Co-administration of resveratrol and beta-aminopropionitrile attenuates liver fibrosis development via targeting lysyl oxidase in CCl<sub>4</sub>-induced liver fibrosis in rats

Mohseni, Roohollah; Sadeghabadi, Zahra Arab; Goodarzi, Mohammad Taghi; Karimi, Jamshid

doi:10.1080/08923973.2019.1688829

Cited by 17 publications

(11 citation statements)

References 32 publications

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“…Rivera et al [102] examined the effect of resveratrol on CCI4-induced hepatotoxicity (carbon tetrachloride). After liver CCl4-induced damage, in cultured cells of hepatocytes, lipid peroxidation and γ-glutamyl transpeptidase activity are significantly increased [103]. In this context, resveratrol partially prevents increases in lipid peroxidation and γ-glutamyl transpeptidase [104].…”

Section: Chemical Liver Injurymentioning

confidence: 94%

The Role of Resveratrol in Liver Disease: A Comprehensive Review from In Vitro to Clinical Trials

et al. 2021

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Many studies have shown that resveratrol has a lot of therapeutic effects on liver disorders. Its administration can significantly increase the survival rate after liver transplantation, reduce fat deposition and ischemia-induced necrosis and apoptosis in Wistar rats. Resveratrol can provide Liver protection against chemical, cholestatic, and alcohol-mediated damage. It can improve glucose metabolism and lipid profile, reduce liver fibrosis, and steatosis. Additionally, it is capable of altering the fatty acid composition of the liver cells. Resveratrol may be a potential treatment option for the management of non-alcoholic fatty liver disease (NAFLD) due to its anti-inflammatory, antioxidant, and calorie-restricting effects. There are also studies that have evaluated the effect of resveratrol on lipid and liver enzyme profiles among patients with metabolic syndrome (MetS) and related disorders. Based on the extent of liver disease worldwide and the need to find new treatment possibilities, this review critically examines current in vitro and in vivo preclinical studies and human clinical studies related to liver protection.

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Section: Chemical Liver Injurymentioning

confidence: 94%

The Role of Resveratrol in Liver Disease: A Comprehensive Review from In Vitro to Clinical Trials

et al. 2021

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“…Liver fibrosis can be found in SSc patients [ 23 ] and CCl4-induced liver fibrosis is a standard model to induce severe damage. It has been shown that lysyl oxidases are upregulated in CCl4-induced fibrosis [ 24 ]. When CCl4 was given twice weekly for 8 weeks, strong fibrosis developed as measured by Picro-Sirius red staining.…”

Section: Resultsmentioning

confidence: 99%

“…In contrast to these models, the severe UUO model resembling SSc, where all lysyl oxidase isoforms were elevated, pan-lysyl oxidase inhibition with PXS-5505 as potent anti-fibrotic therapeutic strategy was required and confirming previous data with BAPN [ 42 ]. Likewise, while selective LOXL2/3 inhibition can be sufficient to reduce fibrosis in the CCl4 rat model [ 40 ], in more severe models where expression of LOX and LOXL2 expression is upregulated, treatment with BAPN has been shown to downregulate LOX expression [ 24 ]. Owing to the severity of SSc, it is expected that the pan-lysyl oxidase inhibitor PXS-5505 may produce the desired high level of antifibrotic efficacy which LOXL2 antibody simtuzumab was lacking [ 19 ] while having better clinical tolerability compared to BAPN.…”

Section: Discussionmentioning

confidence: 99%

Pan-Lysyl Oxidase Inhibitor PXS-5505 Ameliorates Multiple-Organ Fibrosis by Inhibiting Collagen Crosslinks in Rodent Models of Systemic Sclerosis

Yao

Findlay

Stolp

et al. 2022

IJMS

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Systemic sclerosis (SSc) is characterised by progressive multiple organ fibrosis leading to morbidity and mortality. Lysyl oxidases play a vital role in the cross-linking of collagens and subsequent build-up of fibrosis in the extracellular matrix. As such, their inhibition provides a novel treatment paradigm for SSc. A novel small molecule pan-lysyl oxidase inhibitor, PXS-5505, currently in clinical development for myelofibrosis treatment was evaluated using in vivo rodent models resembling the fibrotic conditions in SSc. Both lysyl oxidase and lysyl oxidase-like 2 (LOXL2) expression were elevated in the skin and lung of SSc patients. The oral application of PXS-5505 inhibited lysyl oxidase activity in the skin and LOXL2 activity in the lung. PXS-5505 exhibited anti-fibrotic effects in the SSc skin mouse model, reducing dermal thickness and α-smooth muscle actin. Similarly, in the bleomycin-induced mouse lung model, PXS-5505 reduced pulmonary fibrosis toward normal levels, mediated by its ability to normalise collagen/elastin crosslink formation. PXS-5505 also reduced fibrotic extent in models of the ischaemia-reperfusion heart, the unilateral ureteral obstruction kidney, and the CCl4-induced fibrotic liver. PXS-5505 consistently demonstrates potent anti-fibrotic efficacy in multiple models of organ fibrosis relevant to the pathogenesis of SSc, suggesting that it may be efficacious as a novel approach for treating SSc.

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“…Past studies have shown that inhibition of LOX activity reduces its own expression, thus indicating that LOX can auto-regulate its expression (31-33). Our findings agree with these observations as inhibiting LOX activity in HRECs with BAPN (Fig.…”

Section: Resultsmentioning

confidence: 99%

Lysyl oxidase-dependent subendothelial matrix stiffening promotes RAGE-mediated retinal endothelial activation in diabetes

Chandrakumar

Tierno

Agarwal

et al. 2022

Preprint

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Endothelial cell (EC) activation is a crucial determinant of retinal vascular inflammation associated with diabetic retinopathy (DR), a major microvascular complication of diabetes. We previously showed that, similar to abnormal biochemical factors, aberrant mechanical cues in the form of lysyl oxidase (LOX)-dependent subendothelial matrix stiffening also contribute significantly to retinal EC activation in diabetes. Yet, how LOX is itself regulated and precisely how it mechanically controls retinal EC activation in diabetes is poorly understood. Here we show that high glucose-induced LOX upregulation in human retinal ECs (HRECs) is mediated by proinflammatory RAGE (receptor for advanced glycation end products/AGEs). HRECs treated with methylglyoxal (MGO), an active precursor to the AGE MG-H1, exhibited LOX upregulation that was blocked by a RAGE inhibitor, thus confirming the ability of RAGE to promote LOX expression. Crucially, as a downstream effector of RAGE, LOX was found to mediate both the proinflammatory and matrix remodeling effects of MGO/RAGE, primarily through its ability to crosslink/stiffen matrix. Finally, using decellularized HREC-derived matrices and a mouse model of diabetes, we demonstrate that LOX-dependent matrix stiffening feeds back to enhance RAGE, thereby achieving its autoregulation and proinflammatory effects. These fresh insights into the regulation and proinflammatory role of LOX-dependent mechanical cues may help identify new therapeutic targets to block AGE/RAGE signaling in DR.

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Co-administration of resveratrol and beta-aminopropionitrile attenuates liver fibrosis development via targeting lysyl oxidase in CCl₄-induced liver fibrosis in rats

Cited by 17 publications

References 32 publications

The Role of Resveratrol in Liver Disease: A Comprehensive Review from In Vitro to Clinical Trials

The Role of Resveratrol in Liver Disease: A Comprehensive Review from In Vitro to Clinical Trials

Pan-Lysyl Oxidase Inhibitor PXS-5505 Ameliorates Multiple-Organ Fibrosis by Inhibiting Collagen Crosslinks in Rodent Models of Systemic Sclerosis

Lysyl oxidase-dependent subendothelial matrix stiffening promotes RAGE-mediated retinal endothelial activation in diabetes

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Co-administration of resveratrol and beta-aminopropionitrile attenuates liver fibrosis development via targeting lysyl oxidase in CCl4-induced liver fibrosis in rats

Cited by 17 publications

References 32 publications

The Role of Resveratrol in Liver Disease: A Comprehensive Review from In Vitro to Clinical Trials

The Role of Resveratrol in Liver Disease: A Comprehensive Review from In Vitro to Clinical Trials

Pan-Lysyl Oxidase Inhibitor PXS-5505 Ameliorates Multiple-Organ Fibrosis by Inhibiting Collagen Crosslinks in Rodent Models of Systemic Sclerosis

Lysyl oxidase-dependent subendothelial matrix stiffening promotes RAGE-mediated retinal endothelial activation in diabetes

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Co-administration of resveratrol and beta-aminopropionitrile attenuates liver fibrosis development via targeting lysyl oxidase in CCl₄-induced liver fibrosis in rats