Roles of mitochondrial ROS and NLRP3 inflammasome in multiple ozone-induced lung inflammation and emphysema

Li, Feng; Xu, Menglong; Wang, Muyun; Wang, Lei; Wang, Hanying; Zhang, Hai; Chen, Yuqing; Gong, Jicheng; Zhang, Junfeng Jim; Adcock, Ian M.; Chung, Kian Fan; Zhou, Xin

doi:10.1186/s12931-018-0931-8

Cited by 88 publications

(56 citation statements)

References 38 publications

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“…VX765 is a potent, selective caspase-1 inhibitor that inhibits the expressions of pyroptosis-associated inflammasomes and IL-1β as well as IL-18 production and attenuates pyroptosis in vitro [33,34]. Previous researches have shown that VX765 inhibits the expressions as well as the activities of NLRP3 and caspase-1 pathways in the lung [35]. Others have reported that VX765 can prevent bone erosion and reduce serum cytokine levels in arthritis [70].…”

Section: Discussionmentioning

confidence: 99%

“…Mice were isolated and reared for 1 week and then randomized into four groups: sham surgery, controlled cortical impact (CCI), CCI+vehicle (DMSO), and CCI+VX765. VX765 (catalog number: HY-13205; MedChemExpress, Monmouth Junction, NJ, USA) dissolved in DMSO was injected intraperitoneally (100 mg/kg) 1 h after CCI and every 2 days after CCI for two weeks [33,35]. At the same time point, the CCI+vehicle group was given an equal volume of DMSO.…”

Section: Methodsmentioning

confidence: 99%

“…We found that the expression levels of IL-1β (Figure 1 and 1(f)) also identified the above results. Therefore, VX765 concentration of 100 mg/kg was adopted in subsequent experiments [35].…”

Section: The Effects Of Caspase-1 Inhibitor Vx765 On Il-1β and Il-18mentioning

confidence: 99%

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VX765 Attenuates Pyroptosis and HMGB1/TLR4/NF-κB Pathways to Improve Functional Outcomes in TBI Mice

Sun

Nyanzu

Yang

et al. 2020

Oxidative Medicine and Cellular Longevity

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Background. Traumatic brain injury (TBI) refers to temporary or permanent damage to brain function caused by penetrating objects or blunt force trauma. TBI activates inflammasome-mediated pathways and other cell death pathways to remove inactive and damaged cells, however, they are also harmful to the central nervous system. The newly discovered cell death pattern termed pyroptosis has become an area of interest. It mainly relies on caspase-1-mediated pathways, leading to cell death. Methods. Our research focus is VX765, a known caspase-1 inhibitor which may offer neuroprotection after the process of TBI. We established a controlled cortical impact (CCI) mouse model and then controlled the degree of pyroptosis in TBI with VX765. The effects of caspase-1 inhibition on inflammatory response, pyroptosis, blood-brain barrier (BBB), apoptosis, and microglia activation, in addition to neurological deficits, were investigated. Results. We found that TBI led to NOD-like receptors (NLRs) as well as absent in melanoma 2 (AIM2) inflammasome-mediated pyroptosis in the damaged cerebral cortex. VX765 curbed the expressions of indispensable inflammatory subunits (caspase-1 as well as key downstream proinflammatory cytokines such as interleukin- (IL-) 1β and IL-18). It also inhibited gasdermin D (GSDMD) cleavage and apoptosis-associated spot-like protein (ASC) oligomerization in the injured cortex. In addition to the above, VX765 also inhibited the inflammatory activity of the high-mobility cassette -1/Toll-like receptor 4/nuclear factor-kappa B (HMGB1/TLR4/NF-kappa B) pathway. By inhibiting pyroptosis and inflammatory mediator expression, we demonstrated that VX765 can decrease blood-brain barrier (BBB) leakage, apoptosis, and microglia polarization to exhibit its neuroprotective effects. Conclusion. In conclusion, VX765 can counteract neurological damage after TBI by reducing pyroptosis and HMGB1/TLR4/NF-κB pathway activities. VX765 may have a good therapeutic effect on TBI.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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VX765 Attenuates Pyroptosis and HMGB1/TLR4/NF-κB Pathways to Improve Functional Outcomes in TBI Mice

Sun

Nyanzu

Yang

et al. 2020

Oxidative Medicine and Cellular Longevity

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“…It inhibits collagen-induced arthritis and lung inflammation in mouse models. 130,131 It partly decreases bone resorption in the periapical lesion of rat experimental apical periodontitis. 80 In addition to its anti-inflammatory effect, VX-765 also has a protective role against cell death.…”

Section: Inflammasome Inhibitorsmentioning

confidence: 99%

Interleukin-1β is a potential therapeutic target for periodontitis: a narrative review

et al. 2020

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Interleukin(IL)-1β, a pro-inflammatory cytokine, was elevated and participates in periodontitis. Not only the link between IL-1β and periodontitis was proved by clinical evidence, but also the increased IL-1β triggers a series of inflammatory reactions and promotes bone resorption. Currently, IL-1β blockage has been therapeutic strategies for autoimmune and autoinflammatory diseases such as rheumatoid arthritis, cryopyrin-associated periodic syndromes, gout and type II diabetes mellitus. It is speculated that IL-1β be a potential therapeutic target for periodontitis. The review focuses on the production, mechanism, present treatments and future potential strategies for IL-1β in periodontitis.

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“…NLRs form multisubunit protein complexes termed inflammasomes that activate caspase-1 resulting in proteolytic cleavage and pro-inflammatory cytokine IL-1β maturation [153,154]. Pathogenassociated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) such as lipopolysaccharide (LPS), asbestos, ATP and uric acid activate NLR family pyrin domain containing 3 (NLRP3) inflammasome via mROS generation [155,156]. Pharmacologic or genetic inhibition of autophagy elevates mROS concentration, which heightens inflammasome activation [157,158].…”

Section: Immunitymentioning

confidence: 99%

Physiological Functions of Mitochondrial Reactive Oxygen Species

Choi¹,

Kim²

2020

Free Radical Medicine and Biology

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Mitochondria are the major energy producers within a cell in the form of adenosine triphosphate by oxidative phosphorylation. Normal mitochondrial metabolism inevitably generates reactive oxygen species (ROS), which have been considered to solely cause cellular damage. Increase of oxidative stress has been linked to various pathologies. Thus, mitochondrial ROS (mROS) were basically proposed as byproducts of oxidative metabolism, which undergo normalized by antioxidant enzymes. However, the mROS have extensively been esteemed to function as signalling molecules to regulate a wide variety of physiology. These phenomena are indeed dependent on mitochondrial redox status, which is dynamically altered under different physiological and pathological conditions. The oxidative stress is incurred by which the redox status is inclined to exceeded oxidation or reduction. Here, we attempt to integrate the recent advances in our understanding of the physiological functions of mROS.Keywords: mitochondrial ROS, oxidative stress, oxidative metabolism, redox signaling, mitochondrial physiology Free Radical Medicine and Biology 2 reactive metabolites of O 2 , including superoxide anion (O 2 ·− ) and hydrogen peroxide (H 2 O 2 ), formed by one-and two-electron reductions of O 2 , respectively [7].In the presence of transition metal ions, the more reactive hydroxyl radical (OH · ) is formed. The O 2 ·− is rapidly dismutated to H 2 O 2 by two dismutases including Cu/ Zn-superoxide dismutase (Cu/ZnSOD) in mitochondrial intermembrane space and manganese-dependent superoxide dismutase (MnSOD) in mitochondrial matrix. Unless the dismutation of O 2 ·− is catalyzed into H 2 O 2 , the radical oxidant promotes DNA damage, protein oxidation and lipid peroxidation in many types of cells. H 2 O 2 is also cell damaging molecule to be degraded to water by catalase [8]. Although the O 2 ·− generation by respiratory complexes is a well-established phenomenon, it is still poorly understood in mechanism [9].Mitochondria have been implicated in the regulation of a number of physiological and pathological processes, including proliferation, differentiation, programmed cell death, innate immunity, autophagy, redox signalling, calcium homeostasis, hypoxic stress responses and stem cell reprogramming [10][11][12][13][14][15][16]. The mROS production contributes to mitochondrial damage in a range of pathologies, which is also is closely related to redox signalling in the cell [4,17]. However, accumulating evidences show that mROS are not only deleterious molecules derived from the cellular metabolism but also indispensable participants in diverse cellular signalling and regulations [18][19][20].In this chapter, we briefly summarize recent developments in our understanding of the involvement of mROS as signalling mediators in redox biology, rather than pathological stress, underlying physiological conditions.

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Roles of mitochondrial ROS and NLRP3 inflammasome in multiple ozone-induced lung inflammation and emphysema

Cited by 88 publications

References 38 publications

VX765 Attenuates Pyroptosis and HMGB1/TLR4/NF-κB Pathways to Improve Functional Outcomes in TBI Mice

VX765 Attenuates Pyroptosis and HMGB1/TLR4/NF-κB Pathways to Improve Functional Outcomes in TBI Mice

Interleukin-1β is a potential therapeutic target for periodontitis: a narrative review

Physiological Functions of Mitochondrial Reactive Oxygen Species

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