1.Effects of Li-Dan-He-Ji on regulating oxidative stress and antagonising infantile cholestatic hepatic fibrosis.
Wei YI ; Suqi YAN ; Jianqiao TANG ; Xiang MA ; Mengjie SU ; Hong LI
Chinese Critical Care Medicine 2023;35(7):741-745
OBJECTIVE:
To explore the clinical effect of Li-Dan-He-Ji in the treatment of infantile cholestatic hepatic fibrosis.
METHODS:
Patients who met the diagnostic criteria of infantile cholestatic hepatic fibrosis in the department of integrated traditional Chinese and Western medicine and the department of gastroenterology of Wuhan Children's Hospital Affiliated to Tongji Medical College of Huazhong University of Science and Technology from January to December 2021 were included in the study by prospective randomized controlled trial. They were divided into the conventional treatment group and Li-Dan-He-Ji group according to the random number table. The patients in the conventional treatment group were given conventional treatment according to the guidelines. In the Li-Dan-He-Ji group, the self-made Chinese medicinal compound Li-Dan-He-Ji (prescription: Herba Artemisiae Scopariae, Fructus Forsythiae, Radix et Rhizoma Rhei preparata, Radix Polygoni Multiflori Preparata, Radix Paeoniae Rubra, Ramulus Cinnamomi, Fructus Aurantii, Rhizoma Atractylodis Macrocephalae, Fructus Schisandrae Chinensis, Carapax Trionycis, and Radix Glycyrrhizae) was given on the basis of the routine treatment, by oral, enema or nasal feeding, 60 mL each day, divided into 2 or 3 times, for 28 days. Outpatient follow-up was maintained for 4 weeks. Before and after treatment, serum liver fibrosis 4 items [type IV collagen (IV-C), hyaluronidase (HA), type III procollagen (PC III), laminin (LN)], liver function and cholestasis-related markers [total bilirubin (TBil), direct bilirubin (DBil), total bile acid (TBA), alkaline phosphatase (ALP), γ-glutamyl transpeptidase (γ-GGT), alanine aminotransferase (ALT), aspartate aminotransferase (AST)], oxidative stress markers [superoxide dismutase (SOD), malondialdehyde (MDA), and glutathione (GSH)], liver stiffness measurement (LSM) detected by transient elastography (TE), aspartate aminotransferase-to-platelet ratio index (APRI), and liver and spleen retraction time were recorded in the two groups.
RESULTS:
During the observation period, a total of 40 cases of cholestatic hepatic fibrosis were treated, including 21 cases in the conventional treatment group and 19 cases in the Li-Dan-He-Ji group. Before treatment, the differences in serum liver fibrosis 4 items, serum liver function and cholestasis-related markers, oxidative stress indexes, LSM and APRI of the two groups were not statistically significant. After treatment, the liver fibrosis 4 items, liver function and cholestasis-related markers, LSM, and APRI were all significantly decreased in both groups, and the indexes in the Li-Dan-He-Ji group were significantly lower than those in the conventional treatment group [HA (ng/L): 165.81±21.57 vs. 203.87±25.88, PC III (μg/L): 69.86±9.32 vs. 81.82±7.39, IV-C (μg/L): 204.14±38.97 vs. 239.08±24.93, LN (μg/L): 162.40±17.39 vs. 190.86±15.97, TBil (μmol/L): 37.58±27.63 vs. 53.06±45.09, DBil (μmol/L): 20.55±19.34 vs. 30.08±27.39, ALP (U/L): 436.50±217.58 vs. 469.60±291.69, γ-GGT (U/L): 66.78±35.84 vs. 87.00±32.82, ALT (U/L): 64.75±50.53 vs. 75.20±50.19, AST (U/L): 77.25±54.23 vs. 96.80±59.77, TBA (μmol/L): 74.35±44.44 vs. 85.45±39.50, LSM (kPa): 5.24±0.39 vs. 7.53±3.16, APRI: 0.52±0.39 vs. 0.98±0.29, all P < 0.05]. After treatment, MDA in the two groups were significantly lower than those before treatment, and SOD and GSH were significantly higher than those before treatment. The level of SOD in the Li-Dan-He-Ji group was significantly higher than that in the conventional treatment group (kU/L: 64.56±6.69 vs. 51.58±5.98, P < 0.05). In addition, the liver retraction time (day: 20.13±10.97 vs. 24.33±13.46) and spleen retraction time (day: 25.93±13.01 vs. 29.14±14.52) in the Li-Dan-He-Ji group were significantly shorter than those in the conventional treatment group (both P < 0.05).
CONCLUSIONS
The use of Li-Dan-He-Ji in the treatment of cholestatic hepatic fibrosis can effectively improve the indicators of cholestasis, hepatic fibrosis, oxidative stress and clinical symptoms in children.
Child
;
Humans
;
Prospective Studies
;
Cholestasis/pathology*
;
Liver
;
Liver Cirrhosis/drug therapy*
;
Bilirubin/pharmacology*
;
Oxidative Stress
;
Aspartate Aminotransferases/metabolism*
;
Superoxide Dismutase/metabolism*
2.Mechanism of Cinnamomi Ramulus improving rat model of intrahepatic cholestasis induced by ANIT by regulating FXR pathway.
Xin CAI ; Ren-Wu QIN ; Yu-Qing LIU ; Yao WANG ; Lei LUO ; Fan YANG
China Journal of Chinese Materia Medica 2019;44(12):2594-2599
To study the mechanism and action of Cinnamomi Ramulus in ameliorating intrahepatic cholestasis induced by α-isothiocyanate( ANIT) in rats by regulating FXR pathway. Forty SD rats were randomly divided into normal group,model group,positive control( ursodeoxycholic acid) group( 60 mg·kg~(-1)),Cinnamomi Ramulus treatment( 60 mg·kg~(-1)·d~(-1)) group,and Cinnamomi Ramulus treatment( 20 mg·kg~(-1)·d~(-1)) group,with 8 rats in each group. Except for the normal control group,the other groups were intragastrically administered with the corresponding concentrations of continuous aqueous solution( 0. 005 m L·g~(-1)),once a day,for 7 days.Except for the normal group,the other groups were treated with ANIT( 100 mg·kg~(-1)),once a day,for 3 days. Blood was taken from the abdominal aorta 24 hours after the last administration,and serum alanine aminotransferase( ALT),aspartate aminotransferase( AST),total bilirubin( TBi L),and total bile acid( TBA) were measured. 1. 5-2 cm of rat liver tissue was taken. After fixation with10% formaldehyde,paraffin-embedded sections were taken,HE staining was performed,and immunohistochemistry( IHC) was used to analyze the expression of FXR. RNA and protein were extracted from rat liver tissue to detect FXR mRNA expression,as well as bile acid synthesis and detoxification,transport related SHP,UGT2 B4,BSEP protein expressions at downstream of FXR. Compared with the normal group,serum ALT,AST,TBi L,and TBA levels were elevated in the model group( P<0. 01),liver damage was severe,FXR protein's optical density decreased,FXR mRNA expression decreased,and SHP,UGT2 B4,BSEP protein expressions were decreased( P<0. 05,P<0. 01). Compared with the model group,the drug group could reduce serum ALT,AST,TB,TBA levels to different degrees( P<0. 05,P<0. 01),alleviate liver tissue damage,increase the optical density of FXR protein,and promote the expressions of FXR mRNA and FXR,SHP,BSEP and UGT2 B4 proteins( P<0. 05,P<0. 01). Cinnamomi Ramulus can alleviate ANIT-induced intrahepatic cholestasis,and reduce hepatocyte injury and serum ALT,AST,TBi L and TBA levels. The mechanism may be through FXR-SHP,FXR-UGT2 B4,FXR-BSEP signaling pathways. Therefore,in the pathogenesis of intrahepatic cholestasis,we can try to further explore in alleviating intrahepatic cholestasis with Cinnamomi Ramulus,so as to provide effective drugs for clinical treatment of intrahepatic cholestasis.
Alanine Transaminase
;
blood
;
Animals
;
Aspartate Aminotransferases
;
blood
;
Bile Acids and Salts
;
blood
;
Bilirubin
;
blood
;
Cholestasis, Intrahepatic
;
chemically induced
;
drug therapy
;
Cinnamomum
;
chemistry
;
Isothiocyanates
;
Liver
;
Plant Extracts
;
pharmacology
;
RNA-Binding Proteins
;
metabolism
;
Random Allocation
;
Rats
;
Rats, Sprague-Dawley
3.Doxazosin Treatment Attenuates Carbon Tetrachloride-Induced Liver Fibrosis in Hamsters through a Decrease in Transforming Growth Factor beta Secretion.
Martin Humberto MUNOZ-ORTEGA ; Raul Wiliberto LLAMAS-RAMIREZ ; Norma Isabel ROMERO-DELGADILLO ; Tania Guadalupe ELIAS-FLORES ; Edgar DE JESUS TAVARES-RODRIGUEZ ; Maria DEL ROSARIO CAMPOS-ESPARZA ; Daniel CERVANTES-GARCIA ; Luis MUNOZ-FERNANDEZ ; Martin GERARDO-RODRIGUEZ ; Javier VENTURA-JUAREZ
Gut and Liver 2016;10(1):101-108
BACKGROUND/AIMS: The development of therapeutic strategies for the treatment of cirrhosis has become an important focus for basic and clinical researchers. Adrenergic receptor antagonists have been evaluated as antifibrotic drugs in rodent models of carbon tetrachloride (CCl4)-induced cirrhosis. The aim of the present study was to evaluate the effects of carvedilol and doxazosin on fibrosis/cirrhosis in a hamster animal model. METHODS: Cirrhotic-induced hamsters were treated by daily administration of carvedilol and doxazosin for 6 weeks. Hepatic function and histological evaluation were conducted by measuring biochemical markers, including total bilirubin, aspartate aminotransferase, alanine aminotransferase and albumin, and liver tissue slices. Additionally, transforming growth factor beta (TGF-beta) immunohistochemistry was analyzed. RESULTS: Biochemical markers revealed that hepatic function was restored after treatment with doxazosin and carvedilol. Histological evaluation showed a decrease in collagen type I deposits and TGF-beta-secreting cells. CONCLUSIONS: Taken together, these results suggest that the decrease in collagen type I following treatment with doxazosin or carvedilol is achieved by decreasing the profibrotic activities of TGF-beta via the blockage of alpha1- and beta-adrenergic receptor. Consequently, a diminution of fibrotic tissue in the CCl4-induced model of cirrhosis is achieved.
Adrenergic alpha-1 Receptor Antagonists/*pharmacology
;
Alanine Transaminase/blood
;
Animals
;
Aspartate Aminotransferases/blood
;
Bilirubin/blood
;
Carbazoles/*pharmacology
;
Carbon Tetrachloride
;
Collagen Type I/drug effects/metabolism
;
Cricetinae
;
Doxazosin/*pharmacology
;
Liver/metabolism/pathology
;
Liver Cirrhosis/blood/chemically induced/*drug therapy
;
Liver Function Tests
;
Propanolamines/*pharmacology
;
Serum Albumin/analysis
;
Transforming Growth Factor beta/blood/*drug effects
4.Protective effects of Radix Astragali injection on multiple organs of rats with obstructive jaundice.
Zhe-Wei FEI ; Xi-Ping ZHANG ; Jie ZHANG ; Xin-Mei HUANG ; Di-Jiong WU ; Hong-Hao BI
Chinese journal of integrative medicine 2016;22(9):674-684
OBJECTIVETo investigate the protective effects and mechanisms of Radix Astragali Injection on multiple organs of rats with obstructive jaundice (OJ).
METHODSA total of 180 rats were randomly divided into the sham-operated, model control and treated groups (60 in each group). On 7, 14, 21 and 28 days after operation, the serum contents of alanine aminotransferase (ALT), aspartate aminotransferase (AST), r-glutamyl transpeptidase (r-GT), total bilirubin (TBil), direct bilirubin (DBil), blood urine nitrogen (BUN), and creatinine (CREA) were determined. And the pathological changes of livers, kidneys and lungs, and protein expressions of toll-like receptor-4 (TLR-4) of livers, intercellular adhesion molecule-1 (ICAM-1) of lungs, Bax and nuclear factor-kappa B (NF-κB), as well as apoptotic indexes of multiple organs were observed, respectively.
RESULTSThe pathological severity scores of multiple organs (including livers on 7, 14, 21 and 28 days, kidneys on 14 and 28 days, and lungs on 14 days), serum contents of ALT (14 and 21 days), AST (14 days), TBil (7, 14, 21 and 28 days), DBil (14 and 21 days), BUN (28 days), protein expressions of TLR-4 (in livers, 28 days), Bax (in livers and kidneys, 21 days), and apoptotic indexes in livers (7 and 21 days) in the treated group were significantly lower than those in the model control group (P<0.05 or P<0.01).
CONCLUSIONRadix Astragali Injection exerts protective effects on multiple organs of OJ rats by improving the pathological changes of lung, liver and kidney, decreasing the serum index of hepatic and renal function as well as inhibiting the protein expression of TLR-4 and Bax in the livers and Bax in the kidneys.
Alanine Transaminase ; blood ; Animals ; Apoptosis ; drug effects ; Aspartate Aminotransferases ; blood ; Bilirubin ; blood ; Blood Urea Nitrogen ; Creatinine ; blood ; Drugs, Chinese Herbal ; pharmacology ; therapeutic use ; Immunohistochemistry ; Injections ; Intercellular Adhesion Molecule-1 ; metabolism ; Jaundice, Obstructive ; blood ; drug therapy ; Kidney ; drug effects ; pathology ; Liver ; drug effects ; pathology ; Lung ; drug effects ; pathology ; Male ; NF-kappa B ; metabolism ; Organ Specificity ; drug effects ; Plant Extracts ; pharmacology ; Protective Agents ; pharmacology ; therapeutic use ; Rats, Sprague-Dawley ; Toll-Like Receptor 4 ; metabolism ; bcl-2-Associated X Protein ; metabolism ; gamma-Glutamyltransferase ; metabolism
5.The toxic and protective effects of Polygonum multiflorum on normal and liver injured rats based on the symptom-based prescription theory.
Jing-yao PANG ; Zhao-fang BAI ; Ming NIU ; Can TU ; Zhi-jie MA ; Yan-ling ZHAO ; Kui-jun ZHAO ; Yun YOU ; Jia-bo WANG ; Xiao-he XIAO
Acta Pharmaceutica Sinica 2015;50(8):973-979
The dosage-efficacy/toxicity relationship of the 50% alcohol extracts of Polygonum multiflorum was comparatively investigated on either normal or CCl4-induced chronic liver injury rats, by determining the general condition, serum biochemical indices and liver histopathology, coupled with the factor analysis. The dosages were 10 and 20 g raw materials per kg body weight. Compared with the normal control group, the normal high dose group showed significant increases of the serum alanine transaminase (ALT), total bilirubin (TBIL), high mobility group box 1 (HMGB-1) and interleukin-1β (IL-1β) (P < 0.05 or P < 0.01), as well the frequent incidences of inflammatory cell infiltration, hepatic sinus enlargement and fiber stripes formation in histopathological sections. Compared with the model control group, the model low dose group showed significant declines of serum ALT, aspartate transaminase (AST) and total bile acid (TBA) (P < 0.05), as well the alleviation of vacuoles of hepatocytes, but no amelioration of the inflammatory cell infiltration and fibrous tissue hyperplasia; moreover, the model high dose group showed significant degeneration declines of serum HMGB-1, tumor necrosis factor-α (TNF-α) and IL-1β (P < 0.05, P < 0.01), as well the evident alleviation of vacuoles degeneration of hepatocytes, inflammatory cells infiltration and fibrosis degree. The factor analysis showed that the low dosage treatment had almost neither injuring effect on the normal rats nor protective effect on the model rats; while the high dosage treatment showed observable injuring effect on the normal rats, expressed by the significant increases of the factor-1 (HMGB-1, TNF-α and IL-1β as the main contributors) and factor-2 (TBIL, ALT and TBA as the main contributors) relative to the normal control group. The liver protective effect of the high dosage treatment could be observed with the significant reduction of the factor-1, indicating the effective alleviation of the expression of inflammatory cytokines. In conclusion, it could illustrated the phenomenon of symptom-based prescription theory of Polygonum multiflorum on rat livers: the high dosage of the herb had either an injuring effect on normal rats, or a therapeutic effect on the rats with chronic liver injury.
Alanine Transaminase
;
blood
;
Animals
;
Aspartate Aminotransferases
;
blood
;
Bile Acids and Salts
;
metabolism
;
Bilirubin
;
blood
;
Chemical and Drug Induced Liver Injury
;
drug therapy
;
Drugs, Chinese Herbal
;
pharmacology
;
Fallopia multiflora
;
chemistry
;
HMGB1 Protein
;
metabolism
;
Hepatocytes
;
drug effects
;
Interleukin-1beta
;
metabolism
;
Liver
;
drug effects
;
pathology
;
Plant Extracts
;
pharmacology
;
Rats
;
Tumor Necrosis Factor-alpha
;
metabolism
6.Clinical application of blood purification (artificial liver) in treatment of acute liver failure in children.
Xuan XU ; Bang YU ; Bin ZHU ; Haili REN ; Zhichun FENG
Chinese Journal of Pediatrics 2014;52(6):433-437
OBJECTIVETo investigate the clinical application, indication, timing and prognosis of blood purification (artificial liver, BP) in treatment of acute liver failure in children.
METHODArtificial liver was used to treat 30 cases of pediatric acute liver failure (PALF), who were hospitalized in pediatric intensive care unit of Bayi Children's Hospital Affiliated to Beijing Military Command General Hospital, during March 2010 to July 2013. Simple plasma exchange (PE) mode was used for PALF without complications, while PE combined with continuous veno-venous hemodiafiltration (CVVHDF) mode was used for PALF with cerebral edema and/or hepatorenal syndrome and/or serious abnormality of electrolyte and acid-base balance.
RESULTSixteen cases survived and restored hepatic function, with a survival rate of 53.3%. Single PE therapy could significantly decrease total bilirubin (TBIL) from (293.96 ± 214.52) µmol/L to (155.64 ± 140.97) µmol/L (P = 0.033), increase prothrombin time activity (PTA) from (34.50 ± 18.34) % to (60.50 ± 33.97) % (P = 0.013), while it did not significantly influence ammonia from (156.43 ± 67.23) µmol/L to (124.03 ± 62.58) µmol/L (P = 0.156) and alanine transarninase (ALT) from (752.53 ± 1 291.84) U/L to (132.00 ± 98.57) U/L (P = 0.066). PE + CVVHDF therapy could significantly ameliorate TBIL from (326.90 ± 233.85) µmol/L to (157.53 ± 125.31) µmol/L (P = 0.033), ALT from (1 476.64 ± 1 728.18) U/L to (169.38 ± 207.18) U/L (P = 0.019), ammonia from (215.83 ± 83.92) µmol/L to (141.25 ± 63.09) µmol/L (P = 0.022) and PTA from (36.68 ± 23.13)% to (71.75 ± 50.50) % (P = 0.044). Prothrombin time (PT) from (29.71 ± 17.75)s to (16.27 ± 6.38)s (P = 0.008) , ALT from (1 574.11 ± 1 775.96) U/L to (145.81 ± 113.89 ) U/L (P = 0.003) , TBIL from (233.16 ± 219.70) µmol/L to (75.19 ± 86.07) µmol/L (P = 0.012) , ammonia from (182.75 ± 90.07) µmol/L to (101.81 ± 37.14) µmol/L (P = 0.002) and PTA from (38.38 ± 20.39)% to (83.13 ± 41.68)% (P = 0.001) in survived cases significantly ameliorated after BP therapy. TBIL from (394.04 ± 192.80) µmol/L to (249.34 ± 113.97) µmol/L (P = 0.023) in died cases declined significantly after BP therapy, while alteration of PT, ALT, ammonia , and PTA had no statistical significance (P > 0.10) after BP therapy.
CONCLUSIONPE + CVVHDF therapy could significantly ameliorate not only TBIL and PTA but also ammonia and ALT compared with single PE therapy. The decline of only an index like TBIL or ALT after BP therapy could not improve the prognosis. The inconsistency between serum bilirubin and ALT levels was an important factor that suggested poor prognosis of ALF, and it might increase survival rate to use BP therapy before that inconsistency emerged.
Adolescent ; Bilirubin ; blood ; Biomarkers ; blood ; Brain Edema ; etiology ; therapy ; Child ; Child, Preschool ; Female ; Hemodiafiltration ; methods ; Heparin ; pharmacology ; Hepatorenal Syndrome ; etiology ; therapy ; Humans ; Infant ; Liver Failure, Acute ; blood ; complications ; mortality ; therapy ; Liver Function Tests ; Male ; Plasma Exchange ; Prothrombin Time ; Survival Rate ; Treatment Outcome
7.Effect of ulinastatin on liver function of patients after bilateral total knee arthroplasty.
Shuai TANG ; Zhong-huang XU ; Shuo LIU ; Hong YANG ; Li-ying REN ; Wen-wei QIAN ; Yu-guang HUANG
Acta Academiae Medicinae Sinicae 2014;36(5):526-529
OBJECTIVETo investigate the effect of ulinastatin, a urinary trypsin inhibitor, on the postoperative liver function in patients who have received bilateral total knee arthroplasty (TKA) under pneumatic tourniquet.
METHODSTotally 40 patients who were scheduled to receive bilateral TKA under thigh tourniquet were randomly assigned into trial group (U group, receiving intravenous ulinastatin) and control group (C group, receiving natural saline). All patients received the same general anesthesia and postoperative analgesia. The plasma concentrations of alanine transaminase (ALT), total bilirubin (TBil), and direct bilirubin (DBil) were recorded and compared preoperatively and 4, 24, 48, and 72 hours after the surgery.
RESULTSThe demographic data were not significantly different between these two groups (P>0.05). The ALT was not significantly changed after the surgery in the C group (P>0.05) but was significantly decreased 48 hours (P=0.002) and 72 hours (P=0.001) after the surgery in the U group. TBil and DBil were significantly increased 48 hours (P=0.012, P=0.000) and 72 hours (P=0.000, P=0.000) after the surgery in C group, while only that at 48 hours (P=0.010, P=0.038) was significantly increased in the U group. ALT 4 hours (P=0.026), 48 hours (P=0.013), 72 hours (P=0.004) after the surgery were significantly lower in the U group than those in C group. TBil at the 72 hours postoperatively in U group was significantly lower than that in C group (P=0.036). DBil was not significantly different between C group and U group at all time points (all P>0.05).
CONCLUSIONThe application of ulinastatin in bilateral TKA can protect postoperative liver function.
Adolescent ; Adult ; Aged ; Aged, 80 and over ; Alanine Transaminase ; blood ; Arthroplasty, Replacement, Knee ; Bilirubin ; blood ; Female ; Glycoproteins ; pharmacology ; Humans ; Liver ; drug effects ; physiopathology ; Male ; Middle Aged ; Postoperative Period ; Young Adult
8.Effect of Bilirubin on Triglyceride Synthesis in Streptozotocin-Induced Diabetic Nephropathy.
Jianwei XU ; Eun Seong LEE ; Seon Ha BAEK ; Shin Young AHN ; Sejoong KIM ; Ki Young NA ; Dong Wan CHAE ; Ho Jun CHIN
Journal of Korean Medical Science 2014;29(Suppl 2):S155-S163
We aimed to elucidate the effect of bilirubin on dyslipidemia and nephropathy in a diabetes mellitus (DM) type I animal model. Sprague-Dawley rats were separated into control, DM, and bilirubin-treated DM (Bil) groups. The Bil group was injected intraperitoneally with 60 mg/kg bilirubin 3 times per week and hepatoma cells were cultured with bilirubin at a concentration of 0.3 mg/dL. The Bil group showed lower serum creatinine levels 5 weeks after diabetes onset. Bilirubin treatment also decreased the amount of mesangial matrix, lowered the expression of renal collagen IV and transforming growth factor (TGF)-beta1, and reduced the level of apoptosis in the kidney, compared to the DM group. These changes were accompanied by decreased tissue levels of hydrogen superoxide and NADPH oxidase subunit proteins. Bilirubin decreased serum total cholesterol, high-density lipoprotein cholesterol (HDL-C), free fatty acids, and triglycerides (TGs), as well as the TG content in the liver tissues. Bilirubin suppressed protein expression of LXRalpha, SREBP-1, SCD-1, and FAS, factors involved in TG synthesis that were elevated in the livers of DM rats and hepatoma cells under high-glucose conditions. In conclusion, bilirubin attenuates renal dysfunction and dyslipidemia in diabetes by suppressing LXRalpha and SREBP-1 expression and oxidative stress.
Animals
;
Bilirubin/pharmacology/*therapeutic use
;
Cell Line, Tumor
;
Creatine/blood
;
Diabetes Mellitus, Experimental/chemically induced/complications/*pathology
;
Diabetic Nephropathies/*drug therapy/etiology
;
Disease Models, Animal
;
Kidney/pathology
;
Lipoproteins, HDL/blood
;
Liver/metabolism
;
Male
;
Mice
;
Mice, Inbred C57BL
;
NADPH Oxidase/metabolism
;
Orphan Nuclear Receptors/antagonists & inhibitors/genetics/metabolism
;
Oxidative Stress/drug effects
;
Rats
;
Rats, Sprague-Dawley
;
Reactive Oxygen Species/metabolism
;
Streptozocin/toxicity
;
Triglycerides/analysis/*biosynthesis/blood
9.Bilirubin Activates Transcription of HIF-1alpha in Human Proximal Tubular Cells Cultured in the Physiologic Oxygen Content.
Sung Gyun KIM ; Shin Young AHN ; Eun Seong LEE ; Sejoong KIM ; Ki Young NA ; Dong Wan CHAE ; Ho Jun CHIN
Journal of Korean Medical Science 2014;29(Suppl 2):S146-S154
The expression of hypoxia-inducible factor (HIF) is influenced by reactive oxygen species (ROS). Effect of bilirubin on HIF-1 expression in proximal tubular cells was investigated under physiological oxygen concentration, which is relative hypoxic condition mimicking oxygen content in the medulla of renal tissue. The human kidney (HK2) cells were cultured in 5% oxygen with or without bilirubin. HIF-1alpha protein expression was increased by bilirubin treatment at 0.01-0.2 mg/dL concentration. The messenger RNA expression of HIF-1alpha was increased by 1.69+/-0.05 folds in the cells cultured with 0.1 mg/dL bilirubin, compared to the control cells. The inhibitors of PI3K/mTOR, PI3K/AKT, and ERK 1/2 pathways did not attenuate increased HIF-1alpha expression by bilirubin. HIF-1alpha expression decreased by 10 microM exogenous hydrogen peroxide (H2O2); scavenger of ROS with or without bilirubin in the HK2 cells increased HIF-1alpha concentration more than that in the cells without bilirubin. Exogenous H2O2 decreased the phosphorylation of P70S6 kinase, which was completely reversed by bilirubin treatment. Knockdown of NOX4 gene by small interfering RNA (siRNA) increased HIF-1alpha mRNA expression. In coonclusion, bilirubin enhances HIF-1alpha transcription as well as the up-regulation of HIF-1alpha protein translation through the attenuation of ROS and subunits of NADPH oxidase.
Bilirubin/*pharmacology
;
Cell Line
;
Epithelial Cells/cytology/metabolism
;
Humans
;
Hydrogen Peroxide/toxicity
;
Hypoxia-Inducible Factor 1, alpha Subunit/genetics/*metabolism
;
Kidney Tubules, Proximal/cytology
;
Mitogen-Activated Protein Kinase 1/metabolism
;
Mitogen-Activated Protein Kinase 3/metabolism
;
NADPH Oxidase/antagonists & inhibitors/genetics/metabolism
;
Oxygen/*pharmacology
;
Phosphatidylinositol 3-Kinases/metabolism
;
Phosphorylation/drug effects
;
Proto-Oncogene Proteins c-akt/metabolism
;
RNA Interference
;
Ribosomal Protein S6 Kinases, 70-kDa/metabolism
;
Signal Transduction/drug effects
;
TOR Serine-Threonine Kinases/metabolism
;
Transcriptional Activation/*drug effects
;
Up-Regulation/drug effects
10.Protection of Grateloupia filicina polysaccharide against hepatotoxicity induced by Dioscorea bulbifera L.
Yi-Bo MA ; Li-Li JI ; Shun-Chun WANG ; Song-Shan SHI ; Zheng-Tao WANG
Acta Pharmaceutica Sinica 2013;48(8):1253-1258
The present study was designed to observe the protection of Grateloupia filicina polysaccharide (GFP) against hepatotoxicity induced by Dioscorea bulbifera L in mice and its underlying mechanism. GFP was intragastrically (ig) given to mice at various doses. After 6 days, the mice were treated with ethyl acetate extract of Dioscorea bulbifera L (EF, ig). Serum levels of alanine/aspartate aminotransferase (ALT/AST), alkaline phosphatase (ALP), total bilirubin (TB) were measured, and liver histological evaluation was conducted. Furthermore, reductions of liver glutathione (GSH) amount and glutamate cysteine ligase (GCL) activity were tested. The expressions of GCL-c, GCL-m, and HO-1 (heme oxygenase-1) in liver were observed by Western-blot. The results showed that GFP (600 mg x kg(-1)) decreased EF-induced the increase of serum ALT, AST and TB, and GFP (400, 600 mg x kg(-1)) inhibited EF-induced the increase of serum ALP. Liver histological evaluation showed that the liver injury induced by EF was relieved after treated with GFP. GFP further increased liver GSH amount and reversed EF-induced the decrease of GCL activity. The Western-blot result showed that GFP augmented EF-induced the increase of HO-1, and reversed EF-induced the decrease of GCL-c. In conclusion, GFP can act against the oxidative stress liver injury induced by Dioscorea bulbifera L in mice.
Alanine Transaminase
;
blood
;
Alkaline Phosphatase
;
blood
;
Animals
;
Aspartate Aminotransferases
;
blood
;
Bilirubin
;
blood
;
Chemical and Drug Induced Liver Injury
;
blood
;
metabolism
;
Dioscorea
;
toxicity
;
Glutamate-Cysteine Ligase
;
metabolism
;
Glutathione
;
metabolism
;
Heme Oxygenase-1
;
metabolism
;
Heterocyclic Compounds, 4 or More Rings
;
antagonists & inhibitors
;
isolation & purification
;
toxicity
;
Liver
;
metabolism
;
pathology
;
Male
;
Mice
;
Mice, Inbred ICR
;
Oxidative Stress
;
drug effects
;
Plants, Medicinal
;
chemistry
;
Polysaccharides
;
isolation & purification
;
pharmacology
;
Random Allocation
;
Rhodophyta
;
chemistry

Result Analysis
Print
Save
E-mail