Pharmacology-Based Prediction of the Targets and Mechanisms for Icariin against Myocardial Infarction.

Background and Objectives: This study aims to illustrate the mechanisms underlying the therapeutic effect of Icariin after myocardial infarction (MI). Materials and Methods: Based on the network pharmacology strategy, we predict the therapeutic targets of Icariin against MI and investigate the pharmacological molecular mechanisms. A topological network was created. Biological process and Kyoto Encyclopedia of Genes and Genomes pathway enrichment were also performed. We also conducted the molecular docking analysis to stimulate the component-target interaction further and validate the direct bind effect. Results: Network pharmacology analysis identified 61 candidate genes related to the therapeutic effect of Icariin against MI. EGFR, AKT1, TP53, JUN, ESR1, PTGS2, TNF, RELA, HSP90AA1, and BCL2L1 were identified as hub genes. The biological processes of the candidate targets were significantly involved in the reactive oxygen species metabolic process, response to hypoxia, response to decreased oxygen levels, response to oxidative stress, regulation of reactive oxygen species metabolic process, and so forth. Overall, biological process enrichment analysis indicated that the protective effect of Icariin against MI might be associated with oxidative stress. Moreover, the pathway analysis showed that the candidate targets were closely associated with lipid and atherosclerosis, AGE-RAGE signaling pathway in diabetic complications, HIF-1 signaling pathway, etc. We identified the conformation with the lowest affinity score as the docking conformation. The simulated molecular docking was displayed to illustrate the topical details of the binding sites between Icariin and TNF protein. Conclusions: This study provides an overview of the mechanisms underlying the protective effect of Icariin against MI.

Is there any association between early trimester Triglyceride-glucose index and incidence of hypertensive disorder of pregnancy and adverse pregnancy outcomes?

Background: Insulin resistance (IR) is a normal feature of pregnancy and plays a crucial role in the pathophysiology of hypertensive disorder of pregnancy (HDP). The triglyceride-glucose index (TyG index) has been shown as a simple and reliable alternative IR marker. This work aimed to investigate the association between the TyG index and the incidence of HDP and adverse pregnancy outcomes. Methods: From January 2016 to December 2018, 289 women with HDP and 861 women without HDP were recruited at Shanghai Fifth People's Hospital, Fudan University to determine the relationship between the TyG index and the incidence of HDP and adverse pregnancy outcomes. Results: In the case-control study, the incidence of HDP was found to be significantly associated with the TyG index. Moreover, logistic regression indicated that the TyG index is an independent risk factor for HDP development and incidence of low birth weight (LBW) and fetal distress. In the cohort study, the results showed that the TyG index increased, there was a stepwise increase in HDP incidence, SBP, and DBP levels one week before delivery as well as in LBW and fetal distress incidence. The early trimester TyG index was positively associated with pre-pregnancy BMI, systolic blood pressure (SBP), and diastolic blood pressure (DBP) one week before delivery. Spline regression showed that there was a significant linear association between HDP incidence and early trimester TyG index when it was >8.5. Conclusions: This work suggested that the early trimester TyG index was closely associated with the development of HDP and adverse pregnancy outcomes.

Association Between METS-IR and Prehypertension or Hypertension Among Normoglycemia Subjects in Japan: A Retrospective Study.

Aim: Our study aimed to investigate the association between the novel non-insulin-based metabolic score for insulin resistance (METS-IR) index and pre-hypertension (HTN) or HTN in normoglycemia Japanese participants. Methods: The NAGALA medical examination program at Murakami Memorial Hospital in Gifu, Japan was found in 1994. 15,453 participants enrolled in this program from 2004 to 2015 was included in this retrospective study to explore the association between the METS-IR index and pre-HTN or HTN. Covariates included serum biomarkers and clinicodemographic characteristics. Logistic regression was applied to explore the association between METS-IR level and pre-HTN or HTN. Results: This study includes a total of 15453 participants. The prevalence rates of pre-HTN and HTN were 28.55% (4412/15453) and 6.23% (962/15453), respectively. Adjusted for confounding factors in the multivariable logistic regression analysis models, when METS-IR was used as a categorical variable, high METS-IR was significantly associated with both pre-HTN (adjusted odds ratio (OR) = 1.95, 95% confidence interval (CI): 1.61-2.36) and HTN (adjusted OR = 2.12, 95% CI: 1.44-3.11). When METS-IR was used as a continuous variable, each 1 unit increase in METS-IR was associated with a 7% increase in the prevalence of pre-HTN (adjusted OR = 1.07, 95% CI: 1.06-1.08) and with a 13% increase in the prevalence of HTN (adjusted OR = 1.13, 95% CI: 1.10-1.16). Stratified analyses indicated a positive correlation between METS-IR and pre-HTN or HTN in normoglycemia subjects with different characteristics. Conclusions: METS-IR levels are significantly associated with pre-HTN or HTN in normoglycemia individuals in Gifu, Japan. METS-IR may be used as a monitoring indicator for the development of HTN primary prevention and management strategies in the future, but it still needs more research to confirm.

RNA sequencing profiling reveals key mRNAs and long noncoding RNAs in atrial fibrillation.

Long noncoding RNAs (lncRNAs) are an emerging class of RNA species that could participate in some critical pathways and disease pathogenesis. However, the underlying molecular mechanism of lncRNAs in atrial fibrillation (AF) is still not fully understood. In the present study, we analyzed RNA-seq data of paired left and right atrial appendages from five patients with AF and other five patients without AF. Based on the gene expression profiles of 20 samples, we found that a majority of genes were aberrantly expressed in both left and right atrial appendages of patients with AF. Similarly, the dysregulated pathways in the left and right atrial appendages of patients with AF also bore a close resemblance. Moreover, we predicted regulatory lncRNAs that regulated the expression of adjacent protein-coding genes (PCGs) or interacted with proteins. We identified that NPPA and its antisense RNA NPPA-AS1 may participate in the pathogenesis of AF by regulating the muscle contraction. We also identified that RP11 - 99E15.2 and RP3 - 523K23.2 could interact with proteins ITGB3 and HSF2, respectively. RP11 - 99E15.2 and RP3 - 523K23.2 may participate in the pathogenesis of AF via regulating the extracellular matrix binding and the transcription of HSF2 target genes, respectively. The close association of the lncRNA-interacting proteins with AF further demonstrated that these two lncRNAs were also associated with AF. In conclusion, we have identified key regulatory lncRNAs implicated in AF, which not only improves our understanding of the lncRNA-related molecular mechanism underlying AF but also provides computationally predicted regulatory lncRNAs for AF researchers.

H19 lncRNA identified as a master regulator of genes that drive uterine leiomyomas.

Uterine leiomyomas or fibroids (UFs) are benign tumors characterized by hyperplastic smooth muscle cells and excessive deposition of extracellular matrix (ECM). Afflicting ~80% of women, and symptomatic in 25%, UFs bring tremendous suffering and are an economic burden worldwide; they cause severe pain and bleeding, and are the leading cause of hysterectomy. Yet, UFs are severely understudied with few effective treatment options available; those that are available frequently have significant side effects such as menopausal symptoms. Recently, integrated genome-scale studies have revealed mutations and fibroid subtype-specific expression changes in key driver genes, with MED12 and HMGA2 together contributing to nearly 90% of all UFs, but their regulation of expression is poorly characterized. Here we report that the expression of H19 long noncoding RNA (lncRNA) is aberrantly increased in UFs. Using cell culture and genome-wide transcriptome and methylation profiling analyses, we demonstrate that H19 promotes expression of MED12, HMGA2, and key ECM-remodeling genes via multiple mechanisms including a new class of epigenetic modification by TET3. Our results mark the first example of an evolutionarily conserved lncRNA in pathogenesis of UFs and regulation of TET expression. Given the link between a H19 single-nucleotide polymorphism (SNP) and increased risk and tumor size of UFs, and the existence of multiple fibroid subtypes driven by key pathway genes regulated by H19, we propose a unifying mechanism for pathogenesis of uterine fibroids mediated by H19 and identify a pathway for future exploration of novel target therapies for uterine leiomyomas.

Identification and Functional Characterization of an ISL1 Mutation Predisposing to Dilated Cardiomyopathy.

Dilated cardiomyopathy (DCM) is the most prevalent cause of non-ischemic cardiac failure and the commonest indication for cardiac transplantation. Compelling evidence highlights the pivotal roles of genetic defects in the occurrence of DCM. Nevertheless, the genetic determinants underpinning DCM remain largely obscure. In this study, the coding regions of ISL1, which encodes a transcription factor critical for embryonic cardiogenesis and postnatal cardiac remodeling, were sequenced in 216 unrelated patients with DCM, and a novel heterozygous ISL1 mutation, NM_002202.2: c.631A>T; p.(Lys211*), was identified in a proband. The mutation, which co-segregated with DCM in the family, was absent in 238 unrelated controls, as well as in the Genome Aggregation and the Exome Aggregation Consortium population databases. Functional analyses unveiled that the mutant ISL1 protein lost transcriptional activity alone or in synergy with TBX20 or GATA4, two other transcription factors associated with DCM. These findings indicate ISL1 as a new gene of DCM.

HAND2 loss-of-function mutation causes familial dilated cardiomyopathy.

As two members of the basic helix-loop-helix family of transcription factors, HAND1 and HAND2 are both required for the embryonic cardiogenesis and postnatal ventricular structural remodeling. Recently a HAND1 mutation has been reported to cause dilated cardiomyopathy (DCM). However, the association of a HAND2 mutation with DCM is still to be ascertained. In this research, the coding regions and splicing junction sites of the HAND2 gene were sequenced in 206 unrelated patients affected with idiopathic DCM, and a new heterozygous HAND2 mutation, NM_021973.2: c.199G > T; p.(Glu67*), was discovered in an index patient with DCM. The nonsense mutation was absent in 300 unrelated, ethnically-matched healthy persons. Genetic scan of the mutation carrier's family members revealed that the genetic mutation co-segregated with DCM, which was transmitted in an autosomal dominant fashion, with complete penetrance. Functional deciphers unveiled that the mutant HAND2 protein had no transcriptional activity. In addition, the mutation abrogated the synergistic transcriptional activation between HAND2 and GATA4 or between HAND2 and NKX2.5, two other cardiac transcription factors that have been implicated in DCM. These research findings firstly suggest HAND2 as a novel gene predisposing to DCM in humans, which adds novel insight to the molecular pathogenesis of DCM, implying potential implications in the design of personized preventive and therapeutic strategies against DCM.

A SHOX2 loss-of-function mutation underlying familial atrial fibrillation.

Atrial fibrillation (AF), as the most common sustained cardiac arrhythmia, is associated with substantially increased morbidity and mortality. Aggregating evidence demonstrates that genetic defects play a crucial role in the pathogenesis of AF, especially in familial AF. Nevertheless, AF is of pronounced genetic heterogeneity, and in an overwhelming majority of cases the genetic determinants underlying AF remain elusive. In the current study, 162 unrelated patients with familial AF and 238 unrelated healthy individuals served as controls were recruited. The coding exons and splicing junction sites of the SHOX2 gene, which encodes a homeobox-containing transcription factor essential for proper development and function of the cardiac conduction system, were sequenced in all study participants. The functional effect of the mutant SHOX2 protein was characterized with a dual-luciferase reporter assay system. As a result, a novel heterozygous SHOX2 mutation, c.580C>T or p.R194X, was identified in an index patient, which was absent from the 476 control chromosomes. Genetic analysis of the proband's pedigree revealed that the nonsense mutation co-segregated with AF in the family with complete penetrance. Functional assays demonstrated that the mutant SHOX2 protein had no transcriptional activity compared with its wild-type counterpart. In conclusion, this is the first report on the association of SHOX2 loss-of-function mutation with enhanced susceptibility to familial AF, which provides novel insight into the molecular mechanism underpinning AF, suggesting potential implications for genetic counseling and individualized management of AF patients.

H19 lncRNA Promotes Skeletal Muscle Insulin Sensitivity in Part by Targeting AMPK.

Skeletal muscle plays a pivotal role in regulating systemic glucose homeostasis in part through the conserved cellular energy sensor AMPK. AMPK activation increases glucose uptake, lipid oxidation, and mitochondrial biogenesis, leading to enhanced muscle insulin sensitivity and whole-body energy metabolism. Here we show that the muscle-enriched H19 long noncoding RNA (lncRNA) acts to enhance muscle insulin sensitivity, at least in part, by activating AMPK. We identify the atypical dual-specificity phosphatase DUSP27/DUPD1 as a potentially important downstream effector of H19. We show that DUSP27, which is highly expressed in muscle with previously unknown physiological function, interacts with and activates AMPK in muscle cells. Consistent with decreased H19 expression in the muscle of insulin-resistant human subjects and rodents, mice with genetic H19 ablation exhibit muscle insulin resistance. Furthermore, a high-fat diet downregulates muscle H19 via both posttranscriptional and epigenetic mechanisms. Our results uncover an evolutionarily conserved, highly expressed lncRNA as an important regulator of muscle insulin sensitivity.

Elevated hepatic expression of H19 long noncoding RNA contributes to diabetic hyperglycemia.

Excessive hepatic glucose production (HGP) contributes significantly to the hyperglycemia of type 2 diabetes; however, the molecular mechanism underlying this dysregulation remains poorly understood. Here, we show that fasting temporally increases the expression of H19 long noncoding RNA (lncRNA) in nondiabetic mouse liver, whereas its level is chronically elevated in diet-induced diabetic mice, consistent with the previously reported chronic hepatic H19 increase in diabetic patients. Importantly, liver-specific H19 overexpression promotes HGP, hyperglycemia, and insulin resistance, while H19 depletion enhances insulin-dependent suppression of HGP. Using genome-wide methylation and transcriptome analyses, we demonstrate that H19 knockdown in hepatic cells alters promoter methylation and expression of Hnf4a, a master gluconeogenic transcription factor, and that this regulation is recapitulated in vivo. Our findings offer a mechanistic explanation of lncRNA H19's role in the pathogenesis of diabetic hyperglycemia and suggest that targeting hepatic H19 may hold the potential of new treatment for this disease.

Efficacy and safety of traditional Chinese medicine on thromboembolic events in patients with atrial fibrillation: A systematic review and meta-analysis.

OBJECTIVES: Traditional Chinese medicine (TCM) in combination with Western medicine (WM) has been widely used worldwide. This systematic review aimed to evaluate the efficacy and safety of TCM in prevention of thromboembolic events in patients with atrial fibrillation (AF). METHODS: Potential studies were searched through the Cochrane Library, PubMed, EMBASE, CBM, VIP, CNKI, and Wanfang databases up to February 2016. Randomized controlled trials (RCTs) investigating the thromboembolic events and/or safety outcome of TCM in patients with AF were included. RESULTS: A total of 905 AF patients from 9 RCTs were identified. Meta-analysis showed that TCM in combination with warfarin was better than warfarin alone for preventing total thromboembolic events with a 68% reduction of risk (risk ratio [RR] 0.32; 95% confidence interval [CI] 0.13-0.78) without increasing the risk of total bleeding (RR 0.71; 95% CI 0.29-1.72). Compared with warfarin, TCM therapy was associated with lower risk of total bleeding (RR 0.13; 95% CI 0.04-0.47), but increased the risk of total thromboembolic events (RR 1.84; 95% CI 1.03-3.27). CONCLUSIONS: This meta-analysis suggests that TCM combined with warfarin is superior to warfarin alone for the prevention of total thromboembolic events in patients with AF, with equal risk of bleeding as warfarin alone.