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1.
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
2.
Vet Microbiol ; 258: 109126, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34020176

RESUMO

Mycobacterium bovis (M. bovis) infection triggers cytokine production via pattern recognition receptors. These cytokines include type I interferons (IFNs) and interleukin-1ß (IL-1ß). Excessive type I IFN levels impair host resistance to M. bovis infection. Therefore, strict control of type I IFN production is helpful to reduce pathological damage and bacterial burden. Here, we found that a deficiency in caspase-1, which is the critical component of the inflammasome responsible for IL-1ß production, resulted in increased IFN-ß production upon M. bovis infection. Subsequent experiments demonstrated that caspase-1 activation reduced cyclic GMP-AMP synthase (cGAS) expression, thereby inhibiting downstream TANK-binding kinase 1 (TBK1)- interferon regulatory factor 3 (IRF3) signaling and ultimately reducing IFN production. A deficiency in caspase-1 activation enhanced the bacterial burden during M. bovis infection in vitro and in vivo and aggravated pathological lesion formation. Thus, caspase-1 activation reduced IFN-ß production upon M. bovis infection by dampening cGAS-TBK1-IRF3 signaling, suggesting that the inflammasome protects hosts by negatively regulating harmful cytokines.


Assuntos
Caspase 1/metabolismo , Animais , Inibidores de Caspase/farmacologia , Sobrevivência Celular , Dipeptídeos/farmacologia , Feminino , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Inflamassomos , Fator Regulador 3 de Interferon/genética , Fator Regulador 3 de Interferon/metabolismo , Interferon beta , Camundongos , Camundongos Endogâmicos C57BL , Mycobacterium bovis , Nucleotidiltransferases , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Distribuição Aleatória , para-Aminobenzoatos/farmacologia
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.
Animals (Basel) ; 11(3)2021 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-33668845

RESUMO

BACKGROUND: The use of wheat and flaxseed to produce omega-3 (ω-3) enriched poultry meat and eggs is very popular in the world. However, wheat and flaxseed contain some anti-nutritional factors (ANFs), and enzymes are usually used to alleviate the deleterious influence of ANFs. METHOD: A 2 × 3 two factors design was used in the experiment. A total of 540 twenty-week-old Nongda-3 laying hens were randomly allocated to six dietary treatments, two diets (corn/flaxseed and wheat/flaxseed), and three enzymes (enzyme-a contains neutral protease 10,000, xylanase 35,000, ß-mannanase 1500, ß-glucanase 2000, cellulose 500, amylase 100, and pectinase 10,000 (U g-1); enzyme-b contains alkaline protease 40,000 and neutral protease 10,000 (U g-1); enzyme-c contains alkaline protease 40,000, neutral protease 10,000, and cellulase 4000 (U g-1). RESULTS: There was an interaction between dietary treatment and supplemental enzymes for liver weight and liver inflammatory cytokines of broilers. A significant increase was observed in the fat weight of birds fed a corn diet as compared with a wheat diet. A corn diet and wheat diet with the addition of enzyme-a (p < 0.001) showed the highest level of liver fat followed by enzyme-c (p < 0.01) and enzyme-b. Moreover, a high level of secretory IL-1ß, IL-6, and IL-10 and comparatively higher inflammatory changes in the liver tissue were found in birds fed a corn diet as compared with a wheat diet, and enzyme-b showed more beneficial effects as compared with enzyme-a and -c. The gut microbial composition of hens fed a corn diet was significantly different than that of birds fed a wheat diet. Bacteroides were significantly (p < 0.05) abundant in the corn-fed birds as compared with wheat-fed birds. However, Firmicutes were less abundant in the wheat-fed birds than the corn-fed birds (16.99 vs. 31.80%, respectively). The microbial community at the genus level differed significantly in the dietary groups and we observed that Bacteroides are the predominant cecal microbiota. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways of co-factors, carbohydrates, vitamins, protein, and energy were expressed at slightly higher levels in the microbiota of the wheat-fed birds, whereas, metabolic pathways for nucleotides, lipids, and glycine were expressed at higher levels in the wheat-fed birds. Furthermore, expression of the growth and cellular processes pathway and endocrine system pathway levels were predicted to be higher for the wheat-fed group as compared with the corn-fed group. CONCLUSIONS: In conclusion, our findings suggest that inflammatory changes in laying birds were mediated by a corn diet with flaxseed and enzymes instead of a wheat diet. Additionally, in the wheat-fed group, enzyme-b and -c showed more encouraging results as compared to enzyme-a.

5.
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
6.
Pathogens ; 10(2)2021 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-33503864

RESUMO

Mycobacterium tuberculosis (MTB) infection is characterized by granulomatous lung lesions and systemic inflammatory responses during active disease. Inflammasome activation is involved in regulation of inflammation. Inflammasomes are multiprotein complexes serving a platform for activation of caspase-1, which cleaves the proinflammatory cytokines such as interleukin-1ß (IL-1ß) and IL-18 into their active forms. These cytokines play an essential role in MTB control. MTB infection triggers activation of the nucleotide-binding domain, leucine-rich-repeat containing family, pyrin domain-containing 3 (NLRP3) and absent in melanoma 2 (AIM2) inflammasomes in vitro, but only AIM2 and apoptosis-associated speck-like protein containing a caspase-activation recruitment domain (ASC), rather than NLRP3 or caspase-1, favor host survival and restriction of mycobacterial replication in vivo. Interferons (IFNs) inhibits MTB-induced inflammasome activation and IL-1 signaling. In this review, we focus on activation and regulation of the NLRP3 and AIM2 inflammasomes after exposure to MTB, as well as the effect of inflammasome activation on host defense against the infection.

7.
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.

8.
Cell Commun Signal ; 18(1): 186, 2020 11 25.
Artigo em Inglês | MEDLINE | ID: mdl-33239048

RESUMO

Mitochondria are important cellular organelles involved in many different functions, from energy generation and fatty acid oxidation to cell death regulation and immune responses. Accumulating evidence indicates that mitochondrial stress acts as a key trigger of innate immune responses. Critically, the dysfunctional mitochondria can be selectively eliminated by mitophagy. The elimination of dysfunctional mitochondria may function as an effective way employed by mitophagy to keep the immune system in check. In addition, mitophagy can be utilized by pathogens for immune evasion. In this review, we summarize how mitochondrial stress triggers innate immune responses and the roles of mitophagy in innate immunity and in infection, as well as the molecular mechanisms of mitophagy. Video Abstract.

10.
Microb Pathog ; 147: 104402, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32712114

RESUMO

Bovine tuberculosis caused by Mycobacterium bovis remains a major cause of economic loss in cattle industries worldwide. However, the pathogenic mechanisms remain poorly understood. Post-translation modifications (PTM) such as phosphorylation play a crucial role in pathogenesis. While the change of transcriptome and proteome during the interaction between M. bovis and cattle were studied, there are no reports on the phosphoproteome change. We apply Tandem Mass Tag-based (TMT) quantitative proteomics coupled with immobilized metal-chelated affinity chromatography (IMAC) enrichment to obtain the quantified phosphorylation in vivo of M. bovis infected cattle lung tissue. The phosphorylated proteins are widespread in the nucleus, cytoplasm and plasma membrane. By using a change fold of 1.2, 165 phosphosites from 147 proteins were enriched, with 88 upregulated and 77 downregulated sites respectively. We further constructed the protein-protein interaction (PPI) networks of STAT3, SRRM2 and IRS-1 based on their number of differential phosphorylation sites and KEGG pathways. Similar patterns of gene expression dynamics of selected genes were observed in Mycobacterium tuberculosis infected human sample GEO dataset, implicating crucial roles of these genes in pathogenic Mycobacteria - host interaction. The first phosphorproteome reveals the relationship between bovine tuberculosis and glucose metabolism, and will help further refinement of target proteins for mechanistic study.


Assuntos
Pulmão , Mycobacterium bovis , Proteoma , Tuberculose Bovina , Animais , Bovinos , Pulmão/microbiologia , Pulmão/patologia , Mycobacterium bovis/patogenicidade , Fosforilação
11.
Aging (Albany NY) ; 12(11): 11139-11151, 2020 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-32526704

RESUMO

Prion diseases are neurodegenerative diseases associated with neuron damage and behavioral disorders in animals and humans. Melatonin is a potent antioxidant and is used to treat a variety of diseases. We investigated the neuroprotective effect of melatonin on prion-induced damage in N2a cells. N2a cells were pretreated with 10 µM melatonin for 1 hour followed by incubation with 100 µM PrP106-126 for 24 hours. Melatonin markedly alleviated PrP106-126-induced apoptosis of N2a cells, and inhibited PrP106-126-induced mitochondrial abnormality and dysfunction, including mitochondrial fragmentation and overproduction of reactive oxygen species (ROS), suppression of ATP, reduced mitochondrial membrane potential (MMP), and altered mitochondrial dynamic proteins dynamin-related protein 1 (DRP1) and optic atrophy protein 1 (OPA1). Our findings identify that pretreatment with melatonin prevents the deleterious effects of PrPSc on mitochondrial function and dynamics, protects synapses and alleviates neuron damage. Melatonin could be a novel and effective medication in the therapy of prion diseases.


Assuntos
Apoptose/efeitos dos fármacos , Melatonina/farmacologia , Dinâmica Mitocondrial/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Animais , Linhagem Celular Tumoral , Dinaminas/genética , Dinaminas/metabolismo , GTP Fosfo-Hidrolases/genética , GTP Fosfo-Hidrolases/metabolismo , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Neurônios/patologia , Fármacos Neuroprotetores/farmacologia , Doenças Priônicas/tratamento farmacológico , Doenças Priônicas/patologia , Espécies Reativas de Oxigênio/metabolismo
12.
Cells ; 9(5)2020 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-32423023

RESUMO

The NLRP3 (nucleotide-binding domain, leucine-rich-repeat-containing family, pyrin domain-containing 3) inflammasome senses pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs), and activates caspase-1, which provokes release of proinflammatory cytokines such as interleukin-1ß (IL-1ß) and IL-18 as well as pyroptosis to engage in innate immune defense. The endoplasmic reticulum (ER) is a large and dynamic endomembrane compartment, critical to cellular function of organelle networks. Recent studies have unveiled the pivotal roles of the ER in NLRP3 inflammasome activation. ER-mitochondria contact sites provide a location for NLRP3 activation, its association with ligands released from or residing in mitochondria, and rapid Ca2+ mobilization from ER stores to mitochondria. ER-stress signaling plays a critical role in NLRP3 inflammasome activation. Lipid perturbation and cholesterol trafficking to the ER activate the NLRP3 inflammasome. These findings emphasize the importance of the ER in initiation and regulation of the NLRP3 inflammasome.


Assuntos
Retículo Endoplasmático/metabolismo , Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Animais , Sinalização do Cálcio , Estresse do Retículo Endoplasmático , Humanos , Modelos Biológicos
13.
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.

14.
Neurobiol Dis ; 135: 104704, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31837420

RESUMO

Evidence of the gut microbiota influencing neurodegenerative diseases has been reported for several neural diseases. However, there is little insight regarding the relationship between the gut microbiota and prion disease. Here, using fecal samples of 12 prion-infected mice and 25 healthy controls, we analyzed the structure of the gut microbiota and metabolic changes by 16S rRNA sequencing and LC-MS-based metabolomics respectively as multi-omic analyses. Additionally, SCFAs and common amino acids were detected by GC-MS and UPLC respectively. Enteric changes induced by prion disease affected both structure and abundances of the gut microbiota. The gut microbiota of infected mice displayed greater numbers of Proteobacteria and less Saccharibacteria at the phylum level and more Lactobacillaceae and Helicobacteraceae and less Prevotellaceae and Ruminococcaceae at the family level. A total of 145 fecal metabolites were found to be significantly different in prion infection, and most (114) of these were lipid metabolites. Using KEGG pathway enrichment analysis, we found that 3 phosphatidylcholine (PC) compounds significantly decreased and 4 hydrophobic bile acids significantly increased. Decreases of 8 types of short-chain acids (SCFAs) and increases of Cys and Tyr and decreases of His, Trp, and Arg were observed in prion infection. Correlation analysis indicated that the gut microbiota changes observed in our study may have been the shared outcome of prion disease. These findings suggest that prion disease can cause significant shifts in the gut microbiota. Certain bacterial taxa can then respond to the resulting change to the enteric environment by causing dramatic shifts in metabolite levels. Our data highlight the health impact of the gut microbiota and related metabolites in prion disease.


Assuntos
Bactérias/patogenicidade , Disbiose/metabolismo , Microbioma Gastrointestinal/fisiologia , Doenças Priônicas/microbiologia , Animais , Ácidos e Sais Biliares/análise , Disbiose/microbiologia , Fezes/química , Fezes/microbiologia , Feminino , Metabolômica/métodos , Camundongos Endogâmicos C57BL , RNA Ribossômico 16S/genética
15.
J Infect Dis ; 221(3): 438-448, 2020 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-31495880

RESUMO

BACKGROUND: Mycobacterium bovis persistently survives in macrophages by developing multiple strategies to evade host immune responses, and the early induction of interferon-ß (IFN-ß) is one of these critical strategies. The mitochondrial transcription factor A (TFAM) plays a vital role in mitochondrial DNA (mtDNA) metabolism and has been suggested to influence IFN-ß production in response to viral infection. However, its role in the production of IFN-ß by M. bovis has not been elucidated. METHODS: In the current study, we investigated the role of TFAM in the production of IFN-ß in M. bovis-infected macrophages. RESULTS: We found that knockdown of TFAM expression significantly reduced M. bovis-induced IFN-ß production, mtDNA copy numbers and cytosolic mtDNA were increased in murine macrophages with M. bovis infection, cytosolic mtDNA contributed to IFN-ß production, and TFAM was required for the increase in mtDNA copy numbers induced by M. bovis. We also observed that TFAM affected the intracellular survival of M. bovis. CONCLUSIONS: Our results suggest that TFAM plays an essential role in M. bovis-induced IFN-ß production by regulating mtDNA copy numbers. This might be a new strategy adopted by M. bovis for its intracellular survival.


Assuntos
Replicação do DNA , DNA Mitocondrial/genética , Proteínas de Ligação a DNA/metabolismo , Proteínas de Grupo de Alta Mobilidade/metabolismo , Interferon beta/biossíntese , Macrófagos/imunologia , Mycobacterium bovis/imunologia , Tuberculose/imunologia , Tuberculose/veterinária , Animais , Linhagem Celular Tumoral , Citosol/metabolismo , DNA Mitocondrial/metabolismo , Proteínas de Ligação a DNA/genética , Técnicas de Silenciamento de Genes , Proteínas de Grupo de Alta Mobilidade/genética , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/metabolismo , Mycobacterium bovis/metabolismo , Transdução de Sinais/genética , Tuberculose/microbiologia
16.
BMC Infect Dis ; 19(1): 1031, 2019 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-31801478

RESUMO

BACKGROUND: Mycobacterium bovis (M. bovis) is the principal causative agent of bovine tuberculosis; however, it may also cause serious infection in human being. Type I IFN is a key factor in reducing viral multiplication and modulating host immune response against viral infection. However, the regulatory pathways of Type I IFN signaling during M. bovis infection are not yet fully explored. Here, we investigate the role of Type I IFN signaling in the pathogenesis of M. bovis infection in mice. METHODS: C57BL/6 mice were treated with IFNAR1-blocking antibody or Isotype control 24 h before M. bovis infection. After 21 and 84 days of infection, mice were sacrificed and the role of Type I IFN signaling in the pathogenesis of M. bovis was investigated. ELISA and qRT-PCR were performed to detect the expression of Type I IFNs and related genes. Lung lesions induced by M. bovis were assessed by histopathological examination. Viable bacterial count was determined by CFU assay. RESULTS: We observed an abundant expression of Type I IFNs in the serum and lung tissues of M. bovis infected mice. In vivo blockade of Type I IFN signaling reduced the recruitment of neutrophils to the lung tissue, mediated the activation of macrophages leading to an increased pro-inflammatory profile and regulated the inflammatory cytokine production. However, no impact was observed on T cell activation and recruitment in the early acute phase of infection. Additionally, blocking of type I IFN signaling reduced bacterial burden in the infected mice as compared to untreated infected mice. CONCLUSIONS: Altogether, our results reveal that Type I IFN mediates a balance between M. bovis-mediated inflammatory reaction and host defense mechanism. Thus, modulating Type I IFN signaling could be exploited as a therapeutic strategy against a large repertoire of inflammatory disorders including tuberculosis.


Assuntos
Interferon Tipo I/metabolismo , Mycobacterium bovis/patogenicidade , Tuberculose/tratamento farmacológico , Tuberculose/metabolismo , Animais , Anticorpos/farmacologia , Citocinas/metabolismo , Feminino , Humanos , Interferon Tipo I/antagonistas & inibidores , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Pulmão/patologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Macrófagos/patologia , Camundongos Endogâmicos C57BL , Mycobacterium bovis/imunologia , Receptor de Interferon alfa e beta/antagonistas & inibidores , Receptor de Interferon alfa e beta/imunologia , Transdução de Sinais/efeitos dos fármacos
17.
Int J Mol Sci ; 20(23)2019 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-31795474

RESUMO

Mycobacterium bovis (M. bovis) is the causative agent of bovine tuberculosis in cattle population across the world. Human beings are at equal risk of developing tuberculosis beside a wide range of M. bovis infections in animal species. Autophagic sequestration and degradation of intracellular pathogens is a major innate immune defense mechanism adopted by host cells for the control of intracellular infections. It has been reported previously that the catalytic subunit of protein phosphatase 2A (PP2Ac) is crucial for regulating AMP-activated protein kinase (AMPK)-mediated autophagic signaling pathways, yet its role in tuberculosis is still unclear. Here, we demonstrated that M. bovis infection increased PP2Ac expression in murine macrophages, while nilotinib a tyrosine kinase inhibitor (TKI) significantly suppressed PP2Ac expression. In addition, we observed that TKI-induced AMPK activation was dependent on PP2Ac regulation, indicating the contributory role of PP2Ac towards autophagy induction. Furthermore, we found that the activation of AMPK signaling is vital for the regulating autophagy during M. bovis infection. Finally, the transient inhibition of PP2Ac expression enhanced the inhibitory effect of TKI-nilotinib on intracellular survival and multiplication of M. bovis in macrophages by regulating the host's immune responses. Based on these observations, we suggest that PP2Ac should be exploited as a promising molecular target to intervene in host-pathogen interactions for the development of new therapeutic strategies towards the control of M. bovis infections in humans and animals.


Assuntos
Proteínas Quinases Ativadas por AMP/imunologia , Macrófagos/imunologia , Mycobacterium bovis/imunologia , Proteína Fosfatase 2/imunologia , Tuberculose/veterinária , Animais , Autofagia , Bovinos , Interações Hospedeiro-Patógeno , Humanos , Macrófagos/microbiologia , Camundongos , Mycobacterium bovis/fisiologia , Fagocitose , Células RAW 264.7 , Tuberculose/imunologia , Tuberculose/microbiologia , Tuberculose Bovina/imunologia , Tuberculose Bovina/microbiologia
18.
Front Neurol ; 10: 1155, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31781020

RESUMO

It is well-recognized that the gut microbiota (GM) is crucial for gut function, metabolism, and energy cycles. The GM also has effects on neurological outcomes via many mechanisms, such as metabolite production and the gut-brain axis. Emerging evidence has gradually indicated that GM dysbiosis plays a role in several neurological diseases, such as Parkinson's disease (PD), Alzheimer's disease, depression, and multiple sclerosis. Several studies have observed that PD patients generally suffer from gastrointestinal disorders and GM dysbiosis prior to displaying motor symptoms, but the specific link between the GM and PD is not clearly understood. In this review, we aim to summarize what is known regarding the correlation between the GM and PD pathologies, including direct, and indirect evidence.

19.
Cell Death Dis ; 10(10): 710, 2019 09 24.
Artigo em Inglês | MEDLINE | ID: mdl-31551424

RESUMO

Prion diseases caused by the cellular prion protein (PrPC) conversion into a misfolded isoform (PrPSc) are associated with multiple mitochondrial damages. We previously reported mitochondrial dynamic abnormalities and cell death in prion diseases via modulation of a variety of factors. Optic atrophy 1 (OPA1) is one of the factors that control mitochondrial fusion, mitochondrial DNA (mtDNA) maintenance, bioenergetics, and cristae integrity. In this study, we observed downregulation of OPA1 in prion disease models in vitro and in vivo, mitochondria structure damage and dysfunction, loss of mtDNA, and neuronal apoptosis. Similar mitochondria findings were seen in OPA1-silenced un-infected primary neurons. Overexpression of OPA1 not only alleviated prion-induced mitochondrial network fragmentation and mtDNA loss, decrease in intracellular ATP, increase in ADP/ATP ratio, and decrease in mitochondrial membrane potential but also protected neurons from apoptosis by suppressing the release of cytochrome c from mitochondria to cytosol and activation of the apoptotic factor, caspase 3. Our results demonstrated that overexpression of OPA1 alleviates prion-associated mitochondrial network fragmentation and cristae remodeling, mitochondrial dysfunction, mtDNA depletion, and neuronal apoptosis, suggesting that OPA1 may be a novel and effective therapeutic target for prion diseases.


Assuntos
DNA Mitocondrial/metabolismo , GTP Fosfo-Hidrolases/biossíntese , Mitocôndrias/metabolismo , Neurônios/metabolismo , Atrofia Óptica Autossômica Dominante/metabolismo , Doenças Priônicas/metabolismo , Animais , Células Cultivadas , Córtex Cerebral/metabolismo , Córtex Cerebral/patologia , Feminino , GTP Fosfo-Hidrolases/genética , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Doenças Priônicas/genética , Doenças Priônicas/patologia , Transfecção
20.
Cell Prolif ; 52(5): e12633, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31264317

RESUMO

OBJECTIVES: Matrix metalloproteinase 9 (MMP-9) has been frequently noticed in the breast cancers. In this study, we aim to investigate the associations of MMP-9 with the activation of transforming growth factor beta (TGF-ß)/SMAD signalling and the malignancy of breast malignant tumour cells. MATERIALS AND METHODS: The distributions of MMP-9 and TGF-ß in the tissues of canine breast cancers were screened by immunohistochemical assays. A recombinant plasmid expressing mouse MMP-9 was generated and transiently transfected into three different breast cancer cell lines. Cell Counting Kit-8 and colony formation assay were used to study cell viability. Migration and invasion ability were analysed by wound assay and transwell filters. Western blot and quantitative real-time PCR were used to determine the protein and mRNA expression. RESULT: Remarkable strong MMP-9 and TGF-ß signals were observed in the malignant tissues of canine breast cancers. In the cultured three cell lines receiving recombinant plasmid expressing mouse MMP-9, the cell malignancy was markedly increased, including the cell colony formation, migration and epithelial-mesenchymal transition. The levels of activated TGF-ß, as well as SMAD4, SMAD2/3 and phosphorylation of SMAD2, were increased, reflecting an activation of TGF-ß/SMAD signalling. We also demonstrated that the inhibitors specific for MMP-9 and TGF-ß sufficiently blocked the overexpressing MMP-9 induced the activation of SMAD signalling and enhancement on invasion in the tested breast cancer cell lines. CONCLUSION: Overexpression of MMP-9 increases the malignancy of breast cancer cell lines, largely via activation of the TGF-ß/SMAD signalling.


Assuntos
Metaloproteinase 9 da Matriz/metabolismo , Proteínas Smad/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Transição Epitelial-Mesenquimal , Feminino , Humanos , Metaloproteinase 9 da Matriz/química , Metaloproteinase 9 da Matriz/genética , Fosforilação , Transdução de Sinais , Fator de Crescimento Transformador beta/antagonistas & inibidores
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