Search

Background/aim: SARS-CoV-2 infection presents different severity levels that suggest the influence of genetic factors on the clinical outcome of the disease. In cases of severe COVID-19, the presence of elevated coagulation markers, increased platelet activation and aggregation and the risk of thrombotic complications are described. Given the participation of these cells in several serious viral infections and their negative role when associated with a prothrombotic response, it is important to understand the mechanistic role of SARS-CoV-2 in platelet physiology. This study evaluated the hyperexpression of platelet-activating factor receptor (PTAFR) and platelet factor 4 (PF4) in unvaccinated and hospitalized patients with COVID-19., Patients and Methods: The study included 43 COVID-19 patients stratified according to WHO guidelines. Subsequently, the expression of the PTAFR and PF4 genes were evaluated using the real-time quantitative PCR and their possible correlation with the severity of the disease and clinical variables including hospitalization, outcome, sex, age and laboratory parameters (platelet count, INR and D-dimer)., Results: The analysis demonstrated a significant (p<0.05) hyperexpression of these genes COVID-19 patients (n=43) compared to healthy controls. Expression of these genes in patients was not statistically significant (p>0.05) different between patients stratified according to clinical variables., Conclusion: The expression of PTAFR and PF4 suggests an important molecular pathway in the pathophysiology of the disease and may be valuable platelet biomarkers to indicate increased risk in patients with COVID-19 who require hospital care, contributing to personalized intervention strategies and improving their clinical management., (Copyright © 2024, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background:  Olfactory dysfunction (OD) represents a frequent manifestation of the coronavirus disease 2019 (COVID-19). Apolipoprotein E (APOE) is a protein that interacts with the angiotensin-converting enzyme receptor, essential for viral entry into the cell. Previous publications have suggested a possible role of APOE in COVID-19 severity. As far as we know, no publications found significant associations between this disease's severity, OD, and APOE polymorphisms (E2, E3, and E4)., Objective:  To analyze the epidemiology of OD and its relationship with APOE polymorphisms in a cohort of Long-COVID patients., Methods:  We conducted a prospective cohort study with patients followed in a post-COVID neurological outpatient clinic, with OD being defined as a subjective reduction of olfactory function after infection, and persistent OD being defined when the complaint lasted more than 3 months after the COVID-19 infection resolution. This cross-sectional study is part of a large research with previously reported data focusing on the cognitive performance of our sample., Results:  The final sample comprised 221 patients, among whom 186 collected blood samples for APOE genotyping. The persistent OD group was younger and had a lower hospitalization rate during the acute phase of the disease ( p  < 0.001). Furthermore, the APOE variant E4 allele frequency was lower in this group ( p  = 0.035). This study evaluated OD in an outpatient population with COVID-19. In the current literature on this disease, anosmia is associated with better clinical outcomes and the E4 allele is associated with worse outcomes., Conclusion:  Our study provides new information to these correlations, suggesting APOE E4 as a protective factor for OD., Competing Interests: The authors have no conflict of interest to declare., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution 4.0 International License, permitting copying and reproduction so long as the original work is given appropriate credit (https://creativecommons.org/licenses/by/4.0/).)

APOE ε4 polymorphism has been recently described as a possible association with cognitive deficits in COVID-19 patients. This research aimed to establish the correlation between COVID-19 and cognitive impairment, and the APOE gene polymorphism among outpatients. We performed a cross-sectional study with confirmed COVID-19 patients and neurological symptoms that persisted for more than three months from onset. APOE genotypes were determined. The final number of patients included in this study was 219, of which 186 blood samples were collected for APOE genotyping, evaluated 4.5 months after COVID-19. Among the participants, 143 patients (65.3%) reported memory impairment symptoms as their primary concern. However, this complaint was objectively verified through screening tests (Addenbrooke Cognitive Examination-Revised and Mini-Mental State Examination) in only 36 patients (16.4%). The group experiencing cognitive decline exhibited a higher prevalence of the APOE ε4 allele than the normal group (30.8% vs. 16.4%, respectively, p = 0.038). Furthermore, the APOE ε4 allele and anxiety symptoms remained significant after multivariate analysis. This study assessed an outpatient population where cognitive changes were the primary complaint, even in mild cases. Moreover, the ε4 allele, sleep disorders, and anxiety symptoms were more frequent in the cognitive decline group.

Gastric cancer (GC) is among the most-diagnosed and deadly malignancies worldwide. Deregulation in cellular bioenergetics is a hallmark of cancer. Based on the importance of metabolic reprogramming for the development and cancer progression, inhibitors of cell metabolism have been studied as potential candidates for chemotherapy in oncology. Mebendazole (MBZ), an antihelminthic approved by FDA, has shown antitumoral activity against cancer cell lines. However, its potential in the modulation of tumoral metabolism remains unclear. Results evidenced that the antitumoral and cytotoxic mechanism of MBZ in GC cells is related to the modulation of the mRNA expression of glycolic targets SLC2A1, HK1, GAPDH, and LDHA. Moreover, in silico analysis has shown that these genes are overexpressed in GC samples, and this increase in expression is related to decreased overall survival rates. Molecular docking revealed that MBZ modifies the protein structure of these targets, which may lead to changes in their protein function. In vitro studies also showed that MBZ induces alterations in glucose uptake, LDH's enzymatic activity, and ATP production. Furthermore, MBZ induced morphologic and intracellular alterations typical of the apoptotic cell death pathway. Thus, this data indicated that the cytotoxic mechanism of MBZ is related to an initial modulation of the tumoral metabolism in the GC cell line. Altogether, our results provide more evidence about the antitumoral mechanism of action of MBZ towards GC cells and reveal metabolic reprogramming as a potential area in the discovery of new pharmacological targets for GC chemotherapy., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2023. Published by Elsevier Inc.)

Staphylococcus aureus forms biofilms, a structure that protects bacterial cells, conferring more resistance to difficult treatment. Synthetic peptides surge as an alternative to overcome the biofilm of multidrug-resistant pathogens. Mo -CBP 3 -PepI, when combined with Ciprofloxacin, reduced preformed S. aureus biofilm by 50% at low concentrations (0.2 and 6.2 μg. mL -1 , respectively). The goal of this study was to evaluate the proteomic profile of biofilms after treatment with the Mo -CBP 3 -PepI combined with ciprofloxacin. Here, proteomic analysis confirmed with more depth previously described mechanisms and revealed changes in the accumulation of proteins related to DNA and protein metabolism, cell wall biosynthesis, redox metabolism, quorum sensing, and biofilm formation. Some proteins related to DNA and protein metabolism were reduced, while other proteins, like redox system proteins, disappeared in Ciprofloxacin+ Mo -CBP 3 -PepI treatment. Our results indicated a synergistic effect of these two molecules with several mechanisms against S. aureus biofilm and opened new doors for combined treatments with other drugs.

Specific and sensitive tools for the diagnosis and monitoring of accidents by venomous animals are urgently needed. Several diagnostic and monitoring assays have been developed; however, they have not yet reached the clinic. This has resulted in late diagnoses, which represents one of the main causes of progression from mild to severe disease. Human blood is a protein-rich biological fluid that is routinely collected in hospital settings for diagnostic purposes, which can translate research progress from the laboratory to the clinic. Although it is a limited view, blood plasma proteins provide information about the clinical picture of envenomation. Proteome disturbances in response to envenomation by venomous animals have been identified, allowing mass spectrometry (MS)-based plasma proteomics to emerge as a tool in a range of clinical diagnostics and disease management that can be applied to cases of venomous animal envenomation. Here, we provide a review of the state of the art on routine laboratory diagnoses of envenomation by snakes, scorpions, bees, and spiders, as well as a review of the diagnostic methods and the challenges encountered. We present the state of the art on clinical proteomics as the standardization of procedures to be performed within and between research laboratories, favoring a more excellent peptide coverage of candidate proteins for biomarkers. Therefore, the selection of a sample type and method of preparation should be very specific and based on the discovery of biomarkers in specific approaches. However, the sample collection protocol (e.g., collection tube type) and the processing procedure of the sample (e.g., clotting temperature, time allowed for clotting, and anticoagulant used) are equally important to eliminate any bias.

The present study evaluates the proteome of early antral follicles from Ovis aries. Fifty follicles were collected from ovaries of adult ewes and extracted proteins were trypsin-digested, desalted and analyzed by LC-MS/MS. Genes were screened for potential modulation by miRNAs and protein data, subjected to functional enrichment analysis. Label-free mass spectrometry allowed the identification of 2503 follicle proteins, confirming vimentin, actin, lamin, heat shock proteins and histones as the most abundant ones. In silico analyses indicated that miRNAs modulate the expression of genes coding proteins of the sheep follicles involved in cell cycle, cell differentiation, aging, apoptosis, cell death, adipocyte differentiation, cell division. The most important biological processes associated with the follicle proteins were innate immune response, translation, adaptive immune response and protein folding, while molecular functions linked to the proteome of sheep antral follicles related to metal ion binding, ATP binding, oxygen binding, RNA binding and GTP binding, among others. Upload of 2503 Uniport accession codes through DAVID platform matched 1274 genes, associated with translation, metabolic process, proteolysis involved in cellular protein catabolic process, zona pellucida receptor complex and others. KEEG pathways analysis indicated genes correlated with ovine follicular development, with major pathways listed as carbon metabolism, biosynthesis of amino acids, glutathione metabolism, oxidative phosphorylation, fatty acid degradation and oocyte meiosis. This represents a comprehensive atlas of proteins expressed in sheep early antral follicles and will contribute to future identification of biomarkers for follicular development and oocyte maturation., Competing Interests: Conflict of interest The authors declare no conflicts of interest., (Copyright © 2022 Elsevier B.V. All rights reserved.)

The use of growth-promoting microorganisms with biostimulant characteristics is an important biological asset for the acclimatization of micropropagated seedlings. The present study aimed to evaluate the efficacy of the application of Trichoderma spp. on the promotion of the growth of micropropagated banana seedlings during acclimatization. The experiment was performed in an 8 × 6 completely randomized design using the following treatments: water, seedlings fertilized with controlled-release fertilizer, commercial biological inputs (A: T. asperellum, B/C: T. harzianum), and LPPC299 and LPPC300 strains. Plant height, pseudostem diameter, number of leaves, total leaf area, root length, fresh and dry mass of the plant, and accumulation of sodium, macronutrients, and micronutrients were evaluated 60 days after inoculation. Strains LPPC299 and LPPC300 were subjected to molecular identification by DNA sequencing of the ITS/5.8S locus. In vitro detection of growth promotion-related mechanisms and mycelial growth of biostimulants were performed using scanning electron microscopy. LPPC299 and LPPC300 had a greater similarity to T. longibrachiatum. LPPC299 was able to promote greater pseudostem diameter, number of leaves, and total leaf area in banana seedlings. T. asperellum (A) favored seedling performance in terms of fresh and dry mass of the plants. The strains were able to produce siderophores, indoleacetic acid, and catalase in vitro. Seedlings inoculated with the strains accumulated Mn, S (LPPC300), and Mg (LPPC299). LPPC299 from the banana rhizosphere was efficient in promoting performance in banana seedlings, showing its potential as a biostimulant for this crop., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)

In the Northeast of Brazil, Ceará was the second state most impacted by COVID-19 in number of cases and death rate. Despite that, the early dynamics of the pandemic in Ceará was not yet well understood due the low genomic surveillance of SARS-CoV-2 in 2020. In this study, we analyze the circulating lineages and the genomic variation of the virus in Ceará state. Thirty-four genomes were sequenced and combined with sequences available in GISAID database from March 2020 to June 2021 to compose the study dataset. The most prevalent lineages detected were B.1.1.33, in 2020, and P.1, in 2021. Other lineages were found, such as P.2, sublineages of P.1, B.1, B.1.1, B.1.1.28 and B.1.212. Analyzing the mutations, a total of 202 single-nucleotide polymorphisms (SNPs) were identified among the 34 genomes sequenced, of which 127 were missense, 74 synonymous, and one was a nonsense mutation. Among the missense mutations, C14408T, A23403G, T27299C, G28881A G28883C, and T29148C were the most prevalent within the dataset. Although SARS-CoV-2 sequencing data was limited in 2020, our results could provide insights to better understand the genetic diversity of the circulating lineages in Ceará., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Despite advances in cancer chemotherapy, gastric cancer (GC) continues to have high recurrence rates and poor prognosis with limited treatment options. Understanding the etiology of GC and developing more effective, less harmful therapeutic approaches are vital and urgent. Therefore, this work describes a novel kinase target in malignant gastric cells as a potential therapeutic strategy. Our results demonstrate that among 147 kinase inhibitors (KI), only three molecules were significantly cytotoxic for the AGP-01 cell line. Hence, these three molecules were further characterized in their cellular mode of action. There was significant cell cycle impairment due to the expression modulation of genes such as TP53 , CDKN1A , CDC25A , MYC , and CDK2 with subsequent induction of apoptosis. In fact, the Gene Ontology analysis revealed a significant enrichment of pathways related to cell cycle regulation (GO:1902749 and GO:1903047). Moreover, the three selected KIs significantly reduced cell migration and Vimentin mRNA expression after treatment. Surprisingly, the three KIs share the same target, ALK and INSR , but only the ALK gene was found to have a high expression level in the gastric cancer cell line. Additionally, lower survival rates were observed for patients with high ALK expression in TCGA-STAD analysis. In summary, we hypothesize that ALK gene overexpression can be a promising biomarker for prognosis and therapeutic management of gastric adenocarcinoma.

Chronic myeloid leukemia (CML) is caused by constitutively active fusion protein BCR-ABL1, and targeting ABL1 is a promising therapy option. Imatinib, dasatinib, and nilotinib have all been shown to work effectively in clinical trials. ABL1 mutations, particularly the T315I gate-keeper mutation, cause resistance in patients. As a result, broad-spectrum ABL1 medicines are desperately needed. In order to screen potential drugs targeting CML, mebendazole (MBZ) was subjected to the in vitro test against CML cell lines (K562 and FEPS) and computational assays. The antiproliferative effect of MBZ and the combination with tyrosine kinase inhibitors (TKIs) was tested using end-point viability assays, cell cycle distribution analysis, cell membrane, and mitochondrial dyes. By interrupting the cell cycle and causing cell death, MBZ and its combination with imatinib and dasatinib have a significant antiproliferative effect. We identified MBZ as a promising "new use" drug targeting wild-type and mutant ABL1 using molecular docking. Meanwhile, we determined which residues in the allosteric site are important in ABL1 drug development. These findings may not only serve as a model for repositioning current authorized medications but may also provide ABL1-targeted anti-CML treatments a fresh lease of life., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Daniel, Mesquita, Da Silva, de Souza, Lima, de Oliveira, de Moraes, Moreira-Nunes, Burbano, Zanatta and Montenegro.)

Introduction: Few studies have objectively evaluated cognitive deficits after the acute phase of COVID-19 disease. Moreover, the role of apolipoprotein E (APOE) genotypes in cognitive decline in patients with COVID-19 has not been evaluated yet., Methods: This cross-sectional study was conducted in confirmed cases of COVID-19 patients with neurological symptoms that persisted for more than 3 months from the onset. We determined APOE genotypes., Results: The final sample consisted of 141 patients. The most frequent APOE genotype was E3/E3 ( N = 95; 67.3%). In total, 93 patients (65.9%) had memory impairment symptoms as the main complaint, objectively confirmed through screening tests in 25 patients (17.7%). Patients with cognitive impairment had a lower frequency of anosmia than the normal and subjective cognitive decline (SCD) groups ( p = 0.005). In addition, depression was recurrent in the cognitive impairment group and the SCD group ( p = 0.046). Cognitive impairment was significantly more frequent in hospitalized patients and those with a lower education level. Cognitive status was not associated with APOE genotypes., Discussion: Hospitalized patients had more severe infection with a greater possibility of systemic complications, greater inflammatory response, and prolonged hospitalization, which could impact cognitive performance. Cognitive impairment in patients with COVID-19 does not necessarily involve specific APOE polymorphisms. However, psychiatric disorders may also be responsible for cognitive complaints. Cognitive complaints are frequent in patients with COVID-19, even after the acute phase of the disease and in mild cases. Hospitalized participants and depressed patients may have a higher risk of cognitive impairment. APOE genotypes or haplotypes may not significantly play a role in COVID-19 cognitive impairment., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Tavares-Júnior, Oliveira, da Silva, Feitosa, Sousa, Cunha, Gaspar, Gomes, de Oliveira, Moreira-Nunes, Montenegro, Sobreira-Neto and Braga-Neto.)

Leptin mediates the interaction between reproductive function and energy balance. However, leptin receptors are not expressed in neurons that produce gonadotropin-releasing hormone (GnRH), likely indicating an indirect action through interneurons. Among likely neurons that modulate the secretion of GnRH are NO (nitric oxide) neurons. We assessed whether estradiol and feeding conditions modulate a possible interaction between leptin and NO in brain areas related to the control of reproductive function. Estradiol-treated and untreated ovariectomized rats were normally fed or fasted for 48 h. Then, saline (control) or leptin (3 μg/1 μl) intracerebroventricular microinjections were administered, and after thirty minutes, the brains collected subsequent to the decapitation or transcardially perfusion. Leptin and estradiol increased NO synthase (nNOS) gene expression (RT-PCR) and content (Western blotting) in the medial preoptic area (MPOA) and medial basal hypothalamus (MBH) only in fasted rats. Leptin increased: 1-phosphorylated-signal transducer and activator of transcription-3(pSTAT3) (immunohistochemistry) in the MPOA and various hypothalamic nuclei [arcuate (ARC); ventromedial (VMH); dorsal/ventral dorsomedial (dDMH/vDMH); premammilar ventral (PMV)], effects potentiated by estradiol/fasting interaction; 2- nNOS/pSTAT3 coexpression in the MPOA only in estradiol-treated, fasted rats; 3- nNOS-immunoreactive cell expression in the VMH, DMH and PMV (areas related to reproductive function control) of estradiol -treated rats. Thus, when leptin is reduced during fasting, leptin replacement effectively increased the expression of nitric oxide, which activated the HPG axis only in the presence of estradiol. Estradiol modulates the nitrergic system, leptin sensitivity and consequently leptin's effects on the nitrergic system in hypothalamus and in particular vDMH and PMV., (Copyright © 2020. Published by Elsevier Ltd.)