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Background Increasing studies indicated the involvement of extracellular vesicles (EVs) in cardiovascular diseases. However, the role of circular RNAs (circRNAs) in cardiac EVs (cEVs) during ischemia/reperfusion (I/R) injury remain unclear. Methods We isolated the cEVs from I/R injured hearts and performed RNA sequencing (RNA-seq) to identify the profile of circRNA in cEVs and investigated their potential roles in I/R pathological process. Results Cardiac I/R induced a significantly elevated release of EVs in heart within 24 h. RNA-seq of cEVs identified 185 significantly differentially expressed (DE) circRNAs including 119 down-regulated and 66 up-regulated circRNAs in I/R group compared with the sham. GO and pathway analysis showed that these DE-circRNAs were associated with protein binding and kinase activator activity and mainly involved in the metabolic process. The circRNA-miRNA analysis exhibited the broad potentials of the DE-circRNAs to regulate target genes by acting on the miRNAs. Conclusions These findings revealed for the first time the specific expression pattern of circRNAs in EVs derived from sham and I/R heart tissues and provided some potential targets and pathways involving in I/R injury which may provide important evidences for the role of both circRNA and EVs in the pathology of cardiac I/R.

Aim: This study aimed to test the predictive power of serum uric acid (UA) levels on new-onset cardiometabolic risk in the Chinese population.Methods: Older people who visited a community health center for a yearly health check (N = 5,000; men: 47%, women: 53%) were enrolled. Participants were followed for 4 years from baseline (median: 48 months), with the endpoints being development of heart failure, atrial fibrillation, diabetes, hypertension, metabolic syndrome, or kidney disease.Results: During follow-up, 342 men (7.4%) and 360 women (8.6%) developed hypertension; 98 men (2.48%) and 135 women (3.06%) developed diabetes; and 175 men (5.04%) and 214 women (4.51%) developed metabolic syndrome. Incident diabetes, hypertension, and metabolic syndrome increased with increased UA levels at baseline (P < 0.001). A multivariate Cox proportional hazards analysis revealed a significant, independent association between the baseline UA level and the onset and future hypertension and/or diabetes in both men and women. However, UA is associated with the development of metabolic syndrome in men, but not in women.Conclusion: UA is an independent predictor of new-onset diabetes and hypertension in both women and men and a predictor of new-onset metabolic syndrome only in men.

Persistent ventricular remodeling following myocardial ischemia/reperfusion (MI/R) injury results in functional decompensation and eventual progression to heart failure. VCP979, a novel small‑molecule compound developed in‑house, possesses anti‑inflammatory and anti‑fibrotic activities. In the present study, no significant pathological effect was observed following the administration of VCP979 on multiple organs in mice and no difference of aspartate transaminase/alanine aminotransferase/lactate dehydrogenase levels was found in murine serum. Treatment with VCP979 ameliorated cardiac dysfunction, pathological myocardial fibrosis and hypertrophy in murine MI/R injury models. The administration of VCP979 also inhibited the infiltration of inflammatory cells and the pro‑inflammatory cytokine expression in hearts post MI/R injury. Further results revealed that the addition of VCP979 prevented the primary neonatal cardiac fibroblasts (NCFs) from Angiotensin II (Ang II)‑induced collagen synthesis and neonatal cardiac myocytes (NCMs) hypertrophy. In addition, VCP979 attenuated the activation of p38‑mitogen‑activated protein kinase in both Ang II‑induced NCFs and hearts subjected to MI/R injury. These findings indicated that the novel small‑molecule compound VCP979 can improve ventricular remodeling in murine hearts against MI/R injury, suggesting its potential therapeutic function in patients subjected to MI/R injury.

Ischemic cardiomyopathy (ICM) and dilated cardiomyopathy (DCM), with distinct long-term prognosis and responses to treatment, are two major problems that lead to heart failure (HF) ultimately. In this study, we investigated the long noncoding RNA (lncRNA) and messenger RNA (mRNA) expressions in the plasma of patients with DCM and ICM and analyzed the different lncRNA profile between the two groups. The microarray analysis identified 3,222 and 1,911 significantly differentially expressed lncRNAs and mRNAs between DCM and ICM group. The most enriched upregulated functional terms included positive regulation of I-kappaB kinase/nuclear factor-kappaB signaling and regulation of cellular localization, while the top 10 downregulated genes mainly consisted of acid secretion and myosin heavy chain binding. Furthermore, the Kyoto Encyclopedia of Genes and Genomes pathway analysis revealed that the differentially expressed lncRNA-coexpressed mRNAs between DCM and ICM group were significantly enriched in the natural killer cell mediated cytotoxicity and ras signaling pathway respectively. Quantitative real-time PCR confirmed 8 of 12 lncRNAs were upregulated in DCM group compared to ICM group which was consistent with the initial microarray results. The lncRNA/mRNA coexpression network indicated the possible functions of the validated lncRNAs. These findings revealed for the first time the specific expression pattern of both protein-coding RNAs and lncRNAs in plasma of HF patients due to DCM and ICM which may provide some important evidence to conveniently identify the etiology of myocardial dysfunctions and help to explore a better strategy for future HF prognosis evaluation.

Acute allograft rejection is a principal conundrum in lung obliterative bronchiolitis (OB). Monocytes/macrophages infiltration has been proved to be the main reason for acute rejection. IL-17 contributes to the recruitment and function of macrophages. However, the mechanism of IL-17 underlying OB progression remains elusive. In the present study, we showed that the deficiency of IL-17 attenuated the pathology of murine heterotopic trachea allografts. Compared to WT recipients, IL-17-/- mice displayed higher frequency of CD206+ cells and lower ratio of CD86+ cells among F4/80+ macrophages in allografts and spleens on day 7 post heterotopic trachea transplantation. Moreover, mRNA levels of pro-inflammatory cytokines including IL-6, TNF-α, and IL-1β decreased in allografts of IL-17-/- recipients, but these of MRC1 and Arg-1 increased in comparison with WT. IL-17 deficiency can inhibit LPS induced M1 while promote IL-4 induced M2 polarization of bone marrow-derived macrophages. Further data demonstrated that the deficiency of IL-17 suppressed the lipopolysaccharide-induced M1 polarization and function through prevention of phosphorylation of both STAT3 and STAT5. Therefore, IL-17 contributes to OB pathogenesis through regulating macrophages function, thereby it may unravel part of the complexity of IL-17 in OB and enhance future therapeutic development.

Background: Effective interventions to improve the outcome of patients subjected to myocardial ischemia reperfusion (MI/R) are urgent in clinical settings. Tanshinone IIA (TSA) is reported to attenuate myocardial injury and improve ventricular remodeling post MI/R. Here, we evaluated the efficacy of AFC1 compound that is similar to TSA structure in murine MI/R models. We found that AFC1 had a comparable effect of improving murine cardiac function after MI/R while it was superior to TSA in safety profile. Administration of AFC1 reduced reactive oxygen species (ROS) production, inflammatory cells infiltration, and the expression of platelet derived growth factor receptors (PDGFR) in infarcted myocardium. Treatment with AFC1 also attenuated MI/R-induced cardiac remodeling and contributed to the recovery of cardiac function. Additionally, AFC1 reversed the elevation of PDGFR expression induced by PDGF-AB in both neonatal rat cardiomyocytes (NCMs) and neonatal rat cardiac fibroblasts (NCFs) and suppressed PDGF-AB induced NCM hypertrophy via STAT3 pathway and NCF collagen synthesis through p38-MAPK signaling in vitro. Similarly, AFC1 may contribute to the recovery of cardiac function in mice post MI/R via suppressing STAT signaling. Our results confirmed that AFC1 exerts anti-hypertrophic and anti-fibrotic effects against MI/R-induced cardiac remodeling, and suggest that AFC1 may have a promising potential in improving the outcome of patients who suffered from MI/R.

CD4+ T-cells play crucial roles in the injured heart. However, the way in which different CD4+ T subtypes function in the myocardial infarction/reperfusion (MI/R) heart is still poorly understood. We aimed to detect the dynamic profile of distinct CD4+ subpopulation-associated cytokines/chemokines by relying on a closed-chest acute murine MI/R model. The protein levels of 26 CD4+ T-cell-associated cytokines/chemokines were detected in the heart tissues and serum of mice at day 7 and day 14 post-MI/R or sham surgery. The mRNA levels of IL-4, IL-6, IL-13, IL-27, MIP-1β, MCP-3, and GRO-α were measured in blood mononuclear cells. The protein levels of IL-4, IL-6, IL-13, IL-27, MIP-1β, MCP-3, and GRO-α increased in both injured heart tissues and serum, while IFN-γ, IL-12P70, IL-2, IL-1β, IL-18, TNF-α, IL-5, IL-9, IL-17A, IL-23, IL-10, eotaxin, MIP-1α, RANTES, MCP-1, and MIP-2 increased only in MI/R heart tissues in the day 7 and day 14 groups compared to the sham group. In serum, the IFN-γ, IL-23, and IL-10 levels were downregulated in the MI/R model at both day 7 and day 14 compared to the sham. Compared with the protein expressions in injured heart tissues at day 7, IFN-γ, IL-12P70, IL-2, IL-18, TNF-α, IL-6, IL-4, IL-5, IL-9, IL-17A, IL-23, IL-27, IL-10, eotaxin, IP-10, RANTES, MCP-1, MCP-3, and GRO-α were reduced, while IL-1β and MIP-2 were elevated at day 14. IL-13 and MIP-1β showed higher levels in the MI/R serum at day 14 than at day 7. mRNA levels of IL-4, IL-6, IL-13, and IL-27 were increased in the day 7 group compared to the sham, while MIP-1β, MCP-3, and GRO-α mRNA levels showed no significant difference between the MI/R and sham groups in blood mononuclear cells. Multiple CD4+ T-cell-associated cytokines/chemokines were upregulated in the MI/R hearts at the chronic stage. These results provided important evidence necessary for developing future immunomodulatory therapies after MI/R.

B lymphoma Mo-MLV insertion region 1 (BMI1) has been reported to be an oncoprotein. BMI1 represses tumor suppressors to promote cell proliferation, epithelial-mesenchymal transition (EMT), and cancer progression. Although it is known that the expression of BMI1 is increased in many cancer types, the mechanism of BMI1 upregulation is not yet clear. We performed integrative analysis for 3 sets of prostate cancer (PCa) genomic data, and found that BMI1 and androgen receptor (AR) were positively correlated, suggesting that AR might regulate BMI1. Next, we showed that dihydrotestosterone (DHT) upregulated both mRNA and protein levels of BMI1 and that BMI1 was increased in castration-resistant prostate cancer (CRPC) from both human patients and a mouse xenograph model. We further identified an AR binding site in the promoter/enhancer region of BMI1, and confirmed BMI1 as the direct target of AR using gene-editing technology. We also demonstrated that high expression of BMI1 is critical for the development of castration-resistance. Our data also suggest that BMI1-specific inhibitors could be an effective treatment of CRPC.

Elevated circulating concentrations of the gut bacteria choline metabolite trimethylamine N-oxide (TMAO) were found in patients with type 2 diabetes mellitus (T2DM). However, whether a high level of TMAO is related to the risk of diabetes has not been studied. We aimed to synthesize the evidence on the relation between TMAO levels and the risk of diabetes mellitus (DM) and to investigate the association further in a dose-response meta-analysis. PubMed, Web of Science, and Scopus databases were searched for studies from inception to June 2018. A total of 12 clinical studies were included in this study, and 15 314 enrolled subjects were included. A meta-analysis of two-class variables and continuous variables were used to obtain pooled effects. Dose-response meta-analysis was used to investigate the dose-response relationship between TMAO concentrations and the risk of DM. Meta-regression and subgroup analyses were applied to identify the source of heterogeneity in this study. High levels of circulating TMAO were associated with an increased risk of DM (odds ratio [OR] = 1.89) using the two-class meta-analysis. Plasma levels of TMAO in patients with diabetes were higher than in subjects without diabetes (standardized mean difference [SMD]: 0.36) using a meta-analysis of continuous variables. The OR for DM prevalence increased by 54% per 5 μmol L-1 increment of plasma TMAO (OR = 1.54) according to the dose-response meta-analysis. This is the first systematic review and meta-analysis to demonstrate a positive dose-dependent association between circulating TMAO levels and increased diabetes risk.

Taenia saginata, Taenia solium and Taenia asiatica (beef, pork and Asian tapeworms, respectively) are parasitic flatworms of major public health and food safety importance. Among them, T. asiatica is a newly recognized species that split from T. saginata via an intermediate host switch ∼1.14 Myr ago. Here we report the 169- and 168-Mb draft genomes of T. saginata and T. asiatica. Comparative analysis reveals that high rates of gene duplications and functional diversifications might have partially driven the divergence between T. asiatica and T. saginata. We observe accelerated evolutionary rates, adaptive evolutions in homeostasis regulation, tegument maintenance and lipid uptakes, and differential/specialized gene family expansions in T. asiatica that may favour its hepatotropism in the new intermediate host. We also identify potential targets for developing diagnostic or intervention tools against human tapeworms. These data provide new insights into the evolution of Taenia parasites, particularly the recent speciation of T. asiatica.

Pulmonary hypertension (PH) due to left heart disease (LHD) is a common condition associated with significant morbidity. It contributes to the elevation of pulmonary vascular resistance and mean pulmonary pressure, eventually leading to heart failure and even mortality. The present study aimed to explore the potential efficacy of late and long‑term treatment with a Rho‑kinase (ROCK) signaling inhibitor, namely fasudil, in a rat model of end‑stage PH‑LHD. The PH‑LHD model was established by supracoronary aortic banding, and the effect of fasudil treatment on the progression of PH‑LHD was monitored. After 9 weeks (63 days) of supracoronary aortic banding, a significant increase in mean pulmonary pressure and RV systolic pressure was observed in the rats, associated with increased RhoA/ROCK activity in the lungs. Therapy with fasudil (30 mg/kg/day, intraperitoneal) for 4 weeks from postoperative day 35 reversed the hemodynamic disorder and prevented pulmonary vascular remodeling in rats with PH‑LHD. In addition, the blockade of ROCK signaling by fasudil decreased the protein levels of endothelin‑1 (ET‑1) and the mRNA expression levels of endothelin A receptor and promoted the production of nitric oxide (NO) in rats with PH‑LHD. Furthermore, fasudil inhibited the migration of human pulmonary microvascular endothelial cells and the proliferation of pulmonary artery smooth muscle cells induced by ET‑1. Therefore, this late, long‑term blockade of the ROCK pathway by fasudil may be a promising strategy to reverse hemodynamic dysfunction and impede the development of end‑stage PH‑LHD in patients.

Obliterative bronchiolitis (OB) remains the major limitations for the long-term survival of allografts after lung transplantation. Th17 cells and IL-17 have been recognized as mediators of the development of OB in both animal models and human beings. IL-25, also called IL-17E, is the only anti-inflammatory cytokine of the IL-17 family, capable of regulating Th17 cells function in autoimmune inflammations. Whether IL-25 affects Th17 cells responses and the development of OB remains poorly understood. Acute rejection (AR) of the lung allograft has been regarded as the main problem for the development of OB, in which infiltrations of monocytes/macrophages play important roles. This study explored the potential role of IL-25 in regulation of macrophages polarization and inhibition of IL-17 production in the progression of OB. Here, we showed that IL-25 directly suppressed the expression of inflammatory cytokines, such as IL-6, IL-23, TNF-α, and IL-1β in LPS-induced pro-inflammatory M1 macrophages in vitro. In vivo data demonstrated that IL-25 deficiency promoted the polarization and function of M1 macrophages and aggravated the progression of OB in murine models of both orthotopic and heterotopic trachea transplantation. In conclusion, these data indicated that IL-25 attenuated OB by suppressing the function of M1 macrophages and IL-17 expression, providing an alternative strategy to intervene the development of OB.

Chronic feeding of HCD (high-carbohydrate diet) is one of the major contributors to the prevailing of metabolic diseases. ATF4 (activating transcription factor 4) has been shown to play an important role in the regulation of glucose metabolism and obesity development; however, it is unclear how ATF4−/− mice respond to HCD. In the present study, we show that 8 weeks of HCD results in significant higher accumulation of TAGs (triacylglycerols) in livers and impairment in glucose tolerance in ATF4+/+ mice, but not in ATF4−/− mice, compared with those on a normal diet. Meanwhile, energy expenditure is further enhanced by HCD in ATF4−/− mice. Moreover, we show that ATF4 deficiency suppresses HCD-induced SCD1 (stearoyl-CoA desaturase 1) expression, furthermore, oral supplementation of the main product of SCD1 oleate (18:1) increases TAG accumulation in livers of ATF4−/− mice. Taken together, these results suggest that ATF4 deficiency is protective for HCD-induced hepatic steatosis and impairment of glucose tolerance and insulin sensitivity. Furthermore, the resistance to hepatic steatosis is at least in part due to suppression of SCD1 expression under HCD.

OBJECTIVE We have previously shown that serum insulin levels decrease threefold and blood glucose levels remain normal in mice fed a leucine-deficient diet, suggesting increased insulin sensitivity. The goal of the current study is to investigate this possibility and elucidate the underlying cellular mechanisms. RESEARCH DESIGN AND METHODS Changes in metabolic parameters and expression of genes and proteins involved in regulation of insulin sensitivity were analyzed in mice, human HepG2 cells, and mouse primary hepatocytes under leucine deprivation. RESULTS We show that leucine deprivation improves hepatic insulin sensitivity by sequentially activating general control nonderepressible (GCN)2 and decreasing mammalian target of rapamycin/S6K1 signaling. In addition, we show that activation of AMP-activated protein kinase also contributes to leucine deprivation–increased hepatic insulin sensitivity. Finally, we show that leucine deprivation improves insulin sensitivity under insulin-resistant conditions. CONCLUSIONS This study describes mechanisms underlying increased hepatic insulin sensitivity under leucine deprivation. Furthermore, we demonstrate a novel function for GCN2 in the regulation of insulin sensitivity. These observations provide a rationale for short-term dietary restriction of leucine for the treatment of insulin resistance and associated metabolic diseases.

s S265 period of 42 days in both groups. Long term survival of the animals is currently under investigation. Conclusion: Delayed administration of anti-CD4 antibody 3 days after lung transplantation appears to preferentially suppress the CD4+ effector arm rather than CD4+ regulatory T cells. This finding may be advantageous for promoting donor-specific tolerance in lung transplantation.