Treatment of non-small cell lung cancer with Yiqi Buxue prescriptions combined with adjuvant chemotherapy on the cancer therapy-related cardiovascular toxicity: A systematic review and meta-analysis.

ETHNOPHARMACOLOGICAL RELEVANCE: The treatment and prognosis of patients with non-small cell lung cancer (NSCLC) was affected by the occurrence of cancer therapy-related cardiovascular toxicity (CTR-CVT). Yiqi Buxue prescriptions were a class of traditional single or compounded formulations that have become a consensus for NSCLC. There was no clear information and or summary available for Yiqi Buxue prescriptions combined with adjuvant chemotherapy for NSCLC in reducing CTR-CVT. AIM OF THE STUDY: To systematically evaluate the Yiqi Buxue prescriptions combined with adjuvant chemotherapy in reducing CTR-CVT for patients with NSCLC. MATERIALS AND METHODS: Search strategies were developed to identify relevant randomized controlled trials (RCTs) in PubMed, Embase, Web of Science, The Cochrane Library, China National Knowledge Infrastructure (CNKI), SinoMed and WanFang Data from database inception date to October 2022. The methodological quality of evidence was assessed using the Cochrane risk of bias (ROBs) assessment tool, and the meta-analysis was analyzed using RevMan 5.3. RESULTS: A total of 9 studies were included. Compared with the adjuvant chemotherapy group, Yiqi Buxue prescriptions combined with adjuvant chemotherapy group showed no statistically significant in reducing CTR-CVT (RR 0.67, 95%CI 0.11 to 3.93, P = 0.65) and in CD4+/CD8+(MR 0.32, 95%CI -0.13 to 0.77, P = 0.16). However, it significantly improved the objective response rate (ORR) (RR 1.57, 95%CI 1.32 to 1.87, P < 0.00001), disease control rate (DCR) (RR 1.25, 95%CI 1.15 to 1.35, P < 0.00001), Karnofsky performance status (KPS) improvement rate (RR 1.34, 95%CI 1.16 to 1.55, P < 0.0001), CD3+ (MR 4.17, 95%CI 3.68 to 4.66, P < 0.00001), CD4+ (MR 4.87, 95%CI 4.28 to 5.46, P < 0.00001), and CD8+ (MR 3.12, 95%CI 2.57 to 3.67, P < 0.00001). CONCLUSIONS: The current RCTs are hampered by small sample sizes and poor methodological quality. More rigorously designed and large sample RCTs with primary outcome of CTR-CVT are needed to investigate the effectiveness of Yiqi Buxue prescriptions combined with adjuvant chemotherapy in reducing CTR-CVT for patients with NSCLC.

Paeoniflorin Protects against ANIT-Induced Cholestatic Liver Injury in Rats via the Activation of SIRT1-FXR Signaling Pathway.

Paeoniflorin (PF), a water-soluble monoterpene glycoside, is initially isolated from the dried roots of Paeonia lactiflora Pall., which has effects on ameliorating cholestasis in our previous study. However, comprehensive approaches for understanding the protective effects and mechanisms underlying cholestatic liver injury from the regulating of bile acid metabolism have not been sufficiently elucidated. This study was aimed to explore the effectiveness as well as potential mechanism of PF on alpha-naphthylisothiocyanate (ANIT)-induced cholestatic liver injury. Rats with cholestasis induced by ANIT was used to evaluate the protective effects and mechanism of PF by regulating SIRT1/FXR and NF-κB/NLRP3 signaling pathway. Rats were intragastrically administrated with ANIT to establish cholestatic liver injury model. Serum levels of ALT, AST, TBA, TBIL, ALP, γ-GT and ALB in rats were detected. The histopathology of the liver of rats was analyzed in vivo. The relative mRNA expression and protein expression levels of IL-18, IL-1ß, TNF-α, HO-1, Nrf2, TLR4, NLRP3, Caspase-1, ASC, NF-κB, FXR, and SIRT1 in liver of rats were investigated. The results showed that the serum indexes and the liver histopathology were significantly improved by PF. The overexpression of IL-18, IL-1ß, TNF-α, NLRP3, ASC, and Caspase-1 in liver was markedly reduced by PF. Furthermore, PF dramatically increased the mRNA and protein expressions of SIRT1, FXR, HO-1, and Nrf2, but decreased NF-κB p65 and TLR4 levels in liver of rats. Taken together, the protective effects of PF on cholestatic liver injury were possibly related to the activation of the SIRT1/FXR and inhibition of NF-κB/NLRP3 inflammasome signaling pathway. These findings might provide a potential protection for cholestatic liver injury.

Treatment of primary biliary cirrhosis with ursodeoxycholic acid combined with traditional Chinese medicine: A protocol for systematic review and meta analysis.

OBJECTIVE: Ursodeoxycholic acid is the priority drug of primary biliary cirrhosis (PBC) and is usually combined with traditional Chinese medicine. This study aimed to systematically evaluate the benefits of integrated Chinese and western interventions for PBC. METHODS: Searched the randomized controlled trials in PubMed, Web of Science, CNKI, CBM, Wanfang, VIP databases. The Cochrane risk of bias tool was used for methodological quality assessment and all data analysis was performed using Revman5.3 and Stata14.2 software. RESULT: 30 randomized controlled trials involving 10 interventions with a total of 1948 participants were included. Identified the direct and indirect evidence of trials, and used network meta analyses ranked the benefits of different interventions based on pairwise meta analysis. The primary outcom was clinical efficacy rate. Secondary outcome was liver function, including alkaline phosphataseand total bilirubin. CONCLUSION: The conclusion of this systematic review provide credible evidence - based for the relative advantages of integrated Chinese and western interventions for PBC.

Pharmacokinetics, tissue distribution and excretion of 6-O-demethylmenisporphine, a bioactive oxoisoaporphine alkaloid from Menispermi Rhizoma, as determined by a HPLC-MS/MS method.

6-O-demethylmenisporphine, a major active oxoisoaporphine alkaloid isolated from Menispermi Rhizoma, has been confirmed to possess significant bioactivities, including anti-cancer and anti-hypoxia effects. However, few researches on quantifying 6-O-demethylmenisporphine in biosamples have been performed. In this research, a sensitive HPLC-MS/MS approach for determining 6-O-demethylmenisporphine in various biological matrices (plasma, tissue, urine, bile and feces) of rat has been constructed. Carbamazepine was chosen as the internal standard (IS). All biosamples were prepared using a simple one-step acetonitrile precipitation. A Capcell Pak C18 column coupled with an isocratic mobile phase consisted of acetonitrile (0.1% formic acid)-water (90:10, v/v), was employed to separate 6-O-demethylmenisporphine from endogenous interferences. Peak responses were detected by multiple reaction monitoring (MRM) transitions with m/z 308.0 â†’ 264.9 for 6-O-demethylmenisporphine and m/z 237.0 â†’ 194.1 for IS in positive-ion mode. The approach exhibited perfect linearity over a range of 5-2000 ng/mL for plasma and 2-1000 ng/mL for various tissue, urine, bile and feces. The lower limit of quantification (LLOQ) for analyte among different biological samples ranged from 2 ng/mL to 5 ng/mL. The newly established method was simple, efficient and sensitive, which was successfully applied to investigate the absorption, distribution, and excretion of 6-O-demethylmenisporphine after oral dosing to rats. The results indicated that 6-O-demethylmenisporphine could be well absorbed into blood circulation and widely distributed in various tissues after oral dosing, the oral bioavailability was up to 51.52%. Meanwhile, it was widely metabolized in vivo and eliminated as the metabolites, the unconverted form was excreted mainly by feces route. The bioavailability, tissue distribution and excretion characteristics of 6-O-demethylmenisporphine were firstly revealed, which will provide references for further development of 6-O-demethylmenisporphine as an anti-tumor drug candidate.

Kaji-Ichigoside F1 and Rosamultin Protect Vascular Endothelial Cells against Hypoxia-Induced Apoptosis via the PI3K/AKT or ERK1/2 Signaling Pathway.

As a pair of differential isomers, Kaji-ichigoside F1 and Rosamultin are both pentacyclic triterpenoids isolated from the subterranean root of Potentilla anserina L., a plant used in folk medicine in western China as antihypoxia and anti-inflammatory treatments. We demonstrated that Kaji-ichigoside F1 and Rosamultin effectively prevented hypoxia-induced apoptosis in vascular endothelial cells. We established a hypoxia model, using EA.hy926 cells, to further explore the mechanisms. Hypoxia promoted the phosphorylation of AKT, ERK1/2, and NF-κB. In hypoxic cells treated with Kaji-ichigoside F1, p-ERK1/2 and p-NF-κB levels were increased, while the level of p-AKT was decreased. Treatment with Rosamultin promoted phosphorylation of ERK1/2, NF-κB, and AKT in hypoxic cells. Following the addition of LY294002, the levels of p-AKT, p-ERK1/2, and p-NF-κB decreased significantly. Addition of PD98059 resulted in reduced levels of p-ERK1/2 and p-NF-κB, while p-AKT levels were increased. Pharmacodynamic analysis demonstrated that both LY294002 and PD98059 significantly inhibited the positive effects of Kaji-ichigoside F1 on cell viability during hypoxia, consistent with the results of hematoxylin-eosin (H&E) staining, DAPI staining, and flow cytometry. The antihypoxia effects of Rosamultin were remarkably inhibited by LY294002 but promoted by PD98059. In Kaji-ichigoside F1- and Rosamultin-treated cells, Bcl2 expression was significantly upregulated, while expression of Bax and cytochrome C and levels of cleaved caspase-9 and cleaved caspase-3 were reduced. Corresponding to pharmacodynamic analysis, LY294002 inhibited the regulatory effects of Kaji-ichigoside F1 and Rosamultin on the above molecules, while PD98059 inhibited the regulatory effects of Kaji-ichigoside F1 but enhanced the regulatory effects of Rosamultin. In conclusion, Kaji-ichigoside F1 protected vascular endothelial cells against hypoxia-induced apoptosis by activating the ERK1/2 signaling pathway, which positively regulated the NF-κB signaling pathway and negatively regulated the PI3K/AKT signaling pathway. Rosamultin protected vascular endothelial cells against hypoxia-induced apoptosis by activating the PI3K/AKT signaling pathway and positively regulating ERK1/2 and NF-κB signaling pathways.

Predictors of poor outcomes in 488 patients with herb-induced liver injury.

BACKGROUND/AIMS: Herb-induced liver injury (HILI) can lead to chronic liver injury, liver transplantation, or even death. This study aimed to identify the predictors of poor HILI outcomes, especially chronic HILI. MATERIALS AND METHODS: Clinical data of 488 patients with HILI were retrospectively analyzed from a Chinese center between January 2010 and January 2014. Logistic regression and C-statistic were used to identify risk factors and prognostic models for HILI outcomes. RESULTS: In all patients, 69 (14.1%) developed chronic HILI, and 20 (4.1%) died due to liver injury or underwent liver transplantation. To predict the fatal HILI prognosis, the model for end-stage liver disease (MELD) with a C-statistic of 0.981 (95%CI 0.968-0.995) was better than Hy's law (C-statistic 0.569; 95%CI 0.449-0.689). The latency, course of peak alanine aminotransferase decreasing >50% after discontinuation of herb application, peak triglyceride value, and platelet count at liver injury onset were identified as independent risk factors for chronicity with the adjusted odds ratios of 1.268 (95% confidence interval [CI] 1.034-1.554), 2.303 (95%CI 1.588-3.340), 0.580 (95%CI 0.343-0.978), and 0.183 (95%CI 0.091-0.368), respectively. A prognostic model for chronic HILI based on these four factors yielded the best prediction with a C-statistic of 0.812 (95%CI 0.755-0.868), compared with MELD (C-statistic 0.506; 95%CI 0.431-0.581) and Hy's law (C-statistic 0.418; 95%CI 0.343-0.492). CONCLUSION: Model for end-stage liver disease can be used to predict the fatal prognosis of HILI. A long latency, slow recovery, and low triglyceride value and platelet counts are important determinants for chronic HILI.

Therapeutic Effects of a Traditional Chinese Medicine Formula Plus Tamoxifen vs. Tamoxifen for the Treatment of Mammary Gland Hyperplasia: A Meta-Analysis of Randomized Trials.

As a common disorder that accounts for over 70% of all breast disease cases, mammary gland hyperplasia (MGH) causes a severe problem for the quality of patients' life, and confers an increased risk of breast carcinoma. However, the etiology and pathogenesis of MGH remain unclear, and the safety and efficacy of current western drug therapy for MGH still need to be improved. Therefore, a meta-analysis was conducted by our team to determine whether a TCM formula named Ru-Pi-Xiao in combination with tamoxifen or Ru-Pi-Xiao treated alone can show more prominent therapeutic effects against MGH with fewer adverse reactions than that of tamoxifen. Studies published before June 2017 were searched based on standardized searching rules in several mainstream medical databases. A total of 27 articles with 4,368 patients were enrolled in this meta-analysis. The results showed that the combination of Ru-Pi-Xiao and tamoxifen could exhibit better therapeutic effects against MGH than that of tamoxifen (OR: 3.79; 95% CI: 3.09-4.65; P < 0.00001) with a lower incidence of adverse reactions (OR: 0.35; 95% CI: 0.28-0.43; P < 0.00001). The results also suggested that this combination could improve the level of progesterone (MD: 2.22; 95% CI: 1.72-2.71; P < 0.00001) and decrease the size of breast lump (MD: -0.67; 95% CI: -0.86 to -0.49; P < 0.00001) to a greater extent, which might provide a possible explanation for the pharmacodynamic mechanism of Ru-Pi-Xiao plus tamoxifen. In conclusion, Ru-Pi-Xiao and related preparations could be recommended as auxiliary therapy combined tamoxifen for the treatment of MGH.

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.

Inhibition activity of a traditional Chinese herbal formula Huang-Lian-Jie-Du-Tang and its major components found in its plasma profile on neuraminidase-1.

Huang-Lian-Jie-Du-Tang (HLJDT), a traditional formula with four TCM herbs, has been used for hundred years for different diseases. The current study aimed to assess the inhibitory activity of HLJDT against H1N1 neuraminidase (NA-1), and identify potent NA-1 inhibitors from its plasma profile. The in vitro NA-1 study has shown that the water extract of HLJDT potently inhibited NA-1 (IC50 = 112.6 µg/ml; Ki = 55.6 µg/ml) in a competitive mode. The IC50 values of the water extracts of its four herbs were as follows: Coptidis Rhizoma, 96.1 µg/ml; Phellodendri Chinensis Cortex, 108.6 µg/ml; Scutellariae Radix, 303.5 µg/ml; Gardeniae Fructus, 285.0 µg/ml. Thirteen compounds found in the plasma profile of HLJDT were also identified as potent NA-1 inhibitors, which included jatrorrhizine, palmatine, epiberberine, geniposide, oroxylin A, berberine, coptisine, baicalein, wogonoside, phellodendrine, wogonin, oroxylin A-7-O-glucuronide and baicalin (sorted in ascending order by their IC50 values). Their inhibitory activities were consistent with molecular docking analysis when considering crystallographic water molecules in the ligand-binding pocket of NA-1. Our current findings suggested that HLJDT can be used as a complementary medicine for H1N1 infection and its potent active compounds can be developed as NA-1 inhibitors.

Establishment and reliability evaluation of the design space for HPLC analysis of six alkaloids in Coptis chinensis (Huanglian) using Bayesian approach.

Coptis chinensis (Huanglian) is a commonly used traditional Chinese medicine (TCM) herb and alkaloids are the most important chemical constituents in it. In the present study, an isocratic reverse phase high performance liquid chromatography (RP-HPLC) method allowing the separation of six alkaloids in Huanglian was for the first time developed under the quality by design (QbD) principles. First, five chromatographic parameters were identified to construct a Plackett-Burman experimental design. The critical resolution, analysis time, and peak width were responses modeled by multivariate linear regression. The results showed that the percentage of acetonitrile, concentration of sodium dodecyl sulfate, and concentration of potassium phosphate monobasic were statistically significant parameters (P < 0.05). Then, the Box-Behnken experimental design was applied to further evaluate the interactions between the three parameters on selected responses. Full quadratic models were built and used to establish the analytical design space. Moreover, the reliability of design space was estimated by the Bayesian posterior predictive distribution. The optimal separation was predicted at 40% acetonitrile, 1.7 g·mL(-1) of sodium dodecyl sulfate and 0.03 mol·mL(-1) of potassium phosphate monobasic. Finally, the accuracy profile methodology was used to validate the established HPLC method. The results demonstrated that the QbD concept could be efficiently used to develop a robust RP-HPLC analytical method for Huanglian.

Metabolomics Coupled with Multivariate Data and Pathway Analysis on Potential Biomarkers in Cholestasis and Intervention Effect of Paeonia lactiflora Pall.

BACKGROUND: The dried root of Paeonia lactiflora Pall. (PLP) is a classical Chinese herbal medicine that has been used to treat hepatic disease for 1000s of years. Our previous work suggested that PLP can be used to treat hepatitis with severe cholestasis. This study explored the mechanism by which PLP affects ANIT-induced cholestasis in rats using a metabolomics approach. METHODS: The effects of PLP on serum indices (TBIL, DBIL, AST, ALT, ALP, and TBA) and the histopathology of the liver were analyzed. Moreover, UHPLC-Q-TOF was performed to identify the possible effect of PLP on metabolites. The pathway analysis was conducted to illustrate the pathways and network by which PLP treats cholestasis. RESULT: High-dose PLP remarkably down-regulated the serum indices and alleviated histological damage to the liver. Metabolomics analyses showed that the therapeutic effect of high-dose PLP is mainly associated with the regulation of several metabolites, such as glycocholic acid, taurocholic acid, glycochenodeoxycholic acid, L(D)-arginine, and L-tryptophan. A pathway analysis showed that the metabolites were related to bile acid secretion and amino acid metabolism. In addition, the significant changes in bile acid transporters also indicated that bile acid metabolism might be involved in the therapeutic effect of PLP on cholestasis. Moreover, a principal component analysis indicated that the metabolites in the high-dose PLP group were closer to those of the control, whereas those of the moderate dose or low-dose PLP group were closer to those of the ANIT group. This finding indicated that metabolites may be responsible for the differences between the effects of low-dose and moderate-dose PLP. CONCLUSION: The therapeutic effect of high-dose PLP on cholestasis is possibly related to regulation of bile acid secretion and amino acid metabolism. Moreover, these findings may help better understand the mechanisms of disease and provide a potential therapy for cholestasis.

Serum Metabolomic Profiling in a Rat Model Reveals Protective Function of Paeoniflorin Against ANIT Induced Cholestasis.

Cholestasis is a leading cause of hepatic accumulation of bile acids resulting in liver injury, fibrosis, and liver failure. Paeoniflorin displays bright prospects in liver protective effect. However, its molecular mechanism has not been well-explored. This study was designed to assess the effects and possible mechanisms of paeoniflorin against alpha-naphthylisothiocyanate-induced liver injury. Ultraperformance liquid chromatography coupled with quadrupole time-of-flight combined with principle component analysis and partial least squares discriminant analysis were integrated to obtain differentiating metabolites for the pathways and clarify mechanisms of disease. The results indicated that paeoniflorin could remarkably downregulate serum biochemical indexes and alleviate the histological damage of liver tissue. Different expression of 14 metabolites demonstrated that paeoniflorin mainly regulated the dysfunctions of glycerophospholipid metabolism and primary bile acid biosynthesis. Moreover, several pathways such as arginine and proline metabolism, ether lipid metabolism, and arachidonic acid metabolism were also related to the efficacy. In conclusion, paeoniflorin has indicated favorable pharmacological effect on serum biochemical indexes and pathological observation on cholestatic model. And metabolomics is a promising approach to unraveling hepatoprotective effects by partially regulating the perturbed pathways, which provide insights into mechanisms of cholestasis.

[Near infrared spectrum monitoring of scale up process for macroporous resin purification of Grardeniae extract].

To establish a fast detection method during the purifying process of the extracts from Grardeniae using macroporous resin based on near infrared spectroscopy. First, the ethanol eluent was collected from the purification process of small size sample; and near infrared (NIR) spectrum was collected. Then the content of the geniposide was determined by HPLC method, and partial least squares (PLS) method was used to establish the quantitative model to predict the content of geniposide by NIR spectrum. This model was used to supervise the changes of geniposide concentrations in ethanol eluent during medium scale process. Experimental results showed that the NIR small scale model can accurately predict the concentrations of geniposide in the production process of medium scale. However, with the proceeding of batch processes, the prediction performance of the model was decreased, so model updating method was employed to maintain the model. After twice updates, the NIR quantitative model can accurately predict the concentrations of the geniposide during medium scale process. Therefore, through model updates, the established NIR quantitative model can be applied in different scales of macroporous resin purification processes, to improve the data utilization efficiency of small scale process and save the cost of rebuilding the quantitative model of medium scale.

Paeonia lactiflora Pall. protects against ANIT-induced cholestasis by activating Nrf2 via PI3K/Akt signaling pathway.

BACKGROUND: Paeonia lactiflora Pall. (PLP), a traditional Chinese herbal medicine, has been used for hepatic disease treatment over thousands of years. In our previous study, PLP was shown to demonstrate therapeutic effect on hepatitis with severe cholestasis. The aim of this study was to evaluate the antioxidative effect of PLP on alpha-naphthylisothiocyanate (ANIT)-induced cholestasis by activating NF-E2-related factor 2 (Nrf2) via phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway. MATERIALS AND METHODS: Liquid chromatography-mass spectrometry (LC-MS) was performed to identify the main compounds present in PLP. The mechanism of action of PLP and its therapeutic effect on cholestasis, induced by ANIT, were further investigated. Serum indices such as total bilirubin (TBIL), direct bilirubin (DBIL), aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), γ-glutamyl transpeptidase (γ-GT), and total bile acid (TBA) were measured, and histopathology of liver was also performed to determine the efficacy of treatment with PLP. Moreover, in order to illustrate the underlying signaling pathway, liver glutathione (GSH) content and mRNA or protein levels of glutamate-cysteine ligase catalytic subunit (GCLc), glutamate-cysteine ligase modulatory subunit (GCLm), Akt, heme oxygenase-1 (HO-1), NAD(P)H/quinone oxidoreductase 1 (Nqo1), and Nrf2 were further analyzed. In addition, validation of PLP putative target network was also performed in silico. RESULTS: Four major compounds including paeoniflorin, albiflorin, oxypaeoniflorin, and benzoylpaeoniflorin were identified by LC-MS analysis in water extract of PLP. Moreover, PLP could remarkably downregulate serum levels of TBIL, DBIL, AST, ALT, ALP, γ-GT, and TBA, and alleviate the histological damage of liver tissue caused by ANIT. It enhanced antioxidative system by activating PI3K/Akt/Nrf2 pathway through increasing Akt, Nrf2, HO-1, Nqo1, GCLc, and GCLm expression. The putative targets network validation also confirmed the important role of PLP in activating Akt expression. CONCLUSION: The potential mechanism of PLP in alleviating ANIT-induced cholestasis could to be related to the induction of GSH synthesis by activating Nrf2 through PI3K/Akt-dependent pathway. This indicates that PLP might be a potential therapeutic agent for cholestasis.

Paeoniflorin ameliorates ANIT-induced cholestasis by activating Nrf2 through an PI3K/Akt-dependent pathway in rats.

Cholestasis causes hepatic accumulation of bile acids leading to liver injury, fibrosis and liver failure. Paeoniflorin, the major active compound isolated from the roots of Paeonia lactiflora pall and Paeonia veitchii Lynch, is extensively used for liver diseases treatment in China. However, the mechanism of paeoniflorin's hepatoprotective effect on cholestasis has not been investigated yet. In this study, we administered paeoniflorin to rats for 3 days prior to alpha-naphthylisothiocyanate (ANIT) administration for once, then went on administering paeoniflorin to rats for 3 days. The data demonstrated that paeoniflorin significantly prevented ANIT-induced change in serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphates (ALP), serum total bilirubin (TBIL), direct bilirubin (DBIL), total bile acid (TBA) and gamma-glutamyl transpeptidase (γ-GT). Histology examination revealed that paeoniflorin treatment rats relieved more liver injury and bile duct proliferation than ANIT-administered rats. Moreover, our data indicated that paeoniflorin could restore glutathione (GSH) and its related synthase glutamate-cysteine ligase catalytic subunit (GCLc) and glutamate-cysteine ligase modifier subunit (GCLm) in ANIT-treated group. In addition, the RNA and protein expression of Akt and nuclear factor-E2-related factor-2 (Nrf2) were also activated by paeoniflorin in ANIT-induced rats. These findings indicated that paeoniflorin protected ANIT-induced cholestasis and increased GSH synthesis by activating Nrf2 through PI3K/Akt-dependent pathway. Therefore, paeoniflorin might be a potential therapeutic agent for cholestasis.

Large dose means significant effect--dose and effect relationship of Chi-Dan-Tui-Huang decoction on alpha-naphthylisothiocyanate-induced cholestatic hepatitis in rats.

BACKGROUND: Large dose application of traditional Chinese medicines has attracted more and more attentions in recent years. However, the scientific connotation of large dose application has not been clarified so far. The present study was designed to investigate the protective effects of Chi-Dan-Tui-Huang decoction (CDTHD) against Alpha-naphthylisothiocyanate (ANIT) induced acute cholestatic hepatitis in rats and explore the dose-effect relationship of CDTHD as a reference for clinical application. METHODS: The administration of CDTHD at a series of doses was performed twice each day for 5 days. The acute cholestasic hepatitis models were induced by intragastric administration of ANIT on the third day of CDTHD administration. Then, the protective effects on cholestatic hepatitis were investigated by examining the following parameters: body weights of rats, morphological and histopathological liver changes, the levels of serum biomarkers including alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, total bilirubin, direct bilirubin and γ-glutamyltranspeptidase. Furthermore, the dose-effect relationship was investigated with the application of correspondence analysis. RESULT: In the tested range of doses, CDTHD at the maximum tolerance dose did not show any toxicity as time went on. The efficacy result showed that CDTHD from 21.6 g/kg⋅d to 86.4 g/kg⋅d exhibited significant hepatoprotective effect against ANIT-induced acute cholestatic hepatitis. It alleviated liver injury and reversed adverse biochemical and histopathological changes in a dose-dependent manner. Correspondence analysis showed that Radix Paeoniae Rubra in CDTHD was the main effective component and CDTHD could enhance the integrated efficacy in dose-dependent manner. CONCLUSIONS: CDTHD is beneficial to liver protection in a dose-dependent manner. Especially large dose demonstrates potent efficacy and Radix Paeoniae Rubra in the formula contributes the main effect on ANIT-induced acute cholestatic hepatitis without toxicity.

Yinchenhao decoction in the treatment of cholestasis: A systematic review and meta-analysis.

ETHNOPHARMACOLOGICAL RELEVANCE: Yinchenhao decoction, a well-known Chinese herbal formula, has been widely used in Chinese Medicine for thousands of years. However, no systematic review of Yinchenhao decoction in treating cholestasis has been completed. This study aims to evaluate the efficacy and safety of the Yinchenhao decoction in treating cholestasis. MATERIALS AND METHODS: The major databases (PubMed, Embase, Cochrane Library, Chinese Biomedical Database, Wanfang database, VIP medicine information system and China National Knowledge Infrastructure) were searched from the databases' inception through November 2014. Randomized controlled trials (RCTs) of Yinchenhao decoction reported in publications for treatment of cholestasis were extracted by two reviewers. The RCTs examined included total efficacy rate and biochemical indices including alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBIL) and direct bilirubin (DBIL). The Cochrane tool was applied to assess the risk of bias of the trials. The main outcomes of the trials were analyzed using Review Manager 5.3 software. The odds ratio (OR) or mean difference (MD) with a 95% confidence interval (CI) was used to measure the effect. RESULTS: Among the 698 studies identified in the literature search, 15 studies involving 1405 subjects with cholestasis were included in the analysis. Yinchenhao decoction demonstrated efficacy in cholestasis treatment whether in a combined application or not. Additionally, the decoction significantly reduced the elevated levels of cholestasis serum markers, such as ALT, AST, TBIL and DBIL, with a significant difference observed in short and long curative time periods. Remarkably, Yinchenhao decoction displayed a significant efficacy in treating the long-term disease. CONCLUSION: No serious adverse event was reported. This meta-analysis provides evidence that Yinchenhao decoction is an effective and safe treatment for cholestasis.

Causes, Features, and Outcomes of Drug-Induced Liver Injury in 69 Children from China.

BACKGROUND/AIMS: Drug-induced liver injury (DILI) is a frequent cause of pediatric liver disease; however, the data on DILI are remarkably limited. METHODS: All 69 children hospitalized with DILI between January 2009 and December 2011 were retrospectively studied. RESULTS: A total of 37.7% of the children had medical histories of respiratory infection. The clinical injury patterns were as follows hepatocellular 89.9%, cholestatic 2.9%, and mixed 7.2%. Liver biopsies from 55 children most frequently demonstrated chronic (47.3%) and acute (27.3%) hepatitis. Hypersensitivity features, namely, fever (31.9%), rash (21.7%), and eosinophilia (1.4%), were found. Twenty-four children (34.8%) developed chronic DILI. Antibiotics (26.1%) were the most common Western medicines (WMs) causing DILI, and the major implicated herbs were Ephedra sinica and Polygonum multiflorum. Compared with WM, the children whose injuries were caused by Chinese herbal medicine (CHM) showed a higher level of total bilirubin (1.4 mg/dL vs. 16.6 mg/dL, p=0.004) and a longer prothrombin time (11.8 seconds vs. 17.3 seconds, p=0.012), but they exhibited less chronic DILI (2/15 vs. 18/39, p=0.031). CONCLUSIONS: Most cases of DILI in children are caused by antibiotics or CHM used to treat respiratory infection and present with hepatocellular injury. Compared with WM, CHM is more likely to cause severe liver injury, but liver injury caused by CHM is curable.

Spectrum-effect relationships between UPLC fingerprints and bioactivities of crude secondary roots of Aconitum carmichaelii Debeaux (Fuzi) and its three processed products on mitochondrial growth coupled with canonical correlation analysis.

ETHNOPHARMACOLOGICAL RELEVANCE: The crude secondary roots of Aconitum carmichaelii Debeaux (Fuzi), together with its processed products, including Yanfuzi, Heishunpian and Paofupian, are commonly applied in clinic using for thousands of years, such as collapse, syncope, rheumatic fever, painful joints and various tumors. AIM OF THE STUDY: To explore the different effects of Fuzi and its processed products on energy metabolism, with mitochondria as the model with the aim of guiding the clinical use of Fuzi and its products. fingerprints of Fuzi, Yanfuzi, Heishunpian and Paofupian were established by Ultra-high Performance Liquid Chromatography (UPLC) and effects of Fuzi and its processed products on rat's liver׳s mitochondrial metabolism were studied by microcalorimetry. Spectrum-effect relationships between UPLC fingerprints and energy metabolism of mitochondria were investigated using canonical correlation analysis (CCA). RESULTS: Because of their inherent differences in chemical compositions, the main activities of energy metabolism of mitochondria were different among Fuzi and its processed products. The potential bioactivity sequence of the tested products was Fuzi>Heishunpian>Paofupian>Yanfuzi. RESULTS of CCA showed that compounds mesaconitine, benzoylaconitine, and benzoylhypacoitine might be the principal active components. CONCLUSION: Altogether, this work provides a general model of combination of UPLC and microcalorimetry to study the spectrum-effect relationships of Fuzi and its processed products which can offer some references for detecting principal components of traditional Chinese medicine on bioactivity to mitochondrial growth.

Microcalorimetry coupled with chemometric techniques for toxicity evaluation of Radix Aconiti Lateralis Preparata (Fuzi) and its processed products on Escherichia coli.

As a widely used traditional Chinese medicine (TCM), Radix Aconiti Lateralis Preparata (Fuzi) is not only efficacious but also poisonous. Its toxicity and processed products should be taken into account and effectively evaluated. In this study, a non-invasive and non-destructive microcalorimetric method was employed to evaluate and compare the toxicity of Fuzi and its three processed products including Yanfupian, Heifupian, and Danfupian on Escherichia coli (E. coli). Some important metabolic information, such as the power-time curves and some quantitative thermokinetic parameters including growth rate constant k, heat output power P, inhibitory ratio I, and half inhibitory concentration IC50, of E. coli growth affected by various concentrations of Fuzi and its processed products were obtained. Combined with chemometric techniques including multivariate analysis of variance and principal component analysis on this information, it could be seen that Fuzi and its processed products could be distinguished according to their toxic effects on E. coli. The IC50 values of 14.6 mg/mL for Fuzi, 59.2 mg/mL for Yanfupian, 118.3 mg/mL for Heifupian, and 182.7 mg/mL for Danfupian illustrated that the sequence of toxicity on E. coli was Fuzi > Yanfupian > Heifupian > Danfupian. This study provided a useful method and idea of the combination of microcalorimetry and chemometrics for studying the toxic effects of TCMs and other substances.