Clinical science最新文献

{"title":"Deficiency of mineralocorticoid receptor signalling in myeloid cells protects cardiac and kidney function in hypertensive diabetic mice.","authors":"Gregory H Tesch, Elyce Ozols, James Morgan, Morag J Young, David J Nikolic-Paterson","doi":"10.1042/CS20256132","DOIUrl":"10.1042/CS20256132","url":null,"abstract":"<p><p>Mineralocorticoid receptor antagonists (MRAs) reduce hypertension, inflammation and tissue injury in human and experimental diabetes. Inflammation and injury in diabetic hearts and kidneys is also dependent on infiltrating macrophages. Therefore, we hypothesised that the tissue protective effects of MRAs in diabetes are dependent on mineralocorticoid receptor (MR) signalling in macrophages. To evaluate this hypothesis, transgenic mice with intact myeloid MR (MRflox/flox) or myeloid MR deficiency (MRflox/flox LysMCre) were developed on the hypertensive endothelial nitric oxide synthase deficient (Nos3-/-) mouse strain. Groups of these mice were made diabetic with streptozotocin and were assessed after 15 weeks for development of hypertension, cardiomyopathy and nephropathy. Nos3-/- mice with myeloid MR deficiency had equivalent diabetes and hypertension as myeloid MR intact controls but were protected against cardiac and renal function impairment. In diabetic hearts, myeloid MR deficiency reduced cardiomyocyte hypertrophy, capillary loss and fibrosis in association with reduced macrophage accumulation and a switch from an M1 to an M2 macrophage phenotype. In diabetic kidneys, myeloid MR deficiency reduced renal dysfunction (elevated plasma cystatin C) but did not protect against albuminuria, glomerulosclerosis or tubular damage; this was associated with a partial reduction in glomerular macrophages and an M1 to M2 macrophage phenotype switch. Therefore, MR signalling in macrophages promotes dysfunction in the diabetic heart and kidneys of Nos3-/- mice without affecting hypertension. Furthermore, abolishing macrophage MR signalling provides greater protection to hearts than kidneys during type 1 diabetes and hypertension, giving new insight into the mechanisms by which MRAs suppress tissue injury during diabetes.</p>","PeriodicalId":10475,"journal":{"name":"Clinical science","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12794314/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145660558","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":"Molecular drivers of osteogenesis imperfecta: a cellular and extracellular collagen disease.","authors":"Silvia Cotti, Wendy Pérez Franco, Antonella Forlino","doi":"10.1042/CS20255642","DOIUrl":"10.1042/CS20255642","url":null,"abstract":"<p><p>The clinical hallmarks of osteogenesis imperfecta (OI), often referred to as 'brittle-bone disease', are bone fragility and skeletal deformities that are usually accompanied by extra skeletal manifestations. OI is a family of collagen I-related disorders, currently classified into 23 distinct types and 5 OI-like forms, with variable phenotypic severity ranging from mild to lethal. At the molecular level, the pathophysiology of OI is driven by alterations in collagen I structure, primarily caused by dominant mutations in collagen genes (affecting approximately 85% of patients). It can also result from dominant, recessive, or X-linked defects in proteins involved in collagen biosynthesis, extracellular matrix organization, mineralization, or bone forming cell differentiation and/or activity. This review illustrates the different OI forms from a collagen I perspective, its complex biosynthetic process is first described, followed by a classification of the OI and OI-like causative mutations grouped based on whether the resulting collagen molecule is overmodified, undermodified, or unaltered. The underlying molecular mechanisms and the consequences at cellular and extracellular levels leading to the OI phenotype are discussed. An overview is provided on how newly discovered molecular pathways altered in OI can guide the development of innovative therapies aiming at increasing bone mass and improving bone quality in OI patients.</p>","PeriodicalId":10475,"journal":{"name":"Clinical science","volume":"139 24","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12794382/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145773857","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":"Lauryl gallate promotes platelet activation and thrombus formation: a promising application to stop bleeding.","authors":"Basma Hadjkacem, Cédric Garcia, Jennifer Series, Véronique Pons, Asma Mahmoudi, Céline Gales, Sophie Voisin, Agnès Ribes, Marie-Pierre Gratacap, Ali Gargouri, Bernard Payrastre","doi":"10.1042/CS20257213","DOIUrl":"10.1042/CS20257213","url":null,"abstract":"<p><p>Lauryl gallate (LG, E312) is an antioxidant with hydrophobic properties that contribute to its activity by increasing affinity for membranes and acting on the lipid phase transition and likely the lateral membrane organization. Here, we show that LG at a low concentration has the ability to spontaneously induce washed human platelet shape change, filopodia emission, granule secretion, and aggregation. LG was able to activate intracellular signaling pathways, including Akt, p38MAP kinase, inositol phosphate, and calcium responses, as well as to trigger cyclic adenosine monophosphate decrease and αIIbβ3 integrin activation. LG significantly potentiated platelet aggregation induced by low concentrations of agonists, and the addition of low doses of LG to human blood strongly increased the platelet thrombotic response under arterial flow on a collagen matrix. Morphological analysis by scanning electron microscopy indicated that contrary to low doses, high concentrations of LG induced dramatic platelet membrane modifications associated with calcium influx, lactate dehydrogenase leakage, and a slow platelet aggregation response. Interestingly, a local flash application of LG efficiently decreased the tail bleeding time in rats. LG action was rapid and significantly more efficient than tranexamic acid, an antifibrinolytic agent, pointing to its hemostatic potential. Overall, our results indicate that LG, likely through its capacity to modify membrane lateral organization, has important pro-aggregant and antihemorrhagic properties.</p>","PeriodicalId":10475,"journal":{"name":"Clinical science","volume":"139 24","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12794321/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145773794","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":"HDL protein composition differs between young white European and South Asian men before and after weight gain.","authors":"Jack D Beazer, James McLaren, Christina Christoffersen, Maria J Ferraz, Monique T Mulder, Delyth Graham, Helen Karlsson, Stefan A Ljunggren, Jason M R Gill, Dilys J Freeman","doi":"10.1042/CS20258040","DOIUrl":"10.1042/CS20258040","url":null,"abstract":"<p><p>South Asians (SAs) in the UK are at an increased risk of cardiovascular disease (CVD), develop type 2 diabetes mellitus at a lower age and body mass index, and have a lower high-density lipoprotein cholesterol (HDL-C) concentration than their white European (EU) counterparts. The failure of HDL-C raising therapies for CVD risk reduction has turned attention to its composition and function. A previous study comparing the effect of moderate weight gain on SA and EU men found baseline and weight gain-induced ethnic differences in body composition, adipocyte function and insulin resistance (ClinicalTrials.gov registration: NCT02399423). This study investigated differences in HDL protein composition, subclass distribution and in vitro vascular functions at baseline and after weight gain in the same cohort of men. HDL protein composition was determined by nano liquid chromatography tandem mass spectrometry using label-free quantification. HDL subclass distribution was measured by native gel electrophoresis. HDL in vitro paraoxonase-1 (PON-1) activity was measured by monitoring the PON-1 mediated hydrolysis of phenylacetate. In vitro HDL anti-inflammatory function was assessed in an endothelial cell assay of adhesion molecule inhibition. SAs had higher levels of immunity- and inflammation-related proteins and a detrimental profile of lipid metabolism-related proteins at baseline and with weight gain (including lower apolipoprotein (apo) A-IV and apoF and higher apoC-III) compared with EU. HDL subclass distribution and in vitro vascular function were not different between EUs and SAs. HDL protein composition reflects systemic physiology and acts as a mechanistic marker of impaired lipid metabolism in SAs.</p>","PeriodicalId":10475,"journal":{"name":"Clinical science","volume":"139 24","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12794315/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145793678","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":"Blood pressure reduction and anti-inflammatory macrophage augmentation attenuate uterine immune dysregulation and inflammation in mice with salt-sensitive hypertension.","authors":"Shobana Navaneethabalakrishnan, Bethany L Goodlett, Hannah L Smith, Alyssa Cardenas, Robert A Montalvo Ii, Gabriella C Peterson, Brett M Mitchell","doi":"10.1042/CS20255879","DOIUrl":"10.1042/CS20255879","url":null,"abstract":"<p><p>Salt-sensitive hypertension (SSHTN) promotes systemic inflammation, pro-inflammatory immune cell infiltration, and end-organ damage, including in the kidneys and gonads. However, its impact on uterine immune cell populations remains unclear. We hypothesized that SSHTN alters immune cell homeostasis, induces inflammation, and promotes lymphangiogenesis in the uterus, and that these effects can be mitigated by pharmacological blood pressure (BP) reduction and anti-inflammatory macrophage augmentation. To test the hypothesis, female C57BL6/J mice were given nitro-L-arginine methyl ester hydrochloride (0.5 mg/ml) in drinking water for 2 weeks, followed by a 2-week washout period. Mice were then subjected to a 4% high-salt diet (SSHTN) for 3 weeks. Another group of mice received either hydralazine (HYD; 250 mg/l in drinking water), a vasodilator (SSHTN+HYD), or AVE0991 (AVE; 0.58 µmol/kg body weight/day), a nonpeptide Mas receptor agonist, through daily intraperitoneal injections (SSHTN+AVE). Control mice received tap water and a standard diet for the entire treatment period. Flow cytometry data revealed a significant decrease in total uterine CD45+ immune cells, along with an increase in tissue macrophages, in all SSHTN groups compared with the control group. SSHTN mice had increased uterine pro-inflammatory macrophages, dendritic cells, natural killer cells, and CD4+ pro-inflammatory T cells, all of which were mitigated by HYD and AVE treatments. SSHTN promoted uterine inflammation, lymphatic vessel expansion, and altered hormone receptor expression, which were mitigated by pharmacological intervention, highlighting their therapeutic potential in preserving uterine homeostasis and improving reproductive health in women with SSHTN.</p>","PeriodicalId":10475,"journal":{"name":"Clinical science","volume":" ","pages":"1629-1642"},"PeriodicalIF":7.7,"publicationDate":"2025-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12751045/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145238094","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":"Targeting mitochondria to protect the heart: a matter of balance?","authors":"Fouad A Zouein, George W Booz","doi":"10.1042/CS20258287","DOIUrl":"10.1042/CS20258287","url":null,"abstract":"<p><p>Mitochondria are dynamic, undergoing both fission and fusion. Evidence indicates that a balance between these two processes is necessary to maintain a healthy state. With ischemia/reperfusion (I/R) of the heart, fission is enhanced and is associated with mitochondrial swelling, depolarization, and production of reactive oxygen species, as well as apoptosis. Accumulating evidence indicates that blocking fission is effective in reducing I/R-induced tissue damage and contractile dysfunction. In theory, enhancing fusion should also serve to prevent I/R-related heart damage. In this perspective article, we present evidence from preclinical studies over the last several years supporting the conclusion that targeting mitochondrial dynamics is a promising pharmacological strategy to protect the heart. Such an approach has great value in limiting heart damage from not only myocardial infarction but also medical interventional reperfusion, alcohol consumption, chemotherapy, and sepsis.</p>","PeriodicalId":10475,"journal":{"name":"Clinical science","volume":"139 23","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12751048/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145707693","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":"Incretin receptor agonism during pregnancy: implications for mother and baby.","authors":"Laura Dearden, Susan E Ozanne","doi":"10.1042/CS20258493","DOIUrl":"10.1042/CS20258493","url":null,"abstract":"<p><p>Obesity has been described by the WHO as the largest health threat facing mankind. More than 55% of pregnancies in the United Kingdom occur in women who are overweight or living with obesity. Obesity in pregnancy increases the risk of developing gestational diabetes mellitus (GDM), a condition that affects one in seven pregnancies globally and is associated with short- and long-term risks for both mother and baby. Therefore, optimising treatment to effectively treat both obesity and GDM in the perinatal period could have wide-ranging benefits for mother and child. Stabilised analogues of glucagon-like peptide-1 (GLP-1) have revolutionised the treatment of metabolic disease and obesity as they promote weight loss and lower blood glucose. However, the wider action of these analogues, especially in the context of pregnancy, is underexplored. In the United States, the number of young female users of GLP-1 receptor agonists (GLP1RAs), such as Ozempic (semaglutide), increased 659% between 2020 and 2023. Ozempic is not currently licensed for use in pregnancy; however, increased semaglutide use in women of reproductive age has resulted in a rise in 'Ozempic babies', when women have unplanned pregnancies while using semaglutide. The potential for GLP1RA use prior to or during pregnancy to limit the transmission of obesity risk between mothers with obesity and their offspring by lowering maternal body weight or correcting maternal glycemia has not been explored. Rodent studies suggest that GLP1RA administration to the dam in pregnancy alters fetal growth, and GLP1RA administration directly to neonates alters development of the hypothalamus. However, recent emerging case reports of human pregnancies where exposure to GLP1RAs has occurred through unplanned pregnancies suggest no harm to the fetus. Given both the potential for GLP1RAs to improve health outcomes in pregnant women with obesity and GDM, and the rapidly rising incidence of fetal exposure, we review the current literature base on the effects of semaglutide use in pregnancy on maternal and offspring health and explore potential broader impacts of use of these agents during the perinatal period based on their known site of action.</p>","PeriodicalId":10475,"journal":{"name":"Clinical science","volume":"139 23","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12794308/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145707737","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":"Caspase-1 inhibition mitigates neonatal hyperoxia-induced vascular and cardiopulmonary inflammation in neonatal rats.","authors":"Astrid H León Silva, Runxia Tian, Sydne Ballengee, Aden Jamal, Swathi Menon, Shreeya V Chalikonda, Roberta M Lassance-Soares, April Tan, Joanne Duara, Augusto Schmidt, Karen Young, Shu Wu, Noel Ziebarth, Merline Benny","doi":"10.1042/CS20242275","DOIUrl":"10.1042/CS20242275","url":null,"abstract":"<p><p>There is a fundamental knowledge gap regarding the effects of neonatal hyperoxia exposure on the systemic vasculature and its repercussions on the cardiopulmonary system. Neonatal hyperoxia exposure induces a pro-inflammatory profile. However, the role of inflammation in the developing vascular tree and cardiopulmonary system is poorly understood. Caspase-1 mediates activation of inflammatory cytokines (IL-1β and IL-18) and gasdermin D (GSDMD), causing pyroptosis and inflammation. We hypothesized that caspase-1 is a critical contributor in neonatal hyperoxia-induced systemic vascular and cardiopulmonary inflammation and that caspase-1 inhibition attenuates hyperoxia-induced vascular stiffness, cardiopulmonary inflammation, and bronchopulmonary dysplasia (BPD) phenotype in a neonatal rat model. Newborn rats randomized to room air (RA) or hyperoxia (85% O2) from postnatal day (P) 1 to 14 received caspase-1 inhibitor, VX-765, or placebo. Hyperoxia-exposed pups had increased cardiovascular inflammation and fibrosis, aortic stiffness, pulmonary vascular rarefaction and remodeling, alveolar simplification, and right ventricular hypertrophy. Administration of a caspase-1 inhibitor decreased IL-1β and GSDMD gene and protein expression in the aorta and left ventricle. This was accompanied by reduced aortic stiffness and cardiac fibrosis, improved alveolar structure, pulmonary vascular density and vascular remodeling, and attenuation of right ventricular hypertrophy. Together, our findings suggest that inhibition of the caspase-1 pathway leads to decreased cardiopulmonary inflammation and remodeling. In conclusion, targeting caspase-1 signaling may be a therapeutic strategy to prevent the consequences of vascular and cardiopulmonary inflammation associated with preterm birth and oxygen therapy.</p>","PeriodicalId":10475,"journal":{"name":"Clinical science","volume":" ","pages":"1611-1627"},"PeriodicalIF":7.7,"publicationDate":"2025-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12751044/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145502467","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":"Nanoparticle-mediated overexpression of RacGAP1 protects against renal ischemia/reperfusion injury by maintaining mitochondrial homeostasis.","authors":"Weiran Zhou, Shiqiang Tong, Jinbo Yu, Jun Chen, Yi Fang, Yuxin Nie, Yiqin Shi, Nana Song, Xuesen Cao, Xiaoqiang Ding, Shuan Zhao","doi":"10.1042/CS20256110","DOIUrl":"10.1042/CS20256110","url":null,"abstract":"<p><p>Acute kidney injury (AKI) is recognized as a critical clinical problem, and pharmacological therapeutic options for AKI remain limited. Our previous study confirmed that Rac GTPase-activating protein 1 (RacGAP1) effectively promoted the repair of tubular epithelial cells in vitro. Further investigation is needed to determine whether boosting the expression of RacGAP1 in vivo helps protect against AKI. Herein, lipid-coated calcium phosphate (LCP) nanoparticles loaded with RacGAP1 plasmids (pRacGAP1-LCP) were generated and subsequently characterized based on their size, zeta potential, and morphological features. Animal models of AKI induced by ischemia/reperfusion (I/R) injury (IRI) were established in C57BL/6 mice, and pRacGAP1-LCP was injected into the tail vein to explore the role of RacGAP1 on renal IRI in vivo. The therapeutic efficacy of pRacGAP1-LCP against IRI was assessed through western blotting, real-time PCR, and histological analyses. The effects of RacGAP1 on mitochondrial homeostasis were further examined in mouse renal tubular epithelial cells (mRTECs). Serial administrations of pRacGAP1-LCP led to a significant increase in RacGAP1 expression in murine kidneys. This therapeutic intervention effectively attenuated AKI, as evidenced by down-regulation of AKI biomarkers, amelioration of renal histopathological damage, and suppression of both apoptosis and inflammatory responses. Characteristic mitochondrial abnormalities, diminished ATP production, and excessive lipid droplet accumulation were observed in tubular cells of IRI mice. Notably, pRacGAP1-LCP treatment reversed these pathological alterations and up-regulated the expression of PGC-1α and CPT-1α, indicating that RacGAP1 exerted its reno-protective effects through enhanced mitochondrial biogenesis and fatty acid oxidation (FAO). To further investigate the role of RacGAP1 in mitochondrial homeostasis, we employed an ATP depletion-repletion (ATP D-R) model in mRTECs. Crucially, RacGAP1 effectively restored ATP production, mtDNA copy number, and oxygen consumption rate (OCR) in mRTECs after ATP D-R treatment. RacGAP1 overexpression also suppressed mitochondrial depolarization, fragmentation, and reactive oxygen species (ROS) generation. Conversely, RacGAP1 knockdown exacerbated mitochondrial defects in mRTECs exposed to ATP D-R. In summary, this study uncovers that RacGAP1 overexpression protects against renal injury and mitochondrial dysfunction, highlighting its therapeutic promise for AKI. The LCP nanoparticle exhibits potential as a precise and efficient delivery platform and presents a viable option for AKI therapy.</p>","PeriodicalId":10475,"journal":{"name":"Clinical science","volume":" ","pages":"1571-1590"},"PeriodicalIF":7.7,"publicationDate":"2025-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12751063/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145502401","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":"Maternal dietary fibre intake results in sex-specific single-cell molecular changes in the heart of the offspring.","authors":"Chaoran Yang, Hamdi A Jama, Malathi S I Dona, Gabriella E Farrugia, Crisdion Krstevski, Charles D Cohen, Alexander R Pinto, Francine Z Marques","doi":"10.1042/CS20257187","DOIUrl":"10.1042/CS20257187","url":null,"abstract":"<p><p>Some types of dietary fibre undergo fermentation by the gut microbiome, producing microbial metabolites called short-chain fatty acids (SCFAs) - these are protective against cardiovascular disease (CVD). Emerging evidence suggests that maternal fibre intake also protects the offspring. Here, we aimed to determine whether delivery of SCFAs during pregnancy results in sex- and cell-specific molecular changes to the offspring's heart. Female mice were subjected to high or low-fibre diets during pregnancy and lactation, while all offspring received a standard-fibre diet. We then studied the single-cell transcriptome (scRNA-seq, n = 16) and immune composition (fluorescence-activated cell sorting, n = 27) of the hearts and gut microbiome profiles (16S rRNA, n = 28) of six-week-old male and female offspring. Maternal fibre intake induced significant changes in the cardiac cellular and immunological landscapes, revealing sex-specific signatures at the single-cell level. High-fibre intake reduced the number of monocytes in the hearts of male offspring and the number of B cells in both female and male offspring. Cardiac fibroblasts in both male and female offspring of high-fibre intake dams showed an anti-fibrotic transcriptome. In contrast, only male offspring showed an anti-inflammatory transcriptome in macrophages and endothelial cells. Our findings suggest that high-fibre intake during pregnancy may induce a CVD-protective transcriptome (i.e., anti-fibrotic and anti-inflammatory), especially in male offspring. These findings underscore the relevance of maternal dietary choices during pregnancy influencing cardiovascular health outcomes in the offspring.</p>","PeriodicalId":10475,"journal":{"name":"Clinical science","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12751069/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145285635","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}