Mitochondria, the NLRP3 Inflammasome, and Sirtuins in Type 2 Diabetes: New Therapeutic TargetsReviewing Editors:<i>Markus Bachschmid, Dylan Burger, Vittorio Calabrese, Amadou Camara, Lukas Kubala, Giuseppe Poli, and Chandan K. Sen</i>

Rovira‐Llopis, Susana; Apostolova, Nadezda; Bañuls, Celia; Muntané, Jordi; Rocha, Milagros; Víctor, Víctor M.

doi:10.1089/ars.2017.7313

Cited by 73 publications

(24 citation statements)

References 397 publications

(415 reference statements)

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“…There has been increasing attention on the molecular mechanisms of NLRP3 in a number of diseases. Recent studies have reported significant protective effects resulting from suppression of NLRP3 inflammasome activation in liver fibrosis, systemic sclerosis, systemic lupus erythematosus, systemic sclerosis, diabetes, inflammasome-related eye disease, inflammatory bowel disease, rheumatoid arthritis, and CNS diseases (Zhou et al, 2016;Alegre et al, 2017;Rovira-Llopis et al, 2018;Shen et al, 2018;Yerramothu et al, 2018;Chen et al, 2019a). Meng et al (2019) demonstrated that PPARγ activation exerts an anti-inflammatory effect by suppressing NLRP3 inflammasome activation in spinal cord-derived neurons.…”

Section: Discussionmentioning

confidence: 99%

MCC950, a Selective Inhibitor of NLRP3 Inflammasome, Reduces the Inflammatory Response and Improves Neurological Outcomes in Mice Model of Spinal Cord Injury

Jiao

Zhao

Wang

et al. 2020

Front. Mol. Biosci.

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Spinal cord injury (SCI) is a serious condition that affects bodily function; however, there is no effective therapy in clinical practice. MCC950, a selective NOD-like receptor protein-3 (NLRP3) inflammasome inhibitor, has been reported to alleviate canonical and non-canonical NLRP3 inflammasome activation of the inflammatory response in vitro and in vivo. However, the effect of MCC950 treatment on neurological post-SCI recovery remains unclear. In this study, we assessed the pharmacological effect of MCC950 on an experimental SCI model in vivo and neuronal injury in vitro. We found that MCC950 improved the grip strength, hind limb movements, spinal cord edema, and pathological injury in the SCI mice. We demonstrated that it exerted this effect by blocking NLRP3 inflammasome assembly, including NLRP3-ASC and NLRP3-Caspase-1 complexes, as well as the release of pro-inflammatory cytokines TNF-α, IL-1β, and IL-18. Moreover, we found that MCC950 reduced spinal neuron injury and NLRP3 inflammasome activation, which had been induced by oxygen-glucose deprivation (OGD) or lipopolysaccharides (LPS) in vitro. In conclusion, our findings indicate that MCC950 alleviates inflammatory response and improves functional recovery in the acute mice model of SCI by blocking NLRP3 inflammasome assembly and alleviating downstream neuroinflammation. Therefore, these findings could prove useful in the development of effective therapeutic strategies for the treatment and prognosis of SCI.

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Section: Discussionmentioning

confidence: 99%

MCC950, a Selective Inhibitor of NLRP3 Inflammasome, Reduces the Inflammatory Response and Improves Neurological Outcomes in Mice Model of Spinal Cord Injury

Jiao

Zhao

Wang

et al. 2020

Front. Mol. Biosci.

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“…Here, we reveal a new function of M in the activation of the NLRP3 inflammasome and IL-1␤. As a crucial component of the innate immune system, the inflammasome not only plays an important role in host defense against pathogen infections but also is involved in the progression of inflammatory diseases, such as gout and type 2 diabetes (47,48). DENV triggers NLRP3 inflammasome assembly in platelets, and platelets may contribute to increased vascular permeability by regulating IL-1␤ (37).…”

Section: Figmentioning

confidence: 99%

Dengue Virus M Protein Promotes NLRP3 Inflammasome Activation To Induce Vascular Leakage in Mice

Pan

Zhang

Liu

et al. 2019

J Virol

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Dengue virus (DENV) infection causes serious clinical symptoms, including dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS). Vascular permeability change is the main feature of the diseases, and the abnormal expression of proinflammatory cytokines is the important cause of vascular permeability change. However, the mechanism underlying vascular permeability induced by DENV has not been fully elucidated. Here, we reveal a distinct mechanism by which DENV infection promotes NLRP3 inflammasome activation and interleukin-1 beta (IL-1β) release to induce endothelial permeability and vascular leakage in mice. DENV M protein interacts with NLRP3 to facilitate NLRP3 inflammasome assembly and activation, which induce proinflammatory cytokine IL-1β activation and release. Notably, M can induce vascular leakage in mouse tissues by activating the NLRP3 inflammasome and IL-1β. More importantly, inflammatory cell infiltration and tissue injuries are induced by M in wild-type (WT) mouse tissues, but they are not affected by M in NLRP3 knockout (NLRP3−/−) mouse tissues. Evans blue intensities in WT mouse tissues are significantly higher than in NLRP3−/− mouse tissues, demonstrating an essential role of NLRP3 in M-induced vascular leakages in mice. Therefore, we propose that upon DENV infection, M interacts with NLRP3 to facilitate inflammasome activation and IL-1β secretion, which lead to the induction of endothelial permeability and vascular leakage in mouse tissues. The important role of the DENV-M-NLRP3-IL-1β axis in the induction of vascular leakage provides new insights into the mechanisms underlying DENV pathogenesis and DENV-associated DHF and DSS development. IMPORTANCE Dengue virus (DENV) is a mosquito-borne pathogen, and infections by this virus are prevalent in over 100 tropical and subtropical countries or regions, with approximately 2.5 billion people at risk. DENV infection induces a spectrum of clinical symptoms, ranging from classical dengue fever (DF) to severe dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS). Therefore, it is important to understand the mechanisms underlying DENV pathogenesis. In this study, we reveal that the DENV membrane protein (M) interacts with the host NLRP3 protein to promote NLRP3 inflammasome activation, which leads to the activation and release of a proinflammatory cytokine, interleukin-1 beta (IL-1β). More importantly, we demonstrate that M protein can induce vascular permeability and vascular leakage and that NLRP3 is required for M-induced vascular leakage in mouse tissues. Collectively, this study reveals a distinct mechanism underlying DENV pathogeneses and provides new insights into the development of therapeutic agents for DENV-associated diseases.

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“…Another group of mitochondria-targeted antioxidants includes water-soluble Szeto Schiller (SS) peptides, small cell permeable antioxidants that are selectively and rapidly taken up into the IMM of different types of cells, including renal, embryonic and endothelial cells. It has been shown that they can modulate mitochondrial ROS production and reduce the mitochondrial permeability transition, preventing necrosis and apoptosis, which are promoted by inhibition of the mitochondrial ETC or oxidative stress [144]. Another current strategy under evaluation for mitochondrial targeting is that of liposomes, of interest due to their clearance rates after systemic injection.…”

Section: Microbiota and Mitochondria: Potential Therapeutic Strategiementioning

confidence: 99%

“…Liposomes are self-assembling colloidal structures mainly composed of phosphatidylglycerol, cholesterol and phosphatidylcholine. In addition, several studies suggest that mitochondria-targeting liposomes are able to enhance the drug efficacy in both in vitro and in vivo models by delivering therapeutic moieties to the mitochondria [144].…”

Section: Microbiota and Mitochondria: Potential Therapeutic Strategiementioning

confidence: 99%

Microbiota-Mitochondria Inter-Talk: A Potential Therapeutic Strategy in Obesity and Type 2 Diabetes

et al. 2020

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The rising prevalence of obesity and type 2 diabetes (T2D) is a growing concern worldwide. New discoveries in the field of metagenomics and clinical research have revealed that the gut microbiota plays a key role in these metabolic disorders. The mechanisms regulating microbiota composition are multifactorial and include resistance to stress, presence of pathogens, diet, cultural habits and general health conditions. Recent evidence has shed light on the influence of microbiota quality and diversity on mitochondrial functions. Of note, the gut microbiota has been shown to regulate crucial transcription factors, coactivators, as well as enzymes implicated in mitochondrial biogenesis and metabolism. Moreover, microbiota metabolites seem to interfere with mitochondrial oxidative/nitrosative stress and autophagosome formation, thus regulating the activation of the inflammasome and the production of inflammatory cytokines, key players in chronic metabolic disorders. This review focuses on the association between intestinal microbiota and mitochondrial function and examines the mechanisms that may be the key to their use as potential therapeutic strategies in obesity and T2D management.

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Mitochondria, the NLRP3 Inflammasome, and Sirtuins in Type 2 Diabetes: New Therapeutic TargetsReviewing Editors:Markus Bachschmid, Dylan Burger, Vittorio Calabrese, Amadou Camara, Lukas Kubala, Giuseppe Poli, and Chandan K. Sen

Cited by 73 publications

References 397 publications

MCC950, a Selective Inhibitor of NLRP3 Inflammasome, Reduces the Inflammatory Response and Improves Neurological Outcomes in Mice Model of Spinal Cord Injury

MCC950, a Selective Inhibitor of NLRP3 Inflammasome, Reduces the Inflammatory Response and Improves Neurological Outcomes in Mice Model of Spinal Cord Injury

Dengue Virus M Protein Promotes NLRP3 Inflammasome Activation To Induce Vascular Leakage in Mice

Microbiota-Mitochondria Inter-Talk: A Potential Therapeutic Strategy in Obesity and Type 2 Diabetes

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