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1.
Anticancer Res ; 39(10): 5515-5524, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31570445

RESUMO

BACKGROUND/AIM: Administration of cisplatin in cancer patients is limited by the kidney-related adverse effects; however, a protective strategy is absent. We hypothesized that fucoidan protects the proximal tubule epithelial (TH-1) cells against the effects of cisplatin. MATERIALS AND METHODS: To assess the effect of fucoidan, its effect on reactive oxygen species (ROS) formation, endoplasmic reticulum (ER) stress response, DNA damage response (DDR), apoptosis, and cell-cycle arrest in TH-1 cells was investigated. RESULTS: Cisplatin increased the accumulation of ROS, leading to excessive ER stress. In presence of cisplatin, treatment of TH-1 cells with fucoidan significantly reduced the ER stress by maintaining the complex of GRP78 with PERK and IRE1α. In particular, fucoidan enhanced the antioxidative capacity through up-regulation of PrPC Furthermore, fucoidan suppressed cisplatin-induced apoptosis and cell-cycle arrest, whereas silencing of PRNP blocked these effects of fucoidan. CONCLUSION: Fucoidan may be a potential adjuvant therapy for cancer patients treated with cisplatin as it preserves renal functionality.


Assuntos
Cisplatino/farmacologia , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Células Epiteliais/efeitos dos fármacos , Túbulos Renais Proximais/efeitos dos fármacos , Polissacarídeos/farmacologia , Substâncias Protetoras/farmacologia , Antioxidantes/metabolismo , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular , Células Epiteliais/metabolismo , Proteínas de Choque Térmico/metabolismo , Humanos , Rim/efeitos dos fármacos , Rim/metabolismo , Túbulos Renais Proximais/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Células Th1/efeitos dos fármacos , Células Th1/metabolismo , Regulação para Cima/efeitos dos fármacos , eIF-2 Quinase/metabolismo
2.
APMIS ; 127(10): 681-687, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31274211

RESUMO

Ulcerative colitis (UC) is a chronic recurrent inflammation of the colon. It has been proposed that the UC pathogenesis may be related to vitamin D deficiency and/or vitamin D administration in UC patients may have an ameliorating effect on the intestinal inflammation. The aim of this study was to assess the effect of vitamin D on the serum levels of immune cytokines in UC patients. In this double-blind randomized controlled trial, 90 mild-to-moderate UC patients were assigned to get either a single muscular injection of 7.5 mg vitamin D3 or 1 mL normal saline as placebo. Three months later serum levels of IL-4, IL-10, IL-12p70, IFN-γ, and TNF-α were measured. Two group variables were compared using independent t-test and analysis of covariance (ANCOVA). There was a significant increase in vitamin D only in the vitamin D group. Compared to placebo, vitamin D had significant decreasing effects on serum TNF-α, IFN-γ, and IL12p70 levels, but it had no significant effect on serum levels of IL4 and IL10. Vitamin D seems to inhibit Th1 immune responses and have no effect on Th2 responses. The findings of this study support several in vitro studies, which suggest a therapeutic immunomodulatory potential of vitamin D.


Assuntos
Colite Ulcerativa/tratamento farmacológico , Citocinas/sangue , Vitamina D/administração & dosagem , Adolescente , Adulto , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Placebos/administração & dosagem , Soro/química , Células Th1/efeitos dos fármacos , Resultado do Tratamento , Adulto Jovem
3.
Genomics Proteomics Bioinformatics ; 17(2): 129-139, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-31229590

RESUMO

The activation mechanism of chimeric antigen receptor (CAR)-engineered T cells may differ substantially from T cells carrying native T cell receptor, but this difference remains poorly understood. We present the first comprehensive portrait of single-cell level transcriptional and cytokine signatures of anti-CD19/4-1BB/CD28/CD3ζ CAR-T cells upon antigen-specific stimulation. Both CD4+ helper T (TH) cells and CD8+ cytotoxic CAR-T cells are equally effective in directly killing target tumor cells and their cytotoxic activity is associated with the elevation of a range of TH1 and TH2 signature cytokines, e.g., interferon γ, tumor necrotic factor α, interleukin 5 (IL5), and IL13, as confirmed by the expression of master transcription factor genes TBX21 and GATA3. However, rather than conforming to stringent TH1 or TH2 subtypes, single-cell analysis reveals that the predominant response is a highly mixed TH1/TH2 function in the same cell. The regulatory T cell activity, although observed in a small fraction of activated cells, emerges from this hybrid TH1/TH2 population. Granulocyte-macrophage colony stimulating factor (GM-CSF) is produced from the majority of cells regardless of the polarization states, further contrasting CAR-T to classic T cells. Surprisingly, the cytokine response is minimally associated with differentiation status, although all major differentiation subsets such as naïve, central memory, effector memory, and effector are detected. All these suggest that the activation of CAR-engineered T cells is a canonical process that leads to a highly mixed response combining both type 1 and type 2 cytokines together with GM-CSF, supporting the notion that polyfunctional CAR-T cells correlate with objective response of patients in clinical trials. This work provides new insights into the mechanism of CAR activation and implies the necessity for cellular function assays to characterize the quality of CAR-T infusion products and monitor therapeutic responses in patients.


Assuntos
Diferenciação Celular , Ativação Linfocitária/imunologia , Receptores de Antígenos Quiméricos/metabolismo , Análise de Célula Única/métodos , Células Th1/citologia , Células Th2/citologia , Antígenos/metabolismo , Antígeno CTLA-4/metabolismo , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular , Citocinas/metabolismo , Citotoxicidade Imunológica/efeitos dos fármacos , Fator Estimulador de Colônias de Granulócitos e Macrófagos/farmacologia , Humanos , Ativação Linfocitária/efeitos dos fármacos , Subpopulações de Linfócitos/efeitos dos fármacos , Subpopulações de Linfócitos/metabolismo , Fenótipo , Proteômica , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/metabolismo , Células Th1/efeitos dos fármacos , Células Th2/efeitos dos fármacos , Transcrição Genética/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos
4.
Braz J Med Biol Res ; 52(5): e7992, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31038546

RESUMO

The aim of this study was to evaluate the influence of artesunate on Th1 differentiation and its anti-tumor effect on ovarian cancer. A Murine ovarian cancer model was established by ID8 cells transplantation. The expression of miR-142 and Sirt1 proteins in peripheral CD4+ T cells were quantified with qRT-PCR and western blot, respectively. Peripheral CD4+ T cells were induced for Th1 differentiation. The percentages of apoptosis of Th1/CD4+ T cells and ovarian cancer cells were analyzed by flow cytometry. The IFN-γ level was examined through enzyme-linked immunosorbent assay. Artesunate promoted miR-142 expression in peripheral CD4+ T cells and Th1 differentiation from CD4+ T cells. Artesunate promoted cell apoptosis of ovarian cancer cells by inducing Th1 differentiation. By up-regulating miR-142, artesunate suppressed Sirt1 level and promoted Th1 differentiation. Artesunate enhanced the pro-apoptotic effects of Th1 cells on ovarian cancer via the miR-142/Sirt1 pathway. Artesunate promoted Th1 differentiation from CD4+ T cells by down-regulating Sirt1 through miR-142, thereby enhancing cell apoptosis in ovarian cancer.


Assuntos
Apoptose , Artesunato/farmacologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , MicroRNAs/metabolismo , Neoplasias Ovarianas/tratamento farmacológico , Células Th1/efeitos dos fármacos , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Artesunato/uso terapêutico , Linfócitos T CD4-Positivos/citologia , Diferenciação Celular , Regulação para Baixo , Feminino , Citometria de Fluxo , Camundongos , Camundongos Endogâmicos C57BL , Neoplasias Ovarianas/imunologia , Células Th1/citologia
5.
Arch Immunol Ther Exp (Warsz) ; 67(3): 143-151, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31032529

RESUMO

Depression is one of the most frequently diagnosed condition in psychiatry. Despite the availability of many preparations, over 30% of treated patients do not achieve remission. Recently the emphasis is put on the contribution of the body's inflammatory response as one of the causes of depression. The interactions between nervous and immune systems are the main issue addressed by psychoneuroimmunology. In patients suffering from depression changes in the plasma concentrations of cytokines and in the number and level of activation of immune cells has been found. Attention is paid to the high levels of pro-inflammatory cytokines, the prevalence of Th1 responses to Th2, weakening of NK cell cytotoxicity and changes in lymphocyte proliferation and apoptosis. A number of studies focus on influence of antidepressants and non-standard methods of depression treatment, such as ketamine infusion, on patients' immunology. Many of them seem to regulate the immune responses. The study results encourage to look for new ways to treat depression with immunomodulatory drugs. In this article authors present the current knowledge about immune system changes accompanying depression as well as the study results showing the influence of drugs on the immune system, especially in the context of reducing the symptoms of depression.


Assuntos
Antidepressivos/farmacologia , Depressão/tratamento farmacológico , Fatores Imunológicos/farmacologia , Ativação Linfocitária/efeitos dos fármacos , Antidepressivos/uso terapêutico , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Citocinas/sangue , Citocinas/imunologia , Citocinas/metabolismo , Depressão/sangue , Depressão/imunologia , Quimioterapia Combinada/métodos , Humanos , Fatores Imunológicos/uso terapêutico , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Ativação Linfocitária/imunologia , Neurotransmissores/imunologia , Neurotransmissores/metabolismo , Ensaios Clínicos Controlados Aleatórios como Assunto , Células Th1/efeitos dos fármacos , Células Th1/imunologia , Células Th1/metabolismo , Células Th2/efeitos dos fármacos , Células Th2/imunologia , Células Th2/metabolismo , Resultado do Tratamento
6.
Curr Med Sci ; 39(2): 285-290, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31016523

RESUMO

In our previous study, we found that Shoutai pills could improve the embryo implantation rate as well as the levels of estrogen, progesterone and estrogen receptor in rats with stimulated ovulation. However, the mechanism is not clear. This study was designed to investigate the effect of Shoutai pills on the levels of Th1 and Th2 cytokines in rats with stimulated ovulation and the mechanism. The rat model of stimulated ovulation was established by combined injection of pregnant mare serum gonadotropin (PMSG) and human chorionic gonadotropin (HCG). Then the rats were randomly divided into model group (M), Shoutai pills group (S), progesterone group (P) and normal group (N). All the pregnant rats were treated from the first day. The S and P groups were administrated with gavage of Shoutai pills and injection of progesterone respectively, and N and M groups were given the same volume of normal saline and distilled water respectively. After treatment for 7 days, the animals were executed for serum and uterine tissues. The ELISA method was adopted to detect the contents of Th1 cytokines [interferon-γ (INF-γ), interleukin-2 (IL-2)] and Th2 cytokines (IL-4, IL-6, IL-10). The expression of leukemia inhibitory factor (LIF) and leukemia inhibitory factor receptor (LIFR) was detected by Western blotting and real-time PCR. As compared with N group, the expression levels of IFN-γ and IL-2 in M group were significantly increased, and those of IL-4, IL-6, IL-10, LIF and LIFR were significantly decreased (P<0.05). As compared with M group, the levels of IL-4, IL-6, IL-10, LIF and LIFR in S group were significantly increased (P<0.05), and those of IFN-γ and IL-2 were significantly decreased (P<0.05). It was suggested that Shoutai pills can increase the levels of IL-4, IL-6, IL-10, LIF and LIFR as well as reduce the levels of INF-γ and IL-2 in rats with stimulated ovulation. The Shoutai pills may improve endometrial receptivity and promote embryo implantation by maintaining the balance of Th1/Th2 cytokines.


Assuntos
Citocinas/sangue , Citocinas/metabolismo , Medicamentos de Ervas Chinesas/farmacologia , Endométrio/efeitos dos fármacos , Células Th1/efeitos dos fármacos , Células Th2/efeitos dos fármacos , Animais , Endométrio/metabolismo , Feminino , Fator Inibidor de Leucemia/metabolismo , Masculino , Medicina Tradicional Chinesa/métodos , Ovulação/efeitos dos fármacos , Ovulação/metabolismo , Indução da Ovulação/métodos , Progesterona , Ratos , Ratos Wistar , Células Th1/metabolismo , Células Th2/metabolismo
7.
Int J Mol Sci ; 20(7)2019 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-30934882

RESUMO

GLP-1 (glucagon-like peptide-1) has been reported to play a vital role in neuroprotection. Experimental autoimmune encephalomyelitis (EAE) is a well-established animal model widely used to study human multiple sclerosis, a chronic demyelination disease in the central nervous system (CNS). Recently, important studies have designated that the signaling axis of GLP-1 and its receptor controls the clinical manifestations and pathogenesis of EAE. However, it is elusive whether GLP-1 receptor signaling regulates the phenotype of autoreactive T cells in the CNS. We administered dulaglutide, a well-established GLP-1 receptor agonist (GLP-1 RA), to treat EAE mice prophylactically or semi-therapeutically and subsequently analyzed the mononuclear cells of the CNS. In this study, dulaglutide treatment significantly alleviates the clinical manifestations and histopathological outcomes of EAE. Dulaglutide decreases incidences of encephalitogenic Th1/Th17 cells and Th1 granulocyte-macrophage-colony-stimulating factor (GM-CSF) expression in the CNS. Administration of dulaglutide failed to control the chemotactic abilities of encephalitogenic Th1 and Th17 cells; however, prophylactic treatment considerably decreased the populations of dendritic cells and macrophages in the CNS parenchyma. These results obtained indicate that dulaglutide modulates the differentiation of encephalitogenic Th1/Th17 and the pathogenicity of Th1 cells by influencing antigen presenting cells quantities, providing mechanism insight on T cells regulation in ameliorating EAE by GLP-1.


Assuntos
Sistema Nervoso Central/patologia , Encefalomielite Autoimune Experimental/tratamento farmacológico , Encefalomielite Autoimune Experimental/imunologia , Peptídeos Semelhantes ao Glucagon/análogos & derivados , Fragmentos Fc das Imunoglobulinas/uso terapêutico , Proteínas Recombinantes de Fusão/uso terapêutico , Células Th1/imunologia , Células Th17/imunologia , Animais , Quimiotaxia/efeitos dos fármacos , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/metabolismo , Progressão da Doença , Regulação para Baixo/efeitos dos fármacos , Encefalomielite Autoimune Experimental/patologia , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Peptídeos Semelhantes ao Glucagon/administração & dosagem , Peptídeos Semelhantes ao Glucagon/farmacologia , Peptídeos Semelhantes ao Glucagon/uso terapêutico , Fator Estimulador de Colônias de Granulócitos e Macrófagos/farmacologia , Imunização , Fragmentos Fc das Imunoglobulinas/administração & dosagem , Fragmentos Fc das Imunoglobulinas/farmacologia , Subpopulações de Linfócitos/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Glicoproteína Mielina-Oligodendrócito , Proteínas Recombinantes de Fusão/administração & dosagem , Proteínas Recombinantes de Fusão/farmacologia , Células Th1/efeitos dos fármacos , Células Th17/efeitos dos fármacos
8.
Biomed Pharmacother ; 114: 108849, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30974386

RESUMO

Many studies have shown that antibiotic therapy can attenuate colitis in IL10-deficient (IL10-/-) mice. However, these results have indicated that antibiotics were more successful in preventing, rather than treating established colitis. Those antibiotic treatments attempted to only partially alter the intestinal microbiota and to not eliminate it completely. Therefore, we treated IL10-/- mice with the multiantibiotic regimen that was used to develop a pseudo-germ-free mouse model to determine whether multi-antibiotics attenuated or exacerbated colitis. We evaluated the colitis in IL10-/- mice receiving the antibiotic treatment versus those receiving the water control; furthermore, we investigated the gut microbiota, the intestinal immune cell proportions and the cytokine secretion. Surprisingly, the IL10-/- mice receiving the antibiotic treatment had more severe intestinal colitis and a swollen cecum than those receiving the water control. Moreover, the abundance of microbiota and content of short-chain fatty acids (SCFAs) in the colon were dramatically decreased. Additionally, the proportions of Treg cells and Th1 cells in the colons of IL10-/- mice were also decreased. The mechanism may be that the decrease in the microbiota leads to a decrease in the proportions of Treg cells and SCFAs, which are necessary to maintain intestinal homeostasis. All changes lead to further exacerbated colitis in IL10-/- mice with antibiotic treatment.


Assuntos
Antibacterianos/farmacologia , Colite/tratamento farmacológico , Ácidos Graxos Voláteis/metabolismo , Microbioma Gastrointestinal/efeitos dos fármacos , Interleucina-10/metabolismo , Linfócitos T Reguladores/efeitos dos fármacos , Animais , Ceco/efeitos dos fármacos , Ceco/microbiologia , Colite/metabolismo , Colite/microbiologia , Colo/efeitos dos fármacos , Colo/microbiologia , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Masculino , Camundongos , Linfócitos T Reguladores/metabolismo , Células Th1/efeitos dos fármacos , Células Th1/metabolismo
9.
J Neuroinflammation ; 16(1): 52, 2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-30823934

RESUMO

BACKGROUND: Amlexanox (ALX), a TBK1 inhibitor, can modulate immune responses and has anti-inflammatory properties. To investigate its role in regulating the progression of experimental autoimmune encephalomyelitis (EAE), we studied the effect of ALX on the maturation of dendritic cells (DCs) and the responses of effector and regulatory T cells (Tregs). METHODS: In vitro, bone marrow-derived DCs (BMDCs) were cultured and treated with ALX. Their proliferation, maturation, and their stimulatory function to induce T cells responses were detected. In vivo, the development of EAE from different groups was recorded. At the peak stage of disease, HE, LFB, and electronic microscope (EM) were used to evaluate inflammation and demyelination. Maturation of splenic DC and Th1/Th17/Treg response in the CNS and peripheral were also detected. To further explore the mechanism underlying the action of ALX in DC maturation, the activation of TBK1, IRF3, and AKT was analyzed. RESULTS: Our data indicated that ALX significantly inhibited the proliferation and maturation of BMDCs, characterized by the reduced MHCII, a co-stimulatory molecule, IL12, and IL-23 expression, along with morphological alterations. Co-culture of ALX-treated BMDCs inhibited allogeneic T cell proliferation and MOG-specific T cell response. In EAE mice, ALX significantly attenuated the EAE development by decreasing inflammatory infiltration and demyelination in the spinal cords, accompanied by reduced frequency of splenic pathogenic Th1 and Th17 cells and increased Tregs. Moreover, ALX treatment decreased Th1 and Th17 cytokines, but increased Treg cytokines in the CNS and spleen. Notably, ALX treatment reduced the frequency and expression of CD80 and CD86 on splenic DCs and lowered IL-12 and IL-23 secretion, further supporting an impaired maturation of splenic DCs. In addition, ALX potently reduced the phosphorylation of IRF3 and AKT in BMDC and splenic DCs, both of which are substrates of TBK1 and associated with DC maturation. CONCLUSIONS: ALX, a TBK1 inhibitor, mitigated EAE development by inhibiting DC maturation and subsequent pathogenic Th1 and Th17 responses while increasing Treg responses through attenuating the TBK1/AKT and TBK1/IRF3 signaling.


Assuntos
Aminopiridinas/farmacologia , Células Dendríticas/efeitos dos fármacos , Encefalomielite Autoimune Experimental/imunologia , Linfócitos T/efeitos dos fármacos , Animais , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/imunologia , Fator Regulador 3 de Interferon/efeitos dos fármacos , Fator Regulador 3 de Interferon/metabolismo , Ativação Linfocitária/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Proteínas Serina-Treonina Quinases/efeitos dos fármacos , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Células Th1/efeitos dos fármacos , Células Th1/imunologia , Células Th17/efeitos dos fármacos , Células Th17/imunologia
10.
Nat Commun ; 10(1): 498, 2019 01 30.
Artigo em Inglês | MEDLINE | ID: mdl-30700717

RESUMO

The mechanisms controlling CD4+ T cell switching from an effector to an anti-inflammatory (IL-10+) phenotype play an important role in the persistence of chronic inflammatory diseases. Here, we identify the cholesterol biosynthesis pathway as a key regulator of this process. Pathway analysis of cultured cytokine-producing human T cells reveals a significant association between IL-10 and cholesterol metabolism gene expression. Inhibition of the cholesterol biosynthesis pathway with atorvastatin or 25-hydroxycholesterol during switching from IFNγ+ to IL-10+ shows a specific block in immune resolution, defined as a significant decrease in IL-10 expression. Mechanistically, the master transcriptional regulator of IL10 in T cells, c-Maf, is significantly decreased by physiological levels of 25-hydroxycholesterol. Strikingly, progression to rheumatoid arthritis is associated with altered expression of cholesterol biosynthesis genes in synovial biopsies of predisposed individuals. Our data reveal a link between sterol metabolism and the regulation of the anti-inflammatory response in human CD4+ T cells.


Assuntos
Colesterol/biossíntese , Interferon gama/metabolismo , Interleucina-10/metabolismo , Células Th1/metabolismo , Atorvastatina/farmacologia , Humanos , Hidroxicolesteróis/farmacologia , Células Th1/efeitos dos fármacos
11.
Int J Mol Sci ; 20(3)2019 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-30717232

RESUMO

The perspectives of regenerative medicine are still severely hampered by the host response to biomaterial implantation, despite the robustness of technologies that hold the promise to recover the functionality of damaged organs and tissues. In this scenario, the cellular and molecular events that decide on implant success and tissue regeneration are played at the interface between the foreign body and the host inflammation, determined by innate and adaptive immune responses. To avoid adverse events, rather than the use of inert scaffolds, current state of the art points to the use of immunomodulatory biomaterials and their knowledge-based use to reduce neutrophil activation, and optimize M1 to M2 macrophage polarization, Th1 to Th2 lymphocyte switch, and Treg induction. Despite the fact that the field is still evolving and much remains to be accomplished, recent research breakthroughs have provided a broader insight on the correct choice of biomaterial physicochemical modifications to tune the reaction of the host immune system to implanted biomaterial and to favor integration and healing.


Assuntos
Materiais Biocompatíveis/farmacologia , Reação a Corpo Estranho/prevenção & controle , Fatores Imunológicos/farmacologia , Macrófagos/efeitos dos fármacos , Neutrófilos/efeitos dos fármacos , Próteses e Implantes , Imunidade Adaptativa/efeitos dos fármacos , Materiais Biocompatíveis/química , Diferenciação Celular/efeitos dos fármacos , Reação a Corpo Estranho/imunologia , Humanos , Imunidade Inata/efeitos dos fármacos , Fatores Imunológicos/química , Macrófagos/citologia , Macrófagos/imunologia , Ativação de Neutrófilo/efeitos dos fármacos , Neutrófilos/citologia , Neutrófilos/imunologia , Linfócitos T Reguladores/citologia , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Células Th1/citologia , Células Th1/efeitos dos fármacos , Células Th1/imunologia , Equilíbrio Th1-Th2/efeitos dos fármacos , Células Th2/citologia , Células Th2/efeitos dos fármacos , Células Th2/imunologia , Tecidos Suporte
12.
Toxicology ; 414: 14-26, 2019 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-30611761

RESUMO

Atmospheric particulate matter (PM) is a complex component of air pollution and the leading environmental risk factor for death worldwide. PM is formed from a combination of primary sources that emit PM directly into the atmosphere and secondary sources that emit gaseous precursors which oxidize in the atmosphere to form PM and composed of both inorganic and organic components. Currently, all PM is regulated by total mass. This regulatory strategy does not consider individual chemical constituents and assumes all PM is equally toxic. The chemically-extracted organic fraction (OF) of PM retains most organic constituents such as polycyclic aromatic hydrocarbons (PAHs) and excludes inorganics. PAHs are ubiquitous environmental toxicants and known aryl hydrocarbon receptor (AHR) ligands. This study addressed the role of individual components, specifically PAHs, of PM and how differences in chemical composition of real-world samples drive differential responses. This study tested the hypothesis that real-world extracts containing different combinations and concentrations of PAHs activate the AHR and enhance T helper (Th)17 differentiation to different degrees based on specific PAHs present in each sample, and not simply the mass of PM. The ability of the real-world OF, with different PAH compositions, to enhance Th17 differentiation and activate the AHR was tested in vitro. Cumulatively, the results identified PAHs as possible candidate components of PM contributing to increased inflammation and demonstrated that the sum concentration of PAHs does not determine the extent to which each PM activates the AHR and enhances Th17 differentiation suggesting individual components of each PM, and interactions of those components with others in the mixture, contribute to the inflammatory response. This demonstrates that not all PM are the same and suggests that when regulating PM based on its ability to cause human pathology, a strategy based on PM mass may not reduce pathologic potential of exposures.


Assuntos
Poluentes Atmosféricos/toxicidade , Fatores de Transcrição Hélice-Alça-Hélice Básicos/agonistas , Diferenciação Celular/efeitos dos fármacos , Material Particulado/toxicidade , Hidrocarbonetos Policíclicos Aromáticos/toxicidade , Receptores de Hidrocarboneto Arílico/agonistas , Células Th1/efeitos dos fármacos , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Células Cultivadas , Citocromo P-450 CYP1A1/biossíntese , Citocromo P-450 CYP1A1/genética , Relação Dose-Resposta a Droga , Indução Enzimática , Feminino , Masculino , Camundongos Endogâmicos C57BL , Receptores de Hidrocarboneto Arílico/metabolismo , Medição de Risco , Transdução de Sinais/efeitos dos fármacos , Células Th1/metabolismo
13.
J Immunol ; 202(5): 1350-1362, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30674573

RESUMO

MYMD-1 is a synthetic derivative of tobacco alkaloids, compounds that possess immunoregulatory properties and have been linked to the epidemiological observation that smoking reduces the odds of developing thyroid Abs and hypothyroidism. To assess the effect and mechanism(s) of the action of MYMD-1, we chose the NOD.H-2h4 mouse model of spontaneous thyroiditis. We began in vitro using T cells isolated from NOD.H-2h4 spleens and found that MYMD-1 suppressed TNF-α production by CD4+ T cells in a dose-dependent manner. We then treated 58 NOD.H-2h4 mice for 12 wk with either unsupplemented water that contained (10 mice) or did not contain (16 mice) MYMD-1 (185 mg/l) or water supplemented with sodium iodide (500 mg/l) that contained (16 mice) or did not contain (16 mice) MYMD-1. Mice were bled at baseline and then every 2 wk until sacrifice. MYMD-1 decreased the incidence and severity (p < 0.001) of thyroiditis, as assessed by histopathology. Similarly, the number of CD3+ T cells and CD19+ B cells infiltrating the thyroid was dampened by MYMD-1, as assessed by flow cytometry. Interestingly, the subset of thyroidal CD3+CD4+Tbet+RORγT- effector Th1 cells and the systemic levels of TNF-α were decreased by MYMD-1. Serum thyroglobulin Abs decreased in the MYMD-1 group. Thyroid hormones did not differ among the four groups, whereas thyroid-stimulating hormone increased upon iodine supplementation but remained normal in MYMD-1-treated mice. Overall, the study suggests that MYMD-1 ameliorates thyroiditis acting on specific lymphoid subsets. Further studies, including other models of autoimmunity, will confirm the potential clinical use of MYMD-1 as a novel immunometabolic regulator.


Assuntos
Alcaloides/farmacologia , Mediadores da Inflamação/farmacologia , Tireoidite Autoimune/tratamento farmacológico , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Alcaloides/síntese química , Alcaloides/química , Animais , Feminino , Mediadores da Inflamação/síntese química , Mediadores da Inflamação/química , Masculino , Camundongos , Camundongos Endogâmicos NOD , Células Th1/efeitos dos fármacos , Células Th1/imunologia , Tireoidite Autoimune/imunologia , Tabaco/química , Fator de Necrose Tumoral alfa/imunologia
14.
Molecules ; 24(1)2019 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-30621160

RESUMO

Quillaja saponaria Molina represents the main source of saponins for industrial applications. Q. saponaria triterpenoids have been studied for more than four decades and their relevance is due to their biological activities, especially as a vaccine adjuvant and immunostimulant, which have led to important research in the field of vaccine development. These saponins, alone or incorporated into immunostimulating complexes (ISCOMs), are able to modulate immunity by increasing antigen uptake, stimulating cytotoxic T lymphocyte production (Th1) and cytokines (Th2) in response to different antigens. Furthermore, antiviral, antifungal, antibacterial, antiparasitic, and antitumor activities are also reported as important biological properties of Quillaja triterpenoids. Recently, other saponins from Q. brasiliensis (A. St.-Hill. & Tul.) Mart. were successfully tested and showed similar chemical and biological properties to those of Q. saponaria barks. The aim of this manuscript is to summarize the current advances in phytochemical and pharmacological knowledge of saponins from Quillaja plants, including the particular chemical characteristics of these triterpenoids. The potential applications of Quillaja saponins to stimulate further drug discovery research will be provided.


Assuntos
Saponinas de Quilaia/química , Quillaja/química , Terpenos/química , Células Th1/efeitos dos fármacos , Humanos , ISCOMs/química , ISCOMs/uso terapêutico , Imunomodulação/efeitos dos fármacos , Saponinas de Quilaia/uso terapêutico , Linfócitos T Citotóxicos/efeitos dos fármacos , Terpenos/uso terapêutico , Células Th1/imunologia , Células Th2/efeitos dos fármacos
15.
Pharmacology ; 103(3-4): 136-142, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30602153

RESUMO

To investigate the effect of Tanshinone IIA (TSA) on viral myocarditis (VMC). VMC animal model was established using BALB/c mice by intraperitoneally injecting Coxsackie virus B3 (CVB3). The mice were randomly divided into control group, model group, and TSA group. We detected the survival rate, the heart weight to body weight (HW/BW) ratio and hemodynamic and cardiac function parameters. The pathological features of VMC were measured through H&E staining. The expression of serum enzyme, inflammatory cytokines, and T helper (Th)1/Th2 markers was also investigated. TSA remarkably alleviated CVB3-caused myocardial injury, decreased the HW/BW ratio, and improved survival rate. TSA obviously improved hemodynamic parameters and reversed the damage to the heart pump function. Furthermore, the serum levels of lactate dehydrogenase, creatine kinase, and Th1 cytokines in the TSA group were significantly lower than those in the VMC group, and TSA treatment significantly improved the pathological condition. The interferon-gamma (IFN-γ) and interleukin-2 (IL-2) levels in VMC model group was higher than control group, and lower levels of IL-4 and IL-10 were identified. However, TSA treatment elevated IL-4 and IL-10 levels and decreased IFN-γ and IL-2 levels. TSA could effectively protect the myocardium against CVB3-induced myocarditis by the inhibition of inflammation and modulation Th1/Th2 balance in mice.


Assuntos
Anti-Inflamatórios/farmacologia , Infecções por Coxsackievirus/prevenção & controle , Diterpenos de Abietano/farmacologia , Enterovirus/patogenicidade , Miocardite/prevenção & controle , Miocárdio , Células Th1/efeitos dos fármacos , Células Th2/efeitos dos fármacos , Animais , Infecções por Coxsackievirus/sangue , Infecções por Coxsackievirus/imunologia , Infecções por Coxsackievirus/virologia , Citocinas/sangue , Modelos Animais de Doenças , Enterovirus/imunologia , Mediadores da Inflamação/sangue , Masculino , Camundongos Endogâmicos BALB C , Miocardite/sangue , Miocardite/imunologia , Miocardite/virologia , Miocárdio/imunologia , Miocárdio/metabolismo , Miocárdio/patologia , Células Th1/imunologia , Células Th1/metabolismo , Células Th1/virologia , Equilíbrio Th1-Th2/efeitos dos fármacos , Células Th2/imunologia , Células Th2/metabolismo , Células Th2/virologia
16.
Int Immunopharmacol ; 69: 27-33, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30665041

RESUMO

Allergic rhinitis (AR) is a common upper airway allergic disease caused by allergens triggering a type 2 immune response. The imbalance of CD4+ T cell subsets is the essential immunological feature of AR, which is mainly characterized by the predominance of T helper (Th) 2 cells. Recent studies indicated that the anti-inflammatory factor interleukin (IL)-37 is involved in the immune regulation of AR. However, the mechanism of IL-37 acts on AR has not been fully elucidated. Thus, we sought to assess the protective role of IL-37 in AR and further explore the possible mechanism. An ovalbumin (OVA)-induced AR murine model was established. After IL-37 treatment, the allergic symptoms (sneezes and nasal rubbings), nasal mucosal infiltration with eosinophils, and serum IgE production were found significantly attenuated. For CD4+ T cell subsets, the proliferation and differentiation of Th2 and Th17 cells were restrained. The relevant effector cytokines of IL-4, IL-5, IL-6, and IL-17a protein expression and transcription factors GATA3 and RORγt mRNA levels were obviously decreased. However, IL-37 had no significant effect on Th1 and Treg response including in IFN-γ, IL-10, T-bet, and Foxp3 expression. Furthermore, IL-37 was found down-regulated the STAT6, STAT3, phospho-STAT6, and phospho-STAT3 expression. In conclusion, IL-37 alleviates allergic inflammation in AR possibly through repressing STAT6 and STAT3 signaling pathways.


Assuntos
Eosinófilos/efeitos dos fármacos , Interleucina-1/metabolismo , Rinite Alérgica/imunologia , Células Th1/imunologia , Células Th2/imunologia , Alérgenos/imunologia , Animais , Citocinas/metabolismo , Modelos Animais de Doenças , Eosinófilos/imunologia , Humanos , Imunoglobulina E/sangue , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Ovalbumina/imunologia , Fator de Transcrição STAT3/metabolismo , Fator de Transcrição STAT6/metabolismo , Transdução de Sinais , Células Th1/efeitos dos fármacos , Células Th2/efeitos dos fármacos
17.
J Microbiol Biotechnol ; 29(3): 489-499, 2019 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-30691253

RESUMO

Subunit vaccines are safer and more stable than live vaccines although they have the disadvantage of eliciting poor immune response. To develop a subunit vaccine, an effective delivery system targeting the key elements of the protective immune response is a prerequisite. In this study, oxidized carbon nanospheres (OCNs) were used as a subunit vaccine delivery system and tuberculosis (TB) was chosen as a model disease. TB is among the deadliest infectious diseases worldwide and an effective vaccine is urgently needed. The ability of OCNs to deliver recombinant Mycobacterium tuberculosis (Mtb) proteins, Ag85B and HspX, into bone marrow derived macrophages (BMDMs) and dendritic cells (BMDCs) was investigated. For immunization, OCNs were mixed with the two TB antigens as well as the adjuvant monophosphoryl lipid A (MPL). The protective efficacy was analyzed in vaccinated mice by aerosol Mtb challenge with a virulent strain of Mtb and the bacterial burdens were measured. The results showed that OCNs are highly effective in delivering Mtb proteins into the cytosol of BMDMs and BMDCs. Upon immunization, this vaccine formula induced robust Th1 immune response characterized by cytokine profiles from restimulated splenocytes and specific antibody titer. More importantly, enhanced cytotoxic CD8⁺ T cell activation was observed. However, it did not reduce the bacteria burden in the lung and spleen from the aerosol Mtb challenge. Taken together, OCNs are highly effective in delivering subunit protein vaccine and induce robust Th1 and CD8⁺ T cell response. This vaccine delivery system is suitable for application in settings where cell-mediated immune response is needed.


Assuntos
Carbono/química , Sistemas de Liberação de Medicamentos/métodos , Nanosferas/química , Linfócitos T Citotóxicos/imunologia , Vacinas contra a Tuberculose , Tuberculose/prevenção & controle , Vacinas de Subunidades/química , Vacinas de Subunidades/imunologia , Aciltransferases/genética , Adjuvantes Imunológicos , Administração através da Mucosa , Animais , Antígenos de Bactérias/genética , Antígenos de Bactérias/imunologia , Proteínas de Bactérias/genética , Proteínas de Bactérias/imunologia , Medula Óssea , Citocinas/metabolismo , Células Dendríticas/efeitos dos fármacos , Modelos Animais de Doenças , Feminino , Imunidade Celular , Imunização , Pulmão/microbiologia , Macrófagos/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Mycobacterium tuberculosis/patogenicidade , Baço/microbiologia , Células Th1/efeitos dos fármacos , Vacinas Atenuadas/administração & dosagem , Vacinas Atenuadas/imunologia , Vacinas de Subunidades/administração & dosagem , Vacinas Sintéticas
18.
Phytomedicine ; 54: 56-65, 2019 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-30668383

RESUMO

BACKGROUND: Multiple sclerosis (MS) is an autoimmune disorder resulting in paralysis, and the responses of reactive T cells against self-antigens are hallmarks. Glycyrrhizae Radix (GR) has been used for detoxification and reducing inflammation. However, very few reports have described the effects of GR on MS. PURPOSE: The immunomodulatory effects of GR extract on autoimmune responses were evaluated through in vitro, ex vivo, and in vivo assays using primary mouse splenocytes (SPLC), mouse microglia BV2 cell line, and a mouse model of experimental autoimmune encephalomyelitis (EAE). STUDY DESIGN: Ethanol extract of GR was used in vitro with primary SPLC in the condition of anti-CD3/CD28 stimulation and interferon (IFN)-γ-producing CD4+ (TH1)/CD8+ (TC1) polarization as well as IFN-γ-stimulated BV2 cells. For EAE induction, female C57BL/6 mice were immunized with 200 µg of myelin oligodendrocyte glycoprotein (MOG)35-55 without pertussis toxin. EAE SPLC (ex vivo) and EAE mice (in vivo) were treated with GR extract to evaluate the changes in antigen-specific responses. SPLC media containing antigen-specific responses were used to stimulate BV2 cells. RESULTS: GR extract effectively modulated the responses of reactive splenic T cells through the reduction in IFN-γ+ T cell populations, the expressions of cell adhesion molecules (CAMs), and secretions of cytokines containing IFN-γ and a chemokine IFN-γ-induced protein 10 (IP-10) in vitro. In addition, GR extract significantly decreased nitric oxide production and secretion of tumor necrosis factor (TNF)-α and IP-10 in IFN-γ-stimulated BV2 cells. The antigen-specific TH1 and TC1 populations were decreased following administration of 100 mg/kg of GR extract, whereas CD8+IL-17A+ (TC17) population was increased on day 36 after EAE induction. Moreover, IFN-γ, which showed the highest secretion among examined cytokines, and IP-10 decreased on day 36. SPLC media derived from 100 mg/kg GR extract-administered EAE mice revealed the ameliorative effects on BV2 cell stimulation. CONCLUSION: This is the first report on the immunomodulatory effects of GR extract on antigen-specific SPLC responses in EAE. These results could be helpful for the discovery of drug candidates for MS by focusing on IFN-γ-related autoimmune responses.


Assuntos
Encefalomielite Autoimune Experimental/tratamento farmacológico , Glycyrrhiza/química , Extratos Vegetais/farmacologia , Baço/imunologia , Animais , Células Cultivadas , Citocinas/metabolismo , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/metabolismo , Etanol/química , Feminino , Interferon gama/metabolismo , Interleucina-17 , Camundongos Endogâmicos C57BL , Microglia/efeitos dos fármacos , Glicoproteína Mielina-Oligodendrócito/imunologia , Óxido Nítrico/metabolismo , Fragmentos de Peptídeos/imunologia , Extratos Vegetais/química , Baço/citologia , Baço/efeitos dos fármacos , Células Th1/efeitos dos fármacos , Células Th1/imunologia
19.
Nat Commun ; 10(1): 19, 2019 01 03.
Artigo em Inglês | MEDLINE | ID: mdl-30604761

RESUMO

Protein methyltransferases (PMTs) comprise a major class of epigenetic regulatory enzymes with therapeutic relevance. Here we present a collection of chemical probes and associated reagents and data to elucidate the function of human and murine PMTs in cellular studies. Our collection provides inhibitors and antagonists that together modulate most of the key regulatory methylation marks on histones H3 and H4, providing an important resource for modulating cellular epigenomes. We describe a comprehensive and comparative characterization of the probe collection with respect to their potency, selectivity, and mode of inhibition. We demonstrate the utility of this collection in CD4+ T cell differentiation assays revealing the potential of individual probes to alter multiple T cell subpopulations which may have implications for T cell-mediated processes such as inflammation and immuno-oncology. In particular, we demonstrate a role for DOT1L in limiting Th1 cell differentiation and maintaining lineage integrity. This chemical probe collection and associated data form a resource for the study of methylation-mediated signaling in epigenetics, inflammation and beyond.


Assuntos
Inibidores Enzimáticos/farmacologia , Epigênese Genética/efeitos dos fármacos , Histonas/metabolismo , Metiltransferases de Proteína/antagonistas & inibidores , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Animais , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/genética , Ensaios Enzimáticos/métodos , Epigenômica/métodos , Células HEK293 , Humanos , Células Jurkat , Metilação/efeitos dos fármacos , Metiltransferases/antagonistas & inibidores , Metiltransferases/metabolismo , Camundongos Endogâmicos C57BL , Metiltransferases de Proteína/metabolismo , Processamento de Proteína Pós-Traducional/genética , Células Th1/efeitos dos fármacos , Células Th1/fisiologia
20.
BMC Infect Dis ; 19(1): 52, 2019 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-30642265

RESUMO

BACKGROUND: Leprosy is an ideal human disease to study T cell regulation as patients show correlation between cytokine skewed Th1-Th2 responses and clinical forms of the disease. The Role of transcription factors on the modulation of Th1 and Th2 responses by M. leprae antigens has not been adequately studied. In the present study, we studied the effect of M. leprae antigens on transcription factors STAT-4, STAT-6 and CREB and their correlation with Th1/Th2 cell mediated immune responses in leprosy. METHODS: Leprosy patients of both categories of tuberculoid leprosy (BT/TT) and lepromatous leprosy (BL/LL) were selected from the OPD of NJ1L & OMD, (ICMR), Agra and healthy individuals (H) were chosen from the staff and students working in the institute. Peripheral blood mononuclear cells (PBMCs) of the study subjects were stimulated with M. leprae antigens (WCL, MLSA, and PGL-1). Sandwich ELISA was done in the culture supernatants of healthy and leprosy patients to detect IL-4, IL-10 and IFN-γ. Further, expression of IFN-γ and IL-4 and activation of STAT4, STAT6 and CREB transcription factors in CD4+ T cell with or without stimulation of M. leprae antigens was investigated by flow cytometry. RESULTS: Lepromatous leprosy patients showed significantly lower IFN-γ and higher IL-4 levels in culture supernatant and significantly low expression of IFN-γ and higher expression of IL-4 by CD4+ T cells than healthy individuals with or without antigenic stimulation. Antigenic stimulation significantly increased IL-10 in BL/LL patients but not in BT/TT patients or healthy individuals. PGL-1 stimulation led to significantly higher activation of STAT-6 in BT/TT and BL/LL patients in comparison to healthy individuals. All the three antigens led to activation of CREB in healthy and BT/TT patients but not in BL/LL patients. CONCLUSION: Our findings show that M. leprae antigens differentially modulate activation of T cell transcription factors STAT-4/STAT-6 and CREB. These transcription factors are well known to regulate Th1 and Th2 mediated immune response which in turn could play vital role in the clinical manifestations of leprosy. These observations may help to determine how these T cell transcription factors affect the development of immune dysfunction and whether these new pathways have a role in immunomodulation in intracellular diseases like leprosy and TB.


Assuntos
Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Hanseníase/imunologia , Mycobacterium leprae/imunologia , Fator de Transcrição STAT4/metabolismo , Fator de Transcrição STAT6/metabolismo , Adulto , Antígenos de Bactérias/farmacologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Estudos de Casos e Controles , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/imunologia , Citocinas/metabolismo , Humanos , Hanseníase/metabolismo , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/microbiologia , Pessoa de Meia-Idade , Mycobacterium leprae/patogenicidade , Fator de Transcrição STAT4/imunologia , Fator de Transcrição STAT6/imunologia , Células Th1/efeitos dos fármacos , Células Th1/imunologia , Células Th1/metabolismo , Células Th2/efeitos dos fármacos , Células Th2/imunologia , Células Th2/metabolismo
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