Jia Cui

Antihyperglycemic, hypolipidemic and antioxidant activities of total saponins extracted from Aralia taibaiensis in experimental type 2 diabetic rats.

ETHNOPHARMACOLOGICAL RELEVANCE As a well-known traditional Chinese medicine the root bark of Aralia taibaiensis has multiple pharmacological activities, including relieving rheumatism, promoting blood circulation to arrest pain, inducing diuresis to reduce edema, and antidiabetic action. It has long been used as a folk medicine for the treatment of traumatic injury, rheumatic arthralgia, nephritis, edema, hepatitis and diabetes mellitus in China. AIM OF STUDY To evaluate the antihyperglycemic, hypolipidemic and antioxidant activities of total saponins extracted from Aralia taibaiensis (SAT) in experimental type 2 diabetic mellitus (T2DM) rats. MATERIALS AND METHODS Acute toxicity was studied in rats to determine the safe oral dose of SAT. Then, SAT was given orally to normal and streptozotocin-nicotinamide induced T2DM rats at 80, 160 and 320 mg/kg doses for a series of 28 days to determine the antihyperglycemic activity. Glibenclamide (600 μg/kg), a standard antidiabetic drug, was used as a positive control drug. At the end of treatment, biochemical parameters and antioxidant levels were measured to evaluate the hypolipidemic and antioxidant activities of SAT. RESULTS Oral administration of SAT did not exhibit toxicity and death at a dose not more than 2000 mg/kg. SAT dose-dependently improved the symptoms of polydipsia, polyuria, polyphagia and weight loss in diabetic rats. Compared with diabetic control group, administration of 320 mg/kg SAT resulted in significant (P<0.05) fall in the levels of fasting blood glucose, glycosylated hemoglobin, creatinine, urea, alanine transarninase, aspartate aminotransferase, total cholesterol, triglycerides, low density lipoprotein cholesterol and malondialdehyde, but significant (P<0.05) increase in the levels of serum insulin, superoxide dismutase and reduced glutathione. However, SAT did not have any effect on the normal rats. CONCLUSIONS SAT had excellent antihyperglycemic, hypolipidemic and antioxidant activities in T2DM rats and might be a promising drug in the therapy of diabetes mellitus and its complications.

Protective effect of butin against ischemia/reperfusion-induced myocardial injury in diabetic mice: involvement of the AMPK/GSK-3β/Nrf2 signaling pathway.

Hyperglycemia-induced reactive oxygen species (ROS) generation contributes to development of diabetic cardiomyopathy (DCM). This study was designed to determine the effect of an antioxidant butin (BUT) on ischemia/reperfusion-induced myocardial injury in diabetic mice. Myocardial ischemia/reperfusion (MI/R) was induced in C57/BL6J diabetes mice. Infarct size and cardiac function were detected. For in vitro study, H9c2 cells were used. To clarify the mechanisms, proteases inhibitors or siRNA were used. Proteins levels were investigated by Western blotting. In diabetes MI/R model, BUT significantly alleviated myocardial infarction and improved heart function, together with prevented diabetes-induced cardiac oxidative damage. The expression of Nrf2, AMPK, AKT and GSK-3β were significantly increased by BUT. Furthermore, in cultured H9c2 cardiac cells silencing Nrf2 gene with its siRNA abolished the BUT’s prevention of I/R-induced myocardial injury. Inhibition of AMPK and AKT signaling by relative inhibitor or specific siRNA decreased the level of BUT-induced Nrf2 expression, and diminished the protective effects of BUT. The interplay relationship between GSK-3β and Nrf2 was also verified with relative overexpression and inhibitors. Our findings indicated that BUT protected against I/R-induced ROS-mediated apoptosis by upregulating the AMPK/Akt/GSK-3β pathway, which further activated Nrf2-regulated antioxidant enzymes in diabetic cardiomyocytes exposed to I/R.

Aralia taibaiensis Protects Cardiac Myocytes against High Glucose-Induced Oxidative Stress and Apoptosis.

Patients with type 2 diabetes have increased cardiovascular disease risk compared with those without diabetes. Hyperglycemia can induce reactive oxygen species (ROS) generation, which contributes to the development of diabetic cardiomyopathy. Our previous study has demonstrated that the total saponins of Aralia taibaiensis (sAT), a frequently-used antidiabetic medicine in traditional Chinese medicine (TCM), can scavenge free radicals in vitro and have good anti-oxidant ability on lipid peroxidation of rat liver microsomes. This work was designed to investigate whether sAT could protect the heart while it was used in the treatment of diabetes. Oxidative stress was induced in H9c2 cells by high glucose (33 mM) and glucose oxidase (15 mU, G/GO) and the protective effects of sAT were evaluated. Treatment of H9c2 cells with G/GO resulted in an increase in cell death, intracellular ROS level and cell oxidative injury, which were markedly reduced by sAT treatment. Further study revealed that sAT induced the nuclear translocation of Nrf2 and expression of its downstream targets. Moreover, Nrf2 siRNA markedly abolished the cytoprotective effects of sAT. sAT exerted cytoprotective effects against oxidative stress induced by hyperglycemia and the cardioprotective effects of sAT might be through the Nrf2/ARE pathway. Thus, sAT might be a promising candidate for the treatment of diabetic cardiomyopathy.

Safflor yellow A protects neonatal rat cardiomyocytes against anoxia/reoxygenation injury in vitro.

Aim:To investigate the effects of safflor yellow A (SYA), a flavonoid extracted from Carthamus tinctorius L, on cultured rat cardiomyocytes exposed to anoxia/reoxygenation (A/R).Methods:Primary cultured neonatal rat cardiomyocytes were exposed to anoxia for 3 h followed by reoxygenation for 6 h. The cell viability was measured using MTT assay. The releases of lactate dehydrogenase (LDH) and creatine kinase (CK), level of malondialdehyde (MDA), and activities of glutathione (GSH), superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px) were analyzed. Hoechst 33258 staining and changes in Bcl-2/Bax ratio and caspase 3 activity were used to examine A/R-induced apoptosis.Results:The A/R exposure markedly decreased the viability of cardiomyocytes, suppressed the activities of SOD, GSH, CAT and GSH-Px, and Bcl-2 protein expression. Meanwhile, the A/R exposure markedly increased the release of LDH and CK, and MDA production in the cardiomyocytes, and increased the rate of apoptosis, caspase 3 activity, Bax protein expression. Pretreatment with SYA (40, 60 and 80 nmol/L) concentration-dependently blocked the A/R-induced changes in the cardiomyocytes. Pretreatment of the cardiomyocytes with the antioxidant N-acetylcysteine (NAC, 200 μmol/L) produced protective effects that were comparable to those caused by SYA (80 nmol/L).Conclusion:SYA protects cultured rat cardiomyocytes against A/R injury, maybe via inhibiting cellular oxidative stress and apoptosis.

Iridoid glycosides from the flowers of Gentiana macrophylla Pall. ameliorate collagen-induced arthritis in rats

BACKGROUND The flowers of Gentiana macrophylla have been usually applied to cure the joint inflammation and rheumatoid arthritis in Traditional Chinese Medicine. HYPOTHESIS/PURPOSE This work aimed to investigate the anti-rheumatoid arthritic effect and possible mechanism of iridoid glycosides from G. macrophylla (GMI) using an animal model of collagen-induced rheumatoid arthritis (CIA) in rats. STUDY DESIGN All rats were randomly divided into five groups: normal control, CIA, dexamethasone, 15mg/kg and 30mg/kg GMI. METHODS CIA was induced (day 0) in male Sprague-Dawley rats by intradermal injection of complete Bovine CII at the base of the tail. Dexamethasone was chosen as the positive drug. The administration of different drugs started from day 1 and continued for 28 days. Paw swelling, arthritis score and histopathological changes were examined to assess the severity of arthritis. In addition, the serum levels of tumor necrosis factor α (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), and cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) expressions in joint synovial tissues were detected. RESULTS GMI reduced paw edema, arthritis scores and the index of spleen and thymus from day 7 to 21 after CIA compared with those in the CIA group. Our data also demonstrated that GMI inhibited pro-inflammatory cytokines such as TNF-α, IL-1β and IL-6, regulated the expression of iNOS and COX-2 compared with those in the CIA group. We also obtained four major components from GMI, identified as loganic acid, swertamarin, gentiopicroside and sweroside, and the contents of them were also calculated respectively. CONCLUSION Taken together, our results shed light on the therapeutic efficacy of GMI in rats rheumatoid arthritis model by reducing the levels of IL-1β, IL-6 and TNF-α in serum as well as down-regulating the levels of iNOS and COX-2. Therefore, GMI may be an effective therapy for the treatment of rheumatoid arthritis.

Insulin-secretagogue activity of eleven plant extracts and twelve pure compounds isolated from Aralia taibaiensis.

AIMS To investigate the insulinogenic activities of the eleven saponins enriched traditional Chinese medicine (TCM) extracts. MAIN METHODS Radioimmunoassay and trypan blue exclusion assay were used to investigate the insulinogenic activity and cytotoxic effects respectively. KEY FINDINGS The total saponin extract of Aralia taibaiensis (sAT) exhibited highest insulinogenic activity and no cytotoxicity was recorded. Twelve pure compounds from sAT stimulated insulin secretion from a mouse insulinoma βTC3 cells in a concentration-dependent manner. TA35 outperformed the other compounds which suggested that the active insulinogenic ingredient of sAT was probably TA35. In addition, both sAT and TA35 markedly potentiated glucose-induced insulin secretion. SIGNIFICANCE Our study is the first to show that sAT dramatically stimulated insulin secretion and its antidiabetic activity may be related to its high saponin content. These findings suggested that sAT and the compound TA35 isolated from sAT may provide novel therapeutic tools for the treatment of non-insulin dependent diabetes mellitus (NIDDM).

Regulatory Mechanisms of Annexin-Induced Chemotherapy Resistance in Cisplatin Resistant Lung Adenocarcinoma

Adenocarcinoma of lung has high incidence and a poor prognosis, woith chemotherapy as the main therapeutic tool, most commonly with cisplatin. However, chemotherapy resistance develops in the majority of patients during clinic treatment. Mechanisms of resistance are complex and still unclear. Although annexin play important roles in various tumor resistance mechanisms, their actions in cisplatin-resistant lung adenocarcinoma remain unclear. Preliminary studies by our group found that in cisplatin-resistant lung cancer A549 cells and lung adenocarcinoma tissues, both mRNA and protein expression of annexins A1, A2 and A3 is increased. Using a library of annexin A1, A2 and A3 targeting combined molecules already established by ourselves we found that specific targeting decreased cisplatin-resistance. Taken together, the underlined effects of annexins A1, A2 and A3 on drug resistance and suggest molecular mechanisms in cisplatin-resistant A549 cells both in vivo and in vitro. Furthermore, the study points to improved research on occurrence and development of lung adenocarcinoma, with provision of effective targets and programmes for lung adenocarcinoma therapy in the clinic.

Chikusetsu saponin IVa confers cardioprotection via SIRT1/ERK1/2 and Homer1a pathway

Hyperglycemia-induced reactive oxygen species (ROS) generation and Ca2+ overload contribute to the development of diabetic cardiomyopathy. In this study, we aimed to study the protective effects of Chikusetsu saponin IVa (CHS) from Aralia taibaiensis against hyperglycemia-induced myocardial injuries. Treatment of H9c2 cells with high glucose (HG) for 24 h resulted in a loss of cell viability and increase of ROS, LDH and Ca2+ levels, and also induced cell apoptosis, and those changes were all markedly reversed by the administration of CHS. In further studies, CHS dose-dependently increased the expression of Homer1a, ERK1/2 and SIRT1 in both H9c2 cells and rat primary cardiomyocytes. However, transfection of Homer1a-specific siRNA abolished the ability of CHS in controlling the ROS and Ca2+ homeostasis. Moreover, specific SIRT1 inhibitors or siRNA significantly suppressed the enhanced phosphorylation of ERK1/2 and expression of Homer1a induced by CHS as well as its cytoprotective effect. CHS induced Homer1a expression was also suppressed by siERK1/2. Additionally, results in diabetic mice also showed that CHS protected myocardium from I/R-introduced apoptosis by activating the SIRT1/ERK1/2/Homer1a pathway. These results demonstrated that CHS protected against hyperglycemia-induced myocardial injury through SIRT1/ERK1/2 and Homer1a pathway in vivo and in vitro.

The Effects of a Propofol/Alfentanil Admixture on Total Intravenous Anaesthesia in Dogs undergoing Splenectomy

The aim of this study was to compare the cardiovascular and respiratory effects and the bispectral scale index (BIS) as well as the recovery period characteristics in response to treatment with a propofol/alfentanil admixture of different concentrations in dogs undergoing splenectomy. We conducted a prospective, randomised, blinded experimental trial. Anaesthesia was induced and maintained by continuous-infusion anaesthesia of propofol and alfentanil or a propofol/alfentanil admixture after premedication with acepromazine (0.03 mg/kg). Dogs were assigned to receive different concentrations of the admixture. Changes in BIS value, heart rate (HR), respiratory rate (f R ), non-invasive arterial blood pressure, pulse oximetry (SpO 2 ), end-tidal carbon dioxide concentrations (ETCO 2 ) and rectal temperature (RT) were recorded at predefined time points during anaesthesia. Data [mean ± standard deviation (SD)] were analysed by analysis of variance (ANOVA) for repeated measures followed by a Dunnetts test and Students t-test (P <0.05) and where necessary, the Mann-Whitney U-test. No significant differences were found between groups with respect to age, body mass, SpO 2 , ETCO 2 , f R , systolic, diastolic and mean arterial blood pressure (SAP, DAP and MAP). BIS values were significantly lower in Group 2 when compared to Group 1 at T7, T8, T9. The HR of Group 2 was significantly lower at T2 to T9 when compared to Group 1. The propofol and alfentanil admixture provided satisfactory results in dogs undergoing splenectomy. Thus, an admixture of propofol/alfentanil may be used for total IV anaesthesia in dogs at the infusion rates determined in this study.

Insulinotropic effect of Chikusetsu saponin IVa in diabetic rats and pancreatic β-cells

ETHNOPHARMACOLOGICAL RELEVANCE As a well-known traditional Chinese medicine the root bark of Aralia taibaiensis has traditionally been used as the medicine considered alleviating several disorders including diabetes mellitus (DM). Chikusetsu saponin IVa (CHS) has been defined as a major active ingredient of triterpenoid saponins extracted from Aralia taibaiensis. The scientific evidence of anti-diabetic effect for CHS remains unknown and the purpose of our study was to study its hypoglycemic and insulin secretagogue activities. MATERIALS AND METHODS In vivo studies were performed on type 2 diabetic mellitus (T2DM) rats given CHS for 28 days to test the antihyperglycemic activity. The in vitro effects and possible mechanisms of CHS on the insulin secretion in pancreatic β-cell line βTC3 were determined. RESULTS Oral administration of CHS dose-dependently increased the level of serum insulin and decreased the rise in blood glucose level in an in vivo treatment. In vitro, CHS potently stimulated the release of insulin from βTC3 cells at both basal and stimulatory glucose concentrations, the effect which was changed by the removal of extracellular Ca(2+). Two methods showed that CHS enhanced the intracellular calcium levels in βTC3 cells. CHS was capable of enhancing the phosphorylation of extracellular signal-regulated protein kinases C (PKC), which could be reversed by a PKC inhibitor (RO320432), and the insulin secretion induced by CHS was also inhibited by RO320432. Further study also showed that the insulinotropic effect, intracellular calcium levels and the phosphorylation of PKC were reduced by inhibiting G protein-coupled receptor 40 (GPR40) by a GPR40 inhibitor (DC126026). CONCLUSION These observations suggest that the signaling of CHS-induced insulin secretion from βTC3 cells via GPR40 mediated calcium and PKC pathways and thus CHS might be developed into a new potential for therapeutic agent used in T2DM patients.