Clinical science最新文献

{"title":"Antimicrobial and Immune-Modulating Effects of Recombinant Pancreatitis Associated Protein in the Treatment of MRSA-Induced Severe Septic Arthritis.","authors":"Luting Yu, Guanghao Lin, Shenglong Jiang, Yuanxin Li, Lili Ren, Guoguang Chen","doi":"10.1042/CS20250060","DOIUrl":"https://doi.org/10.1042/CS20250060","url":null,"abstract":"<p><p>Septic arthritis is a severe infection caused by bacteria directly invading the synovial joints. It leads to inflammatory damage to articular cartilage and may result in significant functional impairment, with a high recurrence rate. The rapid spread of antibiotic-resistant bacterial strains has further exacerbated the threat to human health, particularly in septic arthritis cases. Based on the antibacterial activity and regenerative properties of pancreatitis associated protein (PAP), this study aims to investigate the therapeutic potential of exogenous recombinant PAP for treating methicillin-resistant Staphylococcus aureus (MRSA)-induced septic arthritis. The prepared PAP exhibited favorable bactericidal effects against both Staphylococcus aureus (S. aureus) and MRSA, with a dose-dependent manner. The antibacterial efficacy in the high-dose group was comparable to that of vancomycin. Additionally, 10 nM PAP significantly promoted the proliferation of RAW264.7 macrophages and enhanced their resistance to oxidative stress. Intra-articular injection of PAP accelerated the recovery from MRSA-induced septic arthritis by alleviating joint swelling, clearing the bacteria within the joint cavity, and mitigating inflammation. Transcriptomic results indicated that PAP administration significantly downregulated the expression of inflammatory markers and slightly increased the proportion of monocytes/macrophages. Further studies on the immunomodulatory effects of PAP revealed that it attenuated lipopolysaccharide (LPS)-induced M1 polarization and markedly diminished the expression of pro-inflammatory cytokines, including TNF-α, IFN-γ, and IL-6. Meanwhile, PAP partially induced M2 polarization of macrophages and elevated anti-inflammatory IL-4 levels. In conclusion, PAP exhibited antibacterial, tissue repair, and immunomodulatory activities, highlighting its potential as a therapeutic candidate for septic arthritis.</p>","PeriodicalId":10475,"journal":{"name":"Clinical science","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147834493","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":"Extracellular vimentin promotes neutrophil-dominant granulomatous inflammation in progressive pulmonary sarcoidosis.","authors":"Olympia Nteris, Elizabeth Verghese, Quynh Anh Nguyen, Joshua Iscaro, Stanley M H Chan, Kwok Ho Yip, Angel F Lopez, Adam Quek, Nick Wilson, Catherine M Owczarek, Ross Vlahos, Jonathan McQualter, Steven Bozinovski, Hao Wang","doi":"10.1042/CS20250651","DOIUrl":"https://doi.org/10.1042/CS20250651","url":null,"abstract":"<p><p>Pulmonary sarcoidosis has a heterogeneous clinical course, with a subset of patients progressing to chronic disease and fibrosis despite first-line corticosteroid therapy. The mechanisms driving disease progression are poorly understood, although limited evidence suggests a role for neutrophils. This study aimed to characterise neutrophils and neutrophil effector molecules in progressive pulmonary sarcoidosis. We first performed in silico transcriptomic analyses to evaluate neutrophil gene signatures in granulomatous lung tissue from patients with progressive, fibrotic sarcoidosis comparing to self-resolving disease. In parallel, we employed vimentin-induced mouse models and performed single-cell RNA-sequencing (scRNA-seq), flow cytometry, and immunostaining to examine neutrophils and assess their contribution to lung injury and fibrosis. Neutrophil gene signatures were significantly enriched in progressive sarcoidosis and positively associated with fibrosis-related pathways while inversely correlating with lung function. In the vimentin-induced model, scRNA-seq, flow cytometry, and bronchoalveolar lavage (BAL) differential analyses demonstrated neutrophil infiltration with altered transcriptomic profile and enhanced activation, which were amplified by repeated vimentin challenge. BAL myeloperoxidase (MPO) activity and total protein, markers of neutrophil activation and lung injury, were significantly elevated and correlated with neutrophil content. Within granulomas, neutrophils were also abundant and neutrophil extracellular traps (NETs) were identified, along with the detection of collagen deposition and fibroblast activation. Together, these findings demonstrate that activation of neutrophil-driven inflammatory pathways is a prominent feature of progressive pulmonary sarcoidosis and can be triggered by extracellular vimentin. Its strong association with lung injury and fibrosis highlights neutrophils and NETosis as potential therapeutic targets for modifying disease trajectory in progressive sarcoidosis.</p>","PeriodicalId":10475,"journal":{"name":"Clinical science","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147834465","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":"GPER1Unravelling the effects of selective estrogen receptor modulators on colorectal cancer: a prognostic role for insulin-like growth factor binding protein-5.","authors":"Xiaoyu Su, Rachel M Barker, Kalina Biernacka, Kathryn McCarthy, Astor Mak, Claire M Perks","doi":"10.1042/CS20258451","DOIUrl":"https://doi.org/10.1042/CS20258451","url":null,"abstract":"<p><p>Obesity contributes to colorectal cancer (CRC) by elevating levels of estrogen, 27-hydroxycholesterol(27-OHC), and insulin-like growth factors (IGFs). Paradoxically, epidemiological studies show that hormone replacement therapy reduces CRC incidence and mortality, particularly in postmenopausal women, suggesting a protective role for estrogen. Estrogen and 27-OHC signal via ERα, ERβ, and GPER1, with ERβ being the predominant estrogen receptor in the colon. We observed a strong positive correlation between ERβ and IGFBP-5 in CRC tissues, and high IGFBP-5 expression was significantly associated with poor patient outcomes. Functional assays revealed that ERβ knockdown inhibited colon cancer cell proliferation and migration, accompanied by a marked reduction in IGFBP-5 expression. Co-immunoprecipitation confirmed a direct interaction between ERβ and IGFBP-5. Both estrogen and 27-OHC suppressed CRC cell proliferation and IGFBP-5 expression, but this was independent of ERβ. Combined ERβ silencing and estrogen or 27-OHC treatment enhanced DNA damage and apoptosis. Transcriptome analysis identified GPER1 as a downstream estrogen-responsive gene. Subsequent in vitro validation confirmed that GPER1 activation mediates the tumour-suppressive effects of estrogen and 27-OHC. Collectively, our findings highlight IGFBP-5 as a potential prognostic marker, demonstrate the tumour-inhibitory effect of ERβ silencing, and identify GPER1 as a promising therapeutic target linking estrogen signalling, lipid metabolism, and CRC progression.</p>","PeriodicalId":10475,"journal":{"name":"Clinical science","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147764232","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":"Carnosine Augments the Efficacy of Pulmonary Rehabilitation in COPD: Insights from a Preclinical Model.","authors":"Ross Vlahos, Suleman Abdullah Almerdasi, Stanley M H Chan, Rana Abdullah Alateeq, Wei Wang, Simone De Luca, Alina Akhtar, Kevin Mou, Huei Jiunn Seow, Steven Bozinovski, Stavros Selemidis","doi":"10.1042/CS20260348","DOIUrl":"https://doi.org/10.1042/CS20260348","url":null,"abstract":"<p><p>Pulmonary rehabilitation (PR) improves exercise tolerance and dyspnoea in chronic obstructive pulmonary disease (COPD) but does not address the elevated cardiovascular disease (CVD) risk. Vascular dysfunction, an early CVD feature, is driven by oxidative stress-a shared pathogenic mechanism in COPD and CVD. Carnosine, a bioactive dipeptide with antioxidant and pH-buffering properties, may enhance muscle performance and protect against vascular injury. This study sought to determine whether carnosine supplementation combined with exercise training could modify early CVD features in a preclinical COPD model. Male BALB/c mice were exposed to room air or cigarette smoke (CS; 9 cigarettes/day, 5 days/week, 8 weeks) with or without carnosine (1 mg/mL in drinking water) and with or without treadmill exercise training (50% maximal speed; 30 min/day, 5 days/week). After 8 weeks, blood pressure, exercise capacity, resting heart rate, lung inflammation, systemic oxidative stress, aortic endothelial function, and platelet activation were assessed. CS impaired weight gain, reduced exercise capacity, elevated resting heart rate, and induced airway inflammation (p<0.0001). CS also caused severe endothelial dysfunction and platelet activation (p<0.0001). Exercise alone did not reverse these vascular abnormalities. In contrast, carnosine plus exercise restored weight gain, exercise capacity, and heart rate, preserved endothelial function, and prevented platelet adhesion and activation, without altering airway inflammation. Exercise training alone is insufficient to counteract CS-induced vascular injury. Carnosine supplementation provides synergistic vascular protection, highlighting its potential as an adjunct to PR to mitigate oxidative stress-driven CVD risk in COPD.</p>","PeriodicalId":10475,"journal":{"name":"Clinical science","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147763961","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":"The unfolded protein response and its activation by insulin in muscle are not altered by obesity or type 2 diabetes.","authors":"Rikke Kruse, Jonas Møller Kristensen, Birgitte Falbe Vind, Stine Juhl, Jacob Volmer Stidsen, Rugivan Sabaratnam, Kurt Højlund","doi":"10.1042/CS20250639","DOIUrl":"https://doi.org/10.1042/CS20250639","url":null,"abstract":"<p><p>Insulin resistance in obesity and type 2 diabetes (T2D) is characterized by reduced insulin-stimulated glucose uptake, accumulation of triacylglycerol, mitochondrial dysfunction, and altered protein metabolism in skeletal muscle. This may involve disturbed endoplasmic reticulum (ER) homeostasis, leading to alterations in the unfolded protein response (UPR), and hence the protein folding capacity. Here, we investigated if markers of UPR activity are elevated in skeletal muscle in obesity and T2D, and to what extent insulin regulates these UPR markers. In a case-control design, we determined mRNA expression, protein abundance, and phosphorylation of key UPR markers in skeletal muscle biopsies obtained from patients with T2D, matched to glucose-tolerant individuals with obesity and lean individuals, before and after 4-h insulin infusion during a hyperinsulinemic-euglycemic clamp. The mRNA expression or protein abundance of GRP78, the canonical ER stress sensors (ATF6, PERK, and IRE-1α), several downstream UPR markers, and related markers of mitochondrial dynamics did not differ between groups. Insulin increased the mRNA expression of ATF6, ERN1 (encoding IRE-1α), XBP1, DDIT3 (encoding CHOP), and a marker of mitochondrial fission DNM1l (encoding DRP1), as well as eIF2α Ser51 phosphorylation in skeletal muscle in all groups (all p<0.05), with no between-group differences. Our results demonstrate that markers of UPR activity are not elevated in skeletal muscle in obesity or T2D. Interestingly, insulin increases the expression of UPR markers and activates eIF2α, which is necessary for increasing the protein folding capacity of ER in muscle, and these responses are intact in obesity and T2D.</p>","PeriodicalId":10475,"journal":{"name":"Clinical science","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147764219","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":"Chronic pyridostigmine is antiarrhythmic in Spontaneously hypertensive rats (SHR) but detrimental in normotensive WKY rats.","authors":"Almos Boroš, Miloslava Chalupová, Jaroslav Hrdlička, Ivana Vaněčková, Lenka Řezáčová, Jan Neckář, Josef Zicha, Michal Behuliak","doi":"10.1042/CS20250921","DOIUrl":"https://doi.org/10.1042/CS20250921","url":null,"abstract":"<p><p>SHR are a model of genetic hypertension, cardiac hypertrophy and autonomic nervous system imbalance. SHR with transgenic constitutive expression of human C-reactive protein (SHR-CRP) exhibit chronic inflammation. We hypothesized that cholinergic potentiation prior to acute myocardial infarction would induce cardioprotection due to effects on heart contractility, vascular tone and immunomodulation in both hypertensive strains. Male WKY, SHR and SHR-CRP rats were subjected to acute, short-term 2-week or long-term 8-week administration of pyridostigmine (peripheral acetylcholinesterase inhibitor). We evaluated blood pressure, heart rate, and cardiac parasympathetic tone. Myocardial infarction was induced in acutely and long-term treated rats. Moreover, arrhythmogenesis, blood pressure, and heart rate changes were assessed in short-term treated animals after acute adrenaline administration. Acute pyridostigmine administration reduced ischemic arrhythmogenesis in WKY rats. Short-term pyridostigmine reduced adrenaline-induced arrhythmogenesis in SHR rats but prolonged bradycardia due to atrio-ventricular conduction blockade. Moreover, it delayed blood pressure recovery after adrenaline administration in WKY rats to that of SHR. Long-term pyridostigmine treatment reduced ischemic arrhythmogenesis in SHRs, but prolonged ischemic tachyarrhythmia duration in WKY rats. This was associated with changes of cardiac connexin gene and protein expressions. It also tended to reduce infarct size in SHR-CRP rats. Long-term pyridostigmine treatment lowered rat CRP in plasma, MCP-1 protein expression in the left ventricle, and TNF-alpha protein expression in the spleen. Acetylcholinesterase inhibition by pyridostigmine provides positive cardiovascular effects in animals with autonomic nervous system imbalance and cardiovascular disease. However, it is not suitable for healthy animals or subjects due to possible adverse effects.</p>","PeriodicalId":10475,"journal":{"name":"Clinical science","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147763957","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":"Early pregravid correction of hemostasis assessed by novel biomarkers improves the outcomes of pregnancies in women with bad obstetric history.","authors":"Svetlana I Safiullina, Nataila G Evtugina, Alina D Peshkova, John W Weisel, Rustem I Litvinov","doi":"10.1042/CS20260246","DOIUrl":"https://doi.org/10.1042/CS20260246","url":null,"abstract":"<p><p>Premorbid hypercoagulability causes obstetric complications; therefore, anticoagulation from the preconception period and throughout pregnancy may be beneficial in cases of bad obstetric history(BOH). The aim of the study is to test this hypothesis, 115 patients with BOH and 38 healthy women without prior obstetric complications were examined. Patients with antiphospholipid syndrome were excluded, and the groups were matched based on the frequency of congenital thrombophilia. Hemostasis was assessed before and during pregnancy using the Thrombodynamics assay and routine coagulation tests. Platelet function was characterized using a blood clot contraction assay and flow cytometry. All patients with BOH received enoxaparin(low molecular weight heparin, LMWH) starting from the preconception period and aspirin after the 10th week of pregnancy. Doses were adjusted based on dynamic laboratory monitoring. In women with BOH, premorbid hypercoagulability was associated with platelet dysfunction due to chronic activation and exhaustion. With enoxaparin and aspirin treatment before and during pregnancy, hemostasis and platelet function improved progressively. By the second trimester, these parameters were comparable to normal levels. In patients with BOH receiving enoxaparin and aspirin, pregnancy outcomes were significantly more favorable compared to previous pregnancies. No hemorrhagic complications were observed. For women with BOH, the early and controlled use of LMWH starting from the preconception period, along with aspirin from the 10th through the 34th week of pregnancy, improves hemostasis, prevents obstetric complications, and significantly increases the likelihood of a favorable pregnancy outcome. These results were achieved through dynamic laboratory monitoring using novel hemostatic assays and platelet contractility as biomarkers.</p>","PeriodicalId":10475,"journal":{"name":"Clinical science","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147764030","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":"ASGR1 induces neutrophil extracellular traps formation to exacerbate sepsis-induced myocardial injury and cardiac dysfunction through SLC7A11 ubiquitination.","authors":"Rui Shi, Fang Wang, Chaozhong Li, Chuang Xiao, Chunyun Bai, Alex F Chen, Weimin Yang","doi":"10.1042/CS20250290","DOIUrl":"https://doi.org/10.1042/CS20250290","url":null,"abstract":"<p><strong>Background: </strong>Cardiac dysfunction is a crucial culprit for the high mortality of sepsis in intensive care units. The underlying targets and mechanisms of sepsis-induced myocardial dysfunction (SIMD) in sepsis are awaiting profound exploration. The present study investigates the contribution and mechanism of ASGR1 to the progression of SIMD. Herein, we show that ASGR1 in heart tissue is highly related to SIMD. Anti-Ly6G and GSK484 deplete neutrophils and neutrophil extracellular traps (NETs), alleviating myocardial injury and cardiac dysfunction, and promoting survival of LPS-challenged mice. Neutrophils and NETs are observably declined in ASGR1 knockout mice and conditional knockout neutrophils, respectively. In ASGR1 deficiency mice, LPS challenge results in elevated neutrophils and NETs using FACS and confocal microscopy, respectively, leading to reduced myocardial dysfunction and mortality. ASGR1 promotes neutrophil activation and NET accumulation via SLC7A11-dependent ferroptosis. ASGR1 acts as a bridge to transfer the attached ubiquitin to SLC7A11 and facilitates K48-linked ubiquitination degradation of SLC7A11 by SOCS2. Our findings suggest that ASGR1 is a principal indicator of SIMD by inducing NET formation. In addition, the regulation of NET formation could be a potential treatment for SIMD.</p>","PeriodicalId":10475,"journal":{"name":"Clinical science","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147764714","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":"Retraction: Short-term early exposure to thirdhand cigarette smoke increases lung cancer incidence in mice.","authors":"Antoine Snijders, Jian-Hua Mao, Bo Hang, Yunshan Wang, Yurong Huang, Pin Wang, Sasha A Langley, Lei Bi, Altaf H Sarker, Suzaynn F Schick, Christopher Havel, Peyton Jacob, Neal Benowitz, Hugo Destaillats, Xiaochen Tang, Yankai Xia, Kuang-Yu Jen, Lara A Gundel","doi":"10.1042/CS20171521_RET","DOIUrl":"10.1042/CS20171521_RET","url":null,"abstract":"","PeriodicalId":10475,"journal":{"name":"Clinical science","volume":"140 4","pages":"569"},"PeriodicalIF":7.7,"publicationDate":"2026-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13124014/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147510154","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":"Correction: Targeting mitochondria to protect the heart: a matter of balance?","authors":"Fouad A Zouein, George W Booz","doi":"10.1042/CS20258287_COR","DOIUrl":"10.1042/CS20258287_COR","url":null,"abstract":"","PeriodicalId":10475,"journal":{"name":"Clinical science","volume":"140 4","pages":"491"},"PeriodicalIF":7.7,"publicationDate":"2026-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13124015/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147442733","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}