Therapeutic effects and potential mechanism of dehydroevodiamine on N-methyl-N'-nitro-N-nitrosoguanidine-induced chronic atrophic gastritis.

BACKGROUNDS: Dehydroevodiamine (DHE) is a quinazoline alkaloid isolated from a Chinese herbal medicine, named Euodiae Fructus (Wu-Zhu-Yu in Chinese). This study aimed to investigate the therapeutic effects and potential mechanism of DHE on N-methyl-N'-nitro-N-nitrosoguanidine (MNNG)-induced chronic atrophic gastritis (CAG) based on integrated approaches. METHODS: Therapeutic effects of DHE on serum biochemical indices and histopathology of gastric tissue in MNNG-induced CAG rats were analyzed. MNNG-induced GES-1 human gastric epithelial cell injury model was established. Cell viability and proliferation was quantified by a cell counting kit-8 assay. Cell morphology and mitochondrial membrane potential (MMP) were detected by a high content screening (HCS) assay. Cell migration and invasion were detected by a Transwell chamber. Moreover, UHPLC-Q-TOF/MS was performed to investigate the potential metabolites and signaling pathway affecting the protective effects of DHE on MNNG-induced cell migration and invasion of GES-1. Furthermore, in view of the key role of angiogenesis in the transformation of inflammation and cancer, this study explored relative mRNA and protein expression levels of HIF-1α-mediated VEGF pathway in vivo and in vitro by RT-PCR and Western Blotting, respectively. RESULTS: The results showed that the therapeutic effects of DHE on CAG rats were presented in down-regulation serum biochemical indices and alleviating histological damage of gastric tissue. Besides, DHE has an effect on increasing cell proliferation of GES-1 cells, ameliorating MNNG-induced gastric epithelial cell damage and mitochondrial dysfunction. In addition, DHE could inhibit MNNG induced migration and invasion of GES-1 cells. Cell metabolomics analyses showed that the protective effect of DHE on GES-1 cells is mainly associated with the regulation of inflammation metabolites and energy metabolism related pathways. It was found that DHE has a regulating effect on tumor angiogenesis and can inhibit the relative gene and protein expression of HIF-1α-mediated VEGF signaling pathway. CONCLUSIONS: The present work highlighted the role of DHE ameliorated gastric injury in MNNG-induced CAG rats in vivo and GES-1 cell migration in vitro by inhibiting HIF-1α/VEGF angiogenesis pathway. These results suggest that DHE may be the effective components of Euodiae Fructus, which provides a new agent for the treatment of CAG.

Upregulation of long noncoding RNA W42 promotes tumor development by binding with DBN1 in hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is a malignancy found globally. Accumulating studies have shown that long noncoding RNAs (lncRNAs) play critical roles in HCC. However, the function of lncRNA in HCC remains poorly understood. AIM: To understand the effect of lncRNA W42 on HCC and dissect the underlying molecular mechanisms. METHODS: We measured the expression of lncRNA W42 in HCC tissues and cells (Huh7 and SMMC-7721) by quantitative reverse transcriptase polymerase chain reaction. Receiver operating characteristic curves were used to assess the sensitivity and specificity of lncRNA W42 expression. HCC cells were transfected with pcDNA3.1-lncRNA W42 or shRNA-lncRNA W42. Cell functions were detected by cell counting Kit-8 (CCK-8), colony formation, flow cytometry and Transwell assays. The interaction of lncRNA W42 and DBN1 was confirmed by RNA immunoprecipitation and RNA pull down assays. An HCC xenograft model was used to assess the role of lncRNA W42 on tumor growth in vivo. The Kaplan-Meier curve was used to evaluate the overall survival and recurrence-free survival after surgery in patients with HCC. RESULTS: In this study, we identified a novel lncRNA (lncRNA W42), and investigated its biological functions and clinical significance in HCC. LncRNA W42 expression was upregulated in HCC tissues and cells. Overexpression of lncRNA W42 notably promoted the proliferative and invasion of HCC, and inhibited cell apoptosis. LncRNA W42 directly bound to DBN1 and activated the downstream pathway. LncRNA W42 knockdown suppressed HCC xenograft tumor growth in vivo. The clinical investigation revealed that HCC patients with high lncRNA W42 expression exhibited shorter survival times. CONCLUSION: In vitro and in vivo results suggested that the novel lncRNA W42, which is upregulated in HCC, may serve as a potential candidate prognostic biomarker and therapeutic target in HCC patients.

Screening for Susceptibility-Related Factors and Biomarkers of Xianling Gubao Capsule-Induced Liver Injury.

Although increasing reports from the literature on herbal-related hepatotoxicity, the identification of susceptibility-related factors and biomarkers remains challenging due to idiosyncratic drug-induced liver injury (IDILI). As a well-known Chinese medicine prescription, Xianling Gubao Capsule (XLGB) has attracted great attention due to reports of potential liver toxicity. But the mechanism behind it is difficult to determine. In this paper, we found that XLGB-induced liver injury belongs to IDILI through the analysis of clinical liver injury cases. In toxicological experiment assessment, co-exposure to XLGB and non-toxic dose of lipopolysaccharide (LPS) could cause evident liver injury as manifested by significantly increased plasma alanine aminotransferase activity and obvious liver histological damage. However, it failed to induce observable liver injury in normal rats, suggesting that mild immune stress may be a susceptibility factor for XLGB-induced idiosyncratic liver injury. Furthermore, plasma cytokines were determined and 15 cytokines (such as IL-1ß, IFN-γ, and MIP-2α etc) were acquired by receiver operating characteristic (ROC) curves analysis. The expression of these 15 cytokines in LPS group was significantly up-regulated in contrast to the normal group. Meanwhile, the metabolomics profile showed that mild immune stress caused metabolic reprogramming, including sphingolipid metabolism, phenylalanine metabolism, and glycerophospholipid metabolism. 8 potential biomarkers (such as sphinganine, glycerophosphoethanolamine, and phenylalanine etc.) were identified by correlation analysis. Therefore, these results suggested that intracellular metabolism and immune changes induced by mild immune stress may be important susceptibility mechanisms for XLGB IDILI.

Exploration in the mechanism of rhubarb for the treatment of hyperviscosity syndrome based on network pharmacology.

ETHNOPHARMACOLOGICAL RELEVANCE: Hyperviscosity syndrome (HVS) is a major risk factor for thrombotic diseases. Rhubarb, well-known as a traditional Chinese medicine, exhibits multiple pharmacological activities, especially for promoting blood circulation to remove blood stasis (PBRB), which has been become a functional health food for decreasing the risk of cardiovascular diseases. However, due to the complexity of rhubarb components, it is still difficult to clarify the specific targets of effective substances in PBRB, and the pharmacodynamic mechanism needs to be further probed. MATERIALS AND METHODS: The "compound-target-cell-disease" network analysis was initially used to predict potential targets and bioactive compounds. The effect of rhubarb for the treatment of HVS was examined by histopathology and biochemical assays based on the HVS rat model. RESULTS: Through the "compound-target-cell-disease" network analysis, eight potential therapeutic targets were eventually screened out, and platelets were predicted as the main effector cells of rhubarb in PBRB. Among targets coagulation factor II (prothrombin, F2) and fibrinogen gamma chain (FGG) were closely related to platelets, and five compounds associated with F2 and FGG were predicted including emodin-8-O-beta-D-glucopyranoside (Emo), physcion-8-O-beta-D-glucopyranoside (Phy), procyanidin B-5,3'-O-gallate, torachrysone-8-O-beta-D-(6'-oxayl)-glucoside and epicatechin. Furthermore, thoracic aorta histopathology and biochemical examinations showed middle dose of rhubarb (0.42 g/kg/day) significantly ameliorated pathological changes, hemorheology parameters, as well as levels of representative biomarkers such as plasma P-selectin (P-sel) and thromboxane (TXB2) in platelet activation compared to HVS rat model, whose effects were comparable to the positive drug aspirin or even better. Finally, it was further validated F2 and FGG as the major effective targets of rhubarb as well as its two active ingredients Emo and Phy in PBRB. CONCLUSIONS: This study may provide an innovative way and scientific information to further understand the main effective components of rhubarb and its mechanisms about targets of F2 and FGG in PBRB, especially the new therapeutic target FGG, which also provide a basis for establishing a quality control for rhubarb by bioassays that could correlate the clinical efficacy and its mechanism.

Corrigendum: Inflammatory Stress Potentiates Emodin-Induced Liver Injury in Rats.

[This corrects the article DOI: 10.3389/fphar.2015.00233.].

Therapeutic effects of Aconiti Lateralis Radix Praeparata combined with Zingiberis Rhizoma on doxorubicin-induced chronic heart failure in rats based on an integrated approach.

OBJECTIVES: This study was aimed to explore the mechanism of Aconiti Lateralis Radix Praeparata (ALRP) and Zingiberis Rhizoma (ZR) on doxorubicin (DOX)-induced chronic heart failure (CHF) in rats by integrated approaches. METHODS: Effects of ALRP and ZR on cardiac function, serum biochemical indicators and histopathology in rats were analysed. Moreover, UHPLC-Q-TOF/MS was performed to identify the potential metabolites affecting the pathological process of CHF. Metabolomics and network pharmacology analyses were conducted to illustrate the possible pathways and network in CHF treatment. The predicted gene expression levels in heart tissue were verified and assessed by RT-PCR. KEY FINDINGS: ALRP-ZR demonstrated remarkable promotion of hemodynamic indices and alleviated histological damage of heart tissue. Metabolomics analyses showed that the therapeutic effect of ALRP and ZR is mainly associated with the regulation of eight metabolites and ten pathways, which may be responsible for the therapeutic efficacy of ALRP-ZR. Moreover, the results of RT-PCR showed that ALRP-ZR could substantially increase the expression level of energy metabolism-related genes, including PPARδ, PPARγ, Lpl, Scd, Fasn and Pla2g2e. CONCLUSIONS: The results highlighted the role of ALRP-ZR in the treatment of CHF by influencing the metabolites related to energy metabolism pathway via metabolomics and network pharmacology analyses.

Susceptibility-Related Factor and Biomarkers of Dietary Supplement Polygonum multiflorum-Induced Liver Injury in Rats.

Polygonum multiflorum [PM, synonym Reynoutria multiflora (Thunb.) Moldenke.], a well-known and commonly used Traditional Chinese Medicine and herbal dietary supplement for nourishing the kidney and liver, etc., has aroused wide concern for its reported potential hepatotoxicity. Previous clinical cases and experimental studies have suggested that mild immune stress (MIS) may be one of the susceptibility-related factors of idiosyncratic drug-induced liver injury (IDILI) caused by PM. In this paper, we found that the same dose of PM caused abnormal liver biochemical indicators and liver tissue damage in MIS model rats, while it did not result in liver injury in normal rats, further confirming that MIS is a susceptibility factor for PM-IDILI. Plasma chemokine/cytokine profiling indicated that the MIS model group was significantly different from the other groups, showing a significant upregulation of plasma chemokines, while the MIS/PM group showed upregulated expression of chemokines or pro-inflammatory cytokines. Liver histopathological examination indicated a small amount of inflammatory cytokine infiltration in the MIS group, but no hepatocyte injury, consistent with the plasma profiles of increased chemokines and unchanged inflammatory cytokines. Notably, metabolomics characterization showed that MIS caused reprogramming of these metabolic pathways (such as phenylalanine and glutamate pathways), which was associated with acute phase reactions and inflammatory responses. These results suggested that MIS may promote an immune response to the initial cellular injury induced by PM in the liver, and MIS-induced upregulation of chemokines and metabolic reprogramming may an important mechanism that mediates the susceptibility to PM-IDILI. Furthermore, via receiver operating characteristic (ROC) curves analysis, we identified 12 plasma cytokines (e.g., IP-10, MCP-1 and MIP-1α) and nine metabolomics biomarkers (e.g., L-Phenylalanine, Creatinine, and L-glutamine) with differential capabilities (all ROC AUC > 0.9) of identifying susceptibility model animals from normal ones, which might be of referable value for the clinical recognition of PM-IDILI susceptible individuals.

A systems pharmacology-oriented discovery of a new therapeutic use of the TCM formula Liuweiwuling for liver failure.

Multiple components of traditional Chinese medicine (TCM) formulae determine their treatment targets for multiple diseases as opposed to a particular disease. However, discovering the unexplored therapeutic potential of a TCM formula remains challenging and costly. Inspired by the drug repositioning methodology, we propose an integrated strategy to feasibly identify new therapeutic uses for a formula composed of six herbs, Liuweiwuling. First, we developed a comprehensive systems approach to enrich drug compound-liver disease networks to analyse the major predicted diseases of Liuweiwuling and discover its potential effect on liver failure. The underlying mechanisms were subsequently predicted to mainly attribute to a blockade of hepatocyte apoptosis via a synergistic combination of multiple effects. Next, a classical pharmacology experiment was designed to validate the effects of Liuweiwuling on different models of fulminant liver failure induced by D-galactosamine/lipopolysaccharide (GalN/LPS) or thioacetamide (TAA). The results indicated that pretreatment with Liuweiwuling restored liver function and reduced lethality induced by GalN/LPS or TAA in a dose-dependent manner, which was partially attributable to the abrogation of hepatocyte apoptosis by multiple synergistic effects. In summary, the integrated strategy discussed in this paper may provide a new approach for the more efficient discovery of new therapeutic uses for TCM formulae.

San-Cao Granule () Ameliorates Hepatic Fibrosis through High Mobility Group Box-1 Protein/Smad Signaling Pathway.

OBJECTIVE: To investigate the possible mechanism of San-Cao Granule (SCG, ) mediating antiliver fibrosis. METHODS: A total of 60 male Sprague-Dawley rats were randomly divided into the normal control group, porcine serum-treated group, ursodesoxycholic acid (UDCA, 60 mg/kg), SCG (3.6 g/kg) group, SCG (1.8 g/kg) group and SCG (0.9 g/kg) group, with 10 rats in each group. Liver fibrosis was induced with porcine serum by intraperitoneal injection for 8 weeks, except for the normal control group. Then, the rats in the three SCG-treated groups and UDCA group were administered SCG and UDCA respectively for 4 weeks. The serum levels of alanine transaminase (ALT), aspartate transaminase (AST), albumin (ALB), total bilirubin (TBIL), hyaluronic acid (HA), laminin (LN), and type IV collagen (IVC) were examined using commercial kits and hepatic histopathology was examined with hematoxylin and eosin and Masson staining. Moreover, the protein expression levels of high mobility group box-1 protein (HMGB1), transforming growth factor ß1 (TGF-ß1), phosphorylated mothers against decapentaplegic homolog 3 (p-Smad3), Smad7, toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88), nuclear factor-kappa B (NF-κB) and α-smooth muscle actin (α-SMA) were determined by western blot, immunohistochemistry and real time quantitative-reverse transcription polymerase. RESULTS: Both SCG (3.6 and 1.8 g/kg) and UDCA significantly ameliorated the liver fibrosis induced by porcine serum as indicated by retarding the serum levels increasing of ALT, AST, TBIL, HA, LN and IVC and preventing the serum level reducing of ALB compared with the model group (all P<0.01). Meanwhile, the collagen deposition was attenuated by SCG and UDCA treatment. Furthermore, SCG markedly reduced the expressions of HMGB1, TGF-ß1, p-Smad3, TLR4, MyD88, NF-κB and α-SMA, and enhanced the expression of the Smad7 compared with the model group (all P<0.01). CONCLUSION: SCG ameliorates hepatic fibrosis possibly through inhibiting HMGB1, TLR4/NF-κB and TGF-ß1/Smad signaling pathway.

Paeoniflorin attenuates ANIT-induced cholestasis by inhibiting apoptosis in vivo via mitochondria-dependent pathway.

Apoptosis induced by the bile acids in the liver is considered to play a pivotal role in the pathogenesis of cholestatic disease. Increasing evidence has demonstrated that Paeoniflorin (PF) exerts therapeutic effect on severe cholestatic liver diseases. However, whether PF could protect against alpha-naphthylisothiocyanate (ANIT)-induced cholestasis by inhibiting apoptosis remains unclear. In this study, we mainly investigated the effect and anti-apoptosis mechanism of PF on cholestasis. Experimental results indicated that PF pretreatment could attenuate liver damage and cholestasis by ANIT in rats, lift the biliary excretion in addition to decrease serum indices (ALT, AST, DBIL, TBIL, TBA, ALP and ϒ-GT) and conspicuous neutrophil infiltration and cell apoptosis in liver evidenced by TUNEL staining. Furthermore, the pro-apoptosis genes expression of Bax, Caspase-9 and Caspase-3 increased by ANIT were prominently reduced after PF treatment. The increase of anti-apoptosis gene and main regulator Bcl-2 in mitochondria by ANIT was largely reversed by PF pre-treatment. In summary, our study demonstrated that PF pre-treatment not only significantly attenuated ANIT-induced cholestasis and liver injury, but also largely reduced cell apoptosis in liver, thus may act as a potential therapeutic agent for cholestasis disease.

Metabolomic Study on Idiosyncratic Liver Injury Induced by Different Extracts of Polygonum multiflorum in Rats Integrated with Pattern Recognition and Enriched Pathways Analysis.

Currently, numerous liver injury cases related to a famous Chinese herb- Polygonum Multiflorum (Heshouwu in Chinese) have attracted great attention in many countries. Our previous work showed that Heshouwu-induced hepatotoxicity belonged to idiosyncratic drug-induced liver injury (IDILI). Unfortunately, the components and mechanisms attributed to IDILI of Heshouwu are difficult to determine and thus remain unknown. Attempts to explore puzzles, we prepared the chloroform (CH)-, ethyl acetate (EA)-, and residue (RE) extracts of Heshouwu to investigate IDILI constituents and underlying mechanisms, using biochemistry, histopathology, and metabolomics examinations. The results showed that co-treatment with non-toxic dose of lipopolysaccharide (LPS) and EA extract could result in evident liver injury, indicated by the significant elevation of plasma alanine aminotransferase and aspartate aminotransferase activities, as well as obvious liver histologic damage; whereas other two separated fractions, CH and RE extracts, failed to induce observable liver injury. Furthermore, 21 potential metabolomic biomarkers that differentially expressed in LPS/EA group compared with other groups without liver injury were identified by untargeted metabolomics, mainly involved two pathways: tricarboxylic acid cycle and sphingolipid metabolism. This work illustrated EA extract had close association with the idiosyncratic hepatotoxicity of Heshouwu and provided a metabolomic insight into IDILI of different extracts from Heshouwu.

Lignans-rich extract from Herpetospermum caudigerum alleviate physical fatigue in mice.

OBJECTIVE: To ascertain anti-fatigue constituents and mechanisms of Herpetospermum caudigerum. METHODS: The 80% ethanol extracts of Herpetospermum caudigerum were partitioned with chloroform, ethyl acetate and n-butanol, respectively. Male Kunming mice were divided into 13 groups with 16 mice in each group: a control group fed with water, 9 groups treated with 3 fractions of Herpetospermum caudigerum (chloroform fraction, ethyl acetate fraction and n-butanol fraction) at dose of 80, 160 and 320 mg/kg for the low-dose group, medium-dose group and high-dose group, 3 herpetrione (HPE) treated groups fed with HPE at dose of 15, 30, and 60 mg/kg for the low-dose group, medium-dose group and high-dose group. All animals were treated once per day for 30 days. Anti-fatigue activity was assessed through the forced swimming test and serum biochemical parameters including blood lactic acid (BLA), blood urea nitrogen (BUN), malondialdehyde (MDA), hepatic glycogen (HG), lactic dehydrogenase (LDH), superoxide dismutase (SOD) and glutathione peroxidase (GPx) determined following the recommended procedures provided by the commercial kits. RESULTS: Compared with the control group, the lignans extract (ethyl acetate fraction) of Herpetospermum caudigerum and HPE could signifificantly prolonged the exhaustive swimming time (P<0.05 or P<0.01), and also increased the HG levels (P<0.05 or P<0.01) and the activities of antioxidant enzymes (SOD, GPx and LDH, P<0.05 or P<0.01); BLA and MDA levels were decreased considerably in lignans extract and HPE treated groups (P<0.05 or P<0.01). HPE also could significantly decrease the BUN contents compared with the control group (P<0.05). The chloroform and n-butanol fraction showed no effect on swimming time and biochemical parameters. CONCLUSIONS: The lignans extract had antifatigue activities and HPE may be partly responsible for the anti-fatigue effects of Herpetospermum caudigerum. The possible mechanisms of anti-fatigue activity were related to the decrease of BUN and BLA, the increase of the HG storage and protecting corpuscular membrane by preventing lipid oxidation via modifying several enzyme activities.

Untargeted Metabolomics Reveals Intervention Effects of Total Turmeric Extract in a Rat Model of Nonalcoholic Fatty Liver Disease.

Nonalcoholic fatty liver disease (NAFLD) is one of the most common forms of chronic liver disease. Currently, there are no recognized medical therapies effective for NAFLD. Previous studies have demonstrated the effects of total turmeric extract on rats with NAFLD induced by high-fat diet. In this study, serum metabolomics was employed using UHPLC-Q-TOF-MS to elucidate the underlying mechanisms of HFD-induced NAFLD and the therapeutic effects of TE. Supervised orthogonal partial least-squares-discriminant analysis was used to discover differentiating metabolites, and pathway enrichment analysis suggested that TE had powerful combined effects of regulating lipid metabolism by affecting glycerophospholipid metabolism, glycerolipid metabolism, and steroid hormone biosynthesis signaling pathways. In addition, the significant changes in glycerophospholipid metabolism proteins also indicated that glycerophospholipid metabolism might be involved in the therapeutic effect of TE on NAFLD. Our findings not only supply systematic insight into the mechanisms of NAFLD but also provide a theoretical basis for the prevention or treatment of NAFLD.

Toxic Constituents Index: A Toxicity-Calibrated Quantitative Evaluation Approach for the Precise Toxicity Prediction of the Hypertoxic Phytomedicine-Aconite.

Complex chemical composition is an important reason for restricting herbal quality evaluation. Despite the multi-components determination method significantly promoted the progress of herbal quality evaluation, however, which mainly concerned the total amount of multiple components and ignored the activity variation between each one, and did not accurately reflect the biological activity of botanical medicines. In this manuscript, we proposed a toxicity calibrated contents determination method for hyper toxic aconite, called toxic constituents index (TCI). Initially, we determined the minimum lethal dose value of mesaconitine (MA), aconitine (AC), and hypaconitine (HA), and established the equation TCI = 100 × (0.3387 ×X MA + 0.4778 ×X AC + 0.1835 ×X HA). Then, 10 batches of aconite were selected and their evaluation results of toxic potency (TP), diester diterpenoid alkaloids (DDAs), and TCI were compared. Linear regression analysis result suggested that the relevance between TCI and TP was the highest and the correlation coefficient R was 0.954. Prediction error values study also indicated that the evaluation results of TCI was highly consistent with that of TP. Moreover, TCI and DDAs were both applied to evaluate 14 batches of aconite samples oriented different origins; from the different evaluation results, we found when the proportion of HA was reached 25% in DDAs, the pharmacopeia method could generate false positive results. All these results testified the accuracy and universality of TCI method. We believe that this study method is rather accurate, simple, and easy operation and it will be of great utility in studies of other foods and herbs.

Oxymatrine attenuates CCl4-induced hepatic fibrosis via modulation of TLR4-dependent inflammatory and TGF-ß1 signaling pathways.

Oxymatrine (OMT) is able to effectively protect against hepatic fibrosis because of its anti-inflammatory property, while the underlying mechanism remains incompletely understood. In this study, forty rats were randomly divided into five groups: control group, model group (carbon tetrachloride, CCl4) and three OMT treatment groups (30, 60, 120mg/kg). After CCl4 alone, the fibrosis score was 20.2±0.8, and the level of alanine aminotransferase (ALT), aspartate aminotransferase (AST), hydroxyproline content, and collagen I expression was elevated, but OMT blunted these parameters. Treatment with OMT prevented CCl4-induced increases in expression of pro-inflammatory and pro-fibrotic cytokines interleukin (IL)-6 and tumor necrosis factor (TNF)-α, meanwhile OMT promoted the expression of anti-inflammatory and anti-fibrotic factors such as interleukin (IL)-10 and bone morphogenetic protein and activin membrane-bound inhibitor (Bambi). Moreover, lipopolysaccharides (LPS) and high mobility group box-1 (HMGB1), which activates Toll-like receptor 4 (TLR4) and modulate hepatic fibrogenesis through hepatic stellate cells (HSCs) or Kupffer cells, were significantly decreased by OMT treatment. These results were further supported by in vitro data. First, OMT suppressed the expression of TLR4 and its downstream pro-inflammatory cytokines, lowered the level of HMGB1, TGF-ß1 in macrophages. Then, OMT promoted Bambi expression and thereby inhibited activation of HSCs mediated by transforming growth factor (TGF)-ß1. In conclusion, this study showed that OMT could effectively attenuate the CCl4-induced hepatic fibrosis, and this effect may be due to modulation of TLR4-dependent inflammatory and TGF-ß1 signaling pathways.

The Therapeutic Efficacy and Safety of Compound Kushen Injection Combined with Transarterial Chemoembolization in Unresectable Hepatocellular Carcinoma: An Update Systematic Review and Meta-Analysis.

BACKGROUND: Compound Kushen Injection (CKI) is a Chinese patent medicine approved by the China Food and Drug Administration for the treatment of various types of solid tumors. CKI, combined with transarterial chemoembolization (TACE), is believed to increase the therapeutic efficacy of unresectable hepatocellular carcinoma (HCC). We report an updated and extended meta-analysis with detailed outcomes of both the efficacy and adverse events (AEs) of CKI combined with TACE therapy. MATERIALS AND METHODS: Electronic databases, including PubMed, Embase, the Cochrane Library, the Chinese Biomedical Database (CBM), Wanfang, the VIP medicine information system (VMIS) and the China National Knowledge Infrastructure (CNKI), were examined for relevant articles before November 13, 2015. An odds ratio (OR) was used to estimate tumor response (TR), Karnofsky Performance Scale (KPS) improvement, Child-Pugh (CP) improvement, survival rate (SR) and AEs. A publication bias and a subgroup analysis were also assessed. RESULTS: Eighteen studies, with a total of 1,338 HCC patients who met the criteria for the meta-analysis, were included. TR, KPS improvement and CP improvement were significantly enhanced for the combination therapy compared to TACE alone (OR = 1.84, 95% CI: [1.46, 2.33], P < 0.00001; OR = 2.37, 95% CI: [1.76, 3.18], P < 0.00001; OR = 1.81, 95% CI: [1.08, 3.03], P = 0.02, respectively). The combination therapy was associated with an improvement in 1-year and 2-year SRs but not an improved 3-year SR (OR = 2.40; 95% CI: [1.59, 3.62], P < 0.0001; OR = 2.49, 95% CI: [1.24, 5.00], P = 0.01; OR = 2.49, 95% CI: [0.94, 6.61], P = 0.07, respectively). A safety analysis indicated that AEs (including nausea/vomiting, fever, hepatalgia, increased transaminase, increased bilirubin and leukopenia) were reduced for the combination treatment compared to TACE alone. CONCLUSION: The combination treatment of TACE and CKI was associated with improved TR, KPS and CP improvement and improved 1- and 2-year SRs in patients with unresectable HCC. The 3-year SR was not improved. The combination therapy resulted in a reduction in AEs. The findings of this study should be interpreted with caution because of the small sample size and study limitations.

Rhubarb Anthraquinones Protect Rats against Mercuric Chloride (HgCl2)-Induced Acute Renal Failure.

Mercury (Hg) causes severe nephrotoxicity in subjects with excess exposure. This work attempted to identify whether a natural medicine--rhubarb--has protective effects against mercuric chloride (HgCl2)-induced acute renal failure (ARF), and which of its components contributed most to the treatment. Total rhubarb extract (TR) were separated to the total anthraquinones (TA), the total tannins (TT) and remaining component extract (RC). Each extract was orally pre-administered to rats for five successive days followed by HgCl2 injection to induce kidney injury. Subsequently, renal histopathology and biochemical examinations were performed in vitro to evaluate the protective effects. Pharmacological studies showed that TR and TA, but not TT or RC manifested significant protection activity against HgCl2-induced ARF. There were also significant declines of serum creatine, urea nitrogen values and increases of total protein albumin levels in TR and TA treated groups compared to HgCl2 alone (p < 0.05). At last, the major components in TA extract were further identified as anthraquinones by liquid chromatography coupled mass spectroscopy. This study thus provides observational evidences that rhubarb could ameliorate HgCl2-induced ARF and its anthraquinones in particular are the effective components responsible for this activity in rhubarb extract.

Inflammatory stress potentiates emodin-induced liver injury in rats.

Herbal medicines containing emodin, widely used for the treatment of hepatitis in clinic, have been reported with hepatotoxicity in individuals. A modest inflammatory stress potentiating liver injury has been linked to the idiosyncratic drug-induced liver injury (IDILI). In this study, we investigated the hypothesis that lipopolysaccharide (LPS) interacts with emodin could synergize to cause liver injury in rats. Emodin (ranging from 20, 40, to 80 mg/kg), which is in the range of liver protection, was administered to rats, before LPS (2.8 mg/kg) or saline vehicle treatment. The biochemical tests showed that non-toxic dosage of LPS coupled with emodin caused significant increases of plasma ALT and AST activities as compared to emodin alone treated groups (P < 0.05). In addition, with LPS or emodin alone could not induce any changes in ALT and AST activity, as compared with the control group (0.5% CMC-Na treatment). Meanwhile, the plasma proinflammatory cytokines, TNF-α, IL-1ß, and IL-6 increased significantly in the emodin/LPS groups compared to either emodin groups or the LPS (P < 0.05). Histological analysis showed that liver damage was only found in emodin/LPS cotreatmented rat livers samples. These results indicate that non-toxic dosage of LPS potentiates the hepatotoxicity of emodin. This discovery raises the possibility that emodin and herbal medicines containing it may induce liver injury in the inflammatory stress even in their therapeutic dosages.

Anti-fibrotic effects of the Masson pine pollen aqueous extract on hepatic fibrosis rat model.

AIM: To observe the antifibrotic effects of Masson Pine Pollen aqueous extract. METHODS: Adult Sprague-Dawley rats were randomly divided into control (CG), hepatic fibrosis model (MG), MPPAE low dose (LG), MPPAE high dose (HG), and MPP original powder (MPPOP; OG) groups. Each group was treated with specific protocols and sacrificed 8 weeks later. Multiple indicators such as serum transaminase, HE staining of the liver tissue, and relevant indexes to fibrosis were determined. RESULTS: Severe hyperplasia of fibrous connective tissues was observed in livers of the MG group rats, while aspartate transaminase and alanine transaminase levels and collagen content obviously increased, superoxide dismutase and glutathione peroxidase activities and MMPs expression decreased, malondialdehyde (MDA) and 8-hydroxy-2'-deoxyguanosine concentrations increased, while mRNA expressions of hepatic stellate cell (HSC)-related cytokines such as transforming growth factor-ß1 and platelet-derived growth factor, transcription factors such as nuclear factor-κB p65, and signaling protein α-smooth muscle actin were all increased significantly. CONCLUSIONS: MPPAE effectively inhibited the fibrotic process in this CCl4-induced hepatic fibrosis rat model. It may be associated with synergic functions of antioxidant activity, inhibitory activity on HSC proliferation, collagen synthesis, and MMPs expression induction.

Influence of drug physicochemical characteristics on in vitro transdermal absorption of hydrophobic drug nanosuspensions.

The purpose of this paper was to study the influence of drug physicochemical characteristics on in vitro transdermal absorption of hydrophobic drug nanosuspensions. Four drug nanosuspensions were produced by high-pressure homogenization technique, which were the same in stabilizer and similar in particle size. Differential scanning calorimetry and powder X-ray diffraction analysis showed that the crystalline state of the nanocrystals did not change. In vitro permeation study demonstrated that the drug nanosuspensions have a higher rate of permeation that ranged from 1.69- to 3.74-fold compared to drug microsuspensions. Correlation analysis between drug physicochemical properties and Jss revealed that log P and pKa were factors that influenced the in vitro transdermal absorption of hydrophobic drug nanosuspensions, and drugs with a log P value around 3 and a higher pKa value (when pKa < pH+2) would gain higher Jss in this paper.