OBJECTIVE: To explore the role of 5-hydroxytryptamine (5-HT) in type 2 diabetes mellitus (T2DM)-related hepatic inflammation and fibrosis. METHODS: Male C57BL/6J mice were used to establish T2DM model by high-fat diet feeding combined with intraperitoneal injection of streptozotocin. Then, the mice with hyperglycemia were still fed with high-fat diet for nine weeks, and treated with or without 5-HT_2A receptor (5-HT_2AR) antagonist sarpogrelate hydrochloride (SH) and 5-HT synthesis inhibitor carbidopa (CDP) (alone or in combination). To observe the role of 5-HT in the myofibroblastization of hepa-tic stellate cells (HSCs), human HSCs LX-2 were exposed to high glucose, and were treated with or without SH, CDP or monoamine oxidase A (MAO-A) inhibitor clorgiline (CGL). Hematoxylin & eosin and Masson staining were used to detect the pathological lesions of liver tissue section, immunohistochemistry and Western blot were used to analyze protein expression, biochemical indicators were measured by ELISA or enzyme kits, and levels of intracellular reactive oxygen species (ROS) were detected by fluorescent probe. RESULTS: There were up-regulated expressions of 5-HT_2AR, 5-HT synthases and MAO-A, and elevated levels of 5-HT in the liver of the T2DM mice. In addition to reduction of the hepatic 5-HT levels and MAO-A expression, treatment with SH and CDP could effectively ameliorate liver lesions in the T2DM mice, both of which could ameliorate hepatic injury and steatosis, significantly inhibit the increase of hepatic ROS (H₂O₂) levels to alleviate oxidative stress, and markedly suppress the production of transforming growth factor β1 (TGF-β1) and the development of inflammation and fibrosis in liver. More importantly, there was a synergistic effect between SH and CDP. Studies on LX-2 cells showed that high glucose could induce up-regulation of 5-HT_2AR, 5-HT synthases and MAO-A expression, increase intracellular 5-HT level, increase the production of ROS, and lead to myofibroblastization of LX-2, resulting in the increase of TGF-β1 synthesis and production of inflammatory and fibrosis factors. The effects of high glucose could be significantly inhibited by 5-HT_2AR antagonist SH or be markedly abolished by mitochondrial 5-HT degradation inhibitor CGL. In addition, SH significantly suppressed the up-regulation of 5-HT synthases and MAO-A induced by high glucose in LX-2. CONCLUSION Hyperglycemia-induced myofibroblastization and TGF-β1 production of HSCs, which leads to hepatic inflammation and fibrosis in T2DM mice, is probably due to the up-regulation of 5-HT_2AR expression and increase of 5-HT synthesis and degradation, resulting in the increase of ROS production in mitochondria. Among them, 5-HT_2AR is involved in the regulation of 5-HT synthases and MAO-A expression.
Male ; Mice ; Humans ; Animals ; Hepatic Stellate Cells/pathology* ; Transforming Growth Factor beta1/pharmacology* ; Serotonin/metabolism* ; Reactive Oxygen Species/metabolism* ; Diabetes Mellitus, Type 2/complications* ; Hydrogen Peroxide/metabolism* ; Mice, Inbred C57BL ; Liver Cirrhosis/etiology* ; Hyperglycemia/pathology* ; Monoamine Oxidase/metabolism* ; Inflammation ; Glucose/metabolism* ; Cytidine Diphosphate/pharmacology*

Mesothelial cells (MCs) cover the surface of visceral organs and the parietal walls of cavities, and they synthesize lubricating fluids to create a slippery surface that facilitates movement between organs without friction. Recent studies have indicated that MCs play active roles in liver development, fibrosis, and regeneration. During liver development, the mesoderm produces MCs that form a single epithelial layer of the mesothelium. MCs exhibit an intermediate phenotype between epithelial cells and mesenchymal cells. Lineage tracing studies have indicated that during liver development, MCs act as mesenchymal progenitor cells that produce hepatic stellate cells, fibroblasts around blood vessels, and smooth muscle cells. Upon liver injury, MCs migrate inward from the liver surface and produce hepatic stellate cells or myofibroblast depending on the etiology, suggesting that MCs are the source of myofibroblasts in capsular fibrosis. Similar to the activation of hepatic stellate cells, transforming growth factor β induces the conversion of MCs into myofibroblasts. Further elucidation of the biological and molecular changes involved in MC activation and fibrogenesis will contribute to the development of novel approaches for the prevention and therapy of liver fibrosis.
Epithelial Cells/*physiology ; Epithelium/metabolism ; Hepatic Stellate Cells/*physiology ; Humans ; Liver/*cytology/injuries/*physiology ; Liver Cirrhosis/etiology/prevention & control ; Liver Regeneration/*physiology ; Mesenchymal Stromal Cells/physiology ; Myofibroblasts/physiology

BACKGROUND/AIMS: Chronic liver disease leads to liver fibrosis, and although the liver does have a certain regenerative capacity, this disease is associated with dysfunction of the liver vessels. C-reactive protein (CRP) is produced in the liver and circulated from there for metabolism. CRP was recently shown to inhibit angiogenesis by inducing endothelial cell dysfunction. The objective of this study was to determine the effect of CRP levels on angiogenesis in a rat model of liver dysfunction induced by bile duct ligation (BDL). METHODS: The diameter of the hepatic vein was analyzed in rat liver tissues using hematoxylin and eosin (H&E) staining. The expression levels of angiogenic factors, albumin, and CRP were analyzed by real-time PCR and Western blotting. A tube formation assay was performed to confirm the effect of CRP on angiogenesis in human umbilical vein endothelial cells (HUVECs) treated with lithocholic acid (LCA) and siRNA-CRP. RESULTS: The diameter of the hepatic portal vein increased significantly with the progression of cirrhosis. The expression levels of angiogenic factors were increased in the cirrhotic liver. In contrast, the expression levels of albumin and CRP were significantly lower in the liver tissue obtained from the BDL rat model than in the normal liver. The CRP level was correlated with the expression of albumin in hepatocytes treated with LCA and siRNA-CRP. Tube formation was significantly decreased in HUVECs when they were treated with LCA or a combination of LCA and siRNA-CRP. CONCLUSION: CRP seems to be involved in the abnormal formation of vessels in hepatic disease, and so it could be a useful diagnostic marker for hepatic disease.
Angiogenic Proteins/genetics/metabolism ; Animals ; Bile Ducts/surgery ; C-Reactive Protein/*analysis/genetics/metabolism ; Cells, Cultured ; Disease Models, Animal ; Hepatic Veins/abnormalities ; Hepatocytes/cytology/metabolism ; Human Umbilical Vein Endothelial Cells ; Humans ; Lithocholic Acid/pharmacology ; Liver/metabolism/pathology ; Liver Cirrhosis/etiology ; Liver Diseases/metabolism/*pathology ; Male ; Microscopy, Fluorescence ; Mitochondria/drug effects/metabolism ; RNA Interference ; RNA, Small Interfering/metabolism ; Rats ; Rats, Sprague-Dawley ; Real-Time Polymerase Chain Reaction ; Serum Albumin/genetics/metabolism

Inflammation is one of the most prominent characteristic features of chronic liver disease, liver fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). Most of HCC cases develop in patients with cirrhosis and cirrhosis develops in patients with chronic liver inflammation. Therefore, there is no doubt that there exist some strong connection among inflammation, fibrosis, and cancer. In fact, chronic unresolved inflammation is associated with persistent hepatic injury and concurrent regeneration, leading to sequential development of fibrosis, cirrhosis, and eventually HCC. This review will discuss the common mechanism of inflammation and fibrosis in chronic liver diseases, and then demonstrate why HCC develops in inflammatory and fibrotic conditions.
Carcinoma, Hepatocellular/*etiology ; Gram-Negative Bacteria/growth & development ; Hepatitis, Chronic/*complications/metabolism/microbiology ; Humans ; Hypoxia ; *Inflammation ; Lipopolysaccharides/metabolism ; Liver/metabolism/pathology ; Liver Cirrhosis/*complications ; Liver Neoplasms/*etiology ; Toll-Like Receptors/metabolism

OBJECTIVEThe aim of this study was to explore the diagnostic value of liver stiffness measurement combined with serum high-sensitivity C-reactive protein detection in HBV-related cirrhosis patients complicated with primary liver cancer.

METHODSA total of 156 previously untreated chronic hepatitis B-related cirrhosis patients and 50 healthy subjects were included in this study. The 156 patients were divided into two groups: those with primary liver cancer (67 cases) and without liver cancer (89 cases). The 50 healthy subjects were considered as normal control group. Liver stiffness measurement (LSM) was conducted and serum high-sensitivity C-reactive protein (CRP) level was assayed in all the 156 patients and 50 normal individuals, and their measurement values were statistically compared and analyzed.

RESULTSThe LSM value was (39.72±29.05) kPa in the liver cancer patients, significantly higher than the (27.81±18.46) kPa in the cirrhosis alone patients and (4.25±0.74) kPa in the healthy controls (P<0.01 for both). Serum hs-CRP levels in the liver cancer patients was 5.81mg/L, significantly higher than 1.78 mg/L in the cirrhosis alone patients and 0.38mg/L in healthy controls, (P<0.01 for both). The higher the grade of LSM values was, the positive rate of CRP was higher in the cirrhosis patients complicated with primary liver cancer. In patients with LSM values ≥27.6 kPa, the serum CRP positive rate was 64.2% in patients with primary liver cancer, significantly higher than the 38.0% in patients with cirrhosis alone (P<0.01). In the 67 HBV-related cirrhosis patients complicated primary liver cancer, the LSM value and serum hs-CRP level in AFP-positive patients were (48.95±28.59) kPa and 4.91 mg/L, respectively, higher than those in the AFP-negative patients (28.64±26.83) kPa and 4.16 mg/L, but with a non-significant difference (P>0.05).

CONCLUSIONLiver stiffness measurement combined with serum high-sensitivity C-reactive protein detection may have potential diagnostic implications as a marker of primary liver cancer occurrence in patients with HBV-related cirrhosis.

Biomarkers ; C-Reactive Protein ; metabolism ; Elasticity Imaging Techniques ; Fibrosis ; Hepatitis B, Chronic ; complications ; metabolism ; Humans ; Liver Cirrhosis ; etiology ; metabolism ; virology ; Liver Neoplasms

Animals ; Cannabinoid Receptor Antagonists ; therapeutic use ; Cannabinoids ; pharmacology ; Fibrosis ; metabolism ; Humans ; Liver Cirrhosis ; etiology ; metabolism ; therapy ; Piperidines ; therapeutic use ; Pyrazoles ; therapeutic use ; Receptor, Cannabinoid, CB1 ; metabolism ; Receptor, Cannabinoid, CB2 ; metabolism ; Receptors, Cannabinoid ; metabolism ; Scleroderma, Diffuse ; metabolism ; Signal Transduction ; drug effects ; Skin ; metabolism ; Smad Proteins ; metabolism ; Transforming Growth Factor beta1 ; metabolism

OBJECTIVETo identify non-invasive biomarkers for diagnosis and/or prognosis of liver fibrosis in chronic hepatitis B (CHB).

METHODSPeripheral blood samples were obtained from 48 patients with CHB, including 24 with mild fibrosis (stage 1, S1) and 24 with severe fibrosis (stage 4, S4), and subjected to Ficoll density gradient centrifugation in order to obtain enriched samples of peripheral blood mononuclear cells (PBMCs).The PBMC proteomes of the two groups were assessed by first separating the total proteins by two-dimensional gel electrophoresis (2DE) and then identifying the differentially expressed proteins by liquid chromatography combined with tandem mass spectrometry (LCMS/MS).

RESULTSThe enriched PBMC samples from the S1 group and the S4 group had similar amounts of platelets [(19.268+/- 6.413) * 109/L and(19.480+/- 6.538) * 109/L, respectively); however, for both, the platelet amounts were 5 to 15-fold lower than that of the normal reference (100-300 *109/L). There was no significant difference found between the platelet amounts in the S1 patients and healthy controls (P=0.930). Twelve differentially expressed proteins were identified through 2DE-LC-MS/MS, including proteins such as moesin and NADH dehydrogenase [ubiquinone] iron-sulfur protein 3 that are involved in various biological processes like cell movement, cell adhesion, kinase signaling and transcription.

CONCLUSIONs The 12 proteins with differential expression in S1 and S4 patients with CHB and liver fibrosis may represent markers related to development and/or progression of liver fibrosis.

Biomarkers ; Disease Progression ; Electrophoresis, Gel, Two-Dimensional ; Hepatitis B, Chronic ; complications ; Humans ; Leukocytes, Mononuclear ; chemistry ; metabolism ; Liver Cirrhosis ; etiology ; metabolism ; pathology ; Mass Spectrometry ; Prognosis ; Proteome ; Proteomics ; Tandem Mass Spectrometry

Previous studies reported that oxaliplatin is associated with sinusoidal obstruction syndrome. However few reports on oxaliplatin induced liver fibrosis are found in the literature. Furthermore pathogenesis of liver fibrosis is not well known. We report a case of 45-yr-old Korean man in whom liver fibrosis with splenomegaly developed after 12 cycles of oxaliplatin based adjuvant chemotherapy for colon cancer (T4N2M0). Thorough history taking and serological examination revealed no evidence of chronic liver disease. Restaging CT scans demonstrated a good response to chemotherapy. Five month after chemotherapy, he underwent right hepatectomy due to isolated metastatic lesion. The liver parenchyma showed diffuse sinusoidal dilatation and centrilobular vein fibrosis with necrosis without steatosis. We could conclude that splenomegaly was due to perisinusoidal liver fibrosis and liver cell necrosis induced portal hypertension by oxaliplatin. In addition, to investigate the pathogenesis of liver fibrosis, immunohistochemical stains such as CD31 and alpha-smooth muscle actin (alpha-SMA) were conducted with control group. The immunohistochemical stains for CD31 and alpha-SMA were positive along the sinusoidal space in the patient, while negative in the control group. Chemotherapy with oxaliplatin induces liver fibrosis which should be kept in mind as a serious complication.
Actins/metabolism ; Antigens, CD31/metabolism ; Antineoplastic Combined Chemotherapy Protocols/*therapeutic use ; Camptothecin/*analogs & derivatives/therapeutic use ; Chemotherapy, Adjuvant ; Colonic Neoplasms/*drug therapy ; Fluorouracil/therapeutic use ; Humans ; Hypertension, Portal/etiology ; Immunohistochemistry ; Leucovorin/therapeutic use ; Liver Cirrhosis/*diagnosis/etiology/pathology ; Liver Neoplasms/secondary/surgery ; Male ; Middle Aged ; Organoplatinum Compounds/*administration & dosage/adverse effects/therapeutic use ; Splenomegaly/*diagnosis/etiology ; Thrombocytopenia/etiology ; Tomography, X-Ray Computed

The lymphatic system is part of the circulatory system and plays a key role in normal vascular function. Its failure plays a crucial role in the development and maintenance of various diseases including liver diseases. Lymphangiogenesis (the growth of lymphatic vessels) and changes in the properties of lymphatic vessels are associated with pathogenesis of tumor metastases, ascites formation, liver fibrosis/cirrhosis and portal hypertension. Despite its significant role in liver diseases and its importance as a potential therapeutic target for those diseases, the lymphatic vascular system of the liver is poorly understood. Therefore, how the lymphatic vascular system in general and lymphangiogenesis in particular are mechanistically related to the pathogenesis and maintenance of liver diseases are largely unknown. This article summarizes: 1) the lymphatic vascular system; 2) its role in liver tumors, liver fibrosis/cirrhosis and portal hypertension; and 3) its role in ascites formation.
Ascites/*etiology ; Humans ; Hypertension, Portal/complications/pathology ; Liver Cirrhosis/complications/pathology ; Liver Diseases/complications/*pathology ; Liver Neoplasms/complications/pathology ; Lymphangiogenesis ; Lymphatic Vessels/metabolism/physiopathology

Animals ; Cholestasis ; complications ; Fibrosis ; etiology ; Gallbladder ; pathology ; Humans ; Kidney ; pathology ; Lipid Metabolism ; Liver Cirrhosis ; etiology ; therapy ; Myocardium ; pathology ; Receptors, Cytoplasmic and Nuclear ; physiology