Proximity extension assay-based proteomics studies in neurodegenerative disorders and multiple sclerosis.

Neurodegenerative diseases impact the structure and operation of the nervous system, causing progressive and irreparable harm. Efforts for distinguishing neurodegenerative diseases in their early stages are continuing. Despite several biomarkers being identified, there is always search for more accurate and abundant ones. Additionally, it can be difficult to pinpoint the precise neurodegenerative disorder affecting a patient as the symptoms of these conditions frequently overlap. Numerous studies have shown that pathological changes occur years before clinical signs appear. Therefore, it is crucial to discover blood-based biomarkers for neurodegenerative diseases for easier and earlier diagnosis. Proximity extension assay is a unique proteomics method that uses antibodies linked to oligonucleotides for quantifying proteins with real-time PCR. Proximity extension assay can identify even low-quantity proteins using a small volume of specimens with increased sensitivity compared to conventional methods. In this article, we reviewed the employment of proximity extension assay technology to detect biomarkers or protein profiles for several neurodegenerative diseases.

Bilirubin induces microglial NLRP3 inflammasome activation in vitro and in vivo.

Despite current advancements in neonatal care, hyperbilirubinemia resulting in bilirubin-induced neurological dysfunction (BIND) continues to be one of the major reasons of mortality or lifelong disability. Although the exact mechanisms underlying brain injury upon bilirubin exposure remains unelucidated, inflammation is considered to be one of the major contributors to BIND. This study investigates the role of the NLRP3 inflammasome in bilirubin-induced injury using in vitro and in vivo models. We successfully demonstrated that the upregulation of NLRP3 expression is significantly associated with the release of active caspase-1 and IL-1ß in N9 microglial cells exposed to bilirubin. Functional in vitro experiments with NLRP3 siRNA confirms that bilirubin-induced inflammasome activation and cell death are mediated by the NLRP3 inflammasome. Following injection of bilirubin into the cisterna magna of a neonatal mouse, activation of the NLRP3 inflammasome and microglia were determined by double staining with Iba1-NLRP3 and Iba1-Caspase-1. Upon injection of bilirubin into the cisterna magna, neuronal loss was significantly higher in the wild-type mouse compared to Nlrp3-/- and Caspase-1-/- strains. Collectively, these data indicate that NLRP3 inflammasome has a crucial role in microglial activation and bilirubin-induced neuronal damage.

A New Perspective on the Pathogenesis of Infantile Colic: Is Infantile Colic a Biorhythm Disorder?

OBJECTIVES: In this study, we investigated the relationship between infantile colic, migraine, and biorhythm regulation, by evaluating biochemical and molecular parameters. STUDY DESIGN: Healthy infants with and without infantile colic were eligible for this prospective cohort study. A questionnaire was applied. Between the 6th and 8th postnatal weeks, day and night circadian histone gene H3f3b mRNA expression and spot urine excretion of serotonin, cortisol, and 6-sulphatoxymelatonin were analyzed. RESULTS: Among the 95 infants included, 49 were diagnosed with infantile colic. In the colic group, defecation difficulty, sensitivity to light/sound, and maternal migraine frequency increased and sleep disruption was typical. In the melatonin analysis, the difference between day and night levels was significant in the control group, indicating an established circadian rhythm ( P = 0.014). In the colic group, there was no day-night difference ( P = 0.216) in melatonin, but serotonin levels were higher at night. In the cortisol analysis, day-night values were similar in both groups. Day-night variability of H3f3b mRNA levels between the groups was significant, indicating circadian rhythm disturbance in the colic group compared to the control group ( P = 0.003). Fluctuations in circadian genes and hormones expected in healthy rhythm were revealed in the control group, but were missing in the colic group. CONCLUSION: Due to the gaps in the etipathogenesis in infantile colic, a unique effective agent has not been discovered so far. This study, which demonstrated for the first time that infantile colic is a biorhythm disorder using molecular methods, fills the gap in this regard and points to a completely different perspective in terms of treatment.

Melatonin Alters the miRNA Transcriptome of Inflammasome Activation in Murine Microglial Cells.

Systemic inflammation can have devastating effects on the central nervous system via its resident immune cells, the microglia. One of the primary mediators of this inflammation is inflammasomes, multiprotein complexes that trigger a release of inflammatory proteins when activated. Melatonin, a hormone with anti-inflammatory effects, is an attractive candidate for suppressing such inflammation. In this study, we have investigated how melatonin alters the microRNA (miRNA) transcriptome of microglial cells. For that purpose, we have performed RNA sequencing on a lipopolysaccharide and adenosine triphosphate (LPS + ATP) induced NLR family pyrin domain containing 3 (NLRP3) inflammasome activation model in the N9 mouse microglial cell line, with and without melatonin pre-treatment. We have identified 136 differentially expressed miRNAs in cells exposed to LPS + ATP compared to controls and 10 differentially expressed miRNAs in melatonin pre-treated cells compared to the inflammasome group. We have identified miR-155-3p as a miRNA that is upregulated with inflammasome activation and downregulated with melatonin treatment. We further confirmed this pattern of miR-155-3p expression in the brains of mice injected intraperitoneally with LPS. Moreover, an overexpression study with miRNA-155-3p mimic supported the idea that the protective effects of melatonin in NLRP3 inflammasome activation are partly associated with miRNA-155-3p inhibition.

Lithium inhibits oxidative stress-induced neuronal senescence through miR-34a.

Neuronal senescence, triggered by telomere shortening, oncogene activation, DNA damage, or oxidative stress, has been associated with neurodegenerative diseases' pathogenesis. Therefore, preventing neuronal senescence could be a novel treatment strategy for neurodegenerative diseases. Lithium (Li), the first-line treatment against bipolar disorder, has been shown to have neuroprotective effects in clinical, pre-clinical, and in vitro studies. Li can protect cells from senescence, and its effect on neuronal senescence was investigated in our study. Furthermore, we also investigated the effects of Li on the senescence-associated miR-34a/Sirt1/p53 pathway. In this study, hydrogen peroxide was used as an inducer for the "stress-induced premature senescence" model. In the senescence model, we have assessed Li's effects on senescence by analyzing ß-galactosidase activity, Sudan Black B, and senescence-associated heterochromatin foci (SAHF) stainings, and on cell cycle arrest by BrdU staining. Furthermore, expression levels of senescence and cell cycle arrest-related proteins (p53, p21, p16INK4a, and SIRT1) by western blotting. Finally, the effects of Li on senescence-associated miR-34a levels were measured by quantitative PCR. We show via Sudan Black B staining, ß-Gal activity assay, and by detecting SAHF, Li protects against senescence in neuronal cells. Then, Li's effect on signaling has also been determined on pathways involved in senescence and cell cycle arrest. Moreover, we have observed that Li has a modulatory effect on miR-34a expression. Therefore, we posit that Li suppresses senescence in neuronal cells and that this effect is mediated through miR-34a/Sirt1/p53 axis.

Stem Cell Therapy for Multiple Sclerosis.

Multiple sclerosis (MS) is a chronic inflammatory, autoimmune, and neurodegenerative disease of the central nervous system (CNS). It is characterized by demyelination and neuronal loss that is induced by attack of autoreactive T cells to the myelin sheath and endogenous remyelination failure, eventually leading to functional neurological disability. Although recent evidence suggests that MS relapses are induced by environmental and exogenous triggers such as viral infections in a genetic background, its very complex pathogenesis is not completely understood. Therefore, the efficiency of current immunosuppression-based therapies of MS is too low, and emerging disease-modifying immunomodulatory agents such as fingolimod and dimethyl fumarate cannot stop progressive neurodegenerative process. Thus, the cell replacement therapy approach that aims to overcome neuronal cell loss and remyelination failure and to increase endogenous myelin repair capacity is considered as an alternative treatment option. A wide variety of preclinical studies, using experimental autoimmune encephalomyelitis model of MS, have recently shown that grafted cells with different origins including mesenchymal stem cells (MSCs), neural precursor and stem cells, and induced-pluripotent stem cells have the ability to repair CNS lesions and to recover functional neurological deficits. The results of ongoing autologous hematopoietic stem cell therapy studies, with the advantage of peripheral administration to the patients, have suggested that cell replacement therapy is also a feasible option for immunomodulatory treatment of MS. In this chapter, we overview cell sources and applications of the stem cell therapy for treatment of MS. We also discuss challenges including those associated with administration route, immune responses to grafted cells, integration of these cells to existing neural circuits, and risk of tumor growth. Finally, future prospects of stem cell therapy for MS are addressed.

Nrf2 activator Diethyl Maleate attenuates ROS mediated NLRP3 inflammasome activation in murine microglia.

Microglia are the tissue-resident immune cells of the central nervous system. As a part of the innate immune response, NLR Family Pyrin Domain Containing Protein 3 (NLRP3) inflammasome activation leads to cleavage of caspase-1 and triggers secretion of proinflammatory cytokines and may also result in pyroptotic cell death. Inflammasome activation plays a crucial role in inflammatory conditions; aberrant activation of inflammasome contributes to the pathogenesis of neurodegenerative diseases. Diethyl Maleate (DEM) is a promising antiinflammatory chemical to alleviate inflammasome activation. In this study, NLRP3 inflammasome was activated in N9 murine microglia via 1 µg/ml LPS (Lipopolysaccharide) for 4 h and 5 mM ATP (Adenosine 5'-triphosphate) for 1 h, respectively. We demonstrated that 1 h pretreatment of DEM attenuated NLRP3 inflammasome activation in microglial cells. Besides, mitochondrial ROS decreased upon DEM pretreatment in inflammasome-induced cells. Likewise, it ameliorated pyroptotic cell death in microglia. DEM is a potent activator of Nrf2 transcription factor, the key regulator of the antioxidant response pathway. Nrf2 has been a significant target to decrease aberrant inflammasome activation through the antioxidant compounds, including DEM. Here, we have shown that DEM increased Nrf2 translocation to the nucleus, resulting in Nrf2 target gene expression in microglia. In conclusion, DEM is a promising protective agent against NLRP3 inflammasome activation.

Biomarkers of NRF2 signalling: Current status and future challenges.

The cytoprotective transcription factor NRF2 regulates the expression of several hundred genes in mammalian cells and is a promising therapeutic target in a number of diseases associated with oxidative stress and inflammation. Hence, an ability to monitor basal and inducible NRF2 signalling is vital for mechanistic understanding in translational studies. Due to some caveats related to the direct measurement of NRF2 levels, the modulation of NRF2 activity is typically determined by measuring changes in the expression of one or more of its target genes and/or the associated protein products. However, there is a lack of consensus regarding the most relevant set of these genes/proteins that best represents NRF2 activity across cell types and species. We present the findings of a comprehensive literature search that according to stringent criteria identifies GCLC, GCLM, HMOX1, NQO1, SRXN1 and TXNRD1 as a robust panel of markers that are directly regulated by NRF2 in multiple cell and tissue types. We assess the relevance of these markers in clinically accessible biofluids and highlight future challenges in the development and use of NRF2 biomarkers in humans.

Neurodegenerative disease phenotypes in carriers of MAPT p.A152T, a risk factor for frontotemporal dementia spectrum disorders and Alzheimer disease.

Recently, Coppola and colleagues demonstrated that a rare microtubule-associated protein tau (MAPT) sequence variant, c.454G>A (p.A152T) significantly increases the risk of frontotemporal dementia (FTD) spectrum disorders and Alzheimer disease (AD) in a screen of 15,369 subjects. We describe clinical features of 9 patients with neurodegenerative disease (4 women) harboring p.A152T, aged 51 to 79 years at symptom onset. Seven developed FTD spectrum clinical syndromes, including progressive supranuclear palsy syndrome (n=2), behavioral variant FTD (bvFTD, n=1), nonfluent variant primary progressive aphasia (nfvPPA, n=2), and corticobasal syndrome (n=2); 2 patients were diagnosed with clinical AD. Thus, MAPT p.A152T is associated with a variety of FTD spectrum clinical presentations, although patients with clinical AD are also identified. These data warrant larger studies with clinicopathologic correlation to elucidate the influence of this genetic variant on neurodegenerative disease.

Mitochondrial DNA oxidation, methylation, and copy number alterations in major and bipolar depression.

Background: Mood disorders are common disabling psychiatric disorders caused by both genetic and environmental factors. Mitochondrial DNA (mtDNA) modifications and epigenetics are promising areas of research in depression since mitochondrial dysfunction has been associated with depression. In this study we aimed to investigate the mtDNA changes in depressive disorder (MDD) and bipolar disorder (BD). Methods: Displacement loop methylation (D-loop-met), relative mtDNA copy number (mtDNA-cn) and mtDNA oxidation (mtDNA-oxi) were investigated in DNA samples of individuals with MDD (n = 34), BD (n = 23), and healthy controls (HC; n = 40) using the Real-Time Polymerase Chain Reaction (RT-PCR). Blood samples were obtained from a subset of individuals with MDD (n = 15) during a depressive episode (baseline) and after remission (8th week). Results: The study groups exhibited significant differences in D-loop-met (p = 0.020), while relative mtDNA-cn and mtDNA-oxi showed comparable results. During the remission phase (8th week), there were lower levels of relative mtDNA-cn (Z = -2.783, p = 0.005) and D-loop-met (Z = -3.180, p = 0.001) compared to the acute MDD baseline, with no significant change in mtDNA-oxi levels (Z = -1.193, p = 0.233). Conclusion: Our findings indicate significantly increased D-loop methylation in MDD compared to BD and HCs, suggesting distinct mtDNA modifications in these conditions. Moreover, the observed alterations in relative mtDNA-cn and D-loop-met during remission suggest a potential role of mtDNA alterations in the pathophysiology of MDD. Future studies may provide valuable insights into the dynamics of mtDNA modifications in both disorders and their response to treatment.

Resveratrol reduces matrix metalloproteinase-2 activity induced by oxygen-glucose deprivation and reoxygenation in human cerebral microvascular endothelial cells.

The main pathophysiology in cerebral ischemia is the structural alteration in the neurovascular unit, coinciding with neurovascular matrix degradation. Among the human matrix metalloproteinases (MMPs), MMP-2 and -9, known as gelatinases, are the key enzymes for degrading type IV collagen, which is the major component of the basal membrane that surrounds the cerebral blood vessel. In the present study, we investigated the effects of resveratrol on cytotoxicity, reactive oxygen species (ROS), and gelatinases (MMP-2 and -9) in human cerebral microvascular endothelial cells exposed to 6 hours of oxygen-glucose deprivation and a subsequent 24 hours of reoxygenation with glucose (OGD/R), to mimic ischemia/reperfusion in vivo. Lactate dehydrogenase increased significantly, in comparison to that in the normoxia group. ROS was markedly increased in the OGD/R group, compared to normoxia. Correspondingly, ROS was significantly reduced with 50 µM of resveratrol. The proMMP-2 activity in the OGD/R group showed a statistically significant increase from the control cells. Resveratrol preconditioning decreased significantly the proMMP-2 in the cells exposed to OGD/R in comparison to that in the OGD/R group. Our results indicate that resveratrol regulates MMP-2 activity induced by OGD/R via its antioxidant effect, implying a possible mechanism related to the neuroprotective effect of resveratrol.

Targeting NLRP3 Inflammasome With Nrf2 Inducers in Central Nervous System Disorders.

The NLRP3 inflammasome is an intracellular multiprotein complex that plays an essential role in the innate immune system by identifying and eliminating a plethora of endogenous and exogenous threats to the host. Upon activation of the NLRP3 complex, pro-inflammatory cytokines are processed and released. Furthermore, activation of the NLRP3 inflammasome complex can induce pyroptotic cell death, thereby propagating the inflammatory response. The aberrant activity and detrimental effects of NLRP3 inflammasome activation have been associated with cardiovascular, neurodegenerative, metabolic, and inflammatory diseases. Therefore, clinical strategies targeting the inhibition of the self-propelled NLRP3 inflammasome activation are required. The transcription factor Nrf2 regulates cellular stress response, controlling the redox equilibrium, metabolic programming, and inflammation. The Nrf2 pathway participates in anti-oxidative, cytoprotective, and anti-inflammatory activities. This prominent regulator, through pharmacologic activation, could provide a therapeutic strategy for the diseases to the etiology and pathogenesis of which NLRP3 inflammasome contributes. In this review, current knowledge on NLRP3 inflammasome activation and Nrf2 pathways is presented; the relationship between NLRP3 inflammasome signaling and Nrf2 pathway, as well as the pre/clinical use of Nrf2 activators against NLRP3 inflammasome activation in disorders of the central nervous system, are thoroughly described. Cumulative evidence points out therapeutic use of Nrf2 activators against NLRP3 inflammasome activation or diseases that NLRP3 inflammasome contributes to would be advantageous to prevent inflammatory conditions; however, the side effects of these molecules should be kept in mind before applying them to clinical practice.

MicroRNAs in Genetic Etiology of Human Diseases.

Since their first discovery more than 20 years ago, miRNAs have been subject to deliberate research and analysis for revealing their physiological or pathological involvement. Regulatory roles of miRNAs in signal transduction, gene expression, and cellular processes in development, differentiation, proliferation, apoptosis, and homeostasis also imply their critical role in disease pathogenesis. Their roles in cancer, neurodegenerative diseases, and other systemic diseases have been studied broadly. In these regulatory pathways, their mutations and target sequence variations play critical roles to determine their functional repertoire. In this chapter, we summarize studies that investigated the role of mutations, polymorphisms, and other variations of miRNAs in respect to pathological processes.

Role of Exosomal MicroRNAs in Cell-to-Cell Communication.

Exosomes, a type of extracellular vesicle, are small vesicles (30-100 nm) secreted into extracellular space from almost all types of cells. Exosomes mediate cell-to-cell communication carrying various biologically active molecules including microRNAs. Studies have shown that exosomal microRNAs play fundamental roles in healthy and pathological conditions such as immunity, cancer, and inflammation. In this chapter, we introduce the current knowledge on exosome biogenesis, techniques used in exosome research, and exosomal miRNA and their functions in biological and pathological processes.

In vitro effects of H2O2 on neural stem cell differentiation.

The development of the CNS is a complex and well-regulated process, where stem cells differentiate into committed cells depending on the stimuli from the microenvironment. Alterations of oxygen levels were stated to be significant in terms of brain development and neurogenesis during embryonic development, as well as the adult neurogenesis. As a product of oxygen processing, hydrogen peroxide (H2O2) has been established as a key regulator, acting as a secondary messenger, of signal transduction and cellular biological functions. H2O2 is involved in survival, proliferation, and differentiation of neural stem cells into committed cells of the CNS. Effects of different concentrations of exogenous H2O2 on neuronal differentiation and the molecular pathways involved are yet to be clearly understood. Here, we investigated the concentration-dependent effects of H2O2 on differentiation of neural stem cells using CGR8 embryonic mouse stem cell line. We have demonstrated that treated doses of H2O2 suppress neural differentiation; additionally, our study suggests that relatively high doses of exogenous H2O2 suppress the differentiation process of neural stem cells through AKT and p38 pathways.

Alteration of miRNAs in Small Neuron-Derived Extracellular Vesicles of Alzheimer's Disease Patients and the Effect of Extracellular Vesicles on Microglial Immune Responses.

Alzheimer's disease (AD) is one of the most severe neurodegenerative diseases observed in the elderly population. Although the hallmarks of AD have been identified, the methods for its definitive diagnosis and treatment are still lacking. Extracellular vesicles (EVs) have become a promising source for biomarkers since the identification of their content. EVs are released from multiple cell types and, when released from neurons, they pass from the brain to the blood with their cargo molecules. Hence, neuron-specific EV-resident microRNAs (miRNAs) are promising biomarkers for diagnosis of AD. This study aimed to identify altered miRNA content in small neuron-derived extracellular vesicles (sNDEVs) isolated from AD patients and healthy individuals. Furthermore, we examined the role of sNDEV-resident miRNAs in neuron-glia cellular interaction to understand their role in AD propagation. We identified 10 differentially expressed miRNAs in the sNDEVs of patients via next-generation sequencing and validated the most dysregulated miRNA, let-7e, with qRT-PCR. Let-7e was significantly increased in the sNDEVs of AD patients compared with those of healthy controls in a larger cohort. First, we evaluated the diagnostic utility of let-7e via ROC curve analysis, which revealed an AUC value of 0.9214. We found that IL-6 gene expression was increased in human microglia after treatment with sNDEVs of AD patients with a high amount of let-7e. Our study suggests that sNDEV-resident let-7e is a potential biomarker for AD diagnosis, and that AD patient-derived sNDEVs induce a neuroinflammatory response in microglia.

Pros and cons of NRF2 activation as adjunctive therapy in rheumatoid arthritis.

Rheumatoid arthritis (RA) is an autoimmune disease with an important inflammatory component accompanied by deregulated redox-dependent signaling pathways that are feeding back into inflammation. In this context, we bring into focus the transcription factor NRF2, a master redox regulator that exerts exquisite antioxidant and anti-inflammatory effects. The review does not intend to be exhaustive, but to point out arguments sustaining the rationale for applying an NRF2-directed co-treatment in RA as well as its potential limitations. The involvement of NRF2 in RA is emphasized through an analysis of publicly available transcriptomic data on NRF2 target genes and the findings from NRF2-knockout mice. The impact of NRF2 on concurrent pathologic mechanisms in RA is explained by its crosstalk with major redox-sensitive inflammatory and cell death-related pathways, in the context of the increased survival of pathologic cells in RA. The proposed adjunctive therapy targeted to NRF2 is further sustained by the existence of promising NRF2 activators that are in various stages of drug development. The interference of NRF2 with conventional anti-rheumatic therapies is discussed, including the cytoprotective effects of NRF2 for alleviating drug toxicity. From another perspective, the review presents how NRF2 activation would be decreasing the efficacy of synthetic anti-rheumatic drugs by increasing drug efflux. Future perspectives regarding pharmacologic NRF2 activation in RA are finally proposed.

Inhibitory effects of sulforaphane on NLRP3 inflammasome activation.

SFN, a dietary phytochemical, is a significant member of isothiocyanates present in cruciferous vegetables at high levels in broccoli. It is a well-known activator of the Nrf2/ARE antioxidant pathway. Long since, the therapeutic effects of SFN have been widely studied in several different diseases. Other than the antioxidant effect, SFN also exhibits an anti-inflammatory effect through suppression of various mechanisms, including inflammasome activation. Considerably, SFN has been demonstrated to inhibit multiple inflammasomes, including NLRP3 inflammasome. NLRP3 inflammasome induces secretion of pro-inflammatory cytokines and promotes inflammatory cell death. The release of pro-inflammatory cytokines enhances the inflammatory response, in turn leading to tissue damage. These self-propelling inflammatory responses would need modulation with exogenous therapeutic agents to suppress them. SFN is a promising candidate molecule for the mitigation of NLRP3 inflammasome activation, which has been related to the pathogenesis of numerous disorders. In this review, we have provided fundamental knowledge about Sulforaphane, elaborated its characteristics, and evidentially focused on its mechanisms of action with regard to its anti-inflammatory, anti-oxidative, and neuroprotective features. Thereafter, we have summarized both in vitro and in vivo studies regarding SFN effect on NLRP3 inflammasome activation.

The Role of Melatonin on NLRP3 Inflammasome Activation in Diseases.

NLRP3 inflammasome is a part of the innate immune system and responsible for the rapid identification and eradication of pathogenic microbes, metabolic stress products, reactive oxygen species, and other exogenous agents. NLRP3 inflammasome is overactivated in several neurodegenerative, cardiac, pulmonary, and metabolic diseases. Therefore, suppression of inflammasome activation is of utmost clinical importance. Melatonin is a ubiquitous hormone mainly produced in the pineal gland with circadian rhythm regulatory, antioxidant, and immunomodulatory functions. Melatonin is a natural product and safer than most chemicals to use for medicinal purposes. Many in vitro and in vivo studies have proved that melatonin alleviates NLRP3 inflammasome activity via various intracellular signaling pathways. In this review, the effect of melatonin on the NLRP3 inflammasome in the context of diseases will be discussed.

Resveratrol Inhibits NLRP3 Inflammasome-Induced Pyroptosis and miR-155 Expression in Microglia Through Sirt1/AMPK Pathway.

Resveratrol is a natural polyphenolic compound with a wide range of biological activities such as antioxidant, anti-carcinogenic, anti-obesity, anti-aging, anti-inflammatory, immunomodulatory properties. Accumulating evidence suggests that resveratrol has pharmacological benefits in life-threatening diseases, including cardiovascular disease, cancer, diabetes, and neurodegenerative diseases. Resveratrol is widely known for its anti-inflammatory properties; however, signaling mechanisms of anti-inflammatory action are still elusive. Studies have illustrated that resveratrol can control different regulatory pathways by altering the expression and consequently regulatory effects of microRNAs. Our study aims to clarify the regulatory mechanisms of resveratrol in its anti-inflammatory features in the N9 microglial cell line. Our results demonstrated that resveratrol inhibits LPS- and ATP-activated NLRP3 inflammasome and protects microglial cells upon oxidative stress, proinflammatory cytokine production, and pyroptotic cell death resulting from inflammasome activation. Additionally, resveratrol inhibits nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling and activates AMPK/Sirt1 pathways. Furthermore, our results indicated that resveratrol downregulated inflammasome-induced miR-155 expression. Then, inhibition of AMPK and Sirt1 pathways has significantly reversed protective effect of resveratrol on miR-155 expression. To sum up, our results suggest that resveratrol suppresses the NLRP3 inflammasome and miR-155 expression through AMPK and Sirt1 pathways in microglia.