Tamoxifen upregulates the peroxisomal ß-oxidation enzyme Enoyl CoA hydratase and 3-hydroxyacyl CoA hydratase ameliorating hepatic lipid accumulation in mice.

Tamoxifen is an estrogen receptor modulator that has been reported to alleviate hepatic lipid accumulation in mice, but the mechanism is still unclear. Peroxisome fatty acid ß-oxidation is the main metabolic pathway for the overload of long-chain fatty acids. As long-chain fatty acids are a cause of hepatic lipid accumulation, the activation of peroxisome fatty acid ß-oxidation might be a novel therapeutic strategy for metabolic associated fatty liver disease. In this study, we investigated the mechanism of tamoxifen against hepatic lipid accumulation based on the activation of peroxisome fatty acid ß-oxidation. Tamoxifen reduced liver long-chain fatty acids and relieved hepatic lipid accumulation in high fat diet mice without sex difference. In vitro, tamoxifen protected primary hepatocytes against palmitic acid-induced lipotoxicity. Mechanistically, the RNA-sequence of hepatocytes isolated from the liver revealed that peroxisome fatty acid ß-oxidation was activated by tamoxifen. Protein and mRNA expression of enoyl CoA hydratase and 3-hydroxyacyl CoA hydratase were significantly increased in vivo and in vitro. Small interfering RNA enoyl CoA hydratase and 3-hydroxyacyl CoA hydratase in primary hepatocytes abolished the therapeutic effects of tamoxifen in lipid accumulation. In conclusion, our results indicated that tamoxifen could relieve hepatic lipid accumulation in high fat diet mice based on the activation of enoyl CoA hydratase and 3-hydroxyacyl CoA hydratase-mediated peroxisome fatty acids ß-oxidation.

Obeticholic acid protects against lithocholic acid-induced exogenous cell apoptosis during cholestatic liver injury.

AIMS: Lithocholic acid (LCA)-induced cholestasis was accompanied by the occurrence of apoptosis, which indicated that anti-apoptosis was a therapeutic strategy for primary biliary cholangitis (PBC). As an agonist of (Farnesoid X receptor) FXR, we supposed that the hepatoprotection of Obeticholic acid (OCA) against cholestatic liver injury is related to anti-apoptosis beside of the bile acids (BAs) regulation. Herein, we explored the non-metabolic regulating mechanism of OCA for resisting LCA-induced cholestatic liver injury via anti-apoptosis. MAIN METHODS: LCA-induced cholestatic liver injury mice were pretreated with OCA to evaluate its hepatoprotective effect and mechanism. Biochemical and pathological indicators were used to detect the protective effect of OCA on LCA-induced cholestatic liver injury. The bile acids (BAs) profile in serum was detected by LC-MS/MS. Hepatocyte BAs metabolism, apoptosis and inflammation related genes and proteins alteration were investigated by biochemical determination. KEY FINDINGS: OCA improved LCA-induced cholestasis and hepatic apoptosis in mice. The BA profile in serum was changed by OCA mainly manifested as a reduction of taurine-conjugated bile acids, which was due to the upregulation of FXR-related bile acid efflux transporters bile salt export pump (BSEP), multi-drug resistant associated protein 2 (MRP2), MRP3 and multi-drug resistance 3 (MDR3). Apoptosis related proteins cleaved caspase-3, cleaved caspase-8 and cleaved PARP were obviously reduced after OCA treatment. SIGNIFICANCE: OCA improved LCA-induced cholestatic liver injury via FXR-induced exogenous cell apoptosis, which will provide new evidence for the application of OCA to ameliorate PBC in clinical.

Hyperoside ameliorates cisplatin-induced acute kidney injury by regulating the expression and function of Oat1.

Cisplatin is a widely used chemotherapeutic agent to treat solid tumours in clinics. However, cisplatin-induced acute kidney injury (AKI) limits its clinical application. This study investigated the effect of hyperoside (a flavonol glycoside compound) on regulating AKI.The model of cisplatin-induced AKI was established, and hyperoside was preadministered to investigate its effect on improving kidney injury.Hyperoside ameliorated renal pathological damage, reduced the accumulation of SCr, BUN, Kim-1 and indoxyl sulphate in vivo, increased the excretion of indoxyl sulphate into the urine, and upregulated the expression of renal organic anion transporter 1 (Oat1). Moreover, evaluation of rat kidney slices demonstrated that hyperoside promoted the uptake of PAH (p-aminohippurate, the Oat1 substrate), which was confirmed by transient over-expression of OAT1 in HEK-293T cells. Additionally, hyperoside upregulated the mRNA expression of Oat1 upstream regulators hepatocyte nuclear factor-1α (HNF-1α) and pregnane X receptor (PXR).These findings indicated hyperoside could protect against cisplatin-induced AKI by promoting indoxyl sulphate excretion through regulating the expression and function of Oat1, suggesting hyperoside may offer a potential tactic for cisplatin-induced AKI treatment.

Association between dinner timing and glucose metabolism in rural China: A large-scale cross-sectional study.

OBJECTIVES: Meal timing is a major risk factor for metabolic disease. The aim of this study was to assess the relationship between dinner timing and glucose metabolism in the rural Chinese population. METHODS: This cross-sectional study included 7701 participants from a Henan rural cohort study. Basic information was collected by in-person questionnaires. Multiple linear regression analysis was used to evaluate the relationship between dinner timing and fasting insulin (FINS), fasting plasma glucose (FPG), and homeostatic model assessment for insulin resistance (HOMA-IR). Restricted cubic spline was employed to investigate the dose-response relationship between dinner timing and FINS, FPG, and HOMA-IR. A generalized linear model was used to explore the interaction effect of age and dinner timing on FINS, FPG, and HOMA-IR. RESULTS: After adjusting for confounding factors, FINS concentration was reduced by 0.482 mmol/L (P < 0.001) for each hour delay in dinner timing. Furthermore, the HOMA-IR index decreased by 0.122 mmol/L for each hour delay. The results indicated a noticeable trend of decreasing values associated with later dinner timing (FINS: Poverall association < 0.001, Pnonlinear association = 0.144; HOMA-IR: Poverall association = 0.001, Pnonlinear association = 0.186). The interaction between age and dinner time significantly correlated with FINS and HOMA-IR (P < 0.05). This relationship was statistically significant before 69 y (P < 0.05). CONCLUSION: A significant association between dinner timing and glucose metabolism was observed in the rural Chinese population. Delayed dinner timing may be associated with lower fasting insulin. The negative effect of dinner timing on FINS and HOMA-IR was diminished with age.

8-methoxypsoralen protects against acetaminophen-induced liver injury by antagonising Cyp2e1 in mice.

This study aimed to investigate the effect and mechanism of 8-methoxypsoralen (8-MOP) on acetaminophen (APAP)-induced hepatotoxicity in mice. The study found that 1 h after intraperitoneal injection of 300 mg/kg APAP, treatment with 40 mg/kg, 80 mg/kg and 120 mg/kg 8-MOP could reduce serum transaminase level and histopathological liver necrosis area. Elevated mRNA expression of liver inflammatory mediators caused by excessive APAP was also reversed. 8-MOP significantly reduced APAP-induced hepatotoxicity dose-dependently, and the highest therapeutic dose of 8-MOP (120 mg/kg) had no harmful effects on the liver. Cocktail probe assay revealed that 8-MOP can inhibit Cyp2e1 enzymatic activities of mice, thereby reducing the production of acetaminophen-cysteine (APAP-CYS), a toxic metabolite of APAP. 8-MOP had no significant effect on the protein and gene expression of Cyp2e1. The three-dimensional structures of mouse Cyp2e1 were constructed by homologous modeling. Molecular docking showed that 8-MOP had a good binding effect on the enzyme activity site of Cyp2e1. In summary, 8-MOP dose-dependently attenuated APAP-induced hepatotoxicity by binding to Cyp2e1 and occupying the active center of the enzyme, thus competitively inhibiting the oxidative metabolism of APAP, and reducing the generation of toxic product APAP-CYS.

Glycocholic acid aggravates liver fibrosis by promoting the up-regulation of connective tissue growth factor in hepatocytes.

AIMS: The precise role of bile acid in the progression of liver fibrosis has yet to be elucidated. In this study, common bile duct ligation was used as an in vivo mouse model for the evaluation of bile acids that promote liver connective tissue growth factor expression. MAIN METHODS: Primary rat and mice hepatocytes, as well as primary rat hepatic stellate and HepaRG cells were evaluated as in vitro models for promoting the expression of connective tissue growth factor by bile acids. KEY FINDINGS: Compared with taurochenodeoxycholic acid, glycochenodeoxycholic acid, and taurocholic acid, glycocholic acid (GCA) most strongly promoted the secretion of connective tissue growth factor in mouse primary hepatocytes, rat primary hepatocytes and HepaRGs. GCA did not directly promote the activation of hepatic stellate cells. The administration of GCA in mice with ligated bile ducts promotes the progression of liver fibrosis, which may promote the yes-associated protein of hepatocytes into the nucleus, resulting in the hepatocytes secreting more connective tissue growth factor for hepatic stellate cell activation. In conclusion, our data showed that GCA can induce the expression of connective tissue growth factor in hepatocytes by promoting the nuclear translocation of yes-associated protein, thereby activating hepatic stellate cells. SIGNIFICANCE: Our findings help to elucidate the contribution of GCA to the progression of hepatic fibrosis in cholestatic disease and aid the clinical monitoring of cholestatic liver fibrosis development.

Proteomics analysis reveals novel insights into the mechanism of hepatotoxicity induced by Tripterygium wilfordii multiglycoside in mice.

Tripterygium wilfordii multiglycoside (GTW), extracted and purified from the peeled roots of T. wilfordii Hook.f. (TwHF), is a well-known traditional Chinese medicine and applied to various autoimmune diseases clinically. However, it has been reported to cause severe liver injury. At present, the mechanism underlying GTW-induced hepatotoxicity remain poorly defined. Here, we evaluated the effects of GTW on mouse liver and elucidated the associated mechanisms via label-free proteomics combined with bioinformatics analysis. Male C57BL/6J mice were randomly divided into normal group, a low-dose GTW (70 mg/kg) group and a high-dose GTW (140 mg/kg) group. After 1-week administration, GTW dose-dependently induced hepatotoxicity. Further analysis showed that GTW could act on the intestinal immune network for IgA production pathway, which plays an important role in maintaining intestinal homeostasis and influences the crosstalk between gut and liver. Western blots confirmed that GTW could decrease pIgR protein expression in the liver and ileum, and, as a result, the secretion of IgA into gut lumen was reduced. Further validation showed that intestinal barrier integrity was impaired in GTW-treated mice, promoting bacteria transferring to the liver and triggering proinflammatory response. Our study demonstrated that gut-liver axis may play a vital part in the progression of GTW-induced hepatotoxicity, which provides guidance for basic research and clinical application of GTW.

Influence of Zhuanggu Guanjie Pill on Seven Cytochrome P450 Enzymes Based on Probe Cocktail and Pharmacokinetics Approaches.

BACKGROUND: The use of herbal medicines has tremendously increased over the past few decades. Case reports and controlled clinical investigations of herbal-drug interactions have been reported. Since Cytochrome P450 (CYP) enzymes play an important role in drug interactions. The evaluation of the influence of herbal medicines on the activities of CYPs is beneficial to promote scientific and rational clinical use of herbal medicines. OBJECTIVE: Herein, we aimed to develop and validate a method to simultaneously quantify seven CYP cocktail probe drugs consisting of phenacetin (PNC), bupropion (BPP), losartan potassium (LK), omeprazole (OMP), dextromethorphan (DM), chlorzoxazone (CZZ) and midazolam (MDZ) and their respective metabolites in a single acquisition run and use this method to evaluate the influence of Zhuanggu Guanjie Pill (ZGGJP) on seven CYPs. METHODS: A cost-effective and simple UHPLC-(±)ESI-MS/MS method for simultaneous determination of seven probe drugs and metabolites in rat plasma was developed and validated. Male and female rats were randomly divided into three groups and treated with 1.2 g/kg/d ZGGJP, 5 g/kg/d ZGGJP and 0.5% CMC-Na for 14 consecutive days. After 24 h of the last administration, all rats were administrated orally with probe drugs. The influence of ZGGJP on the CYPs was carried out by comparing the metabolic ratio (Cmax, AUC0-t) of metabolites/probe drugs in rats. RESULTS: The calibration curves were linear, with correlation coefficient > 0.99 for seven probe drugs and their corresponding metabolites. Intra- and inter-day precisions were not greater than 15% RSD and the accuracies were within ±15% of nominal concentrations. The ZGGJP showed significant inductive effect on CYP1A2, CYP2B6, CYP2C9 and CYP3A in male and female rats. CONCLUSION: ZGGJP had inductive effects on CYP1A2, CYP2B6, CYP2C9 and CYP3A in male and female rats.

Sex differences in the association between dinner-bedtime interval and abdominal obesity: a large-scale cross-sectional study.

PURPOSE: Dinner-bedtime interval was reported to be associated with general obesity. However, the association between dinner-bedtime interval and abdominal obesity is still unclear. This study was conducted to investigate the association of dinner-bedtime interval and abdominal obesity. METHODS: A total of 7600 participants from Henan rural cohort study were included in this study. A standard questionnaire was used to obtain the time of dinner and sleep by the way of face-to-face interview. Sleep quality of each participant was evaluated by Pittsburgh Sleep Quality Index. Logistic regression and restricted cubic spline were used to assess the association between dinner-bedtime interval and abdominal obesity. Line regression was used to estimate the association between dinner-bedtime interval and lipid metabolism indexes. The mediation effect of sleep quality on the relationship between dinner-bedtime interval and abdominal obesity was evaluated. RESULTS: In male, increased dinner-bedtime interval was associated with abdominal obesity risk (Adjusted OR: 1.084, 95% CI 1.009-1.164). Compared with participants with dinner-bedtime interval ≤ 2 h, those dinner-bedtime interval > 2 h had an elevated risk of abdominal obesity (Adjusted OR: 1.199, 95% CI 1.009-1.425). In addition, a positive linear dose-response relationship was detected between dinner-bedtime interval and abdominal obesity. Moreover, total cholesterol concentration increased by 0.047 mmol/L for each 1-h increase in dinner-bedtime interval (P = 0.019). In addition, sleep quality mediated 11.45% of the relationship between dinner-bedtime interval and abdominal obesity (adjusted mediation effect: - 0.010, 95% CI - 0.019 to - 0.003). But in female, these associations were not significant. CONCLUSION: It is suggested that increased dinner-bedtime interval was related to a higher risk of abdominal obesity in rural China and this association was differed by sex. LEVEL OF EVIDENCE: Level V: cross-sectional descriptive study.

[Determination of concentrations and toxicokinetics of triptolide in plasma and liver of mice by UHPLC-MS/MS].

This study aims to establish an ultra-high performance liquid chromatography-tandem mass spectrometry(UHPLC-MS/MS) method for determining the concentrations of triptolide(TP) in plasma and liver, and to explore the toxicokinetics of TP and the relationship between TP exposure and liver injury in C57 BL/6 mice, so as to provide reference for dissecting the toxicity mechanism of TP. The liquid chromatography was conducted with ZORBAX SB-C_(18) column(3.0 mm×100 mm, 3.5 µm) and the mobile phase of methanol-0.05 mmol·L~(-1) ammonium acetate. Electrospray ionization(ESI) and multiple reaction monitoring(MRM) mode were employed for mass spectrometry. After oral administration of TP(toxic dose 600 µg·kg~(-1)), the blood and liver tissues of the C57 BL/6 mice were collected at different time points to measure the TP concentrations in plasma and liver tissues. Furthermore, the blood biochemical indexes, including alkaline phosphatase(ALP), alanine aminotransferase(ALT), aspartate aminotransferase(AST), and total bile acid(TBA), were determined. After being processed by DAS 2.0, the experiment data showed that the TP in mice had the toxicokinetic parameters of T_(max)=5 min, C_(max)=14.38 ng·mL~(-1), t_(1/2)=0.76 h, AUC_(0-t)=5.63 h·ng·mL~(-1), MRT_(0-t)=0.56 h, and CL_(Z/F)=103.19 L·h~(-1)·kg~(-1). The trend of TP concentration in mouse liver tissue was consistent with that in plasma. The concentration of TP peaked at the time point of 5 min and then decreased until TP was completely metabolized. The plasma biochemical indexes(ALT, AST, ALP, and TBA) showed no significant changes within 3 h after TP administration. TP had high clearance rate and short residence time and did not significantly increase the blood biochemical indexes in mice. The results suggested that the exposure amount of free TP in vivo cannot directly cause liver injury, which might be caused by the binding of TP to some substances or the stimulation of inflammation and immune response.

Comparison of bile acids profiles in the enterohepatic circulation system of mice and rats.

Bile acids (BAs) were selected as biomarkers for the diagnosis and prevention of multiple liver diseases, and they were also considered as an important signal transductor via "liver-gut" axis. As important factors for maintaining the normal function and tissue morphology, BA homeostasis throughout the enterohepatic circulation system was guaranteed by BA synthases and transporters, nuclear receptors (NRs) and gut microbiota, all of which presented significant species differences. Thus, we simultaneously quantify BA profiles in the enterohepatic circulation of SD rats and C57BL/6 mice to reveal the species differences of BA homeostasis between these two main rodents of preclinical studies. Our results showed that BA profiles of mice plasma, bile and liver were most dissimilar from these of rats. Meanwhile, BAs profiles also presented obvious species differences in the intestine of mice and rats, especially small intestine. Unlike rats, taurine-conjugated bile acids (T-BAs) were predominant in mice small intestine content and tissue, in which taurocholic acid (TCA) was the most prominent BAs. BAs dynamic analysis showed that compared with rats, mice showed stranger taurine and glycine de-conjugations in lager intestine. However, both the ratios of unconjugated bile acids (Un-BAs) to conjugated BAs, and secondary BAs to primary BAs in mice small content and tissue were all much lower than these in rats. Furthermore, ileum BAs profiles also showed significantly separation trend between rats and mice, whether content or tissue. Our data revealed that the patterns of BAs homeostasis in mice enterohepatic circulation system were significantly different from these in rats (especially in intestine), suggesting that more cautious should be paid to the selection of BAs as biomarkers for disease diagnosis or/and drug induced toxicity, and the certain role and mechanism of individual BA in the pathological process of BA-related diseases via "liver-gut" axis should be verified by using of multiple species.

Study on the effects of Zhuanggu Guanjie Pill, a modern Chinese medicine formula, on the activities and mRNA expression of seven CYP isozymes in rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Zhuanggu Guanjie Pill (ZGGJP), a modern Chinese medicine formula, is composed of 12 herbs and has been used to treat osteoporosis in China for almost 30 years. However, no in vivo study of the influences of ZGGJP on the cytochrome P450 (CYP) activities have been reported. AIM OF THE STUDY: The aim of this study was to evaluate the effects of ZGGJP on the activities and the mRNA expression of CYP enzymes (CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A) and their corresponding nuclear receptor levels in rats. MATERIALS AND METHODS: After 7 days oral treatment of ZGGJP at low- and high-dose, cocktail solution was given to rats. Blood samples were collected at series of time points. The plasma concentrations of probe drugs and their corresponding metabolites were determined by UPLC-MS/MS. The influence of ZGGJP on the activities of seven CYPs were evaluated the metabolic ratios (Cmax and AUC0-t) for metabolites/probe drugs. In addition, the effects of ZGGJP on the mRNA expression of CYPs and their corresponding nuclear receptors in rat liver were evaluated by real-time PCR. RESULTS: ZGGJP showed significant inductive effects on CYP1A2 and CYP2B6 of both male and female rats. The influence of ZGGJP on CYP2C9 and CYP3A showed gender difference. ZGGJP could induce the activities of CYP2C9 and CYP3A in female rats, but have no influence on the activities in male rats. ZGGJP had no effects on CYP2D6, CYP2C19 and CYP2E1. The mRNA expression results of CYPs were in accordance with the pharmacokinetic results. The mRNA expression levels of constitutive androstane receptor (CAR) and vitamin D receptor (VDR) were increased significantly in female rats at high dosage, but no significant changes were observed in male rats. CONCLUSION: ZGGJP had inductive effects on CYP1A2 and CYP2B6 in both male and female rats. The results showed that ZGGJP could induce the activities of CYP2C9 and CYP3A in female rats, but had no effect in male rats. This may suggest that the influence of ZGGJP on CYP2C9 and CYP3A exhibit gender difference. The inductive effects of ZGGJP on the activities of CYPs, exhibiting gender difference, may be regulated by CAR and VDR. Therefore, co-administration of ZGGJP with other drugs, especially using CYP2C9 and CYP3A substrates in females, may need dose adjustment to avoid herb-drug interaction.

SEW2871 attenuates ANIT-induced hepatotoxicity by protecting liver barrier function via sphingosine 1-phosphate receptor-1-mediated AMPK signaling pathway.

Cholestatic liver injury, a group of diseases characterized with dysregulated bile acid (BA) homeostasis, was partly resulted from BA circulation disorders, which is commonly associated with the damage of hepatocyte barrier function. However, the underlying hepatocyte barrier-protective molecular mechanisms of cholestatic liver injury remain poorly understood. Interestingly, recent studies have shown that sphingosine-1-phosphate (S1P) participated in the process of cholestasis by activating its G protein-coupled receptors S1PRs, regaining the integrity of hepatocyte tight junctions (TJs). Here, we showed that SEW2871, a selective agonist of sphingosine-1-phosphate receptor 1(S1PR1), alleviated ANIT-induced TJs damage in 3D-cultured mice primary hepatocytes. Molecular mechanism studies indicated that AMPK signaling pathways was involved in TJs protection of SEW2871 in ANIT-induced hepatobiliary barrier function deficiency. AMPK antagonist compound C (CC) and agonist AICAR were all used to further identify the important role of AMPK signaling pathway in SEW2871's TJs protection of ANIT-treated mice primary hepatocytes. The in vivo data showed that SEW2871 ameliorated ANIT-induced cholestatic hepatotoxicity. Further protection mechanism research demonstrated that SEW2871 not only regained hepatocyte TJs by the upregulated S1PR1 via AMPK signaling pathway, but also recovered hepatobiliary barrier function deficiency, which was verified by the restored BA homeostasis by using of high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS). These results revealed that the increased expression of S1PR1 induced by SEW2871 could ameliorate ANIT-induced cholestatic liver injury through improving liver barrier function via AMPK signaling and subsequently reversed the disrupted BA homeostasis. Our study provided strong evidence that S1PR1 may be a promising therapeutic approach for treating intrahepatic cholestatic liver injury. Graphical abstract.

A prospective study on the treatment of immediate post-operative scar with narrowband intense pulsed light under polarized dermoscopy.

(a) To evaluate the efficacy and safety of narrow-band intense-pulsed light (DPL) in immediate post-operative scar. (b) To observe the process of scar formation under dermoscopy in the first 6 months. Nine patients with postoperative scars were enrolled in the randomized, prospective, split-scar study. Patients were treated in one half of the scar with DPL for cosmetic improvement at a wavelength of 500-600 nm and the other half was not treated as control. The laser treatments were initiated 2 weeks after the surgery and were given 3 times over a 4-week period. All patients were followed-up for 3 months from the last treatment. Photographs and dermoscopy digital images were collected each time. (a) Neither DPL or control produce statistically significant improvements in Vancouver Scar Scale. Moreover, comparatively, there was no statistical difference in Vancouver Scar Scale between DPL or control. However, 6 out of 9 patients treated with DPL had reduced scores in vascularity sooner compared with control. (b) Under dermoscopy, redness, and swelling were obvious from 2 weeks after surgery, but were gradually alleviated. The surface of the scar gradually became uneven and rough. DPL might be beneficial in early recovery of immediate post-operative scar.

Sphingosine 1-phosphate receptor-1 specific agonist SEW2871 ameliorates ANIT-induced dysregulation of bile acid homeostasis in mice plasma and liver.

Dysregulated bile acid (BA) homeostasis is an extremely significant pathological phenomenon of intrahepatic cholestasis, and the accumulated BA could further trigger hepatocyte injury. Here, we showed that the expression of sphingosine-1-phosphate receptor 1 (S1PR1) was down-regulated by α-naphthylisothiocyanate (ANIT) in vivo and in vitro. The up-regulated S1PR1 induced by SEW2871 (a specific agonist of S1PR1) could improve ANIT-induced deficiency of hepatocyte tight junctions (TJs), cholestatic liver injury and the disrupted BA homeostasis in mice. BA metabolic profiles showed that SEW2871 not only reversed the disruption of plasma BA homeostasis, but also alleviated BA accumulation in the liver of ANIT-treated mice. Further quantitative analysis of 19 BAs showed that ANIT increased almost all BAs in mice plasma and liver, all of which were restored by SEW2871. Our data demonstrated that the top performing BAs were taurine conjugated bile acids (T-), especially taurocholic acid (TCA). Molecular mechanism studies indicated that BA transporters, synthetase, and BAs nuclear receptors (NRs) might be the important factors that maintained BA homeostasis by SEW2871 in ANIT-induced cholestasis. In conclusion, these results demonstrated that S1PR1 selective agonists might be the novel and potential effective agents for the treatment of intrahepatic cholestasis by recovering dysregulated BA homeostasis.

Efficacy and safety of Qinzhuliangxue decoction for treating atopic eczema: a randomized controlled trial.

BACKGROUND: Atopic eczema is the most common type of skin disorder in both children and adults. It is characterized by erythema, pruritus, papules, xeransis, and lichenification. Qinzhuliangxue decoction (QZLXD), a Chinese herbal medicine (CHM) prepared with several ingredients that are used to treat eczema, was formulated according to the traditional Chinese medicine (TCM) theory. This study aimed to investigate the efficacy and safety of QZLXD administration for treating atopic eczema compared to those of Runzaozhiyang capsules (RZZYC). METHODS: A total of 176 patients were enrolled at the Shanghai Yueyang Hospital and were randomly assigned to the QZLXD treatment group (n=82) or the RZZYC control group (n=86). The differences in Eczema Area and Severity Index (EASI), Dermatology Life Quality Index, itching score, recurrence rate, and adverse events (AEs) were compared between the groups. RESULTS: The EASI score (x2=14.181, P=0.003), recurrence rate (x2=7.398, P=0.007), and itching score (F=-3.427, P=0.001) were lower in the QZLXD group than in the RZZYC group. Incidence of AEs was similar between the RZZYC and QZLXD groups (P=0.434). CONCLUSIONS: QZLXD is recommended for the treatment of subacute atopic eczema because QZLXD showed good efficiency with low recurrence rate and tolerable AEs.

Exploration and Preparation of a Dose-Flexible Regulation System for Levetiracetam Tablets via Novel Semi-Solid Extrusion Three-Dimensional Printing.

Levetiracetam therapy is often associated with high levels of individual variation in the recommended dose required to achieve preferential treatment. Thus, a reliable and dynamic regulation system to accurately tailor dose is necessary. The main objective of this study is to explore and prepare a dose-flexible control system suitable for rapid release tablets equipped with high drug loading and a cylindrical model design. Semi-solid extrusion 3-dimensional printing was utilized to fabricate a series of tablets of increased volume. This method was compatible with 3 patterns to regulate the volumes to manipulate the tablet mass and achieve tailored personalized precision dosing. All tablets from each pattern exhibited a smooth surface and regular shape, as well as sufficient mechanical strength. A good linear correlation between the mass and theoretical volume of the tablets was maintained, regardless of the pattern used. The range of dose accuracy was between 103.3% and 96.2%, with an acceptable variation coefficient in the range of 0.6%-3.2%. Faster release behavior for levetiracetam can be achieved from the small-sized tablets due to their larger surface area/mass ratio. All the results demonstrated the potential and capability of semi-solid extrusion 3-dimensional printing as a novel pharmaceutical manufacturing technique to provide a dynamic and highly accurate controllable system for preparing patient-tailored medicines.

Ag3PO4 nanoparticles loaded on 3D flower-like spherical MoS2: a highly efficient hierarchical heterojunction photocatalyst.

Novel 3D hierarchical Ag3PO4/MoS2 composites were successfully prepared through a facile and reproducible hydrothermal-in situ precipitation method. The 3D flower-like spherical MoS2 nanoarchitectures acted as an excellent supporting matrix for the in situ growth of Ag3PO4 nanoparticles. The photocatalytic performance of the composites and the effect of the amount of MoS2 were investigated. The obtained hierarchical Ag3PO4/MoS2 composites exhibited significantly enhanced performance for photocatalytic oxidation of Rhodamine B (RhB) compared with pure Ag3PO4 under visible light irradiation. Ag3PO4/MoS2 composites with 15 wt% of MoS2 showed the optimal photoactivity for the degradation of RhB, which was approximately 4.8 times as high as that of pure Ag3PO4. What's more, the optimal Ag3PO4/MoS2 composite also showed better photodegradation efficiency for methyl orange (MO) and p-chlorophenol (4-CP) than pure Ag3PO4. More attractively, the stability of Ag3PO4 was improved after the in situ deposition of Ag3PO4 particles on the surface of MoS2 nanoflakes due to the conductivity of MoS2 itself as electron acceptors. The enhanced performance of the hierarchical Ag3PO4/MoS2 composites under visible light was caused by a synergistic effect including the improved separation of photogenerated charge carriers, boosted light harvesting, a relatively high surface area and matching energy band structures between the two components. Interestingly, the heterostructured Ag3PO4/MoS2 composite reduced the use of the noble metal silver, thereby effectively reducing the cost of the Ag3PO4 based photocatalyst. Ultimately, a MoS2 involved photocatalytic mechanism for the hierarchical Ag3PO4/MoS2 composites was also proposed.

CeO2 nanorod/g-C3N4/N-rGO composite: enhanced visible-light-driven photocatalytic performance and the role of N-rGO as electronic transfer media.

A novel CeO2 nanorod/g-C3N4/N-rGO ternary composite was synthesized using a simple ultrasonic-heat treatment method for application in the photocatalytic degradation of organic pollutants under the irradiation of visible light. This material shows superior photocatalytic activity compared with pure g-C3N4 and CeO2 nanorods, and the photodegradation rate of RhB is up to 2.1-fold higher than that of the g-C3N4/N-rGO (at the optimum content of 0.25 wt% N-rGO) catalyst when the content of CeO2 nanorods was 2 wt%. The enhancement of photocatalytic activity could be attributed to the synergistic effect among CeO2, g-C3N4 and N-rGO (serves as a conductive network), which was found to lead to more efficient separation of photogenerated electron-hole pairs, resulting in the effective photodegradation of organic pollutants. In addition, superoxide radical anions (˙O2(-)) and holes (h(+)) were considered as the main reactive species during the photodegradation process, and the ternary composite also exhibited preferable stability for the decomposition of RhB. This work provides an in-depth perspective for understanding the N-doped graphene-involved photocatalytic mechanism.

Antioxidant Activities of Stilbenoids from Rheum emodi Wall.

Rheum emodi Wall has been reported to possess protective effect in many inflammatory diseases and oxidative stress-related injuries. This study aims to investigate antioxidant power of stilbenoids from R. emodi and then explore the material basis for its antioxidant potential. The most abundant stilbenoid piceatannol-4'-O-ß-D-glucopyranoside (PICG) and its aglycon piceatannol (PICE) were isolated from R. emodi rhizome. Using well-accepted antioxidant chemicals as reference, antioxidant activity of these stilbenoids was examined by measuring DPPH and superoxide anion radical scavenging, ferric reducing power, and inhibition of lipid peroxidation in vitro. Both PICG and PICE displayed promising antioxidant activity in all the four assays. Comparisons among the tested compounds indicated that PICE has the most potent antioxidant activity and the presence of 3'-hydroxyl group may enhance antioxidant activity of stilbenoids. The antioxidative effect of PICE at the cellular level was further demonstrated on the model of hydrogen-peroxide-induced H9c2 rat cardiomyoblasts injury. Taking into account the rapid in vivo metabolic transformation of PICG into PICE it can be inferred that the most abundant stilbenoid PICG may be an important constituent responsible for the antioxidant potential of R. emodi and promising to be developed as an antioxidant agent for supplementary or therapeutic use.