Anti-aging Effects of Alu Antisense RNA on Human Fibroblast Senescence Through the MEK-ERK Pathway Mediated by KIF15.

OBJECTIVE: To investigate whether human short interspersed nuclear element antisense RNA (Alu antisense RNA; Alu asRNA) could delay human fibroblast senescence and explore the underlying mechanisms. METHODS: We transfected Alu asRNA into senescent human fibroblasts and used cell counting kit-8 (CCK-8), reactive oxygen species (ROS), and senescence-associated beta-galactosidase (SA-ß-gal) staining methods to analyze the anti-aging effects of Alu asRNA on the fibroblasts. We also used an RNA-sequencing (RNA-seq) method to investigate the Alu asRNA-specific mechanisms of anti-aging. We examined the effects of KIF15 on the anti-aging role induced by Alu asRNA. We also investigated the mechanisms underlying a KIF15-induced proliferation of senescent human fibroblasts. RESULTS: The CCK-8, ROS and SA-ß-gal results showed that Alu asRNA could delay fibroblast aging. RNA-seq showed 183 differentially expressed genes (DEGs) in Alu asRNA transfected fibroblasts compared with fibroblasts transfected with the calcium phosphate transfection (CPT) reagent. The KEGG analysis showed that the cell cycle pathway was significantly enriched in the DEGs in fibroblasts transfected with Alu asRNA compared with fibroblasts transfected with the CPT reagent. Notably, Alu asRNA promoted the KIF15 expression and activated the MEK-ERK signaling pathway. CONCLUSION: Our results suggest that Alu asRNA could promote senescent fibroblast proliferation via activation of the KIF15-mediated MEK-ERK signaling pathway.

Effects of TYROBP Deficiency on Neuroinflammation of a Alzheimer's Disease Mouse Model Carrying a PSEN1 p.G378E Mutation.

Objective To study the effects of TYRO protein kinase-binding protein (TYROBP) deficiency on learning behavior, glia activation and pro-inflammatory cycokines, and Tau phosphorylation of a new Alzheimer's disease (AD) mouse model carrying a PSEN1 p.G378E mutation.Methods A new AD mouse model carrying PSEN1 p.G378E mutation was built based on our previously found AD family which might be ascribed to the PSEN1 mutation, and then crossed with TYROBP deficient mice to produce the heterozygous hybrid mice (PSEN1G378E/WT; Tyrobp+/-) and the homozygous hybrid mice (PSEN1G378E/G378E; Tyrobp-/-). Water maze test was used to detect spatial learning and memory ability of mice. After the mice were sacrificed, the hippocampus was excised for further analysis. Immunofluorescence was used to identify the cell that expresses TYROBP and the number of microglia and astrocyte. Western blot was used to detect the expression levels of Tau and phosphorylated Tau (p-Tau), and ELISA to measure the levels of pro-inflammatory cytokines. Results Our results showed that TYROBP specifically expressed in the microglia of mouse hippocampus. Absence of TYROBP in PSEN1G378E mutation mouse model prevented the deterioration of learning behavior, decreased the numbers of microglia and astrocytes, and the levels of interleukin-6, interleukin-1ß and tumor necrosis factor-α in the hippocampus (all P < 0.05). The ratios of AT8/Tau5, PHF1/Tau5, pT181/Tau5, pT231/Tau5 and p-ERK/ERK were all higher in homozygous hybrid mice (PSEN1G378E/G378E; Tyrobp-/- mice) compared with PSEN1G378E/G378E mice (all P < 0.05). Conclusions TYROBP deficiency might play a protective role in the modulation of neuroinflammation of AD. However, the relationship between neuroinflammation processes involving microglia and astrocyte activation, and release of pro-inflammatory cytokines, and p-Tau pathology needs further study.

Exploration of dilated cardiomyopathy for biomarkers and immune microenvironment: evidence from RNA-seq.

BACKGROUND: The pathogenic mechanism of dilated cardiomyopathy (DCM) remains to be defined. This study aimed to identify hub genes and immune cells that could serve as potential therapeutic targets for DCM. METHODS: We downloaded four datasets from the Gene Expression Omnibus (GEO) database: GSE141910, GSE3585, GSE42955 and GSE79962. Weighted gene coexpression network analysis (WGCNA) and differential expression analysis were performed to identify gene panels related to DCM. Meanwhile, the CIBERSORT algorithm was used to estimate the immune cells in DCM tissues. Multiple machine learning approaches were used to screen the hub genes and immune cells. Finally, the diagnostic value of the hub genes was assessed by receiver operating characteristic (ROC) analysis. An experimental mouse model of dilated cardiomyopathy was used to validate the bioinformatics results. RESULTS: FRZB and EXT1 were identified as hub biomarkers, and the ROC curves suggested an excellent diagnostic ability of the above genes for DCM. In addition, naive B cells were upregulated in DCM tissues, while eosinophils, M2 macrophages, and memory CD4 T cells were downregulated in DCM tissues. The increase in two hub genes and naive B cells was validated in animal experiments. CONCLUSION: These results indicated that FRZB and EXT1 could be used as promising biomarkers, and eosinophils, M2 macrophages, resting memory CD4 T cells and naive B cells may also affect the occurrence of DCM.

Pyroptosis Patterns Are Involved in Immune Microenvironment Regulation of Dilated Cardiomyopathy.

The importance of cell pyroptosis in immunity regulation is becoming increasingly obvious, especially in diseases of the cardiovascular system. Nevertheless, it is unknown whether the pyroptosis signalling pathway is involved in the immune microenvironment regulation of dilated cardiomyopathy (DCM). Therefore, the purpose of the study was to investigate the influence of pyroptosis on the immune environment in dilated cardiomyopathy. We found that expression of 19 pyrolysis-related genes (PRGs) in DCM samples was altered compared to healthy samples. Subsequently, based on these 12 hub pyrolysis-related genes, we developed a classifier that can distinguish between healthy samples and DCM samples. Among the hub pyrolysis-related genes, RT-PCR analyses demonstrated that five of them exhibited significant differential expression in DCM. Interestingly, we observed that immune characteristics are correlated with pyroptosis: higher expression of GSDMD is positively correlated with infiltrating activated pDCs; GSDMD is negatively correlated with Tregs; CASP1 is positively related to parainflammation; and CASP9 is negatively related to the type II IFN response. In addition, distinct pyroptosis-mediated patterns were identified, and immune characteristics under distinct patterns were revealed: pattern B mediates an active immune response, and pattern A leads to a relatively mild immune response to DCM. We also compared the biological functions between these patterns. Compared with pattern A, pattern B had more abundant pathways, such as the NOTCH signalling pathway and pentose phosphate pathway. In summary, this study proves the important influence of pyrolysis on the immune microenvironment of dilated cardiomyopathy and provides new clues for understanding the pathogenesis of dilated cardiomyopathy.

Diabetes Mellitus and COVID-19: Associations and Possible Mechanisms.

Coronavirus disease 2019 (COVID-19) is a recently emerged disease with formidable infectivity and high mortality. Emerging data suggest that diabetes is one of the most prevalent comorbidities in patients with COVID-19. Although their causal relationship has not yet been investigated, preexisting diabetes can be considered as a risk factor for the adverse outcomes of COVID-19. Proinflammatory state, attenuation of the innate immune response, possibly increased level of ACE2, along with vascular dysfunction, and prothrombotic state in people with diabetes probably contribute to higher susceptibility for SARS-CoV-2 infection and worsened prognosis. On the other hand, activated inflammation, islet damage induced by virus infection, and treatment with glucocorticoids could, in turn, result in impaired glucose regulation in people with diabetes, thus working as an amplification loop to aggravate the disease. Therefore, glycemic management in people with COVID-19, especially in those with severe illness, is of considerable importance. The insights may help to reduce the fatality in the effort against COVID-19.

Double-endpoint Genotoxicity Quantification and PAHs Characterization of Drinking Water Source alongside Polluted Yinghe River with High Tumor Mortality.

The etiology for the high tumor mortality in heavy polluted Yinghe river basin is still unclear and polycyclic aromatic hydrocarbons (PAHs) belong to the priority pollutants in water based on the former surveillance data. In order to explore the potential genotoxicants contributing to the double-endpoint genotoxicity of polluted drinking water source, 12 groundwater and 3 surface water samples were collected from 3 villages and the nearby rivers alongside Yinghe river basin, respectively and their comprehensive genotoxicity was estimated with a bioassay group of SOS/umu test and micronucleus (MN) test (MNT). Some groundwater samples showed positive genotoxicity and all surface water samples were highly genotoxic. Eight groundwater samples showed DNA genotoxic effect with the average 4-NQO equivalent concentration (TEQ(4-NQO)) of 0.067 µg/L and 0.089 µg/L in wet and dry season, respectively. The average MN ratios of groundwater samples were 14.19‰ and 17.52‰ in wet and dry season, respectively. Groundwater samples showed different genotoxic effect among 3 villages. The total PAHs concentrations in all water samples ranged from 8.98 to 25.17 ng/L with an average of 14.97±4.85 ng/L. BaA, CHR, BkF, BaP and DBA were the main carcinogenic PAHs contributing to the genotoxicity of water samples. In conclusion, carcinogenic PAHs are possibly related to the high tumor mortality in the target area. Characterization of carcinogenic PAHs to genotoxicity of drinking water source may shed light on the etiology study for high tumor mortality in Yinghe river basin.

Ubiquitin C-terminal hydrolase L1 (UCHL1) regulates post-myocardial infarction cardiac fibrosis through glucose-regulated protein of 78 kDa (GRP78).

Abnormal cardiac fibrosis indicates cardiac dysfunction and poor prognosis in myocardial infarction (MI) patients. Many studies have demonstrated that the ubiquitin proteasome system (UPS) plays a significant role in the pathogenesis of fibrosis. Ubiquitin C-terminal hydrolase L1 (UCHL1), a member of the UPS, is related to fibrosis in several heart diseases. However, whether UCHL1 regulates cardiac fibrosis following MI has yet to be determined. In the present study, we found that UCHL1 was dramatically increased in infarct hearts and TGF-ß1-stimulated cardiac fibroblasts (CFs). Inhibition of UCHL1 with LDN57444 (LDN) reversed the myocardial fibrosis in post-MI heart and improved cardiac function. Treatment of LDN or UCHL1 siRNA abolished the TGF-ß1-induced fibrotic response of CFs. We further identified GRP78 as an interactor of UCHL1 through screening using immunoprecipitation-mass spectrometer. We determined that UCHL1 interacted with glucose-regulated protein of 78 kDa (GRP78) and prompted GRP78 degradation via ubiquitination. Furthermore, we found that GRP78 was upregulated after UCHL1 knockdown and that the GRP78 inhibitor HA15 diminished the antifibrotic function exerted by UCHL1 knockdown in CFs stimulated with TGF-ß1. This suggests that UCHL1 regulates cardiac fibrosis post MI through interactions with GRP78. This work identifies that the UCHL1-GRP78 axis is involved in cardiac fibrosis after MI.

Paeoniflorin Attenuates Myocardial Fibrosis in Isoprenaline-induced Chronic Heart Failure Rats via Inhibiting P38 MAPK Pathway.

Paeoniforin (Pae) is a monoterpenoid glycoside compound and has many biological activities, such as immunosuppression, anti-inflammation and anti-cell proliferation. However, the effects and mechanisms of Pae on chronic heart failure (CHF) remain unclear. This study was conducted to assess the effects and mechanisms of Pae on myocardial fbrosis in isoprenaline (Iso)-induced CHF rats. Pae (20 mg/kg) was intragastrically administrated to CHF rats for 6 weeks. Cardiac structure and function were assessed. The protein and mRNA levels of transforming growth factor ß1 (TGF-ß1) and p38 were detected. Compared to Iso group, Pae could alleviate myocardial fibrosis and improve cardiac function in CHF rats. The levels of collagen volume fraction (13.75%±3.77% vs. 30.97%±4.22%, P<0.001) and perivascular collagen volume area (14.32%±2.50% vs. 28.31%±3.16%, P<0.001) were signifcantly reduced in Pae group as compared with those in Iso group. The expression of TGF-ß1 protein (0.30±0.07 vs. 0.66±0.07, P<0.05) and mRNA (3.51±0.44 vs. 7.58±0.58, P<0.05) decreased signifcantly in Pae group as compared with that in Iso group. The expression of p38 protein (0.36±0.12 vs. 0.81±0.38, P<0.05) and mRNA (3.84±0.05 vs. 4.40±0.17, P<0.05) also decreased markedly in Pae group as compared with that in Iso group. Pae could attenuate myocardial fbrosis and improve cardiac function in CHF rats by down-regulating the p38 MAPK signaling pathway.

Mechanical chest compression with LUCAS device does not improve clinical outcome in out-of-hospital cardiac arrest patients: A systematic review and meta-analysis.

BACKGROUND: Cardiac arrest (CA) is a serious threat to human health. Cardiopulmonary resuscitation (CPR) is an effective treatment for CA. Early and high-quality CPR is closely related to the survival rate of patients with CA. But manual chest compression has a lot of defects. To solve the defects and improve the quality of CPR, mechanical CPR device was invented. However, it has still controversy whether manual chest compression or mechanical chest compression is better. This systematic review was aimed to investigate the difference in clinical outcomes between manual chest compression and Lund University Cardiac Assist System (LUCAS) assisted CPR in patients with out-hospital CA. METHODS: Original research studies, conducted on adult out-of-hospital CA, were included. PubMed/Medline, EMBASE, Scopus, Cochrane Library, CNKI, and Wanfang database were searched from the setting to February 21, 2019. Odds ratio (OR) with 95% confidence interval (CI) was selected as effect scale index for evaluation of the difference in return of spontaneous circulation (ROSC), survival to hospital admission, survival to hospital discharge, and survival to 30 days. Random effects model was used in this study to estimate overall mean effects. RESULTS: A total of 6 articles, including 4 randomized controlled trials and 2 nonrandomized controlled trials, were selected. And 8501 subjects were involved to analyze the clinical outcomes of LUCAS and manual chest compression for patients with out-hospital CA. Comparisons of ROSC (33.3% vs 33.0%, P = .98; OR = 1; 95% CI: [0.89,1.13]), survival to hospital admission (22.7% vs 24.3%, P = .32; OR = 0.86; 95% CI: [0.65,1.15]), survival to hospital discharge (8.6% vs 10.7%, P = .50; OR = 0.92; 95% CI: [0.73,1.17]), and survival to 30 days (7.5% vs 8.5%, P = .50; OR = 0.92; 95% CI: [0.73,1.17]) were made. No significant difference was found. CONCLUSION: The synthesis of available evidence does not support that mechanical chest compression with LUCAS device improves clinical outcome in out-of-hospital CA patients compared with manual chest compression. Large scale studies with improved designs are still needed in the future.

Association between serum adropin level and coronary artery disease: a systematic review and meta-analysis.

BACKGROUND: Recent studies have found that adropin is associated with coronary artery disease (CAD). This meta-analysis sought to assess the relationship between serum adropin level and CAD. METHODS: Online databases including the Cochrane Library, PubMed, EMbase, Ovid, CBM, CNKI, VIP and WanFang Data were electronically searched for the clinical study concerning the relationship between serum adropin levels and CAD, including acute myocardial infarction (AMI), unstable angina pectoris (UAP), and stable angina pectoris (SAP). Two reviewers independently screened literature, extracted data and assessed methodological quality of included studies. Standard mean difference (SMD) with its 95% confidence interval (CI) was used as the effect size in this study. Then meta-analysis was performed using RevMan 5.2 software. RESULTS: A total of seven articles involved 945 participants were included. The results indicated that serum adropin level in CAD group was lower than healthy control group (SMD =-2.44, P=0.0008). In the subgroup analysis, the levels of serum adropin in AMI group (SMD =-2.96, P<0.00001), UAP group (SMD =-2.09, P=0.0001) and SAP group (SMD =-1.23, P=0.007) were also lower than that of healthy control. CONCLUSIONS: Serum adropin level in patients with CAD was lower than healthy individuals, indicating that the decrease of adropin concentration might play an important role in the development of CAD.

Platelet microparticles-containing miR-4306 inhibits human monocyte-derived macrophages migration through VEGFA/ERK1/2/NF-κB signaling pathways.

Platelets are major sources of microparticles (MPs) in peripheral bloodstream, and platelet-secreted MPs (P-MPs) transfer biological information to neighboring cells. In the present study, we found that the platelet- and P-MPs-derived microRNA-4306 (miR-4306) expression were downregulated in coronary artery disease (CAD) and platelet-derived miR-4306 was an independent poor prognostic factor in CAD. Plasma miRNA-4306 mainly cofractionated with MPs instead of Argonaute2 complexes or HDL. P-MPs could effectively deliver miR-4306 into human monocyte-derived macrophages (HMDMs). MiR-4306 noticeably inhibited the HMDMs migration in vitro and reduced the number of macrophage cells in cardiac tissue in myocardial infarction mice. This functional impact of miR-4306 was mediated directly through VEGFA to inhibit ERK/NF-κB signaling. In conclusion, our study suggested that intercellular transfer of miR-4306 by platelet microparticles inhibited the HMDMs migration through VEGFA/ERK1/2/NF-κB signaling pathways.

Morroniside alleviates coxsackievirus B3-induced myocardial damage apoptosis via restraining NLRP3 inflammasome activation.

Coxsackievirus B3 (CVB3)-induced myocardial damage always leads to serious heart failure by inducing cardiac injury. NLRP3 inflammasome activation has been identified as a central player in the pathogenesis of CVB3-induced viral myocarditis. Therefore, restraining NLRP3 inflammasome activation has been supposed to significantly alleviate the severity of myocardial damage and improve cardiac function. Morroniside (MR), one of the main iridoid glycosides, has the ability to depress the production of reactive oxygen species (ROS) and restrain the expression of caspase-3 and -9. Of importance, ROS and caspase are essential for NLRP3 inflammasome activation in response to CVB3 infection. Therefore, in the present study, MR was selected as a model drug to alleviate CVB3-induced myocardial damage. The results of cardiac function index determination showed that abnormal indexes including mean arterial pressure, heart rate, and left ventricular systolic pressure of myocardial damage rats could be recovered by treating with MR. Such results can be further verified by histopathological evaluation, with the heart tissues of CVB3-infected rats displaying the most amount of H&E and TUNEL positive cells. The underlying mechanism by which MR improves the cardiac function was subsequently investigated. The detection of various gene levels indicated that NLRP3 inflammasome activation was inhibited by MR through down-regulating the expression of pro-inflammatory cytokines: interleukin (IL)-ß and IL-18, the pivotal factors that lead to inflammatory responses. More importantly, the related genes, cardiac function indexes, and various myocardial damage markers of normal rats treated with MR did not exhibit any obvious changes compared with the control group, indicating a satisfactory biocompatibility of MR. In summary, MR holds a great potential in the alleviation of CVB3-induced myocardial damage with a negligible cytotoxicity to normal heart tissues.

An up-dated meta-analysis of major adverse cardiac events on triple versus dual antiplatelet therapy after percutaneous coronary intervention in patients with type 2 diabetes mellitus.

This meta-analysis is conducted to assess the efficiency and safety of triple antiplatelet therapy in patients with type 2 diabetes mellitus (T2DM) who have received coronary stents implantation. The risk of major adverse cardiac events (MACEs), target vessel revascularization (TVR), target lesion revascularization (TLR), myocardial infarction (MI) and bleeding events were evaluated in this meta-analysis. Eight randomized controlled trials incorporating 1700 participants were included. During a follow-up of 12 months after stents implantation, the risk of TVR, TLR and MACEs in Triple group were lower than that of Dual group. There was no significant difference in the comparison of stent thrombosis and bleeding events between the two groups. Triple antiplatelet therapy is effective in reducing adverse cardiovascular outcomes in T2DM patients after stents implantation, without increasing the risk of bleeding events. Advanced designed and large-scale trails are deserved in the future.

Occurrence of composite cardiac endpoints with change in resting heart rate among Chinese patients with coronary artery disease: Chinese cohort from the real-world BISO-CAD study.

OBJECTIVE: We evaluated change in resting heart rate (RHR) and its impact on prognosis in Chinese coronary artery disease (CAD) patients treated with bisoprolol, and also assessed drug safety and tolerability. METHODS: This phase IV, single arm observational study was a sub-study of the BISO-CAD study conducted across 20 hospitals in China between October 2011 and July 2015 with follow-up at 6, 12 and 18 months after baseline. The primary endpoint was occurrence of composite cardiac events. RESULTS: A total of 663 CAD patients (baseline RHR 75.47 ± 6.62 bpm) were enrolled in the intent-to-treat (ITT) set, and 513 patients were included in the efficacy analysis (EA) set. In the ITT set, the risk and the number of composite cardiac events in patients with mean RHR 69-74 bpm were significantly higher than in the <65 bpm group (ITT: estimate 1.03 ± 0.47, p = .029). The incidence of the composite cardiac endpoint was not affected by continuous mean RHR (p = .5070). RHR significantly decreased from baseline to 18 months, most obviously in the first 6 months (p < .0001). Ejection fraction and fractional shortening significantly improved in both the ITT and EA sets. An average RHR of 69-74 bpm had a significant effect on admission to hospital for acute coronary syndrome in the ITT (estimate 1.10, HR 3.004, p = .0196) and EA (estimate 1.26, HR 3.526, p = .0132) groups. Seven (1.1%) patients reported drug related adverse events. CONCLUSION: Reduction in RHR with bisoprolol lowered the incidence of composite cardiac events along with an acceptable safety and tolerability profile.

MicroRNA-132 protects hippocampal neurons against oxygen-glucose deprivation-induced apoptosis.

Hypoxic-ischemic brain injury (HIBI) results in death or long-term neurologic impairment in both adults and children. In this study, we investigated the effects of microRNA-132 (miR-132) dysregulation on oxygen-glucose deprivation (OGD)-induced apoptosis in fetal rat hippocampal neurons, in order to reveal the therapeutic potential of miR-132 on HIBI. MiR-132 dysregulation was induced prior to OGD exposure by transfection of primary fetal rat hippocampal neurons with miR-132 mimic or miR-132 inhibitor. The effects of miR-132 overexpression and suppression on OGD-stimulated hippocampal neurons were evaluated by detection of cell viability, apoptotic cells rate, and the expression of apoptosis-related proteins. Besides, TargetScan database and dual luciferase activity assay were used to seek a target gene of miR-132. As a result, miR-132 was highly expressed in hippocampal neurons following 2 h of OGD exposure. MiR-132 overexpression significantly increased OGD-diminished cell viability and reduced OGD-induced apoptosis at 12, 24, and 48 h post-OGD. MiR-132 overexpression significantly down-regulated the expressions of Bax, cytochrome c, and caspase-9, but up-regulated BCl-2. Caspase-3 activity was also significantly decreased by miR-132 overexpression. Furthermore, FOXO3 was a direct target of miR-132, and it was negatively regulated by miR-132. To conclude, our results provide evidence that miR-132 protects hippocampal neurons against OGD injury by inhibiting apoptosis.

Mitochondrial mutations in 12S rRNA and 16S rRNA presenting as chronic progressive external ophthalmoplegia (CPEO) plus: A case report.

RATIONALE: Chronic progressive external ophthalmoplegia (CPEO) is a classical mitochondrial ocular disorder characterized by bilateral progressive ptosis and ophthalmoplegia. Kearns -Sayre syndrome (KSS) is a multisystem disorder with PEO, cardiac conduction block, and pigmentary retinopathy. A few individuals with CPEO have other manifestations of KSS, but do not meet all the clinical diagnosis criteria, and this is called "CPEO plus." PATIENT CONCERNS: We report a 48-year-old woman exhibiting limb weakness, ptosis, ophthalmoparesis, and cerebellar dysfunctions. DIAGNOSES: The patient was diagnosed as exhibiting CPEO plus syndrome. INTERVENTIONS: The patient underwent clinical, genetic, histological, and histochemical analysis. She was treated orally with CoQ10, vitamin Bs, L-carnitine, and vitamin E. OUTCOMES: The patient's serum creatine kinase levels, electrocardiography, and nerve conduction study results were normal; an electromyogram revealed myopathic findings. Magnetic resonance imaging showed global brain atrophy, particularly in the brainstem and cerebellum areas. A muscle biopsy showed the presence of abundant ragged red fibers. Sequencing of the mitochondrial DNA from the skeletal muscle biopsy revealed C960del mutation in 12S rRNA and homozygous mutation C2835T in 16S rRNA. She took medicines on schedule, the clinical features were similar as 2 years ago. LESSONS: This is the first report of 2 rRNA mutations in a patient with MRI findings showing global brain atrophy, particularly in brainstem and cerebellum areas. Early recognition and appropriate treatment is crucial. This case highlights the cerebellar ataxia can occur in CPEO plus.

Efficacy and safety of Chinese herbal medicine Wenxin Keli for ventricular premature be ats: A systematic review.

BACKGROUND: To evaluate the efficacy and safety of the Chinese herbal extract Wenxin Keli, alone or in combination with Western medicine, for ventricular premature beats. METHODS: This systematic review was registered at PROSPERO (registration number CRD42013003200). A systematic literature search of 8 core electronic databases and 3 clinical trial registries in Chinese and English, yielded 10 trials whose randomness verified by contacting the authors. The included trials were assessed by the Cochrane risk of bias tool. RESULTS: Wenxin Keli might be more efficacious than placebo (Change of VPBs numbers, RR, 1.61, 95%CI, 1.48-1.76, P<0.00001, I2=0%;VPBs- related symptom, RR, 2.10, 95%CI, 1.91-2.30, P<0.00001, I2=0%), and the dual therapy of Wenxin Keli plus amiodarone might also be more effective than the monotherapy of amiodarone (Change of VPBs numbers, RR, 1.23, 95%CI, 1.10-1.39, P=0.0005, I2=0%; VPBs- related symptom, RR, 1.51., 95%CI, 1.30-1.76, P<0.00001, I2=0%), whereas Wenxin Keli might be comparable to metoprolol, propafenone or mexiletine (Change of VPBs numbers: metoprolol, RR, 1.01, 95%CI, 0.91-1.11, P=0.88, I2=0%; propafenone, RR, 1.05, 95%CI, 0.93-1.19, P=0.44, I2=0%; mexiletine, RR, 1.06, 95%CI, 0.96-1.17, P=0.28. VPBs- related symptom: metoprolol, RR, 0.95, 95%CI, 0.87-1.04, P=0.27, I2=0%, propafenone. RR, 1.10, 95%CI, 0.93-1.30, P=0.29, I2=29%, mexiletine,RR, 0.94, 95%CI, 0.78-1.12, P=0.47). Participants with ventricular premature beats' numbers<360 beats/h or with coronary heart disease benefited the most of the Wenxin Keli therapy (Change of VPBs numbers:RR, 1.10, 95%CI, 1.02-1.20, P=0.02, I2=44%; RR, 1.71, 95%CI, 1.18-2.49, P=0.005, I2=54%, respectively). The safety analysis revealed that Wenxin Keli did not statistically significant differed from the Western medicine in respect of the incidence of total adverse drug reactions (RR, 0.59, 95%CI, 0.35-1.01, P=0.05, I2=0%), but Wenxin Keli might be associated with a reduced risk of proarrhythmic reactions (P=0.007). The quality of the methodology of included trials was generally low. Several limitations existed that affected the validity of the findings, including the small sample size, insufficient randomization methods, poorly defined eligibility criteria, short duration of follow-up, absence of hard endpoints, and high risk of publication bias(P=0.013). CONCLUSIONS: Wenxin Keli might be a promising alternative and complementary medicine for ventricular premature beats.

Quantification for total demethylation potential of environmental samples utilizing the EGFP reporter gene.

The demethylation potential of pollutants is arguably an innate component of their toxicity in environmental samples. A method was developed for determining the total demethylation potential of food samples (TDQ). The demethylation epigenetic toxicity was determined using the Hep G2 cell line transfected with pEGFP-C3 plasmids containing a methylated promoter of the EGFP reporter gene. The total demethylation potential of the sample extracts (the 5-AZA-CdR demethylation toxic equivalency) can be quantified within one week by using a standard curve of the 5-AZA-CdR demethylation agent. To explore the applicability of TDQ for environmental samples, 17 groundwater samples were collected from heavy polluted Kuihe river and the total demethylation potentials of the sample extracts were measured successfully. Meaningful demethylation toxic equivalencies ranging from 0.00050 to 0.01747µM were found in all groundwater sample extracts. Among 19 kinds of inorganic substance, As and Cd played important roles for individual contribution to the total demethylation epigenetic toxicity. The TDQ assay is reliable and fast for quantifying the DNA demethylation potential of environmental sample extracts, which may improve epigenetic toxicity evaluations for human risk assessment, and the consistent consuming of groundwater alongside the Kuihe river pose unexpected epigenetic health risk to the local residents.

The efficacy of traditional Chinese Medical Exercise for Parkinson's disease: a systematic review and meta-analysis.

BACKGROUND AND OBJECTIVE: Several studies assessed the efficacy of traditional Chinese medical exercise in the management of Parkinson's disease (PD), but its role remained controversial. Therefore, the purpose of this systematic review is to evaluate the evidence on the effect of traditional Chinese medical exercise for PD. METHODS: Seven English and Chinese electronic databases, up to October 2014, were searched to identify relevant studies. The PEDro scale was employed to assess the methodological quality of eligible studies. Meta-analysis was performed by RevMan 5.1 software. RESULTS: Fifteen trials were included in the review. Tai Chi and Qigong were used as assisting pharmacological treatments of PD in the previous studies. Tai Chi plus medication showed greater improvements in motor function (standardized mean difference, SMD, -0.57; 95% confidence intervals, CI, -1.11 to -0.04), Berg balance scale (BBS, SMD, -1.22; 95% CI -1.65 to -0.80), and time up and go test (SMD, -1.06; 95% CI -1.44 to -0.68). Compared with other therapy plus medication, Tai Chi plus medication also showed greater gains in motor function (SMD, -0.78; 95% CI -1.46 to -0.10), BBS (SMD, -0.99; 95% CI -1.44 to -0.54), and functional reach test (SMD, -0.77; 95% CI -1.51 to -0.03). However, Tai Chi plus medication did not showed better improvements in gait or quality of life. There was not sufficient evidence to support or refute the effect of Qigong plus medication for PD. CONCLUSIONS: In the previous studies, Tai Chi and Qigong were used as assisting pharmacological treatments of PD. The current systematic review showed positive evidence of Tai Chi plus medication for PD of mild-to-moderate severity. So Tai Chi plus medication should be recommended for PD management, especially in improving motor function and balance. Qigong plus medication also showed potential gains in the management of PD. However, more high quality studies with long follow-up are warrant to confirm the current findings.

Angiotensin II promotes differentiation of mouse c-kit-positive cardiac stem cells into pacemaker-like cells.

Cardiac stem cells (CSCs) can differentiate into cardiac muscle­like cells; however, it remains unknown whether CSCs may possess the ability to differentiate into pacemaker cells. The aim of the present study was to determine whether angiotensin II (Ang II) could promote the specialization of CSCs into pacemaker­like cells. Mouse CSCs were treated with Ang II from day 3-5, after cell sorting. The differentiation potential of the cells was then analyzed by morphological analysis, flow cytometry, reverse transcription­polymerase chain reaction, immunohistochemistry and patch clamp analysis. Treatment with Ang II resulted in an increased number of cardiac muscle­like cells (32.7 ± 4.8% vs. 21.5 ± 4.8%; P<0.05), and inhibition of smooth muscle­like cells (6.2 ± 7.3% vs. 20.5 ± 5.1%; P<0.05). Following treatment with Ang II, increased levels of the cardiac progenitor­specific markers GATA4 and Nkx2.5 were observed in the cells. Furthermore, the transcript levels of pacemaker function­related genes, including hyperpolarization­activated cyclic nucleotide­gated (HCN)2, HCN4, T­box (Tbx)2 and Tbx3, were significantly upregulated. Immunofluorescence analysis confirmed the increased number of pacemaker­like cells. The pacemaker current (If) was recorded in the cells derived from CSCs, treated with Ang II. In conclusion, treatment of CSCs with Ang II during the differentiation process modified cardiac­specific gene expression and resulted in the enhanced formation of pacemaker­like cells.