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1.  A Recipe Composed of Chinese Herbal Active Components Regulates Hepatic Lipid Metabolism of NAFLD In Vivo and In Vitro 
BioMed Research International  2016;2016:1026852.
This study is to investigate the therapeutic effects of the recipe composed of Atractylodes macrocephala polysaccharide, chlorogenic acid, and geniposide (named ACG) on experimental nonalcoholic fatty liver (NAFL). The research was divided into two parts as screening experiment and verification experiment. In the screening experiment, we used high-fat diet (HFD) induced NAFL rat model and uniform design to get the recipe from five Chinese herbal active components. In the verification experiment, HFD induced fatty liver rat and mouse NAFL models and free fatty acid (FFA) induced HepG2 cell model were used to verify the effects of ACG. According to the multiple regression equation of the hepatic triglyceride (TG) contents of each group in the screening experiment, the recipe ACG was obtained and the doses of Atractylodes macrocephala polysaccharide, chlorogenic acid, and geniposide for rats were 266.67, 3.33, and 45 mg/kg, respectively. The results of verification experiment verified that ACG could significantly reduce hepatic TG contents of NAFL rats and mice, as well as the cellular TG content of FFA-induced HepG2 cells. ACG could also improve HOMA-IR and hepatic mitochondrial ultrastructure of NAFL mice. Our study verified that ACG recipe could regulate lipid metabolism of NAFL in vivo and in vitro.
doi:10.1155/2016/1026852
PMCID: PMC4812184  PMID: 27069915
2.  Effect of JIANPI HUOXUE decoction on inflammatory cytokine secretion pathway in rat liver with lipopolysaccharide challenge 
AIM: To evaluate the effect of Chinese traditional medicinal prescription, JIANPI HUOXUE decoction (JHD) on cytokine secretion pathway in rat liver induced by lipopolysaccharide (LPS).
METHODS: Twenty-four male SD rats were divided into normal group (n = 4), model group (n = 10) and JHD group (n = 10) randomly. Rats in model group and JHD group were administrated with normal saline or JHD via gastrogavage respectively twice a day for 3 d. One hour after the last administration, rats were injected with LPS via tail vein, 50 μg/kg. Simultaneously, rats in normal group were injected with equivalent normal saline. After LPS stimulation for 1.5 h, serum and liver tissue were collected. Pathological change of liver tissues was observed through hematoxylin-eosin (H.E.) staining. Tumor necrosis factor alpha (TNF-α) in serum were assayed by enzyme linked immunosorbent assay (ELISA). The protein expression of TNF-α, phosphorylated inhibit-κB (p-IκB) and CD68 in liver were assayed by Western blot. The distribution of CD68 protein in liver was observed through immunohistochemical staining. The mRNA expression of TNF-α, interleukin-6 (IL-6), CD14, toll-like receptor 2 (TLR2) and TLR4 in liver were assayed by real-time RT-PCR.
RESULTS: Predominant microvesicular change, hepatocyte tumefaction and cytoplasm dilution were observed in liver tissues after LPS administration as well as obvious CD68 positive staining in hepatic sinusoidal. After LPS stimulation, serum TNF-α (31.35 ± 6.06 vs 12 225.40 ± 9007.03, P < 0.05), protein expression of CD68 (1.13 ± 0.49 vs 3.36 ± 1.69, P < 0.05), p-IκB (0.01 ± 0.01 vs 2.07 ± 0.83, P < 0.01) and TNF-α (0.27 ± 0.13 vs 1.29 ± 0.37, P < 0.01) in liver and mRNA expression of TNF-α (1.96 ± 2.23 vs 21.45 ± 6.00, P < 0.01), IL-6 (4.80 ± 6.42 vs 193.50 ± 36.36, P < 0.01) and TLR2 (1.44 ± 0.62 vs 4.16 ± 0.08, P < 0.01) in liver were also increased significantly. These pathological changes were all improved in JHD group. On the other hand, TLR4 mRNA (1.22 ± 0.30 vs 0.50 ± 0.15, P < 0.05) was down-regulated and CD14 mRNA increased but not significantly after LPS stimulation.
CONCLUSION: JHD can inhibit cytokine secretion pathway induced by LPS in rat liver, which is probably associated with its regulation on CD68, p-IκB and endotoxin receptor TLR2.
doi:10.3748/wjg.14.1851
PMCID: PMC2700410  PMID: 18350622
JIANPI HUOXUE decoction; Lipopolysaccharide; Kupffer cell; Cytokine; Endotoxin receptor
3.  Protective actions of salvianolic acid A on hepatocyte injured by peroxidation in vitro 
doi:10.3748/wjg.v6.i3.402
PMCID: PMC4688763  PMID: 11819609
Salvianolic acid A; hepatocyte; carbon tetrachloride; liver injury; lipid peroxidation; water soluble vitamin E; ALT; AST; superoxide dismutase; malondiadehyde; catalase; lactase dehydrogenase; glutathione peroxidase; glutathione
4.  Chinese medicine CGA formula ameliorates DMN-induced liver fibrosis in rats via inhibiting MMP2/9, TIMP1/2 and the TGF-β/Smad signaling pathways 
Acta Pharmacologica Sinica  2016;37(6):783-793.
Aim:
Chinese medicine CGA formula consists of polysaccharide from Cordyceps sinensis mycelia (CS-PS), gypenosides and amygdalin, which is derived from Fuzheng Huayu (FZHY) capsule for treating liver fibrosis. In this study we attempted to confirm the therapeutic effects of CGA formula in dimethylnitrosamine (DMN)-induced liver fibrosis in rats, and to identify the mechanisms of anti-fibrotic actions.
Methods:
Rats were injected with DMN (10 mg·kg−1·d−1, ip) for 3 consecutive days per week over a 4-week period. The rats then were orally administered with CGA formula (CS-PS 60 mg·kg−1·d−1, gypenosides 50 mg·kg−1·d−1 and amygdalin 80 mg·kg−1·d−1) daily in the next 2 weeks. CS-PS, gypenosides or amygdalin alone were administered as individual component controls, whereas colchicine and FZHY were used as positive controls. Serum biomarkers were measured. Hepatic injury, collagen deposition and stellate cell activation were examined. The MMP activities, expression of TIMP protein and proteins involved in the TGF-β1/Smad signaling pathways in liver tissues were assayed.
Results:
In DMN-treated rats, administration of CGA formula significantly decreased serum ALT, AST and total bilirubin and hepatic hydroxyproline levels, increased serum albumin level, and attenuated liver fibrosis as shown by histological examination. Furthermore, these effects were comparable to those caused by administration of FZHY, and superior to those caused by administration of colchicine or the individual components of CGA formula. Moreover, administration of CGA formula significantly decreased the protein levels of α-SMA, TGF-β1, TGF-β1 receptor (TβR-I), p-TβR-I, p-TβR-II, p-Smad2, p-Smad3, TIMP1 and TIMP2, as well as MMP2 and MMP9 activities in liver tissues of DMN-treated rats.
Conclusion:
Chinese medicine CGA formula ameliorates DMN-induced liver fibrosis in rats, and this effect was likely associated with the down-regulation of MMP2/9 activities, TIMP1/2 protein expression and the TGF-β1/Smad signaling pathways in the liver.
doi:10.1038/aps.2016.35
PMCID: PMC4954767  PMID: 27133300
Chinese medicine; CGA formula; Fuzheng Huayu capsule; liver fibrosis; dimethylnitrosamine; TGF-β1; Smad; MMP2/9; TIMP1/2
5.  Differences in Metabolites of Different Tongue Coatings in Patients with Chronic Hepatitis B 
Tongue coating is one of the important foundations of tongue diagnosis in traditional Chinese medicine (TCM) and plays an important role in reflecting the occurrence, development, and prognosis of the disease. However, its material basis is still poorly understood. In this study, a urinary metabonomic method based on gas chromatography coupled to mass spectrometry (GC/MS) was developed. The distinct clustering in metabolic profile was observed from Group A (thick yellow coating in patients with chronic hepatitis B), Group B (thick white coating in patients with chronic hepatitis B), and Group C (thin white coating with healthy humans) using orthogonal projections to latent structures (OPLS). Based on the variable of importance in the project (VIP) values, some significantly changed metabolites have been identified. These changes were related to the disturbance in energy metabolism, amino acid metabolism, nucleotide metabolism, and gut microflora, which were helpful to understand the material basis leading to the formation of tongue coating. This study demonstrated that tongue coating may have an objective material basis.
doi:10.1155/2013/204908
PMCID: PMC3652181  PMID: 23690837
6.  Qushi Huayu Decoction Inhibits Hepatic Lipid Accumulation by Activating AMP-Activated Protein Kinase In Vivo and In Vitro 
Qushi Huayu Decoction (QHD), a Chinese herbal formula, has been proven effective on alleviating nonalcoholic fatty liver disease (NAFLD) in human and rats. The present study was conducted to investigate whether QHD could inhibit hepatic lipid accumulation by activating AMP-activated protein kinase (AMPK) in vivo and in vitro. Nonalcoholic fatty liver (NAFL) model was duplicated with high-fat diet in rats and with free fatty acid (FFA) in L02 cells. In in vivo experimental condition, QHD significantly decreased the accumulation of fatty droplets in livers, lowered low-density lipoprotein cholesterol (LDL-c), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) levels in serum. Moreover, QHD supplementation reversed the HFD-induced decrease in the phosphorylation levels of AMPK and acetyl-CoA carboxylase (ACC) and decreased hepatic nuclear protein expression of sterol regulatory element-binding protein-1 (SREBP-1) and carbohydrate-responsive element-binding protein (ChREBP) in the liver. In in vitro, QHD-containing serum decreased the cellular TG content and alleviated the accumulation of fatty droplets in L02 cells. QHD supplementation reversed the FFA-induced decrease in the phosphorylation levels of AMPK and ACC and decreased the hepatic nuclear protein expression of SREBP-1 and ChREBP. Overall results suggest that QHD has significant effect on inhibiting hepatic lipid accumulation via AMPK pathway in vivo and in vitro.
doi:10.1155/2013/184358
PMCID: PMC3614185  PMID: 23573117
7.  Effects of Puerariae Radix Extract on Endotoxin Receptors and TNF-α Expression Induced by Gut-Derived Endotoxin in Chronic Alcoholic Liver Injury 
Kudzu (Pueraria lobata) is one of the earliest medicinal plants used to treat alcohol abuse in traditional Chinese medicine for more than a millennium. However, little is known about its effects on chronic alcoholic liver injury. Therefore, the present study observed the effects of puerariae radix extract (RPE) on chronic alcoholic liver injury as well as Kupffer cells (KCs) activation to release tumor necrosis factor alpha (TNF-α) induced by gut-derived endotoxin in rats and macrophage cell line. RPE was observed to alleviate the pathological changes and lipids deposition in liver tissues as well as the serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), and hepatic gamma-glutamyl transpeptidase (GGT) activity. Meanwhile, RPE inhibited KCs activation and subsequent hepatic TNF-α expression and downregulated the protein expression of endotoxin receptors, lipopolysaccharide binding protein (LBP), CD14, Toll-like receptor (TLR) 2, and TLR4 in chronic alcohol intake rats. Furthermore, an in vitro study showed that RPE inhibited the expression of TNF-α and endotoxin receptors, CD14 and TLR4, induced by LPS in RAW264.7 cells. In summary, this study demonstrated that RPE mitigated liver damage and lipid deposition induced by chronic alcohol intake in rats, as well as TNF-α release, protein expression of endotoxin receptors in vivo or in vitro.
doi:10.1155/2012/234987
PMCID: PMC3485520  PMID: 23133491
8.  Serum levels of microRNAs can specifically predict liver injury of chronic hepatitis B 
AIM: To investigate whether circulating microRNAs (miRNAs) can serve as molecular markers to predict liver injury resulted from chronic hepatitis B (CHB).
METHODS: The profiles of serum miRNA expression were first generated with serum samples collected from 10 patients with CHB and 10 healthy donors (Ctrls) by microarray analysis. The levels of several miRNAs were further quantitated by real-time reverse transcription polymerase chain reaction with serum samples from another 24 CHB patients and 24 Ctrls. Serum samples of 20 patients with nonalcohlic steatohepatitis (NASH) were also included for comparison. The comparison in the levels of miRNAs between groups (CHB, NASH and Ctrl) was analyzed with Mann-Whitney U-test. The correlation between miRNAs and clinical pathoparameters was analyzed using Spearman correlation analysis or canonical correlation analysis. The receiver-operator characteristic (ROC) curves were also generated to determine the specificity and sensitivity of each individual miRNA in distinguishing patients with CHB from Ctrls.
RESULTS: miRNA profile analysis showed that 34 miRNAs were differentially expressed between CHB and Ctrl subjects, in which 12 were up-regulated and 22 down-regulated in CHB subject (fold change > 2.0 and P < 0.01). The median levels of miR-122, -572, -575 and -638 were significantly higher (P < 1.00 × 10-5) while miR-744 significantly lower (P < 1.00 × 10-6) in CHB compared with the Ctrl. The levels of miR-122, -572 and -638 were also higher (P < 1.00 × 10-3) while the level of miR-744 lower in CHB (P < 0.05) than in NASH, although the difference between them was not as significant as that between CHB and Ctrl. ROC curve analysis revealed that the levels of miR-122, -572, -575, -638 and -744 in serum were sensitive and specific enough to distinguish CHB, NASH and Ctrl. Multivariate analysis further showed that the levels of these miRNAs were correlated with the liver function parameters. Most significantly, it was the scatter plot of principal component with the levels of these miRNAs, but not the parameters of liver function, which clearly distinguished CHB, NASH and Ctrl subjects.
CONCLUSION: Serum levels of miR-122, -572, -575, -638 and -744 are deregulated in patients with CHB or NASH. The levels of these miRNAs may serve as potential biomarkers for liver injury caused by CHB and NASH.
doi:10.3748/wjg.v18.i37.5188
PMCID: PMC3468850  PMID: 23066312
Chronic hepatitis B; Nonalcohlic steatohepatitis; Serum microRNAs; Liver injury
9.  Classification of Traditional Chinese Medicine Syndromes in Patients with Chronic Hepatitis B by SELDI-Based ProteinChip Analysis 
Traditional Chinese medicine (TCM) syndrome, also called ZHENG, is the basis concept of TCM theory. It plays an important role in TCM practice. There are excess and deficiency syndromes in TCM syndrome. They are the common syndromes in chronic hepatitis B (CHB) patients. Here we aim to explore serum protein profiles and potential biomarkers for classification of TCM syndromes in CHB patients. 24 healthy controls and two cohorts of CHB patients of excess syndrome (n = 25) or deficiency syndrome (n = 19) were involved in this study. Protein profiles were obtained by surface-enhanced laser desorption ionization time-flight mass spectrometry (SELDI-TOF/MS) and multiple analyses were performed. Based on SELDI ProteinChip data, healthy controls and CHB patients or excess and deficiency syndromes in CHB patients were obviously differentiated by orthogonal partial least square (OPLS) analysis. Two significant serum proteins (m/z 4187 and m/z 5032) for classifying excess and deficiency syndromes were found. Moreover, the area under the receiver operating characteristic (ROC) curve was 0.887 for classifying excess and nonexcess syndrome, and 0.700 for classifying deficiency and nondeficiency syndrome, respectively. Therefore, the present study provided the possibility of TCM syndrome classification in CHB patients using a universally acceptable scientific approach.
doi:10.1155/2012/626320
PMCID: PMC3369440  PMID: 22693531
10.  Preventive effects of 1,25-(OH)2VD3 against ConA-induced mouse hepatitis through promoting vitamin D receptor gene expression 
Acta Pharmacologica Sinica  2010;31(6):703-708.
Aim:
To investigate the immunosuppressive effects of 1,25-dihydroxyvitamin D3 (1,25-(OH)2VD3) on concanavalin A (ConA)-induced hepatitis and elucidate the action mechanism.
Methods:
Female BALB/C mice were intravenously administered ConA (20 mg/kg) to induce acute immunological liver injury. Liver damage was evaluated in respect to serum alanine transaminase (ALT) level and liver histological changes. The proliferation of splenocytes was measured by using [3H]-thymidine incorporation. The cytokine level in the cultured splenocyte supernatant was determined by using enzyme-linked immunosorbent assays (ELISAs). The percentage of different splenic T cell subtypes was analyzed by using flow cytometry. The expression of splenic vitamin D receptor (VDR) mRNA and protein was detected by using real-time qRT-PCR and Western blot, respectively.
Results:
1,25-(OH)2VD3 (2.5 μg/kg, ip) significantly decreased the serum ALT levels and markedly attenuated the histological liver damage. The beneficial effect of 1,25-(OH)2VD3 was associated with: (i) inhibition of CD4+ T cell activation; (ii) reduction of interferon-γ (IFN-γ) and elevation of both IL-4 and IL-5 in supernatants of cultured splenocytes; and (iii) elimination of activated T cells by increasing VDR mRNA and protein expression in the spleen.
Conclusion:
1,25-(OH)2VD3 had a significant protective effect against ConA-induced hepatitis, and its mechanism of action was associated with down-regulation of T cell-mediated immunity and up-regulation of VDR gene expression.
doi:10.1038/aps.2010.53
PMCID: PMC4002975  PMID: 20523341
1,25-dihydroxyvitamin D3; concanavalin A; hepatitis; vitamin D receptor; interferon-γ; interleukin 4; interleukin 5
11.  Yiguanjian decoction and its ingredients inhibit angiogenesis in carbon tetrachloride-induced cirrhosis mice 
Background
Cirrhosis is associated with angiogenesis and disruption of hepatic vascular architecture. Yiguanjian (YGJ) decoction, a prescription from traditional Chinese medicine, is widely used for treating liver diseases. We studied whether YGJ or its ingredients (iYGJ) had an anti-angiogenic effect and explored possible mechanisms underlying this process.
Methods
Cirrhosis was induced with carbon tetrachloride (CCl4) (ip) in C57BL/6 mice for 6 weeks. From week 4 to week 6, cirrhotic mice were randomly divided into four groups: sorafenib-treated, YGJ-treated and iYGJ-treated mice and placebo. Serum biochemistries, hydroxyproline (Hyp) content and histopathological changes of hepatic tissues were measured as were α-smooth muscle actin (α-SMA), collagen I, CD31, vascular endothelial growth factor (VEGF), VEGF receptor (VEGFR) 2 and hypoxia-inducible factor (HIF)-1α.
Results
Both YGJ and iYGJ improved serum biochemistries. Changes of histopathology showed that YGJ and iYGJ reduced hepatic tissue necroinflammatory and collagen fiber deposition in cirrhosis mice. Compared to the CCl4 treated animals, Hyp, α-SMA, collagen I, CD31, VEGF, VEGFR, and HIF-1α expression decreased in YGJ and iYGJ groups.
Conclusions
YGJ and iYGJ inhibited liver angiogenesis in cirrhotic mice treated with CCl4 by inhibiting the HIF-1α/VEGF signaling pathway, suggesting that anti-angiogenic effects of YGJ and iYGJ are associated with improving the hepatic hypoxic microenvironment.
doi:10.1186/s12906-015-0862-6
PMCID: PMC4591631  PMID: 26427787
Cirrhosis; Angiogenesis; Yiguanjian
12.  Serum cytokine profiling analysis for zheng differentiation in chronic hepatitis B 
Chinese Medicine  2015;10:24.
Background
Liver-gallbladder dampness-heat (LGDH) and liver kidney yin deficiency (LKYD) syndromes are Chinese medicine (CM) zhengs in chronic hepatitis B (CHB) patients. This study aims to investigate the changes in cytokines and their profiles accompanied by different biological responses in LGDH and LKYD in CHB.
Methods
During 2010–2012, a total of 138 morning fasting venous blood samples were obtained from participants in Shuguang Hospital, Shanghai University of Traditional Chinese Medicine in Shanghai, China. First, serum samples from 20 health controls (HCs) and 40 CHB patients (20 LGDH, 20 LKYD) were collected to detect the profiles of cytokines by multiplex biometric ELISA-based immunoassay. Random forest (RF) with a fivefold cross-validation was used to analyze the significant cytokines. Then the significant cytokines were validated using serum samples from an independent cohort of 60 CHB patients (30 LGDH, 30 LKYD) and 18 HCs.
Results
There were different profiles of cytokines in LGDH and LKYD. Twenty-three significantly differentially expressed cytokines were detected, among which three cytokines, interleukin (IL)-17, macrophage inflammatory protein (MIP)-1α, and MIP-1β, with the largest Gini scores were identified by RF, and further evaluated for their significant changes in serum levels. A receiver-operator characteristic analysis revealed that the logistic regression panel could differentiate LGDH from LKYD (P < 0.001; AUC = 0.827). A functional pathway analysis showed that cytokine–cytokine receptor interaction, cytosolic DNA-sensing pathway, and chemokine signaling pathway overlapped between LGDH and LKYD, whereas Toll-like receptor signaling pathway, intestinal immune network for IgA production, NOD-like receptor signaling pathway, and Jak-STAT signaling pathway were only enriched in LGDH.
Conclusions
There were characteristic cytokines profiles in LGDH and LKYD with different inflammatory and immune responses. IL-17, MIP-1α, and MIP-1β might be involved in the differentiation of LGDH and LKYD in CHB.
Electronic supplementary material
The online version of this article (doi:10.1186/s13020-015-0055-8) contains supplementary material, which is available to authorized users.
doi:10.1186/s13020-015-0055-8
PMCID: PMC4550060  PMID: 26312063
13.  Multicenter clinical study on Fuzhenghuayu capsule against liver fibrosis due to chronic hepatitis B 
AIM: To study the efficacy and safety of Fuzhenghuayu capsule (FZHY capsule, a capsule for strengthening body resistance to remove blood stasis) against liver fibrosis due to chronic hepatitis B.
METHODS: Multicenter, randomized, double blinded and parallel control experiment was conducted in patients (aged from 18 to 65 years) with liver fibrosis due to chronic hepatitis B. Hepatic histologic changes and HBV markers were examined at wk 0 and 24 during treatment. Serologic parameters (HA, LM, P-III-P, IV-C) were determined and B ultrasound examination of the spleen and liver was performed at wk 0, 12 and 24. Liver function (liver function and serologic parameters for liver fibrosis) was observed at wk 0, 6, 12, 18 and 24. Blood and urine routine test, renal function and ECG were examined before and after treatment.
RESULTS: There was no significant difference between experimental group (110 cases) and control group (106 cases) in demographic features, vital signs, course of illness, history for drug anaphylaxis and previous therapy, liver function, serologic parameters for liver fibrosis, liver histologic examination (99 cases in experimental group, 96 cases in control group), HBV markers, and renal function. According to the criteria for liver fibrosis staging, mean score of fibrotic stage(s) in experimental group after treatment (1.80) decreased significantly compared to the previous treatment (2.33, P<0.05), but there was no significant difference in mean score of fibrotic stage(s) (2.11 and 2.14 respectively). There was a significant difference in reverse rate between experimental group (52%) and control group (23.3%) in liver biopsy. With marked effect on decreasing the mean value of inflammatory activity and score of inflammation (P<0.05), Fuzhenghuayu capsule had rather good effects on inhibiting inflammatory activity and was superior to that of Heluoshugan capsule. Compared to that of pretreatment, there was a significant decrease in HA, LM, P-III-P and IV-C content in experimental group after 12 and 24 wk of treatment. The difference in HA, LM, P-III-P and IV-C content between 12 and 24 wk of treatment and pretreatment in experimental group was significantly greater than that in control group (P<0.01-0.05). The effect, defined as two of four parameters lowering more than 30% of the baseline, was 72.7% in experimental group and 27.4% in control group (P<0.01). Obvious improvement in serum Alb, ALT, AST and GGT was seen in two groups. Compared to that of control group, marked improvement in GGT and Alb was seen in experimental group (P<0.05). The effective rate of improvement in serum ALT was 72.7% in experimental group and 59.4% in control group. No significant difference was seen in blood and urine routine and ECG before and after treatment. There was also no significant difference in stable rate in ALT and serologic parameters for liver fibrosis between experimental group and control group after 12 wk of withdrawal.
CONCLUSION: Fuzhenghuayu capsule has good therapeutic effects on alleviating liver fibrosis due to chronic hepatitis B without any adverse effect and is superior to that of Heluoshugan capsule.
doi:10.3748/wjg.v11.i19.2892
PMCID: PMC4305655  PMID: 15902724
Chronic hepatitis B; Fuzhenghuayu capsule
14.  Clinical observation of salvianolic acid B in treatment of liver fibrosis in chronic hepatitis B 
AIM: To evaluate the clinical efficacy of salvianolic acid B (SA-B) on liver fibrosis in chronic hepatitis B.
METHODS: Sixty patients with definite diagnosis of liver fibrosis with hepatitis B were included in the trial. Interferon-γ (IFN-γ) was used as control drug. The patients took orally SA-B tablets or received muscular injection of IFN-γ in the double blind randomized test. The complete course lasted 6 mo. The histological changes of liver biopsy specimen before and after the treatment were the main evidence in evaluation, in combination with the results of contents of serum HA, LN, IV-C, P-III-P, liver ultrasound imaging, and symptoms and signs.
RESULTS: Reverse rate of fibrotic stage was 36.67% in SA-B group and 30.0% in IFN-γ group. Inflammatory alleviating rate was 40.0% in SA-B group and 36.67% in IFN-γ group. The average content of HA and IV-C was significantly lower than that before treatment. The abnormal rate also decreased remarkably. Overall analysis of 4 serological fibrotic markers showed significant improvement in SA-B group as compared with the IFN-γ group. Score of liver ultrasound imaging was lower in SA-B group than in IFN-γ group (HA 36.7% vs 80%, IV-C 3.3% vs 23.2%). Before the treatment, ALT AST activity and total bilirubin content of patients who had regression of fibrosis after oral administration of SA-B, were significantly lower than those of patients who had aggravation of fibrosis after oral administration of SA-B. IFN-γ showed certain side effects (fever and transient decrease of leukocytes, occurrence rates were 50% and 3.23%), but SA-B showed no side effects.
CONCLUSION: SA-B could effectively reverse liver fibrosis in chronic hepatitis B. SA-B was better than IFN-γ in reduction of serum HA content, overall decrease of 4 serum fibrotic markers, and decrease of ultrasound imaging score. Liver fibrosis in chronic hepatitis B with slight liver injury was more suitable to SA-B in anti-fibrotic treatment. SA-B showed no obvious side effects.
doi:10.3748/wjg.v8.i4.679
PMCID: PMC4656320  PMID: 12174378
15.  Effects of salvianolic acid-A on NIH/3T3 fibroblast proliferation, collagen synthesis and gene expression 
AIM: To investigate the mechanisms of salvianolic acid A (SA-A) against liver fibrosis in vitro.
METHODS: NIH/3T3 fibroblasts were cultured routinely, and incubated with 10-4 mol/L-10-7 mol/L SA-A for 22 h. The cell viability was assayed by [3H]proline incorporation, cell proliferation by [3H]TdR incorporation, cell collagen synthetic rate was measured with [3H]proline impulse and collagenase digestion method. The total RNA was prepared from the control cells and the drug treated cells respectively, and α (1) I pro-collagen mRNA expression was semi-quantitatively analyzed with RT-PCR.
RESULTS: 10-4 mol/L SA-A decreased cell viability and exerted some cytotoxiciy, while 10-5 mol/L-10-7 mol/L SA-A did not affect cell viability, but inhibited cell proliferation significantly, and 10-6 mol/L SA-A had the best effect on cell viability among these concentrations of drugs. 10-5 mol/L-10-6 mol/L SA-A inhibited intracellular collagen synthetic rate, but no significant influence on extracellular collagen secretion. Both 10-5 mol/L and 10-6 mol/L SA-A could decrease α (1) I pro-collagen mRNA expression remarkably.
CONCLUSION: SA-A had potent action against liver fibrosis. It inhibited NIH/3T3 fibroblast proliferation, intracellular collagen synthetic rate and type I pro-collagen gene expression, which may be one of the main mechanisms of the drug.
doi:10.3748/wjg.v6.i3.361
PMCID: PMC4688752  PMID: 11819598
salvianolic acid-A; NIH/3T3 fibroblast; cell viability; cell proliferation; collagen; gene expression
16.  Effects of Fuzheng Huayu 319 recipe on liver fibrosis in chronic hepatitis B 
AIM: To investigate clinic effects of Fuzheng Huayu 319 recipe (319 recipe) on liver fibrosis in chronic hepatitis B.
METHODS: Ninety-five patients with chronic hepatitis B were divide into the treated (63 cases) and control (32 cases) group, and orally administrated with 0.5g 319 capsule or 0.5g Dahuang Zhachong pill tid for 3 months, respectively. The liver functions and serological fibrotic markers were observed before and after treatment, 12 cases in the treated group were examined with liver biopsy.
RESULTS: Three hundreds nineteen recipe could remarkably decreased serum ALT level and total bilirubin and significantly improve serum albumin and A/G ratio. Its effects were better than Dahuang Zhachong pill. Before treatment, patients¡äserum monamine oxidase activities, tissue inhibitor of metalloproteinase (TIMP)-1, procollagen type III and laminin were all higher than those of health peoples. These levels decreased remarkably after treatment, and urine hydroxyproline level increased significantly (P<0.001-0.05). Compared with the control, the improvement in treated group was better than that in the control except TIMP-1. According to the scoring system for staging of chronic hepatitis, the fibrotic extents of 7 cases among 12 cases examined by liver biopsy decreased remarkably (1 case decreased by 3 scores, 5 by 2 scores, 1 by 1 score).
CONCLUSION: Fuzheng Huayu 319 recipe had good therapeutic effects on chronic hepatitis B, it could reverse the development of liver fibross to some extent. In general its effects were better than that of Dahuang Zhachong pill.
doi:10.3748/wjg.v4.i4.348
PMCID: PMC4761559  PMID: 11819318
liver cirrhosis/therapy; hepatitis B; Fuzheng Huayu; procollagen; hyaluronic acid; metalloproteinases; hydroxyproline
17.  Study of ZHENG differentiation in Hepatitis B-caused cirrhosis: a transcriptional profiling analysis 
Background
In traditional Chinese medicine (TCM) clinical practice, ZHENG (also known as TCM syndrome) helps to understand the human homeostasis and guide individualized treatment. However, the scientific basis of ZHENG remains unclear due to limitations of current reductionist approaches.
Methods
We collected the leukocyte samples of three hepatitis B-caused cirrhosis (HBC) patients with dampness-heat accumulation syndrome (DHAS) and three HBC patients with liver depression and spleen deficiency syndrome (LDSDS) for microarray analysis. We generated Gene-Regulatory-Networks (GeneRelNet) from the differentially expressed genes (DEGs) of microarray date. Core genes were validated using anther independent cohort of 40 HBC patients (20 DHAS, 20 LDSDS) with RT-PCR.
Results
There were 2457 mapped genes were differentially expressed between DHAS and LDSDS (Fold change ≥ 2.0, P < 0.05). There were markedly different genes co-expression patterns in DHAS and LDSDS. Furthermore, three differential co-expression genes including purine nucleoside phosphorylase (PNP); aquaporin 7 (AQP7) and proteasome 26S subunit, non-ATPase 2 (PSMD2) were screened by GeneRelNets, and their mRNA expressions were further validated by real time RT-PCR. The results were consistent with microarray. The PNP (P = 0.007), AQP7 (P = 0.038) and PSMD2 (P = 0.009) mRNA expression is significant difference between DHAS and LDSDS using the non-parametric test. Furthermore, we constructed an mRNA panel of PNP, AQP7 and PSMD2 (PAP panel) by logistic regression model, and evaluated the PAP panel to distinguish DHAS from LDSDS by area under the receiver operating characteristic curve (AUC) analysis, which showed a higher accuracy (AUC = 0.835). Gene ontology (GO) analysis indicated that the DHAS is most likely related to system process while the functions overrepresented by LDSDS most related to the response to stimulus.
Conclusions
This study suggested that there are particular transcriptional profiles, genes co-expressions patterns and functional properties of DHAS and LDSDS, and PNP, AQP7, and PSMD2 may be involved in ZHENG differentiation of DHAS and LDSDS in HBC.
Electronic supplementary material
The online version of this article (doi:10.1186/1472-6882-14-371) contains supplementary material, which is available to authorized users.
doi:10.1186/1472-6882-14-371
PMCID: PMC4192401  PMID: 25280538
ZHENG differentiation; Transcriptional profiling; Differentially expressed genes; Gene co-expression; Hepatitis B-caused cirrhosis
18.  Chinese Herbal Medicine-induced Liver Injury 
The widespread use of Chinese herbal medicine (CHM) and the associated adverse reactions has attracted the attention of researchers and physicians. Reports have shown that several types of CHM can cause liver injury, with increasing numbers of cases reported every year. The difficulty in characterizing CHM-induced liver injury stems from clinical manifestations, diagnosis and pathogenesis. The clinical manifestations are varied, but gastrointestinal symptoms are the majority. The Council for International Organizations of Medical Sciences scale is currently the most commonly used method for assessing causality in cases of medicine-induced liver injury with excellent sensitivity, specificity and predictive validity. However, the pathogenesis of CHM-induced liver injury is not well understood. The classic view encompasses a contribution from “toxic metabolites” that either elicit an immune response or directly affect cellular biochemical processes or functions. In addition, poor quality and inappropriate clinical use of CHMs contribute to safety concerns. To ensure the safe use of CHMs and decrease the number of hepatotoxic cases, clinicians, researchers and pharmaceutical companies should share responsibility by regulating clinical use, strengthening basic toxicology research and establishing a strict quality control system.
doi:10.14218/JCTH.2014.00009
PMCID: PMC4521244  PMID: 26355537
Chinese herbal medicine; Liver injury
19.  Circulating miR-583 and miR-663 Refer to ZHENG Differentiation in Chronic Hepatitis B 
Traditional Chinese medicine (TCM) ZHENG as the key pathological principle is to understand the human homeostasis and guide TCM treatment. Here, circulating microRNAs (miRNAs) were utilized to differentiate between ZHENGs including liver-gallbladder dampness-heat syndrome (LGDHS) and liver-kidney yin deficiency syndrome (LKYDS) in chronic hepatitis B (CHB). Sera samples of CHB patients with LGDHS (n = 35), LKYDS (n = 24), and healthy controls (Ctrls, n = 21) were analyzed by microarray and real-time RT-PCR. Receiver-operator characteristic (ROC) curves were established to evaluate the levels of serum miRNA for discriminating LGDHS and LKYDS. The target genes of miRNAs were predicted by TargetScan. Gene Ontology (GO) and pathways were analyzed using DAVID tool. The results showed that 22 miRNAs were differentially expressed between LGDHS and LKYDS (fold change >2.0 and P < 0.01). Circulating miR-583 and miR-663 were significantly higher (P < 0.001) in CHB patients with LGDHS than those with LKYDS and Ctrls. ROC curve analysis revealed that miR-583 and miR-663 were sensitive and specific enough to distinguish LGDHS from LKYDS. Pathway enrichment analysis indicated that 354 putative targets for miR-583 and 68 putative targets for miR-663 were mainly involved in Axon guidance, Neurotrophin, and MAPK signaling pathway. miR-583 and miR-663 may be potential markers for ZHENG differentiation in CHB.
doi:10.1155/2013/751341
PMCID: PMC3608186  PMID: 23554832
20.  Metabonomic Evaluation of ZHENG Differentiation and Treatment by Fuzhenghuayu Tablet in Hepatitis-B-Caused Cirrhosis 
In Traditional Chinese Medicine (TCM), treatment based on ZHENG (also called TCM syndrome and pattern) differentiation has been applied for about 3 thousand years, while there are some difficulties to communicate with western medicine. In the present work, metabonomic methods were utilized to differentiate ZHENG types and evaluate the therapeutic efficiency of Fuzhenghuayu (FZHY) tablet in hepatitis-B-caused cirrhosis (HBC). Urine samples of 12 healthy volunteers (control group, CG) and 31 HBC patients (HBCG) were analyzed by gas chromatography mass spectrometry (GC/MS) and multivariate statistical analysis. The significantly changed metabolites between CG and HBCG were selected by PLS-DA loading plot analysis. Moreover, 4 ZHENGs were differentiated mutually, suggesting that there was urine metabolic material basis in ZHENG differentiation. The efficiency of FZHY tablet on subjects with spleen deficiency with dampness encumbrance syndrome (SDDES) and liver-kidney yin deficiency syndrome (LKYDS) was better than that of other syndromes. The efficiency of FZHY treatment based on ZHENG differentiation indicated that accurately ZHENG differentiating could guide the appropriate TCM treatment in HBC.
doi:10.1155/2012/453503
PMCID: PMC3368351  PMID: 22690245
21.  Ingredients of Huangqi decoction slow biliary fibrosis progression by inhibiting the activation of the transforming growth factor-beta signaling pathway 
Background
Huangqi decoction was first described in Prescriptions of the Bureau of Taiping People's Welfare Pharmacy in Song Dynasty (AD 1078), and it is an effective recipe that is usually used to treat consumptive disease, anorexia, and chronic liver diseases. Transforming growth factor beta 1 (TGFβ1) plays a key role in the progression of liver fibrosis, and Huangqi decoction and its ingredients (IHQD) markedly ameliorated hepatic fibrotic lesions induced by ligation of the common bile duct (BDL). However, the mechanism of IHQD on hepatic fibrotic lesions is not yet clear. The purpose of the present study is to elucidate the roles of TGFβ1 activation, Smad-signaling pathway, and extracellular signal-regulated kinase (ERK) in the pathogenesis of biliary fibrosis progression and the antifibrotic mechanism of IHQD.
Methods
A liver fibrosis model was induced by ligation of the common bile duct (BDL) in rats. Sham-operation was performed in control rats. The BDL rats were randomly divided into two groups: the BDL group and the IHQD group. IHQD was administrated intragastrically for 4 weeks. At the end of the fifth week after BDL, animals were sacrificed for sampling of blood serum and liver tissue. The effect of IHQD on the TGFβ1 signaling pathway was evaluated by western blotting and laser confocal microscopy.
Results
Decreased content of hepatic hydroxyproline and improved liver function and histopathology were observed in IHQD rats. Hepatocytes, cholangiocytes, and myofibroblasts in the cholestatic liver injury released TGFβ1, and activated TGFβ1 receptors can accelerate liver fibrosis. IHQD markedly inhibited the protein expression of TGFβ1, TGFβ1 receptors, Smad3, and p-ERK1/2 expression with no change of Smad7 expression.
Conclusion
IHQD exert significant therapeutic effects on BDL-induced fibrosis in rats through inhibition of the activation of TGFβ1-Smad3 and TGFβ1-ERK1/2 signaling pathways.
doi:10.1186/1472-6882-12-33
PMCID: PMC3419610  PMID: 22471627
Ingredients of Huangqi decoction; Cholestatic liver fibrosis; Transforming growth factor beta 1; Smad-signaling pathway, Extracellular signal-regulated kinase
22.  Notch signaling contributes to the maintenance of both normal neural stem cells and patient-derived glioma stem cells 
BMC Cancer  2011;11:82.
Background
Cancer stem cells (CSCs) play an important role in the development and recurrence of malignant tumors including glioma. Notch signaling, an evolutionarily conserved pathway mediating direct cell-cell interaction, has been shown to regulate neural stem cells (NSCs) and glioma stem cells (GSCs) in normal neurogenesis and pathological carcinogenesis, respectively. However, how Notch signaling regulates the proliferation and differentiation of GSCs has not been well elucidated.
Methods
We isolated and cultivate human GSCs from glioma patient specimens. Then on parallel comparison with NSCs, we inhibited Notch signaling using γ-secretase inhibitors (GSI) and assessed the potential functions of Notch signaling in human GSCs.
Results
Similar to the GSI-treated NSCs, the number of the primary and secondary tumor spheres from GSI-treated GSCs decreased significantly, suggesting that the proliferation and self-renewal ability of GSI-treated GSCs were attenuated. GSI-treated GSCs showed increased differentiation into mature neural cell types in differentiation medium, similar to GSI-treated NSCs. Next, we found that GSI-treated tumor spheres were composed of more intermediate progenitors instead of CSCs, compared with the controls. Interestingly, although inhibition of Notch signaling decreased the ratio of proliferating NSCs in long term culture, we found that the ratio of G2+M phase-GSCs were almost undisturbed on GSI treatment within 72 h.
Conclusions
These data indicate that like NSCs, Notch signaling maintains the patient-derived GSCs by promoting their self-renewal and inhibiting their differentiation, and support that Notch signal inhibitor GSI might be a prosperous candidate of the treatment targeting CSCs for gliomas, however, with GSI-resistance at the early stage of GSCs cell cycle.
doi:10.1186/1471-2407-11-82
PMCID: PMC3052197  PMID: 21342503

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