Increased lipid and protein oxidation and lowered anti-oxidant defenses in systemic lupus erythematosus are associated with severity of illness,autoimmunity, increased adhesion molecules,and Th1 and Th17 immune shift

This study investigated nitro-oxidative stress in patients with systemic lupus erythematosus (SLE) in association with disease activity, immune-inflammatory biomarkers, and adhesion molecules. Two-hundred-four patients with SLE and 256 healthy volunteers were enrolled in this case-control study, which measured nitro-oxidative stress biomarkers, including lipid peroxides (LOOH), advanced oxidation protein products (AOPPs), nitric oxide metabolites (NO_x), sulfhydryl (?SH) groups, products of deoxyribonucleic acid (DNA)/ribonucleic acid (RNA) oxidative degradation, and total radical-trapping anti-oxidant parameter (TRAP). Also measured were anti-nuclear antibodies (ANAs), antibodies against double-stranded DNA (dsDNA), plasma levels of diverse cytokines, C-reactive protein, and adhesion molecules. LOOH (p < 0.001) and AOPP (p < 0.001) were significantly higher, while TRAP was significantly lower (p < 0.001) in SLE patients than in controls. AOPP and LOOH were significantly and positively associated with SLE disease activity index (SLEDAI) scores, anti-nuclear antibodies, and antibodies against double-stranded DNA (anti-dsDNA) levels, while TRAP was significantly and inversely correlated with SLEDAI, ANA, and dsDNA antibody levels. There were significant positive associations between AOPP and LOOH and immune-inflammatory markers, indicating T helper (Th)-17 and Th1 bias and Th1 + Th17/Th2 ratio (p = 0.002 and p = 0.001, respectively). AOPP and LOOH (positively) and TRAP (inversely) were associated with adhesion molecule expression. A model predicting SLE was computed showing that, using LOOH, AOPP, NO_x, adhesion molecules, and body mass index, 94.2% of the patients were correctly classified with a specificity of 91.5%. Increased nitro-oxidative stress takes part in the (auto)immune pathophysiology of SLE and modulates severity of illness and adhesion molecule expression.     

Immune-inflammatory,oxidative stress and biochemical biomarkers predict short-term acute ischemic stroke death

Metabolic Brain Disease - The aim of the study was to define new immune-inflammatory, oxidative stress and biochemical biomarkers, which predict mortality within a period of 3&nbsp;months after...     

<Emphasis Type="Italic">C-reactive protein</Emphasis> +1444CT (rs1130864) genetic polymorphism is associated with the susceptibility to systemic lupus erythematosus and C-reactive protein levels

The T rare allele of +1444CT (rs1130864) polymorphism of C-reactive protein (CRP) has been associated with increased CRP levels in some inflammatory conditions, but its role on systemic lupus erythematosus (SLE) susceptibility and on CRP levels in SLE patients remains uncertain. The objective of the study was to evaluate the association between the rs1130864 CRP polymorphism with SLE susceptibility, disease activity, and CRP levels in SLE Brazilian patients. The study enrolled 176 SLE patients and 137 controls. SLE disease activity was assessed using the SLE Disease Activity Index (SLEDAI). The rs1130864 CRP polymorphism was determined using polymerase chain reaction and restriction fragment length polymorphism. SLE patients presented higher body mass index (p = 0.046) and CRP levels (p = 0.017) than controls. The genotype and allele frequencies of patients differed from controls [CC vs. CT = odds ratio (OR) 1.730, 95% confidence interval (CI) 1.068–2.803, p = 0.035; CC vs. TT = OR 3.667, 95% CI 1.410–9.533, p = 0.009; C vs. T = OR 1.883, 95% CI 1.299–2.728, p = 0.001)]. Patients carrying the T allele presented higher CRP levels (p = 0.009), were more frequent Caucasians (p = 0.018), and with no use of immunosuppressive treatment (p = 0.004) than those carrying the C allele. However, the SLEDAI and anti-double-stranded DNA positivity did not differ from those carrying T vs. C allele (p = 0.595 and p = 0.243, respectively). The rs1130864 CRP polymorphism was associated with SLE susceptibility and CRP levels, but not with disease activity, suggesting that this polymorphism may play a role in the pathophysiology of SLE through increasing the CRP that, probably, plays an inflammatory role in SLE pathophysiology.     

Vitamin D deficiency is associated with acute ischemic stroke,C-reactive protein,and short-term outcome

The aim of this study was to investigate whether vitamin D deficiency (VDD) is associated with acute ischemic stroke, inflammatory markers, and short-term outcome. 168 acute ischemic stroke patients and 118 controls were included. The modified Rankin Scale (mRS) was applied up to 8 h of admission (baseline) and after three-months follow-up, and blood samples were obtained up to 24 h of admission to evaluate serum levels of 25-hydroxivitamin D [25(OH)D] and inflammatory markers. Vitamin D levels classified the individuals in sufficient (VDS?≥?30.0 ng/mL), insufficient (VDI 20.0–29.9 ng/mL), and deficient (VDD?<?20.0 ng/mL) status. Patients had lower levels of 25(OH)D, higher frequency of VDD (43.45% vs. 5.08%, OR: 16.64, 95% CI: 5.66–42.92, p?<?0.001), and higher inflammatory markers than controls (p?<?0.05). Patients with VDD showed increased high sensitivity C-reactive protein (hsCRP) levels than those with VDS status (p?=?0.043); those with poor outcome presented with lower 25(OH)D levels than those with good outcome (p?=?0.008); moreover, 25(OH)D levels were negatively correlated with mRS after three-months follow-up (r?=??0.239, p?=?0.005). The associations between VDD and higher hsCRP levels and between 25(OH)D levels and poor outcome at short-term in acute ischemic stroke patients suggest the important role of vitamin D in the inflammatory response and pathophysiology of this ischemic event.

     

Soy isoflavones reduce electronegative low-density lipoprotein (LDL<Superscript>−</Superscript>) and anti-LDL<Superscript>−</Superscript> autoantibodies in experimental atherosclerosis

Background Isoflavones present in soybean may contribute to soy atheroprotectective effects. Aim of the study To investigate the effect of soy isoflavones supplementation on the formation of electronegative LDL (LDL⁻) and its autoantibodies in blood plasma and aortic atheromas of rabbits fed an atherogenic casein-based diet enriched with isoflavones. Methods New Zealand male rabbits (n = 15) were fed an atherogenic diet (27% casein) supplemented with isoflavones (0.73 or 7.3 mg of isoflavones/kg/day, Low and High Iso groups, respectively) for 180 days. Monthly, blood samples were collected after 12–15 h fasting and at 180 days of treatment all animals were sacrificed. Isoflavones were analyzed in plasma and urine samples by HPLC. LDL⁻ in plasma and atheromas was detected by ELISA and immunohistochemistry, respectively, with a monoclonal antibody reactive to LDL⁻. Autoantibodies reactive to LDL⁻ were analyzed in plasma and aorta by ELISA. Results Low and High Iso groups had decreased LDL-cholesterol, increased HDL-cholesterol and lower levels of LDL⁻ in blood plasma and aortic atherosclerotic lesions than the non-supplemented Control group. IgG autoantibodies reactive to LDL⁻ were higher in plasma of the Control group in comparison with the High and Low Iso groups. In contrast, the aortas from animals that consumed isoflavones showed higher levels of IgG reactive to LDL⁻ than the Control group. Conclusion Soy isoflavones showed hypolipidemic effects and decreased the pro-inflammatory LDL⁻ subfraction in blood plasma and aorta of hypercholesterolemic rabbits.     

Cell adhesion molecules and plasminogen activator inhibitor type-1 (PAI-1) in patients with rheumatoid arthritis: influence of metabolic syndrome

Rheumatoid arthritis (RA) is a chronic inflammatory and systemic disease characterized by endothelial activation. The main objective of this study was to verify the profile of cell adhesion molecules (CAM) in RA patients, and the influence of metabolic syndrome (MetS) and drugs used in the treatment of RA in this profile. A second objective was to propose models of prediction of activity in RA using these biomarkers. A total of 115 healthy individuals and 144 RA patients were enrolled. Disease activity was determined by DAS28 (disease activity score 28) based on erythrocyte sedimentation rate (DAS28-ESR) or C-reactive protein (DAS28-CRP). Serum CAM and plasminogen activator inhibitor type-1 (PAI-1), anthropometric and immunological parameters were measured. Vascular cell adhesion molecule-1 (VCAM-1) was significantly decreased, and PAI-1 was significantly higher in RA patients as compared to controls. Binary logistic regression analysis showed that VCAM-1, CRP, and tumor necrosis factor-α (TNF-α) predicted RA with a sensitivity of 95.9% and a specificity of 89.5%. 42.9% of the variance in DAS28-ESR and 49.2% of the variance in DAS28-CRP are explained by increased PAI-1, TNF-α, body mass index (BMI) and decreased platelet endothelial cell adhesion molecule 1 (PECAM-1). Our data show that lower levels of VCAM-1 are associated with RA independently of MetS, while increased PAI-1 levels were associated with both RA and MetS and increased selectins (E-selectin and P-selectin) were exclusively associated with MetS and not with RA. A model to predict disease activity based on PECAM-1, PAI-1, TNF-α, age and BMI is proposed.     

TNF-β +252 A>G (rs909253) polymorphism is independently associated with presence of autoantibodies in rheumatoid arthritis patients

Clinical and Experimental Medicine - The TNF-β +252 A&gt;G (rs909253) polymorphism has been associated with a risk of development of rheumatoid arthritis (RA) and could influence plasma...     

TGFB1 (rs1800470 and rs1800469) variants are independently associated with disease activity and autoantibodies in rheumatoid arthritis patients

To evaluate the association between TGFB1?+?869 T?>?C (rs1800470) and TGFB1-509 C?>?T (rs1800469) variants with susceptibility for rheumatoid arthritis (RA), disease activity, presence of rheumatoid factor (RF), anti-cyclic citrullinated peptide (anti-CCP) and TGF-β1 plasma levels. A total of 262 patients with RA and 168 control individuals were tested for the TGFB1 variants using a TaqMan genotyping assay. Disease activity score in 28 joints (DAS28) classified RA patients into two groups of disease activity: remission/mild (DAS28?<?3.2) and moderate/severe (DAS28?≥?3.2). TGFB1?+?869 T?>?C and ?509 C?>?T variants, independently or in haplotype combination, were not associated with RA’s susceptibility. Patients with the TGFB1-509 TT genotype had a higher frequency of DAS28?≥?3.2 (OR 2.58, 95% CI 1.04–6.42, p?=?0.041). The TGFB1?+?869 CC genotype in seropositive patients for RF or anti-CCP was associated with decreased TGF-β1 levels (p?=?0.032 and p?=?0.039, respectively). Patients with the TGFB1?+?869 C allele and elevated RF titles demonstrated a higher frequency of DAS28?≥?3.2 (p?=?0.037). The TGFB1?+?869 T?>?C variant was associated with diminished TGF-β1 plasma levels and moderate/severe activity disease only in seropositive RF patients. This is the first study showing that TGF-β1 plasma levels can be modulated by the interaction between the TGFB1?+?869 T?>?C variant and autoantibodies. However, the TGFB1-509 C?>?T variant was associated with moderate/severe activity disease, independently of autoantibodies positivity. Thus, our findings suggest that TGFB1?+?869 T?>?C and ?509 C?>?T variants can predict activity disease in different RA patient subgroups.

     

Disability in multiple sclerosis is associated with age and inflammatory,metabolic and oxidative/nitrosative stress biomarkers: results of multivariate and machine learning procedures

The aim of this study was to evaluate the immune-inflammatory, metabolic, and nitro-oxidative stress (IM&NO) biomarkers as predictors of disability in multiple sclerosis (MS) patients. A total of 122 patients with MS were included; their disability was evaluated using the Expanded Disability Status Scale (EDSS) and IM&NO biomarkers were evaluated in peripheral blood samples. Patients with EDSS ≥3 were older and showed higher homocysteine, uric acid, advanced oxidized protein products (AOPP) and low-density lipoprotein (LDL)-cholesterol and higher rate of metabolic syndrome (MetS), while high-density lipoprotein (HDL)-cholesterol was lower than in patients with EDSS <3; 84.6% of all patients were correctly classified in these EDSS subgroups. We found that 36.3% of the variance in EDSS score was explained by age, Th17/T regulatory (Treg) and LDL/HDL ratios and homocysteine (all positively related) and body mass index (BMI) (inversely related). After adjusting for MS treatment modalities, the effects of the LDL/HDL and zTh17/Treg ratios, homocysteine and age on disability remained, whilst BMI was no longer significant. Moreover, carbonyl proteins were associated with increased disability. In conclusion, the results showed that an inflammatory Th17 profile coupled with age and increased carbonyl proteins were the most important variables associated with high disability followed at a distance by homocysteine, MetS and LDL/HDL ratio. These data underscore that IM&NO pathways play a key role in increased disability in MS patient and may be possible new targets for the treatment of these patients. Moreover, a panel of these laboratory biomarkers may be used to predict the disability in MS.

     

Elevated plasma homocysteine levels are associated with disability progression in patients with multiple sclerosis

The aims of this study were to verify whether hyperhomocysteinemia is associated with disability progression in Multiple Sclerosis (MS) patients and whether TNF pathways and cellular adhesion molecules (CAM) are involved in this process. This study included 180 MS patients, who were divided according to their levels of homocysteine (Hyperhomocysteinemia ≥11.35 μmol/L) and 204 healthy individuals (control group). MS patients showed higher levels of homocysteine (p?<?0.001), tumor necrosis factor alpha (TNF-α, p?<?0.001), TNF receptor 1 (TNFR1, p?=?0.038), TNF receptor 2 (TNFR2, p?<?0.001), and lower levels of PECAM (p?=?0.001), ICAM (p?<?0.001) and VCAM (p?=?0.005) than controls. The multivariate binary logistic regression analysis showed that plasma levels of homocysteine, TNFR1, TNFR2 and PECAM were associated with the presence of disease. MS patients with hyperhomocysteinemia showed higher disease progression evaluated by the Multiple Sclerosis Severity Score (MSSS, p?<?0.001), disability evaluated by Expanded Disability Status Score EDSS (p?<?0.001), TNFR1 (p?=?0.039) and ICAM (p?=?0.034) than MS patients with lower levels of homocysteine. Hyperhomocysteinemia was independently associated with MSSS in MS patients, but were not associated with TNF-α, TNFR, and CAM. Homocysteine levels was higher in progressive forms than relapsing-remitting MS (p?<?0.001), independently of sex and age. In conclusion, this is the first study in which homocysteinemia was associated with progression of the disease (MSSS), although this finding was not directly related to TNF-α and TNFR pathways or to CAM.