Clinical Science (London, England : 1979)最新文献

{"title":"Maintaining energy provision in the heart: the creatine kinase system in ischaemia–reperfusion injury and chronic heart failure","authors":"C. Lygate","doi":"10.1042/CS20230616","DOIUrl":"https://doi.org/10.1042/CS20230616","url":null,"abstract":"Abstract The non-stop provision of chemical energy is of critical importance to normal cardiac function, requiring the rapid turnover of ATP to power both relaxation and contraction. Central to this is the creatine kinase (CK) phosphagen system, which buffers local ATP levels to optimise the energy available from ATP hydrolysis, to stimulate energy production via the mitochondria and to smooth out mismatches between energy supply and demand. In this review, we discuss the changes that occur in high-energy phosphate metabolism (i.e., in ATP and phosphocreatine) during ischaemia and reperfusion, which represents an acute crisis of energy provision. Evidence is presented from preclinical models that augmentation of the CK system can reduce ischaemia–reperfusion injury and improve functional recovery. Energetic impairment is also a hallmark of chronic heart failure, in particular, down-regulation of the CK system and loss of adenine nucleotides, which may contribute to pathophysiology by limiting ATP supply. Herein, we discuss the evidence for this hypothesis based on preclinical studies and in patients using magnetic resonance spectroscopy. We conclude that the correlative evidence linking impaired energetics to cardiac dysfunction is compelling; however, causal evidence from loss-of-function models remains equivocal. Nevertheless, proof-of-principle studies suggest that augmentation of CK activity is a therapeutic target to improve cardiac function and remodelling in the failing heart. Further work is necessary to translate these findings to the clinic, in particular, a better understanding of the mechanisms by which the CK system is regulated in disease.","PeriodicalId":519494,"journal":{"name":"Clinical Science (London, England : 1979)","volume":"48 9","pages":"491 - 514"},"PeriodicalIF":0.0,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140797693","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Smoking-induced microbial dysbiosis in health and disease.","authors":"Hagit Shapiro,&nbsp;Kim Goldenberg,&nbsp;Karina Ratiner,&nbsp;Eran Elinav","doi":"10.1042/CS20220175","DOIUrl":"https://doi.org/10.1042/CS20220175","url":null,"abstract":"<p><p>Smoking is associated with an increased risk of cancer, pulmonary and cardiovascular diseases, but the precise mechanisms by which such risk is mediated remain poorly understood. Additionally, smoking can impact the oral, nasal, oropharyngeal, lung and gut microbiome composition, function, and secreted molecule repertoire. Microbiome changes induced by smoking can bear direct consequences on smoking-related illnesses. Moreover, smoking-associated dysbiosis may modulate weight gain development following smoking cessation. Here, we review the implications of cigarette smoking on microbiome community structure and function. In addition, we highlight the potential impacts of microbial dysbiosis on smoking-related diseases. We discuss challenges in studying host-microbiome interactions in the context of smoking, such as the correlations with smoking-related disease severity versus causation and mechanism. In all, understanding the microbiome's role in the pathophysiology of smoking-related diseases may promote the development of rational therapies for smoking- and smoking cessation-related disorders, as well as assist in smoking abstinence.</p>","PeriodicalId":519494,"journal":{"name":"Clinical Science (London, England : 1979)","volume":" ","pages":"1371-1387"},"PeriodicalIF":6.0,"publicationDate":"2022-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9527826/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33481114","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ANGPTL1, Foxo3a-Sox2, and colorectal cancer metastasis.","authors":"Kai Jiang,&nbsp;Haiyan Chen,&nbsp;Kefeng Ding","doi":"10.1042/CS20220394","DOIUrl":"https://doi.org/10.1042/CS20220394","url":null,"abstract":"<p><p>In the present commentary, we discuss new observations stating that angiopoietin-like protein 1 (ANGPTL1) attenuates cancer metastasis and stemness through Forkhead box O-3a (Foxo3a)-SRY-related HMG-box-2 (Sox2) axis in colorectal cancer (Clin. Sci. (2022) 136, 657-673, https://doi.org/10.1042/CS20220043). ANGPTL1 has been reported to play a critical role in cancer progression and metastasis. However, the underlying mechanisms remain controversial. Here, we integrate the possible mechanisms for ANGPTL1 inhibiting colorectal cancer liver metastasis and discuss the regulation of ANGPTL1 on the Foxo3a-Sox2 pathway. Although ANGPTL1 showed multifunctional potential, there is still a long way to go for ANGPTL1 to be an effective treatment strategy in the clinic.</p>","PeriodicalId":519494,"journal":{"name":"Clinical Science (London, England : 1979)","volume":" ","pages":"1367-1370"},"PeriodicalIF":6.0,"publicationDate":"2022-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9527825/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33482090","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Severe psychiatric disorders and general medical comorbidities: inflammation-related mechanisms and therapeutic opportunities.","authors":"Antonio L Teixeira,&nbsp;Lais B Martins,&nbsp;Michael Berk,&nbsp;Moisés E Bauer","doi":"10.1042/CS20211106","DOIUrl":"https://doi.org/10.1042/CS20211106","url":null,"abstract":"<p><p>Individuals with severe psychiatric disorders, such as mood disorders and schizophrenia, are at increased risk of developing other medical conditions, especially cardiovascular and metabolic diseases. These medical conditions are underdiagnosed and undertreated in these patients contributing to their increased morbidity and mortality. The basis for this increased comorbidity is not well understood, possibly reflecting shared risks factors (e.g. lifestyle risk factors), shared biological mechanisms and/or reciprocal interactions. Among overlapping pathophysiological mechanisms, inflammation and related factors, such as dysbiosis and insulin resistance, stand out. Besides underlying the association between psychiatric disorders and cardiometabolic diseases, these mechanisms provide several potential therapeutic targets.</p>","PeriodicalId":519494,"journal":{"name":"Clinical Science (London, England : 1979)","volume":" ","pages":"1257-1280"},"PeriodicalIF":6.0,"publicationDate":"2022-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40351181","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Circulating cell-free micro-RNA as biomarkers: from myocardial infarction to hypertension.","authors":"Jessica L Faulkner,&nbsp;Jennifer C Sullivan","doi":"10.1042/CS20220056","DOIUrl":"https://doi.org/10.1042/CS20220056","url":null,"abstract":"<p><p>MicroRNA (miRNA) are small, single strand non-coding RNA molecules involved in the post-transcriptional regulation of target genes. Since their discovery in 1993, over 2000 miRNAs have been identified in humans and there is growing interest in both the diagnostic and therapeutic potential of miRNA. The identification of biomarkers for human disease progression remains an active area of research, and there is a growing number of miRNA and miRNA combinations that have been linked to the development and progression of numerous cardiovascular diseases, including hypertension. In 2010, Chen et al. reported in Clinical Science that cell-free circulating miRNA could serve as novel biomarkers for acute myocardial infarction [1]. In this commentary, we expand on this topic to discuss the potential of using miRNA as biomarkers for hypertension and hypertension-related end-organ damage.</p>","PeriodicalId":519494,"journal":{"name":"Clinical Science (London, England : 1979)","volume":" ","pages":"1341-1346"},"PeriodicalIF":6.0,"publicationDate":"2022-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40373895","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multicellular regulation of miR-196a-5p and miR-425-5 from adipose stem cell-derived exosomes and cardiac repair.","authors":"Nathalia C de Almeida Oliveira,&nbsp;Elida A Neri,&nbsp;Caio M Silva,&nbsp;Iuri C Valadão,&nbsp;Miriam H Fonseca-Alaniz,&nbsp;Camila Zogbi,&nbsp;Débora Levy,&nbsp;Sergio P Bydlowski,&nbsp;Jose Eduardo Krieger","doi":"10.1042/CS20220216","DOIUrl":"https://doi.org/10.1042/CS20220216","url":null,"abstract":"<p><p>Cardiac transplantation of adipose-derived stem cells (ASC) modulates the post-myocardial infarction (post-MI) repair response. Biomolecules secreted or shuttled within extracellular vesicles, such as exosomes, may participate in the concerted response. We investigated the exosome's microRNAs due to their capacity to fine-tune gene expression, potentially affecting the multicellular repair response. We profiled and quantified rat ASC-exosome miRNAs and used bioinformatics to select uncharacterized miRNAs down-regulated in post-MI related to cardiac repair. We selected and validated miR-196a-5p and miR-425-5p as candidates for the concerted response in neonatal cardiomyocytes, cardiac fibroblasts, endothelial cells, and macrophages using a high-content screening platform. Both miRNAs prevented cardiomyocyte ischemia-induced mitochondrial dysfunction and reactive oxygen species production, increased angiogenesis, and polarized macrophages toward the anti-inflammatory M2 immunophenotype. Moreover, miR-196a-5p reduced and reversed myofibroblast activation and decreased collagen expression. Our data provide evidence that the exosome-derived miR-196a-5p and miR-425-5p influence biological processes critical to the concerted multicellular repair response post-MI.</p>","PeriodicalId":519494,"journal":{"name":"Clinical Science (London, England : 1979)","volume":" ","pages":"1281-1301"},"PeriodicalIF":6.0,"publicationDate":"2022-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40549879","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Interactions between the intrarenal dopaminergic and the renin-angiotensin systems in the control of systemic arterial pressure.","authors":"Pedro Alves Soares Vaz de Castro,&nbsp;Pedro A Jose,&nbsp;Ana Cristina Simões E Silva","doi":"10.1042/CS20220338","DOIUrl":"https://doi.org/10.1042/CS20220338","url":null,"abstract":"<p><p>Systemic arterial hypertension is one of the leading causes of morbidity and mortality in the general population, being a risk factor for many cardiovascular diseases. Although its pathogenesis is complex and still poorly understood, some systems appear to play major roles in its development. This review aims to update the current knowledge on the interaction of the intrarenal renin-angiotensin system (RAS) and dopaminergic system in the development of hypertension, focusing on recent scientific hallmarks in the field. The intrarenal RAS, composed of several peptides and receptors, has a critical role in the regulation of blood pressure (BP) and, consequently, the development of hypertension. The RAS is divided into two main intercommunicating axes: the classical axis, composed of angiotensin-converting enzyme, angiotensin II, and angiotensin type 1 receptor, and the ACE2/angiotensin-(1-7)/Mas axis, which appears to modulate the effects of the classical axis. Dopamine and its receptors are also increasingly showing an important role in the pathogenesis of hypertension, as abnormalities in the intrarenal dopaminergic system impair the regulation of renal sodium transport, regardless of the affected dopamine receptor subtype. There are five dopamine receptors, which are divided into two major subtypes: the D1-like (D1R and D5R) and D2-like (D2R, D3R, and D4R) receptors. Mice deficient in any of the five dopamine receptor subtypes have increased BP. Intrarenal RAS and the dopaminergic system have complex interactions. The balance between both systems is essential to regulate the BP homeostasis, as alterations in the control of both can lead to hypertension.</p>","PeriodicalId":519494,"journal":{"name":"Clinical Science (London, England : 1979)","volume":" ","pages":"1205-1227"},"PeriodicalIF":6.0,"publicationDate":"2022-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40719558","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The negative regulation of gene expression by microRNAs as key driver of inducers and repressors of cardiomyocyte differentiation.","authors":"Eleonora Cianflone,&nbsp;Mariangela Scalise,&nbsp;Fabiola Marino,&nbsp;Luca Salerno,&nbsp;Nadia Salerno,&nbsp;Konrad Urbanek,&nbsp;Daniele Torella","doi":"10.1042/CS20220391","DOIUrl":"https://doi.org/10.1042/CS20220391","url":null,"abstract":"<p><p>Cardiac muscle damage-induced loss of cardiomyocytes (CMs) and dysfunction of the remaining ones leads to heart failure, which nowadays is the number one killer worldwide. Therapies fostering effective cardiac regeneration are the holy grail of cardiovascular research to stop the heart failure epidemic. The main goal of most myocardial regeneration protocols is the generation of new functional CMs through the differentiation of endogenous or exogenous cardiomyogenic cells. Understanding the cellular and molecular basis of cardiomyocyte commitment, specification, differentiation and maturation is needed to devise innovative approaches to replace the CMs lost after injury in the adult heart. The transcriptional regulation of CM differentiation is a highly conserved process that require sequential activation and/or repression of different genetic programs. Therefore, CM differentiation and specification have been depicted as a step-wise specific chemical and mechanical stimuli inducing complete myogenic commitment and cell-cycle exit. Yet, the demonstration that some microRNAs are sufficient to direct ESC differentiation into CMs and that four specific miRNAs reprogram fibroblasts into CMs show that CM differentiation must also involve negative regulatory instructions. Here, we review the mechanisms of CM differentiation during development and from regenerative stem cells with a focus on the involvement of microRNAs in the process, putting in perspective their negative gene regulation as a main modifier of effective CM regeneration in the adult heart.</p>","PeriodicalId":519494,"journal":{"name":"Clinical Science (London, England : 1979)","volume":" ","pages":"1179-1203"},"PeriodicalIF":6.0,"publicationDate":"2022-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/d4/a2/cs-136-cs20220391.PMC9411751.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40719559","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The complex genetic basis of fibromuscular dysplasia, a systemic arteriopathy associated with multiple forms of cardiovascular disease.","authors":"Adrien Georges,&nbsp;Nabila Bouatia-Naji","doi":"10.1042/CS20210990","DOIUrl":"https://doi.org/10.1042/CS20210990","url":null,"abstract":"<p><p>Artery stenosis is a common cause of hypertension and stroke and can be due to atherosclerosis accumulation in the majority of cases and in a small fraction of patients to arterial fibromuscular dysplasia (FMD). Artery stenosis due to atherosclerosis is widely studied with known risk factors (e.g. increasing age, male gender, and dyslipidemia) to influence its etiology, including genetic factors. However, the causes of noninflammatory and nonatherosclerotic stenosis in FMD are less understood. FMD occurs predominantly in early middle-age women, a fraction of the population where cardiovascular risk is different and understudied. FMD arteriopathies are often diagnosed in the context of hypertension and stroke and co-occur mainly with spontaneous coronary artery dissection, an atypical cause of acute myocardial infarction. In this review, we provide a comprehensive overview of the recent advances in the understanding of molecular origins of FMD. Data were obtained from genetic studies using complementary methodological approaches applied to familial, syndromic, and sporadic forms of this intriguing arteriopathy. Rare variation analyses point toward mechanisms related to impaired prostacyclin signaling and defaults in fibrillar collagens. The study of common variation, mainly through a recent genome-wide association study, describes a shared genetic link with blood pressure, in addition to point at potential risk genes involved in actin cytoskeleton and intracellular calcium homeostasis supporting impaired vascular contraction as a key mechanism. We conclude this review with future strategies and approaches needed to fully understand the genetic and molecular mechanisms related to FMD.</p>","PeriodicalId":519494,"journal":{"name":"Clinical Science (London, England : 1979)","volume":" ","pages":"1241-1255"},"PeriodicalIF":6.0,"publicationDate":"2022-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/f5/87/cs-136-cs20210990.PMC9434409.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40333057","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Maternal immune activation in rats induces dysfunction of placental leucine transport and alters fetal brain growth.","authors":"Hager M Kowash,&nbsp;Harry G Potter,&nbsp;Rebecca M Woods,&nbsp;Nick Ashton,&nbsp;Reinmar Hager,&nbsp;Joanna C Neill,&nbsp;Jocelyn D Glazier","doi":"10.1042/CS20220245","DOIUrl":"https://doi.org/10.1042/CS20220245","url":null,"abstract":"<p><p>Maternal infection during pregnancy increases the offspring risk of developing a variety of neurodevelopmental disorders (NDDs), including schizophrenia. While the mechanisms remain unclear, dysregulation of placental function is implicated. We hypothesised that maternal infection, leading to maternal immune activation and stimulated cytokine production, alters placental and yolk sac amino acid transport, affecting fetal brain development and thus NDD risk. Using a rat model of maternal immune activation induced by the viral mimetic polyinosinic:polycytidylic acid (poly(I:C)), we investigated placental and yolk sac expression of system L amino acid transporter subtypes which transport several essential amino acids including branched-chain amino acids (BCAA), maternal and fetal BCAA concentration, placental 14C-leucine transport activity and associated impacts on fetal growth and development. Poly(I:C) treatment increased acutely maternal IL-6 and TNFα concentration, contrasting with IL-1β. Transcriptional responses for these pro-inflammatory cytokines were found in placenta and yolk sac following poly(I:C) treatment. Placental and yolk sac weights were reduced by poly(I:C) treatment, yet fetal body weight was unaffected, while fetal brain weight was increased. Maternal plasma BCAA concentration was reduced 24 h post-poly(I:C) treatment, yet placental, but not yolk sac, BCAA concentration was increased. Placental and yolk sac gene expression of Slc7a5, Slc7a8 and Slc43a2 encoding LAT1, LAT2 and LAT4 transporter subtypes, respectively, was altered by poly(I:C) treatment. Placental 14C-leucine transport was significantly reduced 24 h post-treatment, contrasting with a significant increase 6 days following poly(I:C) treatment. Maternal immune activation induces dysregulated placental transport of amino acids affecting fetal brain development, and NDD risk potential in offspring.</p>","PeriodicalId":519494,"journal":{"name":"Clinical Science (London, England : 1979)","volume":" ","pages":"1117-1137"},"PeriodicalIF":6.0,"publicationDate":"2022-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9366863/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40616474","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}