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1. Diabetes is often accompanied with depression and hypercholesterolemia. It is possible that paroxetine and pravastatin are co-administered to diabetic patients. The aim of this study was to research the differential effect of pravastatin on plasma exposure of paroxetine in normal and diabetic rats. 2. Pharmacokinetics of paroxetine was investigated following oral administration of paroxetine with and without pravastatin in normal and diabetic rats. Effects of pravastatin on metabolism, intestinal absorption and hepatic uptake of paroxetine were investigated. Activity and expression of hepatic Oatp1 and Oatp2 were also assessed. 3. Pravastatin decreased plasma exposure of paroxetine in normal rats, but increased exposure of paroxetine in diabetic rats. Pravastatin neither affected metabolism nor intestinal absorption of paroxetine. Data from hepatocytes demonstrated that hepatic uptake of paroxetine were involved in Oatp1 and Oatp2. Diabetes suppressed Oatp1 activity and expression, but enhanced Oatp2 activity and expression. Pravastatin stimulated Oatp1 but inhibited Oatp2 activity. 4. We concluded that differential effects of pravastatin on plasma exposure of paroxetine in normal and diabetic rats was partly due to the fact that diabetes suppressed Oatp1 activity and expression but enhanced Oatp2 activity and expression as well as that pravastatin stimulated Oatp1 activity but inhibited Oatp2 activity. [ABSTRACT FROM AUTHOR]

Hyponatremia is a common condition encountered in clinical practice. A number of studies have associated low serum sodium levels with increased mortality in various patient populations, such as hospitalized patients and patients with various comorbid conditions; recent studies have shown that individuals with chronic kidney disease also are afflicted by hyponatremia. However, few studies have focused on patients with hemodialysis. Evidence supporting the incidence and prevalence of hyponatremia, clinical characteristics and the association with patient outcomes with hemodialysis is limited. In the present review, we examined the physiology and pathophysiology of water and sodium balance with a special emphasis on changes occurring during end-stage renal disease. The outcomes in patients undergoing hemodialysis were associated with low serum sodium. We evaluated the associations between hyponatremia and mineral bone abnormalities and discussed the elevated incidence and prevalence of difficult clinical outcomes associated with hyponatremia. We also provided specific recommendations for hemodialysis treatment in hyponatremic patients. [ABSTRACT FROM AUTHOR]

1. Liver distribution and systemic exposure of pravastatin were the determinant factors of efficacy and toxicity of pravastatin. Aim of the present study was to investigate the effect of paroxetine on the liver distribution and systemic exposure of pravastatin in diabetic rats induced by combining high fat diet (HFD) and low-dose streptozotocin (STZ). 2. Plasma concentrations and liver distribution of pravastatin were measured in the presence of paroxetine. Effect of paroxetine on pravastatin excretionviabile, intestine, feces and urine, as well as pravastatin absorptionviaintestine was documented. Freshly isolated hepatocytes and Caco-2 cells were used to investigate the effect of paroxetine on pravastatin transport. 3. Paroxetine increased the systemic exposure of pravastatin and decreased hepatic distribution of pravastatin in diabetic rats.In vitro, paroxetine inhibited the hepatic uptake of pravastatin and promoted the efflux of pravastatin in freshly isolated hepatocytes, which may partly explain the decreased hepatic distribution of pravastatin by paroxetine. It was also observed that paroxetine promoted the absorption of pravastatinviajejunum and the uptake of pravastatin in Caco-2 cells. 4. We concluded that paroxetine increased the systemic exposure of pravastatin partlyviapromoting absorptionviajejunum and inhibiting hepatic uptake of pravastatin. [ABSTRACT FROM PUBLISHER]

Aim:Simvastatin is frequently administered to diabetic patients with hypercholesterolemia. The aim of the study was to investigate the pharmacokinetics of simvastatin and its hydrolysate simvastatin acid in a rat model of type 2 diabetes.Methods:Diabetes was induced in 4-week-old rats by a treatment of high-fat diet combined with streptozotocin. After the rats received a single dose of simvastatin (20 mg/kg, po, or 2 mg/kg, iv), the plasma concentrations of simvastatin and simvastatin acid were determined. Simvastatin metabolism and cytochrome P4503A (Cyp3a) activity were assessed in hepatic microsomes, and its uptake was studied in freshly isolated hepatocytes. The expression of Cyp3a1, organic anion transporting polypeptide 2 (Oatp2), multidrug resistance-associated protein 2 (Mrp2) and breast cancer resistance protein (Bcrp) in livers was measured using qRT-PCR.Results:After oral or intravenous administration, the plasma concentrations and areas under concentrations of simvastatin and simvastatin acid were markedly decreased in diabetic rats. Both simvastatin metabolism and Cyp3a activity were markedly increased in hepatocytes of diabetic rats, accompanied by increased expression of hepatic Cyp3a1 mRNA. Furthermore, the uptake of simvastatin by hepatocytes of diabetic rats was markedly increased, which was associated with increased expression of the influx transporter Oatp2, and decreased expression of the efflux transporters Mrp2 and Bcrp.Conclusion:Diabetes enhances the metabolism of simvastatin and simvastatin acid in rats via up-regulating hepatic Cyp3a activity and expression and increasing hepatic uptake. [ABSTRACT FROM AUTHOR]

Objectives Plant sterols are thought to treat hypercholesterolemia via inhibiting intestinal cholesterol absorption. The aim of this study was to evaluate the contribution of impaired ATP-binding cassette transporter G5/8 ( ABCG5/8) expression by diabetes to the increased β-sitosterol ( BS) exposure and impact of increased BS on integrity of blood-brain barrier ( BBB). Methods Basal BS level in tissues of streptozotocin-inducted rats and ABCG5/8 protein levels in liver and intestine were investigated; pharmacokinetics of BS was studied following oral dose; and primarily cultured rat brain microvessel endothelial cells ( rBMECs) were used to study BS transportation across BBB and effect of BS on BBB integrity. Key findings Diabetic rats showed greatly upgraded basal levels of BS in plasma, intestine, cerebral and hippocampus, accompanied by impairment of ABCG5/8 protein expression in liver and intestine. Pharmacokinetics studies demonstrated higher AUC0-48 and Cmax, and lower faecal recoveries of BS after oral administration, indicating enhancement of absorption or efflux impairment. In-vitro data showed increased ratio of BS/cholesterol in high levels BS-treated rBMECs was associated with increased BBB permeability of some biomarkers including BS itself. Conclusions Impaired ABCG5/8 protein expression by diabetes led to increase in BS exposure, which may be harmful to BBB function. [ABSTRACT FROM AUTHOR]

Abstract: Aim of study: The fruit of Melia toosendan Sieb. et Zucc. (MTF) is a traditional Chinese herbal medicine in the treatment of stomachache and many acute or chronic inflammations, as well as ascariasis. This paper aimed to investigate the anti-inflammatory and analgesic activities of the MTF extract and two main limonoid-type triterpenoids isolated from MTF. Materials and methods: The ethanolic extract of MTF and two limonoids, isotoosendanin (1) and 1-O-tigloyl-1-O-debenzoylohchinal (2) were evaluated for their anti-inflammatory and analgesic activities. Acetic acid-induced vascular permeability and λ-carrageenan-induced hind paw edema tests in mice were used to investigate anti-inflammatory activity; and acetic acid-induced writhing and hot-plate tests in mice were used to determine analgesic effect. Results: Both the ethanolic extract and two limonoids displayed significant anti-inflammatory effects. Although the ethanolic extract showed remarkable analgesic effects in both writhing and hot-plate tests, the two limonoids had analgesic effects just in writhing test. Conclusion: The results suggested that the ethanolic extract of MTF had obvious anti-inflammatory and analgesic activities, and the two limonoids were the active constituents contributing to the anti-inflammatory and analgesic effects of MTF. [Copyright &y& Elsevier]

Baibutang (BBT) is an ancient prescription for the treatment of pulmonary fibrosis. Previous experiments have shown that BBT had a good therapeutic effect on pulmonary fibrosis. However, there had been no study on the synergy between drugs composed of BBT. Due to the interaction between the constituent drugs, exploring their synergy profile is of great significance for explaining the essence of BBT's efficacy in improving pulmonary fibrosis. Based on the pharmacodynamic value, this study aimed to explore a method for the evaluation of the synergy profile between constituent drugs in traditional Chinese medicine (TCM) compounds. Nine herbs of BBT were divided into Zhikeqingre (ZK), Yangyinyiqi (YY) and Lishijianpi (LS) groups. A rat model of Yin -deficiency pulmonary fibrosis induced by thyroxine-bleomycin was used to evaluate the effects of BBT and the three groups. The pathological changes of lung tissue and the changes of biomarkers associated with fibrosis, Yin -deficiency and water-fluid metabolism were detected. After standardization of pharmacodynamics value (PV), the compatibility coefficient (CC) of the three groups, the relative PV (RPV) and contribution value (CV) of each group on every index were calculated. The average CC on fibrosis indexes was 0.44, indicating that 44% of the efficacy of BBT came from the synergistic effect of the three groups. ZK group had the highest RPV (0.80) in improving fibrosis indexes such as histopathological changes, α-SMA, collagen-I and renin-angiotensin system. The average CC on Yin -deficiency indexes was 0.25, and YY group had the highest RPV (0.96) in improving deficiency indexes such as body temperature, cAMP/cGMP ratio, and PDEs, PGE2 and COX-2 levels. The average CC on water-fluid metabolism indexes was 0.15, and LS group had the highest RPV (1.52) in improving water-fluid metabolism indexes such as aquaporins, mucins, and surfactant proteins. The results also showed that 29% of the improvement effect of BBT on all indexes came from the synergistic effect of the three groups, and the contribution of ZK, YY and LS groups to the efficacy of BBT were 25%, 25% and 21%, respectively. The established semiquantitative method can clearly and simply evaluate the synergy of the three groups in BBT, which will help to promote the research on the synergy of TCM compounds and other multiple-components combinations. [Display omitted] • The nine herbs of Baibutang (BBT) was divided into three functional groups. • BBT was superior to any of the above groups in improving lung fibrosis (same dose). • Synergy of the three groups in BBT was evaluated by compatibility coefficient (CC). • An average CC of 0.44 indicated that the synergy accounted for 44% of the BBT effect. [ABSTRACT FROM AUTHOR]

Neotuberostemonine (NTS) is one of the main antitussive alkaloids in the root of Stemona tuberosa Lour. This study aimed to investigate the effects of NTS on bleomycin (BLM)-induced pulmonary fibrosis in mice and the underlying mechanism. After BLM administration, NTS were orally administered to mice at 20 and 40 mg/kg per day from days 8 to 21, with nintedanib as a positive control. The effect of NTS on BLM-induced mice was assessed via histopathological examination by HE and Masson's trichrome staining, TGF-β1 level and macrophage recruitment by immunohistochemical staining, expression of profibrotic media and M1/M2 polarization by western blot. RAW 264.7 cells were used to evaluate whether NTS (1, 10, 100 μM) directly affected macrophages. The results revealed that NTS treatment significantly ameliorated lung histopathological changes and decreased inflammatory cell counts in the bronchoalveolar lavage fluid. The over-expression of collagen, α-SMA and TGF-β1 was reduced by NTS. Furthermore, NTS markedly lowered the expression of MMP-2 and TIMP-1 while raised the expression of MMP-9. A further analysis showed that NTS was able to decrease the recruitment of macrophages and to inhibit the M2 polarization in mice lung tissues. The experiment in vitro showed that NTS significantly reduced the arginase-1 (marker for M2) expression in a dose-dependent manner but down-regulated the iNOS (marker for M1) expression only at 100 μM. In conclusion, our study demonstrated for the first time that NTS has a significant protective effect on BLM-induced pulmonary fibrosis through suppressing the recruitment and M2 polarization of macrophages. [ABSTRACT FROM AUTHOR]

Astins (including astin B) are a class of halogenated cyclic pentapeptides isolated from the medicinal herb of Aster tataricus . However, our previous works showed that the herbal medicine was hepatotoxic in vivo , and a toxicity-guided isolation method led to the identification of a cyclopeptide astin B. Astin B is structurally similar to cyclochlorotine, a well-known hepatotoxic mycotoxin. Thus, the aim of this study was to determine the potential cytotoxic effects and the underlying mechanism of astin B on human normal liver L-02 cells. We found that astin B has hepatotoxic effects in vitro and in vivo and that hepatic injury was primarily mediated by apoptosis in a mitochondria/caspase-dependent manner. Astin B provoked oxidative stress-associated inflammation in hepatocytes as evidenced by increased levels of reactive oxygen species (ROS), reduced contents of intracellular glutathione (GSH), and enhanced phosphorylation of c-Jun N-terminal kinase (JNK). Furthermore, the mitochondria-dependent apoptosis was evidenced by the depolarization of the mitochondrial membrane potential, the release of cytochrome c into cytosol, the increased ratio of Bax/Bcl-2, and the increased activities of caspases-9 and -3. Interestingly, astin B treatment also induces autophagy in L-02 cells, characterized by acidic-vesicle fluorescence, increased LC3-II and decreased p62 expression. Autophagy is a protective mechanism that is used to protect cells from apoptosis. The presence of autophagy is further supported by the increased cytotoxicity and the enhanced cleaved caspase-3 after co-treatment of cells with an autophagy inhibitor, also by increased LC3-II and decreased p62 after co-treatment with a caspase inhibitor. Taken together, astin B, most likely together with other members of astins, is the substance that is primarily responsible for the hepatotoxicity of A . tat a ricus . [ABSTRACT FROM AUTHOR]