Clinical science最新文献

{"title":"Site-1 protease-derived sPRR contributes to renal ischemia-reperfusion injury in mice by promoting macrophage classical activation.","authors":"Ye Feng, Huaqing Zheng, Fei Wang, Renfei Luo, Chuanming Xu, Tianxin Yang","doi":"10.1042/CS20250604","DOIUrl":"10.1042/CS20250604","url":null,"abstract":"<p><p>Soluble (pro) renin receptor (sPRR), the product of site-1 protease (S1P)-mediated cleavage of PRR, has emerged as an important player in the physiological and pathophysiological processes in the kidney. However, a potential role of S1P-derived sPRR in acute ischemia-reperfusion injury (IRI) still needs to be explored. Hence, the current study comprehensively examined the involvement of S1P-derived sPRR in the pathogenesis of renal IRI in mice. The mouse model of IRI was generated by inducing 30 min of bilateral ischemia, followed by reperfusion. Various parameters of renal injury were assessed at 24 h after acute kidney injury (AKI). The production of sPRR was blocked by pharmacological inhibition of S1P using PF-429242 or mutagenesis of the cleavage site of PRR (PRRR279V/L282V). The severity of AKI was estimated by plasma creatinine (Cr), blood urea nitrogen (BUN), urine microalbumin/Cr ratio, and tubular injury. Administration of PF-429242 significantly improved IRI-induced renal dysfunction, albuminuria, and tubular injury, accompanied by suppressed macrophage infiltration and M1 polarization. In parallel, IRI elevated plasma sPRR and urinary renin levels, which were both blunted by PF-429242 treatment. These findings were all recapitulated in PRRR279V/L282V mice. Together, these results suggest that S1P-derived sPRR plays a key role in the pathogenesis of renal IRI through macrophage M1 polarization.</p>","PeriodicalId":10475,"journal":{"name":"Clinical science","volume":" ","pages":"261-273"},"PeriodicalIF":7.7,"publicationDate":"2026-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146003036","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":"Disrupted renal clock and blood pressure rhythms in type 2 diabetic nephropathy.","authors":"Biyang Xu, Marharyta Semenikhina, Ratnakar Tiwari, Vladislav Levchenko, Olha Kravtsova, Melissa Lowe, Oleg Palygin, Alexander Staruschenko","doi":"10.1042/CS20258642","DOIUrl":"10.1042/CS20258642","url":null,"abstract":"<p><p>Type 2 diabetes mellitus (T2DM), accounting for approximately 90% of adult-onset diabetes cases, is a major risk factor for diabetic kidney disease (DKD). Emerging evidence has linked T2DM with disrupted circadian rhythms. However, its role in the progression of DKD remains poorly understood. To investigate the relationship between circadian rhythms and DKD, we used the type 2 diabetic nephropathy (T2DN) rat, a non-obese model that replicates key features of human DKD. Circadian rhythms were assessed in both male and female T2DN rats at 20 and >35 weeks (young and old) by continuous measurements of mean arterial pressure (MAP), systolic blood pressure (SBP), heart rate, and locomotor activity. Differential expression of circadian genes was evaluated by RNA sequencing of kidney cortex. In separate cohorts, the effects of renal denervation and melatonin treatment on circadian parameters were examined. T2DN rats exhibited impaired circadian rhythms in MAP and SBP, while heart rate and locomotor activity retained rhythmicity. Transcriptomic analysis revealed altered expression of several circadian-related genes, including core circadian gene Per1 and multiple circadian-controlled genes involved in insulin sensitivity, lipid metabolism, and immune regulation between different groups of T2DN rats. Neither renal denervation nor melatonin administration restored normal circadian rhythms of T2DN rats. Our data suggest that circadian rhythm disruption of blood pressure is a consistent feature of T2DN rats and that targeting circadian clock components such as Per1 could offer potential therapeutic strategies.</p>","PeriodicalId":10475,"journal":{"name":"Clinical science","volume":" ","pages":"291-306"},"PeriodicalIF":7.7,"publicationDate":"2026-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145997399","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":"Sex-dependent differences in the progression of renal injury and fibrosis following ischemic acute kidney injury.","authors":"Tingfang Zhang, Zoe McArdle, Brianna K Moore, Alyssa Di Muzio, Kate M Denton, Robert E Widdop, Sharon D Ricardo","doi":"10.1042/CS20250136","DOIUrl":"10.1042/CS20250136","url":null,"abstract":"<p><p>Sex differences critically influence the renal response to ischemic injury, yet the mechanisms underlying differing recovery between males and females remain incompletely understood. Using a unilateral ischemia-reperfusion model with contralateral nephrectomy (uIRIx), we performed a longitudinal analysis of the transition from acute kidney injury (AKI) to chronic kidney disease (CKD) in male and female mice following uIRIx over 98 days. Male mice developed sustained renal dysfunction, characterized by persistent proteinuria, a marked reduction in glomerular filtration rate, and progressive increases in urinary albumin/creatinine ratio, consistent with an ongoing functional decline. Histologically, males displayed extensive tubular dilation, interstitial fibrosis, and elevated kidney injury molecule-1 expression, together with persistent macrophage and T-cell infiltration indicative of unresolved inflammation. In contrast, females exhibited partial functional recovery with improved glomerular filtration rate, reduced proteinuria, and attenuated structural damage, including less fibrosis and tubular injury across all timepoints. Morphometric analysis revealed smaller glomerular cross-sectional areas in males at day 14, suggesting early maladaptive remodelling, whereas females demonstrated adaptive hypertrophy that may preserve filtration capacity. Assessment of peritubular capillaries (CD31) indicated more effective microvascular preservation in females, consistent with estrogen-mediated endothelial protection. Collectively, these findings demonstrate that females are protected from the maladaptive progression of ischemic AKI to CKD, highlighting longitudinal sex-specific dynamics in renal repair and chronic disease development.</p>","PeriodicalId":10475,"journal":{"name":"Clinical science","volume":" ","pages":"275-290"},"PeriodicalIF":7.7,"publicationDate":"2026-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13108846/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146003081","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fenofibrate ameliorates salt-sensitive hypertension by improving renal metabolic homeostasis.","authors":"Pengfei Yang, Mingxiao Liu, Yuchen Li, Luxin Zhou, Limei Wu, Di Gao, Zhe Yang, Li Zeng, Xuewei Zheng, Jianjun Mu, Zhongmin Tian","doi":"10.1042/CS20250379","DOIUrl":"10.1042/CS20250379","url":null,"abstract":"<p><p>Salt-sensitive hypertension (SSH) presents a formidable clinical challenge, given its intricate pathophysiology and a scarcity of targeted treatment options. The present study investigates the therapeutic potential and underlying mechanisms of fenofibrate, a peroxisome proliferator-activated receptor α (PPARα) activator, in SSH. Clinical observations indicate that SSH in male patients is often accompanied by dyslipidemia, with a positive correlation observed between blood pressure and lipid profiles-particularly triglycerides. In male Dahl salt-sensitive (SS) rats, a four-week oral administration of fenofibrate (100 mg/kg/day) prevented high-salt diet (HSD)-induced hypertension, dyslipidemia, and renal injury, without affecting body weight or food intake. Renal untargeted metabolomics demonstrated that HSD induced significant alterations in amino acid metabolism, the TCA cycle, pentose phosphate pathway, and arginine biosynthesis. Fenofibrate treatment reversed these metabolic abnormalities, notably restoring the levels of key amino acids such as arginine, serine, and branched-chain amino acids. Furthermore, fenofibrate stimulated the expression of renal PPARα and PPARγ. It potentiated nitric oxide (NO) synthesis by up-regulating endothelial nitric oxide synthase protein expression and increasing arginine availability, improved the redox balance by enhancing antioxidant capacity, and elevated the cellular energy charge in the kidney. These findings demonstrate that fenofibrate ameliorates SSH by restoring renal metabolic homeostasis, enhancing NO synthesis, reducing oxidative stress, and improving bioenergetics, highlighting its promise as a therapeutic strategy for SSH, particularly in male patients with concurrent hyperlipidemia.</p>","PeriodicalId":10475,"journal":{"name":"Clinical science","volume":" ","pages":"469-489"},"PeriodicalIF":7.7,"publicationDate":"2026-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146225774","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":"Dysregulated iron metabolism associates with neutrophilic airway inflammation in COPD.","authors":"James Baker, Andrew Higham, Christopher McCrae, Mohammadali Yavari Ramsheh, Christopher Brightling, Simon Lea, Dave Singh","doi":"10.1042/CS20257442","DOIUrl":"10.1042/CS20257442","url":null,"abstract":"<p><p>Pulmonary iron levels are increased in chronic obstructive pulmonary disease (COPD), possibly due to increased red blood cell leakage from the microvasculature. Neutrophils cause endothelial cell damage which may cause vascular dysfunction and iron dysregulation in COPD. We investigate the relationships between neutrophilic inflammation, iron metabolism and vascular dysfunction in COPD. Using gene and protein analysis, associations between neutrophilic inflammation, iron dysregulation and vascular dysfunction were investigated in two COPD bronchoscopy cohorts: EvA (n=51) and Manchester (n=33). Patients were sub-grouped based on bronchoalveolar lavage (BAL) neutrophil percentage (neutrophilhigh≥3% and neutrophillow<3%). Heme was measured in BAL by LC-MS. BAL cell gene expression of neutrophilic inflammation markers such as C-X-C Motif Chemokine Ligand 8 (CXCL8) and interleukin 6 receptor (IL6R) were significantly increased in neutrophilhigh compared with neutrophillow patients in both cohorts; fold change (FC) differences 1.06-17. We found increased markers of iron and iron trafficking including lactoferrin (LTF), lipocalin-2 (LCN2) and myoglobin (MB) in neutrophilhigh patients in both cohorts. BAL cell gene expression and BAL fluid protein levels of the vascular dysfunction marker, vascular endothelial growth factor (VEGF), were significantly higher in neutrophilhigh compared with neutrophillow patients. Fibrinogen and heme were significantly increased in neutrophilhigh BAL fluid. In vitro experiments revealed that blood neutrophils had significantly increased expression of LTF and VEGFA following LPS-stimulation and heme induces endothelial dysfunction. COPD patients with distal lung neutrophilic inflammation have dysregulated iron metabolism which may be a consequence of increased vascular leakage into the airways.</p>","PeriodicalId":10475,"journal":{"name":"Clinical science","volume":" ","pages":"307-319"},"PeriodicalIF":7.7,"publicationDate":"2026-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13108851/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146017595","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Th17 cell mediated oligodendrocyte precursor cell arrest drives hippocampal demyelination in diabetic cognitive dysfunction.","authors":"Jia-Wei Hu, Hong-Dan Yu, Sheng-Xue Yu, Wen-Qiang Liu, Yu-Fei Wang, Ya-Li Wang, Xin-Yuan Chen, Quan-Ling Miao, Yi-Rong Yuan, Wei Dai, Meng-Ren Liu, Na Zhang, Jia-Heng Sui, Xue-Zheng Liu, Wei Shan, Zhong-Fu Zuo","doi":"10.1042/CS20257295","DOIUrl":"https://doi.org/10.1042/CS20257295","url":null,"abstract":"<p><p>Demyelination is pivotal in diabetic cognitive dysfunction (DCD), with Th17 cells gaining attention, yet their hippocampal infiltration and mechanisms in diabetes remain unelucidated. Using streptozotocin (STZ)-induced diabetic mice, we demonstrated Th17 cell infiltration and elevated IL-17A in the hippocampus via CD4/IL-17A immunofluorescence and Western blot. Administering IL-17A neutralizing antibodies (NAbs) improved cognitive performance (Morris water maze: reduced escape latency, increased platform crossings/target quadrant time), attenuated neuroinflammation (reduced IL-17A, TNF-α, IL-1β, IL-6; increased IL-10, IL-4; decreased microglial activation/IBA-1), restored blood-brain barrier integrity (increased ZO-1, Occludin), and promoted remyelination (increased MBP, CNPase; decreased NG2, olig2; Luxol fast blue). IL-17A NAbs also enhanced phosphorylated ERK1/2 (p-ERK). Crucially, co-treatment with the ERK inhibitor PD98059 partially reversed the protective effects of IL-17A NAbs on these parameters. These findings indicate that IL-17A, secreted by infiltrating Th17 cells, exacerbates hippocampal demyelination in DCD by inhibiting oligodendrocyte precursor cell (OPC) maturation via suppression of the ERK1/2 pathway and concurrently activating microglia to amplify neuroinflammation, ultimately driving cognitive impairment.</p>","PeriodicalId":10475,"journal":{"name":"Clinical science","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147376307","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":"Persistent DNA methylation and down-regulation of homeostatic genes in astrocytes after pilocarpine-induced status epilepticus: implications for epileptogenesis.","authors":"Dante Gómez Cuautle, Alicia Rossi, Milton Paul Márquez Cadena, Alejandro Villarreal, Luciana D'Alessio, Alberto Javier Ramos","doi":"10.1042/CS20256367","DOIUrl":"10.1042/CS20256367","url":null,"abstract":"<p><p>Epilepsy is a debilitating neurological disorder characterized by recurrent seizures, affecting millions of patients worldwide. Retrospective studies in temporal lobe epilepsy (TLE) patients have shown a high incidence of an initial precipitating event (IPE) in early childhood, followed by a silent period where epileptogenesis occurs to end up in chronic epilepsy. Epileptogenesis, the process through which a normal brain undergoes structural and functional changes leading to epilepsy, is not completely understood. We hypothesized that epigenetics may be involved in epileptogenesis, specifically affecting astrocytes through pathological remodeling. To study this process, we used three approaches: the lithium-pilocarpine model of TLE in rats, primary astroglial cultures exposed to epileptogenic DAMP named HMGB1, and brain tissue samples resected from TLE patients with drug-resistant epilepsy. We found that the IPE achieved by lithium-pilocarpine treatment (127/30 mg/kg IP) induced the DNA methylation of astrocytes at 7-, 21-, and 35-days post-IPE, indicating persistent epigenetic alterations in astrocytes during the epileptogenic period. In addition, we observed the down-regulation of homeostatic astroglial genes, including AQP4, glutamine synthase (GS), and Kir4.1, along with increased expression of proinflammatory genes (C3, MAFG) and DNA methyltransferases (DNMT). These alterations were mimicked in primary astrocyte cultures exposed to the epileptogenic HMGB1 (500 ng/ml; 18 h), which resulted in the hypermethylation of homeostatic astroglial genes and repression of homeostatic genes. HMGB1-induced repression of astroglial homeostatic genes was prevented by the treatment with DNMT inhibitor decitabine. Interestingly, astrocytes from TLE patients brains showed reactive astrogliosis, increased DNA methylation, and down-regulation of homeostatic genes Kir4.1 and GS. Taken together, these findings show that astrocytes are pathologically altered during the epileptogenic period by epigenetic modifications, combining the proinflammatory gain of function with the loss of homeostatic profile. This may contribute to the long-term alterations underlying epileptogenesis.</p>","PeriodicalId":10475,"journal":{"name":"Clinical science","volume":" ","pages":"221-237"},"PeriodicalIF":7.7,"publicationDate":"2026-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145997424","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":"Tolerogenic dendritic cells immunotherapy protects against IgA nephropathy.","authors":"Xiaohong Zheng, Hao Yang, Juan Jiang, Liru Shang, Lin Peng, Ji Wang, Yingyue Zeng, Xiaoyun Jiang","doi":"10.1042/CS20257275","DOIUrl":"10.1042/CS20257275","url":null,"abstract":"<p><p>This study aimed to investigate the therapeutic efficacy of tolerogenic dendritic cells (tolDCs) in IgA nephropathy (IgAN) mice. Male C57BL/6 mice were used to construct an IgAN model via oral mucosal immunization, while tolDCs were generated by exposing bone marrow-derived dendritic cells (BMDCs) to IL-10 and characterized for their immunosuppressive phenotype and function; wild-type (WT) and IgAN mice then received either PBS or tolDCs treatments, followed by comprehensive assessments of renal functional parameters, histopathological changes, and inflammatory cytokines profiles. The IgAN mouse model was successfully established by week 8 post-immunization, exhibiting characteristic renal pathology including glomerular mesangial IgA deposition, accompanied by mesangial cells hyperplasia and mesangial matrix expansion. IL-10-induced tolDCs exhibited a stable immunosuppressive phenotype: Compared with BMDCs, tolDCs exhibited a 3.5-fold up-regulation in PD-L1 surface expression and a 7.7-fold increase in IL-10 protein level, while IL-12 protein expression remained unchanged. Functionally, tolDCs demonstrated targeted migration to the kidneys and promoted regulatory T cells (Tregs) differentiation in IgAN mice. Therapeutic administration of tolDCs significantly attenuated disease progression: compared with the IgAN-PBS group, the IgAN-tolDCs group showed 59.3% and 55.4% reductions in glomerular and tubulointerstitial IgA deposition, respectively, accompanied by 5.5-fold and 2.9-fold increases in Tregs infiltration. At the inflammatory cytokines level, the mRNA and protein expression of renal IL-10 was up-regulated, while renal IL-12 and TGF-β was down-regulated in the IgAN-tolDCs group. Renal function parameters remained stable in the IgAN-tolDCs group, confirming the safety of tolDCs immunotherapy. In conclusion, IL-10-induced tolDCs exhibit a stable immunosuppressive phenotype and can migrate to the kidneys of IgAN mice, and their therapeutic administration alleviates renal IgA deposition, promotes renal Treg accumulation, and suppresses pro-inflammatory cytokine expression, collectively attenuating renal immunoinflammatory injury, supporting tolDCs as a promising targeted therapy for IgAN.</p>","PeriodicalId":10475,"journal":{"name":"Clinical science","volume":" ","pages":"239-255"},"PeriodicalIF":7.7,"publicationDate":"2026-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146017501","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":"Beyond αβ T cells: unlocking the potential of diverse immune cells in CAR modification.","authors":"Yangyang Gao, Feifei Guo, Min Li, Naifei Chen, Chao Niu, Jiuwei Cui","doi":"10.1042/CS20256571","DOIUrl":"10.1042/CS20256571","url":null,"abstract":"<p><p>Chimeric antigen receptor (CAR) T cell therapy has emerged as a groundbreaking advancement in cancer immunotherapy, demonstrating remarkable success in treating hematologic malignancies. However, its application in solid tumors remains challenging. The complex manufacturing process and severe treatmentrelated toxicities further limit its broader clinical application. To address these challenges, researchers are investigating alternative CAR-engineered immune cells, including CAR-NK cells, CAR-γδ T cells, and CARmacrophages (CAR-M), which offer distinct advantages over conventional CAR-T therapy. Notably, CAR-NK and CAR-γδ T cells exhibit HLA-independent cytotoxicity, making them promising 'off-the-shelf' therapeutic options. Meanwhile, CAR-M not only phagocytose tumor cells and present antigens but also remodel the immunosuppressive tumor microenvironment. Despite their potential, these innovative therapies still face several challenges in clinical application. This review systematically summarizes recent advances in CAR-T cells, CAR-NK cells, CAR-γδ T cells, and CAR-M for cancer treatment, providing a comprehensive analysis of their respective strengths, limitations, and future optimization strategies to support the clinical translation of next-generation CAR-based immunotherapies.</p>","PeriodicalId":10475,"journal":{"name":"Clinical science","volume":"140 2","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12954532/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146009187","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Platelets from older adults exhibit differences in mitochondrial function associated with impaired glucose metabolism.","authors":"Gargi Mahapatra, Zhengrong Gao, James R Bateman, Samuel Neal Lockhart, Jaclyn Bergstrom, Jemima Elizabeth Piloso, Suzanne Craft, Anthony J A Molina","doi":"10.1042/CS20242841","DOIUrl":"10.1042/CS20242841","url":null,"abstract":"<p><p>Impaired glucose tolerance (IGT) and insulin resistance (IR), including prediabetes and diabetes, increase risk of developing age-related disorders, such as cardiovascular disorders, kidney disorders, and Alzheimer's disease. We analyzed mitochondrial bioenergetics of platelets collected from 208 adults, 55 years and older, with IGT and IR and without normoglycemic (NG). Platelets from IGT participants exhibited unique mitochondrial bioenergetic profiles exemplified by higher mitochondrial respiration compared with NG. IGT platelets exhibited higher glucose-dependent maximal respiration (Max) and spare respiratory capacities (SRCs) and higher fatty acid oxidation (FAO)-dependent maximal coupled (MaxOXPHOS) and uncoupled (maximal electron transport system) respiration compared with NG. Correlating mitochondrial bioenergetics from all 208 participants with measures of glucose tolerance (oral glucose tolerance test values measured 120 min after glucose administration, and oral glucose tolerance test area under the curve), and historical glucose measures [hemoglobin A1 (HbA1c)] revealed significant positive associations. Most associations were unaltered with age, sex, and body mass index adjustments. Examining NG and IGT participants separately, we found platelet respiration and HbA1c exhibited positive association in NG participants. Significant positive associations emerged between platelet SRC, FAO, FAO+CI (oxygen flux due to FAO + complex I activities), and HbA1c. No significant associations were observed in the IGT group. Given the utilization of blood-based mitochondrial bioenergetic profiling strategies in clinical research, this work provides new insights into the clinical features of IR that can affect platelet mitochondrial bioenergetics.</p>","PeriodicalId":10475,"journal":{"name":"Clinical science","volume":" ","pages":"65-79"},"PeriodicalIF":7.7,"publicationDate":"2026-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12862959/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145660554","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}