American journal of physiology. Cell physiology最新文献

{"title":"Cellular and molecular contractile function in aged human skeletal muscle is altered by phosphate and acidosis and partially reversed with an ATP analog.","authors":"Aurora D Foster, Chad R Straight, Philip C Woods, Christopher Lee, Jane A Kent, Stuart R Chipkin, Edward P Debold, Mark S Miller","doi":"10.1152/ajpcell.00332.2024","DOIUrl":"10.1152/ajpcell.00332.2024","url":null,"abstract":"<p><p>Skeletal muscle fatigue occurs, in part, from the accumulation of hydrogen (H⁺) and phosphate (P_i); however, the molecular basis through which these ions inhibit function is not fully understood. Therefore, we examined the effects of these metabolites on myosin-actin cross-bridge kinetics and mechanical properties in skeletal muscle fibers from older (65-75 yr) adults. Slow-contracting myosin heavy chain (MHC) I and fast-contracting MHC IIA fibers were examined under control (5 mM P_i, pH 7.0) and fatigue (30 mM P_i, pH 6.2) conditions at maximal calcium-activation [5 mM adenosine triphosphate (ATP)] and rigor (0 mM ATP). In MHC I and IIA fibers, fatigue decreased force per fiber size (23%-37%), which was accompanied by reduced strongly bound myosin head characteristics (number and/or stiffness; 21%-47%) and slower cross-bridge kinetics [longer myosin attachment times (22%-46%) and reduced rates of force production (20%-33%)] compared with control. MHC I myofilaments became stiffer with fatigue, a potential mechanism to increase force production. In rigor, which causes the myosin that can bind actin to be strongly bound, fatigue decreased force per fiber size (32%-33%) in MHC I and IIA fibers, indicating less force was generated per cross bridge. By replacing ATP with 2-deoxy-ATP, the fatigue-induced slowing of cross-bridge kinetics in MHC I and IIA fibers was reversed, and reduced force production in MHC I fibers was partially improved, revealing potential mechanisms to help mitigate fatigue in older adults. Overall, our results identify novel fiber type-specific changes in cross-bridge kinetics, force per cross bridge, and myofilament stiffness that help explain fatigue in older adults.<b>NEW & NOTEWORTHY</b> Skeletal muscle fatigue is caused, in part, by increased production of phosphate and hydrogen ions, resulting in decreased force generation. We found that reduced force in fibers from older adults was due to altered function of myosin and actin, including slower protein interactions and reduced force per myosin head. Additionally, an ATP analog, dATP, partially reversed contractile dysfunction induced by increased phosphate and hydrogen, improving force production and altering myosin-actin interactions dependent upon fiber type.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C1220-C1233"},"PeriodicalIF":5.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143565776","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":"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":"10.1152/ajpcell.01036.2024","url":null,"abstract":"<p><p>High-salt diets (HSDs) 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). 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 wk. Two subgroups in the HSD condition received telmisartan or enalapril. We assessed blood pressure, glucose homeostasis, liver inflammation, pancreatic function, and gut microbiota composition. HSD rats exhibited significantly higher blood pressure [130 ± 2 mmHg in normal diet (ND) vs. 144 ± 4 mmHg in HSD; <i>P</i> < 0.01], reduced fasting insulin (1.33 ± 0.14 ng/mL in ND vs. 0.60 ± 0.05 ng/mL in HSD; <i>P</i> < 0.01), and gut microbiota dysbiosis, with a 71% reduction in Ruminococcus species (<i>P</i> = 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. 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 multitargeted interventions to mitigate high-salt diet effects.<b>NEW & NOTEWORTHY</b> High-salt diet induces multisystem disruptions, including liver inflammation, reduced insulin levels, and gut microbiota imbalance. ACEIs and ARBs showed limited efficacy, highlighting the need for comprehensive therapeutic approaches.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C1366-C1382"},"PeriodicalIF":5.0,"publicationDate":"2025-04-01","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":"Modulation of fatty acid metabolism via lactate-HCA1 signaling: potential therapeutic implications.","authors":"Isaac A Chavez-Guevara, Manuel Fernández-Escabias, Marco A Hernández-Lepe, Francisco J Amaro-Gahete","doi":"10.1152/ajpcell.00969.2024","DOIUrl":"10.1152/ajpcell.00969.2024","url":null,"abstract":"","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C1333-C1337"},"PeriodicalIF":5.0,"publicationDate":"2025-04-01","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":"Lasmiditan induces mitochondrial biogenesis in primary mouse renal peritubular endothelial cells and augments wound healing and tubular network formation.","authors":"Austin D Thompson, Kai W McAlister, Natalie E Scholpa, Jaroslav Janda, John Hortareas, Rick G Schnellmann","doi":"10.1152/ajpcell.00116.2025","DOIUrl":"10.1152/ajpcell.00116.2025","url":null,"abstract":"<p><p>Kidney disease (KD) is a progressive and life-threatening illness that has manifested into a global health crisis, impacting >10% of the general population. Hallmarks of KD include tubular interstitial fibrosis, renal tubular cell atrophy/necrosis, glomerulosclerosis, persistent inflammation, microvascular endothelial cell (MV-EC) dysfunction/rarefaction, and mitochondrial dysfunction. Following acute kidney injury (AKI), and/or during KD onset/progression, MV-ECs of the renal peritubular endothelial capillaries (RPECs) are highly susceptible to injury, dysfunction, and rarefaction. Pharmacological induction of mitochondrial biogenesis (MB) via 5-hydroxytryptamine receptor 1F (HTR1F) agonism has been shown to enhance mitochondrial function and renal vascular recovery post-AKI in mice; however, little is known about MB in relation to renal MV-ECs and RPEC repair mechanisms. To address this gap in knowledge, the in vitro effects of the potent and selective FDA-approved HTR1F agonist lasmiditan were tested on primary mouse renal peritubular endothelial cells (MRPECs). Lasmiditan increased mitochondrial maximal respiration rates, mRNA and protein expression of MB-related genes, and mitochondrial number in MRPECs. MRPECs were then exposed to pro-inflammatory agents associated with renal MV-EC dysfunction, AKI, and KD (i.e., lipopolysaccharides, transforming growth factor-β1, and tumor necrosis factor-α), in the presence/absence of lasmiditan. Lasmiditan treatment augmented MRPEC wound healing, endothelial tubular network formation (ETNF), enhanced barrier integrity, and blunted inflammatory-induced MV-EC dysfunctions. Together, these data suggest that lasmiditan induces MB and improves wound healing and ETNF of primary MRPECs in the presence/absence of pro-inflammatory agents, highlighting a potential therapeutic role for lasmiditan treatment in renal MV-EC dysfunction, AKI, and/or KD.<b>NEW & NOTEWORTHY</b> Lasmiditan, an FDA-approved HTR1F agonist, induces mitochondrial biogenesis (MB) and enhances recovery following acute kidney injury in mice. Renal microvascular endothelial cells (MV-ECs) are highly susceptible to dysfunction/rarefaction postinjury. The effect of MB on MV-EC repair/recovery is unknown. We show that lasmiditan induces MB in primary mouse renal peritubular endothelial cells and improves wound healing, endothelial tubular network formation, and barrier integrity after inflammatory-induced dysfunction, indicative of its potential for the treatment of kidney diseases.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C1318-C1332"},"PeriodicalIF":5.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143623183","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":"Skeletal dysplasia-causing mutations in TRPV4 alter the chondrocyte transcriptomic response to mechanical loading.","authors":"Zainab Harissa, Yuseon Kim, Amanda R Dicks, Nancy Steward, Farshid Guilak","doi":"10.1152/ajpcell.01066.2024","DOIUrl":"10.1152/ajpcell.01066.2024","url":null,"abstract":"<p><p>Transient receptor potential vanilloid 4 (TRPV4) is a mechanosensitive ion channel highly expressed in chondrocytes that supports cartilage development and homeostasis. Mutations in the channel can cause skeletal dysplasias, including the gain-of-function mutations V620I and T89I, which lead to brachyolmia and metatropic dysplasia, respectively. These mutations suppress hypertrophic differentiation, but the mechanisms by which they alter chondrocyte response to mechanical load remain to be elucidated. To determine the effect of these mutations on chondrocyte mechanotransduction, tissue-engineered cartilage was derived from differentiated clustered regularly interspaced short palindromic repeats (CRISPR)-edited human-induced pluripotent stem cells (hiPSCs) harboring the moderate V620I or severe T89I TRPV4 mutations. Wild-type and mutant tissue-engineered hiPSC-derived cartilage contructs were subjected to compressive mechanical loading at physiological levels, and transcriptomic signatures were assessed by RNA-sequencing. Our results demonstrate that the V620I and T89I mutations diminish the mechanoresponsiveness of chondrocytes, as evidenced by reduced gene expression downstream of TRPV4 activation, including those involved in endochondral ossification. Changes in the expression of genes involved in extracellular matrix production and organization were found to contribute toward the phenotype in V620I mutant chondrocytes, whereas dysregulated retinoic acid signaling was linked to T89I, and disrupted proliferation was common to both. Our findings suggest that dysfunctional mechanotransduction due to V620I and T89I mutations in TRPV4 contribute to the developmental phenotypes, supporting TRPV4 modulation as a potential pharmacologic target.<b>NEW & NOTEWORTHY</b> Gain-of-function mutations in TRPV4, a mechano- and osmosensitive ion channel, are linked to skeletal dysplasias, but their effects on chondrocyte mechanotransduction remain unknown. Using human iPSCs harboring skeletal dysplasia-causing mutations, we developed and mechanically loaded tissue-engineered cartilage. Our findings show that V620I and T89I mutations reduce chondrocyte mechanoresponsiveness, evidenced by decreased gene expression downstream of TRPV4 activation, providing insight into TRPV4-related skeletal disorders and potential pharmacological targets.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C1135-C1149"},"PeriodicalIF":5.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143522439","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":"Identification of a senescence-associated transcriptional program in skeletal muscle of cachectic pancreatic-tumor-bearing mice.","authors":"Jeremy B Ducharme, Madison E Carelock, Martin M Schonk, Nour M Al-Zaeed, Weizhou Zhang, Sarah M Judge, Andrew R Judge","doi":"10.1152/ajpcell.00816.2024","DOIUrl":"10.1152/ajpcell.00816.2024","url":null,"abstract":"<p><p>Cancer cachexia is the involuntary loss of body and skeletal muscle mass, which negatively impacts physical function, quality of life, treatment tolerance, and survival. Skeletal muscles of cachectic people and mice with pancreatic tumors also exhibit skeletal muscle damage, nonresolute immune cell infiltration, and impaired regeneration. These phenotypes may be influenced by the accumulation of senescent cells, which secrete factors detrimental to skeletal muscle health. However, there is currently no comprehensive research on the senescent cell accumulation in the skeletal muscle of tumor-bearing hosts, with or without chemotherapy. To address this gap, we cross-referenced the SenMayo panel of 125 senescence-related genes with our RNA-seq dataset in mouse skeletal muscle during the initiation and progression of cancer cachexia, which revealed a differential expression of 39 genes at precachexia, 64 genes at cachexia onset, and 72 genes when cachexia is severe. Since p16 is a canonical marker of senescence, we subsequently orthotopically injected p16-tdTomato reporter mice with murine KPC pancreatic cancer cells and treated a subset of mice with chemotherapy. At experimental endpoint, when KPC treatment-naïve mice were cachectic, we observed an increased accumulation of p16+ cells, along with increased mRNA levels of hallmark senescence markers (<i>Cdkn1a/p21</i>, <i>Cdkn2a/p16</i>, <i>Glb1/</i>senescent-associated-β-galactosidase), which were exacerbated by chemotherapy. Finally, we demonstrate an increase in <i>CDKN1A/p21</i> in the muscle of cachectic patients with pancreatic cancer, which associated with cachexia severity. These findings suggest that senescent cells accumulate in skeletal muscle of cachectic pancreatic tumor-bearing hosts and that chemotherapy can exacerbate this accumulation.<b>NEW & NOTEWORTHY</b> To the best of our knowledge, this study is the first to investigate senescent cell accumulation in skeletal muscle of tumor-bearing hosts and its exacerbation by chemotherapy. Our findings identify an accumulation of senescent cells and reveal a senescence-related transcriptional program in skeletal muscle during the initiation and progression of cancer cachexia that is exacerbated by chemotherapy treatment. This highlights a novel potential therapeutic mechanism that can be targeted for the prevention of cancer-induced muscle pathologies.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C1125-C1134"},"PeriodicalIF":5.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143490522","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 Abílio de Souza Teixeira, David C Wright, Alice L Mui, Jonathan P Little","doi":"10.1152/ajpcell.00124.2025","DOIUrl":"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 yr, HbA1c: 7.2 ± 1.1%) and their age-matched counterparts without diabetes (<i>n</i> = 19, 65 ± 8 yr, 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) (<i>P</i> < 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 (<i>P</i> < 0.01)-a defect associated with lower IL-10 receptor expression on both cell types (<i>P</i> < 0.05). This upstream signaling defect was accompanied by attenuated suppressor of cytokine signaling 3 mRNA levels in IL-10-treated mononuclear cells (<i>P</i> = 0.059) and higher lipopolysaccharide (LPS)-stimulated cytokine secretion from blood leukocytes exposed to IL-10 (<i>P</i> < 0.01). Our findings identify defective IL-10-mediated signaling and gene expression as a potential mechanism underpinning IL-10 resistance in T2D, highlighting the need for further investigation into therapeutic approaches targeting IL-10.<b>NEW & NOTEWORTHY</b> Our findings demonstrate that immune cells from people with type 2 diabetes (T2D) are less responsive to the anti-inflammatory actions of interleukin-10 (IL-10), which may drive chronic inflammation in this population. We identify T2D-associated defects at multiple steps of the IL-10 cascade-including IL-10 receptor expression, STAT3 signaling, SOCS3 mRNA, and cytokine secretion. Our findings highlight defective IL-10 action as a potential therapeutic target to ameliorate inflammation in T2D.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C1293-C1302"},"PeriodicalIF":5.0,"publicationDate":"2025-04-01","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}

{"title":"Compositional changes of the lung extracellular matrix in acute respiratory distress syndrome.","authors":"YiWen Fan, Jill Moser, Rianne M Jongman, Theo Borghuis, Judith M Vonk, Wim Timens, Matijs van Meurs, Janesh Pillay, Janette K Burgess","doi":"10.1152/ajpcell.01007.2024","DOIUrl":"10.1152/ajpcell.01007.2024","url":null,"abstract":"<p><p>Acute respiratory distress syndrome (ARDS) is pathologically characterized by diffuse alveolar damage (DAD) and is associated with high morbidity and mortality rates. Although pulmonary injury initiates alveolar-capillary barrier damage in ARDS, remodeling of the extracellular matrix (ECM), which is pivotal for both tissue repair and organ recovery, may play a large role in persistent ARDS. This study investigated the compositional changes in the ECM in different DAD stages in ARDS. Paraffin-embedded lung sections collected during autopsy or from posttransplant lungs were obtained from patients with ARDS (<i>n</i> = 28) admitted to the University Medical Center Groningen between 2010 and 2020. Sections were stained histochemically, and immunohistochemically for collagen III α1 chain (Col IIIa1), IV α3 chain (Col IVa3), VI α1 chain (Col VIa1), periostin (PSTN), lumican (LUM), and fibronectin (FN). The sections were divided into 118 regions based on DAD stages (54 early vs. 64 advanced). The differences in the expression of selected proteins were compared between DAD stages or across ARDS duration (<7 days, 7-14 days, and >14 days). The fiber pattern of Col VIa1 was analyzed using CellProfiler. Higher tissue density, lower proportional areas of Col IIIa1, Col IVa3, and LUM, and more concentrated Col VIa1 fibers were observed in the advanced DAD stage than in the early DAD stage. Areas with higher proportions of total collagen and FN, and lower proportional areas of Col IIIa1, Col IVa3, and LUM were detected in lung regions from patients with ARDS >14-days duration. These findings revealed proportional changes in ECM components, strongly suggesting that dynamic changes in ECM proteins play a role in pathophysiology in ARDS during progression.<b>NEW & NOTEWORTHY</b> Our study revealed ECM protein compositional differences in lung parenchyma between stages of DAD. In advanced DAD, tissue density was higher, but collagen type III, type IV, and lumican were proportionally lower compared with early DAD. The organization of collagen type VI fibers was highly concentrated in advanced DAD. Our results indicate that both composition and organization of ECM were remodeled in advanced DAD, suggesting a role in manifesting acute respiratory distress syndrome.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C1279-C1292"},"PeriodicalIF":5.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143584297","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":"Abnormal purine metabolism in nasal epithelial cells affects allergic rhinitis by regulating Th17/Treg cells.","authors":"Ting Xu, Shitong Xia, Xingjie Zhang, Yixiao Yuan","doi":"10.1152/ajpcell.00873.2024","DOIUrl":"10.1152/ajpcell.00873.2024","url":null,"abstract":"<p><p>We aimed to explore novel pathogenesis in young children with allergic rhinitis (AR), and thus finding novel nasal spray reagents for them, especially under 4 yr old. In this study, nontargeted metabolomics analyses were used to explore the differential metabolites in nasal lavage fluid (NALF) of children with AR. Cell Counting Kit-8 (CCK-8) and flow cytometry were used to assess cell proliferation and apoptosis in human nasal mucosal epithelial cells (HNEpCs). HNEpCs were cocultured with CD4⁺ T cells, and flow cytometry was used to detect Th17/regulatory T (Treg) cells. RNA sequencing was used to assess the key pathways in xanthine-treated Jurkat T cells. Finally, both the in vitro and in vivo experiments were used to assess the effect of 1, 3-dipropyl-8 cyclopentylxanthine (DPCPX, Adora1 inhibitor) on activating transcription factor 4 (ATF4) expression and Th17/Treg cells. Xanthine and uric acid levels were increased in the NALF of children with AR. Xanthine dehydrogenase (XDH), purine nucleoside phosphatase (PNP), xanthine/hypoxanthine, and uric acid levels were elevated in Derp1-treated HNEpCs, and si-XDH reversed the reduced cell viability and increased cell apoptosis in Derp1-treated HNEpCs. Both xanthine and Derp1-treated HNEpCs increased the Th17/Treg ratio. The endoplasmic reticulum stress (ERS) pathway was affected in xanthine-treated Jurkat T cells, and ATF4 was markedly reduced in xanthine-treated Jurkat T cells. Xanthine exhibited no effect on Adora1 expression, whereas DPCPX elevated ATF4 expression and reduced the Th17/Treg ratio in xanthine-treated Jurkat T cells. The in vitro experiments revealed that DPCPX reduced inflammatory infiltration, Th17/Treg ratio, interleukin (IL)-17, tumor necrosis factor (TNF)-α, and IL-6 in AR mice. These results demonstrated that xanthine inhibited ATF4 expression via Adora1 to elevate the Th17/Treg ratio in the nasal cavity, thus participating in AR progression. These findings may provide novel therapeutic interventions for young children with AR.<b>NEW & NOTEWORTHY</b> Current nasal spray hormones exhibited some adverse reactions for young children with allergic rhinitis (AR), and there were no suitable nasal spray hormones for children with AR under 4 yr old. This study emphasized the important role of purine metabolism in the nasal cavity in children with AR and provided novel therapeutic interventions for children with AR.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C1193-C1205"},"PeriodicalIF":5.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143456818","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":"ChREBP mediates metabolic remodeling in FBP1-deficient liver.","authors":"Chen-Ma Wang, Qiu-Fang Bai, Ya-Jin Liu, Jie Lin, Chun-Chun Wei, Xian-Hua Ma, Jia-Mu Zhao, Meng Zhu, Yu-Xia Chen, Ya-Nan Shi, Jian-Hui Shi, Weiping J Zhang","doi":"10.1152/ajpcell.00875.2024","DOIUrl":"10.1152/ajpcell.00875.2024","url":null,"abstract":"<p><p>The deficiency of fructose-1,6-bisphosphatase 1 (FBP1), a key enzyme of gluconeogenesis, causes fatty liver. However, its underlying mechanism and physiological significance are not fully understood. Here we demonstrate that carbohydrate response element-binding protein (ChREBP) mediates lipid metabolic remodeling and promotes progressive triglyceride accumulation against metabolic injury in adult FBP1-deficient liver. Inducible liver-specific deletion of Fbp1 gene caused progressive hepatomegaly and hepatic steatosis, with a marked increase in hepatic de novo lipogenesis (DNL) as well as a decrease in plasma β-hydroxybutyrate levels. Notably, FBP1 deficiency resulted in a persistent activation of ChREBP and its target genes involved in glycolysis, lipogenesis, and fatty acid oxidation, even under fasting conditions. Furthermore, liver-specific ChREBP disruption could markedly restore the phenotypes of enhanced DNL and triglyceride accumulation in FBP1-deficient liver but exacerbated its hepatomegaly and liver injury, which was associated with remarkable energy deficit, impaired mammalian target of rapamycin (mTOR) activation, and increased oxidative stress. Furthermore, metabolomics analysis revealed a robust elevation of phosphoenolpyruvate, phosphoglycerates, phospholipids, and ceramides caused by ChREBP deletion in FBP1-deficient liver. Put together, these results suggest that overactivation of ChREBP pathway mediates liver metabolic remodeling in the absence of FBP1, which contributes to the pathogenesis of progressive hepatic steatosis and provides a protection against liver injury. Thus, our findings point to a beneficial role of ChREBP in metabolic remodeling in the context of excessive gluconeogenic intermediates.<b>NEW & NOTEWORTHY</b> FBP1 deficiency in adulthood causes progressive hepatic steatosis due to the overactivation of ChREBP pathway, which enhances lipid synthesis and inhibits fat oxidation. ChREBP-mediated metabolic remodeling protects against liver injury caused by energy deficit and oxidative stress in FBP1-deficient liver.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":" ","pages":"C1234-C1246"},"PeriodicalIF":5.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143584285","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}