Morin, a dietary bioflavonol suppresses monosodium urate crystal-induced inflammation in an animal model of acute gouty arthritis with reference to NLRP3 inflammasome, hypo-xanthine phospho-ribosyl transferase, and inflammatory mediators

Dhanasekar, Chitra; Rasool, Mahaboobkhan

doi:10.1016/j.ejphar.2016.06.005

Cited by 53 publications

(30 citation statements)

References 36 publications

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“…Expression of the proinflammatory mRNA marker iNOS was also returned to normal in PBI-4050-treated livers. Several natural compounds such as Morin, a plant-derived flavonoid, have been shown to ameliorate liver fibrosis by suppressing iNOS (Dhanasekar and Rasool, 2016). Finally, treatment with PBI-4050 improved liver function, as observed with the reduction of AST activity in mice with CCl 4 -induced liver injury.…”

Section: Pbi-4050 Reduces Liver Fibrosismentioning

confidence: 95%

PBI-4050 Reduces Stellate Cell Activation and Liver Fibrosis through Modulation of Intracellular ATP Levels and the Liver Kinase B1/AMP-Activated Protein Kinase/Mammalian Target of Rapamycin Pathway

Grouix¹,

Sarra‐Bournet²,

Leduc³

et al. 2018

J Pharmacol Exp Ther

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Hepatic fibrosis is a major cause of morbidity and mortality for which there is currently no effective therapy. We previously showed that 2-(3-pentylphenyl)acetic acid (PBI-4050) is a dual G protein-coupled receptor GPR40 agonist/GPR84 antagonist that exerts antifibrotic, anti-inflammatory, and antiproliferative action. We evaluated PBI-4050 for the treatment of liver fibrosis in vivo and elucidated its mechanism of action on human hepatic stellate cells (HSCs). The antifibrotic effect of PBI-4050 was evaluated in carbon tetrachloride (CCl)- and bile duct ligation-induced liver fibrosis rodent models. Treatment with PBI-4050 suppressed CCl-induced serum aspartate aminotransferase levels, inflammatory marker nitric oxide synthase, epithelial to mesenchymal transition transcription factor Snail, and multiple profibrotic factors. PBI-4050 also decreased GPR84 mRNA expression in CCl-induced injury, while restoring peroxisome proliferator-activated receptor (PPAR) to the control level. Collagen deposition and -smooth muscle actin (-SMA) protein levels were also attenuated by PBI-4050 treatment in the bile duct ligation rat model. Transforming growth factor--activated primary HSCs were used to examine the effect of PBI-4050 and its mechanism of action in vitro. PBI-4050 inhibited HSC proliferation by arresting cells in the G0/G1 cycle phase. Subsequent analysis demonstrated that PBI-4050 signals through a reduction of intracellular ATP levels, activation of liver kinase B1 (LKB1) and AMP-activated protein kinase (AMPK), and blockade of mammalian target of rapamycin (mTOR), resulting in reduced protein and mRNA levels of -SMA and connective tissue growth factor and restored PPAR mRNA expression. Our findings suggest that PBI-4050 may exert antifibrotic activity in the liver through a novel mechanism of action involving modulation of intracellular ATP levels and the LKB1/AMPK/mTOR pathway in stellate cells, and PBI-4050 may be a promising agent for treating liver fibrosis.

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Section: Pbi-4050 Reduces Liver Fibrosismentioning

confidence: 95%

PBI-4050 Reduces Stellate Cell Activation and Liver Fibrosis through Modulation of Intracellular ATP Levels and the Liver Kinase B1/AMP-Activated Protein Kinase/Mammalian Target of Rapamycin Pathway

Grouix¹,

Sarra‐Bournet²,

Leduc³

et al. 2018

J Pharmacol Exp Ther

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“…Relative amount of transcripts was calculated using the 2 −ΔΔCt formula. β‐actin served as the reference gene . The sequences of primers used in the present study were given in Supplemental Table 1.…”

Section: Methodsmentioning

confidence: 99%

Frontline Science: Reprogramming COX-2, 5-LOX, and CYP4A-mediated arachidonic acid metabolism in macrophages by salidroside alleviates gouty arthritis

Liu

Tang

Liu

et al. 2018

Journal of Leukocyte Biology

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Cyclooxygenase-2 (COX-2), 5-lipoxygenase (5-LOX), and cytochrome P450 (CYP) 4A-mediated arachidonic acid (AA) metabolism play an essential role in human inflammatory disorders. Blocking COX-2 pathway would shunt AA metabolism to the other pathway, thereby decreasing the efficacy and exacerbating adverse effects. Here we demonstrated that reprogramming COX-2, 5-LOX, and CYP4A-mediated AA metabolism in macrophages by salidroside (Sal) ameliorates monosodium urate (MSU) crystal-induced inflammation. Compared with COX-2 inhibitor celecoxib, Sal (80 mg/kg) presented a superior anti-arthritic profile in MSU crystal-treated rats, accompanied with the decreased expression of COX-2, 5-LOX, and CYP4A and production of prostaglandin E2 (PGE 2 ), leukotriene B4 (LTB 4 ), and 20-hydroxyeicosatetraenoic acid in the synovial fluid macrophages. Sal decreased representative M1 marker (iNOS and CD86, etc.) expression and M1 cytokine (TNF-and IL-1 ) production, whereas it increased M2 marker (CD206 and Arg-1) expression and M2 cytokine (TGF-and IL-10) production. The injection of conditioned medium from MSU crystal-treated macrophages into the ankle joint of rats reproduced the gouty inflammation, which was attenuated by Sal. Mechanistically, down-regulation of COX-2, 5-LOX, and CYP4A in the RAW264.7 and NR8383 macrophages by Sal skewed macrophage polarization away from the M1 phenotype, and thereby prevented neutrophil migration and chondrocyte degradation with STAT1 and NF-B inactivation. Conversely, overexpression of COX-2, 5-LOX, CYP4A or STAT1, or exogenous addition of IL-1 or TNF-partially abolished these effects. Together, inhibition of COX-2, 5-LOX, and CYP4A in macrophages by Sal ameliorates MSU crystal-induced inflammation through decreasing TNF-and IL-1 production, and may serve as a novel therapeutic strategy. K E Y W O R D Sarachidonic acid, gouty inflammation, macrophage, metabolism, salidroside INTRODUCTIONGout is the most common inflammatory arthritis in men older than 40 years. 1 Nonsteroidal anti-inflammatory drugs (NSAIDs) are used as Abbreviations: 20-HETE, 20-hydroxyeicosatetraenoic acid; 5-LOX, 5-lipoxygenase; ADAMTS-5, a disintegrin and metalloproteinase with thrombospondin motif 5; Clod, clodronate liposome; COX-2, cyclooxygenase-2; CYP4A, cytochrome P450 4A; LTB 4 , leukotriene B 4 ; MMP-13, Matrix metalloproteinase-13; MSU, monosodium urate; NF-B, nuclear transcription factor kappa B; PGE 2 , prostaglandin E 2 ; Sal, salidroside; STAT1, signal transducers and activators of transcription 1; ZA, zoledronic acid first-line therapy to manage gouty arthritis, whereas the inevitable gastrointestinal or cardiovascular side effects restrict their utilization. 2 Newly developed anti-IL-1 drugs appear to be highly effective, but present limitations such as high cost and hematopoietic disorders. 3 Therefore, there is an urgent need to identify novel agents for gouty arthritis treatment.Gout is triggered by monosodium urate (MSU) crystal deposition in and around joints. Macrophages play a pivotal role in the initiati...

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“…Morin (3,5,7,2′,4′‐pentahydroxyflavone, Figure ) is a bioflavonoid that exists in many herbal medicines such as Morus alba L. (Moraceae) and Otostegia persica (Lamiaceae) . It is also an ingredient of common foods such as figs, apples, onions, tea, and cereal grains . Previous studies have demonstrated that morin has various pharmacological activities, including anti‐inflammatory, antioxidant, anti‐angiogenic, and anticancer effects .…”

Section: Introductionmentioning

confidence: 99%

Morin Exerts Anti‐Arthritic Effects by Attenuating Synovial Angiogenesis via Activation of Peroxisome Proliferator Activated Receptor‐γ

Yue

Zeng

Xia

et al. 2018

Molecular Nutrition Food Res

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Morin, a dietary bioflavonol suppresses monosodium urate crystal-induced inflammation in an animal model of acute gouty arthritis with reference to NLRP3 inflammasome, hypo-xanthine phospho-ribosyl transferase, and inflammatory mediators

Cited by 53 publications

References 36 publications

PBI-4050 Reduces Stellate Cell Activation and Liver Fibrosis through Modulation of Intracellular ATP Levels and the Liver Kinase B1/AMP-Activated Protein Kinase/Mammalian Target of Rapamycin Pathway

PBI-4050 Reduces Stellate Cell Activation and Liver Fibrosis through Modulation of Intracellular ATP Levels and the Liver Kinase B1/AMP-Activated Protein Kinase/Mammalian Target of Rapamycin Pathway

Frontline Science: Reprogramming COX-2, 5-LOX, and CYP4A-mediated arachidonic acid metabolism in macrophages by salidroside alleviates gouty arthritis

Morin Exerts Anti‐Arthritic Effects by Attenuating Synovial Angiogenesis via Activation of Peroxisome Proliferator Activated Receptor‐γ

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