scholarly journals Metformin Corrects Glucose Metabolism Reprogramming and NLRP3 Inflammasome-Induced Pyroptosis via Inhibiting the TLR4/NF-κB/PFKFB3 Signaling in Trophoblasts: Implication for a Potential Therapy of Preeclampsia

2021 ◽  
Vol 2021 ◽  
pp. 1-22
Author(s):  
Yang Zhang ◽  
Weifang Liu ◽  
Yanqi Zhong ◽  
Qi Li ◽  
Mengying Wu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Nlrp3 Inflammasome ◽  
Low Dose ◽  
Therapeutic Potential ◽  
Metabolic Phenotypes ◽  
Pyrin Domain ◽  
Underlying Mechanisms ◽  
And Oxidative Stress ◽  
Receptor Family

NOD-like receptor family, pyrin domain-containing protein 3 (NLRP3) inflammasome-mediated pyroptosis is a crucial event in the preeclamptic pathogenesis, tightly linked with the uteroplacental TLR4/NF-κB signaling. Trophoblastic glycometabolism reprogramming has now been noticed in the preeclampsia pathogenesis, plausibly modulated by the TLR4/NF-κB signaling as well. Intriguingly, cellular pyroptosis and metabolic phenotypes may be inextricably linked and interacted. Metformin (MET), a widely accepted NF-κB signaling inhibitor, may have therapeutic potential in preeclampsia while the underlying mechanisms remain unclear. Herein, we investigated the role of MET on trophoblastic pyroptosis and its relevant metabolism reprogramming. The safety of pharmacologic MET concentration to trophoblasts was verified at first, which had no adverse effects on trophoblastic viability. Pharmacological MET concentration suppressed NLRP3 inflammasome-induced pyroptosis partly through inhibiting the TLR4/NF-κB signaling in preeclamptic trophoblast models induced via low-dose lipopolysaccharide. Besides, MET corrected the glycometabolic reprogramming and oxidative stress partly via suppressing the TLR4/NF-κB signaling and blocking transcription factor NF-κB1 binding on the promoter PFKFB3, a potent glycolytic accelerator. Furthermore, PFKFB3 can also enhance the NF-κB signaling, reduce NLRP3 ubiquitination, and aggravate pyroptosis. However, MET suppressed pyroptosis partly via inhibiting PFKFB3 as well. These results provided that the TLR4/NF-κB/PFKFB3 pathway may be a novel link between metabolism reprogramming and NLRP3 inflammasome-induced pyroptosis in trophoblasts. Further, MET alleviates the NLRP3 inflammasome-induced pyroptosis, which partly relies on the regulation of TLR4/NF-κB/PFKFB3-dependent glycometabolism reprogramming and redox disorders. Hence, our results provide novel insights into the pathogenesis of preeclampsia and propose MET as a potential therapy.

scholarly journals The NLRP3 Inflammasome as a Critical Actor in the Inflammaging Process

Cells ◽  
2020 ◽  
Vol 9 (6) ◽  
pp. 1552
Author(s):  
Maria Sebastian-Valverde ◽  
Giulio M. Pasinetti
Keyword(s):  
Nlrp3 Inflammasome ◽  
Low Grade ◽  
Cellular Mechanisms ◽  
Pyrin Domain ◽  
Human Lifespan ◽  
Age Related ◽  
Inflammatory State ◽  
Chronic Activation ◽  
Receptor Family

As a consequence of the considerable increase in the human lifespan over the last century, we are experiencing the appearance and impact of new age-related diseases. The causal relationships between aging and an enhanced susceptibility of suffering from a broad spectrum of diseases need to be better understood. However, one specific shared feature seems to be of capital relevance for most of these conditions: the low-grade chronic inflammatory state inherently associated with aging, i.e., inflammaging. Here, we review the molecular and cellular mechanisms that link aging and inflammaging, focusing on the role of the innate immunity and more concretely on the nucleotide-binding oligomerization domain (NOD)-like receptor family pyrin domain containing 3 (NLRP3) inflammasome, as well as how the chronic activation of this inflammasome has a detrimental effect on different age-related disorders.

scholarly journals NUPR1: A Critical Regulator of the Antioxidant System

Cancers ◽  
2021 ◽  
Vol 13 (15) ◽  
pp. 3670
Author(s):  
Can Huang ◽  
Patricia Santofimia-Castaño ◽  
Juan Iovanna
Keyword(s):  
Oxidative Stress ◽  
Antioxidant System ◽  
Mitochondrial Function ◽  
Therapeutic Potential ◽  
Current Knowledge ◽  
Redox Homeostasis ◽  
Antioxidant Genes ◽  
Intrinsically Disordered ◽  
And Oxidative Stress

Nuclear protein 1 (NUPR1) is a small intrinsically disordered protein (IDP) activated in response to various types of cellular stress, including endoplasmic reticulum (ER) stress and oxidative stress. Reactive oxygen species (ROS) are mainly produced during mitochondrial oxidative metabolism, and directly impact redox homeostasis and oxidative stress. Ferroptosis is a ROS-dependent programmed cell death driven by an iron-mediated redox reaction. Substantial evidence supports a maintenance role of the stress-inducible protein NUPR1 on cancer cell metabolism that confers chemotherapeutic resistance by upregulating mitochondrial function-associated genes and various antioxidant genes in cancer cells. NUPR1, identified as an antagonist of ferroptosis, plays an important role in redox reactions. This review summarizes the current knowledge on the mechanism behind the observed impact of NUPR1 on mitochondrial function, energy metabolism, iron metabolism, and the antioxidant system. The therapeutic potential of genetic or pharmacological inhibition of NUPR1 in cancer is also discussed. Understanding the role of NUPR1 in the antioxidant system and the mechanisms behind its regulation of ferroptosis may promote the development of more efficacious strategies for cancer therapy.

scholarly journals Melatonin Attenuates Contrast-Induced Nephropathy in Diabetic Rats: The Role of Interleukin-33 and Oxidative Stress

2016 ◽  
Vol 2016 ◽  
pp. 1-10 ◽  
Author(s):  
Didem Onk ◽  
Oruc Alper Onk ◽  
Kultigin Turkmen ◽  
Huseyin Serkan Erol ◽  
Tulin Akarsu Ayazoglu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Therapeutic Potential ◽  
Kidney Tissue ◽  
Diabetic Rats ◽  
Sprague Dawley ◽  
Contrast Induced Nephropathy ◽  
Interleukin 33 ◽  
Sprague Dawley Rats ◽  
And Oxidative Stress

Background.Inflammation and oxidative stress (OxS) contribute to the pathogenesis of diabetic kidney disease (DKD) and contrast-induced nephropathy (CIN). Patients with DKD were found to be more prone to CIN. Interleukin-33 (IL-33) is a proinflammatory cytokine, but its role in DKD and CIN is unknown.Methods.Thirty male Sprague-Dawley rats were enrolled. The first group was comprised of healthy rats (HRs), whereas the other four groups were made up of diabetic rats (DRs), diabetic rats with contrast-induced nephropathy (CIN + DRs), melatonin-treated diabetic rats (MTDRs), and melatonin-treated CIN + DRs (MTCIN + DRs). All groups except the HRs received 50 mg/kg/day streptozotocin (STZ). CIN + DRs were constituted by administrating 1.5 mg/kg of intravenous radiocontrast dye on the 35th day. MTDRs and MTCIN + DRs were given 20 mg/kg/day of intraperitoneal injection of melatonin (MT) from the 28th day for the constitutive seven days.Results.We observed increased IL-33 in the kidney tissue following induction of CIN in DRs. To determine whether MT is effective in preventing CIN, we administered MT in CIN + DRs and demonstrated that kidney tissue levels of OxS markers, inflammatory cytokines, and IL-33 were significantly diminished in MTCIN + DRs compared with other groups without MT treatment (p<0.05).Conclusion.Inhibition of IL-33 with MT provides therapeutic potential in DKD with CIN.

scholarly journals The Role and Mechanism of Oxidative Stress and Nuclear Receptors in the Development of NAFLD

2021 ◽  
Vol 2021 ◽  
pp. 1-25
Author(s):  
Ting Hong ◽  
Yiyan Chen ◽  
Xiaoying Li ◽  
Yan Lu
Keyword(s):  
Oxidative Stress ◽  
Nuclear Receptors ◽  
Metabolic Stress ◽  
Hepatic Metabolism ◽  
Ros Generation ◽  
Nonalcoholic Fatty Liver ◽  
Oxidation Damage ◽  
Underlying Mechanisms ◽  
And Oxidative Stress

The overproduction of reactive oxygen species (ROS) and consequent oxidative stress contribute to the pathogenesis of acute and chronic liver diseases. It is now acknowledged that nonalcoholic fatty liver disease (NAFLD) is characterized as a redox-centered disease due to the role of ROS in hepatic metabolism. However, the underlying mechanisms accounting for these alternations are not completely understood. Several nuclear receptors (NRs) are dysregulated in NAFLD, and have a direct influence on the expression of a set of genes relating to the progress of hepatic lipid homeostasis and ROS generation. Meanwhile, the NRs act as redox sensors in response to metabolic stress. Therefore, targeting NRs may represent a promising strategy for improving oxidation damage and treating NAFLD. This review summarizes the link between impaired lipid metabolism and oxidative stress and highlights some NRs involved in regulating oxidant/antioxidant turnover in the context of NAFLD, shedding light on potential therapies based on NR-mediated modulation of ROS generation and lipid accumulation.

scholarly journals The Role of the Interplay Between Autophagy and NLRP3 Inflammasome in Metabolic Disorders

2021 ◽  
Vol 9 ◽  
Author(s):  
Shuangyu Lv ◽  
Honggang Wang ◽  
Xiaotian Li
Keyword(s):  
Nlrp3 Inflammasome ◽  
Metabolic Disorders ◽  
Interleukin 1 ◽  
Basic Research ◽  
Interleukin 1 Beta ◽  
Cell Composition ◽  
Pyrin Domain ◽  
Receptor Family ◽  
Oligomerization Domain

Autophagy is an important and conserved cellular pathway in which cells transmit cytoplasmic contents to lysosomes for degradation. It plays an important role in maintaining the balance of cell composition synthesis, decomposition and reuse, and participates in a variety of physiological and pathological processes. The nucleotide-binding oligomerization domain-like receptor family, pyrin domain-containing 3 (NLRP3) inflammasome can induce the maturation and secretion of Interleukin-1 beta (IL-1β) and IL-18 by activating caspase-1. It is involved in many diseases. In recent years, the interplay between autophagy and NLRP3 inflammasome has been reported to contribute to many diseases including metabolic disorders related diseases. In this review, we summarized the recent studies on the interplay between autophagy and NLRP3 inflammasome in metabolic disorders to provide ideas for the relevant basic research in the future.

scholarly journals Endothelial Dysfunction, Inflammation, and Oxidative Stress in COVID-19—Mechanisms and Therapeutic Targets

2021 ◽  
Vol 2021 ◽  
pp. 1-15
Author(s):  
Adriana Fodor ◽  
Brandusa Tiperciuc ◽  
Cezar Login ◽  
Olga H. Orasan ◽  
Andrada L. Lazar ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Respiratory Failure ◽  
Endothelial Dysfunction ◽  
Clinical Manifestations ◽  
Therapeutic Targets ◽  
Lung Damage ◽  
Wide Range ◽  
Underlying Mechanisms ◽  
And Oxidative Stress

The outbreak of the COVID-19 pandemic represents an ongoing healthcare emergency responsible for more than 3.4 million deaths worldwide. COVID-19 is the disease caused by SARS-CoV-2, a virus that targets not only the lungs but also the cardiovascular system. COVID-19 can manifest with a wide range of clinical manifestations, from mild symptoms to severe forms of the disease, characterized by respiratory failure due to severe alveolar damage. Several studies investigated the underlying mechanisms of the severe lung damage associated with SARS-CoV-2 infection and revealed that the respiratory failure associated with COVID-19 is the consequence not only of acute respiratory distress syndrome but also of macro- and microvascular involvement. New observations show that COVID-19 is an endothelial disease, and the consequent endotheliopathy is responsible for inflammation, cytokine storm, oxidative stress, and coagulopathy. In this review, we show the central role of endothelial dysfunction, inflammation, and oxidative stress in the COVID-19 pathogenesis and present the therapeutic targets deriving from this endotheliopathy.

scholarly journals Hydrogen-Rich Saline Inhibits NLRP3 Inflammasome Activation and Attenuates Experimental Acute Pancreatitis in Mice

2014 ◽  
Vol 2014 ◽  
pp. 1-9 ◽  
Author(s):  
Jian-Dong Ren ◽  
Jie Ma ◽  
Jun Hou ◽  
Wen-Jin Xiao ◽  
Wei-Hua Jin ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Acute Pancreatitis ◽  
Nlrp3 Inflammasome ◽  
Therapeutic Potential ◽  
Animal Experiments ◽  
Therapeutic Benefit ◽  
Pancreatic Tissue ◽  
Inflammasome Activation ◽  
Pyrin Domain ◽  
Nlrp3 Inflammasome Activation

Increasing evidence has demonstrated that reactive oxygen species (ROS) induces oxidative stress and plays a crucial role in the pathogenesis of acute pancreatitis (AP). Hydrogen-rich saline (HRS), a well-known ROS scavenger, has been shown to possess therapeutic benefit on AP in many animal experiments. Recent findings have indicated that the NOD-like receptor family, pyrin domain-containing 3 (NLRP3) inflammasome, an intracellular multiprotein complex required for the maturation of interleukin- (IL-) 1β, may probably be a potential target of HRS in the treatment of AP. Therefore, in this study, we evaluated the activation of NLRP3 inflammasome and meanwhile assessed the degree of oxidative stress and inflammatory cascades, as well as the histological alterations in mice suffering from cerulein-induced AP after the treatment of HRS. The results showed that the activation of NLRP3 inflammasome in AP mice was substantially inhibited following the administration of HRS, which was paralleled with the decreased NF-κB activity and cytokines production, attenuated oxidative stress and the amelioration of pancreatic tissue damage. In conclusion, our study has, for the first time, revealed that inhibition of the activation of NLRP3 inflammasome probably contributed to the therapeutic potential of HRS in AP.

NLRP3 inflammasome as a key driver of vascular disease

2021 ◽  
Author(s):  
Masafumi Takahashi
Keyword(s):  
Nlrp3 Inflammasome ◽  
Inflammatory Diseases ◽  
Vascular Diseases ◽  
Diverse Range ◽  
Pyrin Domain ◽  
Current State ◽  
Key Driver ◽  
Receptor Family ◽  
Oligomerization Domain

Abstract Nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3) is an intracellular innate immune receptor that recognizes a diverse range of stimuli derived from pathogens, damaged or dead cells, and irritants. NLRP3 activation causes the assembly of a large multiprotein complex termed the NLRP3 inflammasome, and leads to the secretion of bioactive interleukin (IL)-1β and IL-18 as well as the induction of inflammatory cell death termed pyroptosis. Accumulating evidence indicates that NLRP3 inflammasome plays a key role in the pathogenesis of sterile inflammatory diseases, including atherosclerosis and other vascular diseases. Indeed, the results of the Canakinumab Anti-inflammatory Thrombosis Outcome Study trial demonstrated that IL-1β-mediated inflammation plays an important role in atherothrombotic events and suggested that NLRP3 inflammasome is a key driver of atherosclerosis. In this review, we will summarize the current state of knowledge regarding the role of NLRP3 inflammasome in vascular diseases, in particular in atherosclerosis, vascular injury, aortic aneurysm, and Kawasaki disease vasculitis, and discuss NLRP3 inflammasome as a therapeutic target for these disorders.

scholarly journals The Role of the Effects of Endoplasmic Reticulum Stress on NLRP3 Inflammasome in Diabetes

2021 ◽  
Vol 9 ◽  
Author(s):  
Shuangyu Lv ◽  
Xiaotian Li ◽  
Honggang Wang
Keyword(s):  
Endoplasmic Reticulum ◽  
Protein Synthesis ◽  
Endoplasmic Reticulum Stress ◽  
Nlrp3 Inflammasome ◽  
Basic Research ◽  
Misfolded Proteins ◽  
Pyrin Domain ◽  
Receptor Family ◽  
Oligomerization Domain

Endoplasmic reticulum (ER) is an important organelle for the protein synthesis, modification, folding, assembly, and the transport of new peptide chains. When the folding ability of ER proteins is impaired, the accumulation of unfolded or misfolded proteins in ER leads to endoplasmic reticulum stress (ERS). The nucleotide-binding oligomerization domain-like receptor family, pyrin domain-containing 3 (NLRP3) inflammasome, can induce the maturation and secretion of interleukin-1beta (IL-1β) and IL-18 through activating caspase-1. It is associated with many diseases. Studies have shown that ERS can regulate NLRP3 inflammasome in many diseases including diabetes. However, the mechanism of the effects of ERS on NLRP3 inflammasome in diabetes has not been fully understood. This review summarizes the recent researches about the effects of ERS on NLRP3 inflammasome and the related mechanism in diabetes to provide ideas for the relevant basic research in the future.

scholarly journals Contradictory Effects of NLRP3 Inflammasome Regulatory Mechanisms in Colitis

2020 ◽  
Vol 21 (21) ◽  
pp. 8145
Author(s):  
Kohei Wagatsuma ◽  
Hiroshi Nakase
Keyword(s):  
Inflammatory Bowel Disease ◽  
Bowel Disease ◽  
Nlrp3 Inflammasome ◽  
Experimental Colitis ◽  
Regulatory Mechanisms ◽  
Pyrin Domain ◽  
Complex Interactions ◽  
Inflammatory Bowel ◽  
Receptor Family

The inflammasome is an intracellular molecular complex, which is mainly involved in innate immunity. Inflammasomes are formed in response to danger signals, associated with infection and injury, and mainly regulate the secretion of interleukin-1β and interleukin-18. Inflammasome dysregulation is known to be associated with various diseases and conditions, and its regulatory mechanisms have become of great interest in recent years. In the colon, inflammasomes have been reported to be associated with autophagy and the microbiota, and their dysregulation contributes to colitis and. However, the detailed role of inflammasomes in inflammatory bowel disease is still under debate because the mechanisms that regulate the inflammasome are complex and the inflammasome components and cytokines show seemingly contradictory multiple effects. Herein, we comprehensively review the literature on inflammasome functioning in the colon and describe the complex interactions of the NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome components with inflammatory cytokines, autophagy, and the microbiota in experimental colitis models and patients with inflammatory bowel disease.

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