Fenretinide inhibits macrophage inflammatory mediators and controls hypertension in spontaneously hypertensive rats via the peroxisome proliferator-activated receptor gamma pathway

Abstract

Fenretinide is a novel anticancer agent reported to exhibit anti-invasive and antimetastatic activities. It has also been shown to improve obesity and diabetes, although the effects of fenretinide on hypertension are still unknown, and the detailed mechanisms remain unclear. In this study, we have shown that treatment with lipopolysaccharide (LPS) decreased the expression of peroxisome proliferator-activated receptor γ (PPARγ) in RAW264.7 macrophages, and pretreatment with fenretinide reversed the effect of LPS on PPARγ expression. In addition, LPS-induced pro-inflammatory cytokine production, including tumor necrosis factor-α, interleukin 6, and monocyte chemoattractant protein 1 were dose-dependently reversed by fenretinide, and the effects of fenretinide on LPS-induced pro-inflammatory cytokine production were blocked by treatment with PPARγ antagonist. Moreover, fenretinide decreased LPS-induced inducible nitric oxide synthase expression and nitrogen oxide production. These effects were blocked by the pretreatment with PPARγ antagonist in a dose-dependent manner, indicating fenretinide activated PPARγ to exert anti-inflammation activity. In view of the role of inflammation in hypertension and the anti-inflammatory action of fenretinide, we found that administration of fenretinide in spontaneously hypertensive rats significantly decreased blood pressure. Taken together, these results indicate that fenretinide might be a potent antihypertensive agent that works by suppressing inflammation via activating PPARγ.

Wide-range screening of anti-inflammatory compounds in tomato using LC-MS and elucidating the mechanism of their functions

“…On the other hand, we demonstrated for the first time that 9-oxo-ODA was not only a PPARα activator but also showed anti-inflammatory properties. In addition, previous studies have reported that PPARγ the subtype of PPARα, is likely to be concerned with anti-inflammatory effect in LPS-stimulated macrophages[ 41 , 42 ]. Therefore, we investigated whether the anti-inflammatory activities of 9-oxo-ODA participated in PPARα and PPARγ by using antagonist with reference to the previous studies[ 19 , 42 ].…”

“…In addition, previous studies have reported that PPARγ the subtype of PPARα, is likely to be concerned with anti-inflammatory effect in LPS-stimulated macrophages[ 41 , 42 ]. Therefore, we investigated whether the anti-inflammatory activities of 9-oxo-ODA participated in PPARα and PPARγ by using antagonist with reference to the previous studies[ 19 , 42 ]. The anti-inflammatory activities of 9-oxo-ODA on NO production was unchanged by PPARα antagonist GW6471 and PPARγ antagonist GW9662 ( S4A and S4B Fig ).…”

Molecular Inverse Comorbidity between Alzheimer’s disease and Lung Cancer: new insights from Matrix Factorization

“…At the same time, fenretinide has been shown to inhibit growth in lung cancer cell lines [38] and it has been proposed as a potential adjuvant for late onset Alzheimer's disease [39]. Moreover, the fenretinide community is tightly linked with the monocytes one, in agreement with its mechanisms of action involving the regulation of the secretion of pro-inflammatory cytokines in human monocytes [40].…”

“…The communities associated to mitochondria span different processes related to their activity: oxidation-reduction process (communities 16,23,40), hypoxia (community 10) and phosphate metabolic process (community 38). Enrichment in hypoxia could correspond to a confounding factor linked to the state of the profiled tissues (post-mortem for AD and fresh tissue biopsy for LC).…”

Fenretinide Inhibits Neutrophil Recruitment and IL-1β Production in Aspergillus fumigatus Keratitis

“… 7 In addition, fenretinide decreased lipopolysaccharide (LPS)-induced proinflammatory cytokine production, including tumor necrosis factor-α, interleukin 6 (IL-6), and monocyte chemoattractant protein 1, nitric oxide synthase expression, and nitrogen oxide production through activating peroxisome proliferator-activated receptor γ in macrophages. 8 Moreover, inflammation and airway hyperresponsiveness induced by ovalbumin were protected by fenretinide, which completely blocked inflammatory cell recruitment into the airways and distinctly reduced goblet cell proliferation. 9 …”