7 research outputs found
Influence of paraoxonase-1 deficiency on metabolic alterations and inflammation
Les malalties cròniques no infecciones i no transmissibles (diabetis, càncer i malalties cardiovasculars) compateixen mecanismes moleculars com l’estrès oxidatiu, la inflamació i les alteracions metabòliques. Les complicacions derivades poden incrementar el risc de desenvolupar altres comorbiditats com la malaltia del fetge gras no alcohòlic (EHNA) i l’aterosclerosi. La EHNA s’associa a resistència a la insulina i a aterosclerosi subclínica, que juntament amb l’estrès oxidatiu, es consideren els principals factors en la progressió de la EHNA cap a esteatohepatitis. La família d’enzims paraoxonasa (PON) és un sistema endogen antioxidant molt important implicat en la protecció front els processos oxidants, contribueixen a la immunitat innata, la bioactivació de fàrmacs, la detoxificació de molècules reactives, la modulació de l’estrès de reticle i la regulació de la proliferació/apoptosi cel·lular.
Creiem que la deficiència de PON1 s’associa a problemes metabòlics severs que poden estar lligats a inflamació i a comorbiditats com la EHNA i l’aterosclerosi.
A l’estudi 1, vam investigar l’efecte de la deficiència de PON1 en el fetge de ratolins alimentats amb dieta rica en greix. Els resultats van mostrar que PON1 sembla tenir un important paper protector en el fetge, fet que comporta una rellevància clínica ja que una activitat de PON1 disminuïda és una alteració primerenca en pacients amb dany hepàtic.
En l’estudi 2 vam investigar la influència de PON1 en les alteracions metabòliques quan cèl·lules endotelials incubades amb oxLDL. Els resultats mostraven que les HDL de ratolins deficients en PON1 tenien menor capacitat de protegir a aquestes cèl·lules de les oxLDL, provocant importants problemes metabòlics.
Els efectes de la metformina en pacients amb problemes hepàtics generen controvèrsia. A l’estudi 3 vam testar els seus efectes en fetges de ratolins deficients en PON1, evidenciant els efectes indesitjats del fàrmac en el fetge dels animals, agreujant inflamació i esteatosi hepàtica.Las enfermedades no infecciosas y no transmisibles crónicas (diabetes, cáncer y enfermedades cardiovasculares) comparten mecanismos moleculares como estrés oxidativo, inflamación y alteraciones metabólicas. Las complicaciones derivadas de estas enfermedades están relacionadas e incrementan el riesgo de desarrollar otras comorbilidades, como la enfermedad hepática no alcohólica (EHNA) y la aterosclerosis.
La EHNA se relaciona con resistencia a la insulina y aterosclerosis, que junto con el estrés oxidativo participan en su progresión a esteatohepatitis no alcohólica. La familia de enzimas paraoxonasa es un sistema antioxidante endógeno implicado en la protección contra el daño oxidativo y la peroxidación lipídica, participa en inmunidad innata, bioactivación de drogas, detoxificación de moléculas reactivas, modulación del estrés en retículo endoplamático y regulación de la proliferación celular/apoptosis.
Creemos que la deficiencia de PON1 está asociada a graves alteraciones hepáticas y podría estar relacionada con inflamación y comorbilidades de enfermedades como la EHNA y la aterosclerosis.
Inicialmente (estudio 1), investigamos como la deficiencia de PON1 afecta histológica y metabólicamente al hígado de ratones alimentados con dieta rica en grasa. Concluimos que PON1 tiene un importante papel protector en hígado pudiendo tener relevancia clinica, ya que una menor actividad de PON1 es una de las primeras alteraciones detectadas en pacientes con daño hepático.
Seguidamente (estudio2), investigamos la influencia de PON1 en las alteraciones metabólicas de células endoteliales incubadas con LDL oxidadas (LDLox). Los resultados mostraron que las HDL de estos ratones tenían menor capacidad de protección frente a las LDLox, llevando a importantes alteraciones metabólicas.
Debido a la controversia de resultados sobre los efectos de la metformina en pacientes con daño hepático, en el estudio 3 testamos los efectos de la metformina en hígado de ratones deficientes en PON1, concluyendo que la administración de metformina produce efectos negativos en los hígados de estos ratones, agravando la inflamación y la esteatosis.Non-communicable diseases (NCD) are non-infectious and non-transmissible chronic diseases, such as diabetes, cancer and cardiovascular disease. They share common molecular mechanisms including oxidative stress, inflammation and metabolic alterations. NCD complications are interrelated, increasing risk to develop other comorbidities such as non-alcoholic fatty liver disease (NAFLD) and atherosclerosis.. NAFLD is associated with insulin resistance and subclinical atherosclerosis, that together with oxidative stress are considered driving factors in the progression of NAFLD to NASH (non-alcoholic steatohepatitis). The paraoxonase (PON) family of enzymes is an important endogenous antioxidant system implicated in protection against oxidative damage and lipid peroxidation, contribution to innate immunity, bioactivation of drugs, detoxification of reactive molecules, modulation of endoplasmic reticulum stress, and regulation of cell proliferation/apoptosis.
We hypothesize that PON1 deficiency is associated to severe metabolic disturbances that may be related to inflammation and the comorbidities of some NCD, such as NAFLD and atherosclerosis.
In Study 1, we investigated the effect of PON1 deficiency on histological alterations and hepatic metabolism in mice fed a high-fat high-cholesterol diet. Results showed that PON1 seems to have an important protective role in the liver which may have clinical relevance since reduced serum and liver PON1 activity is an early alteration in patients with liver impairment.
In Study 2 we investigated the influence of PON1 on metabolic alterations when endothelial cells are incubated with oxLDL . The results showed that HDL from PON1 deficient mice has an impaired capacity to protect endothelial cells from oxLDL, triggering important metabolic disturbances.
As there are controversial results about the effects of metformin in patients with liver impairment, in Study 3, we wanted to test metformin effects on the liver of PON1 deficient mice. Results showed that metformin administration produces undesirable effects in the liver of PON1 deficient mice, aggravating inflammation and steatosis
Clonal chromosomal mosaicism and loss of chromosome Y in elderly men increase vulnerability for SARS-CoV-2
The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, COVID-19) had an estimated overall case fatality ratio of 1.38% (pre-vaccination), being 53% higher in males and increasing exponentially with age. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, we found 133 cases (1.42%) with detectable clonal mosaicism for chromosome alterations (mCA) and 226 males (5.08%) with acquired loss of chromosome Y (LOY). Individuals with clonal mosaic events (mCA and/or LOY) showed a 54% increase in the risk of COVID-19 lethality. LOY is associated with transcriptomic biomarkers of immune dysfunction, pro-coagulation activity and cardiovascular risk. Interferon-induced genes involved in the initial immune response to SARS-CoV-2 are also down-regulated in LOY. Thus, mCA and LOY underlie at least part of the sex-biased severity and mortality of COVID-19 in aging patients. Given its potential therapeutic and prognostic relevance, evaluation of clonal mosaicism should be implemented as biomarker of COVID-19 severity in elderly people. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, individuals with clonal mosaic events (clonal mosaicism for chromosome alterations and/or loss of chromosome Y) showed an increased risk of COVID-19 lethality
Proteomic analysis reveals oxidative stress response as the main adaptative physiological mechanism in cows under different production systems
Novel genes and sex differences in COVID-19 severity.
Here we describe the results of a genome-wide study conducted in 11 939 COVID-19 positive cases with an extensive clinical information that were recruited from 34 hospitals across Spain (SCOURGE consortium). In sex-disaggregated genome-wide association studies for COVID-19 hospitalization, genome-wide significance (p < 5x10-8) was crossed for variants in 3p21.31 and 21q22.11 loci only among males (p = 1.3x10-22 and p = 8.1x10-12, respectively), and for variants in 9q21.32 near TLE1 only among females (p = 4.4x10-8). In a second phase, results were combined with an independent Spanish cohort (1598 COVID-19 cases and 1068 population controls), revealing in the overall analysis two novel risk loci in 9p13.3 and 19q13.12, with fine-mapping prioritized variants functionally associated with AQP3 (p = 2.7x10-8) and ARHGAP33 (p = 1.3x10-8), respectively. The meta-analysis of both phases with four European studies stratified by sex from the Host Genetics Initiative confirmed the association of the 3p21.31 and 21q22.11 loci predominantly in males and replicated a recently reported variant in 11p13 (ELF5, p = 4.1x10-8). Six of the COVID-19 HGI discovered loci were replicated and an HGI-based genetic risk score predicted the severity strata in SCOURGE. We also found more SNP-heritability and larger heritability differences by age (<60 or ≥ 60 years) among males than among females. Parallel genome-wide screening of inbreeding depression in SCOURGE also showed an effect of homozygosity in COVID-19 hospitalization and severity and this effect was stronger among older males. In summary, new candidate genes for COVID-19 severity and evidence supporting genetic disparities among sexes are provided
Xenohormetic and anti-aging activity of secoiridoid polyphenols present in extra virgin olive oil
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Effects of pre-operative isolation on postoperative pulmonary complications after elective surgery: an international prospective cohort study an international prospective cohort study
We aimed to determine the impact of pre-operative isolation on postoperative pulmonary complications after elective surgery during the global SARS-CoV-2 pandemic. We performed an international prospective cohort study including patients undergoing elective surgery in October 2020. Isolation was defined as the period before surgery during which patients did not leave their house or receive visitors from outside their household. The primary outcome was postoperative pulmonary complications, adjusted in multivariable models for measured confounders. Pre-defined sub-group analyses were performed for the primary outcome. A total of 96,454 patients from 114 countries were included and overall, 26,948 (27.9%) patients isolated before surgery. Postoperative pulmonary complications were recorded in 1947 (2.0%) patients of which 227 (11.7%) were associated with SARS-CoV-2 infection. Patients who isolated pre-operatively were older, had more respiratory comorbidities and were more commonly from areas of high SARS-CoV-2 incidence and high-income countries. Although the overall rates of postoperative pulmonary complications were similar in those that isolated and those that did not (2.1% vs 2.0%, respectively), isolation was associated with higher rates of postoperative pulmonary complications after adjustment (adjusted OR 1.20, 95%CI 1.05–1.36, p = 0.005). Sensitivity analyses revealed no further differences when patients were categorised by: pre-operative testing; use of COVID-19-free pathways; or community SARS-CoV-2 prevalence. The rate of postoperative pulmonary complications increased with periods of isolation longer than 3 days, with an OR (95%CI) at 4–7 days or ≥ 8 days of 1.25 (1.04–1.48), p = 0.015 and 1.31 (1.11–1.55), p = 0.001, respectively. Isolation before elective surgery might be associated with a small but clinically important increased risk of postoperative pulmonary complications. Longer periods of isolation showed no reduction in the risk of postoperative pulmonary complications. These findings have significant implications for global provision of elective surgical care. We aimed to determine the impact of pre-operative isolation on postoperative pulmonary complications after elective surgery during the global SARS-CoV-2 pandemic. We performed an international prospective cohort study including patients undergoing elective surgery in October 2020. Isolation was defined as the period before surgery during which patients did not leave their house or receive visitors from outside their household. The primary outcome was postoperative pulmonary complications, adjusted in multivariable models for measured confounders. Pre-defined sub-group analyses were performed for the primary outcome. A total of 96,454 patients from 114 countries were included and overall, 26,948 (27.9%) patients isolated before surgery. Postoperative pulmonary complications were recorded in 1947 (2.0%) patients of which 227 (11.7%) were associated with SARS-CoV-2 infection. Patients who isolated pre-operatively were older, had more respiratory comorbidities and were more commonly from areas of high SARS-CoV-2 incidence and high-income countries. Although the overall rates of postoperative pulmonary complications were similar in those that isolated and those that did not (2.1% vs 2.0%, respectively), isolation was associated with higher rates of postoperative pulmonary complications after adjustment (adjusted OR 1.20, 95%CI 1.05–1.36, p = 0.005). Sensitivity analyses revealed no further differences when patients were categorised by: pre-operative testing; use of COVID-19-free pathways; or community SARS-CoV-2 prevalence. The rate of postoperative pulmonary complications increased with periods of isolation longer than 3 days, with an OR (95%CI) at 4–7 days or ≥ 8 days of 1.25 (1.04–1.48), p = 0.015 and 1.31 (1.11–1.55), p = 0.001, respectively. Isolation before elective surgery might be associated with a small but clinically important increased risk of postoperative pulmonary complications. Longer periods of isolation showed no reduction in the risk of postoperative pulmonary complications. These findings have significant implications for global provision of elective surgical care