Clinical science最新文献_第2页

Differential changes in end organ immune cells and inflammation in salt-sensitive hypertension: effects of lowering blood pressure. 盐敏感性高血压终末器官免疫细胞和炎症的不同变化：降低血压的影响

IF 6.7 2区医学

Clinical science Pub Date : 2024-07-17 DOI: 10.1042/CS20240698

Shobana Navaneethabalakrishnan, Bethany L Goodlett, Hannah L Smith, Alyssa Cardenas, Asia Burns, Brett M Mitchell

{"title":"Differential changes in end organ immune cells and inflammation in salt-sensitive hypertension: effects of lowering blood pressure.","authors":"Shobana Navaneethabalakrishnan, Bethany L Goodlett, Hannah L Smith, Alyssa Cardenas, Asia Burns, Brett M Mitchell","doi":"10.1042/CS20240698","DOIUrl":"10.1042/CS20240698","url":null,"abstract":"We reported that salt-sensitive hypertension (SSHTN) is associated with increased pro-inflammatory immune cells, inflammation, and inflammation-associated lymphangiogenesis in the kidneys and gonads of male and female mice. However, it is unknown whether these adverse end organ effects result from increased blood pressure (BP), elevated levels of salt, or both. We hypothesized that pharmaceutically lowering BP would not fully alleviate the renal and gonadal immune cell accumulation, inflammation, and lymphangiogenesis associated with SSHTN. SSHTN was induced in male and female C57BL6/J mice by administering nitro-L-arginine methyl ester hydrochloride (L-NAME; 0.5 mg/ml) in their drinking water for 2 weeks, followed by a 2-week washout period. Subsequently, the mice received a 3-week 4% high salt diet (SSHTN). The treatment group underwent the same SSHTN induction protocol but received hydralazine (HYD; 250 mg/L) in their drinking water during the diet phase (SSHTN+HYD). Control mice received tap water and a standard diet for 7 weeks. In addition to decreasing systolic BP, HYD treatment generally decreased pro-inflammatory immune cells and inflammation in the kidneys and gonads of SSHTN mice. Furthermore, the decrease in BP partially alleviated elevated renal and gonadal lymphatics and improved renal and gonadal function in mice with SSHTN. These data demonstrate that high systemic pressure and salt differentially act on end organ immune cells, contributing to the broader understanding of how BP and salt intake collectively shape immune responses and highlight implications for targeted therapeutic interventions.","PeriodicalId":10475,"journal":{"name":"Clinical science","volume":null,"pages":null},"PeriodicalIF":6.7,"publicationDate":"2024-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11250109/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141466693","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}

引用次数: 0

Differential changes in end organ immune cells and inflammation in salt-sensitive hypertension: effects of increasing M2 macrophages. 盐敏感性高血压终末器官免疫细胞和炎症的不同变化：增加 M2 巨噬细胞的影响。

IF 6.7 2区医学

Clinical science Pub Date : 2024-07-17 DOI: 10.1042/CS20240699

Shobana Navaneethabalakrishnan, Bethany L Goodlett, Hannah L Smith, Robert A Montalvo, Alyssa Cardenas, Brett M Mitchell

{"title":"Differential changes in end organ immune cells and inflammation in salt-sensitive hypertension: effects of increasing M2 macrophages.","authors":"Shobana Navaneethabalakrishnan, Bethany L Goodlett, Hannah L Smith, Robert A Montalvo, Alyssa Cardenas, Brett M Mitchell","doi":"10.1042/CS20240699","DOIUrl":"10.1042/CS20240699","url":null,"abstract":"Salt-sensitive hypertension (SSHTN) is associated with M1 macrophage polarization and inflammatory responses, leading to inflammation-associated lymphangiogenesis and functional impairment across multiple organs, including kidneys and gonads. However, it remains unclear whether promoting M2 macrophage polarization can alleviate the hypertension, inflammation, and end organ damage in mice with salt sensitive hypertension (SSHTN). Male and female mice were made hypertensive by administering nitro-L-arginine methyl ester hydrochloride (L-NAME; 0.5 mg/ml) for 2 weeks in the drinking water, followed by a 2-week interval without any treatments, and a subsequent high salt diet for 3 weeks (SSHTN). AVE0991 (AVE) was intraperitoneally administered concurrently with the high salt diet. Control mice were provided standard diet and tap water. AVE treatment significantly attenuated BP and inflammation in mice with SSHTN. Notably, AVE promoted M2 macrophage polarization, decreased pro-inflammatory immune cell populations, and improved function in renal and gonadal tissues of mice with SSHTN. Additionally, AVE decreased lymphangiogenesis in the kidneys and testes of male SSHTN mice and the ovaries of female SSHTN mice. These findings highlight the effectiveness of AVE in mitigating SSHTN-induced elevated BP, inflammation, and end organ damage by promoting M2 macrophage polarization and suppressing pro-inflammatory immune responses. Targeting macrophage polarization emerges as a promising therapeutic approach for alleviating inflammation and organ damage in SSHTN. Further studies are warranted to elucidate the precise mechanisms underlying AVE-mediated effects and to assess its clinical potential in managing SSHTN.","PeriodicalId":10475,"journal":{"name":"Clinical science","volume":null,"pages":null},"PeriodicalIF":6.7,"publicationDate":"2024-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11250104/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141466692","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}

引用次数: 0

Skeletal muscle dysfunction with advancing age. 随着年龄的增长，骨骼肌功能出现障碍。

IF 6.7 2区医学

Clinical science Pub Date : 2024-07-17 DOI: 10.1042/CS20231197

Pardeep Pabla, Eleanor J Jones, Mathew Piasecki, Bethan E Phillips

{"title":"Skeletal muscle dysfunction with advancing age.","authors":"Pardeep Pabla, Eleanor J Jones, Mathew Piasecki, Bethan E Phillips","doi":"10.1042/CS20231197","DOIUrl":"10.1042/CS20231197","url":null,"abstract":"As a result of advances in medical treatments and associated policy over the last century, life expectancy has risen substantially and continues to increase globally. However, the disconnect between lifespan and 'health span' (the length of time spent in a healthy, disease-free state) has also increased, with skeletal muscle being a substantial contributor to this. Biological ageing is accompanied by declines in both skeletal muscle mass and function, termed sarcopenia. The mechanisms underpinning sarcopenia are multifactorial and are known to include marked alterations in muscle protein turnover and adaptations to the neural input to muscle. However, to date, the relative contribution of each factor remains largely unexplored. Specifically, muscle protein synthetic responses to key anabolic stimuli are blunted with advancing age, whilst alterations to neural components, spanning from the motor cortex and motoneuron excitability to the neuromuscular junction, may explain the greater magnitude of function losses when compared with mass. The consequences of these losses can be devastating for individuals, their support networks, and healthcare services; with clear detrimental impacts on both clinical (e.g., mortality, frailty, and post-treatment complications) and societal (e.g., independence maintenance) outcomes. Whether declines in muscle quantity and quality are an inevitable component of ageing remains to be completely understood. Nevertheless, strategies to mitigate these declines are of vital importance to improve the health span of older adults. This review aims to provide an overview of the declines in skeletal muscle mass and function with advancing age, describes the wide-ranging implications of these declines, and finally suggests strategies to mitigate them, including the merits of emerging pharmaceutical agents.","PeriodicalId":10475,"journal":{"name":"Clinical science","volume":null,"pages":null},"PeriodicalIF":6.7,"publicationDate":"2024-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11250095/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141589823","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}

引用次数: 0

Gstp1 negatively regulates blood pressure in hypertensive rat via promoting APLNR ubiquitination degradation mediated by Nedd4. Gstp1 通过促进 Nedd4 介导的 APLNR 泛素化降解，对高血压大鼠的血压进行负向调节。

IF 6.7 2区医学

Clinical science Pub Date : 2024-07-17 DOI: 10.1042/CS20241113

Jianzhen Lei, Fen Zheng, Luyao Chen, Ruyi Zhang, Yang Yang, Zhimin Yin, Lan Luo

{"title":"Gstp1 negatively regulates blood pressure in hypertensive rat via promoting APLNR ubiquitination degradation mediated by Nedd4.","authors":"Jianzhen Lei, Fen Zheng, Luyao Chen, Ruyi Zhang, Yang Yang, Zhimin Yin, Lan Luo","doi":"10.1042/CS20241113","DOIUrl":"10.1042/CS20241113","url":null,"abstract":"Hypertension is a leading risk factor for disease burden worldwide. Vascular contraction and remodeling contribute to the development of hypertension. Glutathione S-transferase P1 (Gstp1) plays several critical roles in both normal and neoplastic cells. In this study, we investigated the effect of Gstp1 on hypertension as well as on vascular smooth muscle cell (VSMC) contraction and phenotypic switching. We identified the higher level of Gstp1 in arteries and VSMCs from hypertensive rats compared with normotensive rats for the first time. We then developed Adeno-associated virus 9 (AAV9) mediated Gstp1 down-regulation and overexpression in rats and measured rat blood pressure by using the tail-cuff and the carotid catheter method. We found that the blood pressure of spontaneously hypertensive rats (SHR) rose significantly with Gstp1 down-regulation and reduced apparently after Gstp1 overexpression. Similar results were obtained from the observations of 2-kidney-1-clip renovascular (2K1C) hypertensive rats. Gstp1 did not influence blood pressure of normotensive Wistar-Kyoto (WKY) rats and Sprague-Dawley (SD) rats. Further in vitro study indicated that Gstp1 knockdown in SHR-VSMCs promoted cell proliferation, migration, dedifferentiation and contraction, while Gstp1 overexpression showed opposite effects. Results from bioinformatic analysis showed that the Apelin/APLNR system was involved in the effect of Gstp1 on SHR-VSMCs. The rise in blood pressure of SHR induced by Gstp1 knockdown could be reversed by APLNR antagonist F13A. We further found that Gstp1 enhanced the association between APLNR and Nedd4 E3 ubiquitin ligases to induce APLNR ubiquitination degradation. Thus, in the present study, we discovered a novel anti-hypertensive role of Gstp1 in hypertensive rats and provided the experimental basis for designing an effective anti-hypertensive therapeutic strategy.","PeriodicalId":10475,"journal":{"name":"Clinical science","volume":null,"pages":null},"PeriodicalIF":6.7,"publicationDate":"2024-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141497304","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}

引用次数: 0

Skeletal muscle immobilisation-induced atrophy: mechanistic insights from human studies. 骨骼肌固定诱发的萎缩：人体研究的机理启示。

IF 6.7 2区医学

Clinical science Pub Date : 2024-06-19 DOI: 10.1042/CS20231198

Colleen S Deane, Matthew Piasecki, Philip J Atherton

引用次数: 0

Correction: Enhanced expression of pro-inflammatory mediators and liver X-receptor-regulated lipogenic genes in non-alcoholic fatty liver disease and hepatitis C. 更正：在非酒精性脂肪肝和丙型肝炎中，促炎介质和肝 X 受体调控的致脂基因表达增强。

IF 6.7 2区医学

Clinical science Pub Date : 2024-06-19 DOI: 10.1042/CS-2010-0387_COR

引用次数: 0

Galectin-3 inhibition alleviated LPS-induced periodontal inflammation in gingival fibroblasts and experimental periodontitis mice. 抑制 Galectin-3 可减轻 LPS 诱导的牙龈成纤维细胞和实验性牙周炎小鼠的牙周炎症。

IF 6.7 2区医学

Clinical science Pub Date : 2024-06-19 DOI: 10.1042/CS20240036

Song Wenjing, Liu Mengmeng, Shang Lingling, Ding Tian, Kang Wenyan, Ge Shaohua

{"title":"Galectin-3 inhibition alleviated LPS-induced periodontal inflammation in gingival fibroblasts and experimental periodontitis mice.","authors":"Song Wenjing, Liu Mengmeng, Shang Lingling, Ding Tian, Kang Wenyan, Ge Shaohua","doi":"10.1042/CS20240036","DOIUrl":"10.1042/CS20240036","url":null,"abstract":"Objectives: Clinical studies have confirmed that galectin-3 (Gal-3) levels are significantly elevated in periodontitis patients. The present study aimed to explore the effects of Gal-3 inhibition on periodontal inflammation in vitro and in vivo.Methods: Human gingival fibroblasts (HGFs) with or without Gal-3 knockdown were stimulated by lipopolysaccharide (LPS), and a ligation-induced mouse periodontitis model treated with a Gal-3 inhibitor was established. Hematoxylin-eosin (H&E) and immunohistochemistry (IHC) staining were used to evaluate Gal-3 levels in gingival tissues. Quantitative real-time polymerase chain reaction (qRT-PCR) and enzyme-linked immunosorbent assay (ELISA) were used to detect Gal-3, interleukin (IL)-6, IL-8, and C-C motif ligand 2 (CCL2) expression. Immunofluorescence and western blotting were used to detect NF-κB and ERK signaling pathway activation. Micro-computed tomography was used to analyse the degree of bone loss.Results: Gal-3 was significantly up-regulated in inflamed gingival tissues and LPS-induced HGFs. Gal-3 knockdown markedly decreased LPS-induced IL-6, IL-8, and CCL2 expression and blocked NF-κB and ERK signaling pathway activation in HGFs. In the mouse periodontitis model, Gal-3 inhibition significantly alleviated IL-1β and IL-6 infiltration in gingival tissue and mitigated periodontal bone loss.Conclusions: Gal-3 inhibition notably alleviated periodontal inflammation partly through blocking NF-κB and ERK signaling pathway activation.","PeriodicalId":10475,"journal":{"name":"Clinical science","volume":null,"pages":null},"PeriodicalIF":6.7,"publicationDate":"2024-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141261326","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}

引用次数: 0

Targeting the endothelium by combining endothelin-1 antagonism and SGLT-2 inhibition: better together? 结合内皮素-1 拮抗剂和 SGLT-2 抑制剂靶向内皮：两者结合效果更好？

IF 6 2区医学

Clinical science Pub Date : 2024-06-05 DOI: 10.1042/CS20240605

Phil Ambery, Peter J Greasley, Robert I Menzies, Lena Brynne, Spoorthy Kulkarni, Jan Oscarsson, Anthony P Davenport

引用次数: 0

Precision diagnostics in transplanted organs using microarray-assessed gene expression: concepts and technical methods of the Molecular Microscope® Diagnostic System (MMDx). 利用芯片评估基因表达对移植器官进行精确诊断：分子显微镜®诊断系统（MMDx）的概念和技术方法。

IF 6 2区医学

Clinical science Pub Date : 2024-06-05 DOI: 10.1042/CS20220530

Katelynn S Madill-Thomsen, Philip F Halloran

{"title":"Precision diagnostics in transplanted organs using microarray-assessed gene expression: concepts and technical methods of the Molecular Microscope® Diagnostic System (MMDx).","authors":"Katelynn S Madill-Thomsen, Philip F Halloran","doi":"10.1042/CS20220530","DOIUrl":"10.1042/CS20220530","url":null,"abstract":"There is a major unmet need for improved accuracy and precision in the assessment of transplant rejection and tissue injury. Diagnoses relying on histologic and visual assessments demonstrate significant variation between expert observers (as represented by low kappa values) and have limited ability to assess many biological processes that produce little histologic changes, for example, acute injury. Consensus rules and guidelines for histologic diagnosis are useful but may have errors. Risks of over- or under-treatment can be serious: many therapies for transplant rejection or primary diseases are expensive and carry risk for significant adverse effects. Improved diagnostic methods could alleviate healthcare costs by reducing treatment errors, increase treatment efficacy, and serve as useful endpoints for clinical trials of new agents that can improve outcomes. Molecular diagnostic assessments using microarrays combined with machine learning algorithms for interpretation have shown promise for increasing diagnostic precision via probabilistic assessments, recalibrating standard of care diagnostic methods, clarifying ambiguous cases, and identifying potentially missed cases of rejection. This review describes the development and application of the Molecular Microscope® Diagnostic System (MMDx), and discusses the history and reasoning behind many common methods, statistical practices, and computational decisions employed to ensure that MMDx scores are as accurate and precise as possible. MMDx provides insights on disease processes and highly reproducible results from a comparatively small amount of tissue and constitutes a general approach that is useful in many areas of medicine, including kidney, heart, lung, and liver transplants, with the possibility of extrapolating lessons for understanding native organ disease states.","PeriodicalId":10475,"journal":{"name":"Clinical science","volume":null,"pages":null},"PeriodicalIF":6.0,"publicationDate":"2024-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11147747/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141178807","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}

引用次数: 0

Is endothelin targeting finally ready for prime time? 内皮素靶向疗法终于准备好进入黄金时代了吗？

IF 6 2区医学

Clinical science Pub Date : 2024-06-05 DOI: 10.1042/CS20240607

Francesca Schinzari, Manfredi Tesauro, Carmine Cardillo

{"title":"Is endothelin targeting finally ready for prime time?","authors":"Francesca Schinzari, Manfredi Tesauro, Carmine Cardillo","doi":"10.1042/CS20240607","DOIUrl":"10.1042/CS20240607","url":null,"abstract":"The endothelin family of peptides has long been recognized as a physiological regulator of diverse biological functions and mechanistically involved in various disease states, encompassing, among others, the cardiovascular system, the kidney, and the nervous system. Pharmacological blockade of the endothelin system, however, has encountered strong obstacles in its entry into the clinical mainstream, having obtained only a few proven indications until recently. This translational gap has been attributable predominantly to the relevant side effects associated with endothelin receptor antagonism (ERA), particularly fluid retention. Of recent, however, an expanding understanding of the pathophysiological processes involving endothelin, in conjunction with the development of new antagonists of endothelin receptors or adjustment of their doses, has driven a flourish of new clinical trials. The favorable results of some of them have extended the proven indications for ET targeting to a variety of clinical conditions, including resistant arterial hypertension and glomerulopathies. In addition, on the ground of strong preclinical evidence, other studies are ongoing to test the potential benefits of ERA in combination with other treatments, such as sodium-glucose co-transporter 2 inhibition in fluid retentive states or anti-cancer therapies in solid tumors. Furthermore, antibodies providing long-term blockade of endothelin receptors are under testing to overcome the short half-life of most small molecule endothelin antagonists. These efforts may yet bring new life to the translation of endothelin targeting strategies in clinical practice.","PeriodicalId":10475,"journal":{"name":"Clinical science","volume":null,"pages":null},"PeriodicalIF":6.0,"publicationDate":"2024-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141086914","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}

引用次数: 0