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Proteins in Jumonji family function as histone demethylases and participate in cardiac development. Jumonji domain containing 5 (JMJD5) is responsible for the embryonic development through removing methyl moieties from H3K36me2 histone, and has pro‐proliferative effect on heart and eye development. However, the protective role of JMJD5 against oxygen–glucose deprivation and reperfusion (OGD/R)‐induced injury in cardiomyocytes has not been fully understood. Firstly, myocardial ischemia/reperfusion (I/R) rat model was established by ligation of left coronary artery. OGD/R was performed in non‐transfected H9C2 or H9C2 transfected with pcDNA‐JMJD5 plasmid to induce cell cytotoxicity. Data from qRT‐PCR and western blot showed that JMJD5 was reduced in the heart tissues of myocardial I/R rat model and OGD/R‐induced H9C2. Secondly, JMJD5 over‐expression attenuated OGD/R‐induced decrease in cell viability and increase in lactate dehydrogenase secretion and cell apoptosis in H9C2. Mitophagy was promoted by pcDNA‐mediated over‐expression of JMJD5 with enhanced protein expression of LC3‐I, LC3‐II, Atg5, and Beclin 1. Thirdly, knockdown of JMJD5 aggravated OGD/R‐induced decrease in hypoxia‐inducible factor‐1α (HIF‐1α), whereas JMJD5 over‐expression enhanced BNIP3 (Bcl‐2/adenovirus E1B 19‐kDa interacting protein) through upregulation of HIF‐1α. Lastly, BNIP3 silencing promoted cell apoptosis, suppressed mitophagy, and attenuated the protective effects of JMJD5 over‐expression against OGD/R‐induced injury in H9C2. In conclusion, JMJD5 exerted protective effects against OGD/R‐induced injury in cardiomyocytes through upregulation of HIF‐1α‐BNIP3.

We characterized the structure of prepared citrus pectin oligosaccharides (POS) and investigated the immunometabolism-modulating effects of POS and their microbial metabolites on human macrophages. Both POS and metabolites activated immune responses and exhibited anti-inflammatory properties in the presence of lipopolysaccharide (LPS) via regulating expressions of inflammatory cytokines and nuclear factor-kappa B. Cholesterol efflux was also facilitated via increased gene expressions of the liver X receptor-α-adenosine triphosphate-binding cassette transporter (ABC) A1/ABCG1 pathway and suppressed cholesterol synthesis via suppressing expressions of 3-hydroxy-3-methylglutaryl-coenzyme A reductase. Microbial degradation prevented POS from attenuating palmitoyl-3-cysteine-serine-lysine-4-induced inflammation and promoting M2 polarization, but it is capable of inhibiting cholesterol uptake-related genes CD36 and SR-A. These findings indicate that immunometabolism-modulating effects of POS are not solely microbiota-dependent effects. Both POS and their microbial metabolites are potential immunometabolism modulators via different mechanisms.

We investigated the regulatory effects of citrus pectin oligosaccharides (POS) from an innovative, chemically controllable degradation process on cholesterol metabolism and the gut microbial composition. The modulatory role of the intestinal flora was explored. Four-week-old male C57BL/6 mice were fed either a standard diet; a high-fat (HF) diet; or a HF diet with 0.15, 0.45, and 0.9 g/kg body weight POS for 30 days. POS reduced serum total cholesterol (TC) and low-density lipoprotein-cholesterol (LDL-C) in a dose-dependent manner. The relative abundances of specific bacterial groups in the feces and the concentrations of their metabolites were higher in the POS groups. There were significant correlations among Bifidobacterium, Lactobacillus, and Bacteroides and short-chain fatty acids, as well as among serum TC, LDL-C, fecal bile acids, and liver cholesterol 7-α-hydroxylase and 3-hydroxy-3-methylglutaryl-coenzyme A reductase. These findings indicate that the prepared POS exhibited hypocholesterolemic effects and that the potential regulatory mechanisms of citrus POS on cholesterol metabolism are modulated by specific bacterial groups together with their metabolites.

Background: Platelet activation occurs upon ischemia/reperfusion and is related to the generation of reactive oxygen species (ROS) during this process. Vitamin C (VC) is a powerful antioxidant. VC scavenges ROS, reduces platelet activation, and attenuates reperfusion injury. However, the effects of VC on platelets undergoing hypoxia/reoxygenation (H/R) remain unclear. Objectives: Herein, we evaluated the effects of VC on platelets in vitro following H/R and the related mechanisms. Method: Fresh platelets were collected from 67 volunteers at the Blood Center of Hebei Province. Platelets were diluted with saline to a concentration of 2.00 × 1011/L. Aggregation and the curve slope were evaluated within 4 h with a whole-blood impedance analyzer. To determine the optimal experimental time, platelets were treated with hypoxia or reoxygenation for different times, and impedance aggregometry was carried out by measuring changes in electrical impedance induced by arachidonic acid (0.5 mM) and adenosine diphosphate (10 µM), thereby establishing the H/R model. Three antioxidants (VC, melatonin, and probucol) were used to treat platelets after H/R, and impedance aggregometry was used to determine their effects on platelet aggregation. The influence of VC on apoptosis-related indicators was detected. ROS and the mitochondrial membrane potential were observed by inverted fluorescence microscopy and flow cytometry, respectively. Related protein levels were detected by Western blotting. Results: ROS scavengers inhibited platelet activation and aggregation in a concentration-dependent manner. VC post-conditioning scavenged ROS, downregulated cytochrome C, Bax, and caspase-9 proteins, and upregulated Bcl-2 protein. These effects collectively blocked platelet apoptosis and inhibited platelet aggregation. Conclusions: VC inhibited platelet aggregation by blocking apoptosis. Thus, VC may have applications in the treatment of platelet-related diseases.

Scope The prebiotic regulation of the gut microbiota is a promising strategy to induce protective humoral and mucosal immune responses. The potential immune-improving effects of pectin oligosaccharides (POS) in healthy mice and the potential mechanism mediated by specific intestinal bacteria are investigated. Methods and results POS is prepared using a hydrogen-peroxide-assisted degradation. Mice that consumed diets containing POS are tested for microbial community shifts, short-chain fatty acids (SCFAs), and immunoglobulin (Ig) production using quantitative real-time polymerase chain reaction, gas chromatography, and ELISA kits. Pearson's correlation analyses are performed between Ig production and specific intestinal bacteria or SCFAs. POS treatment significantly improves the growth of healthy mice. Moreover, 4-week POS administration results in a profound change in intestinal microbial composition and a significantly higher fecal concentration of acetate, which leads to substantial increases of the levels of fecal secretory immunoglobulin A and serum IgG. Conclusions The results suggest that the inclusion of POS in a diet can increase Ig production and optimize the composition of the gut microbiota. A significant correlation is observed between changes in Ig production and specific intestinal bacteria or acetate, providing insight into the mechanism of POS as a potential immune-enhancing supplement.

Objective The study was established to inquire into the protective effect of the HIF-1α (Hypoxia-inducible factor-1α)/ BNIP3(Bcl-2/adenovirus E1B 19-kDa interacting protein) signal path-induced-autophagy during myocardial ischemia/ reperfusion (I/R) and oxygen–glucose deprivation/recovery (OGD/R) injury in heart-derived H9C2 cells as well as its potential underlying mechanism. Methods Immediate myocardial I/R in SD (Spraque Dawley) rats and cytotoxicity of OGD/R injury on H9C2 cells with and without inhibitors or agonists of HIF-1α and BNIP3 were evaluated. Expression of mitochondrial autophagic protein were detected by Western blot and immunofluorescence. And the mitochondrial autophagosome were detected using Transmission Electron Microscope (TEM). Results I/R and OGD/R injury increased the expression level of HIF-1α, activated the downstream BNIP3 and subsequently triggered mitochondria-dependent autophagy. Up-regulation the expression of HIF-1α and BNIP3 may promote the cardiac myocytes of SD rats of I/R injure and OGD/R injury-induced autophagy of H9C2 cells. Moreover, down-regulation the expression of HIF-1α or BNIP3-siRNA decreased H9C2 cells autophagy under OGD/R injury. Conclusions Together, our studies indicated that HIF-1α synchronization regulate BNIP3 during OGD/R injury-induced autophagy in H9C2 cells, though BNIP3-induced autophagy acting as a survival mechanism.

Lead (Pb) is a well-recognized and potent heavy metal with non-biodegradable nature and can induce the oxidative stress, degenerative damages in tissues, and neural disorders. Certain lactic acid bacterial strains retain the potential to mitigate the lethal effects of Pb. The present work was carried out to assess the Pb bio-sorption and tolerance capabilities of Lactobacillus plantarum spp. Furthermore, potato resistant starch (PRS)-based microencapsulated and non-encapsulated L. plantarum KLDS 1.0344 was utilized for bioremediation against induced chronic Pb toxicity in mice. The experimental mice were divided into two main groups (Pb exposed and non-Pb exposed) and, each group was subsequently divided into three sub groups. The Pb exposed group was exposed to 100 mg/L Pb(NO3)2 via drinking water, and non-Pb exposed group was supplied with plain drinking water during 7 weeks prolonged in vivo study. The accumulation of Pb in blood, feces, renal, and hepatic tissues and its pathological damages were analyzed. The effect of Pb toxicity on the antioxidant enzyme capabilities in blood, serum, as well as, on levels of essential elements in tissues was also calculated. Moreover, KLDS 1.0344 displayed remarkable Pb binding capacity 72.34% and Pb tolerance (680 mg/L). Oral administration of both non- and PRS- encapsulated KLDS 1.0344 significantly provided protection against induced chronic Pb toxicity by increasing fecal Pb levels (445.65 ± 22.28 μg/g) and decreasing Pb in the blood up to 137.63 ± 2.43 μg/L, respectively. KLDS 1.0344 microencapsulated with PRS also relieved the renal and hepatic pathological damages and improved the antioxidant index by inhibiting changes in concentrations of glutathione peroxidase, glutathione, superoxide dismutase, malondialdehyde, and activated oxygen species, which were affected by the Pb exposure. Overall, our results suggested that L. plantarum KLDS 1.0344 either in free or encapsulated forms hold the potentiality to deliver a dietetic stratagem against Pb lethality.

Haijuan Hu, Jidong Zhang, Yan Wang, Zejun Tian, Demin Liu, Guangming Zhang, Guoqiang Gu, Hongmei Zheng, Ruiqin Xie, Wei Cui Department of Cardiology, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, People’s Republic of China Background: The objective of the study was to investigate the relationship between baseline blood pressure (BP) and the magnitude of BP reduction in patients with essential hypertension treated with nifedipine gastrointestinal therapeutic system (NGTS).Methods and patients: One hundred and thirty-eight patients with essential hypertension were enrolled in this prospective, single-arm, open-label study. NGTS was administered for 24 weeks to achieve target BP of 140/90 mmHg. The dose could be uptitrated to 60 mg/d in case of unsatisfactory BP reduction after 4-week treatment. Home blood pressure measurement was recorded through the initial 1–14 days, and office BP and heart rate were evaluated at 2, 4, 8, 12, and 24 weeks.Results: One hundred and seventeen patients (84.8%) completed the study, and their average BP decreased by 19.0/11.3 mmHg after 24 weeks. The reduction of either systolic or diastolic BP was positively correlated with baseline BP at weeks 2, 4, or 24 after treatment (r=0.603–0.762, all p

Statins are widely used as hypolipidemic drugs, and have beneficial effects in reducing cardiovascular events. In addition, recent studies on the pleiotropic effects of statins (i.e., simvastatin) reveal that these drugs have many additional anti-atherogenic effects, including antiplatelet activity. The mechanisms may be partly related to activation of peroxisome proliferator-activated receptors (PPARs), which are present in human platelets, and whose activation inhibits platelet aggregation. However, the details of the signaling pathway by which simvastatin inhibits platelet activation via PPARs have not yet been completely established. The aim of this study was to examine the mechanisms by which the PPAR-mediated pathways contribute to the antiplatelet activity of simvastatin. Simvastatin (3-50 μM) induced PPARα and PPARγ activation in a dose-dependent manner in washed platelets. Additionally, simvastatin inhibited collagen-induced platelet aggregation, expression of CD62 and PAC-1, and Ca 2 + mobilization. These effects of simvastatin on platelet responses were strongly reduced by adding a selective PPARγ antagonist (GW9662), but not PPARα antagonist (GW6471). Moreover, in the presence of GW9662, simvastatin-mediated increase of cyclic adenosine monophosphate (cAMP) production, vasodilator-stimulated phosphoprotein (VASP) Ser 157 phosphorylation and inhibition of Akt phosphorylation were markedly reversed. Furthermore, simvastatin was found to inhibit phosphorylation of mitogen-activated protein kinases (MAPKs, i.e., p38 MAPK, ERK) by increasing the association between PPARγ and the components of MAPKs after platelet activation. Taken together, the present results confirm that simvastatin inhibition of platelet activation is mediated by PPARγ-dependent processes, which involves mediating MAPKs signaling, increase of cAMP formation and VASP Ser 157 phosphorylation, inhibition of Akt phosphorylation and intracellular Ca 2 + mobilization.

Aims Vascular smooth muscle cells (VSMCs) played an important role in vascular remodeling. dl -3- n -butylphthalide (NBP) was extracted as a pure component from seeds of Apium graveolens Linn (Chinese celery) for protecting neurons activity, but the role of NBP on VSMCs was not clearly clarified. Main methods Cell proliferation was measured by MTS and flow cytometry. Western blot analysis and transmission electron microscopy were performed to analyze the relative protein expression and autophagosome. Moreover, the autophagic inhibitor and β-catenin inhibitor were used to evaluate the effects of NBP on autophagy and the function of β-catenin on cell proliferation respectively. Key findings NBP significantly suppressed platelet derived growth factor-BB (PDGF-BB)-stimulated VSMC proliferation, and the inhibitory effects of NBP on proliferation were caused by inducing autophagy. In addition, the inhibitory effects of NBP on proliferation were associated with the β-catenin signaling pathway. Moreover, β-catenin overexpression reversed the induction effect of NBP on autophagy and the β-catenin inhibitor JW74 enhanced these effects. Significance Our findings demonstrated that NBP protected VSMC from PDGF-BB-stimulated proliferation by inducing autophagy through suppression of the β-catenin signaling pathway, confirming the induction of autophagy might be a therapeutic strategy for use in the proliferative cardiovascular diseases.

A number of clinical trials have shown that a high loading dose of atorvastatin (Ator) within 24h before percutaneous coronary intervention (PCI) exerts protective effects on the cardiovascular system. However, the potential mechanisms regarding this rapid benefit of Ator remain elusive. Our study introduced three different ischaemia/reperfusion (I/R) models: I/R in vivo, I/R in vitro and oxygen-glucose deprivation/recovery (OGD/R) in primary neonatal rat cardiac myocytes to observe the protective effect of a single loading dose of Ator pre-treatment and further to explore the potential mechanisms of this protective effect with confocal laser scanning microscopy, flow cytometry, biochemical and morphology methods. We found that the pre-treatment of high-dose Ator decreased the cardiac injury and maintained the integrity of mitochondria in all three of the I/R models, which was similar to ischaemic pre-conditioning (IPC). We used the mitochondrial K(ATP) channels (mitoKATP channels) inhibitor 5-hydroxydecanoate (5-HD) and the mitochondrial permeability transition pore (mPTP) opener lonidamine (LND) to analyse the underlying mechanisms. The results showed that the pre-treatment of Ator significantly decreased I/R-induced injury, and maintained the functional integrity of mitochondria through alleviating Ca(2+) overload, reactive oxygen species burst, inhibiting the opening of mPTP and preventing mitochondrial membrane potential (ΔΨm) depolarisation. The present results demonstrated that a single dose of Ator might protect the myocardium from I/R-induced injury by inhibiting the mPTP opening through activating the mitoKATP channels. This result may contribute toward the development of novel strategies for clinical cardioprotection against I/R injury.

Objectives Aortic valve interstitial cells (AVICs) play a vital role in the development of aortic valve stenosis. The aim of this study is to observe that whether or not AVICs calcified spontaneously and to detect the expression of osteogenic factors in the formation of calcified cell nodules. Methods AVICs were cultured in explant method, calcification were detected by Von Kossa, alizarin red S stain and a calcium assay kit, and expression of osteogenic factors, such as Cbfa1/ OC/BMP-2/BMP-4, were detected by RT-PCR and western-blot analysis at different times. Results AVICs aggregated and formed small cell nodules after 4∼6 day culture, and the number of nodules become more and the diameter is bigger at day 12 than that at day 6. The cell nodules were positive by Von Kossa and alizarin red S stain, which indicated that they were calcified nodules. The statistical analysis indicated that both the content of alizarin red S and calcium at day 12 were higher than that at day 0 and day 6 ( F = 106.167, F = 116.379, respectively; P The statistic analysis of the osteogenic gene expression indicated that the Cbfa1/OC/ BMP- 4 mRNA were lowest at day 0, higher at day 6 and highest at day 12 (F = 410.106, X 2 = 7.200, F = 38.463, respectively; P F = 56.565, P 2 = 7.200, F = 452.482, respectively; P Conclusions AVICs calcified spontaneously with extend culture time, in which the differentiation of AVICs into osteoblasts-like cells may play an important role in the process of calcification.

Objectives Atorvastatin (Ator) has been shown to exert protective properties on cardiovascular systems in vivo . However, its mechanism of action remains elusive. Our study aims to assess the potential of Ator to protect the cardiomyocytes exposed to ischaemia-like conditions of oxygen-glucose deprivation/recovery (OGD/R) in vitro and to determine mitochondrial function upon Ator exposure. Methods Primary cardiomyocytes were isolated from neonatal Sprague-Dawley rats. To establish an in vitro model of OGD/R, which resembles ischaemia/reperfusion in vivo , primary cardiomyocytes were exposed to OGD for 10 h followed by a 3 h recovery. Myocardial cell viability was evaluated using the MTT and lactate dehydrogenase (LDH) release assays. The opening of the mitochondrial permeability transition pore (mPTP), Ca 2+ concentration and mitochondrial membrane potential (ΔΨm) in cardiomyocytes were measured using confocal laser scanning microscopy (CLSM). Reactive oxygen species (ROS) generation was examined using flow cytometry. Results Ator (1 μM) markedly attenuated OGD/R-induced cell injury and maintained the functional integrity of mitochondria by alleviating calcium overload and ROS burst, inhibiting the opening of mPTP and preventing ΔΨm depolarisation ( P ATP channel) blocker 5-hydroxydecanoic acid (5-HD, 100 μM). Conclusions Ator has tremendous pharmacological potential in protecting against OGD/R-induced cell injury by preserving the functional integrity of mitochondria.

Objectives To evaluate the cardioprotective effect of atorvastatin (Ator) via modulation of mitochondrial permeability transition pore (mPTP) through mitochondrial ATP-sensitive potassium channels (mitoK ATP channels). Methods Sprague-Dawley rat hearts were Langendorff-perfused with Krebs-Henseleit (K-H) buffer and subjected to 30 min global ischaemia followed by 120 min of reperfusion. In this study, the mitoK ATP channels inhibitor 5-hydroxydecanoate (5-HD) and the mPTP opener lonidamine (LND) were used to analyse the underlying mechanisms. Rats were randomly divided into 7 groups: (1) control group; (2) ischaemia/reperfusion (I/R) group; (3) Ator group; (4) Ator + 5-HD group; (5)Ator + LND group; (6) 5-HD group; (7) LND group. The parameters of cardiac function, myocardial infarct size, lactate dehydrogenase (LDH) in the coronary effluent and ATP content in myocardium were measured. To investigate the relationship between mitoK ATP channels and mPTP implicated in Ator preconditioning, NAD + content, a marker of mPTP opening, was measured. Results Compared with the I/R group, Ator (1 μM) preconditioning significantly improved cardiac functional recovery, decreased myocardial infarct size, reduced LDH release, prevented ATP and NAD + depletion ( P Conclusions Ator may protect myocardium in response to I/R injury by inhibiting the mPTP opening through activating the mitoK ATP channels. Moreover, the mitoK ATP channels may be upstream of the mPTP.