RESUMO
Type 1 diabetes mellitus is a chronic disease caused by the destruction of pancreatic beta cells. Based on the hygiene hypothesis, a growing body of evidence suggests a negative association between parasitic infections and diabetes in humans and animal models. The mechanism of parasite-mediated prevention of type 1 diabetes mellitus may be related to the adaptive and innate immune systems. Macrophage polarization is a new paradigm for the treatment of type 1 diabetes mellitus, and different host macrophage subsets play various roles during parasite infection. Proinflammatory cytokines are released by M1 macrophages, which are important in the development of type 1 diabetes mellitus. Parasite-activated M2 macrophages prevent the development of type 1 diabetes mellitus and can influence the development of adaptive immune responses through several mechanisms, including Th2 cells and regulatory T cells. Here, we review the role and mechanism of macrophage polarization in parasitic protection against type 1 diabetes mellitus.
Assuntos
Diabetes Mellitus Tipo 1 , Parasitos , Doenças Parasitárias , Humanos , Animais , Diabetes Mellitus Tipo 1/prevenção & controle , Macrófagos , Citocinas , Células Th2 , Ativação de MacrófagosRESUMO
Pulsatile shear (PS) and oscillatory shear (OS) elicit distinct mechanotransduction signals that maintain endothelial homeostasis or induce endothelial dysfunction, respectively. A subset of microRNAs (miRs) in vascular endothelial cells (ECs) are differentially regulated by PS and OS, but the regulation of the miR processing and its implications in EC biology by shear stress are poorly understood. From a systematic in silico analysis for RNA binding proteins that regulate miR processing, we found that nucleolin (NCL) is a major regulator of miR processing in response to OS and essential for the maturation of miR-93 and miR-484 that target mRNAs encoding Krüppel-like factor 2 (KLF2) and endothelial nitric oxide synthase (eNOS). Additionally, anti-miR-93 and anti-miR-484 restore KLF2 and eNOS expression and NO bioavailability in ECs under OS. Analysis of posttranslational modifications of NCL identified that serine 328 (S328) phosphorylation by AMP-activated protein kinase (AMPK) was a major PS-activated event. AMPK phosphorylation of NCL sequesters it in the nucleus, thereby inhibiting miR-93 and miR-484 processing and their subsequent targeting of KLF2 and eNOS mRNA. Elevated levels of miR-93 and miR-484 were found in sera collected from individuals afflicted with coronary artery disease in two cohorts. These findings provide translational relevance of the AMPK-NCL-miR-93/miR-484 axis in miRNA processing in EC health and coronary artery disease.
Assuntos
Doença da Artéria Coronariana/genética , Mecanotransdução Celular/genética , MicroRNAs/metabolismo , Fosfoproteínas/metabolismo , Proteínas de Ligação a RNA/metabolismo , Proteínas Quinases Ativadas por AMP/genética , Proteínas Quinases Ativadas por AMP/metabolismo , Adulto , Idoso , Animais , Estudos de Casos e Controles , Células Cultivadas , Biologia Computacional , Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/patologia , Células Endoteliais/patologia , Endotélio Vascular/citologia , Endotélio Vascular/patologia , Feminino , Técnicas de Silenciamento de Genes , Humanos , Fatores de Transcrição Kruppel-Like/genética , Masculino , Camundongos , MicroRNAs/antagonistas & inibidores , MicroRNAs/sangue , Pessoa de Meia-Idade , Óxido Nítrico Sintase Tipo III/genética , Fosforilação , Processamento de Proteína Pós-Traducional , Processamento Pós-Transcricional do RNA , Serina/metabolismo , Estresse Mecânico , NucleolinaRESUMO
In order to explore the correlation between the medicinal propertiesï¼efficacy and application in the same genetic relationshipï¼explain the scientific connotation of the medicinal properties and effects of traditional Chinese medicines(TCM)ï¼promote the academic development of the theory of traditional Chinese medicinesï¼and provide reference for the research and development of the traditional Chinese medicines of a same genus. In this paper, a literature study of ancient and modern works of Chinese herbal medicine was conducted to investigate the correlation between the properties, meridians tropism, efficacy and application of Alpinia officinarumï¼ A. katsumadaiï¼ Galangae Fructus and Alpinae Oxyphyllae Fructus, four kinds of Alpinia Chinese medicinesï¼The results showed that the similar properties of these four kinds of Alpinia Chinese medicines included that they were acrid, warm,and mainly getting into the spleen and stomach channels; the similar efficacies included that dispelling coldï¼relieving painï¼warming stomachï¼anti-nauseaï¼anti-diarrhealï¼reinforcing spleen to promote digestion and other effects; in application aspects, the similarities were that they were all mainly used in treatment of catching cold or spleen deficiency induced by abdominal painï¼vomitingï¼diarrhea,diet indigestion, etc. indicating that phylogenetic relationship was closely related with the herbal properties, efficacy and application. It is an effective way to exploreï¼collate and research traditional Chinese medicine by using plant phylogenetic relationships in exploring the internal relations and laws of TCM theoriesï¼material bases, pharmacological effects and clinical applications, also with a strong maneuverability to explain their scientific connotation.
Assuntos
Alpinia , Medicamentos de Ervas Chinesas , Meridianos , Medicina Tradicional Chinesa , FilogeniaRESUMO
InN thin films were prepared using reactive radio frequency sputtering on (111) Si substrates under different N2/Ar ratio. The surface morphology and optical properties of InN thin films were characterized by X-ray diffraction, atomic force microscopy, scanning electron microscope, energy dispersive spectrometer, and UV-visible-NIR spectrophotometer at room temperature. It was found that the growth rate and surface RMS roughness of InN layers all significantly decreased with the increasing of N2 content in the sputtering gas. All the InN films were wurtzite structure with the proportion of N2 increasing from 40% to 100% in the mixture gas. The highly c-axis orientation InN films could only be obtained in the composition ratios of N2 higher than 90%. The atomic percentage of N is much higher than that of In at high N2 content films, which mainly due to the chemical reaction on the surface of Si substrate. The apparent optical band gap energy is estimated at 1.83 eV. However, the InN absorption band tail is strongly influenced by the sputtering due to a change in the species of the plasma.
RESUMO
With the aim of finding more potential inhibitors against NADH-fumarate reductase (specific target for treating helminthiasis and cancer) from natural resources, Talaromyces wortmannii was treated with the epigenome regulatory agent suberoylanilide hydroxamic acid, which resulted in the isolation of four new wortmannilactones derivatives (wortmannilactones I-L, 1-4). The structures of these new compounds were elucidated based on IR, HRESIMS and NMR spectroscopic data analyses. These four new compounds showed potent inhibitory activity against NADH-fumarate reductase with the IC50 values ranging from 0.84 to 1.35µM.
Assuntos
Ácidos Hidroxâmicos/farmacologia , Macrolídeos/farmacologia , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/antagonistas & inibidores , Talaromyces/química , Meios de Cultura , Macrolídeos/química , Estrutura Molecular , Análise Espectral/métodos , VorinostatRESUMO
OBJECTIVE: Nuclear factor kappa-B (NF-954;B)-induced inflammation leads to myocarditis and heart dysfunction. How microRNAs (miRNAs) contribute to this process is poorly defined. The aim of this study was to investigate whether miRNAs regulate NF-954;B-induced inflammation in experimental autoimmune myocarditis (EAM) in vivo. METHODS AND RESULTS: NF-954;B and its related proinflammatory genes, including interleukin-6 (IL-6) and tumor necrosis factor-a (TNF-a), were activated in EAM. Profiling of NF-954;B-related miRNAs revealed that miR-590-3p was strikingly reduced in EAM. We found IL-6-induced proinflammatory signaling via miR-590-3p reduction, p50 induction, NF-954;B activation and IL-6/TNF-a expression. Moreover, a luciferase reporter assay demonstrated that miR-590-3p directly interacted with the 3' UTR (untranslated region) of the p50 subunit, and that miR-590-3p overexpression inhibited p50 expression. Finally, miR-590-3p transfection through adeno-associated virus significantly inhibited p50 expression, suppressed NF-954;B activity and blocked IL-6/TNF-a expression in vivo, reducing the lesion area and improving cardiac function in EAM. CONCLUSION: miR-590-3p is a novel NF-954;B-related miRNA that directly targets the p50 subunit. This may provide a novel strategy for the treatment of myocarditis.
Assuntos
Interleucina-6/genética , MicroRNAs/genética , Miocardite/genética , Subunidade p50 de NF-kappa B/genética , Fator de Necrose Tumoral alfa/genética , Animais , Masculino , RatosRESUMO
Gliomas of the brain are characterised by high aggressiveness, high postoperative recurrence rate, high morbidity and mortality, posing a great challenge to clinical treatment. Traditional treatments include surgery, radiotherapy and chemotherapy; they also have significant associated side effects, leading to difficulties in tumour resection and recurrence. Photodynamic therapy has been shown to be a promising new strategy to help treat malignant tumours of the brain. It irradiates the tumour site at a specific wavelength to activate a photosensitiser, which selectively accumulates at the tumour site, triggering a photochemical reaction that destroys the tumour cells. It has the advantages of being minimally invasive, highly targeted and with few adverse reactions, and is expected to be well used in anti-tumour therapy. However, the therapeutic effect of traditional PDT is limited by the weak tissue penetration ability of photosensitiser, hypoxia and immunosuppression in the tumour microenvironment. This paper reviews the current research status on the therapeutic principle of photodynamic therapy in glioma and the mechanism of tumour cell injury, and also analyses the advantages and disadvantages of the current application in glioma treatment, and clarifies the analysis of ideas to improve the tissue penetration ability of photosensitizers. It aims to provide a feasible direction for the improvement of photodynamic therapy for glioma and a reference for the clinical treatment of deep brain tumours.
RESUMO
The human brain has been implicated in the pathogenesis of several complex diseases. Taking advantage of single-cell techniques, genome-wide association studies (GWAS) have taken it a step further and revealed brain cell-type-specific functions for disease loci. However, genetic causal associations inferred by Mendelian randomization (MR) studies usually include all instrumental variables from GWAS, which hampers the understanding of cell-specific causality. Here, we developed an analytical framework, Cell-Stratified MR (csMR), to investigate cell-stratified causality through colocalizing GWAS signals with single-cell eQTL from different brain cells. By applying to obesity-related traits, our results demonstrate the cell-type-specific effects of GWAS variants on gene expression, and indicate the benefits of csMR to identify cell-type-specific causal effect that is often hidden from bulk analyses. We also found csMR valuable to reveal distinct causal pathways between different obesity indicators. These findings suggest the value of our approach to prioritize target cells for extending genetic causation studies.
Assuntos
Encéfalo , Estudo de Associação Genômica Ampla , Análise da Randomização Mendeliana , Obesidade , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Humanos , Obesidade/genética , Obesidade/metabolismo , Encéfalo/metabolismo , Análise de Célula Única/métodos , Predisposição Genética para Doença/genética , Causalidade , Regulação da Expressão Gênica , Expressão Gênica/genéticaRESUMO
A prolonged or excessive adrenergic activation leads to myocyte loss and heart dysfunction; however, how it contributes to heart failure remains poorly defined. Here we show that isoproterenol (ISO) induced aberrant endoplasmic reticulum (ER) stress and apoptotic cell death, which was inhibited by activating the AMP-activated protein kinase (AMPK) in vitro and in vivo. Persistent ISO stimulation suppressed the AMPK phosphorylation and function, resulting in enhanced ER stress and the subsequent cell apoptosis in cardiomyocytes in vitro and in vivo. AMPK activation decreased the aberrant ER stress, apoptosis, and brain natriuretic peptide (BNP) release in ISO-treated cardiomyocytes, which was blocked by AMPK inhibitor Compound C. Importantly, increased ER stress and apoptosis were observed in ISO-treated cardiomyocytes isolated from AMPKα2(-/-) mice. Inhibition of ER stress attenuated the apoptosis but failed to reverse AMPK inhibition in ISO-treated cardiomyocytes. Moreover, metformin administration activated AMPK and reduced both ER stress and apoptosis in ISO-induced rat heart failure in vivo. We conclude that ISO, via AMPK inactivation, causes aberrant ER stress, cardiomyocyte injury, BNP release, apoptosis, and hence heart failure in vivo, all of which are inhibited by AMPK activation.
Assuntos
Proteínas Quinases Ativadas por AMP/genética , Insuficiência Cardíaca/induzido quimicamente , Isoproterenol/efeitos adversos , Metformina/farmacologia , Miócitos Cardíacos/efeitos dos fármacos , Proteínas Quinases Ativadas por AMP/antagonistas & inibidores , Proteínas Quinases Ativadas por AMP/deficiência , Animais , Apoptose/efeitos dos fármacos , Retículo Endoplasmático/efeitos dos fármacos , Retículo Endoplasmático/genética , Retículo Endoplasmático/metabolismo , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Regulação da Expressão Gênica , Insuficiência Cardíaca/enzimologia , Insuficiência Cardíaca/patologia , Insuficiência Cardíaca/prevenção & controle , Masculino , Camundongos , Camundongos Knockout , Miocárdio/enzimologia , Miocárdio/patologia , Miócitos Cardíacos/enzimologia , Miócitos Cardíacos/patologia , Peptídeo Natriurético Encefálico/metabolismo , Fosforilação , Pirazóis/farmacologia , Pirimidinas/farmacologia , Ratos , Ratos Sprague-Dawley , Transdução de SinaisRESUMO
AIMS: This study aimed to explore relationships short chain fatty acids with diabetic nephropathy (DN) in type 2 diabetes (T2D) patients. METHODS: We extracted the clinical and omics data of 100 T2D patients and 100 DN patients from April 2018 to April 2019 from a tertiary hospital. Restricted cubic splines were used to examine full-range associations of short chain fatty acids with DN in T2D.Query Logistic regression was used to obtain odds ratio (OR) and confidence interval (CI). RESULTS: Acetate, butyrate and isovalerate were negatively correlated with DN. Isobutyrate was positively correlated with DN. Propionate ≥ 4.4 µg/mL and isobutyrate ≥ 1.4 µg/mL had threshold effects and their increasing levels above the cutoff points were associated with rapid rises in the risk of DN. The additive interaction between high propionate and high isobutyrate in serum significantly increased the risk of DN (OR34.35; 95%CI 7.11 to 166.08). Presence of hypertension further increased the OR of high propionate for DN to 8.27(95%CI 1.82 to 37.57) with a significant additive interaction. The additive interaction of the high isobutyrate and hypertension was not significant. CONCLUSIONS: Acetate, butyrate and isovalerate were negatively associated with DN. Isobutyrate was positively associated with DN. Serum high propionate and high isobutyrate worked independently and synergistically to increase the risk of DN in T2D. Presence of hypertension further amplified the effect of copresence of high propionate on DN risk.
Assuntos
Diabetes Mellitus Tipo 2 , Nefropatias Diabéticas , Hipertensão , Butiratos , Diabetes Mellitus Tipo 2/complicações , Nefropatias Diabéticas/epidemiologia , Nefropatias Diabéticas/etiologia , Ácidos Graxos Voláteis , Humanos , Hipertensão/complicações , Isobutiratos , PropionatosRESUMO
Objective: This study aimed to investigate the inhibition of human important phase II metabolic enzyme sulfotransferases (SULTs) by phthalate monoesters, which are important metabolites of phthalate esters (PAEs). Method: Recombinant SULT-catalyzed metabolism of p-nitrophenol (PNP) was employed as the probe reactions of SULTs to investigate the inhibition of 8 kinds of phthalate monoesters towards SULT isoforms. An in vitro incubation system was utilized for preliminary screening, and 100 µM of phthalate monoesters was used. Inhibition kinetics were carried out to determine the inhibition of SULTs by phthalate monoesters. Result: Multiple phthalate monoesters have been demonstrated to exert strong inhibition potential towards SULT1A1, SULT1B1, and SULT1E1, and no significant inhibition of phthalate monoesters towards SULT1A3 was found. The activity of SULT1A1 was strongly inhibited by mono-hexyl phthalate (MHP), mono-octyl phthalate (MOP), mono-benzyl phthalate (MBZP), and mono-ethylhexyl phthalate (MEHP). Monobutyl phthalate (MBP), MHP, MOP, mono-cyclohexyl phthalate (MCHP), and MEHP significantly inhibited the activity of SULT1B1. MHP, MOP, and MEHP significantly inhibited the activity of SULT1E1. MOP was chosen as the representative phthalate monoester to determine the inhibition kinetic parameters (Ki) towards SULT1B1 and SULT1E1. The inhibition kinetic parameters (Ki) were calculated to be 2.23 µM for MOP-SULT1B1 and 5.54 µM for MOP-SULT1E1. In silico docking method was utilized to understand the inhibition mechanism of SULT1B1 by phthalate monoesters. Conclusions: All these information will be beneficial for understanding the risk of phthalate monoester exposure from a new perspective.
Assuntos
Ésteres , Sulfotransferases , Humanos , Ácidos Ftálicos , Isoformas de Proteínas , Sulfotransferases/metabolismoRESUMO
Transmembrane and coiled-coil domains 1 (TMCO1) is a recently discovered transmembrane protein of endoplasmic reticulum (ER), which plays a critical role in maintaining calcium homeostasis. TMCO1 dysfunction has been proved to be closely related to a variety of human diseases, including glaucoma, deformities, mental retardation and tumorigenesis. However, the role of TMCO1 in gliomas remains unclear. The purpose of this study was to detect the role of TMCO1 in the pathogenesis and progression of gliomas. This study demonstrated that TMCO1 was upregulated in gliomas and its overexpression predicted poor prognosis. We also revealed that the expression of TMCO1 was associated with the World Health Organization (WHO) grade of gliomas. Knockdown of TMCO1 inhibited the proliferation and induced apoptosis of U87 and U251 cells. In addition, TMCO1 induced GBM cell migration and invasion by promoting epithelial-mesenchymal transition (EMT). These date collectively proved the crucial role of TMCO1 as a novel prognostic factor and underlying therapeutic target for glioma patients.
Assuntos
Transição Epitelial-Mesenquimal , Glioma , Canais de Cálcio/genética , Canais de Cálcio/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Retículo Endoplasmático/metabolismo , Regulação Neoplásica da Expressão Gênica , Glioma/patologia , HumanosRESUMO
OBJECTIVE: To explore the clinical effects of posterior short-segment pedicle screw internal fixation combined with vertebroplasty for the treatment of Kümmell disease with kyphosis. METHODS: Twenty-four patients with Kümmell disease complicated with kyphosis treated by posterior short-segment pedicle screw internal fixation combined with vertebroplasty from January 2016 to December 2018 were retrospectively analyzed, including 6 males and 18 females, aged 63 to 85 (73.1±6.5) years old. The clinical effect was evaluate by visual analogue scale (VAS), Oswestry Disability Index (ODI), the anterior height of injured vertebral body, and the sagittal Cobb angle of the affected segment beforeoperation, at 3 days and final follow up after operation. And the surgical complications were observed. RESULTS: All 24 patients were followed up from 12 to 24 months with an average of (15.5±3.2) months. The VAS score was decreased from 5.21±1.06 preoperatively to 2.38±0.58 at 3 days postoperatively and 1.71±0.75 at final follow-up;ODI was decreased from (50.4±13.5)% preoperatively to (20.9±8.0)% at 3 days postoperatively and (16.7±9.6)% at final follow-up;the anterior height of injured vertebral body was restored from (8.0±4.2) mm before surgery to (18.1±5.0) mm at 3 days after surgery and (16.8±5.1) mm at final follow up;the sagittal Cobb angle of affected segment was decreased from (19.5±6.3)° preoperatively to (7.6±2.1)° at 3 days after surgery and(8.4±1.7)° at final follow-up. VAS, ODI, anterior height of injured vertebral body, and sagittal Cobb angle of affected segment were significantly improved at 3 days after operation and at final follow-up (P<0.05). Two patients had complications, including asymptomaticcement leakage in 1 patient and superficial wound infection in 1 patient. CONCLUSION: Posterior short-segment pedicle screw internal fixation combined with vertebroplasty for the treatment of Kümmell disease with kyphosis has relatively small surgical trauma, excellent clinical results, good vertebral height recovery, satisfactory correction of kyphotic angle, and fewer complications, etc. It is a safe and effective surgical method to treat Kümmell disease with kyphosis.
Assuntos
Cifose , Parafusos Pediculares , Fraturas da Coluna Vertebral , Vertebroplastia , Feminino , Humanos , Cifose/cirurgia , Vértebras Lombares/lesões , Masculino , Estudos Retrospectivos , Vértebras Torácicas/lesões , Vértebras Torácicas/cirurgiaRESUMO
Emerging evidence indicates that circRNAs are broadly expressed in osteosarcoma (OS) cells and play a crucial role in OS progression. Recently, cancer-specific circRNA circPRKAR1B has been identified by high-throughput sequencing and is recorded in publicly available databases. Nevertheless, the detailed functions and underlying mechanisms of circPRKAR1B in OS remains poorly understood. By functional experiments, we found that circPRKAR1B enhanced OS cell proliferation, migration, and promotes OS epithelial-mesenchymal transition (EMT). Mechanistic investigations suggested that circPRKAR1B promotes OS progression through sponging miR-361-3p to modulate the expression of FZD4. Subsequently, we identified that EIF4A3 promoted cirPRKAR1B formation through binding to the downstream target of circPRKAR1B on PRKAR1B mRNA. Further rescue study revealed that overexpression of the Wnt signalling could impair the onco-suppressor activities of the silencing of circPRKAR1B. Interestingly, further experiments indicated that circPRKAR1B is involved in the sensitivity of chemoresistance in OS. On the whole, our results demonstrated that circPRKAR1B exerted oncogenic roles in OS and suggested the circPRKAR1B/miR-361-3p/FZD4 axis plays an important role in OS progression and might be a potential therapeutic target.
Assuntos
Neoplasias Ósseas/metabolismo , Carcinogênese/metabolismo , Subunidade RIbeta da Proteína Quinase Dependente de AMP Cíclico/metabolismo , RNA Helicases DEAD-box/metabolismo , Fator de Iniciação 4A em Eucariotos/metabolismo , Receptores Frizzled/metabolismo , MicroRNAs/metabolismo , Osteossarcoma/metabolismo , RNA Circular/metabolismo , Transdução de Sinais/genética , Animais , Neoplasias Ósseas/genética , Neoplasias Ósseas/patologia , Carcinogênese/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Subunidade RIbeta da Proteína Quinase Dependente de AMP Cíclico/genética , Transição Epitelial-Mesenquimal/genética , Inativação Gênica , Humanos , Masculino , Camundongos , Camundongos Nus , MicroRNAs/genética , Osteossarcoma/genética , Osteossarcoma/patologia , RNA Circular/genética , Transfecção , Carga Tumoral/genética , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Glioblastoma (GBM) is the most common type of primary central nervous system tumor in adults, which has high mortality and morbidity rates, and short survival time, namely <15 months after the diagnosis and application of standard therapy, which includes surgery, radiation therapy and chemotherapy; thus, novel therapeutic strategies are imperative. The activation of the PI3K/AKT signaling pathway plays an important role in GBM. In the present study, U87 and U251 GBM cells were treated with the PI3K/mTORC1/2 inhibitor PQR309, and its effect on glioma cells was investigated. Cell Counting Kit8 assay, 5ethynyl2'deoxyuridine and colony formation assays revealed dose and timedependent cytotoxicity in glioma cells that were treated with PQR309. Flow cytometry and western blotting revealed that PQR309 can significantly induce tumor cell apoptosis and arrest the cell cycle in the G1 phase. Furthermore, the expression levels of AKT, phosphorylated (p)AKT, Bcl2, BclxL, Bad, Bax, cyclin D1, cleaved caspase3, MMP9 and MMP2 were altered. In addition, the migration and invasion of glioma cells, as detected by wound healing, migration and Transwell invasion assays, exhibited a marked suppression after treating the cells with PQR309. These results indicated that PQR309 exerts an antitumor effect by inhibiting proliferation, inducing apoptosis, inducing G1 cell cycle arrest, and inhibiting invasion and migration in human glioma cells. The present study provides evidence supportive of further development of PQR309 for adjuvant therapy of GBM.
Assuntos
Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Glioblastoma/tratamento farmacológico , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glioblastoma/genética , Glioblastoma/patologia , Humanos , Alvo Mecanístico do Complexo 1 de Rapamicina/antagonistas & inibidores , Alvo Mecanístico do Complexo 2 de Rapamicina/antagonistas & inibidores , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Proteínas de Neoplasias/genética , Fosfatidilinositol 3-Quinases/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt , Transdução de Sinais/efeitos dos fármacosRESUMO
OBJECTIVE: Surgery is indicated when antibiotic treatment fails in pyogenic spondylodiscitis, which is caused by pathogens such as the Staphylococcus species. The aim of the present study was to investigate the efficacy and safety of the oblique lateral interbody fusion (OLIF) corridor approach combined with posterior pedicle screw fixation for treating pyogenic spondylodiscitis. METHODS: This was a retrospective case series study. A total of 11 patients with an average age of 60.7 years (range, 40-70 years; 10 males and 1 females) with lumbar pyogenic spondylodiscitis who underwent single-stage debridement and reconstruction using the OLIF corridor combined with posterior pedicle screw fixation were recruited in our study from June 2016 to July 2017. All patients had single-level pyogenic spondylodiscitis between T12 and L5 . The baseline data, perioperative outcomes (operative time, intra-operative blood loss, and intra-operative complication), postoperative laboratory tests (erythrocyte sedimentation rate [ESR], C-reactive protein [CRP], white blood count [WBC], and tissue culture results), long-term complications (recurrence, fixation failure, and bony non-fusion rates), and duration of antibiotic administration were reviewed. Outcomes evaluated using a variety of scales including visual analog scale (VAS) score and Oswestry disability index (ODI), were compared pre-operatively and post-operatively. RESULTS: The mean follow-up period of time was 18.3 months. The average operative time and intra-operative blood loss were 217.0 ± 91.91 min and 220.9 ± 166.10 mL, respectively. There were no intra-operative complications, except in 1 patient who encountered somatosensory evoked potentials changes and 1 patient who had motor evoked potentials changes, both without post-surgery neurological deficits. Causative organisms were identified in 4 patients: Staphylococcus aureus in 1 patient and Streptococcus in 3 patients. At approximately 8.8 weeks after surgery, WBC, CRP, and ESR had returned to normal levels. All patients were pain free with no recurring infection. There was no fixation failure during follow up. Solid bony fusions were observed in all cases within 6 months. At the final follow up, the mean VAS (0.6 ± 0.69) and ODI (14.4 ± 4.27) were significantly lower than those before surgery (P < 0.05). CONCLUSION: One-stage debridement with autogenous iliac bone graft through the OLIF corridor combined with posterior pedicle screw fixation is effective and safe for single-level spontaneous lumbar pyogenic spondylodiscitis after antibiotic treatment fails.
Assuntos
Transplante Ósseo/métodos , Desbridamento/métodos , Discite/cirurgia , Vértebras Lombares/cirurgia , Fusão Vertebral/métodos , Adulto , Idoso , Avaliação da Deficiência , Discite/microbiologia , Feminino , Humanos , Ílio/transplante , Vértebras Lombares/microbiologia , Masculino , Pessoa de Meia-Idade , Medição da Dor , Parafusos Pediculares , Estudos Retrospectivos , Infecções Estafilocócicas/microbiologia , Infecções Estafilocócicas/cirurgiaRESUMO
Glioblastoma is the most common type of primary brain tumour in adults, and its pathogenesis is particularly complicated. Among the many possible mechanisms underlying its pathogenesis, hyperactivation of the PI3K/Akt pathway is essential to the occurrence and development of glioma through the loss of PTEN or somatic activating mutations in PIK3CA. In the present study, we investigated the effect of the PI3Kß inhibitor AZD6482 on glioma cells. The CCK-8 assay showed dose-dependent cytotoxicity in glioma cell lines treated with AZD6482. Additionally, AZD6482 treatment was found to significantly induce apoptosis and cell cycle arrest as detected using flow cytometry. Moreover, as shown using western blot analysis, the levels of p-AKT, p-GSK-3ß, Bcl-2, and cyclin D1 were decreased after AZD6482 treatment. In addition, we found that AZD6482 inhibited the migration and invasion of glioma cells as detected by wound healing and Transwell invasion assays. Taken together, our findings indicate that AZD6482 exerts an antitumour effect by inhibiting proliferation and inducing apoptosis in human glioma cells. AZD6482 may be applied as an adjuvant therapy to improve the therapeutic efficacy of glioblastoma treatment.
Assuntos
Neoplasias Encefálicas/tratamento farmacológico , Classe I de Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Glioblastoma/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Pirimidinonas/farmacologia , ortoaminobenzoatos/farmacologia , Apoptose/efeitos dos fármacos , Neoplasias Encefálicas/genética , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Glioblastoma/genética , Humanos , Mutação , PTEN Fosfo-Hidrolase/genética , PTEN Fosfo-Hidrolase/metabolismo , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinonas/uso terapêutico , Transdução de Sinais/genética , ortoaminobenzoatos/uso terapêuticoRESUMO
Glioma is the most common neoplasm of the central nervous system (CNS); the progression and outcomes of which are affected by a complicated network of genes and pathways. We chose a gene expression profile of GSE66354 from GEO database to search core biomarkers during the occurrence and development of glioma. A total of 149 samples, involving 136 glioma and 13 normal brain tissues, were enrolled in this article. 1980 differentially expressed genes (DEGs) including 697 upregulated genes and 1283 downregulated genes between glioma patients and healthy individuals were selected using GeoDiver and GEO2R tool. Then, gene ontology (GO) analysis as well as Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were carried out using the Database for Annotation, Visualization and Integrated Discovery (DAVID). Moreover, Cytoscape with Search Tool for the Retrieval of Interacting Genes (STRING) and Molecular Complex Detection (MCODE) plug-in was employed to imagine protein-protein interaction (PPI) of these DEGs. The upregulated genes were enriched in cell cycle, ECM-receptor interaction, and p53 signaling pathway, while the downregulated genes were enriched in retrograde endocannabinoid signaling, glutamatergic synapse, morphine addiction, GABAergic synapse, and calcium signaling pathway. Subsequently, 4 typical modules were discovered by the PPI network utilizing MCODE software. Besides, 15 hub genes were chosen according to the degree of connectivity, including TP53, CDK1, CCNB1, and CCNB2, the Kaplan-Meier analysis of which was further identified. In conclusion, this bioinformatics analysis indicated that DEGs and core genes, such as TP53, might influence the development of glioma, especially in tumor proliferation, which were expected to be promising biomarkers for diagnosis and treatment of glioma.
Assuntos
Biomarcadores Tumorais/genética , Neoplasias Encefálicas/genética , Glioma/genética , Biomarcadores Tumorais/metabolismo , Encéfalo/metabolismo , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Glioma/metabolismo , Glioma/patologia , Humanos , TranscriptomaRESUMO
STUDY DESIGN: Experimental study evaluated magnetic resonance imaging (MRI) and histologic changes in the multifidus muscle after anterior spinal fusion. OBJECTIVE: To determine the effect of spinal fusion on the multifidus muscle in an anterior rabbit model through the use of MRI and histologic evaluation. SUMMARY OF BACKGROUND DATA: Retraction and splitting approach are known to be important factors in postoperative injury and atrophy of the multifidus muscle. The effect and possible mechanism of spinal fusion as an independent factor remains unknown. METHODS: Thirty-six New Zealand white rabbits were divided into two groups. Animals in the fusion group underwent two-level anterior spinal fusion whereas those in the control group underwent similar surgery without spinal fusion. The status of the multifidus muscle was evaluated with MRI and histological analysis at preoperative, 3 weeks, 6 weeks, 3 months, 6 months, and 12 months postoperatively. RESULTS: All rabbits in the fusion group achieved solid fusion. The mean T1-weighted and T2-weighted signal intensity ratios of gross multifidus to psoas muscles were all approximately 1.0 postoperatively, with no remarkable difference between the groups. The mean lesser diameter of myofibrils in either group did not significantly differ between the preoperative and postoperative specimens. There was no significant fibrotic change or fatty degeneration for either group. Decrease in acetylcholine activity or granular degeneration of the neuromuscular junction were not observed, and normal shape and size were found in nearly all samples at all time points in both groups (Pâ>â0.05). CONCLUSION: After two-segment anterior spinal fusion, multifidus atrophy was not observed throughout a 12-month follow up. The rabbit model of anterior fusion is better suited to study the effect of fusion alone on the status of the multifidus muscle. LEVEL OF EVIDENCE: 3.
Assuntos
Atrofia Muscular , Músculos Paraespinais/patologia , Músculos Psoas/patologia , Animais , Modelos Animais de Doenças , Seguimentos , Vértebras Lombares/cirurgia , Imageamento por Ressonância Magnética/métodos , Coelhos , Fusão Vertebral/métodosRESUMO
We present two-step phase-shifting differential-recording digital holographic microscopy (TPD-DH in microscopy) for phase imaging of microscopic transparent elements. Two CCDs are employed to record two interferograms at two different defocusing distances. The interferograms on the two CCD cameras are shifted for a phase retarder 0 and π via an all-optics phase shifting unit. A novel algorithm is proposed to reconstruct both amplitude and phase distributions of the object wave from the recorded interferograms. This method has the same spectrum bandwidth and measurement accuracy with those of conventional four-step phase-shifting interferometry (FS-PSI), whereas it reduces the measurement time by half.