1.Cyclooxygenase-2 Inhibitor Reduces Hepatic Stiffness in Pediatric Chronic Liver Disease Patients Following Kasai Portoenterostomy.
Hye Kyung CHANG ; Eun Young CHANG ; Seonae RYU ; Seok Joo HAN
Yonsei Medical Journal 2016;57(4):893-899
PURPOSE: The purpose of this study was to define the role of cyclooxygenase-2 inhibitors (COX-2i) in reducing hepatic fibrosis in pediatric patients with chronic liver disease. MATERIALS AND METHODS: From September 2009 to September 2010, patients over 2 years old who visited our outpatient clinic for follow-up to manage their chronic liver disease after Kasai portoenterostomy for biliary atresia, were included in this study. Volunteers were assigned to the study or control groups, according to their preference. A COX-2i was given to only the study group after obtaining consent. The degree of hepatic fibrosis (liver stiffness score, LSS) was prospectively measured using FibroScan, and liver function was examined using serum analysis before and after treatment. After 1 year, changes in LSSs and liver function were compared between the two groups. RESULTS: Twenty-five patients (18 females and 7 males) were enrolled in the study group. The control group included 44 patients (26 females and 18 males). After 1 year, the least square mean values for the LSSs were significantly decreased by 3.91±0.98 kPa (p=0.004) only in the study group. Serum total bilirubin did not decrease significantly in either group. CONCLUSION: COX-2i treatment improved the LSS in patients with chronic liver disease after Kasai portoenterostomy for biliary atresia.
Biliary Atresia/complications/enzymology/*surgery
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Child
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Child, Preschool
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Chronic Disease
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Cyclooxygenase 2 Inhibitors/*therapeutic use
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Female
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Humans
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Liver Cirrhosis/etiology/pathology/*prevention & control
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Male
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*Portoenterostomy, Hepatic
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Thiazines/*therapeutic use
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Thiazoles/*therapeutic use
2.Effect of Fuzheng Huayu recipe on CYP450 isozymes in normal and liver fibrosis rats.
Tian-hui ZHENG ; Wei LIU ; Shu-ping LI ; Tao YANG ; Chang-hong WANG ; Cheng-hai LIU
China Journal of Chinese Materia Medica 2015;40(6):1166-1172
To study the effect of Fuzheng Huayu recipe (FZHY) on five types of isozymes of cytochrome P450 (CYP450) of normal and liver fibrosis rats by using the cocktail probe method. Dimethylnitrosamine ( DMN) was injected to induce the liver fibrosis model. After the tail vein injection with Cocktail probe solutions prepared with five CYP450s probe substrates (phenacetin-CYP1A2, omeprazole-CYP2C9, tolbutamide-CYP2C19, dextromethorphan-CYP2D6, midazolam-CYP3A4), the plasma concentrations of the five probe substrates were determined by LC-MS/MS, and the pharmacokinetic parameters were calculated by PK solutions 2. After the oral administration with FZHY, normal rats given phenacetin, omeprazole, tolbutamide and dextromethorphan showed increase in AUC(0-t) and decrease in CL to varying degrees, indicating that FZHY obviously inhibited the activities of CYP1A2, CYP2C9, CYP2C19 and CYP2D6 in normal rats, but with no obvious effect on the activity of CYP3A4. After the oral administration with FZHY, liver fibrosis rats treated with CYP2C9 showed the significant increase in AUC(0-t) and significant decrease in Vd, hut with no obvious changes in the pharmacokinetic parameters of other four types of prove substances, suggesting that FZHY could significantly inhibit the activity of CYP2C9 in rats but had no effect on the activities of CYP1A2, CYP2C19, CYP2D6 and CYP3A4. The changes in the activity of CYP450 isozymes in liver fibrosis rats may be the reason for FZHY's different effects on CYP450 isozymes in normal and liver fibrosis rats.
Animals
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Cytochrome P-450 Enzyme System
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genetics
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metabolism
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Disease Models, Animal
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Drugs, Chinese Herbal
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administration & dosage
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chemistry
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pharmacokinetics
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Humans
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Isoenzymes
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genetics
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metabolism
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Liver Cirrhosis
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drug therapy
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enzymology
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genetics
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Male
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Mass Spectrometry
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Rats
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Rats, Wistar
3.Study on effect of scutellarin in resisting liver fibrosis in rats.
Yin-hui WANG ; Ling GENG ; Hui LI
China Journal of Chinese Materia Medica 2015;40(10):1999-2003
Totally 80 rats were randomly divided into the control group, the model group, low, middle and high dose (25, 50, 100 mg x kg(-1)) scutellarin( SC) groups and the colchicine ( Col) group. Apart from the blank group, all of the remaining groups were intraperitoneally injected with 0.5 mL pig serum twice every week for consecutively 13 weeks and orally administered with the corresponding drugs since the 9th week. The blank group and the model group were orally given equal volume of normal saline once every for consecutively four weeks. After the experiment, efforts were made to detect the contents of alanine aminotransferase (ALT), aspertate aminotransferase (AST), albumin (ALB), total protein (TP), total bilirubin (TBIL), hyaluronic acid (HA), laminin (LN) and collagen type IV (CIV), collect liver tissues of fixed positions, observe the pathological changes through hematoxylin-eosin (HE) staining, conduct the pathological grading for liver fibrosis, determine the expressions of hepatic collagen type I and III (C I, C III) and calculate their color rendering index. Compared with the model group, low, middle and high dose (25, 50, 100 mg x kg(-1)) SC groups could decrease the contents of ALT, AST, TBIL, HA, LN, CIV, increase the contents of ALB, TP in serum and reduce the contents of C I, C III in liver tissues. In conclusion, scutellarin has a certain therapeutic effect on immune liver fibrosis in rats induced by pig serum.
Alanine Transaminase
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genetics
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metabolism
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Animals
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Apigenin
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administration & dosage
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Bilirubin
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genetics
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metabolism
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Collagen Type IV
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genetics
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metabolism
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Drugs, Chinese Herbal
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administration & dosage
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Glucuronates
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administration & dosage
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Humans
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Liver
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drug effects
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enzymology
;
metabolism
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Liver Cirrhosis
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drug therapy
;
genetics
;
metabolism
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Male
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Rats
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Rats, Sprague-Dawley
4.Reverse effect of Yinchenhao decoction in dimethyl nitrosamine-induced hepatic fibrosis in rats.
Yong-Hong WANG ; Chen-Xi ZHAO ; Ben-Mei CHEN ; Min HE ; Lin-Qi LIU ; Chun-Yan LI ; Xin CHEN
China Journal of Chinese Materia Medica 2014;39(8):1473-1478
OBJECTIVETo discuss the reverse effect of Yinchenhao decoction(YCHD) in dimethyl nitrosamine (DMN)-induced hepatic fibrosis in rats.
METHODThe rat hepatic fibrosis model was established through the intraperitoneal injection with 1% dimethyl nitrosamine (DMN) with a dose of 1.0 mL x kg(-1) x d(-1) for consecutively three weeks, once for the first three days of each. The rats were randomly divided into six groups: the silymarin positive control group (50.0 mg x kg(-1) x d(-1), YCHD high (20.0 g x kg(-1) d(-1)), middle (8.0 g x kg(-1) x d(-1)) and low (3.2 g x kg(-1) x d(-1)) dose groups, the model group and the normal control group. The model group and the normal control group were orally administered with normal saline for consecutively five weeks. The pathologic changes in liver tissues were observed by HE staining. The levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), g-glutamyltransferase (g-GGT), hyaluronic acid (HA), laminin (LN), collagen type IV (CIV) and type III procollagen amino terminal peptide (PIIINP) in serum were determined. The metabolite profiling of amino acid and the content of hydroxyproline in liver tissues were also measured.
RESULTCompared with the model group, YCHD high and middle dose groups could significantly reverse the pathologic changes in liver tissues of rats. YCHD could reduce the levels of ALT, AST, gamma-GGT, HA, LN, CIV, PIIINP in serum and the content of hydroxyproline in liver tissues in a dose-dependent manner, and altered the metabolite profiling of amino acid in rat liver tissues.
CONCLUSIONYCHD has the effect in reversing dimethyl nitrosamine induced hepatic fibrosis in rats.
Alanine Transaminase ; metabolism ; Animals ; Aspartate Aminotransferases ; metabolism ; Collagen Type IV ; metabolism ; Dimethylnitrosamine ; adverse effects ; Drugs, Chinese Herbal ; administration & dosage ; Humans ; Hydroxyproline ; metabolism ; Liver ; drug effects ; enzymology ; metabolism ; Liver Cirrhosis ; chemically induced ; drug therapy ; enzymology ; Male ; Rats ; Rats, Sprague-Dawley
5.Effects of Ganfukang on expression of connective tissue growth factor and focal adhesion kinase/protein kinase B signal pathway in hepatic fibrosis rats.
Kun ZHANG ; Miao-na JIANG ; Cai-hua ZHANG ; Cong LI ; Yu-jie JIA
Chinese journal of integrative medicine 2014;20(6):438-444
OBJECTIVETo investigate the effect of Ganfukang (GFK) on connective tissue growth factor (CTGF) and focal adhesion kinase (FAK)/protein kinase B (PKB or Akt) signal pathway in a hepatic fibrosis rat model and to explore the underlying therapeutic molecular mechanisms of GFK.
METHODSFifty SD rats were randomly divided into five groups as follows: the control group, the model group (repeated subcutaneous injection of CCl4), and the three GFK treatment groups (31.25, 312.5, and 3125 mg/kg, intragastric administration). Reverse transcriptase-polymerase chain reaction (RT-PCR), Western blotting, and immunohistochemistry were used to examine the expression of CTGF, integrin α5, integrin β1, FAK/Akt signal pathway, cyclinD1, and collagen in the different-treated rats.
RESULTSGFK attenuated the up-regulation of CTGF, integrin α5, and integrin β1 in hepatic fibrosis rats and suppressed both the phosphorylation of FAK and the phosphorylation of Akt simultaneously (P<0.01). At the same time, the expression of cyclinD1, collagen I, and collagen III was decreased by GFK significantly (P<0.01).
CONCLUSIONSCTGF and FAK/Akt signal pathway were activated in the CCl4-induced hepatic fibrosis rats, which contribute to increased expression of cyclinD1 and collagen genes. The mechanisms of the anti-fibrosis activity of GFK may be due to its effects against CTGF and FAk/Akt signal pathway.
Animals ; Collagen ; genetics ; metabolism ; Connective Tissue Growth Factor ; genetics ; metabolism ; Cyclin D1 ; genetics ; metabolism ; Drugs, Chinese Herbal ; pharmacology ; therapeutic use ; Female ; Focal Adhesion Protein-Tyrosine Kinases ; metabolism ; Gene Expression Regulation ; drug effects ; Integrin alpha5 ; genetics ; metabolism ; Integrin beta1 ; genetics ; metabolism ; Liver ; drug effects ; enzymology ; pathology ; Liver Cirrhosis ; drug therapy ; enzymology ; genetics ; pathology ; Male ; Phosphorylation ; drug effects ; Proto-Oncogene Proteins c-akt ; metabolism ; Rats, Sprague-Dawley ; Signal Transduction ; drug effects
6.Fasudil hydrochloride hydrate, a Rho-kinase inhibitor, ameliorates hepatic fibrosis in rats with type 2 diabetes.
Hong ZHOU ; Caixia FANG ; Lihui ZHANG ; Yonggui DENG ; Mian WANG ; Fengling MENG
Chinese Medical Journal 2014;127(2):225-231
BACKGROUNDHyperglycemia may accelerate liver fibrosis. Currently, there is no effective treatment for liver fibrosis induced by type 2 diabetes. The study aim was to investigate whether RhoA/Rho kinase (ROCK) pathway is involved in liver fibrosis in the rats with type 2 diabetes and define the protective effects of fasudil on livers.
METHODSA rat model of type 2 diabetes was established by high fat diet combined with streptozotocin (30 mg/kg, intraperitoneal injection). Animals were randomly assigned to 3 groups: control rats, untreated diabetic rats that received vehicle and fasudil-treated diabetic rats that received ROCK inhibitor fasudil hydrochloride hydrate (10 mg/kg per day, intraperitoneal injection, for 14 weeks). The morphological features of liver were observed by HE staining. Accumulation of collagen in livers was determined by Masson staining and the measurement of hydroxyproline. The mRNA expression of transforming growth factor-β1 (TGFβ1), connective tissue growth factor (CTGF), type-I, and type-III procollagen was assessed with real-time polymerase chain reaction. The phosphorylation of myosin phosphatase target subunit-1 (MYPT1) and the protein levels of TGFβ1 and α-smooth muscle actin (a-SMA) were evaluated by Western blotting.
RESULTSCompared with control rats, untreated diabetic rats showed higher values of collagen and hydroxyproline in livers (P < 0.01), the phosphorylation of MYPT1 and the protein levels of TGFβ1 and α-SMA were increased (P < 0.01), and the mRNA expression of TGFβ1, CTGF, type-I, and type-III procollagen was upregulated (P < 0.01); compared with untreated diabetic rats, treatment with fasudil signifcantly reduced values of collagen and hydroxyproline (P < 0.01), and decreased the phosphorylation of MYPT1 and the levels of TGFβ1 and α-SMA (P < 0.01), concomitant with the downregulation of TGFβ1/CTGF, type-I, and type-III procollagen mRNA expression (P < 0.01).
CONCLUSIONSFasudil ameliorates liver fibrosis in rats with type 2 diabetes at least partly by inhibiting TGFβ1/CTGF pathway and α-SMA expression. Inhibition of RhoA/ROCK may be a novel therapeutic target for liver fibrosis in diabetic non-alcoholic steatohepatitis.
1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine ; analogs & derivatives ; therapeutic use ; Animals ; Connective Tissue Growth Factor ; metabolism ; Diabetes Mellitus, Type 2 ; drug therapy ; Female ; Liver Cirrhosis ; drug therapy ; enzymology ; metabolism ; Protein Kinase Inhibitors ; therapeutic use ; Rats ; Rats, Sprague-Dawley ; Transforming Growth Factor beta1 ; metabolism ; rho-Associated Kinases ; antagonists & inhibitors
7.Total Cholesterol Level for Assessing Pancreatic Insufficiency Due to Chronic Pancreatitis.
Kenji HIRANO ; Tomotaka SAITO ; Suguru MIZUNO ; Minoru TADA ; Naoki SASAHIRA ; Hiroyuki ISAYAMA ; Miho MATSUKAWA ; Gyotane UMEFUNE ; Dai AKIYAMA ; Kei SAITO ; Shuhei KAWAHATA ; Naminatsu TAKAHARA ; Rie UCHINO ; Tsuyoshi HAMADA ; Koji MIYABAYASHI ; Dai MOHRI ; Takashi SASAKI ; Hirofumi KOGURE ; Natsuyo YAMAMOTO ; Yosuke NAKAI ; Kazuhiko KOIKE
Gut and Liver 2014;8(5):563-568
BACKGROUND/AIMS: To determine the nutritional markers important for assessing the degree of pancreatic insufficiency due to chronic pancreatitis in routine clinical practice. METHODS: A total of 137 patients with chronic pancreatitis were followed up for more than 1 year. They were divided into two groups: a pancreatic diabetes mellitus (DM) group, consisting of 47 patients undergoing medical treatment for DM of pancreatic origin, and a nonpancreatic DM group, consisting of 90 other patients (including 86 patients without DM). Serum albumin, prealbumin, total cholesterol, cholinesterase, magnesium, and hemoglobin were compared between the two groups. RESULTS: The total cholesterol was significantly lower in the pancreatic than the nonpancreatic DM group (164 mg/dL vs 183 mg/dL, respectively; p=0.0028). Cholinesterase was significantly lower in the former group (263 U/L vs 291 U/L, respectively; p=0.016). Among the 37 patients with nonalcoholic pancreatitis, there was no difference in the cholinesterase levels between the pancreatic and nonpancreatic (296 U/L vs 304 U/L, respectively; p=0.752) DM groups, although cholesterol levels remained lower in the former (165 mg/dL vs 187 mg/dL, respectively; p=0.052). CONCLUSIONS: Cholinesterase levels are possibly affected by concomitant alcoholic liver injury. The total cholesterol level should be considered when assessing pancreatic insufficiency due to chronic pancreatitis.
Adult
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Aged
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Aged, 80 and over
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Cholesterol/*blood
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Cholinesterases/blood
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Diabetes Mellitus, Type 2/complications
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Exocrine Pancreatic Insufficiency/*blood/etiology
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Female
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Follow-Up Studies
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Humans
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Liver Cirrhosis, Alcoholic/blood
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Male
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Middle Aged
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Nutritional Status
;
Pancreas/enzymology
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Pancreatitis, Alcoholic/blood/complications
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Pancreatitis, Chronic/blood/*complications
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Serum Albumin/analysis
9.Expression of ASMase in alcoholic liver fibrosis in rats.
Mi WANG ; Qin-fang CAO ; Ping LIU ; Xiao-dan LU ; Shu-juan ZHANG ; Wang-xian TANG ; Cui-huan WU
Chinese Journal of Hepatology 2013;21(12):920-923
OBJECTIVETo investigate the expression of the lysosomal enzyme acid sphingomyelinase (ASMase) in alcohol-induced hepatic fibrosis using a rat model.
METHODSThe model of liver fibrosis was induced by administration of alcohol and high fat diet using 20 rats. Six rats given no alcohol and normal diet served as the control group. Real-time PCR, western blotting, and immunohistochemistry were used to evaluate fibrosis-related changes in the mRNA and protein expressions of ASMase.
RESULTSThe fibrotic liver tissues of the model rats showed significantly higher expression levels of ASMase than the non-fibrotic liver tissues of the control rats (P less than 0.05).
CONCLUSIONExpression of ASMase is increased in the fibrotic liver tissue of an alcohol-induced hepatic fibrosis rat model, suggesting that this lysosomal enzyme may contribute to development of this disease condition.
Animals ; Liver ; enzymology ; Liver Cirrhosis, Alcoholic ; enzymology ; Liver Cirrhosis, Experimental ; enzymology ; Male ; Rats ; Rats, Sprague-Dawley ; Sphingomyelin Phosphodiesterase ; metabolism
10.Protective effect of isoorientin on alcohol-induced hepatic fibrosis in rats.
Yong-Xin CHEN ; Quan-Fang HUANG ; Xing LIN ; Jin-Bin WEI
China Journal of Chinese Materia Medica 2013;38(21):3726-3730
OBJECTIVETo observe the effect and mechanism of isoorientin from Gypsophila elegans on alcohol-induced hepatic fibrosis in rats.
METHODninety healthy male Wistar rats were randomly divided into six groups: the normal control group, the model control group, the colchicines group (positive control, 1.0 mg x kg(-1) x d(-1)), the high, middle and low-dose isoorientin groups (20, 50, 100 mg x kg(-1) x d(-1)). The normal control group received normal saline, while other groups received alcohol to cause hepatic fibrosis. After 24-weeks treatment, the alanine aminotransferase (ALT), aspartate aminotransferase (AST), Interleukin 6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), hyaluronic acid (HA), laminin (LN), type III precollagen (PCIII), hydroxyproline (Hyp), Myeloperoxidase (MPO), malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) were assayed according to the manufacturer's instructions, the alpha-SMA and TGF-beta1 were detected by western blotting, and the histopathological changes was observed by H&E staining.
RESULTIsoorientin could improve the liver function by decreasing the activity of ALT, AST, IL-6, TNF-alpha, MDA, MPO, HA, LN, PCIII and Hyp (P < 0.05), increasing the activity of SOD and GSH-Px (P < 0.05), and reducing the expression of alpha-SMA and TGF-beta1 (P < 0.05). In addition, the high and middle-dose isoorientin groups showed more remarkable effect
CONCLUSIONIsoorientin from G. elegans can protect hepatic fibrosis induced by alcohol.
Alanine Transaminase ; blood ; Animals ; Aspartate Aminotransferases ; blood ; Drugs, Chinese Herbal ; administration & dosage ; Ethanol ; adverse effects ; Glutathione Peroxidase ; blood ; Humans ; Liver Cirrhosis ; chemically induced ; drug therapy ; enzymology ; prevention & control ; Luteolin ; administration & dosage ; Male ; Protective Agents ; administration & dosage ; Rats ; Rats, Wistar ; Transforming Growth Factor beta1 ; metabolism

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