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1.
Am J Physiol Cell Physiol ; 321(3): C607-C614, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34378992

RESUMO

Bovine milk exosomes (BMEs) are being explored in drug delivery despite their rapid elimination by macrophages. We aimed at identifying the BME transporter in murine bone marrow-derived macrophages (BMDMs). Fluorophore-labeled BMEs were used in transport studies in BMDMs from C57BL/6J and class A scavenger receptor type 1/2 (CASR-1/2) knockout mice and tissue accumulation in macrophage-depleted C57BL/6J mice. Parametric and nonparametric statistics tests for pairwise and multiple comparisons were used. Chemical inhibitors of phagocytosis by cytochalasin D led to a 69 ± 18% decrease in BME uptake compared with controls (P < 0.05), whereas inhibitors of endocytic pathways other than phagocytosis had a modest effect on uptake (P > 0.05). Inhibitors of class A scavenger receptors (CASRs) including CASR-1/2 caused a 70% decrease in BME uptake (P < 0.05). The uptake of BMEs by BMDMs from CASR-1/2 knockout mice was smaller by 58 ± 23% compared with wild-type controls (P < 0.05). Macrophage depletion by clodronate caused a more than 44% decrease in BME uptake in the spleen and lungs (P < 0.05), whereas the decrease observed in liver was not statistically significant. In conclusion, CASR-1/2 facilitates the uptake of BMEs in BMDMs and C57BL/6J mice.


Assuntos
Exossomos/metabolismo , Macrófagos/metabolismo , Leite/química , Receptores Depuradores Classe A/genética , Animais , Bovinos , Ácido Clodrônico/farmacologia , Citocalasina D/farmacologia , Endocitose/efeitos dos fármacos , Exossomos/química , Feminino , Corantes Fluorescentes/química , Expressão Gênica , Fígado/efeitos dos fármacos , Fígado/metabolismo , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fagocitose/efeitos dos fármacos , Isoformas de Proteínas/deficiência , Isoformas de Proteínas/genética , Receptores Depuradores Classe A/deficiência , Baço/efeitos dos fármacos , Baço/metabolismo , Coloração e Rotulagem/métodos
2.
Int J Mol Sci ; 22(12)2021 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-34199160

RESUMO

Acadesine (ACA), a pharmacological activator of AMP-activated protein kinase (AMPK), showed a promising beneficial effect in a mouse model of colitis, indicating this drug as an alternative tool to manage IBDs. However, ACA displays some pharmacodynamic limitations precluding its therapeutical applications. Our study was aimed at evaluating the in vitro and in vivo effects of FA-5 (a novel direct AMPK activator synthesized in our laboratories) in an experimental model of colitis in rats. A set of experiments evaluated the ability of FA5 to activate AMPK and to compare the efficacy of FA5 with ACA in an experimental model of colitis. The effects of FA-5, ACA, or dexamethasone were tested in rats with 2,4-dinitrobenzenesulfonic acid (DNBS)-induced colitis to assess systemic and tissue inflammatory parameters. In in vitro experiments, FA5 induced phosphorylation, and thus the activation, of AMPK, contextually to the activation of SIRT-1. In vivo, FA5 counteracted the increase in spleen weight, improved the colon length, ameliorated macroscopic damage score, and reduced TNF and MDA tissue levels in DNBS-treated rats. Of note, FA-5 displayed an increased anti-inflammatory efficacy as compared with ACA. The novel AMPK activator FA-5 displays an improved anti-inflammatory efficacy representing a promising pharmacological tool against bowel inflammation.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Benzofuranos/uso terapêutico , Desenvolvimento de Medicamentos , Ativadores de Enzimas/farmacologia , Doenças Inflamatórias Intestinais/tratamento farmacológico , Animais , Benzofuranos/farmacologia , Peso Corporal/efeitos dos fármacos , Linhagem Celular , Colo/efeitos dos fármacos , Colo/patologia , Dinitrofluorbenzeno/análogos & derivados , Eletroforese em Gel Bidimensional , Ontologia Genética , Doenças Inflamatórias Intestinais/patologia , Interleucina-10/metabolismo , Masculino , Malondialdeído/metabolismo , Camundongos , Tamanho do Órgão/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Ratos Sprague-Dawley , Baço/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismo
3.
Ecotoxicol Environ Saf ; 220: 112386, 2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-34090108

RESUMO

Atrazine (ATR) is a herbicide used widely worldwide. Because of its prolonged persistence in the environment and accumulation in the body, ATR exposure is a potential threat to human health. Our previous study showed that subacute exposure to ATR suppresses cellular immune function in mice. In this study, the effects of long-term exposure to ATR on rat immunological system function were measured. Four-week-old female Sprague-Dawley (SD) rats were treated with 0.4 µmol/L, 2 µmol/L and 10 µmol/L ATR for 24 weeks. The results showed that the spleen index increased, white blood cells decreased, and monocytes and eosinophils increased. No obvious changes were detected in the numbers of neutrophils and lymphocytes. Th1, Th2, and Th17 cells decreased significantly, while Treg cells increased after long-term ATR exposure. Moreover, serum levels of cytokines, including TNF-α, INF-γ, IL-6, and IL-12, decreased, while IL-1, IL-4, and IL-5 increased. Degenerative changes and cell apoptosis were found in the spleen; Caspase-3 and Caspase-9 were upregulated, and Bcl-2 was downregulated. These results suggested that long-term ATR exposure may inhibit immune system function.


Assuntos
Apoptose/efeitos dos fármacos , Atrazina/toxicidade , Herbicidas/toxicidade , Baço/efeitos dos fármacos , Animais , Citocinas/genética , Citocinas/metabolismo , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Camundongos , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Baço/citologia , Linfócitos T Auxiliares-Indutores
4.
Fish Shellfish Immunol ; 116: 61-73, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34157396

RESUMO

In aquaculture, commercial fish such as red hybrid tilapia are usually raised at high density to boost the production within a short period of time. This overcrowded environment, however, may cause stress to the cultured fish and increase susceptibility to infectious diseases. Antibiotics and chemotherapeutics are used by fish farmers to overcome these challenges, but this may increase the production cost. Studies have reported on the potential of mushroom polysaccharides that can act as immunostimulants to enhance the immune response and disease resistance in fish. In the current study, hot water extract (HWE) from mushroom stalk waste (MSW) was used to formulate fish feed and hence administered to red hybrid tilapia to observe the activation of immune system. Upon 30 days of feeding, the fish were challenged with pathogen-associated molecular patterns (PAMPs) such as lipopolysaccharides (LPS) and polyinosinic:polycytidylic acid (poly (I:C)) to mimic bacterial and viral infection, respectively. HWE supplementation promoted better feed utilisation in red hybrid tilapia although it did not increase the body weight gain and specific growth rate compared to the control diet. The innate immunological parameters such as phagocytic activity and respiratory burst activity were significantly higher in HWE-supplemented group than that of the control group following PAMPs challenges. HWE-supplemented diet also resulted in higher mRNA transcription of il1b and tnfa in midgut, spleen and head kidney at 1-day post PAMPs injection. Tlr3 exhibited the highest upregulation in the HWE fed fish injected with poly (I:C). At 3-days post PAMPs injection, both ighm and tcrb expression were upregulated significantly in the spleen and head kidney. Results showed that HWE supplementation enhances the immune responses of red hybrid tilapia and induced a higher serum bactericidal activity against S. agalactiae.


Assuntos
Ciclídeos , Misturas Complexas/farmacologia , Suplementos Nutricionais , Lipopolissacarídeos/farmacologia , Padrões Moleculares Associados a Patógenos/farmacologia , Pleurotus , Poli I-C/farmacologia , Ração Animal , Animais , Quimera , Ciclídeos/genética , Ciclídeos/imunologia , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/imunologia , Rim Cefálico/efeitos dos fármacos , Rim Cefálico/imunologia , Temperatura Alta , Imunidade Inata/efeitos dos fármacos , Interleucina-1beta/genética , Leucócitos/efeitos dos fármacos , Leucócitos/imunologia , Fagocitose/efeitos dos fármacos , Baço/efeitos dos fármacos , Baço/imunologia , Streptococcus agalactiae/imunologia , Fator de Necrose Tumoral alfa/genética , Resíduos , Água
5.
Int J Biol Macromol ; 185: 111-121, 2021 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-34119543

RESUMO

Fucoidan is a sulfated polysaccharide, derived from various marine brown seaweeds, that has immunomodulatory effects. In this study, we analyzed the effects of five different fucoidans, which were extracted from Ascophyllum nodosum, Undaria pinnatifida, Macrocystis pyrifera, Fucus vesiculosus, and Ecklonia cava, on natural killer (NK) cell activation in mice. Among these, E. cava fucoidan (ECF) promoted an increase in the number of NK cells in the spleen and had the strongest effect on the activation of NK cells. Additionally, we observed that DC stimulation was required for NK cell activation and that ECF had the most potent effect on splenic dendritic cells (DC). Finally, ECF treatment effectively prevented infiltration of CT-26 carcinoma cells in the lungs of BALB/c mice in an NK cell dependent manner. Collectively, these results suggest that ECF could be a suitable candidate for enhancing NK cell-mediated anti-cancer immunity.


Assuntos
Antineoplásicos/administração & dosagem , Neoplasias do Colo/tratamento farmacológico , Células Matadoras Naturais/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/secundário , Feófitas/química , Polissacarídeos/administração & dosagem , Animais , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Neoplasias do Colo/imunologia , Feminino , Neoplasias Pulmonares/imunologia , Ativação Linfocitária/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Polissacarídeos/farmacologia , Baço/efeitos dos fármacos , Baço/imunologia , Ensaios Antitumorais Modelo de Xenoenxerto
6.
Int J Mol Sci ; 22(11)2021 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-34067318

RESUMO

The effects of a new material based on hydroxyapatite and calcium silicates, named ALBO-MPCA, were investigated on the liver, kidney and spleen. The material was administrated orally for 120 days in an in vivo model in Wistar rats, and untreated animals served as a control. Hematological and biochemical blood parameters were analyzed. Qualitative histological analysis of tissues, change in mitotic activity of cells, and histological characteristics was conducted, as well as quantitative stereological analysis of parenchymal cells, blood sinusoids, and connective tissues. Additionally, the protein expressions of Ki67 and CD68 markers were evaluated. Histological analysis revealed no pathological changes after the tested period. It showed the preservation of the architecture of blood sinusoids and epithelial cells and the presence of mitosis. Additionally, the significantly increased number of the Ki67 in the presence of ALBO-MPCA confirmed the proliferative effect of the material noticed by stereological analysis, while immunoreactive CD68 positive cells did not differ between groups. The study showed non-toxicity of the tested material based on the effects on the hematological, biochemical, and observed histological parameters; in addition, it showed evidence of its biocompatibility. These results could be the basis for further steps toward the application of tested materials in endodontics.


Assuntos
Materiais Biocompatíveis/farmacologia , Compostos de Cálcio/farmacologia , Cimentos Dentários/farmacologia , Durapatita/farmacologia , Rim/efeitos dos fármacos , Fígado/efeitos dos fármacos , Silicatos/farmacologia , Baço/efeitos dos fármacos , Animais , Antígenos CD/metabolismo , Antígenos de Diferenciação Mielomonocítica/metabolismo , Antígeno Ki-67/metabolismo , Rim/metabolismo , Fígado/metabolismo , Masculino , Teste de Materiais/métodos , Ratos , Ratos Wistar , Baço/metabolismo
7.
Cell Physiol Biochem ; 55(S3): 108-130, 2021 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-34043299

RESUMO

Transient receptor potential vanilloid (TRPV) channels are part of the TRP channel superfamily and named after the first identified member TRPV1, that is sensitive to the vanillylamide capsaicin. Their overall structure is similar to the structure of voltage gated potassium channels (Kv) built up as homotetramers from subunits with six transmembrane helices (S1-S6). Six TRPV channel subtypes (TRPV1-6) are known, that can be subdivided into the thermoTRPV (TRPV1-4) and the Ca2+-selective TRPV channels (TRPV5, TRPV6). Contrary to Kv channels, TRPV channels are not primary voltage gated. All six channels have distinct properties and react to several endogenous ligands as well as different gating stimuli such as heat, pH, mechanical stress, or osmotic changes. Their physiological functions are highly diverse and subtype as well as tissue specific. In many tissues they serve as sensors for different pain stimuli (heat, pressure, pH) and contribute to the homeostasis of electrolytes, the maintenance of barrier functions and the development of macrophages. Due to their fundamental role in manifold physiological and pathophysiological processes, TRPV channels are promising targets for drug development. However, drugs targeting specific TRPV channels, that are suitable for drug therapy, are rare. Moreover, selective and potent compounds for further research at TRPV channels are often lacking. In this review different aspects of the structure, the different gating stimuli, the expression pattern, the physiological and pathophysiological roles as well as the modulating mechanisms of synthetic, natural and endogenous ligands are summarized.


Assuntos
Analgésicos/farmacologia , Antineoplásicos/farmacologia , Fatores Imunológicos/farmacologia , Moduladores de Transporte de Membrana/farmacologia , Canais de Cátion TRPV/metabolismo , Analgésicos/química , Analgésicos/classificação , Antineoplásicos/química , Antineoplásicos/classificação , Sítios de Ligação , Encéfalo/citologia , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Humanos , Fatores Imunológicos/química , Fatores Imunológicos/classificação , Ativação do Canal Iônico/efeitos dos fármacos , Ligantes , Pulmão/citologia , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Moduladores de Transporte de Membrana/química , Moduladores de Transporte de Membrana/classificação , Modelos Moleculares , Especificidade de Órgãos , Ligação Proteica , Isoformas de Proteínas/agonistas , Isoformas de Proteínas/antagonistas & inibidores , Isoformas de Proteínas/classificação , Isoformas de Proteínas/metabolismo , Estrutura Secundária de Proteína , Baço/citologia , Baço/efeitos dos fármacos , Baço/metabolismo , Canais de Cátion TRPV/agonistas , Canais de Cátion TRPV/antagonistas & inibidores , Canais de Cátion TRPV/classificação
8.
Toxicol Appl Pharmacol ; 424: 115597, 2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-34051218

RESUMO

Trichloroethene (TCE), a widely used industrial solvent, is associated with the development of autoimmune diseases (ADs), including systemic lupus erythematosus and autoimmune hepatitis. Increasing evidence support a linkage between altered gut microbiome composition and the onset of ADs. However, it is not clear how gut microbiome contributes to TCE-mediated autoimmunity, and initial triggers for microbiome-host interactions leading to systemic autoimmune responses remain unknown. To achieve this, female MRL+/+ mice were treated with 0.5 mg/ml TCE for 52 weeks and fecal samples were subjected to 16S rRNA sequencing to determine the microbiome composition. TCE exposure resulted in distinct bacterial community revealed by ß-diversity analysis. Notably, we observed reduction in Lactobacillaceae, Rikenellaceae and Bifidobacteriaceae families, and enrichment of Akkermansiaceae and Lachnospiraceae families after TCE exposure. We also observed significantly increased colonic oxidative stress and inflammatory markers (CD14 and IL-1ß), and decreased tight junction proteins (ZO-2, occludin and claudin-3). These changes were associated with increases in serum antinuclear and anti-smooth muscle antibodies and cytokines (IL-6 and IL-12), together with increased PD1 + CD4+ T cells in TCE-exposed spleen and liver tissues. Importantly, fecal microbiota transplantation (FMT) using feces from TCE-treated mice to antibiotics-treated mice induced increased anti-dsDNA antibodies and hepatic CD4+ T cell infiltration in the recipient mice. Our studies thus delineate how imbalance in gut microbiome and mucosal redox status together with gut inflammatory response and permeability changes could be the key factors in contributing to TCE-mediated ADs. Furthermore, FMT studies provide a solid support to a causal role of microbiome in TCE-mediated autoimmunity.


Assuntos
Autoimunidade/efeitos dos fármacos , Bactérias/efeitos dos fármacos , Poluentes Ambientais/toxicidade , Microbioma Gastrointestinal/efeitos dos fármacos , Tricloroetileno/toxicidade , Animais , Esquema de Medicação , Feminino , Microbioma Gastrointestinal/fisiologia , Inflamação , Fígado/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos , Estresse Oxidativo , Baço/efeitos dos fármacos
9.
J Toxicol Sci ; 46(5): 223-234, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33952799

RESUMO

Sodium carboxy methyl cellulose (SCMC) is an important absorbable biomaterial for anti-adhesion and hemostasis medical devices used in the abdominal cavity. However, the systemic toxicity of SCMC following intraperitoneal route has not been revealed sufficiently. Three SCMC solutions with gradient concentrations were intraperitoneally injected into 3 groups of rats with the doses of 50 mg/kg, 320 mg/kg and 2000 mg/kg respectively all at once to observe the dose-dependence of systemic reactions of SCMC and 10 rats (5 rats per sex) of each group were sacrificed 3 days, 7 days, 28 days and 90 days after injection to evaluate the time-dependence of the reactions. A range of adverse effects were shown in rats of the high-dose group which were found varied with time extending and virtually disappeared 90 days after injection. Slight reactions were observed in the medium-dose group while negligible effects were found in the low-dose group. The intraperitoneal application of SCMC can induce reversible systemic adverse effects to rats at the dose higher than 320 mg/kg and it is essential to take both dose- and time-dependent effects into account while designing a systemic toxicity study for absorbable biomaterials.


Assuntos
Carboximetilcelulose Sódica/toxicidade , Glândulas Suprarrenais/efeitos dos fármacos , Glândulas Suprarrenais/patologia , Animais , Relação Dose-Resposta a Droga , Feminino , Injeções Intraperitoneais , Rim/efeitos dos fármacos , Rim/patologia , Fígado/efeitos dos fármacos , Fígado/patologia , Masculino , Pâncreas/efeitos dos fármacos , Pâncreas/patologia , Ratos Sprague-Dawley , Baço/efeitos dos fármacos , Baço/patologia , Timo/efeitos dos fármacos , Timo/patologia , Útero/efeitos dos fármacos , Útero/patologia
10.
Toxicology ; 458: 152823, 2021 06 30.
Artigo em Inglês | MEDLINE | ID: mdl-34051339

RESUMO

Ozone exposure induces neuroendocrine stress response, which causes lymphopenia. It was hypothesized that ozone-induced increases in stress hormones will temporally follow changes in circulating granulocytes, monocytes- and lymphocyte subpopulations. The goal of this study was to chronicle the changes in circulating stress hormones, cytokines, and leukocyte trafficking during 4 h exposure to ozone. Male Wistar Kyoto rats were exposed to air or ozone (0.4 or 0.8 ppm) for 0.5, 1, 2, or 4 h. After each time point, circulating stress hormones, cytokines, and lung gene expression were assessed along with live and apoptotic granulocytes, monocytes (classical and non-classical), and lymphocytes (B, Th, and Tc) in blood, thymus, and spleen using flow cytometry. Circulating stress hormones began to increase at 1 h of ozone exposure. Lung expression of inflammatory cytokines (Cxcl2, Il6, and Hmox1) and glucocorticoid-responsive genes (Nr3c1, Fkbp5 and Tsc22d3) increased in both a time- and ozone concentration-dependent manner. Circulating granulocytes increased at 0.5 h of ozone exposure but tended to decrease at 2 and 4 h, suggesting a rapid egress and then margination to the lung. Classical monocytes decreased over 4 h of exposure periods (∼80 % at 0.8 ppm). B and Tc lymphocytes significantly decreased after ozone exposure at 2 and 4 h. Despite dynamic shifts in circulating immune cell populations, few differences were measured in serum cytokines. Ozone neither increased apoptotic cells nor altered thymus and spleen lymphocytes. The data show that ozone-induced increases in adrenal-derived stress hormones precede the dynamic migration of circulating immune cells, likely to the lung to mediate inflammation.


Assuntos
Corticosteroides/metabolismo , Poluentes Atmosféricos/toxicidade , Poluição do Ar/efeitos adversos , Leucócitos/efeitos dos fármacos , Ozônio/toxicidade , Animais , Apoptose/efeitos dos fármacos , Citocinas/metabolismo , Regulação da Expressão Gênica , Granulócitos/efeitos dos fármacos , Pulmão/metabolismo , Linfócitos/efeitos dos fármacos , Masculino , Monócitos/efeitos dos fármacos , Ratos , Ratos Endogâmicos WKY , Baço/citologia , Baço/efeitos dos fármacos , Linfócitos T
11.
Front Immunol ; 12: 581799, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33953705

RESUMO

Forkhead box O 3 (FOXO3) is a transcription factor involved in cell metabolism, inflammation and longevity. Here, we investigated if metformin can activate FOXO3 in human immune cells and affects the subsequent level of reactive oxygen/nitrogen species (ROS/RNS) in immune cells. AMP-activated protein kinase (AMPK) and FOXO3 activation were investigated by immunoblot or flow cytometry (FC) analysis, respectively. FOXO3 target gene expression was quantified by real-time PCR. ROS/RNS measurement using dichlorodihydrofluorescein diacetate (DCFH-DA) dye was investigated by FC. The role of the FOXO3 single nucleotide polymorphisms (SNPs) rs12212067, rs2802292 and rs12206094 on ROS/RNS production was studied using allelic discrimination PCR. Metformin induced activation of AMPK (pT172) and FOXO3 (pS413). ROS/RNS level was reduced in immune cells after metformin stimulation accompanied by induction of the FOXO3 targets mitochondrial superoxide dismutase and cytochrome c. Studies in Foxo3 deficient (Foxo3-/- ) mouse splenocytes confirmed that metformin mediates its effects via Foxo3 as it attenuates ROS/RNS in myeloid cells of wildtype (WT) but not of Foxo3-/- mice. Our results suggest that FOXO3 can be activated by metformin leading to reduced ROS/RNS level in immune cells. This may add to the beneficial clinical effects of metformin observed in large cohort studies on longevity, cardiovascular and cancer risk.


Assuntos
Proteína Forkhead Box O3/metabolismo , Sistema Imunitário/efeitos dos fármacos , Metformina/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Células Cultivadas , Relação Dose-Resposta a Droga , Ativação Enzimática/efeitos dos fármacos , Proteína Forkhead Box O3/genética , Expressão Gênica/efeitos dos fármacos , Humanos , Hipoglicemiantes/farmacologia , Sistema Imunitário/citologia , Sistema Imunitário/metabolismo , Camundongos Knockout , Polimorfismo de Nucleotídeo Único , Baço/citologia , Baço/efeitos dos fármacos , Baço/metabolismo
12.
Molecules ; 26(9)2021 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-33946346

RESUMO

Colitis causes destruction of the intestinal mucus layer and increases intestinal inflammation. The use of antioxidants and anti-inflammatory agents derived from natural sources has been recently highlighted as a new approach for the treatment of colitis. Oxyresveratrol (OXY) is an antioxidant known to have various beneficial effects on human health, such as anti-inflammatory, antibacterial activity, and antiviral activity. The aim of this study was to investigate the therapeutic effect of OXY in rats with dextran sulfate sodium (DSS)-induced acute colitis. OXY ameliorated DSS-induced colitis and repaired damaged intestinal mucosa. OXY downregulated the expression of pro-inflammatory cytokine genes (TNF-α, IL-6, and IL-1ß) and chemokine gene MCP-1, while promoting the production of anti-inflammatory cytokine IL-10. OXY treatment also suppressed inflammation via inhibiting cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) expression in the colon, as well as the activity of myeloperoxidase (MPO). OXY exhibited anti-apoptotic effects, shifting the Bax/Bcl-2 balance. In conclusion, OXY might improve DSS-induced colitis by restoring the intestinal mucus layer and reducing inflammation within the intestine.


Assuntos
Anti-Inflamatórios/farmacologia , Sulfato de Dextrana/efeitos adversos , Extratos Vegetais/farmacologia , Estilbenos/farmacologia , Animais , Biomarcadores , Colite/tratamento farmacológico , Colite/etiologia , Colite/metabolismo , Colo/efeitos dos fármacos , Colo/metabolismo , Colo/patologia , Citocinas/metabolismo , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Expressão Gênica , Humanos , Mediadores da Inflamação/metabolismo , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Óxido Nítrico Sintase Tipo II/metabolismo , Tamanho do Órgão/efeitos dos fármacos , Ratos , Baço/efeitos dos fármacos , Baço/metabolismo , Baço/patologia
13.
Life Sci ; 277: 119625, 2021 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-34015288

RESUMO

AIM: Iron oxide nanoparticles (IONPs) have been widely used in diagnosis, drug delivery, and therapy. However, the biodistribution and toxicity profile of IONPs remain debatable and incomplete, thus limiting their further use. We predict that coating iron oxide nanoparticles using curcumin (Cur-IONPs) will provide an advantage for their safety profile. MATERIALS AND METHODS: In this study, an evaluation of the multidose effect (6 doses of 5 mg/kg Cur-IONPs to male BALB/c mice, on alternating days for two weeks) on the toxicity and biodistribution of Cur-IONPs was conducted. KEY FINDINGS: Serum biochemical analysis demonstrated no significant difference in enzyme levels in the liver and kidney between the Cur-IONP-treated and control groups. Blood glucose level measurements showed a nonsignificant change between groups. However, the serum iron concentration was found to initially increase significantly but then decreased at 10 days after the final injection. Histopathological examination of the liver, spleen, kidneys, and brain showed no abnormalities or differences between the Cur-IONP-treated and control groups. There were no abnormal changes in mouse body weight. The biodistribution results showed that Cur-IONPs accumulated mainly in the liver, spleen, and brain, while almost no Cur-IONPs were found in the kidney. The iron content in the liver remained high even 10 days after the final injection, while the iron content in the spleen and brain had returned to normal levels by this time point, indicating their complete clearance. SIGNIFICANCE: These results are significant and promising for the further application of Cur-IONPs as theragnostic nanoparticles.


Assuntos
Curcumina/administração & dosagem , Curcumina/farmacologia , Nanopartículas Magnéticas de Óxido de Ferro/administração & dosagem , Animais , Encéfalo/efeitos dos fármacos , Curcumina/toxicidade , Compostos Férricos/farmacologia , Ferro/metabolismo , Rim/efeitos dos fármacos , Fígado/efeitos dos fármacos , Nanopartículas Magnéticas de Óxido de Ferro/química , Nanopartículas de Magnetita/química , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Nanopartículas/química , Baço/efeitos dos fármacos , Distribuição Tecidual/efeitos dos fármacos , Distribuição Tecidual/fisiologia
14.
Int J Biol Macromol ; 181: 672-682, 2021 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-33798588

RESUMO

A polysaccharide, CSL-0.1, was isolated from the medicinal lichen, Usnea longissima. CSL-0.1 was a neutral rhamnose-containing glucogalactomannan with a molecular weight of 7.86 × 104 Da. The polysaccharide had a core mannan structure with (1 → 6)-α-d-Manp units as the main chain and was substituted at the O-2 positions with side chains containing (1 → 2)-α-d-Manp residue, [3)-α-Glcp(1 → 4)-α-Glcp(1→] and 6-O-substituted ß-d-Galf units. 2-O- and 2,3-di-O-substituted Rhap units. The effects of CSL-0.1 on intestinal immunity and antioxidant activity were evaluated. CSL-0.1 increased the spleen and thymus indices in a dose-dependent manner and conferred immunomodulation on reversing the Th1/Th2-related cytokine imbalance in cyclophosphamide (CP)-induced immunosuppressed mice. CSL-0.1 could also enhance the levels of secretory immunoglobulin A in CP-injected mice. Additionally, the antioxidant levels in the liver and intestine of the mice were increased 20%-50% after intragastric injection by CSL-0.1.


Assuntos
Imunização , Líquens/química , Parmeliaceae/química , Polissacarídeos/farmacologia , Animais , Antioxidantes/farmacologia , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Citocinas/metabolismo , Feminino , Cromatografia Gasosa-Espectrometria de Massas , Hidrólise , Intestinos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Metilação , Camundongos Endogâmicos ICR , Monossacarídeos/análise , Polissacarídeos/isolamento & purificação , Espectroscopia de Prótons por Ressonância Magnética , Espectrofotometria Infravermelho , Baço/efeitos dos fármacos , Timo/efeitos dos fármacos
15.
Toxins (Basel) ; 13(5)2021 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-33926136

RESUMO

The objective of this study was to determine the impact of Ageratina adenophora (A. adenophora) on splenic immune function in a rat model. Rats were fed with 10 g/100 g normal feed and an experimental feed, which was composed of 3:7 A. adenophora powder and normal feed for 60 days. On days 14, 28, and 60, subsets of rats (n = 8 rats/group/time point) were selected for blood and spleen tissue sample collection. The results showed that the proportion of CD3+ T cells in the spleen was decreased at day 60 (vs. control). Also, mRNA and protein expression of chemokines CCL21 and CCL19 and functional protein gp38 in spleen decreased significantly versus the control at day 60. In addition, ER-TR7 antigen protein expression was also decreased at day 60. Levels of T-helper (Th)1 cells significantly increased, whereas those of Th2 cells decreased significantly versus the control at day 60 in spleen. The finding revealed that A. adenophora could affect splenic immune function in rats by altering the fibroblast reticulocyte (FRC) network, as well as by causing an imbalance in Th1/Th2 cell ratios. This research provides new insights into potential mechanisms of spleen immunotoxicity due to exposures to A. Adenophora.


Assuntos
Ageratina/efeitos adversos , Reticulócitos/efeitos dos fármacos , Baço/efeitos dos fármacos , Células Th1/efeitos dos fármacos , Células Th2/efeitos dos fármacos , Animais , Fibroblastos/efeitos dos fármacos , Contagem de Linfócitos , Masculino , Folhas de Planta , Ratos , Ratos Sprague-Dawley , Baço/citologia , Baço/imunologia
16.
Chem Biodivers ; 18(5): e2100084, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33682992

RESUMO

4,21-Secovincanol (1), a novel C-21/N-4 cleavage monoterpenoid indole alkaloid, along with four analogs (2-5), were obtained from the aerial parts of Kopsia hainanensis. Structurally, compound 1 might be a derivative of epivincanol (2) via C-21/N-4 cleavage. Their structures were confirmed by means of comprehensive spectroscopic data analysis and comparison with the reported data. All isolates significantly inhibited Con A-stimulated mice splenocytes proliferation at 10-40 µM in a dose-dependent manner in vitro. Especially, compound 3 exhibited potent activities comparable to positive control (Dexamethasone, DXM).


Assuntos
Apocynaceae/química , Imunossupressores/farmacologia , Extratos Vegetais/farmacologia , Baço/efeitos dos fármacos , Animais , Proliferação de Células/efeitos dos fármacos , Concanavalina A/antagonistas & inibidores , Concanavalina A/farmacologia , Relação Dose-Resposta a Droga , Imunossupressores/química , Imunossupressores/isolamento & purificação , Camundongos , Estrutura Molecular , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação
17.
Artigo em Inglês | MEDLINE | ID: mdl-33722765

RESUMO

The utilization of pesticides has increased for destroying pests and protecting crops in the agriculture field. Triazophos is a commonly used organophosphorous insecticide that causes alterations in haematological and histological parameters in fish. The present study was designed to evaluate the effect of triazophos induced innate and cell mediated immunotoxicity in freshwater teleost, Channa punctata. Fishes were exposed to triazophos at concentrations 5 and 10% of LC50 value for 10 and 20 days. Splenic and head kidney macrophage phagocytosis, nitric oxide production and superoxide production were assayed to evaluate the innate immunity. Cell-mediated immunity was measured through splenic and head kidney lymphocyte proliferation in presence of T and B cell mitogens. Results of the present study revealed that macrophage phagocytosis was significantly reduced after in vivo triazophos treatment. Differential suppressive effect of triazophos was also observed where mitogen induced splenic and head kidney lymphocyte proliferations were reduced after 10 and 20 days treatment. Concentration dependent effect of triazophos was observed in in vivo studies where the production of reactive oxygen and nitrogen intermediates were suppressed. This study describes the first investigation of the effect of triazophos on immune functions and will help to determine appropriate ecotoxicity and immunotoxicity in freshwater teleosts.


Assuntos
Peixes/metabolismo , Imunidade Celular/efeitos dos fármacos , Organotiofosfatos/toxicidade , Praguicidas/toxicidade , Triazóis/toxicidade , Poluentes Químicos da Água/toxicidade , Animais , Rim Cefálico/citologia , Rim Cefálico/efeitos dos fármacos , Linfócitos/citologia , Linfócitos/efeitos dos fármacos , Fagocitose , Baço/citologia , Baço/efeitos dos fármacos
18.
Front Immunol ; 12: 626200, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33732248

RESUMO

Tick saliva is a rich source of pharmacologically and immunologically active molecules. These salivary components are indispensable for successful blood feeding on vertebrate hosts and are believed to facilitate the transmission of tick-borne pathogens. Here we present the functional and structural characterization of Iripin-3, a protein expressed in the salivary glands of the tick Ixodes ricinus, a European vector of tick-borne encephalitis and Lyme disease. Belonging to the serpin superfamily of protease inhibitors, Iripin-3 strongly inhibited the proteolytic activity of serine proteases kallikrein and matriptase. In an in vitro setup, Iripin-3 was capable of modulating the adaptive immune response as evidenced by reduced survival of mouse splenocytes, impaired proliferation of CD4+ T lymphocytes, suppression of the T helper type 1 immune response, and induction of regulatory T cell differentiation. Apart from altering acquired immunity, Iripin-3 also inhibited the extrinsic blood coagulation pathway and reduced the production of pro-inflammatory cytokine interleukin-6 by lipopolysaccharide-stimulated bone marrow-derived macrophages. In addition to its functional characterization, we present the crystal structure of cleaved Iripin-3 at 1.95 Å resolution. Iripin-3 proved to be a pluripotent salivary serpin with immunomodulatory and anti-hemostatic properties that could facilitate tick feeding via the suppression of host anti-tick defenses. Physiological relevance of Iripin-3 activities observed in vitro needs to be supported by appropriate in vivo experiments.


Assuntos
Imunidade Adaptativa/efeitos dos fármacos , Anticoagulantes/farmacologia , Coagulação Sanguínea/efeitos dos fármacos , Fatores Imunológicos/farmacologia , Proteínas de Insetos/farmacologia , Ixodes/metabolismo , Saliva/metabolismo , Proteínas e Peptídeos Salivares/farmacologia , Animais , Anticoagulantes/isolamento & purificação , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Citocinas/metabolismo , Cobaias , Humanos , Fatores Imunológicos/isolamento & purificação , Proteínas de Insetos/isolamento & purificação , Ativação Linfocitária/efeitos dos fármacos , Linfócitos/efeitos dos fármacos , Linfócitos/imunologia , Linfócitos/metabolismo , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Inibidores de Proteases/isolamento & purificação , Inibidores de Proteases/farmacologia , Coelhos , Proteínas e Peptídeos Salivares/isolamento & purificação , Baço/efeitos dos fármacos , Baço/imunologia , Baço/metabolismo
19.
Aging (Albany NY) ; 13(6): 8895-8915, 2021 03 10.
Artigo em Inglês | MEDLINE | ID: mdl-33714945

RESUMO

Licochalcone A (LA), a flavonoid found in licorice, has anticancer, antioxidant, anti-inflammatory, and neuroprotective properties. Here, we explored the effect of injecting LA into the tail vein of middle-aged C57BL/6 mice on their cognitive ability as measured by the Morris water maze (MWM) test and cerebral blood flow (CBF). The related mechanisms were assessed via RNA-seq, and T (CD3e+) and B (CD45R/B220+) cells in the spleen and whole blood were quantified via flow cytometry. LA improved the cognitive ability, according to the MWM test results, and upregulated the CBF level of treated mice. The RNA-seq results indicate that LA affected the interleukin (IL)-17 signaling pathway, which is related to T- and B-cell proliferation, and the flow cytometry data suggest that LA promoted T- and B-cell proliferation in the spleen and whole blood. We also performed immune reconstruction via a tail vein injection of lymphocytes into B-NDG (NOD-PrkdcscidIl2rgtm1/Bcge) mice before treating them with LA. We tested cognitive ability by subjecting these animals to new object recognition tests and quantified the splenic and whole blood T and B cells. Cognitive ability improved after immune reconstruction and LA treatment, and LA promoted T- and B-cell proliferation in the spleen and whole blood. This study demonstrates that LA, by activating the IL-17 signaling pathway, promotes T- and B-cell proliferation in the spleen and whole blood of mice and improves cognitive ability. Thus, LA may have immune-modulating therapeutic potential for improving cognition.


Assuntos
Linfócitos B/efeitos dos fármacos , Chalconas/farmacologia , Cognição/efeitos dos fármacos , Interleucina-17/imunologia , Linfócitos T/efeitos dos fármacos , Animais , Linfócitos B/imunologia , Proliferação de Células/efeitos dos fármacos , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Baço/efeitos dos fármacos , Baço/imunologia , Linfócitos T/imunologia
20.
Biomed Pharmacother ; 138: 111505, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33773467

RESUMO

Doxorubicin (DOX) is an anthracycline antibiotic used in the fight against many types of cancer. Although it is quite effective for this purpose, its clinical use is limited by its severe side effects, highlighting the relevance of efforts to identify substances that act to minimize these effects. In this work, we sought to verify the ability of andiroba oil (AO) and a nanoemulsion of andiroba oil (AN) to lessen the side effects of DOX. The animals were separated into 7 groups with 6 animals each: mice treated with AO (2000 mg/kg), AN (2000 mg/kg), the antineoplastic agent DOX (40 mg/kg), AO+DOX, AN+DOX and solvent controls was used of negative control (corn oil and nanoemulsion surfactant). AO and AN were administered for 14 consecutive days orally by gavage and on the 13th day, applied DOX by intraperitoneal route (i.p.), in order to evaluate the protective potential of andiroba. The animals were euthanized on the 15th day. Hematological, biochemical, histological, and immunohistochemical parameters were analyzed. Andiroba reduced several aspects of the severity of lesions caused by DOX, decreasing hematotoxicity and the severity of histological changes in the liver and kidneys, and reducing the frequency of apoptotic cell death. In many cases, AN showed greater efficacy than AO alone, reflecting the feasibility of using this nanotechnology to improve the pharmacokinetics of lipid compounds in the body. The study sheds new light on the therapeutic benefits of andiroba and suggests new ways for investigating how the quantity and quality of lipid compounds affect exposed organisms.


Assuntos
Antineoplásicos/toxicidade , Doxorrubicina/toxicidade , Emulsões/uso terapêutico , Meliaceae , Óleos Vegetais/uso terapêutico , Animais , Emulsões/isolamento & purificação , Emulsões/farmacologia , Feminino , Injeções Intraperitoneais , Rim/efeitos dos fármacos , Rim/patologia , Fígado/efeitos dos fármacos , Fígado/patologia , Camundongos , Óleos Vegetais/isolamento & purificação , Óleos Vegetais/farmacologia , Baço/efeitos dos fármacos , Baço/patologia
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