Dataset Information

Potential Use of Biological Proteins for Liver Failure Therapy.

ABSTRACT: Biological proteins have unlimited potential for use as pharmaceutical products due to their various biological activities, which include non-toxicity, biocompatibility, and biodegradability. Recent scientific advances allow for the development of novel innovative protein-based products that draw on the quality of their innate biological activities. Some of them hold promising potential for novel therapeutic agents/devices for addressing hepatic diseases such as hepatitis, fibrosis, and hepatocarcinomas. This review attempts to provide an overview of the development of protein-based products that take advantage of their biological activity for medication, and discusses possibilities for the therapeutic potential of protein-based products produced through different approaches to specifically target the liver (or hepatic cells: hepatocytes, hepatic stellate cells, liver sinusoidal endothelial cells, and Kupffer cells) in the treatment of hepatic diseases.

SUBMITTER: Taguchi K

PROVIDER: S-EPMC4588199 | biostudies-literature | 2015 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Potential Use of Biological Proteins for Liver Failure Therapy.

Taguchi Kazuaki K Yamasaki Keishi K Seo Hakaru H Otagiri Masaki M

Pharmaceutics 20150831 3

Biological proteins have unlimited potential for use as pharmaceutical products due to their various biological activities, which include non-toxicity, biocompatibility, and biodegradability. Recent scientific advances allow for the development of novel innovative protein-based products that draw on the quality of their innate biological activities. Some of them hold promising potential for novel therapeutic agents/devices for addressing hepatic diseases such as hepatitis, fibrosis, and hepatoca ...[more]

PMID: 26404356

Similar Datasets

Project description:Background: Interleukin-11 (IL11) was initially identified as a fibroblast secreted factor that supports haematopoietic cell function. This led to its development as a drug to increase platelet counts in patients with thrombocytopenia. However, IL11 was later found redundant for hematopoiesis and its use in humans causes severe and unexplained cardiac side effects. Here we identify and dissect mechanisms underlying previously unappreciated cardiac toxicities associated with IL11 therapy. Methods: We injected recombinant mouse lL11 (rmIl11) at clinically relevant doses to study its effects on myocardial signalling using immunoblotting and genomic variation using qRT-PCR, RNA-seq and ATAC-seq. The physiological impact of Il11 was assessed by echocardiography in vivo and cardiomyocyte contractility assays in vitro. To determine the specific activity of IL11 in cardiomyocytes we generated two distinct cardiomyocyte-specific IL11 receptor knockout (CMKO) mouse models using either AAV9-mediated, Tnnt2-restricted (vCMKO) or mhy6 (m6CMKO) Cre expression in an Il11ra1 floxed mouse strain. In pharmacologic studies, we studied the effects of JAK/STAT inhibition following rmIl11 injection to mice.Results: Injection of rmIl11 to mice caused dose-dependent impairment of left ventricular ejection fraction (LVEF: saline, 64.2%±1.62; rmIl11 (50 mg/kg), 31.6±2.0; p<0.0001). RNA-seq of hearts one and three hours following rmIl11 injection revealed strong upregulation of the TNF, NFkB and JAK/STAT pathways as well as increased Nppa and Rrad levels. vCMKO mice were protected from rmIl11-induced STAT3 activation, Rrad upregulation and LV impairment. Similarly, m6CMKO mice of both sexes, were protected from the molecular, cellular and whole organ cardiac toxicities associated with Il11. Administration of JAK inhibitors prevented rmIl11-induced STAT3 activation and preserved cardiac function. Conclusions: Here we show that Il11 injection to mice is strongly proinflammatory in the heart. Furthermore, Il11 has profound negative inotropic effects that are mediated via its on-target activation of JAK/STAT3 signalling in cardiomyocytes. Our data explain the cardiac side effects associated with IL11 therapy and question its continued use in patients.

Project description:BackgroundParenteral fish-oil (FO) therapy is a safe and effective treatment for intestinal failure-associated liver disease (IFALD). Patients whose cholestasis does not resolve with FO may progress to end-stage liver disease.ObjectiveWe sought to identify factors associated with the failure of FO therapy in treating IFALD to guide prognostication and referral guidelines.DesignProspectively collected data for patients treated with FO at Boston Children's Hospital from 2004 to 2014 were retrospectively reviewed. Resolution of cholestasis was defined as sustained direct bilirubin (DB) <2 mg/dL, and treatment failure as liver transplantation or death while DB was >2 mg/dL as of July 2015. Demographics, laboratory values, and medical history at FO therapy initiation were compared between patients who achieved resolution of cholestasis and those who failed therapy.ResultsAmong 182 patients treated with FO, 86% achieved resolution of cholestasis and 14% failed therapy. Patients who failed therapy had median (IQR) lower birth weight [1020 g (737, 1776 g) compared with 1608 g (815, 2438 g); P = 0.03] and were older at FO initiation [20.4 wk (9.9, 38.6 wk) compared with 11.7 wk (7.3, 21.4 wk); P = 0.02] than patients whose cholestasis resolved. Patients who failed therapy had more advanced liver disease at therapy initiation than patients whose cholestasis resolved, as evidenced by lower median (IQR) γ-glutamyltransferase [54 U/L (41, 103 U/L) compared with 112 U/L (76, 168 U/L); P < 0.001], higher DB [10.4 mg/dL (7.5, 14.1 mg/dL) compared with 4.4 mg/dL (3.1, 6.6 mg/dL); P < 0.001], and a higher pediatric end-stage liver disease (PELD) score [22 (14, 25) compared with 12 (7, 15); P < 0.001]. A PELD score of ≥15, history of gastrointestinal bleeding, age at FO initiation ≥16 wk, presence of nongastrointestinal comorbidities, and mechanical ventilation at FO initiation were independent predictors of treatment failure.ConclusionsMost infants with IFALD responded to FO therapy with resolution of cholestasis, and liver transplantation was rarely required. Early FO initiation once biochemical cholestasis is detected in parenteral nutrition-dependent patients is recommended. This trial was registered at clinicaltrials.gov as NCT00910104.

Dataset Information

Potential Use of Biological Proteins for Liver Failure Therapy.

Publications

Potential Use of Biological Proteins for Liver Failure Therapy.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets