GFAP Promoter-Driven RNA Interference on TGF-β1 to Treat Liver Fibrosis

Yang, Ningning; Mahato, Ram I.

doi:10.1007/s11095-011-0384-y

Cited by 19 publications

(13 citation statements)

References 35 publications

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“…Some studies also conclude that TGF-β enhance collagen production via reactive oxygen intermediates in general, and H 2 O 2 in particular. IL-6 is overexpressed by HSCs in injured liver and implied to upregulate TGF-β expression and accordingly enhances its fibrogenic action (26)(27)(28).…”

Section: Pathogenesis Of Liver Fibrosismentioning

confidence: 99%

Delivery and Targeting of miRNAs for Treating Liver Fibrosis

Kumar

Mahato

2014

Pharm Res

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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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Section: Pathogenesis Of Liver Fibrosismentioning

confidence: 99%

Delivery and Targeting of miRNAs for Treating Liver Fibrosis

Kumar

Mahato

2014

Pharm Res

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“…The vectors used had a primiRNA construct and shRNA expression was under the control of a glial fibrillary acidic protein (GFAP) promoter for reducing off-targeted TGF-β1 gene (139). In another study, our bipartite plasmid vectors co-expressed a vascular endothelial growth factor (VEGF) cDNA and incorporated shRNA to target the inducible nitric oxide synthase (iNOS) gene (Fig.…”

Section: Design Modificationmentioning

confidence: 99%

Subcellular Fate and Off-Target Effects of siRNA, shRNA, and miRNA

2011

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RNA interference (RNAi) strategies include double-stranded RNA (dsRNA), small interfering RNA (siRNA), short hairpin RNA (shRNA), and microRNA (miRNA). As this is a highly specific technique, efforts have been made to utilize RNAi towards potential knock down of disease-causing genes in a targeted fashion. RNAi has the potential to selectively inhibit gene expression by degrading or blocking the translation of the target mRNA. However, delivering these RNAs to specific cells presents a significant challenge. Some of these challenges result from the necessity of traversing the circulatory system while avoiding kidney filtration, degradation by endonucleases, aggregation with serum proteins, and uptake by phagocytes. Further, non-specific delivery may result in side-effects, including the activation of immune response. We discuss the challenges in the systemic delivery to target cells, cellular uptake, endosomal release and intracellular transport of RNAi drugs and recent progress in overcoming these barriers. We also discuss approaches that increase the specificity and metabolic stability and reduce the off-target effects of RNAi strategy.

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“…Progression of hepatic fibrosis in this CCl4-driven model was shown to be linked to and significantly correlated with over-expression of the miR-199 and miR-200 (Murakami et al, 2011). Liver fibrogenesis is known to be mainly induced by abnormal expression of TGF-β1 (Yang and Mahato, 2011). TGFβ-induced factor (TGIF) plays role in the TGFβ signaling pathway, that are the targets of miR-199a* and miR-200b, respectively (Haybaeck et al, 2011).…”

Section: Discussionmentioning

confidence: 92%

Curcumin Reorganizes miRNA Expression in a Mouse Model of Liver Fibrosis

Hassan

Al-Olayan²

2012

Asian Pacific Journal of Cancer Prevention

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Asian Pacific J Cancer Prev, 13 (11), [5405][5406][5407][5408] IntroductionLiver is the main organ involved in gluconeogenesis and in production and transportation of fatty acids and cholesterol in which its metabolic disease is prerequisited for cancer. Tissue fibrosis is a major cause of dysfunction in the hepatic systems (Glass et al., 2011). Hepatic fibrosis is influenced by several epigenetic factors that control the wound-healing response. Fibrosis is the excess deposition of extracellular matrix (ECM) components resulted from an imbalance of ECM molecule metabolism (Jiang et al., 2010; Glass et al., 2011) either by an increased synthesis or decreased degradation of ECM components or both. Collagens are synthesized by mesenchymal cells including fibroblasts and have an important role in the development of fibrosis (Jiang et al., 2010). MiRNAs are the smallest, non-coding RNA, plays important roles in post-transcriptional regulation (Borchert et al., 2006). In the nucleus, the miRNA genes are transcribed as primarymiRNA molecules, next processed forming pre-miRNAs (Lee et al., 2004; Borchert et al., 2006), finally transported to the cytoplasm for further processing (Lee et al., 2003; Lund et al., 2004

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GFAP Promoter-Driven RNA Interference on TGF-β1 to Treat Liver Fibrosis

Abstract: GFAP promoter driven TGF-β1 pri-miRNA producing plasmids have the potential to be used for site-specific gene therapeutics to treat liver fibrosis.

Cited by 19 publications

References 35 publications

Delivery and Targeting of miRNAs for Treating Liver Fibrosis

Delivery and Targeting of miRNAs for Treating Liver Fibrosis

Subcellular Fate and Off-Target Effects of siRNA, shRNA, and miRNA

Curcumin Reorganizes miRNA Expression in a Mouse Model of Liver Fibrosis

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