Inducible knockdown of procollagen I protects mice from liver fibrosis and leads to dysregulated matrix genes and attenuated inflammation

Molokanova, O.; Shi, Kai; Weng, Shih‐Yen; Wang, Xiaoyu; Bros, Matthias; Diken, Mustafa; Ohngemach, Svetlana; Karsdal, Morten A.; Strand, Dennis; Nikolaev, Alexei; Eshkind, Leonid; Schuppan, Detlef

doi:10.1016/j.matbio.2017.11.002

Cited by 23 publications

(14 citation statements)

References 48 publications

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“…Matrix metalloproteinase 1, also known as interstitial collagenase or fibroblast collagenase, 13 is the main protease that can degrade type I collagen, which usually represents the fibrotic scaffold and >50% of the scar protein. 48 This study found that chrysin can upregulate MMP-1 mRNA expression and further stimulate cleavage of the native fibrillar collagens, especially Col I by regulating the ECM balance via TIMP-1/MMP-1 components. Matrix metalloproteinase 1 downregulated in established CCl4-liver fibrosis, is expressed again during the resolution process, and may act through ECM degradation as well as by induction of HSC apoptosis, 49 confirmed by our previous findings.…”

Section: Discussionmentioning

confidence: 70%

Dose-Dependent Antifibrotic Effect of Chrysin on Regression of Liver Fibrosis: The Role in Extracellular Matrix Remodeling

et al. 2018

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Liver fibrosis represents an overaccumulation of extracellular matrix (ECM). This study was designed to investigate the effect of chrysin on established ECM overproduction in carbon tetrachloride (CCl4) mouse liver fibrosis. Experimental fibrosis was induced by intraperitoneal injection of 2 mL/kg CCl4 twice a week, for 7 weeks. Mice were orally treated with 3 doses of chrysin (5,7-dihydroxyflavone). For the assessment of the spontaneous reversion of fibrosis, CCl4-treated mice were investigated after 2 weeks of recovery time. Silymarin was used as a standard of liver protection. In fibrotic livers, the results showed the upregulation of collagen I (Col I) and tissue inhibitors of metalloproteinase 1 (TIMP-1) and modulation of matrix metalloproteinases (MMPs), which led to an altered ECM enriched in Col, confirmed as well by electron microscopy investigations. Treatment with chrysin significantly reduced ultrastructural changes, downregulated Col I, and restored TIMP-1/MMP balance, whereas in the group observed for the spontaneous regression of fibrosis, they remained in the same pattern with fibrotic livers. In this study, we have shown chrysin efficacy to attenuate dose-dependent CCl4-stimulated liver ECM accumulation by regulation of MMP/TIMP imbalance and inhibition of Col production. We have shown the dose-dependent chrysin efficiency in attenuation of CCl4-induced liver ECM accumulation by regulation of MMP/TIMP imbalance and inhibition of Col production. Our findings suggest that chrysin oral administration may introduce a new strategy for treating liver fibrosis in humans.

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Section: Discussionmentioning

confidence: 70%

Dose-Dependent Antifibrotic Effect of Chrysin on Regression of Liver Fibrosis: The Role in Extracellular Matrix Remodeling

et al. 2018

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“…Parenteral treatment hereby led to a 90% decrease in collagen production and 50% decrease of total collagen accumulation [313]. Another study on transgenic mice with inducible Col1 knockdown further reported additional anti-inflammatory effects [314]. Hsp47 is a Col1 chaperone and knockdown by siRNA can be used to block collagen synthesis.…”

Section: Reduction Of Fibrotic Scar Evolution and Contractilitymentioning

confidence: 90%

Liver Fibrosis: Mechanistic Concepts and Therapeutic Perspectives

Roehlen

Crouchet

Baumert

2020

Cells

755

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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“…Zhang et al reported that collagen I stimulated recruitment and aggregation of mouse peritoneal macrophages, as well as the production of pro-inflammatory cytokines by increasing ROS levels 51 . Molokanova et al found that collagen type I deficiency (but not complete absence) attenuated inflammatory cell activation/recruitment in the damaged liver 52 . We detected significantly higher levels of Col1a1 in the blood samples of SCI patients, further underscoring its involvement in post-SCI neuroinflammation.…”

Section: Discussionmentioning

confidence: 99%

TLR4 promotes microglial pyroptosis via lncRNA-F630028O10Rik by activating PI3K/AKT pathway after spinal cord injury

et al. 2020

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Neuroinflammation plays a crucial role in the secondary phase of spinal cord injury (SCI), and is initiated following the activation of toll-like receptor 4 (TLR4). However, the downstream mechanism remains unknown. Pyroptosis is a form of inflammatory programmed cell death, which is closely involved in neuroinflammation, and it can be regulated by TLR4 according to a recent research. In addition, several studies have shown that long non-coding RNAs (lncRNAs) based mechanisms were related to signal transduction downstream of TLR4 in the regulation of inflammation. Thus, in this study, we want to determine whether TLR4 can regulate pyroptosis after SCI via lncRNAs. Our results showed that TLR4 was activated following SCI and promoted the expression of lncRNA-F630028O10Rik. This lncRNA functioned as a ceRNA for miR-1231-5p/Col1a1 axis and enhanced microglial pyroptosis after SCI by activating the PI3K/AKT pathway. Furthermore, we determined STAT1 was the upstream transcriptional factor of IncRNA-F630028O10Rik and was induced by the damage-responsive TLR4/MyD88 signal. Our findings provide new insights and a novel therapeutic strategy for treating SCI.

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Inducible knockdown of procollagen I protects mice from liver fibrosis and leads to dysregulated matrix genes and attenuated inflammation

Cited by 23 publications

References 48 publications

Dose-Dependent Antifibrotic Effect of Chrysin on Regression of Liver Fibrosis: The Role in Extracellular Matrix Remodeling

Dose-Dependent Antifibrotic Effect of Chrysin on Regression of Liver Fibrosis: The Role in Extracellular Matrix Remodeling

Liver Fibrosis: Mechanistic Concepts and Therapeutic Perspectives

TLR4 promotes microglial pyroptosis via lncRNA-F630028O10Rik by activating PI3K/AKT pathway after spinal cord injury

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