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BACKGROUND: Type 2 diabetes mellitus, one of the most prevalent metabolic disorders worldwide, is closely linked with an enhanced risk of atherosclerosis. However, the molecular mechanism of this linkage is not still clear. Genetic variations in the mTOR gene may increase the susceptibility of individuals to these diseases. METHODS: One hundred nine diabetic patients and 375 healthy subjects participated in this study. mTOR Single Nucleotide Polymorphism (SNP) rs2295080 was determined using Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP). RESULTS: Comparison of genotypic, allelic, and genotypic combination frequencies between cases and controls revealed no significant result. Nevertheless, the frequency of rs2295080 GT + TT genotype was significantly more in diabetic women with atherosclerosis compared with those without atherosclerosis (p = 0.047). Besides, the rs2295080 G allele was more frequently detected in diabetic women without atherosclerosis compared to those with atherosclerosis (p = 0.046). CONCLUSION: The rs2295080 GT + TT genotype predisposes Iranian diabetic women to atherosclerosis, while the rs2295080 G allele protects them against atherosclerosis. However, additional experiments using larger sample sizes are needed to verify this result.
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Aterosclerosis , Diabetes Mellitus Tipo 2 , Predisposición Genética a la Enfermedad , Genotipo , Polimorfismo de Nucleótido Simple , Serina-Treonina Quinasas TOR , Humanos , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/epidemiología , Femenino , Aterosclerosis/genética , Aterosclerosis/epidemiología , Irán/epidemiología , Persona de Mediana Edad , Factores de Riesgo , Estudios de Casos y Controles , Serina-Treonina Quinasas TOR/genética , Adulto , Masculino , AncianoRESUMEN
BACKGROUND: IL-17A plays an important role in inflammatory responses in myocardial infarction (MI). IL-17A signals through its receptor, for which, Act1 (TRAF3IP2) functions as a key upstream adaptor in the pathway. AIM: To compare frequencies of functional polymorphisms of TRAF3IP2 (rs13210247, rs33980500) between patients with MI and healthy controls. METHODS: The selected SNPs were studied in 201 Iranian MI patients and 201 healthy blood donors from Fars Province by PCR-RFLP in association with clinicopathologic criteria of patients. CXCL1 plasma levels in 126 MI patients and 50 normal subjects were measured by ELISA. RESULTS: A significant increase in the mutant (T) allele of TRAF3IP2 rs33980500 in patients with diastolic dysfunction of the heart (P = .01) was observed. The highest correlation, however, was observed between the TRAF3IP2 rs33980500 TT genotype and T allele with left main coronary artery stenosis (P = .01, P < .001; OR = 31.03). T allele of TRAF3IP2 rs33980500 was also associated with female gender, family history of cardiovascular disease, and mechanical complications of heart (P = .04, P = .02, and P = .01, respectively). Moreover, TRAF3IP2 rs13210247 (G) correlated with mechanical complications of the heart (P = .01). A significant increase in the plasma levels of CXCL1 chemokine in patients (P = .0006) associated with TT genotype of TRAF3IP2 (rs33980500) was observed (P = .04). CONCLUSION: The gene variants of Act1 adaptor are associated with correlates of poor outcome in patients with MI and plasma CXCL1 levels.
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Inflammation and oxidative stress are important risk factors affecting various cells in the formation of atherosclerosis. MicroRNAs (miRs) are regulators of inflammation and atherogenesis. The expressions of endothelial cell (EC)-specific miR-10a and miR-21 and monocyte-specific miR-33a and miR-221 were investigated using coculture of the ECs and monocytes upon exposure to H2O2 as an oxidative stressor, and endotoxin/lipopolysaccharide (LPS) as a microbial stressor. Human umbilical endothelial cells (HUVECs) and peripheral blood mononuclear cells (or monocytes) were cocultured in M199 complete medium and were incubated with LPS (20 ng/mL) or H2O2 (1%) for 8 hours at 37°C. The HUVECs and monocytes were then separated from the cellular mix using a magnetic bead negative selection technique. The relative expression of miRs was determined by real-time polymerase chain reaction. In both cell types, H2O2 induced miR10a ( P = 0.05) and LPS induced miR21 ( P = 0.0003) compared to the untreated controls. Coculture increased miR-10a and miR-21 expression in monocytes ( P = 0.0008 and <0.0001); however when cultured alone, HUVECs expressed higher levels of miR-10a and miR-21 ( P < 0.0001 and <0.0001). Coculture decreased the expression of miR-33a in monocytes ( P < 0.0001) while increasing miR221 in HUVECs and monocytes ( P < 0.0001 and <0.0001). The expression pattern of miRs in HUVECs and monocytes changes in the coculture compared to culturing alone in response to oxidative and microbial toxic compounds. Moreover, different cellular stressors induce different athero-miRs, which may affect the course of inflammation.
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Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Peróxido de Hidrógeno/toxicidad , Lipopolisacáridos/toxicidad , MicroARNs/metabolismo , Monocitos/efectos de los fármacos , Apoptosis/efectos de los fármacos , Células Cultivadas , Técnicas de Cocultivo , Femenino , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Humanos , Masculino , Monocitos/metabolismoRESUMEN
BACKGROUND: CD138/Syndecan-1 (Sdc-1) is expressed on the tumor and stromal cells of invasive bladder carcinoma. CD138/Sdc-1 shedding from the cell surface is associated with the invasive phenotype in lung and breast cancers. PATIENTS AND METHODS: Soluble CD138/Sdc-1 was measured in the sera of 86 bladder cancer patients and 57 healthy individuals by a commercial ELISA assay. RESULTS: Soluble Sdc-1 was increased in the sera of patients with bladder cancer (138.42 ± 81.85 vs. 86.48 ± 82.58 ng/ml, p = 0.0003). Patients aged over 70 years had higher levels of CD138/Sdc-1 in their sera (159.7 ± 15.77 vs. 124.5 ± 9.99 ng/ml, p = 0.025), and soluble Sdc-1 levels were higher in the sera of patients with moderately differentiated tumors compared to poorly differentiated ones (170.47 ± 85.06 vs. 101.79 ± 68.24 ng/ml, p = 0.01). The soluble Sdc-1 level was higher in muscle-invasive (154.45 ± 83.60 vs. 89.9 ± 55.02 ng/ml) but not lymphatic-invasive (106.25 ± 52.10 vs. 123.43 ± 63.76 ng/ml) tumors (p = 0.027 and 0.45, respectively). A non-significant trend of soluble Sdc-1 increase in the sera of male patients compared to female patients was observed (145.38 ± 85.47 vs. 110.20 ± 59.04 ng/ml, p = 0.054). CONCLUSION: The elevated levels of soluble CD138/Sdc-1 in older bladder cancer patients and those with muscular invasion sheds some light on the mechanisms of the disease invasion.
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Biomarcadores de Tumor/sangre , Diferenciación Celular , Sindecano-1/sangre , Neoplasias de la Vejiga Urinaria/sangre , Anciano , Estudios de Casos y Controles , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Invasividad Neoplásica , Estadificación de Neoplasias , Regulación hacia Arriba , Neoplasias de la Vejiga Urinaria/patologíaRESUMEN
BACKGROUND: Immunosenescence is a multifactorial stress response to different intrinsic and extrinsic insults that cause immune deterioration and is accompanied by genomic or epigenomic perturbations. It is now widely recognized that genes and proteins contributing in the process of immunosenescence are regulated by various noncoding (nc) RNAs, including microRNAs (miRNAs), long ncRNAs, and circular RNAs. AIMS: This review article aimed to evaluate the regulatore RNAs roles in the process of immunosenescence. METHODS: We analyzed publications that were focusing on the different roles of regulatory RNAs on the several aspects of immunosenescence. RESULTS: In the immunosenescence setting, ncRNAs have been found to play regulatory roles at both transcriptional and post-transcriptional levels. These factors cooperate to regulate the initiation of gene expression programs and sustaining the senescence phenotype and proinflammatory responses. CONCLUSION: Immunosenescence is a complex process with pivotal alterations in immune function occurring with age. The extensive network that drive immunosenescence-related features are are mainly directed by a variety of regulatory RNAs such as miRNAs, lncRNAs, and circRNAs. Latest findings about regulation of senescence by ncRNAs in the innate and adaptive immune cells as well as their role in the immunosenescence pathways, provide a better understanding of regulatory RNAs function in the process of immunosenescence.
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Inmunosenescencia , MicroARNs , ARN Largo no Codificante , MicroARNs/genética , ARN no Traducido/genética , ARN no Traducido/metabolismo , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , ARN CircularRESUMEN
Atherosclerosis, a leading cause of mortality worldwide, involves various subsets of macrophages that contribute to its initiation and progression. Current treatment approaches focus on systemic, long-term administration of cholesterol-lowering antioxidants such as statins and certain vitamins, which unfortunately come with prolonged side effects. To overcome these drawbacks, a mannose-containing magnetic nanoparticle (NP) is introduced as a drug delivery system to specifically target macrophages in vitro using simvastatin or niacin and a combinational therapy approach that reduces local inflammation while avoiding unwanted side effects. The synthesized NPs exhibited superparamagnetic behavior, neutrally charged thin coating with a hydrodynamic size of 77.23 ± 13.90 nm, and a metallic core ranging from 15 to 25 nm. Efficient loading of niacin (87.21%) and simvastatin (75.36%) on the NPs was achieved at respective weights of 20.13 and 5.03 (w/w). In the presence of a mannan hydrolyzing enzyme, 79.51% of simvastatin and 67.23% of niacin were released from the NPs within 90 min, with a leakage rate below 19.22%. Additionally, the coated NPs showed no destructive effect on J774A macrophages up to a concentration of 200 µg/mL. Simvastatin-loaded NPs exhibited a minimal increase in IL-6 expression. The low dosage of simvastatin decreased both IL-6 and ARG1 expressions, while niacin and combined simvastatin/niacin increased the level of ARG1 expression significantly. Toxicity evaluations on human umbilical vein endothelial cells and murine liver cells revealed that free simvastatin administration caused significant toxicity, whereas the encapsulated forms of simvastatin, niacin, and a combination of simvastatin/niacin at equivalent concentrations exhibited no significant toxicity. Hence, the controlled release of the encapsulated form of simvastatin and niacin resulted in the effective modulation of macrophage polarization. The delivery system showed suitability for targeting macrophages to atherosclerotic plaque.
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AIM: The interrelation between nicotine and IL-17A in bladder cancer (BC) patients was investigated. METHODS: IL-17A in the sera of 121 BC patients who smoked nicotine, 80 nonsmoker BC patients, 29 and 30 age- and sex-matched healthy smokers and nonsmokers were also measured. RESULTS: IL-17A was elevated in smoker and nonsmoker BC patients compared with smoker and nonsmoker controls (p = 0.004 and p = 0.004, respectively). The level of IL-17A in BC patients who smoked both water pipes and cigarettes were the highest (4.35±8.57 pg/ml), followed by BC water pipe users only (1.33±3.122 pg/ml) and cigarette smokers only (0.79±2.26 pg/ml, p = 0.001). IL-17A was elevated in lower stages (I and II) compared with higher stages (III and IV) of the disease (p = 0.013). CONCLUSION: IL-17A levels are elevated in some BC patients. IL-17A is an important factor in the inflammatory process during tumor progression, either as a defense mechanism or as a tumor-promoting factor.
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Interleucina-17/sangre , Fumar , Neoplasias de la Vejiga Urinaria/sangre , Neoplasias de la Vejiga Urinaria/patología , Estudios de Casos y Controles , Humanos , Clasificación del Tumor , Estadificación de NeoplasiasRESUMEN
The immune system is tightly regulated to prevent immune reactions to self-antigens and to avoid excessive immune responses during and after challenges from non-self-antigens. Inhibitory immune checkpoints (IICPs), as the major regulators of immune system responses, are extremely important for maintaining the homeostasis of cells and tissues. However, the high and sustained co-expression of IICPs in chronic infections, under persistent antigenic stimulations, results in reduced immune cell functioning and more severe and prolonged disease complications. Furthermore, IICPs-mediated interactions can be hijacked by pathogens in order to evade immune induction or effector mechanisms. Therefore, IICPs can be potential targets for the prognosis and treatment of chronic infectious diseases. This is especially the case with regards to the most challenging infectious disease of recent times, coronavirus disease-2019 (COVID-19), whose long-term complications can persist long after recovery. This article reviews the current knowledge about the kinetics and functioning of the IICPs during and post-COVID-19.
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COVID-19 , Humanos , Antígeno CTLA-4 , PronósticoRESUMEN
Background: Buerger's disease, also known as Thromboangiitis Obliterans (TAO), is a progressive, inflammatory vascular disease with unknown etiology. Objective: To address the degree of T cell immunosenescence in this inflammatory disease, the frequency of senescent T cells expressing CD57 and/or CD153 (CD30L) in patients with TAO. Methods: In this study, nine male cigarette smoker patients with TAO, nine male healthy cigarette smokers, and nine male healthy non-smoker blood donors were enrolled. PBMCs were extracted from the blood of all participants and stored in liquid nitrogen before use. The percentages of senescent T cells were detected by flow cytometry. The results were analyzed using non-parametric statistical tests. Results: The frequencies of senescent CD3+CD4+CD57+CD153+ and CD3+CD4+CD57-CD153+ T cells significantly increased in patients compared with the non-smoker controls (p=0.01 and p=0.04, respectively). The frequency of senescent CD3+CD4-CD57-CD153+ T cells was higher in patients compared with the smoker controls (p=0.02). In patients with TAO, CD57+CD153- cells were more frequent in CD3hiCD4- and CD3hiCD4+ T cells compared with the CD3loCD4- and CD3loCD4+ T cells (p=0.008 and p=0.0002, respectively). Conversely, the frequency of CD57-CD153+ T cells was significantly higher in CD3loCD4- T cells compared with the CD3hiCD4- T cells (p=0.004). The percentage of CD3+CD4+CD57+CD153- T cells correlated negatively with smoking level in smoker controls (p=0.02, Spearman r=-0.80). Conclusion: Elevated frequencies of senescent CD4+CD57+CD153+ and CD4+CD57-CD153+ T cells in patients compared with non-smoker and smoker controls suggest the contribution of immunosenescence in TAO.
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Immune system is a versatile and dynamic body organ which offers survival and endurance of human beings in their hostile living environment. However, similar to other cells, immune cells are hijacked by senescence. The ageing immune cells lose their beneficial functions but continue to produce inflammatory mediators which draw other immune and non-immune cells to the senescence loop. Immunosenescence has been shown to be associated with different pathological conditions and diseases, among which atherosclerosis has recently come to light. There are common drivers of both immunosenescence and atherosclerosis; e.g. inflammation, reactive oxygen species (ROS), chronic viral infections, genomic damage, oxidized-LDL, hypertension, cigarette smoke, hyperglycaemia, and mitochondrial failure. Chronic viral infections induce inflammaging, sustained cytokine signaling, ROS generation and DNA damage which are associated with atherogenesis. Accumulating evidence shows that several DNA and RNA viruses are stimulators of immunosenescence and atherosclerosis in an interrelated network. DNA viruses such as CMV, EBV and HBV upregulate p16, p21 and p53 senescence-associated molecules; induce inflammaging, metabolic reprogramming of infected cells, replicative senescence and telomere shortening. RNA viruses such as HCV and HIV induce ROS generation, DNA damage, induction of senescence-associated secretory phenotype (SASP), metabolic reprogramming of infected cells, G1 cell cycle arrest, telomere shortening, as well as epigenetic modifications of DNA and histones. The newly emerged SARS-CoV-2 virus is also a potent inducer of cytokine storm and SASP. The spike protein of SARS-CoV-2 promotes senescence phenotype in endothelial cells by augmenting p16, p21, senescence-associated ß-galactosidase (SA-ß-Gal) and adhesion molecules expression. The impact of SARS-CoV-2 mega-inflammation on atherogenesis, however, remains to be investigated. In this review we focus on the common processes in immunosenescence and atherogenesis caused by chronic viral infections and discuss the current knowledge on this topic.
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Aterosclerosis , COVID-19 , Inmunosenescencia , Aterosclerosis/metabolismo , Células Endoteliales/metabolismo , Humanos , Inflamación/metabolismo , Especies Reactivas de Oxígeno/metabolismo , SARS-CoV-2RESUMEN
Despite the availability of an effective vaccine and antiviral treatments, hepatitis B is still a global public health problem. Hepatitis B vaccination can prevent the disease. Vaccination induces long-lasting protective immune memory, and the identification of memory cell subsets can indicate the effectiveness of vaccines. Here, we compared the frequency of CD4+ memory T cell subsets between responders and nonresponders to HB vaccination. Besides, the frequency of IFN-γ+ memory T cells was compared between studied groups. Study participants were grouped according to their anti-HBsAb titer. For restimulation of CD4+ memory T cells, peripheral blood mononuclear cells (PBMCs) were cultured in the presence of HBsAg and PHA for 48 h. Besides, PMA, ionomycin, and brefeldin were added during the last 5 h of incubation to induce IFN-γ production. Flow cytometry was used for analysis. There was a statistically significant difference in the frequency of CD4+CD95+, CD4+CD95Hi, and CD4+CD95low/med T stem cell memory (TSCM) cells between responder and nonresponder groups. However, the comparison of the frequency of memory T cells producing IFN-γ showed no differences. Our results identified a possible defect of immunological CD4+ memory T cell formation in nonresponders due to their lower frequency of CD4+ TSCM cells.
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Vacunas contra Hepatitis B , Hepatitis B , Linfocitos T CD4-Positivos , Humanos , Memoria Inmunológica , Leucocitos Mononucleares , Células MadreRESUMEN
BACKGROUND: HLA molecules are inherited key molecules in the immune inflammation and specific responses to environmental pathogens. We investigated the association of HLA-A alleles with Varicella zoster virus (VZV) seropositivity in patients with atherosclerosis (AS). MATERIALS AND METHODS: Plasma Anti-VZV IgG and molecular HLA type were detected in 203 (100 AS+ and 103 AS-) individuals. RESULTS: Of 100 AS+ individuals, 66 were anti-VZV+ and 34 were anti-VZV-. Of 103 age/sex-matched AS- individuals, 59 were anti-VZV+ and 44 were anti-VZV-. Anti-VZV-IgG in AS+ cases was higher than AS- controls (p = .034). The mean anti-VZV IgG in HLA-A*02+AS+ individuals was higher than HLA-A*02+AS- controls (p < .001). HLA-A*02 was associated with VZV-seropositivity (p = .01) in AS+ patients. A higher frequency of HLA-A*02-allele in AS+ patients compared to AS- controls (p = .015) and an accumulation of HLA-A*02-allele in AS+ anti-VZV+ group (33.3%, p = .004) was observed. CONCLUSIONS: HLA-A alleles and immune responses to VZV are associated with clinical atherosclerosis.
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Anticuerpos Antivirales/sangre , Aterosclerosis/patología , Antígeno HLA-A2/sangre , Herpesvirus Humano 3/aislamiento & purificación , Infección por el Virus de la Varicela-Zóster/complicaciones , Anticuerpos Antivirales/inmunología , Aterosclerosis/sangre , Aterosclerosis/inmunología , Aterosclerosis/virología , Estudios de Casos y Controles , Femenino , Antígeno HLA-A2/inmunología , Humanos , Masculino , Persona de Mediana Edad , Infección por el Virus de la Varicela-Zóster/virologíaRESUMEN
Background: The significance of cTfh cells and their subsets in atherosclerosis is not well understood. We measured the frequency of cTfh subsets in patients with different degrees of stenosis using flow-cytometry. Methods: Participants included high (≥50%; n = 12) and low (<50%; n = 12) stenosis groups, as well as healthy controls (n = 6). Results: The frequency of CCR7loPD-1hiefficient-cTfh was significantly higher in patients with high stenosis compared to healthy controls (p = 0.003) and correlated with low-density lipoprotein (LDL; p = 0.043), cholesterol (p = 0.043), triglyceride (p = 0.019), neutrophil count (p = 0.032), platelet count (p = 0.024), neutrophil/lymphocyte ratio (NLR; p = 0.046), and platelet/lymphocyte ratio (PLR; p = 0.025) in high stenosis group. The frequency of CCR7hiPD-1lo quiescent-cTfh was higher in healthy controls compared to the high-stenosis group (p = 0.001) and positively correlated with high-density lipoprotein (p = 0.046). The frequency of efficient-cTfh cells was correlated with platelet count (p = 0.043), NLR (p = 0.036), and PLR (p P = 0.035) in low-stenosis group, while that of quiescent-cTfh cells was negatively correlated with LDL (p = 0.034), cholesterol (p = 0.047), platelet count (p = 0.032), and PLR (p = 0.041). Conclusion: High percentages of cTfh and efficient-cTfh cells in patients with advanced atherosclerosis and their correlation with dyslipidemia and white blood cell counts suggest an ongoing cTfh subset deviation, towards efficient phenotype in the milieu of inflammation and altered lipid profile. Efficient cTfh cells have an effector phenotype and could in turn contribute to atherosclerosis progression.
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Aterosclerosis/sangre , Aterosclerosis/inmunología , Movimiento Celular , Dislipidemias/sangre , Dislipidemias/inmunología , Células T Auxiliares Foliculares/inmunología , Aterosclerosis/complicaciones , Dislipidemias/complicaciones , Femenino , Humanos , Recuento de Leucocitos , Masculino , Persona de Mediana EdadRESUMEN
Cellular senescence is an irreversible arrest of cell proliferation triggered by different stimuli, including DNA damage, telomere shortening and oncogenic stress. Senescent cells, by releasing the senescence-associated-secretory-phenotype (SASP), contribute to various diseases pathogenesis. Human atherosclerotic plaque contains cells with multiple markers of senescence that associate with disease severity. We characterized the frequency of senescent cTfh cells and genes expressions before and after treatment with Dasatinib in patients with different degrees of stenosis. Twelve high (≥50%), and twelve low (<50%) stenosis patients and six healthy controls were enrolled. The percentage of senescent CD3+CD4+CXCR5+CD153+CD57+ cells was significantly decreased in Dasatinib treated cells from individuals with low and high stenosis (P = 0.0007 and P = 0.0002, respectively). However, the frequency of total lymphocytes, CD3+ and CD4+ T cells were not significantly different between the groups before and after treatment. The expression levels of P53 (P = 0.0003 and P = 0.0001), P16 (P = 0.0005 and P = 0.0002), p21 (P = 0.0002 and P < 0.0001), SENEX (P = 0.0005 and P < 0.0001) and BCL-2 (P = 0.0005 and P = 0.0002) were decreased in PBMCs of low and high stenosis groups after treatment with Dasatinib, respectively. The percentage of senescent cTfh cells positively correlated with cholesterol (P = 0.034; r = 0.671), C-reactive protein (CRP) (P = 0.029; r = 0.707), Erythrocyte sedimentation rate (ESR) levels (P = 0.030; r = 0.598) and neutrophil counts (P = 0.021; r = 0.799) in patients with high stenosis. The decreased frequency of senescent cTfh cells and the expression levels of senescence genes after Dasatinib treatment in patients with atherosclerosis suggest a role for Dasatinib in partial clearance or rejuvenation of senescent cTfh cells, which may decrease inflammatory mediators and attenuate disease progression.
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Aterosclerosis/inmunología , Senescencia Celular/efectos de los fármacos , Estenosis Coronaria/inmunología , Dasatinib/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Células T Auxiliares Foliculares/efectos de los fármacos , Aterosclerosis/genética , Células Cultivadas , Senescencia Celular/genética , Estenosis Coronaria/genética , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Masculino , Persona de Mediana Edad , Células T Auxiliares Foliculares/inmunologíaRESUMEN
Toll-like receptors (TLRs) are among the players of inflammation during atherosclerosis. We assessed the effects of Eritoran, a TLR-4 antagonist, on lipopolysaccharide (LPS)-induced cytokines production by Peripheral Blood Mononuclear Cells (PBMCs) of patients with high-stenosis (HS) (n = 6) and healthy controls (HCs) (n = 6) co-cultured with Human Umbilical Vein Endothelial Cells (HUVECs). LPS stimulation significantly increased the levels of IL-6 (P = 0.007 and P = 0.005), TNF-α (P = 0.006 and P = 0.005), IL-2 (P = 0.007 and P = 0.002), IFN-γ (P = 0.006 and P = 0.003), IL-17A (P = 0.004 and P = 0.003), IL-17F (P = 0.005 and P = 0.003), IL-5 (P = 0.007 and P = 0.005), IL-13 (P = 0.006 and P = 0.005), IL-9 (P = 0.005 and P = 0.005) and IL-21 (P = 0.007 and P = 0.005) in HUVECs co-cultured with HC and HS PBMCs as compared with un-stimulated co-culture condition, respectively. Eritoran treatment (50 µg/mL and 100 µg/mL) significantly reduced the levels of LPS-induced IL-6 (P = 0.007 and P = 0.006; P = 0.007 and P = 0.007), TNF-α (P = 0.005 and P = 0.003; P = 0.007 and P = 0.005), IL-2 (P = 0.007 and P = 0.005; P = 0.005 and P = 0.004), IFN-γ (P = 0.007 and P = 0.005; P = 0.005 and P = 0.004), IL-17A (P = 0.005 and P = 0.002; P = 0.005 and P = 0.002), IL-17F (P = 0.006 and P = 0.006; P = 0.005 and P = 0.005), IL-5 (P = 0.007 and P = 0.006; P = 0.007 and P = 0.007), IL-9 (P = 0.005 and P = 0.005; P = 0.005 and P = 0.005) and IL-21 (P = 0.007 and P = 0.007; P = 0.005 and P = 0.005) in stimulated HUVECs co-cultured with HC and HS PBMCs, compared to un-treated condition, respectively. Our results demonstrate that attenuating effect of Eritoran on the inflammatory responses to LPS is higher in PBMCs of patients with high stenosis, suggesting its potential role in ameliorating inflammatory conditions in atherosclerosis.
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Aterosclerosis/inmunología , Citocinas/metabolismo , Disacáridos/farmacología , Leucocitos Mononucleares/efectos de los fármacos , Fosfatos de Azúcar/farmacología , Receptor Toll-Like 4/antagonistas & inhibidores , Adulto , Aterosclerosis/tratamiento farmacológico , Estudios de Casos y Controles , Técnicas de Cocultivo , Disacáridos/uso terapéutico , Relación Dosis-Respuesta a Droga , Femenino , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana/inmunología , Humanos , Interferón gamma/metabolismo , Interleucina-17/metabolismo , Interleucina-2/metabolismo , Interleucina-6/metabolismo , Interleucina-9/metabolismo , Interleucinas/metabolismo , Leucocitos Mononucleares/metabolismo , Lipopolisacáridos/farmacología , Masculino , Persona de Mediana Edad , Fosfatos de Azúcar/uso terapéutico , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Regarding the role of micro RNAs (miRNA) in the proliferation and differentiation of T cells as well as the controversy around the role of bacteria in the pathogenesis of abdominal aortic aneurysm (AAA), the effects of Helicobacter pylori (Hp) and Lactobacillus acidophilus (La) were investigated in the induction of miRNAs and apoptosis in CD4+ memory T (Tem) cells of AAA patients and controls. Signature atherosclerosis miRNAs 21, 92a, 146a, 155, 326 and 663 were measured in the sera and tissues of AAA patients and control. PBMCs separately and in co-culture with HUVEC were treated with Hp-water-extract (HpWE) and La-conditioned-medium (LaCM). Apoptosis and miRNA levels were assessed in the isolated Tem by flowcytometry and real-time-PCR. In single-culture, HpWE increased apoptosis and miR-155 and LaCM decreased apoptosis and increased miR-21. In co-culture, apoptosis decreased in both groups in response to CagA+HpWE. Also, all miRNAs increased in patients Tem but in controls, only miR- 146a and 21 showed changes. Although, apoptosis was similar in Tem of patients and controls, the effects of Hp and La were different on the induction of apoptosis and miRNAs and also these bacteria showed different impacts in single and co-culture conditions. Beyond the direct effects of these bacteria on the pathogenesis of diseases, their effects on miRNAs expression may shed light on their roles in the development and the prevention of AAA.
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Aneurisma de la Aorta Abdominal/inmunología , Helicobacter pylori/fisiología , Lactobacillus acidophilus/fisiología , MicroARNs/genética , Linfocitos T/metabolismo , Anciano , Antígenos Bacterianos/farmacología , Antígenos Bacterianos/fisiología , Aneurisma de la Aorta Abdominal/patología , Estudios de Casos y Controles , Células Cultivadas , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana , Humanos , Memoria Inmunológica/genética , Masculino , MicroARNs/metabolismo , Persona de Mediana Edad , Linfocitos T/efectos de los fármacos , Linfocitos T/patologíaRESUMEN
BACKGROUND: Polycystic ovary syndrome (PCOS) is the most frequent endocrine disorder affecting 6-7% of premenopausal women. Recent studies revealed that the immune system, especially CD4+ T helper cells are important in the context PCOS. Proteome analysis of CD4+ T lymphocytes can provide valuable information regarding the biology of these cells in the context of PCOS. OBJECTIVE: To investigate immune dysregulation in CD4+ T lymphocytes at the protein level in the context of PCOS using two-dimensional gel electrophoresis (2DE) and mass spectrometry (MS). METHODS: In the present study, we applied two-dimensional gel electrophoresis / mass spectrometry to identify proteins differentially expressed by peripheral blood CD4+ T cells in ten PCOS women compared with ten healthy women. Western blot technique was used to confirm the identified proteins. RESULTS: Despite the overall proteome similarities, there were significant differences in the expression of seven spots between the two groups (P <0.05). Three proteins, namely phosphatidylethanolaminebinding protein 1, proteasome activator complex subunit 1 and triosephosphate isomerase 1 were successfully identified by Mass technique and confirmed by western blot. All characterized proteins were over-expressed in CD4+ T cells from patients compared to CD4+ T cells from controls (P <0.05). Insilico analysis suggested that the over-expressed proteins interact with other proteins involved in cellular metabolism, especially glycolysis and ferroptosis pathway. CONCLUSION: These findings suggest that metabolic adjustments in CD4+ T lymphocytes, which is in favor of increased glycolysis and Th2 differentiation are important in the context of PCOS.
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Síndrome del Ovario Poliquístico , Linfocitos T CD4-Positivos/metabolismo , Electroforesis en Gel Bidimensional , Femenino , Humanos , Síndrome del Ovario Poliquístico/metabolismo , Proteoma/metabolismo , Proteómica/métodosRESUMEN
BACKGROUND: Diabetes increases the risk of myocardial infarction (MI) by 2 to 3 folds. Tlymphocytes play a role in atherosclerosis, which is the main pathology behind MI. Cellular immune responses to beta-2 glycoprotein I (ß2GPI) are shown in carotid atherosclerosis. OBJECTIVE: To investigate the self-reactive, ß2GPI-specific T-lymphocytes in patients with and without diabetes and atherosclerosis. METHODS: Collectively, 164 subjects with and without diabetes that underwent coronary angiography were divided into four groups based on their diabetes status and coronary stenosis. Group I=Diabetic with ≥50% stenosis: A+D+ (n=66); Group II=Non-diabetic with ≥50% stenosis, A+D- (n=39); Group III=Diabetic with <50% stenosis: A-D+ (n=28); and Group IV=Non-diabetic with <50% stenosis: AD- (n=31). All groups were evaluated for anti-ß2GPI IgG antibody by ELISA method. Then, PBMCs were isolated from 18 subjects and were stimulated with ß2GPI-derived peptides to assess their proliferation in accordance with their HLA-DRB1 alleles. RESULTS: Mean ß2GPI IgG levels were higher in groups with ≥50% stenosis (A+) compared to those with <50% stenosis (A-), (P=0.02). The co-presence of diabetes in A+ individuals increased mean ß2GPI-specific IgG. Auto-reactive ß2GPI-specific T cells were detected in the repertoire of T-lymphocytes in all groups. ß2GPI-peptides showed promiscuous restriction by various HLADRB1. CONCLUSION: ß2GPI is the target of cellular and humoral immune responses in patients with atherosclerosis. Since the T cell responses but not antibodies were detectable in A-D+ and A-D- groups, it is reasonable to assume that cellular responses preceded the humoral responses. Post-translation modifications of ß2GPI under oxidative and glycemic stresses may have increased the IgG levels in patients with diabetes. Finally, identification of antigens that trigger immuno-pathogenesis in atherosclerosis and diabetes may help the development of immunomodulation methods to prevent or treat these debilitating diseases.
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Anticuerpos Anticardiolipina/sangre , Linfocitos T CD4-Positivos/inmunología , Proliferación Celular , Estenosis Coronaria/inmunología , Diabetes Mellitus/inmunología , Activación de Linfocitos , beta 2 Glicoproteína I/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Linfocitos T CD4-Positivos/metabolismo , Células Cultivadas , Angiografía Coronaria , Estenosis Coronaria/diagnóstico por imagen , Estenosis Coronaria/metabolismo , Diabetes Mellitus/diagnóstico , Diabetes Mellitus/metabolismo , Epítopos , Femenino , Cadenas HLA-DRB1/genética , Cadenas HLA-DRB1/inmunología , Humanos , Inmunidad Celular , Inmunidad Humoral , Masculino , Persona de Mediana EdadRESUMEN
The coronavirus disease-2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), appears with a wide spectrum of mild-to-critical clinical complications. Many clinical and experimental findings suggest the role of inflammatory mechanisms in the immunopathology of COVID-19. Hence, cellular and molecular mediators of the immune system can be potential targets for predicting, monitoring, and treating the progressive complications of COVID-19. In this review, we assess the latest cellular and molecular data on the immunopathology of COVID-19 according to the pathological evidence (e.g., mucus and surfactants), dysregulations of pro- and anti-inflammatory mediators (e.g., cytokines and chemokines), and impairments of innate and acquired immune system functions (e.g., mononuclear cells, neutrophils and antibodies). Furthermore, we determine the significance of immune biomarkers for predicting, monitoring, and treating the progressive complications of COVID-19. We also discuss the clinical importance of recent immune biomarkers in COVID-19, and at the end of each section, recent clinical trials in immune biomarkers for COVID-19 are mentioned.
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Biomarcadores/sangre , COVID-19/diagnóstico , COVID-19/terapia , Inmunidad Innata/fisiología , Monitoreo Fisiológico/métodos , Biomarcadores/análisis , COVID-19/sangre , COVID-19/complicaciones , Quimiocinas/análisis , Quimiocinas/sangre , Síndrome de Liberación de Citoquinas/diagnóstico , Síndrome de Liberación de Citoquinas/etiología , Síndrome de Liberación de Citoquinas/terapia , Citocinas/análisis , Citocinas/sangre , Humanos , Pronóstico , Síndrome de Dificultad Respiratoria/diagnóstico , Síndrome de Dificultad Respiratoria/etiología , Síndrome de Dificultad Respiratoria/terapia , SARS-CoV-2/fisiologíaRESUMEN
Frequencies of circulating T follicular helper (cTfh) functional subsets vary in autoimmune diseases. We evaluated the frequencies and clinical relevance of functional subsets of cTfhs in patients with different degrees of stenosis. Blood samples were collected from high (≥50%) (n = 12) and low (<50%) stenosis (n = 12) groups and healthy controls (n = 6). Three subsets of cTfh cells including cTfh1 (CXCR3+ CCR6- ), cTfh2 (CXCR3- CCX6- ), and cTfh17 (CXCR3- CCR6+ ) were detected by flow cytometry. The frequency of cTfh1 cells was higher in control (p = .0006) and low-stenosis groups (p = .005) compared to high-stenosis group. The percentages of cTfh2 and cTfh17 cells were increased in high-stenosis compared to low-stenosis (p = .002 and p = .007) and control groups (p = .0004 and p = .0005), respectively. The frequency of cTfh1 cells negatively correlated with cholesterol (p = .040; r = -.44), C-reactive protein (CRP) (p = .015; r = -.68), erythrocyte sedimentation rate (ESR) (p = .002; r = -.79), neutrophil/lymphocyte ratio (NLR) (p = .028; r = -.67), and cTfh17 (p = .017; r = -.7244) in the high-stenosis group. The percentages of cTfh2 and cTfh17 cells positively correlated with cholesterol (p = .025; r = .77 and p = .033; r = .71), CRP (p = .030; r = .61 and p = .020; r = .73), ESR (p = .027; r = .69 and p = .029; r = .70), NLR (p = .004; r = .76 and p = .005; r = .74), and with each other (p = .022; r = .7382), respectively, in the high-stenosis group. The increased frequencies of cTfh2 and cTfh17 subsets and their correlation with laboratory parameters in patients with atherosclerosis may suggest their role in promoting the inflammatory response and atherosclerosis progression.