Na Jia

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).

Synergistic antinociception of propofol–alfentanil combination in mice

Drug combination is frequently used in pain treatment, which can produce similar analgesia with reduced dosage and side effects. In the present study, we examined the effects of co-administration of propofol, a general anesthetic, and alfentanil, an opioid analgesic drug, and the types of interactions between them in heat induced acute phasic and acetic-acid induced acute tonic pain models using the up-and-down method. In both pain models, alfentanil was administered in fixed-dose fractions of the 50% effective dose (ED50), and the types of interactions were determined by isobolographic analysis. In hot plate test, alfentanil (35.6-50.0 μg/kg, i.v.), propofol (6.5-15.5mg/kg, i.v.), and their combinations (80%, 50%, 30% and 10% of a single drug ED50) produce a significant, dose-dependent antinociception. In the tail-flick test, alfentanil (35.6-50.0 μg/kg, i.v.), propofol (5.0-14.3mg/kg, i.v.), and their combination significantly and dose dependently extend the tail-flick latency. In the acetic-acid induced writhing test, alfentanil (12.5-23.2 μg/kg, i.p.), propofol (15.0-28.5mg/kg, i.p.), and their combination significantly and dose dependently reduce the frequency of writhing. In all the above pain models, isobolographic analysis revealed a significant synergistic interaction between alfentanil and propofol, with about 4-fold reduction of doses of both drugs, in comparison with each single drugs ED50. These data suggest that the combination of alfentanil and propofol synergistically suppresses acute phasic and tonic pain in mice, indicating a potential application in pain treatment.

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.

Propofol Regulates the Surface Expression of GABAA Receptors: Implications in Synaptic Inhibition.

BACKGROUND:The anesthetic propofol is thought to induce rapid hypnotic sedation by potentiating &ggr;-aminobutyric acid receptor (GABAAR) activity. Little is known about the molecular mechanisms of propofol in modulating inhibitory synaptic transmission. We aimed to investigate the role of propofol in modulating surface expression of GABAARs. METHODS:C57BL/6 mice received an intraperitoneal injection of propofol. Hippocampal pyramidal neurons were prepared from embryonic day-18 mice and were treated with propofol. Proteins on the plasma membrane were analyzed using cell surface biotinylation, immunoblotting and enzyme-linked immunosorbent assay. Electrophysiological activities were recorded from hippocampal cells in acute brain slices of mice. The interaction between GABAARs and clathrin adaptor protein 2 was assessed by immunoprecipitation. Phosphorylation of GABAARs was shown by in vitro kinase assay. RESULTS:Propofol facilitated membrane accumulation of GABAAR&bgr;3 subunits. Propofol mediated phosphorylation of GABAAR&bgr;3 by protein kinase C&egr; which blocked the interaction between GABAAR&bgr;3 and the &bgr;-adaptin subunit of adaptor protein 2, resulting in an inhibition of the receptor endocytosis in hippocampal pyramidal neurons. Coincident with increased GABAARs surface level, propofol enhanced evoked and miniature synaptic GABA receptor currents. CONCLUSIONS:This study offers new insight on the regulatory mechanism of propofol in inhibiting neuronal excitability.

A new synthetic Cu(II) compound, [Cu3(p-3-bmb)2Cl4·(CH3OH)2]n, inhibits tumor growth in vivo and in vitro.

Copper(II) mixed-ligand complex, [Cu3(p-3-bmb)2Cl4 (CH3OH)2]n (Cu(II) compound), where p-3-bmb=1((2-(pyridine-3-yl)-1H-benzoimidazol-1-yl) methyl)-1Hbenzotriazole, has been recently found to possess potent anti-tumor activities both in vivo and in vitro. In this study, we demonstrated that Cu(II) compound significantly inhibited tumor growth in mice that inoculated with S180 cells. Meanwhile, the viabilities of HeLa and SGC-7901 cells were inhibited by Cu(II) compound with IC50 values in the range of 5-30 μM. Further mechanistic studies revealed that Cu(II) compound treatment induced cell cycle arrested at G1 phase through p53, p21, cyclinD1, cdk4, pRb and E2F1. Cu(II) compound treatment also induced apoptosis of HeLa and SGC-7901 cells which were accompanied with decrease in mitochondrial membrane potential, increase in reactive oxygen species production, release of cytochrome C, cleavage of caspase-9, caspase-3 and poly ADP-ribose polymerase (PARP) as well as activations of bcl-2 and bax. These results indicate that Cu(II) compound has a promising potential to become a novel anti-cancer agent.

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.

Chikusetsu saponin IVa regulates glucose uptake and fatty acid oxidation: implications in antihyperglycemic and hypolipidemic effects

The aim of this study is to investigate antidiabetic effects and molecular mechanisms of the chemical Chikusetsu saponin IVa (CHS) that isolated from root bark of Aralia taibaiensis, which has multiple pharmacological activity, such as relieving rheumatism, promoting blood circulation to arrest pain and antidiabetic action.

Aloe-Emodin Ameliorates Renal Fibrosis Via Inhibiting PI3K/Akt/mTOR Signaling Pathway In Vivo and In Vitro

Fibrosis is the major pathological feature of chronic kidney disease (CKD). Aloe-emodin (AE), one of the main active compounds in Rhubarb, is widely used for renal protection. However, mechanisms implied in the modulation of kidney fibrosis after AE treatment for CKD remain elusive. Here, we explored the protective effects of AE for renal fibrosis and the involved mechanisms in vivo and in vitro. The renal fibrosis mice model was established by unilateral ureteral obstruction (UUO). We found that AE administration significantly ameliorated UUO-induced impairment of kidney, evidenced by improved histopathological abnormalities, body weight, and abnormal renal function in mice model. Immunohistochemical staining showed that TGF-β1 and Fibronectin expressions were significantly decreased in UUO mice compared with sham group. Meanwhile, we found that AE suppressed the activation of the PI3K/Akt/mTOR pathway induced by TGF-β1 in vivo. AE improved cell survival and decreased the level of fibrosis-related proteins under TGF-β1-induced fibrosis in HK-2 cells as well as in vitro. Furthermore, both wortmannin, an inhibitor of PI3K, and short-hairpin RNAs of PI3K knockdown abrogated TGF-β1-induced phosphorylation of Akt and mTOR, and decreased the suppression of fibrosis. These findings indicated that AE alleviated fibrosis by inhibiting PI3K/Akt/mTOR pathway in vivo and in vitro, which may provide a potential therapeutic option for CKD.