Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 11 de 11
Filtrar
1.
Int Immunopharmacol ; 132: 111889, 2024 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-38531202

RESUMO

Host-directed therapy (HDT) is a new adjuvant strategy that interfere with host cell factors that are required by a pathogen for replication or persistence. In this study, we assessed the effect of dehydrozaluzanin C-derivative (DHZD), a modified compound from dehydrozaluzanin C (DHZC), as a potential HDT agent for severe infection. LPS-induced septic mouse model and Carbapenem resistant Klebsiella pneumoniae (CRKP) infection mouse model was used for testing in vivo. RAW264.7 cells, mouse primary macrophages, and DCs were used for in vitro experiments. Dexamethasone (DXM) was used as a positive control agent. DHZD ameliorated tissue damage (lung, kidney, and liver) and excessive inflammatory response induced by LPS or CRKP infection in mice. Also, DHZD improved the hypothermic symptoms of acute peritonitis induced by CRKP, inhibited heat-killed CRKP (HK-CRKP)-induced inflammatory response in macrophages, and upregulated the proportions of phagocytic cell types in lungs. In vitro data suggested that DHZD decreases LPS-stimulated expression of IL-6, TNF-α and MCP-1 via PI3K/Akt/p70S6K signaling pathway in macrophages. Interestingly, the combined treatment group of DXM and DHZD had a higher survival rate and lower level of IL-6 than those of the DXM-treated group; the combination of DHZD and DXM played a synergistic role in decreasing IL-6 secretion in sera. Moreover, the phagocytic receptor CD36 was increased by DHZD in macrophages, which was accompanied by increased bacterial phagocytosis in a clathrin- and actin-dependent manner. This data suggests that DHZD may be a potential drug candidate for treating bacterial infections.


Assuntos
Infecções por Klebsiella , Klebsiella pneumoniae , Macrófagos , Fagocitose , Sepse , Animais , Camundongos , Fagocitose/efeitos dos fármacos , Infecções por Klebsiella/tratamento farmacológico , Infecções por Klebsiella/imunologia , Klebsiella pneumoniae/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Células RAW 264.7 , Sepse/tratamento farmacológico , Sepse/imunologia , Masculino , Lipopolissacarídeos , Modelos Animais de Doenças , Camundongos Endogâmicos C57BL , Transdução de Sinais/efeitos dos fármacos , Citocinas/metabolismo , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico
2.
Biomed Pharmacother ; 170: 116028, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38113627

RESUMO

Klebsiella pneumoniae (Kpn) is an important pathogen of hospital-acquired pneumonia, which can lead to sepsis and death in severe cases. In this study, we simulated pneumonia induced by Kpn infection in mice to investigate the therapeutic effect of naringin (NAR) on bacterial-induced lung inflammation. Mice infected with Kpn exhibited increases in white blood cells (WBC) and neutrophils in the peripheral blood and pathological severe injury of the lungs. This injury was manifested by increased expression of the inflammatory cytokines interleukin (IL)- 18, IL-1ß, tumor necrosis factor-α (TNF-α) and IL-6, and elevated the expression of NLRP3 protein. NAR treatment could decrease the protein expression of NLRP3, alleviate lung inflammation, and reduce lung injury in mice caused by Kpn. Meanwhile, molecular docking results suggest NAR could bind to NLRP3 and Surface Plasmon Resonance (SPR) analyses also confirm this result. In vitro trials, we found that pretreated with NAR not only inhibited nuclear translocation of nuclear factor (NF)-κB protein P65 but also attenuated the protein interaction of NLRP3, caspase-1 and ASC and inhibited the assembly of NLRP3 inflammasome in mice AMs. Additionally, NAR could reduce intracellular potassium (K+) efflux, inhibiting NLRP3 inflammasome activation. These results indicated that NAR could protect against Kpn-induced pneumonia by inhibiting the overactivation of the NLRP3 inflammasome signaling pathway. The results of this study confirm the efficacy of NAR in treating bacterial pneumonia, refine the mechanism of action of NAR, and provide a theoretical basis for the research and development of NAR as an anti-inflammatory adjuvant.


Assuntos
Inflamassomos , Pneumonia , Camundongos , Animais , Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Klebsiella pneumoniae , Simulação de Acoplamento Molecular , NF-kappa B/metabolismo , Pneumonia/tratamento farmacológico
3.
World J Gastroenterol ; 27(43): 7530-7545, 2021 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-34887647

RESUMO

BACKGROUND: Severe acute pancreatitis (SAP) is a deadly inflammatory disease with complex pathogenesis and lack of effective therapeutic options. N6-methyladenosine (m6A) modification of circRNAs plays important roles in physiological and pathological processes. However, the roles of m6A circRNA in the pathological process of SAP remains unknown. AIM: To identify transcriptome-wide map of m6A circRNAs and to determine their biological significance and potential mechanisms in SAP. METHODS: The SAP in C57BL/6 mice was induced using 4% sodium taurocholate salt. The transcriptome-wide map of m6A circRNAs was identified by m6A-modified RNA immunoprecipitation sequencing. The biological significance of circRNAs with differentially expressed m6A peaks was evaluated through gene ontology and Kyoto Encyclopedia of Genes and Genomes analysis. The underlying mechanism of m6A circRNAs in SAP was analyzed by constructing of m6A circRNA-microRNA networks. The expression of demethylases was determined by quantitative polymerase chain reaction and western blot to deduce the possible mechanism of reversible m6A process in SAP. RESULTS: Fifty-seven circRNAs with differentially expressed m6A peaks were identified by m6A-modified RNA immunoprecipitation sequencing, of which 32 were upregulated and 25 downregulated. Functional analysis of these m6A circRNAs in SAP found some important pathways involved in the pathogenesis of SAP, such as regulation of autophagy and protein digestion. In m6A circRNA-miRNA networks, several important miRNAs participated in the occurrence and progression of SAP were found to bind to these m6A circRNAs, such as miR-24-3p, miR-26a, miR-92b, miR-216b, miR-324-5p and miR-762. Notably, the total m6A level of circRNAs was reduced, while the demethylase alkylation repair homolog 5 was upregulated in SAP. CONCLUSION: m6A modification of circRNAs may be involved in the pathogenesis of SAP. Our findings may provide novel insights to explore the possible pathogenetic mechanism of SAP and seek new potential therapeutic targets for SAP.


Assuntos
MicroRNAs , Pancreatite , Doença Aguda , Adenosina/análogos & derivados , Animais , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/genética , Pancreatite/induzido quimicamente , Pancreatite/genética , RNA Circular
5.
World J Gastroenterol ; 24(45): 5131-5143, 2018 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-30568390

RESUMO

AIM: To investigate the role of peritoneal macrophage (PM) polarization in the therapeutic effect of abdominal paracentesis drainage (APD) on severe acute pancreatitis (SAP). METHODS: SAP was induced by 5% Na-taurocholate retrograde injection in Sprague-Dawley rats. APD was performed by inserting a drainage tube with a vacuum ball into the lower right abdomen of the rats immediately after the induction of SAP. To verify the effect of APD on macrophages, PMs were isolated and cultured in an environment, with the peritoneal inflammatory environment simulated by the addition of peritoneal lavage in complete RPMI 1640 medium. Hematoxylin and eosin staining was performed. The levels of pancreatitis biomarkers amylase and lipase as well as the levels of inflammatory mediators in the blood and peritoneal lavage were determined. The polarization phenotypes of the PMs were identified by detecting the marker expression of M1/M2 macrophages via flow cytometry, qPCR and immunohistochemical staining. The protein expression in macrophages that had infiltrated the pancreas was determined by Western blot. RESULTS: APD treatment significantly reduced the histopathological scores and levels of amylase, lipase, tumor necrosis factor-α and interleukin (IL)-1ß, indicating that APD ameliorates the severity of SAP. Importantly, we found that APD treatment polarized PMs towards the M2 phenotype, as evidenced by the reduced number of M1 macrophages and the reduced levels of pro-inflammatory mediators, such as IL-1ß and L-selectin, as well as the increased number of M2 macrophages and increased levels of anti-inflammatory mediators, such as IL-4 and IL-10. Furthermore, in an in vitro study wherein peritoneal lavage from the APD group was added to the cultured PMs to simulate the peritoneal inflammatory environment, PMs also exhibited a dominant M2 phenotype, resulting in a significantly lower level of inflammation. Finally, APD treatment increased the proportion of M2 macrophages and upregulated the expression of the anti-inflammatory protein Arg-1 in the pancreas of SAP model rats. CONCLUSION: These findings suggest that APD treatment exerts anti-inflammatory effects by regulating the M2 polarization of PMs, providing novel insights into the mechanism underlying its therapeutic effect.


Assuntos
Macrófagos Peritoneais/imunologia , Pancreatite/terapia , Paracentese , Cavidade Peritoneal/citologia , Animais , Biomarcadores/análise , Modelos Animais de Doenças , Humanos , Macrófagos Peritoneais/metabolismo , Masculino , Pancreatite/induzido quimicamente , Pancreatite/diagnóstico , Pancreatite/imunologia , Ratos , Ratos Sprague-Dawley , Índice de Gravidade de Doença , Ácido Taurocólico/toxicidade , Resultado do Tratamento
6.
Clin Neurol Neurosurg ; 171: 168-173, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29920451

RESUMO

OBJECTIVE: The aim of the present study is to investigate the expression profiles of circular RNAs (circRNAs) in IDH-wild type (IDH-wt) glioblastoma and explore the differences in circRNAs expression between IDH-wt glioblastoma and adjacent normal brain. PATIENTS AND METHODS: circRNA expression profiles were detected by circRNA microarray in three matched pairs of IDH-wt glioblastoma and adjacent normal brain. qRT-PCR was used to verify the differential expression of circRNAs from microarray analysis. Bioinformatics analysis was used to analyze potential functions of the differentially expressed circRNAs in IDH-wt glioblastoma. RESULTS: Compared with the adjacent normal brain tissues, 254 circRNAs were upregulated and 361 circRNAs were downregulated in IDH-wt glioblastoma with a ≥1.5-fold change. A total of 12 differentially expressed circRNAs were randomly selected and validated a good correlation of results from circRNA-seq with qRT-PCR. Gene Ontology (GO) analysis revealed the differentially expressed circRNAs possibly involved in cell division, DNA damage repair, cytoskeleton, and protein ubiquitination. 46 and 50 miRNAs were predicted to be adsorbed by the top 10 upregulated circRNAs and top 10 downregulated circRNAs, respectively. CONCLUSION: Differential expression of circRNAs may be associated with IDH-wt glioblastoma development and progression, and these circRNAs can be identified as biomarkers for prognosis prediction and targets for treatment.


Assuntos
Biomarcadores/sangue , Glioblastoma/genética , MicroRNAs/sangue , RNA/sangue , Idoso , Biologia Computacional/métodos , Regulação para Baixo , Humanos , Masculino , MicroRNAs/genética , Pessoa de Meia-Idade , RNA Circular , RNA Mensageiro/metabolismo , Regulação para Cima
7.
Clin Neurol Neurosurg ; 169: 92-97, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29642043

RESUMO

OBJECTIVE: Cytoplasmic polyadenylation element binding protein 4 (CPEB4) is a regulator of gene expression at transcriptional level and has been reported to be associated with biological malignancy in cancers. However, little was known about the correlation between CPEB4 and glioblastoma cell proliferation and the prognostic significance in patients. Our aim was to investigate the functional role and prognostic value of CPEB4 in glioblastoma. PATIENTS AND METHODS: We determined the expression of CPEB4 protein using immunohistochemistry in tissue microarrays containing 278 glioma patients (including 98 primary glioblastomas) and evaluated its association with pathological grades and clinical outcome by univariate and multivariate analyses. And then, lentiviral-mediated RNAi targeting CPEB4 was utilized to study the role of CPEB4 in glioblastoma cell proliferation. RESULTS: In our cohort, CPEB4 expression was positively related to glioma pathological grade (p < 0.01) and elevated in glioblastoma (p < 0.01). High expression of CPEB4 was associated with significantly poor prognosis, and could be identified as an independent risk factor for overall survival (OS) and progression-free survival (PFS) of glioblastoma patients (hazard ratio (HR) = 1.730, p = 0.014 and HR = 1.877, p = 0.004, respectively). In vitro studies further showed that downregulation of CPEB4 significantly reduced the growth rate of T98G and U251 cells comparing with the controls. CONCLUSION: Our study indicated that increased expression of CPEB4 in primary glioblastoma is a novel biomarker for predicting poor outcome of patients and suppression of CPEB4 inhibit tumor cell proliferation, suggesting a potential therapeutic target for glioblastoma.


Assuntos
Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/metabolismo , Proliferação de Células/fisiologia , Glioblastoma/diagnóstico , Glioblastoma/metabolismo , Proteínas de Ligação a RNA/biossíntese , Idoso , Biomarcadores Tumorais/biossíntese , Biomarcadores Tumorais/genética , Neoplasias Encefálicas/genética , Estudos de Coortes , Feminino , Seguimentos , Glioblastoma/genética , Células HEK293 , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Proteínas de Ligação a RNA/genética , Taxa de Sobrevida/tendências , Resultado do Tratamento
8.
Clin Neurol Neurosurg ; 164: 132-137, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29223793

RESUMO

OBJECTIVE: G-protein-coupled receptors 65 (GPR65), identified as an acid-sensing receptor, is overexpressed in several malignancies and promote tumor development. Our aim was to investigate the expression and prognostic value of GPR65 in glioblastoma. MATERIALS AND METHODS: We determined the expression of GPR65 protein using immunohistochemistry in tissue microarrays containing 11 Grade I, 107 Grade II, 47 Grade III, and 102 Grade IV gliomas and 16 normal brains. Then we evaluated its association with pathological grades, prognosis, and recurrence. The Cancer Genome Atlas (TCGA) group (N=528) was further employed to examine transcriptional level of GPR65 in glioblastoma and the correlation between GPR65 expression and clinical outcome. RESULTS: In our cohort, GPR65 expression was positively related to glioma pathological grade (p<0.01) and elevated in glioblastoma (p<0.01). High expression of GPR65 was associated with significantly short overall survival (OS) (p=0.013) and progression-free survival (PFS) (p=0.029), and could be identified as an independent risk factor for OS of glioblastoma patients (Hazard Ratio [HR]=1.596, p=0.037). As an aiding evidence, increased GPR65 mRNA expression was also found in TCGA glioblastoma group (p<0.001) and its high level predicted a poor clinical outcome (OS, p=0.003; PFS, p=0.001). CONCLUSION: Our findings suggest that GPR65 is overexpressed in glioblastoma and its high expression predicts unfavorable clinical outcome for patients. Targeting GPR65 may serve as a potential therapy for treating glioblastoma.


Assuntos
Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Regulação Neoplásica da Expressão Gênica , Glioblastoma/genética , Glioblastoma/patologia , Receptores Acoplados a Proteínas G/genética , Adulto , Neoplasias Encefálicas/metabolismo , Estudos de Coortes , Bases de Dados Genéticas/tendências , Feminino , Glioblastoma/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Receptores Acoplados a Proteínas G/biossíntese
9.
J Pain Res ; 9: 535-42, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27555796

RESUMO

OBJECTIVES: A retrospective study was undertaken to compare the efficacy of stereotactic gamma knife surgery (GKS) and microvascular decompression (MVD) in the treatment of primary trigeminal neuralgia (TN) at a single center. The study included the evaluation of clinical outcomes of pain relief and pain recurrence and complications associated with GKS and MVD. METHODS: The study included 202 patients with primary TN and was conducted between January 2013 and December 2014; about 115 patients were treated with GKS and 87 patients were treated with MVD. TN pain was evaluated using the Barrow Neurological Institute and the visual analog scale scoring systems. Preoperative magnetic resonance tomographic angiography was performed for all patients. Microscope-assisted MVD used the suboccipital retrosigmoid sinus approach. GKS targeted the trigeminal nerve root entry zone with a margin radiation dose of 59.5 Gy, and brainstem dose <12 Gy. Posttreatment follow-up was for 2 years. RESULTS: Postoperative Barrow Neurological Institute scores for patients treated with GKS and MVD were significantly improved compared with preoperative scores (P<0.01). Reduction in postoperative pain following MVD (95.4% patients) was significantly greater than that following GKS (88.7% patients) (P<0.01). Postoperative visual analog scale scores of the MVD group were significantly reduced compared with those of patients treated with GKS at the same postoperative time points (P<0.01). Patients treated with GKS had a significantly increased rate of loss of corneal reflex compared with patients treated with MVD (P=0.002). CONCLUSION: Both GKS and MVD are safe and effective first-line and adjunctive treatment options for patients with TN. The clinical outcomes of pain relief and reduction of pain recurrence were better with MVD. For GKS, this study showed that the optimal radiation therapeutic dose range was 70-90 Gy, but brainstem radiation protection is recommended.

10.
Brain Pathol ; 24(6): 568-83, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24576181

RESUMO

Medulloblastoma is the most frequent malignant central nervous system tumor in children. MicroRNAs (miRs) are small, non-coding RNAs that target protein-coding and non-coding RNAs, and play roles in a variety of cellular processes through regulation of multiple targets. In the present study, we analyzed miR-22 expression and its effect in cell proliferation and apoptosis in medulloblastomas. Quantitative reverse transcription PCR (RT-PCR) revealed significantly lower expression of miR-22 in 19 out of 27 (70%) medulloblastomas, D341, DAOY, ONS-76 medulloblastoma cell lines, compared with normal cerebellum. Forced expression of miR-22 by lentiviral vector transfection reduced cell proliferation and induced apoptosis, while knockdown of miR-22 increased proliferative activity in DAOY and ONS-76 cells. DAOY cells with miR-22 overexpression in nude mice yielded tumors smaller than those originated from control DAOY cells. Microarray analysis in DAOY cells with forced miR-22 expression showed significant changes in expression profiles, PAPST1 being the most significantly (10 folds) downregulated gene. Quantitative RT-PCR revealed PAPST1 mRNA upregulation in 18 out of 27 (67%) medulloblastomas. In addition, a luciferase reporter assay in ONS-76 and DAOY cells suggested that miR-22 directly targets the PAPST1 gene, and lentivirus-mediated knockdown of PAPST1 suppressed proliferation of DAOY and ONS-76 medulloblastoma cells. These results suggest that frequently downregulated miR-22 expression is associated with cell proliferation in medulloblastomas, and this may be at least in part via PAPST1, which is a novel target of miR-22.


Assuntos
Proteínas de Transporte de Ânions/metabolismo , Proliferação de Células/fisiologia , Meduloblastoma/fisiopatologia , Proteínas de Membrana Transportadoras/metabolismo , MicroRNAs/metabolismo , Adolescente , Adulto , Animais , Apoptose/fisiologia , Linhagem Celular Tumoral , Neoplasias Cerebelares/fisiopatologia , Cerebelo/fisiopatologia , Criança , Pré-Escolar , Regulação para Baixo , Humanos , Lactente , Camundongos Nus , Pessoa de Meia-Idade , Transplante de Neoplasias , Transportadores de Sulfato , Adulto Jovem
11.
Med Sci Monit ; 18(5): CS37-41, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-22534715

RESUMO

BACKGROUND: Choroid plexus carcinoma (CPC) is an uncommon, aggressive, malignant, central nervous system neoplasm that typically occurs in children, presenting with the signs and symptoms of intracranial hypertension and cerebrospinal fluid obstruction. CASE REPORT: We report the case of a 2.5-year-old girl with CPC. The tumor was subtotally removed by microsurgery, followed by gamma knife radiosurgery for the residual lesion. H&E staining indicated that this was a rare case of CPC. Neuropathological studies, assayed by immunohistochemical staining, showed that the tumor sample was positive to antibodies against S-100, CgA, AE1/AE3 (cytokeratin), Ki-67, INI1 and TP53, and was negative to antibodies against Nestin, GFAP, CD133, EMA and AFP. Moreover, stainings for transthyretin and vimentin were focally positive. Interestingly, direct DNA sequencing of the paraffin-embedded tumor sample identified a novel R248Q mutation in the TP53 gene. In contrast to previous reports suggesting that TP53 germline mutations were associated with the pathogenesis of CPC, here we provide a rare case of CPC with TP53 somatic mutation, as evidence that the peritumoral tissue possesses the non-mutant TP53 allele. CONCLUSIONS: Our finding suggests that TP53 somatic mutations, in addition to its germline mutations, may also be involved in the pathogenesis of pediatric CPC.


Assuntos
Neoplasias do Plexo Corióideo/genética , Genes p53 , Mutação em Linhagem Germinativa , Pré-Escolar , Evolução Fatal , Humanos , Imuno-Histoquímica , Masculino
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA