Targeted Drug Delivery to Hepatic Stellate Cells for the Treatment of Liver Fibrosis

Chen, Zhijin; Jain, Akshay; Liu, Hao; Zhao, Zhen; Cheng, Kun

doi:10.1124/jpet.118.256156

Cited by 74 publications

(60 citation statements)

References 91 publications

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“…5 Rats with NAFLD showed high hepatic inflammation, necrosis and fatty infiltration. 6 The disease is presumed to be mediated by the effects of the metabolic syndrome on the liver. The production of inflammation-inducing mechanisms and inflammatory cytokines production play a crucial role in the progression of NAFLD.…”

Section: Introductionmentioning

confidence: 99%

<p>Liraglutide Improves Non-Alcoholic Fatty Liver Disease In Diabetic Mice By Modulating Inflammatory Signaling Pathways</p>

Luo¹,

Yang²,

Li³

et al. 2019

DDDT

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These authors contributed equally to this work Background: Many chronic metabolic diseases, such as obesity and type 2 diabetes (T2DM), are closely related to a chronic low-grade inflammatory state in tissues. The high prevalence of non-alcoholic fatty liver disease (NAFLD) in patients with T2DM is related to the role of inflammation in the disease. In this study, we investigated the role of liraglutide in improving lipid metabolism disorders and preventing their progression to NAFLD by modulating inflammatory signaling pathways, thereby providing new treatment options for NAFLD. Methods: We designed a 2×2 factorial analysis experiment. A mouse model of NAFLD with T2DM was established by feeding the animals a high-fat diet (HFD). The NAFLD mice with HFD-induced diabetes were treated with liraglutide for 10 weeks. Hematoxylin and eosin staining, Oil Red O staining and electron microscopy were used to observe the accumulation of triglycerides in the liver. RT-PCR and Western blotting were used to analyze the expression of α-SMA, IL-1β, TNF-α, NF-κB and the NF-κB inhibitory protein IκB in the liver at the gene and protein levels, respectively. Results: Liraglutide reduced the body weight and fasting blood glucose levels of HFD-fed mice. The expression of α-SMA, IL-1β, TNF-α, and NF-κB in the liver of HFD-fed mice was increased at the mRNA and protein levels, but liraglutide treatment decreased the expression of these molecules. The expression of IκB in the liver decreased at the mRNA and protein levels but was upregulated after liraglutide treatment. Conclusion: Based on the current findings, liraglutide can significantly improve hepatic steatosis, primarily by downregulating the expression of inflammatory signaling mediators in the TNF-α pathway.

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Section: Introductionmentioning

confidence: 99%

<p>Liraglutide Improves Non-Alcoholic Fatty Liver Disease In Diabetic Mice By Modulating Inflammatory Signaling Pathways</p>

Luo¹,

Yang²,

Li³

et al. 2019

DDDT

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“…[7] PNAs are oligonucleotide analogues with purine and pyrimidine bases except the phosphodiester backbone is substituted with polyamide. [9] Among many of the targeting ligands that are specific for these HSC receptors, IGF2R-specific peptide, [6b] IGF2R-specific aptamer, [10] and Vitamin A (retinol) [11] have shown tremendous promise. PNA also enhances the thermal and enzymatic stability of annealed nucleic acids.…”

Section: Introductionmentioning

confidence: 99%

“…A number of molecular targets, such as insulin growth factor 2 receptor (IGF2R), low density lipoprotein receptor (LDLR), retinol-binding protein (RBPR), platelet-derived growth factor receptor-beta (PDGFR-β), and integrin, have been explored for HSC-specific delivery of anti-fibrotic agents. [9] Among many of the targeting ligands that are specific for these HSC receptors, IGF2R-specific peptide, [6b] IGF2R-specific aptamer, [10] and Vitamin A (retinol) [11] have shown tremendous promise. Wu et al recently developed a vitamin A conjugated pH sensitive polymeric micelle for miRNA (miR-29B and miR-122) delivery.…”

Section: Introductionmentioning

confidence: 99%

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

Jain

Barve

Zhao

et al. 2019

Advanced Therapeutics

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Liver fibrosis is a wound healing process marked by excessive accumulation of extracellular matrix in the liver. A poly(rC)-binding protein 2 (PCBP2) siRNA that reverses fibrogenesis in activated hepatic stellate cells (HSCs) has been recently discovered. However, targeted delivery of siRNAs to HSCs still remains a daunting challenge. Herein, a new strategy is developed to fabricate a multicomponent nanocomplex using siRNA/peptide nucleic acid (PNA) hybrid instead of chemically conjugated siRNA, thus increasing the scalability and feasibility of the siRNA nanocomplex for animal studies. The nanocomplex is modified with an insulin growth factor 2 receptor -specific peptide, which specifically binds to activated HSCs. The siRNA nanocomplex demonstrates a controllable size, high serum stability, and high cellular uptake in activated HSCs in vitro and in vivo. Anti-fibrotic activity of the siRNA nanocomplex is 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. The histology study reveals that the siRNA nanocomplex efficiently reduces the protein level of type I collagen and reverses liver fibrosis. The data suggests that the nanocomplex efficiently delivers the siRNA to fibrotic liver and produces a potent anti-fibrotic effect.

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“…The increasing incidence of patients with liver cirrhosis, combined with the lack of effective antifibrotic drugs to stop or reverse the disease, urgently demands drug development [14,21]. Clearly, activated HSCs have an important and versatile role in the development and progression of fibrosis of various etiologies, and are therefore an interesting therapeutic target [3,22]. Nowadays, several clinical trials focus on the HSC and study the effects of drugs that directly interfere with this cell type.…”

Section: Discussionmentioning

confidence: 99%

Design of a Gene Panel to Expose the Versatile Role of Hepatic Stellate Cells in Human Liver Fibrosis

et al. 2020

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The pivotal cell involved in the pathogenesis of liver fibrosis, i.e., the activated hepatic stellate cell (HSC), has a wide range of activities during the initiation, progression and even regression of the disease. These HSC-related activities encompass cellular activation, matrix synthesis and degradation, proliferation, contraction, chemotaxis and inflammatory signaling. When determining the in vitro and in vivo effectivity of novel antifibrotic therapies, the readout is currently mainly based on gene and protein levels of α-smooth muscle actin (α-SMA) and the fibrillar collagens (type I and III). We advocate for a more comprehensive approach in addition to these markers when screening potential antifibrotic drugs that interfere with HSCs. Therefore, we aimed to develop a gene panel for human in vitro and ex vivo drug screening models, addressing each of the HSC-activities with at least one gene, comprising, in total, 16 genes. We determined the gene expression in various human stellate cells, ranging from primary cells to cell lines with an HSC-origin, and human liver slices and stimulated them with two key profibrotic factors, i.e., transforming growth factor β (TGFβ) or platelet-derived growth factor BB (PDGF-BB). We demonstrated that freshly isolated HSCs showed the strongest and highest variety of responses to these profibrotic stimuli, in particular following PDGF-BB stimulation, while cell lines were limited in their responses. Moreover, we verified these gene expression profiles in human precision-cut liver slices and showed similarities with the TGFβ- and PDGF-BB-related fibrotic responses, as observed in the primary HSCs. With this study, we encourage researchers to get off the beaten track when testing antifibrotic compounds by including more HSC-related markers in their future work. This way, potential compounds will be screened more extensively, which might increase the likelihood of developing effective antifibrotic drugs.

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Targeted Drug Delivery to Hepatic Stellate Cells for the Treatment of Liver Fibrosis

Cited by 74 publications

References 91 publications

<p>Liraglutide Improves Non-Alcoholic Fatty Liver Disease In Diabetic Mice By Modulating Inflammatory Signaling Pathways</p>

<p>Liraglutide Improves Non-Alcoholic Fatty Liver Disease In Diabetic Mice By Modulating Inflammatory Signaling Pathways</p>

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

Design of a Gene Panel to Expose the Versatile Role of Hepatic Stellate Cells in Human Liver Fibrosis

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