Endophilin A2 protects against renal fibrosis by targeting TGF-ß/Smad signaling.

Renal fibrosis underlies all forms of end-stage kidney disease. Endophilin A2 (EndoA2) plays a role in nephrotic syndrome; however, its effect on renal fibrosis remains unknown. Here, we demonstrate that EndoA2 protects against kidney interstitial fibrosis via the transforming growth factor-ß (TGF-ß)/Smad signaling pathway. Mouse kidneys with fibrosis or kidney biopsy specimens from patients with fibrotic nephropathy had lower levels of EndoA2 protein expression than that in kidneys without fibrosis. In vivo overexpression of EndoA2 with the endophilin A2 transgene (EndoA2Tg ) notably prevented renal fibrosis, decreased the protein expression of profibrotic molecules, suppressed tubular injury, and reduced apoptotic tubular cells in the obstructed kidney cortex of mice with unilateral ureteral obstruction (UUO). In vivo and in vitro overexpression of EndoA2 markedly inhibited UUO- or TGF-ß1-induced phosphorylation of Smad2/3 and tubular epithelial cells dedifferentiation. Furthermore, EndoA2 was co-immunoprecipitated with the type II TGF-ß receptor (TßRII), thus inhibiting the binding of the type I TGF-ß receptor (TßRI) to TßRII. These findings indicate that EndoA2 mitigates renal fibrosis, at least partially, via modulating the TGF-ß/Smad signaling. Targeting EndoA2 may be a new potential therapeutic strategy for treatment of renal fibrosis.

Astragaloside IV Attenuates Polymicrobial Sepsis-Induced Cardiac Dysfunction in Rats via IKK/NF-κB Pathway.

OBJECTIVE: To evaluate the protective effects of Astragaloside IV (AST) in a rat model of myocardial injury induced by cecal ligation and puncture (CLP). METHODS: The model of sepsis-induced cardiac dysfunction was induced by CLP. Using a random number table, 50 specific pathogen free grade of Sprague Dawley rats were randomized into 5 groups: the sham group (sham), the model group (CLP, 18 h/72 h) and AST group (18 h/72 h). Except the sham group, the rats in other groups received CLP surgery to induce sepsis. CLP groups received intragastric administration with normal saline after CLP. AST groups received intragastric administration with AST solution (40 mg/kg) once a day. The levels of inflammatory mediators and oxidative stress markers in the serum of the septic rats were determined via enzyme-linked immunosorbent assay (ELISA) at different time point, such as interleukin 6 (IL-6), IL-10, high mobility group box-1 protein B1 (HMGB-1), superoxide dismutase (SOD), and malondialdehyde (MDA). Cardiac function was determined by echocardiography. Moreover, changes in myocardial pathology were evaluated using hematoxylin and eosin staining. The levels of lactate dehydrogenase (LDH) and creatine kinase-MB (CK-MB) were analysed to determine the status of CLP-induced myocardium. In addition, the apotosis of myocardial cells was analysed by terminal-deoxynucleoitidyl transferase mediated nick end labeling (TUNEL). The protein levels of B-cell lymphoma-2 (Bcl-2), Bcl-2-associated X (Bax), IκB kinase α (IKKα), nuclear factor kappa B p65 (NF-κB p65) were detected by Western blot analysis. Moreover, survival rate was investigated. RESULTS: AST improved the survival rate of CLP-induced rats by up to 33.3% (P<0.05). The cardioprotective effect of AST was observed by increased ejection fraction, fractional shortening and left ventricular internal diameter in diastole respectively (P<0.01 or P<0.05). Subsequently, AST attenuated CLP-induced myocardial apoptosis and the ratio of Bcl-2/Bax in the myocardium, as well as the histological alterations of myocardium (P<0.01 or P<0.05); the generation of inflammatory cytokines (IL-6, IL-10, HMGB-1) and oxidative stress markers (SOD, MDA) in the serum was significantly alleviated (P<0.01 or P<0.05). On the other hand, AST markedly suppressed CLP-induced accumulation of IKK-α and NF-κB p65 subunit phosphorylation (P<0.01 or P<0.05). CONCLUSIONS: AST plays a significant protective role in sepsis-induced cardiac dysfunction and survival outcome. The possible mechanism of cardioprotection is dependent on the activation of the IKK/NF-κB pathway in cardiomyocytes.

The Effect of Xinmailong Infusion on Sepsis-Induced Myocardial Dysfunction: a Pragmatic Randomized Controlled Trial.

ABSTRACT: Sepsis-induced myocardial dysfunction (SIMD) contributes significantly to cardiovascular dysfunction during septic shock. We aimed to evaluate the potential role of Xinmailong injection (XMLI), a polypeptide medicine extracted from Periplaneta americana, in reversing the progression of myocardial damage to SIMD in sepsis patients. This was a multicenter, randomized, double-blind, parallel-group trial. We recruited all patients consecutively admitted to intensive care units (ICUs) who were aged 18 to 85 years old and met the sepsis 3.0 criteria. The primary outcome measure was the incidence of sepsis-induced myocardial dysfunction while in the ICU. Of the 192 patients, 96 were assigned to the treatment group, and 96 to the control group. Subsequently, 41 patients [41/96 (42.7%)] in the XMLI group and 61 patients in the placebo group [61/96 (63.5%)] were confirmed to have diastolic dysfunction on the fifth day (D5). The incidence of diastolic SIMD was significantly different between the two groups (P = 0.004). There were 36 deaths in the two groups during the 28-day follow-up, with a general mortality rate of 18.8% (36/192). The 28-day mortality rates were not significantly different between the groups (P = 0.45). However, the brain natriuretic peptide (BNP) plasma concentration trends on D0, D2, and D5 significantly differed between the two groups (P = 0.049). In septic patients, XMLI decreased the occurrence rate of diastolic SIMD more effectively than the placebo. The improvement in serum BNP concentration was also greater in the XMLI group. XMLI may, therefore, effectively and safely improve cardiac function in patients with sepsis.

Beneficial Effects of Baduanjin Exercise on Left Ventricular Remodelling in Patients after Acute Myocardial Infarction: an Exploratory Clinical Trial and Proteomic Analysis.

BACKGROUND: The beneficial effects of physical exercise on cardiac remodelling improvement after myocardial infarction have already been suggested. However, the results of previous clinical trials have not been consistent. Moreover, the putative molecular mechanisms leading to the clinically observed effects of physical exercise still remain elusive. AIM: We aimed to evaluate whether the well-defined and strictly controlled traditional Chinese Qigong Baduanjin exercise (BE) would attenuate the adverse left ventricular (LV) remodelling in patients with ST-elevation myocardial infarction (STEMI). METHODS: A total of 110 clinically stable STEMI patients, following successful revascularization of their infarcted coronary arteries, were randomized and enrolled in two groups: 56 were subjected to a 12-week BE-based cardiac rehabilitation programme (BE group), and the remaining 54 were exposed to the usual physical exercise (control group) for the same time period. The primary outcome was the change from baseline to 6 months in the echocardiographic LV end-diastolic volume index (ΔLVEDVi). Proteomic analysis was also performed to uncover associated mechanisms. RESULTS: Compared with the control group, the BE group showed significantly lower ΔLVEDVi (-5.1 ± 1.1 vs. 0.3 ± 1.2 mL/m2, P < 0.01). Proteomic analysis revealed BE-induced variations in the expression of 80 proteins linked to regulation the of metabolic process, immune process, and extracellular matrix reorganization. Furthermore, correlation analyses between the validated serum proteomes and primary endpoint demonstrated a positive association between ΔLVEDVi and MMP-9 expression, but a negative correlation between ΔLVEDVi and CXCL1 expression. CONCLUSION: This is the first study indicating that BE in STEMI patients can alleviate adverse LV remodelling associated with beneficial energy metabolism adaptation, inflammation curbing, and extracellular matrix organization adjustment.

Effects on Suxiao Jiuxin Pills in the Treatment of Patients with Acute Coronary Syndrome Undergoing Early Percutaneous Coronary Intervention: A Multicenter Randomized Double-Blind Placebo-Controlled Trial.

Objectives: Acute coronary syndrome (ACS) is an acute disease with high mortality. Although early percutaneous coronary intervention (PCI) is proved to be the practical approach in treating ACS, the incidence of cardiovascular events is still far from satisfactory. The combination of Suxiao Jiuxin Pill (SJP) and Western medicine is one conventional approach in the treatment of ACS. Many elementary and clinical trials have proved the efficacy and safety in the improvement of cardiocerebral vascular conditions. The aim of this project is to evaluate the safety and efficacy of SJP on ACS with early PCI patients. Trial Design: This is a multicenter randomized, double-blind placebo-controlled trial. Trial registration: ChiCTR-TRC-13003053. Settings: Hospitals. Subjects: A total of 200 ACS with early PCI patients were randomly divided into SJP group (n = 100) and placebo group (n = 100). Interventions: The SJP group was treated with routine treatment and SJP (taking eight SJP pills orally each time, three times per day). The placebo group was treated with routine treatment along with equal amounts of SJP placebo. The course of treatment was 6 months and a follow-up visit at 12 months. Outcome Measures: Assessments of major adverse cardiovascular events (MACE), safety assessments, adverse events, left ventricular systolic function (LVEF), Seattle angina questionnaire (SAQ), troponin C (cTNI), C-reactive protein (CRP), fibrinogen (Fib), and cystatin C (cysC). Results: The SJP group had a relatively low incidence of MACE than the placebo (p < 0.05, odds ratio: 1.916, 95% confidence interval [0.999-3.674]). LVEF was significantly higher in the SJP group than the placebo group on the 360-day follow-up (p < 0.01). SJP had a significant increase score in the SAQ subscale of physical limitation, angina frequency, and treatment satisfaction (p < 0.05). There is no significant difference in the cTNI and CRP level between the two groups. The serum concentration of Fib and cysC in the SJP was significantly decreased compared with the placebo (p < 0.05). The numbers of adverse events between the two groups were not statistically different (p > 0.05). Conclusions: SJP is associated with a reduction in MACE, and an improvement of heart function and quality of life in ACS patients with early PCI, and is probably safe to use.

Addition of Chinese herbal remedy, Tongguan Capsules, to the standard treatment in patients with myocardial infarction improve the ventricular reperfusion and remodeling: Proteomic analysis of possible signaling pathways.

ETHNOPHARMACOLOGICAL RELEVANCE: Tongguan Capsules (TGC), a patented Chinese herbal remedy containing Salvia miltiorrhiza, Astragalus membranaceus, Borneolum syntheticum and Grasshopper, has been previously tested in the experimental model of animal hearts subjected to ischemia/reperfusion injury and its cardioprotective effect has been described. AIM OF THE STUDY: This clinical trial was aimed at investigation whether the administration of TGC to patients suffered myocardial infarction (MI), would diminish dilation of the left ventricular (LV) and reduce development of the adverse clinical consequences. METHODS: Eligible patients were enrolled and randomized 1:1 to TGC (4.5 g/d for 6 months) superimposed on standard treatment for MI, or the control group receiving the standard protocol alone. The outcomes of this trial were valued after 6 months and reported as a mean change from the baseline in LV end-systolic volume index (LVESVI) and as a frequency of MI recurrence, target-vessel revascularization, severity of heart failure or significant arrhythmia that required the additional therapy within 6 months. In addition, arrays with a panel of specific antibodies were used to assess levels of major cytokines and other pathophysiologic markers, that prompted conclusions about the mechanisms of the ultimate clinical outcomes in both patient's subgroups. RESULTS: Meaningfully, obtained results indicated that MI patients randomly assigned to the TGC treatment, demonstrated a significant reduction of LVESVI (-4.03 ± 0.73 vs. 1.59 ± 0.43 mL/m2, P < 0.001) and a lower incidence of the major adverse cardiovascular events (5.45% vs. 11.44%, P = 0.033). Meaningfully, those patients consistently demonstrated lower serum levels of major inflammatory cytokines, as well as reduced levels of markers of myocardial apoptosis and fibrosis. CONCLUSION: Addition of TGC to the current conventional treatment of MI patients, significantly reduced their adverse LV remodeling and contributed to the more positive clinical outcome. TRIAL REGISTRATION: ChiCTR-IPR-17011618.

Exploration of Multiple Signaling Pathways Through Which Sodium Tanshinone IIA Sulfonate Attenuates Pathologic Remodeling Experimental Infarction.

The level of maladaptive myocardial remodeling consistently contributes to the poor prognosis of patients following a myocardial infarction (MI). In this study, we investigated whether and how sodium tanshinone IIA sulfonate (STS) would attenuate the post-infarct cardiac remodeling in mice model of MI developing after surgical ligation of the left coronary artery. All mice subjected to experimental MI or to the sham procedure were then treated for the following 4 weeks, either with STS or with a vehicle alone. Results of our studies indicated that STS treatment of MI mice prevented the left ventricular dilatation and improved their cardiac function. Results of further tests, aimed at mechanistic explanation of the beneficial effects of STS, indicated that treatment with this compound enhanced the autophagy and, at the same time, inhibited apoptosis of the cardiomyocytes. Meaningfully, we have also established that myocardium of STS-treated mice displayed significantly higher levels of adenosine monophosphate kinase than their untreated counterparts and that this effect additionally associated with the significantly diminished activities of apoptotic promoters: mammalian target of rapamycin and P70S6 kinase. Moreover, we also found that additional administration of the adenosine monophosphate kinase inhibitor (compound C) or autophagy inhibitor (chloroquine) practically eliminated the observed beneficial effects of STS. In conclusion, we suggest that the described multistage mechanism triggered by STS treatment enhanced autophagy, thereby attenuating pathologic remodeling of the post-infarct hearts.

Danqi soft capsule prevents infarct border zone remodelling and reduces susceptibility to ventricular arrhythmias in post-myocardial infarction rats.

Danqi soft capsule (DQ) is a traditional Chinese medicine containing Salvia miltiorrhiza and Panax notoginseng; it is safe and efficient in treating ischaemic heart diseases. The purpose of the present study was to assess whether DQ could prevent infarct border zone (IBZ) remodelling and decrease ventricular arrhythmias occurrence in post-myocardial infarction (MI) stage. MI was induced by a ligation of the left anterior descending coronary artery. DQ was administered to the post-MI rats started from 1 week after MI surgery for 4 weeks. The results showed that DQ treatment significantly attenuated tachyarrhythmia induction rates and arrhythmia score in post-MI rats. In echocardiography, DQ improved left ventricular (LV) systolic and diastolic function. Histological assessment revealed that DQ significantly reduced fibrotic areas and myocyte areas, and increased connexin (Cx) 43 positive areas in IBZ. Western blot revealed that DQ treatment significantly reduced the protein expression levels of type I and III collagens, α-smooth muscle actin (α-SMA), transforming growth factor-ß1 (TGF-ß1) and Smad3 phosphorylation, while increasing Cx43 amounts. Overall, these findings mainly indicated that DQ intervention regulates interstitial fibrosis, Cx43 expression and myocyte hypertrophy by TGF-ß1/Smad3 pathway in IBZ, inhibits LV remodelling and reduces vulnerability to tachyarrhythmias after MI. This study presents a proof of concept for novel antiarrhythmic strategies in preventing IBZ remodelling, modifying the healed arrhythmogenic substrate and thus reducing susceptibility to ventricular arrhythmias in the late post-MI period.

Sodium tanshinone IIA sulfonate prevents the adverse left ventricular remodelling: Focus on polymorphonuclear neutrophil-derived granule components.

AIMS: The aims of this study were to evaluate the effects of sodium tanshinone IIA sulfonate (STS) on left ventricular (LV) remodelling after for ST-elevated myocardial infarction (STEMI). METHODS AND RESULTS: In this prospective, randomized clinical trial, 101 patients with the ST-elevated MI (STEMI) and a successful reperfusion were immediately randomized to receive STS (80 mg qd for 7 days) or saline control, along with standard therapy. The primary effectiveness endpoint is the % change in LV end diastolic volumes index (%∆ LVEDVi) as measured by echocardiography from baseline to 6 months. Secondary effectiveness endpoints include 6-month period for major adverse cardiac events (MACE), including the occurrence of recurrent myocardial infarction, death, hospitalization for heart failure and malignant arrhythmia. The 6-month changes in %∆ LVEDVi were significantly smaller in the STS group than in the control group [-5.05% vs 3.32%; P < 0.001]. With respect to MACE, there was a significant difference between those who received STS (8.16%) and those patients on control (26.00%) (P = 0.019). Meaningfully, results of parallel tests aimed at mechanistic explanation of the reported clinical effects, revealed a significantly reduced levels of neutrophils-derived granule components in the blood of STS treated patients. CONCLUSION: We found that short-term treatment with STS reduced progressive left ventricular remodelling and subsequent better clinical outcome that could be mechanistically linked to the inhibition of the ultimate damage of infarcted myocardium by infiltrating neutrophils.

Seated-Baduanjin as an adjuvant rehabilitation treatment for dysfunctional ventilatory weaning response: A case report.

RATIONALE: Seated-Baduanjin as adjuvant rehabilitation treatment in a patient with Dysfunctional ventilatory weaning response(DVWR) is extremely rare, and we report a case of a patient's rehabilitation exercise who suffered from DVWR. PATIENT CONCERNS: A 62-year-old patient was admitted for dyspnea for more than a month after surgery. DIAGNOSES: On arrival, the patient was conscious but anxious, and he had difficulty breathing. When attempting to disconnect the ventilator, the patient's autonomous respiration > 25 times /min, and the heart rate > 120 times /min. He had to rely on the ventilator to survive. According to the characteristics of the patient, we considered the patient with DVWR. INTERVENTIONS: We provided the same essential treatment as the last hospital and performed the Seated-Baduanjin for the patient which was a new form of bed exercise, 2 times a day, 30 minutes each time. OUTCOMES: The patient showed a gradual improvement in breathing and muscle strength. LESSONS: In this case report, the Seated-Baduanjin showed a remarkable therapeutic effect on a patient and might be an adjuvant treatment for DVWR.

Association between fibrinogen level and the severity of coronary stenosis in 418 male patients with myocardial infarction younger than 35 years old.

Fibrinogen (Fib) is a useful marker for predicting the severity of coronary artery disease (CAD) in adult population. However, whether Fib can be a predictor for the presence and severity of CAD in very young MI patients (≤35 years old) remains to be determined. A total of 418 males from 61,863 patients with MI who were under 35 years old were sequentially recruited in our study. The patients were divided into two main groups and three subgroups according to coronary angiograph and Gensini score (GS) system: no coronary artery stenosis (group A), the results of the coronary artery stenosis (group B); low GS, intermediate GS and high GS. Data indicated that Fib, body mass index, current smoking, white blood cell count (WBCC) and GS were significantly higher in group B than those in group A (all P < 0.01). Moreover, there were significant differences in Fib, mean age, diabetes mellitus, family history of CAD, WBCC, left ventricular ejection fraction, and GS between high GS and low GS subgroups (all P < 0.01). A positive correlation between Fib levels and GS was found (r = 0.242, p < 0.001). Receiver operating characteristics curve analysis demonstrated that the best cut-off level of Fib predicting the severity of coronary stenosis was 3.475g/L (sensitivity 64%; specificity 70%) and the area under the curve was 0.656. Fib was also independently associated with high GS (OR=2.173, 95%CI 1.011-4.670, P = 0.047) after adjusting for potential confounders. In conclusion, Fib is significantly related to the presence and severity of coronary stenosis in male patients with MI under 35 years old.

Xuebijing injection attenuates pulmonary injury by reducing oxidative stress and proinflammatory damage in rats with heat stroke.

The present study aimed to investigate the protective effect of Xuebijing injection (XBJ) on lung injury in heat-stroke rats and the underlying mechanisms. In total, 54 rats were randomly assigned to non-thermal, saline vehicle and XBJ groups. The rectal temperature (Tc), mean arterial pressure (MAP) and respiratory rate (RR) of the rats were recorded. The time-point of heat stroke and the time of survival were assessed, and indicators of arterial blood gas were regularly measured from 0 to 60 min. The concentration of tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß) and IL-10 was also determined. At the end of the experiment, lung tissue was harvested for histopathological analysis. Inducible nitric oxide synthase (iNOS) and superoxide dismutase (SOD) expression was measured by immunohistochemistry. Terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling was used to measure apoptosis. XBJ pretreatment prolonged the decline of clinical characteristics, as demonstrated by increases in Tc, MAP, RR and indicators in arterial blood gas in rats under heat stress. The time until heat stroke and the survival time in the Saline group were shorter than in rats treated with XBJ. The expression of iNOS in lung tissue and the concentration of TNF-α, IL-1ß and IL-10 in the bronchoalveolar lavage fluid of rats treated with saline was higher than in rats with XBJ pre-treatment. Contrarily, SOD expression in rats treated with saline was decreased compared with that in rats treated with XBJ. Moreover, the apoptotic rate in the lung tissues of rats with saline treatment was higher than that in rats treated with XBJ. In conclusion, XBJ delayed the development of heat stroke and increased the survival time in rats under heat-stress by ameliorating pulmonary failure and acute lung injury. The underlying mechanisms of this effect may be the reduction of inflammatory cytokines as well as attenuation of oxidative stress and apoptosis by XBJ.

Mechanisms of Chinese Medicine Xinmailong's protection against heart failure in pressure-overloaded mice and cultured cardiomyocytes.

Patients with heart failure (HF) have high mortality and mobility. Xinmailong (XML) injection, a Chinese Medicine, is clinically effective in treating HF. However, the mechanism of XML's effectiveness on HF was unclear, and thus, was the target of the present study. We created a mouse model of pressure-overload-induced HF with transverse aortic constriction (TAC) surgery and compared among 4 study groups: SHAM (n = 10), TAC (n = 12), MET (metoprolol, positive drug treatment, n = 7) and XML (XML treatment, n = 14). Dynamic changes in cardiac structure and function were evaluated with echocardiography in vivo. In addition, H9C2 rat cardiomyocytes were cultured in vitro and the phosphorylation of ERK1/2, AKT, GSK3ß and protein expression of GATA4 in nucleus were detected with Western blot experiment. The results showed that XML reduced diastolic thickness of left ventricular posterior wall, increased ejection fraction and fraction shortening, so as to inhibit HF at 2 weeks after TAC. Moreover, XML inhibited the phosphorylation of ERK1/2, AKT and GSK3ß, subsequently inhibiting protein expression of GATA4 in nucleus (P < 0.001). Together, our data demonstrated that XML inhibited the TAC-induced HF via inactivating the ERK1/2, AKT/GSK3ß, and GATA4 signaling pathway.

Salvianolate reduces murine myocardial ischemia and reperfusion injury via ERK1/2 signaling pathways in vivo.

OBJECTIVE: To analyze the effects of salvianolate on myocardial infarction in a murine in vivo model of ischemia and reperfusion (I/R) injury. METHODS: Myocardial I/R injury model was constructed in mice by 30 min of coronary occlusion followed by 24 h of reperfusion and pretreated with salvianolate 30 min before I/R (SAL group). The SAL group was compared with SHAM (no I/R and no salvianolate), I/R (no salvianolate), and ischemia preconditioning (IPC) groups. Furthermore, an ERK1/2 inhibitor PD98059 (1 mg/kg), and a phosphatidylinositol-3-kinase (PI3-K) inhibitor, LY294002 (7.5 mg/kg), were administered intraperitoneal injection (i.p) for 30 min prior to salvianolate, followed by I/R surgery in LY and PD groups. By using a double staining method, the ratio of the infarct size (IS) to left ventricle (LV) and of risk region (RR) to LV were compared among the groups. Correlations between IS and RR were analyzed. Western-blot was used to detect the extracellular signal-regulated kinase 1/2 (ERK1/2) and protein kinase B (AKT) phosphorylation changes. RESULTS: There were no significant differences between RR to LV ratio among the SHAM, I/R, IPC and SAL groups (P>0.05). The SAL and IPC groups had IS of 26.1%±1.4% and 22.3%±2.9% of RR, respectively, both of which were significantly smaller than the I/R group (38.5%±2.9% of RR, P<0.05, P<0.01, respectively). Moreover, the phosphorylation of ERK1/2 was increased in SAL group (P<0.05), while AKT had no significant change. LY294002 further reduced IS, whereas the protective role of salvianolate could be attenuated by PD98059, which increased the IS. Additionally, the IS was not linearly related to the RR (r=0.23, 0.45, 0.62, 0.17, and 0.52 in the SHAM, I/R, SAL, LY and PD groups, respectively). CONCLUSION: Salvianolate could reduce myocardial I/R injury in mice in vivo, which involves an ERK1/2 pathway, but not a PI3-K signaling pathway.

Salvianolic Acid B Alleviates Heart Failure by Inactivating ERK1/2/GATA4 Signaling Pathway after Pressure Overload in Mice.

BACKGROUND: Heart failure(HF) is a dangerous disease that affects millions of patients. Radix Salvia is widely used in Chinese clinics to treat heart diseases. Salvianolic acid B(SalB) is the major active component of Radix Salvia. This study investigated the mechanisms of action and effects of SalB on HF in an experimental mouse model of HF. METHODS: We created a mouse model of HF by inducing pressure overload with transverse aortic constriction(TAC) surgery for 2 weeks and compared among 4 study groups: SHAM group (n = 10), TAC group (n = 9), TAC+MET group (metprolol, positive drug treatment, n = 9) and TAC+SalB group (SalB, 240 mg•kg-1•day-1, n = 9). Echocardiography was used to evaluate the dynamic changes in cardiac structure and function in vivo. Plasma brain natriuretic peptide (BNP) concentration was detected by Elisa method. In addition, H9C2 rat cardiomyocytes were cultured and Western blot were implemented to evaluate the phosphorylation of ERK1/2, AKT, and protein expression of GATA4. RESULTS: SalB significantly inhibited the phosphorylation of Thr202/Tyr204 sites of ERK1/2, but not Ser473 site of AKT, subsequently inhibited protein expression of GATA4 and plasma BNP(P < 0.001), and then inhibited HF at 2 weeks after TAC surgery. CONCLUSIONS: Our data provide a mechanism of inactivating the ERK1/2/GATA4 signaling pathway for SalB inhibition of the TAC-induced HF.

Traditional Chinese medicine, Danlou tablets alleviate adverse left ventricular remodeling after myocardial infarction: results of a double-blind, randomized, placebo-controlled, pilot study.

BACKGROUND: Danlou tablets, a patented Chinese Medicine, have been long approved for the treatment of ischemic heart disease in China. While numerous empirical observations suggested Danlou tablets could decrease frequency and duration of angina pectoris attacks, evidence supporting its efficacy on cardiac remodeling remains inadequate. Therefore, this pilot trial was designed to determine whether Danlou tablets would reduce adverse left ventricular (LV) remodeling in patients with myocardial infarction (MI). METHODS AND RESULTS: Eligible patients with acute MI were enrolled and randomly assigned to Danlou tablets or placebo groups, superimposed on standard treatment for MI. Then, in addition to assessment of the clinical outcome, the changes in LV volumes were evaluated by a serial echocardiography. In total, 83 patients (Danlou tablets 42 and placebo 41) completed 90 days of treatment and had complete baseline and outcome data. Standard echocardiographic evaluations revealed significant differences in the change of LV end-diastolic volume index (LVEDVi) between group of patients treated with Danlou tablets and the placebo group (-4.49 ± 7.29 vs. -0.34 ± 9.01 mL/m2, P < 0.001). The reduction in LVEDVi was independent of beta-blocker, ACE inhibitors/ARBs use. Furthermore, treatment with Danlou tablets significantly reduced LV end-systolic volume index (-4.09 ± 5.85 vs. -0.54 ± 5.72 mL/m2, P < 0.001) and improved the LV ejection fraction (4.83 ± 9.23 vs. 0.23 ± 8.15 %, P < 0.001), as compared to placebo. Meaningfully, the incidence of the major adverse cardiovascular events was also lower in patients receiving Danlou tablets (P < 0.05). CONCLUSION: Superimposed on the standard pharmacologic treatment, Danlou tablets significantly reversed post-MI adverse LV remodeling, thereby contributed to the overall positive clinical outcome. TRIAL REGISTRATION: clinicaltrials.gov identifier NCT02675322 (February 1, 2016).

Gastroprotective Effects of Astragaloside IV against Acute Gastric Lesion in Rats.

BACKGROUND: Protection of the gastric mucosa from acute lesions induced by various irritants is a pertinent issue in the field of critical care medicine. In this study, we investigated the gastroprotective effects of astragaloside IV on acute gastric lesions in rats under stressful conditions. METHODS: Rats were randomized into six groups. Group 1 and 2 received 10% Tween 80 (vehicle). Group 3 received 20 mg/kg of omeprazole, a proton pump inhibitor. Groups 4, 5 and 6 received astragaloside IV at concentration of 1, 10, and 50 mg/kg, respectively. As a means to induce gastric lesions, Groups 2-6 were subjected to water immersion and restraint stress for 12 hours after treatment. RESULTS: Our present studies show that compared to rats in group 2, treatment with 1 to 50 mg/kg astragaloside IV significantly decreased the size of gastric lesions, MDA, TNFα and MCP1 levels, in addition to normalizing gastric pH, gastric mucus and SOD levels (P<0.05). Histomorphological examination confirmed that treatment with astragaloside IV elicited a dosage-dependent protective effect on the gastric mucosa. Furthermore, pretreatment with astragaloside IV resulted in significant elevations in HSP70 and reduction in Bax, along with over-expression of PLCγ response level, which was further confirmed via immunohistochemical analysis. CONCLUSIONS: The acute gastric lesions induced are attenuated by pretreatment with astragaloside IV which is possibly due to the enhancing of the expression of HSP70 with concomitant antioxidant, anti-inflammatory and anti-apoptotic capacity.

[Effect of Xuebijing injection on hemodynamics and endothelial function in patients with severe sepsis: a prospective study].

OBJECTIVE: To investigate the effects of Xuebijing injection on hemodynamics, cardiac function, and endothelial function in patients with severe sepsis in order to study the therapeutic effect of Xuebijing in the treatment of severe sepsis. METHODS: A prospective randomized controlled trial was conducted. Sixty-six severe sepsis patients admitted to the Department of Critical Care Medicine of Guangdong Hospital of Traditional Chinese Medicine from March 2013 to February 2014 were enrolled. The patients were divided into control group (n = 31) and Xuebijing group (n = 35). The patients in both groups were treated according to "2012 international guidelines for management of severe sepsis and septic shock", and the patients in Xuebijing group received Xuebijing injection of 50 mL(added with 100 mL of 0.9% sodium chloride injection) twice a day for 5 days, and those in control group received instead 150 mL of 0.9% sodium chloride injection for 5 days. The heart rate (HR), mean arterial pressure (MAP), central venous pressure (CVP), and dosage of vasoactive drugs before and 1 day and 5 days after treatment were determined for hemodynamics assessment. Blood lactic acid (Lac), central venous oxygen saturation (ScvO2), and difference in arterial-venous blood carbon dioxide pressure (Pv-aCO2) were determined for microcirculation assessment. The left ventricular ejection fraction (LVEF), cardiac output (CO), left ventricular end diastolic diameter (LVEDD), the ratio of blood flow of mitral orifice between rapid filling period and atrial systole period (E/A), and B-type natriuretic peptide (BNP) were determined for cardiac function assessment. Vascular endothelial growth factor (VEGF) and soluble receptor (sFLT-1) were assessed for endothelial function assessment. The relationship among the indexes of the hemodynamics, microcirculation, cardiac function, and endothelial function was analyzed with Pearson related-analysis. RESULTS: After treatment, HR, MAP, CVP, Lac, ScvO2, and Pv-aCO2 were improved in both groups compared with those before treatment, and the dosage of norepinephrine (NE) was decreased in Xuebijing group. Compared with control group, MAP at 5 days after treatment in Xuebijing group was significantly increased [mmHg (1 mmHg = 0.133 kPa): 74.9±10.7 vs. 70.2±6.6, P < 0.05], the dosage of NE was decreased [µg×kg-1×min-1: 0.01 (0.00, 0.22) vs. 0.10 (0.05, 0.80), P < 0.05], LVEF was significantly increased (0.617±0.125 vs. 0.533±0.129, P < 0.05), BNP was significantly decreased [ng/L: 117.3 (52.0, 443.0) vs. 277.2 (67.9, 2 370.2), P < 0.05], while VEGF showed no significant change (ng/L: 101.1±23.2 vs. 89.6±20.5, P > 0.05), and sFLT-1 was significantly decreased (ng/L: 245.7±86.2 vs. 295.1±95.1, P < 0.05). It was shown by Pearson coefficient bivariate correlation analysis that sFLT-1 was negatively correlated with MAP and ScvO2 (r = -0.569, P = 0.000; r = -0.341, P = 0.008) 5 days after treatment, while it was positively associated with Lac and acute physiology and chronic health evaluation II (APACHE II) score (r = 0.749, P = 0.000; r = 0.645, P = 0.000). CONCLUSIONS: After treatment, HR, MAP, CVP, Lac, ScvO2, and Pv-aCO2 were improved in both groups compared with those before treatment, and the dosage of norepinephrine (NE) was decreased in Xuebijing group. Compared with control group, MAP at 5 days after treatment in Xuebijing group was significantly increased [mmHg (1 mmHg = 0.133 kPa): 74.9±10.7 vs. 70.2±6.6, P < 0.05], the dosage of NE was decreased [µg×kg-1×min-1: 0.01 (0.00, 0.22) vs. 0.10 (0.05, 0.80), P < 0.05], LVEF was significantly increased (0.617±0.125 vs. 0.533±0.129, P < 0.05), BNP was significantly decreased [ng/L: 117.3 (52.0, 443.0) vs. 277.2 (67.9, 2 370.2), P < 0.05], while VEGF showed no significant change (ng/L: 101.1±23.2 vs. 89.6±20.5, P > 0.05), and sFLT-1 was significantly decreased (ng/L: 245.7±86.2 vs. 295.1±95.1, P < 0.05). It was shown by Pearson coefficient bivariate correlation analysis that sFLT-1 was negatively correlated with MAP and ScvO2 (r = -0.569, P = 0.000; r = -0.341, P = 0.008) 5 days after treatment, while it was positively associated with Lac and acute physiology and chronic health evaluation II (APACHE II) score (r = 0.749, P = 0.000; r = 0.645, P = 0.000).

Apocynum Tablet Protects against Cardiac Hypertrophy via Inhibiting AKT and ERK1/2 Phosphorylation after Pressure Overload.

Background. Cardiac hypertrophy occurs in many cardiovascular diseases. Apocynum tablet (AT), a traditional Chinese medicine, has been widely used in China to treat patients with hypertension. However, the underlying molecular mechanisms of AT on the hypertension-induced cardiac hypertrophy remain elusive. The current study evaluated the effect and mechanisms of AT on cardiac hypertrophy. Methods. We created a mouse model of cardiac hypertrophy by inducing pressure overload with surgery of transverse aortic constriction (TAC) and then explored the effect of AT on the development of cardiac hypertrophy using 46 mice in 4 study groups (combinations of AT and TAC). In addition, we evaluated the signaling pathway of phosphorylation of ERK1/2, AKT, and protein expression of GATA4 in the cardioprotective effects of AT using Western blot. Results. AT inhibited the phosphorylation of Thr202/Tyr204 sites of ERK1/2, Ser473 site of AKT, and protein expression of GATA4 and significantly inhibited cardiac hypertrophy and cardiac fibrosis at 2 weeks after TAC surgery (P < 0.05). Conclusions. We experimentally demonstrated that AT inhibits cardiac hypertrophy via suppressing phosphorylation of ERK1/2 and AKT.