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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
4.
Int J Comput Assist Radiol Surg ; 16(2): 253-267, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33409837

RESUMO

PURPOSE: In this paper, a method for rapidly constructing a virtual surgical simulation system is proposed. A deformation model based on the mechanical properties of the liver and a rapid collision detection between the surgical micro-instruments and the liver tissue are included in this method. The purpose of this work is to improve the accuracy and real time of particle model deformation interaction in virtual surgery system. METHODS: Firstly, a finite element model is established based on the constitutive model parameters of liver tissue. According to the simulation results, a mathematical model of node displacement is established. Secondly, the virtual liver is established based on the fast model reconstruction method, and the virtual manipulator is controlled by Geomagic Touch manipulator. Based on the hybrid bounding box, a rapid collision detection process between the instrument and liver is realized and the proposed deformation method is used to simulate the deformation of liver tissue. RESULTS: The simulation and experiment results show that the proposed deformation model can achieve high deformation interaction accuracy. The collision detection algorithm based on the hybrid bounding boxes can realize the collision between the liver and the instrument, and the established virtual surgical simulation system can simulate the liver tissue deformation in the case of small loading displacement. CONCLUSIONS: The effectiveness of the collision detection algorithm and deformation model was verified by an established virtual surgery simulation system. The proposed rapid construction method of virtual surgical simulation is feasible.


Assuntos
Simulação por Computador , Fígado/cirurgia , Interface Usuário-Computador , Algoritmos , Análise de Elementos Finitos , Humanos , Modelos Biológicos
5.
Pharmgenomics Pers Med ; 13: 673-678, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33273845

RESUMO

Background: Studies show that MDM4 may play a pivotal role in colorectal cancer (CRC). Recently, a host of studies suggest that MDM4 gene rs4245739 polymorphism may modify the risk of different cancers. Methods: In this study, we were interested whether MDM4 gene rs4245739 polymorphism correlated with the risk and clinical characteristics of CRC. Logistic regression was adopted to estimate the association of rs4245739 polymorphism and CRC risk. Results: We enrolled 444 CRC patients and 530 controls and found MDM4 gene rs4245739 polymorphism may decrease the risk of CRC. Stratified analyses uncovered that this variant was connected to a less risk of CRC in females, non-drinkers, non-smokers, and people under 60 years old. Additionally, rs4245739 polymorphism was related to TNM staging, pathological type, tumor size, and location of CRC. Furthermore, this polymorphism was significantly linked with the survival of CRC. Conclusion: Totally, this study suggests that MDM4 rs4245739 polymorphism is linked with the risk and clinical characteristics of CRC.

7.
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
8.
J Org Chem ; 85(4): 2504-2511, 2020 02 21.
Artigo em Inglês | MEDLINE | ID: mdl-31910620

RESUMO

A complementary and general strategy for the oxidative generation of iminyl radicals from the readily available α-imino-oxy acids has been established through silver-catalyzed decarboxylation. To demonstrate its synthesis utility, the direct C-H cyanoalkylation of heterocycles and quinones with cyclic α-imino-oxy acids via the iminyl radical-mediated C-C bond cleavage is developed. This cost-effective method takes place under mild reaction conditions and exhibits a broad substrate scope.

9.
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
10.
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
11.
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
12.
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
13.
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.

14.
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
15.
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
16.
Front Neurol ; 10: 645, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31293496

RESUMO

Background: The current diagnosis method for Creutzfeldt-Jakob disease (CJD) is post-mortem examination, so early detection of CJD has been historically problematic. Auxiliary detection of CJD based on changes in levels of components of the cerebrospinal fluid (CSF) has become a focus of research. In other neurodegenerative diseases such as Alzheimer's disease (AD), cell-free mitochondrial DNA (mtDNA) in the CSF of patients may serve as a biomarker that could facilitate early diagnosis and studies of the mechanisms underlying the disease. Methods: In this study, the cell-free mitochondrial DNA in the CSF of patients with sCJD and control patients was compared by digital droplet PCR. Results: The cell-free mitochondrial DNA copy number in the CSF of sCJD patients was significantly increased in comparison with that of the control group, and this difference was pathologically related to CJD. Conclusion: Therefore, we speculate that changes in cerebrospinal fluid mitochondrial DNA copy number play an important role in the study of CJD mechanism and diagnosis.

17.
Cell Prolif ; 52(4): e12649, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31199047

RESUMO

Mycobacterium tuberculosis (Mtb) leads to approximately 1.5 million human deaths every year. In pulmonary tuberculosis (TB), Mtb must drive host tissue destruction to cause pulmonary cavitation and dissemination in the tissues. Matrix metalloproteinases (MMPs) are endopeptidases capable of degrading all components of pulmonary extracellular matrix (ECM). It is well established that Mtb infection leads to upregulation of MMPs and also causes disturbance in the balance between MMPs and tissue inhibitors of metalloproteinases (TIMPs), thus altering the extracellular matrix deposition. In TB, secretion of MMPs is mainly regulated by NF-κB, p38 and MAPK signalling pathways. In addition, recent studies have demonstrated the immunomodulatory roles of MMPs in Mtb pathogenesis. Researchers have proposed a new regimen of improved TB treatment by inhibition of MMP activity to hinder matrix destruction and to minimize the TB-associated morbidity and mortality. The proposed regimen involves adjunctive use of MMP inhibitors such as doxycycline, marimastat and other related drugs along with front-line anti-TB drugs to reduce granuloma formation and bacterial load. These findings implicate the possible addition of economical and well-tolerated MMP inhibitors to current multidrug regimens as an attractive mean to increase the drug potency. Here, we will summarize the recent advancements regarding expression of MMPs in TB, their immunomodulatory role, as well as their potential as therapeutic targets to control the deadly disease.


Assuntos
Metaloproteinases da Matriz/metabolismo , Mycobacterium tuberculosis/patogenicidade , Tuberculose Pulmonar/metabolismo , Tuberculose Pulmonar/patologia , Animais , Matriz Extracelular/metabolismo , Humanos , Pulmão/metabolismo , Pulmão/patologia , Transdução de Sinais/fisiologia
18.
Cells ; 8(5)2019 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-31060300

RESUMO

Mycobacterium bovis (M. bovis) is a member of the Mycobacterium tuberculosis (Mtb) complex causing bovine tuberculosis (TB) and imposing a high zoonotic threat to human health. Kallikreins (KLKs) belong to a subgroup of secreted serine proteases. As their role is established in various physiological and pathological processes, it is likely that KLKs expression may mediate a host immune response against the M. bovis infection. In the current study, we report in vivo and in vitro upregulation of KLK12 in the M. bovis infection. To define the role of KLK12 in immune response regulation of murine macrophages, we produced KLK12 knockdown bone marrow derived macrophages (BMDMs) by using siRNA transfection. Interestingly, the knockdown of KLK12 resulted in a significant downregulation of autophagy and apoptosis in M. bovis infected BMDMs. Furthermore, we demonstrated that this KLK12 mediated regulation of autophagy and apoptosis involves mTOR/AMPK/TSC2 and BAX/Bcl-2/Cytochrome c/Caspase 3 pathways, respectively. Similarly, inflammatory cytokines IL-1ß, IL-6, IL-12 and TNF-α were significantly downregulated in KLK12 knockdown macrophages but the difference in IL-10 and IFN-ß expression was non-significant. Taken together, these findings suggest that upregulation of KLK12 in M. bovis infected murine macrophages plays a substantial role in the protective immune response regulation by modulating autophagy, apoptosis and pro-inflammatory pathways. To our knowledge, this is the first report on expression and the role of KLK12 in the M. bovis infection and the data may contribute to a new paradigm for diagnosis and treatment of bovine TB.


Assuntos
Apoptose , Autofagia , Imunidade Inata , Calicreínas/metabolismo , Macrófagos/patologia , Mycobacterium bovis/fisiologia , Tuberculose Bovina/imunologia , Tuberculose Bovina/microbiologia , Animais , Bovinos , Citocinas/metabolismo , Macrófagos/microbiologia , Camundongos , Camundongos Endogâmicos C57BL , Viabilidade Microbiana , Células RAW 264.7 , Transdução de Sinais , Tuberculose Bovina/patologia
19.
Cells ; 8(5)2019 05 26.
Artigo em Inglês | MEDLINE | ID: mdl-31130711

RESUMO

Nilotinib, a tyrosine kinase inhibitor, has been studied extensively in various tumor models; however, no information exists about the pharmacological action of nilotinib in bacterial infections. Mycobacterium bovis (M. bovis) and Mycobacterium avium subspecies paratuberculosis (MAP) are the etiological agents of bovine tuberculosis and Johne's disease, respectively. Although M. bovis and MAP cause distinct tissue tropism, both of them infect, reside, and replicate in mononuclear phagocytic cells of the infected host. Autophagy is an innate immune defense mechanism for the control of intracellular bacteria, regulated by diverse signaling pathways. Here we demonstrated that nilotinib significantly inhibited the intracellular survival and growth of M. bovis and MAP in macrophages by modulating host immune responses. We showed that nilotinib induced autophagic degradation of intracellular mycobacterium occurred via the inhibition of PI3k/Akt/mTOR axis mediated by abelson (c-ABL) tyrosine kinase. In addition, we observed that nilotinib promoted ubiquitin accumulation around M. bovis through activation of E3 ubiquitin ligase parkin. From in-vivo experiments, we found that nilotinib effectively controlled M. bovis growth and survival through enhanced parkin activity in infected mice. Altogether, our data showed that nilotinib regulates protective innate immune responses against intracellular mycobacterium, both in-vitro and in-vivo, and can be exploited as a novel therapeutic remedy for the control of M. bovis and MAP infections.


Assuntos
Autofagia/efeitos dos fármacos , Mycobacterium avium subsp. paratuberculosis/efeitos dos fármacos , Mycobacterium bovis/efeitos dos fármacos , Paratuberculose/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Tuberculose Bovina/tratamento farmacológico , Animais , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/efeitos dos fármacos , Bovinos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Citoplasma/metabolismo , Citoplasma/microbiologia , Feminino , Imunidade Inata/efeitos dos fármacos , Macrófagos/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Proteína Oncogênica v-akt/metabolismo , Paratuberculose/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Proteínas Quinases/administração & dosagem , Proteínas Proto-Oncogênicas c-abl/metabolismo , Pirimidinas/administração & dosagem , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Tuberculose Bovina/metabolismo , Ubiquitina/metabolismo , Ubiquitina-Proteína Ligases/metabolismo
20.
Appl Opt ; 58(10): 2463-2470, 2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-31045038

RESUMO

We theoretically investigate the optical bistability in a composite photonic molecule cavity optomechanical system consisting of two whispering gallery mode microcavities, where one of the optical cavities is optomechanical with a high quality factor, and the other optical cavity is an auxiliary cavity with high cavity dissipation. By controlling the coupling strength J between the two cavities determined by their distance, the decay rate ratio δ of the two cavities, and the pump power P, the optical bistability can be controlled. Further, the transmission spectrum of the signal field can be efficiently attenuated or amplified, depending on the power of a second "gating" (pump) field P, and other parameters. Our study for photonic-molecule optomechanics systems may be a promising candidate for single-photon transistors and pave the way for potential applications in quantum information technologies.

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