Search Results (1,361)

Erebosis is a newly described form of cell death but has been reported only in the gut enterocytes of Drosophila, a group of fast turnover cells. Angiotensin-converting enzyme 2 (ACE2) accumulation in cells is a biomarker for erebotic cells. Brain cell loss is a characteristic of patients with Alzheimer’s disease (AD), the leading neurodegenerative disease. The objectives of this study are to determine whether there is erebosis in the mammalian brain. Here we show that there is more ACE2 staining in the hippocampus of old wild-type (C57BL/6J) male mice, female mice with AD neuropathology (3xTg-AD mice), and human AD sufferers. Some ACE2 positive cells have fragmented or small nuclei, lose NeuN staining and are positive for TUNEL staining, indicators for cell injury/dying. ACE2 positive cells are neurons in the hippocampus and are often positive for phospho-tau in the mice with AD neuropathology. Phospho-tau injected into the hippocampus of wild-type young adult mice increases its ACE2 expression. Some ACE2 staining is extracellular. Our results suggest that erebosis may exist in the mammalian brain and may be increased with aging and AD neuropathology. This form of death may occur in the long-lasting cells like neurons and can be activated by phospho-tau in the brain. Our findings highlight the therapeutic potential of regulating erebosis for attenuating brain aging and AD neuropathology. Full article

Background/Objectives: Pre-discharge NT-proBNP levels may serve as a helpful tool in the algorithm of assessing the long-term risk of mortality after a hospitalization for symptomatic heart failure (HF). The goals were: (a) to identify a cut-off for NT-proBNP concentrations for predicting the two-year all-cause mortality in our sample of patients, and (b) to identify risk factors associated with NT-proBNP concentrations being higher than this cut-off. Methods: The present prospective study included 96 patients diagnosed with symptomatic HF with left ventricular ejection fraction (LVEF) < 50%, who were followed for up to 2 years post-hospital discharge. Results: Levels of pre-discharge NT-proBNP were found to be predictive of all-cause mortality. We determined that an NT-proBNP cut-off score of 8700 pg/mL may predict with 75.8% sensitivity and 70.1% specificity a 4.6-fold increase in mortality risk over a period of two years in our study sample, 95% CI (2–10.8), p = 0.001. Predictors of NT-proBNP concentrations > 8700 pg/mL included: older age, OR 4.73, 95% CI (1.74–12.85), p = 0.002; lack of angiotensin converting enzyme inhibitor (ACE-I) treatment, OR 0.3, 95% CI (0.12–0.74), p = 0.009; low systolic blood pressure (SBP) at admission, OR 3.4, 95% CI (1.36–8.49), p = 0.009; and low serum hemoglobin at admission, OR 3.2, 95% CI (1.38–7.46), p = 0.007. Conclusions: NT-proBNP may serve as a helpful tool for predicting mortality after an episode of HF decompensation, thus allowing the implementation of appropriate long-term monitoring and treatment. Particular attention should be paid to older patients without ACE-I medication, who had SBP < 120 mmHg at admission, and/or low levels of serum hemoglobin—as these patients are more likely to have pre-discharge NT-proBNP concentrations higher than the cut-off. These findings have implications for the long-term community follow-up of patients with HF. Full article

Aging is characterized by a progressive decline in physiological function that impairs performance and increases vulnerability to disease and mortality. Delaying this deterioration is key to promoting healthy aging. Age-associated functional decline is closely linked to alterations in intermediary metabolism, including disrupted lipid metabolism and impaired mitochondrial function. Counteracting these metabolic changes, particularly those affecting basal metabolic rate and energy utilization, may be a feasible strategy to extend healthspan. The Renin-Angiotensin System (RAS), which controls blood pressure through Angiotensin II, an octapeptide hormone generated from Angiotensin I by Angiotensin-Converting Enzyme (ACE), has been identified as a potential target for aging therapies. ACE inhibitors, such as the commonly prescribed vasodilator lisinopril, have been shown to exert beneficial effects on healthspan. Disentangling their systemic effects from direct cellular actions on intermediary metabolism is challenging in humans but can be pursued in model organisms. Drosophila melanogaster expresses two ortholog of mammalian ACE, Ance and Acer, which have diverged to acquire different functions. Since fundamental cellular processes are evolutionarily conserved and flies have an open circulatory system, Drosophila provides a versatile model for translational studies on ACE inhibition and aging. Recent studies in Drosophila reveal sex-, age-, and genetic background-specific effects of lisinopril on metabolic rates and aging-related organismal phenotypes. Integrating preclinical findings from Drosophila with clinical studies will be essential to define the therapeutic potential of RAS inhibition in extending lifespan and delaying aging. Full article

Adipocytes can be infected by SARS-CoV-2, potentially contributing to the obesity-associated severity of COVID-19. Circumstantial evidence points to angiotensin-converting enzyme 2 (ACE2) as the necessary receptor for adipocyte infection, but this has not been demonstrated experimentally. Using differentiated immortalized human preadipocyte lines that we developed, we found that visceral adipocytes express higher levels of ACE2 and are more susceptible to SARS-CoV-2 spike (S)-mediated luciferase-VSV infection than subcutaneous adipocytes. Overexpression of ACE2 significantly increased infection, whereas knockout of ACE2 significantly decreased S-mediated infection. Visceral adipocytes at baseline were susceptible to infection by SARS-CoV-2 (Delta variant); however, increased levels of viral transcript with time were not apparent. ACE2 knockout significantly decreased the susceptibility of visceral adipocytes to SARS-CoV-2, whereas overexpression of ACE2 resulted in increased SARS-CoV-2 infection and was associated with increased viral transcript levels with time, as well as induction of IL6, a marker of the proinflammatory response. Our results demonstrate that ACE2 confers susceptibility to SARS-CoV-2 infection of visceral adipocytes. Higher levels of ACE2 in these cells may play a role in establishment of infection and a proinflammatory response, potentially leading to pathogenesis. Full article

Despite numerous research efforts and several effective vaccines and therapies developed against coronavirus disease 2019 (COVID-19), drug repurposing remains an attractive alternative approach for treatment of SARS-CoV-2 variants and other viral infections that may emerge in the future. Cellular polyamines support viral propagation and tumor growth. Here we tested the antiviral activity of two polyamine metabolism-targeting drugs, an irreversible inhibitor of polyamine biosynthesis, α-difluoromethylornithine (DFMO), and a non-steroidal anti-inflammatory drug (NSAID), Sulindac, which have been previously evaluated for colon cancer chemoprevention. The drugs were tested as single agents and in combination in the human Calu-3 lung adenocarcinoma and Caco-2 colon adenocarcinoma cell lines and the K18-hACE2 transgenic mouse model of severe COVID-19. In the infected human cell lines, the DFMO/Sulindac combination significantly suppressed SARS-CoV-2 N1 Nucleocapsid mRNA by interacting synergistically when cells were pretreated with drugs and additively when treatment was applied to the infected cells. The Sulindac alone and DFMO/Sulindac combination treatments also suppressed the expression of the viral Spike protein and the host angiotensin-converting enzyme 2 (ACE2). In K18-hACE2 mice, the antiviral activity of DFMO and Sulindac as single agents and in combination was tested as prophylaxis (drug supplementation started 7 days before infection) or as treatment (drug supplementation started 24 h post-infection) at the doses equivalent to patient chemoprevention trials (835 ppm DFMO and 167 ppm Sulindac). The drugs’ antiviral activity in vivo was evaluated by measuring the clinical (survival rates and clinical scores), viral (viral load and virus infectivity), and biochemical (plasma polyamine, Sulindac, and Sulindac metabolite levels) endpoints. Prophylaxis with DFMO and Sulindac as single agents significantly increased survival rates in the young male mice (p = 0.01 and p = 0.027, respectively), and the combination was effective in the aged male mice (p = 0.042). Young female mice benefited the most from the prophylaxis with Sulindac alone (p = 0.001) and the DFMO/Sulindac combination (p = 0.018), while aged female mice did not benefit significantly from any intervention. Treatment of SARS-CoV-2-infected animals with DFMO or/and Sulindac did not significantly improve their survival rates. Overall, our studies demonstrated that DFMO and Sulindac administration as the prophylaxis regimen provided strong protection against the lethal outcome of SARS-CoV-2 infection and that male mice benefited more from the polyamine-targeted antiviral treatment than female mice. Our findings underscore the importance of evaluation of the antiviral activity of the drugs in the context of sex and age. Full article

There is increasing interest in the health-promoting potential of plant protein-derived peptides for managing metabolic disorders. This study investigated the impact of pepsin digestion on pre-hydrolysed versus non-hydrolysed pea protein. Pepsin digestion resulted in a higher degree of hydrolysis in pre-hydrolysed samples (64%) compared to the non-hydrolysed samples (~40%). The pepsin hydrolysates from the pre-hydrolysed protein showed stronger inhibition of key metabolic enzymes compared to non-hydrolysed samples. After ultrafiltration to enrich peptides <10 kDa, inhibition of α-amylase, α-glucosidase, and ACE was markedly enhanced, achieving a maximum of 44.5%, 54% and 95%, respectively. Peptidomic analysis identified unique peptide sequences in the ultrafiltered pre-hydrolysed fraction, in silico prediction confirmed their bioactive potential. These findings demonstrate enhanced bioactivity in pre-hydrolysed pea protein samples following pepsin hydrolysis, which was most evident in the ultrafiltrated fractions. Overall, this approach highlights the relevance of enzymatic hydrolysis and peptide enrichment strategies in developing functional ingredients to support glucose regulation and cardiovascular health. Full article

Heparan sulfate proteoglycans serve as initial attachment sites for several viruses and bacteria. Recent studies suggest that SARS-CoV-2 similarly exploits these glycosaminoglycans, facilitating conformational changes in the spike protein that promote the interaction between the receptor-binding domain (S1-RBD) and the cellular angiotensin-converting enzyme 2 receptor (ACE2), thereby triggering the virus internalization process. The molecular details that drive this process, particularly the co-receptor role of heparan sulfate (HS), remain incompletely understood. The interaction between an HS hexasaccharide (hexa) and the N343 glycosylated S1-RBD of the wild-type (WT) and Omicron variant of SARS-CoV-2 was investigated. The conformational properties of hexa with these S1-RBDs in unbound and bound states are explored using multiple independent MD simulations; the protein binding epitope of hexa, as well as the details of its interaction with S1-RBD of the Omicron variant, are characterized by comparing experimental and theoretical ¹H STD NMR signals. This investigation identifies the role played by the glycosyl moiety at N343 in potentially affecting this interaction in both WT and Omicron S1-RBD, explaining the observed low specificity and multi-modal nature of the interaction between HS oligosaccharides and these S1-RBDs. Full article

Damaging mutations of the Angiotensin I-converting enzyme (ACE) that result in low ACE levels may increase the risk of developing late-onset Alzheimer’s disease (AD). We quantified blood ACE levels in EDTA-plasma from 147 subjects with 23 different heterozygous ACE mutations (and 70 controls) and estimated the effect of these mutations on ACE phenotype, using a set of monoclonal antibodies (mAbs) to ACE and two ACE substrates. We identified several mutations in both ACE domains (including the most frequent ACE mutation, Y215C), which led to decreased ACE levels in the blood, and thus could be considered as putative risk factors for late-onset AD. The precipitation of several ACE mutants (Q259R, A725P, C734Y) by specific mAbs changed significantly, and therefore, these mAbs could be markers of these mutations. Analysis of 50 of the most frequent ACE mutations demonstrates that more than 1.5% of the adult population may have mutations which lead to decreased ACE levels, and thus, the role of low ACE levels in the development of AD may be underappreciated. Intriguingly, statistical and cluster analyses of longevity patients revealed trends towards higher frequency of cognitive impairment among affected individuals with damaging ACE mutations. Systematic analysis of blood ACE levels in patients with various ACE mutations identifies individuals with low blood ACE levels who may be at increased risk for late-onset AD. Patients with transport-deficient ACE mutations theoretically could benefit from therapeutic treatment with a combination of chemical and pharmacological chaperones and proteasome inhibitors, as was demonstrated previously on a cell model of the transport-deficient ACE mutation Q1069R. Moreover, clinical association analysis suggests a trend linking damaging ACE mutations with increased risk of cognitive impairment. Full article

Background/Objectives: This systematic review aimed to gather the most recent evidence regarding the link between genetic polymorphisms and physical performance in team sports, with a focus on the practical utility of this information for athlete selection, training personalization, and injury prevention. Methods: Sixteen studies published between 2018 and 2025 were analyzed and selected from six international databases, in accordance with the PRISMA guideline. Only English-language studies were included, which evaluated active athletes in team sports and investigated associations between genetic variations, such as Actinin Alpha 3 (ACTN3 R577X), Angiotensin I Converting Enzyme (ACE I/D), Peroxisome Proliferator-Activated Receptor Alpha (PPARA), Interleukin 6 (IL6), and Nitric Oxide Synthase 3 (NOS3), and physical performance parameters. The methodological quality of the studies was assessed using the Q-Genie tool, with all studies scoring over 45 across all 11 items, indicating high quality. Results: The ACTN3 and ACE genes stood out due to their consistent association with traits such as strength, speed, endurance, and recovery capacity. Other genes, such as PPARA, Fatty Acid Amide Hydrolase (FAAH), Angiotensinogen (AGT), and NOS3, complemented this genetic profile by being involved in the regulation of energy metabolism and injury predisposition. An increasing number of studies have begun to adopt cumulative genotype scores, suggesting a shift from a monogenic approach to complex predictive models. Conclusions: The integration of genetic profiling into the evaluation and management of athletes in team sports is becoming increasingly relevant. Although current evidence supports the applicability of these markers, robust future research conducted under standardized conditions is necessary to validate their use in sports practice and to ensure sound ethical standards. Full article

Edible mushrooms represent great promise for the future of food and medicine due to their excellent nutritional, functional, and therapeutic properties. Macrofungi synthesize numerous bioactive compounds, among which proteins stand out for their remarkable diversity, both in terms of structure and their nutritional and functional roles. Fungi from the phylum Basidiomycota have a high protein content, characterized by a complete and balanced amino acid composition. Proteins and peptides from mushrooms have both nutritional and functional roles, with numerous health benefits, such as antimicrobial, antiviral, antioxidant, anticancer, hypotensive, angiotensin-converting enzyme (ACE) inhibition, immunomodulatory, and enzymatic activities. Functional proteins include lectins, immunomodulatory proteins, enzymes (laccase, cellulase, ribonuclease), enzyme inhibitors, ribosome-inactivating proteins, and hydrophobins. In addition to traditional cultivation, mushrooms can be grown as mycelium on solid substrates or in submerged culture, followed by protein separation and extraction. The main trends in protein biosynthesis from Basidiomycota involve both improving the properties of the producing strains and optimizing the cultivation methods in submerged culture and on solid substrates. Moreover, new techniques in the fields of genomics, proteomics, and metabolomics will enable increasingly promising results. This paper provides a systematic overview of the types and properties of proteins from edible mushrooms, with a focus on the main beneficial effects of their consumption. Full article

Chronic inflammatory conditions often involve the dysregulation of key enzymes, including serine proteases such as transmembrane serine protease 2 (TMPRSS2) and the angiotensin converting enzyme 2 (ACE2), which are key proteins implicated in the cellular entry mechanism of SARS-CoV-2. It remains uncertain whether the gastrointestinal symptoms observed in COVID-19 patients result from direct viral infection of the gastrointestinal tract, a process that may be exacerbated by altered expression of ACE2 or TMPRSS2. In this review, we explore the interplay among ACE2 and TMPRSS2 in the context of inflammatory bowel disease (IBD), including their roles in disease pathology and response to therapy. We also examine methodological approaches for assessing whether protease alterations contribute to increased susceptibility to infection, considering that TMPRSS2 exists in inactive (zymogen) and active forms. Furthermore, while membrane-bound ACE2 facilitates viral entry, soluble ACE2 fragments may act as decoys, preventing virus–receptor interaction. Therefore, the interpretation of changes in full-length versus cleaved forms of ACE2 and related enzymes is critical for understanding vulnerability to SARS-CoV-2 infection. Full article

The inflammatory response plays a central role in the pathophysiology of various chronic diseases such as periodontitis, type 2 diabetes mellitus (T2DM), and coronavirus disease 2019 (COVID-19), whose coexistence is associated with an increase in clinical complications and a more severe and serious course of these diseases. Current evidence on the interrelationship between periodontitis, T2DM, and COVID-19 remains insufficient, highlighting the need for further research to elucidate these associations. The main aim of this narrative review is to provide the current landscape of the most relevant aspects of the interrelationship between periodontitis, T2DM, and COVID-19. This narrative review was carried out through a specialized, exhaustive, and structured search of published studies indexed in the electronic databases PubMed and LILACS, for the inclusion of studies in English and Spanish, respectively, without date restriction. A search strategy was performed using the Boolean operators AND, OR, and NOT, with the following DeCS/MeSH terms: “periodontal disease”, “periodontitis”, “type 2 diabetes mellitus”, “SARS-CoV-2”, and “COVID-19”. A variety of articles were included, focusing on the most relevant aspects of the interrelationship between periodontitis, T2DM, and COVID-19. Findings suggest that inflammation is a unifying mechanism, which leads to the severity of these conditions through four shared axes: (1) a clinicopathological axis involving systemic manifestations; (2) an axis associated with metabolic alterations linked to glycemic dysregulation; (3) an axis related to enzyme overexpression linked to altered angiotensin-converting enzyme (ACE)-2 expression and glucose metabolism; and (4) an inflammatory axis. These synergistic interactions can cause these three diseases to mutually enhance each other, creating a vicious cycle, worsening the patient’s health. Full article

Background: Sacubitril/Valsartan is a first-line treatment for heart failure with reduced ejection fraction (HFrEF) according to international guidelines. However, achieving the target doses of guideline-directed medical therapy (GDMT) remains a challenge in clinical practice and its efficacy at suboptimal dose (<200 mg/day) versus angiotensin-converting enzyme (ACE) inhibitors remains debated. Our objective was to evaluate the titration of Sacubitril/Valsartan within 3 months of hospital discharge in patients with HFrEF. Methods: A cross-sectional study was conducted in a secondary care hospital in Geneva, Switzerland. Patients hospitalized between 2020 and 2022 with HFrEF, discharged with Sacubitril/Valsartan, were included. Physicians managing patients discharged with a Sacubitril/Valsartan dose of less than 200 mg/day were contacted and asked to complete a structured 7-item questionnaire regarding dose adjustments within the first 3 months following hospital discharge. The primary outcome was the proportion of patients who did not achieve GDMT doses of Sacubitril/Valsartan, along with reasons for inadequate titration. Results: Overall, 30 patients out of 79 (38%, 95% confidence interval [27–49%]) had not been titrated to an effective dose of Sacubitril/Valsartan 3 months after hospitalization. Of these thirty patients, the primary reason for not titrating cited by their practitioners (n = 27) was that titration was perceived to be within the cardiologist’s scope of responsibility (15/27, 56%). While most physicians (66%) knew the target doses for Sacubitril/Valsartan, 83% of them were unaware that the clinical benefit of sacubitril/valsartan at doses below 50% of the target compared to ACE inhibitors remains uncertain and is not well supported by current evidence. Conclusions: In this cohort, more than a third of patients with HFrEF were not titrated to guideline-recommended target doses of sacubitril/valsartan within 3 months of hospital discharge. This finding raises questions about the clinical and economic value of initiating sacubitril/valsartan without subsequent dose optimization, especially given the uncertainty surrounding the efficacy of suboptimal dosing compared to ACE inhibitors. Full article

Background/Objectives: Diabetic neuropathy (DN) is one of the most common and disabling complications of diabetes mellitus (DM), affecting motor, sensory, and autonomic nerves. Genetic factors, particularly polymorphisms in the Angiotensin-converting enzyme (ACE) gene, have been proposed as contributors to DN susceptibility. This study aimed to synthesize the scientific evidence on ACE gene polymorphisms and their association with DN through a scoping review combined with scientometric analysis. Methods: A comprehensive search of PubMed, Scopus, and Web of Science was performed in February 2025, following JBI and PRISMA-ScR guidelines. Observational studies involving individuals with DN and the genotyping of ACE polymorphisms were included. Scientometric mapping was conducted using the Bibliometrix package in RStudio to identify publication trends and key thematic terms. Results: From 100 screened articles, 11 met the inclusion criteria. Most studies (72.7%) addressed diabetic peripheral neuropathy, while 27.3% investigated cardiac autonomic neuropathy. All studies analyzed the I/D polymorphism in intron 16 of the ACE gene. The D allele and DD genotype were associated with increased susceptibility to DN in over half of the studies (6/11), while the II genotype was reported as protective in 3/11. Findings varied by ethnicity and study design. The scientometric analysis identified ‘peripheral diabetic neuropathy’, type 2 diabetes’, and ‘ACE gene polymorphism’ as the most frequently co-occurring terms, indicating that research on this topic has been concentrated around these themes, while showing limited diversity in geographic origin and scope. Conclusions: ACE I/D polymorphism appears to modulate susceptibility to DN, though interethnic variability and methodological heterogeneity challenge definitive conclusions. Broader, standardized studies are needed to validate its utility as a predictive biomarker. Full article

Background and Clinical Significance: Arterial and venous thromboses are typically distinct clinical entities, each governed by unique pathophysiological mechanisms. The concurrent manifestation of both, particularly in the setting of massive pulmonary embolism (PE), is exceptionally rare and poses significant diagnostic and therapeutic challenges. Case Presentation: This report describes a 61-year-old male with well-controlled hypertension and type 2 diabetes who developed extensive thromboses involving deep vein thrombosis (DVT) of the right popliteal vein, arterial thrombosis of the left iliac artery, and massive PE. The patient was initially managed conservatively, in accordance with the European Society of Cardiology (ESC) 2019 Guidelines for Acute PE, using unfractionated heparin (UFH), low-molecular-weight heparin, a direct oral anticoagulant (DOAC), and adjunctive therapy. This approach was chosen due to the absence of hemodynamic instability. However, given failed percutaneous revascularization and persistent arterial occlusion, surgical thromboendarterectomy (TEA) was ultimately required. Post hoc genetic testing was prompted by the complex presentation in the absence of classical provoking factors—such as trauma, surgery, malignancy, or antiphospholipid syndrome—consistent with recommendations for selective thrombophilia testing in atypical or severe cases. The analysis revealed four thrombophilia-associated polymorphisms: heterozygous Factor V Leiden (FVL; R506Q genotype), Plasminogen Activator Inhibitor-1 (PAI-1; 4G/5G genotype), Methylenetetrahydrofolate reductase (MTHFR; c.677C > T genotype), and homozygous Angiotensin-Converting Enzyme Insertion/Deletion (ACE I/D; DD genotype). Conclusions: While each variant has been individually associated with thrombotic risk, their co-occurrence in a single patient with simultaneous arterial and venous thromboses has not, to our knowledge, been previously documented. This case underscores the potential for gene–gene interactions to amplify thrombotic risk, even in the presence of variants traditionally considered to confer only modest to moderate risk. It highlights the need for a multidisciplinary approach and raises questions regarding pharmacogenetics, anticoagulation, and future research into cumulative genetic risk in complex thrombotic phenotypes. Full article