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Delivery and Targeting of miRNAs for Treating Liver Fibrosis

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Abstract

Liver fibrosis is a pathological condition originating from liver damage that leads to excess accumulation of extracellular matrix (ECM) proteins in the liver. Viral infection, chronic injury, local inflammatory responses and oxidative stress are the major factors contributing to the onset and progression of liver fibrosis. Multiple cell types and various growth factors and inflammatory cytokines are involved in the induction and progression of this disease. Various strategies currently being tried to attenuate liver fibrosis include the inhibition of HSC activation or induction of their apoptosis, reduction of collagen production and deposition, decrease in inflammation, and liver transplantation. Liver fibrosis treatment approaches are mainly based on small drug molecules, antibodies, oligonucleotides (ODNs), siRNA and miRNAs. MicroRNAs (miRNA or miR) are endogenous noncoding RNA of ~22 nucleotides that regulate gene expression at post transcription level. There are several miRNAs having aberrant expressions and play a key role in the pathogenesis of liver fibrosis. Single miRNA can target multiple mRNAs, and we can predict its targets based on seed region pairing, thermodynamic stability of pairing and species conservation. For in vivo delivery, we need some additional chemical modification in their structure, and suitable delivery systems like micelles, liposomes and conjugation with targeting or stabilizing the moiety. Here, we discuss the role of miRNAs in fibrogenesis and current approaches of utilizing these miRNAs for treating liver fibrosis.

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Abbreviations

Ab:

Antibodies

AP-1:

Activator proteins

α-SMA:

Alpha smooth muscle actin

CBDL:

Common bile duct ligation

DCs:

Dendritic cells

ECM:

Extracellular matrix

EMT:

Epithelial to mesenchymal transition

EXP 5:

Exportin 5

ERK:

Extracellular signal regulated kinase

Hh:

Hedgehog

HCV:

Hepatitis C virus

HSC:

Hepatic stellate cells

ICAM-1:

Intercellular adhesion molecule-1

KC:

Kupffer cells

LNA:

Locked nucleic acid

MMP:

Matrix metalloprotease

miRNA:

MicroRNA

MF:

Myofibroblasts

NO:

Nitric oxide

ODN:

Oligodeoxynucleotide

2′-OMe:

2′-methoxy

PI3-K:

Phosphatidylinositol 3-kinase

PDGF:

Platelet derived growth factor

PPAR-γ:

Peroxisome proliferator-activated receptors

PS:

Phosphothioated

RXR:

Retinoid receptors

RISC:

RNA induced silencing complex

ROS:

Reactive oxygen species

siRNA:

Small interfering RNA

SHh:

Sonic hedgehog

shRNA:

Small hairpin RNA

SMO:

Smoothened

TFO:

Triplex forming oligonucleotide

TGF-β:

Transforming growth factor beta

TIMP:

Tissue inhibitors of metalloprotease

TNF-α:

Tumor necrosis factor -α

TRAIL:

TNF related apoptosis inducing ligand

tTG:

Tissue transglutaminase

UTR:

Untranslated region

VEGF:

Vascular endothelial growth factor

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We would like to thank the University of Nenbraska Medical Center for financial support.

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Kumar, V., Mahato, R.I. Delivery and Targeting of miRNAs for Treating Liver Fibrosis. Pharm Res 32, 341–361 (2015). https://doi.org/10.1007/s11095-014-1497-x

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