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1.
Artigo em Inglês | MEDLINE | ID: mdl-32445660

RESUMO

Researchers have made considerable progress in elucidating psychological and exercise correlates of major depressive disorder (MDD). However, as the largest immune organ, far less is known about the role of gastrointestinal (GI) tract in the therapeutic mechanisms of exercise in MDD. In addition to the sites of the digestive tract that absorb nutrients, the GI tract also serves as a protective barrier against organisms. Inflammation and other consequences caused by disrupted GI barrier integrity are considered to be one of the mechanisms of depression, and the gut-brain axis (GBA) plays a critical role in this process. In this work, we observed the depression-like behaviors, intestinal barrier, central and peripheral inflammation, and related neurotransmitters through exercise intervention in the chronic unpredictable mild stress (CUMS) model, aiming to clarify the mechanisms of exercise to improve depression through GBA. Our results revealed that, following increased expressions of pro-inflammatory factors in intestine of CUMS mice, the levels of pro-inflammatory factors were all significantly raised in serum and brain simultaneously. Further, glial cells were activated in visceral nervous system and its related brain regions at the same time, accompanied by lower expression of occludin in CUMS mice. Importantly, our findings provide the first evidence that eight weeks of running exercise effectively inhibited neuro-immune interactions along gut-brain-axis and contributed obvious improvement of intestinal epithelial barrier (IEB). Finally, multivariate analysis putatively highlighted the role of exercise-induced IEB protection on depression treatment. We hope that our findings could warrant further study of therapeutic mechanisms of exercise in depression, specifically in disentangling the roles of intestinal function and IEB protection, and for developing more targeted clinical depression interventions.

2.
J Exp Clin Cancer Res ; 39(1): 44, 2020 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-32111229

RESUMO

BACKGROUND: FK506-binding protein 9 (FKBP9) is amplified in high-grade gliomas (HGGs). However, the roles and mechanism(s) of FKBP9 in glioma are unknown. METHODS: The expression of FKBP9 in clinical glioma tissues was detected by immunohistochemistry (IHC). The correlation between FKBP9 expression levels and the clinical prognosis of glioma patients was examined by bioinformatic analysis. Glioblastoma (GBM) cell lines stably depleted of FKBP9 were established using lentiviruses expressing shRNAs against FKBP9. The effects of FKBP9 on GBM cells were determined by cell-based analyses, including anchorage-independent growth, spheroid formation, transwell invasion assay, confocal microscopy, immunoblot (IB) and coimmunoprecipitation assays. In vivo tumor growth was determined in both chick chorioallantoic membrane (CAM) and mouse xenograft models. RESULTS: High FKBP9 expression correlated with poor prognosis in glioma patients. Knockdown of FKBP9 markedly suppressed the malignant phenotype of GBM cells in vitro and inhibited tumor growth in vivo. Mechanistically, FKBP9 expression induced the activation of p38MAPK signaling via ASK1. Furthermore, ASK1-p38 signaling contributed to the FKBP9-mediated effects on GBM cell clonogenic growth. In addition, depletion of FKBP9 activated the IRE1α-XBP1 pathway, which played a role in the FKBP9-mediated oncogenic effects. Importantly, FKBP9 expression conferred GBM cell resistance to endoplasmic reticulum (ER) stress inducers that caused FKBP9 ubiquitination and degradation. CONCLUSIONS: Our findings suggest an oncogenic role for FKBP9 in GBM and reveal FKBP9 as a novel mediator in the IRE1α-XBP1 pathway.

3.
Anat Rec (Hoboken) ; 302(11): 2020-2029, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31251832

RESUMO

Multiple sclerosis (MS) is the most common central nervous system disease due to demyelination in young adults, and currently, there is no cure. Some experimental animal models were generated to mimic specific aspects of MS pathological characteristics. Among them, the cuprizone (CPZ)-induced mouse demyelination model presents heterogeneous pathologies with both focal and diffuse lesions. Considering that MS is a progressive disease, it is important to study the spatial and temporal characters of de- and remyelination in MS animal models. However, such data especially in some brain regions such as lateral septal area, fimbria of hippocampus, and hippocampus are still lacking. In this study, we investigated the alterations of myelin in these areas in parallel to the changes in corpus callosum using coronal sections. We found that the progression of demyelinating varied in different brain regions in C57BL/6J mice treated with CPZ for 1 to 5 weeks. This result suggests that each brain region has a distinct sensitivity to CPZ intoxication. Interestingly, activated microglia appeared not only in the active demyelinating areas but also in the non-myelinolysis regions. After CPZ withdrawal, significant remyelination was started in corpus callosum as early as 3 days. The completion of remyelination in the entire brain regions took 3 weeks. Our study detailed characterized the dynamics of myelin alterations and microglial status in the brain of the CPZ model. This information is valuable to facilitate further MS studies utilizing the CPZ model. Anat Rec, 302:2020-2029, 2019. © 2019 American Association for Anatomy.

4.
Exp Cell Res ; 382(2): 111472, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31229505

RESUMO

Increasing evidence indicates that in response to environmental changes, macrophages can dynamically change into two main functional phenotypes, namely M1 and M2. Depending on these different phenotypes, macrophages can produce either pro-inflammatory or anti-inflammatory factors which may affect the outcome of inflammation. Mastering the switching of M1/M2 phenotypes may provide therapeutic approaches to chronic inflammatory disease, such as atherosclerosis, rheumatoid arthritis, even the metabolic disorders. Cathepsin C (CTSC), as a member of the papain family of cysteine proteases, is a key enzyme in the activation of granule serine proteases thereby involved in modulating the inflammatory responses. Moreover, abundant expression of CTSC has been found in M1 macrophages in plaques of atherosclerosis and related to the progression of disease. However, whether CTSC can regulate macrophage activation status in inflammatory responses has not been fully investigated. In the present study, using peritoneal macrophages (PMs) and mouse macrophage cell line RAW264.7 treated with LPS and active monomer of CTSC, we found that CTSC was not only expressed in macrophages in M1 activation status, but also facilitated macrophages towards M1 phenotype, suggesting a self-activation mechanism involved in this process which may lead to a vicious circle in chronic inflammation. Then we attempted to explore the underlying molecular mechanisms of CTSC resulting in M1 activation. Focal adhesion kinase (FAK) is one of the non-receptor cytoplasmic protein tyrosine kinases, serving as an upstream mediator that leads to transcription of many pro-inflammatory factors. We found FAK expression was up-regulated at both mRNA and protein levels following CTSC stimulation, and FAK phosphorylation level was also significantly increased. The p38MAPK/NF-κB pathway, as the downstream of FAK, were also found activated in CTSC-treated macrophages, suggesting that CTSC may promote macrophage towards M1 activation status through FAK-induced p38MAPK/NF-κB signaling pathway activation. Our study provides a new therapeutic target in the treatment of chronic inflammatory diseases.

5.
J Neuroinflammation ; 16(1): 10, 2019 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-30651105

RESUMO

BACKGROUND: Microglia-derived lysosomal cathepsins are important inflammatory mediators to trigger signaling pathways in inflammation-related cascades. Our previous study showed that the expression of cathepsin C (CatC) in the brain is induced predominantly in activated microglia in neuroinflammation. Moreover, CatC can induce chemokine production in brain inflammatory processes. In vitro studies further confirmed that CatC is secreted extracellularly from LPS-treated microglia. However, the mechanisms of CatC affecting neuroinflammatory responses are not known yet. METHODS: CatC over-expression (CatCOE) and knock-down (CatCKD) mice were treated with intraperitoneal and intracerebroventricular LPS injection. Morris water maze (MWM) test was used to assess the ability of learning and memory. Cytokine expression in vivo was detected by in situ hybridization, quantitative PCR, and ELISA. In vitro, microglia M1 polarization was determined by quantitative PCR. Intracellular Ca2+ concentration was determined by flow cytometry, and the expression of NR2B, PKC, p38, IkBα, and p65 was determined by western blotting. RESULTS: The LPS-treated CatCOE mice exhibited significantly increased escape latency compared with similarly treated wild-type or CatCKD mice. The highest levels of TNF-α, IL-1ß, and other M1 markers (IL-6, CD86, CD16, and CD32) were found in the brain or serum of LPS-treated CatCOE mice, and the lowest levels were detected in CatCKD mice. Similar results were found in LPS-treated microglia derived from CatC differentially expressing mice or in CatC-treated microglia from wild-type mice. Furthermore, the expression of NR2B mRNA, phosphorylation of NR2B, Ca2+ concentration, phosphorylation of PKC, p38, IκBα, and p65 were all increased in CatC-treated microglia, while addition of E-64 and MK-801 reversed the phosphorylation of above molecules. CONCLUSION: The data suggest that CatC promotes microglia M1 polarization and aggravates neuroinflammation via activation of Ca2+-dependent PKC/p38MAPK/NF-κB pathway. CatC may be one of key molecular targets for alleviating and controlling neuroinflammation in neurological diseases.


Assuntos
Cálcio/metabolismo , Catepsina C/metabolismo , Polaridade Celular/fisiologia , Encefalite/patologia , Microglia/fisiologia , NF-kappa B/metabolismo , Agregação Patológica de Proteínas/etiologia , Animais , Proteínas de Ligação ao Cálcio/genética , Proteínas de Ligação ao Cálcio/metabolismo , Catepsina C/genética , Polaridade Celular/efeitos dos fármacos , Polaridade Celular/genética , Células Cultivadas , Encefalite/induzido quimicamente , Encefalite/fisiopatologia , Ativação Enzimática/efeitos dos fármacos , Ativação Enzimática/genética , Feminino , Regulação da Expressão Gênica/genética , Lipopolissacarídeos/toxicidade , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Proteínas dos Microfilamentos/genética , Proteínas dos Microfilamentos/metabolismo , Microglia/efeitos dos fármacos , NF-kappa B/genética , Agregação Patológica de Proteínas/genética , Transdução de Sinais/genética , Transdução de Sinais/fisiologia
6.
Behav Brain Res ; 364: 494-502, 2019 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-28572058

RESUMO

The immuno-inflammatory activation triggered by various stresses play an important role in pathophysiology of depression. The immune responses display differential pathological characters in different stresses. However, comparative data and analysis on behavioural, inflammatory and neurochemical changes in different stress-induced depression is limited. To imitate different stressful situations, in this study, mice were subjected to a single injection of LPS (0.5 mg/kg, i.p.) and UCMS (4 week period), respectively. LPS-stressed mice showed more immobility time in FST and TST, as well as more time in periphery in OFT than UCMS-stressed mice. Further, LPS-stressed mice showed robuster expression and release of TNF-α, IL-1ß and IL-6 in serum and depression-related brain areas (prefrontal cortex, hippocampus and striatum) as compared to UCMS-stressed mice. The ELISA results showed that IDO expression was significantly increased following LPS and UCMS stresses, but more increased IDO expression was observed in prefrontal cortex and hippocampus of LPS-stressed mice. The decrease of 5-HT and BDNF was detected only in hippocampus of LPS-stressed mice, but in overall all the brain areas assessed in UCMS-stressed mice as compared to control. The data indicate that LPS induced more severe depressive-like behaviours and robuster immune activation than UCMS. Our study strongly imply that hippocampus is relatively more vulnerable to acute inflammatory challenge in depression, while chronic psychological stress is more likely to cause the multidimensional symptoms of clinical depression. Our findings provide more insight into pathophysiology in various stress-induced depression and also implicate a potential suitability of different stress models.


Assuntos
Depressão/metabolismo , Estresse Psicológico/fisiopatologia , Animais , Comportamento Animal/fisiologia , Encéfalo/metabolismo , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Depressão/induzido quimicamente , Depressão/imunologia , Transtorno Depressivo/imunologia , Transtorno Depressivo/metabolismo , Modelos Animais de Doenças , Hipocampo/metabolismo , Indóis/metabolismo , Inflamação/metabolismo , Lipopolissacarídeos/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Estresse Psicológico/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
9.
Brain Behav ; 8(3): e00929, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29541541

RESUMO

Introduction: Social isolation enhances the aggressive behavior of animals, but the detailed mechanism remains unclear. Epigenetic studies have suggested that Htr2c RNA editing is closely related to aggressive behavior. This study aims to obtain a fundamental understanding of how social isolation impacts adenosine deaminase acting on RNA 1 (ADAR1, RNA editing enzyme) and Htr2c RNA editing, leading to aggressive behavior, and explore the effective solutions for the recovery of this behavior. Methods: We evaluated 21-day-old BALB/c mice with and without isolation for aggressive behavior using a resident-intruder test. Immune-reactivity and protein expression of ADAR1 (p110) were measured using immunohistochemistry and Western blotting. Htr2c RNA editing was evaluated using pyrosequencing. In addition, the 5-HT 2C R antagonist SB243213/5-HT 2C R inverse agonist SB206553 was used to treat the isolated mice, and the performance of both treatments on the behavior, ADAR1 (p110) expression, and Htr2c RNA editing in isolated mice was examined. Results: Both the protein expression and immune-reactivity of ADAR1 (p110) in the amygdala decreased, but the percentage of Htr2c RNA editing at A and B sites of amygdala only showed a moderate increase in isolated BALB/c mice with enhanced aggressive behavior compared to the age-matched group-housed BALB/c mice. Additionally, treatment with the 5-HT 2C R antagonist SB243213/5-HT 2C R inverse agonist SB206553 recovered the enhanced aggressive behavior of isolated mice and returned the protein expression and immune-reactivity of ADAR1 (p110) back to the normal level. Moreover, compared to the age-matched isolated mice treated with physiological saline, isolated mice treated with 5-HT 2C R inverse agonist SB206553 showed a lower percentage of Htr2c RNA editing at both A and B sites, and the same result occurred in isolated mice treated with 5-HT 2C R antagonist SB243213 at B site of Htr2c RNA editing. Conclusions: The 5-HT 2C R antagonist SB243213/5-HT 2C R inverse agonist SB206553 recovered increased aggressive behavior of isolated BALB/c mice mediated by ADAR1 (p110) expression and Htr2c RNA editing.


Assuntos
Adenosina Desaminase/genética , Agressão/psicologia , Edição de RNA/genética , Receptor 5-HT2C de Serotonina/genética , Agonistas do Receptor 5-HT2 de Serotonina/uso terapêutico , Isolamento Social/psicologia , Adenosina Desaminase/metabolismo , Tonsila do Cerebelo/metabolismo , Animais , Western Blotting , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Modelos Animais , Receptor 5-HT2C de Serotonina/metabolismo , Agonistas do Receptor 5-HT2 de Serotonina/metabolismo
10.
Neurochem Res ; 43(1): 89-100, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28623605

RESUMO

Major depression has been interpreted as an inflammatory disease characterized by cell-mediated immune activation, which is generally triggered by various stresses. Microglia has been thought to be the cellular link between inflammation and depression-like behavioural alterations. The expression of cathepsin C (Cat C), a lysosomal proteinase, is predominantly induced in microglia in neuroinflammation. However, little is known about the role of Cat C in pathophysiology of depression. In the present study, Cat C transgenic mice and wild type mice were subjected to an intraperitoneal injection of LPS (0.5 mg/kg) and 6-week unpredictable chronic mild stress (UCMS) exposure to establish acute and chronic stress-induced depression model. We examined and compared the behavioural and proinflammatory cytokine alterations in serum and depression-targeted brain areas of Cat C differentially expressed mice in stress, as well as indoleamine 2,3-dioxygenase (IDO) and 5-hydroxytryptamine (5HT) levels in brain. The results showed that Cat C overexpression (Cat C OE) promoted peripheral and central inflammatory response with significantly increased TNFα, IL-1ß and IL-6 in serum, hippocampus and prefrontal cortex, and resultant upregulation of IDO and downregulation of 5HT expression in brain, and thereby aggravated depression-like behaviours accessed by open field test, forced swim test and tail suspension test. In contrast, Cat C knockdown (Cat C KD) partially prevented inflammation, which may help alleviate the symptoms of depression in mice. To the best of our knowledge, we are the first to demonstrate that Cat C aggravates neuroinflammation involved in disturbances of behaviour and neurochemistry in acute and chronic stress-induced murine model of depression.


Assuntos
Encéfalo/metabolismo , Catepsina C/metabolismo , Depressão/metabolismo , Inflamação/metabolismo , Microglia/metabolismo , Estresse Fisiológico , Animais , Comportamento Animal/efeitos dos fármacos , Catepsina C/genética , Citocinas/metabolismo , Modelos Animais de Doenças , Lipopolissacarídeos/farmacologia , Camundongos Transgênicos , Estresse Fisiológico/efeitos dos fármacos
11.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 25(3): 723-728, 2017 Jun.
Artigo em Chinês | MEDLINE | ID: mdl-28641625

RESUMO

OBJECTIVE: To Study the effect of C677T and MTHFR gene polymorphism on side effects of HD-MTX in ALL children. METHODS: The gene polymorphism of C677T A303G and MTHFR C677T were detected by PCR in 98 ALL children from January 2014 to January 2016. The side effects during HD-MTX therapy were observed, and the relationship among GSTP1, MTHFR gene polymorphism and incidence of side effect of HD-MTX were analyzed. RESULTS: Among 98 ALL children, the gene variation was observed in 61 ALL children (62.24%). Polymorphism study on C677T A303G showed that the gene frequency of A was 84.69%, while that of G was 15.31%; for polymorphism of MTHFR C677T, gene frequency of C was 66.33%, and that of T was 33.67%. Seven patients(7.14%) experienced with bone marrow supression, 23 patients(23.47%) with liver function damage, 15 patients(15.31%) with renal function damage, 48 patients(48.98%) with gastrointestinal reactions and 46 patients(46.94%) with mucosal lesions. After adjustment of sex, age, risk stratification and dosage of MTX, the gene polymorphism had no significant relationship with bone marrow suppression, gastrointestinal reactions and mucosal lesions(P>0.05). However, the number of the mutant genes had statistically significant relationship with liver and renal function damage(P<0.05). CONCLUSION: The risk of side effects during HD-MTX therapy increases in ALL children with combined mutation of MTHFR and C677T.


Assuntos
Antimetabólitos Antineoplásicos/efeitos adversos , Glutationa S-Transferase pi/genética , Metotrexato/efeitos adversos , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Polimorfismo Genético , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Criança , Frequência do Gene , Homocistinúria , Humanos , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico
12.
Oncol Rep ; 37(6): 3509-3519, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28440433

RESUMO

As a natural compound, Ornithogalum caudatum Ait is primarily used as an anti-inflammatory and antitumor agent in Chinese folk medicine. In 1992, OSW-1 was isolated from this compound, which is a new member of cholestane saponin family. In numerous recent studies, OSW-1 has been shown to have powerful cytotoxic anticancer effects against various malignant cells. However, the therapeutic efficacy of OSW-1 on colon cancer and the underlying mechanism are not understood. To explore the mechanism underlying OSW-1 in antitumor therapy, a therapeutic function analysis of OSW-1 on colon cancer was performed in vitro and in vivo. It was shown that with low toxicity on normal colonic cells, OSW-1 suppresses colon cancer cells in vitro and this inhibition was via the intrinsic apoptotic pathway, which increased cellular calcium, changed mitochondrial membrane potential, disrupted mitochondrial morphology, and led to the release of cytochrome c and the activation of caspase-3. Furthermore, in a nude mouse model, OSW-1 had a powerful effect on suppressing colon tumor proliferation without significant side effects through the apoptosis pathway. Taken together, these results demonstrate that OSW-1 is a potential drug for colon cancer treatment.


Assuntos
Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Colestenonas/administração & dosagem , Neoplasias do Colo/tratamento farmacológico , Saponinas/administração & dosagem , Animais , Caspase 3/genética , Linhagem Celular Tumoral , Colestenonas/efeitos adversos , Colestenonas/química , Neoplasias do Colo/genética , Neoplasias do Colo/patologia , Citocromos c/genética , Citometria de Fluxo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Medicina Tradicional Chinesa , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Saponinas/efeitos adversos , Saponinas/química , Ensaios Antitumorais Modelo de Xenoenxerto
14.
Protein Pept Lett ; 24(3): 245-252, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28071581

RESUMO

Backgroud: Neuromyelitis optica (NMO) is an autoimmune inflammatory disorder, which is characterized by severe attacks of optic neuritis and myelitis. Antibodies (Ab) to aquaporin-4 (AQP4) (or NMO-IgG) as a serological biomarker of NMO have been widespread used. Nevertheless, some NMO patients remain seronegative for AQP4-Ab and/or have no detected optic nerve involvement. In addition, no consensus exists on the association between AQP4-Ab serostatus and visual outcome in NMO. To drive a more precise estimate of this postulated relationship, a metaanalysis was performed based on existing relevant studies. METHODS: Studies were searched by PubMed and MEDLINE up to March 2016. Study quality was assessed, and meta-analysis was conducted using the RevMan 5.1. Odds ratios with 95% confidence interval were calculated and funnel plot was applied to assess the potential publication bias. RESULTS: In a total of 1288 relevant studies, 18 studies satisfied the eligibility criteria and were included in the systemic review. Only 9 studies appeared eligible for the meta-analysis, together including 624 AQP4-Ab-positive and 119 AQP4-Ab-negative NMO patients. The results revealed associations between AQP4-Ab seropositivity and visual impairment in NMO (OR, 3.16; 95% CI, 1.09, 9.19; P = 0.03). The results of subgroup analyses based on different methods of AQP-4 detection also showed significantly differences between AQP4-Ab seropositivity and visual impairment in NMO, especially in CBA subgroup. CONCLUSION: This meta-analysis indicates that AQP4-Ab serostatus has the positive with poor visual outcome in NMO.


Assuntos
Aquaporina 4/sangue , Autoanticorpos/sangue , Imunoglobulina G/sangue , Neuromielite Óptica/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Aquaporina 4/antagonistas & inibidores , Aquaporina 4/genética , Aquaporina 4/imunologia , Biomarcadores/sangue , Estudos de Coortes , Feminino , Expressão Gênica/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Neuromielite Óptica/sangue , Neuromielite Óptica/imunologia , Neuromielite Óptica/patologia , Índice de Gravidade de Doença
15.
Front Mol Neurosci ; 9: 152, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-28066178

RESUMO

Although the precise mechanism underlying initial lesion development in multiple sclerosis (MS) remains unclear, CNS inflammation has long been associated with demyelination, and axonal degeneration. The activation of microglia/macrophages, which serve as innate immune cells in the CNS, is the first reaction to even minor pathologic changes in the CNS and is considered an initial pathogenic event in MS. Microglial activation accompanies a variety of gene expressions, including cystatin F (Cys F), which belongs to the cystatin superfamily and is one of the cathepsin inhibitors. In our previous study we showed that Cys F has a unique expression pattern in microglia/macrophages in the demyelination process. Specifically, the timing of Cys F induction correlated with ongoing demyelination, and the sites of Cys F expression overlapped with areas of remyelination. Cys F induction ceased in chronic demyelination when remyelination capacity was lost, suggesting that Cys F expressed by microglia/macrophages may play an important role in demyelination and/or remyelination. The functional role of Cys F in demyelinating disease of the CNS, however, is unclear. Cys F gene knockout mice were used in the current study to clarify the functional role of Cys F in the demyelination process in a cuprizone-induced demyelination animal model. We demonstrated that absence of the Cys F gene and the resulting disinhibition of cathepsin C (Cat C) aggravates the demyelination, and this finding may be related to the increased expression of the glia-derived chemokine, CXCL2, which may attract inflammatory cells to sites of myelin sheath damage. This effect was reversed by knock down of the Cat C gene. The findings gain further insight to function of Cat C in pathophysiology of MS, which may have implications for therapeutics for the prevention of neuroinflammation-involved neurological disorders in the future.

16.
J Neuroinflammation ; 12: 54, 2015 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-25889123

RESUMO

BACKGROUND: Neuroinflammation is a hallmark that leads to selective neuronal loss and/or dysfunction in neurodegenerative disorders. Microglia-derived lysosomal cathepsins are increasingly recognized as important inflammatory mediators to trigger signaling pathways that aggravate neuroinflammation. However, cathepsin H (Cat H), a cysteine protease, has been far less studied in neuroinflammation, compared to cathepsins B, D, L, and S. The expression patterns and functional roles of Cat H in the brain in neuroinflammation remain unknown. METHODS: C57BL/6J mice were intraperitoneally injected with either 0.9% saline or lipopolysaccharide (LPS, 5 mg/kg). Immunohistochemistry (IHC) and in situ hybridization (ISH) were used to analyze expression and localization of Cat H in the brain. Nitrite assay was used to examine microglial activation in vitro; ELISA was used to determine the release of Cat H and proinflammatory cytokines (TNF-α, IL-1ß, IL-6, IFN-γ). Cat H activity was analyzed by cellular Cat H assay kit. Flow cytometry and in situ cell death detection were used to investigate neuronal death. Data were evaluated for statistical significance with one-way ANOVA and t test. RESULTS: Cat H mRNA was only present in perivascular microglia and non-parenchymal sites under normal conditions. After LPS injection, Cat H mRNA expression in activated microglia in different brain regions was increased. Twenty-four hours after LPS injection, Cat H mRNA expression was maximal in SNr; 72 h later, it peaked in cerebral cortex and hippocampus then decreased and maintained at a low level. The expression of Cat H protein exhibited the similar alterations after LPS injection. In vitro, inflammatory stimulation (LPS, TNF-α, IL-1ß, IL-6, and IFN-γ) increased the release and activity of Cat H in microglia. Conversely, addition of Cat H to microglia promoted the production and release of NO, IL-1ß, and IFN-γ which could be prevented by neutralizing antibody. Further, addition of Cat H to Neuro2a cells induced neuronal death. CONCLUSIONS: Taken together, these data indicate that the up-regulated microglial Cat H expression, release, and activity in the brain lead to neuronal death in neuroinflammation. The functional link of Cat H with microglial activation might contribute to the initiation and maintenance of microglia-driven chronic neuroinflammation.


Assuntos
Encéfalo/metabolismo , Catepsina H/metabolismo , Encefalite , Lipopolissacarídeos/toxicidade , Microglia/metabolismo , Regulação para Cima/efeitos dos fármacos , Análise de Variância , Animais , Anticorpos/uso terapêutico , Catepsina H/genética , Morte Celular/efeitos dos fármacos , Células Cultivadas , Citocinas/imunologia , Citocinas/metabolismo , Citocinas/farmacologia , Relação Dose-Resposta a Droga , Encefalite/induzido quimicamente , Encefalite/metabolismo , Encefalite/patologia , Citometria de Fluxo , Marcação In Situ das Extremidades Cortadas , Camundongos , Camundongos Endogâmicos C57BL , Microglia/efeitos dos fármacos , Nitritos , Fosfopiruvato Hidratase/metabolismo , Fatores de Tempo
17.
Eur Spine J ; 23(7): 1531-40, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24801575

RESUMO

PURPOSE: Dural tear is one of the common complications of spinal surgery leading to cerebrospinal fluid leakage followed by serial secondary symptoms. However, little is known about pathological changes of the spinal cord after dural tear. In the present study, we aimed to study the pathological changes in the spinal cord after dural tear with and without autologous fascia repair. METHODS: Sixty Sprague-Dawley rats were used for dural tear and autologous fascia graft repair models. Three days and 1 week after surgery, the pathological changes in the spinal cord were analyzed by immunohistochemistry, Western blot, enzyme-linked immunosorbent assay and spinal somatosensory evoked potentials test. RESULTS: Neuroinflammation was found in the parenchyma of the spinal cord characterized by gliosis, increased expression of inflammatory factors and infiltration of exogenesis immunocells in the rats without repair, which impaired the sensory conduction function of the spinal cord at the early stage of injury. Repairing with autologous fascia could attenuate neuroinflammation and help to maintain normal sensory conduction function of the spinal cord. CONCLUSION: Dural tear could cause a series of inflammatory reactions in the spinal cord and further impair its sensory conduction function at the early stage of injury. Repairing with autologous fascia was a necessary and effective way to prevent the neuroinflammation and to maintain the normal function of the spinal cord.


Assuntos
Dura-Máter/lesões , Fáscia/transplante , Medula Espinal/patologia , Animais , Astrócitos/metabolismo , Western Blotting , Dura-Máter/cirurgia , Ensaio de Imunoadsorção Enzimática , Feminino , Proteína Glial Fibrilar Ácida , Gliose/patologia , Imuno-Histoquímica , Inflamação/patologia , Interleucina-1beta/metabolismo , Microglia/patologia , Proteínas do Tecido Nervoso/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Distribuição Aleatória , Ratos Sprague-Dawley , Medula Espinal/metabolismo , Transplante Autólogo
18.
J Neuroinflammation ; 9: 96, 2012 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-22607609

RESUMO

BACKGROUND: Cathepsin C (Cat C) functions as a central coordinator for activation of many serine proteases in inflammatory cells. It has been recognized that Cat C is responsible for neutrophil recruitment and production of chemokines and cytokines in many inflammatory diseases. However, Cat C expression and its functional role in the brain under normal conditions or in neuroinflammatory processes remain unclear. Our previous study showed that Cat C promoted the progress of brain demyelination in cuprizone-treated mice. The present study further investigated the Cat C expression and activity in lipopolysaccharide (LPS)-induced neuroinflammation in vivo and in vitro. METHODS: C57BL/6 J mice were intraperitoneally injected with either 0.9% saline or lipopolysaccharide (LPS, 5 mg/kg). Immunohistochemistry (IHC) and in situ hybridization (ISH) were used to analyze microglial activation, TNF-α, IL-1ß, IL-6, iNOS mRNAs expressions and cellular localization of Cat C in the brain. Nitrite assay was used to examine microglial activation in vitro; RT-PCR and ELISA were used to determine the expression and release of Cat C. Cat C activity was analyzed by cellular Cat C assay kit. Data were evaluated for statistical significance with paired t test. RESULTS: Cat C was predominantly expressed in hippocampal CA2 neurons in C57BL/6 J mice under normal conditions. Six hours after LPS injection, Cat C expression was detected in cerebral cortical neurons; whereas, twenty-four hours later, Cat C expression was captured in activated microglial cells throughout the entire brain. The duration of induced Cat C expression in neurons and in microglial cells was ten days and three days, respectively. In vitro, LPS, IL-1ß and IL-6 treatments increased microglial Cat C expression in a dose-dependent manner and upregulated Cat C secretion and its activity. CONCLUSIONS: Taken together, these data indicate that LPS and proinflammatory cytokines IL-1ß, IL-6 induce the expression, release and upregulate enzymatic activity of Cat C in microglial cells. Further investigation is required to determine the functional role of Cat C in the progression of neuroinflammation, which may have implications for therapeutics for the prevention of neuroinflammation-involved neurological disorders in the future.


Assuntos
Catepsina C/biossíntese , Regulação Enzimológica da Expressão Gênica , Inflamação/enzimologia , Inflamação/patologia , Lipopolissacarídeos/toxicidade , Microglia/metabolismo , Regulação para Cima/fisiologia , Animais , Encéfalo/irrigação sanguínea , Encéfalo/enzimologia , Encéfalo/patologia , Catepsina C/genética , Catepsina C/metabolismo , Células Cultivadas , Progressão da Doença , Ativação Enzimática/genética , Ativação Enzimática/fisiologia , Inflamação/induzido quimicamente , Lipopolissacarídeos/administração & dosagem , Camundongos , Camundongos Endogâmicos C57BL , Microglia/patologia , Neurônios/metabolismo , Neurônios/patologia , Regulação para Cima/genética
19.
J Neurosci Res ; 89(5): 639-49, 2011 May.
Artigo em Inglês | MEDLINE | ID: mdl-21344476

RESUMO

Demyelination coincides with numerous changes of gene expression in the central nervous system (CNS). Cystatin F, which is a papain-like lysosomal cysteine proteinase inhibitor that is normally expressed by immune cells and not in the brain, is massively induced in the CNS during acute demyelination. We found that microglia, which are monocyte/macrophage-lineage cells in the CNS, express cystatin F only during demyelination. By using several demyelinating animal models and the spinal cord tissues from multiple sclerosis (MS) patients, we examined spatiotemporal expression pattern of cystatin F by in situ hybridization and immunohistochemistry. We found that the timing of cystatin F induction matches with ongoing demyelination, and the places with cystatin F expression overlapped with the remyelinating area. Most interestingly, cystatin F induction ceased in chronic demyelination, in which remyelinating ability was lost. These findings demonstrate that the expression of cystatin F indicates the occurrence of ongoing demyelination/remyelination and the absence of cystatin F expression indicates the cessation of remyelination in the demyelinating area.


Assuntos
Cistatinas/biossíntese , Doenças Autoimunes Desmielinizantes do Sistema Nervoso Central/metabolismo , Microglia/metabolismo , Fibras Nervosas Mielinizadas/metabolismo , Animais , Biomarcadores Tumorais/biossíntese , Biomarcadores Tumorais/deficiência , Biomarcadores Tumorais/metabolismo , Células Cultivadas , Doença Crônica , Cistatinas/deficiência , Cistatinas/metabolismo , Doenças Autoimunes Desmielinizantes do Sistema Nervoso Central/genética , Doenças Autoimunes Desmielinizantes do Sistema Nervoso Central/patologia , Modelos Animais de Doenças , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Camundongos Knockout , Camundongos Mutantes Neurológicos , Camundongos Transgênicos , Microglia/patologia , Fibras Nervosas Mielinizadas/patologia , Regeneração Nervosa/genética , Recuperação de Função Fisiológica/genética
20.
J Neurosci ; 29(26): 8363-71, 2009 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-19571127

RESUMO

Conduction velocity (CV) of myelinated axons has been shown to be regulated by oligodendrocytes even after myelination has been completed. However, how myelinating oligodendrocytes regulate CV, and what the significance of this regulation is for normal brain function remain unknown. To address these questions, we analyzed a transgenic mouse line harboring extra copies of the myelin proteolipid protein 1 (plp1) gene (plp1(tg/-) mice) at 2 months of age. At this stage, the plp1(tg/-) mice have an unaffected myelin structure with a normally appearing ion channel distribution, but the CV in all axonal tracts tested in the CNS is greatly reduced. We also found decreased axonal diameters and slightly abnormal paranodal structures, both of which can be a cause for the reduced CV. Interestingly the plp1(tg/-) mice showed altered anxiety-like behaviors, reduced prepulse inhibitions, spatial learning deficits and working memory deficit, all of which are schizophrenia-related behaviors. Our results implicate that abnormalities in the neuron-glia interactions at the paranodal junctions can result in reduced CV in the CNS, which then induces behavioral abnormalities related to schizophrenia.


Assuntos
Sistema Nervoso Central/patologia , Transtornos Cognitivos , Regulação da Expressão Gênica , Proteína Proteolipídica de Mielina/genética , Fibras Nervosas Mielinizadas/fisiologia , Condução Nervosa/genética , Adaptação Psicológica/fisiologia , Análise de Variância , Animais , Axônios/patologia , Axônios/fisiologia , Axônios/ultraestrutura , Sistema Nervoso Central/metabolismo , Sistema Nervoso Central/ultraestrutura , Transtornos Cognitivos/genética , Transtornos Cognitivos/patologia , Transtornos Cognitivos/fisiopatologia , Comportamento Exploratório/fisiologia , Força da Mão/fisiologia , Canal de Potássio Kv1.2/metabolismo , Aprendizagem em Labirinto/fisiologia , Camundongos , Camundongos Endogâmicos , Camundongos Transgênicos , Microscopia Eletrônica de Transmissão , Fibras Nervosas Mielinizadas/patologia , Fibras Nervosas Mielinizadas/ultraestrutura , Neuroglia/fisiologia , Neurônios/patologia , Testes Neuropsicológicos , Limiar da Dor/fisiologia , Desempenho Psicomotor/fisiologia , Nós Neurofibrosos/patologia , Nós Neurofibrosos/ultraestrutura , Reflexo de Sobressalto/genética , Natação/fisiologia
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