Hepatic Endothelial Dysfunction Research Articles

Role of auto-antibodies in the mechanisms of dengue pathogenesis and its progression: a comprehensive review.

A complex interaction among virulence factors, host-genes and host immune system is considered to be responsible for dengue virus (DENV) infection and disease progression. Generation of auto-antibodies during DENV infection is a major phenomenon that plays a role in the pathophysiology of dengue hemorrhagic fever and dengue shock syndrome. Hemostasis, thrombocytopenia, hepatic endothelial dysfunction, and autoimmune blistering skin disease (pemphigus) are different clinical manifestations of dengue pathogenesis; produced due to the molecular mimicry of DENV proteins with self-antigens like coagulation factors, platelets and endothelial cell proteins. This review elaborately describes the current advancements in auto-antibody-mediated immunopathogenesis which inhibits coagulation cascade and promotes hyperfibrinolysis. Auto-antibodies like anti-endothelial cell antibodies-mediated hepatic inflammation during severe DENV infection have also been discussed. Overall, this comprehensive review provides insight to target auto-antibodies that may act as potential biomarkers for disease severity, and a ground for the development of therapeutic strategy against DENV.

A nutraceutical with Citrus bergamia and Cynara cardunculus improves endothelial function in adults with non-alcoholic fatty liver disease

ObjectivePolyphenol intake may prevent hepatic steatosis and cardiovascular disease by potentially improving endothelial function. The purposes of this study are to investigate the association between fatty liver disease and endothelial dysfunction and to test the effects of a nutraceutical containing extracts made from Citrus bergamia and Cynara cardunculus on peripheral vascular endothelial function in adults with liver steatosis. MethodsWe analyzed data from 32 individuals with hepatic steatosis and endothelial dysfunction (reactive hyperemia index ≤ 1.67). Sixteen subjects took 1 capsule/d (300 mg/d) containing Cynara cardunculus extract and bergamot polyphenol fraction, while the other 16 subjects matched for age, sex, and body mass index took 1 capsule/d of placebo (maltodextrin) for 12 wk. All anthropometric parameters were assessed at baseline and after 12 wk as were lipids, glucose, and reactive hyperemia index using an EndoPAT 2000. ResultsThe mean age was 52 ± 9 y. The mean reactive hyperemia index was 1.15 ± 0.4. After 12 wk, we found a greater increase in reactive hyperemia index in the participants taking the nutraceutical rather than placebo (0.58 ± 0.5 versus 0.13 ± 0.5; P = 0.02, respectively). The stepwise multivariable analysis confirmed a positive association between reactive hyperemia index change and the nutraceutical treatment (B = 0.38; P = 0.025) and negative association with reactive hyperemia index values at baseline (B = –0.81; P < 0.001). No association was found between the reduction in the amount of intrahepatic fat and the improvement of endothelial function (B = 0.002; P = 0.56). ConclusionsA nutraceutical containing bergamot and artichoke extracts improves peripheral vascular endothelial function in adults with hepatic steatosis and early phase of atherosclerosis.

Curcumin Alleviates High-fat Diet-induced Nonalcoholic Steatohepatitis via Improving Hepatic Endothelial Function with Microbial Biotransformation in Rats.

Hepatic endothelial function is central to the development of nonalcoholic steatohepatitis (NASH). Curcumin (Cur) is reportedly hepatoprotective, however, it remains unknown whether Cur improves hepatic endothelial function in NASH. Additionally, the poor bioavailability of Cur renders it difficult to elucidate its hepatoprotective effect, hence, its biotransformation should be considered. Herein, we investigated the effects and mechanisms of Cur and its bioconversion on hepatic endothelial function against high-fat diet-induced NASH in rats. The results revealed that Cur improved hepatic lipid accumulation, inflammation, and endothelial dysfunction by inhibiting NF-κB and PI3K/Akt/HIF-1α pathways, however, these effects were weakened via antibiotic addition, which was closely related to reduced tetrahydrocurcumin (THC) produce in the liver and intestinal content. Moreover, THC exerted a better effect than Cur on restoring liver sinusoidal endothelial cells function to attenuate steatosis and injury in L02 cells. Thus, these findings indicate that the effect of Cur on NASH is closely related to hepatic endothelial function improvement with intestinal microbial biotransformation.

Erianin alleviated liver steatosis by enhancing Nrf2-mediated VE-cadherin expression in vascular endothelium

Non-alcoholic fatty liver disease (NAFLD) is emerging as the most common chronic liver disease and is closely associated with metabolic syndrome. Endothelial dysfunction was involved in many metabolic diseases, but the concrete participation of hepatic vascular endothelial dysfunction in liver steatosis that is an early stage of NAFLD is still unclear. In this study, the formation of liver steatosis and the elevation of serum insulin content were observed accompanying with the decreased vascular endothelial cadherin (VE-cadherin) expression in hepatic vessels from db/db mice, Goto-Kakizaki (GK) and high-fat diet (HFD)-fed rats. Liver steatosis was obviously enhanced in mice after the application of VE-cadherin neutralizing antibody. In vitro results showed that insulin decreased VE-cadherin expression and caused endothelial barrier breakdown. Furthermore, the alteration of VE-cadherin expression was found to be positively related with the transcriptional activation of nuclear erythroid 2-related factor 2 (Nrf2), and chromatin immunoprecipitation (ChIP) assay displayed that Nrf2 could directly regulate VE-cadherin expression. Insulin reduced Nrf2 activation by decreasing sequestosome-1 (p62/SQSTM1) expression downstream of insulin receptor. Moreover, the p300-mediated Nrf2 acetylation was weakened by enhancing the competitive binding of transcription factor GATA-binding protein 4 (GATA4) to p300. Finally, we found that erianin, a natural compound, could promote VE-cadherin expression by inducing Nrf2 activation, thereby alleviating liver steatosis in GK rats. Our results suggest that hepatic vascular endothelial dysfunction owing to the VE-cadherin deficiency dependent on the reduced Nrf2 activation promoted liver steatosis, and erianin alleviated liver steatosis through enhancing Nrf2-mediated VE-cadherin expression.

Preservation of vascular endothelial glycocalyx and barrier by activation of adenosine A2A receptor (A2AR) improved renal dysfunction in cirrhotic rats

Cirrhosis-related hepatic and renal endothelial dysfunction is characterized by macrophage-endothelium adhesion-mediated inflammation, glycocalyx/barrier damage, and impaired vasodilation. Activation of adenosine A2A receptor (A2AR) protects cirrhotic rats from impairment of hepatic microcirculation post hepatectomy. This study evaluates the effects of A2AR activation on the cirrhosis-related hepatic and renal endothelial dysfunction in biliary cirrhotic rats receiving two weeks of A2AR agonist PSB0777 [bile duct ligated (BDL)+PSB0777] treatment.Endothelial dysfunction in cirrhotic liver, renal vessels, and kidney is characterized by downregulation of the A2AR expressions, decreased vascular endothelial vasodilatory (p-eNOS)/anti-inflammatory (IL-10/IL-10R)/barrier [VE-cadherin (CDH5) and β-catenin (CTNNB1)]/glycocalyx [syndecan-1 (SDC1) and hyaluronan synthase-2 (HAS2)] markers, and increased leukocyte-endothelium adhesion molecules (F4/80, CD68, ICAM-1, and VCAM-1). In BDL rats, PSB0777 treatment improves hepatic and renal endothelial dysfunction, ameliorates portal hypertension, and attenuates renal hypoperfusion by restoring of the vascular endothelial anti-inflammatory, barrier, glycocalyx markers and vasodilatory response as well as inhibiting the leukocyte-endothelium adhesion. In an in vitro study, conditioned medium (CM) of bone marrow-derived macrophage (BMDM) of BDL rats [BMDM-CM (BDL)] induced barrier/glycocalyx damage, which was reversed by the PSB0777 pre-treatment. The A2AR agonist is a potential agent that can simultaneously correct cirrhosis-related hepatic and renal endothelial dysfunction, portal hypertension, renal hypoperfusion, and renal dysfunction.

Sonographic Markers Are Useful for Detection of Early Vascular Deterioration in Children with Overweight/Obesity: Effect of a 1-Year Combined Nutritional Education and Physical Exercise Program

As in adults, childhood obesity is associated with several metabolic disorders; however, there is little information regarding complex obesity-derived complications such as hepatic steatosis or endothelial dysfunction at early ages. Therefore, the objective of the present study was to analyze the effect of a nutritional and physical exercise program on obesity comorbidities in the form of subclinical atherosclerosis and non-alcoholic fatty liver in young children. A total of 148 children completed the study. For nine months (one academic year), children carried out a nutritional and physical activity program of 3 h/week. Anthropometric, clinical, liver ultrasound and carotid intima-media thickness (cIMT) parameters were evaluated. Our results showed that the program significantly improved anthropometrical parameters, especially regarding BMI and body fat (p < 0.001 and p = 0.004, respectively). The effect on metabolic parameters was limited, although a significant reduction on triglycerides was observed (p = 0.009). The education program had a great influence on the echogenic parameters, since the percentage of children with light steatosis decreased from 35% to 4% at the end of the study. In addition, cIMT also decreased significantly in both groups, although there was no statistically significant differences between groups. In conclusion, detection of early complications of obesity through sonographic parameters may allow early intervention, as in the present study, to prevent obesity co-morbidities in children.

Attenuation of streptozotocin induced high fat diet exacerbated dyslipidemia mediated hepatic and aortic injuries in male pigs by camel milk

ABSTRACT Dyslipidemia, diabetes, and the upregulation of receptors for oxidized low-density lipoprotein all contribute to hepatic and aortic endothelial dysfunction. The current research examined how camel milk could possibly decrease induced Streptozotocin-high fat diet-aggravated dyslipidemia-mediated damage in male pig hepatic and aortic tissues. Twenty-five pigs were separated into five groups of five pigs each, with five non-atherosclerotic pigs in the control group and twenty atherosclerotic pigs in the experimental groups. Groups 1 and 2 received distilled water as the standard control and atherosclerotic control groups, respectively, while Groups 3 and 4 received camel milk at 250 mL/day and 500 mL/day, respectively, and Group 5 received Metformin at 500 mg/day. The experiment lasted ten weeks. After 10 weeks, all of the pigs were euthanized. The lipid profile and liver enzyme levels were determined from the analysis of blood serum and the histology of the liver and aortic. When pigs administered, camel milk were compared to atherosclerotic control pigs, there was a significant decrease (p 0.05) in cholesterol, triglyceride, low density lipoprotein (LDL), and very low-density lipoprotein (VLDL) levels, while a significant increase in high density lipoprotein levels was observed in pigs that received camel milk. Also, pigs in groups that received camel milk had their liver enzyme parameters (ALP, AST, ALT, GGT, LDH, and CK-MB) significantly lowered when compared with atherosclerotic control pigs. Similarly, treatment with camel milk ameliorates aortic tissues from degradation and reduces histological liver steatosis, and it also decreases the expression of LOX-1 mRNA in the aorta of atherosclerotic pigs.

Beneficial Effects of Carvacrol on In Vitro Models of Metabolically-Associated Liver Steatosis and Endothelial Dysfunction: A Role for Fatty Acids in Interfering with Carvacrol Binding to Serum Albumin.

Carvacrol, a plant phenolic monoterpene, is largely employed as food additive and phytochemical. We aimed to assess the lipid lowering and protective effects of carvacrol in vitro using cellular models of hepatic steatosis and endothelial dysfunction. We also investigated if and how the binding of carvacrol to albumin, the physiological transporter for small compounds in the blood, might be altered by the presence of high levels of fatty acids (FAs). Hepatic FaO cells treated with exogenous FAs mimic hepatosteatosis; endothelial HECV cells exposed to hydrogen peroxide are a model of endothelial dysfunction. In these models, we measured spectrophotometrically lipid accumulation and release, lipoperoxidation, free radical production, and nitric oxide release before and after treatment with carvacrol. The carvacrol binding to albumin in the presence or absence of high levels of FAs was assessed by absorption and emission spectroscopies. Carvacrol counteracted lipid accumulation and oxidative stress in hepatocytes and protected endothelial cells from oxidative stress and dysfunction. Moreover, high levels of FAs reduced the binding of carvacrol to albumin. The results suggest the good potential of carvacrol in ameliorating dysfunction of hepatic and endothelial cells in vitro. High levels of circulating FAs might compete with carvacrol for binding to albumin thus influencing its transport and bio-distribution.

Chronic intermittent hypoxia promotes early intrahepatic endothelial impairment in rats with nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) is a progressive disease that ranges from simple steatosis to cirrhosis. Obstructive sleep apnea syndrome (OSAS) and chronic intermittent hypoxia (CIH) are implicated in the pathogenesis of NAFLD. However, the overlapping consequences of CIH on liver sinusoidal endothelial function over time in NAFLD are largely unknown. We explored endothelial dysfunction in a rat model of NAFLD with a high-fat diet exposed to CIH [12 h/day, every 30 s to fractional concentration of oxygen ([Formula: see text] 8%-10%]. The livers were isolated and perfused, and the endothelial function was determined by testing the vasodilation of the liver circulation to increased concentrations of acetylcholine and von Willebrand factor (vWF) and intercellular adhesion molecule 1 (ICAM-1) expression. Phosphorylated endothelial nitric oxide synthase (p-eNOS), cGMP, and oxidative stress were assessed to determine nitric oxide bioavailability. Inflammation and fibrosis were evaluated by transaminases, myeloperoxidase activity, hydroxyproline, and histological evaluation. Hypoxia-inducible factors (HIFs) were studied as a marker of hypoxia and after a second insult with acetaminophen. CIH exposure provoked typical systemic features of OSAS and provoked a decreased response in vasodilation to acetylcholine. This was associated with increased oxidative stress and reduced p-eNOS and cGMP. The microcirculation impairment due to CIH preceded significant hepatic inflammation and fibrotic changes, despite the presence of HIF expression. In conclusion, CIH exacerbates endothelial dysfunction in NAFLD rats associated with increased oxidative stress and reduced nitric oxide bioavailability. This occurs before inflammation and fibrosis establish. Our results suggest that with CIH endothelial dysfunction should be considered an early target.NEW & NOTEWORTHY We believe the findings are of relevance because we demonstrate that chronic intermittent hypoxia further augments impaired hepatic endothelial dysfunction in nonalcoholic fatty liver disease rats. Because obstructive sleep apnea syndrome is associated with systemic endothelial dysfunction in cardiovascular disorders, and chronic intermittent hypoxia is an independent and reversible risk factor for hypertension and coronary artery disease, we hypothesized that this entity may be of potential relevance in the pathophysiology of nonalcoholic fatty liver disease.

Water soluble dietary fiber from walnut meal as a prebiotic in preventing metabolic syndrome

Abstract Dietary fiber intake is associated with a low incidence of suffering from metabolic syndrome. To explore the potential health benefits of walnut meal dietary fiber (WMDF) as a prebiotic, the functional role of WMDF on metabolic syndrome in mice induced by high fructose diet (20%, HF) was investigated. The animal experiment results showed that administration of WMDF to HF-fed mice alleviated abnormal body weight gain, insulin resistance, oxidative stress, lipid metabolism disorders and inflammation. Histopathological observation confirmed the preventative effects of WMDF on hepatic steatosis and vascular endothelial dysfunction. Also, WMDF intake increased the production of acetic acid, propionic acid and butyric acid. Moreover, WMDF ingestion effectively improved the disorder of gut microbiota caused by HF, increased the diversity of gut microbiota and the relative abundance of short-chain fatty acids-producing bacteria. These findings demonstrate WMDF can be used as a prebiotic to prevent HF-induced metabolic syndrome.

Role of leptin in pathogenesis of hepatic steatosis, steatohepatitis and endothelial dysfunction in obesity: literature review

According to the latest WHO data, in the world there are 2 billion adults and 381 million children and adolescents from 0 to 19 years old, who are overweight or obese. This is due to the presence of many factors affecting the occurrence and development of this disease. One of the important links in the pathogenesis of obesity is hyperleptinemia in combination with leptin resistance.&#x0D; In this article, we attempted to summarize the information on the role of leptin in the pathogenesis of obesity complications such as liver steatosis, steatohepatitis and endothelial dysfunction. Parallels have been drawn between insulin resistance and leptin resistance. The relationship of leptin and insulin was analyzed, and data on the effect of these hormones on carbohydrate and fat metabolism are also presented.

The protective effects of walnut green husk polysaccharide on liver injury, vascular endothelial dysfunction and disorder of gut microbiota in high fructose-induced mice

This study aimed to investigate the protective effects of walnut green husk polysaccharide (WGHP) on liver injury, vascular endothelial dysfunction and disorder of gut microbiota in mice induced by high fructose (HF) diet. The chemical analysis results show that the walnut green husk polysaccharide is a low molecular weight acidic heteropolysaccharide, composed mainly of glucuronic acid, arabinose and galactose. Biochemical analysis showed that WGHP significantly improved glucose metabolism and lipid metabolism and decreased oxidative stress in HF-diet induced obesity mice. Histopathological observation of liver and cardiovascular aorta confirmed the protective effects of WGHP on hepatic steatosis and vascular endothelial dysfunction. Furthermore, 16S rRNA sequencing results demonstrated that WGHP reversed the disorders of gut microbiota caused by HF, decreased the relative abundance of Verrucomicrobia and increased the relative abundance of Deferribacteres at the phylum level, decreased the relative abundance of Akkermansia, Lachnoclostridium and norank_f__Muribaculaceae and increased the relative abundance of Prevotellaceae_UCG-001, Helicobacter, Alloprevotella and Allobaculum at the genus levels. Our results indicate that WGHP may act as a functional polysaccharide for protecting liver and cardiovascular in HF-fed mice.

Low carbohydrate caloric restriction diet prevents non alcoholic fatty liver disease development, improves pro/antioxidant status and nitric oxide bioavailability in obese rat

One of the pathogenic mechanisms of the non-alcoholic fatty liver disease (NAFLD) is the accumulation of reactive oxygen species, which in turn aggravates the disease progress and increase cardiovascular disease (CVD) risk. Caloric restriction is recommended for improvement of obesity related diseases such as NAFLD. However, low carbohydrate caloric restriction (LCCR) diet effects on liver metabolic dysfunction and CV complications associated remain unknown. The effects of LCCR diet on dyslipidemia, hepatic fat accumulation, pro/antioxidant status and endothelial dysfunction were studied in obese rat. Nutritional obesity was induced since weaning by a hyperlipidic diet (HLD) for 10 weeks. Responders rats to HLD were divided into two obese groups. The first group fed LCCR diet and the second, continue to consume the HLD for 4 weeks (obese control (Ob-C)). A normoponderal group was fed a standard diet, and used as control (C group). In LCCR group, a reduction of liver fats accumulation and low-density lipoproteins-cholesterol (C) content was noted compared with Ob-C group, whereas, high-density lipoproteins-C was increased. In addition, the concentrations of thiobarbituric acid reactive substances, lipids hydroperoxides, isoprostans and carbonyls in serum and tissues (liver aorta and heart) were decreased and enzymatic antioxidant defense enhanced, including paraoxonase 1 activity. In addition, an improvement in the bioavailability of nitric oxide in serum and tissues, and in the membrane fluidity was also observed. LCCR diet prevents NAFLD development; improves pro/antioxidant status and the endothelial dysfunction. LCCR diet may be a promising therapeutic strategy to slow down the development of cardiometabolic complications associated with NAFLD.

THU-037-Soluble MAdCAM-1 as a novel marker of hepatic endothelial dysfunction in acutely decompensated cirrhosis

THU-037-Soluble MAdCAM-1 as a novel marker of hepatic endothelial dysfunction in acutely decompensated cirrhosis

Prediction of features of the course of chronic hepatitis C using Bayesian networks.

253 patients with chronic hepatitis C (CHC) and liver cirrhosis were included in the study. Assessment of gene polymorphisms of genes involved in inflammatory reactions and antiviral immunity (IL-1β-511C/T, IL-10 -1082G/A, IL28B C/T, IL28B T/G, TNF-α -238G/A, TGF-β -915G/C, IL-6 -174G/C), activators of local hepatic fibrosis (AGT G-6A, AGT 235 M/T, ATR1 1166 A/C), hemochromatosis (HFE C282Y, HFE H63D), platelet receptors (ITGA2 807 C/T, ITGB3 1565 T/C), coagulation proteins and endothelial dysfunction (FII 20210 G/A, FV 1691G/A, FVII 10976 G/A, FXIII 103 G/T, eNOS 894 G/T, CYBA 242 C/T, FBG -455 G/A, PAI-675 5G/4G, MTHFR 677 C/T) was carried. Using Bayesian networks we studied the predictor value of clinical and laboratory factors for the following conditions - end points (EP): development of cirrhosis (EP1), fibrosis rate (EP2), presence of portal hypertension (EP3) and cryoglobulins (EP4). In addition to traditional factors we have shown the contribution of the following mutations. Predicting EP1- liver cirrhosis - HFE H63D, C282Y, CYBA 242 C/T, AGT G-6G, ITGB31565 T/C gene mutations were significant. We also found a link between the rate of progression of liver fibrosis and gene polymorphisms of AGT G-6G, AGT M235T, FV 1691G/A, ITGB31565 T/C. Among the genetic factors associated with portal hypertension there are gene polymorphisms of PAI-I-675 5G/4G, FII 20210 G/A, CYBA 242 C/T, HFE H63D and Il-6 174GC. Cryoglobulins and cryoglobuliemic vasculitis (EP4) are associated with gene mutations MTHFR C677T, ATR A1166C and HFE H63D. The results obtained allow to detect the major pathophysiological and genetic factors which determine the status of the patient and the outcome of the disease, to clarify their contribution, and to reveal the significance of point mutations of genes that control the main routes of HCV course and progression.

Enoxaparin does not ameliorate liver fibrosis or portal hypertension in rats with advanced cirrhosis.

Recent studies suggest that heparins reduce liver fibrosis and the risk of decompensation of liver disease. Here, we evaluated the effects of enoxaparin in several experimental models of advanced cirrhosis. Cirrhosis was induced in male Sprague-Dawley (SD) rats by: (i) Oral gavage with carbon tetrachloride (CCl4ORAL ), (ii) Bile duct ligation (BDL) and (iii) CCl4 inhalation (CCl4INH ). Rats received saline or enoxaparin s.c. (40IU/Kg/d or 180IU/Kg/d) following various protocols. Blood biochemical parameters, liver fibrosis, endothelium- and fibrosis-related genes, portal pressure, splenomegaly, bacterial translocation, systemic inflammation and survival were evaluated. Endothelial dysfunction was assessed by in situ bivascular liver perfusions. Enoxaparin did not ameliorate liver function, liver fibrosis, profibrogenic gene expression, portal hypertension, splenomegaly, ascites development and infection, serum IL-6 levels or survival in rats with CCl4ORAL or BDL-induced cirrhosis. Contrarily, enoxaparin worsened portal pressure in BDL rats and decreased survival in CCl4ORAL rats. In CCl4INH rats, enoxaparin had no effects on hepatic endothelial dysfunction, except for correcting the hepatic arterial dysfunction when enoxaparin was started with the CCl4 exposure. In these rats, however, enoxaparin increased liver fibrosis and the absolute values of portal venous and sinusoidal resistance. Our results do not support a role of enoxaparin for improving liver fibrosis, portal hypertension or endothelial dysfunction in active disease at advanced stages of cirrhosis. These disease-related factors and the possibility of a limited therapeutic window should be considered in future studies evaluating the use of anticoagulants in cirrhosis.

Amelioration of cirrhotic portal hypertension by targeted cyclooxygenase-1 siRNA delivery to liver sinusoidal endothelium with polyethylenimine grafted hyaluronic acid

Portal hypertension (PH), a leading cause of mortality in cirrhosis, lacks effective clinical therapeutic strategies. The increased thromboxane A2 (TXA2), derived primarily from the upregulation of cyclooxygenase-1 (COX-1) in cirrhotic liver sinusoidal endothelial cells (LSECs), is responsible for hepatic endothelial dysfunction and PH. Thus, blocking the COX-1 pathway in cirrhotic LSECs may benefit the treatment of PH. In this study, hyaluronate-graft-polyethylenimine (HA-PEI) was synthesized for the targeted delivery of COX-1 siRNA to LSECs. Compared to non-targeted PEI, HA-PEI mediated much more efficient siRNA delivery, which resulted in potent targeted gene silencing in LSECs. In vivo, HA-PEI notably increased the accumulation of siRNA along the sinusoidal lining of the liver, inhibited over-activation of the COX-1/TXA2 pathway in LSECs, and successfully reduced portal pressure in cirrhotic mice. These results highlight the potential of HA-PEI complexed siRNA to serve as a LSECs-specific nanomedical system for effective gene therapy in PH.

Inhibition of soluble epoxide hydrolase lowers portal hypertension in cirrhotic rats by ameliorating endothelial dysfunction and liver fibrosis

Epoxyeicostrienoic acids (EETs) are arachidonic acid derived meditators which are catalyzed by soluble epoxide hydrolase (sEH) to less active dihydroeicostrienoics acids (DHETS). The aim of our study is to investigate the effects of sEH inhibition on hepatic and systemic hemodynamics, hepatic endothelial dysfunction, and hepatic fibrosis in CCl4 cirrhotic rats. The sEH inhibitor,trans-4-{4-[3-(4-trifluoromethoxyphenyl)-ureido]cyclohexyloxy}benzoic acid (t-TUCB) was administered to stabilize hepatic EETs by gavage at a dose of 1mg/kg/d. Our results showed that hepatic sEH expression was markedly increased in portal hypertension, and led to a lower ratio of EETs/DHETs which was effectively reversed by t-TUCB administration. t-TUCB significantly decreased portal pressure without significant changes in systemic hemodynamics, which was associated with the attenuation of intrahepatic vascular resistance (IHVR) and liver fibrosis. t-TUCB ameliorated endothelial dysfunction, increased hepatic endothelial nitric oxide synthase (eNOS) phosphorylation and nitric oxide (NO) production. In addition, t-TUCB significantly reduced alpha-Smooth Muscle Actin (α-SMA) expression and liver fibrosis, which was associated with a decrease in NF-κB signaling. Taken together, inhibition of sEH reduces portal pressure, liver fibrosis and attenuates hepatic endothelial dysfunction in cirrhotic rats. Our results indicate that sEH inhbitors may be useful in the treatment of portal hypertension in patients with cirrhosis.

Defibrotide for the treatment of severe hepatic veno-occlusive disease/sinusoidal obstruction syndrome: evidence for clinical benefit

Introduction: Veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS), characterized by hepatic sinusoidal endothelial damage and liver dysfunction, is an unpredictable and potentially life-threatening complication of hematopoietic stem cell transplantation that occurs in an estimated 14% of these patients (range 0 – 62.3%). VOD/SOS typically occurs following high-dose radiotherapy and/or chemotherapy as conditioning. Although mild/moderate VOD/SOS may not progress in some patients and may resolve at an early stage (i.e., within 2 or 3 weeks), in others it develops into severe VOD/SOS, commonly identified by the presence of multi-organ failure (defined by pulmonary and/or renal dysfunction), which, in turn, is associated with mortality rates >80%.Areas covered: This review of severe hepatic VOD/SOS discusses the disease characteristics, diagnostic criteria, prevalence, pathogenesis and current treatment guidelines for VOD/SOS, as well as prophylactic measures. The clinical trial evidence for associated therapies is reviewed, along with evaluations of these therapies by VOD/SOS expert consensus groups. Defibrotide, the only medication approved for the treatment of severe VOD/SOS in the European Union, is discussed in detail with regard to chemistry, pharmacodynamics/pharmacokinetics, proposed mechanisms of action and evidence from clinical trials of efficacy and safety.Expert opinion: Clinical data show that defibrotide reduces the mortality associated with VOD/SOS. Given the lack of therapeutic options and the favorable benefit/risk profile of defibrotide, this agent may therefore help fill an important and unmet therapeutic need.

Diet-induced dyslipidemia leads to nonalcoholic fatty liver disease and oxidative stress in guinea pigs.

Chronic dyslipidemia imposed by a high-fat and high-caloric dietary regime leads to debilitating disorders such as obesity, nonalcoholic fatty liver disease (NAFLD), and insulin resistance. As disease rates surge, so does the need for high validity animal models to effectively study the causal relationship between diet and disease progression. The dyslipidemic guinea pig displays a high similarity with the human lipoprotein profile and may in this aspect be superior to other rodent models. This study investigated the effects of 2 long-term Westernized diets (0.35% cholesterol, 18.5% vegetable oil and either 15% or 20% sucrose) compared with isocaloric standard chow in adult guinea pigs. Biochemical markers confirmed dyslipidemia in agreement with dietary regimens; however, both high-fat groups displayed a decreased tissue fat percentage compared with controls. Macroscopic appearance, histopathologic evaluation, and plasma markers of liver function confirmed NAFLD in high-fat groups, supported by liver redox imbalance and markers suggesting hepatic endothelial dysfunction. Plasma markers indicated endothelial dysfunction in response to a high-fat diet, although atherosclerotic lesions were not evident. Evaluation of glucose tolerance showed no indication of insulin resistance. The 5% increase in sucrose between the 2 high-fat diets did not lead to significant differences between groups. In conclusion, we find the dyslipidemic guinea pig to be a valid model of diet imposed dyslipidemia, particularly with regards to hepatic steatosis and endothelial dysfunction. Furthermore, the absence of obesity supports the present study setup as targeting NAFLD in nonobese individuals.