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1.
HNO ; 68(1): 8-13, 2020 Jan.
Artigo em Alemão | MEDLINE | ID: mdl-31511908

RESUMO

BACKGROUND: While an abundant number of studies concerning tobacco smoke and chewing tobacco show carcinogenic potential, there is little data on the consequences of snuff, especially on the cellular level. Therefore, the mutagenic effect of snuff is difficult to estimate and the WHO assessment of snuff being not carcinogenic is based on very limited data. OBJECTIVES: This paper investigates the potential cytotoxic and genotoxic effects of snuff on human lymphocytes and nasal mucosa cells. MATERIALS AND METHODS: Two types of snuff were used: one without menthol and one with a high degree of menthol. The necessary nasal mucosa cells and lymphocytes were collected from 10 subjects undergoing nasal obstruction surgery and incubated for one hour with a snuff-DMSO mixture (range 0.01-2000 µg/ml). Methods included the trypan blue test, the comet assay, and the micronucleus test. RESULTS: The trypan blue test showed no decrease in cell viability for either cell type. The comet assay revealed a significant increase in the Olive Tail Moment for lymphocytes starting at 100 µg/ml and at 1000 µg/ml for nasal mucosa cells. There was no significant increase in micronuclei according to the micronucleus test. No differences between these two types of tobacco were observed. CONCLUSION: The present study demonstrated genotoxic damage, such as DNA strand breaks, which may be repaired, but no non-repairable elevated micronuclei. The present findings cast doubts on the WHO assessment that snuff is not carcinogenic. However, for a sound assessment of the risk potential of snuff, further research on various genotoxic endpoints in human cells is warranted.


Assuntos
Linfócitos , Mucosa Nasal , Tabaco sem Fumaça , Ensaio Cometa , Dano ao DNA , Humanos , Linfócitos/efeitos dos fármacos , Mucosa Nasal/efeitos dos fármacos , Tabaco sem Fumaça/efeitos adversos
2.
Chemosphere ; 239: 124810, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31520980

RESUMO

Perfluorooctanoic acid (PFOA) is a dispersive persistent organic pollutant in the environment. Accumulating reports suggest that PFOA is toxic to human lymphocytes; however, the toxicological effects of PFOA on these cells remain largely unclear. In this study, ultra-performance liquid chromatography (UPLC)-based metabolomic analysis was employed to identify metabolites in human peripheral blood lymphocytes and to assess the metabolic alterations caused by PFOA exposure. Our comparative metabolomic analysis results demonstrated that PFOA treatment could increase the level of organic acids and reduce the level of lipid molecules. Kyoto Encyclopedia of Genes and Genomes (KEGG) annotation further highlighted the fact that the PFOA treatment interfered with the metabolism of amino acids, carbohydrates and lipids, which may lead to disruption of the immune system.


Assuntos
Caprilatos/farmacologia , Fluorcarbonetos/farmacologia , Linfócitos/efeitos dos fármacos , Metabolômica/métodos , Aminoácidos/efeitos dos fármacos , Células Sanguíneas , Caprilatos/toxicidade , Metabolismo dos Carboidratos/efeitos dos fármacos , Células Cultivadas , Cromatografia Líquida de Alta Pressão/métodos , Poluentes Ambientais/farmacologia , Poluentes Ambientais/toxicidade , Fluorcarbonetos/toxicidade , Humanos , Metabolismo dos Lipídeos , Lipídeos/deficiência , Linfócitos/metabolismo
3.
J Enzyme Inhib Med Chem ; 35(1): 96-108, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31690133

RESUMO

A series of analogues of Amb639752, a novel diacylglycerol kinase (DGK) inhibitor recently discovered by us via virtual screening, have been tested. The compounds were evaluated as DGK inhibitors on α, θ, and ζ isoforms, and as antagonists on serotonin receptors. From these assays emerged two novel compounds, namely 11 and 20, which with an IC50 respectively of 1.6 and 1.8 µM are the most potent inhibitors of DGKα discovered to date. Both compounds demonstrated the ability to restore apoptosis in a cellular model of X-linked lymphoproliferative disease as well as the capacity to reduce the migration of cancer cells, suggesting their potential utility in preventing metastasis. Finally, relying on experimental biological data, molecular modelling studies allow us to set a three-point pharmacophore model for DGK inhibitors.


Assuntos
Indóis/farmacologia , Lipase Lipoproteica/antagonistas & inibidores , Piperazinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Células HEK293 , Humanos , Indóis/síntese química , Indóis/química , Lipase Lipoproteica/metabolismo , Linfócitos/efeitos dos fármacos , Células MCF-7 , Modelos Moleculares , Estrutura Molecular , Monócitos/efeitos dos fármacos , Piperazinas/síntese química , Piperazinas/química , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Relação Estrutura-Atividade , Linfócitos T/efeitos dos fármacos
4.
Fitoterapia ; 139: 104402, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31672661

RESUMO

Rhododendron tomentosum (Ledum palustre) is an aromatic plant traditionally used for alleviating rheumatic complaints which makes it a potential candidate for a natural drug in rheumatoid arthritis (RA) treatment. However, the effects of plants' volatiles on apoptosis of synovial fibroblasts and infiltrating leucocytes of RA synovia, have not been reported. Volatile fraction of R. tomentosum is chemically variable and chemotypes of the plants need to be defined if the oil is to be used for therapeutic purposes. In the presented work, cluster analysis of literature data enabled to define 10 chemotypes of the plant. The volatile fractions of known composition were then tested for bioactivity using a RA-specific in vitro models. Essential oils of two wild types (γ-terpineol and palustrol/ledol type) and one in vitro chemotype (ledene oxide type) were obtained by hydrodistillation and their bioactivity was tested in two in vitro models: I - peripheral blood lymphocytes of healthy volunteers and II - synoviocytes and immune cells isolated from synovia of RA patients. The influence of oils on blood lymphocytes' proliferation and apoptosis rates of synovia-derived cells was determined by flow cytometry. Dose-dependent inhibitory effect of the serial dilutions of R. tomentosum oils on proliferation rates of blood lymphocytes was found. At 1:400 dilutions, all the tested oils increased the number of necrotic cells in synovial fibroblasts from RA synovia. Additionally, increased proportions of late apoptotic cells were observed in leucocyte populations subjected to oils at 1:400 dilution.


Assuntos
Apoptose , Ledum/química , Linfócitos/efeitos dos fármacos , Óleos Voláteis/farmacologia , Óleos Vegetais/farmacologia , Sinoviócitos/efeitos dos fármacos , Adulto , Artrite Reumatoide , Proliferação de Células/efeitos dos fármacos , Feminino , Finlândia , Humanos , Pessoa de Meia-Idade , Estrutura Molecular , Brotos de Planta/química , Polônia
5.
Arq Gastroenterol ; 56(4): 372-376, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31721971

RESUMO

BACKGROUND: Gastric cancer is the second leading cause of cancer-related death globally. Unfortunately, the survival rate of the gastric cancer patients who underwent chemotherapy following surgery has been less than a half. Besides, chemotherapy has many side effects. Current evidence suggests that some antidepressants like duloxetine have growth-inhibiting effects against a number of cancer cell lines. OBJECTIVE: Thus, the aim of this study was to determine the cytotoxic and genotoxic effects of duloxetine on gastric cancer. METHODS: In this regard, the cytotoxicity and genotoxicity of duloxetine were investigated in MKN45 and NIH3T3 cell lines by MTT assay and on peripheral blood lymphocytes by MN assay. For this purpose, cells were cultured in 96 wells plate. Stock solutions of duloxetine and cisplatin were prepared. After cell incubation with different concentrations of duloxetine (1, 10, 25, 50, 100 and 200 µL), MTT solution was added. For micronucleus assay fresh blood was added to RPMI culture medium 1640 supplemented, and different concentrations of duloxetine (1, 10, 25, 50, 100 and 200 µL) were added. RESULTS: The cytotoxicity of duloxetine on MKN45 cancer cell line and NIH3T3 normal cell line were studied followed by MTT assay. duloxetine exhibited higher IC50 in the MKN45 cells in comparison with the NIH3T3 cells. In addition, genotoxic effect of duloxetine was evaluated by micronucleus assay. The results revealed that duloxetine induced more DNA damage at 100 and 200 µM and no significant difference at 200 µM with respect to cisplatin, but it had less genotoxic effects at 100 and 50 µM concentrations. CONCLUSION: Although, in this study, duloxetine had less genotoxicity than cisplatin in concentrations under 200 µM and showed cytotoxic effects as well, due to its IC50, it cannot be considered as a better choice for gastric cancer therapies with respect to cisplatin as a common anticancer drug.


Assuntos
Antineoplásicos/farmacologia , Dano ao DNA/efeitos dos fármacos , Cloridrato de Duloxetina/farmacologia , Linfócitos/efeitos dos fármacos , Animais , Linhagem Celular Tumoral/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Camundongos , Testes de Mutagenicidade , Células NIH 3T3/efeitos dos fármacos , Neoplasias Gástricas/patologia
6.
BMC Complement Altern Med ; 19(1): 284, 2019 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-31660940

RESUMO

BACKGROUND: Stem bark of Luehea ochrophylla (L. ochrophylla) is used by the traditional Brazilian medicine for treatment of rheumatic diseases and tumors. This study aimed to investigate inhibition of acute and chronic inflammations and cytotoxic activity of extracts, fractions, and isolated compounds from L. ochrophylla. METHODS: Hexane (HE) and ethanol (EE) extracts obtained from stem bark of L. ochrophylla were submitted to chromatographic fractionation. In order to test acute inflammation, experimental model of impact injury was used, followed by transdermal application of gels using phonophoresis. Histological analysis was based on scores assigned by the capacity of decreasing the lesion. To evaluate the effect EE and fractions on cell proliferation, human lymphocytes were stimulated with phytohemagglutinin and analyzed using flow cytometry. Proliferation was measured using VPD 450 staining and the calculated proliferative index (PI). The cytotoxic activity was evaluated using MTT colorimetric method against MDA-MB-231, MCF-7, HCT-116, and Vero cells. GraphPad Prism Version 5 was used for statistical analysis. RESULTS: HE and EE provided friedelin, ß-friedelinol, lupeol, mixture of lupeol and pseudotaraxasterol, ß-sitosterol, betulinic acid, mixture of lupeol and taraxasterol, (-)-epicatechin, ß-sitosterol-3-O-ß-D-glucopyranoside, and (+)-epicatechin-(4ß-8)-epicatechin. HE, ethyl acetate fraction (AF), betulinic acid, and ß-sitosterol promoted regeneration of muscle fibers caused by muscle injury. AF significantly (p < 0.05) reduced the lymphocyte proliferation index (1.36 for cultures stimulated with PHA, 0.7 for untreated cultures and 0.12 for cultures stimulated with PHA and treated with AF 25 µg/mL and AF 50 µg/mL, respectively). ß-Sitosterol-3-O-ß-D-glucopyranoside exhibited high cytotoxic activity (IC50 = 1.279 µg/mL) against HCT-116 cell line. CONCLUSION: These results suggest that extracts, fractions, and chemical constituents from L. ochrophylla decreases inflammatory processes generated by muscle injury. The anti-inflammatory activity may be justified by high inhibition of T cell proliferation. These extracts, fractions, and chemical constituents from L. ochrophylla may be useful as a therapeutic agent against rheumatic diseases. Moreover, chemical constituents from L. ochrophylla show potent cytotoxic activity against colon and rectal carcinomas.


Assuntos
Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Malvaceae/química , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Animais , Anti-Inflamatórios/isolamento & purificação , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Humanos , Linfócitos/citologia , Linfócitos/efeitos dos fármacos , Linfócitos/imunologia , Extratos Vegetais/isolamento & purificação
7.
An Acad Bras Cienc ; 91(4): e20190337, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31664310

RESUMO

Black Mulberry (Morus nigra L.) belongs to Moraceae family. The present study evaluated the possible genotoxic and/or protective activities of black mulberry fruit juice (BMFJ), in vitro, using mitomycin C (MMC) as a positive control, by chromosomal aberrations and micronucleus assays. Human lymphocytes were treated with BMFJ concentrations alone (1/1, 1/2, 1/4, 1/8 dilutions), pretreatment (49h) (0.20 µg/ml MMC+ 1/1 BMFJ, 0.20 µg/ml MMC+1/2 diluted BMFJ, 0.20 µg/ml MMC+1/4 diluted BMFJ, 0.20 µg/ml MMC+1/8 diluted BMFJ) and simultaneous-treatment (48h) (0.20 µg/ml MMC+ 1/1 BMFJ, 0.20 µg/ml MMC+1/2 diluted BMFJ, 0.20 µg/ml MMC+1/4 diluted BMFJ, 0.20 µg/ml MMC+1/8 diluted BMFJ). The in vitro results demonstrated that BMFJ showed no genotoxicity, but it significantly decreased chromosomal aberration and micronucleus frequency induced by MMC. Our results showed that all concentrations of BMFJ revealed no genotoxicity but protective activity against genomic changes induced by anti-tumor agent MMC in human lymphocytes. Protective effects of BMFJ on MMC induced chromosomal damages most probably due to its free radical scavenging activity.


Assuntos
Aberrações Cromossômicas/efeitos dos fármacos , Frutas/química , Linfócitos/efeitos dos fármacos , Mitomicina/farmacologia , Extratos Vegetais/farmacologia , Folhas de Planta/química , Antineoplásicos/farmacologia , Antioxidantes/farmacologia , Sucos de Frutas e Vegetais , Humanos , Testes para Micronúcleos
8.
An Acad Bras Cienc ; 91(3): e20180655, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31576914

RESUMO

This study evaluated 24 patients with lung cancer (CA) and 23 individuals with no smoking history or cancer in the family and without respiratory disease in childhood (CO). Peripheral blood lymphocytes was used to perform alkaline comet assay and to assess DNA damage as well as to evaluate methyl methane sulfonate (MMS) DNA repair after one hour and three hours at 37 ºC. The percentage of residual damage (RD) after three hours of MMS treatment, for each patient was assessed. The majority of patients were in the CA group, male patients, former smokers, with a history of smoking for 15 years and without associated comorbidities. Alkaline and residual damages were higher in the CA group when compared to controls (alkaline damage P = 0.015 and RD P = 0.05). After one hour of MMS treatment the DNA damage of the CA increased indicating failure to repair it, compared to the controls, and after three hours DNA repair was observed in both groups. Patients with lung cancer are mostly men, former smokers and with more than 15 years of tobacco consumption, undergoing chemotherapy, have high rates of DNA damage and deficiency in their ability to repair against induced damage when compared to controls.


Assuntos
Dano ao DNA , Reparo do DNA , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Idoso , Antineoplásicos Alquilantes/farmacologia , Estudos de Casos e Controles , Ensaio Cometa/métodos , Estudos Transversais , Feminino , Humanos , Linfócitos/efeitos dos fármacos , Masculino , Metanossulfonato de Metila/farmacologia , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Fumar/efeitos adversos , Fatores de Tempo
9.
Anticancer Res ; 39(10): 5675-5682, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31570466

RESUMO

BACKGROUND/AIM: This study explored the prognostic significance of the neutrophil-to-lymphocyte ratio (NLR) and use of antibiotics in advanced esophageal squamous cell carcinoma (ESCC) patients receiving immune checkpoint inhibitors (ICIs). PATIENTS AND METHODS: Patients were enrolled from two referral centers in Taiwan. Clinical benefit was defined as complete response, partial response, or a stable disease for ≥6 months via Response Evaluation Criteria In Solid Tumors 1.1. Clinicopathological factors' impact on overall survival (OS) and progression-free survival (PFS) was analyzed via Cox proportional hazards model. RESULTS: Forty-nine patients were enrolled. The median PFS and OS were 1.8 and 6.1 months, respectively. The median NLR at baseline was 6.40, and 21 patients received antibiotics. Both high NLR and use of antibiotics were associated with inferior PFS (p=0.028 and p<0.001, respectively) and OS (p<0.001 and p<0.001, respectively) in multivariate analysis. CONCLUSION: High NLR and use of antibiotics were associated with inferior survival in advanced ESCC patients receiving ICIs.


Assuntos
Antibacterianos/uso terapêutico , Neoplasias Esofágicas/tratamento farmacológico , Carcinoma de Células Escamosas do Esôfago/tratamento farmacológico , Fatores Imunológicos/uso terapêutico , Linfócitos/patologia , Neutrófilos/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Esofágicas/mortalidade , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago/mortalidade , Carcinoma de Células Escamosas do Esôfago/patologia , Feminino , Humanos , Linfócitos/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Neutrófilos/efeitos dos fármacos , Prognóstico , Intervalo Livre de Progressão , Estudos Retrospectivos , Taiwan
10.
Ecotoxicol Environ Saf ; 185: 109672, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31541949

RESUMO

The potential toxicity of low-dose benzene exposure to human health has received attention, but the mechanisms of low-dose benzene-induced hematotoxicity remain largely unknown. The purpose of our study was to investigate the relationships between lncRNAVNN3 expression with benzene-induced autophagy and apoptosis in control and benzene-exposed workers. Seventy benzene-exposed workers and seventy non-benzene-exposed healthy workers were recruited. The expression of lncRNAVNN3, serum autophagy-associated and apoptosis-associated proteins were evaluated, and the relationship among them were also analysed. Furthermore, the mechanism of lncRNAVNN3 on autophagy and apoptosis induced by benzene metabolite (1, 4-benzoquinone, 1, 4-BQ) was investigated in vitro. The results showed that the expression of lncRNAVNN3 increased in benzene-exposed workers (p < 0.05). A positive correlation was found between lncRNAVNN3, serum autophagy-associated and apoptosis-associated proteins. In addition, we found that the knockdown of lncRNAVNN3 reduced phosphorylation of beclin1 and Bcl-2, which mediated 1, 4-benzoquinone-induced autophagy and apoptosis. Overall, lncRNAVNN3 mediated 1, 4-benzoquinone-induced autophagy and apoptosis though regulating phosphorylation of beclin1 and Bcl-2, suggesting that lncRNAVNN3 might be a novel early sensitive biomarker of benzene-induced hematotoxicity.


Assuntos
Poluentes Ocupacionais do Ar/toxicidade , Amidoidrolases/metabolismo , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Benzeno/toxicidade , Moléculas de Adesão Celular/metabolismo , Exposição Ocupacional/efeitos adversos , RNA Longo não Codificante/metabolismo , Poluentes Ocupacionais do Ar/sangue , Poluentes Ocupacionais do Ar/urina , Proteína Beclina-1/sangue , Benzeno/metabolismo , Biomarcadores/sangue , Estudos de Casos e Controles , Linhagem Celular , Proteínas Ligadas por GPI/metabolismo , Humanos , Linfócitos/efeitos dos fármacos , Linfócitos/metabolismo , Linfócitos/patologia , Exposição Ocupacional/análise , Proteínas Proto-Oncogênicas c-bcl-2/sangue
11.
J Dairy Sci ; 102(10): 9268-9284, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31400902

RESUMO

Neutrophils are principal host innate immune cell responders to mastitis infections. Thus, therapies have been developed that target neutrophil expansion. This includes the neutrophil-stimulating cytokine granulocyte colony-stimulating factor (gCSF). Pegylated gCSF (PEG-gCSF; Imrestor, Elanco Animal Health, Greenfield, IN) has been shown to reduce the natural incidence of mastitis in periparturient cows in commercial settings and reduce severity of disease against experimental mastitis challenge. Pegylated gCSF stimulates neutrophil expansion but also induces changes in monocyte and lymphocyte circulating numbers, surface protein expression changes, or both. We hypothesized that PEG-gCSF modulates surface expression of monocytes and neutrophils and facilitates their migration to the mammary gland. We challenged 8 mid-lactation Holsteins with approximately 150 cfu of Staphylococcus aureus (Newbould 305) in a single quarter via intramammary infusion. All animals developed chronic infections as assessed by bacteria counts and somatic cell counts (SCC). Ten to 16 wk postchallenge, 4 of the animals were treated with 2 subcutaneous injections of PEG-gCSF 7 d apart. Complete blood counts, SCC, bacterial counts, milk yield, feed intake, neutrophils extracellular trap analysis, and flow cytometric analyses of milk and blood samples were performed at indicated time points for 14 d after the first PEG-gCSF injection. The PEG-gCSF-treated cows had significantly increased numbers of blood neutrophils and lymphocytes compared with control cows. Flow cytometric analyses revealed increased surface expression of myeloperoxidase (MPO) on neutrophils and macrophages in milk but not in blood of treated cows. Neutrophils isolated from blood of PEG-gCSF-treated cows had decreased surface expression of CD62L (L-selectin) in blood, consistent with cell activation. Surprisingly, CD62L cell surface expression was increased on neutrophils and macrophages sourced from milk from treated animals compared with cells isolated from controls. The PEG-gCSF-treated cows did not clear the S. aureus infection, nor did they significantly differ in SCC from controls. These findings provide evidence that PEG-gCSF therapy modifies cell surface expression of neutrophils and monocytes. However, although surface MPO+ cells accumulate in the mammary gland, the lack of bacterial control from these milk-derived cells suggests an incomplete role for PEG-gCSF treatment against chronic S. aureus infection and possibly chronic mammary infections in general.


Assuntos
Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Imunofenotipagem/veterinária , Mastite Bovina/tratamento farmacológico , Leite/citologia , Neutrófilos/imunologia , Polietilenoglicóis/uso terapêutico , Infecções Estafilocócicas/veterinária , Animais , Bovinos , Doença Crônica , Feminino , Selectina L/sangue , Lactação , Contagem de Leucócitos/veterinária , Linfócitos/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Mastite Bovina/sangue , Mastite Bovina/imunologia , Mastite Bovina/microbiologia , Leite/imunologia , Leite/microbiologia , Monócitos/citologia , Monócitos/imunologia , Neutrófilos/citologia , Proteínas Recombinantes/uso terapêutico , Infecções Estafilocócicas/sangue , Infecções Estafilocócicas/imunologia , Staphylococcus aureus/efeitos dos fármacos
12.
Transplant Proc ; 51(6): 2081-2098, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31399186

RESUMO

Sphingosine-1-phosphate (S1P) is a biologically active sphingolipid that acts through the members of a family of 5 G protein-coupled receptors (S1P1 to S1P5). Among these, S1P1 is a major regulator of lymphocyte trafficking. Fingolimod, whose active metabolite, fingolimod phosphate, acts as a nonselective S1P-receptor agonist, exerts its immunomodulatory effect, at least in part, by regulating lymphocyte trafficking via downregulation of S1P1 expression on lymphocytes. Here, we describe the pharmacologic profile of a novel S1P1 agonist, ASP1126. ASP1126 preferentially activated S1P1 compared to S1P3 in rat and human guanosine-5'-(γ-thio)-triphosphate (GTPγS) assays. Oral single administration of ASP1126 decreased the number of peripheral lymphocytes and repeated dosing showed a cumulative effect on lymphopenia in both rats and monkeys. ASP1126 prolonged allograft survival in a rat heterotopic heart transplantation model in combination with a subtherapeutic dose of tacrolimus that was independent of drug-drug interactions. In addition, in nonhuman primate (NHP) renal transplantation, pretreatment with ASP1126 reduced not only the number of naive T cells and central memory T cells but also effector memory T cells in the peripheral blood, all of which could contribute to acute graft rejection and prolonged allograft survival in combination with tacrolimus. Further, we confirmed that ASP1126 has a broad ranging safety margin with respect to its effect on lung weight in rats and bradycardia in NHPs, which were the adverse events found in clinical studies of fingolimod. ASP1126 with improved safety profile has the potential to be an adjunct therapy in combination with tacrolimus in clinical transplantation.


Assuntos
Rejeição de Enxerto/prevenção & controle , Sobrevivência de Enxerto/efeitos dos fármacos , Imunossupressores/farmacologia , Lisofosfolipídeos/agonistas , Esfingosina/análogos & derivados , Aloenxertos/efeitos dos fármacos , Aloenxertos/metabolismo , Animais , Bradicardia/induzido quimicamente , Sinergismo Farmacológico , Humanos , Linfócitos/efeitos dos fármacos , Macaca fascicularis , Masculino , Ratos , Esfingosina/agonistas , Tacrolimo/farmacologia , Transplante Homólogo/métodos
13.
Nutrients ; 11(8)2019 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-31370365

RESUMO

Oxidative damage is involved in the pathophysiology of age-related ailments, including Alzheimer's disease (AD). Studies have shown that the brain tissue and also lymphocytes from AD patients present increased oxidative stress compared to healthy controls (HCs). Here, we use lymphoblastoid cell lines (LCLs) from AD patients and HCs to investigate the role of resveratrol (RV) and selenium (Se) in the reduction of reactive oxygen species (ROS) generated after an oxidative injury. We also studied whether these compounds elicited expression changes in genes involved in the antioxidant cell response and other aging-related mechanisms. AD LCLs showed higher ROS levels than those from HCs in response to H2O2 and FeSO4 oxidative insults. RV triggered a protective response against ROS under control and oxidizing conditions, whereas Se exerted antioxidant effects only in AD LCLs under oxidizing conditions. RV increased the expression of genes encoding known antioxidants (catalase, copper chaperone for superoxide dismutase 1, glutathione S-transferase zeta 1) and anti-aging factors (sirtuin 1 and sirtuin 3) in both AD and HC LCLs. Our findings support RV as a candidate for inducing resilience and protection against AD, and reinforce the value of LCLs as a feasible peripheral cell model for understanding the protective mechanisms of nutraceuticals against oxidative stress in aging and AD.


Assuntos
Envelhecimento/metabolismo , Antioxidantes/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Resveratrol/farmacologia , Selênio/farmacologia , Envelhecimento/genética , Doença de Alzheimer/metabolismo , Antioxidantes/farmacologia , Linhagem Celular , Humanos , Linfócitos/efeitos dos fármacos
14.
Arq Gastroenterol ; 56(2): 155-159, 2019 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-31460579

RESUMO

BACKGROUND: Gastric cancer is known as the fourth most common cancer. Current treatments for cancer have damaged the sensitive tissues of the healthy body, and in many cases, cancer will be recurrent. Therefore, need for treatments that are more effective is well felt. Researchers have recently shifted their attention towards antipsychotic dopamine antagonists to treat cancer. The anticancer activities of aripiprazole remain unknown. OBJECTIVE: This study aimed to evaluate the efficacy and safety of aripiprazole on gastric cancer and normal cell lines. METHODS: In this regard, the cytotoxicity and genotoxicity of aripiprazole were investigated in MKN45 and NIH3T3 cell lines by methyl tetrazolium assay and on peripheral blood lymphocytes by micronucleus assay. For this purpose, cells were cultured in 96 wells plate. Stock solutions of aripiprazole and cisplatin were prepared. After cell incubation with different concentrations of aripiprazole (1, 10, 25, 50, 100 and 200 µL), methyl tetrazolium solution was added. For micronucleus assay fresh blood was added to RPMI culture medium 1640 supplemented, and different concentrations of aripiprazole (50, 100 and 200 µL) were added. RESULTS: The finding of present study showed that the IC50 of aripiprazole in the cancer cell line (21.36 µg/mL) was lower than that in the normal cell line (54.17 µg/mL). Moreover, the micronucleus assay showed that the frequency of micronuclei of aripiprazole at concentrations below 200 µM was much less than cisplatin. CONCLUSION: Aripiprazole can be a good cytotoxic compound and good candidate for further studies of cancer therapy.


Assuntos
Aripiprazol/toxicidade , Linfócitos/efeitos dos fármacos , Animais , Humanos , Camundongos , Testes para Micronúcleos/métodos , Testes de Mutagenicidade , Células NIH 3T3/efeitos dos fármacos
15.
Hum Exp Toxicol ; 38(11): 1266-1274, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31446784

RESUMO

Cyclophosphamide (CYP) and methotrexate (MTX) have been evaluated for their ability to induce toxicity in human peripheral blood lymphocytes (PBLs) and the protective role of mitochondrial and lysosomal stabilizing agents. The potential toxicity effects of CYP and MTX were measured in vitro by cellular parameters assays such as cellular viability, reactive oxygen species (ROS) formation, mitochondrial membrane permeability transition (mitochondrial membrane potential (MMP)) collapse, lysosomal membrane damage, intracellular reduced glutathione (GSH), extracellular oxidized glutathione (GSSG), and lipid peroxidation. Separately, human lymphocytes were treated with concentrations of 0.1, 0.2, 0.4, 0.8, and 1.6 ng/mL for CYP and 1, 2, 5, and 10 µg/mL for MTX for 6 h. Statistical evaluations showed that CYP and MTX significantly decreased the cell viability at the three highest concentrations when compared with both the negative and solvent controls. In addition, CYP and MTX were significantly induced ROS formation, MMP collapse, lysosomal membrane damage, lipid peroxidation, and GSH depletion compared with the controls. Mitochondrial and lysosomal protective agents like cyclosporine A and chloroquine, respectively, decreased cytotoxicity and oxidative stress induced by CYP and MTX. The present results indicate that CYP and MTX are toxic to human PBLs and their toxicity could be ameliorated by mitochondrial and lysosomal protective agents.


Assuntos
Antineoplásicos/toxicidade , Ciclofosfamida/toxicidade , Imunossupressores/toxicidade , Linfócitos/efeitos dos fármacos , Metotrexato/toxicidade , Substâncias Protetoras/farmacologia , Adolescente , Adulto , Hidroxitolueno Butilado/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Cloroquina/farmacologia , Ciclosporina/farmacologia , Glutationa/metabolismo , Humanos , Linfócitos/metabolismo , Lisossomos/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/fisiologia , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Adulto Jovem
16.
Molecules ; 24(16)2019 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-31426277

RESUMO

Multidrug resistance (MDR) causes challenging tasks in medicine. Human cancer cells, as well as microorganisms, can acquire multiresistance due to the up-regulation of efflux pumps (ABC transporters) and are difficult to treat. Here, we evaluated the effects of chlorophyll, the most abundant pigment on the globe, and its derivative, pheophytin, on cancer cells and methicillin-resistant Staphylococcus aureus (MRSA). We found that both substances have significant reversal effects on multidrug-resistant CEM/ADR5000 cells (RRpheophytin = 3.13, combination index (CI)pheophytin = 0.438; RRchlorophyll = 2.72, CIchlorophyll < 0.407), but not on drug-sensitive CCRF-CEM cells when used in combination with doxorubicin. This indicates that the porphyrins could interact with efflux pumps. Strong synergism was also observed in antimicrobial tests against MRSA when combining ethidium bromide with chlorophyll (FICI = 0.08). As there is a strong need for new drugs in order to reliably treat MDR cells, our research provides potential candidates for further investigation.


Assuntos
Antibacterianos/farmacologia , Antineoplásicos/farmacologia , Clorofila/farmacologia , Doxorrubicina/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Etídio/farmacologia , Feofitinas/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Combinação de Medicamentos , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Sinergismo Farmacológico , Humanos , Concentração Inibidora 50 , Linfócitos/efeitos dos fármacos , Linfócitos/patologia , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Staphylococcus aureus Resistente à Meticilina/crescimento & desenvolvimento , Testes de Sensibilidade Microbiana
17.
Med Sci Monit Basic Res ; 25: 179-186, 2019 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-31451678

RESUMO

BACKGROUND With the continued demand for new, effective, and safe endodontic therapies, the aim of this study was assessment of efficiency of the ethyl acetate (EthOAc) extract of Tanacetum vulgare (L.) against Candida albicans. MATERIAL AND METHODS The antifungal effectiveness of the EthOAc extract of T. vulgare was determined using the agar disk diffusion method. The inhibition zones induced by the EthOAc extract were compared after 5 minutes, 60 minutes, and 24 hours to those induced by standard solutions (2% chlorhexidine, saturated calcium hydroxide, and 2% sodium hypochlorite). Statistical analysis of the results was performed using the Kruskal-Wallis test and one-way ANOVA. RESULTS The inhibition zone of chlorhexidine against C. albicans was 30.3-19.3 mm, but in combination with EthOAc extract (100 mg/mL) of T. vulgare, this inhibition was from 32.7-30 mm, indicating that this combination exerted a marked synergistic effect against C. albicans. The inhibition zone of sodium hypochlorite (69.7-65 mm) was higher than the inhibition zone of EthOAc extract and chlorhexidine. The combination of EthOAc extract with sodium hypochlorite resulted in a loss of antifungal activity. Furthermore, the activity of the EthOAc extract against C. albicans was decreased after mixing the extract with dentine at a concentration of 25 mg/50 µL (30.3-20.7 mm). The EthOAc extract did not show a genotoxic effect on lymphocyte cells. CONCLUSIONS The EthOAc extract of T. vulgare may be a useful tool to discover natural bioactive agents that have antifungal activity against C. albicans and could be used as endodontic therapies.


Assuntos
Acetatos/química , Antifúngicos/farmacologia , Candida albicans/efeitos dos fármacos , Extratos Vegetais/farmacologia , Tanacetum/química , Candida albicans/crescimento & desenvolvimento , Dentina/metabolismo , Sinergismo Farmacológico , Humanos , Linfócitos/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Mutagênicos/toxicidade
18.
J Dairy Sci ; 102(10): 8862-8873, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31421880

RESUMO

The aim of this study was to determine the effect of docosahexaenoic acid-rich algae (DHA-RA) supplementation in milk replacer (MR) on performance, selected cytokine expression in lymphocytes, and blood immunoglobulin concentration in newborn dairy calves. Forty female Holstein-Friesian calves (8.6 ± 0.8 d old and 41.1 ± 4.3 kg; mean ± standard deviation) were blocked by date of birth and allocated into 4 experimental groups (10 animals/group): (1) not supplemented with DHA-RA, (2) supplemented with 9 g of DHA-RA/d in MR, (3) supplemented with 18 g of DHA-RA/d in MR, and (4) supplemented with 27 g of DHA-RA/d in MR. Milk replacer was fed in an amount equal to 900 g of MR powder/d (as fed), 2 times a d, for 49 d. Starter mixture (SM) was fed ad libitum beginning on d 15 of the study. Each calf was in the study over a period of 49 d. The MR and SM intake and fecal score were recorded daily and body weight was recorded weekly. Blood samples were collected before the morning feeding, at the beginning of the study, every consecutive week, and at the end of the study for morphology and smear analysis, serum immunoglobulin level (IgG, IgA, and IgM), and lymphocyte isolation. The mRNA isolated from lymphocytes was checked for TNFα, IL-1ß, IL-6, and p65 expression. Average daily gain between d 1 to 14 of the study increased quadratically with increasing dose of DHA-RA. However, average daily gain between d 15 to 49 of the study tended to linearly decrease and over the whole study linearly decreased with increasing dose of DHA-RA. The MR intake decreased linearly between d 1 to 14 of the study and over the whole study, and mean SM intake decreased quadratically with increasing dose of DHA-RA. Feed efficiency increased quadratically and fecal score decreased quadratically during the first 14 d of the study. Increasing dose of DHA-RA led to cubic changes in feed efficiency and fecal score between d 15 and 49 of the study. Overall, over the whole study period a tendency was observed for lower fecal score for the DHA-RA supplemented groups. Interleukin-1ß mRNA expression decreased linearly, whereas the mRNA expression of p65 and TNFα as well as serum IgG concentration tended to decrease linearly with increasing dose of supplemental DHA-RA. No effect of group was found on IgA and IgM serum level and the majority of blood parameters. Altogether, treatment worsened production variables but seemed to have a beneficial effect on the immune system of calves.


Assuntos
Ração Animal , Bovinos , Suplementos Nutricionais , Ácidos Docosa-Hexaenoicos/farmacologia , Substitutos do Leite/farmacologia , Estramenópilas , Ração Animal/análise , Animais , Animais Recém-Nascidos , Peso Corporal , Dieta/veterinária , Feminino , Sistema Imunitário/efeitos dos fármacos , Linfócitos/efeitos dos fármacos , Linfócitos/metabolismo , Leite , Substitutos do Leite/química , Desmame
19.
Lancet Haematol ; 6(10): e521-e529, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31378662

RESUMO

BACKGROUND: Anti-B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T-cell therapy has been shown to have activity in patients with relapsed or refractory multiple myeloma. Reports have suggested that a small subgroup of less differentiated myeloma clones express CD19 and anti-CD19 CAR T-cell therapy has shown activity in some of these patients. We aimed to assess the activity and safety of a combination of humanised anti-CD19 and anti-BCMA CAR T cells in patients with relapsed or refractory multiple myeloma. METHODS: We did a single-centre, single-arm, phase 2 trial at the Affiliated Hospital of Xuzhou Medical University in China. Patients were eligible if they were aged 18-69 years, had histologically confirmed multiple myeloma, a Karnofsky Performance Score of 50 points or more, and met the International Myeloma Working Group diagnostic criteria for relapsed or refractory disease. Fludarabine (three daily doses of 30mg/m2) and cyclophosphamide (one daily dose of 750 mg/m2) were used to deplete lymphocytes before infusion of humanised anti-CD19 CAR T cells (1 × 106 cells per kg) and murine anti-BCMA CAR T cells (1 × 106 cells per kg). The primary outcome was the proportion of patients who achieved an overall response. Responses were assessed according to the International Myeloma Working Group criteria. This study is registered with the Chinese Clinical Trial Registration Center, number ChiCTR-OIC-17011272. FINDINGS: From May 1, 2017, to Jan 20, 2019, 22 patients were enrolled and 21 received an infusion of CAR T cells and were evaluable for safety and activity analyses. At a median follow-up of 179 days (IQR 72-295), 20 (95%) of 21 patients had an overall response, including nine (43%) stringent complete responses, three (14%) complete responses, five (24%) very good partial responses, and three (14%) partial responses. The most common adverse events included cytokine release syndrome (19 [90%] of 21), including 18 patients (86%) with grade 1-2 cytokine release syndrome. The most common serious adverse events were haematological toxicities, which occurred in 20 (95%) of 21 patients. Common grade 3 or higher adverse events included neutropenia (18 [86%]), anaemia (13 [62%]), and thrombocytopenia (13 [62%]). One patient died due to cerebral hemorrhage, which was considered related to sustained thrombocytopenia. No deaths were judged to be treatment-related. INTERPRETATION: Our results confirm that combined infusion of humanised anti-CD19 and anti-BCMA CAR T cells is feasible in patients with relapsed or refractory multiple myeloma, and the preliminary activity observed warrants further investigation in randomised trials. This dual CAR-T cell combinations might be a promising treatment option for relapsed or refractory multiple myeloma. FUNDING: National Natural Science Foundation of China, Natural Science Foundation, Key Research and Development Plan of Jiangsu.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antígenos CD19/imunologia , Antígeno de Maturação de Linfócitos B/imunologia , Mieloma Múltiplo/tratamento farmacológico , Adolescente , Adulto , Idoso , Anticorpos Monoclonais Humanizados/efeitos adversos , Ciclofosfamida/farmacologia , Feminino , Doenças Hematológicas/etiologia , Humanos , Linfócitos/citologia , Linfócitos/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/patologia , Recidiva , Índice de Gravidade de Doença , Resultado do Tratamento , Vidarabina/análogos & derivados , Vidarabina/farmacologia , Adulto Jovem
20.
Curr Pharm Biotechnol ; 20(12): 1028-1036, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31364512

RESUMO

BACKGROUND & OBJECTIVE: The present study was aimed at characterizing the conformational alterations induced in human transferrin, the iron regulatory protein by glyoxal. Since protein aggregation is at the core of many disorders, thus interest in this domain has increased significantly during the past years. METHODS: In our present study, the effect of glyoxal was monitored on human transferrin using multispectroscopic and multi-microscopic studies. RESULTS: Intrinsic fluorescence spectroscopy suggested changes in native conformation of human transferrin evident by decreased fluorescence and blue shift in the presence of glyoxal. Further, extrinsic fluorescence was retorted and the results showed the formation of aggregates; apparent by increased Congo red (CR) absorbance, Thioflavin T (ThT) and ANS fluorescence and TEM of human transferrin in the presence of glyoxal. Molecular docking was also employed to see which residues are at core of human transferrin and glyoxal interaction. Reactive oxygen species (ROS) generation assays revealed enhanced ROS levels by human transferrin after treatment with glyoxal. CONCLUSION: Thus, our study proposes that glyoxal induces the formation of aggregates in human transferrin. These aggregates further generate ROS which are key players in the complications associated with diabetes mellitus, giving our study clinical perspective.


Assuntos
Glioxal/química , Glioxal/farmacologia , Agregados Proteicos/efeitos dos fármacos , Transferrina/química , Células Cultivadas , Humanos , Linfócitos/efeitos dos fármacos , Linfócitos/metabolismo , Microscopia Eletrônica de Transmissão , Simulação de Acoplamento Molecular , Ligação Proteica , Espécies Reativas de Oxigênio , Espectrometria de Fluorescência
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