NLRP3 Research Articles

Autoinflammation with arthritis and dyskeratosis an inflammasomopathy: Case report and review of literature

Inherited disorders of the inflammasome pathway causes dysregulated inflammasome activation, which presents with inflammation and other clinical features linked to the defective protein. Eight mutations have been previously described in the NLRP1 inflammasome protein, causing different inflammatory skin disorders. Two of these mutations are associated with “autoinflammation with arthritis and dyskeratosis (AIADK),” a novel Mendelian auto-inflammatory disorder, in the 2017 International Union of Immunological Societies phenotypic classification for primary immunodeficiencies. We report a 22-year-old female, with recurrent generalized urticaria, periodic fever and pain abdomen, inflammatory polyarthritis, cutaneous lesions over the extremities, and persistently elevated inflammatory markers. On next-generation sequencing, a heterozygous missense mutation in exon 4 of the NLRP1 gene (chr17:G.5461839C>T) was detected, which results in the amino acid substitution of glutamine for arginine at codon 726 (c.2177G>A; p.Arg726Gln). A probable diagnosis of AIADK, possibly caused by this mutation was proposed, and patient responded well to colchicine.

Терапия хронической герпесвирусной инфекции у часто болеющих детей. Возможные причины неэффективности

Background: therapy for frequently ill children (FIC) with chronic herpesvirus infection includes antivirals and immunomodulators as these patients are considered immunocompromised. According to our data based on the prevalence of diseases and the viral replication activity, therapy may fail in 22% of cases. Aim: to identify a spectrum of rare genetic variants associated with primary immunodeficiency (PID) detected in FIC with stable, active persistence of herpesvirus infections that were resistant to repeat courses of antiviral and immunotropic therapy Patients and Methods: DNA samples of 33 frequently ill children with chronic herpesvirus infection who did not respond to therapy were analyzed using targeted high-throughput multigene sequencing to identify mutations in PID-associated genes. Results: pathogenic variants matching the potential diagnosis of PID were identified in two (6.1%) children. Rare genetic variants associated with the development of autoinflammatory diseases were found in 54.5% of cases. The p.Gln705Lys NLRP3 gene variant was the most common finding — it was detected in 5 (15.2%) children. Rare variants of the MEFV gene (MEFV p.Thr767Ile and MEFV p.Lys695Arg) were found in three (9.2%) children. In seven (21.2%) children rare variants of the NOD2 gene were identified, in four of them (12.2%) it was NOD2 p.Leu1007fs. Conclusions: the inefficiency of therapy in frequently ill children with chronic herpesvirus infection could be associated with characteristics of the innate immune system. Such children should be referred to immunology consultant and undergo molecular genetic testing. The detection of rare genetic variants associated with autoinflammatory diseases in more than half of the patients indicates that frequent (occurring every month) diseases with fever may mimic hidden or sometimes typical autoinflammatory diseases, despite the detection of the markers of viral and bacterial agents in a child KEYWORDS: frequently ill children, chronic herpesvirus infection, rare genetic variants, primary immunodeficiency. FOR CITATION: Levina A.S., Babachenko I.V., Skripchenko N.V. et al. Therapy of chronic herpesvirus infection in frequently ill children. Possible causes of inefficiency. Russian Journal of Woman and Child Health. 2022;5(4):332–339 (in Russ.). DOI: 10.32364/2618-8430- 2022-5-4-332-339.

Advanced glycation end products and their related signaling cascades in adult survivors of childhood Hodgkin lymphoma: A possible role in the onset of late complications

Hodgkin lymphoma (HL) is today one of the most curable pediatric cancers. Despite survival rates now exceeding 90%, survivors of pediatric HL are still at higher risk to develop late effects of cancer therapy. Premature aging has been proposed as a paradigm to explain the onset of long-term complications in these subjects. High levels of advanced glycation end products (AGEs), together with chronic inflammation and oxidative unbalance, have been shown to be among the main factors contributing to aging. The present study aims to evaluate glycoxydation, inflammatory status, and oxidative stress in plasma and peripheral blood mononuclear cells (PBMC) obtained from 20 adult survivors of pediatric HL and 40 age- and sex-matched healthy controls. After the isolation of PBMC and the collection of plasma, we performed the analyses of gene expression by qRT-PCR and measured inflammatory and oxidative-stress markers. AGEs plasma levels, expressed as Nϵ-carboxymethyl-lysine and methylglyoxal hydroimidazolone, were markedly higher in HL survivors than in healthy subjects. HL survivors also showed a condition of higher oxidative stress, as demonstrated by an increased expression of NADPH oxidase on PBMC. Antioxidant defenses, evaluated in terms of alpha-tocopherol, GSSG/GSH ratio and catalase plasma levels, were strongly impaired in survivors. This pro-oxidative condition led to the over-expression of both NLRP3 and NFkB genes in PBMC and, consequently, to increased plasma levels of interleukin(IL)-1β and IL-6. Finally, the expression of the receptors for AGEs in PBMC confirmed the dysregulated AGE pathways. Data show AGEs accumulation in survivors of pediatric HL. The consequent activation of the receptor for AGEs leads to the persistent activation of intracellular signaling toward inflammation. These results suggest that the co-existence of AGEs accumulation, unbalanced oxidative status, and inflammation could play a role in the onset of late complications in HL survivors.

The effect of Borago officinalis on the signaling pathway of the NLRP3 inflammasome complex, TLR4 and some inflammatory cytokines in type II diabetic patients with acute respiratory distress syndrome.

Acute respiratory distress syndrome (ARDS) is a life-threatening condition in which the lungs become severely inflamed, causing the alveoli to constrict or fill with fluid, which prevents the lungs from functioning properly. This disease becomes more dangerous when it occurs in patients with diabetes. Because of the clinical condition of these patients, it is not possible to treat them with usual medicines. One of the best options for treating these people is to use herbs. Borage (Borago officinalis) is a medicinal herb that, in addition to its anti-inflammatory properties, is also able to control blood sugar. Therefore, in the current study, the effect of borage oil was considered on the signaling pathway of the NLRP3 inflammasome complex, TLR4, and serum levels of inflammatory cytokines (IL-1? and IL-18) in type II diabetic patients with ARDS. For this purpose, 25 diabetic type II patients with ARDS were divided into three groups by ARDS Berlin Definition. Then, after providing the demographic and clinical characteristics of the patients, they were treated with 30 mg/day borage oil for seven days. The expression of NLRP3 and TLR4 genes (by Real-time PCR technique) and serum levels of IL-1? and IL-18 (by ELISA test) were evaluated before and after treatment with borage oil through blood samples taken from patients. The results showed that serum levels of inflammatory cytokines (IL-1? and IL-18), NLRP3 gene, and TLR4 gene were significantly decreased in diabetic type II patients with mild ARDS by treating with borage oil. IL-1? serum level and TLR4 were significantly decreased in diabetic type II patients with moderate ARDS. But there was not any significant decrease or increase in IL-1?, IL-18, NLRP3 gene, and TLR4 gene in diabetic type II patients with severe ARDS after 7 days of treatment with borage oil. According to the obtained results, borage oil can act as a double-edged blade. Thus, in the early and middle stages of ARDS, borage oil can be effective in reducing the inflammasome pathway of inflammation and also reduce blood sugar levels in these diabetic patients. But in the severe stage of ARDS, it not only does not help to treat the ARDS; it also increases systolic and diastolic blood pressure in diabetic patients.

Expression of NLRP3 and P2X7 transcripts in gingival tissues of chronic periodontitis patients and its correlation with P. gingivalis load and periodontal parameters

BackgroundInflammasomes are pivotal regulators of the host innate defense in periodontal tissues. Porphyromonas gingivalis modulates NLRP3 inflammasome complex and P2X7 receptor for survival in tissues through its virulence factors. AimTo estimate the expression of NLRP3 and P2X7 in gingival tissues of chronic periodontitis patients and to assess its correlation with periodontal clinical parameters and P. gingivalis load in subgingival plaque samples. Materials and methodsInterproximal gingival tissue and subgingival plaque samples (collected from same site) from systemically healthy chronic periodontitis patients (n = 22) and healthy controls (n = 22) were collected and stored in −80 °C. NLRP3 and P2X7 gene expression in gingival tissues and load of P. gingivalis in sub gingival plaque were assessed using real time Polymerase Chain Reaction. ResultsThe expression of NLRP3 in chronic periodontitis was marginally higher than healthy controls though the difference was statistically insignificant. P2X7 expression was higher in healthy controls and down regulated in chronic periodontitis patients (p = 0.04). A statistically significant correlation was observed between the probing pocket depth and expression of P2X7 gene in chronic periodontitis (p = 0.04). Correlation between P. gingivalis load and expression of the genes in tissues was either moderate (P2X7 control group) or negligible (both test and control of NLRP3). ConclusionA marginal increase in expression of NLRP3 and statistically significant decrease in P2X7 expression in chronic periodontitis patients was present. A statistically significant correlation was observed between P2X7 and P. gingivalis load in control group and periodontal parameters in test group. The study confirms involvement of genes in periodontal pathogenesis.

Caspase-3/NLRP3 signaling in the mesenchymal stromal niche regulates myeloid-biased hematopoiesis

BackgroundThe fate of hematopoietic stem cells (HSCs) is determined by a complex regulatory network that includes both intrinsic and extrinsic signals. In the past decades, many intrinsic key molecules of HSCs have been shown to control hematopoiesis homeostasis. Non-hematopoietic niche cells also contribute to the self-renewal, quiescence, and differentiation of HSCs. Mesenchymal stromal cells (MSCs) have been identified as important components of the niche. However, the regulatory role of MSCs in hematopoiesis has not been fully understood.MethodsCaspase-3 and NLRP3 gene knockout mice were generated respectively, and hematopoietic development was evaluated in the peripheral circulation and bone marrow by flow cytometry, colony formation assay, and bone marrow transplantation. Bone-associated MSCs (BA-MSCs) were then isolated from gene knockout mice, and the effect of Caspase-3/NLRP3 deficient BA-MSCs on hematopoiesis regulation was explored in vivo and ex vivo.ResultsWe report that Caspase-3 deficient mice exhibit increased myelopoiesis and an aberrant HSC pool. Ablation of Caspase-3 in BA-MSCs regulates myeloid lineage expansion by altering the expression of hematopoietic retention cytokines, including SCF and CXCL12. Interestingly, NLRP3 gene knockout mice share phenotypic similarities with Caspase-3 deficient mice. Additionally, we found that NLRP3 may play a role in myeloid development by affecting the cell cycle and apoptosis of hematopoietic progenitors.ConclusionsOur data demonstrate that the Caspase-3/NLRP3 signaling functions as an important regulator in physiological hematopoiesis, which provides new insights regarding niche signals that influence hematopoiesis regulation in the bone marrow.

Case Report: Infantile Urticaria as a Herald of Neonatal Onset Multisystem Inflammatory Disease With a Novel Mutation in NLRP3

Neonatal multisystem onset inflammatory disorder (NOMID) is a severe autoinflammatory syndrome that can have an initial presentation as infantile urticaria. Thus, an immediate recognition of the clinical symptoms is essential for obtaining a genetic diagnosis and initiation of early therapies to prevent morbidity and mortality. Herein, we describe a neonate presenting with urticaria and systemic inflammation within hours after birth who developed arthropathy and neurologic findings. Pathologic evaluation of the skin revealed an infiltration of lymphocytes, eosinophils, and scattered neutrophils. Genetic analysis identified a novel heterozygous germline variant of unknown significance in the NLRP3 gene, causing the missense mutation M408T. Variants of unknown significance are common in genetic sequencing studies and are diagnostically challenging. Functional studies of the M408T variant demonstrated enhanced formation and activity of the NLRP3 inflammasome, with increased cleavage of the inflammatory cytokine IL-1β. Upon initiation of IL-1 pathway blockade, the infant had a robust response and improvement in clinical and laboratory findings. Our experimental data support that this novel variant in NLRP3 is causal for this infant’s diagnosis of NOMID. Rapid assessment of infantile urticaria with biopsy and genetic diagnosis led to early recognition and targeted anti-cytokine therapy. This observation expands the NOMID-causing variants in NLRP3 and underscores the role of genetic sequencing in rapidly identifying and treating autoinflammatory disease in infants. In addition, these findings highlight the importance of establishing the functional impact of variants of unknown significance, and the impact this knowledge may have on therapeutic decision making.

A novel probiotic strain exerts therapeutic effects on mouse model of multiple sclerosis by altering the expression of inflammasome and IDO genes and modulation of T helper cytokine profile.

Multiple sclerosis is an inflammatory demyelinating disease that commences to neuronal cell destruction. Recently, a promising evidence of synergic effects of combined supplementation with vitamin D and probiotics in modulating the gut microbiota and metabolome is emerging. Bacillus Coagulans IBRC-M10791 as a novel strain was chosen, prevention and treatment impacts of regular administered were studied in Cuprizone-induced C57bl/6 mouse of demyelination. The mice were divided into six groups and received a daily dose of cuprizone or probiotics. To investigate the effect of probiotic, the IDO-1, CYP27B1, NLRP1, NLRP3, and AIM2 expression were estimated by Real-Time PCR, and IL-4, IL-17, IFN-gamma, and TGF-beta cytokines were measured by ELISA. The results showed that there was significant decrease in IL-17 and IFN-γ and modulatory effects on IL-4 and TGF-β. On the other hand, we demonstrated that there are significant decrease for expression of IDO-1, CYP27b1, NLRP1, NLRP3 and AIM2 genes in prevention and treatment groups compared to cuprizone group. Also, a significant enhancement in rate of remyelination and alternations proved by LFB staining and Y-Maze test. In conclusion, our study provides insight into how the therapeutic effect of the chosen strain of probiotic was correlated with the modulation of the level of inflammatory and anti-inflammatory cytokines. Further, we demonstrated that the expression of genes related to Tryptophan, Vitamin D and Inflammasome pathways could be affected by B.coagulans. Our study could be beneficial to provide a novel Co-therapeutic strategy for Multiple sclerosis.

Association of IL-1β, NLRP3, and COX-2 Gene Polymorphisms with Autoimmune Thyroid Disease Risk and Clinical Features in the Iranian Population.

Background Grave's disease (GD) and Hashimoto's thyroiditis (HT) are autoimmune diseases of the thyroid gland in which genetic predisposition plays a major role in their development. Currently, the role of NLRP3 inflammasome and COX-2 has been documented in many autoimmune diseases. The purpose of the study is to delineate the impact of IL-1β (rs1143634), NLRP3 (rs3806265), and COX-2 (rs2745557) gene polymorphisms in the development of GD and HT. Methods A total of 256 newly diagnosed patients with autoimmune thyroid disease (135 patients with HT and 121 GD patients) as case groups and 145 controls were included in the study. Results Recessive and overdominant models showed a significant association between IL-1β rs1143634 SNP and HT development risk. The frequency of TT genotype and T allele of IL-1β rs1143634 SNP in the control group was significantly higher than the GD group. There was no significant association between NLRP3 rs3806265 polymorphism and HT and GD development. The frequency of GA genotype of COX-2 (rs2745557) in the control group was significantly higher than that in the HT group. There was no significant association between COX-2 rs2745557 genotypic and allelic distribution and GD development risk. The results revealed a significant relationship between some clinical features of HT and GD groups and SNPs studied. Conclusion The results manifest the significant impact of IL-1β rs1143634 and COX-2 (rs2745557) SNPs and HT development and IL-1β rs1143634 SNP on GD occurrence risk. Furthermore, a significant relationship was observed between some clinical features of HT and GD groups and studied SNPs.

Predictive Value of miR-146a rs2431697 Polymorphism to Myelofibrosis Progression in Patients with Myeloproliferative Neoplasm.

Background:Bone marrow myelofibrosis (BMF) that develop on top of Polycythaemia vera (PV) and essential thrombocythemia leads to shortening of the patient’s overall survival. This study aimed to address the impact of miR-146a rs2431697 polymorphism on inflammatory biomarkers and genes expression and the hazards of myelofibrosis progression. Patients and Methods:The study included 88 myeloproliferative neoplasm (40 PV; 27 ET; 21 MF) and 90 healthy controls. For all investigated subjects miR-146a rs2431697 genotypes were identified by sequencing and the expression of miR-146a; IL-1β; NF-κB; a NOD-like receptor family, pyrin domain containing 3 (NLRP3) genes were estimated by real time PCR. Results:miR146a genotypes revealed that there was significant association between TT and TC genotypes with MF. The degree of miR146a expression was significantly reduced in MF as compared to both PV and ET. In contrast; the levels of IL-1β; NF-κB; NLRP3 genes expression were significantly elevated in MF patients group as compared to PV and ET patients’ group. Multivariate analysis identified TT genotype as poor predictor of MF progression. Conclusion:miR-146a rs2431697 TT genotype is associated with high risk of MF progression in MPN patients. Targeting of IL-1β; NF-κB; NLRP3 genes might help in hindering of MF progression in MPN patients,

Neuronal accumulation of peroxidated lipids promotes demyelination and neurodegeneration through the activation of the microglial NLRP3 inflammasome.

Peroxidated lipids accumulate in the presence of reactive oxygen species and are linked to neurodegenerative diseases. Here we find that neuronal ablation of ARF1, a small GTPase important for lipid homeostasis, promoted accumulation of peroxidated lipids, lipid droplets and ATP in the mouse brain and led to neuroinflammation, demyelination and neurodegeneration, mainly in the spinal cord and hindbrain. Ablation of ARF1 in cultured primary neurons led to an increase in peroxidated lipids in co-cultured microglia, activation of the microglial NLRP3 inflammasome and release of inflammatory cytokines in an Apolipoprotein E-dependent manner. Deleting the Nlrp3 gene rescued the neurodegenerative phenotypes in the neuronal Arf1-ablated mice. We also observed a reduction in ARF1 in human brain tissue from patients with amyotrophic lateral sclerosis and multiple sclerosis. Together, our results uncover a previously unrecognized role of peroxidated lipids released from damaged neurons in activation of a neurotoxic microglial NLRP3 pathway that may play a role in human neurodegeneration.

NLRP3 Inflammasome Blocking as a Potential Treatment of Central Insulin Resistance in Early-Stage Alzheimer's Disease.

Background: Alzheimer’s disease (AD) is a devastating neurodegenerative disorder. In recent years, attention of researchers has increasingly been focused on studying the role of brain insulin resistance (BIR) in the AD pathogenesis. Neuroinflammation makes a significant contribution to the BIR due to the activation of NLRP3 inflammasome. This study was devoted to the understanding of the potential therapeutic roles of the NLRP3 inflammasome in neurodegeneration occurring concomitant with BIR and its contribution to the progression of emotional disorders. Methods: To test the impact of innate immune signaling on the changes induced by Aβ1-42 injection, we analyzed animals carrying a genetic deletion of the Nlrp3 gene. Thus, we studied the role of NLRP3 inflammasomes in health and neurodegeneration in maintaining brain insulin signaling using behavioral, electrophysiological approaches, immunohistochemistry, ELISA and real-time PCR. Results: We revealed that NLRP3 inflammasomes are required for insulin-dependent glucose transport in the brain and memory consolidation. Conclusions NLRP3 knockout protects mice against the development of BIR: Taken together, our data reveal the protective role of Nlrp3 deletion in the regulation of fear memory and the development of Aβ-induced insulin resistance, providing a novel target for the clinical treatment of this disorder.

Associations between inflammasome‐related gene NLRP3 Polymorphisms (rs10754558 and rs35829419) and risk of bladder cancer in a Chinese population

BackgroundNLRP3 inflammasome as a component of immune system has been found related to several cancers, but no study has assessed NLRP3 polymorphisms on risk of bladder cancer (BC). We aim to investigate whether NLRP3 polymorphisms are associated with the risk and clinical features of bladder cancer (BC) in a Chinese population.MethodsGenotype frequency of two commonly studied NLRP3 SNPs (rs10754558 and rs35829419) was examined in 154 patients with BC and the 308 healthy controls. NLRP3 gene polymorphisms were genotyped by polymerase chain reaction‐restriction fragment length polymorphism method.ResultsThe distribution frequencies of GG, AG+GG, GG, and G allele in NLRP3 (rs10754558) genotypes were significantly different between case and control group (OR = 2.296, P = .022; OR = 1.598, P = .020; OR = 1.998, P = .049; OR = 1.557, P = .006), but no statistical difference existed for rs35829419. Among smokers and alcohol drinkers, for rs10754558, individuals with AG, GG, and GG+AG genotypes had a higher BC risk compared with individuals with AA; for rs35829419, individuals with variant genotypes (AG and GG+AG) had a stronger risk of developing BC compared with individuals with AA (all P < .05). In stratified analyses of tumor size and tumor node metastasis, AG or GG genotypes of rs10754558 and rs35829419 SNPs were associated with BC risk (both P < .05).ConclusionNLRP3 polymorphisms (rs10754558 and rs35829419) were related to BC risk and tumor size and lymph node metastasis, especially among smokers and alcohol drinkers.

Sterile inflammation through Ca2+/ Calmodulin-dependent protein kinase II signaling is essential for adverse cardiac remodeling

Abstract Introduction and hypothesis Sterile inflammation is associated with cardiac remodeling in response to non-ischemic stress, but how it is initiated in the absence of cell death and how it is propagated are not well elucidated. We tested the hypothesis that activation of CaMKII in cardiomyocytes and macrophages in response to pressure overload initiates inflammatory responses leading to adverse cardiac remodeling. Methods and results Cardiomyocyte specific CaMKIIδ knockout (CKO) mice were subjected to transverse aortic constriction (TAC). CaMKII and NFkB activation were significantly increased in control fl/fl (CTL) but not in CKO hearts. Cardiac mRNA levels for pro-inflammatory cytokines also increased vs sham. These responses were significantly attenuated in the CKO mice. Activated NLRP3 inflammasome was shown by elevated caspase-1 activity in isolated cardiomyocytes of CTL while attenuated in CKO. Macrophage accumulation was attenuated in the CKO and NLRP3 inhibitor MCC950 treated mice. Cardiac fibrosis and subsequent cardiac dysfunction were less impaired in the CKO vs CTL (ejection fraction 43±3% vs 33±5%). Upregulated NLRP3 gene expression, elevated CaMKII and caspase-1 activity were observed in neonatal mouse cardiomyocytes (NMCMs) in response to osmotic stretch. Increased caspase-1 activity was observed in macrophages cultured with media from osmotic-stretched NMCMs and it was attenuated by pretreatment of CaMKII inhibitor KN-93. Coincubation with stretched NMCMs induced inflammatory responses in isolated macrophages from wild-type mice but not in isolated macrophages from KN-93 pretreated mice. Conclusions Activated CaMKIIδ in response to pressure overload triggers inflammatory signals including NLRP3 inflammasome cascade in cardiomyocytes. CaMKII could also contribute amplification of inflammasome signal in macrophages leading fibrosis and consequent cardiac dysfunction. CaMKII in cardiomyocytes and macrophages could be a therapeutic target to prevent progression of non-ischemic heart failure. Funding Acknowledgement Type of funding sources: None.

Immunopathophysiology of Juvenile Spondyloarthritis (jSpA): The "Out of the Box" View on Epigenetics, Neuroendocrine Pathways and Role of the Macrophage Migration Inhibitory Factor (MIF).

Juvenile spondyloarthritis (jSpA) is a an umbrella term for heterogeneous group of related seronegative inflammatory disorders sharing common symptoms. Although it mainly affects children and adolescents, it often remains active during adulthood. Genetic and environmental factors are involved in its occurrence, although the exact underlying immunopathophysiology remains incompletely elucidated. Accumulated evidence suggests that, in affected patients, subclinical gut inflammation caused by intestinal dysbiosis, is pivotal to the future development of synovial–entheseal complex inflammation. While the predominant role of IL17/23 axis, TNF-α, and IL-7 in the pathophysiology of SpA, including jSpA, is firmly established, the role of the cytokine macrophage migration inhibitory factor (MIF) is generally overlooked. The purpose of this review is to discuss and emphasize the role of epigenetics, neuroendocrine pathways and the hypothalamic-pituitary (HPA) axis, and to propose a novel hypothesis of the role of decreased NLRP3 gene expression and possibly MIF in the early phases of jSpA development. The decreased NLRP3 gene expression in the latter, due to hypomethylation of promotor site, is (one of) the cause for inflammasome malfunction leading to gut dysbiosis observed in patients with early jSpA. In addition, we highlight the role of MIF in the complex innate, adaptive cellular and main effector cytokine network, Finally, since treatment of advanced bone pathology in SpA remains an unmet clinical need, I suggest possible new drug targets with the aim to ultimately improve treatment efficacy and long-term outcome of jSpA patients.

Melatonin ameliorates trimethyltin chloride-induced cardiotoxicity: The role of nuclear xenobiotic metabolism and Keap1-Nrf2/ARE axis-mediated pyroptosis.

Trimethyltin chloride (TMT) is a stabilizer for polyvinyl chloride plastics that causes serious health hazards in nontarget organisms. Melatonin (MT) exhibits powerful protective effects in cardiac diseases. As a new environmental pollutant, TMT-induced cardiotoxicity and the protective effects of MT remain unclear. To explore this, the mice were treated with TMT (2.8mg/kg) and/or MT (10mg/kg) for 7 days. Firstly, the histopathological and ultrastructural evaluation showed that TMT induced cardiac damage, tumescent rupture and nuclear pyknosis. Moreover, TMT elevated the expressions of pyroptosis genes NLRP3, ASC and Cas1 and inflammation factors IL-6, IL-17 and TNFα. Secondly, TMT reduced antioxidant enzymes (GSH, CAT and T-AOC) via decreasing the expression of genes associated with the Keap1-Nrf2/ARE pathway to increase oxidative stress. Thirdly, TMT decreased the expression of genes associated with the ARE-driven drug metabolizing enzymes (DMEs), including Akr7a3, Akr1b8, and Akr1b10. Besides, TMT upregulated the mRNA expression of nuclear Xenobiotic metabolism on cytochrome P450s enzymes via increasing the expression of CAR, PXP, and AHR genes. Furthermore, MT treatment mitigated the aforementioned adverse changes induced by TMT. Overall, these results demonstrated that TMT caused pyroptosis and inflammation to aggravate cardiac damage via inducing excessive oxidative stress, imbalance of DMEs homeostasis, and nuclear Xenobiotic metabolism disorder, which could be alleviated by MT.

Preventive Effects of Sinigrin Against the Memory Deterioration in the Pentylenetetrazole-Kindled Male Wistar Rats: Possible Modulation of NLRP3 Pathway.

Mainly found in brussels sprouts, broccoli, and black mustard seeds, sinigrin (2-propenyl glucosinolate) has enjoyed some attention currently for its effects on health and disease prevention. The present research design is aimed at investigating the effects of sinigrin on inflammation, oxidative stress (OS) and memory. Randomly, six groups of male Wistar rats were categorized into the control and experimental groups. The experimental groups were treated with sinigrin (10 and 20mg/kg, orally). The control positive group was given the pentylenetetrazole (PTZ) treatment and the control negative one was given normal saline. All groups were kindled by the sub-threshold dose (35mg/kg, i.p.) of PTZ for 12 times in one month. When the kindling procedure was done, the seizure behaviors and the behavioral function were evaluated. For cognitive parameters, the shuttle box test was employed. When the experiment was terminated, the rats were euthanized and their blood serum as well as brain samples were isolated for respective measuring of OS and gene expression parameters. The treatment with sinigrin significantly delayed the appearance of the seizure symptoms in comparison to that of the PTZ group. It also significantly increased the memory parameters like retention latency and the total time having been spent in the light compartment in the epileptic rats. In addition, sinigrin increased the superoxide dismutase and catalase levels. Treatment with sinigrin suppressed the Il1b and Nlrp3 gene expression at hippocampal level. In sum, sinigrin prevents inflammation, OS and memory impairment against the PTZ-kindling epilepsy in rats.

The Expression of Allele Changes in NLRP3 (rs35829419) and IL-1β (+3954) Gene Polymorphisms in Periodontitis and Coronary Artery Disease.

Background: Inflammasomes have been shown to play a pivotal role in periodontal disease pathogenesis. However, their role in periodontitis subjects with coronary heart disease remains unclear. This study aimed to obtain the expression of NLRP3 (rs35829419) and IL-1β (+3954) gene polymorphisms in the subgingival plaque and blood samples of generalized periodontitis (GP) subjects with and without coronary heart disease (CHD). Methods: A total of 70 subjects were grouped into two; GP and GP with CHD. Demographic variables and periodontal and cardiac parameters were recorded from both the groups. Subgingival plaque and blood samples were obtained from both the groups and were further subjected to the identification of NLRP3 (rs35829419) and IL-1β (+3954) expression and allele change using a conventional polymerase chain reaction (PCR) and gene sequencing (Sanger’s method). Results: Amongst the demographic variables, age and monthly income were statistically significant between the two groups. Plaque index (PI), clinical attachment level (CAL), high-density lipoprotein (HDL), and low density-lipoprotein (LDL) exhibited statistically significant levels between the two groups. The NLRP3 (rs35829419) and IL-1β (+3954) genes showed a statistically significant association with allele change (frequency) among the groups. The general comparison of all the parameters with the allele change of NLRP3 (rs35829419) and IL-1β (+3954) in the subgingival plaque and blood samples showed statistically significant associations among the two groups. Conclusion: The present study highlighted an allele change in IL-1β (+3954) gene polymorphisms which may play an important role in the pathogenesis of periodontitis and coronary heart disease.

The protective effects of neural stem cells and neural stem cells-conditioned medium against inflammation-induced prenatal brain injury

Intrauterine inflammation affects fetal development of the nervous system and may cause prenatal brain injury in offspring. Previously, neural stem cells have been extensively used as a therapeutic choice for nervous system diseases. Recently, the therapeutic ability of conditioned medium, harvested from cultured stem cells, has captured the attention of researchers in the field. Our study aimed to compare the therapeutic effect of neural stem cells (NSCs) or NSC-conditioned medium (NSC-CM) after prenatal brain injury. The animal model was induced by intraperitoneal injection of lipopolysaccharide into the pregnant mice and NSCs or NSC-CM were transplanted into the lateral ventricle of embryos in treatment groups. Inflammation and apoptosis were evaluated postpartum in offspring via measuring the expression of NLRP3 gene and protein, the expression and the activity of caspase-3, and the expression of pro-inflammatory cytokines by real-time PCR, immunohistochemistry, western blotting, ELISA, and colorimetric assay kit. A rotarod test was performed for motor function evaluation. Data showed that although NSC-CM fought against the inflammation and apoptosis and improved the motor function, NSCs acted more efficiently. In conclusion, the results of our study contend that NSCs have a better therapeutic effect than CM in prenatal brain injury.

Bilateral papilledema caused by chronic infantile neurological cutaneous and articular syndrome in a child with a novel (p. D305N) mutation in NLRP3 gene: a case report

Bilateral papilledema caused by chronic infantile neurological cutaneous and articular syndrome in a child with a novel (p. D305N) mutation in NLRP3 gene: a case report