Knockdown of MVK does not lead to changes in NALP3 expression or activation

Mutations in the Mevalonate Kinase gene (MVK) are causes of a rare autoinflammatory disease: Mevalonate Kinase Deficiency and its more acute manifestation, Mevalonic Aciduria. The latter is characterized, among other features, by neuroinflammation, developmental delay and ataxia, due to failed cerebellar development or neuronal death through chronic inflammation. Pathogenesis of neuroinflammation in Mevalonate Kinase Deficiency and Mevalonic Aciduria has not yet been completely clarified, however different research groups have been suggesting the inflammasome complex as the key factor in the disease development. A strategy to mimic this disease is blocking the mevalonate pathway, using HMG-CoA reductase inhibitors (Statins), while knock-out mice for Mevalonate Kinase are non-vital and their hemyzygous (i.e only one copy of gene preserved) littermate display almost no pathological features

NLRP1 and NLRP3 polymorphisms in mesothelioma patients and asbestos exposed individuals a population-based autopsy study from North East Italy

NRLP1 (rs12150220, rs9889625, rs9900356, rs6502867, rs2670660) and NLRP3 (rs35829419, rs10754558) polymorphisms have been analyzed in 69 subjects with documented asbestos exposure and death for malignant pleural mesothelioma and 59 patients with documented asbestos exposure but death for other causes, all from a North East Italy. No association was found between NLRP1 and NLRP3 polymorphisms and susceptibility to develop mesothelioma using the general, dominant or recessive models. Also haplotype analysis did not reveal any significant association with mesothelioma. Our findings, being controversial with respect to another study on Italian patients, do suggest the need of further studies to unravel the contribution of NLRP1 and NLRP3 in susceptibility to mesothelioma

Blue Laser Light Counteracts HSV-1 in the SH-SY5Y Neuronal Cell Model of Infection

Herpes simplex virus 1 (HSV-1) is wide-spread virus that triggers painful and recurrent infections, as herpes labialis, causing blister lesions on the lip. HSV-1 infection can be a lifelong condition starting from childhood due to the latency of the virus hidden in the trigeminal ganglia. Despite the use of antiviral treatments, there is not a resolutive cure for herpes. In our study, we tested blue light against HSV-1 in a neuronal cellular model, aimed at mimicking the neuronal tropism of HSV-1. Two laser protocols employing continuous wave and pulse modalities were delivered to infected cell cultures and to the virus alone. A significant reduction of viral replication was observed when the beam was directly applied to the virus, along with an increase in cell survival. Our findings, considering the limitation of the still-unknown mechanisms by which the blue light acts on the virus, suggested a potential use of photobiomodulation therapy for clinical applications against herpes labialis in pediatric patients

Molecular analysis of inflammatory diseases.

If we try to describe the search for molecular actors involved in inflammatory diseases, the picture best representing this task is a mission to unexplored worlds. However, researchers nowadays have powerful tools to support this journey to the complexity of the unknown: Next generation Sequencing technologies have provided a plethora of data describing the different OMICs possibly involved in the different inflammatory diseases. Here, we focused on autoinflammatory skin diseases showing the progress of OMICs-related findings in the understanding of Syndromic HS pathogenesis. We described the studies reporting possible genotype/phenotype correlation in PASH and PAPASH patients (both unrelated or familial cases), highlighting those just genetic variations associated with the diseases have been observed, but the information on common pathways shared by PASH and PAPASH patients were lacking, thus rendering difficult to decipher the common molecular basis of these autoinflammatory conditions. Aimed at filling this gap of knowledge, we proposed an integrated OMICs approach able to identify common pathways shared by subjects suffering from PASH and PAPASH: pathway-based whole sequencing analysis allowed the identification of 4 pathways, keratinization, formation of the cornified envelope steroid metabolism and Vitamin D metabolism, disrupted in PASH and PAPASH patients. Finally, we mentioned the novel bioinformatic platform, named PlatOMICs, capable of integrating OMICs experimental findings also with the ones already reported in public repositories supporting the efforts of the researchers and clinicians to discover molecular pathways shared by individuals suffering of a disease, confronting and integrating the bench findings with the in-silico ones.This work is supported by the EraPerMed 2018-137 project entitled “Biomolecular Analyses for Tailored Medicine in Acne iNversa.” Open Access funding provided by the Qatar National Library

Evolution of the hepcidin gene in primates

<p>Abstract</p> <p>Background</p> <p>Hepcidin/LEAP-1 is an iron regulatory hormone originally identified as an antimicrobial peptide. As part of a systematic analysis of the evolution of host defense peptides in primates, we have sequenced the orthologous gene from 14 species of non-human primates.</p> <p>Results</p> <p>The sequence of the mature peptide is highly conserved amongst all the analyzed species, being identical to the human one in great apes and gibbons, with a single residue conservative variation in Old-World monkeys and with few substitutions in New-World monkeys.</p> <p>Conclusion</p> <p>Our analysis indicates that hepcidin's role as a regulatory hormone, which involves interaction with a conserved receptor (ferroportin), may result in conservation over most of its sequence, with the exception of the stretch between residues 15 and 18, which in New-World monkeys (as well as in other mammals) shows a significant variation, possibly indicating that this structural region is involved in other functions.</p

Antiretroviral Treatment in HIV-1-Positive Mothers: Neurological Implications in Virus-Free Children

Since the worldwide introduction of antiretroviral therapy (ART) in human immunodeficiency virus type 1, HIV-1-positive mothers, together with HIV-1 testing prior to pregnancy, caesarian birth and breastfeeding cessation with replacement feeding, a reduction of HIV-1 mother-to-child transmission (MTCT) has been observed in the last few years. As such, an increasing number of children are being exposed in utero to ART. Several questions have arisen concerning the neurological effects of ART exposure in utero, considering the potential effect of antiretroviral drugs on the central nervous system, a structure which is in continuous development in the fetus and characterized by great plasticity. This review aims at discussing the possible neurological impairment of children exposed to ART in utero, focusing attention on the drugs commonly used for HIV-1 MTCT prevention, clinical reports of ART neurotoxicity in children born to HIV-1-positive mothers, and neurologic effects of protease inhibitors (PIs), especially ritonavir-"boosted" lopinavir (LPV/r) in cell and animal central nervous system models evaluating the potential neurotoxic effect of ART. Finally, we present the findings of a meta-analysis to assess the effects on the neurodevelopment of children exposed to ART in utero

Lack of Prenylated Proteins, Autophagy Impairment and Apoptosis in SH-SY5Y Neuronal Cell Model of Mevalonate Kinase Deficiency

Mevalonate Kinase Deficiency (MKD), is a hereditary disease due to mutations in mevalonate kinase gene (MVK). MKD has heterogeneous clinical phenotypes: the correlation between MVK mutations and MKD clinical phenotype is still to be fully elucidated. Deficiency of prenylated proteins has been hypothesized as possible MKD pathogenic mechanism. Based on this hypothesis and considering that neurologic impairment characterizes Mevalonic Aciduria (MA), the most severe form of MKD, we studied the effects of I268T and N301T MVK mutations on protein prenylation, autophagy and programmed cell death in SH-SY5Y neuroblastoma cell lines

Copy number variation, gene expression and histological localization of human beta-defensin 2 in patients with adeno-tonsillar hypertrophy

Both bacterial infections and innate oral immunity response participate in development of adeno-tonsillar hypertrophy (ATH). ATH can lead to obstructive sleep apnea. We investigated the beta-defensin 2 (hBD-2) encoding gene, DEFB4, by analyzing the copy number variations (CNVs) of the defensin gene cluster in patients with ATH and by correlating CNV with DEFB4 gene expression. We enrolled 79 patients with ATH, 21 of whom presented with only adenoid hypertrophy, while 58 exhibited hypertrophy of both adenoid and tonsil. CNVs of the defensin gene cluster, DEFB4 mRNA, and hBD-2 protein expression were assessed. Also, beta-defensin 2 was localized histologically using immunohistochemistry. The distribution of defensin gene cluster CNV was similar among the 79 subjects. DEFB4 expression analysis exhibited considerable inter-individual variability, but with neither specific differences among subjects nor correlation with the CNV number. Immunohistochemistry enabled localization of hBD-2 in the tonsil and adenoid epithelium. No differences in localization between the two ATH presentations were found. Inducible antimicrobial defensin peptides exhibited great inter-individual variability in terms of both CNV and gene expression, but no correlation with presentation of ATH was found

Increased risk of dizziness in human immunodeficiency virus-infected patients taking zidovudine and efavirenz combination: a Brazilian cohort study.

Abstract Objectives Neuropsychiatric adverse effects (NPAE) related to efavirenz, mainly dizziness, is detrimental to human immunodeficiency virus (HIV) treatment. Our study aims at evaluating if zidovudine use potentiates the risk of dizziness related to efavirenz when used together and whether there are significant differences in over time distribution of this NPAE and others relatively frequents regarding efavirenz regimen without zidovudine. Methods Human immunodeficiency virus-infected patients under efavirenz-containing different therapy were enrolled. A retrospective analysis of official medical records was accomplished to collect clinical data regarding NPAE occurrence and severity. Univariate statistic and statistical model based on survival analyses were performed. Key findings One hundred sixty-two patients were included, of these seventy-seven (47.5%) had NPAE reported, such as dizziness (more frequent), depression and insomnia. Univariate statistical analysis demonstrated that the combined use of efavirenz with zidovudine increased the NPAE risk (OR: 2.5; P-value: 0.008), mainly dizziness risk (OR: 3.5; P-value: 0.009) and survival analysis showed that such combination is associated with dizziness occurrence faster (HR: 2.9; P-value: 0.02). Conclusions The results may contribute to clarify the dizziness occurrence dynamics in therapy with efavirenz and zidovudine by identifying susceptibilities and assisting in the choice of combined antiretroviral therapy

Transient Receptor Potential Ankyrin 1 (TRPA1) Methylation and Chronic Pain: A Systematic Review

Background and objective: Chronic pain represents a major global health issue in terms of psycho-physiological, therapeutic, and economic burden, not limited to adults but also to the pediatric age. Despite its great impact, its molecular mechanisms have still not been completely unraveled. Focusing on the impact of epigenetics in the pain complex trait, we assessed the association between chronic pain and the methylation pattern of TRPA1, a key gene related to pain sensitivity. Methods: We conducted a systematic review retrieving articles from three different databases. After deduplication, 431 items were subjected to manual screening, and then 61 articles were selected and screened again. Of these, only six were maintained for meta-analysis and analyzed using specific R packages. Results: Six articles were divided into two groups (group 1: comparison of mean methylation levels between healthy subjects and patients with chronic pain; group 2: correlation between mean methylation levels and pain sensation). A non-significant mean difference was obtained from the analysis of group 1 with a value of 3.97 (95% C.I. -7.79; 15.73). Analysis of group 2 showed a high level of variability between studies (correlation = 0.35, 95% C.I. -0.12; 0.82) due to their heterogeneity (I2 = 97%, p < 0.01). Conclusions: Despite the high variability observed in the different studies analyzed, our results suggest that hypermethylation and increased pain sensitivity could be connected, possibly due to the variation of TRPA1 expression