Inhibitory Effect of Antisense Oligonucleotide Targeting TIMP-2 on Immune-Induced Liver Fibrosis

Nie, Qiang; Zhu, Chuanlong; Zhang, Yafei; Yang, Jie; Zhang, Jiu-Cong; Gao, R.T.

doi:10.1007/s10620-009-0858-5

Cited by 15 publications

(5 citation statements)

References 28 publications

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“…Interestingly, some anti-fibrotic properties have been shown using an antisense oligonucleotide against TIMP in rats with liver fibrosis. 48 In conclusion, by using immunohistochemistry on paraffin-embedded tissue from patients with nephrogenic systemic fibrosis, we found that TIMP-1 is strongly expressed while MMP-1 is largely absent, similar to findings previously reported in other profibrotic conditions. No a-smooth muscle actinepositive spindle cells were seen in our NSF samples, which suggests that myofibroblasts are not present in this fibrosing disorder.…”

Section: Discussionsupporting

confidence: 90%

The imbalanced expression of matrix metalloproteinases in nephrogenic systemic fibrosis

Kelly

Markle

Vickers

et al. 2010

Journal of the American Academy of Dermatology

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Section: Discussionsupporting

confidence: 90%

The imbalanced expression of matrix metalloproteinases in nephrogenic systemic fibrosis

Kelly

Markle

Vickers

et al. 2010

Journal of the American Academy of Dermatology

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“…For example, Timp2 downregulation by AONs ameliorated fibrogenesis in rats and in line with our model reported here, significantly reduced collagen deposition, while in contrast to us, HSC activation (αSMA expression) remained unchanged. 47 Likewise, Uchio et al 48 described mild preventive effects of TgfB1 and Ctgf -directed AON treatment in CCl 4 -induced liver fibrosis as measured by procollagen mRNA expression.…”

Section: Discussionmentioning

confidence: 99%

TGF-β2 silencing to target biliary-derived liver diseases

Dropmann

Dooley

Dewidar

et al. 2020

Gut

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ObjectiveTGF-β2 (TGF-β, transforming growth factor beta), the less-investigated sibling of TGF-β1, is deregulated in rodent and human liver diseases. Former data from bile duct ligated and MDR2 knockout (KO) mouse models for human cholestatic liver disease suggested an involvement of TGF-β2 in biliary-derived liver diseases.DesignAs we also found upregulated TGFB2 in liver tissue of patients with primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC), we now fathomed the positive prospects of targeting TGF-β2 in early stage biliary liver disease using the MDR2-KO mice. Specifically, the influence of TgfB2 silencing on the fibrotic and inflammatory niche was analysed on molecular, cellular and tissue levels.ResultsTgfB2-induced expression of fibrotic genes in cholangiocytes and hepatic stellate cellswas detected. TgfB2 expression in MDR2-KO mice was blunted using TgfB2-directed antisense oligonucleotides (AON). Upon AON treatment, reduced collagen deposition, hydroxyproline content and αSMA expression as well as induced PparG expression reflected a significant reduction of fibrogenesis without adverse effects on healthy livers. Expression analyses of fibrotic and inflammatory genes revealed AON-specific regulatory effects on Ccl3, Ccl4, Ccl5, Mki67 and Notch3 expression. Further, AON treatment of MDR2-KO mice increased tissue infiltration by F4/80-positive cells including eosinophils, whereas the number of CD45-positive inflammatory cells decreased. In line, TGFB2 and CD45 expression correlated positively in PSC/PBC patients and localised in similar areas of the diseased liver tissue.ConclusionsTaken together, our data suggest a new mechanistic explanation for amelioration of fibrogenesis by TGF-β2 silencing and provide a direct rationale for TGF-β2-directed drug development.

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“…In the other study hydrodynamic injection of Timp-2 antisense ODNs had a preventive effect on an immune-induced liver fibrosis in rats. Because ECM is degraded by a family of proteolytic enzymes called Mmps, and the activity of Mmps is regulated by Timps 81 .…”

Section: Gene Deliverymentioning

confidence: 99%

Efficient drug and gene delivery to liver fibrosis: rationale, recent advances, and perspectives

Mahdinloo

Kiaie

Amiri

et al. 2020

Acta Pharmaceutica Sinica B

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Liver fibrosis results from chronic damages together with an accumulation of extracellular matrix, and no specific medical therapy is approved for that until now. Due to liver metabolic capacity for drugs, the fragility of drugs, and the presence of insurmountable physiological obstacles in the way of targeting, the development of efficient drug delivery systems for anti-fibrotics seems vital. We have explored articles with a different perspective on liver fibrosis over the two decades, then collected and summarized the information by providing corresponding in vitro and in vivo cases. We have discussed the mechanism of hepatic fibrogenesis with different ways of fibrosis induction in animals. Furthermore, the critical chemical and herbal anti-fibrotics, biological molecules such as micro-RNAs, siRNAs, and growth factors, which can affect cell division and differentiation, are mentioned. Likewise, drug and gene delivery and therapeutic systems on in vitro and in vivo models are summarized in the data tables. This review article enlightens recent advances in emerging drugs and nanocarriers and represents perspectives on targeting strategies employed in liver fibrosis treatment.

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Inhibitory Effect of Antisense Oligonucleotide Targeting TIMP-2 on Immune-Induced Liver Fibrosis

Abstract: The results suggested that TIMP-2 ASON could prevent the progression of liver fibrosis in this rat model. It is possible that this could form the basis for exploration of new liver anti-fibrosis drugs at a genetic level.

Cited by 15 publications

References 28 publications

The imbalanced expression of matrix metalloproteinases in nephrogenic systemic fibrosis

The imbalanced expression of matrix metalloproteinases in nephrogenic systemic fibrosis

TGF-β2 silencing to target biliary-derived liver diseases

Efficient drug and gene delivery to liver fibrosis: rationale, recent advances, and perspectives

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