Inhibition of canonical WNT signaling pathway by β-catenin/CBP inhibitor ICG-001 ameliorates liver fibrosis in vivo through suppression of stromal CXCL12

Akcora, Büsra Öztürk; Storm, Gert; Bansal, Ruchi

doi:10.1016/j.bbadis.2017.12.001

Cited by 84 publications

(82 citation statements)

References 46 publications

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“…Moreover, ICG-001 administration in a murine CCl 4 induced mouse model of fibrosis attenuated HSC activation and ECM accumulation. Mechanistically, ICG-001 was found to affect macrophage infiltration and thereby reduce hepatic inflammation by affecting Wnt-dependent secretion of CCL12 by HSCs [295]. Apart from the liver, ICG-001 has also been reported to suppress pulmonary [296] and renal interstitial fibrosis [297].…”

Section: Inhibition Of Hsc Activationmentioning

confidence: 99%

Liver Fibrosis: Mechanistic Concepts and Therapeutic Perspectives

Roehlen

Crouchet

Baumert

2020

Cells

756

440

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Liver fibrosis due to viral or metabolic chronic liver diseases is a major challenge of global health. Correlating with liver disease progression, fibrosis is a key factor for liver disease outcome and risk of hepatocellular carcinoma (HCC). Despite different mechanism of primary liver injury and disease-specific cell responses, the progression of fibrotic liver disease follows shared patterns across the main liver disease etiologies. Scientific discoveries within the last decade have transformed the understanding of the mechanisms of liver fibrosis. Removal or elimination of the causative agent such as control or cure of viral infection has shown that liver fibrosis is reversible. However, reversal often occurs too slowly or too infrequent to avoid life-threatening complications particularly in advanced fibrosis. Thus, there is a huge unmet medical need for anti-fibrotic therapies to prevent liver disease progression and HCC development. However, while many anti-fibrotic candidate agents have shown robust effects in experimental animal models, their anti-fibrotic effects in clinical trials have been limited or absent. Thus, no approved therapy exists for liver fibrosis. In this review we summarize cellular drivers and molecular mechanisms of fibrogenesis in chronic liver diseases and discuss their impact for the development of urgently needed anti-fibrotic therapies.

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Section: Inhibition Of Hsc Activationmentioning

confidence: 99%

Liver Fibrosis: Mechanistic Concepts and Therapeutic Perspectives

Roehlen

Crouchet

Baumert

2020

Cells

756

440

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“…A 3-dimensional (3D) collagen I gel contraction assay was performed as previously described (5). Briefly, collagen suspension (5.0 ml) containing 3.0 ml Collagen G1 (5 mg/ml; Matrix Biosciences, Mörlenbach, Germany), 0.5 ml 10-times M199 medium, 85 ml 1N NaOH (MilliporeSigma), and sterile water was prepared and mixed with 1.0 ml (2 3 10 6 ) LX2 cells.…”

Section: Three-dimensional Collagen I Gel Contraction Assaymentioning

confidence: 99%

“…In the liver, macrophages undergo functional and phenotypic transformation in response to the cytokines and growth factors into classically activated proinflammatory M1 macrophages and alternatively activated restorative M2 macrophages (6)(7)(8). There is a continuous crosstalk between HSCs and macrophages during liver diseases (5,9), which implies that combined therapies targeting both HSCs and macrophages or HSC-macrophage crosstalk will be an effective approach for the treatment of hepatic fibrosis.…”

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confidence: 99%

TG101348, a selective JAK2 antagonist, ameliorates hepatic fibrogenesis in vivo

et al. 2019

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Hepatic fibrosis, characterized by an excessive extracellular matrix (ECM) accumulation, leading to scar‐tissue formation is a growing health problem worldwide. Hepatocellular damage due to liver injury triggers inflammation and transdifferentiation of quiescent hepatic stellate cells (HSCs) into proliferative, contractile, and ECM‐producing myofibroblasts. Involvement of the Janus kinase (JAK)‐2 pathway in the pathogenesis of fibrosis has been reported earlier. However, in this study, we have investigated the effect of selective JAK2 antagonist TG101348 in fibroblasts and inflammatory macrophages and in vivo in an acute carbon tetrachloride–induced liver injury mouse model. In vitro, TG101348 significantly inhibited TGF‐β‐induced collagen I expression in murine 3T3 fibroblasts. In human HSCs (LX2 cells), TG101348 potently attenuated TGF‐β‐induced contractility and the protein and gene expression of major fibrotic parameters (collagen I, vimentin, and α‐smooth muscle actin). In LPS‐ and IFN‐γ‐stimulated inflammatory macrophages, TG101348 significantly reduced the NO release and strongly inhibited the expression of inflammatory markers (inducible nitric oxide synthase, C‐C motif chemokine ligand 2, IL‐1β, IL‐6, and C‐C chemokine receptor type 2). In vivo in an acute liver injury mouse model, TG101348 significantly attenuated collagen accumulation and HSC activation. Interestingly, TG101348 drastically inhibited macrophage infiltration and intrahepatic inflammation. Pharmacological inhibition of the JAK2 signaling pathway in activated HSCs and inflammatory macrophages using TG101348 suggests a potential therapeutic approach for the treatment of liver fibrosis.—Akcora, B. O., Dathathri, E., Ortiz‐Perez, A., Gabriël, A. V., Storm, G., Prakash, J., Bansal, R. TG101348, a selective JAK2 antagonist, ameliorates hepatic fibrogenesis in vivo. FASEB J. 33, 9466–9475 (2019). http://www.fasebj.org

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“… 152 Furthermore, in a study on liver fibrogenesis, ICG-001 significantly inhibits fibrotic parameters in vitro , and significantly attenuates collagen accumulation and inhibits macrophage infiltration, intrahepatic inflammation, and angiogenesis in vivo. 153 The mechanism of the healthy aging effect of ICG-001 is related to inhibition of the Wnt/β-catenin signaling pathway. By inhibiting the binding of β-catenin with the transcription coactivator CBP, ICG-001 is able to inhibit the downstream signaling transduction of the Wnt/β-catenin pathway.…”

Section: Therapeutic Drugs Targeting Senescencementioning

confidence: 99%

Advancements in therapeutic drugs targeting of senescence

Zhu

Meng

Ling

et al. 2020

Therapeutic Advances in Chronic Disease

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Aging leads to a high burden on society, both medically and economically. Cellular senescence plays an essential role in the initiation of aging and age-related diseases. Recent studies have highlighted the therapeutic value of senescent cell deletion in natural aging and many age-related disorders. However, the therapeutic strategies for manipulating cellular senescence are still at an early stage of development. Among these strategies, therapeutic drugs that target cellular senescence are arguably the most highly anticipated. Many recent studies have demonstrated that a variety of drugs exhibit healthy aging effects. In this review, we summarize different types of drugs promoting healthy aging – such as senolytics, senescence-associated secretory phenotype (SASP) inhibitors, and nutrient signaling regulators – and provide an update on their potential therapeutic merits. Taken together, our review synthesizes recent advancements in the therapeutic potentialities of drugs promoting healthy aging with regard to their clinical implications.

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Inhibition of canonical WNT signaling pathway by β-catenin/CBP inhibitor ICG-001 ameliorates liver fibrosis in vivo through suppression of stromal CXCL12

Cited by 84 publications

References 46 publications

Liver Fibrosis: Mechanistic Concepts and Therapeutic Perspectives

Liver Fibrosis: Mechanistic Concepts and Therapeutic Perspectives

TG101348, a selective JAK2 antagonist, ameliorates hepatic fibrogenesis in vivo

Advancements in therapeutic drugs targeting of senescence

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