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Generation of Self-Induced Myocardial Ischemia in Large-Sized Cardiac Spheroids without Alteration of Environmental Conditions Recreates Fibrotic Remodeling and Tissue Stiffening Revealed by Constriction Assays.
Paz-Artigas, L, González-Lana, S, Polo, N, Vicente, P, Montero-Calle, P, Martínez, MA, Rábago, G, Serra, M, Prósper, F, Mazo, MM, et al
ACS biomaterials science & engineering. 2024;(2):987-997
Abstract
A combination of human-induced pluripotent stem cells (hiPSCs) and 3D microtissue culture techniques allows the generation of models that recapitulate the cardiac microenvironment for preclinical research of new treatments. In particular, spheroids represent the simplest approach to culture cells in 3D and generate gradients of cellular access to the media, mimicking the effects of an ischemic event. However, previous models required incubation under low oxygen conditions or deprived nutrient media to recreate ischemia. Here, we describe the generation of large spheroids (i.e., larger than 500 μm diameter) that self-induce an ischemic core. Spheroids were generated by coculture of cardiomyocytes derived from hiPSCs (hiPSC-CMs) and primary human cardiac fibroblast (hCF). In the proper medium, cells formed aggregates that generated an ischemic core 2 days after seeding. Spheroids also showed spontaneous cellular reorganization after 10 days, with hiPSC-CMs located at the center and surrounded by hCFs. This led to an increase in microtissue stiffness, characterized by the implementation of a constriction assay. All in all, these phenomena are hints of the fibrotic tissue remodeling secondary to a cardiac ischemic event, thus demonstrating the suitability of these spheroids for the modeling of human cardiac ischemia and its potential application for new treatments and drug research.
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Toward Prevention and Reduction of Alzheimer's Disease.
González-Madrid, A, Calfío, C, González, A, Lüttges, V, Maccioni, RB
Journal of Alzheimer's disease : JAD. 2023;(2):439-457
Abstract
Different investigations lead to the urgent need to generate validated clinical protocols as a tool for medical doctors to orientate patients under risk for a preventive approach to control Alzheimer's disease. Moreover, there is consensus that the combined effects of risk factors for the disease can be modified according to lifestyle, thus controlling at least 40% of cases. The other fraction of cases are derived from candidate genes and epigenetic components as a relevant factor in AD pathogenesis. At this point, it appears to be of critical relevance the search for molecular biomarkers that may provide information on probable pathological events and alert about early detectable risks to prevent symptomatic events of the disease. These precocious detection markers will then allow early interventions of non-symptomatic subjects at risk. Here, we summarize the status and potential avenues of prevention and highlight the usefulness of biological and reliable markers for AD.
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Exercise training-induced changes in exerkine concentrations may be relevant to the metabolic control of type 2 diabetes mellitus patients: A systematic review and meta-analysis of randomized controlled trials.
García-Hermoso, A, Ramírez-Vélez, R, Díez, J, González, A, Izquierdo, M
Journal of sport and health science. 2023;(2):147-157
Abstract
BACKGROUND This study investigates the effects of exercise training on exerkines in patients with type 2 diabetes mellitus to determine the optimal exercise prescription. METHODS A systematic search for relevant studies was performed in 3 databases. Randomized controlled trials investigating the effects of exercise training on at least one of the following exerkines were included: adiponectin, apelin, brain-derived neurotrophic factor, fetuin-A, fibroblast growth factor-21, follistatin, ghrelin, interleukin (IL)-6, IL-8, IL-10, IL-15, IL-18, leptin, myostatin, omentin, resistin, retinol-binding protein 4, tumor necrosis factor-α, and visfatin. RESULTS Forty randomized controlled trials were selected for data extraction (n = 2160). Exercise training induces changes in adiponectin, fetuin-A, fibroblast growth factor-21, IL-6, IL-10, leptin, resistin, and tumor necrosis factor-α levels but has no significant effects on apelin, IL-18, and ghrelin compared to controls. Physical exercise training favored large and positive changes in pooled exerkines (i.e., an overall effect size calculated from several exerkines) (Hedge's g = 1.02, 95% confidence interval (95%CI): 0.76-1.28), which in turn were related to changes in glycated hemoglobin (mean difference (MD) = -0.81%, 95%CI: -0.95% to -0.67%), fasting glucose (MD = -23.43 mg/dL, 95%CI: -30.07 mg/dL to -16.80 mg/dL), waist circumference (MD = -3.04 cm, 95%CI: -4.02 cm to -2.07 cm), and body mass (MD = -1.93 kg, 95%CI: -2.00 kg to -1.86 kg). Slightly stronger effects were observed with aerobic, resistance, or high-intensity interval protocols at moderate- to vigorous-intensity and with programs longer than 24 weeks that comprise at least 3 sessions per week and more than 60 min per session. CONCLUSION Exercise training represents an anti-inflammatory therapy and metabolism-improving strategy with minimal side effects for patients with type 2 diabetes mellitus.
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Novel Nutraceutical Compounds in Alzheimer Prevention.
Maccioni, RB, Calfío, C, González, A, Lüttges, V
Biomolecules. 2022;(2)
Abstract
Alzheimer's disease (AD) incidence is increasing worldwide at an alarming rate. Considering this increase, prevention efforts, stemming from scientific research, health education, and public policies, are critical. Clinical studies evidenced that healthy lifestyles along with natural multitarget and disease-modifying agents have a preventative impact on AD or mitigate symptoms in diagnosed patients. The pathological alterations of AD start 30 years before symptoms, and it is essential to develop the capacity to detect those changes. In this regard, molecular biomarkers that detect early pathological manifestations are helpful. Based on markers data, early preventive interventions could reduce more than 40% of AD cases. Protective actions include exercise, shown to induce neurogenesis, cognitive stimulation, intellectual-social activity, and nutrition among others. Mediterranean diet, preprobiotics, and nutraceuticals containing bioactive molecules with antioxidant and anti-inflammatory properties are relevant. Antiprotein aggregation molecules whose mechanisms were described are important. Anti-inflammatory agents with anti-aggregation properties that help to control cognitive impairment, include quercetin, biocurcumin, rosemarinic acid, and Andean shilajit. Anthocyanidins, e.g., delphinidin, malvidin, and natural flavonoids, are also included. Quercetin and hydroxy-tyrosol are antiaging molecules and could have anti-AD properties. We emphasize the relevance of nutraceuticals as a main actor in the prevention and/or control of dementia and particularly AD.
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Yeast as a biological platform for vitamin D production: A promising alternative to help reduce vitamin D deficiency in humans.
Kessi-Pérez, EI, González, A, Palacios, JL, Martínez, C
Yeast (Chichester, England). 2022;(9):482-492
Abstract
Vitamin D is an important human hormone, known primarily to be involved in the intestinal absorption of calcium and phosphate, but it is also involved in various nonskeletal processes (molecular, cellular, immune, and neuronal). One of the main health problems nowadays is the vitamin D deficiency of the human population due to lack of sun exposure, with estimates of one billion people worldwide with vitamin D deficiency, and the consequent need for clinical intervention (i.e., prescription of pharmacological vitamin D supplements). An alternative to reduce vitamin D deficiency is to produce good dietary sources of it, a scenario in which the yeast Saccharomyces cerevisiae seems to be a promising alternative. This review focuses on the potential use of yeast as a biological platform to produce vitamin D, summarizing both the biological aspects of vitamin D (synthesis, ecology and evolution, metabolism, and bioequivalence) and the work done to produce it in yeast (both for vitamin D2 and for vitamin D3 ), highlighting existing challenges and potential solutions.
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Glucose metabolism and AD: evidence for a potential diabetes type 3.
González, A, Calfío, C, Churruca, M, Maccioni, RB
Alzheimer's research & therapy. 2022;(1):56
Abstract
BACKGROUND Alzheimer's disease is the most prevalent cause of dementia in the elderly. Neuronal death and synaptic dysfunctions are considered the main hallmarks of this disease. The latter could be directly associated to an impaired metabolism. In particular, glucose metabolism impairment has demonstrated to be a key regulatory element in the onset and progression of AD, which is why nowadays AD is considered the type 3 diabetes. METHODS We provide a thread regarding the influence of glucose metabolism in AD from three different perspectives: (i) as a regulator of the energy source, (ii) through several metabolic alterations, such as insulin resistance, that modify peripheral signaling pathways that influence activation of the immune system (e.g., insulin resistance, diabetes, etc.), and (iii) as modulators of various key post-translational modifications for protein aggregation, for example, influence on tau hyperphosphorylation and other important modifications, which determine its self-aggregating behavior and hence Alzheimer's pathogenesis. CONCLUSIONS In this revision, we observed a 3 edge-action in which glucose metabolism impairment is acting in the progression of AD: as blockade of energy source (e.g., mitochondrial dysfunction), through metabolic dysregulation and post-translational modifications in key proteins, such as tau. Therefore, the latter would sustain the current hypothesis that AD is, in fact, the novel diabetes type 3.
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Influence of ejection fraction on biomarker expression and response to spironolactone in people at risk of heart failure: findings from the HOMAGE trial.
Ferreira, JP, Verdonschot, JAJ, Girerd, N, Bozec, E, Pellicori, P, Collier, T, Mariottoni, B, Cosmi, F, Hazebroek, M, Cuthbert, J, et al
European journal of heart failure. 2022;(5):771-778
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Abstract
AIMS: Left ventricular ejection fraction (LVEF) can provide haemodynamic information and may influence the response to spironolactone and other heart failure (HF) therapies. We aimed to study patient characteristics and circulating protein associations with LVEF, and whether LVEF influenced the response to spironolactone. METHODS AND RESULTS HOMAGE enrolled patients aged >60 years at high risk of developing HF with a LVEF ≥45%. Overall, 527 patients were randomized to either spironolactone or standard of care for ≈9 months, and 276 circulating proteins were measured using Olink® technology. A total of 364 patients had available LVEF determined by the Simpson's biplane method. The respective LVEF tertiles were: tertile 1: <60% (n = 122), tertile 2: 60%-65% (n = 121), and tertile 3: >65% (n = 121). Patients with a LVEF >65% had smaller left ventricular chamber size and volumes, and lower natriuretic peptide levels. Compared to patients with a LVEF <60%, those with LVEF >65% had higher levels of circulating c-c motif chemokine ligand-23 and interleukin-8, and lower levels of tissue plasminogen activator, brain natriuretic peptide (BNP), S100 calcium binding protein A12, and collagen type I alpha 1 chain (COL1A1). Spironolactone significantly reduced the circulating levels of BNP and COL1A1 without significant treatment-by-LVEF heterogeneity: BNP change β = -0.36 log2 and COL1A1 change β = -0.16 log2 (p < 0.0001 for both; interaction p > 0.1 for both). Spironolactone increased LVEF from baseline to month 9 by 1.1% (p = 0.007). CONCLUSION Patients with higher LVEF had higher circulating levels of chemokines and inflammatory markers and lower levels of stretch, injury, and fibrosis markers. Spironolactone reduced the circulating levels of natriuretic peptides and type 1 collagen, and increased LVEF.
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Alzheimer's Disease and Tau Self-Assembly: In the Search of the Missing Link.
González, A, Singh, SK, Churruca, M, Maccioni, RB
International journal of molecular sciences. 2022;(8)
Abstract
Alzheimer's disease (AD) is a multifactorial neurodegenerative disease characterized by progressive cognitive impairment, apathy, and neuropsychiatric disorders. Two main pathological hallmarks have been described: neurofibrillary tangles, consisting of tau oligomers (hyperphosphorylated tau) and Aβ plaques. The influence of protein kinases and phosphatases on the hyperphosphorylation of tau is already known. Hyperphosphorylated tau undergoes conformational changes that promote its self-assembly. However, the process involving these mechanisms is yet to be elucidated. In vitro recombinant tau can be aggregated by the action of polyanions, such as heparin, arachidonic acid, and more recently, the action of polyphosphates. However, how that process occurs in vivo is yet to be understood. In this review, searching the most accurate and updated literature on the matter, we focus on the precise molecular events linking tau modifications, its misfolding and the initiation of its pathological self-assembly. Among these, we can identify challenges regarding tau phosphorylation, the link between tau heteroarylations and the onset of its self-assembly, as well as the possible metabolic pathways involving natural polyphosphates, that may play a role in tau self-assembly.
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Alimentary and Pharmaceutical Approach to Natural Antimicrobials against Clostridioides difficile Gastrointestinal Infection.
Tortajada-Girbés, M, Rivas, A, Hernández, M, González, A, Ferrús, MA, Pina-Pérez, MC
Foods (Basel, Switzerland). 2021;(5)
Abstract
Incidence of Clostridioides difficile infection (CDI) has been increasing in recent decades due to different factors, namely (i) extended use of broad-spectrum antibiotics, (ii) transmission within asymptomatic and susceptible patients, and (iii) unbalanced gastrointestinal microbiome and collateral diseases that favor C. difficile gastrointestinal domination and toxin production. Although antibiotic therapies have resulted in successful control of CDI in the last 20 years, the development of novel strategies is urged in order to combat the capability of C. difficile to generate and acquire resistance to conventional treatments and its consequent proliferation. In this regard, vegetable and marine bioactives have emerged as alternative and effective molecules to fight against this concerning pathogen. The present review examines the effectiveness of natural antimicrobials from vegetable and algae origin that have been used experimentally in in vitro and in vivo settings to prevent and combat CDI. The aim of the present work is to contribute to accurately describe the prospective use of emerging antimicrobials as future nutraceuticals and preventive therapies, namely (i) as dietary supplement to prevent CDI and reduce CDI recurrence by means of microbiota modulation and (ii) administering them complementarily to other treatments requiring antibiotics to prevent C. difficile gut invasion and infection progression.
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COVID-19 vaccination in patients with heart failure: a position paper of the Heart Failure Association of the European Society of Cardiology.
Rosano, G, Jankowska, EA, Ray, R, Metra, M, Abdelhamid, M, Adamopoulos, S, Anker, SD, Bayes-Genis, A, Belenkov, Y, Gal, TB, et al
European journal of heart failure. 2021;(11):1806-1818
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Abstract
Patients with heart failure (HF) who contract SARS-CoV-2 infection are at a higher risk of cardiovascular and non-cardiovascular morbidity and mortality. Regardless of therapeutic attempts in COVID-19, vaccination remains the most promising global approach at present for controlling this disease. There are several concerns and misconceptions regarding the clinical indications, optimal mode of delivery, safety and efficacy of COVID-19 vaccines for patients with HF. This document provides guidance to all healthcare professionals regarding the implementation of a COVID-19 vaccination scheme in patients with HF. COVID-19 vaccination is indicated in all patients with HF, including those who are immunocompromised (e.g. after heart transplantation receiving immunosuppressive therapy) and with frailty syndrome. It is preferable to vaccinate against COVID-19 patients with HF in an optimal clinical state, which would include clinical stability, adequate hydration and nutrition, optimized treatment of HF and other comorbidities (including iron deficiency), but corrective measures should not be allowed to delay vaccination. Patients with HF who have been vaccinated against COVID-19 need to continue precautionary measures, including the use of facemasks, hand hygiene and social distancing. Knowledge on strategies preventing SARS-CoV-2 infection (including the COVID-19 vaccination) should be included in the comprehensive educational programmes delivered to patients with HF.