Fenretinide attenuates lipopolysaccharide (LPS)-induced blood-brain barrier (BBB) and depressive-like behavior in mice by targeting Nrf-2 signaling

Li, Ting; Zheng, Lemin; Han, Xiuhua

doi:10.1016/j.biopha.2019.109680

Cited by 44 publications

(38 citation statements)

References 63 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Fen does not directly modulate expression of TJPs, as we did not detect changes in TJP mRNA and protein expression in pair-fed Fen-treated mice (Figures 2A-F,S,T). Moreover, in contrast to findings reported by Li et al (Li et al, 2020), who showed that Fen mitigates LPS disruption of TJPs at the blood brain barrier through stimulation of the Nrf2antioxidant pathway, our data show that perseveration of TJP expression in EtOH + Fen-treated mice (Supplementary Figures 2S,T) does not involve modulation of Nrf2 and oxidative stress (Supplemental Figures 3E-G).…”

Section: Fenretinide Preserves Gut Barrier In Alcohol Liver Diseasecontrasting

confidence: 99%

“…Previous studies have demonstrated that Fen can inhibit LPS and TNF-α mediated inflammation (López-Vales et al, 2010), and LPS mediated disruption of TJPs at the blood brain barrier (BBB) though activation of the Nrf2-antioxidant response element signaling pathway and reductions in reactive oxygen species (ROS) and oxidative stress (Li et al, 2020). Moreover, data show that modulation of cellular ROS is involved in the chemopreventive actions of Fen in a number of cancers (Hail et al, 2006;Sheikh et al, 1995).…”

Section: Fenretinide Does Not Alter Tight Junction Protein Expression Through Modulation Of Oxidative Stressmentioning

confidence: 99%

“…Fen inhibits cancer cell proliferation through the induction of reactive oxygen species (ROS) and apoptosis through mechanisms that are incompletely understood [reviewed in (Hail et al, 2006)]. Recently, studies have demonstrated that Fen possesses anti-inflammatory properties (López-Vales et al, 2010;Lachance et al, 2013;Kanagaratham et al, 2014;Lin et al, 2016), marked by inhibition of LPS-induced expression of inflammatory mediators such as IL-1β and TNF-α in mouse models of allergic asthma (Kanagaratham et al, 2014), and LPSdisruption of the blood brain barrier TJP occludin (Li et al, 2020). Moreover, evidence shows that Fen also possesses antidiabetic properties (Preitner et al, 2009) and can mitigate hepatic fatty steatosis in genetic and dietary models of non-alcoholic fatty liver disease (NAFLD) (Preitner et al, 2009;Koh et al, 2012), which shares pathological features of ALD (Sanyal et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Fenretinide Improves Intestinal Barrier Function and Mitigates Alcohol Liver Disease

et al. 2021

View full text Add to dashboard Cite

Alcohol liver disease (ALD) is a major cause of liver-related mortality globally, yet there remains an unmet demand for approved ALD drugs. The pathogenesis of ALD involves perturbations to the intestinal barrier and subsequent translocation of bacterial endotoxin that, acting through toll-like receptor 4 (TLR4), promotes hepatic inflammation and progression of ALD. In the present study we investigated the ability of fenretinide (Fen) [N-(4-hydroxyphenyl) retinamide], a synthetic retinoid with known anti-cancer and anti-inflammatory properties, to modulate intestinal permeability and clinical hallmarks of ALD in a mouse model of chronic ethanol (EtOH) exposure. Our results show that EtOH-treated mice had reductions in mRNA and protein expression of intestinal tight junction proteins, including claudin one and occludin, and increases in intestinal permeability and endotoxemia compared to pair-fed mice. Also, EtOH-treated mice had marked increases in hepatic steatosis, liver injury, and expression of pro-inflammatory mediators, including TNF-α, and TLR4-positive macrophages, Kupffer cells, and hepatocytes in the intestines and liver, respectively. In contrast, EtOH + Fen-treated mice were resistant to the effects of EtOH on promoting intestinal permeability and had higher intestinal protein levels of claudin one and occludin. Also, EtOH + Fen-treated mice had significantly lower plasma levels of endotoxin, and reductions in expression of TNF-α and TLR4 positive macrophages, Kupffer cells, and hepatocytes in the intestine and liver. Lastly, we found that EtOH + Fen-treated mice exhibited major reductions in hepatic triglycerides, steatosis, and liver injury compared to EtOH-treated mice. Our findings are the first to demonstrate that Fen possesses anti-ALD properties, potentially through modulation of the intestinal barrier function, endotoxemia, and TLR4-mediated inflammation. These data warrant further pre-clinical investigations of Fen as a potential anti-ALD drug.

show abstract

Section: Fenretinide Preserves Gut Barrier In Alcohol Liver Diseasecontrasting

confidence: 99%

Section: Fenretinide Does Not Alter Tight Junction Protein Expression Through Modulation Of Oxidative Stressmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Fenretinide Improves Intestinal Barrier Function and Mitigates Alcohol Liver Disease

et al. 2021

View full text Add to dashboard Cite

show abstract

“…In LPS-exposed mouse brain microvascular endothelial cells (bEnd.3 cells), fenretinide showed inhibitory effects on the release of pro-inflammatory cytokines (IL-1β, MCP1, iNOS, and TNF-α). Fenretinide may inhibit NF-κB signaling by reducing its nuclear translocation via downregulation of IKKβ and IκBα phosphorylation [26]. This hampers the secretion of inflammatory modulators that is closely associated with the activation of NF-κB signaling.…”

Section: Anti-inflammatory Activity Of Fenretinidementioning

confidence: 99%

“…The combinations of thalidomide or lenalidomide with fenretinide are expected to be very effective due to the multiplicity of mechanisms involved in the anti-inflammatory activity of both types of drugs. Particularly, the decrease of TNF-α [25,26] and the antiangiogenic effect [97,98] provided by fenretinide, added to the same effects provided by thalidomide and lenalidomide, should boost the anti-inflammatory response elicited by the combination. Fenretinide and lenalidomide were evaluated, by intravenous administration, in a mouse model of neuroblastoma.…”

Section: Possible Fenretinide Combinations With Drugs Currently Used In Covid-19mentioning

confidence: 99%

Pulmonary Delivery of Fenretinide: A Possible Adjuvant Treatment in COVID-19

Orienti

Gentilomi

Farruggia

2020

IJMS

View full text Add to dashboard Cite

At present, there is no vaccine or effective standard treatment for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection (or coronavirus disease-19 (COVID-19)), which frequently leads to lethal pulmonary inflammatory responses. COVID-19 pathology is characterized by extreme inflammation and amplified immune response with activation of a cytokine storm. A subsequent progression to acute lung injury (ALI) or acute respiratory distress syndrome (ARDS) can take place, which is often followed by death. The causes of these strong inflammatory responses in SARS-CoV-2 infection are still unknown. As uncontrolled pulmonary inflammation is likely the main cause of death in SARS-CoV-2 infection, anti-inflammatory therapeutic interventions are particularly important. Fenretinide N-(4-hydroxyphenyl) retinamide is a bioactive molecule characterized by poly-pharmacological properties and a low toxicity profile. Fenretinide is endowed with antitumor, anti-inflammatory, antiviral, and immunomodulating properties other than efficacy in obesity/diabetic pathologies. Its anti-inflammatory and antiviral activities, in particular, could likely have utility in multimodal therapies for the treatment of ALI/ARDS in COVID-19 patients. Moreover, fenretinide administration by pulmonary delivery systems could further increase its therapeutic value by carrying high drug concentrations to the lungs and triggering a rapid onset of activity. This is particularly important in SARS-CoV-2 infection, where only a narrow time window exists for therapeutic intervention.

show abstract

Raspberry Ketone Prevents LPS‐Induced Depression‐Like Behaviors in Mice by Inhibiting TLR‐4/NF‐κB Signaling Pathway via the Gut‐Brain Axis

Liu,

Dai,

Wang

et al. 2024

Molecular Nutrition Food Res

View full text Add to dashboard Cite

ScopeDepression, a prevalent mental disorder, has significantly impacted the lives of 350 million people, yet it holds promise for amelioration through food‐derived phenolics. Raspberries, renowned globally for their delectable flavor, harbor a phenolic compound known as raspberry ketone (RK). However, the impact of RK on depressive symptoms remains ambiguous. This study aims to investigate the impact of RK on lipopolysaccharide (LPS)‐induced depressed mice and elucidates its potential mechanisms, focusing on the gut‐brain axis.Methods and resultsThrough behavioral tests, RK exerts a notable preventive effect on LPS‐induced depression‐like behaviors in mice. RK proves capable of attenuating gut inflammation, repairing gut barrier impairment, modulating the composition of the gut microbiome (Muribaculaceae, Streptococcus, Lachnospiraceae, and Akkermansia), and promoting the production of short‐chain fatty acids. Furthermore, RK alleviates neuroinflammation by suppressing the TLR‐4/NF‐κB pathway and bolsters synaptic function by elevating levels of neurotrophic factors and synapse‐associated proteins.ConclusionThe current study provides compelling evidence that RK effectively inhibits the TLR‐4/NF‐κB pathway via the gut‐brain axis, leading to the improvement of LPS‐induced depression‐like behaviors in mice. This study addresses the research gap in understanding the antidepressant effects of RK and illuminates the potential of utilizing RK as a functional food for preventing depression.

show abstract

Fenretinide attenuates lipopolysaccharide (LPS)-induced blood-brain barrier (BBB) and depressive-like behavior in mice by targeting Nrf-2 signaling

Cited by 44 publications

References 63 publications

Fenretinide Improves Intestinal Barrier Function and Mitigates Alcohol Liver Disease

Fenretinide Improves Intestinal Barrier Function and Mitigates Alcohol Liver Disease

Pulmonary Delivery of Fenretinide: A Possible Adjuvant Treatment in COVID-19

Raspberry Ketone Prevents LPS‐Induced Depression‐Like Behaviors in Mice by Inhibiting TLR‐4/NF‐κB Signaling Pathway via the Gut‐Brain Axis

Contact Info

Product

Resources

About