Comparative Pharmacokinetic Study of Mangiferin in Normal and Alloxan-Induced Diabetic Rats after Oral and Intravenous Administration by UPLC-MS/MS.

BACKGROUNDS: Diabetes mellitus (DM)-induced morphological and/or functional complications may alter the pharmacokinetic profiles of mangiferin. This study aims to compare pharmacokinetic profiles of mangiferin in normal and alloxan-induced diabetic rats after oral and intravenous administration. METHODS: Mangiferin was administered orally (10 mg/kg) and intravenously (2 mg/kg) to normal and alloxan-induced diabetic Sprague-Dawley (SD) rats (n = 8). Blood samples were collected at different time points post-dose. Mangiferin and esculentoside (internal standard)  were analyzed by Waters Acquity ultra-performance liquid chromatography system and TSQ Quantum Ultra triple quadrupole mass spectrometer (UPLC-MS/MS). RESULTS: Mangiferin in normal and alloxan-induced diabetic rats experienced serious first-pass effect, which resulted in 1.71 and 0.80% of oral bioavailability respectively. Meanwhile, mangiferin was predominantly restricted to blood but not extensively distributed to organ tissues after intravenous administration. Compared with normal rats, the diabetic condition induced 53.26 and 50.90% decreases in Cmax and AUC0-t, respectively, for mangiferin after oral administration, and 63.08% decreases in Cmax after intravenous administration. CONCLUSIONS: Compared to normal rats, pharmacokinetic parameters of mangiferin were altered in diabetic condition induced by alloxan. The findings might help to provide useful evidence for modeling of diabetic rats and the clinical applications of mangiferin.

Cav-1 promotes atherosclerosis by activating JNK-associated signaling.

The objective of the study is to calculate the role and underlying the molecular mechanisms of caveolin-1 (Cav-1) in atherosclerosis (AS). Cav-1 was mainly expressed in the endothelial cells of atherosclerotic lesions in both human patients and apolipoprotein E deficient (ApoE-/-) mice. Cav-1 deficiency (Cav-1-/-) attenuated high-fat diet (HFD)-induced atherosclerotic lesions in ApoE-/- mice, supported by the reduced aortic plaques. Cav-1-/- reduced the macrophage content and decreased the release of inflammation-related cytokines or chemokine in serum or abdominal aortas, accompanied with the inactivation of inhibitor κB kinase κ (IKKß)/p65/IκBα signaling pathway. Also, the activity of mitogen-activated protein kinases 7/c-Jun-N-terminal kinase (MKK7/JNK) signaling was decreased by Cav-1-/-. In addition, oxidative stress induced by HFD in ApoE-/- mice was alleviated by Cav-1-/-. In response to HFD, Cav-1-/- markedly reduced triglyceride (TG), total cholesterol (TC), low-density lipoprotein-cholesterol (LDLC) and very low-density lipoprotein-cholesterol (VLDLC) in serum of HFD-fed ApoE-/- mice, whereas enhanced high-density lipoprotein-cholesterol (HDLC) contents. Consistent with these findings, haematoxylin and eosin (H&E) and Oil Red O staining showed fewer lipid droplets in the liver of Cav-1-deficient mice. Further, real time-quantitative PCR (RT-qPCR) analysis indicated that Cav-1-/- alleviated dyslipidemia both in liver and abdominal aortas of ApoE-/- mice fed with HFD. Cav-1 inhibition-induced attenuation of inflammatory response, oxidative stress and dyslipidemia were confirmed in vitro using mouse vascular smooth muscle cells (VSMCs) treated with ox-LDL. Surprisingly, the processes regulated by Cav-1-knockdown could be abolished through promoting JNK activation in ox-LDL-treated VSMCs. In conclusion, Cav-1 expression could promote HFD-induced AS in a JNK-dependent manner.

Long-term fructose consumption prolongs hepatic stearoyl-CoA desaturase 1 activity independent of upstream regulation in rats.

Dietary fructose is considered a risk factor for metabolic disorders, such as fatty liver disease. However, the mechanism underlying the effects of fructose is not well characterized. We investigated the hepatic expression of key regulatory genes related to lipid metabolism following fructose feeding under well-defined conditions. Rats were fed standard chow supplemented with 10% w/v fructose solution for 5 weeks, and killed after chow-fasting and fructose withdrawal (fasting) or chow-fasting and continued fructose (fructose alone) for 14 h. Hepatic deposition of triglycerides was found in rats from both groups. As expected, fructose alone increased mRNA levels of lipogenesis-related genes and correspondingly decreased mRNA levels of lipid oxidative genes in the liver. Interesting, hepatic levels of stearoyl-CoA desaturase (SCD)1 mRNA remained elevated under fructose withdrawn conditions, although expression levels of other genes, including two key transcription factors (carbohydrate response element binding protein (ChREBP) and sterol regulatory element-binding protein (SREBP)-1c) fell to normal levels, indicating that long-term fructose intake increased SCD1 activity, independent of upstream regulatory genes, such as ChREBP and SREBP-1c. In conclusion, SCD1 overexpression in fatty liver disease is not affected by fasting after long-term fructose consumption in rats. Regulation of SCD1 plays an important role in fructose-induced hepatic steatosis.

An updated comparison of high- and low-viscosity cement vertebroplasty in the treatment of osteoporotic thoracolumbar vertebral compression fractures: A retrospective cohort study.

OBJECTIVE: This study mainly aimed to evaluate complications of cement leakage for osteoporotic thoracolumbar vertebral compression fractures by PVP using HVC, and access the clinical efficacy. METHODS: Between May 2013 and June 2015, 66 patients with osteoporotic thoracolumbar vertebral compression fractures, who underwent PVP (36 HVC and 30 LVC) in our hospital, were enrolled. Cement leakage, Visual Analog Scale (VAS), Oswestry Disability Index (ODI), refracture of the cemented vertebrae, and adjacent vertebral fractures were evaluated. The follow-up time was 1 year. RESULTS: The overall cement leakage rate was 30.55% in the HVC group, lower than 77.77% obtained in the LVC group (P = 0.00). The incidence rates of cement leakage into paravertebral area (P = 0.02) and vein (P = 0.04) in the HVC group were significantly lower than those of the LVC group; however, no differences were found for disc space (P = 0.72) and intraspinal space (P = 0.58). There were no differences in VAS, ODI, refracture of cemented vertebrae, and adjacent vertebral fracture between the two groups (P > 0.05). CONCLUSIONS: PVP using HVC not only can reduce cement leakage, especially in the paravertebral area and peripheral vein, but also has satisfactory clinical effect.

Allicin induces the upregulation of ABCA1 expression via PPARγ/LXRα signaling in THP-1 macrophage-derived foam cells.

Allicin is considered anti-atherosclerotic due to its antioxidant and anti-inflammatory effects, which makes it an important drug for the prevention and treatment of atherosclerosis. However, the effects of allicin on foam cells are unclear. Thus, in this study, we examined the effects of allicin on lipid accumulation via peroxisome proliferator-activated receptor Î³ (PPARγ)/liver X receptor α (LXRα) in THP­1 macrophage-derived foam cells. THP­1 cells were exposed to 100 nM phorbol myristate acetate (PMA) for 24 h, and then to oxydized low-density lipoprotein (ox-LDL; 50 mg/ml) to induce foam cell formation. The results of Oil Red O staining and high-performance liquid chromatography (HPLC) revealed showed that pre-treatment of the foam cells with allicin decreased total cholesterol, free cholesterol (FC) and cholesterol ester levels in cells, and also decreased lipid accumulation. Moreover, allicin upregulated ATP binding cassette transporter A1 (ABCA1) expression and promoted cholesterol efflux. However, these effects were significantly abolished by transfection with siRNA targeting ABCA1. Furthermore, PPARγ/LXRα signaling was activated by allicin treatment. The allicin-induced upregulation of ABCA1 expression was also abolished by PPARγ inhibitor (GW9662) and siRNA or LXRα siRNA co-treatment. Overall, our data demonstrate that the allicin-induced upregulation of ABCA1 promotes cholesterol efflux and reduces lipid accumulation via PPARγ/LXRα signaling in THP­1 macrophage-derived foam cells.

[Protective effects of total alkaloids from rhizoma Coptis chinensis on alcohol-induced gastric lesion in rats].

OBJECTIVE: To study the effects of total alkaloids(TA) from rhizoma Coptis chinensis on alcohol-induced gastric lesion in rats and the possible mechanisms. METHOD: The experimental gastric damges were established by intragastric(ig) absolute ethanol, and possible protective effects of TA given orally previously were evaluated by following parameters: gastric damage indexes, gastric juice volume, acidity, and mucus quantity. The contents of NO, MDA, *OH, and SOD activity were also measured in gastric mucosa. RESULT: TA showed significantly inhibitive effects on gastric damages induced by ig ethanol in a dose dependent manner. The effects of TA (120 mg x kg(-1)) were stronger than that of both cimitidine(70 mg x kg(-1)) and berberine(100 mg x kg(-1)), the quantity of later was equal to TA as calculated with berberine. TA significantly suppressed secretion of gastric acid caused by ethanol without clear influences on gastric juice volume and mucus secretion. TA obviously blunted ethanol-induced elevation of MDA and *OH, as well as decrease of NO level and SOD activity from gastric mucosa. CONCLUSION: It is suggested that the TA is a potent protective agent against ethanol-induced gastric damages. The mechanism of actions may be related with inhibiting the secretion of gastric acid and blunting the increase of MDA and *OH, as well as the decrease of NO level and SOD activity from gastric mucus.

Curcumin enhanced cholesterol efflux by upregulating ABCA1 expression through AMPK-SIRT1-LXRα signaling in THP-1 macrophage-derived foam cells.

Curcumin, a traditional Chinese derivative from the rhizomes of Curcuma longa, is beneficial to health by modulating lipid metabolism and suppressing atherogenesis. A key part of atherosclerosis is the failure of macrophages to restore their cellular cholesterol homeostasis and the formation of foam cells. In this study, results showed that curcumin dramatically increased the expression of ATP-binding cassette transporter 1 (ABCA1), promoted cholesterol efflux from THP-1 macrophage-derived foam cells, and reduced cellular cholesterol levels. Curcumin activated AMP-activated protein kinase (AMPK) and SIRT1, and then activated LXRα in THP-1 macrophage-derived foam cells. Inhibiting AMPK/SIRT1 activity by its specific inhibitor or by small interfering RNA could inhibit LXRα activation and abolish curcumin-induced ABCA1 expression and cholesterol efflux. Thus, curcumin enhanced cholesterol efflux by upregulating ABCA1 expression through activating AMPK-SIRT1-LXRα signaling in THP-1 macrophage-derived foam cells. This study describes a possible mechanism for understanding the antiatherogenic effects of curcumin on attenuating the progression of atherosclerosis.