Interplay of Postprandial Triglyceride-Rich Lipoprotein Composition and Adipokines in Obese Adolescents.

In the context of the alarming rise of infant obesity and its health implications, the present research aims to uncover disruptions in postprandial lipid metabolism and the composition of triglyceride-rich lipoproteins in obese adolescents. A double-blind, controlled clinical trial in the postprandial phase on 23 adolescents aged 12 to 16 years was carried out. Twelve participants were categorized as obese (BMI > 30 kg/m2 and percentile > 95) and 11 as normal-weight (BMI = 20-25 kg/m2, percentile 5-85). Blood samples were collected after a 12-h overnight fast and postprandially after consumption of a standardized breakfast containing olive oil, tomato, bread, orange juice, and skimmed milk. Obese adolescents exhibited elevated triglyceride concentrations in both fasting and postprandial states and higher TG/apo-B48 ratios, indicating larger postprandial triglyceride-rich lipoprotein (TRL) particle size, which suggests impaired clearance. Obese subjects also exhibited higher n-6 PUFA concentrations, potentially linked to increased TRL hydrolysis and the release of pro-inflammatory adipokines. In contrast, TRL from normal-weight individuals showed higher concentrations of oleic acid and DHA (n-3 PUFA), with possible anti-inflammatory effects. The results indicate an interplay involving postprandial TRL metabolism and adipokines within the context of adolescent obesity, pointing to potential cardiovascular implications in the future.

The efficacy of intensive lipid-lowering therapies on the reduction of LDLc and of major cardiovascular events.

BACKGROUND: Statins are the cornerstone of lipid-lowering therapy (LLT) for reduction of low-density lipoprotein cholesterol (LDLc) levels and high percentage of patients require LLT combinations or alternative treatments for adequate LDLc control. METHODS: We performed an intention-to-treat meta-analysis of published data of phase III trials evaluating LLT efficacy on major adverse cardiovascular events (MACE). The primary endpoint was MACE incidence, as reported in each trial, and secondary analyses included myocardial infarction, stroke and mortality. RESULTS: Eleven clinical trials and 135,688 patients were included; seven trials tested high intensity LLT and 4 LLT combinations. Intensive LLT reduced MACE risk by 15% (12.03% vs. 13.79%, HR: 0.85 95% CI 0.80-0.90; p<0.001). The number needed to treat was 56 patients. Meta-regression analyses showed a linear correlation between absolute LDLc reductions and the risk of MACE. Significant reductions in myocardial infarction (HR: 0.83, 95% CI 0.80-0.86) and stroke (HR: 0.81, 95% CI 0.75-0.87) were observed. Cardiovascular death rate was 3.32% in LLT treatment arm vs. 3.56% in controls, resulting in a HR: 0.94 (95% CI 0.88-0.99; p = 0.03); no effect on all-cause mortality was observed (HR: 0.97 95% CI 0.93-1.01; p = 0.09). The sensitivity analyses verified the lack of heterogeneity, except for MACE that was mainly driven by the divergent results of the 2 trials. Small study effect was detected for the assessment of mortality. CONCLUSIONS: Current evidence consistently supports the efficacy of available intensity LLT for LDLc decrease on MACE and cardiovascular mortality reduction.

A guide to sharing open healthcare data under the General Data Protection Regulation.

Sharing healthcare data is increasingly essential for developing data-driven improvements in patient care at the Intensive Care Unit (ICU). However, it is also very challenging under the strict privacy legislation of the European Union (EU). Therefore, we explored four successful open ICU healthcare databases to determine how open healthcare data can be shared appropriately in the EU. A questionnaire was constructed based on the Delphi method. Then, follow-up questions were discussed with experts from the four databases. These experts encountered similar challenges and regarded ethical and legal aspects to be the most challenging. Based on the approaches of the databases, expert opinion, and literature research, we outline four distinct approaches to openly sharing healthcare data, each with varying implications regarding data security, ease of use, sustainability, and implementability. Ultimately, we formulate seven recommendations for sharing open healthcare data to guide future initiatives in sharing open healthcare data to improve patient care and advance healthcare.

Polypill in cardiovascular disease prevention: recent advances.

Triple therapy with lipid­lowering, antihypertensive, and antiplatelet agents reduces the risk of recurrent cardiovascular fatal and nonfatal events, cardiovascular mortality, and total mortality in secondary prevention. In real life, however, effective implementation of these optimal treatments both in primary and secondary prevention is low, and thus their contribution to cardiovascular prevention is much lower than it could be, based on research data. One of the main barriers to the adequate implementation of these strategies is low adherence to the elevated number of pills, as adherence is adversely affected by the complexity of the prescribed treatment regimen, and can be considerably improved by treatment simplification. This review updates the findings provided by recent epidemiological and clinical studies favoring a polypill­based approach to cardiovascular prevention. The increased prevalence of patients with multiple cardiovascular risk factors and comorbidities provides the rationale for a therapeutic strategy based on a combination of drugs against different risk factors in a single pill. Pharmacologic studies have demonstrated that different cardiovascular drugs can be combined in a single pill with no loss of their individual efficacy, and this favors adherence to and persistence of treatment, as well as multiple risk factor control. Recently, a randomized clinical trial SECURE (Secondary Prevention of Cardiovascular Disease in the Elderly) has shown a significant, 30% reduction in cardiovascular events, and a 33% reduction in cardiovascular death in patients after myocardial infarction treated with a polypill, as compared with usual care, thus supporting the polypill use as an integral part of any cardiovascular prevention strategy.

Medication Non-Adherence in Rheumatology, Oncology and Cardiology: A Review of the Literature of Risk Factors and Potential Interventions.

Medication adherence is directly associated with health outcomes. Adherence has been reviewed extensively; however, most studies provide a narrow scope of the problem, covering a specific disease or treatment. This project's objective was to identify risk factors for non-adherence in the fields of rheumatology, oncology, and cardiology as well as potential interventions to improve adherence and their association with the risk factors. The project was developed in three phases and carried out by a Steering Committee made up of experts from the fields of rheumatology, oncology, cardiology, general medicine, and hospital and community pharmacy. In phase 1, a bibliographic review was performed, and the articles/reviews were classified according to the authors' level of confidence in the results and their clinical relevance. In phase 2, 20 risk factors for non-adherence were identified from these articles/reviews and agreed upon in Steering Committee meetings. In phase 3, potential interventions for improving adherence were also identified and agreed upon. The results obtained show that adherence is a dynamic concept that can change throughout the course of the disease, the treatments, and other factors. Educational interventions are the most studied ones and have the highest level of confidence in the authors' opinion. Information and education are essential to improve adherence in all patients.

Polypill Strategy in Secondary Cardiovascular Prevention.

BACKGROUND: A polypill that includes key medications associated with improved outcomes (aspirin, angiotensin-converting-enzyme [ACE] inhibitor, and statin) has been proposed as a simple approach to the secondary prevention of cardiovascular death and complications after myocardial infarction. METHODS: In this phase 3, randomized, controlled clinical trial, we assigned patients with myocardial infarction within the previous 6 months to a polypill-based strategy or usual care. The polypill treatment consisted of aspirin (100 mg), ramipril (2.5, 5, or 10 mg), and atorvastatin (20 or 40 mg). The primary composite outcome was cardiovascular death, nonfatal type 1 myocardial infarction, nonfatal ischemic stroke, or urgent revascularization. The key secondary end point was a composite of cardiovascular death, nonfatal type 1 myocardial infarction, or nonfatal ischemic stroke. RESULTS: A total of 2499 patients underwent randomization and were followed for a median of 36 months. A primary-outcome event occurred in 118 of 1237 patients (9.5%) in the polypill group and in 156 of 1229 (12.7%) in the usual-care group (hazard ratio, 0.76; 95% confidence interval [CI], 0.60 to 0.96; P = 0.02). A key secondary-outcome event occurred in 101 patients (8.2%) in the polypill group and in 144 (11.7%) in the usual-care group (hazard ratio, 0.70; 95% CI, 0.54 to 0.90; P = 0.005). The results were consistent across prespecified subgroups. Medication adherence as reported by the patients was higher in the polypill group than in the usual-care group. Adverse events were similar between groups. CONCLUSIONS: Treatment with a polypill containing aspirin, ramipril, and atorvastatin within 6 months after myocardial infarction resulted in a significantly lower risk of major adverse cardiovascular events than usual care. (Funded by the European Union Horizon 2020; SECURE ClinicalTrials.gov number, NCT02596126; EudraCT number, 2015-002868-17.).

Potential Molecular Targets of Oleanolic Acid in Insulin Resistance and Underlying Oxidative Stress: A Systematic Review.

Oleanolic acid (OA) is a natural triterpene widely found in olive leaves that possesses antioxidant, anti-inflammatory, and insulin-sensitizing properties, among others. These OA characteristics could be of special interest in the treatment and prevention of insulin resistance (IR), but greater in-depth knowledge on the pathways involved in these properties is still needed. We aimed to systematically review the effects of OA on the molecular mechanisms and signaling pathways involved in the development of IR and underlying oxidative stress in insulin-resistant animal models or cell lines. The bibliographic search was carried out on PubMed, Web of Science, Scopus, Cochrane, and CINHAL databases between January 2001 and May 2022. The electronic search produced 5034 articles but, after applying the inclusion criteria, 13 animal studies and 3 cell experiments were identified, using SYRCLE's Risk of Bias for assessing the risk of bias of the animal studies. OA was found to enhance insulin sensitivity and glucose uptake, and was found to suppress the hepatic glucose production, probably by modulating the IRS/PI3K/Akt/FoxO1 signaling pathway and by mitigating oxidative stress through regulating MAPK pathways. Future randomized controlled clinical trials to assess the potential benefit of OA as new therapeutic and preventive strategies for IR are warranted.

Lipophilic Bioactive Compounds Transported in Triglyceride-Rich Lipoproteins Modulate Microglial Inflammatory Response.

Microglial cells can contribute to Alzheimer's disease by triggering an inflammatory response that leads to neuronal death. In addition, the presence of amyloid-ß in the brain is consistent with alterations in the blood-brain barrier integrity and triglyceride-rich lipoproteins (TRL) permeation. In the present work, we used lab-made TRL as carriers of lipophilic bioactive compounds that are commonly present in dietary oils, namely oleanolic acid (OA), α-tocopherol (AT) and ß-sitosterol (BS), to assess their ability to modulate the inflammatory response of microglial BV-2 cells. We show that treatment with lab-made TRL increases the release and gene-expression of IL-1ß, IL-6, and TNF-α, as well as NO and iNOS in microglia. On the other hand, TRL revealed bioactive compounds α-tocopherol and ß-sitosterol as suitable carriers for oleanolic acid. The inclusion of these biomolecules in TRL reduced the release of proinflammatory cytokines. The inclusion of these biomolecules in TRL reduced the release of proinflammatory cytokines. AT reduced IL-6 release by 72%, OA reduced TNF-α release by approximately 50%, and all three biomolecules together (M) reduced IL-1ß release by 35% and TNF-α release by more than 70%. In addition, NO generation was reduced, with the inclusion of OA by 45%, BS by 80% and the presence of M by 88%. Finally, a recovery of the basal glutathione content was observed with the inclusion of OA and M in the TRL. Our results open the way to exploiting the neuro-pharmacological potential of these lipophilic bioactive compounds through their delivery to the brain as part of TRL.

Oleanolic Acid: Extraction, Characterization and Biological Activity.

Oleanolic acid, a pentacyclic triterpenoid ubiquitously present in the plant kingdom, is receiving outstanding attention from the scientific community due to its biological activity against multiple diseases. Oleanolic acid is endowed with a wide range of biological activities with therapeutic potential by means of complex and multifactorial mechanisms. There is evidence suggesting that oleanolic acid might be effective against dyslipidemia, diabetes and metabolic syndrome, through enhancing insulin response, preserving the functionality and survival of ß-cells and protecting against diabetes complications. In addition, several other functions have been proposed, including antiviral, anti-HIV, antibacterial, antifungal, anticarcinogenic, anti-inflammatory, hepatoprotective, gastroprotective, hypolipidemic and anti-atherosclerotic activities, as well as interfering in several stages of the development of different types of cancer; however, due to its hydrophobic nature, oleanolic acid is almost insoluble in water, which has led to a number of approaches to enhance its biopharmaceutical properties. In this scenario, the present review aimed to summarize the current knowledge and the research progress made in the last years on the extraction and characterization of oleanolic acid and its biological activities and the underlying mechanisms of action.

Unravelling data for rapid evidence-based response to COVID-19: a summary of the unCoVer protocol.

INTRODUCTION: unCoVer-Unravelling data for rapid evidence-based response to COVID-19-is a Horizon 2020-funded network of 29 partners from 18 countries capable of collecting and using real-world data (RWD) derived from the response and provision of care to patients with COVID-19 by health systems across Europe and elsewhere. unCoVer aims to exploit the full potential of this information to rapidly address clinical and epidemiological research questions arising from the evolving pandemic. METHODS AND ANALYSIS: From the onset of the COVID-19 pandemic, partners are gathering RWD from electronic health records currently including information from over 22 000 hospitalised patients with COVID-19, and national surveillance and screening data, and registries with over 1 900 000 COVID-19 cases across Europe, with continuous updates. These heterogeneous datasets will be described, harmonised and integrated into a multi-user data repository operated through Opal-DataSHIELD, an interoperable open-source server application. Federated data analyses, without sharing or disclosing any individual-level data, will be performed with the objective to reveal patients' baseline characteristics, biomarkers, determinants of COVID-19 prognosis, safety and effectiveness of treatments, and potential strategies against COVID-19, as well as epidemiological patterns. These analyses will complement evidence from efficacy/safety clinical trials, where vulnerable, more complex/heterogeneous populations and those most at risk of severe COVID-19 are often excluded. ETHICS AND DISSEMINATION: After strict ethical considerations, databases will be available through a federated data analysis platform that allows processing of available COVID-19 RWD without disclosing identification information to analysts and limiting output to data aggregates. Dissemination of unCoVer's activities will be related to the access and use of dissimilar RWD, as well as the results generated by the pooled analyses. Dissemination will include training and educational activities, scientific publications and conference communications.

Oleanolic Acid-Enriched Olive Oil Alleviates the Interleukin-6 Overproduction Induced by Postprandial Triglyceride-Rich Lipoproteins in THP-1 Macrophages.

Oleanolic acid (OA), a triterpene that is highly present in olive leaves, has been proposed as a component of functional foods for the prevention of metabolic syndrome, due to its anti-inflammatory activity. We analyzed the effects of OA on inflammatory parameters and signaling proteins in LPS-stimulated THP-1 macrophages. Thus, THP-1 macrophages were incubated with LPS for 48 h after pretreatment with OA at different concentrations. Pretreatment with OA was significantly effective in attenuating IL-6 and TNF-α overproduction induced by LPS in macrophages, and also improved the levels of AMPK-α. We also evaluated the effects of human triglyceride-rich lipoproteins (TRLs) derived from individuals consuming an OA-enriched functional olive oil. For this purpose, TRLs were isolated from healthy adolescents before, 2 and 5 h postprandially after the intake of a meal containing the functional olive oil or common olive oil, and were incubated with THP-1 macrophages. THP-1 macrophages incubated with TRLs isolated at 2 h after the consumption of the OA-enriched olive oil showed significant lower levels of IL-6 compared to the TRLs derived from olive oil. Our results suggest that OA might have potential to be used as a lipid-based formulation in functional olive oils to prevent inflammatory processes underlying metabolic syndrome in adolescents.

The Mevalonate Pathway, a Metabolic Target in Cancer Therapy.

A hallmark of cancer cells includes a metabolic reprograming that provides energy, the essential building blocks, and signaling required to maintain survival, rapid growth, metastasis, and drug resistance of many cancers. The influence of tumor microenviroment on cancer cells also results an essential driving force for cancer progression and drug resistance. Lipid-related enzymes, lipid-derived metabolites and/or signaling pathways linked to critical regulators of lipid metabolism can influence gene expression and chromatin remodeling, cellular differentiation, stress response pathways, or tumor microenviroment, and, collectively, drive tumor development. Reprograming of lipid metabolism includes a deregulated activity of mevalonate (MVA)/cholesterol biosynthetic pathway in specific cancer cells which, in comparison with normal cell counterparts, are dependent of the continuous availability of MVA/cholesterol-derived metabolites (i.e., sterols and non-sterol intermediates) for tumor development. Accordingly, there are increasing amount of data, from preclinical and epidemiological studies, that support an inverse association between the use of statins, potent inhibitors of MVA biosynthetic pathway, and mortality rate in specific cancers (e.g., colon, prostate, liver, breast, hematological malignances). In contrast, despite the tolerance and therapeutic efficacy shown by statins in cardiovascular disease, cancer treatment demands the use of relatively high doses of single statins for a prolonged period, thereby limiting this therapeutic strategy due to adverse effects. Clinically relevant, synergistic effects of tolerable doses of statins with conventional chemotherapy might enhance efficacy with lower doses of each drug and, probably, reduce adverse effects and resistance. In spite of that, clinical trials to identify combinatory therapies that improve therapeutic window are still a challenge. In the present review, we revisit molecular evidences showing that deregulated activity of MVA biosynthetic pathway has an essential role in oncogenesis and drug resistance, and the potential use of MVA pathway inhibitors to improve therapeutic window in cancer.

Prognostic implications of neutrophil-lymphocyte ratio in COVID-19.

BACKGROUND: The clinical presentation of COVID-19 ranges from a mild, self-limiting disease, to multiple organ failure and death. Most severe COVID-19 cases present low lymphocytes counts and high leukocytes counts, and accumulated evidence suggests that in a subgroup of patients presenting severe COVID-19, there may be a hyperinflammatory response driving a severe hypercytokinaemia which may be, at least in part, signalling the presence of an underlying endothelial dysfunction. In this context, available data suggest a prognostic role of neutrophil-lymphocyte ratio (NLR) in various inflammatory diseases and oncological processes. Following this rationale, we hypothesized that NLR, as a marker of endothelial dysfunction, may be useful in identifying patients with a poor prognosis in hospitalized COVID-19 cases. DESIGN: A retrospective observational study performed at Hospital Universitario HM Puerta del Sur, Madrid, Spain, which included 119 patients with COVID-19 from 1 March to 31 March 2020. Patients were categorized according to WHO R&D Expert Group. RESULTS: Forty-five (12.1%) patients experienced severe acute respiratory failure requiring respiratory support. Forty-seven (12.6%) patients died. Those with worse outcomes were older (P = .002) and presented significantly higher NLR at admission (P = .001), greater increase in Peak NLR (P < .001) and higher increasing speed of NLR (P = .003) compared with follow-up patients. In a multivariable logistic regression, age, cardiovascular disease and C-reactive protein at admission and Peak NLR were significantly associated with death. CONCLUSIONS: NLR is an easily measurable, available, cost-effective and reliable parameter, which continuous monitoring could be useful for the diagnosis and treatment of COVID-19.

Modulation of Lipid Transport and Adipose Tissue Deposition by Small Lipophilic Compounds.

Small lipophilic molecules present in foods of plant origin have relevant biological activities at rather low concentrations. Evidence suggests that phytosterols, carotenoids, terpenoids, and tocopherols can interact with different metabolic pathways, exerting beneficial effects against a number of metabolic diseases. These small molecules can modulate triacylglycerol absorption in the intestine and the biosynthesis of chylomicrons, the lipid carriers in the blood. Once in the bloodstream, they can impact lipoprotein clearance from blood, thereby affecting fatty acid release, incorporation into adipocytes and triglyceride reassembling and deposit. Consequently, some of these molecules can regulate pathophysiological processes associated to obesity and its related conditions, such as insulin resistance, metabolic syndrome and type-2 diabetes. The protective capacity of some lipophilic small molecules on oxidative and chemotoxic stress, can modify the expression of key genes in the adaptive cellular response, such as transcription factors, contributing to prevent the inflammatory status of adipose tissue. These small lipophilic compounds can be incorporated into diet as natural parts of food but they can also be employed to supplement other dietary and pharmacologic products as nutraceuticals, exerting protective effects against the development of metabolic diseases in which inflammation is involved. The aim of this review is to summarize the current knowledge of the influence of dietary lipophilic small biomolecules (phytosterols, carotenoids, tocopherols, and triterpenes) on lipid transport, as well as on the effects they may have on pathophysiological metabolic states, related to obesity, insulin resistance and inflammation, providing an evidence-based summary of their main beneficial effects on human health.

Estimation of the major cardiovascular events prevention with Inclisiran.

BACKGROUND AND AIMS: The ORION 10-11 trials have reported the efficacy of Inclisiran on low-density lipoprotein cholesterol (LDLc) reduction, and also suggested prevention of major cardiovascular events (MACE) incidence. METHODS: We have performed a meta-analysis of the available studies, involving PCSK9 inhibitors or Inclisiran for >6 months, that reported the incidence of MACE. The primary endpoint was MACE incidence, as reported in outcomes-based randomized clinical trials (OB-RCT) and non OB-RCT. Analyses were performed using fixed effect models and fractional polynomial regression. RESULTS: The meta-analysis included a total of 57,431 patients, 1592 treated with Inclisiran and 28,259 with PSCK9 inhibitors (17,244 with evolocumab and 11,015 with alirocumab). Baseline mean LDLc was 104.1 (12.9) mg globally. On-treatment mean LDLc was 40.1 (7.8) mg/dl and mean absolute LDLc reduction was 60.6 (10.3) mg/dl. A total of 5389 MACE were reported, 2482 in patients receiving the study drug and 2907 in patients assigned to placebo. Treatment was associated with OB-RCT and no heterogeneity was observed. The estimation of MACE reduction associated with LDLc reduction, adjusted by age, diabetes, hypertension and baseline LDLc, provided a linear trend in the risk of MACE and LDLc reduction that was linear and all studies fitted properly. CONCLUSIONS: The results of the ORION 10-11 trials are in concordance with results of trials involving treatment with PCSK9 inhibitors. The results of the ORION-4 trial will provide definite evidence on the effects of Inclisiran on MACE reduction.

Oleanolic Acid Exerts a Neuroprotective Effect Against Microglial Cell Activation by Modulating Cytokine Release and Antioxidant Defense Systems.

Microglia respond to adverse stimuli in order to restore brain homeostasis and, upon activation, they release a number of inflammatory mediators. Chronic microglial overactivation is related to neuroinflammation in Alzheimer's disease. In this work, we show that oleanolic acid (OA), a natural triterpene present in food and medicinal plants, attenuates the activation of BV2 microglial cells induced by lipopolysaccharide (LPS). Cell pretreatment with OA inhibited the release of IL-1ß, IL-6, TNF-α, and NO, which was associated with the downregulation of the expression of genes encoding for these cytokines and inducible nitric oxide synthase (iNOS), and the reinforcement of the endogenous antioxidant cell defense. These findings advocate considering OA as a novel neuroprotective agent to inhibit oxidative stress and inflammatory response in activated microglia associated with Alzheimer's disease.

Prevention of type 2 diabetes in prediabetic patients by using functional olive oil enriched in oleanolic acid: The PREDIABOLE study, a randomized controlled trial.

AIM: To assess whether the regular intake of an oleanolic acid (OA)-enriched olive oil is effective in the prevention of diabetes. METHODS: In the PREDIABOLE study, prediabetic individuals (impaired fasting glucose and impaired glucose tolerance) of both sexes (176 patients, aged 30-80 years) were randomized to receive 55 mL/day of OA-enriched olive oil (equivalent dose 30 mg OA/day) [intervention group (IG)] or the same oil not enriched [control group (CG)]. The main outcome was the incidence of new-onset type 2 diabetes in both groups. RESULTS: Forty-eight new diabetes cases occurred, 31 in the CG and 17 in the IG. The multivariate-adjusted hazard ratio was 0.45 (95% CI, 0.24-0.83) for the IG compared with the CG. Intervention-related adverse effects were not reported. CONCLUSIONS: The intake of OA-enriched olive oil reduces the risk of developing diabetes in prediabetic patients. The results of the PREDIABOLE study promote the use of OA in new functional foods and drugs for the prevention of diabetes in individuals at risk of developing it.