Si-Miao-Yong-An decoction ameliorates cardiac function through restoring the equilibrium of SOD and NOX2 in heart failure mice.

Si-Miao-Yong-An decoction (SMYAD), a Chinese herbal formula, has been used in treating ischemic cardiovascular diseases. However, the cardioprotective mechanism of SMYAD treating heart failure (HF) remains unclear. Herein we investigated the effect of SMYAD on isoprenaline (ISO)-induced HF in C57BL/6 mice. Cardiac function and pathological changes in myocardial tissue were evaluated as well as A-type natriuretic peptide (ANP) and brain natriuretic peptide (BNP) expression. The underlying mechanism of SMYAD was deciphered using UHPLC MS/MS coupled with bioinformatics and was verified. SMYAD treatment significantly ameliorated cardiac function, reduced collagen deposition and cardiomyocyte apoptosis, reversed cardiac hypertrophy and down-regulated the expression levels of ANP and BNP mRNA compared with those in HF mice. Decipherment analyses based on 138 ingredients prompted that anti-oxidation was the key mechanism of SMYAD treating HF. In vitro and in vivo, SMYAD showed antioxidant activity, significantly up-regulated superoxide dismutase (SOD)-1 and SOD-2 mRNA expression levels and reduced NADP/NADPH ratio. Moreover, the increased expression levels of NADPH oxidase 2 (NOX2), p47phox and Rac family small GTPase 1 (Rac1) were obviously ameliorated after SMYAD treatment. Together, this study reveals that SMYAD can apparently improve heart function of ISO-induced HF mice by inhibiting the myocardial oxidative stress through restoring the equilibrium of SOD and NOX2.

Qishen granule attenuates cardiac fibrosis by regulating TGF-ß /Smad3 and GSK-3ß pathway.

BACKGROUND: Cardiac fibrosis is a common pathological progress of cardiovascular disease resulting from the excessive accumulation of extracellular matrix (ECM). Transforming growth factor (TGF)-ß/SMADs pathway is a canonical signaling pathway which directly induces expressions of ECM related genes. Qishen Granule (QSG), a traditional Chinese formula developed from Zhen-Wu Decoration for heart failure (HF), has been proven to have definite therapeutic effects on cardiac fibrosis. However, its underlying mechanisms remain unclear. PURPOSE: To investigate the effects of QSG on TGF-ß pathway and the downstream mediators including Smad3 and Glycogen synthase kinase (GSK)-3ß. METHODS: HF model was induced by ligation of left coronary artery on male Sprague-Dawley (SD) rats. Rat were randomly divided into four groups including sham group, model group, QSG group and Fosinopril control group. Rats in each group were treated for 28 days, and 2D echocardiography was adopted to evaluate the heart function. The degree of cardiac fibrosis was assessed by Hematoxylin-Eosin (HE), Masson's trichrome and Picrosirius red (PSR) staining. Contents of collagen Ⅰ and Ⅲ were assessed by immunohistochemical method. Expressions of genes and proteins in TGF-ß/SMADs and PI3K-GSK-3 signaling pathways were detected by Real-time Fluorescence Quantitative PCR (RT-qPCR) and Western blot respectively. TGF-ß1-treated cardiac fibroblasts of neonatal SD rats were adopted for in vitro studies. RESULTS: 28 days after the surgery, cardiac ejection fraction (EF) and fractional shortening (FS) values in the model group showed a remarkable decrease, indicating the induction of HF model. QSG and Fosinopril elevated the EF and FS values, demonstrating cardio-protective effects. Pathological staining and immunohistochemistry showed that the contents of collagen I and III dramatically increased in the cardiac tissue of the model group compared with the sham group while QSG treatment reduced collagen contents. Furthermore, expressions of TGF-ß1, p-Smad3 and p-GSK-3ß were significantly decreased in the QSG treatment group compared with the model group, suggesting that the QSG may attenuate cardiac fibrosis through regulating TGF-ß/Smad3 pathway. In vitro study further showed that the productions of type Ⅰ and Ⅲ collagen and α-smooth muscle actin (α-SMA) of cardiac fibroblasts were significantly increased by incubation with TGF-ß1. QSG could markedly reduce the secretion of collagen Ⅰ and Ⅲ and α-SMA expression. Protein expressions of p-Smad3, PI3K, p-Akt and p-GSK-3ß were significantly up-regulated by stimulation of TGF-ß1. Treatment with QSG could suppress the activity of Smad3 and PI3K-GSK-3ß signaling pathway in cardiac fibroblasts. CONCLUSION: QSG improves cardiac function through inhibiting cardiac fibrosis. The anti-fibrotic effects are potentially mediated by the inhibition of the TGF-ß/Smad3 pathway and the phosphorylation of GSK-3ß.

[Anti-inflammatory mechanism of heat-clearing and detoxifying Chinese herbs].

Heat-clearing and detoxifying Chinese herbs (HDCHs) are mainly used to treat carbuncle, sore throat, erysipelas, gills, dysentery and other diseases induced by heat-toxicity. Inflammation is a defensive response to damaging factors in living organism with vascular system. In recent years, a large amount of experimental and clinical studies showed that HDCHs had good therapeutic effect on inflammation. This review analyzed the anti-inflammatory mechanism of 11 HDCHs by retrieving literature in past 5 years, including Lonicerae Japonicae Flos (Jinyinhua), Lonicerae Flos (Jinyinhua), Lonicerae Japonicae Caulis (Rendongteng), Forsythiae Fructus (Lianqiao), Rhizoma Coptidis（Huanglian）, Gardeniae Fructus (Zhizi), Andrographis Herba (Chuanxinlian), Taraxaci Herba (Pugongying), Scrophulariae Radix (Xuanshen), Pulsatillae Radix (Baitouweng), and Agrimoniae Herba (Xianhecao). The data showed that the regulatory effect of HDCHs on inflammation may be involved mainly in the nuclear factor-κB (NF-κB), mitogen-activated protein kinase (MAPK) or janus kinase-signal transducers and activators of transcription (JAK-STAT) pathway, with similarity of action links among these three. Based upon the analysis of literature, we proposed some promising directions in this research field, providing a reliable theoretical basis for both experimental researches and clinical practices of HDCHs.

Decomposing the Mechanism of Qishen Granules in the Treatment of Heart Failure by a Quantitative Pathway Analysis Method.

Qishen granules (QSG) have beneficial therapeutic effects for heart failure, but the effects of decomposed recipes, including Wenyang Yiqi Huoxue (WYH) and Qingre Jiedu (QJ), are not clear. In this study, the efficacy of WYH and QJ on heart failure is evaluated by using transverse aortic constriction (TAC) induced mice and the significantly changed genes in heart tissues were screened with a DNA array. Furthermore, a new quantitative pathway analysis tool is developed to evaluate the differences of pathways in different groups and to identify the pharmacological contributions of the decomposed recipes. Finally, the related genes in the significantly changed pathways are verified by a real-time polymerase chain reaction and a Western blot. Our data show that both QJ and WYH improve the left ventricular ejection fraction, which explain their contributions to protect against heart failure. In the energy metabolism, QJ achieves the therapeutic effects of QSG through nicotinamide nucleotide transhydrogenase (Nnt)-mediated mechanisms. In ventricular remodeling and inflammation reactions, QJ and WYH undertake the therapeutic effects through 5'-nucleotidase ecto (Nt5e)-mediated mechanisms. Together, QJ and WYH constitute the therapeutic effects of QSG and play important roles in myocardial energy metabolism and inflammation, which can exert therapeutic effects for heart failure.