Buyang Huanwu Decoction Enhances Revascularization via Akt/GSK3ß/NRF2 Pathway in Diabetic Hindlimb Ischemia.

BACKGROUND: Peripheral arterial disease (PAD) is a typical disease of atherosclerosis, most commonly influencing the lower extremities. In patients with PAD, revascularization remains a preferred treatment strategy. Buyang Huanwu decoction (BHD) is a popular Chinese herbal prescription which has showed effects of cardiovascular protection through conducting antioxidant, antiapoptotic, and anti-inflammatory effects. Here, we intend to study the effect of BHD on promoting revascularization via the Akt/GSK3ß/NRF2 pathway in diabetic hindlimb ischemia (HLI) model of mice. MATERIALS AND METHODS: All db/db mice (n = 60) were randomly divided into 6 groups by table of random number. (1) Sham group (N = 10): 7-0 suture thread passed through the underneath of the femoral artery and vein without occlusion. The remaining 5 groups were treated differently on the basis of the HLI (the femoral artery and vein from the inguinal ligament to the knee joint were transected and the vascular stump was ligated with 7-0 silk sutures) model: (2) HLI+NS group (N = 15): 0.2 ml NS was gavaged daily for 3 days before modeling and 14 days after occlusion; (3) HLI+BHD group (N = 15): 0.2 ml BHD (20 g/kg/day) was gavaged daily for 3 days before modeling and 14 days after occlusion; (4) HLI+BHD+sh-NC group (N = 8): local injection of adenovirus vector carrying the nonsense shRNA (Ad-GFP) in the hindlimbs of mice before treatment; (5) HLI+BHD+sh-NRF2 group (N = 8): knockdown of NRF2 in the hindlimbs of mice by local intramuscular injection of adenovirus vector carrying NRF2 shRNA (Ad-NRF2-shRNA) before treatment; and (6) HLI+BHD+LY294002 group (N = 4): intravenous injection of LY294002 (1.5 mg/kg) once a day for 14 days on the basis of the HLI+BHD group. Laser Doppler examination, vascular cast, and immunofluorescence staining were applied to detect the revascularization of lower limbs in mice. Western blot analysis was used to detect the expression of vascular endothelial growth factor (VEGF), interleukin-1beta (IL-1ß), interleukin-6 (IL-6), tumor necrosis factor- (TNF-) α, heme oxygenase-1 (HO-1), NAD(P)H dehydrogenase quinone-1 (NQO-1), catalase (CAT), glyceraldehyde-3-phosphate dehydrogenase (GAPDH), phosphorylated protein kinase B (p-AKT), and phosphorylated glycogen synthase kinase-3 beta (p-GSK3ß). HE staining was used to assess the level of muscle tissue damage and inflammation in the lower extremities. Local multipoint injection of Ad-NRF2-shRNA was used to knock down NRF2, and qPCR was applied to detect the mRNA level of NRF2. The blood glucose, triglyceride, cholesterol, MDA, and SOD levels of mice were tested using corresponding kits. The SPSS 20.0 software and GraphPad Prism 6.05 were used to do all statistics. Values of P < 0.05 were considered as statistically significant. Results and Conclusions. BHD could enhance the revascularization of lower limbs in HLI mice, while BHD has no effect on blood glucose and lipid level in db/db mice (P > 0.05). BHD could elevate the protein expression of VEGF, HO-1, NQO-1, and CAT (P < 0.05) and decrease the expression of IL-1ß, IL-6, and TNF-α (P < 0.05) in HLI mice. Meanwhile, BHD could activate NRF2 and promote the phosphorylation of AKT/GSK3ß during revascularization (P < 0.05). In contrast, knockdown of NRF2 impaired the protective effects of BHD on HLI (P < 0.05). LY294002 inhibited the upregulation of NRF2 activated by BHD through inhibiting the phosphorylation of the AKT/GSK3ß pathway (P < 0.05). The present study demonstrated that BHD could promote revascularization on db/db mice with HLI through targeting antioxidation, anti-inflammation, and angiogenesis via the AKT/GSK3ß/NRF2 pathway.

Traditional Chinese Medicine for Coronary Heart Disease: Clinical Evidence and Possible Mechanisms.

Coronary heart disease (CHD) remains a major cause of mortality with a huge economic burden on healthcare worldwide. Here, we conducted a systematic review to investigate the efficacy and safety of Chinese herbal medicine (CHM) for CHD based on high-quality randomized controlled trials (RCTs) and summarized its possible mechanisms according to animal-based researches. 27 eligible studies were identified in eight database searches from inception to June 2018. The methodological quality was assessed using seven-item checklist recommended by Cochrane Collaboration. All the data were analyzed using Rev-Man 5.3 software. As a result, the score of study quality ranged from 4 to 7 points. Meta-analyses showed CHM can significantly reduce the incidence of myocardial infarction and percutaneous coronary intervention, and cardiovascular mortality (P < 0.05), and increase systolic function of heart, the ST-segment depression, and clinical efficacy (P < 0.05). Adverse events were reported in 11 studies, and CHMs were well tolerated in patients with CHD. In addition, CHM exerted cardioprotection for CHD, possibly altering multiple signal pathways through anti-inflammatory, anti-oxidation, anti-apoptosis, improving the circulation, and regulating energy metabolism. In conclusion, the evidence available from present study revealed that CHMs are beneficial for CHD and are generally safe.

Buyang Huanwu Decoction Exerts Cardioprotective Effects through Targeting Angiogenesis via Caveolin-1/VEGF Signaling Pathway in Mice with Acute Myocardial Infarction.

BACKGROUND: Acute myocardial infarction (AMI) remains a leading cause of morbidity and mortality worldwide. The idea of therapeutic angiogenesis in ischemic myocardium is a promising strategy for MI patients. Buyang Huanwu decoction (BHD), a famous Chinese herbal prescription, exerted antioxidant, antiapoptotic, and anti-inflammatory effects, which contribute to cardio-/cerebral protection. Here, we aim to investigate the effects of BHD on angiogenesis through the caveolin-1 (Cav-1)/vascular endothelial growth factor (VEGF) pathway in MI model of mice. MATERIALS AND METHODS: C57BL/6 mice were randomly divided into 3 groups by the table of random number: (1) sham-operated group (sham, n = 15), (2) AMI group (AMI+sham, n = 20), and (3) BHD-treated group (AMI+BHD, n = 20). 2,3,5-Triphenyltetrazolium chloride solution stain was used to determine myocardial infarct size. Myocardial histopathology was tested using Masson staining and hematoxylin-eosin staining. CD31 immunofluorescence staining was used to analyze the angiogenesis in the infarction border zone. Western blot analysis, immunofluorescence staining, and/or real-time quantitative reverse transcription polymerase chain reaction was applied to test the expression of Cav-1, VEGF, vascular endothelial growth factor receptor 2 (VEGFR2), and/or phosphorylated extracellular signal-regulated kinase (p-ERK). All statistical analyses were performed using the SPSS 20.0 software and GraphPad Prism 6.05. Values of P < 0.05 were considered as statistically significant. RESULTS AND CONCLUSION: Compared with the AMI group, the BHD-treated group showed a significant improvement in the heart weight/body weight ratio, echocardiography images, cardiac function, infarct size, Mason staining of the collagen deposition area, and density of microvessel in the infarction border zone (P < 0.05). Compared with the AMI group, BHD promoted the expression of Cav-1, VEGF, VEGFR2, and p-ERK in the infarction border zone after AMI. BHD could exert cardioprotective effects on the mouse model with AMI through targeting angiogenesis via Cav-1/VEGF signaling pathway.

Chinese herbal medicine for Alzheimer's disease: Clinical evidence and possible mechanism of neurogenesis.

Currently, there is lack of cure or disease-modifying treatment for Alzheimer's disease (AD). Chinese herbal medicine (CHM) is purported to ameliorate AD progression, perhaps by promoting hippocampal neurogenesis. Here, we conducted an updated systematic review to investigate the efficacy and safety of CHM for AD based on high-quality randomized controlled trials (RCTs) and reviewed its possible mechanisms of neurogenesis according to animal-based researches. Twenty eligible studies with 1767 subjects were identified in eight database searches from inception to February 2017. The studies investigated the CHM versus placebo (n=3), CHM versus donepezil (n=9 with 10 comparisons), CHM plus donepezil versus donepezil (n=3), CHM versus a basic treatment (n=3), and CHM plus basic treatment versus basic treatment (n=2). Adverse events were reported in 11 studies, analyzed but not observed in 3 studies, and not analyzed in 6 studies. The main findings of present study are that CHM as adjuvant therapy exerted an additive anti-AD benefit, whereas the efficacy of CHM as a monotherapy was inconclusive. Additionally, CHMs were generally safe and well tolerated in AD patients. Active molecules in frequent constituents of CHMs can alter multiple critical signaling pathways regulating neurogenesis. Thus, the present evidence supports, to a limited extent, the conclusion that CHM can be recommended for routine use in AD patients and its possible mechanism enhances adult hippocampal neurogenesis through activating the multi-signal pathways.

Shexiang Baoxin Pills for Coronary Heart Disease in Animal Models: Preclinical Evidence and Promoting Angiogenesis Mechanism.

Shexiang Baoxin Pill (SBP) originated from a classical TCM Fufang Suhexiang Pill for chest pain with dyspnea in the Southern Song Dynasty (1107-110 AD). Here, we aimed to evaluate preclinical evidence and possible mechanism of SBP for experimental coronary heart disease (CHD). Studies of SBP in animal models with CHD were identified from 6 databases until April 2016. Study quality for each included article was evaluated according to the CAMARADES 10-item checklist. Outcome measures were myocardial infarction area, vascular endothelial growth factor (VEGF) and microvessel count (MVC). All the data were analyzed by using RevMan 5.1 software. As a consequence, 25 studies with 439 animals were identified. The quality score of studies ranged from 2 to 5, with the median of 3.6. Meta-analysis of seven studies showed more significant effects of SBP on the reduction of the myocardial infarction area than the control (P < 0.01). Meta-analysis of eight studies showed significant effects of SBP for increasing VEGF expression compared with the control (P < 0.01). Meta-analysis of 10 studies indicated that SBP significantly improved MVC compared with the control (P < 0.01). In conclusion, these findings preliminarily demonstrated that SBP can reduce myocardial infarction area, exerting cardioprotective function largely through promoting angiogenesis.

Salvianolic Acid Exerts Cardioprotection through Promoting Angiogenesis in Animal Models of Acute Myocardial Infarction: Preclinical Evidence.

Radix Salviae miltiorrhizae, danshen root (danshen), is one of the widely used Chinese herbal medicines in clinics, containing rich phenolic compounds. Salvianolic acid is the main active compound responsible for the pharmacologic effects of danshen. Here, we aimed to evaluate the effects of salvianolic acid on cardioprotection through promoting angiogenesis in experimental myocardial infarction. Studies of salvianolic acid in animal models of myocardial infarction were obtained from 6 databases until April 2016. The outcome measures were vascular endothelium growth factor (VEGF), blood vessel density (BVD), and myocardial infarct size. All the data were analyzed using Rev-Man 5.3 software. Ultimately, 14 studies were identified involving 226 animals. The quality score of studies ranged from 3 to 6. The meta-analysis of six studies showed significant effects of salvianolic acid on increasing VEGF expression compared with the control group (P < 0.01). The meta-analysis of the two salvianolic acid A studies and three salvianolic acid B studies showed significantly improving BVD compared with the control group (P < 0.01). The meta-analysis of five studies showed significant effects of salvianolic acid for decreasing myocardial infarct size compared with the control group (P < 0.01). In conclusion, these findings demonstrated that salvianolic acid can exert cardioprotection through promoting angiogenesis in animal models of myocardial infarction.

Ginsenoside Rb1 for Myocardial Ischemia/Reperfusion Injury: Preclinical Evidence and Possible Mechanisms.

Ginseng is an important herbal drug that has been used worldwide for many years. Ginsenoside Rb1 (G-Rb1), the major pharmacological extract from ginseng, possesses a variety of biological activities in the cardiovascular systems. Here, we conducted a preclinical systematic review to investigate the efficacy of G-Rb1 for animal models of myocardial ischemia/reperfusion injury and its possible mechanisms. Ten studies involving 211 animals were identified by searching 6 databases from inception to May 2017. The methodological quality was assessed by using the CAMARADES 10-item checklist. All the data were analyzed using RevMan 5.3 software. As a result, the score of study quality ranged from 3 to 7 points. Meta-analyses showed that G-Rb1 can significantly decrease the myocardial infarct size and cardiac enzymes (including lactate dehydrogenase, creatine kinase, and creatine kinase-MB) when compared with control group (P < 0.01). Significant decrease in cardiac troponin T and improvement in the degree of ST-segment depression were reported in one study (P < 0.05). Additionally, the possible mechanisms of G-Rb1 for myocardial infarction are antioxidant, anti-inflammatory, antiapoptosis, promoting angiogenesis and improving the circulation. Thus, G-Rb1 is a potential cardioprotective candidate for further clinical trials of myocardial infarction.