RESUMO

Introducción: Diversas investigaciones han establecido la relación entre temperatura y duración del embarazo, la exposición a temperaturas altas durante el embarazo plantea interrogantes en especial el papel que esta juega frente a los partos prematuros y partos de bajo peso, es indispensable determinar si las temperaturas altas o bajas tienen un comportamiento protector o de riesgo sobre el feto durante la gestación en regiones tropicales. Objetivo: describir la relación entre la exposición a temperaturas altas y bajas durante el embarazo y su efecto en la edad gestacional y peso al momento del parto en los recién nacidos del departamento del Guaviare-Colombia. Metodología: Estudio tipo observacional, analítico, retrospectivo de corte transversal que busco determinar la relación entre exposición a temperaturas altas y bajas durante el embarazo y su efecto en la edad gestacional y peso al momento del parto en los recién nacidos, el universo estuvo conformado por 10.137 nacidos vivos, de los cuales 9.932 cumplieron los criterios de inclusión. Se determinó Odds Ratio para estimar la asociación entre las variables. Resultados: Dentro de la semana de retraso 3 el estar expuesto a temperaturas máximas percentil 90 es un factor protector para la ganancia ponderal de peso OR < 1, la exposición a temperaturas mínimas percentil 10 se asoció como factor protector para el parto prematuro en la semana de retraso 1 y 2 OR < 1.Conclusión: A pesar del beneficio de las altas y bajas temperaturas durante el embarazo en la ganancia ponderal de peso y disminución del parto prematuro, es recomendable prevenir la exposición a temperaturas extremas durante el periodo de gestación[AU]

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Introduction: Various investigations have established the relationship between temperature and duration of pregnancy. Exposure to high temperatures during pregnancy raises questions, especially the role it plays in premature births and low-weight births. It is essential to determine whether high temperatures or low have a protective or risky behavior on the fetus during pregnancy in tropical regions.Objective: to describe the relationship between exposure to high and low temperatures during pregnancy and its effect on gestational age and weight at the time of delivery in newborns in the department of Guaviare-Colombia.Methodology:Observational, analytical, retrospective cross-sectional study that sought to determine the relationship between exposure to high and low temperatures during pregnancy and its effect on gestational age and weight at the time of delivery in newborns. The universe was made up of 10,137 births. alive, of which 9,932 met the inclusion criteria. Odds Ratio was determined to estimate the association between the variables.Results:Within the 3rd week of delay, being exposed to maximum temperatures at the 90th percentile is a protective factor for weight gain OR < 1, exposure to minimum temperatures at the 10th percentile was associated as a protective factor for premature birth in the week. of delay 1 and 2 OR < 1. Conclusion: Despite the benefit of high and low temperatures during pregnancy in weight gain and reduction in premature birth, it is advisable to prevent exposure to extreme temperatures during the gestation period[AU]

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Introdução: Várias investigações estabeleceram a relação entre temperatura e duração da gravidez. A exposição a altas temperaturas durante a gravidez levanta questões, especialmente o papel que desempenha nos partos prematuros e nos nascimentos de baixo peso. É essencial determinar se as temperaturas altas ou baixas têm um comportamento protetor ou de risco para o feto durante a gravidez em regiões tropicais. Objetivo:descrever a relação entre a exposição a altas e baixas temperaturas durante a gravidez e seu efeito na idade gestacional e no peso no momento do parto em recém-nascidos no departamento de Guaviare-Colômbia. Metodologia: Estudo observacional, analítico, retrospectivo e transversal que buscou determinar a relação entre a exposição a altas e baixas temperaturas durante a gravidez e seu efeito na idade gestacional e no peso no momento do parto em recém-nascidos. O universo foi composto por 10.137 nascimentos. vivos, dos quais 9.932 preencheram os critérios de inclusão. O Odds Ratio foi determinado para estimar a associação entre as variáveis. Resultados:Na 3ª semana de atraso, a exposição a temperaturas máximas no percentil 90 é fator de proteção para ganho de peso OR < 1, a exposição a temperaturas mínimas no percentil 10 foi associada como fator de proteção para parto prematuro na semana. de atraso 1 e 2 OR < 1.Conclusão:Apesar do benefício das altas e baixas temperaturas durante a gravidez no ganho de peso e redução do parto prematuro, é aconselhável evitar a exposição a temperaturas extremas durante o período de gestação[AU]

Assuntos

Humanos , Feminino , Gravidez , Recém-Nascido de muito Baixo Peso , Parto , Colômbia

RESUMO

Current treatments for type 2 diabetes (T2D) mainly rely on exercise, dietary control, and anti-diabetic drugs to enhance insulin secretion and improve insulin sensitivity. However, there is a need for more therapeutic options, as approved drugs targeting different pharmacological objectives are still unavailable. One potential target that has attracted attention is the protein tyrosine phosphatase 1B (PTP1B), which negatively regulates the insulin signaling pathway. In this work, a comprehensive computational screening was carried out using cheminformatics and molecular docking on PTP1B, employing a rigorous repurposing approach. The screening involved approved drugs and compounds under research as anti-diabetics that bind to targets such as peroxisome proliferator-activated receptor gamma (PPAR-γ) and α-glucosidase. Several computational hits were then meticulously tested in vitro against PTP1B, with 13-cis-retinoic acid (3a) showing an IC50 of 0.044 mM and competitive inhibition. Molecular dynamics studies further confirmed that 3a can bind to the catalytic binding site of PTP1B. Finally, 3a is the first time it has been reported as an inhibitor of PTP1B, making it a potentially valuable candidate for further studies in D2T treatment.

RESUMO

INTRODUCTION: Chimeric antigen receptor T (CAR-T) cell therapy is an innovative technology that has shown promising results in clinical trials. Treatment is based on modifying the patient's own T cells to express artificial surface receptors to specifically recognize and attack the tumor cells. OBJECTIVE: To synthesize available evidence on the incidence and management strategies of cytokine release syndrome in patients with diffuse large B-cell lymphoma who received CAR-T cell therapy. METHODS: This is a systematic literature review. The search was conducted in the PubMed, Scopus, and Web of science databases. This review followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. The systematic review protocol is registered in the International Prospective Register of Systematic Reviews (PROSPERO) database under number CRD42022359258. RESULTS: Nineteen studies were included with a total of 1193 patients who received CAR-T cell therapy. Of these patients, 804 (67%) developed some degree of cytokine release syndrome. The frequencies of Grade 3 and 4 cytokine release syndrome were 10% and 3%, respectively. The regimen most used in the management of the syndrome included tocilizumab and/or glucocorticoids. CONCLUSION: The results obtained in this review demonstrate high rates of cytokine release syndrome in patients with diffuse large B-cell lymphoma treated with CAR-T cell therapy, however these events are manageable, supporting the conclusion that this therapy is safe in these patients.

RESUMO

Parasites have been associated with possible anticancer activity, including Trypanosoma cruzi, which has been linked to inhibiting the growth of solid tumors. To better understand this antitumor effect, we investigated the association of anti-T. cruzi antibodies with B cells of the acute lymphoblastic leukemia (ALL) SUPB15 cell line. The antibodies were generated in rabbits. IgGs were purified by affinity chromatography. Two procedures (flow cytometry (CF) and Western blot(WB)) were employed to recognize anti-T. cruzi antibodies on SUPB15 cells. We also used CF to determine whether the anti-T. cruzi antibodies could suppress SUPB15 cells. The anti-T. cruzi antibodies recognized 35.5% of the surface antigens of SUPB15. The complement-dependent cytotoxicity (CDC) results demonstrate the cross-suppression of anti-T. cruzi antibodies on up to 8.4% of SUPB15 cells. For the WB analysis, a band at 100 kDa with high intensity was sequenced using mass spectrometry, identifying the protein as nucleolin. This protein may play a role in the antitumor effect on T. cruzi. The anti-T. cruzi antibodies represent promising polyclonal antibodies that have the effect of tumor-suppressive cross-linking on cancer cells, which should be further investigated.

Assuntos

Anticorpos Antiprotozoários , Leucemia-Linfoma Linfoblástico de Células Precursoras , Trypanosoma cruzi , Trypanosoma cruzi/imunologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/imunologia , Humanos , Linhagem Celular Tumoral , Animais , Coelhos , Anticorpos Antiprotozoários/imunologia , Proteínas de Ligação a RNA/imunologia , Proteínas de Ligação a RNA/metabolismo , Nucleolina , Fosfoproteínas/imunologia , Fosfoproteínas/metabolismo

RESUMO

Advanced glycated end products (AGEs) are cytotoxic compounds that are mainly increased in diabetes mellitus (DM), kidney failure, inflammation, and in response to the ingestion of AGE-rich diets. AGEs can also impair glycemic homeostasis by decreasing the expression of the Slc2a4 (solute carrier family 2 member 4) gene and its GLUT4 (solute carrier family 2, facilitated glucose transporter member 4) protein in muscle. However, the mechanisms underlying AGE's effect on adipocytes have not been demonstrated yet. This study investigated the effects of AGEs upon Slc2a4/GLUT4 expression in 3T3-L1 adipocytes, as well as the potential role of NFKB (nuclear factor NF-kappa-B) activity in the effects observed. Adipocytes were cultured in the presence of control albumin (CA) or advanced glycated albumin (GA) at concentrations of 0.4, 3.6, and 5.4 mg/mL for 24 h or 72 h. Slc2a4, Rela, and Nfkb1mRNAs were measured by RT-qPCR, GLUT4, IKKA/B, and p50/p65 NFKB subunits using Western blotting, and p50/p65 binding into the Slc2a4 promoter was analyzed by chromatin immunoprecipitation (ChIP) assay. GA at 0.4 mg/mL increased Slc2a4/GLUT4 expression after 24 h and 72 h (from 50% to 100%), but at 5.4 mg/mL, Slc2a4/GLUT4 expression decreased at 72 h (by 50%). Rela and Nfkb1 expression increased after 24 h at all concentrations, but this effect was not observed at 72 h. Furthermore, 5.4 mg/mL of GA increased the p50/p65 nuclear content and binding into Slc2a4 at 72 h. In summary, this study reveals AGE-induced and NFKB-mediated repression of Slc2a4/GLUT4 expression. This can compromise the adipocyte glucose utilization, contributing not only to the worsening of glycemic control in DM subjects but also the impairment of glycemic homeostasis in non-DM subjects under the high intake of AGE-rich foods.

Assuntos

Células 3T3-L1 , Adipócitos , Transportador de Glucose Tipo 4 , Produtos Finais de Glicação Avançada , Fator de Transcrição RelA , Animais , Camundongos , Adipócitos/metabolismo , Adipócitos/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Transportador de Glucose Tipo 4/metabolismo , Transportador de Glucose Tipo 4/genética , Produtos Finais de Glicação Avançada/metabolismo , Produtos Finais de Glicação Avançada/farmacologia , NF-kappa B/metabolismo , Subunidade p50 de NF-kappa B/metabolismo , Subunidade p50 de NF-kappa B/genética , Regiões Promotoras Genéticas , Fator de Transcrição RelA/metabolismo , Fator de Transcrição RelA/genética

RESUMO

A T-cell-independent (TI) pathway activated by microbiota results in the generation of low-affinity homeostatic IgA with a critical role in intestinal homeostasis. Moderate aerobic exercise (MAE) provides a beneficial impact on intestinal immunity, but the action of MAE on TI-IgA generation under senescence conditions is unknown. This study aimed to determine the effects of long-term MAE on TI-IgA production in young (3 month old) BALB/c mice exercised until adulthood (6 months) or aging (24 months). Lamina propria (LP) from the small intestine was obtained to determine B cell and plasma cell sub-populations by flow cytometry and molecular factors related to class switch recombination [Thymic Stromal Lymphopoietin (TSLP), A Proliferation-Inducing Ligand (APRIL), B Cell Activating Factor (BAFF), inducible nitric oxide synthase (iNOS), and retinal dehydrogenase (RDH)] and the synthesis of IgA [α-chain, interleukin (IL)-6, IL-21, and Growth Factor-ß (TGF-ß)]; and epithelial cells evaluated IgA transitosis [polymeric immunoglobulin receptor (pIgR), tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), IL-4] by the RT-qPCR technique. The results were compared with data obtained from sedentary age-matched mice. Statistical analysis was computed with ANOVA, and p < 0.05 was considered to be a statistically significant difference. Under senescence conditions, MAE promoted the B cell and IgA+ B cells and APRIL, which may improve the intestinal response and ameliorate the inflammatory environment associated presumably with the downmodulation of pro-inflammatory mediators involved in the upmodulation of pIgR expression. Data suggested that MAE improved IgA and downmodulate the cytokine pro-inflammatory expression favoring homeostatic conditions in aging.

Assuntos

Envelhecimento , Homeostase , Imunoglobulina A , Camundongos Endogâmicos BALB C , Condicionamento Físico Animal , Animais , Imunoglobulina A/metabolismo , Imunoglobulina A/imunologia , Camundongos , Envelhecimento/imunologia , Citocinas/metabolismo , Linfócitos B/imunologia , Linfócitos B/metabolismo , Fator Ativador de Células B/metabolismo , Fator Ativador de Células B/genética , Mucosa Intestinal/metabolismo , Mucosa Intestinal/imunologia , Intestino Delgado/imunologia , Intestino Delgado/metabolismo , Masculino , Plasmócitos/imunologia , Plasmócitos/metabolismo , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral/metabolismo , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral/genética

RESUMO

DENV infection outcomes depend on the host's variable expression of immune receptors and mediators, leading to either resolution or exacerbation. While the NS3 protein is known to induce robust immune responses, the specific impact of its protease region epitopes remains unclear. This study investigated the effect of recombinant NS3 protease region proteins from all four DENV serotypes on splenocyte activation in BALB/c mice (n = 5/group). Mice were immunized with each protein, and their splenocytes were subsequently stimulated with homologous antigens. We measured the expression of costimulatory molecules (CD28, CD80, CD86, CD152) by flow cytometry, along with IL-2 production, CD25 expression, and examined the antigen-specific activation of CD4 + and CD8 + T cells. Additionally, the expression of IL-1, IL-10, and TGF-ß1 in splenocytes from immunized animals was assessed. Apoptosis was evaluated using Annexin V/PI staining and DNA fragmentation analysis. Stimulation of splenocytes from immunized mice triggered apoptosis (phosphatidylserine exposure and caspase 3/7 activation) and increased costimulatory molecule expression, particularly CD152. Low IL-2 production and low CD25 expression, as well as sustained expression of the IL-10 gene. These results suggest that these molecules might be involved in mechanisms by which the NS3 protein contributes to viral persistence and disease pathogenesis.

Assuntos

Apoptose , Antígeno CTLA-4 , Vírus da Dengue , Camundongos Endogâmicos BALB C , Baço , Proteínas não Estruturais Virais , Animais , Camundongos , Baço/imunologia , Baço/virologia , Vírus da Dengue/imunologia , Vírus da Dengue/genética , Antígeno CTLA-4/genética , Antígeno CTLA-4/imunologia , Proteínas não Estruturais Virais/imunologia , Proteínas não Estruturais Virais/genética , Proteínas Recombinantes/imunologia , Proteínas Recombinantes/genética , Imunização , Dengue/imunologia , Dengue/virologia , Citocinas/metabolismo , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia

RESUMO

Humans are exposed every day to innumerable external stimuli, both environmental and microbial. Immunological memory recalls each specific stimulus and mounts a secondary response that is faster and of a larger magnitude than the primary response; this process constitutes the basis for vaccine development. The COVID-19 pandemic offers a unique opportunity to study the development of immune memory against an emergent microorganism. Memory T cells have an important role in the resolution of COVID-19, and they are key pillars of immunological memory. In this review, we summarize the main findings regarding anti-SARS-CoV-2 memory T cells after infection, after vaccination, and after the combination of these two events ("hybrid immunity"), and analyze how these cells can contribute to long-term protection against the infection with SARS-CoV-2 variants.

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Los humanos se exponen cada día a innumerables estímulos externos, tanto ambientales como microbianos. La memoria inmunológica registra de manera específica un estímulo y articula una respuesta secundaria más rápida y de mayor magnitud que la respuesta primaria; este proceso constituye la base del desarrollo de vacunas. La pandemia de COVID-19 ofreció la oportunidad de estudiar el desarrollo de la memoria inmunológica contra un microorganismo emergente. Las células T de memoria tienen un papel importante en la resolución de COVID-19 y son pilares importantes de la memoria inmunológica. En esta revisión se resumen los principales hallazgos de la respuesta de las células T de memoria contra la infección por SARS-CoV-2, a la vacunación o a la combinación de ambos procesos ("inmunidad híbrida"), y se discute cómo estas células pueden contribuir a la protección a largo plazo contra distintas variantes del virus.

Assuntos

Vacinas contra COVID-19 , COVID-19 , Memória Imunológica , Células T de Memória , SARS-CoV-2 , Humanos , COVID-19/imunologia , COVID-19/prevenção & controle , Memória Imunológica/imunologia , Células T de Memória/imunologia , Vacinas contra COVID-19/imunologia , SARS-CoV-2/imunologia

RESUMO

American Tegumentary Leishmaniasis (ATL) is a disease of high severity and incidence in Brazil, in addition to being a worldwide concern in public health. Leishmania amazonensis is one of the etiological agents of ATL, and the inefficiency of control measures, associated with the high toxicity of the treatment and the lack of effective immunoprophylactic strategies, makes the development of vaccines indispensable and imminent. In this light, the present study proposes to elaborate a chimeric protein (rChiP), based on the fusion of multiple epitopes of CD4+/CD8+ T cells, identified in the immunoproteome of the parasites L. amazonensis and L. braziliensis. The designed chimeric protein was tested in the L. amazonensis murine model of infection using the following formulations: 25 µg of the rChiP in saline (rChiP group) and 25 µg of the rChiP plus 25 µg of MPLA-PHAD® (rChiP+MPLA group). After completing immunization, CD4+ and CD8+ T cells, stimulated with SLa-Antigen or rChiP, showed an increased production of nitric oxide and intracytoplasmic pro-inflammatory cytokines, in addition to the generation of central and effector memory T cells. rChiP and rChiP+MPLA formulations were able to promote an effective protection against L. amazonensis infection determined by a reduction in the development of skin lesions and lower parasitic burden. Reduction in the development of skin lesions and lower parasitic burden in the vaccinated groups were associated with an increase of nitrite, CD4+/CD8+IFN-γ+TNF-α+ and CD4+/CD8+CD44highCD62Lhigh/low T cells, IgGTotal, IgG2a, and lower rates of IgG1 and CD4+/CD8+IL-10+. This data suggests that proposed formulations could be considered potential tools to prevent ATL.

Assuntos

Adjuvantes Imunológicos , Linfócitos T CD4-Positivos , Linfócitos T CD8-Positivos , Epitopos de Linfócito T , Memória Imunológica , Vacinas contra Leishmaniose , Leishmaniose Cutânea , Animais , Leishmaniose Cutânea/prevenção & controle , Leishmaniose Cutânea/imunologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD4-Positivos/imunologia , Epitopos de Linfócito T/imunologia , Camundongos , Vacinas contra Leishmaniose/imunologia , Feminino , Adjuvantes Imunológicos/administração & dosagem , Camundongos Endogâmicos BALB C , Proteínas Recombinantes de Fusão/imunologia , Proteínas Recombinantes de Fusão/genética , Leishmania braziliensis/imunologia , Lipídeo A/análogos & derivados , Lipídeo A/imunologia , Anticorpos Antiprotozoários/imunologia , Citocinas/metabolismo , Citocinas/imunologia , Modelos Animais de Doenças , Antígenos de Protozoários/imunologia

RESUMO

Goto-Kakizaki (GK) rats develop a well-defined insulin resistance (IR) and type 2 diabetes mellitus (T2DM) without presenting obesity. The lymphocyte profile in nonobese diabetic conditions is not yet characterized. Therefore, GK rats were chosen to explore T lymphocyte (TL) dynamics at various stages (21, 60, and 120 days) compared to Wistar rats. GK rats exhibit progressive disruption of glucose regulation, with early glucose intolerance at 21 days and reduced insulin sensitivity at 60 days, confirming IR. Glucose transporter 1 (GLUT1) expression was consistently elevated in GK rats, suggesting heightened TL activation. T-regulatory lymphocyte markers diminished at 21 days. However, GK rats showed increased Th1 markers and reduced Gata-3 expression (crucial for Th2 cell differentiation) at 120 days. These findings underscore an early breakdown of anti-inflammatory mechanisms in GK rats, indicating a proinflammatory TL profile that may worsen chronic inflammation in T2DM.

RESUMO

Chimeric Antigen Receptor T-cell (CAR-T) therapies are transforming the treatment of B-cell lymphoproliferative disorders and multiple myeloma, yet global access challenges and barriers for their implementation persist. Global access disparities persist, particularly for persons living in low and middle-income countries and for underserved populations in high income countries. In this review we address patient-related factors including age, comorbidities, fitness, race and ethnicity, and geographic location for CAR-T access. Also, we review disease-related and health system barriers like disease biology, potential for short and long-term toxicity, insurance access, referrals, supply and manufacturing, regulation, costs and treatment center capacity. Lastly, alternatives for overcoming these barriers exemplified by research efforts worldwide are discussed, emphasizing the need for a multifaceted approach from all stakeholders to improve global accessibility and ensure equitable access and improved outcomes for patients worldwide.

RESUMO

Hypothyroidism is a prevalent thyroid condition in which the thyroid gland fails to secrete an adequate amount of thyroid hormone into the bloodstream. This condition may develop due to genetic or acquired factors. The most frequent cause of acquired hypothyroidism is chronic autoimmune thyroiditis, also known as Hashimoto's disease. Acquired hypothyroidism is diagnosed when patients present with overt hypothyroidism (also known as clinical hypothyroidism), as they exhibit increased TSH and decreased T3 and T4 serum levels. This article examines the prevalence of psychiatric disorders among patients diagnosed with acquired hypothyroidism with or without Levothyroxine treatment. We discuss the available evidence indicating that acquired hypothyroidism may be a risk factor for psychiatric disorders, and the effectiveness of thyroid treatment in relieving psychiatric symptoms. Additionally, we provide critical details on thyroid hormone cutoff values reported in the literature, their potential clinical importance, and their correlation with psychiatric symptoms. Finally, we examined the various mechanisms by which acquired hypothyroidism can lead to depression. The high rate of comorbidity between hypothyroidism and psychiatric disorders deserves special attention, indicating the importance of consistent monitoring and timely identification of psychiatric symptoms to prevent disease exacerbation and facilitate therapeutic management. On the other hand, several mechanisms underlie the strong association between depression and acquired hypothyroidism. Deeper research into these mechanisms will allow knowledge of the pathophysiology of depression in patients with acquired hypothyroidism and will provide clues to design more precise therapeutic strategies for these patients.

RESUMO

Despite the highly conserved nature of the genetic code, the frequency of usage of each codon can vary significantly. The evolution of codon usage is shaped by two main evolutionary forces: mutational bias and selection pressures. These pressures can be driven by environmental factors, but also by the need for efficient translation, which depends heavily on the concentration of transfer RNAs (tRNAs) within the cell. The data presented here supports the proposal that tRNA modifications play a key role in shaping the overall preference of codon usage in proteobacteria. Interestingly, some codons, such as CGA and AGG (encoding arginine), exhibit a surprisingly low level of variation in their frequency of usage, even across genomes with differing GC content. These findings suggest that the evolution of GC content in proteobacterial genomes might be primarily driven by changes in the usage of a specific subset of codons, whose usage is itself influenced by tRNA modifications.

RESUMO

BACKGROUND: Evidence shows that CD4+ T cells are altered in obesity and play a significant role in the systemic inflammation in adults with the disease. OBJECTIVES: Because the profile of these cells is poorly understood in the pediatric population, this study aims to investigate the profile of CD4+ T lymphocytes and the plasma levels of cytokines in this population. METHODS: Using flow cytometry, we compared the expression profile of lymphocyte markers, master transcription factors, cytokines, and molecules involved in the regulation of the immune response in CD4+ T cells from children and adolescents with obesity (OB group, n = 20) with those with eutrophy group (EU group, n = 16). Plasma levels of cytokines in both groups were determined by cytometric bead array (CBA). RESULTS: The OB group presents a lower frequency of CD3+ T cells, as well as a decreased frequency of CD4+ T cells expressing CD28, IL-4, and FOXP3, but an increased frequency of CD4+IL-17A+ cells compared with the EU group. The frequency of CD28 is increased in Th2 and Treg cells in the OB group, whereas CTLA-4 is decreased in all subpopulations compared with the EU group. Furthermore, Th2, Th17, and Treg profiles can differentiate the EU and OB groups. IL-10 plasma levels are reduced in the OB group and negatively correlated with adiposity and inflammatory parameters. CONCLUSIONS: CD4+ T cells have an altered pattern of expression in children and adolescents with obesity, contributing to the inflammatory state and clinical characteristics of these patients.

Assuntos

Linfócitos T CD4-Positivos , Citocinas , Humanos , Criança , Adolescente , Feminino , Masculino , Linfócitos T CD4-Positivos/imunologia , Citocinas/sangue , Citocinas/metabolismo , Obesidade/imunologia , Subpopulações de Linfócitos T/imunologia , Obesidade Infantil/imunologia , Fatores de Transcrição Forkhead/metabolismo , Fatores de Transcrição Forkhead/genética , Antígeno CTLA-4/metabolismo , Interleucina-4/sangue , Antígenos CD28/metabolismo

RESUMO

PURPOSE: This study aims to develop radiomics models and a nomogram based on machine learning techniques, preoperative dual-energy computed tomography (DECT) images, clinical and pathological characteristics, to explore the tumor microenvironment (TME) of clear cell renal cell carcinoma (ccRCC). METHODS: We retrospectively recruited of 87 patients diagnosed with ccRCC through pathological confirmation from Center I (training set, n = 69; validation set, n = 18), and collected their DECT images and clinical information. Feature selection was conducted using variance threshold, SelectKBest, and the least absolute shrinkage and selection operator (LASSO). Radiomics models were then established using 14 classifiers to predict TME cells. Subsequently, we selected the most predictive radiomics features to calculate the radiomics score (Radscore). A combined model was constructed through multivariate logistic regression analysis combining the Radscore and relevant clinical characteristics, and presented in the form of a nomogram. Additionally, 17 patients were recruited from Center II as an external validation cohort for the nomogram. The performance of the models was assessed using methods such as the area under the receiver operating characteristic curve (AUC), calibration curve, and decision curve analysis (DCA). RESULTS: The validation set AUC values for the radiomics models assessing CD8+, CD163+, and αSMA+ cells were 0.875, 0.889, and 0.864, respectively. Additionally, the external validation cohort AUC value for the nomogram reaches 0.849 and shows good calibration. CONCLUSION: Radiomics models could allow for non-invasive assessment of TME cells from DECT images in ccRCC patients, promising to enhance our understanding and management of the tumor.

RESUMO

Despite advances in understanding systemic lupus erythematosus (SLE), many challenges remain in unraveling the precise mechanisms behind the disease's development and progression. Recent evidence has questioned the role of programmed cell death protein 1 (PD-1) in suppressing autoreactive CD4+ T cells during autoimmune responses. Research has investigated the potential impacts of PD-1 on various CD4+ T-cell subpopulations, including T follicular helper (Tfh) cells, circulating Tfh (cTfh) cells, and T peripheral helper (Tph) cells, all of which exhibit substantial PD-1 expression and are closely related to several autoimmune disorders, including SLE. This review highlights the complex role of PD-1 in autoimmunity and emphasizes the imperative for further research to elucidate its functions during autoreactive T-cell responses. Additionally, we address the potential of PD-1 and its ligands as possible therapeutic targets in SLE.

Assuntos

Autoimunidade , Lúpus Eritematoso Sistêmico , Receptor de Morte Celular Programada 1 , Lúpus Eritematoso Sistêmico/imunologia , Lúpus Eritematoso Sistêmico/metabolismo , Humanos , Receptor de Morte Celular Programada 1/metabolismo , Receptor de Morte Celular Programada 1/imunologia , Animais , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo

RESUMO

INTRODUCTION: Memory CD8+ T cells are essential for long-term immune protection in viral infections, including COVID-19. METHODS: This study examined the responses of CD8+ TEM, TEMRA, and TCM subsets from unvaccinated individuals who had recovered from mild and severe COVID-19 by flow cytometry. RESULTS AND DISCUSSION: The peptides triggered a higher frequency of CD8+ TCM cells in the recovered mild group. CD8+ TCM and TEM cells showed heterogeneity in CD137 expression between evaluated groups. In addition, a predominance of CD137 expression in naïve CD8+ T cells, TCM, and TEM was observed in the mild recovered group when stimulated with peptides. Furthermore, CD8+ TCM and TEM cell subsets from mild recovered volunteers had higher TNF-α expression. In contrast, the expression partner of IFN-γ, IL-10, and IL-17 indicated an antiviral signature by CD8+ TEMRA cells. These findings underscore the distinct functional capabilities of each memory T cell subset in individuals who have recovered from COVID-19 upon re-exposure to SARS-CoV-2 antigens.

Assuntos

Linfócitos T CD8-Positivos , COVID-19 , Células T de Memória , SARS-CoV-2 , Membro 9 da Superfamília de Receptores de Fatores de Necrose Tumoral , Fator de Necrose Tumoral alfa , Humanos , COVID-19/imunologia , Membro 9 da Superfamília de Receptores de Fatores de Necrose Tumoral/metabolismo , Membro 9 da Superfamília de Receptores de Fatores de Necrose Tumoral/imunologia , SARS-CoV-2/imunologia , Linfócitos T CD8-Positivos/imunologia , Fator de Necrose Tumoral alfa/metabolismo , Células T de Memória/imunologia , Masculino , Adulto , Pessoa de Meia-Idade , Feminino , Memória Imunológica/imunologia

RESUMO

Aflatoxin B1 (AFB1) and fumonisin B1 (FB1) are mycotoxins widely found as cereal contaminants, and their co-consumption is associated with liver cancer. Both are immunotoxic, but their interactions have been little studied. This work was aimed to evaluate in mouse spleen mononuclear cells (SMC) the effects of the exposure to AFB1 (5-50 µM), FB1 (25-250 µM), and AFB1-FB1 mixtures (MIX) on the in vitro differentiation of regulatory T cells (Treg and Tr1-like) and Th17 cells, as well as elucidate the contribution of aryl hydrocarbon receptor (Ahr) in such effects. AFB1 and mainly MIX induced cytotoxicity in activated CD4 cells via Ahr signaling. AFB1 (5 µM) increased the Treg cell differentiation, but its combination with FB1 (25 µM) also reduced Th17 cell expansion by Ahr-dependent mechanisms. Therefore, this mixture could enhance the Treg/Th17 cell ratio and favor immunosuppression and escape from tumor immunosurveillance to a greater extent than individual mycotoxins. Whereas, AFB1-FB1 mixtures at medium-high doses inhibited the Tr1-like cell expansion induced by the individual mycotoxins and affected Treg and Th17 cell differentiation in Ahr-independent and dependent manners, respectively, which could alter anti-inflammatory and Th17 immune responses. Moreover, individual FB1 altered regulatory T and Th17 cell development independently of Ahr. In conclusion, AFB1 and FB1 interact by modifying Ahr signaling, which is involved in the immunotoxicity as well as in the alteration of the differentiation of Treg, Tr1-like, and Th17 cells induced by AFB1-FB1 mixtures. Therefore, Ahr is implicated in the regulation of the anti- and pro-inflammatory responses caused by the combination of AFB1 and FB1.

Assuntos

Aflatoxina B1 , Diferenciação Celular , Fumonisinas , Receptores de Hidrocarboneto Arílico , Linfócitos T Reguladores , Células Th17 , Receptores de Hidrocarboneto Arílico/metabolismo , Aflatoxina B1/toxicidade , Animais , Células Th17/efeitos dos fármacos , Linfócitos T Reguladores/efeitos dos fármacos , Fumonisinas/toxicidade , Camundongos , Diferenciação Celular/efeitos dos fármacos

RESUMO

CD4+ T lymphocytes play a key role in the modulation of the immune response by orchestrating both effector and regulatory functions. The effect of metformin on the immunometabolism of CD4+ T lymphocytes has been scarcely studied, and its impact under high glucose conditions, particularly concerning effector responses and glucose metabolism, remains unknown. This study aims to evaluate the effect of metformin on the modulation of the effector functions and glucose metabolism of CD4+ T lymphocytes under normo- and hyperglycemic conditions. CD4+ T lymphocytes, obtained from peripheral blood from healthy volunteers, were anti-CD3/CD28-activated and cultured for 4 days with three concentrations of metformin (0.1 mM, 1 mM, and 5 mM) under normoglycemic (5.5 mM) and hyperglycemic (25 mM) conditions. Effector functions such as proliferation, cell count, cell cycle analysis, activation markers and cytokine secretion were analyzed by flow cytometry. Glucose uptake was determined using the 2-NBDG assay, and levels of glucose, lactate, and phosphofructokinase (PFK) activity were assessed by colorimetric assays. Metformin at 5 mM restrained the cell counts and proliferation of CD4+ T lymphocytes by arresting the cell cycle in the S/G2 phase at the beginning of the cell culture, without affecting cell activation, cytokine production, and glucose metabolism. In fact, CD69 expression and IL4 secretion by CD4+ T lymphocytes was higher in the presence of 5 mM than the untreated cells in both glucose conditions. Overall, metformin inhibited proliferation through mechanisms associated with cell cycle arrest, leading to an increase in the S/G2 phases at the expense of G1 in activated CD4+ T lymphocytes in normo- and hyperglycemic conditions. Despite the cell cycle arrest, activated CD4+ T lymphocytes remained metabolically, functionally, and phenotypically activated.

Assuntos

Linfócitos T CD4-Positivos , Pontos de Checagem do Ciclo Celular , Proliferação de Células , Hiperglicemia , Metformina , Metformina/farmacologia , Humanos , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/metabolismo , Proliferação de Células/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Hiperglicemia/tratamento farmacológico , Hiperglicemia/metabolismo , Glucose/metabolismo , Hipoglicemiantes/farmacologia , Células Cultivadas , Masculino , Adulto

RESUMO

The first step in comprehending the properties of Au10 clusters is understanding the lowest energy structure at low and high temperatures. Functional materials operate at finite temperatures; however, energy computations employing density functional theory (DFT) methodology are typically carried out at zero temperature, leaving many properties unexplored. This study explored the potential and free energy surface of the neutral Au10 nanocluster at a finite temperature, employing a genetic algorithm coupled with DFT and nanothermodynamics. Furthermore, we computed the thermal population and infrared Boltzmann spectrum at a finite temperature and compared it with the validated experimental data. Moreover, we performed the chemical bonding analysis using the quantum theory of atoms in molecules (QTAIM) approach and the adaptive natural density partitioning method (AdNDP) to shed light on the bonding of Au atoms in the low-energy structures. In the calculations, we take into consideration the relativistic effects through the zero-order regular approximation (ZORA), the dispersion through Grimme's dispersion with Becke-Johnson damping (D3BJ), and we employed nanothermodynamics to consider temperature contributions. Small Au clusters prefer the planar shape, and the transition from 2D to 3D could take place at atomic clusters consisting of ten atoms, which could be affected by temperature, relativistic effects, and dispersion. We analyzed the energetic ordering of structures calculated using DFT with ZORA and single-point energy calculation employing the DLPNO-CCSD(T) methodology. Our findings indicate that the planar lowest energy structure computed with DFT is not the lowest energy structure computed at the DLPN0-CCSD(T) level of theory. The computed thermal population indicates that the 2D elongated hexagon configuration strongly dominates at a temperature range of 50-800 K. Based on the thermal population, at a temperature of 100 K, the computed IR Boltzmann spectrum agrees with the experimental IR spectrum. The chemical bonding analysis on the lowest energy structure indicates that the cluster bond is due only to the electrons of the 6 s orbital, and the Au d orbitals do not participate in the bonding of this system.