Interleukin-1 Receptor Antagonist Protein Research Articles

Altered proteome profiles related to visceral adiposity may mediate the favorable effect of green Mediterranean diet: the DIRECT-PLUS trial.

The objective of this study was to explore the effects of a green Mediterranean (green-MED) diet, which is high in dietary polyphenols and green plant-based protein and low in red/processed meat, on cardiovascular disease and inflammation-related circulating proteins and their associations with cardiometabolic risk parameters. In the 18-month weight loss trial Dietary Intervention Randomized Controlled Trial Polyphenols Unprocessed Study (DIRECT-PLUS), 294 participants with abdominal obesity were randomized to basic healthy dietary guidelines, Mediterranean (MED), or green-MED diets. Both isocaloric MED diet groups consumed walnuts (28 g/day), and the green-MED diet group also consumed green tea (3-4 cups/day) and green shakes (Mankai plant shake, 500 mL/day) and avoided red/processed meat. Proteome panels were measured at three time points using Olink CVDII. At baseline, a dominant protein cluster was significantly related to higher phenotypic cardiometabolic risk parameters, with the strongest associations attributed to magnetic resonance imaging-assessed visceral adiposity (false discovery rate of 5%). Overall, after 6 months of intervention, both the MED and green-MED diets induced improvements in cardiovascular disease and proinflammatory risk proteins (p < 0.05, vs. healthy dietary guidelines), with the green-MED diet leading to more pronounced beneficial changes, largely driven by dominant proinflammatory proteins (IL-1 receptor antagonist protein, IL-16, IL-18, thrombospondin-2, leptin, prostasin, galectin-9, and fibroblast growth factor 21; adjusted for age, sex, and weight loss; p < 0.05). After 18 months, proteomics cluster changes presented the strongest correlations with visceral adiposity reduction. Proteomics clusters may enhance our understanding of the favorable effect of a green-MED diet that is enriched with polyphenols and low in red/processed meat on visceral adiposity and cardiometabolic risk.

Pre-diagnostic plasma proteomics profile for hepatocellular carcinoma.

Proteomics may discover pathophysiological changes related to hepatocellular carcinoma (HCC), an aggressive and lethal type of cancer with low sensitivity for early-stage diagnosis. We measured 1,305 pre-diagnostic (median 12.7 years) SOMAscan proteins from 54 pairs of healthy individuals who subsequently developed HCC and matched non-HCC controls from the Nurses' Health Study (NHS) and the Health Professionals Follow-up Study (HPFS). Candidate proteins were validated in the independent, prospective UK Biobank Pharma Proteomics Project (UKB-PPP). In NHS/HPFS, we identified 56 elevated proteins in HCC with absolute fold-change >1.2 and Wald test P < .05 in conditional logistic regression analysis. Ingenuity Pathway Analysis identified enrichment of pathways associated with cell viability, adhesion, proteolysis, apoptosis, and inflammatory response. Four proteins, chitinase-3-like protein 1, growth/differentiation factor 15, interleukin-1 receptor antagonist protein, and E-selectin, showed strong positive associations with HCC and were thus validated by ELISA (odds ratio ranged 2.48-14.7, all P < .05) in the NHS/HPFS and by Olink platform (hazard ratio ranged 1.90-3.93, all P < .05) in the UKB-PPP. Adding these four proteins to a logistic regression model of traditional HCC risk factors increased the area under the curve (AUC) from 0.67 to 0.87 in the NHS/HPFS. Consistently, model AUC was 0.88 for HCC risk prediction in the UKB-PPP. However, the limited number of HCC cases in the cohorts necessitates caution in interpreting our findings, emphasizing the need for further validation in high-risk populations.

Heat Shock Protein SSA1 Enriched in Hypoxic Secretome of Candida albicans Exerts an Immunomodulatory Effect via Regulating Macrophage Function.

Candida albicans is an opportunistic pathogenic yeast that can survive in both normoxic and hypoxic environments. The involvement of C. albicans secretome on host biological processes has been demonstrated. However, the immunoregulatory function of C. albicans secretome released under hypoxic condition remains unclear. This study demonstrated the differences in cytokine responses and protein profiles between secretomes prepared under normoxic and hypoxic conditions. Furthermore, the immunoregulatory effects of heat shock protein SSA1(Ssa1), a protein candidate enriched in the hypoxic secretome, were investigated. Stimulation of mouse bone marrow-derived macrophages (BMMs) with Ssa1 resulted in the significant production of interleukin (IL)-10, IL-6, and tumor necrosis factor (TNF)-α as well as the significant expression of M2b macrophage markers (CD86, CD274 and tumor necrosis factor superfamily member 14), suggesting that C. albicans Ssa1 may promote macrophage polarization towards an M2b-like phenotype. Proteomic analysis of Ssa1-treated BMMs also revealed that Ssa1 reduced inflammation-related factors (IL-18-binding protein, IL-1 receptor antagonist protein, OX-2 membrane glycoprotein and cis-aconitate decarboxylase) and enhanced the proteins involved in anti-inflammatory response (CMRF35-like molecule 3 and macrophage colony-stimulating factor 1 receptor). Based on these results, we investigated the effect of Ssa1 on C. albicans infection and showed that Ssa1 inhibited the uptake of C. albicans by BMMs. Taken together, our results suggest that C. albicans alters its secretome, particularly by promoting the release of Ssa1, to modulate host immune response and survive under hypoxic conditions.

Using trials of caloric restriction and bariatric surgery to explore the effects of body mass index on the circulating proteome

Thousands of proteins circulate in the bloodstream; identifying those which associate with weight and intervention-induced weight loss may help explain mechanisms of diseases associated with adiposity. We aimed to identify consistent protein signatures of weight loss across independent studies capturing changes in body mass index (BMI). We analysed proteomic data from studies implementing caloric restriction (Diabetes Remission Clinical trial) and bariatric surgery (By-Band-Sleeve), using SomaLogic and Olink Explore1536 technologies, respectively. Linear mixed models were used to estimate the effect of the interventions on circulating proteins. Twenty-three proteins were altered in a consistent direction after both bariatric surgery and caloric restriction, suggesting that these proteins are modulated by weight change, independent of intervention type. We also integrated Mendelian randomisation (MR) estimates of the effect of BMI on proteins measured by SomaLogic from a UK blood donor cohort as a third line of causal evidence. These MR estimates provided further corroborative evidence for a role of BMI in regulating the levels of six proteins including alcohol dehydrogenase-4, nogo receptor and interleukin-1 receptor antagonist protein. These results indicate the importance of triangulation in interrogating causal relationships; further study into the role of proteins modulated by weight in disease is now warranted.

Microglial IL-1RA ameliorates brain injury after ischemic stroke by inhibiting astrocytic CXCL1-mediated neutrophil recruitment and microvessel occlusion.

Acute ischemic stroke (AIS), one of the leading causes of mortality worldwide, is characterized by a rapid inflammatory cascade resulting in exacerbation of ischemic brain injury. Microglia are the first immune responders. However, the role of postischemic microglial activity in ischemic brain injury remains far from being fully understood. Here, using the transgenic mouse line CX3 CR1creER :R26iDTR to genetically ablate microglia, we showed that microglial deletion exaggerated ischemic brain injury. Associated with this worse outcome, there were increased neutrophil recruitment, microvessel blockade and blood flow stagnation in the acute phase, accompanied by transcriptional upregulation of chemokine (C-X-C motif) ligand 1 (CXCL1). Our study showed that microglial interleukin-1 receptor antagonist (IL-1RA) suppressed astrocytic CXCL1 expression induced by oxygen and glucose deprivation and inhibited neutrophil migration. Furthermore, neutralizing antibody therapy against CXCL1 or the administration of recombinant IL-1RA protein reduced brain infarct volume and improved motor coordination performance of mice after ischemic stroke. Our study suggests that microglia protect against acute ischemic brain injury by secreting IL-1RA to inhibit astrocytic CXCL1 expression, which reduces neutrophil recruitment and neutrophil-derived microvessel occlusion.

Starch intake, amylase gene copy number variation, plasma proteins, and risk of cardiovascular disease and mortality

BackgroundSalivary amylase, encoded by the AMY1 gene, initiate the digestion of starch. Whether starch intake or AMY1 copy number is related to disease risk is currently rather unknown. The aim was to investigate the association between starch intake and AMY1 copy number and risk of cardiovascular disease (CVD) and mortality and whether there is an interaction. In addition, we aim to identify CVD-related plasma proteins associated with starch intake and AMY1 copy number.MethodsThis prospective cohort study used data from 21,268 participants from the Malmö Diet and Cancer Study. Dietary data were collected through a modified diet history method and incident CVD and mortality were ascertained through registers. AMY1 gene copy number was determined by droplet digital polymerase chain reaction, a risk score of 10 genetic variants in AMY1 was measured, and a total of 88 selected CVD-related proteins were measured. Cox proportional hazards regression was used to analyze the associations of starch intake and AMY1 copy number with disease risk. Linear regression was used to identify plasma proteins associated with starch intake and AMY1 copy number.ResultsOver a median of 23 years’ follow-up, 4443 individuals developed CVD event and 8125 died. After adjusting for potential confounders, a U-shape association between starch intake and risk of CVD (P-nonlinearity = 0.001) and all-cause mortality (P-nonlinearity = 0.03) was observed. No significant association was found between AMY1 copy number and risk of CVD and mortality, and there were no interactions between starch intake and AMY1 copy number (P interaction > 0.23). Among the 88 plasma proteins, adrenomedullin, interleukin-1 receptor antagonist protein, fatty acid-binding protein, leptin, and C-C motif chemokine 20 were associated with starch intake after adjusting for multiple testing.ConclusionsIn this large prospective study among Swedish adults, a U-shaped association between starch intake and risk of CVD and all-cause mortality was found. Several plasma proteins were identified which might provide information on potential pathways for such association. AMY1 copy number was not associated with CVD risk or any of the plasma proteins, and there was no interaction between starch intake and AMY1 copy number on disease risk.

A PILLAR OF CARDIOVASCULAR DISEASES: INFLAMMAGING

With the prolongation of life expectancy, the increase in the number of elderly individuals in societies and the high rates of disability, frailty and morbidity associated with this situation have led to the acceptance of old age as a prior social problem. And since the 2000s, many studies have been carried out in this field. Inflammation is a very important physiological function and a complex biological process that is initiated by the immune system in response to infection, injury or tissue damage. In connection with this process, inflammaging refers to the chronic, low-grade inflammation that occurs with aging. As one ages, the immune system undergoes changes including a descent in the production of new immune cells and a decrease in the ability of existing immune cells to function properly that can contribute to a state of chronic inflammation. Clinical trials suggest that modulating inflammation prevents many of the chronic diseases, frailty, and disability that increases at older age. In the light of existing information, one can predict that a possible reason for long life today is the capability of reaching an optimal balance between pro- inflammatory (C-Reactive Protein, Interleukin 6, Tumor necrosis factor-alpha) and anti-inflammatory (Interleukin-1 receptor antagonist protein, Cortisol, Interleukin-10) molecules. Keywords: Aging; Cellular Senescence; Inflammation; Immunosenescence.

Interleukin-1 receptor antagonist: From synthesis to therapeutic applications

The cytokine channel’s mechanism for self-regulation involves the application of antagonistic cytokines that are synthesized to connect to the receptors and release soluble cytokine receptors. The very first receptor antagonist of cytokine that was naturally present was interleukin-1 receptor antagonist (IL-1Ra). The IL-1Ra protein forms are disinfected from supernatants of cultured monocytes on stacked IgG. The family of IL-1 consists of IL-1α, IL-1β and IL-1Ra. Human monocytes regulate the production of IL-Ra. IL-Ra takes part in normal physiological functions by using specific antibodies, and acts as an anti-inflammatory agent. IL-Ra is synthesized in the tissues during the period of active disease and can be systematically measured and/or estimated. Maintenance of the levels of IL-Ra and IL-1 is the main factor for host resistance in patients during diseased conditions, as IL-Ra acts as an inherent regulator of various inflammatory responses. In this article, we focuse on how IL-Ra is synthesized and performs its functions once the inflammatory responses are activated.

2179. Multiple cytokine analysisbased on QuantiFERON-TB Gold Plus in different tuberculosis infection status:anexploratory study

Abstract Background To explore the differences of multiple cytokines secretion based on QuantiFERON-TB Gold Plus(QFT-Plus)antigens stimulation, and to screen cytokines with potential to differentiate tuberculosis infection status. Methods Twenty patients diagnosed microbiologically with active tuberculosis(ATB)in Peking Union Medical College Hospitaland Beijing Chest Hospital from February to April 2022 were enrolled.Fifteen healthcare workers(HCWs) with latent TB infection(LTBI),10 HCWs with previous TB and 10 HCWs as healthy control(HC) were recruited during the same period. After stimulated by QFT-Plus antigens,the secretion of interferon gamma(IFN-γ),tumor necrosisfactor-α(TNF-α), interleukin(IL)-2(IL-2), IL-6, IL-5, IL-10, interferon-inducible protein-10(IP-10), IL-1 receptor antagonist(IL-1Ra),chemokine(C-X-C)Ligand-1(CXCL-1)and macrophage chemoattractant protein 1(MCP-1)) in Plasma were measured by Luminex Assays. Results 1.After stimulation with QFT-Plus TB1 orTB2 antigens, the level of IFN-γin ATB and LTBI groups was significantly higher than that in HC group(p&amp;lt;0.05),while there was no significant difference between ATB and LTBI groups(p &amp;gt;0.05).Cytokines including IL-2,IL-1Ra, CXCL-1have the similar secretion patterns to IFN-γ. 2.After stimulation with TB1 antigen, the level of IP-10 in ATB group was significantly higher thanthat inLTBI,previous TBand HC groups(p&amp;lt;0.05).After stimulation with TB2 antigen, the level of IL-6in ATB group was significantly higher thanthat in LTBI and HC groups(p&amp;lt;0.05). 3.There was no significant difference incytokines secretion levels in QFT-Plus specific CD8 response(TB2-TB1) in most groups. Conclusion In addition to IFN-γ, thedetection of IL-2, IL-1Ra, CXCL-1by QFT-Plusmay havethe potential to detect tuberculosis infection.Combined detection of IP-10 and IL-6 levels may have the potential to differentiate ATB from LTBI Disclosures All Authors: No reported disclosures.

Early Mid-pregnancy Blood-Based Proteins as Possible Biomarkers of Increased Infant Birth Size in Sex-Stratified Analyses

The objective of this study was to evaluate the associations of 92 maternal blood-based proteins with increased infant birth size. The study was performed at the Uppsala University Hospital, Sweden, and included 857 mother and child dyads. The mean age of the women was 30.3 years, and 53.2% were nulliparous. Blood samples were collected at mean 18 + 2 weeks’ gestation, and the Olink cardiovascular II panel was used to measure 92 proteins, either known to be or suspected to be markers of cardiovascular and inflammatory disease in humans. Multiple linear regression models adjusted for maternal age, parity, pre-conception BMI, height, and smoking were performed to evaluate the association of each individual protein with infant birth size. We also performed sex-stratified analyses. Eight proteins (Matrix metalloproteinase-12 (MMP-12), Prostasin (PRSS8), Adrenomedullin (ADM), Pappalysin-1 (PAPP-A), Angiotensin-converting enzyme 2 (ACE2), Sortilin (SORT1), Lectin-like oxidized LDL receptor 1 (LOX-1), and Thrombomodulin (TM)) were associated with infant birth size after false discovery rate adjustment. In the analyses including only female infants, ten proteins (MMP-12, Growth/differentiation factor 2 (GDF-2), PRSS8, SORT1, ADM, Interleukin-1 receptor antagonist protein (IL-1ra), Leptin (LEP), ACE2, TM, and Tumor necrosis factor receptor superfamily member 11A (TNFRSF11A)) were associated with infant birth size. Two proteins (PAPP-A and PRSS8) were associated with infant birth size among male infants. Our study suggests several proteins as potential biomarkers for increased birth weight, and our findings could act as a base for future research to identify new potential markers that could be added to improve screening for large infants.

IL-1 receptor antagonist, MIS-C, and the peculiar autoimmunity of SARS-CoV-2

IL-1 receptor antagonist, MIS-C, and the peculiar autoimmunity of SARS-CoV-2

In Silico Approach for Pro-inflammatory Protein Interleukin 1β and Interleukin-1 Receptor Antagonist Protein Docking as Potential Therapy for COVID-19 Disease

Background: Interleukin-1 receptor antagonist (IL-1Ra) also known as Anakinra is a receptor antagonist of IL-1 especially IL-1β. IL-1β increased in infected COVID-19 patient groups. This study aimed that the IL-1Ra contained in Conditioned Medium Wharton’s Jelly Mesenchymal Stem Cells (CM-WJMSCs) has the potential to inhibit IL-1β which is one of the cytokine storms that occur in COVID patients through an in-silico approach. Objective: This study aims to determine the effect of in silico approach pro-inflammatory protein interleukin 1β (IL-1 β) and interleukin-1 receptor antagonist protein as cytokine WJ-MSCs for potential treatment of COVID-19 disease. Methods: 3D structure using the homology modeling method on Swiss Model web-server. Molecular docking was performed to analyze the binding mode of the IL-1β related to COVID-19 with IL-1Ra and the docking results were fixed using FireDock web-server. Results: These results of the docking of proteins between IL-1β and the CM-WJMSCs component, namely IL-1Ra showed that IL-1Ra has criteria for docking on IL-1β such as the good score for QMEAN, good CscoreLB, and BS-score results, and the lowest energy obtained was -585.1 KJ/mol. It can be predicted that IL-1Ra can inhibit IL-1β which causes cytokine storms in COVID-19 patients. Conclusion: So that there is a potential treatment of CM-WJMSCs on the severity of Covid-19 infection.

Effects of interleukin-1 receptor antagonist overexpression in a mouse model of tauopathy.

Innate immune activation is suggested to exacerbate tauopathy. Interluekin-1 (IL-1) is a cytokine that can initiate innate immune activation and has been argued to play a central role in Alzheimer's pathogenesis. The Interleukin-1 receptor antagonist (IL-1RA) is an endogenous agent that regulates IL-1 signaling by interfering with activation of the IL-1 receptor. Anakinra is an FDA approved version of IL-1RA. Mouse IL-1RA was cloned by PCR and demonstrated activity in a HEK cell reporter line stimulated with IL-1beta. Three month old Tg4510 mice were treated with AAV9 expressing either IL-1RA or GFP unilaterally in the hippocampus and anterior cortex. Tissues were collected at 7 mo of age and the anterior brain processed for ELISA measurements and the posterior half prepared for histochemistry. In vitro, IL-1RA protein was secreted into the cell culture media. IL-1 reporter cell lines transfected with IL-1RA greatly reduced reporter expression in response to IL-1 exposure, indicating the gene product had antagonist activity. Studies in Tg4510 mice detected increases in IL-1 RNA at 6 and 8 mo of age, but not at 4 mo. Measures of IL-1RA by ELISA indicated an over 100 fold increased expression in mice injected with AAV-IL-1RA. However, the only significant impact of IL-1RA expression on tauopathy was a slight reduction in the ELISA values for detergent insoluble p-Ser199-tau in the IL-1RA mice. No differences were found in any of the histological measures of tauopathy or ELISA measures of total tau or p-Ser-396tau CONCLUSION: IL-1RA had a minimal impact on the accumulation of tauopathy in the Tg4510 mice. The overexpression of IL-1RA preceded the endogenous increase in IL-1 in this model. Other studies have found that blocking IL-1 production through inflammasome deletion did reduce tauopathy (Ising et al, Nature (2019) 575:669). These authors used a different mouse model with lower overall expression of tau. The minimal effect seen in this study may relate to the model of tauopathy used, the extent of IL-1 signaling reduction, or the possibility that the effects of inflammasome deletion are mediated through effector molecules other than the IL-1 receptor.

Proteins associated with incident metabolic syndrome in population-based cohorts

BackgroundThe metabolic syndrome (MetS) identifies persons with clustering of multiple cardiometabolic risk factors. The underlying pathology inducing this clustering is not fully known. We used a targeted proteomics assay to identify associations of circulating proteins with MetS and its components, cross-sectionally and longitudinally.MethodsWe explored and validated associations of 86 cardiovascular proteins, assessed using a proximity extension assay, with the MetS in two independent cohorts; the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS, n = 996) and Uppsala Longitudinal Study of Adult Men (ULSAM, n = 785). The analyses were adjusted for smoking, exercise habits, education, and energy and alcohol intake.ResultsNine proteins were associated with all five components of the MetS in PIVUS using FDR < 0.05 in a cross-sectional analysis. Of those nine proteins, only Interleukin-1 receptor antagonist protein (IL-1RA) was associated with all five components of the MetS in ULSAM using p < 0.05. IL-1RA levels were associated with incident MetS (n = 109) in PIVUS during a 5-year follow-up (HR 1.76 for a 1 SD change (95% CI 1.38, 2.24), p = 4.3*10–6). IL-1RA was however not causally related to MetS in a two-sample Mendelian randomization analysis using published data.ConclusionCirculating IL-1RA was related to all five components of the MetS in a cross-sectional analysis in two independent samples, as well as to incident MetS in a longitudinal analysis. However, Mendelian randomization analyses did not provide support for a causal role for IL-1RA in the development of MetS.

Effect of intravenous tiludronate disodium administration on the radiographic progression of osteoarthritis of the fetlock joint in Standardbred racehorses.

To compare the effects of tiludronate disodium and 3 other medical treatments on clinical and radiographic findings and biomarkers of disease progression in horses with osteoarthritis of the fetlock joint. 100 Standardbred racehorses with spontaneous traumatic injury of the fetlock joint. Horses were retrospectively grouped by whether they received tiludronate IV or triamcinolone acetonide and hyaluronan, polysulfated glycosaminoglycan, or interleukin-1 receptor antagonist protein intra-articularly. Data were collected on clinical, radiographic, and ultrasonographic findings and results for serum and synovial samples obtained before and 6 months after treatment. Lameness score, joint flexion test response, radiographic score, serum concentrations of tumor necrosis factor-α and carboxy-terminal telopeptides of collagen types I and II (CTX-I and II, respectively), and synovial fluid concentrations of interleukin-1β, prostaglandin E2, and CTX-II were compared among treatments. All treatments resulted in a significant improvement in lameness score and joint flexion test response at 6 months. In horses that received triamcinolone acetonide and hyaluronan, synovial fluid interleukin-1β, prostaglandin E2, and CTX-II concentrations decreased after treatment, suggesting this treatment inhibited progression of hyaline cartilage degeneration and inflammatory processes. Horses that received tiludronate were the only group that had a decrease in radiographic score and serum CTX-I concentration after treatment, supporting the effect of tiludronate on bone metabolism. Tiludronate treatment was also followed by increases in serum and synovial fluid concentrations of CTX-II, a marker of cartilage damage. Tiludronate appeared to inhibit the radiographic progression of osteoarthritis in high-motion joints of racehorses at 6 months after treatment by inhibiting subchondral bone remodeling. Whether this effect was associated with a worsening of progressive cartilage damage remains to be ascertained.

Drug Repurposing Patent Applications April–June 2021

Drug Repurposing Patent Applications April–June 2021

Upregulation of IL-1 Receptor Antagonist by Aspirin in Glial Cells via Peroxisome Proliferator-Activated Receptor-Alpha.

Background:Neuroinflammation is a recognized aspect of Alzheimer’s disease (AD) and other neurological illnesses. Interleukin 1 receptor antagonist (IL-1Ra) is an anti-inflammatory molecule, which inhibits inflammatory molecules in different cells including brain cells. However, mechanisms for upregulating IL-1Ra in brain cells are poorly understood.Objective:Since aspirin is a widely available pain reliever that shows promise beyond its known pain-relieving capacity, we examined whether aspirin could upregulate the IL-1Ra in the brain.Methods:We employed PCR, real-time PCR, western blot, immunostaining, chromatin immunoprecipitation (ChIP), and lentiviral transduction in glial cells. 5xFAD mice, an animal model of AD, were treated with aspirin orally via gavage.Results:Aspirin increased the expression of IL-1Ra mRNA and protein in primary mouse astrocytes and mouse BV-2 microglial cells. While investigating the mechanism, we found that the IL-1Ra gene promoter harbors peroxisome proliferator response element (PPRE) and that aspirin upregulated IL-1Ra in astrocytes isolated from peroxisome proliferator-activated receptor-beta knockout (PPARβ–/–), but not PPARα–/–, mice. Moreover, we observed that aspirin bound to tyrosine 314 residue of PPARα to stimulate IL-1Ra and that aspirin treatment also increased the recruitment of PPARα to the IL-1Ra promoter. Accordingly, aspirin increased IL-1Ra in vivo in the brain of wild type and PPARβ–/–, but not in PPARα–/– mice. Similarly, aspirin treatment also increased astroglial and microglial IL-1Ra in the cortex of 5xFAD, but not 5xFAD/PPARα–/– mice.Conclusion:Aspirin may reduce the severity of different neurological conditions by upregulating IL-1Ra and reducing the inflammation.

CHRONIC INFLAMMATION IN THE ELDERLY: MECHANISMS AND ASSOCIATION WITH ATHEROSCLEROSIS

In 2000 Claudio Franceschi first used the term “inflammageing” derived from the English words “inflammation” and “age”. This term refers to the development of chronic inflammation in the elderly, which is characterized by a high level of pro-inflammatory markers of cells and tissues. Cellular aging can be triggered by a variety of factors: critical telomere shortening, permanent DNA damage, epigenetic damage, mitochondrial dysfunction, and an increase in the number of molecular fragments associated with cell damage.A large number of markers have been found to reveal the pro-inflammatory status, such as interleukin (IL) 1, IL-1ra (IL-1 receptor antagonist protein), IL-6, -8, -13, -18, C-reactive protein, interferons α, β, transforming growth factor β, tumor necrosis factor α and its soluble receptors and SAA-1 (serum amyloid А1). The molecular mechanisms associated with aging and age-related diseases are not clear yet, while sluggish chronic inflammation is one of the leading mechanisms for the atherosclerosis development. Remodeling of the immune system with the increasing production of pro-inflammatory cytokines and NLRP3 inflammasomes also play a key role in the maintenance of chronic inflammation due to its ability to pick up a variety of age-related dangerous signals that trigger the immune response and subsequent inflammation and may act as a factor of the atherosclerosis development.Thus, pro-inflammatory factors of the immune system play an important role in pathogenesis of atherosclerosis,especially at an early stage, involving various mechanisms of action that boost atherosclerotic changes.

SALIVARY PROTEOME PROFILING IN ORAL SUBMUCOUS FIBROSIS AND ORAL CANCER

<h3>Background</h3> Proteomics, which focuses on evaluating a range of proteins, has emerged as one of the main analytical strategies in cancer research. A number of proteins may show alteration in oral cancer and high-risk potentially malignant disorders such as oral submucous fibrosis. Salivary diagnostics has received increasing importance owing to its ease of collection, proximity to the lesion, and efficient analysis of different proteins and peptides present in saliva. <h3>Objective</h3> (1) To evaluate the salivary proteomic profile in healthy controls, oral submucous fibrosis, and oral squamous cell carcinoma. (2) To compare the differential regulation of proteins among the 3 groups. <h3>Methods</h3> Saliva samples were collected from the study participants using standard protocols. The samples were processed and proteomic analysis was performed using Orbitrap high-performance liquid chromatography-mass spectrometry. Data analysis of the altered proteins was done using Thermo Proteome Discoverer 2.2. UniProt Homo sapiens was the database used for the identification and comparison of proteins. Further, differentially regulated proteins in oral submucous fibrosis and oral squamous cell carcinoma were evaluated. <h3>Results</h3> The proteins that were upregulated in the diseased group included alpha 1 antitrypsin, S-100 protein, histone, and adenylyl cyclase–associated proteins. Downregulated proteins included glucose-6-phosphate 1-dehydrogenase, statherin, calponin, lactoferrin, small proline-rich protein, and interleukin-1 receptor antagonist protein. <h3>Conclusions</h3> Differentially regulated proteins may serve as potential biomarkers in early diagnosis of oral cancer and in understanding the behavior of oral potentially malignant disorders.

Relationships Between Age, Frailty, Length of Care Home Residence and Biomarkers of Immunity and Inflammation in Older Care Home Residents in the United Kingdom.

Aging is associated with changes to the immune system, collectively termed immunosenescence and inflammageing. However, the relationships among age, frailty, and immune parameters in older people resident in care homes are not well described. We assessed immune and inflammatory parameters in 184 United Kingdom care home residents aged over 65 years and how they relate to age, frailty index, and length of care home residence. Linear regression was used to identify the independent contribution of age, frailty, and length of care home residence to the various immune parameters as dependent variables. Participants had a mean age (±SD) of 85.3 ± 7.5 years, had been residing in the care home for a mean (±SD) of 1.9 ± 2.2 years at the time of study commencement, and 40.7% were severely frail. Length of care home residence and frailty index were correlated but age and frailty index and age and length of care home residence were not significantly correlated. All components of the full blood count, apart from total lymphocytes, were within the reference range; 31% of participants had blood lymphocyte numbers below the lower value of the reference range. Among the components of the full blood count, platelet numbers were positively associated with frailty index. Amongst plasma inflammatory markers, C-reactive protein (CRP), interleukin-1 receptor antagonist (IL-1ra), soluble E-selectin and interferon gamma-induced protein 10 (IP-10) were positively associated with frailty. Plasma soluble vascular cell adhesion molecule 1 (sVCAM-1), IP-10 and tumor necrosis factor receptor II (TNFRII) were positively associated with age. Plasma monocyte chemoattractant protein 1 was positively associated with length of care home residence. Frailty was an independent predictor of platelet numbers, plasma CRP, IL-1ra, IP-10, and sE-selectin. Age was an independent predictor of activated monocytes and plasma IP-10, TNFRII and sVCAM-1. Length of care home residence was an independent predictor of plasma MCP-1. This study concludes that there are independent links between increased frailty and inflammation and between increased age and inflammation amongst older people resident in care homes in the United Kingdom. Since, inflammation is known to contribute to morbidity and mortality in older people, the causes and consequences of inflammation in this population should be further explored.