bims-kimdis 2023-01-01 papers

bims-kimdis

Biomed News

on Ketones, inflammation and mitochondria in disease

Issue of 2023‒01‒01
eleven papers selected by
Matías Javier Monsalves Álvarez

β-hydroxybutyrate improves cognitive impairment caused by chronic cerebral hypoperfusion via amelioration of neuroinflammation and blood-brain barrier damage.
Low carbohydrate ketogenic diets reduce cardiovascular risk factor levels in obese or overweight patients with T2DM: A meta-analysis of randomized controlled trials.
Lipoxin A4 attenuates MSU-crystal-induced NLRP3 inflammasome activation through suppressing Nrf2 thereby increasing TXNRD2.
Inhibiting the inflammasome with MCC950 counteracts muscle pyroptosis and improves Duchenne muscular dystrophy.
Short-Chain Fatty Acids in Gut-Heart Axis: Their Role in the Pathology of Heart Failure.
The NLRP3 Genetic Variant (rs10754555) Reduces the Risk of Adverse Outcome in Middle-Aged Patients with Chronic Coronary Syndrome.
Argon mitigates post-stroke neuroinflammation by regulating M1/M2 polarization and inhibiting NF-κB/NLRP3 inflammasome signaling.
Mitochondria and peroxisomes: partners in autophagy.
Impact of early time-restricted eating on diet quality, meal frequency, appetite, and eating behaviors: A randomized trial.
Short-chain fatty acid-mediated epigenetic modulation of inflammatory T cells in vitro.
NLRP3 Inflammasome Inhibitor MCC950 Reduces Cerebral Ischemia/Reperfusion Induced Neuronal Ferroptosis.

Brain Res Bull. 2022 Dec 26. pii: S0361-9230(22)00352-5. [Epub ahead of print]193 117-130

β-hydroxybutyrate improves cognitive impairment caused by chronic cerebral hypoperfusion via amelioration of neuroinflammation and blood-brain barrier damage.

Zhitian Wang, Tian Li, Miaoyu Du, Lei Zhang, Linling Xu, Hao Song, Junjian Zhang.

  BACKGROUND: Vascular cognitive impairment (VCI) is the second most common type of dementia after Alzheimer's disease (AD) in elderly people. Chronic cerebral hypoperfusion (CCH) is the early pathophysiological basis of VCI. β-Hydroxybutyrate (BHB) is one of the important components of ketone bodies, an intermediate product of endogenous energy metabolism, which can mitigate neuroinflammation in stroke and neurodegenerative diseases. The present study aimed to investigate whether BHB can improve cognitive impairment caused by CCH and the underlying mechanism.METHODS: The CCH model was established by permanent bilateral common carotid artery occlusion (2VO). CCH rats were intraperitoneally injected with BHB (1.5 mmol/kg/d) every day for 8 consecutive weeks from 2 weeks before surgery. The hippocampal blood flow of rats was measured by using a laser Doppler velocimetry. Used the Morris water maze test (MWM) to assess spatial learning and memory of rats, and harvested brain tissues for molecular, biochemical, and pathological tests.
RESULTS: We found that BHB intervention for 8 weeks could effectively restore hippocampal blood flow and improve spatial learning and memory in CCH rats. BHB can protect the blood-brain barrier (BBB), as manifested by reducing the ultrastructural damage and leakage of the BBB, restoring the expression of tight junction-related proteins and reducing the expression of Matrix Metalloproteinases-9 (MMP-9). Additionally, after BHB intervention, microglia activation was reduced, oligodendrocyte motility was active, and the expression levels of pro-inflammatory factors such as tumor necrosis factor (TNF-α), interleukin-1β (IL-1β), nuclear factor-κB (NF-κB) and advanced glycation end-products (RAGE) were lower, which also indicated that BHB had a beneficial effect in mitigating neuroinflammation.
CONCLUSION: BHB can improve the cognitive impairment caused by CCH. The potential mechanisms of BHB may be through reducing neuroinflammation and protecting BBB.

Keywords:  Blood-brain barrier; Chronic cerebral hypoperfusion; Cognitive impairment; Neuroinflammation; β-hydroxybutyrate

DOI:  https://doi.org/10.1016/j.brainresbull.2022.12.011
Front Nutr. 2022 ;9 1092031

Low carbohydrate ketogenic diets reduce cardiovascular risk factor levels in obese or overweight patients with T2DM: A meta-analysis of randomized controlled trials.

Wei Luo, Jin Zhang, Dan Xu, Yao Zhou, Zhen Qu, Qin Yang, Qiujv Lv.

  Background: The purpose of this meta-analysis was to explore the effects of low-carbohydrate ketogenic diets on cardiovascular risk factors in overweight or obese patients. However, there are limited literature data about effects of low-carbohydrate ketogenic diets on cardiovascular risk factors in obese or overweight patients.Methods: We systematically searched PubMed, EMBASE, Web of Science, OVID, and Cochrane Library databases (last updated in September 2022) for randomized controlled trials (RCTs) which recruited overweight or obesity patients on ketogenic diets in order to control cardiovascular risk factors (blood glucose, weight, and lipids). The overall effect size for continuous variables was expressed as a weighted standardized mean difference (SMD) with a confidence interval of 95%. Considering type 2 diabetes mellitus (T2DM) status at baseline, subgroup analyses were performed when appropriate, based on T2DM comorbidity among patients. The effect model was selected according to heterogeneity.
Results: We finally selected 21 studies. Low carbohydrate ketogenic diets exerted a greater impact on cardiovascular risk factors in obese/ overweight patients with T2DM when compared with those on non-ketogenic diets, with lower fasting plasma glucose (FPG) (SMD, -0.75; P < 0.001) and hemoglobin A1c (HbA1c) (SMD, -0.53; P < 0.001) levels identified. Low-carbohydrate ketogenic diets significantly reduced body mass index (BMI) (SMD, -2.27; P = 0.032), weight (SMD, -6.72; P < 0.001), and waist circumference (SMD, -4.45; P = 0.003) in obese/ overweight patients with T2DM. Also, ketogenic diets improved lipid profiles in these patients; triglyceride (TG) (SMD, -0.32; P = 0.013) levels were lowered and high density lipoprotein (HDL) showed an upward trend with the P-value close to statistically significant level (SMD, -0.32; P = 0.052). In general, irrespective of diabetic status at baseline, ketogenic diets were more effective in reducing TG (SMD, -0.2; P = 0.02) and increasing HDL (SMD, 0.11; P = 0.03) levels when compared with non-ketogenic diets.
Conclusions: Low-carbohydrate ketogenic diets effectively improved cardiovascular risk factors (blood glucose, weight, and lipids) in obese/ overweight patients, especially those with T2DM when compared with non-ketogenic diets.

Keywords:  T2DM; cardiovascular risk; low-carbohydrate ketogenic diet; obesity; overweight

DOI:  https://doi.org/10.3389/fnut.2022.1092031
Front Immunol. 2022 ;13 1060441

Lipoxin A4 attenuates MSU-crystal-induced NLRP3 inflammasome activation through suppressing Nrf2 thereby increasing TXNRD2.

You Zhou, Yongjun Chen, Xiaowu Zhong, Hongtao Xia, Mingcai Zhao, Mengyuan Zhao, Lei Xu, Xiaolan Guo, Chong-Ge You.

  Gout is a common inflammatory disease. The activation of NLRP3 inflammasome induced by monosodium urate (MSU) crystals has a critical role in gout, and its prevention is beneficial for patients. Lipoxin A4 (LXA4) is an endogenous lipoxygenase-derived eicosanoid mediator with powerful anti-inflammatory properties. However, whether LXA4 can suppress NLRP3 inflammasome activation induced by MSU crystals remains unclear. This study aimed to investigate the protective effect of LXA4 on MSU-crystal-induced NLRP3 inflammasome activation and its underlying molecular mechanisms. We found that LXA4 inhibited MSU-crystal-induced NLRP3 inflammasome activation, interleukin (IL)-1β maturation, and pyroptosis. More specifically, LXA4 suppressed the assembly of the NLRP3 inflammasome, including oligomerization and speck formation of ASC, and ASC-NLRP3 interaction. Furthermore, LXA4 suppressed oxidative stress, the upstream events for NLRP3 inflammasome activation, as evidenced by the fact that LXA4 eliminated total reactive oxygen species (ROS) generation and alleviated nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activation and mitochondrial dysfunction. However, LXA4 also depressed the Nrf2 activation, a critical molecule in the antioxidant pathway, and then exerted an inhibitory impact on Klf9 expression and promotional impact on TXNRD2 expression, two molecules located downstream of Nrf2 in sequence. Knockdown of TXNRD2 reversed the LXA4-induced depression of ROS and NLRP3 inflammasome. Moreover, LXA4 alleviated joint inflammation and decreased the production of cleaved caspase-1 and matured IL-1β in gouty arthritis rats. Taken together, our findings demonstrate that LXA4 can attenuate MSU-crystal-induced NLRP3 inflammasome activation, probably through suppressing Nrf2 activation to increase TXNRD2 expression. The present study highlights the potential of LXA4 as an attractive new gout treatment candidate.

Keywords:  MSU; NLRP3 inflammasome; Nrf2; ROS; TXNRD2; gout; lipoxinA4

DOI:  https://doi.org/10.3389/fimmu.2022.1060441
Front Immunol. 2022 ;13 1049076

Inhibiting the inflammasome with MCC950 counteracts muscle pyroptosis and improves Duchenne muscular dystrophy.

Nicolas Dubuisson, María A Davis-López de Carrizosa, Romain Versele, Camille M Selvais, Laurence Noel, P Y D Van den Bergh, Sonia M Brichard, Michel Abou-Samra.

  Background: Duchenne muscular dystrophy (DMD) is the most common inherited human myopathy. Typically, the secondary process involving severe inflammation and necrosis exacerbate disease progression. Previously, we reported that the NLRP3 inflammasome complex plays a crucial role in this disorder. Moreover, pyroptosis, a form of programmed necrotic cell death, is triggered by NLRP3 via gasdermin D (GSDMD). So far, pyroptosis has never been described either in healthy muscle or in dystrophic muscle. The aim of this study was to unravel the role of NLRP3 inflammasome in DMD and explore a potentially promising treatment with MCC950 that selectively inhibits NLRP3.Methods: Four-week-old mdx mice (n=6 per group) were orally treated for 2 months with MCC950 (mdx-T), a highly potent, specific, small-molecule inhibitor of NLRP3, and compared with untreated (mdx) and wild-type (WT) mice. In vivo functional tests were carried out to measure the global force and endurance of mice. Ex vivo biochemical and molecular analyses were performed to evaluate the pathophysiology of the skeletal muscle. Finally, in vitro tests were conducted on primary cultures of DMD human myotubes.
Results: After MCC950 treatment, mdx mice exhibited a significant reduction of inflammation, macrophage infiltration and oxidative stress (-20 to -65%, P<0.05 vs untreated mdx). Mdx-T mice displayed considerably less myonecrosis (-54%, P<0.05 vs mdx) and fibrosis (-75%, P<0.01 vs mdx). Moreover, a more mature myofibre phenotype, characterized by larger-sized fibres and higher expression of mature myosin heavy chains 1 and 7 was observed. Mdx-T also exhibited enhanced force and resistance to fatigue (+20 to 60%, P<0.05 or less). These beneficial effects resulted from MCC950 inhibition of both active caspase-1 (-46%, P=0.075) and cleaved gasdermin D (N-GSDMD) (-42% in medium-sized-fibres, P<0.001). Finally, the anti-inflammatory action and the anti-pyroptotic effect of MCC950 were also recapitulated in DMD human myotubes.
Conclusion: Specific inhibition of the NLRP3 inflammasome can significantly attenuate the dystrophic phenotype. A novel finding of this study is the overactivation of GSDMD, which is hampered by MCC950. This ultimately leads to less inflammation and pyroptosis and to a better muscle maturation and function. Targeting NLRP3 might lead to an effective therapeutic approach for a better management of DMD.

Keywords:  Duchenne muscular dystrophy (DMD); MCC950; N-GSDMD; NLRP3 inflammasome; gasdermin; muscle inflammation; pyroptosis

DOI:  https://doi.org/10.3389/fimmu.2022.1049076
J Pers Med. 2022 Nov 01. pii: 1805. [Epub ahead of print]12(11):

Short-Chain Fatty Acids in Gut-Heart Axis: Their Role in the Pathology of Heart Failure.

Midori Yukino-Iwashita, Yuji Nagatomo, Akane Kawai, Akira Taruoka, Yusuke Yumita, Kazuki Kagami, Risako Yasuda, Takumi Toya, Yukinori Ikegami, Nobuyuki Masaki, Yasuo Ido, Takeshi Adachi.

  Heart failure (HF) is a syndrome with global clinical and socioeconomic burden worldwide owing to its poor prognosis. Accumulating evidence has implicated the possible contribution of gut microbiota-derived metabolites, short-chain fatty acids (SCFAs), on the pathology of a variety of diseases. The changes of SCFA concentration were reported to be observed in various cardiovascular diseases including HF in experimental animals and humans. HF causes hypoperfusion and/or congestion in the gut, which may lead to lowered production of SCFAs, possibly through the pathological changes of the gut microenvironment including microbiota composition. Recent studies suggest that SCFAs may play a significant role in the pathology of HF, possibly through an agonistic effect on G-protein-coupled receptors, histone deacetylases (HDACs) inhibition, restoration of mitochondrial function, amelioration of cardiac inflammatory response, its utilization as an energy source, and remote effect attributable to a protective effect on the other organs. Collectively, in the pathology of HF, SCFAs might play a significant role as a key mediator in the gut-heart axis. However, these possible mechanisms have not been entirely clarified and need further investigation.

Keywords:  G-protein-coupled receptors; acetate; butyrate; heart failure; histone deacetylases; propionate; short-chain fatty acid

DOI:  https://doi.org/10.3390/jpm12111805
J Immunol Res. 2022 ;2022 2366695

The NLRP3 Genetic Variant (rs10754555) Reduces the Risk of Adverse Outcome in Middle-Aged Patients with Chronic Coronary Syndrome.

Trine B Opstad, Jostein Nordeng, Alf-Aage R Pettersen, Sissel Åkra, Vibeke Bratseth, Hani Zaidi, Ragnhild Helseth, Svein Solheim, Ingebjørg Seljeflot.

Background: Inflammation is central in development of cardiovascular disease (CVD). Aberrant function of the Nod-Like Receptor Protein 3 (NLRP3) inflammasome, a central mediator in the proinflammatory response, has been associated with atherosclerosis. The influence of genetic determinants on this inflammatory pathway and its downstream effects is less known. We aimed to investigate the frequency of a single NLRP3 gene variant according to clinical outcome in CVD and its influence on NLRP3-related markers.Methods: In this observational study, we included 1001 patients with chronic coronary syndrome. Blood samples were drawn at inclusion, including whole-blood and PAXgene tubes for DNA and RNA isolation, respectively. Allelic discrimination of the NLRP3 single nucleotide polymorphism rs10754555 was performed; and gene expression of NLRP3, Toll-Like Receptor 4, Interleukin- (IL-) 1β, and IL-18 was relatively quantified, both methods by RT-PCR. Circulating IL-6, high-sensitivity (hs) C-reactive protein, IL-18, and IL-12 were measured by enzyme-like immunosorbent assays. Clinical endpoints during 2 years (n = 106) were a composite of unstable angina pectoris, myocardial infarction, nonhemorrhagic stroke, and death.
Results: Minor allele frequency of the NLRP3 variant was 0.36. In all, no association of the NLRP3 variant with clinical subgroups or outcome was found, neither any significant influence on the genes' mRNA expression or circulating protein. However, in subjects < 56 years (25 percentile), the variant G-allele is associated with significant lower risk of suffering a composite event (OR = 0.43 (95% CI 0.19, 0.97), p = 0.043, adjusted). In the same age group, the NLRP3 gene was accordingly downregulated in G-allele carriers vs. noncarriers, and circulating IL12 was significantly reduced (p < 0.05, both). In subjects > 56 years, no significant effect of the variant was observed.
Conclusion: The age-related reduced risk of composite endpoint in rs10754555 G-allele carriers accompanied by diminished NLRP3 mRNA expression is hypothesis generating and needs to be further explored. The study is registered at http://www.clinicaltrials.gov, with identification number NCT00222261.

DOI: https://doi.org/10.1155/2022/2366695
J Mol Cell Biol. 2022 Dec 27. pii: mjac077. [Epub ahead of print]

Argon mitigates post-stroke neuroinflammation by regulating M1/M2 polarization and inhibiting NF-κB/NLRP3 inflammasome signaling.

Ke Xue, Mian Qi, Tongping She, Zhenglin Jiang, Yunfeng Zhang, Xueting Wang, Guohua Wang, Lihua Xu, Bin Peng, Jiayi Liu, Xinjian Song, Yuan Yuan, Xia Li.

  Neuroinflammation plays a vital role in cerebral ischemic stroke (IS). In the acute phase of IS, microglia are activated towards the pro-inflammatory (M1) and anti-inflammatory (M2) phenotypes. Argon, an inert gas, can reduce neuroinflammation and alleviate ischemia/reperfusion (I/R) injury. However, whether argon regulates M1/M2 polarization to protect against I/R injury as well as the underlying mechanism has not been reported. In this study, we analyzed the activation and polarization of microglia after I/R injury with or without argon administration and explored the effects of argon on NLRP3 inflammasome-mediated inflammation in microglia in vitro and in vivo. The results showed that argon application inhibited the activation of M1 microglia/macrophage in the ischemic penumbra and the expression of proteins related to NLRP3 inflammasome and pyroptosis in microglia. Argon administration also inhibited the expression and processing of IL-1β, a primary pro-inflammatory cytokine. Thus, argon alleviates I/R injury by inhibiting pro-inflammatory reactions via suppressing microglial polarization towards M1 phenotype and inhibiting the NF-κB/NLRP3 inflammasome signaling pathway. More importantly, we showed that argon worked better than the specific NLRP3 inflammasome inhibitor MCC950 in suppressing neuroinflammation and protecting against cerebral I/R injury, suggesting the therapeutic potential of argon in neuroinflammation-related neurodegeneration diseases as a potent gas inhibitor of the NLRP3 inflammasome signaling pathway.

Keywords:  NLRP3 inflammasome; argon; ischemia/reperfusion injury; microglial polarization; neuroinflammation; pyroptosis

DOI:  https://doi.org/10.1093/jmcb/mjac077
Autophagy. 2022 Dec 26. 1-2

Mitochondria and peroxisomes: partners in autophagy.

Léa P Wilhelm, Ian G Ganley.

  Mitochondria, often called "the powerhouse" of the cell due to their role as the main energy supplier, regulate numerous complex processes including intracellular calcium homeostasis, reactive oxygen species (ROS) production, regulation of immune responses, and apoptosis. So, mitochondria are a fundamental metabolic hub that also control cell survival and cell death. However, they are not unique in all these functions. Indeed, peroxisomes are small cytoplasmic organelles that also ensure metabolic functions such as fatty acid oxidation and ROS production. This common relationship also extends beyond function as peroxisomes themselves can form from mitochondrial-derived precursors. Given this interconnection between mitochondria and peroxisomes involving biogenesis and function, in our recent work we determined if their turnover was also linked.

Keywords:  Autophagy; BNIP3L; NIX; mitophagy; pexophagy

DOI:  https://doi.org/10.1080/15548627.2022.2155368
Obesity (Silver Spring). 2022 Dec 27.

Impact of early time-restricted eating on diet quality, meal frequency, appetite, and eating behaviors: A randomized trial.

Felicia L Steger, Humaira Jamshed, Corby K Martin, Joshua S Richman, David R Bryan, Cody J Hanick, Sarah-Jeanne Salvy, Amy H Warriner, Courtney M Peterson.

OBJECTIVE: Time-restricted eating (TRE) can reduce body weight, but it is unclear how it influences dietary patterns and behavior. Therefore, this study assessed the effects of TRE on diet quality, appetite, and several eating behaviors.METHODS: Adults with obesity were randomized to early TRE plus energy restriction (eTRE + ER; 8-hour eating window from 7:00 a.m. to 3:00 p.m.) or a control eating schedule plus energy restriction (CON + ER; ≥12-hour window) for 14 weeks. Food intake was assessed via the Remote Food Photography Method, while eating patterns, appetite, and eating behaviors were assessed via questionnaires.
RESULTS: A total of 59 participants completed the trial, of whom 45 had valid food records. eTRE + ER did not affect eating frequency, eating restraint, emotional eating, or the consistency of mealtimes relative to CON + ER. eTRE + ER also did not affect overall diet quality. The intensity and frequency of hunger and fullness were similar between groups, although the eTRE + ER group was hungrier while fasting.
CONCLUSIONS: When combined with a weight-loss program, eTRE does not affect diet quality, meal frequency, eating restraint, emotional eating, or other eating behaviors relative to eating over more than a 12-hour window. Rather, participants implement eTRE as a simple timing rule by condensing their normal eating patterns into a smaller eating window.

DOI: https://doi.org/10.1002/oby.23642
Drug Deliv Transl Res. 2022 Dec 24.

Short-chain fatty acid-mediated epigenetic modulation of inflammatory T cells in vitro.

David A McBride, Nicholas C Dorn, Mina Yao, Wade T Johnson, Wei Wang, Nunzio Bottini, Nisarg J Shah.

  Short-chain fatty acids (SCFAs) are major metabolic products of indigestible polysaccharides in the gut and mediate the function of immune cells to facilitate homeostasis. The immunomodulatory effect of SCFAs has been attributed, at least in part, to the epigenetic modulation of immune cells through the inhibition the nucleus-resident enzyme histone deacetylase (HDAC). Among the downstream effects, SCFAs enhance regulatory T cells (Treg) over inflammatory T helper (Th) cells, including Th17 cells, which can be pathogenic. Here, we characterize the potential of two common SCFAs-butyrate and pentanoate-in modulating differentiation of T cells in vitro. We show that butyrate but not pentanoate exerts a concentration-dependent effect on Treg and Th17 differentiation. Increasing the concentration of butyrate suppresses the Th17-associated RORγtt and IL-17 and increases the expression of Treg-associated FoxP3. To effectively deliver butyrate, encapsulation of butyrate in a liposomal carrier, termed BLIPs, reduced cytotoxicity while maintaining the immunomodulatory effect on T cells. Consistent with these results, butyrate and BLIPs inhibit HDAC and promote a unique chromatin landscape in T cells under conditions that otherwise promote conversion into a pro-inflammatory phenotype. Motif enrichment analysis revealed that butyrate and BLIP-mediated suppression of Th17-associated chromatin accessibility corresponded with a marked decrease in bZIP family transcription factor binding sites. These results support the utility and further evaluation of BLIPs as an immunomodulatory agent for autoimmune disorders that are characterized by chronic inflammation and pathogenic inflammatory T cells.

Keywords:  Epigenetic modulation; Immunomodulation; Short-chain fatty acids; T cells

DOI:  https://doi.org/10.1007/s13346-022-01284-6
Neurosci Lett. 2022 Dec 26. pii: S0304-3940(22)00593-6. [Epub ahead of print] 137032

NLRP3 Inflammasome Inhibitor MCC950 Reduces Cerebral Ischemia/Reperfusion Induced Neuronal Ferroptosis.

Xiang Wu, Bo Wang, Yunfei Zhou, Zhongbo Yang, Liangchao Jiang, Zhiyan Kou, Jiaxi Li, Xudong Ma, Jinning Song.

  The role of nucleotide-binding oligomerization domainlike receptor pyrin domain containing 3 (NLRP3) inflammasome in cerebral ischemia-reperfusion (I/R) induced neuroinflammation and neuronal pyroptosis has been widely recognized. Latest studies revealed that NLRP3 inflammasome engage in not only pyroptosis but also other types of cell death. Ferroptosis has been proved to be closely associated with cerebral I/R injury. In this study, our objectives were to verify the inhibitory effect of the NLRP3-specific inhibitor MCC950 on cerebral I/R-mediated neuronal pyroptosis, and to explore the regulation and possible mechanism of MCC950 on cerebral I/R-mediated neuronal ferroptosis. Our data showed that the NLRP3-specific inhibitor, MCC950, effectively reversed the I/R-mediated NLRP3 inflammasome activation and neuronal pyroptosis. Furthermore, we found that I/R increased iron concentrations and levels of malondialdehyde (MDA), downregulated glutathione peroxidase 4 (GPX4) expression, and upregulated long chain fatty acid-CoA ligase 4 (FACL4) and prostaglandin endoperoxide synthase 2 (PTGS2) expression. Interestingly, these changes were also reversed by the MCC950. Finally, in vitro, we found that MCC950 significantly reduced ROS levels in OGD/R treated HT22 cells. In conclusion, pharmaceutical inhibition of NLRP3 by MCC950 attenuates I/R-induced neuronal ferroptosis, possibly by reducing ROS accumulation.

Keywords:  Cerebral ischemia-reperfusion; Ferroptosis; MCC950; NLRP3 inflammasome; Pyroptosis

DOI:  https://doi.org/10.1016/j.neulet.2022.137032