Clinical science最新文献

{"title":"Retraction: Inhibition of mitochondrial fission as a novel therapeutic strategy to reduce mortality upon myocardial infarction.","authors":"","doi":"10.1042/CS20180671_RET","DOIUrl":"10.1042/CS20180671_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/PMC12493159/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144834375","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 novel AT2 receptor ligand, β-Pro7 Ang III, induces equivalent anti-fibrotic effects to Compound 21 but broader anti-fibrotic effects than pirfenidone in mice with bleomycin-induced pulmonary fibrosis.","authors":"Simon G Royce, Cem Erdem, WeiYi Mao, Yan Wang, Mark P Del Borgo, Robert E Widdop, Chrishan S Samuel","doi":"10.1042/CS20245138","DOIUrl":"10.1042/CS20245138","url":null,"abstract":"<p><p>Angiotensin II AT2 receptor (AT2R) activation leads to significant anti-fibrotic and anti-inflammatory effects in diseased organs, which has led to clinical trial evaluation of the AT2R agonist, Compound 21 (C21), as a treatment for idiopathic pulmonary fibrosis (IPF). In this study, the anti-fibrotic effects of a more selective AT2R ligand, β-Pro7 angiotensin III (β-Pro7 Ang III), with >20,000-fold affinity for the AT2R over the AT1R, were compared with that of C21 or the currently used IPF medication, pirfenidone, in mice with bleomycin (BLM)-induced pulmonary fibrosis. Adult female BALB/c mice received a double intranasal instillation of BLM (20 mg/kg/day) seven days apart and were maintained until day 35, while control mice were instilled with saline (SAL) seven days apart and maintained for the same time period. Sub-groups of BLM-injured mice were then treated on day 28 with vehicle (SAL), C21 (0.3 mg/kg/day) or β-Pro7 Ang III (0.1 mg/kg/day) via seven-day subcutaneously implanted osmotic minipumps, or daily from days 28 to 35 via orally administered pirfenidone (100 mg/kg/day). At day-35 post-injury, measures of lung fibrosis and compliance were evaluated. Compared with their SAL-instilled counterparts, SAL-treated BLM-injured mice presented with a significantly increased lung Ashcroft score, Masson's trichrome-stained and second harmonics generation-measured fibrosis, myofibroblast accumulation, and TGF-β1 expression, but reduced lung dynamic compliance at day-35 post-injury. While all treatments evaluated attenuated the BLM-induced lung myofibroblast accumulation and TGF-β1 expression, AT2R stimulation, but not pirfenidone, attenuated lung collagen deposition after seven days. β-Pro7 Ang III also significantly restored lung compliance and promoted collagen-degrading matrix metalloproteinase-2 activity. These findings highlighted the therapeutic value of selectively targeting the AT2R for treating IPF.</p>","PeriodicalId":10475,"journal":{"name":"Clinical science","volume":" ","pages":"809-824"},"PeriodicalIF":7.7,"publicationDate":"2025-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12409987/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144539175","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":"PiggyBac transposase-mediated inducible trophoblast-specific knockdown of Mtor decreases placental nutrient transport and fetal growth.","authors":"Fredrick J Rosario, Johann Urschitz, Haide Razavy, Marlee Elston, Theresa L Powell, Thomas Jansson","doi":"10.1042/CS20243293","DOIUrl":"10.1042/CS20243293","url":null,"abstract":"<p><p>Abnormal fetal growth is associated with perinatal complications and adult disease. The placental mechanistic target of rapamycin (mTOR) signaling activity is positively correlated with placental nutrient transport and fetal growth. However, if this association represents a mechanistic link, it remains unknown. We hypothesized that trophoblast-specific Mtor knockdown in late pregnant mice decreases trophoblast nutrient transport and inhibits fetal growth. PiggyBac transposase-enhanced pronuclear injection was performed to generate transgenic mice containing a trophoblast-specific Cyp19I.1 promoter-driven, doxycycline-inducible luciferase reporter transgene with a Mtor shRNAmir sequence in its 3' untranslated region (UTR). We induced Mtor knockdown by administration of doxycycline starting at E14.5. Dams were killed at E 17.5, and trophoblastspecific gene targeting was confirmed. Placental mTOR protein expression was reduced in these animals, which was associated with a marked inhibition of mTORC1 and mTORC2 signaling activity. Moreover, we observed a decreased expression of System A amino acid transporter isoform SNAT2 and the System L amino acid transporter isoform LAT1 in isolated trophoblast plasma membranes and lower fetal, placental weight, and fetal:placental weight ratio. We also silence the MTOR in cultured primary human trophoblast cells, which inhibited the mTORC1 and C2 signaling, System A and System L amino acid transport activity, and markedly decreased the trafficking of LAT1 and SNAT2 to the plasma membrane. Inhibition of trophoblast mTOR signaling in late pregnancy is mechanistically linked to decreased placental nutrient transport and reduced fetal growth. Modulating trophoblast mTOR signaling may represent a novel intervention in pregnancies with abnormal fetal growth.</p>","PeriodicalId":10475,"journal":{"name":"Clinical science","volume":" ","pages":"825-845"},"PeriodicalIF":7.7,"publicationDate":"2025-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12409993/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144324671","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":"Urine-derived renal epithelial cells for deep phenotyping and transcriptomic response to therapy in Fabry disease.","authors":"Praveen Dhondurao Sudhindar, Sarah E Orr, Eve Miller-Hodges, Elisa Molinari, Katrina Wood, Shalabh Srivastava, Colin G Miles, Holly R Mabillard, Zachary T Sentell, Marco Trevisan-Herraz, Juliana E Arcila-Galvis, John A Sayer","doi":"10.1042/CS20255570","DOIUrl":"10.1042/CS20255570","url":null,"abstract":"<p><p>Fabry disease is an X-linked lysosomal storage disorder caused by α-galactosidase A deficiency, leading to glycosphingolipid accumulation and progressive organ damage. Renal involvement is a major complication, yet diagnosis often requires an invasive kidney biopsy, and follow-up relies on indirect biomarkers or imaging, which lack specificity. Here, we present human urine-derived renal epithelial cells (hURECs) as a minimally invasive alternative for phenotyping renal Fabry disease and monitoring treatment response. Using hURECs from a newly diagnosed male Fabry disease patient, transmission electron microscopy (TEM) revealed lysosomal inclusions consistent with native kidney biopsy findings. Bulk RNA sequencing (RNA-seq) identified a transcriptomic disease signature, including dysregulated pathways involved in lipid metabolism homeostasis, ion transport, endoplasmic reticulum stress response, and collagen processing. Following systemic treatment of the patient with chaperone therapy, partial amelioration of the hUREC transcriptomic signature was observed during the first few months. However, by nine months, the signature began reverting toward baseline, correlating with continued kidney function decline. This prompted a transition to enzyme replacement therapy, with early evaluations showing transcriptomic stabilization. Our findings demonstrate that hURECs replicate key structural and molecular markers of renal Fabry disease and offer a non-invasive platform for longitudinal assessment of treatment response. TEM of hURECs provides a diagnostic alternative to biopsy, while RNA-seq-based transcriptomic profiling offers a sensitive and dynamic view of molecular changes, including key dysregulated pathways. This dual utility positions hURECs as a novel tool for improving the diagnosis, monitoring, and personalized management of kidney involvement in Fabry disease.</p>","PeriodicalId":10475,"journal":{"name":"Clinical science","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12409995/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144648770","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 circadian clock, metabolism, and inflammation-the holy trinity of inflammatory bowel diseases.","authors":"Oren Froy, Yael Weintraub","doi":"10.1042/CS20256383","DOIUrl":"10.1042/CS20256383","url":null,"abstract":"<p><p>Inflammatory bowel diseases (IBDs), including Crohn's disease and ulcerative colitis, are characterized by relapsing-remitting immune activation and inflammation within the gastrointestinal tract. The immune system activity displays diurnal variation, which is regulated by the circadian clock. This is achieved by modulating the number of circulating lymphocytes, antibody production, cytokine production, host- pathogen interactions, and the activation of innate and adaptive immunity around the circadian cycle. Indeed, intestinal biopsies and peripheral blood cells obtained from patients with active IBD demonstrated reduced circadian clock gene expression. Key clock regulatory proteins, such as retinoic acid receptor-related orphan receptors, REV-ERBs, peroxisome proliferator-activated receptors (PPARs), PPARγ transcriptional co-activator 1α, adenosine monophosphate-activated protein kinase and Sirtuin 1, have a dual function as they regulate clock gene expression as well as the expression of certain pro- and anti-inflammatory factors through the NF-κB signaling pathway. All the aforementioned clock regulatory proteins are also key regulators of metabolism. Thus, these factors form a complex triangular network that regulates the circadian clock, inflammation, and metabolism. Emerging data support the notion that clock disruption is associated with inflammation and aberrant metabolic regulation and that regulators of the circadian clock may play a role in inflammatory and metabolic processes. In this review, we will focus on the interrelations among the circadian clock, metabolism, and inflammation in IBD.</p>","PeriodicalId":10475,"journal":{"name":"Clinical science","volume":"139 13","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12312392/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144559425","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":"Endothelin antagonists for hypertension: has their time finally arrived?","authors":"Ernesto L Schiffrin","doi":"10.1042/CS20255853","DOIUrl":"10.1042/CS20255853","url":null,"abstract":"<p><p>There have been few new treatments introduced for hypertension in the last thirty years. The endothelin (ET) system was discovered in 1988, and in the following years, it was demonstrated that it participated in the elevation of blood pressure and vascular remodeling in experimental models of hypertension, particularly those with more severe forms of hypertension. Several selective and dual antagonists of ETA receptors (ETARs) and ETB receptors (ETBRs) were developed, but none reached marketing for human hypertension. Following a successful trial in resistant hypertension, a novel antihypertensive agent has been approved in Europe and in the U.S.A.: the dual ETAR/ETBR antagonist aprocitentan, which was recently approved for the treatment of hypertension in combination with other antihypertensive drugs, to lower blood pressure in adult patients who are not adequately controlled on other drugs. Thus, the time has finally arrived for ET antagonists in hypertension.</p>","PeriodicalId":10475,"journal":{"name":"Clinical science","volume":"132 13","pages":"769-776"},"PeriodicalIF":7.7,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12312390/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144559426","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":"Evaluating skeletal muscle wasting and weakness in models of critical illness.","authors":"Amy J Bongetti, Marissa K Caldow, Yasmine Ali Abdelhamid, Gordon S Lynch","doi":"10.1042/CS20255458","DOIUrl":"10.1042/CS20255458","url":null,"abstract":"<p><p>Skeletal muscle wasting and weakness are common complications associated with admission to the intensive care unit (ICU), with the loss of muscle mass and function increasing mortality and contributing to physical impairments post-discharge. While our understanding of the pathophysiology of this condition, commonly termed 'ICU-acquired weakness' (ICU-AW), has advanced considerably, no effective therapies are available. ICU-AW broadly encompasses a range of muscle-related impairments in this setting, including, but not limited to, critical illness myopathy and sepsis-induced myopathy. Pre-clinical models of critical illness can provide insights into the mechanisms underlying muscle wasting and weakness. Cell culture systems can provide mechanistic interrogation, by isolating effects to skeletal muscle directly. Small animal models, like rats and mice, allow for mechanistic investigation of ICU-AW using genetic models and testing pharmacological interventions. Larger animal models, including pigs and sheep, facilitate repeated blood and tissue sampling and can more closely recapitulate the standard-of-care within ICU settings. Although animal models can be advantageous for scientific investigation, they also have important limitations. Barriers to developing effective interventions include difficulty in obtaining muscle biopsies from patients, translating experimental findings between animal models and humans and replicating aspects of different ICU settings. This review explores the advantages and shortcomings of different pre-clinical models of critical illness, identifies gaps in understanding muscle wasting and weakness in critical illness and provides recommendations for improving the translation of therapeutics to promote functional recovery for patients post-discharge.</p>","PeriodicalId":10475,"journal":{"name":"Clinical science","volume":"139 13","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12312398/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144539176","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":"Primary bile acid shapes peripheral immunity in inflammatory bowel disease-associated primary sclerosing cholangitis.","authors":"André A Santos, David Pires, Vanda Marques, Nicole Alesina, Elisa Herraez, Pavel Roudnický, Pedro M Rodrigues, Ana Godinho-Santos, Ana Catarina Bravo, Catarina Gouveia, Susana Saraiva, Luís Correia, Ricardo Crespo, João Pereira da Silva, Marília Cravo, David Potesil, Zbyněk Zdráhal, Jesus Maria Banales, Jose J G Marin, Joana Torres, Cecília Maria Pereira Rodrigues","doi":"10.1042/CS20256078","DOIUrl":"10.1042/CS20256078","url":null,"abstract":"<p><p>Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease often associated with underlying inflammatory bowel disease (IBD). This study investigates how PSC predisposes individuals to altered inflammatory immune responses compared with IBD alone. A case-control study was conducted with a cohort of 75 patients, including 16 with PSC (14 with concomitant IBD), 39 with IBD alone, and 20 controls. Serum bile acid profile, proteomic analysis, and immune-related gene expression in the colon tissue were examined. Colonic tissue from PSC patients exhibited up-regulation of immune regulation and inflammatory signaling mRNA markers, including LGR5, IL-8, CCL2, COX2, TWIST1, and SNAIL. Additionally, PSC patients displayed a distinct proinflammatory serum proteomic signature and moderate elevation of some bile acids, such as glycochenodeoxycholic acid (GCDCA). Co-incubation of human-derived monocytes with GCDCA partially replicated the inflammatory profile observed in PSC. These findings suggest that circulating bile acids modulate the peripheral immune system proinflammatory response, contributing to the unique PSC phenotype.</p>","PeriodicalId":10475,"journal":{"name":"Clinical science","volume":" ","pages":"703-716"},"PeriodicalIF":7.7,"publicationDate":"2025-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12312387/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144233397","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":"pH-sensor GPR68 plays a role in how dietary fibre lowers blood pressure in a preclinical model of hypertension.","authors":"Evany Dinakis, Chudan Xu, Rikeish Muralitharan, Hamdi Jama, Liang Xie, Charmaine Leung, Katrina Mirabito Colafella, Zoe McArdle, Ekaterina Salimova, Leticia Camargo Tavares, Matthew Snelson, Chad Johnson, Tracey Gaspari, Charles Mackay, Joanne O'Donnell, Francine Marques","doi":"10.1042/CS20243009","DOIUrl":"https://doi.org/10.1042/CS20243009","url":null,"abstract":"<p><p>Dietary fibre lowers blood pressure (BP) via short-chain fatty acids, acidic metabolites released from fibre fermentation by bacteria in the large intestine. This acidic microenvironment may activate the pH-sensing receptor GPR68, primarily expressed in immune cells. Here, we aimed to investigate whether GPR68 confers the BP-lowering effects of a high-fibre diet in hypertension by regulating inflammatory responses. Baseline BP parameters were measured using telemetry in C57BL/6J wildtype (WT) and GPR68-deficient (Gpr68-/-) male and female mice. Moreover, male mice were fed a control or high-fibre diet following minipump implantation with saline or Angiotensin II (Ang II), where BP was measured weekly by tail-cuff. Cardiac ultrasounds, histological, flow cytometric and gut microbiome (16S) analyses were performed. No BP differences were detected in untreated male and female mice, irrespective of genotype. Similarly to WT mice, Gpr68-/- male mice were susceptible to Ang II-induced hypertension. High-fibre-fed WT mice exhibited blunted elevations in BP and improved cardiac collagen deposition and aortic elastin content compared to control-fed WT mice. These were not observed in high-fibre-fed Gpr68-/- mice. A high-fibre diet decreased pro-inflammatory renal and aortic immune cell counts independently of GPR68. Dietary fibre, rather than GPR68 or Ang II, was the primary factor influencing differences in the gut microbiota. This study provides novel insight into how the pH-sensing receptor GPR68 may be implicated in the protective effects of a high-fibre diet. However, these effects are likely immune-independent.</p>","PeriodicalId":10475,"journal":{"name":"Clinical science","volume":" ","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144483423","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":"Hypertension: a lymphatic disease?","authors":"Sunitha Konatham, Bethany L Goodlett, Hannah L Smith, Brett M Mitchell","doi":"10.1042/CS20245149","DOIUrl":"10.1042/CS20245149","url":null,"abstract":"<p><p>Hypertension affects nearly one in two American adults and is a major risk factor for cardiovascular events and organ damage. Many treatments exist to lower blood pressure in hypertensive patients; however, their degree of effectiveness varies. It is well known that the pathology of hypertension is interwoven with actions of the immune system. Different types of immune cells infiltrate and accumulate in organs under hypertensive conditions and contribute to cytokine release and persistent inflammation. Recently, it has been shown that blood pressure can be lowered by increasing renal-specific lymphangiogenesis, which facilitates the movement of immune cells out of the kidneys. Hypertension is known to be correlated with increased lymphangiogenesis in tissues including the kidneys, heart, gonads, and skin; however, little is known about this relationship. In this brief review article, we explore the connections between hypertension, a well-studied disease, and the lymphatic system, a historically understudied system. We speculate on points of relation and the potential impact of lymphatic-focused hypertension treatments.</p>","PeriodicalId":10475,"journal":{"name":"Clinical science","volume":"139 12","pages":""},"PeriodicalIF":6.7,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12238814/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144474118","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}