Senescent CD4+CD28null cells are increased in chronic hyperuricemia, show aberrant effector phenotypes, and are reversed after allopurinol therapy: a proof-of-concept pilot study.

To characterize CD4+CD28null cells in chronic hyperuricemia and investigate whether allopurinol could restore CD28 expression and the balance of T helper phenotypes. Asymptomatic individuals with chronic hyperuricemia and ultrasonographic findings evocative of urate deposition in the joints. Age- and gender-matched normouricemic individuals were also studied. Oral allopurinol at 150 mg/day for 4 weeks, followed by 300 mg/day through week 12. Color-flow cytometry on peripheral blood mononuclear cells (PBMC) with antibodies against CD4, CD28, T-bet (Th1), GATA-3 (Th2), and RORγt (Th17). Six patients (five men, median age of 53 years) and seven controls were studied. At baseline, hyperuricemic patients had more CD4+CD28null/CD4+ cells than normouricemic subjects (36.8% vs. 6.1%; p = 0.001), with a predominance of T-bet+ cells (98.5% vs. 6.6%; p = 0.001) and few RORγt+ cells (0.7% vs. 89.4%; p = 0.014). In hyperuricemic patients, the number of CD4+ cells/10,000 PBMC was similar before and after allopurinol (3378 vs. 3954; p = 0.843). Conversely, CD4+CD28null cells decreased from 36.8% (23.0-43.7) to 15.8% (4.7-28.1; p = 0.031). CD4+CD28nullT-bet+ cells decreased from 98.5% (95.0-99.4) to 88.3% (75.2-98.9; p = 0.062), CD4+CD28nullGATA-3+ cells increased from 0% (0-4.0) to 2.8% (0.1-15.6; p = 0.156), and CD4+CD28nullRORγt+ cells increased from 0.7% (0.4-7.0) to 4.5% (1.3-28.1; p = 0.031). The CD4+CD28null cell subset is abnormally expanded in chronic hyperuricemia, despite the absence of overt urate-related disease. Allopurinol may partially restore CD28 expression on CD4+ cells while enhancing the homeostatic balance of T helper phenotypes. ClinicalTrials.gov, number NCT04012294.

Citicoline Modifies the Expression of Specific miRNAs Related to Cardioprotection in Patients with ST-Segment Elevation Myocardial Infarction Subjected to Coronary Angioplasty.

Extracellular vesicles are recognized as signaling mediators between cells both in physiological and pathological communication. In this work, we explored the potential effect of citicoline to modify relevant proteins or miRNAs for cardioprotection in the smallest population of such microvesicles; i.e., in exosomes from patients diagnosed with ST-segment elevation myocardial infarction (STEMI) undergoing coronary angioplasty. The plasma-exosome-enriched fraction from these patients was characterized. Their cellular origin was assessed by flow cytometry and Western blot, whereas miRNA expression was evaluated by real-time polymerase chain reaction (qRT-PCR). The content of caveolin-1, caveolin-3, and hnRNPA2B1, which play a relevant role in selective transport of miRNAs into microvesicles, along with the effect on cell viability of the exosomes obtained from citicoline-treated and untreated groups were also analyzed. Our results showed that hypoxic stress increases exosome release into the circulation. Moreover, we found that CD146+ increased in exosomes from citicoline-treated patients, while CD142+ decreased in these patients compared to the placebo group. No changes were detected in the protein levels of caveolin-1, caveolin-3, and hnRNPA2B1. Citicoline administration modified the expression of miR233-3p, miR92, and miR21-5p in exosomes. Cell viability decreased in the presence of exosomes from infarcted patients, while incubation of H9c2 cells with exosomes from patients reperfused with citicoline did not affect cell viability. In conclusion, citicoline administration modifies the expression of specific miRNAs related to cardioprotection in exosomes.

Plant Extracts Obtained with Green Solvents as Natural Antioxidants in Fresh Meat Products.

Plants are rich in bioactive compounds (BACs), mainly polyphenols, which are valuable choices to replace synthetic antioxidants in meat products. These natural antioxidants from plants, in the form of extracts and essential oils (EOs), have been obtained from different sources such as fruits (dragon fruit, guarana, pomegranate), vegetables, (cabbage, onion), herbs, and spices (epazote, ginger, rosemary, sage, thyme, turmeric, winter savory) by several extraction processes. However, in the context of current directives there is a notable incentive for "green" solvents to replace organic ones and conventional techniques, in order to avoid harm to the environment, operator, and consumer health. In addition, the recycling of co-products from the processing of these plant materials allow us to obtain valuable BACs from under-exploited materials, contributing to the revalorization of these wastes. The resulting extracts allow us to maintain the quality of meat products, exhibiting similar or better antioxidant properties compared to those shown by synthetic ones. Their incorporation in fresh meat products would maintain the oxidative stability, stabilizing colour parameters, decreasing the formation of metmyoglobin, lipid, and protein oxidation and the generation of lipid-derived volatile compounds, without affecting sensory attributes. In addition, these novel ingredients contribute to improve both technological and functional characteristics, thus diversifying the offer of so-called "wellness foods". In this review, the application of plant extracts as natural antioxidants in several fresh meat products is presented, showing their efficacy as scavenging radicals and imparting additional health benefits.

Effect of fresh frozen plasma on the in vitro activation of U937 monocytes: a potential role for the age of blood donors and their underlying cytokine profile.

BACKGROUND: Fresh frozen plasma (FFP) administration may increase the risk of nosocomial infections in parallel with the development of immune modulation. This could be driven by soluble mediators, possibly influencing the in vitro activation of human U937 monocyte cells, in a manner dependent on the age of the donors. METHODS: FFP donors were stratified into groups of 19-30 years, 31-40 years or 41-50 years, and U937 cells were cultured with FFP (alone or plus lipopolysaccharide-LPS) for 24 h. Both in FFP and supernatants, TNF, IL-1ß, IL-6, and IL-10 levels were measured by ELISA. Additionally, CD11B, TLR2, and CASP3 gene expression were measured by qtPCR in U937 cells. Total phagocytic activity was also assayed. RESULTS: Elevated IL-10, but low TNF and IL-1ß levels were measured in FFP from individuals aged 19-40 years, whereas in individuals aged 41-50 years FFP were characterized by equalized TNF and IL-10 levels. Elevated IL-6 levels were found in all FFP samples, especially in those from the oldest individuals. FFP stimulation was associated with striking modifications in cytokine production in an age-dependent way. Exposure to FFP attenuates the response to LPS. TLR2 and CD11B expression were enhanced regardless of the age of plasma donors, although CASP3 expression was increased only when FFP from individuals aged 19-40 years were tested. Phagocytosis decreased after exposure to FFP regardless of donor age. CONCLUSION: Our results suggest that soluble mediators in FFP may modulate the functioning of monocytes. Interestingly, this effect appears to be partially influenced by the age of donors.

Type-III interferons and rheumatoid arthritis: Correlation between interferon lambda 1 (interleukin 29) and antimutated citrullinated vimentin antibody levels.

AIM: To assess serum type III or lambda (λ) interferons (IFN) levels and its clinical and laboratory associations in rheumatoid arthritis (RA). METHODS: A cross-sectional study including 43 patients with RA (86% females; age 45.3 ± 10.3 years) and 43 healthy individuals was performed. Clinical data including disease activity, acute-phase reactants, rheumatoid factor and anticyclic citrullinated peptide (anti-CCP) antibodies were collected. Serum IFNλ1, IFNλ2, IFNλ3, CXCL8 and anti-mutated citrullinated vimentin (anti-MCV) antibody levels were measured. RESULTS: Patients with RA had higher IFNλ1 (113.5 ± 118.6 pg/mL versus 55.9 ± 122.3 pg/mL; p < 0.0001) and IFNλ2 (245.4 ± 327.7 pg/mL versus 5.1 ± 11.0 pg/mL; p = 0.009) levels than controls, but not IFNλ3 levels. Notably, IFNλ1 levels were found to be higher in both patients with active disease (124.9 ± 135.9 pg/mL; p < 0.001) and quiescent disease (99.0 ± 93.7 pg/mL; p < 0.01), while IFNλ2 levels were higher only in patients with active disease (264.0 ± 356.1 pg/mL; p = 0.02). A noteworthy association between serum IFNλ1 levels and anti-MCV antibody titers (Spearman's rho coefficient 0.36, 95% CI 0.36 to 0.61; p = 0.02) was observed. CONCLUSION: Serum IFNλ1 and IFNλ2 levels are abnormally elevated in patients with RA and the former are linearly associated with circulating anti-MCV antibody levels. These results may place type-III IFN as an attractive new therapeutic target in RA.

Effect of fresh frozen plasma on the in vitro activation of U937 monocytes: a potential role for the age of blood donors and their underlying cytokine profile

BACKGROUND: Fresh frozen plasma (FFP) administration may increase the risk of nosocomial infections in parallel with the development of immune modulation. This could be driven by soluble mediators, possibly influencing the in vitro activation of human U937 monocyte cells, in a manner dependent on the age of the donors. METHODS: FFP donors were stratified into groups of 19-30 years, 31-40 years or 41-50 years, and U937 cells were cultured with FFP (alone or plus lipopolysaccharide-LPS) for 24 h. Both in FFP and supernatants, TNF, IL-1ß, IL-6, and IL-10 levels were measured by ELISA. Additionally, CD11B, TLR2, and CASP3 gene expression were measured by qtPCR in U937 cells. Total phagocytic activity was also assayed. RESULTS: Elevated IL-10, but low TNF and IL-1ß levels were measured in FFP from individuals aged 19-40 years, whereas in individuals aged 41-50 years FFP were characterized by equalized TNF and IL-10 levels. Elevated IL-6 levels were found in all FFP samples, especially in those from the oldest individuals. FFP stimulation was associated with striking modifications in cytokine production in an age-dependent way. Exposure to FFP attenuates the response to LPS. TLR2 and CD11B expression were enhanced regardless of the age of plasma donors, although CASP3 expression was increased only when FFP from individuals aged 19-40 years were tested. Phagocytosis decreased after exposure to FFP regardless of donor age. CONCLUSION: Our results suggest that soluble mediators in FFP may modulate the functioning of monocytes. Interestingly, this effect appears to be partially influenced by the age of donors.

Association of Nail Dystrophy With Accrued Damage and Capillaroscopic Abnormalities in Systemic Lupus Erythematosus.

BACKGROUND: There are some nail abnormalities described in systemic lupus erythematosus (SLE). OBJECTIVES: The aim of this study was to evaluate the association between nail dystrophy (ND) and disease activity, accrued organ damage, capillaroscopic abnormalities, autoantibodies, and some markers of endothelial cell activation in patients with SLE. METHODS: This was a cross-sectional study of SLE patients from a rheumatology clinic in a tertiary care hospital. Patients were allocated in groups, according to the presence or absence of ND. Demographics, clinical data, disease activity, accrued damage, serology, nailfold capillaroscopy characteristics, serum levels of anti-endothelial cell antibodies, and plasma levels of endothelin 1 were compared between groups. Disease activity was assessed by the Systemic Lupus Erythematosus Disease Activity Index 2000 index and accrued organ damage by the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index. RESULTS: Sixty-one patients were included; 50 patients (82%) were female. Thirty-two patients (52.5%) showed ND, and 29 did not. Besides a more frequent use of cyclophosphamide (46.9% vs 20.7%; P = 0.03) in the ND group, clinical features were similar. A greater organ damage was found in patients with ND (median Systemic Lupus International Collaborating Clinics/American College of Rheumatology index = 0.5, minimum = 0, maximum = 6) than in patients without ND (0, 0, 3, respectively; P = 0.04); specifically, only the skin domain was associated with ND (P = 0.04). Onycholysis (40.6%) and longitudinal ridging (25%) were the most frequent nail changes. Nailfold capillaroscopy changes were more frequent in ND patients (40.6%) than in control subjects (13.8%) (P = 0.02). The most frequent nailfold capillaroscopy findings in the ND group were enlarged capillaries (40.6%) and microhemorrhages (12.5%). There was no association between ND and the autoantibody profile, plasma endothelin 1, or serum anti-endothelial cell antibodies. CONCLUSIONS: Nail dystrophy was associated with higher accrued organ damage and the presence of capillaroscopic abnormalities. This suggests that ND might be related to chronic microvascular damage.