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1.
Adv Sci (Weinh) ; : e2102051, 2021 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-34665528

RESUMO

Liver disease, particularly viral hepatitis and hepatocellular carcinoma (HCC), is a global healthcare burden and leads to more than 2 million deaths per year worldwide. Despite some success in diagnosis and vaccine development, there are still unmet needs to improve diagnostics and therapeutics for viral hepatitis and HCC. The emerging clustered regularly interspaced short palindromic repeat/associated proteins (CRISPR/Cas) technology may open up a unique avenue to tackle these two diseases at the genetic level in a precise manner. Especially, liver is a more accessible organ over others from the delivery point of view, and many advanced strategies applied for nanotheranostics can be adapted in CRISPR-mediated diagnostics or liver gene editing. In this review, the focus is on these two aspects of viral hepatitis and HCC applications. An overview on CRISPR editor development and current progress in clinical trials is first given, followed by highlighting the recent advances integrating the merits of gene editing and nanotheranostics. The promising systems that are used in other applications but may hold potentials in liver gene editing are also discussed. This review concludes with the perspectives on rationally designing the next-generation CRISPR approaches and improving the editing performance.

2.
Langmuir ; 37(35): 10461-10468, 2021 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-34431681

RESUMO

A colloidal nanocrystal cluster (CNC) is a hierarchical nanostructure formed by clustering several nanocrystals into one nano-ensemble, which may exhibit unique optical or catalytic properties different from individual nanocrystals owing to the mutual interactions among neighboring component nanocrystals. However, there is still no universal synthetic route that could be applicable to diverse material compositions with precisely controlled hierarchical structures (i.e., nanocrystal number density, component nanocrystal size, and overall diameter of the CNC) up to now. Herein, a general and novel synthetic strategy was reported for crafting a wide range of inorganic CNCs (i.e., noble metal, semiconductor, and metal oxide) via utilizing amphiphilic star-like poly(4-vinylpyridine)-block-polystyrene diblock copolymers as nanoreactors prepared by sequential atom transfer radical polymerization. The hierarchical structure of rationally designed CNCs could be readily tailored by varying the P4VP molecular weight of star-like nanoreactors and the parameter optimization during the CNC preparation process, which was inaccessible by conventional synthetic methods.

4.
Front Pharmacol ; 12: 678631, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34177587

RESUMO

Objectives: Chinese herb medicine (CHM) is one of the most popular complementary and alternative therapies, which has been widely used to treat Refractory Mycoplasma Pneumoniae Pneumonia (RMPP). However, the effect and safety of CHM remain controversial. Hence, we conducted this meta-analysis to evaluate whether CHM combination therapy could bring benefits to children and adolescents with RMPP. Methods: Seven databases were used for data searching through November 11, 2020 following the PRISMA checklist generally. Review Manager 5.3, Trial sequential analysis 0.9.5.10 Beta software and Stata16.0 were applied to perform data analyses. Mean difference or risk ratio was adopted to express the results, where a 95% confidence interval (CI) was applied. Results: In general, this research enrolled 17 trials with 1,451 participants. The overall pooled results indicated that CHM was beneficial for children and adolescents with RMPP by improving the clinical efficacy rate [RR = 1.20, 95% CI (1.15, 1.25), p < 0.00001], shortening antipyretic time [MD = -2.60, 95% CI (-3.06, -2.13), p < 0.00001], cough disappearance time [MD = -2.77, 95% CI (-3.12, -2.42), p < 0.00001], lung rale disappearance time [MD = -2.65, 95% CI (-3.15, -2.15), p < 0.00001], lung X-ray infiltrates disappearance time [MD = -2.75, 95% CI (-3.33, -2.17), p < 0.00001], reducing TNF-α level [MD = -5.49, 95% CI (-7.21, -3.77), p < 0.00001]. Moreover, subgroup results suggested that removing heat-phlegm and toxicity therapy had more advantages in shortening antipyretic time, cough disappearance time, lung X-ray infiltrates disappearance time and reducing TNF-α level. Meanwhile promoting blood circulation therapy seemed to be better at relieving lung rale. However, regarding adverse events, the two groups displayed no statistical difference [RR = 0.97, 95% CI (0.60, 1.57), p = 0.91]. Conclusion: Despite of the apparently positive results in relieving clinical symptoms, physical signs and reducing inflammation, it is premature to confirm the efficacy of CHM in treating RMPP because of the limitation of quality and the number of the included studies. More large-scale, double-blind, well-designed, randomized controlled trials are needed in future research.

5.
Front Cardiovasc Med ; 8: 680604, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34164443

RESUMO

Elderly with comorbidities have shown a higher rate of fatal outcomes when suffering coronavirus disease 2019 (COVID-19). However, a delineation of clinical significances of hematologic indices and underlying comorbidities in the progression and outcome of COVID-19 remains undefined. Six hundred two COVID-19 patients with established clinical outcomes (discharged or deceased) from Hankou Hospital of Wuhan, China between January 14, 2020 and February 29, 2020 were retrospectively analyzed. Of the 602 patients with COVID-19, 539 were discharged and 63 died in the hospital. The deceased group showed higher leukocyte and neutrophil counts but lower lymphocyte and platelet counts. Longer activated partial thromboplastin time (APTT) and prothrombin time (PT), as well as higher D-dimer and C-reactive protein levels, were found in non-survivors. Our observations suggest that these parameters could serve as potential predictors for the fatal outcome and in the discharged group. A higher neutrophil count and D-dimer level but lower lymphocyte were associated with a longer duration of hospitalization. A multivariable Cox regression analysis showed that higher neutrophil count, prolonged PT, and low lymphocyte count were risk factors for patients with COVID-19. Also, we found an association of lower lymphocyte count and higher C-reactive protein levels with the elderly group and those with cardiovascular-related comorbidities. The significantly different hematologic profiles between survivors and non-survivors support that distinct hematologic signatures in COVID-19 patients will dictate different outcomes as a prognostic marker for recovery or fatality. Lymphopenia and aggressive inflammatory response might be major causes for fatal outcomes in the elderly male and especially those with cardiovascular-related comorbidities.

6.
Int J Biol Sci ; 17(2): 562-573, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33613113

RESUMO

Identifying high specificity and sensitivity biomarkers has always been the focus of research in the field of non-invasive cancer diagnosis. Exosomes are extracellular vesicles with a lipid bilayer membrane that can be released by all types of cells, which contain a variety of proteins, lipids, and a variety of non-coding RNAs. Increasing research has shown that the lipid bilayer can effectively protect the nucleic acid in exosomes. In cancers, tumor cell-derived exosomal circRNAs can act on target cells or organs through the transport of exosomes, and then participate in the regulation of tumor development and metastasis. Since exosomes exist in various body fluids and circRNAs in exosomes exhibit high stability, exosomal circRNAs have the potential as biomarkers for early and minimally invasive cancer diagnosis and prognosis judgment. In this review, we summarized circRNAs and their biological roles in cancers, with the emerging value biomarkers in cancer diagnosis, disease judgment, and prognosis observation. In addition, we briefly compared the advantages of exosomal circRNAs as biomarkers and the current obstacles in the exosome isolation technology, shed light to the future development of this technology.

7.
Onco Targets Ther ; 13: 6681-6697, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32764959

RESUMO

Purpose: Pediatric acute promyelocytic leukemia (APL) accounts for 10% of pediatric acute myelogenous leukemia (AML) case and is accompanied by a tendency to hemorrhage. miR-188-5p plays an important role in adult AML. Therefore, the purpose of this study was to explore the effects of miR-188-5p on cell proliferation and apoptosis and tumor growth, and its mechanism in pediatric APL patients. Materials and Methods: Survival-associated miRNAs or mRNAs from TCGA database associated with AML were identified via using the "survival R" package in R language. CCK8, clone formation, flow cytometry, RT-PCR, immunohistochemistry and Western blot assays were used to detect the viability, proliferation, apoptosis, cell cycle, and related gene expression in APL cell lines. The prognostic value of miR-188-5p was evaluated using a ROC curve. The tumorigenic ability of APL cell lines was determined using a nude mouse transplantation tumor experiment. Tumor cell apoptosis was determined by TUNEL assay in vivo. The target genes of miR-188-5p were predicted using the miRDB, miRTarBase, and TargetScan databases. A PPI network was constructed using STRING database and the hub gene was identified using the MCODE plug-in of the Cytoscape software. The DAVID database was used to perform GO and KEGG pathway enrichment analyses. A luciferase reporter assay was used to demonstrate the binding of miR-188-5p to CD2AP. Results: miR-188-5p overexpression or CD2 associated protein (CD2AP) inhibition was significantly associated with poor survival in pediatric APL patients. Upregulation of miR-188-5p was identified in the blood of pediatric APL patients and cell lines. Increased expression of miR-188-5p also promoted the viability, proliferation, and cell cycle progression, and reduced the apoptosis of APL cells. Additionally, upregulation of miR-188-5p regulated the expressions of cyclinD1, p53, Bax, Bcl-2 and cleaved caspase-3. The area under the ROC curve (AUC) of miR-188-5p was 0.661. miR-188-5p overexpression increased the tumorigenic ability of APL and Ki67 expression, and reduced cell apoptosis in vivo. CD2AP was identified as the only overlapping gene from the list of miR-188-5p target genes and survival-related mRNAs of the TCGA database. It was mainly enriched in the "biological process (BP)" and "cellular component (CC)" terms, and was downregulated in the blood of pediatric APL patients and cell lines. The luciferase reporter, RT-PCR, and Western blot assays demonstrated that the binding of miR-188-5p to CD2AP. CD2AP inhibition promoted the proliferation and inhibited the apoptosis of APL cells. Rescue experiments showed that inhibition of miR-188-5p inhibited cell proliferation, activated the PI3K/AKT/mTOR signaling pathway, induced G0/G1 phase arrest, regulated gene expression, and promoted cell apoptosis, which were reversed by CD2AP inhibition. Conclusion: miR-188-5p, an oncogene, promoted tumor growth and progression of pediatric APL in vitro and in vivo via targeting CD2AP and activating the PI3K/AKT/mTOR signaling pathway.

8.
Drug Des Devel Ther ; 14: 1813-1823, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32494123

RESUMO

Introduction: Berberine has been reported to inhibit cancer cell growth by apoptosis induction and exhibits a protective role against cancer progression. The current study aims to investigate the effects of berberine on acute lymphoblastic leukemia (ALL) and the mechanism beyond apoptosis. Methods: Cell viability was determined in ALL cell lines EU-6 and SKW-3 using trypan blue staining. Cell autophagy was determined by immunofluorescence and Western blot. ALL xenograft mice were established to investigate the anti-tumor effects of BBR. The molecular mechanism was explored in ALL cell lines using siRNA and signaling inhibitors. Results: Herein, we show that berberine treatment significantly inhibits ALL cell viability and promotes cell death by inducing autophagy in a dose-dependent manner. Moreover, berberine significantly alleviates the aggressive pathological condition in ALL xenograft mice. Mechanistic studies exhibit that berberine induces autophagic death in ALL cells by inactivating AKT/mTORC1 signaling. Chemically targeting AKT/mTORC1 signaling controls berberine-induced cell autophagy in vitro, and blockade of autophagic process blunts berberine-alleviated pathological condition in vivo. Discussion: In conclusion, our study reveals that berberine could induce ALL cell autophagic death by inactivating AKT/mTORC1 signaling that could be used to develop small molecule drug for ALL treatment.


Assuntos
Antineoplásicos/farmacologia , Berberina/farmacologia , Alvo Mecanístico do Complexo 1 de Rapamicina/antagonistas & inibidores , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Adolescente , Adulto , Idoso , Morte Celular Autofágica/efeitos dos fármacos , Criança , Pré-Escolar , Humanos , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Pessoa de Meia-Idade , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Adulto Jovem
9.
Langmuir ; 36(24): 6690-6697, 2020 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-32493013

RESUMO

We reported the synthesis of a well-defined hollow polymer nanoparticle derived from star-shaped unimolecular micelles. ß-Cyclodextrin was first applied as an efficient macroinitiator to prepare a star-shaped PCL via ring-opening polymerization (ROP). Then, the star-shaped PCL was modified to be a macro-RAFT agent for photoinduced electron/energy transfer-reversible addition-fragmentation chain transfer (PET-RAFT) polymerization of S-Cl monomers. The prepared unimolecular micelles can be photocross-linked under UV irradiation after a simple nucleophilic substitution reaction, which made -Cl groups to be -N3 groups. After the selective removal of the PCL core, hollow polymer nanoparticles were achieved and exhibited to be a general nanoreactor strategy for the fabrication of nanocrystals with well-controlled architectures. Compared with unimolecular micelle templates, the nanocrystals prepared by hollow templates are absolutely pure as no polymer chains are embedded in the inorganic nanocrystals. In addition, by changing the concentration of the precursor, the structure of the nanocrystal can be changed from a normal spherical structure to a hollow structure.

10.
Lab Invest ; 100(9): 1223-1237, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32461588

RESUMO

MicroRNAs regulate gene expression at the posttranscriptional level, and this process has been shown to be implicated in the pathological processes of temporal lobe epilepsy. At present, studies about the impact of microRNA-181a (miR-181a) on epilepsy have focused on hippocampal neurons, and the effect of miR-181a on other cells in the hippocampus remains poorly understood. Herein, we explored the role of miR-181a-5p in a lithium-pilocarpine model of epilepticus in immature rats. We found that the hippocampal expression level of miR-181a-5p was increased. Inhibition of miR-181a-5p protected the hippocampus against epilepsy, including hippocampal insults, neuronal apoptosis, astrocyte and microglia activation, neuroinflammation, oxidative stress, mitochondrial function, and cognitive dysfunction. Moreover, miR-181a-5p inhibition exerted a seizure-suppressing effect via SIRT1 upregulation. Overall, our findings reveal the potential role of the miR-181a-5p/SIRT1 pathway in the development of temporal lobe epilepsy, and this pathway may represent a novel target for ameliorating epilepsy and its sequelae.


Assuntos
Astrócitos/metabolismo , Epilepsia do Lobo Temporal/genética , MicroRNAs/genética , Estresse Oxidativo , Sirtuína 1/genética , Fatores Etários , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Epilepsia do Lobo Temporal/induzido quimicamente , Epilepsia do Lobo Temporal/metabolismo , Regulação da Expressão Gênica , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/patologia , Masculino , Microglia/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Pilocarpina , Ratos Sprague-Dawley , Sirtuína 1/metabolismo
11.
Eur J Med Chem ; 182: 111615, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31434038

RESUMO

Multi-drug resistant infections caused by Gram-negative bacteria have become one of the most important reasons for the failure of clinical anti-infective treatment. Siderophore-antibiotic conjugates, which were designed based on a "Trojan horse" strategy wherein features enabled active uptake to bypass the Gram-negative cell wall, have been expected to be a weapon for anti-infective treatment in the clinic. Herein, we review antibiotic drug design strategies based on mimics of nature siderophores reported in recent years, we also focus our attention on the relationship between the type of linker and the corresponding antibacterial activity.


Assuntos
Antibacterianos/farmacologia , Bactérias Gram-Negativas/efeitos dos fármacos , Sideróforos/farmacologia , Antibacterianos/química , Relação Dose-Resposta a Droga , Humanos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Sideróforos/química , Relação Estrutura-Atividade
12.
J Cell Biochem ; 120(11): 18901-18909, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31318092

RESUMO

Germacrone (GM) is an anti-inflammatory compound extracted from Rhizoma curcuma. Here, we strived to investigate the neuroprotective effects of GM in rat models of transient middle cerebral artery occlusion/reperfusion injury. Rats immediately after cerebral ischemia were intraperitoneally injected with GM at doses of 5, 10, and 20 mg/kg. After 1 day of reperfusion, the water content in the brain, infarct volume, and neurological deficits were assessed. Hippocampus neurons were histopathologically examined by hematoxylin and eosin and terminal deoxynucleotidyl transferase dUTP nick end labeling staining. Activities of glutathione (GSH), superoxide dismutase (SOD), malondialdehyde (MDA), and glutathione peroxidase (GSH-PX) in brain tissue were detected. Real-time PCR and Western blotting were utilized to quantify the expression of apoptosis markers, such as caspase-3, Bax, and Bcl-2. The content of phospho-Akt (p-Akt) was also measured using Western blotting. GM treatment markedly decreased the brain water content, infarct volume and the neurological deficits, which was corroborated by attenuated histopathologic change. MDA levels were reduced and activities of GSH, SOD, and GSH-PX were elevated after GM treatment. Caspase-3 and Bax were decreased, and Bcl-2 was increased at both messenger RNA and protein levels by GM treatment. The p-Akt expression was increased by GM. Our data indicated that the neuroprotective effects of GM may attenuate the injuries from cerebral ischemia/reperfusion in rats through antioxidative and antiapoptotic mechanisms.


Assuntos
Apoptose/efeitos dos fármacos , Encefalopatias , Hipocampo , Traumatismo por Reperfusão , Sesquiterpenos de Germacrano/farmacologia , Animais , Proteínas Reguladoras de Apoptose/metabolismo , Encefalopatias/tratamento farmacológico , Encefalopatias/metabolismo , Encefalopatias/patologia , Hipocampo/metabolismo , Hipocampo/patologia , Masculino , Oxirredução/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia
13.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 35(6): 808-811, 2018 Dec 10.
Artigo em Chinês | MEDLINE | ID: mdl-30512151

RESUMO

OBJECTIVE: To detect potential mutation in a Chinese pedigree affected with split hand/split foot malformation (SHFM). METHODS: The patients were screened for genome-wide copy number variations with single nucleotide polymorphism (SNP) microarray. Copy number variations were verified by real-time fluorescence quantitative PCR. RESULTS: There were 3 SHFM patients from three generations, which conformed to an autosomal dominant inheritance. SNP microarray assay revealed that all patients have carried a 0.34 Mb duplication in 10q24.31-q24.32 (102 993 649-103 333 271) encompassing the BTRC and DPCD genes. The result was verified by real-time fluorescence quantitative PCR, confirming that the duplication has co-segregated with the SHFM phenotype in the pedigree. CONCLUSION: The 10q24.31-q24.32 duplication probably underlies the pathogenesis of SHFM in this pedigree. Tiny copy number variations can result in diseases featuring autosomal dominant inheritance.


Assuntos
Cromossomos Humanos Par 10/genética , Variações do Número de Cópias de DNA , Deformidades Congênitas do Pé/genética , Deformidades Congênitas da Mão/genética , Grupo com Ancestrais do Continente Asiático , China , Duplicação Cromossômica , Humanos , Mutação , Linhagem , Polimorfismo de Nucleotídeo Único
14.
Sci Total Environ ; 628-629: 1518-1530, 2018 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-30045570

RESUMO

A comprehensive model for groundwater risk assessment was proposed by combining the hazard of contaminated sources (H), groundwater intrinsic vulnerability (V) and groundwater function value (F), and verified in Jilin City of northeast China. This model is characterized by integrating groundwater resource, ecology, and geological environment under the impact of climate change and human activities. The hazard of potential polluted sources was assessed by quantifying the properties and the potential infiltrating load of contaminants. The groundwater intrinsic vulnerability was evaluated by the DRASTIC model. The groundwater function value was assessed by multiplying seventeen indexes with their corresponding weightings. The groundwater pollution risk mapping of Jilin City was generated based on ArcGIS and validated by the level difference method between the risk classification and the pollution classification. The results showed that groundwater has a relatively low possibility of pollution because the area with less than, or equal to, the medium classification of risk accounted for 67.61% of the study area. The hazard harmfulness from the different contaminant sources played the most important role in determining the high groundwater pollution risk areas. Different influencing factors lead to relatively high pollution risk in specific areas. According to the validation of the level difference method, areas correctly identified by groundwater pollution risk mapping accounted for 95.81% of the study area, which is nearly twice as high as that of specific vulnerability mapping. The HVF model proved to be suitable for assessing groundwater pollution risk in Jilin City of northeast China. The groundwater pollution risk mapping can be applied for the effective protection and sustainable supply of groundwater.

15.
Epilepsy Res ; 139: 14-19, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29144992

RESUMO

OBJECTIVE: Status epilepticus (SE) is a common, life-threatening neurological emergency that confers a high degree of morbidity and mortality. Increasing evidence indicates that neuroinflammation plays a critical role in the pathogenesis of SE. MicroRNA-146a (miR-146a) has been reported to be an important posttranscriptional inflammation-associated microRNA. The aim of this study was to investigate the effect of miR-146a in SE and the mechanism by which it operates. METHODS: To study the effect of miR-146a in SE, we chose intracerebroventricular injection for rat at 21-28days old, and made a lithium-pilocarpine-induced SE rat model. We assessed latency time and Lado grade by behavior observation. We performed qPCR, ELISA and western blot tests on rat hippocampus to measure the expression levels of miR-146a, IL-1ß, TNF-α, TLR4 and NF-κB. RESULTS: In the miR-146a antagomir injection group, the latency to generalized convulsions was shorter, the duration and degree of seizures were more severe, the expression level of miR-146a was clearly decreased, and IL-1ß, TNF-α, TLR4 and NF-κB were all significantly up-regulated. The opposite was true for rats treated with miR-146a agomir. CONCLUSION: Our findings elucidate the role of inflammation in the pathogenesis of SE in immature rats, and show that regulating the expression level of miR-146a may provide a novel insights into the pathogenesis of SE.


Assuntos
MicroRNAs/metabolismo , Convulsões/metabolismo , Estado Epiléptico/metabolismo , Animais , Antagomirs/administração & dosagem , Modelos Animais de Doenças , Hipocampo/metabolismo , Inflamação/metabolismo , Compostos de Lítio , Masculino , MicroRNAs/genética , Pilocarpina , Distribuição Aleatória , Ratos Sprague-Dawley
16.
Zhongguo Dang Dai Er Ke Za Zhi ; 18(10): 1030-1034, 2016 Oct.
Artigo em Chinês | MEDLINE | ID: mdl-27751226

RESUMO

OBJECTIVE: To study the effect of a microRNA-132 antagonist on lithium-pilocarpine-induced status epilepticus (SE) in young Sprague-Dawley (SD) rats. METHODS: Forty-five 3-week-old SD rats were randomly and equally divided into epilepticus model group, microRNA-132 antagonist group, and microRNA-132 antagonist negative control group. The young SD rat model of SE was established using lithium-pilocarpine. For the microRNA-132 antagonist group and the negative control group, pretreatment was performed 24 hours before the model establishment. Behavioral observation was performed to assess the latency of SE and success rate of induction of SE. The scale of Lado was used to evaluate the seizure severity. Electroencephalography (EEG) was used to assess the frequency and amplitude of epileptiform discharges. The mortality rate was calculated in each group. RESULTS: There was no significant difference in the success rate of induction of SE between the three groups (P>0.05). Compared with the microRNA-132 negative control group and the epilepticus model group, the microRNA-132 antagonist group had significantly prolonged SE latency after model establishment (P<0.05), a significantly lower Lado score of seizure (P<0.05), significantly lower frequency and amplitude of epileptiform discharges on EEG (P<0.05), and a slightly reduced mortality rate. CONCLUSIONS: The treatment with the microRNA-132 antagonist shows an inhibitory effect on the development and progression of lithium-pilocarpine-induced SE in young SD rats. The inhibition of microRNA-132 is likely to be a potential target or direction for drug treatment of SE.


Assuntos
MicroRNAs/antagonistas & inibidores , Pilocarpina/farmacologia , Estado Epiléptico/tratamento farmacológico , Animais , Eletroencefalografia , Masculino , Ratos , Ratos Sprague-Dawley , Estado Epiléptico/induzido quimicamente
17.
Arch Immunol Ther Exp (Warsz) ; 64(5): 417-23, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27197661

RESUMO

Program death-1 (PD-1) is a co-inhibitory receptor inducibly expressed on activated T cells. PD-1 has been reported to be associated with the development of several autoimmune diseases including rheumatoid arthritis, but the precise cellular and molecular mechanisms have not been fully elucidated. To study the role of PD-1 in the pathogenesis of rheumatoid arthritis and the possible underlying mechanisms, we performed collagen-induced arthritis (CIA) in C57BL/6 mice. Here, we show that PD-1 deficiency leads to the development of severe CIA in mice. When analyzing T cells from CIA mice ex vivo, we noticed aberrant antigen-specific Th17 responses in mice lacking PD-1. This is possibly due to deregulated activation of PKC-θ and Akt. In support of this notion, treating Pdcd1 (-/-) mice with an inhibitor of PI3-kinase that is upstream of PKC-θ and Akt significantly suppressed the disease severity. Therefore, our data indicate that PD-1 dampens antigen-specific Th17 response, thus inhibiting the disease.


Assuntos
Artrite Reumatoide/imunologia , Doenças Autoimunes/imunologia , Receptor de Morte Celular Programada 1/metabolismo , Células Th17/citologia , Animais , Artrite/imunologia , Artrite/metabolismo , Artrite Experimental , Artrite Reumatoide/metabolismo , Doenças Autoimunes/metabolismo , Diferenciação Celular , Colágeno/química , Modelos Animais de Doenças , Citometria de Fluxo , Humanos , Ativação Linfocitária , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação
18.
Zhongguo Dang Dai Er Ke Za Zhi ; 17(12): 1354-9, 2015 Dec.
Artigo em Chinês | MEDLINE | ID: mdl-26695679

RESUMO

OBJECTIVE: To study the roles of PKCα on the proliferation, apoptosis, differentiation, cytokine production and inducible regulatory T cell (iTreg) induction of T cells. METHODS: T cells from WT (PKCα⁺/⁺) or PKCα knockout (PKCα⁻/⁻) mice were isolated and cultured in vitro. T cell proliferation and apoptosis were determined using ³H thymidine incorporation and CSFE/Annexin V staining. Cytokines production (IL-2, IL-4, IFN-γ and IL-17) was detected using ELISA. CD4⁺T cells were isolated and cultured in vitro via Th17 or iTreg biased condition. Flow cytometry was used to detect the cell differentiation. RESULTS: The production of IL-2 upon TCR stimulation increased, while the contents of IL-4 and IL-17 decreased in the PKCα⁻/⁻ group compared with the PKCα⁺/⁺ group. The differentiation rate of Th17 cells decreased, while the iTreg production increased in the PKCα⁻/⁻ group compared with the PKCα⁺/⁺ group. CONCLUSIONS: PKC-α is proinflammatory.


Assuntos
Proteína Quinase C-alfa/fisiologia , Linfócitos T/fisiologia , Animais , Diferenciação Celular , Citocinas/biossíntese , Ativação Linfocitária , Camundongos , Receptores de Antígenos de Linfócitos T/fisiologia , Células Th17/imunologia
19.
J Mol Neurosci ; 57(1): 28-37, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25957996

RESUMO

Astrocyte activation, associated with the release of pro-inflammatory cytokines interleukin 1-ß (IL-1ß), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF-α), is a hallmark of multiple brain diseases, including mesial temporal lobe epilepsy. In recent years, several microRNAs have emerged as important controllers of Toll-like receptor (TLR) signaling. In this study, we investigated the effect of miR-132, miR-146a, and miR-155 on myeloid-related protein-8 (MRP8) induced astrocyte-related inflammation. Using quantitative polymerase chain reaction (qPCR) and western blot, we found clear upregulation of TLR4 and downstream inflammatory cytokines, along with dysregulation of miR-132, miR-146a, and miR-155 in in vitro astrocytes after exposing them to different concentrations of MRP8. In addition, we focused on the effect of miR-132 on astrocyte-related inflammation induced by MRP8 via lentiviral infection then evaluated the expression of its possible target genes: acetylcholinesterase (AChE) and interleukin-1 receptor-associated kinase (IRAK4). Our results show that miR-132 is a negative feedback regulator of IL-1ß and IL-6, but not TNF-α, by targeting IRAK4. Together, our findings demonstrate the novel role of TLR4-related microRNAs, especially miR-132, in the regulation of MRP8-induced astrocyte activation and highlight the importance of miR-132 in the modulation of innate immune response induced by endogenous ligands in neurological diseases.


Assuntos
Transportadores de Cassetes de Ligação de ATP/metabolismo , Astrócitos/metabolismo , MicroRNAs/genética , Receptor 4 Toll-Like/metabolismo , Transportadores de Cassetes de Ligação de ATP/genética , Acetilcolinesterase/genética , Acetilcolinesterase/metabolismo , Linhagem Celular Tumoral , Humanos , Inflamação/metabolismo , Quinases Associadas a Receptores de Interleucina-1/genética , Quinases Associadas a Receptores de Interleucina-1/metabolismo , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Receptor 4 Toll-Like/genética , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
20.
J Neuroimmunol ; 282: 110-7, 2015 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-25903737

RESUMO

Recently, the role of inflammation in the pathogenesis of mesial temporal lobe epilepsy (MTLE) has garnered great attention. Increasing evidence indicated that interleukin-1ß (IL-1ß) plays a critical role in the pathogenesis of MTLE. In this study, we cultured primary hippocampal neurons, using IL-1ß to mimic the process of inflammatory reaction in neurons, then inhibited the inflammation using inhibitors of the PI3K/Akt/mTOR signaling pathway. The expression of proteins related to the PI3K/Akt/mTOR signaling pathway in rat hippocampal neurons was detected by western blot, and similar methods were applied to the hippocampi obtained from children with MTLE and normal controls. Neuronal somatic size and dendritic length were measured by immunohistochemistry and digital imaging. We observed that stimulation with IL-1ß in neuron led to the up-regulation of p-Akt and p70S6K and promoted the growth of cell somatic size and dendritic length via the PI3K/Akt/mTOR signaling pathway. Pre-treatment with inhibitors of the pathway, LY294002 and rapamycin, decreased the expression of p-Akt and p70S6K and alleviated the morphological changes induced by IL-1ß in hippocampal neurons. We further verified the increasement of P-Akt and p70S6K in the hippocampi of children with MTLE. These data are the first to demonstrate that the inflammatory response induced by IL-1ß promotes seizures and plays an important role in the pathogenesis of MTLE via the PI3K/Akt/mTOR signaling pathway. Therefore, modulation of the PI3K/Akt/mTOR signaling pathway may be a novel therapeutic target for the treatment of MTLE.


Assuntos
Epilepsia do Lobo Temporal/patologia , Hipocampo/citologia , Hipocampo/metabolismo , Interleucina-1beta/metabolismo , Neurônios/metabolismo , Transdução de Sinais/fisiologia , Animais , Animais Recém-Nascidos , Células Cultivadas , Criança , Cromonas/farmacologia , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/farmacologia , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Hipocampo/patologia , Humanos , Interleucina-1beta/farmacologia , Masculino , Proteínas Associadas aos Microtúbulos/metabolismo , Morfolinas/farmacologia , Neurônios/efeitos dos fármacos , Neurônios/ultraestrutura , Proteína Oncogênica v-akt/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Ratos , Ratos Sprague-Dawley , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo
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