Search Results (955)

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

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

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

Heat shock protein 60 (Hsp60) plays a crucial role in cellular homeostasis and stress responses. Recent evidence highlights its involvement in COVID-19 pathophysiology, particularly in immune modulation, inflammation, and endothelial dysfunction. Extracellular Hsp60 can interact with Toll-like receptors, amplifying inflammatory responses and contributing to cytokine storm and tissue damage. Additionally, since the presence of several common epitopes with SARS-CoV-2 proteins, its role in molecular mimicry suggests a potential link also to post-infectious autoimmune disorders. Hsp60 has also been implicated in endothelial damage and thromboembolic complications observed in severe COVID-19 cases. Beyond its pathogenic roles, Hsp60 could emerge as a potential biomarker for disease severity as well as a target for therapeutic strategies aimed at modulating immune responses. Finally, the structural similarity with SARS-CoV-2 proteins raises important considerations regarding both vaccine safety and the unexpected potential for anti-tumor immunity. This review critically examines the multifaceted roles of Hsp60 in COVID-19, specifically from a morpho-functional point of view, highlighting its implications in disease progression, post-viral complications, and therapeutic opportunities. Full article

Proteases constitute one of the largest sub-classes of enzymes, accounting for ca. 2% of the proteins encoded in the human genome. They play a key role in protein degradation and signaling, regulating a variety of physiological processes. Dysregulation of their activity is associated with various pathological conditions like cancer, neurodegenerative disorders, inflammatory or cardiovascular diseases. Protease activity can be controlled by regulating enzyme concentrations, but also by inhibitors, molecules that modulate enzyme function, inspiring the development of small molecule protease inhibitors for therapeutic purposes. Protease inhibitors can be designed from the corresponding substrates by isostere replacement at the scissile bond. This process yields a first-generation of inhibitors that usually exhibit poor drug-like profiles that need subsequently be improved to generate a second-generation, by smoothing their peptide-like features. This process is reviewed in the present report and exemplified in the successful discovery stories of different inhibitors that correspond to four types of proteases, including the angiotensin converting enzyme (metalloprotease); HIV protease (aspartate protease); thrombin (serine protease) and the proteasome (threonine protease). A detailed description of the stories behind their design from their initial discovery to the final product is described in this report. Moreover, despite successful discovery stories, the challenges associated with designing novel protease inhibitors are examined. Finally, the relevance of these drugs in the present drug market is also reported. Full article

Background/Objectives: Angiotensin receptor–neprilysin inhibitor (ARNI) has a well-established advantage over angiotensin-converting enzyme inhibitor or angiotensin receptor blocker (ACEI/ARB) therapy in patients (pts) with heart failure with reduced ejection fraction (HFrEF), but in pts after acute myocardial infarction (AMI) with left ventricular (LV) systolic dysfunction, the advantage of ARNI has not been clearly proven. The efficacy of ARNI is compared with that of ACEI/ARB therapy in patients with their first AMI in terms of improvement of post-infarction LV systolic function. Methods: The study was conducted as a retrospective one-center cross-sectional analysis. Overall, 1473 pts (990 M, median age 71 [64; 77]) with AMI (their first AMI, complete coronary revascularization, no prior coronary revascularization or history of HF) hospitalized in 2022–2024 were enrolled in a retrospective cross-sectional analysis. The study population was categorized into pts receiving ARNI and ACEI/ARB. Then, based on the ARNI subgroup, matching that included age, sex, and LV ejection fraction (LVEF) was performed by using the 1:1 nearest neighbor method without returning. Finally, two groups (ARNI vs. ACEI/ARB) of 30 pts were obtained and analyzed at baseline and at a 6-week follow-up. The improvement of post-infarction LV systolic function was obtained in terms of LVEF, ΔLVEF, and relative ΔLVEF values (ΔLVEF/baseline LVEF). Results: The comparison of baseline characteristics revealed borderline lower initial LVEF (30 vs. 36%, p = 0.076) and a higher frequency of SGLT-2 inhibitor use (70% vs. 36.7%, p = 0.01) in the ARNI subgroup. At the 6-week follow-up, in both subgroups, a significant improvement in the median LVEF values was achieved—from a median LVEF value of 30% (27.3; 38) to 37% (30; 43; p = 0.0008) in the ARNI subgroup and from a median LVEF value of 36% (33; 39) to 45% (42; 52; p < 0.0001) in the ACEI/ARB subgroup. The median ΔLVEF in the ACEI/ARB subgroup was higher [10% (6; 12)] than in the ARNI subgroup [6% (2; 10.25), p = 0.018]. Similarly, the median relative ΔLVEF was higher in the ACEI/ARB subgroup [30% (15.4; 40)] than in the ARNI group [17.5% (7; 31.9), p = 0.047]. The vast majority of patients, particularly in the ARNI group (99.7%), were treated with the lowest available dose of the drug. Conclusions: Our current experience in ARNI therapy after AMI is promising; however, it is limited to a small group of patients with severe impairment of LV systolic function. Regardless of the significant improvement in the baseline LVEF observed in patients receiving both ACEI/ARB and ARNI at the 6-week follow-up, the absolute and relative increases in the LVEF were higher in subjects treated with ACEI/ARB. However, the clinical benefits of ARNI therapy may emerge more gradually, and its advantages could become more apparent over a longer follow-up period. The clinical efficacy of early use of ARNI in the setting of AMI needs further evaluation. 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

Luteolin is a natural flavonoid compound with multifaceted pharmacological properties, including anti-oxidant, anti-inflammatory, antiviral, and anti-tumor activities. Network pharmacology analysis has been utilized to decipher the underlying mechanisms and multitargets of luteolin against coronavirus disease 2019 (COVID-19). This review aims to provide a systematic and comprehensive summary of luteolin, as a potential novel remedy with anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) activity, as well as its anti-oxidant mechanisms. We systematically delineate the epidemiological profile, genomic architecture, and replicative dynamics of SARS-CoV-2, thereby constructing a multiscale framework to decode its pathogenic mechanisms. Employing a multi-level network pharmacology analytical strategy, we identify 46 core targets through protein interaction network construction, followed by Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analysis. Molecular investigations reveal luteolin’s dual antiviral mechanisms, including direct targeting of SARS-CoV-2 proteins and host-directed intervention through suppression of angiotensin-converting enzyme 2 receptor engagement/transmembrane protease serine 2-mediated viral priming. The polypharmacological profile of luteolin demonstrates synergistic effects in blocking viral entry, replication, and host inflammatory cascades. This phytochemical repurposing study of luteolin provides a novel mechanistic paradigm for developing multitarget antiviral agents, highlighting the translational value of natural compounds in combating emerging viral variants. 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

Angiotensin-converting enzyme 2 (ACE2) is a key mediator of SARS-CoV-2 host cell entry, making it an attractive target for drug delivery strategies. Nafamostat (NM), a multifunctional agent with antiviral and anti-inflammatory properties, holds promise for COVID-19 treatment. In this study, we developed PLGA-PEG nanoparticles encapsulating NM (NM-PP NPs) and further conjugated them with specific ACE2 decoys (CTC-445.2d or SI5α) to generate NM-PP-Pro/Pep NPs. Both unmodified and ACE2-decoy-modified NPs exhibited uniform size distributions (diameter < 200 nm) and negative surface charges, as confirmed by dynamic light scattering and zeta potential measurements. The nanoparticles maintained structural integrity for at least 18 days at 4 °C and room temperature. In vitro release studies revealed sustained and controlled NM release kinetics. Notably, NM-PP-Pro NPs displayed potent antiviral activity, with an IC₅₀ < 0.05 nM against wild-type SARS-CoV-2 and remained effective against the D614G variant (IC₅₀ = 2 nM). These results underscore the potential of NM-PP-Pro NPs as a versatile nanotherapeutic platform for targeting SARS-CoV-2 and its emerging variants. Full article

The renin-angiotensin system (RAS) has evolved from being considered solely a peripheral endocrine system for cardiovascular control to being recognized as a complex molecular network with important functions in the central nervous system (CNS) and peripheral nervous system (PNS). Here we examine the organization, mechanisms of action, and clinical implications of cerebral RAS in physiological conditions and in various neurological pathologies. The cerebral RAS operates autonomously, synthesizing its main components locally due to restrictions imposed by the blood–brain barrier. The key elements of the system are (pro)renin; (pro)renin receptor (PRR); angiotensinogen; angiotensin-converting enzyme types 1 and 2 (ACE1 and ACE2); angiotensin I (AngI), angiotensin II (AngII), angiotensin III (AngIII), angiotensin IV (AngIV), angiotensin A (AngA), and angiotensin 1-7 (Ang(1-7)) peptides; RAS-regulating aminopeptidases; and AT1 (AT1R), AT2 (AT2R), AT4 (AT4R/IRAP), and Mas (MasR) receptors. More recently, alamandine and its MrgD receptor have been included. They are distributed in specific brain regions such as the hypothalamus, hippocampus, cerebral cortex, and brainstem. The system is organized into two opposing axes: the classical axis (renin/ACE1/AngII/AT1R) with vasoconstrictive, proinflammatory, and prooxidative effects, and the alternative axes AngII/AT2R, AngIV/AT4R/IRAP, ACE2/Ang(1-7)/MasR and alamandine/MrgD receptor, with vasodilatory, anti-inflammatory, and neuroprotective properties. This functional duality allows us to understand its role in neurological physiopathology. RAS dysregulation is implicated in multiple neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), and neuropsychiatric disorders such as depression and anxiety. In brain aging, an imbalance toward hyperactivation of the renin/ACE1/AngII/AT1R axis is observed, contributing to cognitive impairment and neuroinflammation. Epidemiological studies and clinical trials have shown that pharmacological modulation of the RAS using ACE inhibitors (ACEIs) and AT1R antagonists (ARA-II) not only controls blood pressure but also offers neuroprotective benefits, reducing the incidence of cognitive decline and dementia. These effects are attributed to direct mechanisms on the CNS, including reduction of oxidative stress, decreased neuroinflammation, and improved cerebral blood flow. Full article