BBG enhances OLT1177-induced NLRP3 inflammasome inactivation by targeting P2X7R/NLRP3 and MyD88/NF-κB signaling in DSS-induced colitis in rats

Saber, Sameh; Youssef, Mahmoud E.; Sharaf, Hossam; Amin, Noha A.; El-Shedody, Ruwyda; Aboutouk, Farah H.; El-Galeel, Yumna Abd; El-Hefnawy, Amr; Shabaka, Dina; Khalifa, Arwa; Saleh, Renad; Osama, Donya; El-Zoghby, Ghada; Gobba, Naglaa A.

doi:10.1016/j.lfs.2021.119123

Cited by 42 publications

(22 citation statements)

References 61 publications

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“…This was previously shown in type I model of diabetes induced by STZ in mice, where IL-6 knock out lessened the progress of diabetic cardiomyopathy and enhanced cardiac function (Zhang et al 2016). Moreover, NF-κB activation increased the release of ROS (Saber et al 2021), which could be due to the increased activity of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (Mariappan et al 2010). Pyrrolidine dithiocarbamate derived inhibition of NF-κB restored cardiac function in diabetic animals and improved the mitochondrial structural integrity and prevented oxidative stress (Mariappan et al 2010).…”

Section: Discussionmentioning

confidence: 99%

Electrocardiographic and histopathological characterizations of diabetic cardiomyopathy in rats

Youssef

El-Azab

Abdel-Dayem

et al. 2021

Environ Sci Pollut Res

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Diabetes is a clinical condition that is associated with insulin de ciency and hyperglycemia.Cardiomyopathy, retinopathy, neuropathy, and nephropathy are well known complications of the elevated blood glucose. Diabetic cardiomyopathy is a clinical disorder that is associated with systolic and diastolic dysfunction along with cardiac brosis, in ammation, and elevated oxidative stress. In this study, diabetes was induced by intraperitoneal injection of streptozotocin (STZ) 50 mg/kg. We determined the plasma levels of cardiac troponin-T (cTnT), and creatinine kinase MB (CK-MB) by ELISA.Diabetic rats showed abnormal cardiac architecture and increased collagen production. signi cant elevation in ST-segment, prolonged QRS and QT-intervals, and increased ventricular rate were detected. Additionally, diabetic rats showed a prolongation in P wave duration and atrial tachyarrhythmia was observed. Plasma levels of cTnT and CK-MB were elevated. In conclusion, these electrocardiographic changes (elevated ST-segment, prolonged QT interval, and QRS complex, and increased heart rate) along with histopathological changes and increased collagen formation could be markers for the development of diabetic cardiomyopathy in rats.

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Section: Discussionmentioning

confidence: 99%

Electrocardiographic and histopathological characterizations of diabetic cardiomyopathy in rats

Youssef

El-Azab

Abdel-Dayem

et al. 2021

Environ Sci Pollut Res

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“…Inflammasomes are multiprotein complexes that are directly involved in the inflammation process by the excessive activation of caspase-1, interleukin 1β (IL-1β), and interleukin 18 (IL-18) ( Zheng et al, 2020 ; Saber et al, 2021a ; Saber et al, 2021b ; El-Rous et al, 2021 ). Five candidates of the pattern recognition receptor (PRR) participate in the inflammasome formation.…”

Section: Introductionmentioning

confidence: 99%

“…These members are nucleotide-binding oligomerization domain (NOD), absent-in-melanoma 2 (AIM2), pyrin, leucine-rich repeat (LRR)-containing proteins (NLR) family (NLRP1, NLRP3) in addition to other reported PRRs including NLRP2, NLRP6, NLRP7, and NLRP12 ( Kelley et al, 2019 ). Several inflammatory conditions are associated with NLRP3 inflammasome assembly and activation, including gout ( Wang et al, 2019 ), hepatitis ( Neumann et al, 2018 ), and ulcerative colitis ( Saber et al, 2021a ). It is believed that there is a crosstalk between AMPK, mTOR, and NLRP3 inflammasome signaling.…”

Section: Introductionmentioning

confidence: 99%

Interference With the AMPKα/mTOR/NLRP3 Signaling and the IL-23/IL-17 Axis Effectively Protects Against the Dextran Sulfate Sodium Intoxication in Rats: A New Paradigm in Empagliflozin and Metformin Reprofiling for the Management of Ulcerative Colitis

et al. 2021

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Empagliflozin and metformin are widely used for the treatment of type 2 diabetes. These drugs showed marked anti-inflammatory effects in different animal models via enhancing AMPK activity. Yet, the protective anti-inflammatory effects of their combination against ulcerative colitis have not been previously investigated. The current study aimed to explore the potential of empagliflozin/metformin combination to mitigate the DSS-induced rat colitis model. The modulating effects of empagliflozin and metformin on the AMPK/mTOR/NLRP3 axis and T cell polarization were delineated. In this study, distal colons were examined for macroscopic and microscopic pathological alterations. ELISA, qRT-PCR, and immunohistochemistry techniques were applied to detect proteins and cytokines involved in AMPK/mTOR/NLRP3 axis and T Cell polarization. Oral administration of empagliflozin (10 mg/kg/day) and metformin (200 mg/kg/day) combination alleviated colitis as revealed by the reduced disease activity index, macroscopic damage index, colon weight/length ratio, and histopathologic scoring values. Interestingly, empagliflozin/metformin combination significantly enhanced AMPK phosphorylation and depressed mTOR and NLRP3 expression leading to a subsequent reduction in caspase-1 cleavage and inhibition of several inflammatory cytokines, including IL-1β, and IL-18. Reduced mTOR expression and reduced IL-6 levels led to a reduction in Th17 cell polarization and maintenance. Together, the current study reveals that the protective effects of empagliflozin and metformin against DSS-induced colitis are fundamentally mediated via enhancing AMPK phosphorylation. Since adult humans with diabetes mellitus are at greater risk for developing inflammatory bowel diseases, clinical application of empagliflozin/metformin combination represents a novel therapeutic approach for treating diabetic patients with ulcerative colitis.

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“…Recent studies showed that new mode of administration can also promote the efficacy of NLRP3 inflammasome inhibitors. The combined administration of BBG (a P2X7R blocker) and OLT1177 (a selective NLRP3 inhibitor) effectively alleviates UC by complementary effects ( 73 ). The effect of NLRP3 inflammasome inhibitors in IBD has not been comprehensively understood, which deserves further study.…”

Section: Nlrp3 Inflammasome In Autoimmune Diseasesmentioning

confidence: 99%

NLRP3 Inflammasome: Checkpoint Connecting Innate and Adaptive Immunity in Autoimmune Diseases

Zhang

Yang

et al. 2021

Front. Immunol.

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Autoimmune diseases are a broad spectrum of human diseases that are characterized by the breakdown of immune tolerance and the production of autoantibodies. Recently, dysfunction of innate and adaptive immunity is considered to be a key step in the initiation and maintenance of autoimmune diseases. NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome is a multimeric protein complex, which can detect exogenous pathogen irritants and endogenous danger signals. The main function of NLRP3 inflammasome is to promote secretion of interleukin (IL)-1β and IL-18, and pyroptosis mediated by caspase-1. Served as a checkpoint in innate and adaptive immunity, aberrant activation and regulation of NLRP3 inflammasome plays an important role in the pathogenesis of autoimmune diseases. This paper reviewed the roles of NLRP3 inflammasome in autoimmune diseases, which shows NLRP3 inflammasome may be a potential target for autoimmune diseases deserved further study.

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BBG enhances OLT1177-induced NLRP3 inflammasome inactivation by targeting P2X7R/NLRP3 and MyD88/NF-κB signaling in DSS-induced colitis in rats

Cited by 42 publications

References 61 publications

Electrocardiographic and histopathological characterizations of diabetic cardiomyopathy in rats

Electrocardiographic and histopathological characterizations of diabetic cardiomyopathy in rats

Interference With the AMPKα/mTOR/NLRP3 Signaling and the IL-23/IL-17 Axis Effectively Protects Against the Dextran Sulfate Sodium Intoxication in Rats: A New Paradigm in Empagliflozin and Metformin Reprofiling for the Management of Ulcerative Colitis

NLRP3 Inflammasome: Checkpoint Connecting Innate and Adaptive Immunity in Autoimmune Diseases

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