Antioxidant and anti-inflammatory effects of allicin in the kidney of an experimental model of metabolic syndrome.

Background: Recent studies have suggested that metabolic syndrome (MS) encompasses a group of risk factors for developing chronic kidney disease (CKD). This work aimed to evaluate the antioxidant and anti-inflammatory effects of allicin in the kidney from an experimental model of MS. Methods: Male Wistar rats (220-250 g) were used, and three experimental groups (n = 6) were formed: control (C), metabolic syndrome (MS), and MS treated with allicin (16 mg/Kg/day, gastric gavage) (MS+A). MS was considered when an increase of 20% in at least three parameters (body weight, systolic blood pressure (SBP), fasting blood glucose (FBG), or dyslipidemia) was observed compared to the C group. After the MS diagnosis, allicin was administered for 30 days. Results: Before the treatment with allicin, the MS group showed more significant body weight gain, increased SBP, and FBG, glucose intolerance, and dyslipidemia. In addition, increased markers of kidney damage in urine and blood. Moreover, the MS increased oxidative stress and inflammation in the kidney compared to group C. The allicin treatment prevented further weight gain, reduced SBP, FBG, glucose intolerance, and dyslipidemia. Also, markers of kidney damage in urine and blood were decreased. Further, the oxidative stress and inflammation were decreased in the renal cortex of the MS+A compared to the MS group. Conclusion: Allicin exerts its beneficial effects on the metabolic syndrome by considerably reducing systemic and renal inflammation as well as the oxidative stress. These effects were mediated through the Nrf2 pathway. The results suggest allicin may be a therapeutic alternative for treating kidney injury induced by the metabolic syndrome risk factors.

Two murine models of sepsis: immunopathological differences between the sexes-possible role of TGFß1 in female resistance to endotoxemia.

Endotoxic shock (ExSh) and cecal ligature and puncture (CLP) are models that induce sepsis. In this work, we investigated early immunologic and histopathologic changes induced by ExSh or CLP models in female and male mice. Remarkable results showed that females supported twice the LD100 of LPS for males, CLP survival and CFU counts were similar between genders, high circulating LPS levels in ExSh mice and low levels of IgM anti-LPS in males. In the serum of ExSh males, TNF and IL-6 increased in the first 6 h, in CLP males at 12 h. In the liver of ExSh mice, TNF increased at 1.5 and 12 h, IL-1 at 6 h. TGFß1 increased in females throughout the study and at 12 h in males. In CLP mice, IL-6 decreased at 12 h, TGFß1 increased at 6-12 h in males and at 12 h in females. In the lungs of ExSh males, IL-1ß increased at 1.5-6 h and TGFß1 at 12 h; in females, TNF decrease at 6 h and TGFß1 increased from 6 h; in CLP females, TNF and IL-1ß decreased at 12 h and 1.5 h, respectively, and TGFß1 increased from 6 h; in males, TGFß1 increased at 12 h. In the livers of ExSh mice, signs of inflammation were more common in males; in the CLP groups, inflammation was similar but less pronounced. ExSh females had leucocytes with TGFß1. The lungs of ExSh males showed patches of hyaline membranes and some areas of inflammatory cells, similar but fewer and smaller lesions were seen in male mice with CLP. In ExSh females, injuries were less extent than in males, similar pulmonary lesions were seen in female mice with CLP. ExSh males had lower levels of TGFß1 than females, and even lower levels were seen in CLP males. We conclude that the ExSh was the most lethal model in males, associated with high levels of free LPS, low IgM anti-LPS, exacerbated inflammation and target organ injury, while females showed early TGFß1 production in the lungs and less tissue damage. We didn't see any differences between CLP mice.

The molecular profile of the inflammatory process differs among various neurodevelopmental disorders with or without cognitive component: A hypothesis of persistent systemic dysfunction and hyper-resolution.

Introduction: Challenges of diverse origin in childhood can alter the growth and development of the central nervous system, affecting structures and functions. As a consequence of the damage suffered during the perinatal period, long periods of dysfunctionality may occur, such as regulatory disorders, which may result in remaining in a process of low-grade inflammation. We previously found that perinatal risks and neurological signs are associated with long-term changes in circulating concentrations of molecules of the inflammatory process, findings that are consistent with the postulate that long periods of dysfunction may condition long-lasting low-grade inflammation or parainflammation. The aim of this study was to assess whether different expressions of neurological disorders show variations in their inflammatory molecule profiles or whether there is a common pattern. Methods: We included screening for (a) caregiver-perceived risk detection of regulatory disturbances, using the DeGangi instrument; (b) dysautonomia or asymmetries, through neurodevelopmental assessments; (c) cognitive developmental disturbances (using the Bailey instrument). We assessed protein molecules on a multiplex system, and lipid molecules by ELISA. Results: We found a similar, although not identical, pattern of cytokine profiles with the presence of risk of regulatory disturbances, dysautonomia and asymmetries; but an opposite inflammatory profile was associated with cognitive impairment. Discussion: Our results suggest that there are diverse, probably limited, molecular footprints associated with impaired function, and that these footprints may depend on the response requirements necessary to adjust to the altered internal environment. Here we propose a theoretical model that suggests possible scenarios for inflammatory outcomes associated with chronic challenges.

Association of the Heart Rate Variability Response to Active Standing with the Severity of Calcific Aortic Valve Disease: Novel Insights of a Neurocardiovascular Pathology.

The aim of this work was to obtain insights of the participation of the autonomic nervous system in different stages of calcific aortic valve disease (CAVD) by heart rate variability (HRV) analysis. Studying subjects with no valve impairments and CAVD patients, we also sought to quantify the independent contribution or explanatory capacity of the aortic valve echocardiographic parameters involved in the HRV changes caused by active standing using hierarchical partitioning models to consider other variables or potential confounders. We detected smaller adjustments of the cardiac autonomic response at active standing caused specifically by the aortic valve deterioration. The highest association (i.e., the highest percentage of independent exploratory capacity) was found between the aortic valve area and the active standing changes in the short-term HRV scaling exponent α1 (4.591%). The valve's maximum pressure gradient echocardiographic parameter was present in most models assessed (in six out of eight models of HRV indices that included a valve parameter as an independent variable). Overall, our study provides insights with a wider perspective to explore and consider CAVD as a neurocardiovascular pathology. This pathology involves autonomic-driven compensatory mechanisms that seem generated by the aortic valve deterioration.

An approach to cellular tropism of SARS-CoV-2 through protein-protein interaction and enrichment analysis.

COVID-19, caused by SARS-CoV-2, is a primarily pulmonary disease that can affect several organs, directly or indirectly. To date, there are many questions about the different pathological mechanisms. Here, we generate an approach to identify the cellular-level tropism of SARS-CoV-2 using human proteomics, virus-host interactions, and enrichment analysis. Through a network-based approach, the molecular context was visualized and analyzed. This procedure was also performed for SARS-CoV-1. We obtained proteomes and interactomes from 145 different cells corresponding to 57 different tissues. We discarded the cells without the proteins known for interacting with the virus, such as ACE2 or TMPRSS2. Of the remaining cells, a gradient of susceptibility to infection was observed. In addition, we identified proteins associated with the coagulation cascade that can be directly or indirectly affected by viral proteins. As a whole we identified 55 cells that could be potentially controlled by the virus, with different susceptibilities, mainly being pneumocytes, heart, kidney, liver, or small intestine cells. These results help to explain the molecular context and provide elements for possible treatments in the current situation. This strategy may be useful for other viruses, especially those with limited reported PPI, such as a new virus.

Circulating miR-146a as a possible candidate biomarker in the indeterminate phase of Chagas disease.

BACKGROUND: Chagas disease is considered important and presents intense inflammatory and fibrotic processes induced by the perpetuation of the parasite in the affected tissues and organs. Therefore, it is necessary to inquire about the host defense and attack mechanisms to have a more detailed knowledge about Chagas disease. MicroRNAs are found in blood, tissues and extracellular vesicles. These small regulators of gene expression are involved in physiological and pathological processes in both mammals and parasites. Several microRNAs have deregulated expression in chagasic heart disease, although little is known about their extracellular expression. Our main objective was to evaluate the involvement of miR-21, miR-146a and miR-155 in several samples from mice infected with the TcI Ninoa strain from the acute and indeterminate phases. We also explored a potential functional association of the selected microRNAs using STRING software. This software identified 23 pathways associated with Trypanosoma cruzi infection. In addition, eleven genes were identified through bioinformatics analysis, and we found that SMAD family member 5 was downregulated in both phases. This gene serves as a mediator in the TGF-ß signaling pathway. Thus, forty female mice of the CD1 strain were distributed into 4 groups and the expression levels of miR-21, miR-146a and miR-155 were measured in samples of heart tissue, total plasma and plasma extracellular vesicles by quantitative real-time polymerase chain reaction. RESULTS: Overexpression of miR-21, miR-146a and miR-155 was observed in heart and plasma in both phases. Moreover, in extracellular vesicles miR-21 and miR-146a were also overexpressed in the acute phase, whereas in the indeterminate chronic phase we found only miR-146a up-regulated. CONCLUSIONS: The expression of inflammatory microRNAs miR-21, miR-146a and miR-155 were up-regulated in each of the samples from acutely and chronically infected mice. The relevant finding was that miR-146a was up-regulated in each sample in both phases; therefore, this miRNA could be a possible candidate biomarker in Chagas disease.

Cardiac Autonomic Response to Active Standing in Calcific Aortic Valve Stenosis.

Aortic stenosis is a progressive heart valve disorder characterized by calcification of the leaflets. Heart rate variability (HRV) analysis has been proposed for assessing the heart response to autonomic activity, which is documented to be altered in different cardiac diseases. The objective of the study was to evaluate changes of HRV in patients with aortic stenosis by an active standing challenge. Twenty-two volunteers without alterations in the aortic valve (NAV) and twenty-five patients diagnosed with moderate and severe calcific aortic valve stenosis (AVS) participated in this cross-sectional study. Ten minute electrocardiograms were performed in a supine position and in active standing positions afterwards, to obtain temporal, spectral, and scaling HRV indices: mean value of all NN intervals (meanNN), low-frequency (LF) and high-frequency (HF) bands spectral power, and the short-term scaling indices (α1 and αsign1). The AVS group showed higher values of LF, LF/HF and αsign1 compared with the NAV group at supine position. These patients also expressed smaller changes in meanNN, LF, HF, LF/HF, α1, and αsign1 between positions. In conclusion, we confirmed from short-term recordings that patients with moderate and severe calcific AVS have a decreased cardiac parasympathetic supine response and that the dynamic of heart rate fluctuations is modified compared to NAV subjects, but we also evidenced that they manifest reduced autonomic adjustments caused by the active standing challenge.

Effectiveness and Safety of Extracorporeal Shockwave Myocardial Revascularization in Patients With Refractory Angina Pectoris and Heart Failure.

Extracorporeal shockwave myocardial revascularization (ESMR) is a therapy for refractory angina pectoris. Our aim was to assess the efficacy and safety of ESMR in the management of patients with stable coronary artery disease (CAD) and heart failure as well as its effects on inflammation and angiogenesis. In this single-arm prospective trial, we included 48 patients with CAD, myocardial ischemia assessed by radionuclide imaging, echocardiographic evidence of left ventricular systolic dysfunction and without revascularization options. Changes in angina grading score, myocardial perfusion, left ventricular ejection fraction, and six-minute walk test after ESMR therapy were used for efficacy assessment. Changes of inflammation and angiogenesis biomarkers were also evaluated. ESMR therapy was performed using a commercially available cardiac shockwave generator system (Cardiospec; Medispec). After 9 weeks of ESMR therapy, a significant improvement was found regarding the initial angina class, severity of ischemia, left ventricular ejection fraction, and six-minute walk test in most patients. No deleterious side effects after treatment were detected. Regarding biomarkers, endothelial progenitor cells and angiopoietin-3 were significantly increased whereas IL-18 and TGF-ß were significantly decreased after ESMR in the total group. Notably, VEGF, IL-1ß, and lipoxin A4 levels were significantly increased only in patients with myocardial ischemia improvement. In conclusion, ESMR therapy is safe and effective in most but not all patients with CAD and heart failure. ESMR is associated with increased markers of angiogenesis and decreased markers of inflammation. Myocardial ischemia improvement after ESMR is associated with increased markers of angiogenesis and pro-resolving mediators.

Clinical phenotypes, aetiologies, management, and mortality in acute heart failure: a single-institution study in Latin-America.

AIMS: Little is known regarding acute heart failure (AHF) clinical characteristics and its hospital outcome in Latin America. This study sought to assess the prevalence of, and identify differences among, in-hospital outcomes in patients hospitalized for AHF who were stratified by clinical phenotype at a hospital in Latin America. METHODS AND RESULTS: This is a retrospective cohort study of patients with AHF who were hospitalized in the coronary care unit of a Latin American teaching hospital from January 2006 to December 2018. Cox regression analysis was used to identify predictors of mortality. Of 21 042 patients admitted, 7759 (36.6%) had AHF. Their median age was 62 years, and 35% were women. De novo heart failure was seen in 39.4% of patients. Most common was AHF-associated acute coronary syndromes (ACS-HF) in 43.0%, decompensated heart failure (DHF) in 33.7%, hypertensive heart failure (HT-HF) in 11.8%, and cardiogenic shock (CS) in 5.2%. Pulmonary oedema (PO) (3.3%) and right heart failure (RHF) (3.0%) were least frequent. Coronary artery disease was the most frequent aetiology in 56.5% of patients, valvular heart disease in 22.4%, and cardiomyopathies in 12.3%. Other less frequent aetiology included adult congenital heart disease (2.5%), lung diseases (2.1%), acute aortic syndromes (1.4%), pericardial diseases (0.8%), and intracardiac tumours (0.3%). Aetiology could not be established in 1.6% of patients. Before admission, patients with worsening chronic heart failure and reduced ejection fraction were treated with renin-angiotensin system blockers (60.4%), beta-blockers (42.5%), or spironolactone (34.4%). The percentages of patients given in-hospital management with intravenous diuretics, vasodilators, inotropes, and vasopressors were 81.2%, 33.4%, 18.9%, and 20.4%, respectively. The overall in-hospital mortality was 17.9% (71.3%, 43.9%, 23.8%, 14.9%, 13.6%, and 10.1% for CS, PO, RHF, DHF, ACS-HF, and HT-HF, respectively; P < 0.0001). Multivariate analysis revealed that PO (hazard ratio [HR] 2.68, 95% confidence interval [CI] 1.73-4.14, P < 0.0001) and CS (HR 3.37, 95% CI 2.12-5.35, P < 0.0001) were independent predictors of in-hospital mortality. Use of intravenous diuretics was linked to reduction of in-hospital mortality (HR 0.70, 95% CI 0.59-0.59, P < 0.0001). By contrast, increased in-hospital mortality was associated with the use of intravenous inotrope or vasopressor (HR 1.49, 95% CI 1.27-1.76 and HR 2.91, 95% CI 2.41-3.51, P < 0.0001, respectively). CONCLUSIONS: Real-world evidence from a university hospital in Latin America shows that the high mortality among patients with AHF may depend, among other factors, on patients' AHF clinical phenotypes. The clinical characteristics and aetiologies of AHF appear to differ between these data from Mexico and those from European and US registries.

Circulating miR-146a as a possible candidate biomarker in the indeterminate phase of Chagas disease

BACKGROUND: Chagas disease is considered important and presents intense inflammatory and fibrotic processes induced by the perpetuation of the parasite in the affected tissues and organs. Therefore, it is necessary to inquire about the host defense and attack mechanisms to have a more detailed knowledge about Chagas disease. Micro-RNAs are found in blood, tissues and extracellular vesicles. These small regulators of gene expression are involved in physiological and pathological processes in both mammals and parasites. Several microRNAs have deregulated expression in chagasic heart disease, although little is known about their extracellular expression. Our main objective was to evaluate the involvement of miR-21, miR-146a and miR-155 in several samples from mice infected with the TcI Ninoa strain from the acute and indeterminate phases. We also explored a potential functional association of the selected microRNAs using STRING software. This software identified 23 pathways associated with Trypanosoma cruzi infection. In addition, eleven genes were identified through bioinformatics analysis, and we found that SMAD family member 5 was downregulated in both phases. This gene serves as a mediator in the TGF-ß signaling pathway. Thus, forty female mice of the CD1 strain were distributed into 4 groups and the expression levels of miR-21, miR-146a and miR-155 were measured in samples of heart tissue, total plasma and plasma extracellular vesicles by quantitative real-time polymerase chain reaction. RESULTS: Overexpression of miR-21, miR-146a and miR-155 was observed in heart and plasma in both phases. Moreover, in extracellular vesicles miR-21 and miR-146a were also overexpressed in the acute phase, whereas in the indeterminate chronic phase we found only miR-146a up-regulated. CONCLUSIONS: The expression of inflammatory microRNAs miR-21, miR-146a and miR-155 were up-regulated in each of the samples from acutely and chronically infected mice. The relevant finding was that miR-146a was up-regulated in each sample in both phases; therefore, this miRNA could be a possible candidate biomarker in Chagas disease.

The Severity of Neurological Dysfunction in Preschool Children, Secondary to Damage Generated During the Perinatal Period, is Associated With a Pro-Inflammatory Pattern of Serum Molecules.

Disorders in the child's neurological development caused by perinatal risks can lead to long-term altered neurological signs that begin at an early age and involve persistent functional disorders. Recent data suggest that tissue dysfunction, not just acute damage, may initiate or perpetuate an inflammatory response. The aim of this study was to find out if any neurological dysfunction in preschool children secondary to damage generated during the perinatal period is associated with the magnitude of perinatal risks and long-term modifications in the serum concentrations of inflammatory molecules. The participants, aged 1-4 years, were on neurodevelopmental follow-up and rehabilitation therapy from the first three months of life and had no acute disease data. We classified the children into three groups according to the importance of their perinatal risks: low, medium, and high. The results show that 1) the magnitude of perinatal risks correlated with the severity of neurological dysfunction; 2) the greatest changes in the concentrations of the molecules of the inflammatory process were associated with the most altered neurological signs. This suggests that persistent nervous system dysfunction keeps inflammatory responses active even in the absence of an acute process of infection or damage.

Derivation and validation of a simple inflammation-based risk score system for predicting in-hospital mortality in acute coronary syndrome patients.

BACKGROUND: Accurate assessment of inflammatory status of patients during acute coronary syndrome (ACS) has become of great importance in their risk classification and in the research of new anti-inflammatory therapies. METHOD: The study cohort included 7396 patients with ACS. We sought to derive and internally validate an inflammation-based score that included high-sensitivity C-reactive protein, white blood cell count, and serum albumin level at admission to evaluate the predictive role of systemic inflammation in the clinical outcome of these patients. We randomly assigned patients into derivation (66.6%) and validation (33.4%) cohorts. A total of four categories of systemic inflammation were defined. RESULTS: Assessed individually, the three biomarkers were associated with a higher rate of in-hospital mortality. When we combined them into an inflammation score, in-hospital mortality was significantly different across the four categories of inflammation in the derivation cohort (1.8%, 2.8%, 4.1%, and 13.8% for without, mild, moderate, and severe inflammation, respectively; p<0.0001, C-statistic, 0.71). These results were similar in the validation cohort (1.1%, 2.9%, 5.2%, and 12.6%, respectively; p<0.0001, C-statistic, 0.71). After multivariate adjustment, only the category of severe systemic inflammation was associated with a threefold increased risk of in-hospital mortality (odds ratios 3.02, p<0.0001) and was the most powerful predictor of mortality. In the whole cohort, after subsetting patients based on GRACE risk score, the severe inflammation category was associated with a significant increase of in-hospital mortality across all sub-groups, mainly in patients with higher GRACE risk score. The inflammation-based risk score reclassified 25.3% of the population. The net reclassification index was 8.2% (p=0.001). CONCLUSION: A risk score system based on biomarkers of inflammation readily available at admission in patients with ACS, could better assess the inflammatory status and predict in-hospital mortality, as well as severe systemic inflammation that contributes to a worse outcome independently of clinical risk factors.

Co-ordinated expression of the VEGF system components in granulosa cells to develop a proangiogenic autocrine milieu during ovarian follicle development.

In the present study, we investigated the temporal relationship between angiogenic and antiangiogenic vascular endothelial growth factor isoforms (VEGFxxxa and VEGFxxxb, respectively), the receptors VEGFR1 and VEGFR2, their soluble forms, and the kinases and the splicing factors regulating the synthesis of VEGF isoforms in healthy and atretic antral follicles. The results show a higher (p < 0.05) messenger RNA (mRNA) expression of VEGF120a, VEGF164a, and VEGF120b in healthy than in atretic follicles, but the mRNA expression of VEGF164b was not detected. The mRNA of serine-arginine protein kinase 1 ( SRPK1) was higher ( p < 0.05) in large healthy follicles than in large atretic follicles. In contrast, atretic follicles had higher mRNA expression of a soluble form of the receptor 2 of VEGF ( sVEGFR2) than healthy follicles ( p < 0.05). Additionally, we observed a positive relationship ( p < 0.05) between SRPK1 and serine-arginine-rich splicing factor 1 ( SRSF1) with the angiogenic isoforms VEGF120a and VEGF164a and between CDC-like kinases-1 ( CLK1) and SRSF6 with the antiangiogenic VEGF120b isoform. Principal components analysis (PCA) resulted in two PC explaining 71% of the variation, which was formed by the VEGF isoforms, the kinases and the splicing factor (PC1) and by the VEGF receptors (PC2). When PC analysis was carried out within follicular health status, there were no differences for PC1 between follicular status, whereas PC2 differed between healthy and atretic follicles. In conclusion, the higher mRNA expression for VEGF120a and VEGF164a, the low expression of sVEGFR2, and absent expression of mRNA for VEGF164b provide evidence of a proangiogenic autocrine milieu to support granulosa cells during follicle development.

[Los niveles de mediadores prorresolutivos no corresponden con los de mediadores inflamatorios en enfermedades isquémicas coronarias].

BACKGROUND: Inflammation can be grouped into three phases: proinflammatory, anti-inflammatory, and resolution. The latter, mainly attributed to lipid mediators, is the most recently described, and has been studied little in coronary ischemic diseases. OBJECTIVE: To evaluate 1) if acute coronary syndromes (ACS) manifest different circulating levels of resolution mediators compared with stable angina (SA); 2) if their concentrations are related to those of pro and anti-inflammatory mediators; and 3) if such concentrations are associated with the severity of the disease and the damage produced. METHOD: LTB4, RvD1, LXA4, ET-1, MMP-2, MMP-9, TIMP-1, IL-1ß, IL-6, IL-8 and IL-10 were measured in serum. The GRACE score was established as parameter of gravity, and LVEF as a damage parameter. RESULTS: Thirty patients with SA, 37 with NEST-ACS, 38 with STEMI, and 10 individuals with non-cardiogenic chest pain were included. Patients with coronary artery disease showed elevated levels of inflammatory cytokines and low levels of resolution mediators. CONCLUSIONS: The low resolution response even in patients with acute coronary disease suggests an inability to repair damage. Testing this hypothesis would have the potential to suggest new therapies for the management of chronic cardiovascular inflammation.

ANTECEDENTES: La inflamación puede agruparse en tres fases: proinflamatoria, antiinflamatoria y de resolución. Esta última, principalmente atribuida a mediadores lipídicos, es la de más reciente descripción y se ha estudiado poco en las enfermedades isquémicas coronarias. OBJETIVOS: Evaluar 1) si los síndromes coronarios agudos (SICA) manifiestan niveles circulantes distintos de mediadores de resolución comparados con la angina estable (AE); 2) si sus concentraciones se relacionan con las de mediadores proinflamatorios y antiinflamatorios; y 3) si dichas concentraciones se asocian con la gravedad de la enfermedad y el daño producido. MÉTODO: Se midieron LTB4, RvD1, LXA4, ET-1, MMP-2, MMP-9, TIMP-1, IL-1ß, IL-6, IL-8 e IL-10 en suero. Se establecieron la puntuación GRACE como parámetro de gravedad y la fracción de eyección del ventrículo izquierdo (FEVI) como parámetro de daño. RESULTADOS: Se incluyeron 30 pacientes con AE, 37 con SICA sin elevación del segmento ST (SICA-SEST), 38 con Infarto agudo del miocardio con elevación del segmetno ST(IAM-CEST) y 10 con dolor torácico no cardiogénico. Los pacientes con enfermedad coronaria mostraron niveles elevados de citocinas inflamatorias y bajos de mediadores de resolución. CONCLUSIONES: La escasa respuesta de resolución aun en pacientes con enfermedad coronaria aguda sugiere una incapacidad para reparar daños. Probar esta hipótesis tendría el potencial de sugerir nuevas terapias para el manejo de la inflamación cardiovascular crónica.

Cytokine and microRNA levels during different periods of paradoxical sleep deprivation and sleep recovery in rats.

BACKGROUND: Sleep has a fundamental role in the regulation of homeostasis. The aim of this study was to assess the effect of different periods of paradoxical sleep deprivation (PSD) and recovery on serum levels of cytokines and miRNAs related to inflammatory responses. METHODS: Male Wistar rats were submitted to a PSD of 24, 96, or 192 h, or of 192 h followed by 20 days of recovery (192 h PSD+R). The concentrations of corticosterone, cytokines (IL-6, TNF, IL-10, Adiponectin) and miRNAs (miR-146a, miR-155, miR-223, miR-16, miR-126, miR-21) in serum were evaluated. RESULTS: At PSD 24 h a significant increase of IL-6 and decrease of IL-10 were observed. At PSD 96h adiponectin increased. At 192 h of PSD IL-6 increased significantly again, accompanied by a threefold increase of IL-10 and an increase of serum corticosterone. After 20 days of recovery (192 h PSD+R) corticosterone, IL-6 and TNF levels increased significantly, while IL-10 decreased also significantly. Regarding the miRNAs at 24 h of PSD serum miR-146a, miR-155, miR-223, and miR-16 levels all increased. At 96 h of PSD miR-223 decreased. At 192 h of PSD decreases in miR-16 and miR-126 were observed. After recovery serum miR-21 increased and miR-16 decreased. CONCLUSION: PSD induces a dynamic response likely reflecting the induced cellular stress and manifested as variating hormonal and inflammatory responses. Sleep deprivation disturbed corticosterone, cytokine and miRNA levels in serum related to the duration of sleep deprivation, as short-term PSD produced effects similar to those of an acute inflammatory response and long-term PSD induced long-lasting disturbances of biological mediators.

Serum of Patients with Psoriasis Modulates the Production of MMP-9 and TIMP-1 in Cells of Monocytic Lineage.

Psoriasis is triggered by several stimuli that share a systemic production of interferon (IFN)-γ and other inflammatory mediators, which are key to regulate the production of matrix metalloproteinase (MMP)-9 and its inhibitor (TIMP)-1 by cells of monocytic lineage. This study evaluates the effect of the sera of 55 patients with psoriasis and 41 non-psoriatic individuals on the production of MMP-9 and TIMP-1 in cultured monocytes from a single healthy blood donor and in U937 cells. The effect of IFN-γ stimulation was also evaluated. Serum and supernatant concentrations of IFN-γ, MMP-9, and TIMP-1 were measured by enzyme-linked immunoassays, and the MMP-9/TIMP-1 ratios were calculated. In monocytes, incubation with psoriasis' sera increased the production of MMP-9 and TIMP-1 in comparison with both baseline and monocytes incubated with non-psoriatic sera. Although the MMP-9/TIMP-1 ratio was significantly higher compared to the baseline, no differences between groups were observed. In contrast, IFN-γ stimulation in monocytes previously exposed to psoriasis' sera increased MMP-9 levels and decreased TIMP-1 levels, whereas stimulation in monocytes exposed to non-psoriatic sera did not further modify the levels of MMP-9 or TIMP-1. Consequently, the MMP-9/TIMP-1 ratio in cells exposed to psoriatic serum was significantly higher than in cells exposed to non-psoriatic sera (24.5 versus 16.7; P < 0.05). Similar results were observed in U937 cells. Therefore, our results suggest that soluble mediators in psoriatic sera may enhance the proteolytic phenotype of monocytes when stimulated with IFN-γ, which supports the existence of a primed state in the inflammatory cells of patients with psoriasis.

Cytidine-5'-Diphosphocholine Protects the Liver From Ischemia/Reperfusion Injury Preserving Mitochondrial Function and Reducing Oxidative Stress.

Cytidine-5'-diphosphocholine (CDP-choline) participates as an intermediary in the synthesis of phosphatidylcholine, an essential component of cellular membranes. Citicoline treatment has shown beneficial effects in cerebral ischemia, but its potential to diminish reperfusion damage in liver has not been explored. In this work, we evaluated the hepatoprotective effect of citicoline and its possible association with inflammatory/oxidative stress and mitochondrial function because they are the main cellular features of reperfusion damage. Ischemia/reperfusion (I/R) in rat livers was performed with the Pringle's maneuver, clamping the 3 elements of the pedicle (hepatic artery, portal vein, and biliary tract) for 30 minutes and then removing the clamp to allow hepatic reperfusion for 60 minutes. The I/R + citicoline group received the compound before I/R. Liver injury was evaluated by measuring aspartate aminotransferase and alanine aminotransferase as well as lactic acid levels in serum; proinflammatory cytokines, proresolving lipid mediators, and nuclear factor kappa B content were determined as indicators of the inflammatory response. Antioxidant effects were evaluated by measuring markers of oxidative stress and antioxidant molecules. Oxygen consumption and the activities of the respiratory chain were used to monitor mitochondrial function. CDP-choline reduced aspartate aminotransferase (AST), alanine aminotransferase (ALT), as well as lactic acid levels in blood samples from reperfused rats. Diminution in tumor necrosis factor alpha (TNF-α) and increase in the proresolving lipid mediator resolvin D1 were also observed in the I/R+citicoline group, in comparison with the I/R group. Oxidative/nitroxidative stress in hepatic mitochondria concurred with deregulation of oxidative phosphorylation, which was associated with the loss of complex III and complex IV activities. In conclusion, CDP-choline attenuates liver damage caused by ischemia and reperfusion by reducing oxidative stress and maintaining mitochondrial function. Liver Transplantation XX XX-XX 2018 AASLD.

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.

Hyperuricemia on Admission Predicts Short-Term Mortality due to Myocardial Infarction in a Population with High Prevalence of Cardiovascular Risk Factors.

BACKGROUND: National health surveys have revealed an outstandingly high prevalence of obesity, hypertension, and diabetes in Mexico. OBJECTIVE: To assess whether serum uric acid levels on admission may predict short-term mortality in patients with ST-segment elevation myocardial infarction in a population with an unusually high prevalence of classic cardiovascular risks. METHODS: A total of 795 ST-segment elevation myocardial infarction patients undergoing primary reperfusion therapy were classified as having normouricemia or hyperuricemia according to serum uric acid levels at admission, and the occurrence of mortality and major adverse cardiovascular events during coronary care unit stay was assessed. RESULTS: Patients with hyperuricemia (n = 291; mean age 61.2 ± 11.9 years; 74.8% males) were older, obese, hypertensive, and had a higher Killip class at admission than those with normouricemia (n = 504; mean age 57.6 ± 11.3 years; 88.9% males). Mortality rates were 1.7 and 0.7 cases/100 patients per day of coronary care unit stay in hyperuricemic and normouricemic patients, respectively. Comparatively, no association was observed for the occurrence of major adverse cardiovascular events. After multivariate adjustments, independent predictors for short-term mortality were only Killip class ≥ 2 (HR: 13.15; 95% CI: 5.29-29.85; p < 0.0001) and elevated serum uric acid levels (HR: 1.99; 95% CI: 1.08-3.66; p = 0.026). CONCLUSIONS: Hyperuricemia on admission remains associated with short-term mortality in ST-segment elevation myocardial infarction patients from a population with an unusually high prevalence of cardiovascular risk factors.

Type III Interferons in Systemic Lupus Erythematosus: Association Between Interferon λ3, Disease Activity, and Anti-Ro/SSA Antibodies.

OBJECTIVE: The aim of this study was to assess associations between serum type III (λ) interferons (IFN-λ) and disease activity in systemic lupus erythematosus (SLE). METHODS: Serum levels of IFN-λ1, IFN-λ2, and IFN-λ3 were measured in 93 SLE patients and 67 healthy individuals. The associations with overall disease activity, organ-specific damage, and SLE-related antibodies were assessed. RESULTS: Median IFN-λ1 levels were 0 pg/mL (range, 0-510 pg/mL) and 0 pg/mL (0-171 pg/mL; P = 0.814) in SLE patients and control subjects, respectively. These figures were 0 pg/mL (0-28 pg/mL) and 0 pg/mL (0-43 pg/mL; P = 0.659) for IFN-λ2, as well as 83 pg/mL (0-965 pg/mL) and 42 pg/mL (0-520 pg/mL; P = 0.002) for IFN-λ3, respectively. According to the Systemic Lupus Erythematosus Disease Activity Index categories, IFN-λ3 levels were 44 pg/mL (0-158 pg/mL) in quiescent, 117 pg/mL (0-344 pg/mL) in mild, 79 pg/mL (0-965 pg/mL) in moderate, and 78 pg/mL (0-329 pg/mL) in severe disease, with the highest levels found in patients with serosal or cutaneous involvement. In line with this, IFN-λ3 levels were inversely correlated with C3 (ρ = -0.44; 95% confidence interval, -0.62 to -0.20; P = 0.0003) and C4 (ρ = -0.40; 95% confidence interval, -0.59 to -0.15; P = 0.0001) complement proteins. In addition, higher IFN-λ3 levels were found in patients positive for anti-Ro/SSA antibodies than in those negative for that antibody (122 pg/mL [0-965 pg/mL] vs. 0 pg/mL [0-165 pg/mL]; P = 0.001). The concentration of IFN-λ3 also was higher in patients receiving glucocorticoids (104 pg/mL [0-965 pg/mL] vs. 30 pg/mL [0-165 pg/mL]; P = 0.009), and a dose-related effect was observed. CONCLUSIONS: Interferon λ3, a subtype of type III IFNs, is associated with the extent of lupus activity, in particular with active serosal and cutaneous disease. This association could be mechanistically related to anti-Ro/SSA antibodies.