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1.
Environ Health Prev Med ; 26(1): 8, 2021 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-33451279

RESUMO

BACKGROUND: Prenatal stress can cause neurobiological and behavioral defects in offspring; environmental factors play a crucial role in regulating the development of brain and behavioral; this study was designed to test and verify whether an enriched environment can repair learning and memory impairment in offspring rats induced by prenatal stress and to explore its mechanism involving the expression of insulin-like growth factor-2 (IGF-2) and activity-regulated cytoskeletal-associated protein (Arc) in the hippocampus of the offspring. METHODS: Rats were selected to establish a chronic unpredictable mild stress (CUMS) model during pregnancy. Offspring were weaned on 21st day and housed under either standard or an enriched environment. The learning and memory ability were tested using Morris water maze and Y-maze. The expression of IGF-2 and Arc mRNA and protein were respectively measured by using RT-PCR and Western blotting. RESULTS: There was an elevation in the plasma corticosterone level of rat model of maternal chronic stress during pregnancy. Maternal stress's offspring exposed to an enriched environment could decrease their plasma corticosterone level and improve their weight. The offspring of maternal stress during pregnancy exhibited abnormalities in Morris water maze and Y-maze, which were improved in an enriched environment. The expression of IGF-2, Arc mRNA, and protein in offspring of maternal stress during pregnancy was boosted and some relationships existed between these parameters after being exposed enriched environment. CONCLUSIONS: The learning and memory impairment in offspring of prenatal stress can be rectified by the enriched environment, the mechanism of which is related to the decreasing plasma corticosterone and increasing hippocampal IGF-2 and Arc of offspring rats following maternal chronic stress during pregnancy.


Assuntos
Proteínas do Citoesqueleto/genética , Regulação da Expressão Gênica , Fator de Crescimento Insulin-Like II/genética , Deficiências da Aprendizagem/genética , Transtornos da Memória/genética , Proteínas do Tecido Nervoso/genética , Efeitos Tardios da Exposição Pré-Natal/genética , Meio Social , Estresse Psicológico/genética , Animais , Proteínas do Citoesqueleto/metabolismo , Feminino , Hipocampo/metabolismo , Fator de Crescimento Insulin-Like II/metabolismo , Aprendizagem , Deficiências da Aprendizagem/psicologia , Masculino , Transtornos da Memória/psicologia , Proteínas do Tecido Nervoso/metabolismo , Gravidez , Efeitos Tardios da Exposição Pré-Natal/psicologia , Distribuição Aleatória , Ratos , Ratos Wistar
2.
J Proteome Res ; 20(2): 1371-1381, 2021 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-33356298

RESUMO

This study aims to identify biomarkers for evaluating the therapeutic efficacy of mesalazine on ulcerative colitis by metabolomics and lipidomics. A dextran sulfate sodium-induced mouse model was used. The disease status was assessed by a disease activity index, the TNF-α level of colon was measured by an enzyme-linked immunosorbent assay, and the pathological changes of colon tissue was examined by hematoxylin-eosin staining. Serum metabolomics and lipidomics analysis based on ultraperformance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry were applied to decipher the metabolic profile changes. Multivariate analysis was applied to differentiate the metabolites of controls, models, and mesalazine-treated mice. By the receiver operating characteristic (ROC) analysis, 40 differential metabolites with an area under curve (AUC) >0.80 were screened out between control and model groups. Among them, four potential biomarkers (palmitoyl glucuronide, isobutyrylglycine, PC (20:3 (5Z, 8Z, 11Z)/15:0) and L-arginine) had a signficantly reversed level of peak areas in the mesalazine group, and three of them were closely correlated with mesalazine efficacy by linear regression analysis. Furthermore, metabolic pathway analysis revealed several dysregulated pathways in colitis mice, including glycerophospholipid metabolism, pyrimidine metabolism, linoleic acid metabolism, arginine biosynthesis, etc. This study indicates that serum metabolomics is a useful approach that can noninvasively evaluate the therapeutic effect and provide unique insights into the underlying mechanism of mesalazine.

3.
Exp Ther Med ; 20(6): 221, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33193836

RESUMO

Rupture of abdominal aortic aneurysm (AAA) is a devastating event that can be prevented by inhibiting the growth of small aneurysms. Therapeutic strategies targeting certain events that promote the development of AAA must be developed, in order to alter the course of AAA. Chronic inflammation of the aortic mural is a major characteristic of AAA and is related to AAA formation, development and rupture. Daphnetin (DAP) is a coumarin derivative with anti-inflammatory properties that is extracted from Daphne odora var. However, the effect of DAP on AAA development remains unclear. The present study investigated the effect of DAP on the formation and development of experimental AAAs and its potential underlying mechanisms. A mice AAA model was established by intra-aortic infusion of porcine pancreatic elastase (PPE), and mice were intraperitoneally injected with DAP immediately after PPE infusion. The maximum diameter of the abdominal aorta was measured by ultrasound system, and aortic mural changes were investigated by Elastica van Gieson (EVG) staining and immunohistochemical staining. The results demonstrated that DAP significantly suppressed PPE-induced AAA formation and attenuated the depletion of aortic medial elastin and smooth muscle cells in the media of the aorta. Furthermore, the density of mural macrophages, T cells and B cells were significantly attenuated in DAP-treated AAA mice. In addition, treatment with DAP resulted in a significant reduction in mural neovessels. These findings indicated that DAP may limit the formation and progression of experimental aneurysms by inhibiting mural inflammation and angiogenesis. These data confirmed the translational potential of DAP inclinical AAA inhibition strategies.

4.
J Proteome Res ; 19(2): 600-609, 2020 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-31821004

RESUMO

Identification of new biomarkers may help in the early diagnosis of inflammatory bowel disease (IBD). In this study, ultrahigh-performance liquid chromatography equipped with quadrupole time-of-flight mass spectrometry (UPLC-QTOF-MS) was used to analyze the untargeted lipidomics and compare plasma lipid profiles between IBD patients and control subjects. The principal component analysis and partial least-squares-discriminant analysis were carried out to distinguish IBD patients from control subjects. Using univariate and multivariate analysis, 55 significantly different metabolites from five lipid classes, fatty acyls (n = 19), glycerophospholipids (n = 5), prenol lipids (n = 10), sphingolipids (n = 2), and sterol lipids (n = 19) were identified. Forty-four of the 55 metabolites were analyzed by receiver operating characteristic (ROC) curve and area under curve (AUC) of >0.80. After validation in an independent cohort, IBD patients were differentiated from the control subjects by significantly altered plasma level of palmitic acid, 7alpha, 25-dihydroxycholesterol, 20-hydroxyeicosatetraenoic (HETE)-d6, (+/-)5,6-epoxy-eicosatrienoic acid (EpETrE), docosahexaenoic acid (DHA), 9-heptadecylenic acid, lactucaxanthin, α-carotene, traumatic acid, and neoquassin with both sensitivity and specificity above 80%. Pathway analysis suggested that IBD dysregulation was related to the biosynthesis of primary bile acid, the metabolism of arachidonic acid, the metabolism of sphingolipid, fatty acid elongation, and glycerophospholipid metabolism. Our results suggest that the lipidomic profiling of patients plasma could be a potential method for IBD diagnosis.

5.
Front Oncol ; 9: 545, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31293977

RESUMO

Hepatocellular carcinoma (HCC) is the fourth largest cause of cancer-related deaths worldwide with limited therapeutic interventions. Renewed interest in natural products as drug leads has resulted in a paradigm shift toward the rapid screening of medicinal plants for the discovery of new chemical entities. Rotundic acid (RA), a plant-derived triterpenoid, has been anecdotally reported to possess anti-inflammatory and cardio-protective abilities. The present study highlights the anti-cancer efficacy of RA on HCC in vitro and in vivo. The inhibitory effects of RA on HCC cell viability was determined by MTT. Soft agar colony formation and clonogenic assays also showed that RA inhibited HCC cell proliferation. Flow cytometry, confocal, and western blot results further indicated that RA induced cell cycle arrest, DNA damage, and apoptosis by modulating the AKT/mTOR and MAPK pathways. Besides the suppression of migration and invasion, tube formation and VEGF-ELISA revealed the anti-angiogenic abilities of RA on HCC. Moreover, RA also inhibited tumor growth in a HepG2 xenograft mouse model. To our best knowledge, this is the first extensive study of the anticancer activity of RA on HCC. The results demonstrate that RA could be a potential drug candidate for HCC treatment.

6.
Biomed Chromatogr ; 33(9): e4568, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31042300

RESUMO

Febuxostat is a novel nonpurine type of highly selective xanthine oxidoreductase inhibitor. A rapid and sensitive ultra-high-performance liquid chromatography-quadrupole time-of-flight mass spectrometry method for simultaneous separation and determination of febuxostat and its metabolites in rat serum and urine was developed at various time points after oral administration to the rats. The febuxostat metabolites were predicted by biotransformation software and transformed to a personal compound database to quickly determine the possible metabolites from the MS1 data. The possibility of the MS/MS fragmentation was calculated by the Molecular Structure Correlator software. As a result, five phase I and two phase II metabolites in rat serum, and seven phase I and three phase II metabolites in rat urine were identified, of which four metabolites (M2, M5, M6, M7) have not been reported before. The metabolite toxicities are predicted, and the results are helpful for the design of new xanthine oxidoreductase inhibitors.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Febuxostat , Espectrometria de Massas em Tandem/métodos , Animais , Febuxostat/sangue , Febuxostat/química , Febuxostat/metabolismo , Febuxostat/urina , Masculino , Ratos , Ratos Sprague-Dawley
7.
J Sep Sci ; 41(24): 4469-4479, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30354005

RESUMO

Vortioxetine is a multimodal antidepressant that has been recently utilized globally. Vortioxetine hemi-hydrochloride is a novel salt that was previously reported in our research. However, the pharmacokinetics of this salt and the metabolites of Vortioxetine in vivo remain unknown. In this study, the pharmacokinetics of the Vortioxetine hemi-hydrochloride salt is explored in rats through a newly developed ultra-performance liquid chromatography with tandem mass spectrometry method. In addition, ultra-performance liquid chromatography coupled with quadrupole time of flight mass spectrometry was used to identify the metabolites of Vortioxetine in vivo. The results demonstrate that after a single, 3 mg/kg oral dose, the maximum concentration for the Vortioxetine hemi-hydrochloride salt is 14.63 ± 4.00 ng/mL, and is attained in 1.00∼4.00 h. The area under the plasma concentration-time curve from time 0 to 24 h is 67.30 ± 23.78 ng·h·mL-1 . Additionally, 29 metabolites were identified after the oral administration of 10 mg/kg, including 17 metabolites in the plasma, nine in the urine, and 12 in the feces. Eleven metabolites were novel. The major metabolic pathways include methylation, hydroxylation, oxidation, and glucuronidation. In conclusion, this study provides insight for further development of the Vortioxetine hemi-hydrochloride salt.


Assuntos
Vortioxetina/metabolismo , Vortioxetina/farmacocinética , Animais , Cromatografia Líquida de Alta Pressão , Masculino , Ratos , Ratos Sprague-Dawley , Espectrometria de Massas em Tandem , Vortioxetina/análise
8.
Dig Dis Sci ; 63(12): 3307-3316, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30206757

RESUMO

BACKGROUND: To date, mechanisms of intestinal immunoglobulin (Ig) dysfunction following intestinal ischemia/reperfusion (I/R) remain unclear. Programmed death 1 (PD-1) is associated with immune responses of lymphocytes. AIM: We aimed to verify the hypothesis that activation of PD-1 may improve intestinal immune dysfunction by regulating IL-10/miR-155 production after intestinal IR injury. METHODS: Intestinal I/R injury was induced in mice by clamping the superior mesenteric artery for 1 h followed by 2-h reperfusion. PD-L1 fusion Ig, anti-interleukin (IL)-10 monoclonal antibody (mAb), and microRNA (miR)-155 agomir were administered. PD-1 expression, IL-10 mRNA, and protein expression in Peyer's patches (PP) CD4+ cells were measured. MiR-155 levels, tumor necrosis factor (TNF)-α and IL-1ß concentration, and activation-induced cytidine deaminase (AID), a key enzyme for intestinal immune antibodies, in PP tissues were measured, respectively. Importantly, the production and cecal bacteria-binding capacity of IgA and IgM were detected. RESULTS: Intestinal I/R led to decreased PD-1 expression, imbalanced production, and impaired bacteria-binding capacity of IgA and IgM. Activating PD-1 by PD-L1 Ig facilitated IL-10 synthesis, then decreased miR-155 levels, and subsequently promoted AID expression and reduced TNF-α, IL-1ß concentration. Upregulation of AID improved the disruptions of intestinal immune barrier caused by IgA and IgM dysfunction. Anti-IL-10 mAb and miR-155 agomir abolished the protective effects of PD-L1 Ig on the intestinal immune defense. CONCLUSION: Activation of PD-1 with PD-L1 Ig relieves intestinal immune defensive injury through IL-10/miR-155 pathway following intestinal I/R attack. PD-1, IL-10, and miR-155 may be potential targets for the damages of intestinal barrier and immunity.


Assuntos
Interleucina-10/metabolismo , Mucosa Intestinal/metabolismo , MicroRNAs/metabolismo , Receptor de Morte Celular Programada 1/metabolismo , Traumatismo por Reperfusão/metabolismo , Transdução de Sinais/fisiologia , Animais , Interleucina-10/imunologia , Mucosa Intestinal/imunologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , MicroRNAs/imunologia , Receptor de Morte Celular Programada 1/imunologia , Distribuição Aleatória , Traumatismo por Reperfusão/imunologia , Traumatismo por Reperfusão/prevenção & controle
9.
Virology ; 522: 260-270, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30055516

RESUMO

The foot-and-mouth disease virus capsid precursor, P1-2A, is cleaved by the 3C protease (3Cpro) to VP0, VP3, VP1 and 2A. The P1-2A precursor (wt or mutant) was expressed alone or with 3Cpro and processing of P1-2A was determined. The VP2 K217R and VP3 I2P substitutions (near the VP0/VP3 junction) strongly reduced the processing at this junction by 3Cpro while the substitution VP2 K217E blocked cleavage. At the VP3/VP1 junction, the substitutions VP3 Q2221P and VP1 T1P each severely inhibited processing at this site. Blocking cleavage at either junction did not prevent processing elsewhere in P1-2A. These modifications were also introduced into full-length FMDV RNA; only wt and the VP2 K217R mutant were viable. Uncleaved VP0-VP3 and the processed products were observed within cells infected with the mutant virus. The VP0-VP3 was not incorporated into empty capsids or virus particles. The three junctions within P1-2A are processed by 3Cpro independently.


Assuntos
Proteínas do Capsídeo/metabolismo , Cisteína Endopeptidases/metabolismo , Vírus da Febre Aftosa/enzimologia , Vírus da Febre Aftosa/fisiologia , Precursores de Proteínas/metabolismo , Processamento de Proteína Pós-Traducional , Proteínas Virais/metabolismo , Animais , Proteólise
10.
Biomed Res Int ; 2018: 6216853, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29955606

RESUMO

Hepacivirus has been identified in cattle in Africa, Europe, and South America. In this survey of bovine hepacivirus (BovHepV) in 131 serum samples from Chinese cattle herds using RT-PCR, five of 131 sera were BovHepV positive, with the infection rate of 3.82%. Phylogenetic analysis based on the partial NS3 coding sequence showed that the BovHepV of the five positive samples clustered with other BovHepV but formed a separate branch. The results indicated that these new BovHepV represent emerging and novel strains. Further investigations are necessary to determine the epidemiology and viral pathogenesis of these BovHepV strains, as well as the potential threat to ruminant and livestock workers in China.


Assuntos
Hepacivirus , Hepatite C , Filogenia , Animais , Bovinos , China , Hepacivirus/isolamento & purificação , Hepacivirus/patogenicidade , Hepatite C/diagnóstico , Hepatite C/epidemiologia , Humanos
11.
Artigo em Inglês | MEDLINE | ID: mdl-29445338

RESUMO

It has been generally accepted that pain can cause imbalance between excitation and inhibition (homeostasis) at the synaptic level. However, it remains poorly understood how this imbalance (allostasis) develops in the CNS under different pain conditions. Here, we analyzed the changes in both excitatory and inhibitory synaptic transmission and modulation of the dentate gyrus (DG) under two pain conditions with different etiology and duration. First, it was revealed that the functions of the input-output (I/O) curves for evoked excitatory postsynaptic currents (eEPSCs) following the perforant path (PP) stimulation were gained under both acute inflammatory and chronic neuropathic pain conditions relative to the controls. However, the functions of I/O curves for the PP-evoked inhibitory postsynaptic currents (eIPSCs) differed between the two conditions, namely it was greatly gained under inflammatory condition, but was reduced under neuropathic condition in reverse. Second, both the frequency and amplitude of miniature IPSCs (mIPSCs) were increased under inflammatory condition, however a decrease in frequency of mIPSCs was observed under neuropathic condition. Finally, the spike discharge of the DG granule cells in response to current injection was significantly increased by neuropathic pain condition, however, no different change was found between inflammatory pain condition and the control. These results provide another line of evidence showing homeostatic and allostatic modulation of excitatory synaptic transmission by inhibitory controls under different pathological pain conditions, hence implicating use of different therapeutic approaches to maintain the homeostasis between excitation and inhibition while treating different conditions of pathological pain.

12.
Environ Toxicol ; 33(1): 104-111, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29087020

RESUMO

Dibutyltin (DBT) is the degradation products of TBT, which is generally considered higher toxicity than TBT in the immune system. In order to learn more about the mechanisms of immune-toxic of DBT, we exposed zebrafish (Danio rerio) to 0, 1, 10 and 100 ng/L DBT for 8 weeks. At the end of the experiment, we determined the immune parameters and immune-related genes. The results showed that with an increase in TBT dose, lysozyme activities and IgM, C3, C4 content in intestine, skin and spleen were all significantly inhibited by the DBT exposure. Fish exposed to 10 ng/L and 100 ng/L showed significantly lower lysozyme activities and IgM, C3, C4 content than those of the control group. Zebrafish exposed to 10 ng/L and 100 ng/L DBT, the mRNA transcript levels of interleukin-1ß (IL-1ß), interleukin-6 (IL-6), interleukin-8 (IL-8), tumor necrosis factor-α (TNF-α), interferon γ2 (INFγ2), nuclear factor-κB p65 (NF-kB p65), inhibitor protein-κBα (IκBα), IκB kinases ß (IKKß), Janus family of protein tyrosine kinases (JAKs) and the signal transducers and activators of transcription proteins (STATs) all increased with the DBT levels in the intestine and spleen. Those parameters showed significantly higher values in 10 ng/L and 100 ng/L than those of fish in the control group. However, no significant difference was found in IκB kinases α (IKKα) and IκB kinase γ (IKKγ) mRNA levels in the intestine and spleen. These data imply that DBT might be via suppression on IKKß/IkBa/NF-kBp65 and JAK/STAT signaling pathways to regulate the immunity of zebrafish.


Assuntos
Compostos Orgânicos de Estanho/toxicidade , Transdução de Sinais/efeitos dos fármacos , Peixe-Zebra/metabolismo , Animais , Quinase I-kappa B/genética , Quinase I-kappa B/metabolismo , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Interleucina-8/genética , Interleucina-8/metabolismo , Mucosa Intestinal/metabolismo , Intestinos/efeitos dos fármacos , Intestinos/imunologia , Janus Quinase 2/genética , Janus Quinase 2/metabolismo , Inibidor de NF-kappaB alfa/genética , Inibidor de NF-kappaB alfa/metabolismo , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo , Pele/efeitos dos fármacos , Pele/imunologia , Pele/metabolismo , Baço/efeitos dos fármacos , Baço/imunologia , Baço/metabolismo , Fator de Transcrição RelA/genética , Fator de Transcrição RelA/metabolismo , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo , Peixe-Zebra/imunologia
13.
J Neurooncol ; 136(2): 243-254, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29116484

RESUMO

Methionine aminopeptidases (MetAPs) have been pharmacologically linked to cell growth, angiogenesis, and tumor progression, which make it an attractive target for cancer therapy. We investigated MetAP2's biological role in glioblastoma (GBM), an aggressive tumor characterized by massive neovascularization. We examined the effect of anti-MetAP2 RNA interference on proliferation and angiogenesis in GBM cell line. The biological effects of MetAP2 knockdown were assessed by comparing the proliferation, tumorigenecity, and angiogenesis of parental cells and MetAP2 knockdown cells. We generated MetAP2 knockdown cells using lentiviral short hairpin RNAs against MetAP2 in SNB19 GBM cells, which normally express high levels of MetAP2. MetAP2 knockdown cells were less proliferative and less tumorigenic when compared to the parental cells. MetAP2 knockdown decreased vascular endothelial growth factor (VEGF) secretion and expression at the mRNA and protein levels. Decreased VEGF expression in MetAP2 knockdown cells correlated very well with decreased vessel formation in a tube formation assay. We showed that VEGF suppression in MetAP2 knockdown cells was mediated by the von Hippel-Lindau protein. In in vivo animal studies using an intracranial SNB19 tumor model, MetAP2 knockdown also reduced the tumor growth rate and angiogenesis, which in turn prolonged the survival of mice in xenograft model. Our results show that MetAP2 regulates angiogenesis in GBM and identify MetAP2-specific substrates that may serve as candidates for clinical assay development.


Assuntos
Aminopeptidases/metabolismo , Neoplasias Encefálicas/metabolismo , Glioblastoma/metabolismo , Glicoproteínas/metabolismo , Neovascularização Patológica/metabolismo , Aminopeptidases/genética , Animais , Neoplasias Encefálicas/complicações , Pontos de Checagem do Ciclo Celular , Linhagem Celular Tumoral , Sobrevivência Celular , Técnicas de Silenciamento de Genes , Glioblastoma/complicações , Glicoproteínas/genética , Humanos , Metionil Aminopeptidases , Camundongos Nus , Neovascularização Patológica/complicações , RNA Interferente Pequeno/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
14.
Dig Dis Sci ; 63(1): 81-91, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29063417

RESUMO

BACKGROUND: To date, mechanisms of sepsis-induced intestinal epithelial injury are not well known. P2X7 receptor (P2X7R) regulates pyroptosis of lymphocytes, and propofol is usually used for sedation in septic patients. AIMS: We aimed to determine the occurrence of enterocyte pyroptosis mediated by P2X7R and to explore the effects of propofol on pyroptosis and intestinal epithelial injury after lipopolysaccharide (LPS) challenge. METHODS: A novel regimen of LPS challenge was applied in vitro and in vivo. Inhibitors of P2X7R (A438079) and NLRP3 inflammasome (MCC950), and different doses of propofol were administered. The caspase-1 expression, caspase-3 expression, caspase-11 expression, P2X7R expression and NLRP3 expression, extracellular ATP concentration and YO-PRO-1 uptake, and cytotoxicity and HMGB1 concentration were detected to evaluate enterocyte pyroptosis in cultured cells and intestinal epithelial tissues. Chiu's score, diamine oxidase and villus length were used to evaluate intestinal epithelial injury. Moreover, survival analysis was performed. RESULTS: LPS challenge activated caspase-11 expression and P2X7R expression, enhanced ATP concentration and YO-PRO-1 uptake, and led to increased cytotoxicity and HMGB1 concentration. Subsequently, LPS resulted in intestinal epithelial damage, as evidenced by increased levels of Chiu's score and diamine oxidase, and shorter villus length and high mortality of animals. A438079, but not MCC950, significantly relieved LPS-induced enterocyte pyroptosis and intestinal epithelial injury. Importantly, propofol did not confer the protective effects on enterocyte pyroptosis and intestinal epithelia although it markedly decreased P2X7R expression. CONCLUSION: LPS attack leads to activation of caspase-11/P2X7R and pyroptosis of enterocytes. Propofol does not reduce LPS-induced pyroptosis and intestinal epithelial injury, although it inhibits P2X7R upregulation.


Assuntos
Enterócitos/efeitos dos fármacos , Mucosa Intestinal/efeitos dos fármacos , Lipopolissacarídeos/toxicidade , Propofol/farmacologia , Piroptose/efeitos dos fármacos , Animais , Linhagem Celular , Enterócitos/metabolismo , Hipnóticos e Sedativos/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Ratos , Organismos Livres de Patógenos Específicos
15.
Front Mol Neurosci ; 10: 226, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28785202

RESUMO

Central post-stroke pain (CPSP) is an intractable central neuropathic pain that has been poorly studied mechanistically. Here we showed that stromal cell-derived factor 1 (SDF1 or CXCL12), a member of the CXC chemokine family, and its receptor CXCR4 played a key role in the development and maintenance of thalamic hemorrhagic CPSP through hypoxia inducible factor 1α (HIF-1α) mediated microglial-astrocytic-neuronal interactions. First, both intra-thalamic collagenase (ITC) and SDF1 injections could induce CPSP that was blockable and reversible by intra-thalamic administration of both AMD3100 (a selective CXCR4 antagonist) and inhibitors of microglial or astrocytic activation. Second, long-term increased-expression of SDF1 and CXCR4 that was accompanied by activations of both microglia and astrocytes following ITC could be blocked by both AMD-3100 and YC-1, a selective inhibitor of HIF-1α. AMD-3100 could also inhibit release of proinflammatory mediators (TNFα, IL1ß and IL-6). Increased-expression of HIF-1α, SDF1, CXCR4, Iba1 and GFAP proteins could be induced by both ITC and intra-thalamic CoCl2, an inducer of HIF-1α that was blockable by both HIF-1α inhibition and CXCR4 antagonism. Finally, inhibition of HIF-1α was only effective in prevention, but not in treatment of ITC-induced CPSP. Taken together, the present study demonstrated that in the initial process of thalamic hemorrhagic state HIF-1α up-regulated SDF1-CXCR4 signaling, while in the late process SDF1-CXCR4 signaling-mediated positive feedback plays more important role in glial-glial and glial-neuronal interactions and might be a novel promising molecular target for treatment of CPSP in clinic.

16.
Fish Shellfish Immunol ; 68: 84-91, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28698125

RESUMO

The aim of the present study was to investigate effects of dietary Lactobacillus delbrueckii (L. delbrueckii) on immune response, disease resistance against Aeromonas hydrophila (A. hydrophila), antioxidant capability and growth performance of Cyprinus carpio Huanghe var. 450 fish (mean weight of 1.05 ± 0.03 g) were randomly distributed into five groups that fed diets containing different levels of L. delbrueckii (0, 1 × 105, 1 × 106, 1 × 107 and 1 × 108 CFU g-1) for 8 weeks. The results showed that intestinal immune parameters such as lysozyme, acid phosphatase, and myeloperoxidase activities, immunoglobulin M content, and the survival rate were improved in fish fed with 1 × 106 and 1 × 107 CFU g-1L. delbrueckii. In addition, 1 × 107 CFU g-1L. delbrueckii supplementation down-regulated mRNA levels of TNF-α, IL-8, IL-1ß and NF-κBp65, and up-regulated IL-10 and TGF-ß mRNA levels in the intestine. The survival rate was significantly (P < 0.05) higher (68.33%) in fish fed 1 × 106 CFU g-1L. delbrueckii than the control diet-fed group (40%) after challenge by A. hydrophila. Fish fed with diet containing 1 × 106 CFU g-1L. delbrueckii showed higher antioxidant enzyme activities such as superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPX), and total antioxidant capacity (T-AOC) and lower MDA concentrations than those of the control group (P < 0.05). The relative gene expression (SOD, CAT, GPX) showed the same trend with their activities. In addition, the growth performance was significantly improved in fish fed with the diet containing 1 × 106 and 1 × 107 CFU g-1L. delbrueckii (P < 0.05). These results demonstrated that dietary optimal levels of L. delbrueckii enhanced immunity, disease resistance against A. hydrophila antioxidant capability and growth performance in Cyprinus carpio Huanghe var.


Assuntos
Carpas , Suplementos Nutricionais , Resistência à Doença , Doenças dos Peixes/prevenção & controle , Infecções por Bactérias Gram-Negativas/veterinária , Imunidade Inata , Lactobacillus delbrueckii , Aeromonas hydrophila/fisiologia , Ração Animal/análise , Animais , Antioxidantes/metabolismo , Carpas/crescimento & desenvolvimento , Dieta/veterinária , Suplementos Nutricionais/análise , Doenças dos Peixes/imunologia , Doenças dos Peixes/microbiologia , Infecções por Bactérias Gram-Negativas/imunologia , Infecções por Bactérias Gram-Negativas/microbiologia , Infecções por Bactérias Gram-Negativas/prevenção & controle , Lactobacillus delbrueckii/química , Lactobacillus delbrueckii/imunologia , Distribuição Aleatória
17.
Pain Physician ; 20(5): E673-E685, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28727712

RESUMO

BACKGROUND: In a 5-year follow-up study in a hospital in southern China, it was shown that intervertebral foramen (IVF) injection of ozone at the involved segmental levels could significantly alleviate paroxysmal spontaneous pain and mechanical allodynia in patients with chronic, intractable postherpetic neuralgia (PHN) and improve the quality of life. However, so far no proof-of-concept studies in animals have been available. OBJECTIVE: This study was designed to investigate whether IVF ozone has an analgesic effect on animal models of neuropathic and inflammatory pain. STUDY DESIGN: Experimental trial in rats. SETTING: Institute for Biomedical Sciences of Pain. METHODS: By IVF injection, a volume of 50 µl containing 30 µg/mL ozone-oxygen mixture or 50 µl air was carried out on male Sprague-Dawley rats of naïve, inflammatory pain states produced by injections of either bee venom or complete Freud's adjuvant, and neuropathic pain state produced by spared nerve injury, respectively. The effects of IVF ozone on pain-related behaviors were evaluated for 2 weeks or one month. Then combined use of gabapentin (100 mg/1 kg body weight) with IVF ozone was evaluated in rats with neuropathic pain by intraperitoneal administration 5 days after the ozone treatment. Finally, the analgesic effects of another 4 drugs, AMD3100 (a CXCR4 antagonist), A-803467 (a selective Nav1.8 blocker), rapamycin (the mTOR inhibitor), and MGCD0103 (a selective histone deacetylase inhibitor) were evaluated for long term through IVF injection, respectively. RESULTS: (1) IVF injection of ozone at L4-5 was only effective in suppression of mechanical allodynia in rats with neuropathic pain but not with inflammatory pain; (2) the analgesic effects of IVF ozone lasted much longer (> 14 days) than other selective molecular target drugs (< 48 hours) inhibiting or antagonizing at Nav1.8 (A-803467), CXCR4 (AMD3100), mTOR (rapamycin), and histone deacetylase (MGCD0103); (3) combined use of systemic gabapentin and IVF ozone produced a synergistic analgesic effect in rats with neuropathic pain. LIMITATIONS: Evaluation of the possible analgesic effects of the intraplantar injection of ozone was not performed. CONCLUSIONS: In the present study, we provided a line of evidence for the first time that IVF injection of ozone selectively relieved neuropathic pain but not inflammatory pain, and enhanced the analgesic effect of gabapentin. KEY WORDS: Chronic pain, neuropathic pain, inflammatory pain, ozone therapy, interventional therapy, gabapentin, spared nerve injury, bee venom, complete Freud's adjuvant.


Assuntos
Aminas/farmacologia , Analgésicos/farmacologia , Ácidos Cicloexanocarboxílicos/farmacologia , Hiperalgesia/terapia , Neuralgia/terapia , Ozônio/uso terapêutico , Ácido gama-Aminobutírico/farmacologia , Aminas/administração & dosagem , Analgésicos/administração & dosagem , Animais , Ácidos Cicloexanocarboxílicos/administração & dosagem , Modelos Animais de Doenças , Seguimentos , Gabapentina , Hiperalgesia/tratamento farmacológico , Injeções Espinhais , Masculino , Neuralgia/tratamento farmacológico , Ratos , Ratos Sprague-Dawley , Ácido gama-Aminobutírico/administração & dosagem
18.
Ultrason Sonochem ; 38: 9-18, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28633861

RESUMO

This study investigated for the first time the feasibility of using a magnetic field for sludge disintegration. Approximately 41.01% disintegration degree (DD) was reached after 30min at 180mT magnetic field intensity upon separate magnetic field treatment. Protein and polysaccharide contents significantly increased. This test was optimized using a Box-Behnken design (BBD) with response surface methodology (RSM) to fit the multiple equation of the DD. The maximum DD was 43.75% and the protein and polysaccharide contents increased to 56.71 and 119.44mg/L, respectively, when the magnetic field strength was 119.69mT, reaction time was 30.49min, and pH was 9.82 in the optimization experiment. We then analyzed the effects of ultrasound alone. We are the first to combine magnetic field with ultrasound to disintegrate waste-activated sludge (WAS). The optimum effect was obtained with the application of ultrasound alone at 45kHz frequency, with a DD of about 58.09%. By contrast, 62.62% DD was reached in combined magnetic field and ultrasound treatment. This combined test was also optimized using BBD with RSM to fit the multiple equation of DD. The maximum DD of 64.59% was achieved when the magnetic field intensity was 197.87mT, ultrasonic frequency was 42.28kHz, reaction time was 33.96min, and pH was 8.90. These results were consistent with those of particle size and electron microscopy analyses. This research proved that a magnetic field can effectively disintegrate WAS and can be combined with other physical techniques such as ultrasound for optimal results.


Assuntos
Campos Magnéticos , Esgotos , Sonicação , Gerenciamento de Resíduos/métodos , Concentração de Íons de Hidrogênio , Fatores de Tempo
19.
J Gen Virol ; 98(4): 671-680, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28452293

RESUMO

Foot-and-mouth disease virus is a picornavirus and its RNA genome encodes a large polyprotein. The N-terminal part of this polyprotein is the leader protein, a cysteine protease, termed Lpro. The virus causes the rapid inhibition of host cell cap-dependent protein synthesis within infected cells. This results from the Lpro-dependent cleavage of the cellular translation initiation factor eIF4G. Lpro also releases itself from the virus capsid precursor by cleaving the L/P1 junction. Using site-directed mutagenesis of the Lpro coding sequence, we have investigated the role of 51 separate amino acid residues in the functions of this protein. These selected residues either are highly conserved or are charged and exposed on the protein surface. Using transient expression assays, within BHK-21 cells, it was found that residues around the active site (W52, L53 and A149) of Lpro and others located elsewhere (K38, K39, R44, H138 and W159) are involved in the induction of eIF4G cleavage but not in the processing of the L/P1 junction. Modified viruses, encoding such amino acid substitutions within Lpro, can replicate in BHK-21 cells but did not grow well in primary bovine thyroid cells. This study characterizes mutant viruses that are deficient in blocking host cell responses to infection (e.g. interferon induction) and can assist in the rational design of antiviral agents targeting this process and in the production of attenuated viruses.


Assuntos
Endopeptidases/metabolismo , Fator de Iniciação 4G em Eucariotos/metabolismo , Vírus da Febre Aftosa/enzimologia , Vírus da Febre Aftosa/fisiologia , Proteínas Mutantes/metabolismo , Proteólise , Animais , Bovinos , Células Cultivadas , Cricetinae , Análise Mutacional de DNA , Endopeptidases/genética , Vírus da Febre Aftosa/genética , Mutagênese Sítio-Dirigida , Proteínas Mutantes/genética
20.
Oxid Med Cell Longev ; 2016: 6190504, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27829984

RESUMO

The aim of this paper is to observe the change of mitochondrial aldehyde dehydrogenase 2 (ALDH2) when diabetes mellitus (DM) rat heart was subjected to ischemia/reperfusion (I/R) intervention and analyze its underlying mechanisms. DM rat hearts were subjected to 30 min regional ischemia and 120 min reperfusion in vitro and pretreated with ALDH2 activator ethanol (EtOH); cardiomyocyte in high glucose (HG) condition was pretreated with ALDH2 activator Alda-1. In control I/R group, myocardial tissue structure collapse appeared. Compared with control I/R group, left ventricular parameters, SOD activity, the level of Bcl-2/Bax mRNA, ALDH2 mRNA, and protein expressions were decreased and LDH and MDA contents were increased, meanwhile the aggravation of myocardial structure injury in DM I/R group. When DM I/R rats were pretreated with EtOH, left ventricular parameters, SOD, Bcl-2/Bax, and ALDH2 expression were increased; LDH, MDA, and myocardial structure injury were attenuated. Compared with DM + EtOH I/R group, cyanamide (ALDH2 nonspecific blocker), atractyloside (mitoPTP opener), and wortmannin (PI3K inhibitor) groups all decreased left ventricular parameters, SOD, Bcl-2/Bax, and ALDH2 and increased LDH, MDA, and myocardial injury. When cardiomyocyte was under HG condition, CCK-8 activity and ALDH2 protein expression were decreased. Alda-1 increased CCK-8 and ALDH2. Our findings suggested enhanced ALDH2 expression in diabetic I/R rats played the cardioprotective role, maybe through activating PI3K and inhibiting mitoPTP opening.


Assuntos
Diabetes Mellitus Experimental/enzimologia , Etanol/farmacologia , Traumatismo por Reperfusão Miocárdica/enzimologia , Traumatismo por Reperfusão Miocárdica/patologia , Aldeído-Desidrogenase Mitocondrial/genética , Aldeído-Desidrogenase Mitocondrial/metabolismo , Animais , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/fisiopatologia , Modelos Animais de Doenças , Ativação Enzimática/efeitos dos fármacos , Ventrículos do Coração/fisiopatologia , Hemodinâmica/efeitos dos fármacos , Técnicas In Vitro , L-Lactato Desidrogenase/metabolismo , Masculino , Malondialdeído/metabolismo , Traumatismo por Reperfusão Miocárdica/genética , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Miocárdio/patologia , Miocárdio/ultraestrutura , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Perfusão , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos Sprague-Dawley , Superóxido Dismutase/metabolismo , Proteína X Associada a bcl-2/genética , Proteína X Associada a bcl-2/metabolismo
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