4-methylumbelliferone Prevents Liver Fibrosis by Affecting Hyaluronan Deposition, FSTL1 Expression and Cell Localization

Andreichenko, Irina N.; Tsitrina, Alexandra A.; Фокин, А. В.; Gabdulkhakova, Adelya I; Maltsev, Dmitry I; Perelman, Grigory; Bulgakova, Elena; Куликов, А. М.; Mikaelyan, Arsen; Kotelevtsev, Yuri

doi:10.3390/ijms20246301

Cited by 25 publications

(22 citation statements)

References 36 publications

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“…Furthermore, we demonstrated that there was a TGF-β1-miR29a-Fstl1 regulatory circuit mediating liver fibrosis. These results are in agreement with previous studies showing Fstl1 was induced in liver fibrosis by CCl 4 treatment [40]. Our observation also confirmed the previous studies that knockdown Fstl1 attenuate liver fibrosis [25,26].…”

Section: Discussionsupporting

confidence: 94%

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Targeting Follistatin like 1 ameliorates liver fibrosis induced by carbon tetrachloride through TGF-β1-miR29a in mice

Liu

et al. 2020

Cell Commun Signal

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Background Hepatic fibrosis is a pathological response of the liver to a variety of chronic stimuli. Hepatic stellate cells (HSCs) are the major source of myofibroblasts in the liver. Follistatin like 1 (Fstl1) is a secreted glycoprotein induced by transforming growth factor-β1 (TGF-β1). However, the precise functions and regulation mechanisms of Fstl1 in liver fibrogenesis remains unclear. Methods Hepatic stellate cell (HSC) line LX-2 stimulated by TGF-β1, primary culture of mouse HSCs and a model of liver fibrosis induced by CCl4 in mice was used to assess the effect of Fstl1 in vitro and in vivo. Results Here, we found that Fstl1 was significantly up regulated in human and mouse fibrotic livers, as well as activated HSCs. Haplodeficiency of Fstl1 or blockage of Fstl1 with a neutralizing antibody 22B6 attenuated CCl4-induced liver fibrosis in vivo. Fstl1 modulates TGF-β1 classic Samd2 and non-classic JNK signaling pathways. Knockdown of Fstl1 in HSCs significantly ameliorated cell activation, cell migration, chemokines C-C Motif Chemokine Ligand 2 (CCL2) and C-X-C Motif Chemokine Ligand 8 (CXCL8) secretion and extracellular matrix (ECM) production, and also modulated microRNA-29a (miR29a) expression. Furthermore, we identified that Fstl1 was a target gene of miR29a. And TGF-β1 induction of Fstl1 expression was partially through down regulation of miR29a in HSCs. Conclusions Our data suggests TGF-β1-miR29a-Fstl1 regulatory circuit plays a key role in regulation the HSC activation and ECM production, and targeting Fstl1 may be a strategy for the treatment of liver fibrosis. Graphical abstract

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Section: Discussionsupporting

confidence: 94%

“…Throughout, data represent means ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001 altered macrophage localization with the downregulation of Fstl1 in CCl 4 treated mice [40]. Further studies are needed to determine whether Fstl1 modulates inflammatory responses in liver fibrosis.…”

Section: Discussionmentioning

confidence: 96%

Targeting Follistatin like 1 ameliorates liver fibrosis induced by carbon tetrachloride through TGF-β1-miR29a in mice

Liu

et al. 2020

Cell Commun Signal

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“…HA bioactivity is dependent on its molecular weight, enzymatic synthesis, and endogenous versus exogenous application [55,201,202]. The disruption or prevention of HA pericellular coat synthesis using hyaluronidase enzymes [203], HAS inhibitors [204,205] or exogenous HA oligosaccharides [59] results in the failure of TGF-β1-stimulated myofibroblast phenotypic acquisition. The inhibition of HAS2 activity [206] or global HAS synthesis of HA [204,205] have demonstrated preventative effects in various models of fibrosis.…”

Section: Experimental and Pre-clinical Interventions For Myofibroblast Differentiationmentioning

confidence: 99%

“…The disruption or prevention of HA pericellular coat synthesis using hyaluronidase enzymes [203], HAS inhibitors [204,205] or exogenous HA oligosaccharides [59] results in the failure of TGF-β1-stimulated myofibroblast phenotypic acquisition. The inhibition of HAS2 activity [206] or global HAS synthesis of HA [204,205] have demonstrated preventative effects in various models of fibrosis. However, given the ubiquitous role of HAS-synthesised HA in tissues, and the lack of specific HAS isoenzyme inhibitors, it is unclear at present whether the inhibition of HA synthesis would be beneficial in a clinical setting.…”

Section: Experimental and Pre-clinical Interventions For Myofibroblast Differentiationmentioning

confidence: 99%

Myofibroblasts: Function, Formation, and Scope of Molecular Therapies for Skin Fibrosis

et al. 2021

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Myofibroblasts are contractile, α-smooth muscle actin-positive cells with multiple roles in pathophysiological processes. Myofibroblasts mediate wound contractions, but their persistent presence in tissues is central to driving fibrosis, making them attractive cell targets for the development of therapeutic treatments. However, due to shared cellular markers with several other phenotypes, the specific targeting of myofibroblasts has long presented a scientific and clinical challenge. In recent years, myofibroblasts have drawn much attention among scientific research communities from multiple disciplines and specialisations. As further research uncovers the characterisations of myofibroblast formation, function, and regulation, the realisation of novel interventional routes for myofibroblasts within pathologies has emerged. The research community is approaching the means to finally target these cells, to prevent fibrosis, accelerate scarless wound healing, and attenuate associated disease-processes in clinical settings. This comprehensive review article describes the myofibroblast cell phenotype, their origins, and their diverse physiological and pathological functionality. Special attention has been given to mechanisms and molecular pathways governing myofibroblast differentiation, and updates in molecular interventions.

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“…Recent experimental data reveal hyaluronan synthase 2 (HAS2) as an important drug target in fibrosis ( Andreichenko et al. 2019 ; Yang et al.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of hyaluronan secretion by novel coumarin compounds and chitin synthesis inhibitors

et al. 2021

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Elevated plasma levels of hyaluronic acid (HA) is a disease marker in liver pathology and other inflammatory disorders. Inhibition of HA synthesis with coumarin 4-methylumbelliferone (4MU) has a beneficial effect in animal models of fibrosis, inflammation, cancer and metabolic syndrome. 4MU is an active compound of approved choleretic drug hymecromone with low bioavailability and a broad spectrum of action. New, more specific, and efficient inhibitors of hyaluronan synthases (HAS) are required. We have tested several newly synthesized coumarin compounds and commercial chitin synthesis inhibitors to inhibit HA production in cell culture assay. Coumarin derivative compound VII (10′-methyl-6′-phenyl-3’H-spiro[piperidine-4,2′-pyrano[3,2-g]chromene]-4′,8′-dione) demonstrated inhibition of HA secretion by NIH3T3 cells with the half-maximal inhibitory concentration (IC50) = 1.69 ± 0.75 μΜ superior to 4MU (IC50 = 8.68 ± 1.6 μΜ). Inhibitors of chitin synthesis, etoxazole, buprofezin, triflumuron, reduced HA deposition with IC50 of 4.21 ± 3.82 μΜ, 1.24 ± 0.87 μΜ, and 1.48 ± 1.44 μΜ, respectively. Etoxazole reduced HA production and prevented collagen fibre formation in the CCl4 liver fibrosis model in mice similar to 4MU. Bioinformatics analysis revealed homology between chitin synthases and HAS enzymes, particularly in the pore-forming domain, containing the proposed site for etoxazole binding.

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4-methylumbelliferone Prevents Liver Fibrosis by Affecting Hyaluronan Deposition, FSTL1 Expression and Cell Localization

Cited by 25 publications

References 36 publications

Targeting Follistatin like 1 ameliorates liver fibrosis induced by carbon tetrachloride through TGF-β1-miR29a in mice

Targeting Follistatin like 1 ameliorates liver fibrosis induced by carbon tetrachloride through TGF-β1-miR29a in mice

Myofibroblasts: Function, Formation, and Scope of Molecular Therapies for Skin Fibrosis

Inhibition of hyaluronan secretion by novel coumarin compounds and chitin synthesis inhibitors

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