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1.
Cancer Med ; 7(6): 2472-2484, 2018 06.
Article in English | MEDLINE | ID: mdl-29673126

ABSTRACT

HACE1 E3 ligase was discovered to be down-regulated in several cancers while its role in regulating tumors was merely understood. This study aimed to explore the specific effect of HACE1 played in gastric tumorigenesis and its potential mechanism. HACE1's expression was found significantly lower in gastric cancer tissues compared with the adjacent normal tissues (P < 0.001). Its protein level in gastric cancer negatively correlated to tumor pathological differentiation (P = 0.019). And in gastric cancer patients with TNM I-IIIa, those with lower HACE1 protein level had poorer overall survival (P = 0.025). Studies, in vivo and in vitro, showed that overexpressing HACE1 inhibited tumor proliferation and migration, and enhanced cell apoptosis. Besides, ectopic expression of HACE1 down-regulated the protein level of ß-catenin and inhibited the activity of the Wnt/ß-catenin signaling pathway. All the cellular functions were abolished when we overexpressed inactive HACE1-deltaHECT. Above all, we demonstrated that HACE1 E3 ligase played a suppressive role in gastric tumorigenesis and inhibited the activity of the Wnt/ß-catenin signaling pathway. Circumventing the decline of HACE1 in early stage of carcinoma may impede the tumorigenesis and malignant process of gastric cancer.


Subject(s)
Gene Expression , Stomach Neoplasms/genetics , Stomach Neoplasms/pathology , Ubiquitin-Protein Ligases/genetics , Adult , Aged , Animals , Apoptosis , Cell Line, Tumor , Cell Movement , Cell Proliferation , Disease Models, Animal , Disease Progression , Female , Gene Knockout Techniques , Humans , Male , Mice , Middle Aged , Neoplasm Grading , Neoplasm Staging , Stomach Neoplasms/metabolism , Stomach Neoplasms/mortality , Ubiquitin-Protein Ligases/metabolism , Wnt Signaling Pathway , Xenograft Model Antitumor Assays
2.
J Cell Mol Med ; 21(10): 2370-2385, 2017 10.
Article in English | MEDLINE | ID: mdl-28378526

ABSTRACT

Placental growth factor (PlGF) is a member of the vascular endothelial growth factor (VEGF) family and is involved in pathological angiogenesis associated with chronic liver diseases. However, the precise mechanisms underlying PlGF signalling contributing to liver fibrosis and angiogenesis remain largely unexplored. This study aimed to assess the effect of reducing PlGF expression using small interfering RNA (siRNA) on experimental liver fibrosis and angiogenesis, and to elucidate the underlying molecular mechanisms. Fibrosis was induced in mice by carbon tetrachloride (CCl4 ) for 8 weeks, and mice were treated with PlGF siRNA or non-targeting control siRNA starting two weeks after initiating CCl4 injections. The results showed that PlGF was highly expressed in cirrhotic human and mice livers; which mainly distributed in activated hepatic stellate cells (HSCs). PlGF silencing robustly reduced liver inflammation, fibrosis, intrahepatic macrophage recruitment, and inhibited the activation of HSCs in vivo. Moreover, PlGF siRNA-treated fibrotic mice showed diminished hepatic microvessel density and angiogenic factors, such as hypoxia-inducible factor-1α (HIF-1α), VEGF and VEGF receptor-1. Moreover, down-regulation of PlGF with siRNA in HSCs inhibited the activation and proliferation of HSCs. Mechanistically, overexpression of PlGF in activated HSCs was induced by hypoxia dependent on HIF-1α, and PlGF induces HSC activation and proliferation via activation the phosphatidylinositol 3-kinase (PI3K)/Akt signalling pathways. These findings indicate that PlGF plays an important role in liver fibrosis-associated angiogenesis and that blockage of PlGF could be an effective strategy for chronic liver disease.


Subject(s)
Hepatic Stellate Cells/metabolism , Liver Cirrhosis/metabolism , Liver Diseases/metabolism , Neovascularization, Pathologic/metabolism , Placenta Growth Factor/metabolism , Animals , Carbon Tetrachloride , Cell Proliferation/genetics , Cells, Cultured , Chronic Disease , Disease Models, Animal , Humans , Liver Cirrhosis/chemically induced , Liver Cirrhosis/genetics , Liver Diseases/genetics , Male , Mice, Inbred BALB C , Neovascularization, Pathologic/genetics , Placenta Growth Factor/genetics , RNA Interference , Rats, Sprague-Dawley , Signal Transduction/genetics
3.
Inflammation ; 39(1): 96-106, 2016 Feb.
Article in English | MEDLINE | ID: mdl-26267064

ABSTRACT

The dietary flavonoid quercetin has hepatoprotective effects. We analyzed the effects of quercetin on concanavalin A (ConA)-induced hepatitis in mice and its underlying molecular mechanisms of action. Mice were administered quercetin (50 mg/kg body weight, i.p.) or vehicle 30 min before intravenous administration of ConA. Quercetin pretreatment significantly reduced the ConA-induced elevations in plasma aminotransferase concentrations and liver necrosis, as well as reducing serum concentrations of the pro-inflammatory cytokines tumor necrosis factor (TNF)-α, interferon-γ, and interleukin-4. Quercetin pretreatment also reduced expression of high-mobility group box 1 protein (HMGB1) and toll-like receptor (TLR)-2 and TLR-4 messenger RNA (mRNA) and protein in liver tissues. Quercetin pretreatment significantly inhibited degradation of inhibitory kappa B alpha and modulated ConA-induced nuclear translocation in the liver of nuclear factor kappa B (NF-κB) p65. These results demonstrate that quercetin protects against ConA-mediated hepatitis in mice by attenuating the HMGB1-TLRs-NF-κB signaling pathway.


Subject(s)
Concanavalin A , HMGB1 Protein/biosynthesis , Hepatitis/drug therapy , NF-KappaB Inhibitor alpha/metabolism , Quercetin/pharmacology , Toll-Like Receptor 2/biosynthesis , Toll-Like Receptor 4/biosynthesis , Transcription Factor RelA/metabolism , Active Transport, Cell Nucleus/drug effects , Animals , Down-Regulation/drug effects , HMGB1 Protein/genetics , Interferon-gamma/blood , Interleukin-4/blood , Liver/pathology , Male , Mice , Mice, Inbred BALB C , RNA, Messenger/biosynthesis , Random Allocation , Toll-Like Receptor 2/genetics , Toll-Like Receptor 4/genetics , Transaminases/blood , Tumor Necrosis Factor-alpha/blood
4.
World J Gastroenterol ; 21(2): 699-703, 2015 Jan 14.
Article in English | MEDLINE | ID: mdl-25593501

ABSTRACT

Genotyping is conclusive for the diagnosis of progressive familial intrahepatic cholestasis type 3 (PFIC3). Here we report a Chinese patient of PFIC3 with compound mutations in the ABCB4 gene. Liver biopsy was performed on a 17-year-old male patient with intrahepatic cholestasis of unknown etiology. Liver histology findings are indicative of intrahepatic cholestasis with extensive fibrosis. Genotyping revealed c.175C>T (p.L59L) mutation in exon 4, c.504C>T (p.N168N) mutation in exon 6, c.711A>T (p.I237I) mutation in exon 8, c.874A>T (p.K292X) in exon 9 and a novel mutation, c.1804G>T (p.G602W) in exon 15. Based on these findings, the patient was diagnosed with PFIC3. The novel mutation p.G602W in exon 15 was predicted as probably damaging by PolyPhen-2 with a score of 0.986 (sensitivity: 0.54; specificity: 0.94) and was predicted to affect protein function with a SIFT score of 0.01.


Subject(s)
ATP Binding Cassette Transporter, Subfamily B/deficiency , Asian People/genetics , Cholestasis, Intrahepatic/genetics , Mutation , ATP Binding Cassette Transporter, Subfamily B/genetics , Adolescent , Amino Acid Sequence , Cholestasis, Intrahepatic/diagnosis , Cholestasis, Intrahepatic/ethnology , DNA Mutational Analysis , Exons , Genetic Predisposition to Disease , Humans , Male , Molecular Sequence Data , Phenotype
5.
Aging Clin Exp Res ; 26(2): 183-91, 2014 Apr.
Article in English | MEDLINE | ID: mdl-24243034

ABSTRACT

BACKGROUND AND AIMS: Functions of the intestinal mucosal barrier are often impaired in the elderly and are closely associated with many age-related diseases. However, mechanisms by which aging influences intestinal barrier function still remain unclear. The aim of this study was to investigate age-related changes in small intestinal morphology, bacteria contents and expression of epithelial tight junction (TJ) proteins. METHODS: Thirty Sprague-Dawley rats were divided into groups: young (3 months), adult (12 months), and old (24 months). The small intestinal mucosal architecture and TJ of intestinal epithelial cells were examined by light microscopy and transmission electron microscopy. Jejunum and cecum contents were cultured to identify and measure bacterial species. mRNA expression of Zonula occludens-1 (ZO-1) and occludin were measured by semi-quantitative RT-PCR. Protein expression of ZO-1 and occludin were detected by immunohistochemistry and Western blot. RESULTS: Normal ileum villi, which were thick and regularly arranged, though increasingly scattered and atrophic in character with shorter and narrower dimensions (P < 0.01), were observed in old rats, along with an elevated number of Gram-positive and Gram-negative bacteria in the jejunum. The TJs of intestinal epithelial cells, as detected by transmission electron microscopy, were wider and discontinuous in old rats. Age-induced down-regulation of mRNA expression and decreased protein expression of ZO-1 and occludin were observed in the ileum (P < 0.01). CONCLUSIONS: Our study indicated that age-related intestinal barrier dysfunction may be associated with mucosal atrophy, damages to TJ structure, increased small intestine bacteria counts, and decreased epithelial TJ protein.


Subject(s)
Aging/pathology , Intestinal Mucosa/pathology , Aging/genetics , Aging/metabolism , Animals , Bacterial Load , Immunohistochemistry , Intestinal Mucosa/metabolism , Intestinal Mucosa/microbiology , Intestine, Small/metabolism , Intestine, Small/microbiology , Intestine, Small/pathology , Male , Microscopy, Electron, Transmission , Occludin/genetics , Occludin/metabolism , RNA, Messenger/genetics , RNA, Messenger/metabolism , Rats , Rats, Sprague-Dawley , Tight Junctions/metabolism , Tight Junctions/pathology , Zonula Occludens-1 Protein/genetics , Zonula Occludens-1 Protein/metabolism
6.
Inflammation ; 36(1): 206-15, 2013 Feb.
Article in English | MEDLINE | ID: mdl-22948514

ABSTRACT

The aims of this study were to examine the anti-inflammatory effect of curcumin on concanavalin A (ConA) induced hepatitis in mice, and to elucidate its underlying molecular mechanisms. Mice received curcumin by gavage before ConA intravenous administration. The results showed that curcumin pretreatment attenuated ConA-induced hepatitis. Enzyme linked immunosorbent assay (ELISA) results showed that serum levels of high mobility group box 1 (HMGB1) increased at 4 h and reached its peak value at 12 h after challenge with ConA; but this increase was significantly inhibited by curcumin. Furthermore, curcumin significantly decreased the HMGB1 translocation from nucleus to cytoplasm of hepatocytes in ConA-induced mice. The levels of HMGB1 mRNA and protein expression in the liver were also significantly lowered in curcumin-treated mice. In addition, curcumin inhibited intrahepatic expression of tumor necrosis factor-α (TNF-α), interleukin (IL)-1ß and IL-6 protein. In conclusion, the results indicated that curcumin protected against ConA-induced hepatitis in mice; and the beneficial effects may be partly through inhibition of HMGB1 translocation in hepatocytes, release into the plasma and expression in livers.


Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Curcumin/therapeutic use , HMGB1 Protein/metabolism , Hepatitis/drug therapy , Hepatitis/prevention & control , Animals , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Concanavalin A , Curcumin/pharmacology , HMGB1 Protein/antagonists & inhibitors , HMGB1 Protein/blood , HMGB1 Protein/genetics , Interleukin-1beta/biosynthesis , Interleukin-6/biosynthesis , Liver/drug effects , Liver/pathology , Male , Mice , Mice, Inbred BALB C , Protein Transport/drug effects , RNA, Messenger/biosynthesis , RNA, Messenger/genetics , RNA, Messenger/metabolism , Transaminases/blood , Tumor Necrosis Factor-alpha/biosynthesis
7.
BMC Complement Altern Med ; 12: 156, 2012 Sep 16.
Article in English | MEDLINE | ID: mdl-22978413

ABSTRACT

BACKGROUND: At present there is no effective and accepted therapy for hepatic fibrosis. Transforming growth factor (TGF)-ß1 signaling pathway contributes greatly to hepatic fibrosis. Reducing TGF-ß synthesis or inhibiting components of its complex signaling pathway represent important therapeutic targets. The aim of the study was to investigate the effect of curcumin on liver fibrosis and whether curcumin attenuates the TGF-ß1 signaling pathway. METHODS: Sprague-Dawley rat was induced liver fibrosis by carbon tetrachloride (CCl4) for six weeks together with or without curcumin, and hepatic histopathology and collagen content were employed to quantify liver necro-inflammation and fibrosis. Moreover, the mRNA and protein expression levels of TGF-ß1, Smad2, phosphorylated Smad2, Smad3, Smad7 and connective tissue growth factor (CTGF) were determined by quantitative real time-PCR, Western blot, or immunohistochemistry. RESULTS: Rats treated with curcumin improved liver necro-inflammation, and reduced liver fibrosis in association with decreased α-smooth muscle actin expression, and decreased collagen deposition. Furthermore, curcumin significantly attenuated expressions of TGFß1, Smad2, phosphorylated Smad2, Smad3, and CTGF and induced expression of the Smad7. CONCLUSIONS: Curcumin significantly attenuated the severity of CCl4-induced liver inflammation and fibrosis through inhibition of TGF-ß1/Smad signalling pathway and CTGF expression. These data suggest that curcumin might be an effective antifibrotic drug in the prevention of liver disease progression.


Subject(s)
Curcuma/chemistry , Curcumin/administration & dosage , Liver Cirrhosis/drug therapy , Liver Cirrhosis/metabolism , Plant Extracts/administration & dosage , Signal Transduction/drug effects , Transforming Growth Factor beta1/metabolism , Animals , Carbon Tetrachloride/adverse effects , Disease Progression , Down-Regulation/drug effects , Humans , Liver Cirrhosis/genetics , Liver Cirrhosis/pathology , Male , Phosphorylation , Rats , Rats, Sprague-Dawley , Smad Proteins/genetics , Smad Proteins/metabolism , Transforming Growth Factor beta1/genetics
8.
World J Gastroenterol ; 18(27): 3617-22, 2012 Jul 21.
Article in English | MEDLINE | ID: mdl-22826629

ABSTRACT

AIM: To evaluate anti-hepatitis B virus (HBV) activity and cytotoxicity of interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α) following lamivudine treatment of HepG2.2.15 cells. METHODS: HepG2.2.15 cells were treated with 2 µmol/L lamivudine for 16 d (lamivudine group), cultured for 10 d, followed by 5 ng/mL TNF-α and 1000 U/mL IFN-γ for 6 d (cytokine group), or treated with 2 µmol/L lamivudine for 10 d followed by 5 ng/mL TNF-α and 1000 U/mL IFN-γ for 6 d (sequential group), or cultured without additions for 16 d (control group). Intracellular DNA was extracted from 3 × 10(5) HepG2.2.15 cells from each group. The extracted DNA was further purified with mung bean nuclease to remove HBV relaxed circular DNA that may have remained. Both HBV covalently closed circular DNA (cccDNA) and HBV DNA were examined with real-time polymerase chain reaction. The titers of hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg) were quantified with enzyme-linked immunosorbent assay. Cell viability was measured with the cell counting kit-8 assay. RESULTS: Compared to lamivudine alone (22.63% ± 0.12%), both sequential (51.50% ± 0.17%, P = 0.034) and cytokine treatment (49.66% ± 0.06%, P = 0.041) showed a stronger inhibition of HBV cccDNA; the difference between the sequential and cytokine groups was not statistically significant (51.50% ± 0.17% vs 49.66% ± 0.06%, P = 0.88). The sequential group showed less inhibition of HBV DNA replication than the lamivudine group (67.47% ± 0.02% vs 82.48% ± 0.05%, P = 0.014); the difference between the sequential and cytokine groups was not statistically significant (67.47% ± 0.02% vs 57.45% ± 0.07%, P = 0.071). The levels of HBsAg and HBeAg were significantly decreased in the sequential treatment group compared to the other groups [HBsAg: 3.48 ± 0.04 (control), 3.09 ± 0.08 (lamivudine), 2.55 ± 0.13 (cytokine), 2.32 ± 0.08 (sequential), P = 0.042 for each between-group comparison; HBeAg: 3.48 ± 0.01 (control), 3.08 ± 0.08 (lamivudine), 2.57 ± 0.15 (cytokine), 2.34 ± 0.12 (sequential), P = 0.048 for each between-group comparison]. Cell viability in the cytokine group was reduced to 58.03% ± 8.03% compared with control cells (58.03% ± 8.03% vs 100%, P = 0.000). Lamivudine pretreatment significantly reduced IFN-γ + TNF-α-mediated toxicity of HepG2.2.15 cells [85.82% ± 5.43% (sequential) vs 58.03% ± 8.03% (cytokine), P = 0.002]. CONCLUSION: Sequential treatment overcame the lower ability of lamivudine alone to inhibit cccDNA and precluded the aggressive cytotoxicity involving IFN-γ and TNF-α by decreasing the viral load.


Subject(s)
Antiviral Agents/pharmacology , Hepatitis B virus/drug effects , Hepatocytes/drug effects , Interferon-gamma/pharmacology , Lamivudine/pharmacology , Tumor Necrosis Factor-alpha/pharmacology , Cell Survival/drug effects , DNA Replication/drug effects , DNA, Viral/biosynthesis , DNA, Viral/drug effects , Enzyme-Linked Immunosorbent Assay , Hep G2 Cells , Hepatitis B Surface Antigens/metabolism , Hepatitis B e Antigens/metabolism , Hepatitis B virus/genetics , Hepatocytes/metabolism , Hepatocytes/pathology , Hepatocytes/virology , Humans , Real-Time Polymerase Chain Reaction , Recombinant Proteins/pharmacology , Time Factors , Transfection , Viral Load , Virus Replication/drug effects
9.
Food Chem Toxicol ; 50(9): 3343-51, 2012 Sep.
Article in English | MEDLINE | ID: mdl-22683883

ABSTRACT

The aim of the study was to investigate the effect of curcumin on the liver fibrosis induced by carbon tetrachloride (CCl(4)) in rats, and to elucidate its underlying molecular mechanisms. Rats were administered with CCl(4) together with or without curcumin for 6 weeks. Hepatic damage was evaluated by analysis of liver function tests in serum. Hepatic histopathology and collagen content were employed to quantify liver fibrosis; and activated hepatic stellate cells were assessed. Moreover, the mRNA and protein expression levels of interleukin (IL)-6, tumor necrosis factor (TNF)-α, monocyte chemotactic protein (MCP)-1, high-mobility group box 1 (HMGB1), Toll like receptor (TLR) 2 and TLR4 were determined by quantitative real time PCR, Western blot or immunohistochemistry. Treatment with curcumin significantly attenuated CCl(4)-induce liver injury, hepatic inflammation and reduced the levels of proinflammatory mediators (TNF-α, IL-6 and MCP-1). Moreover, curcumin significantly inhibited extracellular matrix deposition, reduced the number of activated stellate cells, and decreased the levels of HMGB1, TLR4 and TLR2 expression in the rat model of fibrogenesis. These results suggest that curcumin could be an effective agent for preventing liver fibrosis and its mechanism may in part be a consequence of the reduction TLR2, TLR4 and HMGB1 expression.


Subject(s)
Carbon Tetrachloride/toxicity , Curcumin/therapeutic use , HMGB1 Protein/metabolism , Liver Cirrhosis/drug therapy , Toll-Like Receptor 2/metabolism , Toll-Like Receptor 4/metabolism , Animals , Base Sequence , DNA Primers , Liver Cirrhosis/chemically induced , Male , Polymerase Chain Reaction , Rats , Rats, Sprague-Dawley
10.
Int Immunopharmacol ; 12(1): 151-7, 2012 Jan.
Article in English | MEDLINE | ID: mdl-22138522

ABSTRACT

Curcumin has antiviral, antioxidant, and anti-inflammatory properties. However, the hepatoprotective effects and molecular mechanisms of curcumin on acute liver injury have not been carefully examined. The aims of this study were to examine the anti-inflammatory effect of curcumin on Concanavalin A (Con A) induced hepatitis, and to elucidate its underlying molecular mechanisms in mice. Mice received curcumin (200 mg/kg body weight) by gavage before Con A intravenous administration. We found that curcumin pretreatment was able to significantly reduce the elevated plasma aminotransferase levels and liver necrosis in Con A-induced hepatitis. Also, curcumin pretreatment reduced intrahepatic expression of genes encoding pro-inflammatory molecules such as tumor necrosis factor α (TNF-α) and interferon γ (IFN-γ) as compared with the vehicle controls, but augmented anti-inflammatory cytokine interleukin 10 (IL-10) by enzyme linked immunosorbent assay (ELISA). Furthermore, the expression levels of Toll-like receptor (TLR) 2, TLR4 and TLR9 mRNA or protein in liver tissues were significantly lowered by curcumin treatment. Curcumin pretreatment did not affect hepatic Kupffer cell numbers after Con A injection. These results suggest that curcumin pretreatment protects against T cell-mediated hepatitis in mice. The beneficial effect of curcumin may be partly mediated by inhibiting the expression levels of TLR2, TLR4 and TLR9 in the liver.


Subject(s)
Anti-Inflammatory Agents/therapeutic use , Chemical and Drug Induced Liver Injury/drug therapy , Curcumin/therapeutic use , Immunologic Factors/therapeutic use , Toll-Like Receptors/antagonists & inhibitors , Alanine Transaminase/blood , Animals , Anti-Inflammatory Agents/pharmacology , Aspartate Aminotransferases/blood , Chemical and Drug Induced Liver Injury/immunology , Chemical and Drug Induced Liver Injury/pathology , Concanavalin A/toxicity , Curcumin/pharmacology , Disease Models, Animal , Immunologic Factors/pharmacology , Interleukin-1/immunology , Kupffer Cells/drug effects , Kupffer Cells/immunology , Male , Mice , Mice, Inbred BALB C , Mitogens/toxicity , RNA, Messenger/immunology , Toll-Like Receptors/genetics , Toll-Like Receptors/immunology
11.
J Dig Dis ; 13(1): 33-9, 2012 Jan.
Article in English | MEDLINE | ID: mdl-22188914

ABSTRACT

OBJECTIVE: Hepatic sinusoidal obstruction syndrome (HSOS) induced by a Chinese medicinal herb Tusanqi is increasingly being reported in recent years. The aim of the study was to investigate the possibility of using blood pyrrole-protein adducts test as a confirmatory diagnostic method. METHODS: Patients with HSOS according to international diagnostic criteria associated with Tusanqi from January 2006 to August 2010 in Zhongshan Hospital Fudan University were included and clinical features were collected. Pyrrole-protein adducts in blood sample were determined with ultra performance liquid chromatography-mass spectrometry (UPLC-MS) while pyrrolizidine alkaloids (PAs) in available herbal preparations were analyzed by high performance liquid chromatography-ultraviolet (HPLC-UV). RESULTS: Five patients (age 41-72 years, median age 54 years, all women) were included. Ascites (5/5), jaundice (5/5) and hepatomegaly (4/5) were common manifestations. The imaging features were diffused, patchy hepatic enhancement, periportal edema and ascites. Pathology ascertained that blood flow was obstructive at the site of sinusoid. PAs (Seneionine and seneciphylline) were identified in all the three available herbal preparations ingested by the HSOS patients. Pyrrole-protein adducts were unequivocally found in all the five blood samples. Two patients recovered, two developed chronic illness and one died due to liver failure and hepatic encephalopathy. CONCLUSIONS: The detection of blood pyrrole-protein adducts using a UPLC-MS approach is a specific, reliable, unambiguous and confirmatory test for HSOS induced by PA, and should be used together with the conventional HSOS clinical diagnostic criteria for the definitive diagnosis of PA-induced HSOS.


Subject(s)
Drugs, Chinese Herbal/adverse effects , Hepatic Veno-Occlusive Disease/chemically induced , Hepatic Veno-Occlusive Disease/diagnosis , Pyrrolizidine Alkaloids/adverse effects , Adult , Aged , Ascites/blood , Ascites/chemically induced , Ascites/diagnosis , Biomarkers/blood , Blood Proteins/metabolism , Female , Hepatic Veno-Occlusive Disease/blood , Humans , Liver Failure/blood , Liver Failure/chemically induced , Liver Failure/diagnosis , Middle Aged , Pyrroles/blood
12.
World J Gastroenterol ; 17(43): 4810-6, 2011 Nov 21.
Article in English | MEDLINE | ID: mdl-22147983

ABSTRACT

AIM: To evaluate the impacts of Schistosoma japonicum (S. japonicum) ova on the tight junction barriers in a trinitrobenzenesulfonic acid (TNBS)-induced colitis model. METHODS: Balb/c mice were randomly divided into three groups: control group; TNBS(+)ova(-) group and TNBS(+)ova(+) group. TNBS was used intracolonic to induce colitis and mice of the TNBS(+)ova(+) group were pre-exposed to S. japonicum ova as a prophylactic intervention. Colon inflammation was quantified using following variables: mouse mortality, weight loss, colon extent and microscopic inflammation score. Serum expression of tumor necrosis factor-α and interferon-γ were assessed to evaluate the systemic inflammatory response. NOD2 and its mRNA were also tested. Bacterial translocations were tested by culturing blood and several tissues. ZO-1 and occludin were chosen as the representations of tight junction proteins. Both the proteins and mRNA were assessed. RESULTS: Ova pre-treatment contributed to the relief of colitis and decreased the mortality of the models. NOD2 expression was significantly downregulated when pretreated with the ova. The TNBS injection caused a significant downregulation of ZO-1 and occludin mRNA together with their proteins in the colon; ova pre-exposure reversed these alterations. Treatment with S. japonicum ova in the colitis model caused lower intestinal bacterial translocation frequency. CONCLUSION: S. japonicum ova can maintain epithelial barrier function through increasing tight junction proteins, thus causing less exposure of NOD2 to the luminal antigens which may activate a series of inflammatory factors and induce colitis.


Subject(s)
Colitis/chemically induced , Intestinal Mucosa/metabolism , Ovum/metabolism , Schistosoma japonicum/cytology , Tight Junctions/metabolism , Animals , Colitis/pathology , Colon/anatomy & histology , Colon/drug effects , Colon/metabolism , Colon/pathology , Inflammation/chemically induced , Inflammation/metabolism , Inflammation/pathology , Intestinal Mucosa/drug effects , Intestinal Mucosa/pathology , Membrane Proteins/genetics , Membrane Proteins/metabolism , Mice , Mice, Inbred BALB C , Nod2 Signaling Adaptor Protein/genetics , Nod2 Signaling Adaptor Protein/metabolism , Occludin , Phosphoproteins/genetics , Phosphoproteins/metabolism , Random Allocation , Trinitrobenzenesulfonic Acid/pharmacology , Zonula Occludens-1 Protein
13.
Mol Cell Biochem ; 358(1-2): 53-60, 2011 Dec.
Article in English | MEDLINE | ID: mdl-21695461

ABSTRACT

The effect of curcumin on liver injury caused by Concanavalin A (Con A) has not been carefully examined. This study was designed to evaluate the protective effect of curcumin on Con A-induced hepatitis in mice. Liver injured mice received curcumin by gavage at a dose of 200 mg/kg body weight before Con A intravenous administration. Curcumin was effective in reducing the elevated plasma levels of aminotransferases and the incidence of liver necrosis compared with Con A-injected control group. Enzyme-linked immunosorbent assay (ELISA) showed that curcumin suppressed proinflammatory cytokines such as tumor necrosis factor (TNF)-α, interferon (IFN)-γ, and interleukin (IL)-4 production in Con A-injected mice. The reduced severity of hepatitis in curcumin pretreated mice correlated with decrease in numbers of liver CD4(+) T cells but not CD8(+) T cells by immunohistochemical analysis. Furthermore, the expression levels of intercellular adhesion molecule-1 (ICAM-1) and the interferon-inducible chemokine CXCL10 in hepatic tissue were significantly decreased by curcumin pretreatment. In conclusion, curcumin pretreatment protects against T cell-mediated hepatitis in mice.


Subject(s)
Chemokine CXCL10/metabolism , Curcumin/therapeutic use , Hepatitis/drug therapy , Hepatitis/prevention & control , Intercellular Adhesion Molecule-1/metabolism , Liver/metabolism , Protective Agents/therapeutic use , Alanine Transaminase/blood , Animals , Aspartate Aminotransferases/blood , CD4-Positive T-Lymphocytes/drug effects , CD8-Positive T-Lymphocytes/drug effects , Cell Movement/drug effects , Chemokine CXCL10/genetics , Concanavalin A , Curcumin/pharmacology , Cytokines/metabolism , Gene Expression Regulation/drug effects , Hepatitis/blood , Hepatitis/pathology , Intercellular Adhesion Molecule-1/genetics , Liver/drug effects , Liver/pathology , Male , Mice , Mice, Inbred BALB C , RNA, Messenger/genetics , RNA, Messenger/metabolism
14.
Int J Cancer ; 129(10): 2463-72, 2011 Nov 15.
Article in English | MEDLINE | ID: mdl-21213214

ABSTRACT

We performed our study to determine whether plasma macrophage migration inhibitory factor (MIF) levels have diagnostic and prognostic value in hepatocellular carcinoma (HCC) patients. Enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry were used to measure the expression of MIF in plasma and tissues, respectively. Plasma MIF levels were compared to HCC occurrence, clinicopathological features and outcomes. Cutpoints of plasma MIF levels for diagnosis and prognosis were, respectively, determined by receiver operating characteristic analysis and X-tile in corresponding training cohort, and then were confirmed in the validation cohort. The postoperative plasma MIF levels of HCC patients were detected in an independent cohort (80 HCC patients). As a result, MIF expression in situ was mainly observed in the cytoplasm of HCC cells. Intratumoral MIF expression was positively correlated with plasma MIF levels (r = 0.759, p < 0.001). Compared to serum α-fetoprotein (AFP), plasma MIF had a higher diagnostic value for discrimination of HCC from controls at 35.3 ng/ml. With determined cutpoints, plasma MIF levels demonstrated a significant association with overall survival (OS) and disease-free survival (DFS) of HCC patients even in patients with normal serum AFP levels and Tumor Node Metastasis (TNM) stage I. In addition, the plasma MIF levels were identified as an independent factor for OS [hazard ratio (HR) = 1.754; p = 0.012] and DFS (HR = 2.121; p < 0.001). Plasma MIF levels decreased markedly within 30 days after tumor resection (p < 0.001). Therefore, plasma MIF levels have potential as a diagnostic and prognostic factor for HCC.


Subject(s)
Biomarkers, Tumor/blood , Carcinoma, Hepatocellular/blood , Liver Neoplasms/blood , Macrophage Migration-Inhibitory Factors/blood , Carcinoma, Hepatocellular/diagnosis , Carcinoma, Hepatocellular/surgery , Disease-Free Survival , Female , Humans , Liver Neoplasms/diagnosis , Liver Neoplasms/surgery , Male , Middle Aged , Predictive Value of Tests , Prognosis , Recurrence , Sensitivity and Specificity
15.
Zhonghua Zhong Liu Za Zhi ; 32(1): 33-6, 2010 Jan.
Article in Chinese | MEDLINE | ID: mdl-20211064

ABSTRACT

OBJECTIVE: To establish decision tree and logistic regression classification models for diagnosing pancreatic adenocarcinoma (PaCa) and for screening serum biomarkers related to evaluation of different stages and curative effects. METHODS: Serum samples obtained from subjects with pancreatic adenocarcinoma (n = 58) and normal pancreas (n = 51) were applied to strong anion exchange chromatography (SAX2) chips for protein profiling by SELDI-TOF-MS to screen multiple serum biomarkers. Biomarker Wizard software and several statistical methods including algorithm of decision tree, logistic regression and ROC curves were used to construct the decision tree or logistic regression classification models. RESULTS: Average of 61 mass peaks were detected at the molecular range of 2000-30,000, ten decision trees with the highest cross validation rate were chosen to construct the classification models, which can differentiate PaCa from normal pancreas with a sensitivity of 83.3% and a specificity of 100%. Logistic regression was used to achieve the AUC (0.976 +/- 0.011, P < 0.001) with a sensitivity of 77.6% - 91.4% and a specificity of 92.2% - 100%. Six mass peaks were combined by logistic regression to achieve the AUC 0.897 +/- 0.054, 0.978 +/- 0.021 and 0.792 +/- 0.107 (P < 0.05) in the three groups (patients at stage I and II, stage II and III, stage III and IV). One mass peak (M/Z 4,016) was screened (P < 0.05) significantly between the preoperative and postoperative PaCa samples and the intensity decreased weeks after operation. CONCLUSION: Decision tree and logistic regression classification models of the mass peaks screened by SELDI-TOF-MS serum profiling can be used to differentiate pancreatic adenocarcinoma from normal pancreas, and is superior to CA 199. The detected mass peaks are helpful for the evaluation of curative effect and prognosis of pancreatic adenocarcinoma.


Subject(s)
Adenocarcinoma/blood , Biomarkers, Tumor/blood , Blood Proteins/analysis , Pancreatic Neoplasms/blood , Adenocarcinoma/diagnosis , Adenocarcinoma/pathology , Adenocarcinoma/surgery , Adult , Aged , Aged, 80 and over , Area Under Curve , Chromatography, Ion Exchange/methods , Decision Trees , Female , Humans , Logistic Models , Male , Middle Aged , Neoplasm Staging , Pancreatic Neoplasms/diagnosis , Pancreatic Neoplasms/pathology , Pancreatic Neoplasms/surgery , Prognosis , Protein Array Analysis , Proteomics , ROC Curve , Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
16.
Zhonghua Yi Xue Za Zhi ; 87(30): 2149-51, 2007 Aug 14.
Article in Chinese | MEDLINE | ID: mdl-17988539

ABSTRACT

OBJECTIVE: To investigate the effects of intraperitoneal injected schistosome ova on TNBS-induced colitis and on the intestinal TLR4 expression in mice. METHODS: 40 BALB/c mice were randomized into 3 groups: normal control group (10 mice), TNBS group (20 mice) in which mice were exposed to trinitrobenzesulfonic acid (TNBS) and were induced with colitis, and the schistosome ova group (10 mice) in which mice were intraperitoneal injected with freeze-killed schistosome ova and later exposed to TNBS. The following variables were observed: mortality, pathological appearance of the colon, histological scoring of the specimen, serum TNF-alpha level, and intestinal TLR4 expression detected by RT-PCR and Immunohistochemistry. RESULTS: Mortality of schistosome ova group was lower than that of the TNBS group (20% vs 70%, P < 0.05). Inflammation of the mice colon in the schistosome ova group was less severe than that of the TNBS group (1.4 +/- 0.5 vs 4.2 +/- 0.6, P < 0.01, Ameho criteria scoring). TLR4 expression of colon was up-regulated in mice of TNBS group and down-regulated in schistosome ova group which was still higher than that of normal controls (0.762 +/- 0.054 vs 0.325 +/- 0.029 vs 0.237 +/- 0.021, P < 0.01). CONCLUSION: Intraperitoneal injected schistosome ova can obviously reduce TNBS-induced colitis in mice, which may be attributed to down-regulated TLR4 expression in colon.


Subject(s)
Inflammatory Bowel Diseases/parasitology , Intestinal Mucosa/parasitology , Ovum/physiology , Schistosoma japonicum , Animals , Colon/metabolism , Colon/parasitology , Colon/pathology , Immunohistochemistry , Inflammatory Bowel Diseases/chemically induced , Inflammatory Bowel Diseases/prevention & control , Injections, Intraperitoneal , Intestinal Mucosa/metabolism , Intestinal Mucosa/pathology , Male , Mice , Mice, Inbred BALB C , Random Allocation , Reverse Transcriptase Polymerase Chain Reaction , Toll-Like Receptor 4/biosynthesis , Toll-Like Receptor 4/genetics , Trinitrobenzenesulfonic Acid
17.
Zhonghua Gan Zang Bing Za Zhi ; 11(9): 539-41, 2003 Sep.
Article in Chinese | MEDLINE | ID: mdl-14552714

ABSTRACT

OBJECTIVES: To further investigate the effects of cisapride on intestinal bacterial overgrowth (IBO), bacterial and endotoxin translocation, intestinal transit and permeability in cirrhotic rats. METHODS: 25 normal control rats, 25 cirrhotic rats, 20 cirrhotic rats received saline, and 20 cirrhotic rats treated with cisapride were included in the study. All animals were assessed with many variables including bacterial and endotoxin translocation, IBO, intestinal transit and permeability. RESULTS: Bacterial translocation was found in 48%(12/25) cirrhotic rats and none of control rats. Among the 20 rats with IBO, there were 11 rats with bacterial translocation (BT) while only one rats occurred BT out of the 5 rats without IBO. Cirrhotic rats with IBO had a significantly higher rate of endotoxin translocation, higher intestinal permeability and longer intestinal transit than those without IBO. BT of a specific organism was always associated with IBO of that organism. Compared with the placebo group, cisapride-treated rats had lower rates of bacterial and endotoxin translocation and IBO, which had close relationship with shorter intestinal transit and lower permeability. CONCLUSION: Endotoxin and bacterial translocation in cirrhotic rats may be the result of IBO and higher permeability. IBO may be the result of longer transit. Cisapride which can accelerate intestinal transit and improve intestinal permeability is helpful in preventing and treating intestinal bacterial and endotoxin translocation.


Subject(s)
Bacterial Translocation/drug effects , Cisapride/pharmacology , Endotoxins/metabolism , Liver Cirrhosis, Experimental/microbiology , Animals , Biological Transport , Male , Permeability , Rats , Rats, Sprague-Dawley
18.
World J Gastroenterol ; 9(3): 534-8, 2003 Mar.
Article in English | MEDLINE | ID: mdl-12632513

ABSTRACT

AIM: To investigate the effects of cisapride on intestinal bacterial overgrowth (IBO), bacterial and endotoxin translocation, intestinal transit and permeability in cirrhotic rats. METHODS: All animals were assessed with variables including bacterial and endotoxin translocation, intestinal bacterial overgrowth, intestinal transit and permeability. Bacterial translocation (BT) was assessed by bacterial culture of MLN, liver and spleen, IBO by a jejunal bacterial count of the specific organism, intestinal permeability by determination of the 24-hour urinary (99m)Tc-DTPA excretion and intestinal transit by measurement of the distribution of (51)Cr in the intestine. RESULTS: Bacterial translocation (BT) and IBO was found in 48 % and 80 % cirrhotic rats respectively and none in control rats. Urinary excretion of (99m)Tc-DTPA in cirrhotic rats with BT (22.2+/-7.8) was greater than these without BT (10.5+/-2.9). Intestinal transit (geometric center ratio) was significantly delayed in cirrhotic rats (0.31+/-0.06) and further more delayed in cirrhotic rats with BT (0.24+/-0.06) than these without BT (0.38+/-0.11). Cirrhotic rats with IBO had significantly higher rates of intestinal bacterial and endotoxin translocation, slower intestinal transit time and higher intestinal permeability than those without IBO. It was also found that BT was closely associated with IBO and the injury of intestinal barrier. Compared with the placebo group, cisapride-treated rats had lower rates of bacterial/endotoxin translocation and IBO, which was closely associated with increased intestinal transit and improved intestinal permeability by cisapride. CONCLUSION: These results indicate that endotoxin and bacterial translocation in cirrhotic rats may be attributed to IBO and increased intestinal permeability. Cisapride that accelerates intestinal transit and improve intestinal permeability might be helpful in preventing intestinal bacterial and endotoxin translocation.


Subject(s)
Bacterial Physiological Phenomena/drug effects , Cisapride/pharmacology , Endotoxins/pharmacokinetics , Gastrointestinal Agents/pharmacology , Gastrointestinal Transit/drug effects , Intestines/microbiology , Liver Cirrhosis, Experimental/metabolism , Liver Cirrhosis, Experimental/microbiology , Animals , Bacteria/drug effects , Bacteria/growth & development , Bacterial Translocation/drug effects , Biological Transport/drug effects , Intestinal Mucosa/metabolism , Male , Rats , Rats, Sprague-Dawley
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