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1.
APMIS ; 128(11): 593-602, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32870528

RESUMO

Induction of broad Th1 cellular immune responses and cytokines is crucial characteristics for vaccines against intracellular infections such as hepatitis C virus (HCV). Plants (especially oilseed tissues) and plant-immunomodulators (like oil bodies) offer cost-effective and scalable possibilities for the production of immunologically relevant and safe vaccine antigens and adjuvants, respectively. Herein, we provide data of the murine immunization by transgenic canola oilseed-derived HCV core protein (HCVcp) soluble extract (TSE) and Escherichia coli- derived rHCVcp in combination with Canola oil bodies (oil) compared to that of the Freund's (FA) adjuvant. Mice immunized by TSE+ oil developed both strong humeral (IgG) and Th1-biased cellular responses, manifested by high levels of IFN-γ and lower IgG1/IgG2a ratio and IL-4 secretion. Results of the intracellular cytokine staining indicated that TSE+ oil immunization in mice triggered both CD4+ and CD8+ T cells to release IFN-γ, while CD4+ cells were mostly triggered when FA was used. Analyses by qRT-PCR indicated that a combination of rHCVcp/TSE with oil body induced high levels of IL-10 cytokines compared to that of the FA adjuvant. These characteristics are important properties for the design of an HCV vaccine candidate and indicate the potential of Canola-derived antigen and oil bodies in addressing these concerns.


Assuntos
Hepacivirus/efeitos dos fármacos , Hepatite C Crônica/prevenção & controle , Proteínas Recombinantes/administração & dosagem , Células Th1/efeitos dos fármacos , Proteínas do Core Viral/administração & dosagem , Vacinas contra Hepatite Viral/administração & dosagem , Adjuvantes Imunológicos/administração & dosagem , Adjuvantes Imunológicos/química , Animais , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/virologia , Escherichia coli/genética , Escherichia coli/metabolismo , Feminino , Hepacivirus/imunologia , Hepacivirus/patogenicidade , Hepatite C Crônica/imunologia , Hepatite C Crônica/patologia , Hepatite C Crônica/virologia , Imunidade Celular/efeitos dos fármacos , Imunoglobulina G/biossíntese , Interferon gama/biossíntese , Interferon gama/imunologia , Interleucina-10/biossíntese , Interleucina-10/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Óleo de Brassica napus/administração & dosagem , Óleo de Brassica napus/química , Proteínas Recombinantes/biossíntese , Proteínas Recombinantes/imunologia , Células Th1/imunologia , Células Th1/virologia , Proteínas do Core Viral/biossíntese , Proteínas do Core Viral/imunologia , Vacinas contra Hepatite Viral/biossíntese
2.
Front Immunol ; 11: 2056, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32973814

RESUMO

The pandemic of coronavirus disease 2019 (COVID-19), a disease which causes severe lung injury and multiple organ damage, presents an urgent need for new drugs. The case severity and fatality of COVID-19 are associated with excessive inflammation, namely, a cytokine storm. Metformin, a widely used drug to treat type 2 diabetes (T2D) mellitus and metabolic syndrome, has immunomodulatory activity that reduces the production of proinflammatory cytokines using macrophages and causes the formation of neutrophil extracellular traps (NETs). Metformin also inhibits the cytokine production of pathogenic Th1 and Th17 cells. Importantly, treatment with metformin alleviates various lung injuries in preclinical animal models. In addition, a recent proteomic study revealed that metformin has the potential to directly inhibit SARS-CoV-2 infection. Furthermore, retrospective clinical studies have revealed that metformin treatment reduces the mortality of T2D with COVID-19. Therefore, metformin has the potential to be repurposed to treat patients with COVID-19 at risk of developing severe illness. This review summarizes the immune pathogenesis of SARS-CoV-2 and addresses the effects of metformin on inhibiting cytokine storms and preventing SARS-CoV-2 infection, as well as its side effects.


Assuntos
Antivirais/uso terapêutico , Betacoronavirus , Infecções por Coronavirus/tratamento farmacológico , Fatores Imunológicos/uso terapêutico , Lesão Pulmonar/tratamento farmacológico , Metformina/uso terapêutico , Pneumonia Viral/tratamento farmacológico , Animais , Antivirais/efeitos adversos , Antivirais/farmacologia , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Citocinas/antagonistas & inibidores , Reposicionamento de Medicamentos/métodos , Armadilhas Extracelulares/efeitos dos fármacos , Humanos , Fatores Imunológicos/efeitos adversos , Fatores Imunológicos/farmacologia , Inflamação/tratamento farmacológico , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Metformina/efeitos adversos , Metformina/farmacologia , Pandemias , Pneumonia Viral/imunologia , Pneumonia Viral/virologia , Células Th1/efeitos dos fármacos , Células Th1/imunologia , Células Th17/efeitos dos fármacos , Células Th17/imunologia
3.
Arch Endocrinol Metab ; 64(3): 243-250, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32555990

RESUMO

OBJECTIVE: Intrathyroid injection of dexamethasone (IID) was used for decrease the relapse rate of hyperthyroidism in the treatment of Graves' disease (GD), but the mechanism is still unclear. We aimed to explore the effect of IID on T help (Th)1/Th2 cells and their chemokine in patients with GD. SUBJECTS AND METHODS: A total of 42 patients with GD who were euthyroidism by methimazole were randomly divided into IID group (n = 20) and control group (n = 22). Thyroid function and associated antibody, Th1/Th2 cells proportion, serum CXCL10 and CCL2 levels, and CXCR3/CCR2 mRNA expression in peripheral blood mononuclear cells before and after 3-month IID treatment were tested by chemiluminescence assay, Flow cytometry, ELISA, and real-time PCR, respectively. Thyroid follicular cells were stimulated by IFN-γ and TNF-α and treated with dexamethasone in vitro. CXCL10 and CCL2 levels in supernatant were determined. RESULTS: After 3-month therapy, the proportion of Th2 cells and serum CCL2 levels, as well as TPOAb, TRAb levels and thyroid volume decreased in IID group (p < 0.05). However, the proportion of Th1 and CXCL10 levels had no change in IID group and control (p > 0.05). The CXCR3/CCR2 ratio had no change in both groups (p > 0.05). CONCLUSION: IID therapy could inhibit peripheral Th2 cells via decreasing CCL2 level in peripheral blood, and this result partly explain the effects of IID therapy on prevention of relapse of GD. Arch Endocrinol Metab. 2020;64(3):243-50.


Assuntos
Anti-Inflamatórios/administração & dosagem , Dexametasona/administração & dosagem , Doença de Graves/tratamento farmacológico , Células Th1/efeitos dos fármacos , Células Th2/efeitos dos fármacos , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva , Prevenção Secundária , Resultado do Tratamento
4.
PLoS One ; 15(5): e0226539, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32413046

RESUMO

A murine model to study the effect of cold-induced stress (CIS) on Chlamydia muridarum genital infection and immune response has been developed in our laboratory. Previous results in the lab show that CIS increases the intensity of chlamydia genital infection, but little is known about the effects and mechanisms of CIS on the differentiation and activities of CD4+ T cell subpopulations and bone marrow-derived dendritic cells (BMDCs). The factors that regulate the production of T helper 1 (Th1) or T helper 2 (Th2) cytokines are not well defined. In this study, we examined whether CIS modulates the expressions of beta-adrenergic receptor (ß-AR), transcription factors, hallmark cytokines of Th1 and Th2, and differentiation of BMDCs during C. muridarum genital infection in the murine model. Our results show that the mRNA level of the beta2-adrenergic receptor (ß2-AR) compared to ß1-AR and ß3-AR was high in the mixed populations of CD4+ T cells and BMDCs. Furthermore, we observed decreased expression of T-bet, low level of Interferon-gamma (IFN-γ) production, increased expression of GATA-3, and Interleukin-4 (IL-4) production in CD4+ T cells of stressed mice. Exposure of BMDCs to Fenoterol, ß2-AR agonist, or ICI118,551, ß2-AR antagonist, revealed significant ß2-AR stimulation or inhibition, respectively, in stressed mice. Moreover, co-culturing of mature BMDCs and naïve CD4+ T cells increased the production of IL-4, IL-10, L-17, and IL-23 cytokines, suggesting that stimulation of ß2-AR leads to the increased production of Th2 cytokines. Overall, our results show for the first time that CIS promotes the switching from a Th1 to Th2 cytokine environment. This was evidenced in the murine stress model by the overexpression of GATA-3 concurrent with elevated IL-4 production, reduced T-bet expression, and IFN-γ secretion.


Assuntos
Infecções por Chlamydia/imunologia , Resposta ao Choque Frio , Células Th1/imunologia , Células Th2/imunologia , Agonistas Adrenérgicos beta/farmacologia , Antagonistas Adrenérgicos beta/farmacologia , Animais , Células Cultivadas , Chlamydia muridarum , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/imunologia , Feminino , Fenoterol/farmacologia , Interferon gama/genética , Interferon gama/metabolismo , Interleucinas/genética , Interleucinas/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Propanolaminas/farmacologia , Receptores Adrenérgicos beta/genética , Receptores Adrenérgicos beta/metabolismo , Proteínas com Domínio T/genética , Proteínas com Domínio T/metabolismo , Células Th1/efeitos dos fármacos , Células Th2/efeitos dos fármacos , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
5.
Med Sci Monit ; 26: e920583, 2020 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-32249275

RESUMO

BACKGROUND Bifidobacteria are among the probiotics used in treating intestinal diseases and are rarely used for allergic asthma treatment. The present study investigated the mechanism of B. infantis in treating allergic asthma in mice. MATERIAL AND METHODS A total of 40 male Balb/c mice were randomized into control, ovalbumin (OVA), montelukast (Mon), and B. infantis (B10) groups, and allergic asthma was induced in the OVA, Mon, and B10 groups. Airway reactivity was measured on day 29 by methacholine at various doses. The numbers of total cells and inflammatory cells in bronchoalveolar lavage fluid (BALF) were counted by blood cell counter and Diff-Quik staining. Hematoxylin-eosin (HE) staining was performed to observe inflammatory cell infiltration in lung tissues. Total IgE and OVA-specific IgE in serum were measured by ELISA. Mucin 5AC expression was detected by Western blot to evaluate airway obstruction. The levels of Th1 (IFN-γ, IL-2) and Th2 (IL-4, IL-5, IL-13) cytokines in BALF and tissues were detected by ELISA and qRT-PCR, respectively. RESULTS The mice in the OVA group had airway hyperreactivity, while the symptoms in the B10 group and Mon group were effectively relieved. B10 reduced the number of inflammatory cells in BALF as well as inflammatory cell infiltration in tissues. Moreover, the levels of total serum IgE, OVA-specific IgE, and Mucin 5AC were increased in the OVA group, but were reduced in the Mon group and B10 group. B. infantis increased the levels of Th1 cytokines and decreased those of Th2 cytokines. CONCLUSIONS B. infantis can reduce the infiltration of inflammatory cells induced by OVA-specific antibodies in mice. B. infantis has therapeutic effects on allergic asthma by promoting Th1 and inhibiting Th2 immune responses.


Assuntos
Asma/terapia , Bifidobacterium longum subspecies infantis , Animais , Líquido da Lavagem Broncoalveolar/citologia , Líquido da Lavagem Broncoalveolar/imunologia , Citocinas/imunologia , Modelos Animais de Doenças , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico , Imunoglobulina E/sangue , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Ovalbumina/imunologia , Distribuição Aleatória , Células Th1/efeitos dos fármacos , Células Th1/imunologia , Células Th2/efeitos dos fármacos , Células Th2/imunologia
7.
Cancer Immunol Immunother ; 69(9): 1725-1735, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32328672

RESUMO

Surface exposed phosphatidylserine (PS) of cancer aids it to evade immune surveillance and thereby results in tumor progression. Earlier, we reported that PS targeting cationic liposomes, phosphatidylcholine-stearylamine (PC-SA), alone and in combination with doxorubicin can result in complete remission of B16F10 melanoma in C57BL/6 mice without signs of toxicity. Inducing an immunogenic response is highly crucial for any cancer therapy as it is essential in improving the tumor microenvironment for any drug to act. Herein, we demonstrate that PC-SA, besides having tumor reducing ability, elicits a strong immune response. The combination therapy (PC-SA-DOX) is superior to free DOX in enhancing the anti-tumor immune effect on CD4-positive and CD8-positive T cells for IFN-γ, IL-2 and TNF-α production in sera and splenic culture supernatants of B16F10 tumor-induced mice. An upregulation of IL-12 and NO production is evidenced in spleen cultures of these mice, thereby showing a promising role of both Th1 type and innate immune response for host anti-tumor activity. Complete elimination of cancer is sometimes accomplished by surgery, but its effectiveness is often limited due to the propensity of cancers to spread to distant organs by metastasis. In our present study, we show that in PC-SA-DOX treated mice, the elevated Th1 cytokine levels create an immuno-protective environment which thereby facilitates in curing lung metastasis. Our results, therefore, warrant the need of effective immune stimulation by anticancer formulations for inhibition of solid tumors and metastasis, demonstrated by the liposomal DOX formulation.


Assuntos
Aminas/farmacologia , Citocinas/metabolismo , Doxorrubicina/farmacologia , Lipossomos/farmacologia , Metástase Neoplásica/tratamento farmacológico , Células Th1/efeitos dos fármacos , Animais , Linhagem Celular Tumoral , Modelos Animais de Doenças , Feminino , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Melanoma/patologia , Camundongos , Camundongos Endogâmicos C57BL , Baço/efeitos dos fármacos , Baço/metabolismo , Células Th1/metabolismo , Microambiente Tumoral/efeitos dos fármacos
8.
Arch Virol ; 165(6): 1445-1451, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32248293

RESUMO

The use of the nanocapsulated adjuvant Sapomax increased the expression of innate immunity genes (H2Q10, Ddx58, Tyk2, Tlr3, Tlr7, and TNF) responsible for the primary recognition of influenza virus, i.e., those belonging to the RLR and TLR families; genes involved in stimulating the production of type I and III IFN and pro-inflammatory cytokines; and Th1 and Th2 cellular immunity genes (Ccr4, Ccr5, IFNγ, IL-2, IL-4, and IL-10) responsible for triggering regulatory immune mechanisms in the cell. The high immunological activity of the plant-derived nanocapsulated adjuvant Sapomax may be used to enhance the efficacy of vaccines.


Assuntos
Adjuvantes Imunológicos/administração & dosagem , Imunidade Inata/efeitos dos fármacos , Saponaria/química , Vacinas/imunologia , Adjuvantes Imunológicos/genética , Animais , Citocinas/imunologia , Composição de Medicamentos , Feminino , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Nanocápsulas , Células Th1/efeitos dos fármacos , Células Th1/imunologia , Células Th2/efeitos dos fármacos , Células Th2/imunologia
9.
J Immunol Res ; 2020: 2714257, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32149156

RESUMO

Pseudorabies is an important infectious disease of swine, and immunization using attenuated pseudorabies virus (aPrV) vaccine is a routine practice to control this disease in swine herds. This study was to evaluate a saline solution containing ginseng stem-leaf saponins (GSLS) and sodium selenite (Se) as a vaccine adjuvant for its enhancement of immune response to aPrV vaccine. The results showed that aPrV vaccine diluted with saline containing GSLS-Se (aP-GSe) induced significantly higher immune responses than that of the vaccine diluted with saline alone (aP-S). The aP-GSe promoted higher production of gB-specific IgG, IgG1, and IgG2a, neutralizing antibody titers, secretion of Th1-type (IFN-γ, IL-2, IL-12), and Th2-type (IL-4, IL-6, IL-10) cytokines, and upregulated the T-bet/GATA-3 mRNA expression when compared to aP-S. In addition, cytolytic activity of NK cells, lymphocyte proliferation, and CD4+/CD8+ ratio was also significantly increased by aP-GSe. More importantly, aP-GSe conferred a much higher resistance of mice to a field virulent pseudorabies virus (fPrV) challenge. As the present study was conducted in mice, further study is required to evaluate the aP-GSe to improve the vaccination against PrV in swine.


Assuntos
Adjuvantes Imunológicos , Panax/química , Saponinas/farmacologia , Selênio/farmacologia , Células Th1/efeitos dos fármacos , Células Th1/imunologia , Células Th2/efeitos dos fármacos , Células Th2/imunologia , Vacinas/imunologia , Animais , Anticorpos Neutralizantes/imunologia , Biomarcadores , Relação CD4-CD8 , Citocinas/metabolismo , Feminino , Expressão Gênica , Imunoglobulina G/imunologia , Camundongos , Vacinas contra Pseudorraiva/imunologia , Saponinas/química , Selênio/química , Soluções , Baço/efeitos dos fármacos , Baço/imunologia , Baço/metabolismo , Suínos , Subpopulações de Linfócitos T/efeitos dos fármacos , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Células Th1/metabolismo , Células Th2/metabolismo
10.
Int J Nanomedicine ; 15: 17-29, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32021162

RESUMO

Background: Honokiol has been reported to possess anti-inflammatory and neuroprotective activities. However, the poor aqueous solubility of honokiol limits its clinical application for systemic administration. Purpose: This study aims to develop a novel formulation of nanosome-encapsulated honokiol (NHNK) for intravenous therapy against mouse experimental autoimmune encephalomyelitis (EAE) that mimics human multiple sclerosis. Methods: Nanosomes and NHNK were prepared by using an ultra-high pressure homogenization (UHPH) method. Mice were treated with NHNK or empty nanosomes during the peak phase of EAE symptoms. Symptoms of EAE were monitored and samples of the spinal cord were obtained for histopathological examinations. Results: The stock of NHNK containing honokiol in the nanosome formulation, which showed the structure of single phospholipid bilayer membranes, was well formulated with the particle size of 48.0 ± 0.1 nm and the encapsulation efficiency 58.1 ± 4.2%. Intravenous administration of NHNK ameliorated the severity of EAE accompanied by a significant reduction of demyelination and inflammation in the spinal cord. Furthermore, NHNK decreased the number of IL-6+, Iba-1+TNF +, Iba-1+IL-12 p40+, and CD3+IFN-γ+ cells infiltrating the spinal cord. Conclusion: The UHPH method simplified the preparation of NHNK with uniformly distributed nanosize and high encapsulation efficiency. Intravenous administration of NHNK ameliorated the severity of EAE by suppressing the infiltration of activated microglia and Th1 cells into the spinal cord. Collectively, these results suggest that the formulation of NHNK is a prospective therapeutic approach for inflammatory CNS diseases, such as multiple sclerosis.


Assuntos
Compostos de Bifenilo/administração & dosagem , Encefalomielite Autoimune Experimental/tratamento farmacológico , Lignanas/administração & dosagem , Nanoestruturas/administração & dosagem , Animais , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/farmacologia , Sistemas de Liberação de Medicamentos/métodos , Encefalomielite Autoimune Experimental/etiologia , Feminino , Injeções Intravenosas , Camundongos Endogâmicos C57BL , Microglia/efeitos dos fármacos , Microglia/patologia , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/etiologia , Mielite/tratamento farmacológico , Mielite/etiologia , Nanoestruturas/química , Fármacos Neuroprotetores/farmacologia , Medula Espinal/patologia , Células Th1/efeitos dos fármacos , Células Th1/patologia
11.
Transplantation ; 104(6): e151-e163, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32108749

RESUMO

BACKGROUND: Obliterative bronchiolitis (OB) remains the major complication limiting long-term survival of patients after lung transplantation. We aimed to explore the effects of the selective NACHT, LRR, and PYD domains-containing protein 3 (Nlrp3) inflammasome inhibitor MCC950 on the pathogenesis of OB. METHODS: Mouse orthotopic tracheal transplants were performed to mimic OB. MCC950 (50 mg/kg) or saline was intraperitoneally injected daily. The luminal occlusion rate and collagen deposition were evaluated by hematoxylin and eosin and Masson's trichrome staining, respectively. Infiltration of CD4+, CD8+ T cells, and neutrophils was detected with immunohistochemical staining. The frequencies of T helper 1 cell (Th1), T helper 17 cell (Th17), and regulatory T cells (Treg) were measured by flow cytometry. Cytokine levels were measured by ELISA kits. RESULTS: MCC950 treatment significantly inhibited Nlrp3 inflammasome activation after allogeneic tracheal transplant and markedly decreased the luminal occlusion rate and collagen deposition in the allograft. The numbers of infiltrating CD4+, CD8+ T cells, and neutrophils in the allograft were also significantly reduced by MCC950 treatment. MCC950 dramatically decreased the frequencies of Th1/Th17 cells and the levels of interferon gamma/interleukin (IL)-17A and increased the Treg cell frequencies and IL-10 level; however, these effects were abolished by the addition of IL-1ß and IL-18 both in vitro and in vivo. OB was also rescued by the addition of IL-1ß and/or IL-18. CONCLUSIONS: Blocking Nlrp3 inflammasome activation with MCC950 ameliorates OB lesions. The mechanistic analysis showed that MCC950 regulated the balance of Th1/Th17 and Treg cells and that this process is partially mediated by inhibition of IL-1ß and IL-18. Therefore, targeting the Nlrp3 inflammasome is a promising strategy for controlling OB after lung transplantation.


Assuntos
Bronquiolite Obliterante/tratamento farmacológico , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Inflamassomos/antagonistas & inibidores , Transplante de Pulmão/efeitos adversos , Complicações Pós-Operatórias/tratamento farmacológico , Sulfonas/farmacologia , Animais , Bronquiolite Obliterante/imunologia , Modelos Animais de Doenças , Compostos Heterocíclicos de 4 ou mais Anéis/uso terapêutico , Humanos , Inflamassomos/imunologia , Masculino , Camundongos , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Complicações Pós-Operatórias/imunologia , Sulfonas/uso terapêutico , 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 , Traqueia/transplante
12.
J Med Chem ; 63(6): 3290-3297, 2020 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-32101001

RESUMO

We have prepared a number of saponin-based vaccine adjuvant candidates. These unnatural saponins have a different terminal-functionalized side chain incorporated into the glucuronic acid unit that is attached to a triterpenoid core at its C3 position. The semisynthetic saponin adjuvants have shown significantly different immunostimulatory activities, suggesting that the structure of the side chain, triterpenoid core, and oligosaccharide domain together orchestrate saponin adjuvant's potentiation of immune responses. Among these new adjuvant candidates, VSA-2 (5b), a derivative of Momordica saponin (MS) II, showed consistent enhancement of immunoglobulin G2a (IgG2a) production when it was in formulation with either ovalbumin or recombinant hemagglutinin B (rHagB) antigen. With rHagB antigen, it induced a significantly higher IgG2a response than the positive control GPI-0100, a well-studied semisynthetic saponin adjuvant mixture derived from Quillaja saponaria Molina saponins, known for its ability to induce a balanced Th1/Th2 immunity. These results confirm that Momordica saponins are a viable natural source to provide potent saponin adjuvants after simple chemical derivatization and identify VSA-2 (5b) as another MS-based promising immunostimulant lead owing to its distinctive ability in potentiating the IgG2a response.


Assuntos
Adjuvantes Imunológicos/farmacologia , Saponinas/farmacologia , Adesinas Bacterianas/imunologia , Adjuvantes Imunológicos/síntese química , Animais , Formação de Anticorpos/efeitos dos fármacos , Galinhas , Feminino , Imunoglobulina G/imunologia , Imunoglobulina G/metabolismo , Lectinas/imunologia , Camundongos Endogâmicos BALB C , Estrutura Molecular , Ovalbumina/imunologia , Saponinas/síntese química , Saponinas/imunologia , Células Th1/efeitos dos fármacos
13.
J Ethnopharmacol ; 248: 112313, 2020 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-31655147

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Oliveria decumbens vent is a valuable plant in Iran, used as a vegetable. Traditionally, the aerial parts of this plant are used to treat the cancer-related symptoms, inflammation, pain, and feverish conditions. However, the scientific evidence related to its traditional effects especially the possible cellular and molecular mechanisms needs to be illuminated. AIM OF THE STUDY: The main objectives of our study were to explore in-vitro anti-cancer properties of OEO in 2D and 3D conditions, to understand the mechanism of OEO in the induction of death in cancer cells, and to identify in-vivo anti-tumor effect of OEO and induced immunomodulatory effects. MATERIAL AND METHODS: OEO was extracted by hydrodistillation and analyzed by GC-MS method. To evaluate the cytotoxic effect of OEO on 4T1 cancer monolayer cells (2D culture) and spheroids (3D cultures), MTT (3-(4, 5-Dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide) assay was used. Fluorescence staining, various flow cytometry techniques, colorimetric assay, electrophoresis, and comet assay were performed to understand the anti-cancer mechanisms of OEO and determine the death mode in treated 4T1 cells. In animal studies, mouse mammary tumor model was established, the anti-tumor effect of OEO was investigated and ultimately by using the ELISA cytokine assay, immunostimulatory of OEO was studied. RESULTS: According to GC/MS analysis, thymol, carvacrol, p-cymene, and γ-terpinene were identified as main components of OEO. Based on MTT assay, OEO inhibited viability in 4T1 cancer cell without any significant effect on L929 normal cells in 2D, also the anti-proliferative effects of OEO on 4T1 spheroids (3D) was significant but less extent. Our results revealed that OEO induces apoptosis through ROS generation, mitochondrial membrane potential (ΔΨm) disruption, caspase3 activation, and DNA damage. Evaluating the effectiveness of OEO on 4T1 tumor-challenging mice and cytokine assay confirmed anti-tumor effects of OEO and development of an immune response related to Th1 expansion. CONCLUSION: These data shed light on the apoptotic mechanisms related to OEO cytotoxicity and introduced this compound as a candidate in cancer therapy.


Assuntos
Adenocarcinoma/tratamento farmacológico , Antineoplásicos Fitogênicos/farmacologia , Apiaceae , Apoptose/efeitos dos fármacos , Neoplasias da Mama/tratamento farmacológico , Óleos Voláteis/farmacologia , Óleos Vegetais/farmacologia , Adenocarcinoma/imunologia , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Animais , Antineoplásicos Fitogênicos/isolamento & purificação , Apiaceae/química , Neoplasias da Mama/imunologia , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Citocinas/metabolismo , Feminino , Camundongos Endogâmicos BALB C , Óleos Voláteis/isolamento & purificação , Óleos Vegetais/isolamento & purificação , Transdução de Sinais , Baço/efeitos dos fármacos , Baço/imunologia , Baço/metabolismo , Células Th1/efeitos dos fármacos , Células Th1/imunologia , Células Th1/metabolismo , Carga Tumoral/efeitos dos fármacos
14.
Immunol Cell Biol ; 98(2): 152-164, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31845380

RESUMO

Depending on the microenvironment conditions, macrophages display phenotypic and functional heterogeneity. This study characterized the programmed cell death-ligand 2 (PD-L2)-expressing macrophage-like cells drained from surgical wound zones, and investigated their influence on helper T (Th) cell responses. Although all CD14+ myeloid cells possessed macrophage-like features, CD206+ and CD163+ cells constituted a specific subpopulation with high PD-L2 expression. There was a modest correlation between the PD-L2 levels on CD206+ macrophages and the amount of interferon (IFN)-γ in the drainage fluid. The adhesion-independent macrophages simultaneously presented both classically-activated M1 and alternatively-activated M2 characteristics. CD206+ and PD-L2+ cells were identified with high granularity and size, expressed arginase-1 and costimulatory molecules, had enhanced phagocytic activity and produced reactive oxygen species. The genes associated with macrophage differentiation (MERTK, AXL and TYRO3) were also upregulated. These cells provided costimulation to Th cells; yet, when PD-L2 was blocked, T-cell proliferation and IFNγ production were enhanced. Under defined conditions devoid of activation stimuli and matrix adhesion, ex vivo-generated monocyte-derived macrophages displayed limited capacity to stimulate T cells. Upon exposure to IFNγ, they significantly upregulated programmed death 1 ligands, especially PD-L2. These cells did not completely abrogate T-cell differentiation; however, PD-L2 checkpoint blockade restored Th1 proliferation and secretion of interleukin-2, tumor necrosis factor-α and IFNγ. In conclusion, upregulation of PD-L2 on the wound zone macrophages may constitute a negative feedback loop that restrains the Th1 effector responses and avoids exacerbation of inflammation during tissue healing.


Assuntos
Diferenciação Celular/imunologia , Inflamação/metabolismo , Macrófagos/metabolismo , Proteína 2 Ligante de Morte Celular Programada 1/metabolismo , Células Th1/imunologia , Cicatrização/fisiologia , Adulto , Apoptose/efeitos dos fármacos , Apoptose/imunologia , Arginase/metabolismo , Antígeno B7-H1/metabolismo , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Feminino , Humanos , Interferon gama/farmacologia , Interleucina-2/metabolismo , Lectinas Tipo C/metabolismo , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Masculino , Lectinas de Ligação a Manose/metabolismo , Pessoa de Meia-Idade , Receptor de Morte Celular Programada 1/metabolismo , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Receptores Proteína Tirosina Quinases/genética , Receptores Proteína Tirosina Quinases/metabolismo , Receptores de Superfície Celular/metabolismo , Células Th1/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismo , Cicatrização/efeitos dos fármacos , c-Mer Tirosina Quinase/genética , c-Mer Tirosina Quinase/metabolismo
15.
Cancer Lett ; 472: 142-150, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31874244

RESUMO

A therapeutic strategy capable of skewing toward a Th1-type immune response is crucial for cancer treatment. Recently, we reported Mycobacterium paragordonae (Mpg) as a potential live vaccine for mycobacterium infections. In this study, we explored the immunotherapeutic potential of heat-killed Mpg (HK-Mpg) in a mouse tumor xenograft model and elucidated its underlying antitumor mechanisms. MC38 cells derived from murine colon adenocarcinoma were implanted by subcutaneously injecting mice. The anticancer effects of HK-Mpg therapy were compared with HK-M. bovis BCG, an effective adjuvant for cancer immunotherapy. HK-Mpg treatment enhanced tumor reduction and mouse survival. Furthermore, HK-Mpg treatment synergistically enhanced the anticancer therapeutic effect of cisplatin. In addition, HK-Mpg enhanced inflammatory cytokine production and recruitment of immune cell into tumor-infiltrating sites and splenocytes in vaccinated mice. Our mechanistic study demonstrates that HK-Mpg therapy elicits a strong antitumor immune response in mice, mainly through natural killer cell-mediated oncolytic activity via the activation of dendritic cells (DCs) and by enhancing inflammatory cytokines production such as IL-12 from DC. Hence, HK-Mpg can be a potential immunotherapy adjuvant, enhancing the effect of cancer chemotherapy.


Assuntos
Adenocarcinoma/terapia , Vacinas Anticâncer/farmacologia , Neoplasias do Colo/terapia , Mycobacterium/imunologia , Adenocarcinoma/imunologia , Adenocarcinoma/microbiologia , Adenocarcinoma/patologia , Animais , Vacinas Anticâncer/imunologia , Neoplasias do Colo/imunologia , Neoplasias do Colo/microbiologia , Neoplasias do Colo/patologia , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/imunologia , Modelos Animais de Doenças , Xenoenxertos , Temperatura Alta , Humanos , Imunidade Celular/efeitos dos fármacos , Imunidade Celular/imunologia , Camundongos , Células Th1/efeitos dos fármacos , Células Th1/imunologia
16.
J Pharm Pharmacol ; 72(1): 92-100, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31724745

RESUMO

OBJECTIVES: Myricetin is a bioactive compound in many edible plants with anti-inflammatory and anticarcinogenic activity. The current study aimed to determine the protective effects and mechanism of myricetin against ulcerative colitis (UC). METHODS: Myricetin was orally administered at doses of 40 and 80 mg/kg to C57BL/6 mice with UC induced using dextran sulfate sodium. The disease-associated index and colon length were determined at the end of the experiment, the proportion of Treg, Th1 and Th17 was analysed by cytometry, and cytokines were detected using ELISA. KEY FINDINGS: Myricetin (80 mg/kg) ameliorated the severity of inflammation in acute UC and significantly improved the condition. Myricetin (80 mg/kg) elevated the levels of IL-10 and transforming growth factor ß. In addition, the proportion of regulatory T cells significantly increased in mice in the myricetin treatment group. CONCLUSIONS: Taking together, these results suggest that myricetin exhibits significant protective effects against UC and it could be used as a potential treatment for UC.


Assuntos
Anti-Inflamatórios/farmacologia , Colite Ulcerativa/prevenção & controle , Colo/efeitos dos fármacos , Sulfato de Dextrana , Flavonoides/farmacologia , Linfócitos T Reguladores/efeitos dos fármacos , Animais , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/imunologia , Colite Ulcerativa/metabolismo , Colo/imunologia , Colo/metabolismo , Colo/patologia , Modelos Animais de Doenças , Feminino , Interleucina-10/metabolismo , Camundongos Endogâmicos C57BL , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Células Th1/efeitos dos fármacos , Células Th1/imunologia , Células Th1/metabolismo , Células Th17/efeitos dos fármacos , Células Th17/imunologia , Células Th17/metabolismo , Fator de Crescimento Transformador beta/metabolismo
17.
Sci Adv ; 5(12): eaaw9051, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31840058

RESUMO

Epigenetic modifications play critical roles in inducing long-lasting immunological memory in innate immune cells, termed trained immunity. Whether similar epigenetic mechanisms regulate dendtritic cell (DC) function to orchestrate development of adaptive immunity remains unknown. We report that DCs matured with IFNγ and TNFα or matured in the lungs during invasive fungal infection with endogenous TNFα acquired a stable TNFα-dependent DC1 program, rendering them resistant to both antigen- and cytokine-induced alternative activation. TNFα-programmed DC1 had increased association of H3K4me3 with DC1 gene promoter regions. Furthermore, MLL1 inhibition blocked TNFα-mediated DC1 phenotype stabilization. During IFI, TNFα-programmed DC1s were required for the development of sustained TH1/TH17 protective immunity, and bone marrow pre-DCs exhibited TNFα-dependent preprogramming, supporting continuous generation of programmed DC1 throughout the infection. TNFα signaling, associated with epigenetic activation of DC1 genes particularly via H3K4me3, critically contributes to generation and sustenance of type 1/17 adaptive immunity and the immune protection against persistent infection.


Assuntos
Polaridade Celular , Citoproteção , Células Dendríticas/metabolismo , Epigênese Genética , Linfócitos T/citologia , Fator de Necrose Tumoral alfa/metabolismo , Animais , Polaridade Celular/efeitos dos fármacos , Reprogramação Celular/efeitos dos fármacos , Cryptococcus/efeitos dos fármacos , Cryptococcus/fisiologia , Citoproteção/efeitos dos fármacos , Células Dendríticas/efeitos dos fármacos , Epigênese Genética/efeitos dos fármacos , Feminino , Histona-Lisina N-Metiltransferase/metabolismo , Histonas/metabolismo , Imunomodulação/efeitos dos fármacos , Lisina/metabolismo , Metilação , Camundongos Endogâmicos CBA , Proteína de Leucina Linfoide-Mieloide/metabolismo , Fenótipo , Regiões Promotoras Genéticas/genética , Supressão Genética/efeitos dos fármacos , Linfócitos T/efeitos dos fármacos , Células Th1/efeitos dos fármacos , Células Th1/imunologia , Fator de Necrose Tumoral alfa/farmacologia
18.
Int J Chron Obstruct Pulmon Dis ; 14: 2697-2709, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31819402

RESUMO

Purpose: Elastin peptides (EP) can induce lung inflammation and emphysema. Erythromycin has been shown to decrease acute exacerbation frequency and delay lung function decline in chronic obstructive pulmonary disease patients and ameliorate emphysema in murine models; however, the mechanism remains unclear. We aimed to observe the preventive and immunomodulatory effects of erythromycin in a mouse model of EP-induced emphysema. Methods: In the in vivo study, Balb/c mice were treated with EP intranasally on day 0, and then administered erythromycin (100 mg/kg) or vehicle orally on day 1, which was continued every other day. Mice exposed to cigarette smoke were used as an emphysema positive control. The severity of emphysema and inflammation in the lungs of EP-exposed mice with or without erythromycin treatment were observed on day 40 after EP administration. In the in vitro study, naïve CD4+T cells were isolated from healthy mice spleens and stimulated by EP with or without erythromycin incubation. Flow cytometry was used to measure the proportions of Th1, Th17, and Treg cells. ELISA was used to detect cytokine levels of IFN-γ, IL-17, IL-6, and TGF-ß. Transcript levels of Ifnγ, IL17a, and Foxp3 were evaluated by qRT-PCR. Results: After exposure to EP, Th1 and Th17 cell percentages and the levels of inflammatory cytokines increased in vivo and in vitro, while Treg cells decreased in vivo. Erythromycin reduced IFN-γ, IL-17, IL-6 inflammatory cytokines, MLI, and the inflammation score in the lungs of EP-exposed mice. In vitro, erythromycin also limited Th17 and Th1 cell differentiation and downregulated transcript levels of Ifnγ and IL17a in the EP-stimulated CD4+T cells. Conclusion: The Th1 and Th17 cell responses were increased in EP-induced emphysema. Prophylactic use of erythromycin effectively ameliorated emphysema and modulated CD4+T cells responses in EP-induced lung inflammation in mice.


Assuntos
Anti-Inflamatórios/farmacologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Citocinas/metabolismo , Elastina , Eritromicina/farmacologia , Mediadores da Inflamação/metabolismo , Pulmão/efeitos dos fármacos , Fragmentos de Peptídeos , Pneumonia/tratamento farmacológico , Enfisema Pulmonar/tratamento farmacológico , Animais , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Células Cultivadas , Citocinas/genética , Modelos Animais de Doenças , Pulmão/imunologia , Pulmão/metabolismo , Masculino , Camundongos Endogâmicos BALB C , Pneumonia/induzido quimicamente , Pneumonia/imunologia , Pneumonia/metabolismo , Enfisema Pulmonar/induzido quimicamente , Enfisema Pulmonar/imunologia , Enfisema Pulmonar/metabolismo , Transdução de Sinais , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Células Th1/efeitos dos fármacos , Células Th1/imunologia , Células Th1/metabolismo , Células Th17/efeitos dos fármacos , Células Th17/imunologia , Células Th17/metabolismo
19.
PLoS One ; 14(12): e0224517, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31790411

RESUMO

OBJECTIVE: Macmoondongtang has been used as a traditional medicine to treat pulmonary disease in Korea. However, the mechanism underlying its therapeutic effect has yet to be reported. In the present study, the role of macmoondongtang as a respiratory medicine, especially as an anti-asthmatic agent, has been attributed to the down-regulation of interleukin (IL)-4 and tumor necrosis factor (TNF)-α. MATERIALS & METHODS: BALB/c mice were divided into five groups: control, asthma-induced control, dexamethasone treatment, treatment with 150 mg/kg macmoondongtang, and treatment with 1500 mg/kg macmoondongtang. To evaluate the anti-asthmatic effect of macmoondongtang, we investigated its suppressive or inhibitory effects against typical asthmatic changes such as differential cell count in bronchioalveolar fluid (BALF), serum IgE levels, lung morphology, expression of Th1/Th2 cell transcription factors such as T-bet and GATA-3, and Th1-/Th2-/Th17-related cytokines such as interferon (IFN)-γ, IL-12p40, IL-4, -5, -13, TNF-α, and IL-6. The active ingredients in macmoondongtang were further analyzed. RESULTS: Macmoondongtang treatment down-regulated serum IgE level, a very important marker of hyper-responsiveness. It reversed typical morphological changes such as mucous hypersecretion, lung epithelial cell hyperplasia, and inflammatory cell infiltration near bronchioalveolar space and veins. Macmoondongtang significantly decreased neutrophil count in BALF, as well as reduced T-bet, IFN-γ, and TNF-α expression in the lung. It also showed a dose-dependent control of inflammatory cells in BALF, controlled the expression of IL-12, IL-4, and IL-5 genes in the lung, and the protein expression of IL12p40, GATA-3, IL-4, IL-5, and IL-13. The component analysis revealed glycyrrhizin and liquiritin as the active ingredients. CONCLUSIONS: Macmoondongtang treatment alleviates asthma symptoms and modulate the Th1-/Th2- related cytokines. Glycyrrhizin and liquiritin could be the major the active therapeutic components.


Assuntos
Asma/tratamento farmacológico , Citocinas/metabolismo , Células Th1/efeitos dos fármacos , Células Th1/metabolismo , Células Th2/efeitos dos fármacos , Células Th2/metabolismo , Animais , Asma/imunologia , Lavagem Broncoalveolar , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Células Th1/imunologia , Células Th2/imunologia
20.
Ann Clin Lab Sci ; 49(6): 722-729, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31882422

RESUMO

Thymic stromal lymphopoietin (TSLP) activates lung dendritic cells (DCs) to promote a T helper type 2 lymphocyte (Th2) response in animal models. However, the mechanism behind this process remains unclear. In this study, we investigate the role of a nuclear factor for activated T-cells 1 (NFATc1) in the TSLP-induced polarisation towards a Th2 response. A cluster of differentiated (CD)14+ peripheral blood mononuclear cells (PBMCs) and naïve T cells were isolated from blood collected from healthy human volunteers, and TSLP was used to induce DC maturation. The effects of TSLP-DCs and treatments with FK506, an NFATc1 inhibitor, on naïve T cell differentiation were monitored by measuring the interleukin (IL)-4, IL-13, and interferon-γ (IFN-γ) expression levels. In addition, the mRNA levels of T-box expression in T cells (T-bet), GATA binding protein 3 (GATA-3), TSLP, and NFATc1 were measured for the same purpose. IL-4, IL-13, and mRNA levels of GATA-3 and NFATc1 significantly increased with TSLP-DC induction (P<0.01), indicating polarization towards the Th2 response. These changes were reversed by treatment with FK506 (P<0.01). Our findings suggest that NFATc1 plays a key role in the TSLP-induced differentiation of T cells to Th2, and NFATc1 is a potential therapeutic target for treating allergic diseases.


Assuntos
Citocinas/metabolismo , Fatores de Transcrição NFATC/metabolismo , Células Th2/citologia , Diferenciação Celular , Polaridade Celular , Células Cultivadas , Citocinas/genética , Citocinas/farmacologia , Células Dendríticas , Humanos , Leucócitos Mononucleares/citologia , Leucócitos Mononucleares/metabolismo , Receptores de Lipopolissacarídeos/metabolismo , Fatores de Transcrição NFATC/antagonistas & inibidores , Fatores de Transcrição NFATC/genética , Tacrolimo/farmacologia , Células Th1/efeitos dos fármacos , Células Th1/metabolismo , Células Th2/efeitos dos fármacos , Células Th2/metabolismo
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