Ying Zhu, Wanlin Liu, Chunyuan Yang, Teng Ma, Mingfei Han, Jinxu Zhang, Yunping Zhu, Jie Ma
{"title":"Temperature-Gradient Transcriptomic Atlas Reveals the PPAR Signaling Pathway Dysfunction in Heat Stroke Induced Liver Injury","authors":"Ying Zhu, Wanlin Liu, Chunyuan Yang, Teng Ma, Mingfei Han, Jinxu Zhang, Yunping Zhu, Jie Ma","doi":"10.1096/fba.2025-00308","DOIUrl":"10.1096/fba.2025-00308","url":null,"abstract":"<p>Heat stroke (HS) is the most severe form of hyperthermia, with mortality exceeding 50% in severe cases. The liver is highly vulnerable to HS-induced injury, often triggering multi-organ failure. Although rapid cooling remains the primary treatment, the molecular mechanisms underlying hepatic damage remain elusive, highlighting an urgent need for mechanistic insights, especially given global extreme heat events. We established a HS model by gradually increasing the core temperature of mice from 40°C to 43°C. Mice were sacrificed at each target temperature to collect blood and liver tissues for hematological, biochemical, and histopathological analyses. Transcriptomic profiling was conducted on murine livers, and differentially expressed genes (DEGs) were identified and analyzed. The peroxisome proliferator-activated receptor (PPAR) signaling pathway was identified as a significantly enriched pathway and 12 key DEGs were validated by reverse transcription quantitative PCR (RT-qPCR) to assess temperature-dependent metabolic reprogramming. The expression of CD36, ACOX3, and PPARα was validated by immunohistochemistry at the protein level to investigate their response to heat stress. A graded murine HS model was established and histopathology analysis showed significant liver injury with core temperatures ≥ 42°C, manifesting as weight loss, elevated serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), neutrophilia, thrombocytopenia, hepatocyte necrosis, and sinusoidal congestion. Transcriptomic profiling revealed temperature-dependent DEGs from 41°C onward mainly involved in inflammatory/immune, lipid metabolism, apoptosis, and stress response pathways. DEGs consistently dysregulated across different temperatures were enriched in PPAR, insulin signaling, and endoplasmic reticulum (ER) stress-related pathways. RT-qPCR analysis revealed the altered expression of PPAR-related key genes, indicating functional disruption in lipid metabolism. Immunohistochemistry further confirmed these transcriptomic findings at the protein level, suggesting that heat stress induced reprogramming of the PPAR signaling pathway. Together, these findings suggest that HS-induced liver injury is closely associated with progressive metabolic reprogramming, with dysregulated lipid metabolism playing a central pathogenic role. By combining a murine stepwise HS model and transcriptomic analysis, we identified dysregulated PPAR signaling as a key temperature-dependent feature of liver injury, suggesting its potential role as a temperature-sensing node and therapeutic target. This work provides a framework with precise temporal windows and molecular candidates for the development of mechanism-directed intervention strategies for HS.</p>","PeriodicalId":12093,"journal":{"name":"FASEB bioAdvances","volume":"8 3","pages":""},"PeriodicalIF":2.0,"publicationDate":"2026-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://faseb.onlinelibrary.wiley.com/doi/epdf/10.1096/fba.2025-00308","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147568924","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"The Oxygen Equivalent of Lactate Accumulation and Sex: Similar Work–Lactate Slopes in Men and Women Regardless of Body or Fat-Free Mass Scaling","authors":"Benedikt Meixner, Mascha Lenk, Billy Sperlich","doi":"10.1096/fba.2025-00330","DOIUrl":"10.1096/fba.2025-00330","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <p>The oxygen equivalent of blood lactate accumulation (ΔLa) is commonly expressed relative to body mass (BM), yet BM includes adipose tissue which does not substantially contribute to glycolytic energy production nor lactate distribution space and may confound sex comparisons. We examined whether replacing BM with fat-free mass (FFM) (i) improves the correspondence between calculated glycolytic work and 15-s sprint work and (ii) attenuates sex differences in the work–lactate relationship. Seventy-one trained cyclists (48 men, 23 women) performed a 15-s all-out seated cycling sprint on a Cyclus2 ergometer. Blood lactate was sampled at rest and repeatedly for 8 min post-sprint; ΔLa was defined as peak minus pre-exercise lactate. Glycolytic work (W<sub>Gly</sub>) was calculated using an oxygen-equivalent approach with ΔLa scaled to either BM or FFM. General linear models included glycolytic work, sex, and 15-s work. Men exhibited higher 15-s work and ΔLa than women, but the slope of the relationship between W<sub>Gly</sub> and 15-s work did not differ by sex for either BM or FFM. Regression models using FFM explained slightly more variance in 15-s work than BM (<i>R</i><sup>2</sup> = 0.79 vs. 0.75). Adding sex improved model fit for both formulations (<i>R</i><sup>2</sup> = 0.85 and 0.85, respectively), indicating primarily an intercept effect rather than a slope difference. Replacing BM with FFM provides only a small improvement in explaining 15-s work and does not reveal sex-specific differences in the work–lactate slope. Thus, the lactate oxygen equivalent appears sex-invariant while FFM-based scaling may still be preferred for a more physiologically grounded estimate of W<sub>Gly</sub>.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12093,"journal":{"name":"FASEB bioAdvances","volume":"8 3","pages":""},"PeriodicalIF":2.0,"publicationDate":"2026-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://faseb.onlinelibrary.wiley.com/doi/epdf/10.1096/fba.2025-00330","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147566579","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Fahd Alhamdan, Yi-Cheng Sin, Erik Malm, Hanna Van Pelt, Samuel Kim, LeeAnn Higgins, Yue Chen, Koichi Yuki
{"title":"Plasma Proteomic Signatures of Pediatric Sepsis Reveal Persistent Inflammation and Phase-Specific Biomarkers","authors":"Fahd Alhamdan, Yi-Cheng Sin, Erik Malm, Hanna Van Pelt, Samuel Kim, LeeAnn Higgins, Yue Chen, Koichi Yuki","doi":"10.1096/fba.2026-00006","DOIUrl":"10.1096/fba.2026-00006","url":null,"abstract":"<p>Sepsis remains a leading cause of pediatric morbidity and mortality, yet its molecular underpinnings are poorly understood. Here, we performed mass spectrometry–based plasma proteomics and cytokine profiling in pediatric sepsis patients at the acute phase (AP) and recovery phase (RP), alongside preoperative surgical controls. In AP vs. control, we identified 41 differentially abundant (DA) proteins, including acute-phase reactants and complement factors, with persistent but attenuated expression in RP. Pathway analysis revealed sustained enrichment in inflammatory and complement activation processes during both AP and RP, with partial restoration of immune surveillance and vascular homeostasis in recovery. Machine learning highlighted complement components (C9, C1R) and LRG1 as candidate AP biomarkers, and S100A9 as an RP-associated marker. Comparative analysis with adult sepsis proteomes uncovered age-specific complement activation patterns: adults displayed higher classical pathway activity, whereas pediatric patients exhibited enhanced alternative pathway activity. Cytokine profiling confirmed sustained immune activation and endothelial perturbation across sepsis phases. We also compared the sepsis cohort with the sterile inflammation (SI) cohort, which revealed distinct adaptive immune enrichment in sepsis while innate immune predominance in SI, enabling the identification of potential sepsis-specific protein signatures. Together, these findings delineate the dynamic immune and vascular proteomic landscape of pediatric sepsis, reveal biomarkers distinguishing sepsis from sterile inflammation, and highlight age-related complement pathway differences with potential therapeutic implications.</p><p><b>Trial Registration:</b> ClinicalTrials.gov: NCT04103268, NCT04299828</p>","PeriodicalId":12093,"journal":{"name":"FASEB bioAdvances","volume":"8 3","pages":""},"PeriodicalIF":2.0,"publicationDate":"2026-03-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12972194/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147431672","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Mapping Intestinal Paracellular Perm Eability in Mice: Regional and Cellular Variability Under Physiological and Stimulated Conditions","authors":"Mathilde Miquel, Kadirey Verwaerde, Anissa Edir-Kibri, Mikael Albin, Florence Blas-Y-Estrada, Audrey Samper, Elodie Rousseau-Bacquie, Hervé Robert, Hélène Eutamène, Vassilia Théodorou, Christine Coméra","doi":"10.1096/fba.2025-00325","DOIUrl":"10.1096/fba.2025-00325","url":null,"abstract":"<p>Intestinal paracellular permeability was analyzed ex vivo by incubation of tissue segments at 0°C with the fluorescent dyes FM1-43FX (FM) or TRITC-dextran 3 kDa lysine-fixable (TD3L) and confocal microscopy in (i) healthy mice and (ii) mice submitted to chronic stress or lipid diets. In the small intestine of healthy mice, FM staining was restricted to the apical surface of enterocytes but fully penetrated around Goblet cells, enteroendocrine cells, tuft cells, and apoptotic cells. The same cell types were similarly labeled in the colon when located on the tissue surface but not within the crypts. TD3L exhibited a comparable labeling pattern but also showed moderate staining of the basolateral surface of enterocytes at the tips of small intestinal villi, and also substantial penetration around colonic epithelial cells at the surface or top of crypts. The study reveals patterns of permeability likely corresponding to the “leak” pathway of paracellular transport through the intestinal epithelium, because transcellular endocytosis is blocked at 0°C. This pathway is found around specific cell populations involved in the luminal detection of food, antigens, microbes, or their secretions. These trigger immune, neural, and tissue responses that maintain intestinal homeostasis. Chronic stress induced by glucocorticoid exposure increased FITC-dextran 4 kDa permeability in vivo. Using FM, increased paracellular permeability was also detected ex vivo and selectively localized in the colon of stressed mice. A single oral administration of a lipid-rich food also increased ex vivo permeability around jejunal enterocytes. Pathophysiological increases in paracellular permeability are therefore detectable using the FM methodology.</p>","PeriodicalId":12093,"journal":{"name":"FASEB bioAdvances","volume":"8 3","pages":""},"PeriodicalIF":2.0,"publicationDate":"2026-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12963463/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147376484","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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