A New ERAP2/Iso3 Isoform Expression Is Triggered by Different Microbial Stimuli in Human Cells. Could It Play a Role in the Modulation of SARS-CoV-2 Infection?

Following influenza infection, rs2248374-G ERAP2 expressing cells may transcribe an alternative spliced isoform: ERAP2/Iso3. This variant, unlike ERAP2-wt, is unable to trim peptides to be loaded on MHC class I molecules, but it can still dimerize with both ERAP2-wt and ERAP1-wt, thus contributing to profiling an alternative cellular immune-peptidome. In order to verify if the expression of ERAP2/Iso3 may be induced by other pathogens, PBMCs and MDMs isolated from 20 healthy subjects were stimulated with flu, LPS, CMV, HIV-AT-2, SARS-CoV-2 antigens to analyze its mRNA and protein expression. In parallel, Calu3 cell lines and PBMCs were in vitro infected with growing doses of SARS-CoV-2 (0.5, 5, 1000 MOI) and HIV-1BAL (0.1, 1, and 10 ng p24 HIV-1Bal/1 7 106 PBMCs) viruses, respectively. Results showed that: (1) ERAP2/Iso3 mRNA expression can be prompted by many pathogens and it is coupled with the modulation of several determinants (cytokines, interferon-stimulated genes, activation/inhibition markers, antigen-presentation elements) orchestrating the anti-microbial immune response (Quantigene); (2) ERAP2/Iso3 mRNA is translated into a protein (western blot); (3) ERAP2/Iso3 mRNA expression is sensitive to SARS-CoV-2 and HIV-1 concentration. Considering the key role played by ERAPs in antigen processing and presentation, it is conceivable that these enzymes may be potential targets and modulators of the pathogenicity of infectious diseases and further analyses are needed to define the role played by the different isoforms

Sphingolipid serum profiling in vitamin D deficient and dyslipidemic obese dimorphic adults

Recent studies on Saudi Arabians indicate a prevalence of dyslipidemia and vitamin D deficiency (25(OH)D) in both normal weight and obese subjects. In the present study the sphingolipid pattern was investigated in 23 normolipidemic normal weight (NW), 46 vitamin D deficient dyslipidemic normal weight (-vitDNW) and 60 vitamin D deficient dyslipidemic obese (-vitDO) men and women by HPTLC-primuline profiling and LC-MS analyses. Results indicate higher levels of total ceramide (Cer) and dihydroceramide (dhCers C18\u201322) and lower levels of total sphingomyelins (SMs) and dihydrosphingomyelin (dhSM) not only in -vitDO subjects compared to NW, but also in \u2013vitDNW individuals. A dependency on body mass index (BMI) was observed analyzing specific Cer acyl chains levels. Lower levels of C20 and 24 were observed in men and C24.2 in women, respectively. Furthermore, LC-MS analyses display dimorphic changes in NW, -vitDNW and \u2013vitDO subjects. In conclusion, LC-MS data identify the independency of the axis high Cers, dhCers and SMs from obesity per se. Furthermore, it indicates that long chains Cers levels are specific target of weight gain and that circulating Cer and SM levels are linked to sexual dimorphism status and can contribute to predict obese related co-morbidities in men and women

Favorable Changes in Fasting Glucose in a 6-month Self-Monitored Lifestyle Modification Programme Inversely Affects Spexin Levels in Females with Prediabetes

Spexin (SPX) is a novel peptide thought to have a role in various metabolic regulations. Given its presumed body-weight regulatory functions, we aimed to determine whether lifestyle intervention programs on weight loss and fasting glucose (FG) improvement among people with impaired glucose regulation also alter levels of circulating SPX. A total of 160 Saudi adult males and females with prediabetes were randomly selected from a larger cohort (N = 294) who underwent a 6-month lifestyle modification program to improve their glycemic status. Participants were split into two groups based on differences in glucose levels post-intervention, with the first 50% (improved group) having the most significant reduction in FG. SPX was measured at baseline and after 6 months. Changes in SPX was significant only in the improved group [baseline: median (Q1\u2013Q3) of 164 pg/ml (136\u2013227) vs follow-up: 176 pg/ml (146\u2013285); p < 0.01]. When stratified by sex, the significant increase was observed only in females [159 pg/ml (127\u2013252) vs 182.5 (152,369.1); p < 0.01]. Furthermore, SPX levels showed a significant inverse association with FG (\u3b2 = 120.22, p = 0.003) even after adjustment with age and BMI, again only in females. Circulating SPX levels increase over time in people with prediabetes, particularly women who responded favorably in a 6-month lifestyle intervention program. Whether an unknown mechanism regulating the sexual disparity seen in SPX levels post-intervention exists should be further investigated using a larger sample size

SNPs in FNDC5 (irisin) are associated with obesity and modulation of glucose and lipid metabolism in Saudi subjects

Background: Irisin is a recently identified myokine that plays an important role in preventing obesity and insulin resistance. We investigated whether the common FNDC5 (irisin precursor) gene variants influence susceptibility to obesity and type 2 diabetes (T2D) and verified the impact of FNDC5 gene variants on serum irisin levels, glucose and lipid metabolism in a Saudi population. Methods: Genomic DNA from 814 (394 T2DM and 414 controls) subjects were genotyped for the five common SNPs (rs3480A/G, rs1746661G/T, rs1298190A/G, rs726344A/G and rs1570569G/T) of the FNDC5 gene using the TaqMan genotyping assay. Biochemical parameters and hematic concentrations of irisin and insulin as well as anthropometric indices were collected. Results: Serum irisin levels were higher in T2DM patients compared to controls (p < 0.0001). Analyses of FNDC5 SNPs showed that: 1) The rs3480 GG associates with decreased risk of obesity (p = 0.005; odds ratio: 0.48) and lower body mass index (BMI) values (p = 0.03). In addition, GGAAG was identified as the protective haplotype against risk of obesity (p = 0.001; odds ratio: 0.23). 2) The rs1746661 G allele associates with higher triglyceride (TG) levels (p = 0.019). 3) The rs157069 TT genotype associates with higher fasting insulin (p = 0.029) and HOMA-IR (p = 0.002) as well as with lower circulating irisin levels (p = 0.016). Conclusions: SNPs in FNDC5 gene correlates with obesity and glucose-lipid metabolism possibly because they modulate the serum levels of irisin

The Italian Version of the Borderline Personality Disorder Severity Index IV:Psychometric Properties, Clinical Usefulness, and Possible Diagnostic Implications

Borderline personality disorder (BPD) has a core embodied in affective and behavioral dysregulations, impulsivity, and relational disturbance. Clinical presentation might be heterogeneous due to a combination of different symptoms listed in the DSM-5. Clinical diagnosis and assessment of the severity of manifestations might be improved through the administration of structured interviews such as the Borderline Personality Disorder Severity Index, 4th edition (BPDSI-IV). The psychometric properties of the Italian version of the BPDSI-IV were examined for the first time in 248 patients affected by BPD and 113 patients affected by bipolar disorder, proving to be a valid and accurate instrument with good internal consistency and high accuracy. The Italian version also demonstrates significant validity in the discrimination between these clinical groups (p < .001)

The NLRP3 Inflammasome Is Upregulated in HIV-Infected Antiretroviral Therapy-Treated Individuals with Defective Immune Recovery

Background: Inflammasome-mediated activation of caspase-1 regulates inflammatory responses and pyroptosis. We analyzed possible associations between inflammasome-related genes and immune reconstitution in HIV-infected antiretroviral therapy (ART)-treated patients. Methods: Cross-sectional, case-control study. HIV-infected patients on ART for 6524\u2009months with HIV-RNA<50 cp/mL for 6512\u2009months were enrolled and defined as immunological responders (IR) or non-responders (INR) if CD4 count was 65500 or 64350 cells/\u3bcL, respectively. Expression of inflammasome genes, caspases 1, 3, 4, 5 and \u3b3-interferon-inducible protein 16 (IFI16) was measured in unstimulated and LPS- or aldrithiol-2-treated HIV-1BaL virions-stimulated peripheral blood mononuclear cells. Microbial translocation markers were evaluated. Results: Thirty-nine patients (22 IRs; 17 INRs) were enrolled. LPS-stimulated inflammasome genes were significantly upregulated in INRs. Whereas HIV-1BaL stimulation induced (NOD)-like receptor (NLR) family pyrin domain containing 3 (NLRP3) expression in both IRs and INRs, NLRP3 and IL-18 expression was significantly increased in INRs compared to IRs. Significant higher caspase-1 expression was seen as well, whereas caspase 3, 4, and 5 expression was similar in both groups. No differences in microbial translocation markers (LPS and soluble CD14) were detected in the two groups. Conclusion: Upregulation of NLRP3 and caspase-1 is observed in INR patients. This could play a role in persistent immune activation that characterize INRs. Caspase-1 upregulation could induce CD4 T-cell loss via pyroptosis, contributing to unsatisfactory CD4 T-cells recovery

Beyond IL-17 : new cytokines in the pathogenesis of HIV infection

PURPOSE OF THE REVIEW: Alterations in cytokine production have been described since the dawn of HIV research. Cytokinology is rapidly evolving because the cytokine-like functions of arrays of proteins are being recognized. Thus, new cytokines are being investigated within the context of HIV pathogenesis. This review describes novel functions of 'old' cytokines and summarizes the potential role of 'new' cytokines in this disease. RECENT FINDINGS: Old cytokines, such as the common gamma (gamma) chain cytokines, were shown to have previously unsuspected biological roles; new cytokines, for example, IL-18, IL-27, IL-32, were recognized as important players in the immunopathogenesis of HIV infection. Finally, hepatocytes were demonstrated to be the main producers of IL-7 in response to various inflammatory signals, transforming overnight the liver in one of the tissues primarily involved in the modulation of immune responses. SUMMARY: Data summarized herein underline the intricacies of cytokine networks. The concept of modulating the immune response using single cytokines is unlikely to succeed. Future therapeutic uses of cytokines will not be effective unless a 'cytokinomics' approach to the study of these important immune modulators is employed. Systematic analyses of cytokine production and of their effects in a biological system will be required

Immunomodulants for the treatment of HIV infection : the search goes on

The natural history of HIV infection has been greatly modified by the introduction of powerful antiretroviral agents that act on multiple steps of HIV replication. Thus, antiretroviral therapy (ART) has prolonged the life of HIV-infected individuals, significantly impacting on the progression to AIDS. It was assumed that ART-induced suppression of HIV would have resulted in a degree of immune recovery sufficient enough to allow immune control over HIV replication independently of the use of drugs. Unfortunately, interruption of therapy, even after long periods of full suppression of viral replication, is almost inevitably associated with a prompt rebound of HIV viraemia. The outcome of this observation is that ART has to be considered as a lifelong therapy, with the associated resulting problems of the emergence of multi-drug resistant viral strains, toxic effects, costs and compliance. The use of immunomodulants in association with ART could achieve the goal of boosting the immune response to a threshold, permitting the immune response to indefinitely suppress HIV replication

Historical perspective on HIV\u2010exposed seronegative individuals : has nature done the experiment for us?

Multiple and frequent exposure to the human immunodeficiency virus (HIV) does not necessarily result in HIV infection. Approximately 15% of HIV exposed seronegative individuals repeatedly resist infection, a phenomenon that has been observed in all investigated HIV-exposed cohorts. This brief report provides a limited historic perspective of the discovery of these cohorts and outlines some of the immunologic and genetic parameters that are associated with resistance. We raise the possibility that assessing immunologic parameters of the phenomenon might provide insights that might be relevant for effective AIDS vaccine design