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Objective:To take zebrafish embryo as the research object, in order to investigate the development toxicity, cardiotoxicity, liver toxicity and kidney toxicity of water extract of Jiaotaiwan (JTW) on zebrafish embryo. Method:Zebrafish embryos with normal development at 12 h (hpf) after fertilization were selected as model animals for the growth and cardiotoxicity experiments. The embryos were treated with 125, 250, 500 mg·L-1 of JTW water extracts, and the effects of the drugs on the heart rate and morphology of the embryos and LD50 were observed at 72 h (hpf) after fertilization. Zebrafish embryos with normal development at 72 h (hpf) after fertilization were used as model animals for the liver and kidney toxicity experiments. The embryos were treated with 125，250，500 mg·L-1 of JTW water extracts, and the effect of the drugs on morphological changes, Alanine aminotransferase(ALT), Aspartate aminotransferase (AST) activity, and creatinine content of the larvae and LD50 were observed at 72 d (dpf) after fertilization. Result:The zebrafish embryos in control group developed normally, the heart was well developed, and the heartbeat was even and powerful. The LD50 of JTW water extract on zebrafish embryos for 72 h was 1 023 mg·L-1. Compared with the embryos in the control group, 250，500 mg·L-1 treatment groups in the development toxicity had a smaller head, shorter body lengths (P<0.05), and decreased eye size (P<0.05). Compared with the control group embryos, the pericardial edema was observed in the 500 mg·L-1 group, the heart rate was significantly decreased in the 250，500 mg·L-1 JTW water extract groups (P<0.01), the atrial and ventricular areas were significantly reduced (P<0.05), the distance of SV-BA became significantly larger (P<0.05), the distance of AV channel became significantly larger (P<0.01), and the in-flow distance was significantly shorter (P<0.01). In the acute toxicity experiment, the LD50 of JTW water extract for zebrafish larvae for 72 h was 1 067 mg·L-1. Compared with control group, JTW water extract significantly reduced ALT activity in zebrafish larvae (P<0.05). Conclusion:This experiment found that JTW has an obvious toxicity in embryonic development, which is mainly manifested as delayed growth and severe cardiotoxicity. Great attention shall be paid to clinical administration to pregnant women, lactating women and patients with heart disease.
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Objective: Jiaotaiwan is a classic prescription in traditional Chinese medicine for insomnia. Modern clinical research has proved its anti-diabetes effect by "the same treatment for different diseases" theory, so it is necessary to study its pharmacological mechanism for anti-diabetes effect. Method: In this study, the integrative pharmacology platform of traditional Chinese medicine (TCMIP) was used to explore the potential target and mechanism of Jiaotaiwan, and construct its core target network for diabetes. Then the enrich analysis of GO and KEGG on key targets was conducted to build the visual multilayer association network of "Jiaotaiwan-active composition-core target-key pathway". Result:28 active ingredients were obtained from Jiaotaiwan in this study. Its anti-diabetes effect was relevant to 187 core targets,including 15 known disease targets such as vasopressin V2 receptor (AVPR2), receptor activity-modifying protein 1 (RAMP1), receptor activity-modifying protein 3 (RAMP3), insulin receptor (INSR), and insulin-like growth factor 1 receptor (IGF1R); as well as 71 predictive drug targets such as cyclin-dependent kinase 9 (CDK9), glucokinase (GCK), NF-kappa-B inhibitor alpha (NFKBIA), NF-kappa-B p100 subunit (NFKB2), and hypoxia inducible factor-1 alpha (HIF1A). Conclusion:The anti-diabetes mechanism of Jiaotaiwan may be associated with activation of adenylate cyclase activity, cellular response to glucagon stimulus, activation of mitogen-activated protein kinase (MAPK) activity, endocrine system, gonadotropin-releasing hormone (GnRH) signaling pathway, Chemokine signaling pathway, phosphatidylinositol 3-kinase-serine/threonine kinases (PI3K-Akt) signaling pathway and other related biological processes and pathways. This study provides a scientific evidence for further study of the anti-diabetes mechanism of Jiaotaiwan.
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Objective: To explore effect and mechanism of Jiaotaiwan (JTW) on cognitive impairment in diabetic mice. Method: The 40 db/db mice of spontaneous diabetes were randomly divided into model group, JTW 1 group (1.68 g·kg-1), JTW 2 group (3.36 g·kg-1), and JTW 3 group (8.40 g·kg-1), with 8 mice in each group, and 8 C57BL/6J mice were included into normal group. After 8 weeks of treatment, behavioral test,fasting blood glucose (FBG), fasting insulin (Fins), insulin resistance index (HOMA-IR), total triglyceride (TG), total cholesterol (TC), free fatty acids (FFA), high density lipoprotein (HDL), and low density lipoprotein (LDL) were detected. Western blot was used to detect protein expressions of pSer199, pSer202, pSer214, p-Akt, glycogen synthase kinase-3β(GSK-3β), phospho-GSK-3β(p-GSK-3β). Result: Compared with model group, FBG, Fins, HOMA-IR, TG, TC, HDL, FFA in JTW group decreased significantly (P0.01), with a significant improvement in cognitive function (P0.01), protein expressions of taupSer199, pSer202, pSer214 and GSK-3β in hippocampus of mice decreased significantly (PP0.01), and expressions of p-Akt and p-GSK3 beta significantly increased (P0.01). Conclusion: JTW 3 (Coptidis Rhizoma-Cinnamomi Cortex 10:1) can alleviate insulin resistance and cognitive impairment. The mechanism may be related to the inhibition of over-phosphorylation of tau protein, the down-regulation of GSK-3β protein expression and the up-regulation of p-Akt and p-GSK-3β expressions.
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This study aims to explore the effect and mechanism of Jiao-tai-wan (JTW) on systemic and tissue-specific inflammation and insulin resistance in obesity-resistant (OR)rats with chronic partial sleep deprivation (PSD).OR rats with PSD were orally given JTW and Estazolam for 4 weeks.The amount of food intake and metabolic parameters such as body weight increase rate,fasting plasma glucose (FPG),fasting insulin (FINS),homeostasis model assessment-insulin resistance (HOMA-IR) and plasma inflammatory markers were measured.The expression levels of circadian proteins cryptochrome 1 (Cry1)and cryptochrome 2 (Cry2) in hypothalamus,adipose and liver tissues were also determined.Meanwhile,the mRNA expression of inflammatory markers,activity of nuclear factor kappa B (NF-κB) p65 protein,as well as the expression levels of insulin signaling pathway proteins in hypothalamus,adipose and liver tissues were measured.Additionally,cyclic adenosine 3',5'-monophosphate (cAMP) and activity of vasodilator-stimulated phosphoprotein (VASP)in hypothalamus tissue were measured.JTW significantly decreased the body weight increase rate and food intake,ameliorated systemic inflammation and insulin resistance.JTW effectively ameliorated inflammation and increased PI3K/AKT signaling activation in hypothalamus,adipose and liver.Interestingly,all these changes were associated with the up-regulation of circadian gene Cryl and Cry2 protein expression.We also found that in hypothalamus tissue of P SD rats,down-regulation of Cry 1 and Cry2 activated cAMP/PKA signaling and then led to inflammation,while JTW inhibited this signaling.These results suggested that JTW has the beneficial effect on ameliorating inflammation and insulin resistance in partially sleep-deprived rats by up-regulating Cry expression.
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This study aims to explore the effect and mechanism of Jiao-tai-wan (JTW) on systemic and tissue-specific inflammation and insulin resistance in obesity-resistant (OR)rats with chronic partial sleep deprivation (PSD).OR rats with PSD were orally given JTW and Estazolam for 4 weeks.The amount of food intake and metabolic parameters such as body weight increase rate,fasting plasma glucose (FPG),fasting insulin (FINS),homeostasis model assessment-insulin resistance (HOMA-IR) and plasma inflammatory markers were measured.The expression levels of circadian proteins cryptochrome 1 (Cry1)and cryptochrome 2 (Cry2) in hypothalamus,adipose and liver tissues were also determined.Meanwhile,the mRNA expression of inflammatory markers,activity of nuclear factor kappa B (NF-κB) p65 protein,as well as the expression levels of insulin signaling pathway proteins in hypothalamus,adipose and liver tissues were measured.Additionally,cyclic adenosine 3',5'-monophosphate (cAMP) and activity of vasodilator-stimulated phosphoprotein (VASP)in hypothalamus tissue were measured.JTW significantly decreased the body weight increase rate and food intake,ameliorated systemic inflammation and insulin resistance.JTW effectively ameliorated inflammation and increased PI3K/AKT signaling activation in hypothalamus,adipose and liver.Interestingly,all these changes were associated with the up-regulation of circadian gene Cryl and Cry2 protein expression.We also found that in hypothalamus tissue of P SD rats,down-regulation of Cry 1 and Cry2 activated cAMP/PKA signaling and then led to inflammation,while JTW inhibited this signaling.These results suggested that JTW has the beneficial effect on ameliorating inflammation and insulin resistance in partially sleep-deprived rats by up-regulating Cry expression.
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<p><b>OBJECTIVE</b>To explore the effect and mechanism of Jiaotai Pill (, JTW) on intestinal mucosal damage in rats with chronic partial sleep deprivation (PSD).</p><p><b>METHODS</b>Obesity resistant (OR) rats were selected, and underwent 4 h PSD by being exposed to environmental noise for 4 weeks. During the whole PSD period, JTW and estazolam were orally given to the rats respectively in the treating groups. Plasma concentration of lipopolysaccharide (LPS) which is the marker of gut-origin endotoxemia was examined. Intestinal morphology changes were observed by optical microscopy. The protein expression of occludin (Ocln) in the intestine was measured by immunofluorescence technique and Western blot. The expressions of circadian proteins cryptochromes (Cry1 and Cry2) in the intestine were also determined.</p><p><b>RESULTS</b>The treatment of JTW significantly decreased LPS level in OR rats with PSD (P<0.05). JTW also attenuated insomnia-induced intestinal injury like shorter, sparse and incomplete villus, wide gap between the villus, mucosal swelling and congesting (P<0.05). These changes were associated with the effect of JTW on up-regulating the expressions of Cry1 protein, Cry2 protein and Ocln protein in the intestine.</p><p><b>CONCLUSIONS</b>JTW has the beneficial effect on improving intestinal mucosal damage caused by PSD. The mechanism appears to be related to the modulation of the expressions of circadian proteins and Ocln protein in the intestine, thereby attenuating inflammation and improving insulin resistance in insomnia rats.</p>
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The effects of Cinnamon granules on pharmacokinetics of berberine in Rhizoma Coptidis granules in healthy male volunteers,and the compatibility mechanism of Jiao-Tai-Wan (JTW) composed of Rhizoma Coptidis granules and Cinnamon granules were investigated.The concentration of berberine in plasma of healthy male volunteers was determined directly by high performance liquid chromatography (HPLC) after an oral administration of Rhizoma Coptidis granules alone or combined with Cinnamon granules (JTW).The plasma concentration-time curves of berberine were plotted.The data were analyzed with Drug and Statistics (DAS) 2.0 pharmacokinetic program (Chinese Pharmacology Society)to obtain the main pharmacokinetic parameters.The results showed that the plasma concentration-time curve of berberine was described by a two-compartment model.The Cmax,Tmax,t1/2 and CLz/F of berberine in Rhizoma Coptidis granules were 360.883 μg/L,2.0 h,3.882 h,119.320 L·h-1·kg-1 respectively,and those of berberine in JTW were 396.124 μg/L,1.5 h,4.727 h,57.709 L·h-1·kg-1 respectively.It was suggested that Rhizoma Coptidis granules combined with Cinnamon granules could increase the plasma concentration of berberine,promote berberine absorption and lengthen the detention time of berberine in healthy male volunteers.