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Major Depressive Disorder (MDD, ICD-10: F-33) is a prevalent illness in which the pathogenic mechanism remains elusive. Recently an important role has been attributed to ...neuro-inflammation, and specifically the NLRP3-inflammasome complex, in the pathogenesis of MDD. This suggests a key role for immunomodulation as a key pathway in the treatment of this disorder. This study evaluates the involvement of nine common antidepressants in the NLRP3-inflammasome complex (fluoxetine, paroxetine, mianserin, mirtazapine, venlafaxine, desvenlafaxine, amitriptyline, imipramine and agomelatine), both in in vitro THP-1 cells stimulated by ATP, and in a stress-induced depressive animal or MDD patients. Antidepressant treatment induced inflammasome inhibition was observed by decreased serum levels of IL-1β and IL-18 and decrease of NLRP3 and IL-1β (p17) protein expression. This was also observed under stress-induced depressive behaviour and inflammasome activation in C57Bl/6 mice in vivo. Deletion of key autophagy mediator Atg5 in embryonic fibroblasts (MEF cells) showed an autophagy dependent-NLRP3-inflammasome inhibition by antidepressant treatment. These results suggest the NLRP3-inflammasome could be a biomarker for antidepressant treatment response in MDD patients, and therefore the monitoring of NLRP3 expression levels and/or IL-1β/IL-18 release may have clinical value in drug selection. Existing evidence suggests an anti-inflammatory effect of some antidepressants shown by IL-1β, IL-6 and TNF-α. Our data have shown that antidepressant-mediated autophagy may have a role in restoration of certain metabolic and immunological pathways in MDD patients.
Inflammation is a hallmark of aging and accelerated aging syndromes such as Hutchinson–Gilford progeria syndrome (HGPS). In this study, we present evidence of increased expression of the components ...of the NLRP3 inflammasome pathway in HGPS skin fibroblasts, an outcome that was associated with morphological changes of the nuclei of the cells. Lymphoblasts from HGPS patients also showed increased basal levels of NLRP3 and caspase 1. Consistent with these results, the expression of caspase 1 and Nlrp3, but not of the other inflammasome receptors was higher in the heart and liver of Zmpste24−/− mice, which phenocopy the human disease. These data were further corroborated in LmnaG609G/G609G mice, another HGPS animal model. We also showed that pharmacological inhibition of the NLRP3 inflammasome by its selective inhibitor, MCC950, improved cellular phenotype, significantly extended the lifespan of progeroid animals, and reduced inflammasome‐dependent inflammation. These findings suggest that inhibition of the NLRP3 inflammasome is a potential therapeutic approach for the treatment of HGPS.
SYNOPSIS
This study reveals a critical role of the NLRP3‐inflammasome complex in the pathogenesis of Hutchinson‐Gilford Progeria (HGPS). Targeting NLRP3 may be a novel potential therapeutic strategy for progeria treatment.
NLRP3 signalling is hyperactivated in the skin fibroblasts and lymphoblast of HPGS patients and animal models.
Inhibition of NLRP3 ameliorates phenotype of skin fibroblasts from patients and improves survival and bodyweight of animal models.
Inhibition of NLRP3 suppresses the inflammasome‐dependent inflammation in animal models.
This study reveals a critical role of the NLRP3‐inflammasome complex in the pathogenesis of Hutchinson‐Gilford Progeria (HGPS). Targeting NLRP3 may be a novel potential therapeutic strategy for progeria treatment.
Background
αB‐crystallin is a promiscuous protein involved in numerous cell functions. Mutations in CRYAB have been found in patients with different pathological phenotypes that are not properly ...understood. Patients can present different diseases like cataracts, muscle weakness, myopathy, cardiomyopathy, respiratory insufficiency or dysphagia, but also a variable combination of these pathologies has been found. These mutations can show either autosomal dominant or recessive mode of inheritance and variable penetrance and expressivity. This is the first report of congenital cataracts and myopathy described in childhood due to a CRYAB mutation with autosomal dominant mode of inheritance.
Methods
The whole exome sequence was subjected to phenotype‐driven analysis and a novel variant in CRYAB was detected: c.514delG, p.(Ala172ProfsTer14). The mutation was located in the C‐terminal domain of the protein, which is essential for chaperone activity. The deduced protein was analyzed searching for alterations of the relevant physico‐chemical properties described for this domain. A muscle biopsy was also tested for CRYAB with immunohistochemical and histoenzymatic techniques.
Results
CRYAB displayed a mild immunoreactivity in the subsarcolemmal compartment with no pathological sarcoplasmic accumulation. It agrees with an alteration of the physico‐chemical properties predicted for the C‐terminal domain: hydrophobicity, stiffness, and isomerization.
Conclusions
The described mutation leads to elongation of the protein at the carboxi‐terminal domain (CTD) with altered properties, which are essential for solubility and activity. It suggests that can be the cause of the severe conditions observed in this patient.
The isolation of DNA and whole exome sequencing led us to discover a novel mutation in a CRYAB which causes cataracts, myopathies and other conditions observed in the proband. The predicted altered physico‐chemical properties of the C‐terminal are related with low activity and low solubility. This new condition agrees with the muscle biopsy where the cell is depleted and the mutated protein is found attached to the membrane cell.
Background
Distal motor neuropathies with a genetic origin have a heterogeneous clinical presentation with overlapping features affecting distal nerves and including spinal muscular atrophies and ...amyotrophic lateral sclerosis. This indicates that their genetic background is heterogeneous.
Patient and methods
In this work, we have identified and characterized the genetic and molecular base of a patient with a distal sensorimotor neuropathy of unknown origin. For this study, we performed whole‐exome sequencing, molecular modelling, cloning and expression of mutant gene, and biochemical and cell biology analysis of the mutant protein.
Results
A novel homozygous recessive mutation in the human VRK1 gene, coding for a chromatin kinase, causing a substitution (c.637T > C; p.Tyr213His) in exon 8, was detected in a patient presenting since childhood a progressive distal sensorimotor neuropathy and spinal muscular atrophy syndrome, with normal intellectual development. Molecular modelling predicted this mutant VRK1 has altered the kinase activation loop by disrupting its interaction with the C‐terminal regulatory region. The p.Y213H mutant protein has a reduced kinase activity with different substrates, including histones H3 and H2AX, proteins involved in DNA damage responses, such as p53 and 53BP1, and coilin, the scaffold for Cajal bodies. The mutant VRK1(Y213H) protein is unable to rescue the formation of Cajal bodies assembled on coilin, in the absence of wild‐type VRK1.
Conclusion
The VRK1(Y213H) mutant protein alters the activation loop, impairs the kinase activity of VRK1 causing a functional insufficiency that impairs the formation of Cajal bodies assembled on coilin, a protein that regulates SMN1 and Cajal body formation.
Fibromyalgia (FM) is a worldwide diffuse musculoskeletal chronic pain condition that affects up to 5% of the general population. Many symptoms associated with mitochondrial diseases are reported in ...patients with FM such as exercise intolerance, fatigue, myopathy and mitochondrial dysfunction. In this study, we report a mutation in cytochrome b gene of mitochondrial DNA (mtDNA) in a family with FM with inflammasome complex activation.
mtDNA from blood cells of five patients with FM were sequenced. We clinically and genetically characterised a patient with FM and family with a new mutation in mtCYB. Mitochondrial mutation phenotypes were determined in skin fibroblasts and transmitochondrial cybrids.
After mtDNA sequence in patients with FM, we found a mitochondrial homoplasmic mutation m.15804T>C in the mtCYB gene in a patient and family, which was maternally transmitted. Mutation was observed in several tissues and skin fibroblasts showed a very significant mitochondrial dysfunction and oxidative stress. Increased NLRP3-inflammasome complex activation was observed in blood cells from patient and family.
We propose further studies on mtDNA sequence analysis in patients with FM with evidences for maternal inheritance. The presence of similar symptoms in mitochondrial myopathies could unmask mitochondrial diseases among patients with FM. On the other hand, the inflammasome complex activation by mitochondrial dysfunction could be implicated in the pathophysiology of mitochondrial diseases.
Conventional cardiovascular risk factors (CVRFs) are accepted to identify asymptomatic individuals with high risk of acute myocardial infarction (AMI). However, AMI affects many patients previously ...classified at low risk. New biomarkers are needed to improve risk prediction. We propose to evaluate the NLRP3-inflammasome complex as a potential conventional cardiovascular risk (CVR) indicator in healthy males and post-AMI patients and compare both groups by known CVRFs. We included 109 men with no history of cardiovascular disease (controls) and 150 AMI patients attending a cardiac rehabilitation program. AMI patients had higher mean of body mass index (BMI) and waist circumference than the controls. However, high percentages of the controls had a high BMI and a waist circumference >95 cm. The controls also had higher systolic blood pressure (p > 0.001), total and low-density lipoprotein cholesterol, dietary nutrient, and calorific intake. Fuster BEWAT score (FBS) correlated more closely than Framingham risk score (FRS) with most CVRF, groups. However, only the FBS showed a correlation with inflammasome cytokine interleukin 1β (IL-1β). Several CVRFs were significantly better in AMI patients; however, this group also had higher mRNA expression of the inflammasome gene NLRP3 and lower expression of the autophagy gene MAP-LC3. The controls had high levels of CVRF, probably reflecting unhealthy lifestyle. FBS reflects the efficiency of strategies to induce lifestyle changes such as cardiac rehabilitation programs, and could provide a sensitive evaluation CVR. These results lead to the hypothesis that NLRP3-inflammasome and associated IL-1β release have potential as CVR biomarkers, particularly in post-AMI patients with otherwise low risk scores. Antioxid. Redox Signal. 27, 269-275.
Aging is the major risk factor for many metabolic chronic diseases. Several metabolic pathways suffer a progressive impairment during aging including body composition and insulin resistance which are ...associated to autophagy dysfunction and increased inflammation. Many of these alterations are aggravated by non-healthy lifestyle such as obesity and hypercaloric diet which have been shown to accelerate aging. Here, we show that the deleterious effect of hypercaloric diets is reverted by the NLRP3 inflammasome inhibition. NLRP3 deficiency extends mean lifespan of adult mice fed a high-fat diet. This lifespan extension is accompanied by metabolic health benefits including reduced liver steatosis and cardiac damage, improved glucose and lipid metabolism, and improved protein expression profiles of SIRT-1, mTOR, autophagic flux, and apoptosis. These findings suggest that the suppression of NLRP3 prevented many age-associated changes in metabolism impaired by the effect of hypercaloric diets.
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