Levels Of Hepatic Growth Factor Research Articles

Targeted Immune and Growth Factor Proteomics of Right Heart Adaptation to Pulmonary Arterial Hypertension Reveals a Potential Role of the Hepatic Growth Factor

Although inflammatory features have been reported in the pressure-overloaded right ventricle, prior proteomic studies of pulmonary arterial hypertension (PAH) have mainly focused on identifying circulating biomarkers associated with pulmonary vascular disease severity or outcomes. This study sought to determine the circulating proteomic immune profile associated with right heart maladaptive phenotype (RHMP) in PAH. In this observational study of PAH patients enrolled at Stanford University from 2008-2011 (n=121, discovery cohort) and from 2011-2014 (n=76, validation cohort), we carried out plasma proteomic profiling using Luminex® multiplex immunoassay (48-plex of interleukins, chemokines and growth factors). RHMP was defined by the Mayo right heart score (based on echocardiographic right ventricular RV strain, NYHA class and NT-proBNP) and Stanford right heart score (based on RV end-systolic remodeling index, NYHA class and NT-proBNP). The association between cytokines and RHMP was assessed by partial least square regression (PLS-R). To further validate the circulating markers associated with RHMP, we confirmed tissue-level expression in RV biopsies from PAH patients. Median age was 50 [39-59] years in the discovery cohort, where the majority of patients was female (74%) and PAH was most commonly associated with connective tissue disease (33%). Patients from the validation cohort had more severe features (lower six minute walk test distance, lower cardiac index and higher levels of NT-proBNP) than patients from the discovery cohort, with similar resistance levels and right heart echocardiography metrics. High levels of hepatic growth factor (HGF), stem cell growth factor beta (SCGFβ), nerve growth factor (NGF) and SDF1 were significantly associated with worst Mayo and Stanford scores but not with pulmonary vascular resistance or mean pulmonary arterial pressure, in both cohorts. In the right ventricle of deceased PAH patients, we confirmed expression of HGF and its receptor cMet using immunofluorescence. High plasma levels of HGF, SCGFβ, NGF and SDF1 are associated with RHMP in PAH, independent of pulmonary vascular disease severity. The HGF-cMet pathway warrants further exploration to investigate a potential RV specific therapeutic target.

Is There a Link between Basal Metabolic Rate, Spleen Volume and Hepatic Growth Factor Levels in Patients with Obesity-Related NAFLD?

Background: Recent pieces of research point to a link between basal metabolic rate (BMR) and non-alcoholic fatty liver disease (NAFLD) or hepatic steatosis (HS). The spleen in obese patients is associated with the cardiovascular system. Enlargement of the spleen is suggestive of nonalcoholic steatohepatitis (NASH). Patients with NASH present an increase in growth factor (HGF) as well as those with advanced heart failure. Interleukin-16 and interleukin-12p40 levels were found to correlate significantly with BMI, and waist circumference. Aim: We tried to find a relationship between BMR, spleen length and HGF. Methods: We analysed retrospective data from 80 obese patients with NAFLD. We evaluated indices of indirect calorimetry by the bioimpendance analysis; carotid intima-media thickness (IMT), spleen length (SLD) and HS by ultrasonography; serum HGF, IL-16, IL-12p40 and IL-6 concentrations by a magnetic bead-based multiplex immunoassays and the severity of NAFLD by BARD score > 2. Results: HGF levels of the obese were higher than those of controls, p < 0.001. At linear regression, BMR was foreseen by spleen length (p < 0.001), which was predicted by HGF (p = 0.04). BMR was predicted by IL-16 (p = 0.005), which predicted HGF, p = 0.034. Only fat mass, among other factors, predicted early atherosclerosis, p = 0.017; IL-12p40 did not predict IMT, HGF and BMR (p = 0.57, 0.09 and 0.59, respectively). The BARD score > 2 was negatively predicted by BMR and FFM (p =0.032 and 0.031, respectively), at the logistic regression. Interesting findings at the extended regression (mediation effect) were: IL-16 was likely causal in predicting BMR by HGF levels; HGF was influential in predicting BMR by SLD level. HS was predicted by SLD in males (p = 0.014), of advanced age (p < 0.001) and by BMR (p < 0.001). IL-6 concentrations, but not BMR were influential in the prediction of HS by SLD. Conclusion: These data reinforce the concept that the immune system is a sensor of the metabolic state, showing a link between HGF levels and BMR, which is mediated by IL-16 (cytokine inducing a cascade of inflammatory factors), and ascertaining the influential effect of the spleen, as main immune organ.

Biochemical mechanism underlying hypertriglyceridemia and hepatic steatosis/hepatomegaly induced by acute schisandrin B treatment in mice

BackgroundIt has been demonstrated that acute oral administration of schisandrin B (Sch B), an active dibenzocyclooctadiene isolated from Schisandrae Fructus (a commonly used traditional Chinese herb), increased serum and hepatic triglyceride (TG) levels and hepatic mass in mice. The present study aimed to investigate the biochemical mechanism underlying the Sch B-induced hypertriglyceridemia, hepatic steatosis and hepatomegaly.MethodsMale ICR mice were given a single oral dose of Sch B (0.25–2 g/kg). Sch B-induced changes in serum levels of biomarkers, such as TG, total cholesterol (TC), apolipoprotein B48 (ApoB 48), very-low-density lipoprotein (VLDL), non-esterified fatty acid (NEFA) and hepatic growth factor (HGF), as well as hepatic lipids and mass, epididymal adipose tissue (EAT) and adipocyte size, and histological changes of the liver and EAT were examined over a period of 12–120 h after Sch B treatment.ResultsSerum and hepatic TG levels were increased by 1.0–4.3 fold and 40–158% at 12–72 h and 12–96 h, respectively, after Sch B administration. Sch B treatment elevated serum ApoB 48 level (up to 12%), a marker of exogenous TG, but not VLDL, as compared with the vehicle treatment. Treatment with Sch B caused a time-/dose-dependent reduction in EAT index (up to 39%) and adipocyte size (up to 67%) and elevation in serum NEFA level (up to 55%). Sch B treatment induced hepatic steatosis in a time-/dose-dependent manner, as indicated by increases in total vacuole area (up to 3.2 fold vs. the vehicle control) and lipid positive staining area (up to 17.5 × 103 μm2) in liver tissue. Hepatic index and serum HGF levels were increased by 18–60% and 42–71% at 12–120 h and 24–72 h post-Sch B dosing, respectively. In addition, ultrastructural changes, such as increase in size and disruption of cristae, in hepatic mitochondria were observed in Sch B-treated mice.ConclusionOur findings suggest that exogenous sources of TG and the breakdown of fat storage in the body contribute to Sch B-induced hypertriglyceridemia and hepatic steatosis in mice. Hepatomegaly (a probable hepatotoxic action) caused by Sch B may result from the fat accumulation and mitochondrial damage in liver tissue.

Rat hepatic stellate cells alter the gene expression profile and promote the growth, migration and invasion of hepatocellular carcinoma cells.

The aim of the present study was to examine the effects of activated hepatic stellate cells (HSCs) and their paracrine secretions, on hepatocellular cancer cell growth and gene expression in vitro and in vivo. Differentially expressed genes in McA-RH7777 hepatocellular carcinoma (HCC) cells following non-contact co-culture with activated stellate cells, were identified by a cDNA microarray. The effect of the co-injection of HCC cells and activated HSCs on tumor size in rats was also investigated. Non-contact co-culture altered the expression of 573 HCC genes by >2-fold of the control levels. Among the six selected genes, ELISA revealed increased protein levels of hepatic growth factor, matrix metalloproteinase-2 (MMP-2) and −9 (MMP-9). Incubation of HCC cells with medium conditioned by activated HSCs significantly increased the proliferation rate (P<0.001), migration rate and the number of invasive HCC cells (P=0.001). Co-injection of HCC cells and activated HSCs into rats significantly increased the weight of the resulting HCC tumors (P<0.01). The paracrine activity of activated HSCs markedly altered the gene expression profile of HCC cells and affected their growth, migration and invasiveness. The results from the present study indicate that the interaction between the activated HSCs and HCC has an important role in the development of HCC.

Chronic Allograft Nephropathy in Rats Is Improved by the Intervention of Rhein

AimIn this study, we investigated the therapeutic efficacy and potential mechanisms of rhein to mitigate chronic allograft nephropathy (CAN) in rats. Materials and MethodsFisher rat donors and Lewis rat recipients were used to establish the CAN model. Thirty rats with transplanted kidneys were randomly divided into two groups: 16 untreated and 14 rhein = treated rats. Five Lewis rat controls underwent removal of their right kidneys. The Intervention group was administered rhein oral solution (100 mg kg-1 d-1) by gavage after transplantation. The untreated and control groups were given 0.5% sodium carboxymethyl cellulose. Blood and urine samples were collected at 4, 8, and 16 weeks to examine renal function and total urine protein. Half of the rats in each group were sacrifice at 8 or 16 weeks to examine renal pathology. Immunohistochemical examination and real-time polymerase chain reaction of renal tissues were performed to detect expressions of transforming growth-β1(TGF-β1), hepatic growth factor (HGF), bone morphogenetic protein 7 (BMP7), frobronectin, and collgen IV. ResultsRhein improved renal function and significantly reduced renal fibrosis and interstitial inflammation. The levels of BMP7 and HGF were significantly elevated in the renal tissues of the rhein intervention group. In the meantime, fibronectin and collagen IV were decreased in the extracellular matrix. The expression of TGF-β1 was similar between these two groups. ConclusionRhein improved renal function and reduced renal fibrosis and interstitial inflammation by inducing production of HGF and BMP7.

Tissue plasminogen activator in chronic subdural hematomas as a predictor of recurrence

Chronic subdural hematomas (CSDHs) recur in 7 to 18% of cases. The present study was conducted to determine whether serum or lesion concentrations of coagulofibrinolytic and angiogenic factors, which have been reported to be potential markers of CSDH development, might predict such recurrences. Sixty consecutive patients (mean age 71.5 years) with CSDHs (74 affected sides) were studied. Samples of serum in preoperative peripheral venous blood and of hematomas (obtained during surgery) were collected and analyzed. The CSDH recurred in six (8.1%) of the 74 affected sides in six patients. None of the values of the coagulative factors or tests in serum showed significant variation between cases with and those without recurrence. Among coagulofibrinolytic factors, tissue plasminogen activator (TPA) in hematomas demonstrated significantly greater levels in recurrent than in nonrecurrent cases; a similar tendency was noted for alpha2-plasmin inhibitor-plasmin complex in hematomas. Both factors were greater in the lesions than in the serum. Among the angiogenic factors, levels of hepatic growth factor (HGF) and vascular endothelial growth factor (VEGF) in hematomas were significantly greater than in serum, whereas those of basic fibroblast growth factor were rather lower. Note that comparisons between recurrent and nonrecurrent cases revealed no significant difference. Patients harboring CSDHs with high TPA concentrations on sampling at the initial surgery have a relatively high probability of recurrence and require follow up with computerized tomography scanning. Angiogenic factors, such as HGF and VEGF, might be candidate markers of CSDH enlargement but are not useful as predictors of recurrence.