Gancao decoction attenuates hepatic necroptosis via activating caspase 8 in cholestatic liver injury.

ETHNOPHARMACOLOGICAL RELEVANCE: Gancao Decoction (GCD) is widely used to treat cholestatic liver injury. However, it is unclear whether is related to prevent hepatocellular necroptosis. AIM OF THE STUDY: The purpose of this study is to clarify the therapeutic effects of GCD against hepatocellular necroptosis induced by cholestasis and its active components. MATERIALS AND METHODS: We induced cholestasis model in wild type mice by ligating the bile ducts or in Nlrp3-/- mice by intragastrical administering Alpha-naphthylisothiocyanate (ANIT). Serum biochemical indices, liver pathological changes and hepatic bile acids (BAs) were measured to evaluate GCD's hepatoprotective effects. Necroptosis was assessed by expression of hallmarkers in mice liver. Moreover, the potential anti-necroptotic effect of components from GCD were investigated and confirmed in ANIT-induced cholestasis mice and in primary hepatocytes from WT mouse stimulated with Tumor Necrosis Factor alpha (TNF-α) and cycloheximide (CHX). RESULTS: GCD dose-dependently alleviated hepatic necrosis, reduced serum aminotranferase activity in both BDL and ANIT-induced cholestasis models. More importantly, the expression of hallmarkers of necroptosis, including MLKL, RIPK1 and RIPK3 phosphorylation (p- MLKL, p-RIPK1, p-RIPK3) were reduced upon GCD treatment. Glycyrrhetinic acid (GA), the main bioactive metabolite of GCD, effectively protected against ANIT-induced cholestasis, with decreased expression of p-MLKL, p-RIPK1 and p-RIPK3. Meanwhile, the expression of Fas-associated death domain protein (FADD), long isoform of cellular FLICE-like inhibitory protein (cFLIPL) and cleaved caspase 8 were upregulated upon GA treatment. Moreover, GA significantly increased the expression of active caspase 8, and reduced that of p-MLKL in TNF-α/CHX induced hepatocytes necroptosis. CONCLUSIONS: GCD substantially inhibits necroptosis in cholestatic liver injury. GA is the main bioactive component responsible for the anti-necroptotic effects, which correlates with upregulation of c-FLIPL and active caspase 8.

Effects of huoxin formula on the arterial functions of patients with coronary heart disease.

Context: Huoxin formula is a Traditional Chinese Medicine for coronary heart disease (CHD) treatment. Objective: To explore the therapeutic mechanism of the Huoxin formula on arterial functions in CHD patients. Materials and methods: Fifty-eight CHD patients receiving cardiovascular drugs including ß-receptor blocker, statins, and antiplatelet medications or others were randomized into intervention [additionally 13.5 g Huoxin formula granules dissolved in 150 mL warm water per time, twice a day (n = 30)] and control [only cardiovascular drugs (n = 28)] groups. Serum biomarkers (hs-CRP, IL-18, IL-17, TNF-α, MMP-9), and cardiovascular indicators of the common and internal carotid arteries (ICAs) were monitored before and after the treatments. Results: After 3 months of treatment, the increases of intima-media thicknesses (IMT) of the left and right common carotid arteries (CCAs) as well as of the left and right ICAs and the increases of the left and right cardio-ankle vascular index were all significantly (all p < 0.001) less in the intervention than in control group (all p < 0.001). Serum concentrations reductions of hs-CRP, IL-18, IL-17 and MMP9 (all p < 0.001) levels were higher in the intervention compared to the control group, which correlated with the changes of left ICA (hs-CRP: r = 0.581, p = 0.009; IL-18: r = 0.594, p = 0.007; IL-17: r = 0.575, p = 0.006). Discussion and conclusion: Since the Huoxin formula improved arterial functions and reduced inflammatory factor activities in CHD patients, a large-scale clinical trial is warranted.

Aspirin suppresses TNF-α-induced MMP-9 expression via NF-κB and MAPK signaling pathways in RAW264.7 cells.

Numerous studies have indicated that the expression of matrix metalloproteinase-9 (MMP-9) contributes to the atherosclerotic plaque hemorrhage and rupture. Aspirin, a non-steroidal anti-inflammation drug, has been known for its anti-platelet effect in the prevention of the vascular complications of atherosclerosis. The present study aimed to investigate the pharmacological effects of aspirin on tumor necrosis factor-α (TNF-α)-induced MMP-9 expression and the underlying molecular mechanisms in murine macrophage RAW264.7 cells. Western blot analysis indicated that the protein level of MMP-9 was reduced by aspirin in a dose-dependent manner. In addition, downregulation of MMP-9 mRNA and activity were detected in aspirin-treated cells using quantitative polymerase chain reaction and a gelatin zymography assay separately. It was also observed that aspirin has a suppressive effect on the activation of nuclear factor (NF)-κB and inhibits the phosphorylation of mitogen-activated protein kinases (MAPKs), including extracellular signal-regulated kinases 1/2, p38 and c-Jun N-terminal kinase. Furthermore, subsequent to inhibition of the MAPK pathway by specific inhibitors (PD98059, SB203580 and SP600125), the expression of MMP-9 was reduced, indicating that the inhibitory effect of aspirin on MMP-9 in TNF-α-treated RAW264.7 cells may be, at least in part, through suppression of NF-κB activation and the MAPK pathway. These findings support the notion that aspirin has therapeutic potential application in the prevention and treatment of atherosclerosis disease.

Traditional Chinese Medicine on the Treatment of Coronary Heart Disease in Recent 20 Years.

OBJECTIVE: To analyze the patterns and differences of Chinese herbs in the treatment of coronary heart disease (CHD) in different time periods and different regions in recent 20 years. DESIGN: The literature of controlled clinical trials that focuses on Chinese herbs treating CHD published in China National Knowledge Internet and Wanfang database from January 1, 1996 to December 31, 2015 were screened to analyze the patterns of herb utilization using SPSS 21.0. RESULTS: A total of 1250 articles were enrolled in total covering 29 regions. There were 242 kinds of single herbs, 18 categories, mentioned a total of 11,594 times. In Northeast China, North China, South China, Central China, and Southwest China the most frequently used herb was Radix Salviae Miltiorrhizae, but in East China and Northwest China, the most frequently used herb was Rhizoma Chuanxiong. The most frequently used herb category in North China, Central China, Southwest China, and Northwest China was herbs to invigorate blood, but in Northeast China, East China, and South China the most frequently used herb category was herbs to tonify. CONCLUSION: Single herbs and herb categories to treat CHD in Traditional Chinese Medicine differed from time to time and from region to region.

[Treatment of Chronic Heart Failure with Qi-Yang Deficiency, Blockage of Static Blood Syndrome by Xinmailong Injection: an Open Multi-center Clinical Study].

Objective To assess the safety and effectiveness of Xinmailong Injection (XI) for treating chronic heart failure (CHF) patients with qi-yang deficiency, blockage of static blood syndrome (QYDBSBS). Methods Totally 2 104 patients with QYDBSBS at 25 centers were recruited. XI at 5 mg/kg was intravenously injected to all patients after skin test, twice per day for 5 successive days. The safety and effectiveness were observed within 8 days after injection (5 days of treatment and 3 days of follow- ups). Results were analyzed after full analysis set (FAS) and safety set (SS). Efficacy of heart function (HF) and efficacy of Chinese medicine (CM) syndrome were subgroup analyzed by age ( ≤65 years old or >65 years old) or types of HF (whole HF, right HF, or left HF). Results FAS analysis showed after treatment markedly effective of HF in 550 cases, effective in 873 cases, ineffective in 673 cases, deteriorated in 8 cases. The markedly effective rate was 26.14% and the total effective rate was 67.63%. After treatment markedly effective of CM syndrome was shown in 795 cases, effective in 1 009 cases, ineffective in 288 cases, deteriorated in 12 cases. The markedly effective rate was 37.79% and the total effec- tive rate was 85.74%. Results of CM symptom score: CM symptom score was (11.381 ±4.574) before treatment and (4.987 ±3.984) after treatment, with statistical difference (P <0.01). The decrease rate was 56.8% ±27.0%. Results of subgroup analysis showed that markedly effective rates of HF efficacy and CM syndrome efficacy were superior in patients ≤65 years old than in patients >65 years old (P<0.01 Efficacy of HF was superior in patients with left HF than in those with whole HF or with right HF (P<0.01). In aspect of efficacy of CM, the markedly effective rate and the total effective rate were superior in patients with left HF or with whole HF than in those with right HF (P<0.01 ). No death occurred during the tri- al. No severe adverse event occurred either. Conclusions XI could improve clinical symptoms of CHF patients with QYDBSBS, reduce CM symptom score. No severe adverse event was observed.

[Effects of added therapy with Chinese herbal medicine Kanli Granule on skeletal muscle dysfunction in patients with chronic heart failure].

BACKGROUND: The pathological changes of skeletal muscle dysfunction in chronic heart failure (CHF) have caused widespread concern, and evaluating the functional properties of medication to improve these pathological changes has become a common area of study for clinicians. OBJECTIVE: To investigate the characteristics of skeletal muscle dysfunction in patients with CHF and the effects of Kanli Granule, a compound traditional Chinese herbal medicine, on the skeletal muscle dysfunction based on Western medical treatment in patients with CHF. DESIGN, SETTING, PARTICIPANTS AND INTERVENTIONS: All patients with CHF enrolled in this study were outpatients or inpatients in Shuguang Hospital affiliated to Shanghai University of Traditional Chinese Medicine from December 2005 to December 2007. The patients were divided into Western medicine group (treatment with Western medicine) and Chinese herbs group (treatment with Kanli Granule based on Western medicine) based on their preference. The treatment course lasted for 12 weeks. MAIN OUTCOME MEASURES: The grip strength, grasp times, rate of perceived exertion (RPE), estimated heart rate, peripheral blood lactate levels and lactate dehydrogenase (LDH) isoenzyme activity in patients were measured. RESULTS: A total of 92 patients were recruited and 12 patients withdrew from the Western medicine group, therefore a total of 80 patients were included in the follow-up study. There were 46 cases in the Chinese herbs group and 34 cases in the Western medicine group. After treatment, grip strength and grasp times increased significantly compared with before treatment. RPE score and estimated heart rate significantly decreased in the two groups, showing greater changes in the Chinese herbs group than the Western medicine group (P<0.01). Peripheral blood lactate levels of the CHF patients in a resting state decreased, and the Chinese herbs group displayed a greater decrease than the Western medicine group (P<0.05); lactate levels 3 min after exercise decreased after treatment in both treatment groups, but no significant difference was found compared with before treatment; LDH1 levels in the two treatment groups were decreased compared with before treatment but showed no statistically significant changes; LDH5 levels in the two treatment groups increased after treatment, and an obvious difference was found in the Chinese herbs group (P<0.01). CONCLUSION: Treatment with the addition of Kanli Granule can significantly improve the function of skeletal muscle in patients with CHF by improving skeletal muscle energy metabolism.