Nucleotide Oligomerization Domain-like Receptor Family Research Articles

Targeting RAC1 reactivates pyroptosis to reverse paclitaxel resistance in ovarian cancer by suppressing P21-activated kinase 4.

Pyroptosis may play an important role in the resistance of ovarian cancer (OC) to chemotherapy. However, the mechanism by which pyroptosis modulation can attenuate chemotherapy resistance has not been comprehensively studied in OC. Here, we demonstrated that RAS-associated C3 botulinum toxin substrate 1 (RAC1) is highly expressed in OC and is negatively correlated with patient outcomes. Through cell function tests and in vivo tumor formation tests, we found that RAC1 can promote tumor growth by mediating paclitaxel (PTX) resistance. RAC1 can mediate OC progression by inhibiting pyroptosis, as evidenced by high-throughput automated confocal imaging, the release of lactate dehydrogenase (LDH), the expression of the inflammatory cytokines IL-1β/IL-18 and the nucleotide oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome. Mechanically, RNA-seq, gene set enrichment analysis (GSEA), coimmunoprecipitation (Co-IP), mass spectrometry (MS), and ubiquitination tests further confirmed that RAC1 inhibits caspase-1/gasdermin D (GSDMD)-mediated canonical pyroptosis through the P21-activated kinase 4 (PAK4)/mitogen-activated protein kinase (MAPK) pathway, thereby promoting PTX resistance in OC cells. Finally, the whole molecular pathway was verified by the results of in vivo drug combination tests, clinical specimen detection and the prognosis. In summary, our results suggest that the combination of RAC1 inhibitors with PTX can reverse PTX resistance by inducing pyroptosis through the PAK4/MAPK pathway.

Mice Hepatic Organoids for Modeling Nonalcoholic Fatty Liver Disease and Drug Response.

Nonalcoholic fatty liver disease (NAFLD) is a serious disease. There are no specific drugs for it, in part because of the lack of effective models to aid drug development. However, it has been shown that three-dimensional organoid culture systems can reproduce the organ structure and maintain the gene expression profile of the original tissue. Therefore, we aimed to construct NAFLD models from liver organoids for pharmacological and mechanism studies. We successfully observed morphological changes in normal liver tissue in mouse liver organoids with positive albumin (ALB) expression and potential for differentiation toward hepatocyte-like cells. The mRNA expression of the hepatocyte markers ALB and hepatocyte nuclear factor 4 alpha increased after liver organoid differentiation. We observed free fatty acid (FFA)-induced lipid accumulation in organoids with significant increases in alanine aminotransferase, aspartate aminotransferase, total bilirubin, and triglyceride levels. Moreover, FFA-induced inflammatory cytokines (interleukin-6, tumor necrosis factor-α, and nitric oxide) and fibrosis indicators (collagen type I α1 and laminin α1) were also increased. In addition, RNA sequencing results showed that the expression of key genes [nucleotide oligomerization domain-like receptor (NLR) family apoptosis inhibitory protein, interferon regulatory factor (IRF) 3, and IRF7] involved in NAFLD metabolic abnormalities and insulin resistance in the NLR signaling pathway was altered after FFA induction of the liver organoids. Finally, we found that JC2-11 and lanifibranor limited the FFA-induced increase in oil-red lipid droplets, liver damage, inflammation, and liver fibrosis. In conclusion, tissue structure, gene expression, and the response of mouse liver organoids to drugs can partially mimic invivo liver tissue. Liver organoids can successfully construct NAFLD models for drug discovery research.

Gestational diabetes in mice induces hematopoietic memory that affects the long-term health of the offspring.

Gestational diabetes is a common medical complication of pregnancy that is associated with adverse perinatal outcomes and an increased risk of metabolic diseases and atherosclerosis in adult offspring. The mechanisms responsible for this delayed pathological transmission remain unknown. In mouse models, we found that the development of atherosclerosis in adult offspring born to diabetic pregnancy can be in part linked to hematopoietic alterations. Although they do not show any gross metabolic disruptions, the adult offspring maintain hematopoietic features associated with diabetes, indicating the acquisition of a lasting diabetic hematopoietic memory. We show that the induction of this hematopoietic memory during gestation relies on the activity of the advanced glycation end product receptor (AGER) and the nucleotide binding and oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome, which lead to increased placental inflammation. In adult offspring, we find that this memory is associated with DNA methyltransferase 1 (DNMT1) upregulation and epigenetic changes in hematopoietic progenitors. Together, our results demonstrate that the hematopoietic system can acquire a lasting memory of gestational diabetes and that this memory constitutes a pathway connecting gestational health to adult pathologies.

Combined exposure to lead and high-fat diet induced neuronal deficits in rats: Anti-neuroinflammatory role of SIRT1.

Lead (Pb) exposure and high-fat diet (HFD) trigger neurotoxicity, which may involve neuroinflammation. However, the mechanism by which combined Pb and HFD exposure induces nucleotide oligomerization domain-like receptor family pyrin domain 3 (NLRP3) inflammasome activation has not been fully elucidated. The Sprague-Dawley (SD) rat model of exposure to Pb and HFD was established to reveal the influence of co-exposure on cognition and identify signaling clues that mediate neuroinflammation and synaptic dysregulation. PC12 cells was treated with Pb and PA in vitro. Silent information regulator 1 (SIRT1) agonist (SRT 1720) was employed as intervention agent. Our results showed that Pb and HFD exposure induced cognitive impairment and lead to neurological damage in rats. Meanwhile, Pb and HFD could stimulate the NLRP3 inflammasome assembly and activate caspase 1, releasing proinflammatory cytokines interleukin-1β (IL-1β) and interleukin-18 (IL-18), further promoting neuronal cell activation and amplifying neuroinflammatory responses. Additionally, our findings suggest that SIRT1 plays a role in Pb and HFD induced neuroinflammation. However, the use of SRT 1720 agonists showed some potential in alleviating these impairments. Pb exposure and HFD intake could induce neuronal damage through activation of the NLRP3 inflammasome pathway and synaptic dysregulation, while the NLRP3 inflammasome pathway may be rescued via activating SIRT1.

RBM3 is associated with acute lung injury in septic mice and patients via the NF-κB/NLRP3 pathway.

Sepsis refers to host response disorders caused by infection, leading to life-threatening organ dysfunction. RNA-binding motif protein 3 (RBM3) is an important cold-shock protein that is upregulated in response to mild hypothermia or hypoxia. In this study, we aimed to investigate whether RBM3 is involved in sepsis-associated acute lung injury (ALI). Intraperitoneal injection of LPS (10mg/kg) was performed in wild type (WT) and RBM3 knockout (KO, RBM3-/-) mice to establish an in vivo sepsis model. An NLRP3 inflammasome inhibitor, MCC950 (50mg/kg), was injected intraperitoneally 30min before LPS treatment. Serum, lung tissues, and BALF were collected 24h later for further analysis. In addition, we also collected serum from sepsis patients and healthy volunteers to detect their RBM3 expression. The results showed that the expression of RBM3 in the lung tissues of LPS-induced sepsis mice and the serum of patients with sepsis was significantly increased and positively correlated with disease severity. In addition, RBM3 knockout (KO) mice had a low survival rate, and RBM3 KO mice had more severe lung damage, inflammation, lung cell apoptosis, and oxidative stress than WT mice. LPS treatment significantly increased the levels of nucleotide binding and oligomerization domain-like receptor family 3 (NLRP3) inflammasomes and mononuclear cell nuclear factor-κB (NF-κB) in the lung tissues of RBM3 KO mice. However, these levels were only slightly elevated in WT mice. Interestingly, MCC950 improved LPS-induced acute lung injury in WT and RBM3 KO mice but inhibited the expression of NLRP3, caspase-1, and IL-1β. In conclusion, RBM3 was overexpressed in sepsis patients and LPS-induced mice. RBM3 gene deficiency aggravated sepsis-associated ALI through the NF-κB/NLRP3 pathway.

Regulatory functional role of NLRP3 inflammasome during Mycoplasma hyopneumoniae infection in swine.

Mycoplasma hyopneumoniae causes enzootic pneumonia, a highly contagious respiratory disease in swine that causes significant economic losses worldwide. It is unknown whether the nucleotide oligomerization domain-like receptor (NLR) family pyrin domain containing 3 (NLRP3) inflammasome regulates the immune response in swine during M. hyopneumoniae infection. The current study utilized an in vivo swine model of M. hyopneumoniae infection to investigate the regulatory functional role of the NLRP3 inflammasome during M. hyopneumoniae infection. Notable histopathological alterations were observed in M. hyopneumoniae-infected swine tissues, which were associated with an inflammatory response and disease progression. Swine M. hyopneumoniae infection was associated with an increase in the expression of the NLRP3 inflammasome, which stimulated pro-inflammatory cytokines such as tumor necrosis factor-alpha, interleukin 18, and interleukin 1 beta (IL-1β). The impact of the NLRP3 inhibitor, MCC950 on NLRP3 and pro-inflammatory cytokines in M. hyopneumoniae-infected swine was examined to investigate the relationship between the NLRP3 inflammasome and M. hyopneumoniae infection. Taken together, our findings provide strong evidence that the NLRP3 inflammasome plays a critical regulatory functional role in M. hyopneumoniae infection in swine.

NLRP3 activation contributes to endothelin-1-induced erectile dysfunction.

In the present study, we hypothesized that endothelin (ET) receptors (ETA and ETB ) stimulation, through increased calcium and ROS formation, leads to Nucleotide Oligomerization Domain-Like Receptor Family, Pyrin Domain Containing 3 (NLRP3) activation. Intracavernosal pressure (ICP/MAP) was measured in C57BL/6 (WT) mice. Functional and immunoblotting assays were performed in corpora cavernosa (CC) strips from WT, NLRP3-/- and caspase-/- mice in the presence of ET-1 (100 nM) and vehicle, MCC950, tiron, BAPTA AM, BQ123, or BQ788. ET-1 reduced the ICP/MAP in WT mice, and MCC950 prevented the ET-1 effect. ET-1 decreased CC ACh-, sodium nitroprusside (SNP)-induced relaxation, and increased caspase-1 expression. BQ123 an ETA receptor antagonist reversed the effect. The ETB receptor antagonist BQ788 also reversed ET-1 inhibition of ACh and SNP relaxation. Additionally, tiron, BAPTA AM, and NLRP3 genetic deletion prevented the ET-1-induced loss of ACh and SNP relaxation. Moreover, BQ123 diminished CC caspase-1 expression, while BQ788 increased caspase-1 and IL-1β levels in a concentration-dependent manner (100 nM-10μM). Furthermore, tiron and BAPTA AM prevented ET-1-induced increase in caspase-1. In addition, BAPTA AM blocked ET-1-induced ROS generation. In conclusion, ET-1-induced erectile dysfunction depends on ETA - and ETB -mediated activation of NLRP3 in mouse CC via Ca2+ -dependent ROS generation.

Intestinal Candida albicans Promotes Hepatocarcinogenesis by Up-Regulating NLRP6.

Hepatocellular carcinoma (HCC), a primary liver cancer, is closely associated with the gut microbiota. However, the role of gut fungi in the development of HCC remains unclear. The aim of this study was to explore the influence of intestinal Candida albicans on HCC. Here, We found that patients with HCC showed significantly decreased diversity of the gut mycobiome and increased abundance of C. albicans, compared to the patients with liver cirrhosis. The gavage of C. albicans in the WT models increased the tumor size and weight and influenced the plasma metabolome, which was indicated by alterations in 117 metabolites, such as L-carnitine and L-acetylcarnitine, and several KEGG enriched pathways, such as phenylalanine metabolism and citrate cycle. Moreover, the expression of nucleotide oligomerization domain-like receptor family pyrin domain containing 6 (NLRP6) in the intestinal tissues and primary intestinal epithelial cells of the WT mice interacted with C. albicans increased. Notably, the colonization of C. albicans had no effect on tumor growth in Nlrp6–/– mice. In conclusion, the abnormal colonization of C. albicans reprogrammed HCC metabolism and contributed to the progression of HCC dependent on NLRP6, which provided new targets for the treatment of HCC.

Genome-wide identification and characterization of NLR genes in lamprey (Lethenteron reissneri) and their responses to lipopolysaccharide/poly(I:C) challenge

The nucleotide oligomerization domain (NOD)-like receptor (NLR) is a relatively conserved receptor family involved in natural immunity that plays a key role in the resistance to pathogen invasion and regulation of the innate immune response. Lethenteron reissneri (lamprey) is a representative species of existing ancient jawless vertebrates. Studies of the evolutionary relationship of immune system-related molecules in lampreys can provide an important reference for the origin and evolution of innate immunity. However, the characterization and evolutionary patterns of the NLR family remain unclear in the lamprey genome. Based on the genome database of L. reissneri, we identified nine NLR genes, characterized their functional domains and chromosomal positions, and constructed a network comprising the results of gene structure and gene-collinearity analyses. Comparative genomics studies suggest that Lr-NODa and Lr-NODb most likely share the common ancestor of NOD1 and NOD2 in jawed vertebrates, and that Lr-NODb may have been generated by lamprey-specific tandem duplication of Lr-NODa. Additionally, phylogenetic analysis of the NLRC subfamily suggests that Lr-NLRC3a has ancestral traits and may be derived from the common ancestor of another vertebrate NLRC subfamily. Further analysis of the formation of the NLRC subfamily has shown that exon shuffling, domain recombination, and chromosome rearrangement play important roles in its structural evolution. Furthermore, real-time quantitative polymerase chain reaction shows that most NLR genes in lamprey are highly expressed in the immune tissues of the heart, gill, and supraneural body, with these genes also showing significant responses to polyinosinic-polycytidylic acid infection. These results indicate that NLR genes are involved in the immune protection of L. reissneri and provide an important theoretical foundation for studies of the functional evolution of vertebrate NLRs involved in the innate immune system.

PEG-PEI/siROCK2 inhibits Aβ42-induced microglial inflammation via NLRP3/caspase 1 pathway.

ObjectivesThere is an urgent need to develop therapeutic strategies to improve the treatment outcome of Alzheimer’s disease. The treatment strategy of gene therapy mediated by nanocarrier systems brings new hope for the treatment of Alzheimer’s disease. ROCK2 is involved in various pathological processes of Alzheimer’s disease and may be a potential target for the treatment of Alzheimer’s disease. Our previous study indicated that PEG-PEI/siROCK2 [polyethyleneglycol-polyethyleneimine deliver ROCK2-siRNA, (PPSR)] prevented Aβ42-induced neurotoxicity and showed a promising prospect for the treatment of Alzheimer’s disease. However, whether PPSR has an effect on the microglial inflammation in Alzheimer’s disease is still unclear.Materials and methods3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide assay was used to detect the cytotoxicity of PEG-PEI and PPSR in primary microglial cells. Real-time PCR and western blotting were used to assess the expression of ROCK2 and nucleotide oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3)/caspase 1 pathway in primary microglial cells. ELISA assay was used to measure the effect of PPSR on attenuating the lipopolysaccharide (LPS) + Aβ-induced increase in IL-1β.ResultsPEG-PEI concentration less than 20 μg/ml and the N/P (molar ratio of PEG-PEI amino/siRNA phosphate) ratio of PPSR less than 50 showed no significant cytotoxicity in primary microglia cells. PPSR could effectively inhibit the expression of ROCK2 in primary microglial cells. A further study revealed that PPSR attenuates the LPS+Aβ-induced increase in IL-1β without affecting cell viability. In addition, we found that PPSR suppressed the Aβ-induced NLRP3/caspase 1 pathway in primary microglial cells.ConclusionPPSR inhibits Aβ42-induced microglial inflammation via NLRP3/caspase 1 pathway.

NLRP3 inflammasome is involved in uterine activation for labor at term and preterm.

The nucleotide binding and oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome plays a critical role in various inflammatory diseases. We sought to investigate the role of NLRP3 inflammasome in uterine activation for labor at term and preterm. We found that NLRP3 inflammasome was activated in the myometrium tissues obtained from the pregnant women undergoing labor at term (TL) compared with those not undergoing labor (TNL) at term. NLRP3 inflammasome was also activated in amnion and chorion-deciduas in TL and preterm labor (PTL) groups. In the mouse model, uterine NLRP3 inflammasome and nuclear factor kappaB (NF-κB) were activated toward term and during labor. Treatment of pregnant mice with lipopolysaccharide (LPS) and RU38486 induced preterm birth (PTB) and also promoted uterine NLRP3 inflammasome and NF-κB activation. Treatment of pregnant mice with NLRP3 inflammasome inhibitor BAY11-7082 and MCC950 delayed the onset of labor and suppressed NLRP3 inflammasome and NF-κB activation in uterus. MCC950 postponed labor onset of the mice with LPS and RU38486 treatment and inhibited NLRP3 inflammasome activation in uterus. Our data provide the evidence that NLRP3 inflammasome is involved in uterine activation for labor onset in term and PTB in humans and mouse model.

Aluminum impairs cognitive function by activating DDX3X-NLRP3-mediated pyroptosis signaling pathway

IntroductionAluminum is a kind of chemical contaminants in food which can induce neurotoxicity. Aluminum exposure is closely related to neurodegenerative diseases (ND), in which neuroinflammation might involve. However, the molecular mechanism of aluminum-induced neuroinflammation through pyroptosis is not fully clarified yet. Material and methodsThe mice model of subacute exposure to aluminum chloride (AlCl3) was established. BV2 microglia cells was treated with AlCl3 in vitro. Resveratrol (Rsv) was adopted as intervention agent. ResultsOur results showed that aluminum induced cognitive impairment, destroying blood brain barrier (BBB), and causing nerve injury in mice. Meanwhile, aluminum could stimulate nucleotide oligomerization domain-like receptor family pyrin domain containing protein 3 (NLRP3) inflammasome assembly and activate caspase-1 (CASP1), inducing gasdermin D (GSDMD)-mediated pyroptosis signaling, releasing cytokines IL-1β and IL-18, further promoting the activation of glial cells to magnify neuroinflammatory response. Moreover, DEAD-box helicase 3 X-linked (DDX3X) and stress granule RasGAP SH3-domain-binding protein 1 (G3BP1) both participated in neuroinflammation induced by aluminum. When co-treated with Rsv, these injuries were alleviated to some extent. ConclusionAluminum exposure could induce nerve cell pyroptosis and neuroinflammation by DDX3X-NLRP3 inflammasome signaling pathway, which could be rescued via Rsv activating sirtuin 1 (SIRT1).

Dioscin prevents DSS-induced colitis in mice with enhancing intestinal barrier function and reducing colon inflammation

Dioscin is a natural steroid saponin derived from plants of the genus Dioscoreaceae. Previous studies have proved its effects of antibacterial, anti-inflammatory and hypolipidemic. In this study, our aim was to explore the protective effect and preliminary mechanism of Dioscin on dextran sulfate sodium (DSS)-induced colitis in mice. The results showed that Dioscin reduced DSS-induced disease activity index (DAI) increase, colon length shortening and colon pathological damage. In addition, Dioscin reduced excessive inflammation by reversing the cytokines levels, reducing intestinal macrophage infiltration and promoting macrophage polarization to M2 phenotype. At the same time, Dioscin maintained the intestinal barrier function by increasing the expression of zonula occludens-1 (ZO-1), occludin and mucin (Muc)-2. Moreover, Dioscin inhibited NF-κB, MAPK signaling and nucleotide oligomerization domain-like receptor family pyrin domain ontaining 3(NLRP3) inflammasome pathway in DSS-induced colitis. These results suggest that Dioscin is a competent candidate for ulcerative colitis (UC) therapy in the future.

NLRP6 in host defense and intestinal inflammation.

SUMMARYNLRP6 is a member of the NLR (nucleotide-oligomerization domain-like receptor) family of proteins that recognize pathogen-derived factors and damage-associated molecular patterns in the cytosol. The function of NLRP6 has been attributed to the maintenance of epithelial integrity and host defense against microbial infections. Under some physiological conditions, NLRP6 forms a complex with ASC and caspase-1 or caspase-11 to form an inflammasome complex cleaving pro-interleukin-1β(IL-1β) and IL-18 into their biologically active forms. Here, we summarize recent advances in the understanding of the mechanisms of activation of the NLRP6 inflammasome and discuss its relevance to human disease.

Investigating the possible association between NLRP3 gene polymorphisms and myasthenia gravis.

In this case-control study, we investigated the association between nucleotide oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3) single-nucleotide polymorphisms (SNPs) rs10754558, rs3806265, rs4612666, and rs35829419 and myasthenia gravis (MG). Samples from MG patients were selected from a previous study conducted in our neuromuscular clinic, which investigated the association between human leukocyte antigen (HLA) class II genes and MG. Genetic data of controls were also available from another study. The NLRP3 SNPs genotyping was performed using the TaqMan method. A total of 93 blood samples from eligible Iranian patients with MG and 56 samples from healthy controls were obtained. The NLRP3 rs3806265 "C" allele was significantly more frequent in MG patients (P < .001; odd ratio [OR] = 2.33, 95% confidence interval [CI]: 1.4-4.0) than controls. The "CC" genotype of this SNP was found in 18.27% of patients, but none of the controls (P < .001). The distribution of other SNPs was similar between the groups. These preliminary results suggest that there might be some associations between the NLRP3 gene polymorphism and MG.

The protective role of autophagy against arsenic trioxide-induced cytotoxicity and ROS-dependent pyroptosis in NCTC-1469 cells

Arsenic trioxide (As2O3) is widely used in traditional Chinese medicine to treat tumors. This study investigated the effect of As(III) on pyroptosis in murine hepatocytes in vitro and how this relates to autophagy. NCTC1469-cells were treated with As(III) alone (6, 12 and 18 μM) or in combination with N-acetylcysteine (NAC,1 mM), 3-methyladenine (3-MA, 5 mM) or rapamycin (Rapa,100 nM) for 24 h. The results showed that As(III)-treatment reduced cell viability in a dose-dependent manner, but induced lactic dehydrogenase (LDH) activity. As(III)-treatment also resulted in increased intracellular reactive oxygen species (ROS) levels and decreased mitochondrial membrane potential (MMP), therefore promoting pyroptosis. Moreover, As(III)-treatment upregulated the expression of autophagy and pyroptosis-related genes (LC3-A, LC3-B, P62, Beclin-1, Atg5, Caspase-1, Gasdermin D, IL-18, IL-1β) and downregulated the expression of m-TOR, NLRP3, ASC genes. Meanwhile the accumulation of light chain 3-B/A (LC3B/LC3A), autophagy-related gene 5 (Atg-5), Bcl-2-interacting protein (Beclin-1), Caspase-1, Gasdermin D, interleukin-1β (IL-1β), IL-18 and poptosis-associated speck-like protein (ASC) proteins were upregulated while nucleotide binding and oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) was downregulated in all As(III)-treatment groups. Furthermore, the inhibition of autophagy by 3-MA aggravated AsIII-induced pyroptosis and cytotoxicity. However, NAC or Rapa markedly alleviated the abovementioned phenomenon under As(III) stress. In addition, we speculate that the protective mechanism of NAC on As(III)-induced pyroptosis in hepatocytes mainly include the elimination of ROS because of the chelation of As(III) in the culture medium. In conclusion, these results provide new insight into the mechanisms underlying AsIII-induced cytotoxicity and pyroptosis in hepatocytes in vitro.

Are Migraine Patients at Increased Risk for Symptomatic Coronavirus Disease 2019 Due to Shared Comorbidities?

The coronavirus disease 2019 (COVID-19) pandemic has rapidly transformed the whole world and forced us to look through comorbid diseases and risk factors from a different perspective. COVID-19 shows some inherent risk factors like cardiovascular comorbidities independent from age, gender, and geographic location. One of the most peculiar features of the COVID-19 pandemic is that severe acute respiratory syndrome coronavirus 2 respiratory infections disproportionately impact patients with hypertension, diabetes, and other cardiovascular comorbidities rather than those with allergic respiratory diseases and immune-compromised conditions. Migraine is a complex neuro-vasculo-inflammatory disorder that is also packed frequently with certain medical conditions including vascular disorders, hypertension, allergic diseases such as asthma and systemic inflammatory disorders. Accordingly, 2 different questions arise during the pandemic: (1) Do share comorbidities of cardiovascular diseases and hypertension increase the risk of symptomatic COVID-19 for migraine patients? (2) Do comorbid allergic and atopic diseases, including asthma act as opposite influencers alongside with female gender? This paper focuses on the co-existence of comorbidities of COVID-19, in comparison with migraine, based on a wide clinical dataset and available reports. Discussed mechanisms include potential strategic roles of angiotensin-converting enzyme 2, angiotensin-II, and nucleotide oligomerization domain-like receptor family, pyrin domain containing 3 inflammasome, playing remarkable parts in the pathogenesis of COVID-19 and migraine. There are also some clues about the importance of endothelial and pericyte dysfunction and neuroinflammation in COVID-19 infection, related to complications and survival of the patients. The large epidemiological studies as well as basic research, focusing on migraine patients with COVID-19 will clarify these vital questions during the upcoming periods.

Ketone Metabolite β-Hydroxybutyrate Ameliorates Inflammation After Spinal Cord Injury by Inhibiting the NLRP3 Inflammasome.

Ketogenic diet (KD) has been shown to be beneficial in a range of neurological disorders, with ketone metabolite β-hydroxybutyrate (βOHB) reported to block the nucleotide oligomerization domain-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome in bone marrow-derived macrophages. In this study, we show that pretreatment with KD or in situ βOHB suppressed macrophages/microglia activation and the overproduction of inflammatory cytokines, while KD downregulated the expression of NLRP3 inflammasome. Moreover, KD promoted macrophages/microglia transformation from the M1 phenotype to the M2a phenotype following spinal cord injury (SCI) in the in vivo study. Rats in the KD group demonstrated improved behavioral and electrophysiological recovery after SCI when compared to those rats in the standard diet group. The in vitro study performed on BV2 cells indicated that βOHB inhibited an LPS+ATP-induced inflammatory response and decreased NLRP3 protein levels. Our data demonstrated that pretreatment with KD attenuated neuroinflammation following SCI, probably by inhibiting NLRP3 inflammasome and shifting the activation state of macrophages/microglia from the M1 to the M2a phenotype. Therefore, the ketone metabolite βOHB might provide a potential future therapeutic strategy for SCI.

Aluminum Adjuvant Improves Survival Via NLRP3 Inflammasome and Myeloid Non-Granulocytic Cells in a Murine Model of Neonatal Sepsis.

Neonatal sepsis leads to significant morbidity and mortality with the highest risk of death occurring in preterm (<37 weeks) and low birth weight (<2,500 g) infants. The neonatal immune system is developmentally immature with well-described defects in innate and adaptive immune responses. Immune adjuvants used to enhance the vaccine response have emerged as potential therapeutic options, stimulating non-specific immunity and preventing sepsis mortality. Aluminum salts ("alum") have been used as immune adjuvants for over a century, but their mechanism of action remains poorly understood. This study aims to identify potential mechanisms by which pretreatment with alum induces host protective immunity to polymicrobial sepsis in neonatal mice. Utilizing genetic and cell-depletion studies, we demonstrate here that the prophylactic administration of aluminum adjuvants in neonatal mice improves sepsis survival via activation of the nucleotide oligomerization domain-like receptor family, pyrin-domain-containing 3 inflammasome and dendritic cell activation. Furthermore, this beneficial effect is dependent on myeloid, non-granulocytic Gr1-positive cells, and MyD88-signaling pathway activation. These findings suggest a promising therapeutic role for aluminum-based vaccine adjuvants to prevent development of neonatal sepsis and improve mortality in this highly vulnerable population.

Amelioration of Coagulation Disorders and Inflammation by Hydrogen-Rich Solution Reduces Intestinal Ischemia/Reperfusion Injury in Rats through NF-κB/NLRP3 Pathway.

Intestinal ischemia/reperfusion (I/R) injury often causes inflammatory responses and coagulation disorders, which is further promoting the deterioration of the disease. Hydrogen has anti-inflammatory, antioxidative, and antiapoptotic properties against various diseases. However, the effect of hydrogen on coagulation dysfunction after intestinal I/R and the underlying mechanism remains unclear. The purpose of this study was to explore whether hydrogen-rich solution (HRS) could attenuate coagulation disorders and inflammation to improve intestinal injury and poor survival following intestinal I/R. The rat model of intestinal I/R injury was established by clamping the superior mesenteric artery for 90 min and reperfusion for 2 h. HRS (10 or 20 mL/kg) or 20 mL/kg 0.9% normal saline was intravenously injected at 10 min before reperfusion, respectively. The samples were harvested at 2 h after reperfusion for further analyses. Moreover, the survival rate was observed for 24 h. The results showed that HRS improved the survival rate and alleviated serum diamine oxidase activities, intestinal injury, edema, and apoptosis. Interestingly, HRS markedly improved intestinal I/R-mediated coagulation disorders as evidenced by abnormal conventional indicators of coagulation and thromboelastography. Additionally, HRS attenuated inflammatory responses and the elevated tissue factor (TF) and inhibited nuclear factor kappa beta (NF-κB) and nucleotide binding and oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome activation in peripheral blood mononuclear cells. Moreover, inflammatory factors and myeloperoxidase were closely associated with TF level. This study thus emphasized upon the amelioration of coagulation disorders and inflammation by HRS as a mechanism to improve intestinal I/R-induced intestinal injury and poor survival, which might be partially related to inhibition of NF-κB/NLRP3 pathway.