Limits...
Pharmacological Intervention in Hepatic Stellate Cell Activation and Hepatic Fibrosis.

Schon HT, Bartneck M, Borkham-Kamphorst E, Nattermann J, Lammers T, Tacke F, Weiskirchen R - Front Pharmacol (2016)

Bottom Line: Pharmaceutical interventions are generally hampered by insufficient supply of drugs to the diseased liver tissue and/or by adverse effects as a result of affecting non-target cells.The applicability and efficacy of sequestering molecules, selective protein carriers, lipid-based drug vehicles, viral vectors, transcriptional targeting approaches, therapeutic liver- and HSC-specific nanoparticles, and miRNA-based strategies are discussed.Some of these delivery systems that had already been successfully tested in experimental animal models of ongoing hepatic fibrogenesis are expected to translate into clinically useful therapeutics specifically targeting HSCs.

View Article: PubMed Central - PubMed

Affiliation: Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry, RWTH University Hospital Aachen Aachen, Germany.

ABSTRACT
The activation and transdifferentiation of hepatic stellate cells (HSCs) into contractile, matrix-producing myofibroblasts (MFBs) are central events in hepatic fibrogenesis. These processes are driven by autocrine- and paracrine-acting soluble factors (i.e., cytokines and chemokines). Proof-of-concept studies of the last decades have shown that both the deactivation and removal of hepatic MFBs as well as antagonizing profibrogenic factors are in principle suitable to attenuate ongoing hepatic fibrosis. Although several drugs show potent antifibrotic activities in experimental models of hepatic fibrosis, there is presently no effective pharmaceutical intervention specifically approved for the treatment of liver fibrosis. Pharmaceutical interventions are generally hampered by insufficient supply of drugs to the diseased liver tissue and/or by adverse effects as a result of affecting non-target cells. Therefore, targeted delivery systems that bind specifically to receptors solely expressed on activated HSCs or transdifferentiated MFBs and delivery systems that can improve drug distribution to the liver in general are urgently needed. In this review, we summarize current strategies for targeted delivery of drugs to the liver and in particular to pro-fibrogenic liver cells. The applicability and efficacy of sequestering molecules, selective protein carriers, lipid-based drug vehicles, viral vectors, transcriptional targeting approaches, therapeutic liver- and HSC-specific nanoparticles, and miRNA-based strategies are discussed. Some of these delivery systems that had already been successfully tested in experimental animal models of ongoing hepatic fibrogenesis are expected to translate into clinically useful therapeutics specifically targeting HSCs.

No MeSH data available.


Related in: MedlinePlus

Therapeutic potential of Oxymatrine in hepatic injury.(A,B) Oxymatrine can be extracted from the roots of Sophora plants. Sophora flavescens is an evergreen, slow growing, nitrogen fixing shrub that requires a sunny site for growing. The flowers of this plant grow in simple inflorescences that vary in color from white, yellow, orange, red, or purple. (C) Oxymatrine is a heterocyclic quinolizidine alkaloid that has a variety of therapeutic activities in the liver. Several of these activities that were identified in vitro or in animal models are listed. The photos in (A,B) were kindly provided by Hiroshi Moriyama (http://wildplantsshimane.jp).
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4764688&req=5

Figure 1: Therapeutic potential of Oxymatrine in hepatic injury.(A,B) Oxymatrine can be extracted from the roots of Sophora plants. Sophora flavescens is an evergreen, slow growing, nitrogen fixing shrub that requires a sunny site for growing. The flowers of this plant grow in simple inflorescences that vary in color from white, yellow, orange, red, or purple. (C) Oxymatrine is a heterocyclic quinolizidine alkaloid that has a variety of therapeutic activities in the liver. Several of these activities that were identified in vitro or in animal models are listed. The photos in (A,B) were kindly provided by Hiroshi Moriyama (http://wildplantsshimane.jp).

Mentions: Chai et al. (2012) also applied RGD peptide-labeled liposomes for the specific delivery of OM in order to examine whether this herbal medicinal product would have a beneficial effect on CCl4-induced liver fibrosis in rats. OM is a natural quinolizidine alkaloid obtained from the roots of the Sophora alopecuraides L. and other Sophora plants (Figure 1), which exhibits various pharmacological properties: It blocks the replication of the hepatitis B virus (Chen et al., 2001; Wang et al., 2011) and also stops liver fibrosis (Chen et al., 2001). Besides this antiviral effect, OM additionally shows apoptosis-inducing activity, predominantly observed in several cancer cell lines, for example in human pancreatic cancer cells (Ling et al., 2011) as well as in human hepatoma SMMC-7721 (Song et al., 2006; Liu et al., 2015) and Hep-G2 cells (Liu et al., 2015). An antifibrotic effect has been studied in rats with CCl4-induced liver fibrosis, since OM potently limits the production as well as deposition of collagen, probably by upregulation of SMAD7 and downregulation of SMAD3 and CREBBP (CREB binding protein) gene expression, thus interfering with the canonical TGF-β1 signaling pathway (Wu et al., 2008). Before conducting their experiments, the researchers formed the OM-liposomes using lipids and the OM-containing aqueous solution and afterward coupled the RGD peptides and the OM-liposomes. Then OM-RGD-liposomes, OM-liposomes, and empty liposomes were allocated to three different groups of rats, while a fourth group of rats remained untreated. Liver fibrosis improved upon administration of OM, as assessed by reduced deposition of collagen and reduced expression of genes co-occurring with liver fibrosis, such as MMP-2, TIMP-1, and type I procollagen (Chai et al., 2012). In vitro, apoptosis of HSCs was induced by OM-RGD-liposomes and gene expression of MMP2, TIMP1, and COL1A2 was inhibited. Furthermore, RGD labeling improved binding to HSCs (Chai et al., 2012).


Pharmacological Intervention in Hepatic Stellate Cell Activation and Hepatic Fibrosis.

Schon HT, Bartneck M, Borkham-Kamphorst E, Nattermann J, Lammers T, Tacke F, Weiskirchen R - Front Pharmacol (2016)

Therapeutic potential of Oxymatrine in hepatic injury.(A,B) Oxymatrine can be extracted from the roots of Sophora plants. Sophora flavescens is an evergreen, slow growing, nitrogen fixing shrub that requires a sunny site for growing. The flowers of this plant grow in simple inflorescences that vary in color from white, yellow, orange, red, or purple. (C) Oxymatrine is a heterocyclic quinolizidine alkaloid that has a variety of therapeutic activities in the liver. Several of these activities that were identified in vitro or in animal models are listed. The photos in (A,B) were kindly provided by Hiroshi Moriyama (http://wildplantsshimane.jp).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4764688&req=5

Figure 1: Therapeutic potential of Oxymatrine in hepatic injury.(A,B) Oxymatrine can be extracted from the roots of Sophora plants. Sophora flavescens is an evergreen, slow growing, nitrogen fixing shrub that requires a sunny site for growing. The flowers of this plant grow in simple inflorescences that vary in color from white, yellow, orange, red, or purple. (C) Oxymatrine is a heterocyclic quinolizidine alkaloid that has a variety of therapeutic activities in the liver. Several of these activities that were identified in vitro or in animal models are listed. The photos in (A,B) were kindly provided by Hiroshi Moriyama (http://wildplantsshimane.jp).
Mentions: Chai et al. (2012) also applied RGD peptide-labeled liposomes for the specific delivery of OM in order to examine whether this herbal medicinal product would have a beneficial effect on CCl4-induced liver fibrosis in rats. OM is a natural quinolizidine alkaloid obtained from the roots of the Sophora alopecuraides L. and other Sophora plants (Figure 1), which exhibits various pharmacological properties: It blocks the replication of the hepatitis B virus (Chen et al., 2001; Wang et al., 2011) and also stops liver fibrosis (Chen et al., 2001). Besides this antiviral effect, OM additionally shows apoptosis-inducing activity, predominantly observed in several cancer cell lines, for example in human pancreatic cancer cells (Ling et al., 2011) as well as in human hepatoma SMMC-7721 (Song et al., 2006; Liu et al., 2015) and Hep-G2 cells (Liu et al., 2015). An antifibrotic effect has been studied in rats with CCl4-induced liver fibrosis, since OM potently limits the production as well as deposition of collagen, probably by upregulation of SMAD7 and downregulation of SMAD3 and CREBBP (CREB binding protein) gene expression, thus interfering with the canonical TGF-β1 signaling pathway (Wu et al., 2008). Before conducting their experiments, the researchers formed the OM-liposomes using lipids and the OM-containing aqueous solution and afterward coupled the RGD peptides and the OM-liposomes. Then OM-RGD-liposomes, OM-liposomes, and empty liposomes were allocated to three different groups of rats, while a fourth group of rats remained untreated. Liver fibrosis improved upon administration of OM, as assessed by reduced deposition of collagen and reduced expression of genes co-occurring with liver fibrosis, such as MMP-2, TIMP-1, and type I procollagen (Chai et al., 2012). In vitro, apoptosis of HSCs was induced by OM-RGD-liposomes and gene expression of MMP2, TIMP1, and COL1A2 was inhibited. Furthermore, RGD labeling improved binding to HSCs (Chai et al., 2012).

Bottom Line: Pharmaceutical interventions are generally hampered by insufficient supply of drugs to the diseased liver tissue and/or by adverse effects as a result of affecting non-target cells.The applicability and efficacy of sequestering molecules, selective protein carriers, lipid-based drug vehicles, viral vectors, transcriptional targeting approaches, therapeutic liver- and HSC-specific nanoparticles, and miRNA-based strategies are discussed.Some of these delivery systems that had already been successfully tested in experimental animal models of ongoing hepatic fibrogenesis are expected to translate into clinically useful therapeutics specifically targeting HSCs.

View Article: PubMed Central - PubMed

Affiliation: Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry, RWTH University Hospital Aachen Aachen, Germany.

ABSTRACT
The activation and transdifferentiation of hepatic stellate cells (HSCs) into contractile, matrix-producing myofibroblasts (MFBs) are central events in hepatic fibrogenesis. These processes are driven by autocrine- and paracrine-acting soluble factors (i.e., cytokines and chemokines). Proof-of-concept studies of the last decades have shown that both the deactivation and removal of hepatic MFBs as well as antagonizing profibrogenic factors are in principle suitable to attenuate ongoing hepatic fibrosis. Although several drugs show potent antifibrotic activities in experimental models of hepatic fibrosis, there is presently no effective pharmaceutical intervention specifically approved for the treatment of liver fibrosis. Pharmaceutical interventions are generally hampered by insufficient supply of drugs to the diseased liver tissue and/or by adverse effects as a result of affecting non-target cells. Therefore, targeted delivery systems that bind specifically to receptors solely expressed on activated HSCs or transdifferentiated MFBs and delivery systems that can improve drug distribution to the liver in general are urgently needed. In this review, we summarize current strategies for targeted delivery of drugs to the liver and in particular to pro-fibrogenic liver cells. The applicability and efficacy of sequestering molecules, selective protein carriers, lipid-based drug vehicles, viral vectors, transcriptional targeting approaches, therapeutic liver- and HSC-specific nanoparticles, and miRNA-based strategies are discussed. Some of these delivery systems that had already been successfully tested in experimental animal models of ongoing hepatic fibrogenesis are expected to translate into clinically useful therapeutics specifically targeting HSCs.

No MeSH data available.


Related in: MedlinePlus