PDGFR β-targeted TRAIL specifically induces apoptosis of activated hepatic stellate cells and ameliorates liver fibrosis

In this study, we found that platelet-derived growth factor receptor β (PDGFRβ) was co-expressed with DR5 in aHSCs. And the ZPDGFR β affibody with high affinity for PDGFR β could bind aHSCs and, thus, accumulate in the fibrotic liver. ZPDGFR β was fused to hTRAIL to produce the fusion protein Z-hTRAIL. Compared to hTRAIL, Z-hTRAIL showed greater in vitro cell binding and apoptosis-induction in aHSCs. In addition, Z-hTRAIL induced apoptosis of aHSCs but spared other normal liver cells. In vivo, Z-hTRAIL accumulated preferentially in fibrotic livers and exerted greater effects than hTRAIL in inducing aHSCs apoptosis and reducing extracellular matrix (ECM) deposition. These results demonstrated that the antihepatofibrotic effect of hTRAIL was improved by PDGFR β-targeted delivery. To enhance its pharmacokinetics, Z-hTRAIL was modified with 10 kDa polyethylene glycol (PEG), which significantly (30–40 times) prolonged its half-life. The PEGylated long-acting Z-hTRAIL was more potent than the native Z-hTRAIL in regressing liver fibrosis. These results su ggest that the aHSC-targeting and long-acting Z-hTRAIL might serve as a novel tool for antihepatofibrotic therapy.
Source: Apoptosis - Category: Molecular Biology Source Type: research

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Authors: Jeffrey GP PMID: 33030253 [PubMed - as supplied by publisher]
Source: Medical Journal of Australia - Category: General Medicine Tags: Med J Aust Source Type: research
Non-Alcoholic Fatty Liver Disease (NAFLD), a progressive liver disease that is closely associated with obesity, type 2 diabetes, hypertension and dyslipidaemia, represents an increasing global public health challenge. There is significant variability in the disease course: the majority exhibit only fat accumulation in the liver but a significant minority develop a necroinflammatory form of the disease (non-alcoholic steatohepatitis, NASH) that may progress to cirrhosis and hepatocellular carcinoma.
Source: Contemporary Clinical Trials - Category: Radiology Authors: Source Type: research
Authors: Omar M, Farid K, Emran T, El-Taweel F, Tabll A, Omran M Abstract A b s t r a c t. BACKGROUND: Early detection of hepatocellular carcinoma (HCC) is crucial in providing more effective therapies. As routine laboratory variables are readily accessible, this study aimed to develop a simple noninvasive model for predicting hepatocellular cancer. METHODS: Two groups of patients were recruited: an estimation group (n= 300) and a validation group (n= 625). Each comprised 2 categories: hepatocellular cancer and liver cirrhosis. Logistic regression analyses and receiver operating characteristic (ROCs) curves...
Source: British Journal of Biomedical Science - Category: Laboratory Medicine Tags: Br J Biomed Sci Source Type: research
Conditions:   Hepatocellular Carcinoma;   Liver Cancer;   Advanced Adult Hepatocellular Carcinoma;   Cirrhosis, Liver;   Unresectable Liver Cancer;   Liver Transplant Disorder Intervention:   Sponsor:   Inonu University Completed
Source: ClinicalTrials.gov - Category: Research Source Type: clinical trials
AbstractPurpose of ReviewNonalcoholic fatty liver disease (NAFLD) is an often unrecognized complication of type 2 diabetes (T2DM) associated with significant economic burden and poor long-term hepatic and extrahepatic outcomes. Our goal is to review evidence about the complex association between NAFLD and T2DM and highlight the potential for disease co-management with the available medications used for the treatment of diabetes.Recent FindingsA milieu of metabolic factors such as insulin resistance, glucotoxicity, and lipotoxicity, as well as genetics and other factors, contribute to the pathogenesis and co-existence of NA...
Source: Current Diabetes Reports - Category: Endocrinology Source Type: research
Authors: Wang W, Huang X, Fan X, Yan J, Luan J Abstract Hepatitis C virus (HCV) infection is a global public health problem. Cirrhosis and hepatocellular carcinoma are the main causes of death in patients with chronic hepatitis C (CHC) infection. Liver fibrosis is an important cause of cirrhosis and end‑stage liver disease after CHC infection. Along with the course of infection, liver fibrosis exhibits a progressive exacerbation. Hepatic stellate cells (HSCs) are involved in both physiological and pathological processes of the liver. During the chronic liver injury process, the activated HSCs transform into ...
Source: Molecular Medicine Reports - Category: Molecular Biology Tags: Mol Med Rep Source Type: research
Authors: Midorikawa Y, Takayama T, Higaki T, Aramaki O, Teramoto K, Yoshida N, Mitsuka Y, Tsuji S Abstract Multiplicity is one of the characteristics of hepatocellular carcinoma (HCC), and patients with multiple HCC (≤ 3 nodules) are recommended as candidates for liver resection. To confirm the validity of resecting multiple HCC, we compared the surgical outcomes in patients with synchronous and metachronous multiple HCC. Patients who underwent resection for multiple HCC (2 or 3 nodules) were classified into the "synchronous multiple HCC" group, while those undergoing resection for solitary HCC and rep...
Source: BioScience Trends - Category: Biomedical Science Tags: Biosci Trends Source Type: research
Hepatocellular carcinoma (HCC) has been increasing in incidence and prevalence for more than 30 years. As hepatologists have become more adept at treating underlying liver disease and cirrhosis, patients with cirrhosis are living longer, and with longer duration of cirrhosis comes an increased risk of HCC development. Cirrhosis is the underlying disease in most patients with HCC, although around 10% of HCC occurs without cirrhosis, often in the setting of chronic hepatitis B infection. Unfortunately, even with improving treatments for viral hepatitis, cirrhosis has continued to increase worldwide, due to the epidemic of no...
Source: Clinics in Liver Disease - Category: Gastroenterology Authors: Tags: Preface Source Type: research
Previous studies have demonstrated worse survival in hepatocellular carcinoma (HCC) patients treated at safety net hospitals (SNH). We hypothesized that outcome disparities between SNH patients and their affiliated academic centers (ACAD) may vary by degree of cirrhosis at presentation.
Source: Journal of the American College of Surgeons - Category: Surgery Authors: Tags: Surgical oncology Source Type: research
Surgical resection is indicated in hepatocellular carcinoma (HCC) patients with Child A cirrhosis. We hypothesized that surgical intervention and survival can be limited by advanced disease presentation at safety net (SNH) vs affiliated academic (ACAD) hospitals.
Source: Journal of the American College of Surgeons - Category: Surgery Authors: Tags: Health services research Source Type: research
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