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1.
Autophagy ; : 1-15, 2021 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-34720021

RESUMO

Mitophagy is a selective autophagy mechanism for eliminating damaged mitochondria and plays a crucial role in the immune evasion of some viruses and bacteria. Here, we report that Mycobacterium bovis (M. bovis) utilizes host mitophagy to suppress host xenophagy to enhance its intracellular survival. M. bovis is the causative agent of animal tuberculosis and human tuberculosis. In the current study, we show that M. bovis induces mitophagy in macrophages, and the induction of mitophagy is impaired by PINK1 knockdown, indicating the PINK1-PRKN/Parkin pathway is involved in the mitophagy induced by M. bovis. Moreover, the survival of M. bovis in macrophages and the lung bacterial burden of mice are restricted by the inhibition of mitophagy and are enhanced by the induction of mitophagy. Confocal microscopy analysis reveals that induction of mitophagy suppresses host xenophagy by competitive utilization of p-TBK1. Overall, our results suggest that induction of mitophagy enhances M. bovis growth while inhibition of mitophagy improves growth restriction. The findings provide a new insight for understanding the intracellular survival mechanism of M. bovis in the host.

2.
FASEB J ; 35(9): e21777, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34403519

RESUMO

Mycobacterium bovis is the causative agent of bovine tuberculosis and also responsible for serious threat to public health. Koumiss is a fermented mare's milk product, used as traditional drink. Here, we explored the effect of koumiss on gut microbiota and the host immune response against M bovis infection. Therefore, mice were treated with koumiss and fresh mare milk for 14 days before M bovis infection and continue for 5 weeks after infection. The results showed a clear change in the intestinal flora of mice treated with koumiss, and the lungs of mice treated with koumiss showed severe edema, inflammatory infiltration, and pulmonary nodules in M bovis-infected mice. Notably, we found that the content of short-chain fatty acids was significantly lower in the koumiss-treated group compared with the control group. However, the expression of endoplasmic reticulum stress and apoptosis-related proteins in the lungs of koumiss-treated mice were significantly decreased. Collectively, these findings suggest that koumiss treatment disturb the intestinal flora of, which is associated with disease severity and the possible mechanism that induces lungs pathology. Our current findings can be exploited further to establish the "gut-lung" axis which might be a novel strategy for the control of tuberculosis.


Assuntos
Estresse do Retículo Endoplasmático/efeitos dos fármacos , Microbioma Gastrointestinal/efeitos dos fármacos , Kumis/efeitos adversos , Mycobacterium bovis/efeitos dos fármacos , Tuberculose Pulmonar/microbiologia , Tuberculose Pulmonar/patologia , Animais , Apoptose/efeitos dos fármacos , Modelos Animais de Doenças , Ácidos Graxos/análise , Fezes/química , Fezes/microbiologia , Feminino , Microbioma Gastrointestinal/imunologia , Cavalos , Pulmão/efeitos dos fármacos , Pulmão/microbiologia , Pulmão/patologia , Camundongos , Camundongos Endogâmicos BALB C , Mycobacterium bovis/imunologia , Tuberculose Pulmonar/dietoterapia , Tuberculose Pulmonar/metabolismo
3.
J Infect ; 83(1): 61-68, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33892015

RESUMO

Caspases are classified as inflammatory or apoptotic category. Inflammatory caspases participate in inflammasome activation, while apoptotic caspases mediate apoptotic activation. Previous studies have shown that apoptotic caspases prevent the production of IFN-ß during apoptosis or virus infection. However, the relationship between apoptotic caspases and IFN-ß production during intracellular bacterial infection is still unclear. Here, we investigated the role of apoptotic caspases in IFN-ß production induced by Mycobacterium bovis (M. bovis) infection. M. bovis is an intracellular bacterium and belongs to the Mycobacterium tuberculosis complex. M. bovis infection can cause tuberculosis in animals and human beings. In the current study, we found that M. bovis infection triggered mitochondrial stress, which caused the leakage of cytochrome c into the cytoplasm, and in turn, activated the downstream caspase-9 and-3. Furthermore, our results showed that activation of apoptotic caspases reduced IFN-ß production during M. bovis infection and vice versa. Confocal microscopy analysis revealed that apoptotic caspases prevented IFN-ß production by decreasing p-IRF3 nuclear translocation. Our findings demonstrate that apoptotic caspases negatively regulate the production of IFN-ß induced by an intracellular bacterial infection.


Assuntos
Apoptose , Caspases , Interferon beta/imunologia , Macrófagos/imunologia , Mycobacterium bovis , Animais , Caspases/genética , Macrófagos/microbiologia , Camundongos , Tuberculose
4.
Biomed Pharmacother ; 137: 111341, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33561646

RESUMO

Mycobacterium bovis (M. bovis) is a member of mycobacterium tuberculosis complex (MTBC), and a causative agent of chronic respiratory disease in a wide range of hosts. Bacillus Calmette-Guerin (BCG) vaccine is mostly used for the prevention of childhood tuberculosis. Further substantial implications are required for the development and evaluation of new tuberculosis (TB) vaccines as well as improving the role of BCG in TB control strategies. In this study, we prepared PLGA nanoparticles encapsulated with argF antigen (argF-NPs). We hypothesized, that argF nanoparticles mediate immune responses of BCG vaccine in mice models of M. bovis infection. We observed that mice vaccinated with argF-NPs exhibited a significant increase in secretory IFN-γ, CD4+ T cells response and mucosal secretory IgA against M. bovis infection. In addition, a marked increase was observed in the level of secretory IL-1ß, TNF-α and IL-10 both in vitro and in vivo upon argF-NPs vaccination. Furthermore, argF-NPs vaccination resulted in a significant reduction in the inflammatory lesions in the lung's tissues, minimized the losses in total body weight and reduced M. bovis burden in infected mice. Our results indicate that BCG prime-boost strategy might be a promising measure for the prevention against M. bovis infection by induction of CD4+ T cells responses and mucosal antibodies.


Assuntos
Vacina BCG/administração & dosagem , Vacina BCG/imunologia , Mycobacterium bovis , Nanopartículas/administração & dosagem , Ornitina Carbamoiltransferase/imunologia , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/imunologia , Tuberculose Bovina/prevenção & controle , Administração Intranasal , Animais , Formação de Anticorpos/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Linfócitos T CD4-Positivos/metabolismo , Bovinos , Linhagem Celular , Modelos Animais de Doenças , Feminino , Imunoglobulina A Secretora/metabolismo , Imunoglobulina G/sangue , Interferon gama/metabolismo , Interleucina-10/sangue , Interleucina-1beta/sangue , Pulmão/metabolismo , Pulmão/microbiologia , Pulmão/patologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Camundongos Endogâmicos BALB C , Mycobacterium bovis/crescimento & desenvolvimento , Mycobacterium bovis/patogenicidade , Nanopartículas/química , Ornitina Carbamoiltransferase/administração & dosagem , Ornitina Carbamoiltransferase/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/administração & dosagem , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/química , Proteínas Recombinantes/imunologia , Baço/microbiologia , Baço/patologia , Fator de Necrose Tumoral alfa/sangue
5.
Pharmaceutics ; 12(12)2020 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-33271900

RESUMO

Mycobacterium bovis (M. bovis) is a member of the Mycobacterium tuberculosis complex imposing a high zoonotic threat to human health. The limited efficacy of BCG (Bacillus Calmette-Guérin) and upsurges of drug-resistant tuberculosis require new effective vaccination approaches and anti-TB drugs. Poly (lactic-co-glycolic acid) (PLGA) is a preferential drug delivery system candidate. In this study, we formulated PLGA nanoparticles (NPs) encapsulating the recombinant protein bovine neutrophil ß-defensin-5 (B5), and investigated its role in immunomodulation and antimicrobial activity against M. bovis challenge. Using the classical water-oil-water solvent-evaporation method, B5-NPs were prepared, with encapsulation efficiency of 85.5% ± 2.5%. These spherical NPs were 206.6 ± 26.6 nm in diameter, with a negatively charged surface (ζ-potential -27.1 ± 1.5 mV). The encapsulated B5 protein from B5-NPs was released slowly under physiological conditions. B5 or B5-NPs efficiently enhanced the secretion of tumor necrosis factor α (TNF-α), interleukin (IL)-1ß and IL-10 in J774A.1 macrophages. B5-NPs-immunized mice showed significant increases in the production of TNF-α and immunoglobulin A (IgA) in serum, and the proportion of CD4+ T cells in spleen compared with B5 alone. In immunoprotection studies, B5-NPs-immunized mice displayed significant reductions in pulmonary inflammatory area, bacterial burden in the lungs and spleen at 4-week after M. bovis challenge. In treatment studies, B5, but not B5-NPs, assisted rifampicin (RIF) with inhibition of bacterial replication in the lungs and spleen. Moreover, B5 alone also significantly reduced the bacterial load in the lungs and spleen. Altogether, our findings highlight the significance of the B5-PLGA NPs in terms of promoting the immune effect of BCG and the B5 in enhancing the therapeutic effect of RIF against M. bovis.

6.
Inflammation ; 43(5): 1902-1912, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32519269

RESUMO

Oxidative stress can induce lung damage and aggravate airway inflammation in asthma. Previously, we reported that rosmarinic acid (RA) exerted strong anti-inflammatory effects in a mouse allergic asthma model. Therefore, we hypothesized that RA might also have antioxidative effects in a superimposed asthma mouse model with oxidative lung damage challenged with ovalbumin (Ova) and hydrogen peroxide (H2O2). We evaluated the antioxidative and anti-asthmatic activity of RA and explored its possible mechanisms of action. Mice sensitized to Ova and challenged with Ova and H2O2 were treated with RA 1 h after challenge. RA treatment greatly diminished the number of inflammatory cells; decreased IL-4, IL-5, and IL-13 production; increased IFN-γ secretion; significantly downregulated ROS production; and markedly upregulated the activities of SOD, GPx, and CAT. Furthermore, RA treatment resulted in a significant increase in the expression of Cu/Zn SOD and a notable reduction in NOX-2 and NOX-4 expression in lung tissues. These findings suggest that RA may effectively alleviate oxidative lung damage and airway inflammation in asthma.


Assuntos
Antioxidantes/uso terapêutico , Asma/tratamento farmacológico , Asma/enzimologia , Cinamatos/uso terapêutico , Depsídeos/uso terapêutico , NADPH Oxidases/antagonistas & inibidores , Estresse Oxidativo/efeitos dos fármacos , Animais , Antiasmáticos/farmacologia , Antiasmáticos/uso terapêutico , Antioxidantes/farmacologia , Asma/induzido quimicamente , Cinamatos/farmacologia , Depsídeos/farmacologia , Relação Dose-Resposta a Droga , Feminino , Peróxido de Hidrogênio/toxicidade , Pulmão/efeitos dos fármacos , Pulmão/enzimologia , Camundongos , Camundongos Endogâmicos BALB C , NADPH Oxidases/metabolismo , Ovalbumina/toxicidade , Estresse Oxidativo/fisiologia
7.
Front Microbiol ; 11: 433, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32265874

RESUMO

Mycobacterium bovis is the causative agent of bovine tuberculosis, has been identified a serious threat to human population. It has been found that sodium butyrate (NaB), the inhibitor of histone deacetylase, can promote the expression of cathelicidin (LL37) and help the body to resist a variety of injuries. In the current study, we investigate the therapeutic effect of NaB on the regulation of host defense mechanism against M. bovis infection. We found an increased expression of LL37 in M. bovis infected THP-1 cells after NaB treatment. In contrast, NaB treatment significantly down-regulated the expression of Class I HDAC in THP-1 cells infected with M. bovis. Additionally, NaB reduced the expression of phosphorylated P65 (p-P65) and p-IκBα, indicating the inhibition of nuclear factor-κB (NF-κB) signaling. Furthermore, we found that NaB treatment reduced the production of inflammatory cytokines (IL-1ß, TNF-α, and IL-10) and a key anti-apoptotic marker protein Bcl-2 in THP-1 cell infected with M. bovis. Notably, mice showed high resistance to M. bovis infection after NaB treatment. The reduction of viable M. bovis bacilli indicates that NaB-induced inhibition of M. bovis infection mediated by upregulation of LL37 and inhibition of NF-κB signaling pathway. These observations illustrate that NaB mediate protective immune responses against M. bovis infection. Overall, these results suggest that NaB can be exploited as a therapeutic strategy for the control of M. bovis in animals and human beings.

8.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 33(12): 1669-1675, 2017 Dec.
Artigo em Chinês | MEDLINE | ID: mdl-29382429

RESUMO

Objective To inhibit cisplatin-induced autophagy and improve the cisplatin sensitivity of A549 cells by knockdown the silent information regulator of transcription 1 (SIRT1). Methods Both mRNA and protein levels of SIRT1 in BEAS-2B, A549 and A549/DDP cells were detected by real-time quantitative PCR and Western blotting. After cisplatin treatment, the protein levels of SIRT1, LC3, P62 and beclin-1 in A549 cells were detected by Western blotting. A549 cells were transfected by siRNA to silence SIRT1 expression. Then, the apoptotic morphology was observed by fluorescence microscopy with Hoechst33258 staining. The apoptotic rate was analyzed by flow cytometry. The expressions of SIRT1, LC3, P62, cleaved caspase-3 and poly(ADP-ribose)polymerase (PARP) were measured by Western blotting. Results Both mRNA and protein levels of SIRT1 in A549 cells and A549/DDP cells were significantly higher than those in BEAS-2B cells, and they were higher in A549/DDP cells than in A549 cells. After cisplatin treatment, the protein levels of SIRT1, LC3 and beclin-1 in A549 cells increased, while P62 decreased. After transfected with SIRT1-siRNA, the expression of SIRT1 in A549 cells decreased. Compared with cisplatin group, the number of the apoptotic cells increased with the obvious occurrence of pyknosis and nuclear fragmentation in cisplatin plus SIRT1-siRNA group. Moreover, the expressions of P62, cleaved caspase-3 and PARP were up-regulated accompanied with LC3 decrease. Conclusion SIRT1 is highly expressed in A549 cells. The sensitivity of A549 cells to cisplatin can be improved by inhibiting the cisplatin-induced autophagy through knockdown of SIRT1.


Assuntos
Antineoplásicos/farmacologia , Autofagia/efeitos dos fármacos , Cisplatino/farmacologia , Sirtuína 1/genética , Células A549 , Apoptose/efeitos dos fármacos , Humanos , RNA Interferente Pequeno/genética , Sirtuína 1/análise , Sirtuína 1/antagonistas & inibidores , Sirtuína 1/fisiologia
9.
Int Immunopharmacol ; 41: 90-97, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27825045

RESUMO

Rosmarinic acid (RA) is an active component of a traditional Chinese herbal medicine. Previously, we reported that RA exerted a strong anti-inflammatory effect in a mouse acute lung injury model. Therefore, we hypothesized that RA might also have potential therapeutic effects in a murine model of asthma. In this study, we aimed to evaluate the anti-asthmatic activity of RA and explored its possible molecular mechanisms of action. Female BALB/c mice that had been sensitized to and challenged with ovalbumin (Ova) were treated with RA (20mg/kg) 1h after challenge. The results showed that RA greatly diminished the number of inflammatory cells and the production of Th2 cytokines in the bronchoalveolar lavage fluid (BALF); significantly reduced the secretion of total IgE, Ova-specific IgE, and eotaxin; and markedly ameliorated airway hyperresponsiveness (AHR) compared with Ova-induced mice. Histological studies further revealed that RA substantially decreased inflammatory cells infiltration and mucus hypersecretion compared with Ova-induced mice. Moreover, our results suggested that the protective effects of RA were mediated by the inhibition of JNK and p38 MAPK phosphorylation and nuclear factor-κB (NF-κB) activation. Furthermore, RA treatment resulted in a significant reduction in the mRNA expression of AMCase, CCL11, CCR3, Ym2 and E-selectin in lung tissue. These findings suggest that RA may effectively delay the development of airway inflammation and could thus be used as a therapy for allergic asthma.


Assuntos
Antiasmáticos/uso terapêutico , Asma/tratamento farmacológico , Cinamatos/uso terapêutico , Depsídeos/uso terapêutico , Hipersensibilidade Respiratória/tratamento farmacológico , Alérgenos , Animais , Antiasmáticos/farmacologia , Asma/metabolismo , Asma/patologia , Líquido da Lavagem Broncoalveolar , Quimiocina CCL11/metabolismo , Cinamatos/farmacologia , Citocinas/genética , Citocinas/metabolismo , Depsídeos/farmacologia , Modelos Animais de Doenças , Feminino , Imunoglobulina E/sangue , Imunoglobulina E/metabolismo , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Pulmão/patologia , Camundongos Endogâmicos BALB C , Proteínas Quinases Ativadas por Mitógeno/metabolismo , NF-kappa B/metabolismo , Ovalbumina , RNA Mensageiro/metabolismo , Receptores CCR3/genética , Hipersensibilidade Respiratória/metabolismo , Hipersensibilidade Respiratória/patologia
10.
Molecules ; 21(6)2016 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-27304950

RESUMO

Rosmarinic acid (RA) has numerous pharmacologic effects, including anti-oxidant, anti-inflammatory, and analgesic effects. This study aimed to evaluate the preventive activity of RA in a murine model of asthma and to investigate its possible molecular mechanisms. Female BALB/c mice sensitized and challenged with ovalbumin (Ova) were pretreated with RA (5, 10 or 20 mg/kg) at 1 h before Ova challenge. The results demonstrated that RA markedly inhibited increases in inflammatory cells and Th2 cytokines in the bronchoalveolar lavage fluid (BALF), significantly reduced the total IgE and Ova-specific IgE concentrations, and greatly ameliorated airway hyperresponsiveness (AHR) compared with the control Ova-induced mice. Histological analyses showed that RA substantially decreased the number of inflammatory cells and mucus hypersecretion in the airway. In addition, our results suggested that the protective effects of RA might be mediated by the suppression of ERK, JNK and p38 phosphorylation and activation of nuclear factor-κB (NF-κB). Furthermore, RA pretreatment resulted in a noticeable reduction in AMCase, CCL11, CCR3, Ym2 and E-selectin mRNA expression in lung tissues. These findings suggest that RA may effectively delay the progression of airway inflammation.


Assuntos
Antioxidantes/administração & dosagem , Asma/tratamento farmacológico , Cinamatos/administração & dosagem , Depsídeos/administração & dosagem , Inflamação/tratamento farmacológico , Analgésicos/administração & dosagem , Analgésicos/química , Animais , Antioxidantes/química , Asma/patologia , Líquido da Lavagem Broncoalveolar/química , Cinamatos/química , Depsídeos/química , Modelos Animais de Doenças , Feminino , Humanos , Inflamação/patologia , Pulmão/efeitos dos fármacos , Pulmão/patologia , Camundongos
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