GDH promotes isoprenaline-induced cardiac hypertrophy by activating mTOR signaling via elevation of α-ketoglutarate level.

Numerous studies reveal that metabolism dysfunction contributes to the development of pathological cardiac hypertrophy. While the abnormal lipid and glucose utilization in cardiomyocytes responding to hypertrophic stimuli have been extensively studied, the alteration and implication of glutaminolysis are rarely discussed. In the present work, we provide the first evidence that glutamate dehydrogenase (GDH), an enzyme that catalyzes conversion of glutamate into ɑ-ketoglutarate (AKG), participates in isoprenaline (ISO)-induced cardiac hypertrophy through activating mammalian target of rapamycin (mTOR) signaling. The expression and activity of GDH were enhanced in cultured cardiomyocytes and rat hearts following ISO treatment. Overexpression of GDH, but not its enzymatically inactive mutant, provoked cardiac hypertrophy. In contrast, GDH knockdown could relieve ISO-triggered hypertrophic responses. The intracellular AKG level was elevated by ISO or GDH overexpression, which led to increased phosphorylation of mTOR and downstream effector ribosomal protein S6 kinase (S6K). Exogenous supplement of AKG also resulted in mTOR activation and cardiomyocyte hypertrophy. However, incubation with rapamycin, an mTOR inhibitor, attenuated hypertrophic responses in cardiomyocytes. Furthermore, GDH silencing protected rats from ISO-induced cardiac hypertrophy. These findings give a further insight into the role of GDH in cardiac hypertrophy and suggest it as a potential target for hypertrophy-related cardiomyopathy.

The cardiovascular protective effect and mechanism of calycosin and its derivatives.

Cardiovascular disease is the main cause of mortality and morbidity in the world, especially in developing countries. Drug therapy is one of the main ways to treat cardiovascular diseases. Among them, great progress has been made in the treatment of cardiovascular diseases with traditional Chinese medicine. In terms of experimental research, the mechanism of traditional Chinese medicine in the treatment of cardiovascular diseases has been thoroughly discussed in vitro and in vivo. In terms of clinical treatment, traditional Chinese medicine with flavonoids, saponins and alkaloids as the main effective components has a definite effect on the treatment of cardiovascular diseases such as arrhythmia, myocardial ischemia, angina pectoris and myocardial infarction, with high safety and good application prospects. With the further research on the effective ingredients, mechanism and adverse reactions of traditional Chinese medicine, it will be beneficial to the effectiveness of traditional Chinese medicine, reduce side effects and promote the modernization of traditional Chinese medicine. Calycosin and its derivatives, the main bioactive flavonoids in Astragalus membranaceus have multiple biological effects, such as antioxidant, pro-angiogenesis, anti-tumour, and anti-inflammatory effects. Based on the above biological effects, calycosin has been shown to have good potential for cardiovascular protection. The potent antioxidant effect of calycosin may play an important role in the cardiovascular protective potential. For injured cardiac myocytes, calycosin and its derivatives can alleviate the cell damage mainly marked by the release of myocardial enzymes and reduce the death level of cardiac myocytes mainly characterized by apoptosis through various mechanisms. For vascular endothelial cells, calycosin also has multiple effects and multiple mechanisms, such as promoting vascular endothelial cell proliferation, exerting vasodilating effect and directly affecting the synthesis function of endothelial cells. The present review will address the bioactivity of calycosin in cardiovascular diseases such as protective effects on cardiac myocytes and vascular endothelial cells and elucidate main mechanism of calycosin and its derivatives to exert the above biological effects.

[Discussion on safety evaluation and risk control measures of Epimedii Folium].

Epimedii Folium,a commonly used traditional Chinese medicine,has the effect of tonifying kidney Yang,strengthening bones and treating rheumatism. However,in recent years,the number of reports on adverse reactions of Epimedii Folium and its Chinese patent medicines such as Xianling Gubao Capsules and Zhuanggu Guanjie Pills has been gradually increased,and the toxicity of Epimedii Folium has attracted more and more attention. In this article,the ancient and modern literature on Epimedii Folium was traced through a comprehensive and systematic literature analysis method. According to the 2015 edition of the Chinese Pharmacopoeia,Epimedii Folium refers to the dried leaves of Epimedii Folium brevicomu,E. sugittutum,E. pubescens or E. koreuuum. The Chinese Pharmacopoeia also includes E. wushanense of Wushan Epimedium,which is the same plant variety as Epimedium. The study showed that there were differences in the geographical distribution,composition and toxicity among five species of Epimedium. This paper also explained the toxicity mechanism as well as efficacy enhancing and toxicity reducing effects of Epimedii Folium,and reported its related adverse reaction cases. Through a retrospective comparative study on the toxicity of the modern Chinese patent medicines Xianling Gubao Capsules and Zhuanggu Guanjie Pills containing Epimedii Folium,it was believed that Epimedii Folium had cardiovascular system toxicity,neurotoxicity,hepatotoxicity,long-term toxicity,acute toxicity,genotoxicity and special toxicity; its safe medication factors included patient syndrome,doctor factors,drug factors,processing and compatibility factors. Meanwhile,strategies were proposed to improve patient safety medication awareness,standardize Epimedii Folium varieties and quality supervision,and the toxicity of Epimedii Folium was studied,hoping to draw attention from scholars to the safety of Epimedii Folium,improve the safe use of Epimedii Folium,and prevent adverse reactions.

[Safety evaluation and risk control measures for Aconiti Kusnezoffii Radix].

Through the comprehensive and systematic research of domestic and overseas literature and information, we studied ancient original records on Aconiti Kusnezoffii Radix and its toxicity, analyzed related adverse cases and the animal toxicity experiments in recent years, then systematically analyzed the safety of Aconitum and its preparations, and finally we summarized the clinical characteristics and potential risk factors related to the safety of Aconitum. A report on adverse events of Aconitum in 76 patients with myocardial damage and renal damage accounting for 53.9% and 42.1% respectively, indicated that the safety problems of Aconitum may be related to heart toxicity and liver-kidney toxicity. Aconitum had complex compositions, and based on the animal experiments, Aconitum decoction had the highest toxicity at 2 h, and it reduced significantly at 4 h, which showed that the toxic components mainly depend on the hydrolysis or the decomposition degree of diester diterpenoid alkaloids. According to the toxicity study, Aconitum toxicity might occur in cardiovascular system, nervous system, kidney, embryo, reproductive system, and it was contraindicated in pregnant women. So far, specific antidote for aconitine poisoning is still a blank. The key for treatment is to correct arrhythmia timely and effectively, maintain stable vital signs, and meanwhile, give gastric lavage, intravenous fluid infusion and other therapies. So we suggest that the basic study for Aconitum toxicology should be strengthened, and the pharmacology and mechanism of toxicity, as well as the mechanism of processing for raising efficiency and reducing toxicity, should be further clarified to determine the quantity-effect relationship and eliminate safety hazards in using Aconitum.

Two new flavonoids from Artemisia argyi with their anticoagulation activities.

A new flavone glycoside, eupatilin 7-O-ß-d-glucopyranoside (1) and a new flavone, 5,6,2',4'-tetrahydroxy-7,5'-dimethoxyflavone (2), were isolated from Artemisia argyi. Their structures were unambiguously elucidated by extensive spectroscopic analysis. Both flavonoids were evaluated for in vitro anticoagulation activities. Compound 1 significantly extended thrombin time. Compound 2 had obvious effect in increasing prothrombin time.

Natural nitric oxide (NO) inhibitors from Chloranthus japonicus.

Eight new lindenane sesquiterpenoid dimers, chlojapolides A-H (1-8), along with 11 known analogues were isolated from the whole plant of Chloranthus japonicus. Their structures including absolute configurations were elucidated by spectral and chemical methods. All the compounds were examined for their inhibitory effects on the nitric oxide (NO) production induced by lipopolysaccharide (LPS) in RAW 264.7 macrophages, and compounds 1, 11, 13, and 17 exhibited pronounced inhibition with IC50 values in the range of 6.91-15.75µM, being more active than the positive control, quercetin (IC50=15.90µM).

Risk factors of nocturia (two or more voids per night) in Chinese people older than 40 years.

AIMS: To explore the risk factors of nocturia in Chinese inhabitants aged ≥40 years. METHODS: A randomized, community-based, cross-sectional study was performed on 10,160 inhabitants ≥40 years old in mainland China, via a stratified sampling approach. A questionnaire, including socio-demographics, lifestyle factors and medical history, was completed. Nocturia was defined as a threshold of two or more voids per night. Differences in prevalence between age and gender groups were ascertained by the chi-squared test. Gender-related factors were evaluated by multivariate logistic regression analysis. P < 0.05 was considered to be statistically significant. RESULTS: Data on 9,637 (94.9%) people aged 59.6 ± 9.7 years qualified for final statistical analysis. The overall prevalence of nocturia was 31.7% (3,053/9,637), and this increased with age (P < 0.001). Nocturia was significantly associated with cardiovascular disease and overactive bladder symptom score (OABSS) (P < 0.05), while sporting activities were protective (P < 0.001). Diabetes mellitus (DM) was significantly correlated with nocturia in men (P < 0.05), whereas hypertension was correlated with nocturia in women (P < 0.05). No correlation was found between nocturia and education level, occupation, civil status, tea consumption, body mass index (BMI), female birth history, and International Prostate Symptom Score. CONCLUSIONS: In Chinese people aged ≥40 years, nocturia is associated with aging, OABSS, cardiovascular disease, hypertension, and DM. Sporting activities are negatively associated with nocturia.