scholarly journals Deletion of Thioredoxin-Interacting Protein (TXNIP) Abrogates High Fat Diet-Induced Retinal Leukostasis, Barrier Dysfunction and Microvascular Degeneration in a Mouse Obesity Model

2020 ◽  
Vol 21 (11) ◽  
pp. 3983 ◽  
Author(s):  
Islam N. Mohamed ◽  
Nader Sheibani ◽  
Azza B. El-Remessy
Keyword(s):  
Adhesion Molecules ◽  
Nlrp3 Inflammasome ◽  
High Fat Diet ◽  
Receptor Protein ◽  
Inflammasome Activation ◽  
High Fat ◽  
Barrier Dysfunction ◽  
Interacting Protein ◽  
Thioredoxin Interacting Protein ◽  
The Impact

We have shown that a high fat diet (HFD) induces the activation of retinal NOD-like receptor protein (NLRP3)-inflammasome that is associated with enhanced expression and interaction with thioredoxin-interacting protein (TXNIP). Here, the specific contribution of TXNIP and the impact of HFD on retinal leukostasis, barrier dysfunction and microvascular degeneration were investigated. Wild-type (WT) and TXNIP knockout (TKO) mice were fed with normal diet or 60% HFD for 8–18 weeks. TXNIP was overexpressed or silenced in human retinal endothelial cells (REC). At 8 weeks, HFD significantly induced retinal leukostasis and breakdown of the blood–retina barrier in WT mice, but not in TKO mice. In parallel, HFD also induced retinal expression of adhesion molecules and cleaved IL-1β in WT mice, which were also abrogated in TKO mice. In culture, TXNIP overexpression induced NLRP3, IL-1β, and adhesion molecules expression, while TXNIP silencing inhibited them. Blocking the IL-1β receptor significantly suppressed TXNIP-induced expression of NLRP3-inflammasome and adhesion molecules in HREC. Ex-vivo assay showed that leukocytes isolated from WT-HFD, but not from TKO-HFD, induced leukostasis and cell death. At 18 weeks, HFD triggered development of degenerated (acellular) capillaries and decreased branching density in WT but not in TKO mice. Together, HFD-induced obesity triggered early retinal leukostasis and microvascular dysfunction at least in part via TXNIP-NLRP3-inflammasome activation.

scholarly journals Hydrogen sulfide mitigates myocardial inflammation by inhibiting nucleotide-binding oligomerization domain-like receptor protein 3 inflammasome activation in diabetic rats

2020 ◽  
Vol 245 (3) ◽  
pp. 221-230 ◽  
Author(s):  
Qiang Jia ◽  
Shomaila Mehmood ◽  
Xiaofen Liu ◽  
Shanfeng Ma ◽  
Rui Yang
Keyword(s):  
Hydrogen Sulfide ◽  
Nlrp3 Inflammasome ◽  
Fasting Blood Glucose ◽  
Nucleotide Binding ◽  
Receptor Protein ◽  
Inflammasome Activation ◽  
Interacting Protein ◽  
Sodium Hydrosulfide ◽  
Thioredoxin Interacting Protein ◽  
Oligomerization Domain

Inflammation plays a crucial part in hyperglycemia-induced myocardial damage. Hydrogen sulfide has been found to possess multiple biological activities in previous studies. This study investigated whether hydrogen sulfide conferred cardiac protection against damage in a diabetic rat model by inhibiting nucleotide-binding oligomerization domain-like receptor protein (NLRP) 3 inflammasome activation. Male animals were assigned to control, streptozotocin, streptozotocin + sodium hydrosulfide, and streptozotocin + DL-propargylglycine groups. Animals in the three streptozotocin groups were administrated 55 mg/kg streptozotocin by intraperitoneal injection. Streptozotocin + sodium hydrosulfide and streptozotocin + propargylglycine groups were treated with sodium hydrosulfide (56 μmol/kg) and propargylglycine (40 mg/kg), respectively, for four weeks. Estimation of fasting blood glucose, heart-weight/body-weight, cardiac function, and histopathological analysis, and measurement of myocardial enzymes were done to evaluate the degree of cardiac injury. In order to investigate the redox changes, the levels of total antioxidant capacity, malondialdehyde and lipid peroxidation, and the activities of superoxide dismutase, catalase, and glutathione peroxidase were assessed; the protein expression levels of Thioredoxin and Thioredoxin-interacting protein were measured in myocardial tissue. In addition, inflammatory reactions were assessed by measuring the concentration levels of interleukin-6, tumor necrosis factor-α, interleukin-1β, and interleukin-18 in serum and the expression levels of NLRP3 inflammasome complex-associated proteins in cardiac tissue. In the heart, hyperglycemia significantly induced cardiac dysfunction and injury, redox perturbation, and aggravation of inflammatory reactions. However, except for fasting blood glucose, treatment with sodium hydrosulfide significantly ameliorated these alterations, whereas treatment with propargylglycine further aggravated these alterations. This study highlights the protective properties of hydrogen sulfide against hyperglycemia-induced cardiac injury, and its possible mechanism was shown to involve negative regulation of Thioredoxin-interacting protein-mediated NLRP3 inflammasome activation. Impact statement Diabetic cardiomyopathy is a serious complication of diabetic patients, accompanied by chronic inflammation. The nucleotide-binding oligomerization domain-like receptor protein (NLRP) 3 inflammasome complex is involved in the progression of the inflammatory response of diabetes, including diabetic cardiomyopathy. Hydrogen sulfide (H2S) is a novel endogenous gas messenger. Several pieces of evidence have exhibited that H2S exerts anti-oxidant and anti-inflammatory activities against hyperglycemia-induced myocardial injury, but the mechanism remains unclear. The current study indicated that H2S protected the myocardium against hyperglycemia-induced injury by preventing Thioredoxin-interacting protein (TXNIP)-mediated NLRP3 inflammasome complex activation. The inhibition of TXNIP-mediated NLRP3 inflammasome complex would be an efficient therapy for H2S treatment in diabetic cardiomyocytes.

scholarly journals Sex modulates hepatic mitochondrial adaptations to high-fat diet and physical activity

2019 ◽  
Vol 317 (2) ◽  
pp. E298-E311 ◽  
Author(s):  
Colin S. McCoin ◽  
Alex Von Schulze ◽  
Julie Allen ◽  
Kelly N. Z. Fuller ◽  
Qing Xia ◽  
...  
Keyword(s):  
Physical Activity ◽  
High Fat Diet ◽  
Wheel Running ◽  
Transcriptional Coactivator ◽  
High Fat ◽  
Respiratory Capacity ◽  
Interacting Protein ◽  
Low Fat Diet ◽  
The Impact ◽  
Mitochondrial Adaptations

The impact of sexual dimorphism and mitophagy on hepatic mitochondrial adaptations during the treatment of steatosis with physical activity are largely unknown. Here, we tested if deficiencies in liver-specific peroxisome proliferative activated-receptor-γ coactivator-1α (PGC-1α), a transcriptional coactivator of biogenesis, and BCL-2/ADENOVIRUS EIB 19-kDa interacting protein (BNIP3), a mitophagy regulator, would impact hepatic mitochondrial adaptations (respiratory capacity, H2O2production, mitophagy) to a high-fat diet (HFD) and HFD plus physical activity via voluntary wheel running (VWR) in both sexes. Male and female wild-type (WT), liver-specific PGC-1α heterozygote (LPGC-1α), and BNIP3 null mice were thermoneutral housed (29–31°C) and divided into three groups: sedentary-low-fat diet (LFD), 16 wk of (HFD), or 16 wk of HFD with VWR for the final 8 wk (HFD + VWR) ( n = 5–7/sex/group). HFD did not impair mitochondrial respiratory capacity or coupling in any group; however, HFD + VWR significantly increased maximal respiratory capacity only in WT and PGC-1α females. Males required VWR to elicit mitochondrial adaptations that were inherently present in sedentary females including greater mitochondrial coupling control and reduced H2O2production. Females had overall reduced markers of mitophagy, steatosis, and liver damage. Steatosis and markers of liver injury were present in sedentary male mice on the HFD and were effectively reduced with VWR despite no resolution of steatosis. Overall, reductions in PGC-1α and loss of BNIP3 only modestly impacted mitochondrial adaptations to HFD and HFD + VWR with the biggest effect seen in BNIP3 females. In conclusion, hepatic mitochondrial adaptations to HFD and treatment of HFD-induced steatosis with VWR are more dependent on sex than PGC-1α or BNIP3.

The purinergic 2X7receptor participates in renal inflammation and injury induced by high-fat diet: possible role of NLRP3 inflammasome activation

2013 ◽  
Vol 231 (3) ◽  
pp. 342-353 ◽  
Author(s):  
Anna Solini ◽  
Stefano Menini ◽  
Chiara Rossi ◽  
Carlo Ricci ◽  
Eleonora Santini ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
High Fat Diet ◽  
Inflammasome Activation ◽  
High Fat ◽  
Renal Inflammation ◽  
Nlrp3 Inflammasome Activation

scholarly journals The selective NLRP3 inhibitor MCC950 hinders atherosclerosis development by attenuating inflammation and pyroptosis in macrophages

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Wenyun Zeng ◽  
Danbin Wu ◽  
Yingxin Sun ◽  
Yanrong Suo ◽  
Qun Yu ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
High Fat Diet ◽  
In Vitro Study ◽  
Inflammasome Activation ◽  
Mrna Levels ◽  
High Fat ◽  
Nlrp3 Inflammasome Activation ◽  
Atherosclerosis Development

AbstractNLRP3 inflammasome is a vital player in macrophages pyroptosis, which is a type of proinflammatory cell-death and takes part in the pathogenesis of atherosclerosis. In this study, we used apoE−/− mice and ox-LDL induced THP-1 derived macrophages to explore the mechanisms of MCC950, a selective NLRP3 inhibitor in treating atherosclerosis. For the in vivo study, MCC950 was intraperitoneal injected to 8-week-old apoE−/− mice fed with high-fat diet for 12 weeks. For the in vitro study, THP-1 derived macrophages were treated with ox-LDL and MCC950 for 48 h. MCC950 administration reduced plaque areas and macrophages contents, but did not improve the serum lipid profiles in aortic root of apoE−/− mice. MCC950 inhibited the activation of NLRP3/ASC/Caspase-1/GSDMD-N axis, and alleviated macrophages pyroptosis and the production of IL-1β and IL-18 both in aorta and in cell lysates. However, MCC950 did not affect the expression of TLR4 or the mRNA levels of NLRP3 inflammasome and its downstream proteins, suggesting that MCC950 had no effects on the priming of NLRP3 inflammasome activation in macrophages. The anti-atherosclerotic mechanisms of MCC950 on attenuating macrophages inflammation and pyroptosis involved in inhibiting the assembly and activation of NLRP3 inflammasome, rather than interrupting its priming.

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