Dataset Information

Targeted Delivery of an siRNA/PNA Hybrid Nanocomplex Reverses Carbon Tetrachloride-Induced Liver Fibrosis.

ABSTRACT: Liver fibrosis is a wound healing process with excessive accumulation of extracellular matrix in the liver. We recently discovered a PCBP2 siRNA that reverses fibrogenesis in activated hepatic stellate cells (HSCs), which are the key players in liver fibrogenesis. However, targeted delivery of siRNAs to HSCs still remains a challenge. Herein, we developed a new strategy to fabricate a multicomponent nanocomplex using siRNA/PNA hybrid instead of chemically conjugated siRNA, thus increasing the scalability and feasibility of the siRNA nanocomplex for animal studies. We modified the nanocomplex with an insulin growth factor 2 receptor (IGF2R)-specific peptide, which specifically binds to activated HSCs. The siRNA nanocomplex shows a controllable size and high serum stability. The nanocomplex also demonstrates high cellular uptake in activated HSCs in vitro and in vivo. Anti-fibrotic activity of the siRNA nanocomplex was evaluated in rats with carbon tetrachloride-induced liver fibrosis. Treatment with the PCBP2 siRNA nanocomplex significantly inhibits the mRNA expressions of PCBP2 and type I collagen in fibrotic liver. Histology study revealed that the siRNA nanocomplex efficiently reduces the protein level of type I collagen and reverses liver fibrosis. Our data suggest that the nanocomplex efficiently delivers the siRNA to fibrotic liver and produces a potent anti-fibrotic effect.

SUBMITTER: Jain A

PROVIDER: S-EPMC7567403 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Targeted Delivery of an siRNA/PNA Hybrid Nanocomplex Reverses Carbon Tetrachloride-Induced Liver Fibrosis.

Jain Akshay A Barve Ashutosh A Zhao Zhen Z Fetse John Peter JP Liu Hao H Li Yuanke Y Cheng Kun K

Advanced therapeutics 20190620 8

Liver fibrosis is a wound healing process with excessive accumulation of extracellular matrix in the liver. We recently discovered a PCBP2 siRNA that reverses fibrogenesis in activated hepatic stellate cells (HSCs), which are the key players in liver fibrogenesis. However, targeted delivery of siRNAs to HSCs still remains a challenge. Herein, we developed a new strategy to fabricate a multicomponent nanocomplex using siRNA/PNA hybrid instead of chemically conjugated siRNA, thus increasing the sc ...[more]

PMID: 33072857

Similar Datasets

Project description:Background: Liver fibrosis is a complex inflammatory and fibrogenic process, and the progression of fibrosis leads to cirrhosis. The only therapeutic approaches are the removal of injurious stimuli and liver transplantation. Therefore, the development of anti-fibrotic therapies is desired. Palmitoylethanolamide (PEA) is an endogenous fatty acid amide belonging to the N-acylethanolamines family and contained in foods such as egg yolks and peanuts. PEA has therapeutic anti-inflammatory, analgesic, and neuroprotective effects. However, the effects and roles of PEA in liver fibrosis remain unknown. Here we investigated the therapeutic effects of PEA in rats with liver fibrosis. Methods: We conducted in vitro experiments to investigate the effects of PEA on the activation of hepatic stellate cells (HSCs, LX-2). Liver fibrosis was induced by an intraperitoneal injection of 1.5 mL/kg of 50% carbon tetrachloride twice a week for 4 weeks. Beginning at 3 weeks, PEA (20 mg/kg) was intraperitoneally injected thrice a week for 2 weeks. Then rats were sacrificed and we performed histological and quantitative reverse-transcription polymerase chain reaction analyses. Results: The expression of ?-smooth muscle actin (SMA) induced by transforming growth factor (TGF)-?1 in HSCs was significantly downregulated by PEA. PEA treatment inhibited the TGF-?1-induced phosphorylation of SMAD2 in a dose-dependent manner, and upregulated the expression of SMAD7. The reporter gene assay demonstrated that PEA downregulated the transcriptional activity of the SMAD complex upregulated by TGF-?1. Administration of PEA significantly reduced the fibrotic area, deposition of type I collagen, and activation of HSCs and Kupffer cells in rats with liver fibrosis. Conclusion: Activation of HSCs was significantly decreased by PEA through suppression of the TGF-?1/SMAD signaling pathway. Administration of PEA produced significant improvement in a rat model of liver fibrosis, possibly by inhibiting the activation of HSCs and Kupffer cells. PEA may be a potential new treatment for liver fibrosis.

Dataset Information

Targeted Delivery of an siRNA/PNA Hybrid Nanocomplex Reverses Carbon Tetrachloride-Induced Liver Fibrosis.

Publications

Targeted Delivery of an siRNA/PNA Hybrid Nanocomplex Reverses Carbon Tetrachloride-Induced Liver Fibrosis.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure