Clinical science最新文献

{"title":"Impact of the natural female reproductive aging on the rat serum lipidome.","authors":"Julio Baudin, Anna Antolín, Salvador Fernández-Arroyo, Antoni Del Pino, Francisca Mulero, Francesc Puiggròs, Lluís Arola, Antoni Caimari","doi":"10.1042/CS20255841","DOIUrl":"10.1042/CS20255841","url":null,"abstract":"<p><p>Perimenopause is a transitional phase leading to female reproductive senescence, which can cause vasomotor symptoms and increase the risk of osteoporosis, obesity, and metabolic-related disturbances in middle-aged and older women. Nevertheless, little is known regarding the underlying mechanisms linked to menopausal transition, which could be of great value in designing new interventions addressed to improve the health of both perimenopausal and postmenopausal women. We used an ovarian-intact middle-aged model of rats resembling the characteristics of human perimenopause and applied liquid and gas chromatography quadrupole time-of-flight mass spectrometry approaches for the determination of polar and lipid-related metabolites to identify characteristic circulating signatures across perimenopause. The gradual loss of regularity in the estrous cycle occurring during the natural transition to reproductive senescence was associated with altered circulating levels of estradiol, progesterone, and luteinizing hormone (LH) and, in rats that were in an acyclic state, with ovary atrophy and with a lack of stromal luteinization and corpus luteum. These results were accompanied by progressively significant changes in the 144 lipid-related metabolites detected in serum as the estrous cycles were losing regularity. Furthermore, we identified 18 lipid-related metabolites-including 9 phosphatidylcholines, 4 lysophosphatidylcholines, 2 phosphatidylethanolamines, cholesterol ester (18:2), 5α-androstane-3,17-diol, and 17,18-dihydroxyarachidonic acid-that already changed with the transition from a regular to an irregular estrous cycle and anticipated the changes in blood progesterone, LH, and cholesterol levels that occurred in acyclic rats. These metabolites could be used as a potential multivariate biomarker of early perimenopause. The translational applicability of these findings deserves further research.</p>","PeriodicalId":10475,"journal":{"name":"Clinical science","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144945291","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"T cell knockout attenuates HFD-induced increases in blood pressure in female and male Dahl rats.","authors":"Lindsey A Ramirez, Elizabeth Snyder, Riyaz Mohamed, Justine M Abais-Battad, Hannah R Godley-Boswell, John Henry Dasinger, David L Mattson, Mike W Brands, Babak Baban, Ahmed Elmarakby, Michael J Ryan, Jennifer C Sullivan","doi":"10.1042/CS20257273","DOIUrl":"10.1042/CS20257273","url":null,"abstract":"<p><p>Increased body weight is associated with a higher incidence of hypertension in humans. Pre-clinical evidence shows that a high-fat diet (HFD) promotes hypertension. While T cells have been implicated in hypertension, the contribution of T cells to HFD-induced increases in blood pressure (BP) remains unknown. We tested the hypothesis that T cells mediate HFD-induced increases in BP in female and male Dahl rats. Female and male wildtype (WT) Dahl rats were randomized to a normal-fat diet (0.16% kcal from fat) or HFD (59% kcal from fat) from 5 to 15 weeks of age. Aortic and renal T cells were measured by flow cytometry. Additional female and male WT and CD247 (CD3ζ-chain) knockout (KO) Dahl rats were placed on a HFD from 5 to 15 weeks of age. Body weight and fat and lean mass were measured throughout, and BP was measured by telemetry throughout the last five weeks of treatment. At 15 weeks of age, rats were euthanized, and adipose tissues were weighed. HFD increased pro-inflammatory T cells and decreased anti-inflammatory T regulatory cells in the aorta and kidney in both sexes, indicating an increase in the pro-inflammatory status. HFD increased BP comparably in females and males, and the change in BP in response to HFD was blunted in CD247 KO rats of both sexes. The lower BP in CD247 KO rats was independent of changes in body weight or total fat mass. Our findings suggest that T cells contribute to HFD-induced hypertension in both sexes independent of changes in adiposity.</p>","PeriodicalId":10475,"journal":{"name":"Clinical science","volume":" ","pages":"941-954"},"PeriodicalIF":7.7,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144854793","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction: Elevated phenylacetylglutamine caused by gut dysbiosis associated with type 2 diabetes increases neutrophil extracellular traps formation and exacerbates brain infarction.","authors":"","doi":"10.1042/CS20242943_COR","DOIUrl":"https://doi.org/10.1042/CS20242943_COR","url":null,"abstract":"","PeriodicalId":10475,"journal":{"name":"Clinical science","volume":"139 17","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144991646","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"FAP deficiency attenuates T2DM-associated HFpEF by suppressing the CaMKIIδ-Calcineurin A-NFATc2 signaling pathway.","authors":"Chao Li, Xiao Han, Jia-Kang He, Sheng-Xing Tang, Yun-Long Zhang, Xiao-Hong Yu, Lian-Jun Gao","doi":"10.1042/CS20256808","DOIUrl":"10.1042/CS20256808","url":null,"abstract":"<p><p>Heart failure with preserved ejection fraction (HFpEF) represents the initial phase of cardiac dysfunction associated with type 2 diabetes mellitus (T2DM). To date, the pathophysiological mechanisms underlying T2DM-induced HFpEF are complex and elusive. Fibroblast activation protein (FAP) is a prolyl-specific serine protease whose inhibition or vaccination has been shown to enhance cardiac repair following myocardial infarction (MI). However, the role and underlying molecular mechanisms by which abnormal FAP activity promotes the development of T2DM-induced HFpEF remain to be elucidated. In this study, the plasma activity and level of FAP were significantly higher in the T2DM with HFpEF group compared with the healthy control group. Moreover, plasma FAP activity and level were positively correlated with the likelihood of T2DM with HFpEF. To investigate the mechanistic involvement of FAP in the development of T2DM-associated HFpEF, a chronic T2DM mouse model was established. The results revealed that FAP knockout (KO) significantly improved B-type natriuretic peptide (BNP) level and E/A ratios compared with the wildtype (WT) T2DM group. Additionally, FAP KO and FAP inhibitor Talabostat alleviated myocardial inflammation, fibrosis, cardiomyocyte apoptosis, oxidative stress, and energy metabolism dysfunction. Mechanistically, an abnormal increase in FAP triggered the calmodulin-dependent protein kinase δ (CaMKIIδ)-Calcineurin A-NFATc2 signaling pathway, leading to the aforementioned pathological changes in T2DM-induced HFpEF. In contrast, FAP KO suppressed the CaMKIIδ-Calcineurin A-NFATc2 signaling pathway and attenuated these pathological changes. Overall, these findings suggest that FAP may serve as a critical therapeutic target for T2DM-induced HFpEF.</p>","PeriodicalId":10475,"journal":{"name":"Clinical science","volume":" ","pages":"923-940"},"PeriodicalIF":7.7,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144944941","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Serpina3c deficiency promotes obesity-related hypertriglyceridemia and inflammation through activation of the Hif1α-glycolysis axis in adipose tissue.","authors":"Jiaqi Guo, Zhenjun Ji, Yu Jiang, Ya Wu, Shaofan Wang, Peng Zheng, Mengchen Yang, Yongjun Li, Genshan Ma, Yuyu Yao","doi":"10.1042/CS20242610","DOIUrl":"10.1042/CS20242610","url":null,"abstract":"<p><p>Adipose tissue dysfunction leads to abnormal lipid metabolism and high inflammation levels. This research aims to explore the role of Serpina3c, which is highly expressed in adipocytes, in obesity-related hypertriglyceridemia and metaflammation. Serpina3c global knockout (KO) mice, adipocyte-specific Serpina3c overexpressing mice, Serpina3c knockdown (KD) mice, and hypoxia-inducible factor 1 alpha (Hif1α) KD mice were fed a high-fat diet (HFD) for 16 weeks to generate obesity-related hypertriglyceridemia mice models. In the present study, Serpina3c KO mice and adipocyte-specific Serpina3c KD mice exhibited more severe obesity-related hypertriglyceridemia and metaflammation under HFD conditions. Serpina3c KO epididymal white adipose tissue (eWAT) primary stromal vascular fraction (SVF)-derived adipocytes exhibited higher lipid (triglyceride and non-esterified fatty acid) levels and higher fatty acid synthase expression after palmitic acid (PA) stimulation. Adipocyte-specific Serpina3c overexpression in KO mice prevented the KO group phenotype. The RNA-seq and in vitro validation revealed that Hif1α and the glycolysis pathways were up-regulated in Serpina3c KD adipocytes, which were all validated by in vitro and in vivo reverse experiments. Co-immunoprecipitation (co-IP) provided evidence that Serpina3c bound nuclear factor erythroid 2-related factor 2 (Nrf2) regulates Hif1α. Nrf2 KD reduced Hif1α and Fasn expression, decreased lipid content, and reduced the extracellular acidification rate in Serpina3c KO adipocytes. Metabolomics revealed that lactic acid (LD) levels in eWAT were responsible for adipose-associated macrophage inflammation. In summary, Serpina3c inhibits the Hif1α-glycolysis pathway and reduces de novo lipogenesis (DNL) and LD secretion in adipocytes by binding to Nrf2, thereby improving HFD-induced lipid metabolism disorders and alleviating adipose tissue macrophage inflammation.</p>","PeriodicalId":10475,"journal":{"name":"Clinical science","volume":" ","pages":"897-918"},"PeriodicalIF":7.7,"publicationDate":"2025-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12493168/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142853148","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":"Chemokine receptors in vascular biology: a review of current evidence, implications, and therapeutic targets for hypertension.","authors":"Luis Henrique Oliveira de Moraes, Tyler Beling, Gustavo Felix Pimenta, Thiago Bruder-Nascimento","doi":"10.1042/CS20257214","DOIUrl":"10.1042/CS20257214","url":null,"abstract":"<p><p>Cardiovascular diseases (CVDs) remain the leading cause of death worldwide, including in the United States. Risk factors such as high cholesterol, diabetes, obesity, smoking, physical inactivity, and hypertension contribute significantly to their development. Emerging evidence highlights a central role for chemokines-small signaling molecules that guide immune cell migration to sites of infection, inflammation, or tissue damage-in the initiation and progression of hypertension. This positions chemokines and their receptors as promising pharmacological targets for blood pressure regulation and vascular protection. In this review, we explore the therapeutic potential of targeting chemokines and their receptors and summarize the main strategies reported in the literature for managing hypertension through these pathways. For this purpose, an analysis of drugs that act on the most relevant receptors at the preclinical and clinical levels was performed. After this analysis, their mechanisms of action, selectivity, and possible adverse effects were discussed. In conclusion, we reinforce that the modulation of chemokines and their receptors represents a promising approach in the control of CVDs, especially hypertension, although further clinical studies are needed to validate the efficacy and safety of this strategy, considering possible impacts on other essential immune responses.</p>","PeriodicalId":10475,"journal":{"name":"Clinical science","volume":"139 16","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12493178/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144945402","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":"YTHDF2 regulates ACSL4-dependent ferroptosis of keratinocytes in diabetic wound healing.","authors":"Liangyan Wu, Lanlan Li, Wei Wang, Sifan Chen, Phei Er Saw, Xiaosi Hong, Diefei Liang, Chen Yang, Li Yan, Wei-Jye Lin, Meng Ren","doi":"10.1042/CS20255877","DOIUrl":"10.1042/CS20255877","url":null,"abstract":"<p><p>Delayed diabetic wound healing is a global health issue with unclear pathogenesis. Ferroptosis, a form of cell death involving iron and lipid peroxidation, may contribute to delayed diabetic wound. This study investigates the role of ferroptosis in diabetic wound keratinocytes. We measured lipid peroxidation products (MDA, 4-HNE), ACSL4, and GPX4 protein levels in diabetic keratinocytes and assessed mitochondrial morphology. Ferrostatin-1 (Fer-1) was used to inhibit ferroptosis in diabetic rat wounds, and its effects on healing and expression levels were evaluated. Pull-down assays, silver staining, and mass spectrometry were employed to study ACSL4 mRNA regulation. A YTHDF2 knockdown adenovirus was used to manipulate YTHDF2 expression in rat wounds. Ferroptosis was detected in diabetic keratinocytes, hindering wound healing, a process reversible with Fer-1. High glucose induced ACSL4 expression, driving keratinocyte ferroptosis and delayed healing. YTHDF2 interacts with N6-methyladenosine-modified ACSL4 mRNA, affecting its stability and expression. YTHDF2 knockdown increased ACSL4, promoting ferroptosis and impairing healing. Our findings illustrate the significant involvement of ferroptosis in the dysfunction of diabetic keratinocytes, suggesting that targeting ferroptosis may offer a viable therapeutic approach for improving diabetic wound healing.</p>","PeriodicalId":10475,"journal":{"name":"Clinical science","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12493160/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144815936","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 metformin in a novel experimental model of peripheral artery disease.","authors":"Smriti Murali Krishna, Joseph Moxon, Ann-Katrin Kraeuter, Jonathan Golledge","doi":"10.1042/CS20243343","DOIUrl":"10.1042/CS20243343","url":null,"abstract":"<p><p>Limited drug therapies for peripheral artery disease (PAD)-related walking impairment exist. There has been a recent interest in repurposing the diabetes medication metformin to treat PAD. Animal studies designed to develop new PAD drug therapies have mainly used a model of temporary hind limb ischaemia (HLI). The aim of this study was to test whether metformin improved blood supply and ambulation in a novel mouse model with ongoing HLI. Stable HLI was created in apolipoprotein E-deficient mice by a two-stage surgical procedure. Five days after HLI was induced, mice were randomly allocated to receive metformin (n = 16; 300 mg/kg/day) or vehicle control (n = 15) by oral gavage for four weeks. The primary outcome was hind limb blood supply assessed by laser Doppler. Other outcomes included treadmill performance and molecular changes in the ischaemic limb. Metformin improved hind limb blood supply (P<0.001), but not physical performance, associated with increased phosphorylation of 5' adenosine monophosphate-activated protein kinase and endothelial nitric oxide synthase (P<0.05), reduced expression of thioredoxin interacting protein (P<0.05) and increased expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (P<0.05) in the ischaemic muscles and increased circulating nitric oxide levels (P<0.05). Metformin improved blood supply in a novel model of limb ischaemia associated with molecular changes previously linked with promoting angiogenesis, but these changes did not translate to improved physical performance. The findings suggest that laser Doppler hind limb blood supply may not be an ideal outcome measure to gauge the success of a drug in patients with PAD-related walking impairment.</p>","PeriodicalId":10475,"journal":{"name":"Clinical science","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12493163/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143985948","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":"Retraction: Targeting mitochondria to protect the heart: a matter of balance?","authors":"","doi":"10.1042/CS20200236_RET","DOIUrl":"10.1042/CS20200236_RET","url":null,"abstract":"","PeriodicalId":10475,"journal":{"name":"Clinical science","volume":"139 15","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12493165/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144834376","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":"The death of a myth: Females are not resistant to acute kidney injury.","authors":"Brian Soto Miranda, Carmen De Miguel","doi":"10.1042/CS20257005","DOIUrl":"10.1042/CS20257005","url":null,"abstract":"<p><p>There is an important gap of knowledge regarding the mechanisms behind the greater prevalence of chronic kidney disease (CKD) in females compared with males. Most of the published reports suggest that females are protected from acute kidney injury (AKI) and from the AKI-to-CKD transition; however, in this issue of Clinical Science, Moronge et al. demonstrate that female rats present with subclinical markers of kidney damage post-ischemic reperfusion injury despite normalized levels of plasma creatinine. These studies underscore the potential for this AKI-induced subclinical injury to underlie the higher sensitivity of females to develop CKD later in life.</p>","PeriodicalId":10475,"journal":{"name":"Clinical science","volume":"139 15","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12493162/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144834377","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}