Hepatic Antifibrotic Pharmacotherapy: Are We Approaching Success?

Chang, Yue; Hai, Li

doi:10.14218/jcth.2020.00026

Cited by 27 publications

(24 citation statements)

References 75 publications

(95 reference statements)

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“…Investigations of the molecular mechanisms of hepatic fibrosis have presented several clear targets such as TGF-β1, PPAR, ASK-1, angiotensin, YAP-TEAD, various inflammatory cytokines, and ROS. However, there remains no validated target for novel anti-fibrotic compounds 36 , 37 .…”

Section: Discussionmentioning

confidence: 99%

Identification of hepatic fibrosis inhibitors through morphometry analysis of a hepatic multicellular spheroids model

Song

Kim

Heo

et al. 2021

Sci Rep

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A chronic, local inflammatory milieu can cause tissue fibrosis that results in epithelial-to-mesenchymal transition (EMT), endothelial-to-mesenchymal transition (EndMT), increased abundance of fibroblasts, and further acceleration of fibrosis. In this study, we aimed to identify potential mechanisms and inhibitors of fibrosis using 3D model-based phenotypic screening. We established liver fibrosis models using multicellular tumor spheroids (MCTSs) composed of hepatocellular carcinoma (HCC) and stromal cells such as fibroblasts (WI38), hepatic stellate cells (LX2), and endothelial cells (HUVEC) seeded at constant ratios. Through high-throughput screening of FDA-approved drugs, we identified retinoic acid and forskolin as candidates to attenuate the compactness of MCTSs as well as inhibit the expression of ECM-related proteins. Additionally, retinoic acid and forskolin induced reprogramming of fibroblast and cancer stem cells in the HCC microenvironment. Of interest, retinoic acid and forskolin had anti-fibrosis effects by decreasing expression of α-SMA and F-actin in LX2 cells and HUVEC cells. Moreover, when sorafenib was added along with retinoic acid and forskolin, apoptosis was increased, suggesting that anti-fibrosis drugs may improve tissue penetration to support the efficacy of anti-cancer drugs. Collectively, these findings support the potential utility of morphometric analyses of hepatic multicellular spheroid models in the development of new drugs with novel mechanisms for the treatment of hepatic fibrosis and HCCs.

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Section: Discussionmentioning

confidence: 99%

Identification of hepatic fibrosis inhibitors through morphometry analysis of a hepatic multicellular spheroids model

Song

Kim

Heo

et al. 2021

Sci Rep

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“…Anti-inflammatory drugs are also a therapeutic strategy for the treatment of liver fibrosis [ 182 , 183 ]. This approach may focus on either directly inhibiting the release of inflammatory cytokines or neutralizing them with receptor antagonists.…”

Section: Therapeutic Approaches To Target Liver Fibrosismentioning

confidence: 99%

Pathophysiology and Treatment Options for Hepatic Fibrosis: Can It Be Completely Cured?

Khanam

Saleeb

Kottilil

2021

Cells

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Hepatic fibrosis is a dynamic process that occurs as a wound healing response against liver injury. During fibrosis, crosstalk between parenchymal and non-parenchymal cells, activation of different immune cells and signaling pathways, as well as a release of several inflammatory mediators take place, resulting in inflammation. Excessive inflammation drives hepatic stellate cell (HSC) activation, which then encounters various morphological and functional changes before transforming into proliferative and extracellular matrix (ECM)-producing myofibroblasts. Finally, enormous ECM accumulation interferes with hepatic function and leads to liver failure. To overcome this condition, several therapeutic approaches have been developed to inhibit inflammatory responses, HSC proliferation and activation. Preclinical studies also suggest several targets for the development of anti-fibrotic therapies; however, very few advanced to clinical trials. The pathophysiology of hepatic fibrosis is extremely complex and requires comprehensive understanding to identify effective therapeutic targets; therefore, in this review, we focus on the various cellular and molecular mechanisms associated with the pathophysiology of hepatic fibrosis and discuss potential strategies to control or reverse the fibrosis.

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“…Necrosis itself was categorized in necroptosis, autophagy, or ferroptosis (Aizawa et al, 2020). However, a general blockage of cell death may be challenging since apoptosis is involved in the regression of fibrosis (Aizawa et al, 2020;Chang and Li, 2020). Moreover, induction of cell death is needed to enhance the death of tumor cells.…”

Section: Molecular Mechanism Of Liver Fibrosis and Recent Clinical Trialsmentioning

confidence: 99%

“…Fibrosis may be characterized a dysregulated wound healing process, resulting in the generation of tissue scars (Simkin et al, 2020). The presence of bridging fibers between portal regions is the signs of advanced stages of liver fibrosis (Chang and Li, 2020).…”

Section: Introductionmentioning

confidence: 99%

The Potential Application of Magnetic Nanoparticles for Liver Fibrosis Theranostics

et al. 2021

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Liver fibrosis is a major cause of morbidity and mortality worldwide due to chronic liver damage and leading to cirrhosis, liver cancer, and liver failure. To date, there is no effective and specific therapy for patients with hepatic fibrosis. As a result of their various advantages such as biocompatibility, imaging contrast ability, improved tissue penetration, and superparamagnetic properties, magnetic nanoparticles have a great potential for diagnosis and therapy in various liver diseases including fibrosis. In this review, we focus on the molecular mechanisms and important factors for hepatic fibrosis and on potential magnetic nanoparticles-based therapeutics. New strategies for the diagnosis of liver fibrosis are also discussed, with a summary of the challenges and perspectives in the translational application of magnetic nanoparticles from bench to bedside.

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Hepatic Antifibrotic Pharmacotherapy: Are We Approaching Success?

Cited by 27 publications

References 75 publications

Identification of hepatic fibrosis inhibitors through morphometry analysis of a hepatic multicellular spheroids model

Identification of hepatic fibrosis inhibitors through morphometry analysis of a hepatic multicellular spheroids model

Pathophysiology and Treatment Options for Hepatic Fibrosis: Can It Be Completely Cured?

The Potential Application of Magnetic Nanoparticles for Liver Fibrosis Theranostics

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