Active Ingredient Paeonol of Jijiu Huiyang Decoction Alleviates Isoproterenol-Induced Chronic Heart Failure via the GSK3A/PPARα Pathway.

Background: The pharmacological mechanism of the traditional Chinese medicine formula-Jijiu Huiyang decoction (JJHYD), which contains several herbal medicines for the treatment of chronic heart failure (CHF), is yet unknown. Method and Materials. The main active components of JJHYD were analyzed by ultrahigh-performance liquid chromatography-mass spectrometry (UHPLC-MS/MS). The target genes of JJHYD and CHF were retrieved through multiple databases, a drug-ingredient-target-disease network was created, and KEGG enrichment and GO analyses were carried out. The binding ability of paeonol and Glycogen Synthase Kinase-3 alpha (GSK3A) was confirmed by molecular docking. CHF animal model and cell model were constructed. The effects of paeonol on cardiac dysfunction, myocardial hypertrophy, cardiac lipid accumulation, and myocardial apoptosis were detected by echocardiography, histopathology, and flow cytometry, respectively. The effects of paeonol on the expression of myocardial hypertrophy index, GSK3A, and genes or proteins related to the PPARα pathway were determined by qRT-PCR or western blot. Result: UHPLC-MS/MS analysis combined with database verification showed a total of 227 chemical components in JJHYD, among which paeonol was the one with heart-protective roles and had the highest content. Paeonol alleviated isoproterenol-induced cardiac lipid accumulation, cardiac hypertrophy, and myocardial dysfunction and inhibited the activation of the PPARα pathway, while overexpression of GSK3A reversed these effects of paeonol. However, the reversal effects of GSK3A overexpression could be offset by siPPARα. Conclusion: As the main active substance of JJHYD, paeonol participates in the protection of CHF by targeting the GSK3A/PPARα signaling pathway to reduce lipid toxicity.

USP13 promotes deubiquitination of ZHX2 and tumorigenesis in kidney cancer.

Clear cell renal cell carcinoma (ccRCC) is characterized by the loss of tumor suppressor Von Hippel Lindau (VHL) function. VHL is the component of an E3 ligase complex that promotes the ubiquitination and degradation of hypoxia inducible factor α (HIF-α) (including HIF1α and HIF2α) and Zinc Fingers And Homeoboxes 2 (ZHX2). Our recent research showed that ZHX2 contributed to ccRCC tumorigenesis in a HIF-independent manner. However, it is still unknown whether ZHX2 could be modified through deubiquitination even in the absence of pVHL. Here, we performed a deubiquitinase (DUB) complementary DNA (cDNA) library binding screen and identified USP13 as a DUB that bound ZHX2 and promoted ZHX2 deubiquitination. As a result, USP13 promoted ZHX2 protein stability in an enzymatically dependent manner, and depletion of USP13 led to ZHX2 down-regulation in ccRCC. Functionally, USP13 depletion led to decreased cell proliferation measured by two-dimensional (2D) colony formation and three-dimensional (3D) anchorage-independent growth. Furthermore, USP13 was essential for ccRCC tumor growth in vivo, and the effect was partially mediated by its regulation on ZHX2. Our findings support that USP13 may be a key effector in ccRCC tumorigenesis.

Salidroside protects against cardiomyocyte apoptosis and ventricular remodeling by AKT/HO-1 signaling pathways in a diabetic cardiomyopathy mouse model.

BACKGROUND: Diabetic cardiomyopathy is characterized by both systolic and diastolic dysfunction due to decreased contractility, as well as reduced compliance of the myocardium. Oxidative stress plays a significant role in diabetes mellitus and its cardiovascular complications. Salidroside, a glucoside of the phenylpropanoid tyrosol, reportedly increases the levels of the antioxidative enzymes, nuclear factor erythroid 2-related factor 2, and heme oxygenase-1 (HO-1) to counteract oxidative stress; however, the underlying mechanisms are poorly understood. PURPOSE: Here we investigate the potential cardio-protective effects of salidroside and its mechanism in a diabetic animal model. METHODS: Male db/m, db/db, and age-matched wild-type mice were treated with salidroside at low dose (0.025 mg/kg) or high dose (0.05 mg/kg) by gavage every day for 12 weeks. Cardiac function and structure were assessed by echocardiography and histopathological examination. H9C2 cardiomyocytes were exposed in vitro to advanced glycosylation end products (400 µg/ml) and treated with salidroside (0.1, 1, or 10 µM). The expression of signaling-related genes were explored by western blotting and real-time PCR. RESULTS: Salidroside treatment significantly improved diabetes-induced cardiac dysfunction, hypertrophy, and fibrosis in vivo. Mechanistically, salidroside markedly up-regulates HO-1 expression by activation of the AKT signaling pathway. CONCLUSION: Salidroside protects against cardiomyocyte apoptosis and ventricular remodeling in diabetic mice. This cardio-protective effect of salidroside is dependent on AKT signaling activation.

Safety and efficacy of zotarolimus-eluting stents in the treatment of diabetic coronary lesions in Chinese patients: The RESOLUTE-DIABETES CHINA Study.

BACKGROUND: The RESOLUTE-DIABETES CHINA study was specifically designed to investigate the safety and efficacy of Resolute zotarolimus-eluting stents (ZES; Medtronic, Santa Rosa, CA, USA) in the treatment of diabetic coronary lesions in the Chinese population. METHODS: In all, 945 patients with de novo native coronary lesions and type 2 diabetes mellitus were recruited at 32 cardiac centers across the Chinese mainland and were implanted with Resolute ZES. The primary endpoint was target vessel failure (TVF); secondary endpoints were clinical outcomes, namely all-cause death, stroke, bleeding, target lesion revascularization (TLR), target vessel revascularization (TVR), non-TVR, and stent thrombosis (ST). The follow-up period for all endpoints was 12 months after the procedure. RESULTS: In all, 933 patients (98.73%) had clinical follow-up at 12 months. The rate of TVF was 11.60%, whereas the rate of occurrence of secondary endpoints was 5.47%, with four patients (0.43%) having subacute or late ST. There were no significant differences in TVF rates comparing patients with different HbA1c levels or receiving different glucose control treatments (all P > 0.05). Patients with multivessel lesions had higher TVF rates (95% confidence intervals) than those with single-vessel lesions (16.76% [12.10%-22.97%) vs 9.72% [7.79%-12.11%], respectively; P = 0.006). There were no significant differences in TVF rates in patients with or without small vessels, bifurcated lesions, or chronic total occlusions (all P > 0.05). [Correction added on 17 January 2019, after first online publication: in the second sentence of Results section, "TLF" was changed to "TVF".]. CONCLUSIONS: Resolute ZES may perform well in the Chinese diabetic population, especially in those with poor glucose control, complex lesions, and certain unfavorable clinical features. Further studies are needed to determine why ZES perform well in this population.

Hyperoside Suppresses Lipopolysaccharide-induced Inflammation and Apoptosis in Human Umbilical Vein Endothelial Cells.

Finding the novel drug from the effective components of traditional Chinese herbal medicine is a hotspot of the modern pharmacological research. Hyperoside (HYP) belongs to flavonoid glycosides, and it has various properties, such as anti-inflammation, anti-spasm, anti-diuretic, antitussive, lowering blood pressure, and lowering cholesterol effects as well as protective effects for the cardiac and cerebral blood vessels. The purpose of this study was to investigate the effects of HYP on inflammatory and apoptotic responses in vascular endothelial cells stimulated by lipopolysaccharide (LPS) and further to identify the possible mechanisms underlying these effects. In our study, human umbilical vein endothelial cells (HUVECs) were stimulated with 1 µg/mL LPS in the presence or absence of HYP (10, 20 and 50 µmol/L). Our results indicated that HYP alone exerted no cytotoxicity on HUVECs, while it had an up-regulatory effect on the viability of HUVECs induced by LPS in a dose-dependent manner; increased mRNA expression of IL-1ß, IL-6, TNFα and iNOS induced by LPS was attenuated after treatment with HYP both in a dose-and time-dependent manner; LPS-induced HUVECs apoptosis and cleaved-caspase 8, 9, 3 were all significantly reduced by HYP. Furthermore, the possible pathway involved in apoptosis and inflammation by HYP was detected, and the results showed that when treated with HYP, LPS-induced mitochondrial membrane instability was significantly inhibited through up-regulation of Bcl-2 and down-regulation of Bax. Furthermore, the expression of TLR4 and the phosphorylation of IκBα and p65 in LPS-treated cells were blocked by HYP. Our results suggested that HYP treatment prevented HUVECs from LPSinduced inflammation and apoptosis responses, which might be mediated by inhibiting TLR4/NFκB pathway.

Great Hospitals of Asia: Neurosurgery and Spine Surgery at Xi'an Jiaotong University-Affiliated Honghui Hospital.

Established in 1987, the Spine Surgery Hospital at Honghui Hospital is one of the oldest spinal surgical departments in China. The first chairman, Yuan Fuyong, devoted himself to the development of the department. The current president, Hao Dingjun, assumed the position in November 2008. The current department consists of 5 wards and 235 beds, encompassing the entire spectrum of spinal surgical diseases, with 27 specialized faculty members and care teams. The remarkable growth of the hospital during the last 30 years made it possible to perform 8000 operations in 2017. A total of 300 articles were published in scientific journals, of which more than 100 were published in international journals between 1987 and 2017. At present, the developmental model of neurosurgery and spine surgery at Honghui Hospital is based on the concept of holistic integrative medicine. It was jointly developed by several departments including those of spine surgery, neurosurgery, traditional Chinese medicine rehabilitation, and basic research. This article traces the history, research and teaching accomplishments, academic exchanges, and future directions.

A novel 76-mer peptide mimic with the synergism of superoxide dismutase and glutathione peroxidase.

The balance of oxidation and reduction in the body requires the synergistic effect of various antioxidant enzymes. Therefore, the construction of enzyme mimics with multiple antioxidant activities is important and beneficial for further research on the synergistic effects of antioxidant enzymes and their mechanism of action. To explore the synergistic effect of superoxide dismutase (SOD) and glutathione peroxidase (GPx), a 76-mer selenium-containing peptide (Se-76P) mimic containing the active SOD and GPx centers was designed. Moreover, a cell-penetrating peptide was introduced into Se-76P by structure modeling, and then, Se-76P was expressed by a single-protein production combined with the cysteine auxotrophic double-expression system of Escherichia coli. The results suggest that Se-76P exhibits SOD and GPx activities, following the GPx activity of 109 U/mg protein and the SOD activity of 1218 U/mg protein. The labeled Se-76P with FITC fluorescence was verified to enter the L02 cells successfully; it improved the antioxidant activity in cells and promoted the consumption of glucose and synthesis of glycogen. The injection of Se-76P subcutaneously decreased the levels of blood glucose and malondialdehyde of lipid peroxidation produced in mice, indicating that Se-76P had antioxidative properties and a certain regulatory role of glucose metabolism. The data analysis provides further clarification that Se-76P can regulate insulin signal transduction to play an insulin-like role, which not only has a greater significance for further elucidating the catalytic mechanism of the enzyme and their synergistic effects on each other but also has enormous medicinal potential.

Protective effect of curcumin against myocardium injury in ischemia reperfusion rats.

CONTEXT: Curcumin has long been used as a condiment and a traditional medicine worldwide. OBJECTIVE: The current study investigates the possible protective effect of curcumin on heart function in myocardium ischemia-reperfusion (MIR) rats. MATERIALS AND METHODS: We fed Sprague-Dawley (SD) rats (10 in each group) either curcumin (10, 20 or 30 mg/kg/d) or saline. Twenty days later, the rats were subjected to myocardial injuries by ligating the left anterior descending coronary artery (60 min), and subsequently, the heart (3 h) reperfused by releasing the ligation. Then, lipid profile, lipid peroxidation products, antioxidant enzymes and gene expression were assessed in myocardium tissue. RESULTS: Only the rats that were supplemented with curcumin (10, 20 or 30 mg/kg/d) showed significant (p < 0.05) reductions in oxidative stress (3-fold), infarct size (2.5-fold), which was smaller than that of the control group. The percentage of infarct size in MIR rats with curcumin at 10, 20 or 30 mg/kg/d decreased (from 49.1% to 18.3%) compared to ischemia-reperfusion (I/R). The enhanced phosphorylation of STAT3 was further strengthened by curcumin (10, 20 or 30 mg/kg/d) in a dose-dependent manner. DISCUSSION AND CONCLUSION: Curcumin intake might reduce the risk of coronary heart disease by stimulating JAK2/STAT3 signal pathway, decreasing oxidative damage and inhibiting myocardium apoptosis.

The Yin-Yang Dynamics of DNA Methylation Is the Key Regulator for Smooth Muscle Cell Phenotype Switch and Vascular Remodeling.

OBJECTIVE: DNA methylation plays an important role in chronic diseases such as atherosclerosis, yet the mechanisms are poorly understood. The objective of our study is to indicate the regulatory mechanisms of DNA methylation in vascular smooth muscle cells (VSMCs) and its roles in atherosclerosis. APPROACH AND RESULTS: In ApoE-/- mice fed a Western diet, DNA methyltransferase inhibitor, 5-aza-2'-deoxycytidine, significantly attenuated atherosclerotic lesions (20.1±2.2% versus 30.8±7.5%; P=0.016) and suppressed DNA methyltransferase activity and concomitantly decreased global 5-methylcytosine content in atherosclerotic lesions of ApoE-/- mice. Using a carotid ligation model, we found that 5-aza-2'-deoxycytidine also dramatically inhibited neointimal formation (intimal area: 2.25±0.14×104 versus 4.07±0.22×104 µm2; P<0.01). Abnormal methylation status at the promoter of ten-eleven translocation 2, one of the key demethylation enzymes in mammals, was ameliorated after 5-aza-2'-deoxycytidine treatment, which in turn caused an increase in global DNA hydroxymethylation and 5-hydroxymethylcytosine enrichment at the promoter of Myocardin. In vitro, 5-aza-2'-deoxycytidine treatment or DNA methyltransferase 1 knockdown decreased global 5-methylcytosine content and restored Myocardin expression in VSMCs induced by platelet-derived growth factor, thus preventing excessive VSMCs dedifferentiation, proliferation, and migration. Furthermore, DNA methyltransferase 1 binds to ten-eleven translocation 2 promoter and is required for ten-eleven translocation 2 methylation in VSMCs. CONCLUSIONS: The inhibitory effects of DNA demethylation on global 5-methylcytosine content and ten-eleven translocation 2 hypermethylation in atherosclerotic aorta can recover 5-hydroxymethylcytosine enrichment at the Myocardin promoter and prevent VSMC dedifferentiation and vascular remodeling.

SALVIANOLIC ACID B ALLEVIATING MYOCARDIUM INJURY IN ISCHEMIA REPERFUSION RATS.

BACKGROUND: Salvia miltiorrhiza (SM) Bunge is one of the widely-used Chinese medicinal herbs. Salvianolic acid B (Sal B), a bioactive compound isolated from the Chinese herb Radix Salviae Miltiorrhizae, has been reported to exhibit anti-inflammatory and anti-oxidantive effects. MATERIAL AND METHOD: To study the cardioprotective effects of salvianolic acid B (Sal B) on acute myocardial ischemia reperfusion (MIR) injury rats, on the basis of this investigation, the possible mechanism of salvianolic acid B was elucidated. Male Sprague- Dawley rats (200-220 g) were randomly divided into five groups: sham-operated, MIR, MIR + Sal B (10 mg/kg/day, orally), MIR + Sal B (20 mg/kg/ day, orally) and MIR + Sal B (30 mg/kg/ day, orally). Before operation, the foregoing groups were pretreated with homologous drug once a day for 7 days, respectively. After twelve hours in MIR, the cardioprotective effects of SPJ were evaluated by infarct size, biochemical values, and the antioxidative and antiapoptotic relative gene expressions. RESULTS: Sal B significantly improved heart function and decreased infarct size; remarkably decreased levels of serum TNF-α and IL-Ιß levels, increased contents of myocardium antioxidant enzymes activities; western blot results showed that Sal B ameliorate the increased Bax and caspase-3 protins expressions and decreased Bcl-2 proteins expression and ratios of Bcl-2 to Bax. CONCLUSION: In ischemic myocardium, oxidative stress caused the overgeneration and accumulation of reactive oxygen species (ROS), which was central of cardiac ischemic injury. Sal B exerted beneficially cardioprotective effects on myocardial ischemia injury rats, mainly scavenging oxidative stress-triggered overgeneration and accumulation of ROS, alleviating myocardial ischemia injury and cardiac cell death. List of abbreviations: salvianolic acid B (Sal B); myocardial ischemia reperfusion (MIR); reactive oxygen species (ROS); Left ventricular end-diastolic pressure (LVEDP); left ventricular end-diastolic volume (LVEDV); Malondialdehyde (MDA); superoxide dismutase (SOD); catalase (CAT); Glutathione peroxidase (GSH-Px); glutathione reductase (GR).

Salidroside decreases atherosclerotic plaque formation in low-density lipoprotein receptor-deficient mice.

Salidroside is isolated from Rhodiola rosea and is one of the main active components in Rhodiola species. The present study was designed to evaluate the effects of Salidroside on atherosclerotic plaque formation in high-fat diet-(HFD-) fed female LDL receptor knockout (LDLr(-/-)) mice. LDLr(-/-) mice fed an atherogenic HFD for 12 weeks were divided into two groups. One group was administered Salidroside (50 mg/kg/oral gavage) daily for 8 weeks, while the control group was administered saline. Salidroside treatment reduced serum lipids levels and the plaque area through the arch to the abdominal aorta. Furthermore, Salidroside improved macrophage content and enhanced collagen and smooth muscle cells contents in the aortic sinus. These changes were associated with reduced MCP-1, VCAM-1, and VCAM-1 protein expression in atherosclerotic aortas. All these results suggest that Salidroside decreases atherosclerotic plaques formation via effects on lipid lowering and anti-inflammation in HFD-fed LDLr(-/-) mice.

Initial clinical experience with implantation of left ventricular lead guided by Overlay Ref for the treatment of congestive heart failure.

BACKGROUND: Cardiac resynchronization therapy (CRT) improves clinical outcome in selected patients with advanced congestive heart failure. The Overlay Ref technique may facilitate the procedure for implanting left ventricular (LV) pacing leads to deliver CRT. AIM: To assess the feasibility of deploying a LV pacing lead into a coronary sinus side branch guided by Overlay Ref. METHODS: Data from 88 consecutive patients who met the CRT implantation criteria in our hospital between 28 November 2007 and 30 December 2009 were randomly assigned to two groups. Forty-four patients underwent CRT device implantation using Overlay Ref to guide target vein selection and advance a specifically designed pacing lead into the target vein (Overlay Ref group); 44 patients were conventionally implanted (control group). RESULTS: LV lead implantation was successful in all patients. Mean CRT total procedure times (skin-to-skin) were: Overlay Ref group, 80.7 ± 18.0 min; control group, 98.5 ± 32.2 min; p = 0.029. Mean placement of LV pacing lead into target vein times were: Overlay Ref group, 16.2 ± 7.7 min; control group, 36.4 ± 23.4 min; p=0.004. Mean total fluoroscopy times were: Overlay Ref group, 13.6 ± 4.3 min; control group, 23.8 ± 15.7 min; p=0.007. Mean LV lead fluoroscopy times were: Overlay Ref group, 5.7 ± 2.9 min; control group, 14.4 ± 4.6 min; p=0.003. No major complications occurred. CONCLUSIONS: Overlay Ref facilitates location of and entry into the coronary sinus, and shortens the duration of LV pacing lead implantation into the target vein.