American journal of physiology. Cell physiology最新文献

{"title":"Effects of High-Salt Intake on Glucose Metabolism, Liver Function, and the Microbiome in Rats: Influence of ACE Inhibitors and Angiotensin II Receptor Blockers.","authors":"Xiaoli Zhang, Mohamed M S Gaballa, Ahmed A Hasan, Yvonne Liu, Johann-Georg Hocher, Xin Chen, Liping Liu, Jian Li, Dominik Wigger, Christoph Reichetzeder, Saban Elitok, Burkhard Kleuser, Bernhard K Krämer, Berthold Hocher","doi":"10.1152/ajpcell.01036.2024","DOIUrl":"https://doi.org/10.1152/ajpcell.01036.2024","url":null,"abstract":"<p><p><b>Abstract</b> <b>Background:</b> High-salt diets (HSD) are known to impact blood pressure and cardiovascular health, but their effects on glucose metabolism, liver function, and gut microbiota remain poorly understood. This study investigates how long-term HSD affects these physiological processes and evaluates the potential therapeutic effects of ACE inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs). <b>Methods:</b> Male Sprague-Dawley rats were fed a normal salt diet (0.3% NaCl), a moderate salt diet (2% NaCl), or a high-salt diet (8% NaCl) for 12 weeks. Two subgroups in the HSD condition received telmisartan or enalapril. We assessed blood pressure, glucose homeostasis, liver inflammation, pancreatic function, and gut microbiota composition. <b>Results:</b> HSD rats exhibited significantly higher blood pressure (130 ± 2 mmHg in ND vs. 144 ± 4 mmHg in HSD; p < 0.01), reduced fasting insulin (1.33 ± 0.14 ng/mL in ND vs. 0.60 ± 0.05 ng/mL in HSD; p < 0.01), and gut microbiota dysbiosis, with a 71% reduction in Ruminococcus species (p = 0.018). Liver inflammation, indicated by an increase in CD68+ macrophages, was also observed in the HSD group. Telmisartan treatment significantly reduced liver inflammation but did not fully restore metabolic homeostasis. <b>Conclusion:</b> HSD disrupts multiple physiological systems, including glucose metabolism and liver function, partly through gut microbiota alterations. ACEIs and ARBs provided partial protection, highlighting the need for multi-targeted interventions to mitigate high-salt diet effects.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":""},"PeriodicalIF":5.0,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143662033","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Increased contact between lipid droplets and mitochondria in skeletal muscles of male elite endurance athletes.","authors":"Joachim Nielsen, Kristine Grøsfjeld Petersen, Martin Eisemann de Almeida, Sam O Shepherd, Britt Christensen, Maria Houborg Petersen, Kurt Højlund, Niels Ørtenblad, Kasper Degn Gejl","doi":"10.1152/ajpcell.00123.2025","DOIUrl":"https://doi.org/10.1152/ajpcell.00123.2025","url":null,"abstract":"<p><p>Endurance athletes exhibit higher skeletal muscle mitochondrial and lipid droplet (LD) content compared to recreationally active individuals, along with greater whole-body oxygen uptake and maximal fat oxidation rates. In this study, we investigated if these differences manifest in a greater LD-mitochondria contact and how this may relate to the organelles' size, shape, and numerical densities. We obtained skeletal muscle biopsies from 17 male elite triathletes and road cyclists and 7 recreationally active men. Using quantitative transmission electron microscopy, we found that the endurance athletes had 2-3-fold greater LD-mitochondria total contact length than the recreationally active individuals. This was related to higher numerical densities of both mitochondria (+30%) and LDs (+100%) in the intermyofibrillar space. Adding data from untrained individuals with equally high intermyofibrillar LD density as the endurance athletes revealed a 24% greater total LD-mitochondria contact length in the endurance athletes. We observed small trivial differences in shape of both organelles between populations. However, large mitochondrial profiles were more elongated and irregular in shape than small mitochondrial profiles, while large LD profiles were more circular and less irregular than small LD profiles. Within athletes, large intermyofibrillar LD profiles correlated (r=0.72) with a high fraction of PLIN5-positive LDs and their maximal fat oxidation rate was positively associated with an interaction between the profile size of both intermyofibrillar LDs and mitochondria. In conclusion, male endurance athletes have a greater LD-mitochondria contact than recreationally active and untrained individuals. This muscular phenotype is restricted to the intermyofibrillar space and to fibers rich in mitochondria.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":""},"PeriodicalIF":5.0,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143656109","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Umbilical cord mesenchymal stem cells-derived extracellular vesicles improve excessive autophagy of granulosa cells through METTL3.","authors":"Weiqin Zhou, Ju Zhang, Xuanping Lu, Ziwei Zhao, Yujing Weng, Chunrong Zhu","doi":"10.1152/ajpcell.00785.2024","DOIUrl":"https://doi.org/10.1152/ajpcell.00785.2024","url":null,"abstract":"<p><p><b>Objective:</b> Polycystic ovary syndrome (PCOS) is a prevalent endocrine disorder impacting women's fertility. We assessed the effect of umbilical cord mesenchymal stem cell-derived extracellular vesicles (UC-MSC-EVs) on PTEN-induced kinase 1 (PINK1)/Parkin-mediated excessive autophagy of ovarian granulosa cells (GCs) through methyltransferase-like 3 (METTL3). <b>Methods:</b> Human ovarian GC line KGN was cultured and treated with dehydroepiandrosterone (DHEA) and UC-MSC-EVs. Cell apoptosis and viability, autophagy-related protein levels, adenosine triphosphate (ATP) and mitochondrial membrane potential (MMP) level, and microtubule-associated protein 1 light chain 3 beta (LC3B) and translocase of outer mitochondrial membrane 20 (TOMM20) co-localization were assessed by flow cytometry, CCK-8, western blot, kit, and immunofluorescence. PINK1 N6-methyladenosine (m6A) modification, METTL3 levels, and PINK1 mRNA stability were determined by Me-RIP, RT-qPCR and western blot. The PCOS mouse model was established and treated with UC-MSC-EVs. Serum hormone and ovarian tissue autophagy-related protein levels were determined by ELISA. <b>Results:</b> DHEA decreased KGN cell viability and p62 level, increased PINK1, Parkin, LC3BII/I and Beclin-1 protein levels, ATP content, MMP level, TOMM20⁺LC3B⁺ cell number and apoptosis, which were partly abrogated by UC-MSC-EVs treatment. PINK1 had m6A modification sites. METTL3 was a PINK1 m6A-modified Writer protein. After DHEA treatment, KGN cells showed elevated METTL3 and PINK1 m6A modification levels and mRNA stability, while UC-MSC-EV treatment caused the opposite results. METTL3 overexpression partly averted UC-MSC-EVs-improved PINK1/Parkin-mediated mitophagy. UC-MSC-EVs curbed PINK1/Parkin-mediated excessive autophagy through METTL3 and improved ovarian function in PCOS mice. <b>Conclusions:</b> UC-MSC-EVs suppressed PINK1/Parkin-mediated mitophagy of ovarian GCs through METTL3, thereby improving PCOS.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":""},"PeriodicalIF":5.0,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143662035","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Functional coupling of Piezo1 channels and Ca²⁺-activated ion channels in the plasma membrane: fine-tunable interplay with wide-range signaling effects.","authors":"Valeriia Y Vasileva, Anastasia V Sudarikova, Vladislav I Chubinskiy-Nadezhdin","doi":"10.1152/ajpcell.00094.2025","DOIUrl":"https://doi.org/10.1152/ajpcell.00094.2025","url":null,"abstract":"<p><p>Ca²⁺ is a universal second messenger in living cells, and its concentration should be precisely localized to provide the outstanding specificity of signal transduction. The conception of Ca²⁺ micro- and nanodomains in which Ca²⁺ ions could control the activity of various Ca²⁺-dependent molecules was postulated: the Ca²⁺-permeable ion channels in the plasma membrane provide pathway for Ca²⁺ entry from the extracellular milieu into the cytosol regulating the activity of Ca²⁺-dependent molecules, i.e. functionally co-localized Ca²⁺-activated ion channels. These channel complexes of different molecular composition were observed in the cells of different origin; thus, the phenomenon of ion channel coupling is thought to be a universal property of living cells. Piezo1 is a mechanosensitive Ca²⁺-permeable ion channel that plays a pivotal role in the cellular mechanotransduction and is integrated into various signaling cascades regulating the activity of Ca²⁺-dependent molecules. Here, we summarized recent experimental data on the presence and role of functional complexes of Piezo1 with Ca²⁺-activated channels of different origin and highlighted the complex molecular mechanisms that could control the channel coupling in the plasma membrane.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":""},"PeriodicalIF":5.0,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143656087","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Short-term sustained hypoxia distinctly affects subpopulations of carotid body glomus cells from rats.","authors":"Pedro F Spiller, Henrique J N Morgan, Luiz C C Navegantes, Benedito H Machado, Melina P da Silva, Davi J A Moraes","doi":"10.1152/ajpcell.00967.2024","DOIUrl":"https://doi.org/10.1152/ajpcell.00967.2024","url":null,"abstract":"<p><p>The main O₂ arterial chemoreceptors are the carotid bodies (CBs), which mediate hyperventilation in response to short-term sustained hypoxia (SH). CBs contain glomus cells expressing K⁺ channels, which are inhibited by hypoxia, leading to the neurotransmitters release. ATP released by CBs glomus cells and type II cells has been considered essential for chemosensory processing under physiological and pathophysiological conditions. Although the systemic effects of chronic activation of CBs by SH are well known, the early (first 24 hours) cellular and molecular mechanisms (first 24 hours) in CBs, as well as the effects of short-term SH on populations of glomus cell are still poorly understood. Herein, we show that SH (10% O₂ for 24 hours) depolarizes the membrane potential of one population of glomus cells, mediated by increases in inward current, but does not affect the ATP release by CBs. In addition, SH promotes a reduction in their maximum outward current, mediated by voltage-gated K⁺ channels. SH also affected sensitivity to acute hypoxia in the two glomus cell subpopulations differently. As for the content of mitochondrial proteins, we observed increases in the citrate synthase, Tom-20 and succinate dehydrogenase (mitochondrial complex II) per cell of CBs after SH. Our results demonstrate important cellular and molecular mechanisms of plasticity in CBs from rats after only 24 hours of SH, which may contribute to the generation of cardiovascular and ventilatory adjustments observed in this experimental model.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":""},"PeriodicalIF":5.0,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143646948","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Enteroendocrine Cells Regulate Intestinal Barrier Permeability.","authors":"Jennifer G Nwako, Sparsh D Patel, Taevon J Roach, Saanvi R Gupte, Samara G Williams, Anne Marie Riedman, Heather A McCauley","doi":"10.1152/ajpcell.01077.2024","DOIUrl":"10.1152/ajpcell.01077.2024","url":null,"abstract":"<p><p>The intestinal epithelial barrier is essential for nutrient absorption and protection against ingested pathogens and foreign substances. Barrier integrity is maintained by tight junctions which are sensitive to inflammatory signals, thus creating a feed-forward loop with an increasingly permeable barrier that further drives inflammation and is the hallmark of inflammatory bowel disease. There are currently no therapeutic strategies to improve the intestinal epithelial barrier. We hypothesized that enteroendocrine cells may play an unappreciated role in maintaining barrier integrity. To test this hypothesis, we seeded human intestinal enteroids with genetic loss of enteroendocrine cells on Transwell filters and evaluated transepithelial electrical resistance, paracellular permeability, and the localization and abundance of junctional proteins. We found that enteroendocrine cells were required to maintain a healthy barrier in crypt-like \"stem\" and villus-like differentiated cultures. Additionally, exogenous supplementation of enteroendocrine-deficient cultures with the hormones peptide tyrosine tyrosine (PYY) and the somatostatin analog octreotide was sufficient to rescue many aspects of this barrier defect both at baseline and in the presence of the inflammatory cytokine tumor necrosis factor (TNF). Surprisingly, these improvements in barrier function occurred largely independently of changes in protein abundance of junctional proteins zona-occludens 1, occludin, and claudin-2. These findings support a novel role for enteroendocrine cells in augmenting epithelial barrier function in the presence of inflammatory stimuli and present an opportunity for developing therapies to improve the intestinal barrier.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":""},"PeriodicalIF":5.0,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143646946","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Blocking dopamine receptor 2 decreases gastrin levels in <i>H. pylori</i>-infected mice through increasing gastric somatostatin content.","authors":"Qianying Shen, Yue-Yue Zhou, Yan-Lin Wang, Yao Qi, Dong-Bo Lian, Zhe-Hong Li, Meng-Fei Chen, Xiao-Li Zhang, Yue Zhang, Jin Song, Li-Fei Zheng, Jin-Xia Zhu","doi":"10.1152/ajpcell.00993.2024","DOIUrl":"https://doi.org/10.1152/ajpcell.00993.2024","url":null,"abstract":"<p><p>Long-term infection with <i>Helicobacter pylori</i> (<i>H. pylori</i>) leads to elevated serum gastrin levels, which are closely related to gastric cancer. Eradication of <i>H</i><i>.</i> <i>pylori</i> to treat the high gastrin levels is increasingly challenged by antibiotic resistance. Dopamine (DA) receptor 1 (D₁R) is expressed on G cells in the gastric antrum. Parietal cells produce DA, which inhibits somatostatin (SOM) release through D₂R on D cells in the gastric mucosa. Whether targeted intervention in DRs can improve high gastrin levels after <i>H. pylori</i> infection remains to be explored. In this study, human gastric tissue, <i>H. pylori</i>-infected mice, D₁R and D₂R knockout mice, RT‒qPCR, ELISA, IHC, Western Blot, HE staining and <i>ex vivo</i> incubation of gastric mucosae were used. We found that <i>H. pylori</i> infection destroyed the mitochondria of parietal cells and reduced DA content in the gastric mucosa at 10 weeks after infection. Moreover, gastrin-positive cell numbers and serum gastrin levels were increased. D₁R, but not D₂R, was observed in G cells. DA promoted gastric gastrin secretion. Interestingly, both D1- and D2-like agonists mimicked the effect of DA on the gastrin secretion, which was antagonized by their antagonists. Blocking D₂R with domperidone or knocking out D₂R resulted in decreased gastrin-positive cell numbers and gastrin levels but increased SOM levels at 10 weeks after <i>H. pylori</i> infection. Our findings highlight the key regulatory effect of D₂R on gastrin secretion and elucidate the role of domperidone in reducing the elevated gastrin level associated with <i>H. pylori</i> infection.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":""},"PeriodicalIF":5.0,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143646891","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Modulation of Fatty Acid Metabolism via Lactate-HCA1 Signaling: Potential Therapeutic Implications.","authors":"Isaac A Chavez-Guevara, Manuel Fermandez-Escabias, Marco A Hernandez-Lepe, Francisco J Amaro-Gahete","doi":"10.1152/ajpcell.00969.2024","DOIUrl":"https://doi.org/10.1152/ajpcell.00969.2024","url":null,"abstract":"<p><p>The lactate/HCA1 signaling pathway has emerged as a promising target for the clinical management of metabolic diseases, given its regulatory effects on triglyceride turnover and mobilization. However, the differential roles of this pathway in adipose tissue, skeletal muscle, and the liver raise important questions about whether its activation or inhibition would yield the most favorable outcomes. In adipose tissue, HCA1 activation suppresses lipolysis, while in skeletal muscle, recent evidence suggests that lactate may bypass HCA1 to directly enhance mitochondrial fatty acid oxidation. In the liver, HCA1 activation has been implicated in promoting lipid oxidation, offering potential therapeutic implications. This perspective also explores the potential of the lactate/HCA1 pathway to mediate systemic adaptations induced by exercise training, including enhanced mitochondrial capacity and metabolic flexibility. These insights underscore the pathway's relevance for both metabolic health and exercise physiology. However, the current understanding of the lactate/HCA1 pathway remains incomplete, with critical gaps in knowledge regarding its role in underrepresented populations and the molecular mechanisms underlying its tissue-specific effects. Addressing these limitations will be essential for refining the therapeutic and clinical applications of this pathway.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":""},"PeriodicalIF":5.0,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143646947","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Diurnal differences in postprandial glucose and triglyceride metabolism reveal metabolic flexibility and resilience.","authors":"Rebecca Dörner, Franziska A Hägele, Shauna D O'Donovan, Jennifer L Miles-Chan, Manfred J Müller, Anja Bosy-Westphal","doi":"10.1152/ajpcell.00102.2025","DOIUrl":"https://doi.org/10.1152/ajpcell.00102.2025","url":null,"abstract":"<p><p>Objective The study investigated the diurnal variance in metabolic resilience (i.e., the robustness, the recovery and re-orientation of metabolism) and metabolic flexibility in glucose and fat oxidation rates to three identical test meals. Methods Eight young, healthy subjects consumed identical liquid mixed meals three times a day (33 % of energy requirement each), followed by a defined bout of physical activity conducted in a whole-room indirect calorimeter to continuously assess energy expenditure and postprandial changes in substrate oxidation rates, as a measure of metabolic flexibility. A mathematical metabolic resilience model was used to analyze the postprandial blood parameters. Results Throughout the day, postprandial glucose area under the curve (AUC) increased (breakfast mean ±SD 17.3 ±2.4 vs. dinner 20.8 ±2.0 g/180min; p<0.001) while triglyceride AUC decreased (breakfast 434 ±158 vs. dinner 365 ±104 mg/180min; p=0.039) at identical insulin AUC and energy balance. Fat oxidation increased from breakfast 24.8 ±8.7 to dinner 28.0 ±8.7 g/180min (p=0.029), while respiratory exchange ratio declined from 0.035 ±0.026 to 0.012 ±0.029 (p=0.005). Metabolic resilience model reveals a diurnal increased rate of lipolysis of circulating triglycerides at a concomitant decrease in the rate of exogenous and endogenous triglyceride appearance. Conclusion Meal-to-meal changes in glucose AUC indicate rising insulin resistance during the day. However, this reflects a resilient metabolism that shifts to triglyceride metabolism in the evening while maintaining insulin AUC and energy balance.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":""},"PeriodicalIF":5.0,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143646945","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Interleukin-10 resistance in type 2 diabetes is associated with defective STAT3 signaling in human blood leukocytes.","authors":"Hashim Islam, Garett S Jackson, Jordan Boultbee, Shun-Hsi Tsai, Alfonso Moreno-Cabañas, Alexandre A de Souza Teixeira, David C Wright, Alice L Mui, Jonathan P Little","doi":"10.1152/ajpcell.00124.2025","DOIUrl":"https://doi.org/10.1152/ajpcell.00124.2025","url":null,"abstract":"<p><p>Chronic inflammation is strongly implicated in the pathophysiology of type 2 diabetes (T2D), highlighting the need to better understand inflammatory processes in people living with T2D. Hyperglycemia blunts the anti-inflammatory actions of interleukin-10 (IL-10) - the most potent anti-inflammatory cytokine - but the mechanistic basis remains unclear. To test the hypothesis that signaling defects underpin this hyporesponsiveness to IL-10 action, fasted blood samples were obtained from individuals living with T2D (<i>n</i>=17, age: 64±9 yrs, HbA1c: 7.2±1.1%) and their age-matched counterparts without diabetes (<i>n</i>=19, 65±8 yrs, 5.5±0.3%). Blood leukocytes were analyzed for IL-10-mediated signaling, gene expression, and cytokine secretion using flow cytometry, qPCR, and whole-blood cultures, respectively. Despite no overt elevations in circulating pro- and anti-inflammatory cytokine concentrations, blood leukocytes from individuals with T2D exhibited exaggerated cytokine secretion when exposed to lipopolysaccharide (LPS) (p<0.05). IL-10's ability to activate its canonical transcription factor signal transducer and activator of transcription 3 (STAT3) was blunted in CD14 monocytes and CD4 lymphocytes from people with T2D (p<0.01) - a defect associated with lower IL-10 receptor expression on both cell types (p<0.05). This upstream signaling defect was accompanied by attenuated suppressor of cytokine signaling 3 (SOCS3) mRNA levels in IL-10 treated mononuclear cells (p=0.059) and higher lipopolysaccharide (LPS)-stimulated cytokine secretion from blood leukocytes exposed to IL-10 (p<0.01). Our findings identify defective IL-10-mediated signaling and gene expression as a potential mechanism underpinning IL-10 resistance in T2D, highlighting need for further investigation into therapeutic approaches targeting IL-10.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":""},"PeriodicalIF":5.0,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143623181","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}