Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 9.146
Filtrar
1.
Nat Rev Immunol ; 20(10): 633-643, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32782358

RESUMO

Antibody-dependent enhancement (ADE) is a mechanism by which the pathogenesis of certain viral infections is enhanced in the presence of sub-neutralizing or cross-reactive non-neutralizing antiviral antibodies. In vitro modelling of ADE has attributed enhanced pathogenesis to Fcγ receptor (FcγR)-mediated viral entry, rather than canonical viral receptor-mediated entry. However, the putative FcγR-dependent mechanisms of ADE overlap with the role of these receptors in mediating antiviral protection in various viral infections, necessitating a detailed understanding of how this diverse family of receptors functions in protection and pathogenesis. Here, we discuss the diversity of immune responses mediated upon FcγR engagement and review the available experimental evidence supporting the role of FcγRs in antiviral protection and pathogenesis through ADE. We explore FcγR engagement in the context of a range of different viral infections, including dengue virus and SARS-CoV, and consider ADE in the context of the ongoing SARS-CoV-2 pandemic.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Anticorpos Antivirais/administração & dosagem , Anticorpos Facilitadores/efeitos dos fármacos , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Leucócitos/efeitos dos fármacos , Pneumonia Viral/tratamento farmacológico , Receptores de IgG/imunologia , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/biossíntese , Anticorpos Neutralizantes/administração & dosagem , Anticorpos Neutralizantes/efeitos adversos , Anticorpos Neutralizantes/biossíntese , Anticorpos Antivirais/efeitos adversos , Anticorpos Antivirais/biossíntese , Betacoronavirus/imunologia , Betacoronavirus/patogenicidade , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Dengue/tratamento farmacológico , Dengue/imunologia , Dengue/virologia , Vírus da Dengue/efeitos dos fármacos , Vírus da Dengue/imunologia , Vírus da Dengue/patogenicidade , Regulação da Expressão Gênica , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Interações Hospedeiro-Patógeno/imunologia , Humanos , Leucócitos/imunologia , Leucócitos/virologia , Pandemias , Pneumonia Viral/imunologia , Pneumonia Viral/virologia , Receptores de IgG/antagonistas & inibidores , Receptores de IgG/genética , Vírus da SARS/efeitos dos fármacos , Vírus da SARS/imunologia , Vírus da SARS/patogenicidade , Síndrome Respiratória Aguda Grave/tratamento farmacológico , Síndrome Respiratória Aguda Grave/imunologia , Síndrome Respiratória Aguda Grave/virologia , Transdução de Sinais , Internalização do Vírus/efeitos dos fármacos
2.
Medicine (Baltimore) ; 99(27): e20931, 2020 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-32629693

RESUMO

Various psychotropic drugs may affect the hematological and biochemical profiles of plasma and its metabolism. Carbamazepine, the most well-known psychotropic drug, can cause substantial hyponatremia. Methylphenidate, a piperidine derivative structurally related to amphetamines, acts as a central nervous system stimulant. The current study evaluated whether methylphenidate affects hematological and biochemical parameters of patients diagnosed with attention deficit hyperactivity disorder.Patients undergoing treatment for attention deficit hyperactivity disorder at our Adolescent Psychiatric Clinic were enrolled in the study. Blood samples for complete blood count and common biochemical analyses were collected before patients started methylphenidate and after 3 months of continuous treatment.Participants included 64 patients comprised the study cohort. There were 48 (75%) males and 16 (25%) females, with a median age of 16 years (range 11-31). The total median potassium level decreased by 0.6 mg/dL (P < .0001), while glucose rose by 15 mg/dL (P < .0001), sodium decreased in 0.7meq/L, (P = .006). The white blood count rose by 1350 cells/µL (P < .033) due to neutrophilia, lymphocytosis and eosinophilia. Hemoglobin rose slightly by 0.1 (P = .041). Changes in calcium, phosphorus, protein, albumin, and liver enzyme levels were not significant.The results indicate that methylphenidate may cause hypokalemia and elevated glucose, leukocyte, neutrophil, lymphocyte and eosinophil counts.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Estimulantes do Sistema Nervoso Central/uso terapêutico , Metilfenidato/uso terapêutico , Adolescente , Adulto , Transtorno do Deficit de Atenção com Hiperatividade/sangue , Estimulantes do Sistema Nervoso Central/farmacologia , Criança , Estudos de Coortes , Feminino , Humanos , Hipoglicemia/induzido quimicamente , Leucócitos/efeitos dos fármacos , Masculino , Metilfenidato/farmacologia , Neutrófilos/efeitos dos fármacos , Adulto Jovem
3.
Ars pharm ; 61(2): 135-143, abr.-jun. 2020. tab, graf
Artigo em Espanhol | IBECS | ID: ibc-191334

RESUMO

INTRODUCCIÓN: la solución CM-95 constituye un candidato a medicamento inmunomodulador en la terapia de pacientes con cáncer, el que debe cumplir las Buenas Prácticas de Producción con el correspondiente control de calidad y estabilidad, según las regulaciones vigentes. Se determinó la estabilidad de la solución CM-95 y el conteo de leucocitos en ratones Balb/c en el tiempo de relajación magnética. MÉTODO: se elaboraron tres lotes pilotos, los que fueron sometidos a estudios de estabilidad de vida de estante y acelerado. Los índices de calidad determinados antes y después del tratamiento magnético fueron: características organolépticas, pH, conductividad eléctrica, valoración del cloruro de sodio, concentración del preservo y control microbiológico. Se determinó el conteo de leucocitos totales en ratones Balb/C antes y después del tratamiento. RESULTADOS: se demostró el cumplimiento de los parámetros establecidos en condiciones aceleradas y vida útil de la solución, sin y con tratamiento magnético. Se demostró la utilidad del sistema envase - cierre seleccionado durante el estudio. El conteo total de leucocitos mostró variaciones con respecto al control hasta los dos meses como efecto del tratamiento magnético. CONCLUSIONES: se demostró el cumplimiento de los índices de calidad establecidos de la solución CM-95 tratada magnéticamente, en las condiciones aceleradas y de vida útil empleando ambos tipos de envase. Se evidenció la activación de la respuesta inmune a partir del tratamiento hasta los dos meses. Se comprobó que el tiempo de relajación magnética de la solución fue de dos meses


INTRODUCTION: the CM-95 solution constitutes a candidate for immunomodulatory medication in the therapy of cancer patients, who must comply with Good Production Practices with the corresponding quality and stability control, according to current regulations. It was determined the stability of the CM-95 solution and the leukocyte count in Balb / c mice at the time of magnetic relaxation. METHODS: three pilot lots were prepared, which were subjected to shelf stability and accelerated life studies. The quality indices determined before and after the magnetic treatment were: organoleptic characteristics, pH, electrical conductivity, sodium chloride titration, preservation concentration and microbiological control. Total white blood cell count in Balb / C mice was determined before and after treatment. RESULTS: compliance with the parameters established in accelerated conditions and solution life, without and with magnetic treatment, was demonstrated. The utility of the container-closure system selected during the study was demonstrated. The total white blood cell count showed variations with respect to the control up to two months as an effect of the magnetic treatment. CONCLUSIONS: compliance with the established quality indices of the magnetically treated CM-95 solution was demonstrated, under accelerated conditions and useful life using both types of packaging. The activation of the immune response was evident from the treatment up to two months. It was found that the magnetic relaxation time of the solution was two months


Assuntos
Animais , Masculino , Camundongos , Fenômenos Magnéticos , Relaxamento , Imunomodulação , Antineoplásicos/química , Leucócitos/efeitos dos fármacos , Drogas em Investigação , Projetos Piloto , Camundongos Endogâmicos BALB C
4.
Exp Parasitol ; 216: 107940, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32562606

RESUMO

Therapeutic options for the treatment of leishmaniasis are insufficient and need improvements owing to their low efficiency and high toxicity as well as the emergence of resistant strains. The limited number of new drugs for neglected diseases and lack of innovation in your development are still challenges. In this context, the process of discovery and development of biological assays play a pivotal role for the identification of bioactive compounds. The assays currently used for screening of drugs with cytotoxic activity against Leishmania parasites, include different processes that utilize intact parasite (free or intracellular) or specific enzymes of metabolism as a target cell. These assays allow the screening of large numbers of samples followed by more detailed secondary confirmatory assays to confirm the observed activity and assess their toxicity. In the present study, we described the development of a new functional and more complete assay that enables simultaneous assessment of potential anti-Leishmania compounds through evaluation of internalization of fluorescein-labeled L. braziliensis promastigotes by human peripheral blood monocytes and their cytotoxicity by flow cytometry. We standardized the conditions for parasite labeling to achieve better phagocytosis analysis by setting the ratio of number of parasites per cell as 1 to 2, at incubation time of 6h. The cytotoxicity assessment was performed by the quantification of cells undergoing early/late apoptosis and necrosis using a double labelling platform employing 7AAD for late apoptosis and necrosis analysis and Annexin-V for early apoptosis evaluation. Hemolysis analysis was an additional parameter to test cytotoxicity. Two drugs used on clinic (Amphotericin B and Glucantime®) were used to validate the proposed methodology, and the assay was able to detect their known leishmanicidal activity and immunotoxicity properties. This new predictive assay will contribute to the development of translational medicine strategies in drug discovery for neglected diseases such as leishmaniasis.


Assuntos
Alternativas aos Testes com Animais/métodos , Antiprotozoários/toxicidade , Citometria de Fluxo/métodos , Leishmania/efeitos dos fármacos , Doenças Negligenciadas/tratamento farmacológico , Adulto , Anfotericina B/farmacologia , Anfotericina B/toxicidade , Animais , Antiprotozoários/farmacologia , Antiprotozoários/uso terapêutico , Descoberta de Drogas/métodos , Avaliação Pré-Clínica de Medicamentos/métodos , Fluoresceína-5-Isotiocianato , Corantes Fluorescentes , Humanos , Leishmania braziliensis/efeitos dos fármacos , Leishmaniose/tratamento farmacológico , Leucócitos/efeitos dos fármacos , Leucócitos/parasitologia , Antimoniato de Meglumina/farmacologia , Antimoniato de Meglumina/uso terapêutico , Antimoniato de Meglumina/toxicidade , Microscopia Confocal , Pessoa de Meia-Idade , Monócitos/efeitos dos fármacos , Monócitos/parasitologia , Fatores de Tempo , Adulto Jovem
5.
EMBO Mol Med ; 12(8): e12697, 2020 08 07.
Artigo em Inglês | MEDLINE | ID: mdl-32473600

RESUMO

Baricitinib is an oral Janus kinase (JAK)1/JAK2 inhibitor approved for the treatment of rheumatoid arthritis (RA) that was independently predicted, using artificial intelligence (AI) algorithms, to be useful for COVID-19 infection via proposed anti-cytokine effects and as an inhibitor of host cell viral propagation. We evaluated the in vitro pharmacology of baricitinib across relevant leukocyte subpopulations coupled to its in vivo pharmacokinetics and showed it inhibited signaling of cytokines implicated in COVID-19 infection. We validated the AI-predicted biochemical inhibitory effects of baricitinib on human numb-associated kinase (hNAK) members measuring nanomolar affinities for AAK1, BIKE, and GAK. Inhibition of NAKs led to reduced viral infectivity with baricitinib using human primary liver spheroids. These effects occurred at exposure levels seen clinically. In a case series of patients with bilateral COVID-19 pneumonia, baricitinib treatment was associated with clinical and radiologic recovery, a rapid decline in SARS-CoV-2 viral load, inflammatory markers, and IL-6 levels. Collectively, these data support further evaluation of the anti-cytokine and anti-viral activity of baricitinib and support its assessment in randomized trials in hospitalized COVID-19 patients.


Assuntos
Antivirais/farmacologia , Inteligência Artificial , Azetidinas/farmacologia , Betacoronavirus , Infecções por Coronavirus/tratamento farmacológico , Pandemias , Pneumonia Viral/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Sulfonamidas/farmacologia , Adulto , Idoso , Antivirais/farmacocinética , Antivirais/uso terapêutico , Azetidinas/farmacocinética , Azetidinas/uso terapêutico , Citocinas/antagonistas & inibidores , Avaliação Pré-Clínica de Medicamentos , Reposicionamento de Medicamentos , Feminino , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Leucócitos/efeitos dos fármacos , Fígado , Masculino , Pessoa de Meia-Idade , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Esferoides Celulares/efeitos dos fármacos , Esferoides Celulares/virologia , Sulfonamidas/farmacocinética , Sulfonamidas/uso terapêutico
6.
Ecotoxicol Environ Saf ; 200: 110761, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32470682

RESUMO

Benzo()pyrene [B()P], widely originated from environmental pollution or food process such as roasting and frying, is a strong mutagen and potent carcinogen. Utilization of hawthorn has been reported against physical mutagens. Our study found that hawthorn extract (HE) contained abundant phenolic compounds, wherein chlorogenic acid was 2.78 mg/g, procyanidine B2 was 3.58 mg/g, epicatechin was 2.99 mg/g DW, which may contribute to anti-genotoxicity activity. So, the role of HE against B()P-induced genotoxicity in C57BL/6 mice was further assessed. Fifty mice were distributed into five groups: control group, B()P group (30 mg/kg, i.p.), B()P + HE-L group (100 mg/kg, i.g.), B()P + HE-M group (200 mg/kg, i.g.), B()P + HE-H group (400 mg/kg, i.g.). Mice were orally administered with solutions of HE for 10 days and injected intraperitoneally with B()P for 3 days from the 8th day. Results showed that B()P can induce significantly pathological damage in liver, lung and spleen, as well as decrease white blood cells (WBCs). Remarkably elevated levels of reactive oxygen species (ROS), DNA strand breaks (DSBs) and G1 cell cycle arrest were also found in B()P group, with upregulated expressions of p-H2AX, p-p53 and p21 in bone marrow cells. With administration of HE, liver, lung and spleen injury significantly mitigated, while WBCs were evidently increased in B()P-treated mice. Consistently, HE markedly reduced level of ROS, DSBs and G1 cell cycle arrest accompanied by reducing expressions of p-H2AX, p-p53 and p21 in bone marrow cells. Combined, these results indicated a protective role of HE on B()P-induced genotoxicity.


Assuntos
Benzo(a)pireno/toxicidade , Crataegus/química , Dano ao DNA/efeitos dos fármacos , Mutagênicos/toxicidade , Extratos Vegetais/farmacologia , Substâncias Protetoras/farmacologia , Animais , Células da Medula Óssea/efeitos dos fármacos , Células da Medula Óssea/metabolismo , Expressão Gênica/efeitos dos fármacos , Histonas/genética , Leucócitos/efeitos dos fármacos , Leucócitos/metabolismo , Fígado/efeitos dos fármacos , Fígado/patologia , Pulmão/efeitos dos fármacos , Pulmão/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Extratos Vegetais/isolamento & purificação , Substâncias Protetoras/isolamento & purificação , Espécies Reativas de Oxigênio/metabolismo , Baço/efeitos dos fármacos , Baço/patologia , Proteína Supressora de Tumor p53/genética
7.
Artigo em Inglês | MEDLINE | ID: mdl-32330807

RESUMO

Honey-processed Astragalus is a dosage form of radix Astragali processed with honey, which is deemed to contain better qi-tonifying effects in traditional Chinese medicine theroy. Our previous study has demonstrated that honey-processed Astragalus exhibited a better effect on reinforcing qi (vital energy) and immune improvement toward spleen qi deficiency compared with radix Astragali. However, the detailed mechanisms related to qi-tonifying effects of honey-processed Astragalus is still unclear. In this study, we evaluated the qi-tonifying effects of honey-processed Astragalus on spleen qi deficiency rats and predicted the mechanisms by aggregating metabonomics, lipidomics and network pharmacology. The results revealed that body weights, symptom scores, the levels of red blood cell, white blood cell, lymphocyte, spleen and thymus indexes, and three cytokines (TNF-α, IL-6, IFN-γ) in honey-processed Astragalus treated rats were improved in comparison with spleen qi deficiency rats. In parallel, based on the 26 biomarkers screened in metabonomics and lipidomics, we inferred that glycerophospholipid metabolism significantly regulated in pathway analysis was connected with qi-tonifying effects. Moreover, the network pharmacology analysis concluded that the compounds targets of honey-processed Astragalus CDK2, NOS3, MAPK14, PTGS1 and PTGS2 interacted with markers targets PLA2G(s) family and LYPLA1 could be responsible for regulation of glycerophospholipid metabolism to develop qi-tonifying effects. What's more, the above processes were possibly through VEGF signaling and MAPK signaling pathways.


Assuntos
Astrágalo (Planta)/química , Citocinas/sangue , Medicamentos de Ervas Chinesas/farmacologia , Espectrometria de Massas em Tandem/métodos , Animais , Biomarcadores/sangue , Peso Corporal/efeitos dos fármacos , Cromatografia Líquida de Alta Pressão , Citocinas/metabolismo , Composição de Medicamentos/métodos , Eritrócitos/efeitos dos fármacos , Feminino , Mel , Humanos , Leucócitos/efeitos dos fármacos , Lipidômica , Linfócitos/efeitos dos fármacos , Qi , Ratos , Ratos Sprague-Dawley , Baço/efeitos dos fármacos , Timo/efeitos dos fármacos
8.
Arch Environ Contam Toxicol ; 79(1): 122-130, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32300848

RESUMO

Exposure to polychlorinated biphenyls (PCBs) and organochlorine pesticides (OCPs) through food, water, and air occurred during the life, which may change telomere length (TL) in peripheral blood leukocytes. The present study was designed to investigate the association between TL and serum levels of PCBs and OCPs in Tehran male's population. Whole blood samples were randomly taken from 300 adult males, aged between 25 and 40 years. TL was determined by real-time PCR to measure the number of the telomere (T) repeats to the number of a single-copy gene (S). We applied the multivariate linear regression model to compare the effect of each lipid adjusted serum levels of PCBs and OCPs congener on the TL, with adjustment for age, body mass index, education, smoking, and food patterns. Each doubling of the nondioxin-like PCBs, dioxin-like PCBs, and OCPs levels were associated with 1.9% [95% confidence interval (CI) - 0.70 to 5.40%], 2.5% (95% CI 0.30-8.3%), and - 2.4% (95% CI - 0.70 to - 6.2%) variation in the TL, respectively. The percent difference in the TL with exposure to nondioxin-like PCBs, dioxin-like PCBs, and OCPs for participants with older than age 37 years were 6.45% (95% CI 2.81-16.50%), 4.52% (95% CI 1.60-10.54%), and - 7.44% (95% CI - 1.55 to - 15.51%), respectively. Exposures to nondioxin-like PCBs (except for PCB 28 and 52) with high chlorine in structure and dioxin-like PCBs were related to longer TLs. Conversely, serum levels of OCPs can be associated with oxidative stress and systemic inflammation that lead to telomere shortening.


Assuntos
Hidrocarbonetos Clorados/sangue , Leucócitos/efeitos dos fármacos , Praguicidas/sangue , Bifenilos Policlorados/sangue , Homeostase do Telômero/efeitos dos fármacos , Telômero/efeitos dos fármacos , Adulto , Fatores Etários , Humanos , Hidrocarbonetos Clorados/toxicidade , Irã (Geográfico) , Leucócitos/patologia , Lipídeos/sangue , Masculino , Praguicidas/toxicidade , Bifenilos Policlorados/toxicidade , Distribuição Aleatória , Inquéritos e Questionários
9.
Am J Physiol Renal Physiol ; 318(4): F982-F993, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32150444

RESUMO

Studies examining mechanisms of Dahl salt-sensitive (SS) hypertension have implicated the infiltration of leukocytes in the kidneys, which contribute to renal disease and elevated blood pressure. However, the signaling pathways by which leukocytes traffic to the kidneys remain poorly understood. The present study nominated a signaling pathway by analyzing a kidney RNA sequencing data set from SS rats fed either a low-salt (0.4% NaCl) diet or a high-salt (4.0% NaCl) diet. From this analysis, chemokine (C-C motif) ligand 2 (CCL2) and chemokine (C-C motif) receptor 2 (CCR2) were nominated as a potential pathway modifying renal leukocyte infiltration and contributing to SS hypertension. The functional role of the CCL2/CCR2 pathway was tested by daily administration of CCR2 antagonist (RS-102895 at 5 mg·kg-1·day-1 in DMSO) or DMSO vehicle for 3 or 21 days by intraperitoneal injections during the high salt challenge. Blood pressure, renal leukocyte infiltration, and renal damage were evaluated. The results demonstrated that RS-102895 treatment ameliorated renal damage (urinary albumin excretion; 43.4 ± 5.1 vs. 114.7 ± 15.2 mg/day in vehicle, P < 0.001) and hypertension (144.3 ± 2.2 vs. 158.9 ± 4.8 mmHg in vehicle, P < 0.001) after 21 days of high-salt diet. It was determined that renal leukocyte infiltration was blunted by day 3 of the high-salt diet (1.4 ± 0.1 vs. 1.9 ± 0.2 in vehicle × 106 CD45+ cells/kidney, P = 0.034). An in vitro chemotaxis assay validated the effect of RS-102895 on leukocyte chemotaxis toward CCL2. The results suggest that increased CCL2 in SS kidneys is important in the early recruitment of leukocytes, and blockade of this recruitment by administering RS-102895 subsequently blunted the renal damage and hypertension.


Assuntos
Quimiocina CCL2/metabolismo , Quimiotaxia de Leucócito , Hipertensão/metabolismo , Rim/metabolismo , Leucócitos/metabolismo , Cloreto de Sódio na Dieta , Animais , Anti-Hipertensivos/farmacologia , Pressão Arterial , Benzoxazinas/farmacologia , Células Cultivadas , Quimiocina CCL2/antagonistas & inibidores , Quimiocina CCL2/genética , Quimiotaxia de Leucócito/efeitos dos fármacos , Modelos Animais de Doenças , Hipertensão/patologia , Hipertensão/fisiopatologia , Hipertensão/prevenção & controle , Rim/efeitos dos fármacos , Rim/patologia , Leucócitos/efeitos dos fármacos , Leucócitos/patologia , Masculino , Piperidinas/farmacologia , Ratos Endogâmicos Dahl , Receptores CCR2/antagonistas & inibidores , Receptores CCR2/metabolismo , Transdução de Sinais , Regulação para Cima
10.
PLoS One ; 15(2): e0228617, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32045436

RESUMO

OBJECTIVE: Determine if patient-specific factors modulate absolute lymphocyte count (ALC), neutrophil count (ANC), and/or Neutrophile-lymphocyte ratio (NLR) in Dimethyl Fumarate (DMF) treated patients. METHODS: A retrospective study of patients who initiated DMF between 2013-2018. A multicenter study of two MS clinics: Charlottesville, VA (UVA) and Dallas, TX (DaVA). RESULTS: 103 patients (67-UVA, 36-DaVA) met eligibility. At baseline, the DaVa population was younger (mean±sd: 38.6±9.0 vs 42.2±12.5, p 0.152) and had a higher proportion of males (61% vs. 35%), consistent with a veteran cohort. Pre-treatment, all other laboratory parameters were similar between the two groups. On treatment there was a 30% lowering of mean ALC, with 3% having grade-3 lymphopenia (ALC < 500). Sustained neutropenia occurred in 3.9% of patients and was more common in males. Over 50% of patients had a high NLR at baseline, with a further 44% increase in NLR on-treatment. Age was significantly predictive of lymphopenia, with grade-3 lymphopenia found in 33% of patients ≥ 55 years. Neutropenia was more common in males. Serum BG (sBG) has modest correlation to leukocyte parameters. BMI was not correlated with any leukocyte-related outcomes. CONCLUSIONS: Patient-specific factors, specifically-age, sex, and serum blood glucose, modulate leukocyte response and ratios in DMF treated MS patients. Age appears to be a relevant predictor of lymphopenia and should be a factor in treatment decision making. Neutropenia, independent of lymphopenia, can occur and males may be at increased risk. High sBG may impact leukocyte count and ratios in MS patients and merits further study, particularly in patients with diabetes. NLR is abnormal in MS and increased with DMF-treatment, the clinical implications of this will require further study.


Assuntos
Linfopenia/epidemiologia , Esclerose Múltipla/sangue , Neutropenia/epidemiologia , Adulto , Fatores Etários , Fumarato de Dimetilo/farmacologia , Fumarato de Dimetilo/uso terapêutico , Feminino , Humanos , Imunossupressores/farmacologia , Imunossupressores/uso terapêutico , Leucócitos/efeitos dos fármacos , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/complicações , Esclerose Múltipla/tratamento farmacológico , Modelagem Computacional Específica para o Paciente , Fatores Sexuais
11.
Chemosphere ; 248: 126092, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32041072

RESUMO

Exposure to polychlorinated biphenyls (PCBs) and organochlorine pesticides (OCPs) may change leukocyte telomere length (TL) at the end of the DNA sequence. The purpose of this study was to investigate the association between PCBs and OCPs exposure with TL in Tehran adult males. Whole-blood samples were randomly taken from three hundred adult males in population-based cross-section study from October 2016 to November 2017. We studied the serum levels of PCBs, OCPs as well as socio-demographic characteristics of individuals. The quantitative PCR was used to investigate the number of the telomere (T) repeats to the number of a single copy gene. We measured the effect of each PCBs and OCPs congeners on TL using linear regressions adjusted for age, BMI, smoking, and dietary patterns. The median level of the six non-dioxin-likes, five dioxin-likes PCBs three OCPs and TL in the study population were 344.5, 306.0, 45.0 ng/g lipid and 5377.7 ± 573.4 base pairs, respectively. In the adjusted model, the percent difference in the TLs with exposure to Σnon-dioxin-like PCBs, Σdioxin-like PCBs, and OCPs were 1.93 (-0.70 to 5.4), 3.4 (1.8-8.3) and -2.4 (-0.80 to -6.2), respectively. In the fourth quartile compared to the first quartile, the percent difference in the TLs due to Σnon-dioxin-like PCBs, Σdioxin-like PCBs, and OCP exposure were 0.01 (-0.01 to 0.05), 10.3 (2.9-18.1) and -0.20 (-0.10 to -4.5), respectively. Exposures to ndl-PCBs and dl-PCBs (except for PCB28) were related to longer TLs, but OCPs exposure can be related to telomere shortening.


Assuntos
Hidrocarbonetos Clorados/sangue , Leucócitos/efeitos dos fármacos , Praguicidas/sangue , Bifenilos Policlorados/sangue , Encurtamento do Telômero/efeitos dos fármacos , Telômero/efeitos dos fármacos , Adulto , Estudos Transversais , Feminino , Humanos , Irã (Geográfico) , Leucócitos/ultraestrutura , Masculino , Distribuição Aleatória , Telômero/ultraestrutura , Adulto Jovem
12.
Sci China Life Sci ; 63(3): 375-387, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32048161

RESUMO

Inflammatory leukocytes infiltration is orchestrated by mechanisms involving chemokines, selectins, addressins and other adhesion molecules derived from endothelial cells (ECs), but how they respond to inflammatory cues and coordinate leukocyte transmigration remain elusive. In this study, using hepatic ischemia/reperfusion injury (HIRI) as a model, we identified that endothelial Notch activation was rapidly and dynamically induced in liver sinusoidal endothelial cells (LSECs) in acute inflammation. In mice with EC-specific Notch activation (NICeCA), HIRI induced exacerbated liver damage. Consistently, endothelial Notch activation enhanced neutrophil infiltration and tumor necrosis factor (TNF)-α expression in HIRI. Transcriptome analysis and further qRT-PCR as well as immunofluorescence indicated that endomucin (EMCN), a negative regulator of leukocyte adhesion, was downregulated in LSECs from NICeCA mice. EMCN was downregulated during HIRI in wild-type mice and in vitro cultured ECs insulted by hypoxia/re-oxygenation injury. Notch activation in ECs led to increased neutrophil adhesion and transendothelial migration, which was abrogated by EMCN overexpression in vitro. In mice deficient of RBPj, the integrative transcription factor of canonical Notch signaling, although overwhelming sinusoidal malformation aggravated HIRI, the expression of EMCN was upregulated; and pharmaceutical Notch blockade in vitro also upregulated EMCN and inhibited transendothelial migration of neutrophils. The Notch activation-exaggerated HIRI was compromised by blocking LFA-1, which mediated leukocyte adherence by associating with EMCN. Therefore, endothelial Notch signaling controls neutrophil transmigration via EMCN to modulate acute inflammation in HIRI.


Assuntos
Moléculas de Adesão Celular/metabolismo , Neutrófilos/metabolismo , Traumatismo por Reperfusão/metabolismo , Sialomucinas/genética , Animais , Biópsia , Adesão Celular , Movimento Celular , Modelos Animais de Doenças , Regulação para Baixo , Regulação Neoplásica da Expressão Gênica , Hepatócitos/metabolismo , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Leucócitos/citologia , Leucócitos/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Sialomucinas/metabolismo , Distribuição Tecidual , Fator de Necrose Tumoral alfa/metabolismo
13.
J Fish Biol ; 96(3): 731-746, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31995234

RESUMO

Polyinosinic:polycytidylic acid [poly (I:C)] was administered in vivo to Chinook salmon (Oncorhynchus tshawytscha) post-smolts to determine the immune responses on haematological and cellular functional parameters, including spleen (SP), head kidney (HK) and red blood cell (RBC) cytokine expression, as well as serum metabolomics. Poly (I:C) in vivo (24 h exposure) did not affect fish haematological parameters, leucocyte phagocytic activity and phagocytic index, reactive oxygen species and nitric oxide production. Gas chromatography-mass spectrometry-based metabolomics revealed that poly (I:C) significantly altered the serum biochemistry profile of 25 metabolites. Metabolites involved in the branched-chain amino acid/glutathione and transsulphuration pathways and phospholipid metabolism accumulated in poly (I:C)-treated fish, whereas those involved in the glycolytic and energy metabolism pathways were downregulated. At cytokine transcript level, poly (I:C) induced a significant upregulation of antiviral ifnγ in HK and Mx1 protein in HK, SP and RBCs. This study provides evidence for poly (I:C)-induced, immune-related biomarkers at metabolic and molecular levels in farmed O. tshawytscha in vivo. These findings provide insights into short-term effects of poly (I:C) at haematological, innate and adaptive immunity and metabolic levels, setting the stage for future studies.


Assuntos
Metabolismo Energético/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Sistema Imunitário/efeitos dos fármacos , Poli I-C/farmacologia , Salmão/imunologia , Adjuvantes Imunológicos/farmacologia , Animais , Proteínas de Peixes/genética , Rim Cefálico/efeitos dos fármacos , Leucócitos/efeitos dos fármacos , Fagocitose/efeitos dos fármacos , Salmão/metabolismo
14.
J Med Chem ; 63(2): 714-746, 2020 01 23.
Artigo em Inglês | MEDLINE | ID: mdl-31904959

RESUMO

The bromodomain and extraterminal (BET) family of bromodomain-containing proteins are important regulators of the epigenome through their ability to recognize N-acetyl lysine (KAc) post-translational modifications on histone tails. These interactions have been implicated in various disease states and, consequently, disruption of BET-KAc binding has emerged as an attractive therapeutic strategy with a number of small molecule inhibitors now under investigation in the clinic. However, until the utility of these advanced candidates is fully assessed by these trials, there remains scope for the discovery of inhibitors from new chemotypes with alternative physicochemical, pharmacokinetic, and pharmacodynamic profiles. Herein, we describe the discovery of a candidate-quality dimethylpyridone benzimidazole compound which originated from the hybridization of a dimethylphenol benzimidazole series, identified using encoded library technology, with an N-methyl pyridone series identified through fragment screening. Optimization via structure- and property-based design led to I-BET469, which possesses favorable oral pharmacokinetic properties, displays activity in vivo, and is projected to have a low human efficacious dose.


Assuntos
Ensaios de Triagem em Larga Escala/métodos , Proteínas/antagonistas & inibidores , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/farmacologia , Benzimidazóis/química , Benzimidazóis/farmacocinética , Benzimidazóis/farmacologia , Quimiocina CCL2/biossíntese , Cristalografia por Raios X , Descoberta de Drogas , Avaliação Pré-Clínica de Medicamentos , Sinergismo Farmacológico , Humanos , Interleucina-6/antagonistas & inibidores , Leucócitos/efeitos dos fármacos , Masculino , Camundongos , Modelos Moleculares , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas
15.
Environ Sci Pollut Res Int ; 27(1): 411-423, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31792792

RESUMO

One of the most toxic heavy metals in the environment nowadays is lead (Pb). Even though exposure to lead has been reduced in some developed countries, individuals working in certain occupations are still exposed to lead at dangerous levels. Occupational exposure is of great concern and is also the main cause of lead poisoning. Although experts in various fields have been investigating the toxic effects of lead and its compounds for many years now, the association between chronic lead exposure and geno-toxicity is still an interesting point of research. The study aims to evaluate the possible DNA damage and the oxidative stress status induced by occupational exposure to lead and the role of concomitant smoking. The study was conducted on 60 subjects divided into two groups: an exposed group (40 male workers exposed to lead in their workplaces). This group was further divided into two subgroups; 20 workers were cigarette smokers and the other 20 workers were non-smokers. The other control group consists of 20 healthy males, not exposed to lead and matched by age to the exposed group (10 were smokers and the rest were non-smokers). Venous blood samples were collected from each participant for the determination of the following: blood lead level (BLL), plasma malondialdehyde (MDA) levels, and DNA damage using agarose gel electrophoresis. The exposed workers had significantly higher levels of lead and MDA, as well as a high frequency of DNA fragmentation. Smoking workers showed a greater frequency of DNA fragmentation than non-smokers. A significant relation was revealed between the BLL, as well as the MDA level, and the degree of DNA fragmentation among the lead-exposed workers. The study has shown additional evidence proving the association between Pb exposure and oxidative stress. The results further reinforced the role of cigarette smoking in augmenting such oxidative damage in the Pb-exposed population. However, further studies are recommended to evaluate the effect of cigarette smoking on Pb-exposed workers.


Assuntos
Poluentes Ocupacionais do Ar/análise , Chumbo/análise , Exposição Ocupacional/estatística & dados numéricos , Fumar Tabaco , Adulto , Poluentes Ocupacionais do Ar/toxicidade , Dano ao DNA , Fragmentação do DNA , Humanos , Chumbo/toxicidade , Leucócitos/efeitos dos fármacos , Masculino , Malondialdeído/metabolismo , Pessoa de Meia-Idade , Exposição Ocupacional/análise , Oxirredução , Estresse Oxidativo/efeitos dos fármacos , Fumar
16.
Cancer Immunol Immunother ; 69(2): 255-261, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31781842

RESUMO

A major challenge of cancer immunotherapy is the potential for undesirable effects on bystander cells and tumor-associated immune cells. Fundamentally, we need to understand what effect targeting tumor metabolism has upon the metabolism and phenotype of tumor-associated leukocytes, whose function can be critical for effective cancer therapeutic strategies. Undesirable effects of cancer therapeutics are a major reason for drug-associated toxicity, which confounds drug dosing and efficacy. As with any chemotherapeutic agent, drugs targeting tumor metabolism will exert potent effects on host stromal cells and tumor-associated leukocytes. Any drug targeting glycolysis, for example, could metabolically starve tumor-infiltrating T cells, inhibit their effector function and enable tumor progression. The targeting of oxidative phosphorylation in tumors will have complex effects on the polarization and function of tumor-associated macrophages. In short, we need to improve our understanding of tumor and immune cell metabolism and devise ways to specifically target tumors without compromising necessary host metabolism. Exploiting cell-specific metabolic pathways to directly target tumor cells may minimize detrimental effects on tumor-associated leukocytes.


Assuntos
Metabolismo Energético , Terapia de Alvo Molecular , Neoplasias/metabolismo , Neoplasias/terapia , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Biomarcadores , Comunicação Celular , Metabolismo Energético/efeitos dos fármacos , Metabolismo Energético/efeitos da radiação , Humanos , Imunomodulação , Leucócitos/efeitos dos fármacos , Leucócitos/imunologia , Leucócitos/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/metabolismo , Terapia de Alvo Molecular/métodos , Neoplasias/etiologia , Neoplasias/patologia , Transdução de Sinais/efeitos dos fármacos , Succinatos/metabolismo , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia
17.
Arch Anim Nutr ; 74(3): 189-205, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31851525

RESUMO

This study was conducted to assess the effect of feeding high-surface ZnO instead of common ZnO on the performance, rumen fermentation, blood minerals, leukocytes and antioxidant capacity of pre- and post-weaning calves. Thirty male suckling Holstein calves were allotted to one of three experimental groups (10 replicates) in a completely randomised design. Calves received: (1) a low Zn diet without Zn supplementation (control diet), (2) a high Zn diet containing 50 mg supplementary Zn/kg dry matter (DM) as common ZnO or (3) a high Zn diet containing 50 mg supplementary Zn/kg DM as high-surface ZnO (nano-ZnO). The control diet contained a native Zn content of 35.5, 34.7 or 33.7 mg/kg DM for the age periods of 7 to 30, 31 to 70 and 71 to 100 d, respectively. Supplementation of the diet with Zn did not change the dry matter intake (DMI) of calves during d 7 to 30 but increased the ADG in this period (p < 0.05). During age periods of 31 to 70 and 71 to 100 d, DMI and ADG of the Zn supplemented calves were higher (p < 0.05) than the control animals. The nutrient digestibility and the concentration of rumen volatile fatty acids were positively affected (p < 0.05) and the rumen ammonia-N concentration decreased (p < 0.05) by dietary Zn supplementation. Furthermore, the incidence of diarrhoea and pneumonia was lower in calves receiving the Zn supplemented diets. Irrespective of ZnO source, the blood total antioxidant capacity, leukocyte and haematocrit levels significantly increased (p < 0.05) with the ZnO supplemented diets. The post-weaning DMI, nutrient  digestibility and blood haematocrit levels were higher in calves receiving high-surface ZnO, compared to those supplemented with common ZnO. With inclusion of the Zn sources in pre- and post-weaning diets, the blood Zn concentration increased (p < 0.05), but the blood Cu, Fe, Ca, P and Mg levels remained unchanged. Regardless of source, dietary supplementation of young calves with ZnO improved the performance and decreased rumen ammonia-N and the incidence of diseases. Moreover, high-surface ZnO had advantages over common ZnO in increasing the post-weaning feed intake, digestibility and blood Zn concentration.


Assuntos
Antioxidantes/metabolismo , Bovinos/fisiologia , Leucócitos/metabolismo , Nanopartículas Metálicas , Minerais/sangue , Rúmen/metabolismo , Óxido de Zinco/metabolismo , Ração Animal/análise , Animais , Bovinos/sangue , Dieta/veterinária , Suplementos Nutricionais/análise , Relação Dose-Resposta a Droga , Fermentação , Leucócitos/efeitos dos fármacos , Masculino , Nanopartículas Metálicas/administração & dosagem , Distribuição Aleatória , Desmame , Óxido de Zinco/administração & dosagem
18.
Biochem Biophys Res Commun ; 523(1): 177-182, 2020 02 26.
Artigo em Inglês | MEDLINE | ID: mdl-31843195

RESUMO

Although circulating leukocytes are non-adherent cells, they also undergo adhesion in response to external stimuli. To elucidate this switch mechanism, we investigated PMA-induced cell adhesion in myelomonocytic KG-1 cells. PMA induced microvillius collapse, decrease of cell surface rigidity and exclusion of sialomucin from adhesion sites. All these adhesion-contributing events are linked to dephosphorylation of Ezrin/Radixin/Moesin (ERM) proteins. Indeed, PMA-treatment induced quick decrease of phosphorylated ERM proteins, while expression of Moesin-T558D, a phospho-mimetic mutant, inhibited PMA-induced cell adhesion. PMA-induced cell adhesion and ERM-dephophorylation were inhibited by PKC inhibitors or by a phosphatase inhibitor, indicating the involvement of PKC and protein phophatase in these processes. In peripheral T lymphocytes, ERM-dephosphorylation by adhesion-inducing stimuli was inhibited by a PKC inhibitor. Combined, these findings strongly suggest that external stimuli induce ERM-dephosphorylation via the activation of PKC in leukocytes and that ERM-dephosphorylation leads to leukocytes' adhesion.


Assuntos
Adesão Celular/efeitos dos fármacos , Proteínas do Citoesqueleto/metabolismo , Leucócitos/citologia , Leucócitos/efeitos dos fármacos , Proteínas de Membrana/metabolismo , Proteínas dos Microfilamentos/metabolismo , Proteína Quinase C/metabolismo , Linhagem Celular , Proteínas do Citoesqueleto/química , Relação Dose-Resposta a Droga , Ativação Enzimática/efeitos dos fármacos , Humanos , Leucócitos/metabolismo , Proteínas de Membrana/química , Proteínas dos Microfilamentos/química , Ésteres de Forbol/farmacologia , Fosforilação/efeitos dos fármacos , Proteína Quinase C/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Relação Estrutura-Atividade
19.
Toxicol In Vitro ; 62: 104718, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31706955

RESUMO

Ketamine is a potent uncompetitive NMDA receptor antagonist that provides amnesia, analgesia, environmental dissociation and immobility, where it has its cytotoxic effect well described in the literature. However, the work on its genotoxic/mutagenic potentials are scarce and insufficient and does not allow a reasonable evaluation of its role. Thus, in the present work, we decided to evaluate the genotoxic and mutagenic effects of ketamine on human peripheral blood leukocytes (PBLs) and Salmonella typhimurium (TA98, TA97a, TA100, and TA102) through several well-established experimental protocols based on different parameters in the presence or not of exogenous metabolizing S9 fraction. Our data revealed that ketamine induces a weak cytotoxic effect on human PBLs after 24 h and is devoided of hemolytic effects. A small amount of DNA strand breaks levels were detected in the modified comet assay (employment of FPG enzyme) only at highest concentrations (500 and 700 µg/mL) of ketamine, highlighting our pro-oxidant data regarding ketamine. However, the oxidative DNA lesions were almost completely repaired which reflects in the lack of mutagenesis (micronuclei and chromosomal aberrations) on human PBLs and no increases in revertants numbers on S. typhimurium/microsome test (500 to 5000 µg/plate). In summary, ketamine is a weak oxidative DNA damaging agent and is devoid of mutagenic properties on eukaryotic and prokaryotic models.


Assuntos
Anestésicos Dissociativos/toxicidade , Ketamina/toxicidade , Leucócitos/efeitos dos fármacos , Mutagênicos/toxicidade , Salmonella typhimurium/efeitos dos fármacos , Salmonella typhimurium/genética , Apoptose/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Aberrações Cromossômicas/induzido quimicamente , Ensaio Cometa , Quebras de DNA , Dano ao DNA , Hemólise/efeitos dos fármacos , Humanos , Peroxidação de Lipídeos/efeitos dos fármacos , Testes de Mutagenicidade , Estresse Oxidativo
20.
Biochim Biophys Acta Mol Basis Dis ; 1866(1): 165583, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31676378

RESUMO

Acetaminophen (APAP) is one of the most commonly used drugs worldwide, and APAP-induced liver injury is the most frequent cause of acute liver failure in developed countries. However, the mechanisms of APAP-induced hepatotoxicity are not well understood, and treatment options for the disorder are very limited. Here, we show that TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) is a major mediator of APAP-induced liver injury in mice, and its blockade markedly ameliorates the liver failure. In APAP-treated mice, TRAIL was expressed in the liver, spleen, and peripheral blood primarily by CD11b+Gr1+ neutrophils. The concentration of soluble TRAIL in the blood, and the frequencies of TRAIL+ leukocytes in the spleen and liver positively correlated with the severity of liver injury. APAP sensitized hepatocytes to TRAIL-induced apoptosis by upregulating the expression of the TRAIL receptor DR5 (death receptor 5), presumably through its transcription factor CHOP (C/EBP homologous protein). Importantly, blocking TRAIL with a soluble DR5-Fc fusion protein (sDR5-Fc) significantly attenuated APAP-induced liver injury, the hepatic infiltration of leukocytes, the levels of inflammatory cytokines, and the mortality of mice. When administered alongside N-acetylcysteine, sDR5-Fc further protected against APAP-induced acute liver injury. Thus, the TRAIL-DR5 signaling pathway plays a key role in APAP-induced liver inflammation and failure, and its blockade represents an effective new strategy to treat the liver disease.


Assuntos
Acetaminofen/farmacologia , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Ligante Indutor de Apoptose Relacionado a TNF/metabolismo , Acetilcisteína/metabolismo , Animais , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Linhagem Celular , Citocinas/metabolismo , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Inflamação/induzido quimicamente , Inflamação/metabolismo , Leucócitos/efeitos dos fármacos , Leucócitos/metabolismo , Fígado , Falência Hepática/induzido quimicamente , Falência Hepática/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA