Na Su, Andrew N Boa, Shang-Zhong Xu","doi":"10.3390/biom16091372","DOIUrl":"10.3390/biom16091372","url":null,"abstract":"<p><p>ORAI channels are store-operated Ca²⁺ channels, which play important roles in physiology and pathophysiology. ORAI channel modulators are useful for developing pharmacological interventions. Here, we aimed to investigate the benzhydryl-derived analogues as novel ORAI channel blockers. The effects of benzhydryl-derived analogues TH1177, clemastine, cloperastine, and diphenhydramine were investigated in HEK-293 cells overexpressing individual ORAI isoforms and STIM1. The ORAI currents were recorded by patch-clamp, and cytosolic Ca²⁺ was measured by a fluorescent Ca²⁺ dye. TH1177 inhibited ORAI1, ORAI2, and ORAI3 currents with IC₅₀ values of 18.3 μM, 4.8 μM, and 35.6 μM, respectively. Clemastine inhibited ORAI1 and ORAI2, but showed no effect on ORAI3. Both cloperastine and diphenhydramine, without a pyrrolidine ring structure, only showed minimal inhibition of ORAI1. Intracellular application of TH1177 and outside-out patch demonstrated that TH1177 blocked ORAI3 currents via the extracellular surface. TH1177 did not affect cytosolic STIM1 clustering and movement. Moreover, TH1177 potently inhibited cell proliferation with IC₅₀ values of 2.6 µM for HAEC, 5.2 µM for EA.hy926, and 29.4 µM for HK-2 cells and induced apoptotic cell death. It is concluded that TH1177 is a pan-inhibitor for ORAI1-3 channels, while clemastine inhibits ORAI1 and ORAI2 but shows little effect on ORAI3. The pyrrolidine ring structure in the compounds of TH1177 and clemastine is critical for their inhibitory activity. The two benzhydryl derivatives (cloperastine and diphenhydramine) without the pyrrolidine ring only showed minimal inhibition of ORAI1. Our findings give a new pharmacological profile of ORAI channels.</p>","PeriodicalId":8943,"journal":{"name":"Biomolecules","volume":"16 9","pages":""},"PeriodicalIF":5.6,"publicationDate":"2026-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13604178/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149058427","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":"Nuciferine Ameliorates Ovariectomy-Induced Bone Loss via TFEB-Mediated Autophagy-Lysosomal Pathway.","authors":"Beilei Shi, Ze Gao, Shih-Yu Chen, Jianbing Chen, Liangxu Wei, Wen Fan, Zhiqian Yang, Ying Zhang, Yan Cui, Xiaofeng Zhu","doi":"10.3390/biom16091370","DOIUrl":"10.3390/biom16091370","url":null,"abstract":"<p><p><b>Background:</b> Postmenopausal osteoporosis is a common metabolic bone disease that leads to reduced bone formation and increased fracture risk. Nuciferine, an aporphine alkaloid from the lotus leaf, can regulate the TFEB-mediated autophagy-lysosomal pathway. This pathway is critical for osteogenic differentiation. However, it remains unclear whether nuciferine promotes bone formation and alleviates bone loss through this pathway. We therefore hypothesized that nuciferine activates the TFEB-mediated autophagy-lysosomal pathway to promote osteogenic differentiation, thereby counteracting estrogen deficiency-induced bone loss. <b>Methods:</b> We established an OVX rat model (6-month-old females, 24.0 ± 1.0 weeks, <i>n</i> = 10/group), treated the rats with nuciferine via oral gavage for 12 weeks, and used rat BMSCs for mechanistic studies in vitro. <b>Results:</b> Nuciferine significantly increased bone mineral density (BMD) and improved bone microarchitecture in OVX rats; upregulated serum levels of the bone turnover markers bone-specific alkaline phosphatase (BALP), procollagen type I N-terminal propeptide (PINP) and osteocalcin (BGP); and downregulated serum tartrate-resistant acid phosphatase (TRAP), as measured via ELISA. Nuciferine also restored the expression of osterix (OSX) and transcription factor EB (TFEB) in bone tissue, as detected via TSA staining. Furthermore, it increased the microtubule-associated protein 1 light chain 3 (LC3)-II/LC3-I ratio and decreased p62 expression, as determined through Western blotting, indicating the activation of autophagy. In vitro, nuciferine promoted osteogenic differentiation and TFEB nuclear translocation in BMSCs, whereas TFEB silencing suppressed both, an effect partially reversed by nuciferine, as shown via ALP/ARS staining, Western blotting, RT-qPCR, and immunofluorescence. <b>Conclusions:</b> In conclusion, nuciferine ameliorates bone loss in OVX rats and promotes the osteogenic differentiation of BMSCs. Activation of the TFEB-mediated autophagy-lysosomal pathway is a key mechanism underlying its improvement of bone metabolism.</p>","PeriodicalId":8943,"journal":{"name":"Biomolecules","volume":"16 9","pages":""},"PeriodicalIF":5.6,"publicationDate":"2026-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13604095/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149058185","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":"Associations of <i>ASIC2</i>, <i>IKZF3</i>, and <i>GSDMB</i> Variants with Gestational Diabetes Mellitus and Their Interactions with Environmental Exposures Among Chinese Women.","authors":"Song Wang, Xiao Huang, Xiaoxu Shen, Yi Zhang, Lin Tao, Yuanzhong Zhou, Hongsong Yu, Xin Wang","doi":"10.3390/biom16091373","DOIUrl":"10.3390/biom16091373","url":null,"abstract":"<p><p>Gestational diabetes mellitus (GDM) is a common pregnancy complication associated with adverse maternal and offspring cardiometabolic outcomes. However, the combined effects of genetic susceptibility and environmental exposures on GDM risk remain unclear. We conducted a case-control study of 1564 pregnant women in China. Targeted next-generation sequencing was used to genotype <i>ASIC2</i>/rs12450465, <i>IKZF3</i>/rs2060941, and <i>GSDMB</i>/rs2305479. Associations of individual variants and haplotypes with GDM were evaluated, and interactions with exposure to PM_2.5, O₃, and monoisobutyl phthalate (MIBP) were assessed. Multiple comparisons in the primary covariate-unadjusted analyses were controlled using the Benjamini-Hochberg false discovery rate (FDR) procedure. In the overall study population, the rs12450465-rs2060941-rs2305479 T-T-T haplotype was significantly associated with GDM after FDR correction (nominal <i>p</i> = 0.00266, FDR-adjusted <i>p</i> = 0.0133, OR = 1.741, 95% CI = 1.208-2.509). Several gene-gene and gene-air pollutant interaction signals, particularly those involving O₃ exposure, remained statistically significant after FDR correction in the primary covariate-unadjusted analyses. Among 289 participants with urinary MIBP measurements, the T-T-T haplotype was similarly associated with GDM (nominal <i>p</i> = 0.003837, FDR-adjusted <i>p</i> = 0.0192, OR = 2.980, 95% CI = 1.378-6.446), and additional interaction signals between this haplotype and MIBP exposure were identified. These findings suggest that gene-environment interactions may contribute to susceptibility to GDM and identify the T-T-T haplotype as a potential susceptibility marker. Nevertheless, the results, particularly those from the smaller MIBP subgroup and the covariate-unadjusted interaction analyses, require validation in larger, independent, and more diverse populations.</p>","PeriodicalId":8943,"journal":{"name":"Biomolecules","volume":"16 9","pages":""},"PeriodicalIF":5.6,"publicationDate":"2026-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13604340/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149058159","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":"Rethinking Drug Resistance in Acute Promyelocytic Leukemia: The Regulated Cell Death Network as an Integrative Framework.","authors":"Shiyu Lin, Biaohan Qin, Zhexi Ye, Jiaqi Qing, Hui Zhen, Sennan Yang, Xin Jiang, Yiwen Fan, Lemei Zhu, Juan Liu","doi":"10.3390/biom16091375","DOIUrl":"10.3390/biom16091375","url":null,"abstract":"<p><p>Drug resistance in acute promyelocytic leukemia (APL) remains clinically challenging despite the success of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) therapy. Existing explanations, including promyelocytic leukemia protein-retinoic acid receptor alpha (PML-RARα) mutations and alterations in individual death pathways, do not fully account for the heterogeneity of resistant phenotypes. This review proposes regulated cell death network (RCDN) remodeling as a testable framework for APL resistance. RCDN remodeling is defined as coordinated changes in network coupling, stress routing, and cellular death thresholds. We hypothesize that resistance emerges from coordinated adaptation across redox, survival signaling, and mitochondrial gating, rather than from defects in any single pathway. This predicts coupled shifts across multiple death modules and non-additive responses to combinatorial perturbations, distinguishing network-level remodeling from pathway-specific resistance. We further define experimental criteria for distinguishing network-level remodeling from pathway-specific resistance and discuss Tanshinone IIA (Tan IIA) as a preclinical multi-node perturbation probe.</p>","PeriodicalId":8943,"journal":{"name":"Biomolecules","volume":"16 9","pages":""},"PeriodicalIF":5.6,"publicationDate":"2026-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13604277/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149058296","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":"Bilirubin and the Yellow Players in Ferroptosis: A Delicate Balance in Human Health and Disease, with a Focus on the Liver, Cardiovascular System, and Brain.","authors":"Camilla Dalla Verde, Libor Vitek, Claudio Tiribelli, Silvia Gazzin","doi":"10.3390/biom16091371","DOIUrl":"10.3390/biom16091371","url":null,"abstract":"<p><p>Ferroptosis is a unique form of regulated lytic cell death driven by intracellular iron overload, excessive production of reactive oxygen species, failure of antioxidant defense systems, lipid peroxidation, and subsequent plasma membrane damage. Its initiation and progression involve complex signaling and regulatory networks. Although iron is a defining feature of ferroptosis, it also plays a central role in the heme oxygenase (HO)-biliverdin reductase (BVR) system, a cellular machinery associated with a lower prevalence of chronic diseases and reduced all-cause mortality. The HO-BVR cycle and its products biliverdin and bilirubin (together the yellow players: YPs) act as hormones and transcription factors on multiple signaling pathways, with powerful antioxidant, anti-inflammatory, and many more properties. The convergence between the two systems is suggestive of the existence of a finely tuned balance between the beneficial vs. exacerbating damage effects. Exploration of this equilibrium has just started. This review summarizes the current evidence on the interplay between ferroptosis and the HO-BVR system, in the context of liver, cardiovascular and brain diseases. We also review the therapeutic strategies aimed at modulating these pathways, considering both their potential benefits and their possible adverse consequences within the context of these integrated cellular defense and injury mechanisms.</p>","PeriodicalId":8943,"journal":{"name":"Biomolecules","volume":"16 9","pages":""},"PeriodicalIF":5.6,"publicationDate":"2026-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13604471/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149058254","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":"pH-Dependent Stability and Cooperativity of Protein Unfolding from Differential Scanning Calorimetry Using FitFoldData.","authors":"Knarik Yeritsyan, Vladimir Uversky, Artem Badasyan","doi":"10.3390/biom16091368","DOIUrl":"10.3390/biom16091368","url":null,"abstract":"<p><p>Protein folding is highly sensitive to environmental conditions such as pH, which can influence internal hydrogen bonding and interactions with the solvent. In this study, we use our FitFoldData online tool to analyze published differential scanning calorimetry (DSC) data on the unfolding of four proteins measured across different pH values. For each dataset, we examine the fitted thermodynamic parameters, including the intrapeptide and peptide-solvent hydrogen-bonding energies (<i>h</i> and hps) and the Zimm-Bragg cooperativity parameter (σ). In the analyzed datasets, under both acidic and alkaline conditions, <i>h</i> and hps range from 2 to 8.5 kJ/mol, while σ is on the order of 10-3 to 10-2. In addition, the two-state cooperativity parameter k2 is estimated from the DSC curves as the enthalpy ratio. By considering the size-dependent relative fluctuation, 1/N, we introduce a \"two-state range\" around the value k2=1 for each protein with a given number <i>N</i> of peptide units. We find that pH can shift proteins into or out of the two-state range of k2 values.</p>","PeriodicalId":8943,"journal":{"name":"Biomolecules","volume":"16 9","pages":""},"PeriodicalIF":5.6,"publicationDate":"2026-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13604171/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149058242","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":"Integrative Transcriptomics Reveals a Mitochondria-Related Gene Signature in Periodontitis.","authors":"Siyuan Wu, Miaomiao Feng, Mengyao Liu, Qing Zhang, Gaixin Xu, Mengzhen Gao, Cory J Xian, Hongli Chen, Yuankun Zhai","doi":"10.3390/biom16091369","DOIUrl":"10.3390/biom16091369","url":null,"abstract":"<p><p>Mitochondrial dysfunction contributes to periodontal inflammation and tissue destruction, yet the mitochondria-related transcriptional changes associated with periodontitis remain incompletely characterized. Using an integrative bioinformatics study design with experimental validation in cellular and animal models, we sought to identify a mitochondria-related gene signature in affected periodontal tissues and evaluate selected candidates experimentally. Differential expression analysis and weighted gene co-expression network analysis of GSE16134 were integrated with MitoCarta3.0 annotation. Candidate genes were evaluated using 101 feature-selection and classification combinations across GSE16134, GSE10334, GSE33774, and GSE173078, followed by functional enrichment, pathway-level analysis, and immune-cell deconvolution. Selected candidates were assessed by reverse-transcription quantitative polymerase chain reaction in lipopolysaccharide-stimulated RAW 264.7 macrophages and by immunohistochemistry in a ligature-induced rat periodontitis model. The integrated analysis identified 25 candidate genes. A backward stepwise generalized linear model combined with random forest selected <i>CBR3</i>, <i>CYP24A1</i>, <i>SLC25A45</i>, <i>SSBP1</i>, and <i>TMEM205</i> and achieved the highest mean area under the receiver operating characteristic curve (AUC = 0.819) across the four datasets. The corresponding AUCs were 0.995 in GSE16134, 0.894 in GSE10334, 0.661 in GSE33774, and 0.727 in GSE173078. The model achieved an AUC of 0.870 in the independent validation cohort GSE223924. The selected genes exhibited distinct expression patterns in affected gingival sites and were associated with pathways involving mitochondrial metabolism, cellular respiration, and inflammatory signaling. Immune-cell deconvolution further revealed associations between the selected genes and multiple B- and T-cell subsets. Experimental analyses consistently reproduced decreased CBR3 and increased CYP24A1 and SSBP1 expression in both the macrophage and rat models. These findings delineate a mitochondria-centered transcriptional landscape associated with periodontitis and prioritize <i>CBR3</i>, <i>CYP24A1</i>, and <i>SSBP1</i> as candidate molecular markers for further investigation. By integrating cross-dataset transcriptomic analysis with experimental evidence, this study provides a focused basis for subsequent mechanistic investigation and clinical validation of mitochondria-related candidate markers in periodontitis.</p>","PeriodicalId":8943,"journal":{"name":"Biomolecules","volume":"16 9","pages":""},"PeriodicalIF":5.6,"publicationDate":"2026-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13604177/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149058155","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":"DISC1 Orchestrates Mitochondrial Calcium Overload in Diabetic Encephalopathy Through a Dual Nucleocytoplasmic Mechanism.","authors":"Lu He, Hao Li, Rui Yin, Liangli Dai, Weijian Hang, Yong Liu, Man Li, Tao Liang, Yumei Wang, Juan Chen","doi":"10.3390/biom16091366","DOIUrl":"10.3390/biom16091366","url":null,"abstract":"<p><p>Hyperglycemia-driven mitochondrial dysfunction is a primary driver of diabetic encephalopathy (DE). Here, we identify a novel nucleocytoplasmic \"dual effect\" of DISC1 that coordinates mitochondrial Ca²⁺ overload under high-glucose conditions. Using nucleocytoplasmic fractionation and mass spectrometry, we demonstrate that high glucose triggers PAK2-mediated phosphorylation of DISC1, necessitating its nuclear translocation. In the nucleus, DISC1 acts as a coactivator for the transcription factor RFX1 to induce Grp75, a critical tethering protein of the GRP75/IP3R1/VDAC1 complex that facilitates Ca²⁺ transfer from the endoplasmic reticulum to mitochondria. Conversely, we find that cytoplasmic DISC1 physically sequesters GRP75, hindering the assembly of the Ca²⁺ conduction complex. Enhanced nuclear translocation of DISC1 results in reduced cytoplasmic DISC1 levels. This depletion removes the \"molecular brake\" on Ca²⁺ influx, synergizing with the nuclear signaling pathway to drive mitochondrial Ca²⁺ overload. Together, our findings suggest that high glucose hijacks DISC1 through a bipartite mechanism: the upregulation of Ca²⁺ conduction and the concurrent loss of cytoplasmic inhibition. Targeting DISC1 may represent a potential therapeutic strategy for mitigating neurodegeneration in DE.</p>","PeriodicalId":8943,"journal":{"name":"Biomolecules","volume":"16 9","pages":""},"PeriodicalIF":5.6,"publicationDate":"2026-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13604470/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149058099","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}