Xinfuli Granule improves post-myocardial infarction ventricular remodelingand myocardial fibrosis in rats by regulating TGF-β/Smads signaling pathway

Recent clinical and experimental studies have confirmed the effects of Xinfuli Granule (XG), a compound Chinese medicine in the prevention and treatment of heart failure (HF). This study aimed to investigate the effects and the mechanisms of XG on ventricular reconstruction in rats with acute myocardial infarction (AMI).MethodsSprague-Dawley rats were subjected to left anterior descending branch ligation. The rats that survived 24 h were randomly assigned to five groups: medium-dose of XG group (MI+XGM), high-dose of XG group (MI+XGH), carvedilol group (MI+C), medium-dose of XG + carvedilol group (MI+C+XGM). Fourteen rats underwent identical surgical procedures without artery ligation, serving as sham controls. At 28 days, left ventricular weight to body weight (LVW/BW) and heart weight to body weight (HW/BW) were calculated; left ventricular ejection fraction (LVEF), left ventricular shortening fraction (LVFS), left ventricular internal diameter at systole (LVIDS) were measured by ultrasound; HE staining, Masson staining, and Sirius red staining were used to assess the myocardial pathological and physiological changes as well as myocardial fibrosis area and non-infarct zone I/III collagen ratio. Expression of Smad3 were detected and analyzed by Western blot, immunohistochemistry and immunofluorescence. P-Smad3, Smad2 and Smad7 in the TGF-β/Smads signaling pathway were also analyzed by Western blot.ResultsThe LVIDS (P < 0.01), HW/BW (P < 0.05), type I/III collagen ratio (P < 0.01) and myocardial collagen (P < 0.01) decreased significantly while the LVW/BW, LVFS (P < 0.05) increased significantly in MI+XGM group as compared with those in other groups. The expression of key signal molecules of the TGF-β/Smads signaling pathway, including Smad3, P-Smad3 and Smad2 protein were decreased, while the expression of Smad7 increased in both XG and carvedilol treatment groups as compared to those of the MI group (all P < 0.01). Immunohistochemistry and immunofluorescence further confirmed the down-regulated Smad3 expression.ConclusionXG can improve ventricular reconstruction and inhibit myocardial fibrosis in rats with AMI by regulating TGF-β/Smads signaling pathway.

Qishen capsule safely boosts cardiac function and angiogenesis via the MEK/ERK pathway in a rat myocardial infarction model

Background Qishen(QS) capsules, a Traditional Chinese Medicine, has been widely used to treat coronary heart disease in China. However, evidence of its effectiveness remains unclear. Methods To explore whether QS has cardioprotective efficacy and/or promotes angiogenesis after myocardial infarction (MI), we performed experiments in a preclinical rat MI model. One month after left anterior descending coronary artery ligation, the rats received either QS solution (0.4 g/kg/day) or the same volume of saline by intragastric injection for four weeks. Results Echocardiographic and hemodynamic analyses demonstrated relatively preserved cardiac function in MI rats administered QS. Indeed, QS treatment was associated with reduced infarct scar size and heart weight index, and these beneficial effects were responsible for enhancing angiogenesis. Mechanistically, QS treatment increased phosphorylation of protein kinase B (Akt) and downregulated phosphorylation of mitogen-activated protein kinase/extracellular-regulated kinase (MEK/ERK). Conclusions QS therapy can improve the cardiac function of rats after MI by an underlying mechanism involving increased angiogenesis, at least partially via activation of the Akt signaling pathway and inhibition of MEK/ERK phosphorylation.

Xinfuli improves cardiac function, histopathological changes and attenuate cardiomyocyte apoptosis in rats with doxorubicin-induced cardiotoxicity

Background Xinfuli Granule （XG）, a compound Chinese herbal medicine, has been effectively used in China for the treatment of heart failure for more than fifty years. This study aimed to investigate the effects and the underlying mechanisms of Xinfuli in rats with dox- orubicin-induced cardiotoxicity. Methods Sprague-Dawley rats were treated with intraperitoneal injection of Doxorubicin （DOX, 2.5 mg/kg per week） for six weeks, and then randomly divided into four groups which received intragastrically administration of normal saline （control group） or different dosage of XG （0.675 g/kg per day, 1.35 g/kg per day, and 2.7g/kg per day, respectively） for six weeks. Transtho- racic echocardiography was performed to evaluate the left ventricular fractional shortening （LVFS） and left ventricular ejection fraction （LVEF） before and after the XG treatment and histopathologic changes were also examined. Myocardial cell apoptosis was detected by TUNEL staining. The expression of related genes and proteins were analyzed using immunohistochemical staining. Results Compared to those in the control group, rats in XG treated groups showed significantly improved cardiac function and milder cardiac histopathological changes, lower cardiomyocyte apoptosis index, higher expression of Bcl-2 and lower expression of Bax. Conclusions Administration of XG improves cardiac function and histopathological changes in rats with doxorubicin-induced cardiotoxicity. These effects are associated with inhibition of cardiomyocyte apoptosis, perhaps via regulation of Bcl-2 and Bax protein expression.

Twenty-four-hour ambulatory blood pressure changes in older patients with essential hypertension receiving monotherapy or dual combination antihypertensive drug therapy

Objective To evaluate the differences in 24-hour ambulatory blood pressure (BP) in older patients with hypertension treated with the five major classes of antihypertensive drugs,as monotherapy or dual combination therapy,to improve daytime and nighttime BP control. Methods We enrolled 1920 Chinese community-dwelling outpatients aged ≥ 60 years and compared ambulatory BP values and ambulatory BP control (24-hour BP < 130/80 mmHg;daytime mean BP < 135/85 mmHg;and nighttime mean BP < 120/70 mmHg),as well as nighttime BP dip patterns for monotherapy and dual combination therapy groups. Results Patients’ mean age was 71 years,and 59.5% of patients were women. Calcium channel blockers (CCBs) constituted the most common (60.3% of patients) monotherapy,and renin–angiotensin system (RAS) blockers combined with CCBs was the most common (56.5% of patients) dual combination therapy. Monotherapy with beta-blockers (BB) provided the best daytime BP control. The probabilities of having a nighttime dip pattern and nighttime BP control were higher in patients receiving diuretics compared with CCBs (OR = 0.52,P = 0.05 and OR = 0.41,P = 0.007,respectively). Patients receiving RAS/diuretic combination therapy had a higher probability of having controlled nighttime BP compared with those receiving RAS/CCB (OR = 0.45,P = 0.004). Compared with RAS/diuretic therapy,BB/CCB therapy had a higher probability of achieving daytime BP control (OR = 1.27,P = 0.45). Conclusions Antihypertensive monotherapy and dual combination drug therapy provided different ambulatory BP control and nighttime BP dip patterns. BB-based regimens provided lower daytime BP,whereas diuretic-based therapies provided lower nighttime BP,compared with other antihypertensive regimens.

Complement use of Chinese herbal medicine after percutaneous coronary intervention: a prospective observational study

BACKGROUND Chinese herbal medicine is widely used as a complement or alternative treatment in coronary artery disease(CAD)patients after percutaneous coronary intervention(PCI)in China.We compared the incidence of the major adverse cardi-ovascular event(MACE)of CAD patients with or without the complement use of Chinese herbal medicine after PCI.METHODS In this prospective,observational study that was conducted from September 2016 to August 2019 in Fuwai Hospital(China),we followed up consecutive patients who received PCI treatment for two years.MACE was defined as the composite all-cause mortality,revascularization,and myocardial infarction(MI)and was compared between those using(integrative medicine group)or those not using Chinese herbal medicine as an additional treatment to standard Western medicine,with unadjusted(Kaplan-Meier curves)and risk-adjusted(multivariable Cox regression)analyses.RESULTS A total of 5942 patients after PCI were enrolled in this study,and 5453 patients were included in the final analysis(4189[76.8%]male;mean age:61.9±9.9%years).During the follow-ups,2932(53.8%)patients used only Western medicine while 2521(46.2%)patients had used Chinese herbal medicine as an additional treatment to standard Western medicine.Patients in the integrative medicine group(IM group)were older than the Western medicine group(WM group),had more females and less pre-vious MI.The incidence of MACE was 15.3%(449/2932)in WM group and 11.54%(291/2521)in IM group.Cox regression ana-lysis showed that cumulative incidence of MACE was 27%lower in patients of the IM group than those in WM group(hazard ra-tio=0.73;95%CI:0.63-0.85;P<0.0001).CONCLUSIONS For CAD patients after PCI treatment,complement use of Chinese herbal medicine is associated with a lower 2-year MACE incidence.Randomized prospective studies are warranted to provide higher levels of benefit evidence in these pa-tients.

Inhibition of GLUD1 mediated by LASP1 and SYVN1 contributes to hepatitis B virus X protein-induced hepatocarcinogenesis

Glutamate dehydrogenase 1(GLUD1)is implicated in oncogenesis.However,little is known about the relationship between GLUD1 and hepatocellular carcinoma(HCC).In the present study,we demonstrated that the expression levels of GLUD1 significantly decreased in tumors,which was relevant to the poor prognosis of HCC.Functionally,GLUD1 silencing enhanced the growth and migration of HCC cells.Mechanistically,the upregulation of interleukin-32 through AKT activation contributes to GLUD1 silencing-facilitated hepatocarcinogenesis.The interaction between GLUD1 and AKT,as well asα-ketoglutarate regulated by GLUD1,can suppress AKT activation.In addition,LIM and SH3 protein 1(LASP1)interacts with GLUD1 and induces GLUD1 degradation via the ubiquitin–proteasome pathway,which relies on the E3 ubiquitin ligase synoviolin(SYVN1),whose interaction with GLUD1 is enhanced by LASP1.In hepatitis B virus(HBV)-related HCC,the HBV X protein(HBX)can suppress GLUD1 with the participation of LASP1 and SYVN1.Collectively,our data suggest that GLUD1 silencing is significantly associated with HCC development,and LASP1 and SYVN1 mediate the inhibition of GLUD1 in HCC,especially in HBV-related tumors.