Hypertension is a major global health burden and a leading risk factor for cardiovascular diseases. Although its heritability has been documented previously, contributing loci identified to date account for only a small fraction of blood pressure (BP) variation, which strongly suggests the existence of undiscovered variants. To identify novel variants, we conducted a three staged genetic study in 21,990 hypertensive cases and normotensive controls. Four single nucleotide polymorphisms (SNPs) at three new genes (L3MBTL4 rs403814, Pmeta = 6.128 × 10(-9); LOC729251, and TCEANC) and seven SNPs at five previously reported genes were identified as being significantly associated with hypertension. Through functional analysis, we found that L3MBTL4 is predominantly expressed in vascular smooth muscle cells and up-regulated in spontaneously hypertensive rats. Rats with ubiquitous over-expression of L3MBTL4 exhibited significantly elevated BP, increased thickness of the vascular media layer and cardiac hypertrophy. Mechanistically, L3MBTL4 over-expression could lead to down-regulation of latent transforming growth factor-β binding protein 1 (LTBP1), and phosphorylation activation of the mitogen-activated protein kinases (MAPK) signaling pathway, which is known to trigger the pathological progression of vascular remodeling and BP elevation. These findings pinpointed L3MBTL4 as a critical contributor to the development and progression of hypertension and uncovers a novel target for therapeutic intervention.

Apoptosis is an important mechanism for the development of heart failure. Mitochondria are central to the execution of apoptosis in the intrinsic pathway. The main regulator of mitochondrial pathway of apoptosis is Bcl-2 family which includes pro- and anti-apoptotic proteins. MicroRNAs are small noncoding RNA molecules that regulate gene expression by inhibiting mRNA translation and/or inducing mRNA degradation. It has been proposed that microRNAs play critical roles in the cardiovascular physiology and pathogenesis of cardiovascular diseases. Our previous study has found that microRNA-181c, a miRNA expressed in the myocardial cells, plays an important role in the development of heart failure. With bioinformatics analysis, we predicted that miR-181c could target the 3' untranslated region of Bcl-2, one of the anti-apoptotic members of the Bcl-2 family. Thus, we have suggested that miR-181c was involved in regulation of Bcl-2. In this study, we investigated this hypothesis using the Dual-Luciferase Reporter Assay System. Cultured myocardial cells were transfected with the mimic or inhibitor of miR-181c. We found that the level of miR-181c was inversely correlated with the Bcl-2 protein level and that transfection of myocardial cells with the mimic or inhibitor of miR-181c resulted in significant changes in the levels of caspases, Bcl-2 and cytochrome C in these cells. The increased level of Bcl-2 caused by the decrease in miR-181c protected mitochondrial morphology from the tumour necrosis factor alpha-induced apoptosis.

Mutations in the transcription factor TBX20 (T-box 20) are associated with congenital heart disease. Germline ablation of Tbx20 results in abnormal heart development and embryonic lethality by embryonic day 9.5. Because Tbx20 is expressed in multiple cell lineages required for myocardial development, including pharyngeal endoderm, cardiogenic mesoderm, endocardium, and myocardium, the cell type-specific requirement for TBX20 in early myocardial development remains to be explored.

Obesity has become the most common metabolic disorder worldwide. Promoting brown adipose tissue (BAT) and beige adipose tissue formation, and therefore, a functional increase in energy expenditure, may counteract obesity. Mice lacking type IIβ regulatory subunit of adenosine 3',5' cyclic monophosphate (cAMP)-dependent protein kinase A (PKA-RIIB) display reduced adiposity and resistance to diet-induced obesity. PKA-RIIB, encoded by the Prkar2b gene, is most abundant in BAT and white adipose tissue (WAT) and in the brain. In this study, we show that mice lacking PKA-RIIB have increased energy expenditure, limited weight gain, and improved glucose metabolism. PKA-RIIB deficiency induces brownlike adipocyte in inguinal WAT (iWAT). PKA-RIIB deficiency also increases the expression of uncoupling protein 1 and other thermogenic genes in iWAT and primary preadipocytes from iWAT through a mechanism involving increased PKA activity, which is represented by increased phosphorylation of PKA substrate, cAMP response element binding protein, and P38 mitogen-activated protein kinase. Our study provides evidence for the role of PKA-RIIB deficiency in regulating thermogenesis in WAT, which may potentially have therapeutic implications for the treatment of obesity and related metabolic disorders.

Human heart failure is a complex syndrome and a primary cause of morbidity and mortality in the world. However, the molecular pathways involved in the remodelling process are poorly understood. In this study, we performed exhaustive global proteomic surveys of cardiac ventricle isolated from failing and non-failing human hearts, and determined the regulatory pathway to uncover the mechanism underlying heart failure. Two-dimensional gel electrophoresis (2-DE) coupled with tandem mass spectrometry was used to identify differentially expressed proteins in specimens from failing (n = 9) and non-failing (n = 6) human hearts. A total of 25 proteins with at least 1.5-fold change in the failing heart were identified; 15 proteins were up-regulated and 10 proteins were down-regulated. The altered proteins belong to three broad functional categories: (i) metabolic [e.g. NADH dehydrogenase (ubiquinone), dihydrolipoamide dehydrogenase, and the cytochrome c oxidase subunit]; (ii) cytoskeletal (e.g. myosin light chain proteins, troponin I type 3 and transthyretin) and (iii) stress response (e.g. αB-crystallin, HSP27 and HSP20). The marked differences in the expression of selected proteins, including HSP27 and HSP20, were further confirmed by Western blot. Thus, we carried out full-scale screening of the protein changes in human heart failure and profiled proteins that may be critical in cardiac dysfunction for future mapping.

Micro-RNAs regulate gene expression by directly binding to the target mRNAs. The goal of the study was to examine the expression profiling of miRNAs in human failing hearts and identify the key miRNAs that regulate molecular signalling networks and thus contribute to this pathological process. The levels of miRNAs and expressed genes were analysed in myocardial biopsy samples from patients with end-stage heart failure (n = 14) and those from normal heart samples (n = 8). Four networks were built including the Gene regulatory network, Signal-Network, miRNA-GO-Network and miRNA-Gene-Network. According to the fold change in the network and probability values in the microarray cohort, RT-PCR was performed to measure the expression of five of the 72 differentially regulated miRNAs. miR-340 achieved statistically significant. miR-340 was identified for the first time in cardiac pathophysiological condition. We overexpressed miR-340 in cultured neonatal rat cardiomyocytes to identify whether miR-340 plays a determining role in the progression of heart failure. ANP, BNP and caspase-3 were significantly elevated in the miR-340 transfected cells compared with controls (P < 0.05). The cross-sectional area of overexpressing miR-340 cardiomyocytes (1952.22 ± 106.59) was greater (P < 0.0001) than controls (1059.99 ± 45.59) documented by Laser Confocal Microscopy. The changes of cellular structure and the volume were statistical significance. Our study provided a comprehensive miRNA expression profiling in the end-stage heart failure and identified miR-340 as a key miRNA contributing to the occurrence and progression of heart failure. Our discoveries provide novel therapeutic targets for patients with heart failure.

There is a paucity of evidence on the combination of the SYNTAX score II (SSII) and erythrocyte sedimentation rate (ESR) in assessing the long-term prognosis of patients with ST-elevated myocardial infarction (STEMI) and multivessel disease. The objective of this study was to investigate whether the ESR could enhance the predictive value of SSII on the long-term prognosis of STEMI patients.

Gestational trophoblastic diseases (GTDs) are characterized by vascular abnormalities of the trophoblast, but their pathogenesis is unknown. Angiogenin (ANG) and matrix metalloproteinase (MMP)-2, which are molecules implicated in the angiogenic process, may play some role in this process.

Normally, fish will decrease food intake or even stop feeding during the winter. In previous studies, two widely cultured gibel carp strains (strain A and strain F) showed differences in lipid and glucose metabolism. Therefore, we hypothesized that the physiological changes during the overwintering period would be different between the two strains. Thus, the two strains were starved for 77 days, after which the levels of glucose and lipid metabolism, ER stress, autophagy, and apoptosis were determined. The starvation increased hepatic glycogenolysis and fatty acid β-oxidation but suppressed lipogenesis in both strains overwintering. Considering the effects of genotype, strain F had higher levels of ER stress and autophagy but lower levels of apoptosis than strain A, suggesting that strain F might be more resistant to overwintering starvation. The interactions between strains and starvation periods were observed in plasma triglyceride contents and the mRNA levels of pyruvate kinase (pk), sterol regulatory element binding protein 1 (srebp1), activating transcription factor 4 (atf4), and autophagy protein 12 (atg12). In conclusion, long-term starvation during winter could induce hepatic glycogenolysis and fatty acid β-oxidation but suppress lipogenesis, ER stress, autophagy, and apoptosis in gibel carp, and strain F may be more resistant to starvation during winter. Taken together, these results discovered the responses to prolonged starvation stress during winter in two strains of gibel carp and could provide information for genotype selection, especially for selecting strains better adapted to winter.

Background: Nicorandil prior to reperfusion by primary percutaneous coronary intervention (PCI) in patients with ST-segment elevated myocardial infarction (STEMI) has been suggested to be beneficial. However, results of previous randomized controlled trials (RCTs) were not consistent. We aimed to perform a meta-analysis to systematically evaluate the effect of periprocedural nicorandil in these patients. Methods: Related studies were obtained by searching PubMed, Embase and Cochrane's Library. Effects of perioperative nicorandil on the incidence of no-reflow phenomenon (NRP), corrected thrombolysis in myocardial infarction (TIMI) frame count (CTFC), wall motion score (WMS), left ventricular ejection fraction (LVEF), heart failure (HF) exacerbation of rehospitalization and incidence of major cardiovascular adverse events (MACE) were analyzed. Results: Eighteen RCTs with 2,055 patients were included. Treatment of nicorandil prior to PCI significantly reduced the incidence of NRP (risk ratio [RR]: 0.47, P<0.001), and reduced CTFC (weighed mean difference [WMD]: -4.54, P<0.001) immediately after PCI. Moreover, although nicorandil did not significantly affect WMS (WMD: 0.04, P=0.91), treatment of nicorandil significantly increased LVEF in STEMI patients undergoing primary PCI (WMD: 1.89%, P<0.001). In addition, nicorandil significantly reduced the risk of HF exacerbation or rehospitalization (RR: 0.44, P=0.001) and the incidence of MACE (RR: 0.68, P<0.001). Further analyses showed that effects of nicorandil on LVEF, HF exacerbation and MACE were consistent within one month after PCI and during follow-up. Conclusions: Periprocedural nicorandil improves coronary blood flow, cardiac systolic function and prognosis in STEMI patients receiving primary PCI.

The activation of brown adipose tissue (BAT) is considered as a promising therapeutic target for obesity. APPL1 (Adaptor protein containing the Pleckstrin homology domain, Phosphotyrosine binding domain and Leucine zipper motif) is an intracellular adaptor protein and its genetic variation is correlated with BMI and body fat distribution in diabetic patients. However, little is known about the roles of APPL1 in BAT thermogenesis.

Rationale: Dysbiotic gut microbiota (GM) and NLRP3 inflammasome are proarrhythmic factors in atrial fibrillation (AF). Herein, whether short-chain fatty acid (SCFA) produced from GM fermentation of dietary fiber serving as invisible mediators is yet unclear. Thus, the current study aimed to determine whether SCFA alleviated from NLRP3 signaling-mediated atrial remodeling protects AF development. Methods: First, a cross-sectional study based on the GC-MS metabolomics was performed to explore the association between fecal SCFA levels and AF traits in a cohort consisted of 48 individuals. Then, a well-established mice model fed diet deficient or enriched in dietary fiber was established to elucidate the pathophysiological role of SCFA involved in AF susceptibility, atrial remodeling, and G-protein-coupled receptor 43 (GPR43)/NLRP3 signaling. Finally, the effects of SCFA were verified on HL-1 cells. Results: Fecal SCFA levels were remarkably reduced in AF patients with a declining trend from paroxysmal to persistent AF. Prolonged P wave duration based on surface ECG and increased left atrial diameter gained from echocardiography was identified in low-fiber diet mice but lost in SCFA-supplemented group. Lack of dietary fiber enhanced susceptibility to AF under burst pacing, whereas SCFA might exert a protective effect. The supplementation of SCFA prevented dietary fiber deficiency-upregulated phosphorylation of calmodulin-dependent protein kinase II and ryanodine receptor 2, the disarray fibrosis, collagen expression, and NLRP3 inflammasome activation in atrial tissue. Finally, the AF protective roles of SCFA were identified through GPR43 mediated deactivation of NLRP3 by GPR43 knockdown in HL-1 cells. Conclusions: SCFA derived from dietary fiber fermentation by gut commensals alleviates AF development via GPR43/NLRP3 signaling.

Neoadjuvant chemoradiotherapy (nCRT) could bring tumour shrinking and downstaging and increase the probability of organ preservation for patients with low rectal cancer. But for ultra-low rectal cancer, there is little possibility for organ preservation. Immunotherapy has been shown to have significant survival benefits in microsatellite instability-high patients but poor response in microsatellite stable (MSS) patients. Studies have demonstrated that radiotherapy and immunotherapy have synergistic effects in cancer treatment. There is no existing evidence about the clinical efficacy of immunotherapy combined with nCRT for patients with MSS ultra-low rectal cancer.

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are major causes of COVID-19 mortality. However, drug delivery to lung tissues is impeded by endothelial cell barriers, limiting the efficacy of existing treatments. A prompt and aggressive treatment strategy is therefore necessary.

A renewable source of porcine macrophages derived from pluripotent stem cells (PSCs) would be a valuable alternative to primary porcine alveolar macrophages (PAMs) in the research of host-pathogen interaction mechanisms. We developed an efficient and rapid protocol, within 11 days, to derive macrophages from porcine PSCs (pPSCs). The pPSC-derived macrophages (pPSCdMs) exhibited molecular and functional characteristics of primary macrophages. The pPSCdMs showed macrophage-specific surface protein expression and macrophage-specific transcription factors, similar to PAMs. The pPSCdMs also exhibited the functional characteristics of macrophages, such as endocytosis, phagocytosis, porcine respiratory and reproductive syndrome virus infection and the response to lipopolysaccharide stimulation. Furthermore, we performed transcriptome sequencing of the whole differentiation process to track the fate transitions of porcine PSCs involved in the signaling pathway. The activation of transforming growth factor beta signaling was required for the formation of mesoderm and the inhibition of the transforming growth factor beta signaling pathway at the hematopoietic endothelium stage could enhance the fate transformation of hematopoiesis. In summary, we developed an efficient and rapid protocol to generate pPSCdMs that showed aspects of functional maturity comparable with PAMs. pPSCdMs could provide a broad prospect for the platforms of host-pathogen interaction mechanisms.

To test the hypothesis that effects of dietary carbohydrate and lipid concentrations on growth performance, feeding utilization, glucose and lipid metabolism in gibel carp A strain may be differ from F strain, these two strain of gibel carp were fed with one of three different isonitrogenous diets: HCLL (45% carbohydrate, 2% lipid), MCML (30% carbohydrate, 8% lipid), or LCHL (15% carbohydrate, 14% lipid). After 8 weeks, the HCLL-fed fish had the highest hepatosomatic index, hepatic crude lipid levels, and triglyceride levels and lipid retention efficiency. Enhanced lipogenesis and lipid uptake potential were observed in fish fed HCLL and MCML diets. Moreover, increases in glucose transport (glut2, P = 0.003) and glycolysis (gk, P = 0.012; 6pfk, P = 0.005) in livers of both strains were induced by the high-carbohydrate diet. Genotype-specific effect was identified on plasma lipid content. Plasma triglyceride levels were also greater in the F strain than in the A strain. Furthermore, the F strain had higher levels of fatty acid β-oxidation and glycolysis compared with the A strain. Nutrient retention was affected (P < 0.05) by the interaction between genotype and diet, implied dietary carbohydrate played a vital role in lipid accumulation in gibel carp. As dietary lipids increased, the F strain exhibited better feed utilization and a higher PRE than the A strain. However, the A strain had better growth performance. Overall, the F strain had better glucose uptake, glycolysis potential, and lipid utilization ability than the A strain.

With the establishment of the heart-gut axis concept, accumulating studies suggest that the gut microbiome plays an important role in the pathogenesis of cardiovascular diseases. Yet, little evidence has been reported in characterizing the gut microbiota shift in atrial fibrillation.

Atrial remodeling plays a significant role during the progression of atrial fibrillation (AF). Left atrial wall thickness (LAT) is a subjective and easily acquirable indicator referring to structural remodeling. Therefore, we aimed to investigate the association between LAT and atrial remodeling substrate, and to explore the predictive role of LAT about strong maintenance substrate and poor response to catheter ablation.LAT was measured by cardiac computed tomography in 2 selected locations (roof and floor) in 100 persistent AF patients. Then the low-dose-ibutilide-facilitated catheter ablation was performed and atrial maintenance substrate was categorized as weak, mild, and strong, based on the response to circumferential pulmonary vein isolation or complex fractionated atrial electrograms ablation. During follow-up, the success rate was evaluated. LAT showed a progressive thickening tendency from weak, mild, to strong maintenance substrate (roof: 2.2 mm vs. 2.6 mm vs. 3.9 mm, P < .0001; floor: 1.7 mm vs. 2.0 mm vs. 2.5 mm, P < .0001). During follow-up, the success rate of ablation was decreased with the maintenance substrate strengthening (weak 80%, mild 64.53%, strong 31.43%, P = .009). LA roof thickness >3.10 mm might be the predictor to strong atrial maintenance substrate and poor response to ablation.LAT was associated with the remodeling extent of atrial maintenance substrate and might predict the response to catheter ablation. These findings could help the clinicians to select the appropriate ablative strategy and predict the complexity and prognosis before catheter ablation.

Recent genome-wide association (GWA) studies in Caucasians identified multiple single nucleotide polymorphisms (SNPs) associated with coronary artery disease (CAD). The associations of those SNPs with myocardial infarction (MI) have not been replicated in Asian populations. Among those previously identified SNPs, we selected nine (rs10953541, rs1122608, rs12190287, rs12413409, rs1412444, rs1746048, rs3798220, rs4977574, rs579459, in or near genes 7q22, LDLR, TCF21, CYP17A1, LIPA, CXCL12, LPA, CDKN2A, ABO, respectively) because of the relatively high minor allele frequencies in Chinese individuals and tested the associations of the SNPs with MI and MI related risk factors in Chinese population.

To investigate the effect of premature birth (PTB) on long-term systolic blood pressure (SBP) variability (SBPV) in women.