The Roles of MicroRNAs in Asthma and Emerging Insights into the Effects of Vitamin D3 Supplementation.

Asthma is one of the most common chronic non-communicable diseases worldwide, characterized by variable airflow limitation secondary to airway narrowing, airway wall thickening, and increased mucus resulting from chronic inflammation and airway remodeling. Current epidemiological studies reported that hypovitaminosis D is frequent in patients with asthma and is associated with worsening the disease and that supplementation with vitamin D3 improves asthma symptoms. However, despite several advances in the field, the molecular mechanisms of asthma have yet to be comprehensively understood. MicroRNAs play an important role in controlling several biological processes and their deregulation is implicated in diverse diseases, including asthma. Evidence supports that the dysregulation of miR-21, miR-27b, miR-145, miR-146a, and miR-155 leads to disbalance of Th1/Th2 cells, inflammation, and airway remodeling, resulting in exacerbation of asthma. This review addresses how these molecular mechanisms explain the development of asthma and its exacerbation and how vitamin D3 may modulate these microRNAs to improve asthma symptoms.

Dysregulation of long non-coding RNAs in Takayasu arteritis: A proof-of-concept study.

Takayasu arteritis (TAK) is a rare systemic vasculitis primarily affecting the aorta and its major branches. Early diagnosis is critical to prevent severe vascular complications, yet current biomarkers are insufficient. This proof-of-concept study explores the potential of long non-coding RNAs (lncRNAs) in TAK, an area largely unexplored. In this cross-sectional study, 53 TAK patients, 53 healthy controls, and 10 rheumatoid arthritis (RA) patients were enrolled. Clinical evaluations, disease activity assessments, and lncRNA expression levels were analyzed. TAK patients exhibited significant dysregulation in several lncRNAs, including THRIL (19.4, 11.1-48.8 vs. 62.5, 48.6-91.4 arbitrary units [a.u.]; p < 0.0001), HIF1A-AS1 (4.5, 1.8-16.6 vs. 26.5, 19.8-33.7 a.u.; p < 0.0001), MALAT-1 (26.9, 13.8-52.5 vs. 92.1, 58.5-92.1 a.u.; p < 0.0001), and HOTAIR (8.0, 2.5-24.5 vs. 36.0, 30.0-43.8 a.u.; p < 0.0001), compared to healthy controls. Notably, HOTAIR (area under the ROC curve [AUC] = 0.825), HIF1A-AS1 (AUC = 0.820), and THRIL (AUC = 0.781) demonstrated high diagnostic potential with superior specificity (approximately 95%). While lncRNAs showed diagnostic promise, no significant correlations with TAK activity were observed. Comparative analysis with RA patients revealed distinct lncRNA expression patterns. This study unveils significant dysregulation of lncRNAs THRIL, HIF1A-AS1, and HOTAIR in TAK patients, underscoring their potential as biomarkers and opening avenues for further research into the mechanistic roles of these lncRNAs in TAK pathogenesis.

Influence of anti-carbamylated protein antibodies on disease activity and joint erosions in seronegative and seropositive rheumatoid arthritis.

Anti-carbamylated protein (anti-CarP) antibodies are promising biomarkers in rheumatoid arthritis (RA), although their significance in seronegative disease (SNRA) remains uncertain. To assess the influence of anti-CarP antibodies on disease activity and erosive joint damage in SNRA patients. In RA patients, rheumatoid factor (RF), anti-citrullinated protein antibodies, and anti-CarP antibodies were measured. Disease activity was assessed using DAS28-CRP and SDAI indices, while musculoskeletal ultrasound identified bone erosions. A total of 77 patients were enrolled, comprising 49 with seropositive RA (SPRA) and 28 with SNRA. Notably, 28% of SPRA and 10% of SNRA patients were positive to anti-CarP antibodies. Anti-CarP-positive patients exhibited elevated C-reactive protein (median 10.6, interquartile range 4.6-20.0 vs. 3.4, 1.7-9.9 mg/L; p = 0.005), erythrocyte sedimentation rate (34, 19-46 vs. 16, 7-25 mm/h; p = 0.002), DAS28-CRP (3.2, 2.6-4.2 vs. 2.6, 1.9-3.5; p = 0.048), and SDAI (19.9, 6.3-32.1 vs. 10.9, 5.5-18.1; p = 0.034) indices. Multivariate analysis revealed RF positivity as the sole predictor for anti-CarP antibodies (odds ratio [OR] = 5.9). Musculoskeletal ultrasound revealed bone erosions in 36% of RA patients; 35% among anti-CarP-negative patients and 40% among anti-CarP-positive patients. Notably, RF presence (OR = 44.3) and DAS28-CRP index (OR = 2.4) emerged as predictors of musculoskeletal ultrasound-confirmed erosive joint disease. Anti-CarP antibodies are detected at similar frequencies among both SPRA and SNRA patients. While associated with increased disease activity, these antibodies did not correlate with increased erosive joint damage.

Increased Expression of lncRNA AC000120.7 and SENP3-EIF4A1 in Patients with Acute Respiratory Distress Syndrome Induced by SARS-CoV-2 Infection: A Pilot Study.

COVID-19, a disease caused by the SARS-CoV-2 virus, poses significant threats to the respiratory system and other vital organs. Long non-coding RNAs have emerged as influential epigenetic regulators and promising biomarkers in respiratory ailments. The objective of this study was to identify candidate lncRNAs in SARS-CoV-2-positive individuals compared to SARS-CoV-2-negative individuals and investigate their potential association with ARDS-CoV-2 (acute respiratory distress syndrome). Employing qRT-PCR, we meticulously examined the expression profiles of a panel comprising 84 inflammation-related lncRNAs in individuals presenting upper respiratory infection symptoms, categorizing them into those testing negative or positive for SARS-CoV-2. Notably, first-phase PSD individuals exhibited significantly elevated levels of AC000120.7 and SENP3-EIF4A1. In addition, we measured the expression of two lncRNAs, AC000120.7 and SENP3-EIF4A1, in patients with ARDS unrelated to SARS-CoV-2 (n = 5) and patients with ARDS induced by SARS-CoV-2 (ARDS-CoV-2, n = 10), and interestingly, expression was also higher among patients with ARDS. Intriguingly, our interaction pathway analysis unveiled potential interactions between lncRNA AC000120.7, various microRNAs, and genes associated with inflammation. This study found higher expression levels of lncRNAs AC000120.7 and SENP3-EIF4A1 in the context of infection-positive COVID-19, particularly within the complex landscape of ARDS.

Diagnostic Performance of Serum MicroRNAs for ST-Segment Elevation Myocardial Infarction in the Emergency Department.

Prompt diagnosis of ST-segment elevation myocardial infarction (STEMI) is essential for initiating timely treatment. MicroRNAs have recently emerged as biomarkers in cardiovascular diseases. This study aimed to evaluate the discriminatory capacity of serum microRNAs in identifying an ischemic origin in patients presenting with chest discomfort to the Emergency Department. The study included 98 participants (78 with STEMI and 20 with nonischemic chest discomfort). Significant differences in the expression levels of miR-133b, miR-126, and miR-155 (but not miR-1, miR-208, and miR-208b) were observed between groups. miR-133b and miR-155 exhibited 97% and 93% sensitivity in identifying STEMI patients, respectively. miR-126 demonstrated a specificity of 90% in identifying STEMI patients. No significant associations were found between microRNAs and occurrence of major adverse cardiovascular events (MACE). However, patients with MACE had higher levels of interleukin (IL)-15, IL-21, IFN-γ-induced protein-10, and N-terminal pro B-type natriuretic peptide compared to non-MACE patients. Overall, there were significant associations among the expression levels of microRNAs. However, microRNAs did not demonstrate associations with either inflammatory markers or cardiovascular risk scores. This study highlights the potential of microRNAs, particularly miR-133b and miR-126, as diagnostic biomarkers for distinguishing patients with STEMI from those presenting with nonischemic chest discomfort to the Emergency Department.

CD147 rs8259T>A Variant Confers Susceptibility to COVID-19 Infection within the Mexican Population.

BACKGROUND: Coronavirus disease 2019 (COVID-19) is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Clinical manifestations of COVID-19 range from mild flu-like symptoms to severe respiratory failure. Nowadays, extracellular matrix metalloproteinase inducer (EMMPRIN), also known as cluster of differentiation 147 (CD147) or BASIGIN, has been studied as enabling viral entry and replication within host cells. However, the impact of the CD147 rs8259T>A single nucleotide variant (SNV) on SARS-CoV-2 susceptibility remains poorly investigated. OBJECTIVE: To investigate the impact of rs8259T>A on the CD147 gene in individuals from Mexico with COVID-19 disease. METHODS: We genotyped the CD147 rs8359T>A SNV in 195 patients with COVID-19 and 185 healthy controls from Mexico. In addition, we also measured the expression levels of CD147 and TNF mRNA and miR-492 from whole blood of patients with COVID-19 through RT-q-PCR. RESULTS: We observed a significant association between the CD147 rs8259T>A SNV and susceptibility to COVID-19: T vs. A; OR 1.36, 95% CI 1.02-1.81; p = 0.037; and TT vs. AA; OR 1.77, 95% CI 1.01-3.09; p = 0.046. On the other hand, we did not find differences in CD147, TNF or miR-492 expression levels when considering the genotypes of the CD147 rs8259T>A SNV. CONCLUSIONS: Our results suggest that the CD147 rs8259T>A variant is a risk factor for COVID-19.

Extracellular vesicles in COVID-19 prognosis, treatment, and vaccination: an update.

The lethality of the COVID 19 pandemic became the trigger for one of the most meteoric races on record in the search for strategies of disease control. Those include development of rapid and sensitive diagnostic methods, therapies to treat severe cases, and development of anti-SARS-CoV-2 vaccines, the latter responsible for the current relative control of the disease. However, the commercially available vaccines are still far from conferring protection against acquiring the infection, so the development of more efficient vaccines that can cut the transmission of the variants of concerns that currently predominate and those that will emerge is a prevailing need. On the other hand, considering that COVID 19 is here to stay, the development of new diagnosis and treatment strategies is also desirable. In this sense, there has recently been a great interest in taking advantage of the benefits offered by extracellular vesicles (EVs), membrane structures of nanoscale size that carry information between cells participating in this manner in many physiological homeostatic and pathological processes. The interest has been focused on the fact that EVs are relatively easy to obtain and manipulate, allowing the design of natural nanocarriers that deliver molecules of interest, as well as the information about the pathogens, which can be exploited for the aforementioned purposes. Studies have shown that infection with SARS-CoV-2 induces the release of EVs from different sources, including platelets, and that their increase in blood, as well as some of their markers, could be used as a prognosis of disease severity. Likewise, EVs from different sources are being used as the ideal carriers for delivering active molecules and drugs to treat the disease, as well as vaccine antigens. In this review, we describe the progress that has been made in these three years of pandemic regarding the use of EVs for diagnosis, treatment, and vaccination against SARS-CoV-2 infection. KEY POINTS: • Covid-19 still requires more effective and specific treatments and vaccines. • The use of extracellular vesicles is emerging as an option with multiple advantages. • Association of EVs with COVID 19 and engineered EVs for its control are presented.

Therapeutic treatment with fluoxetine using the chronic unpredictable stress model induces changes in neurotransmitters and circulating miRNAs in extracellular vesicles.

The most widely prescribed antidepressant, fluoxetine (FLX), is known for its antioxidant and anti-inflammatory effects when administered post-stress. Few studies have evaluated the effects of FLX treatment when chronic stress has induced deleterious effects in patients. Our objective was to evaluate FLX treatment (20 mg/kg/day, i.v.) once these effects are manifested, and the drug's relation to extracellular circulating microRNAs associated with inflammation, a hedonic response (sucrose intake), the forced swim test (FST), and corticosterone levels (CORT) and monoamine concentrations in limbic areas. A group of Wistar rats was divided into groups: Control; FLX; CUMS (for six weeks of exposure to chronic, unpredictable mild stress); and CUMS + FLX, a mixed group. After CUMS, the rats performed the FST, and serum levels of CORT and six microRNAs (miR-16, -21, -144, -155, -146a, -223) were analyzed, as were levels of dopamine, noradrenaline, and serotonin in the prefrontal cortex, hippocampus, and hypothalamus. CUMS reduced body weight, sucrose intake, and hippocampal noradrenaline levels, but increased CORT, immobility behavior on the FST, dopamine concentrations in the prefrontal cortex, and all miRNAs except miR-146a expression. Administering FLX during CUMS reduced CORT levels and immobility behavior on the FST and increased the expression of miR-16, -21, -146a, -223, and dopamine. FLX protects against the deleterious effects of stress by reducing CORT and has an antidepressant effect on the FST, with minimally-modified neurotransmitter levels. FLX increased the expression of miRNAs as part of the antidepressant effect. It also regulates both neuroinflammation and serotoninergic neurotransmission through miRNAs, such as the miR-16.

Negative Effects of Chronic High Intake of Fructose on Lung Diseases.

In the modern diet, excessive fructose intake (>50 g/day) had been driven by the increase, in recent decades, of the consumption of sugar-sweetened beverages. This phenomenon has dramatically increased within the Caribbean and Latin American regions. Epidemiological studies show that chronic high intake of fructose related to sugar-sweetened beverages increases the risk of developing several non-communicable diseases, such as chronic obstructive pulmonary disease and asthma, and may also contribute to the exacerbation of lung diseases, such as COVID-19. Evidence supports several mechanisms­such as dysregulation of the renin−angiotensin system, increased uric acid production, induction of aldose reductase activity, production of advanced glycation end-products, and activation of the mTORC1 pathway­that can be implicated in lung damage. This review addresses how these pathophysiologic and molecular mechanisms may explain the lung damage resulting from high intake of fructose.

Patients with seronegative rheumatoid arthritis have a different phenotype than seropositive patients: A clinical and ultrasound study.

Introduction: Rheumatoid arthritis (RA) is an inflammatory disease whose clinical phenotype largely depends on the presence of rheumatoid factor (RF) and anti-citrullinated protein antibodies (ACPA). Seronegative RA appears to be a less severe disease, but this remains controversial. This study aimed to assess whether seronegative patients show a less severe disease than seropositive patients. Methods: A cross-sectional study was conducted on RA outpatients from a single center. Clinical activity scales, laboratory evaluations, and cardiovascular risk scores were assessed. Musculoskeletal ultrasound (US) examinations were performed. Results: One hundred and fourteen patients were enrolled. Eighty-five were seropositive (76% women) and 29 seronegative (93% women). Seropositive patients had a younger age at disease onset (43 ± 14 vs. 54 ± 11; p = 0.001) and used sulfasalazine (47 vs. 17%; p = 0.004) and glucocorticoids (36 vs. 10%; p = 0.007) more frequently. No differences in clinical activity scales and in 10-year cardiovascular risk were observed. Pathological US data were found more frequently in seropositive patients in the 2nd metacarpophalangeal (MCP) joint, both in grayscale (71 vs. 38%; p = 0.008) and in power Doppler (PD; 53 vs. 9%; p < 0.001); erosions (36 vs. 9%; p = 0.020) were also more frequent. We found greater severity of PD signals in the 2nd MCP and 3rd MCP joints of the seropositive patients, while synovitis severity was higher only in the 2nd MCP joints. The percentage of total joints with erosions (9 vs. 1%; p < 0.001) and 2nd MCP joints with erosions (25 vs. 7%; p < 0.001) was higher in seropositive patients. Conclusion: RA patients show a differentiated phenotype according to their ACPA and RF status. In seronegative patients, RA begins later in life and has a lower requirement for antirheumatic therapies. On US evaluation, seropositive patients show more joint damage, especially in MCP joints. Despite this, long-term cardiovascular risk is similar among RA patients, regardless of their RF and ACPA status.

The prognostic importance of the angiotensin II/angiotensin-(1-7) ratio in patients with SARS-CoV-2 infection.

BACKGROUND: Information about angiotensin II (Ang II), angiotensin-converting enzyme 2 (ACE2), and Ang-(1-7) levels in patients with COVID-19 is scarce. OBJECTIVE: To characterize the Ang II-ACE2-Ang-(1-7) axis in patients with SARS-CoV-2 infection to understand its role in pathogenesis and prognosis. METHODS: Patients greater than 18 years diagnosed with COVID-19, based on clinical findings and positive RT-PCR test, who required hospitalization and treatment were included. We compared Ang II, aldosterone, Ang-(1-7), and Ang-(1-9) concentrations and ACE2 concentration and activity between COVID-19 patients and historic controls. We compared baseline demographics, laboratory results (enzyme, peptide, and inflammatory marker levels), and outcome (patients who survived versus those who died). RESULTS: Serum from 74 patients [age: 58 (48-67.2) years; 68% men] with moderate (20%) or severe (80%) COVID-19 were analyzed. During 13 (10-21) days of hospitalization, 25 patients died from COVID-19 and 49 patients survived. Compared with controls, Ang II concentration was higher and Ang-(1-7) concentration was lower, despite significantly higher ACE2 activity in patients. Ang II concentration was higher and Ang-(1-7) concentration was lower in patients who died. The Ang II/Ang-(1-7) ratio was significantly higher in patients who died. In multivariate analysis, Ang II/Ang-(1-7) ratio greater than 3.45 (OR = 5.87) and lymphocyte count ⩽0.65 × 103/µl (OR = 8.43) were independent predictors of mortality from COVID-19. CONCLUSION: In patients with severe SARS-CoV-2 infection, imbalance in the Ang II-ACE2-Ang-(1-7) axis may reflect deleterious effects of Ang II and may indicate a worse outcome.

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.

Elevated Levels of Soluble CD147 are Associated with Hyperinflammation and Disease Severity in COVID-19: A Proof-of-Concept Clinical Study.

To evaluate soluble CD147 levels in COVID-19 and identify whether these are associated with hyperinflammation and disease severity. One-hundred and nine COVID-19 patients and 72 healthy blood donors were studied. Levels of CD147, matrix metalloproteases (MMP) and inflammatory markers were measured on hospital arrival, while the need for mechanical ventilation and the occurrence of death during hospitalization were recorded. CD147 levels were higher in COVID-19 (1.6, 1.0-2.3 vs 1.3, 1.0-1.6 ng/ml; P = 0.003) than controls. MMP-2 (9.2, 4.5-12.9 vs 4.2, 3.7-4.6 ng/ml; P < 0.001), MMP-3 (1.1, 0.9-1.3 vs 0.9, 0.7-1.0 ng/ml; P < 0.001) and MMP-9 (0.9, 0.5-1.2 vs 0.4, 0.2-0.6 ng/ml; P < 0.001) were also higher in COVID-19, while MMP-1 (0.6, 0-1.4 vs 0.6, 0.3-0.7 ng/ml; P = 0.711) was not different. Significant correlations were found between CD147 and MMP-2 (ρ = 0.34), MMP-3 (ρ = 0.21), interleukin 6 (ρ = 0.21), and the neutrophil/lymphocyte ratio (ρ = 0.26). Furthermore, CD147 levels were higher in patients who required mechanical ventilation (1.8, 1.4-2.4 vs 1.2, 0.8-1.9 ng/ml; P < 0.001) and in those who ultimately died (1.9, 1.4-2.7 vs 1.4, 0.9-1.9 ng/ml; P = 0.009). CD147 is elevated in COVID-19 and appears to contribute to hyperinflammation and disease severity.

Promoter methylation status of RORC, IL17A, and TNFA in peripheral blood leukocytes in adolescents with obesity-related asthma.

A higher Th17-immune response characterises obesity and obesity-related asthma phenotype. Nevertheless, obesity-related asthma has a more significant Th17-immune response than obesity alone. Retinoid-related orphan receptor C (RORC) is the essential transcription factor for Th17 polarisation. Previous studies have found that adolescents with obesity-related asthma presented upregulation of RORC, IL17A, and TNFA. However, the mechanisms that cause these higher mRNA expression levels in this asthmatic phenotype are poorly understood. Methylation directly regulates gene expression by adding a methyl group to carbon 5 of dinucleotide CpG cytosine. Thus, we evaluated the relationship between RORC, IL17A, and TNFA methylation status and mRNA expression levels to investigate a possible epigenetic regulation. A total of 102 adolescents (11-18 years) were studied in the following four groups: 1) healthy participants (HP), 2) allergic asthmatic participants (AAP), 3) obese participants without asthma (OP), and 4) non-allergic obesity-related asthma participants (OAP). Real-time qPCR assessed the methylation status and gene expression levels in peripheral blood leukocytes. Remarkably, the OAP and AAP groups have lower promoter methylation patterns of RORC, IL17A, and TNFA than the HP group. Notably, the OAP group presents lower RORC promoter methylation status than the OP group. Interestingly, RORC promoter methylation status was moderately negatively associated with gene expression of RORC (r s = -0.39, p < 0.001) and IL17A (r s = -0.37, p < 0.01), respectively. Similarly, the promoter methylation pattern of IL17A was moderately negatively correlated with IL17A gene expression (r s = -0.3, p < 0.01). There is also a moderate inverse relationship between TNFA promoter methylation status and TNFA gene expression (r s = -0.3, p < 0.01). The present study suggests an association between lower RORC, IL17A, and TNFA gene promoter methylation status with obesity-related asthma and allergic asthma. RORC, IL17A, and TNFA gene promoter methylation patterns are moderately inversely correlated with their respective mRNA expression levels. Therefore, DNA methylation may regulate RORC, IL17A, and TNF gene expression in both asthmatic phenotypes.

Nitazoxanide Exerts Immunomodulatory Effects on Peripheral Blood Mononuclear Cells from Type 2 Diabetes Patients.

BACKGROUND: Type 2 diabetes (T2D) is a low-grade inflammatory condition with abnormalities in the immune response mediated by T lymphocytes and macrophages. Drug repositioning for immunomodulatory molecules is an attractive proposal for treating T2D. Nitazoxanide (NTZ) is a broad-spectrum drug with promising immunomodulatory effects. Thus, we investigated the immunomodulatory effect of NTZ on peripheral blood mononuclear cells (PBMCs) from patients with T2D. METHODS: Fifty patients with T2D were selected, and the proliferative response of T lymphocytes and the M1/M2 ratio of macrophages post cell culture were evaluated by flow cytometry, as well as measuring the concentration of cytokines by ELISA and the relative expression of microRNAs (miRNAs) related to the immune response by real-time PCR. RESULTS: NTZ exerts an inhibitory effect on the cell proliferation of T lymphocytes stimulated with anti-CD3 and anti-CD28 antibodies without modifying cell viability, and significant decreases in the supernatant concentrations of interleukin (IL)-1ß, IL-2, IL-6, IL-10, and IL-12. Furthermore, NTZ negatively regulates the relative expression of miR-155-5p without changes in miR-146a-5p. The M1/M2 ratio of monocytes/macrophages decreased the M1 and increased the M2 subpopulation by NTZ. CONCLUSIONS: Our results suggest that NTZ exerts immunomodulatory effects on PBMCs from T2D patients, and shows potential alternative therapeutic benefits.

Usefulness of Easy-to-Use Risk Scoring Systems Rated in the Emergency Department to Predict Major Adverse Outcomes in Hospitalized COVID-19 Patients.

BACKGROUND: Several easy-to-use risk scoring systems have been built to identify patients at risk of developing complications associated with COVID-19. However, information about the ability of each score to early predict major adverse outcomes during hospitalization of severe COVID-19 patients is still scarce. METHODS: Eight risk scoring systems were rated upon arrival at the Emergency Department, and the occurrence of thrombosis, need for mechanical ventilation, death, and a composite that included all major adverse outcomes were assessed during the hospital stay. The clinical performance of each risk scoring system was evaluated to predict each major outcome. Finally, the diagnostic characteristics of the risk scoring system that showed the best performance for each major outcome were obtained. RESULTS: One hundred and fifty-seven adult patients (55 ± 12 years, 66% men) were assessed at admission to the Emergency Department and included in the study. A total of 96 patients (61%) had at least one major outcome during hospitalization; 32 had thrombosis (20%), 80 required mechanical ventilation (50%), and 52 eventually died (33%). Of all the scores, Obesity and Diabetes (based on a history of comorbid conditions) showed the best performance for predicting mechanical ventilation (area under the ROC curve (AUC), 0.96; positive likelihood ratio (LR+), 23.7), death (AUC, 0.86; LR+, 4.6), and the composite outcome (AUC, 0.89; LR+, 15.6). Meanwhile, the inflammation-based risk scoring system (including leukocyte count, albumin, and C-reactive protein levels) was the best at predicting thrombosis (AUC, 0.63; LR+, 2.0). CONCLUSIONS: Both the Obesity and Diabetes score and the inflammation-based risk scoring system appeared to be efficient enough to be integrated into the evaluation of COVID-19 patients upon arrival at the Emergency Department.

Interferon Lambda 3/4 (IFNλ3/4) rs12979860 Polymorphisms Is Not Associated With Susceptibility to Systemic Lupus Erythematosus, Although It Regulates OASL Expression in Patients With SLE.

Systemic lupus erythematosus (SLE) is an autoimmune disease with a complex etiology. Various genetic factors are associated with susceptibility to developing SLE and contribute to its onset and progression. Different single-nucleotide polymorphisms (SNPs) have been associated with SLE in several populations. The rs12979860 SNP in interferon lambda 3/4 (IFNλ3/4) is significantly associated with SLE susceptibility in patients negative for nephritis in Taiwanese people, and interferon-stimulated genes (ISGs) are differentially expressed in normal liver by the rs12979860 genotype. This study aimed to investigate whether rs12979860 is associated with the presence of SLE and lupus nephritis in Mexican individuals as well as with the expression of several ISGs in SLE patients. In total, 439 SLE patients and 358 healthy donors were genotyped for rs12979860 using real-time PCR, and allelic discrimination plots were constructed. Additionally, peripheral blood mononuclear cells (PBMCs) were isolated from the venous blood of SLE patients by centrifugation (n = 78). The mRNA levels of 2'-5'-oligoadenylate synthetase like (OASL), myxovirus resistance 1 (MX1), 2'5'-oligoadenylate synthetase 1 (OAS1), interferon-stimulated gene 15 (ISG15) and lymphocyte antigen 6 complex, locus E (LY6E) were determined using real-time PCR. The distributions of rs12979860 genotypes and allele frequencies were compared between SLE patients and healthy donors; case-control analysis revealed that rs12979860 was not associated with SLE susceptibility (OR 1.18, 95% CI 0.97-1.45, p = 0.08) or with the risk for lupus nephritis (OR 0.913, 95% CI 0.590-1.411, p = 0.682). However, OASL expression levels in PBMCs were significantly different between rs12979860 genotypes in SLE patients: median OASL mRNA levels were significantly higher in patients carrying the CC genotype (197.10, IQR 71.10-411.17) than in those with CT/TT genotypes (173.75, IQR 58.80-278.75, p = 0.016). Our results suggest that the SNP rs12979860 does not play a relevant role in susceptibility to SLE in Mexican individuals. However, IFNλ3/4 genotypes appear to be associated with OASL expression in PBMCs from patients with SLE.

High fructose exposure modifies the amount of adipocyte-secreted microRNAs into extracellular vesicles in supernatants and plasma.

BACKGROUND: High fructose exposure induces metabolic and endocrine responses in adipose tissue. Recent evidence suggests that microRNAs in extracellular vesicles are endocrine signals secreted by adipocytes. Fructose exposure on the secretion of microRNA by tissues and cells is poorly studied. Thus, the aim of this study was to evaluate the effect of fructose exposure on the secretion of selected microRNAs in extracellular vesicles from 3T3-L1 cells and plasma from Wistar rats. METHODS: 3T3-L1 cells were exposed to 550 µM of fructose or standard media for four days, microRNAs levels were determined in extracellular vesicles of supernatants and cells by RT-qPCR. Wistar rats were exposed to either 20% fructose drink or tap water for eight weeks, microRNAs levels were determined in extracellular vesicles of plasma and adipose tissue by RT-qPCR. RESULTS: This study showed that fructose exposure increased the total number of extracellular vesicles released by 3T3-L1 cells (p = 0.0001). The levels of miR-143-5p were increased in extracellular vesicles of 3T3-L1 cells exposed to fructose (p = 0.0286), whereas miR-223-3p levels were reduced (p = 0.0286). Moreover, in plasma-derived extracellular vesicles, miR-143-5p was higher in fructose-fed rats (p = 0.001), whereas miR-223-3p (p = 0.022), miR-342-3p (p = 0.0011), miR-140-5p (p = 0.0129) and miR-146b-5p (p = 0.0245) were lower. CONCLUSION: Fructose exposure modifies the levels of microRNAs in extracellular vesicles in vitro and in vivo. In particular, fructose exposure increases miR-143-5p, while decreases miR-223-3p and miR-342-3p.

Nutraceuticals in the Treatment of Pulmonary Arterial Hypertension.

Pulmonary arterial hypertension (PAH) is a severe disease characterized by the loss and obstructive remodeling of the pulmonary arterial wall, causing a rise in pulmonary arterial pressure and pulmonary vascular resistance, which is responsible for right heart failure, functional decline, and death. Although many drugs are available for the treatment of this condition, it continues to be life-threatening, and its long-term treatment is expensive. On the other hand, many natural compounds present in food have beneficial effects on several cardiovascular conditions. Several studies have explored many of the potential beneficial effects of natural plant products on PAH. However, the mechanisms by which natural products, such as nutraceuticals, exert protective and therapeutic effects on PAH are not fully understood. In this review, we analyze the current knowledge on nutraceuticals and their potential use in the protection and treatment of PAH, as well as whether nutraceuticals could enhance the effects of drugs used in PAH through similar mechanisms.

Chronic diabetes and hypertension impair the in vivo functional response to phenylephrine independent of α1-adrenoceptor expression.

Diabetes and hypertension can coexist and exacerbate each other. In the early stages of diabetes, there is a decreased vascular response of the sympathetic nervous system (SNS), probably due to lower expression of α1-adrenoceptors; however, it is unclear how diabetes in advanced stages changes the functionality of the SNS, especially the expression of α1-adrenoceptors. Thus, the aim of this work was to analyse the functional response to phenylephrine, a selective α1-adrenoceptor agonist, and the expression of α1-adrenoceptors in chronic diabetes and hypertension. Male SHR and WKY rats aged 10-12 weeks were administered either streptozotocin (60 mg/kg i.p.) or a vehicle (control group). Eight weeks after administration, dose-response curves to phenylephrine were generated and the gene and protein expression of α1-adrenoceptor subtypes (α1A-, α1B- and α1D-adrenoceptors) in the heart and aorta were measured. The response to phenylephrine was diminished in hypertensive rats and in normotensive diabetic rats. The coexistence of both diabetes and hypertension produced an even smaller response to phenylephrine than that observed for each condition separately. In the heart and aorta of diabetic rats, no changes in α1A-, α1B- or α1D-adrenoceptor mRNA expression were observed; however, protein expression was increased, mainly for the α1D-adrenoceptor. Hypertension increased mRNA and protein expression of α1-adrenoceptors in a tissue-dependent manner. The coexistence of both diabetes and hypertension produced differences in the regulation of mRNA and protein expression (increase or decrease) in both the heart and aorta. In conclusion, diabetes, hypertension and the coexistence of both pathologies impairs the in vivo response to phenylephrine. However, the differences in α1A-, α1B- and α1D-adrenoceptor expression cannot explain the reduced response to the agonist. This should be further explored in future experiments.