Amelioration of amyloid β-induced retinal inflammatory responses by a LXR agonist TO901317 is associated with inhibition of the NF-κB signaling and NLRP3 inflammasome

Lei, Chunyan; Lin, Rong; Wang, Jiaming; Tao, Lifei; Fu, Xinyu; Qiu, Yiguo; Lei, Bo

doi:10.1016/j.neuroscience.2017.07.053

Cited by 51 publications

(48 citation statements)

References 55 publications

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“…To date, several activating LXR ligands have been reported to modulate lipid metabolism and inflammatory pathways in different injury models, including the eye. Activating LXR with GW3965 has been shown to provide a protective effect in experimental diabetic retinopathy and an inner retinal damage mouse model (56,64), and the LXR agonist TO901317 has been shown to ameliorate amyloid β-induced inflammatory responses in human RPE cells as well as the neural retina (65,66). It is important to note, however, that LXR ligands are not without side effects, most notably temporary hypertriglyceridemia.…”

Section: Discussionmentioning

confidence: 99%

LXRs regulate features of age-related macular degeneration and may be a potential therapeutic target

et al. 2020

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Section: Discussionmentioning

confidence: 99%

LXRs regulate features of age-related macular degeneration and may be a potential therapeutic target

et al. 2020

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“…Additionally, NLRP3 can be activated by various exogenous and endogenous activators such as uric acid, silica, bacteria and toxins [44][45]. Activated NLRP3 inflammasome induces the release of active caspase-1 from its precursor (procaspase-1), which in turn stimulates the release of mature IL-1β and IL-18 from its proform [46,47]. IL-1β is a key inflammatory cytokine produced mainly by activated macrophages.…”

Section: Discussionmentioning

confidence: 99%

Anti-Inflammatory Effects of Vardenafil Against Cholestatic Liver Damage in Mice: a Mechanistic Study

El‐Agamy

Almaramhy

Ahmed

et al. 2018

Cell Physiol Biochem

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Background/Aims: Phosphodiesterase-5 inhibitors have beneficial effects in multiple liver diseases possibly through the reduction of oxidative stress and inflammatory response. However, these effects have not yet been examined in cholestatic liver dysfunction. Hence, this study aimed to explore the ability of vardenafil, a known phosphodiesterase-5 inhibitor, to repress lithocholic acid (LCA)-induced cholestatic liver injury and investigate the possible molecular pathways. Methods: Male Swiss albino mice were treated with LCA (0.125 mg/g) twice daily for 7 days to induce cholestatic liver damage. Vardenafil was administered 3 days before and throughout the administration of LCA. Serum markers of hepatotoxicity and hepatic nitro-oxidative stress along with antioxidant parameters were measured, and the histopathology of liver tissues was assessed. The expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and its target genes was examined using PCR. The activation of nuclear factor kappa-B (NF-κB) and the levels of inflammatory cytokines were determined. NLRP3 inflammasome and its components were studied by PCR and western blot. Results: LCA induced marked cholestatic liver damage as demonstrated by increased serum transaminases, alkaline phosphatase (ALP), lactate dehydrogenase (LDH), bilirubin, and bile acids. Examination of liver specimens confirmed the biochemical results. Nitro-oxidative stress parameters were significantly elevated along with reduced antioxidant capacity in hepatic tissue following LCA administration. LCA suppressed Nrf2 and its target genes and decreased the mRNA expression and binding capacity of Nrf2 as well as the mRNA expression of GCLm, GCLc, Nqo1, and HO-1. Additionally, LCA enhanced the activation of NF-κB, which was accompanied by elevations of inflammatory cytokines. Importantly, LCA induced the activation of NLRP3 inflammasome. LCA increased the expression of NLRP3, ASC, caspase-1, and IL-1β genes and proteins in hepatic tissue. The activities of IL-1β and caspase-1 were increased in the LCA group. Interestingly, vardenafil ameliorated LCA-induced hepatic injury and alleviated all biochemical, histopathological, and inflammatory parameters. Conclusions: These data elucidated the effects of Nrf2 inhibition and NLRP3 inflammasome activation in LCA-induced liver injury. The hepatoprotective activity of vardenafil in LCA-induced cholestatic damage may result from the drug’s ability to activate Nrf2 signaling and prevent the activation of NLRP3, which could suppress the inflammatory responses in hepatic tissue. Thus, vardenafil can be considered a novel anti-inflammatory remedy for cholestatic liver damage.

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“…The genetic background is known to influence susceptibility to diabetes development, insulin resistance, and the efficacy of glucose-lowering drugs [17]. Accumulated evidence suggests that ABCA1 contributes to secreting insulin in pancreatic β-cells and amyloid beta for- mation [18][19][20]. Changes in ABCA1 function can affect the cholesterol metabolism of the islets, because cholesterol deposition and amyloid formation in the islets reduce the function of β-cells, and then increase the risk of T2DM [21][22][23].…”

Section: Discussionmentioning

confidence: 99%

ABCA1 Variants rs1800977 (C69T) and rs9282541 (R230C) Are Associated with Susceptibility to Type 2 Diabetes

Wang

et al. 2020

Public Health Genomics

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Objective: Accumulated evidence suggests that ATP-binding cassette A1 transporter (ABCA1) contributes to secreting insulin in pancreatic β-cells and amyloid beta formation. This study aimed to investigate the association between three single nucleotide polymorphisms (SNPs) of ABCA1 and susceptibility to type 2 diabetes mellitus (T2DM) in a Han Chinese population. Methods: A total of 996 T2DM patients and 1,002 controls were included in the study. Three SNPs in the ABCA1 gene, i.e., rs2230806 (R219K), rs1800977 (C69T), and rs9282541 (R230C), were genotyped by SNaPshot. A genotype model, an allele model, a dominant model, and a recessive model were used to assess susceptibility to T2DM. Results: There were significant associations between rs1800977 and T2DM in different genetic models (TT vs. CC, OR = 0.591 [0.446-0.793], p < 0.001; T vs. C, OR = 0.835 [0.735-0.949], p = 0.006; recessive model, OR = 0.583 [0.449-0.756], p < 0.001). There were also significant associations between rs9282541 and T2DM in different genetic models (CT vs. CC, OR = 1.690 [0.807-1.005], p = 0.048; T vs. C, OR = 1.756 [0.694-1.060], p = 0.029; dominant model, OR = 1.735 [0.715-1.034], p = 0.037). Conclusion: Our case-control study showed that the two SNPs rs1800977 and rs9282541 in the ABCA1 gene are significantly associated with susceptibility to T2DM in our Han Chinese population. Study of further mechanisms should be performed before application to clinical therapy.

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Amelioration of amyloid β-induced retinal inflammatory responses by a LXR agonist TO901317 is associated with inhibition of the NF-κB signaling and NLRP3 inflammasome

Cited by 51 publications

References 55 publications

LXRs regulate features of age-related macular degeneration and may be a potential therapeutic target

LXRs regulate features of age-related macular degeneration and may be a potential therapeutic target

Anti-Inflammatory Effects of Vardenafil Against Cholestatic Liver Damage in Mice: a Mechanistic Study

ABCA1 Variants rs1800977 (C69T) and rs9282541 (R230C) Are Associated with Susceptibility to Type 2 Diabetes

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