Metabolic syndrome is characterized by the coexistence of different metabolic disorders which increase the risk of developing type 2 diabetes mellitus and cardiovascular diseases. Therefore, ...metabolic syndrome leads to a reduction in patients' quality of life as well as to an increase in morbidity and mortality. In the last few decades, it has been demonstrated that seaweeds exert multiple beneficial effects by virtue of their micro- and macronutrient content, which could help in the management of cardiovascular and metabolic diseases. This review aims to provide an updated overview on the potential of brown seaweeds for the prevention and management of metabolic syndrome and its associated diseases, based on the most recent evidence obtained from in vitro and in vivo preclinical and clinical studies. Owing to their great potential for health benefits, brown seaweeds are successfully used in some nutraceuticals and functional foods for treating metabolic syndrome comorbidities. However, some issues still need to be tackled and deepened to improve the knowledge of their ADME/Tox profile in humans, in particular by finding validated indexes of their absorption and obtaining reliable information on their efficacy and long-term safety.
A peculiar role for oxidative stress in non-alcoholic fatty liver disease (NAFLD) and its transition to the inflammatory complication non-alcoholic steatohepatitis (NASH), as well as in its ...threatening evolution to hepatocellular carcinoma (HCC), is supported by numerous experimental and clinical studies. NADPH oxidases (NOXs) are enzymes producing reactive oxygen species (ROS), whose abundance in liver cells is closely related to inflammation and immune responses. Here, we reviewed recent findings regarding this topic, focusing on the role of NOXs in the different stages of fatty liver disease and describing the current knowledge about their mechanisms of action. We conclude that, although there is a consensus that NOX-produced ROS are toxic in non-neoplastic conditions due to their role in the inflammatory vicious cycle sustaining the transition of NAFLD to NASH, their effect is controversial in the neoplastic transition towards HCC. In this regard, there are indications of a differential effect of NOX isoforms, since NOX1 and NOX2 play a detrimental role, whereas increased NOX4 expression appears to be correlated with better HCC prognosis in some studies. Further studies are needed to fully unravel the mechanisms of action of NOXs and their relationships with the signaling pathways modulating steatosis and liver cancer development.
Concerns have been raised about the possibility that inhibitors of the renin–angiotensin–aldosterone system (RAAS) could predispose individuals to severe COVID-19; however, epidemiological evidence ...is lacking. We report the results of a case-population study done in Madrid, Spain, since the outbreak of COVID-19.
In this case-population study, we consecutively selected patients aged 18 years or older with a PCR-confirmed diagnosis of COVID-19 requiring admission to hospital from seven hospitals in Madrid, who had been admitted between March 1 and March 24, 2020. As a reference group, we randomly sampled ten patients per case, individually matched for age, sex, region (ie, Madrid), and date of admission to hospital (month and day; index date), from Base de datos para la Investigación Farmacoepidemiológica en Atención Primaria (BIFAP), a Spanish primary health-care database, in its last available year (2018). We extracted information on comorbidities and prescriptions up to the month before index date (ie, current use) from electronic clinical records of both cases and controls. The outcome of interest was admission to hospital of patients with COVID-19. To minimise confounding by indication, the main analysis focused on assessing the association between COVID-19 requiring admission to hospital and use of RAAS inhibitors compared with use of other antihypertensive drugs. We calculated odds ratios (ORs) and 95% CIs, adjusted for age, sex, and cardiovascular comorbidities and risk factors, using conditional logistic regression. The protocol of the study was registered in the EU electronic Register of Post-Authorisation Studies, EUPAS34437.
We collected data for 1139 cases and 11 390 population controls. Among cases, 444 (39·0%) were female and the mean age was 69·1 years (SD 15·4), and despite being matched on sex and age, a significantly higher proportion of cases had pre-existing cardiovascular disease (OR 1·98, 95% CI 1·62–2·41) and risk factors (1·46, 1·23–1·73) than did controls. Compared with users of other antihypertensive drugs, users of RAAS inhibitors had an adjusted OR for COVID-19 requiring admission to hospital of 0·94 (95% CI 0·77–1·15). No increased risk was observed with either angiotensin-converting enzyme inhibitors (adjusted OR 0·80, 0·64–1·00) or angiotensin-receptor blockers (1·10, 0·88–1·37). Sex, age, and background cardiovascular risk did not modify the adjusted OR between use of RAAS inhibitors and COVID-19 requiring admission to hospital, whereas a decreased risk of COVID-19 requiring admission to hospital was found among patients with diabetes who were users of RAAS inhibitors (adjusted OR 0·53, 95% CI 0·34–0·80). The adjusted ORs were similar across severity degrees of COVID-19.
RAAS inhibitors do not increase the risk of COVID-19 requiring admission to hospital, including fatal cases and those admitted to intensive care units, and should not be discontinued to prevent a severe case of COVID-19.
Instituto de Salud Carlos III.
The purpose of this study was to examine the effects of REL-1017 (esmethadone), a novel
-methyl-d-aspartate receptor (NMDAR) channel blocker, in patients with major depressive disorder who failed to ...benefit from one to three standard antidepressant treatments in their current major depressive episode.
A 7-day phase 2 multicenter randomized double-blind placebo-controlled trial, comprising three arms, was conducted to assess the safety, tolerability, pharmacokinetics, and efficacy of two dosages of REL-1017 (25 mg or 50 mg orally once a day). Patients were randomly assigned in a 1:1:1 ratio to placebo (N=22), REL-1017 25 mg/day (N=19), or REL-1017 50 mg/day (N=21). Safety scales included the 4-item Positive Symptom Rating Scale for psychotomimetic symptoms, the Clinician-Administered Dissociative States Scale for dissociative symptoms, the Clinical Opiate Withdrawal Scale for withdrawal signs and symptoms, and the Columbia-Suicide Severity Rating Scale for suicidality. The primary efficacy endpoint was the Montgomery-Åsberg Depression Scale (MADRS) score. All 62 randomly assigned patients were included in the full analysis set population analysis.
Patients experienced mild or moderate transient adverse events and no evidence of dissociative or psychotomimetic effects, opioid effects, or withdrawal signs and symptoms. The improvement in MADRS score shown on day 4 in both of the REL-1017 dosage groups was sustained through day 7 (last dose) and day 14 (7 days after the last dose), with effect sizes from 0.7 to 1.0.
This trial showed favorable safety, tolerability, and pharmacokinetic profiles and suggests that REL-1017 may have rapid and sustained antidepressant effects compared with placebo in patients with inadequate responses to antidepressant treatments. These results will need confirmation in larger and longer trials.
To assess the relationship between influenza vaccination in the general population and risk of a first ischemic stroke (IS) during pre-epidemic, epidemic, and postepidemic periods.
A nested ...case-control study was conducted in a Spanish primary care database over 2001-2015. Individuals aged 40-99 years with at least 1 year registry and no history of stroke or cancer were selected to conform the source cohort, from which incident IS cases were identified and classified as cardioembolic or noncardioembolic. Five controls per case were randomly selected, individually matched with cases for exact age, sex, and date of stroke diagnosis (index date). A patient was considered vaccinated when he/she had a recorded influenza vaccination at least 14 days before the index date within the same season. Adjusted odds ratios (aORs) and their respective 95% CIs were computed through a conditional logistic regression. Pneumococcal vaccination was used as a negative control.
From a cohort of 3,757,621 patients, we selected 14,322 incident IS cases (9,542 noncardioembolic and 4,780 cardioembolic) and 71,610 matched controls. Of them, 41.4% and 40.5%, respectively, were vaccinated yielding a crude OR of 1.05 (95% CI 1.01-1.10). Vaccinated patients presented a higher prevalence of vascular risk factors, diseases, and comedication than those nonvaccinated, and after full adjustment, the association of influenza vaccination with IS yielded an aOR of 0.88 (95% CI 0.84-0.92), appearing early (aOR
0.79; 95% CI 0.69-0.92) and slightly declining over time (aOR
0.92; 95% CI 0.87-0.98). A reduced risk of similar magnitude was observed with both types of IS, in the 3 epidemic periods, and in all subgroups analyzed (men, women, individuals younger and older than 65 years of age, and those with intermediate and high vascular risk). By contrast, pneumococcal vaccination was not associated with a reduced risk of IS (aOR 1.08; 95% CI 1.04-1.13).
Results are compatible with a moderate protective effect of influenza vaccine on IS appearing early after vaccination. The finding that a reduced risk was also observed in pre-epidemic periods suggests that either the "protection" is not totally linked to prevention of influenza infection or it may be partly explained by unmeasured confounding factors.
Hepatocellular carcinoma (HCC), the primary hepatic malignancy, represents the second-highest cause of cancer-related death worldwide. Many efforts have been devoted to finding novel biomarkers for ...predicting both patients' survival and the outcome of pharmacological treatments, with a particular focus on immunotherapy. In this regard, recent studies have focused on unravelling the role of tumor mutational burden (TMB), i.e., the total number of mutations per coding area of a tumor genome, to ascertain whether it can be considered a reliable biomarker to be used either for the stratification of HCC patients in subgroups with different responsiveness to immunotherapy, or for the prediction of disease progression, particularly in relation to the different HCC etiologies. In this review, we summarize the recent advances on the study of TMB and TMB-related biomarkers in the HCC landscape, focusing on their feasibility as guides for therapy decisions and/or predictors of clinical outcome.
Background Previous studies investigating the relationship of influenza with acute myocardial infarction (AMI) have not distinguished between AMI types 1 and 2. Influenza and cold temperature can ...explain the increased incidence of AMI during winter but, because they are closely related in temperate regions, their relative contribution is unknown. Methods and Results The temporal relationship between incidence rates of AMI with demonstrated culprit plaque (type 1 AMI) from the regional primary angioplasty network and influenza, adjusted for ambient temperature, was studied in Madrid region (Spain) during 5 influenza seasons (from June 2013 to June 2018). A time-series analysis with quasi-Poisson regression models and distributed lag-nonlinear models was used. The incidence rate of type 1 AMI according to influenza vaccination status was also explored. A total of 8240 cases of confirmed type 1 AMI were recorded. The overall risk ratio (RR) of type 1 AMI during epidemic periods, adjusted for year, month, and temperature, was 1.23 (95% CI, 1.03-1.47). An increase of weekly influenza rate of 50 cases per 100 000 inhabitants resulted in an RR for type 1 AMI of 1.16 (95% CI, 1.09-1.23) during the same week, disappearing 1 week after. When adjusted for influenza, a decrease of 1ºC in the minimum temperature resulted in an increase of 2.5% type 1 AMI. Influenza vaccination was associated with a decreased risk of type 1 AMI in subjects aged 60 to 64 years (RR, 0.58; 95% CI, 0.47-0.71) and ≥65 years (RR, 0.53; 95% CI, 0.49-0.57). Conclusions Influenza and cold temperature were both independently associated with an increased risk of type 1 AMI, whereas vaccination was associated with a reduced risk among older patients.
Primary biliary cholangitis (PBC) is an autoimmune liver disease characterised by the immune-mediated destruction of small and medium intrahepatic bile ducts, with variable outcomes and progression. ...This review summarises the state of the art regarding the risk of neoplastic progression in PBC patients, with a particular focus on the molecular alterations present in PBC and in hepatocellular carcinoma (HCC), which is the most frequent liver cancer in these patients. Major risk factors are male gender, viral infections, e.g., HBV and HCV, non-response to UDCA, and high alcohol intake, as well as some metabolic-associated factors. Overall, HCC development is significantly more frequent in patients with advanced histological stages, being related to liver cirrhosis. It seems to be of fundamental importance to unravel eventual dysfunctional molecular pathways in PBC patients that may be used as biomarkers for HCC development. In the near future, this will possibly take advantage of artificial intelligence-designed algorithms.
Ubiquitin is generated by proteolytic cleavage of precursor proteins in which it is fused either to itself, constituting a linear polyubiquitin protein of head‐to‐tail monomers, or as a single ...N‐terminal moiety to one of two ribosomal proteins, eL40 (Ubi1/2 precursors) and eS31 (Ubi3 precursor). It has been proposed that the ubiquitin moiety fused to these ribosomal proteins could act as a chaperone by facilitating their efficient production, folding and ribosome assembly in Saccharomyces cerevisiae. We have previously shown that ubiquitin release from eS31 is required for yeast viability and that noncleaved Ubi3 can get incorporated into translation‐competent 40S subunits. In this study, we have analysed the effects of mutations that partially or totally impair cleavage of the ubiquitin‐eL40A fusion protein. While noncleaved Ubi1 is not able to support growth when it is the sole cellular source of eL40, it can assemble into nascent pre‐60S particles. However, Ubi1‐containing 60S ribosomal subunits are not competent for translation. This is likely due to a steric interference of the unprocessed ubiquitin with the binding and function of factors that interact with the ribosome's GTPase‐associated centre. In agreement with this suggestion, Ubi1‐containing ribosomes affect the efficient recycling of the anti‐association factor Tif6 and have a reduced presence of translation elongation factors. We conclude that the removal of the ubiquitin moiety from ribosomal protein eL40 is an essential prerequisite for both the cytoplasmic maturation and the functionality of 60S ribosomal subunits.
Ubiquitin fused to ribosomal protein eL40 is removed prior to the assembly of eL40 into pre‐60S ribosomes. Here, we demonstrate that incorporation of noncleaved ubiquitin‐eL40 variants into pre‐60S ribosomes impairs their cytoplasmic maturation, as shown by the decreased efficiency in recycling the anti‐association factor Tif6, and prevents 60S ribosomal subunits from efficiently engaging in translation.
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