Frontiers in Pharmacology最新文献

{"title":"Alpha-lipoic acid alleviates oxidative stress and brain damage in patients with sevoflurane anesthesia.","authors":"Kailun Gao, Ying Wu, Yan Zhang, Pei Dang, Huanjia Xue, Teng Li, Meiyan Zhou, Liwei Wang, Yangzi Zhu","doi":"10.3389/fphar.2025.1572156","DOIUrl":"10.3389/fphar.2025.1572156","url":null,"abstract":"<p><p>Sevoflurane, the most commonly used inhalational anesthetic, may negatively impact the brain by inducing oxidative stress. This study investigated the potential protective role of alpha-lipoic acid (ALA) in mitigating sevoflurane-induced oxidative stress and brain damage. A total of 155 patients undergoing sevoflurane anesthesia for liver resection surgery were randomly assigned to receive either ALA or a placebo. Perioperative internal jugular venous blood samples were collected to measure oxidative stress markers (8-OHdG, sORP, and cORP) and brain injury biomarkers (S100β and UCH-L1). Postoperative cognitive function was also evaluated. The results demonstrated that, compared to the placebo group, the ALA group exhibited a significant reduction in 8-OHdG levels by 0.007 nmol/L (95% CI, -0.011 to -0.003; P = 0.03) 24 h after surgery, accompanied by lower sORP levels and higher cORP levels. Furthermore, postoperative levels of S100β and UCH-L1 were significantly lower in the ALA group than in the placebo group (S100β, P = 0.02; UCH-L1, P = 0.03). Additionally, oxidative stress markers were significantly correlated with brain damage 24 h after surgery. Our findings suggest that ALA significantly reduces sevoflurane-induced oxidative stress and brain damage, while also improving postoperative cognitive function, indicating its potential neuroprotective effect. <b>Clinical Trial Registration:</b> https://www.chictr.org.cn/, identifier ChiCTR2300077321.</p>","PeriodicalId":12491,"journal":{"name":"Frontiers in Pharmacology","volume":"16 ","pages":"1572156"},"PeriodicalIF":4.4,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11965138/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143779684","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":"Deciphering gene mutations in the efficacy and toxicity of antineoplastic drugs: an oncology pharmacist's perspective.","authors":"Yucai Jiang, Guolin Alexander Wen","doi":"10.3389/fphar.2025.1574010","DOIUrl":"10.3389/fphar.2025.1574010","url":null,"abstract":"<p><strong>Background/objectives: </strong>This article reviews some key emerging pharmacogenomic topics in oncology pharmacy practice.</p><p><strong>Methods: </strong>Publications selected to review were mainly sourced from the new drug approvals by the Food and Drug Administration and the new regimens listed in the National Comprehensive Cancer Network.</p><p><strong>Results: </strong>Key pharmacogenomic topics were presented, including genetic alterations influencing drug metabolism, drug efficacy, and changes in therapeutic targeting; Relevant clinical updates and advancements were summarized to provide an in-depth understanding.</p><p><strong>Conclusion: </strong>The abundance of pharmacogenomic measures builds a solid foundation and heralds a paradigm shift toward individualized patient care.</p>","PeriodicalId":12491,"journal":{"name":"Frontiers in Pharmacology","volume":"16 ","pages":"1574010"},"PeriodicalIF":4.4,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11965669/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143779691","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":"Cottonseed oil composition and its application to skin health and personal care.","authors":"Janelle Gutierrez, Slavko Komarnytsky","doi":"10.3389/fphar.2025.1559139","DOIUrl":"10.3389/fphar.2025.1559139","url":null,"abstract":"<p><p>The historical use of oils for beauty and hygiene dates back to ancient civilizations. While mineral oil and its derivatives dominated the personal care industry in the 20th century due to chemical stability and low cost, the environmental impact and sustainability concerns have driven a resurgence in the use of vegetable oils. Cottonseed oil derived from <i>Gossypium hirsutum</i> L. (<i>Malvaceae)</i> has been often overlooked in favor of other plant oils, likely due to cotton's primary use as a fiber crop. Yet cottonseed oil stands out in cosmetics for its beneficial linoleic to oleic acid ratio, which supports skin barrier function, and its rich profile of phytosterols and tocopherols that provide higher oxidative stability and extended shelf life. Cottonseed oil is also adaptable for use in a variety of formulations, offering a lightweight, non-greasy emollient base with potential applications in skin care, hair, and cleansing products. This review highlights cottonseed oil as a potentially underutilized ingredient in the personal care sector and emphasizes the need for further research and development to fully exploit its properties.</p>","PeriodicalId":12491,"journal":{"name":"Frontiers in Pharmacology","volume":"16 ","pages":"1559139"},"PeriodicalIF":4.4,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11961985/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143771884","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":"Transdermal administration of herbal essential oil alleviates high-fat diet-induced obesity by regulating metabolism and gut microbiota.","authors":"Zu-Wen Ye, Qi-Yue Yang, Dong-Hua Yang, Qiao-Hong Lin, Xiao-Xia Liu, Feng-Qin Li, Fang-Fang Yan, Ping Luo, Si Qin, Fang Wang","doi":"10.3389/fphar.2025.1565030","DOIUrl":"10.3389/fphar.2025.1565030","url":null,"abstract":"<p><strong>Introduction: </strong>Obesity, a global health challenge, is characterized by excessive fat accumulation and associated metabolic disorders. The ZhiZhu decoction, a traditional Chinese herbal formula consisting of <i>Citrus aurantium</i> L. (ZS, ZhiShi in Chinese) and <i>Atractylodes macrocephala Koidz</i> (BZ, Baizhu in Chinese), is widely recognized in clinics for its gastrointestinal regulatory effects.</p><p><strong>Methods: </strong>The chemical composition of ZS-BZ essential oil (ZBEO) was characterized using gas chromatography-mass spectrometry (GC-MS). Concurrently, we conducted <i>in vitro</i> investigations using HepG2 hepatoma cells to evaluate its anti-lipid deposition potential. To further elucidate the anti-obesity mechanisms, an <i>in vivo</i> model was established through high-fat diet (HFD)-induced obese rats, followed by transdermal ZBEO administration. Systemic analyses were performed integrating serum metabolomic profiling via UPLC-QTOF-MS and gut microbiota dynamics assessment through 16S rRNA gene sequencing.</p><p><strong>Results: </strong>ZBEO, rich in atractylon, D-limonene, and γ-elemene and shown to reduce lipid accumulation. Transdermal ZBEO administration in obese rats led to significant weight loss and improved serum metabolic indexes related to the POMC/CART signaling pathway. Additionally, ZBEO altered gut microbiota, enhancing beneficial bacteria and affecting metabolic pathways linked to obesity.</p><p><strong>Discussion: </strong>We discovered that ZBEO exerts a significant influence on obesity by modulating key biological processes, including glucose metabolism, lipid metabolism, and the composition of gut microbiota.</p>","PeriodicalId":12491,"journal":{"name":"Frontiers in Pharmacology","volume":"16 ","pages":"1565030"},"PeriodicalIF":4.4,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11962428/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143771902","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":"Effect of anti-interleukin-5 antibody on development of vasculitis in an ovalbumin-induced eosinophilic vasculitis mouse model.","authors":"Kiyoto Kageyama, Eri Kikuchi, Nao Hoshino","doi":"10.3389/fphar.2025.1546785","DOIUrl":"10.3389/fphar.2025.1546785","url":null,"abstract":"<p><strong>Background: </strong>Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare and intractable chronic disease. Glucocorticoids are the mainstay of treatment for EGPA. The drugs that target interleukin (IL)-5 signaling have also been marketed or developed in recent years. While no animal model can completely recapitulate EGPA, the ovalbumin (OVA)-induced eosinophilic vasculitis mouse model exhibits pathological similarities in the lungs. However, the effect of an anti-IL-5 drug has not yet been investigated using this model. This study used the OVA-induced eosinophilic vasculitis model to evaluate and characterize its usefulness, focusing on the effects of an anti-IL-5 antibody.</p><p><strong>Methods: </strong>Female C57BL/6NCrSlc mice were intraperitoneally immunized on days 0 and 14 with OVA adsorbed onto an aluminum gel. From days 26-32, the mice were exposed to aerosolized 1% OVA daily for 1 h. Anti-IL-5 antibody or vehicle was injected intravenously or intraperitoneally once on the first day of aerosol exposure (day 26). On day 33, the eosinophil and lymphocyte counts in the blood and bronchoalveolar lavage fluid (BALF) were measured. Lung specimens were used to assess the vascular lesions formed in the pulmonary arteries. Plasma cytokine levels were measured on day 28.</p><p><strong>Results: </strong>The anti-IL-5 antibody significantly reduced eosinophil counts in the blood and BALF. In contrast, it did not inhibit the lymphocyte counts in BALF or vascular lesion formation. The anti-IL-5 antibody significantly blocked the plasma level of IL-5 on day 28. However, the levels of other cytokines (i.e., IL-2, IL-6, tumor necrosis factor-α, granulocyte-macrophage colony-stimulating factor, interferon-γ, IL-12, IL-4, IL-13, and IL-17) were not altered.</p><p><strong>Conclusion: </strong>In the investigated model, lymphocyte infiltration in lung tissue and cytokines other than or in addition to IL-5 were suggested to have contributed to the development of vasculitis. IL-5 signaling has a potential impact on EGPA pathogenesis via a different mechanism or in addition to the mechanism demonstrated in the OVA-induced eosinophilic vasculitis mouse model. The model may be useful for drug discovery targeting both eosinophilic and non-eosinophilic aspects of EGPA pathogenesis.</p>","PeriodicalId":12491,"journal":{"name":"Frontiers in Pharmacology","volume":"16 ","pages":"1546785"},"PeriodicalIF":4.4,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11961647/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143771968","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":"Recent advances of <i>Sargassum pallidum</i> in chemical and biological aspects.","authors":"Ziqin Lei, Xiaoyan Qin, Yan Yang, Min Xu, Nan Zeng","doi":"10.3389/fphar.2025.1492671","DOIUrl":"10.3389/fphar.2025.1492671","url":null,"abstract":"<p><p><i>Sargassum pallidum</i> (Turn.) C.Ag. (SP) is a traditional Chinese marine medicinal material known for its extensive pharmacological activities and is primarily found in coastal regions. With a long history of medicinal use in China, it is commonly employed to treat conditions such as goiter, hyperplasia of mammary glands, hypertension, and obesity. Modern research on its phytochemical metabolites has identified polysaccharides, flavonoids, and lipids as the primary metabolites derived from SP, with polysaccharides being the most extensively studied. Modern pharmacological studies have demonstrated that extracts and secondary metabolites obtained from SP exert various biological activities, including antioxidant effects, antitumor properties, hypolipidemic and hypoglycemic actions, antibacterial activity, and immunomodulatory capabilities. This review aims to serve as a theoretical reference for further utilization and development of functional foods derived from marine resources like SP, summarizing relevant literature from both domestic and international sources. Despite a comprehensive overview of chemical metabolites and pharmacological properties, existing limitations suggest the need for more precise technical tools and additional toxicological and clinical studies to ensure quality, safety, and efficacy.</p>","PeriodicalId":12491,"journal":{"name":"Frontiers in Pharmacology","volume":"16 ","pages":"1492671"},"PeriodicalIF":4.4,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11961962/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143771975","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":"Teriparatide mitigates oxidative stress following spinal cord injury and enhances neurological recovery via the Nrf2/HO-1 signaling pathway.","authors":"Xiong Moliang, Ai Gangtong, Feng Yun, Luo Caiguang, Deng Liang, Guo Jia, Xiao Qiang","doi":"10.3389/fphar.2025.1538857","DOIUrl":"10.3389/fphar.2025.1538857","url":null,"abstract":"<p><strong>Introduction: </strong>Spinal Cord Injury (SCI) represents a devastating form of central nervous system trauma, where oxidative stress plays a critical role in the ensuing pathology. Targeting oxidative stress presents a viable therapeutic avenue. Teriparatide, a synthetic analog of parathyroid hormone, is conventionally utilized for osteoporosis and bone defect management. Emerging evidence suggests teriparatide's potential in modulating oxidative stress in ischemic stroke, yet its efficacy in SCI remains underexplored.</p><p><strong>Methods: </strong>We investigated the neuroprotective effects of teriparatide in a rat spinal cord injury (SCI) model. Teriparatide was administered to animals post-injury, and functional recovery was assessed using the open field test and Basso-Beattie-Bresnahan (BBB) locomotor rating scale. Molecular analyses included evaluation of Nrf2 pathway activation and antioxidant protein expression via immunofluorescence, Western blot, and ELISA. Additionally, glutathione peroxidase (GSH-PX) activity and malondialdehyde (MDA) levels were measured using commercial assay kits.</p><p><strong>Results: </strong>We obtained two significant results: Firstly, teriparatide treatment significantly enhanced motor function recovery post-SCI. Secondly, teriparatide upregulated Nrf2 expression, which subsequently increased the production of the antioxidant proteins HO-1 and SOD2, reduced MDA levels in spinal tissues, and boosted GSH-PX activity.</p><p><strong>Conclusion: </strong>Our findings demonstrate that teriparatide activates the Nrf2/HO-1 antioxidant pathway, effectively mitigating oxidative damage in SCI. This repositioning of an FDA-approved osteoporosis drug presents a clinically translatable strategy for neuroprotection.</p>","PeriodicalId":12491,"journal":{"name":"Frontiers in Pharmacology","volume":"16 ","pages":"1538857"},"PeriodicalIF":4.4,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11962027/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143771977","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":"Unravelling the antitumor mechanism of Ocoxin through cancer cell genomics.","authors":"Iera Hernandez-Unzueta, Uxue Telleria-Gonzalez, Ana María Aransay, José Ezequiel Martin Rodriguez, Eduardo Sanz, Joana Márquez","doi":"10.3389/fphar.2025.1540217","DOIUrl":"10.3389/fphar.2025.1540217","url":null,"abstract":"<p><p>Cancer is one of the leading causes of death worldwide. Many therapies are being used to treat this disease, however, new treatments are now being implemented, since they are not always effective and their secondary effects represent one of the main reasons for cancer patients' loss of life quality during the progression of the disease. In this scenario, Ocoxin is a mixture of plant extracts, amino acids, vitamins and minerals, known for its antioxidant, anti-inflammatory and immunoregulatory properties, which has shown to exert antitumor effects in many cancers. The aim of this study is to elucidate the mechanism of action of the compound in colorectal cancer, triple negative breast cancer, pancreatic cancer and prostate cancer. Analyses performed through RNA sequencing revealed that the main effect of Ocoxin appears to be the alteration of cell metabolism, especially inducing the process of ferroptosis. Nevertheless, the modulation of the cell cycle was also remarkable. Ocoxin altered 13 genes in common in all the four cancers that were not only associated to metabolism and cell cycle but were also involved in the integrated stress response and unfolded protein response, suggesting that the compound causes the induction of cell death through several pathways. Although the mechanisms vary according to the type of cancer, this study highlights the potential of Ocoxin as an adjunctive treatment to improve outcomes in cancer therapy.</p>","PeriodicalId":12491,"journal":{"name":"Frontiers in Pharmacology","volume":"16 ","pages":"1540217"},"PeriodicalIF":4.4,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11961970/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143771904","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":"Impact of statin use on short- and long-term outcomes in patients with sepsis-induced myocardial injury: insights from the MIMIC-IV database.","authors":"Yuan Liu, Jijiang Chen, Yehao Yuan, Pingping Niu, Mengyi Wu, Baoling Shang, Weihui Lu, Xu Zou, Gengzhen Yao","doi":"10.3389/fphar.2025.1520107","DOIUrl":"10.3389/fphar.2025.1520107","url":null,"abstract":"<p><strong>Background: </strong>Sepsis-induced myocardial injury (SIMI) is a critical complication of sepsis, marked by high mortality rates, and lacks effective treatments. The impact of statin therapy on mortality in SIMI patients remains unclear. This study aims to explore the association between statin use and mortality in SIMI patients, focusing on both short-term and long-term outcomes.</p><p><strong>Methods: </strong>A retrospective cohort study was conducted by extracting SIMI patient information from the Medical Information Mart for Intensive Care IV (MIMIC-IV) database. Patients were categorized into statin and non-statin groups. A 1:1 nearest propensity-score matching (PSM) was used to balance baseline characteristics. Survival outcomes were assessed using Kaplan-Meier analysis and robust Cox proportional hazards models to understand the effects of statin use, type and dosage on mortality at 28 days, 90 days, and 1 year. E-Value analysis was used for unmeasured confounding.</p><p><strong>Results: </strong>A total of 2,246 patients meeting SIMI criteria were enrolled in the final cohort, with 17.9% receiving statins during their ICU stay. Statin use was associated with significantly lower mortality at all time points, as shown by Kaplan-Meier analysis. In multivariable robust Cox regression models, statin therapy correlated with a 32% reduction in 28-day mortality (HR = 0.68, 95% CI: 0.49-0.94), a 29% reduction at 90 days (HR = 0.71, 95% CI: 0.54-0.93), and a 28% reduction at 1 year (HR = 0.72, 95% CI: 0.58-0.90), maintaining significance after adjustment for confounders. Simvastatin was particularly effective, and low-dose statins were linked to reduced mortality risk. Subgroup analyses suggested consistent statin benefits. E-Value analysis suggested robustness to unmeasured confounding.</p><p><strong>Conclusion: </strong>Our study demonstrates that statin use is significantly associated with reduced mortality in SIMI patients across 28 days, 90 days, and 1 year. Simvastatin provides substantial benefits, with low-dose statins providing greater advantages compared to high-dose formulations.</p>","PeriodicalId":12491,"journal":{"name":"Frontiers in Pharmacology","volume":"16 ","pages":"1520107"},"PeriodicalIF":4.4,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11962036/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143771777","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":"Sex differences in metabolic regulation by Gi/o-coupled receptor modulation of exocytosis.","authors":"Montana Young, Ryan P Ceddia, Analisa Thompson-Gray, David Reyes, Jackson B Cassada, Julio E Ayala, Owen P McGuinness, Sheila Collins, Heidi E Hamm","doi":"10.3389/fphar.2025.1544456","DOIUrl":"10.3389/fphar.2025.1544456","url":null,"abstract":"<p><strong>Background: </strong>Presynaptic G_i/o coupled GPCRs can act as negative feedback regulators of neurotransmitter release via Gβγ effector modulation through two mechanisms: decreased calcium influx and direct inhibition of membrane fusion by soluble N-ethylmaleimide-sensitive factor attachment protein (SNAP) receptor (SNARE). Previously, we discovered that truncation of the last three C-terminal amino acids of SNAP25 (SNAP25Δ3) prevents Gβγ-SNARE interaction, effectively removing the braking mechanism on neurotransmitter release. We have demonstrated enhanced metabolic protection in male SNAP25^Δ3/Δ3 mice housed at room temperature (22°C), including increased adipose tissue beiging and glucose uptake and enhanced insulin sensitivity, rendering them resistant to diet-induced obesity (DIO). When male SNAP25^Δ3/Δ3 mice were housed at thermoneutrality (30°C), all metabolic protection was abolished, suggesting sympathetic tone is important for the phenotypes.</p><p><strong>Methods: </strong>We housed male and female mice at either standard room temperature (21°C) or at thermoneutrality (30°C) and fed them a high fat diet (HFD) for 8 weeks. Glucose tolerance tests were performed before and after the 8 weeks of HFD along with body composition analyses. Organs were then dissected for mass analysis as well as immunohistochemistry. Additionally, we ovariectomized female mice to investigate the role of sex hormones in our phenotypes. Finally, we housed mice in Sable Promethion chambers at various environmental temperatures to investigate the effect of environmental temperature on basal metabolic rates.</p><p><strong>Results: </strong>We found SNAP25^Δ3/Δ3 female mice exhibited the same metabolic protection at RT (22°C) and displayed enhanced metabolic protection from DIO compared to standard chow just as males did. However, female SNAP25^Δ3/Δ3 mice display persistent metabolic protection even when housed at thermoneutrality. In this study, we investigate the mechanisms behind this sex dependent persistent phenotype. Thermoneutral set point did not differ between sexes nor genotype, suggesting that metabolic protection is not due to a difference in hypothalamic temperature regulation. Metabolic protection in SNAP25^Δ3/Δ3 persisted in ovariectomized mice despite increased weight gain compared to mice receiving sham operations.</p><p><strong>Conclusion: </strong>This study has identified that there is not a sex-dependent difference for thermoneutral set point in mice. Additionally, there is a sex hormone independent mechanism driving the persistent metabolic protection of female SNAP25^Δ3/Δ3 mice housed in thermoneutrality.</p>","PeriodicalId":12491,"journal":{"name":"Frontiers in Pharmacology","volume":"16 ","pages":"1544456"},"PeriodicalIF":4.4,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11962901/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143771976","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}