The glucocorticoid receptor is a member of the nuclear receptor family that controls many distinct gene networks, governing various aspects of development, metabolism, inflammation, and the stress response, as well as other key biological processes in the cardiovascular system. Recently, research in both animal models and humans has begun to unravel the profound complexity of glucocorticoid signaling and convincingly demonstrates that the glucocorticoid receptor has direct effects on the heart and vessels in vivo and in vitro. This research has contributed directly to improving therapeutic strategies in human disease. The glucocorticoid receptor is activated either by the endogenous steroid hormone cortisol or by exogenous glucocorticoids and acts within the cardiovascular system via both genomic and non-genomic pathways. Polymorphisms of the glucocorticoid receptor are also reported to influence the progress and prognosis of cardiovascular disease. In this review, we provide an update on glucocorticoid signaling and highlight the critical role of this signaling in both physiological and pathological conditions of the cardiovascular system. With increasing in-depth understanding of glucocorticoid signaling, the future is promising for the development of targeted glucocorticoid treatments and improved clinical outcomes.

https://www.mdpi.com/2073-4409/8/10/1227/pdf

The Glucocorticoid Receptor in Cardiovascular Health and Disease.

Osteoporosis is a systemic disease that results in loss of bone density and increased fracture risk, particularly in the vertebrae and the hip. This condition and associated morbidity and mortality increase with population ageing. Long noncoding (lnc) RNAs are transcripts longer than 200 nucleotides that are not translated into proteins, but play important regulatory roles in transcriptional and post-transcriptional regulation. Their contribution to disease onset and development is increasingly recognized. Herein, we present an integrative revision on the studies that implicate lncRNAs in osteoporosis and that support their potential use as therapeutic tools. Firstly, current evidence on lncRNAs involvement in cellular and molecular mechanisms linked to osteoporosis and its major complication, fragility fractures, is reviewed. We analyze evidence of their roles in osteogenesis, osteoclastogenesis, and bone fracture healing events from human and animal model studies. Secondly, the potential of lncRNAs alterations at genetic and transcriptomic level are discussed as osteoporosis risk factors and as new circulating biomarkers for diagnosis. Finally, we conclude debating the possibilities, persisting difficulties, and future prospects of using lncRNAs in the treatment of osteoporosis.

Long noncoding RNAs: a missing link in osteoporosis

Sepsis is defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection. In 2017, almost 50 million cases of sepsis were recorded worldwide and 11 million sepsis-related deaths were reported. Therefore, sepsis is the focus of intense research to better understand the complexities of sepsis response, particularly the twin underlying concepts of an initial hyper-immune response and a counter-immunological state of immunosuppression triggered by an invading pathogen. Diagnosis of sepsis remains a significant challenge. Prompt diagnosis is essential so that treatment can be instigated as early as possible to ensure the best outcome, as delay in treatment is associated with higher mortality. In order to address this diagnostic problem, use of a panel of biomarkers has been proposed as, due to the complexity of the sepsis response, no single marker is sufficient. This review provides background on the current understanding of sepsis in terms of its epidemiology, the evolution of the definition of sepsis, pathobiology and diagnosis and management. Candidate biomarkers of interest and how current and developing point-of-care testing approaches could be used to measure such biomarkers is discussed.

https://www.mdpi.com/2072-666X/11/3/286/pdf

Biomarkers for Point-of-Care Diagnosis of Sepsis.

Background: MicroRNAs (miRNAs) are small, single-stranded RNA sequences that regulate gene expression on a post-transcriptional level. In the last few decades, various trials have investigated the diagnostic and therapeutic potential of miRNAs in several disease entities. Here, we provide a review of the available evidence on miRNAs in inflammatory heart diseases (myocarditis, endocarditis, and pericarditis) and sepsis-induced cardiac dysfunction. Methods: Systematic database research using the PubMed and Medline databases was conducted between July and September 2019 using predefined search terms. The whole review was conducted based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Results: In total, 131 studies were screened, 96 abstracts were read, and 69 studies were included in the review. Discussion: In the future, circulating miRNAs could serve as biomarkers for diagnosis and disease monitoring in the context of inflammatory heart diseases and sepsis-induced cardiac dysfunction. Considering the promising results of different animal models, certain miRNAs could also emerge as novel therapeutic approaches in this setting.

/pdf/micrornas-in-inflammatory-heart-diseases-and-sepsis-induced-4t6nq0r23g.pdf

MicroRNAs in Inflammatory Heart Diseases and Sepsis-Induced Cardiac Dysfunction: A Potential Scope for the Future?

Current methods to differentiate cardiomyocytes from human pluripotent stem cells (PSCs) inadequately recapitulate complete development and result in PSC-derived cardiomyocytes (PSC-CMs) with an immature or fetal-like phenotype. Embryonic and fetal development are highly dynamic periods during which the developing embryo or fetus is exposed to changing nutrient, oxygen, and hormone levels until birth. It is becoming increasingly apparent that these metabolic changes initiate developmental processes to mature cardiomyocytes. Mitochondria are central to these changes, responding to these metabolic changes and transitioning from small, fragmented mitochondria to large organelles capable of producing enough ATP to support the contractile function of the heart. These changes in mitochondria may not simply be a response to cardiomyocyte maturation; the metabolic signals that occur throughout development may actually be central to the maturation process in cardiomyocytes. Here, we review methods to enhance maturation of PSC-CMs and highlight evidence from development indicating the key roles that mitochondria play during cardiomyocyte maturation. We evaluate metabolic transitions that occur during development and how these affect molecular nutrient sensors, discuss how regulation of nutrient sensing pathways affect mitochondrial dynamics and function, and explore how changes in mitochondrial function can affect metabolite production, the cell cycle, and epigenetics to influence maturation of cardiomyocytes.

/pdf/mitochondria-and-metabolic-transitions-in-cardiomyocytes-qc0owky5xa.pdf

Mitochondria and metabolic transitions in cardiomyocytes: lessons from development for stem cell-derived cardiomyocytes.

// Tie-Ning Zhang 1 , Da Li 2 , Jing Xia 1 , Qi-Jun Wu 3 , Ri Wen 1 , Ni Yang 1 and Chun-Feng Liu 1 1 Department of Pediatrics, PICU, Shengjing Hospital of China Medical University, Shenyang, China 2 Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, China 3 Department of Clinical Epidemiology, Shengjing Hospital of China Medical University, Shenyang, China Correspondence to: Chun-Feng Liu, email: zhliu258@hotmail.com Keywords: sepsis, non-coding RNA, biogenesis, biomarkers, therapeutic target Received: April 28, 2017     Accepted: September 03, 2017     Published: October 10, 2017 ABSTRACT Sepsis, a syndrome of physiologic, pathologic, and biochemical abnormalities caused by an altered systemic host response to infection, has become the main cause of death among patients admitted to the intensive care units. Recently, genome-wide expression analysis revealed that over 80% of the essential genetic elements were altered in critically ill patients. Notably, non-coding RNAs, including microRNAs, long non-coding RNAs and circular RNAs, have been proven to play essential roles in innate immunity, mitochondrial dysfunction and organ dysfunction. In this review, we introduced the biogenesis of non-coding RNAs briefly and summed up different kinds of non-coding RNAs in regulation of sepsis, which could provide a more comprehensive understanding about pathogenesis of the disease. Additionally, we summarized the limitations of current biomarkers and then recommended some non-coding RNAs as novel potential biomarkers for sepsis and sepsis-induced organ dysfunction. Besides, we also introduced some problems and challenges that need to be overcome during the clinical application of non-coding RNAs. Future research should focus on elucidating their molecular mechanisms, particularly long non-coding RNAs as well as circular RNAs and sepsis, to further understanding of the disease process. With the in-depth understanding of the mechanism of sepsis, non-coding RNAs provide a new insight into sepsis and could become the novel therapeutic targets in the future.

/pdf/non-coding-rna-a-potential-biomarker-and-therapeutic-target-9383lgm4ll.pdf

Non-coding RNA: a potential biomarker and therapeutic target for sepsis.

Septic shock with heart dysfunction is very common in intensive care units. However, whether long noncoding RNA (lncRNA) and mRNA profiles differ between patients with and without myocardial depression is unknown. We generated rat models of hypodynamic septic shock induced by lipopolysaccharide. A total of 12 rat models was constructed and heart tissue from each was collected. Whole genomic RNA sequencing was performed on left ventricular tissue; 6,508 novel lncRNAs and 432 annotated lncRNAs were identified in heart samples, and 74 lncRNAs were expressed differently in the sepsis and control groups. Gene ontology term enrichment indicated apoptosis and its related pathways showed obvious enrichment, which suggested cell apoptosis could play a critical role in the process of myocardial depression. Furthermore, we focused on one lncRNA from the Pvt1 gene. By silencing this lncRNA, we demonstrated knockdown of Pvt1 expression could induce cell apoptosis in lipopolysaccharide-induced heart cells, through increasing the expression of c-Myc, Bid, Bax, and caspase-3 and decreasing the expression of Myd88 and Bcl-2, thereby proving its functional role in myocardial depression. These results demonstrate that lncRNAs both participate in and mediate the pathological process of myocardial depression. Our study improves the understanding of the basic molecular mechanisms underlying myocardial depression.

Characterization of Long Noncoding RNA and mRNA Profiles in Sepsis-Induced Myocardial Depression.

Septic shock with heart dysfunction is common in intensive care units. However, the mechanism underlying myocardial depression is still unclear. Whether circular RNA (circRNA) or microRNA (miRNA) profiles differ between patients with and without myocardial depression is unknown. We generated a hypodynamic septic shock model induced by lipopolysaccharide (LPS) in adolescent rats. A total of 12 rats were utilized and heart tissue from each was collected. RNA sequencing was performed on left ventricular tissue. We focused on features of circRNAs and miRNAs, predicting their function by bioinformatic analysis and constructing circRNA-associated and miRNA-associated regulatory networks in heart tissue. We detected 851 circRNAs in heart samples, and 11 showed differential expression. A total of 639 annotated miRNAs and 91 novel miRNAs were explored including 78 showing differential expression between the two groups. We then constructed the most comprehensive circRNA-associated and miRNA-associated networks to explore their regulatory relationship in septic heart tissue, and demonstrated that different networks could potentially participate in and regulate the pathological process of sepsis. Furthermore, gene ontology term enrichment indicated miRNAs, and miRNA-mRNA networks could be associated with regulation and metabolic process, or influence cellular functions. The construction of regulator networks could improve the understanding of the basic molecular mechanisms underlying myocardial depression. It will be important for future investigations to ascertain the biological mechanisms present during the development of sepsis-induced myocardial depression to influence approaches to treatment.

Characterization of Circular RNA and microRNA Profiles in Septic Myocardial Depression: a Lipopolysaccharide-Induced Rat Septic Shock Model

Sepsis-induced myocardial depression has high mortality and is very common in intensive care units. Previous studies have found that microRNAs play an important role in regulating sepsis-induced myocardial depression. miR-150-5p is involved in many biological processes; however, the mechanism underlying its role in sepsis-induced myocardial depression is still unclear. In this study, we generated rat models of septic shock induced by lipopolysaccharide. Whole genomic RNA sequencing was performed on 12 left ventricles collected after LPS treatment to identify miRNAs. Most of the target genes of the differently expressed microRNAs were involved in apoptosis, according to Gene Ontology. We also observed apoptosis in the heart tissue and in H9C2 cardiomyocytes stimulated with lipopolysaccharide, indicating that cell apoptosis may be an important mechanism in sepsis-induced myocardial depression. Furthermore, the expression of miR-150-5p was reduced, and overexpression of miR-150-5p with mimics resulted in a decrease in apoptosis, decreased expression of cleaved caspase3 and Bax, and increased expression of Bcl-2. Additionally, after H9C2 cells were transfected with miR-150-5p mimics or an inhibitor, the expression of Akt2 decreased or increased, respectively. These findings suggest that miR-150-5p can alleviate apoptosis and may be a novel therapeutic target for sepsis-induced myocardial depression.

/pdf/overexpression-of-mir-150-5p-alleviates-apoptosis-in-sepsis-30qyol3zj1.pdf

Overexpression of miR-150-5p Alleviates Apoptosis in Sepsis-Induced Myocardial Depression.

Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection and is characterized by a hyperinflammatory state accompanied by immunosuppression. Long noncoding RNAs (lncRNAs) are noncoding RNAs longer than 200 nucleotides and have important roles in mediating various biological processes. Recently, lncRNAs were found to exert both promotive and inhibitory immune functions in sepsis, thus participating in sepsis regulation. Additionally, several studies have revealed that lncRNAs are involved in sepsis-induced organ dysfunctions, including cardiovascular dysfunction, acute lung injury, and acute kidney injury. Considering the lack of effective biomarkers for early identification and specific treatment for sepsis, lncRNAs may be promising biomarkers and even targets for sepsis therapies. This review systematically highlights the recent advances regarding the roles of lncRNAs in sepsis and sheds light on their use as potential biomarkers and treatment targets for sepsis.

/pdf/long-noncoding-rna-regulatory-mechanisms-and-therapeutic-5f0j857uk4.pdf

Ri Wen

Papers

Non-coding RNA: a potential biomarker and therapeutic target for sepsis.

Characterization of Long Noncoding RNA and mRNA Profiles in Sepsis-Induced Myocardial Depression.

Characterization of Circular RNA and microRNA Profiles in Septic Myocardial Depression: a Lipopolysaccharide-Induced Rat Septic Shock Model

Overexpression of miR-150-5p Alleviates Apoptosis in Sepsis-Induced Myocardial Depression.

Long Noncoding RNA: Regulatory Mechanisms and Therapeutic Potential in Sepsis.