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BACKGROUND AND PURPOSE: Deep brain stimulation (DBS) has emerged as a promising treatment for movement disorders. This prospective study aims to evaluate the effects of bilateral subthalamic nucleus DBS (STN-DBS) on motor and non-motor symptoms in patients with primary Meige syndrome. METHODS: Thirty patients who underwent bilateral STN-DBS between April 2017 and June 2020 were included. Standardized and validated scales were utilized to assess the severity of dystonia, health-related quality of life, sleep, cognitive function and mental status at baseline and at 1 year and 3 years after neurostimulation. RESULTS: The Burke-Fahn-Marsden Dystonia Rating Scale movement scores showed a mean improvement of 63.0% and 66.8% at 1 year and 3 years, respectively, after neurostimulation. Similarly, the Burke-Fahn-Marsden Dystonia Rating Scale disability scores improved by 60.8% and 63.3% at the same time points. Postoperative quality of life demonstrated a significant and sustained improvement throughout the follow-up period. However, cognitive function, mental status, sleep quality and other neuropsychological functions did not change after 3 years of neurostimulation. Eight adverse events occurred in six patients, but no deaths or permanent sequelae were reported. CONCLUSIONS: Bilateral STN-DBS is a safe and effective alternative treatment for primary Meige syndrome, leading to improvements in motor function and quality of life. Nevertheless, it did not yield significant amelioration in cognitive, mental, sleep status and other neuropsychological functions after 3 years of neurostimulation.
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Estimulação Encefálica Profunda , Distonia , Distúrbios Distônicos , Síndrome de Meige , Núcleo Subtalâmico , Humanos , Síndrome de Meige/terapia , Síndrome de Meige/etiologia , Distonia/terapia , Qualidade de Vida , Estimulação Encefálica Profunda/efeitos adversos , Estudos Prospectivos , Distúrbios Distônicos/terapia , Resultado do Tratamento , Globo PálidoRESUMO
Spontaneous intracerebral hemorrhage (ICH) is associated with high mortality and disability rates. The microglia-induced inflammatory response is a critical factor determining brain tissue damage after ICH. Raddeanin A (RA) is a natural triterpenoid compound with anti-inflammatory effects, although its effects on ICH and the underlying molecular mechanism have not been elucidated. In this study, we found that RA reduced the volume of cerebral hematoma and cerebral edema, attenuated neuronal apoptosis and improved the behavioral indices in a murine model of acute cerebral hemorrhage. Mechanistically, RA downregulated the TLR4-mediated pro-inflammatory effectors, reduced infiltration of microglia in peri-intracerebral hemorrhage and inhibited apoptosis of neurons co-cultured with activated microglia. In conclusion, RA can alleviate ICH-related tissue damage and promote the recovery of neuronal function by suppressing microglia-induced inflammation and apoptosis.
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Edema Encefálico , Receptor 4 Toll-Like , Animais , Edema Encefálico/complicações , Edema Encefálico/etiologia , Hemorragia Cerebral/complicações , Hemorragia Cerebral/tratamento farmacológico , Camundongos , Microglia , SaponinasRESUMO
Objective To evaluate the effect of methylprednisolone sodium succinate combined with tropisetron on postoperative nausea and vomiting(PONV)under microvascular decompression of hemifacial spasm.Methods From January to June 2019,485 patients undergoing microvascular decompression for facial spasm at Department of Neurosurgery,Peking University People's Hospital were randomly assigned into two groups with random number table method.For group A(n=242),2 ml saline was administrated by intravenous drip before induction and 5 mg tropisetron after operation.For group B(n=243),40 mg methylprednisolone sodium succinate was administrated by intravenous drip before induction and 5 mg tropisetron after operation.The anesthesia time,operation time,and incidence of PONV in 0-24 h and 24-48 h were recorded for the comparison of the remedial treatment rate of nausea and vomiting between the two groups.Results There was no significant difference in age,gender,smoking history,body mass index value,American Society of Anesthesiologists score,medical history,surgical side,PONV history,operation time or anesthesia time between the two groups(all P > 0.05).The incidence of PONV in group A was 35.5% and 18.2% during 0-24 h and 24-48 h,respectively,which was significantly higher than that(18.5%,χ 2=7.331,P=0.007;8.2%,χ 2=4.364,P=0.037)in group B.The application rate of antiemetic drugs in group A was 15.2% and 8.7% during 0-24 h and 24-48 h,respectively,which was significantly higher than that(5.3%,χ 2=5.327,P=0.021;2.0%,χ 2=4.432,P=0.035)in group B.Conclusion The combination of methylprednisolone sodium succinate and tropisetron can effectively prevent PONV under microvascular decompression of hemifacial spasm,with the performance superior to single drug treatment.
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Antieméticos , Espasmo Hemifacial , Cirurgia de Descompressão Microvascular , Método Duplo-Cego , Espasmo Hemifacial/tratamento farmacológico , Espasmo Hemifacial/cirurgia , Humanos , Indóis , Hemissuccinato de Metilprednisolona/uso terapêutico , TropizetronaRESUMO
OBJECTIVES: To study the efficacy and safety of bilateral globus pallidus internus deep brain stimulation (GPi-DBS) in refractory Meige syndrome (MS) and evaluate the psychiatric disorders before and after surgery. METHODS: Twenty-two patients with MS treated with bilateral GPi-DBS were retrospectively analysed before surgery and after continuous neurostimulation. Before surgery, patients were assessed by the Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS), Self-Rating Depression Scale, Medical Outcomes Study 36-Item Short-Form General Health Survey (SF-36) and Pittsburgh Sleep Quality Index (PQSI), which corresponded to motor symptoms, depressive state, quality of life and sleep quality, respectively. The implantable pulse generator of each patient was activated at 1 month after surgery. At 1 month, 3 months, 6 months and 12 months after continuous neurostimulation, all patients were evaluated by the same scales above. RESULTS: The BFMDRS movement scores decreased from 15.0±5.3 before surgery to 3.5±4.5 at 12 months after neurostimulation, with a mean improvement of 78% (p<0.001). The BFMDRS disability scores improved from 7.4±4.9 before surgery to 4.0±4.6 at 12 months after neurostimulation, with a mean improvement of 56% (p<0.001). The postoperative SF-36 scores had the remarkable improvement compared with baseline scores. Impaired sleep quality was found in 82% of patients and depression in 64% before surgery, which didn't neither obtained amelioration after continuous neurostimulation. CONCLUSIONS: Bilateral pallidal neurostimulation is a beneficial therapeutic option for refractory MS, which could improve the motor symptoms except for depression and sleep quality.
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Estimulação Encefálica Profunda/métodos , Depressão/psicologia , Globo Pálido , Síndrome de Meige/terapia , Qualidade de Vida , Sono , Idoso , Transtornos da Articulação/epidemiologia , Transtornos de Deglutição/epidemiologia , Tontura/epidemiologia , Feminino , Transtornos Neurológicos da Marcha/epidemiologia , Humanos , Hipestesia/epidemiologia , Neuroestimuladores Implantáveis , Masculino , Síndrome de Meige/fisiopatologia , Síndrome de Meige/psicologia , Pessoa de Meia-Idade , Complicações Pós-Operatórias/epidemiologia , Estudos Retrospectivos , Resultado do TratamentoRESUMO
Verbascoside (VB), a glycosylated phenylpropanoid compound, is derived from the plant Syringa vulgaris (Oleaceae) and has been shown to have antitumor effects in multiple human cancers, including glioblastoma (GBM); however, the underlying mechanism has not been completely elucidated. Epithelial-to-mesenchymal transition (EMT) is the pivotal event in tumor progression. c-Met, a receptor tyrosine kinase, plays an important role in GBM aggressiveness via promoting EMT. The current study aimed to explore whether VB suppresses c-Met-induced EMT and investigated the mechanism of c-Met degradation. We found that VB inhibited GBM cell growth and downregulated c-Met and the EMT markers (snail, vimentin, and zeb1) in vitro and in an orthotopic xenograft mouse model. In addition, overexpressing c-Met in glioblastoma cells abolished the effects of VB on EMT. We also used a microscale thermophoresis (MST) assay to show that VB could directly bind to the c-Met protein, and we showed that VB degraded the c-Met protein via the ubiquitination-proteasome pathway. Our study is the first to identify a new mechanism for the anticancer effects of VB, namely, the inhibition of EMT by directly targeting c-Met; the inhibition of EMT results in c-Met protein degradation through the ubiquitination-proteasome pathway. Our current research indicates that VB is a potential agent to treat GBM via the ubiquitin-mediated degradation of c-Met.
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Antineoplásicos Fitogênicos/farmacologia , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Glioblastoma/tratamento farmacológico , Glucosídeos/farmacologia , Fenóis/farmacologia , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Glioblastoma/metabolismo , Glioblastoma/patologia , Humanos , Proteínas Proto-Oncogênicas c-met/metabolismo , Relação Estrutura-Atividade , Células Tumorais CultivadasRESUMO
Paeoniflorin (PF) is a polyphenolic compound derived from Radix Paeoniae Alba thathas anti-cancer activities in a variety of human malignancies including glioblastoma. However, the underlying mechanisms have not been fully elucidated. Epithelial to mesenchymal transition (EMT), characterized as losing cell polarity, plays an essential role in tumor invasion and metastasis. TGFß, a key member of transforming growth factors, has been demonstrated to contribute to glioblastoma aggressiveness through inducing EMT. Therefore, the present studies aim to investigate whether PF suppresses the expression of TGFß and inhibits EMT that plays an important role in anti-glioblastoma. We found that PF dose-dependently downregulates the expression of TGFß, enhances apoptosis, reduces cell proliferation, migration and invasion in three human glioblastoma cell lines (U87, U251, T98G). These effects are enhanced in TGFß siRNA treated cells and abolished in cells transfected with TGFß lentiviruses. In addition, other EMT markers such as snail, vimentin and N-cadherin were suppressed by PF in these cell lines and in BALB/c nude mice injected with U87 cells. The expression of MMP2/9, EMT markers, are also dose-dependently reduced in PF treated cells and in U87 xenograft mouse model. Moreover, the tumor sizes are reduced by PF treatment while there is no change in body weight. These results indicate that PF is a potential novel drug target for the treatment of glioblastoma by suppression of TGFß signaling pathway and inhibition of EMT.
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Movimento Celular/efeitos dos fármacos , Glioblastoma/tratamento farmacológico , Glucosídeos/farmacologia , Monoterpenos/farmacologia , Invasividade Neoplásica/patologia , Fator de Crescimento Transformador beta/efeitos dos fármacos , Animais , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Transição Epitelial-Mesenquimal/genética , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Glioblastoma/metabolismo , Humanos , Camundongos NusRESUMO
Found in many fruits and plants, Ursolic acid (UA), a pentacyclic triterpene that occurs naturally, is recognized for its anti-cancer effects, especially in combating glioblastoma. However, the intricate molecular mechanisms underpinning its anti-tumor actions are still not fully understood, despite the recognition of these effects. By examining the functions of epithelial-mesenchymal transition (EMT) and angiogenesis, crucial for glioblastoma progression, and their regulation through Transforming Growth Factor Beta (TGFß) - a key marker for glioblastoma, our research aims to fill this knowledge gap. This study explores how ursolic acid can block the progression of glioblastoma by precisely targeting TGFß-triggered EMT and angiogenesis. The findings show that UA successfully blocks the spread, movement, and invasion of glioblastoma cells. Accompanying this, there is a significant reduction in the expression of TGFß and crucial EMT indicators like snail and vimentin. Furthermore, UA shows a reduction in angiogenesis that depends on the dosage, highlighted by decreased vascular endothelial growth factor (VEGF) in human umbilical vein endothelial cells (HUVECs). Interestingly, increased TGFß expression in U87 and U251 glioblastoma cell lines was found to weaken UA's anti-tumor properties, shedding more light on TGFß's critical function in glioblastoma's pathology. Supporting these laboratory results, UA also showed considerable inhibition of tumor growth in a glioblastoma xenograft mouse model. Overall, our research emphasizes Ursolic acid's promise as a new treatment for glioblastoma and clarifies its action mechanism, mainly by inhibiting TGFß signaling and thereby EMT and angiogenesis.
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Objectives: Delayed cerebral ischemia (DCI) contributes to poor aneurysm prognosis. Subarachnoid hemorrhage and DCI have irreversible and severe consequences once they occur; therefore, early prediction and prevention are important. We investigated the risk factors for postoperative complications of DCI in patients with aneurysmal subarachnoid hemorrhage (aSAH) requiring mechanical ventilation in intensive care and validated a prediction model. Methods: We retrospectively analyzed patients with aSAH who were treated in a French university hospital neuro-ICU between January 2010 and December 2015. The patients were randomized into a training group (144) and verification groups (60). Nomograms were validated in the training and verification groups, where receiver operating characteristic curve analysis was used to verify model discrimination; calibration curve and Hosmer-Lemeshow test were used to determine model calibration; and decision curve analysis (DCA) was used to verify clinical validity of the model. Results: External ventricular drain (EVD), duration of mechanical ventilation, and treatment were significantly associated in the univariate analysis; EVD and rebleeding were significantly associated with the occurrence of DCI after aSAH. Binary logistic regression was used to select five clinicopathological characteristics to predict the occurrence of DCI in patients with aSAH requiring mechanical ventilation nomograms of the risk of DCI. Area under the curve values for the training and verification groups were 0.768 and 0.246, with Brier scores of 0.166 and 0.163, respectively. Hosmer-Lemeshow calibration test values for the training and verification groups were x 2 = 3.824 (P = 0.923) and x 2 = 10.868 (P = 0.285), respectively. Calibration curves showed good agreement. DCA indicated that the training and verification groups showed large positive returns in the broad risk range of 0-77% and 0-63%, respectively. Conclusions: The predictive model of concurrent DCI in aSAH has theoretical and practical values and can provide individualized treatment options for patients with aSAH who require mechanical ventilation.
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Isquemia Encefálica , Hemorragia Subaracnóidea , Humanos , Hemorragia Subaracnóidea/complicações , Estudos Retrospectivos , Respiração Artificial/efeitos adversos , Infarto Cerebral/complicações , Isquemia Encefálica/complicaçõesRESUMO
BACKGROUND: Microvascular decompression (MVD) and rhizotomy are all selected for treating vagoglossopharyngeal neuralgia (VGPN). Nonetheless, controversies still exist about their curative effect on VGPN. Here we evaluate the effectiveness of MVD together with rhizotomy of the glossopharyngeal nerve for the treatment of VGPN. METHODS: This study was carried out on 21 patients who were diagnosed with VGPN between the years 2005 and 2010. Patients underwent MVD and glossopharyngeal rhizotomy through a retromastoid keyhole approach. Surgical technique, operation results and complications were our particular concern. RESULTS: Eighteen (85.7%) of 21 patients experienced immediate and complete relief of pain after surgery. In the remaining 3 patients (14.3%), the pain faded away within the following week. No patient complained of dysphonia or dysphagia. All 21 patients reported no change in their outcome at follow-up. CONCLUSIONS: Intracranial vagoglossopharyngeal nerve MVD with glossopharyngeal rhizotomy is an effective and safe procedure to treat VGPN.
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Doenças do Nervo Glossofaríngeo/cirurgia , Nervo Glossofaríngeo/cirurgia , Cirurgia de Descompressão Microvascular/métodos , Rizotomia/métodos , Adulto , Feminino , Seguimentos , Humanos , Masculino , Cirurgia de Descompressão Microvascular/efeitos adversos , Pessoa de Meia-Idade , Medição da Dor , Estudos Retrospectivos , Rizotomia/efeitos adversos , Resultado do TratamentoRESUMO
Epithelial-to-mesenchymal transition (EMT) and angiogenesis have emerged as two pivotal events in cancer progression. Paeoniflorin has been widely studied in experimental models and clinical trials for cancer treatment because of its anti-cancer property. However, the underlying mechanisms of paeoniflorin in EMT and angiogenesis in glioblastoma was not fully elucidated. The present study aimed to investigate whether paeoniflorin inhibits EMT and angiogenesis, which involving c-Met suppression, while exploring the potential ways of c-Met degradation. In our study, we found that paeoniflorin inhibited EMT via downregulating c-Met signaling in glioblastoma cells. Furthermore, overexpressing c-Met in glioblastoma cells abolished the effects of paeoniflorin on EMT. Moreover, paeoniflorin showed anti-angiogenic effects by suppressing cell proliferation, migration, invasion and tube formation through downregulating c-Met in human umbilical vein endothelial cells (HUVECs). And c-Met overexpression in HUVECs offset the effects of paeoniflorin on angiogenesis. Additionally, paeoniflorin induced autophagy activation involving mTOR/P70S6K/S6 signaling and promoted c-Met autophagic degradation, a process dependent on K63-linked c-Met polyubiquitination. Finally, paeoniflorin suppressed mesenchymal makers (snail, vimentin, N-cadherin) and inhibited angiogenesis via the identical mechanism in an orthotopic xenograft mouse model. The in vitro and in vivo experiments showed that paeoniflorin treatment inhibited EMT, angiogenesis and activated autophagy. What's more, for the first time, we identified c-Met may be a potential target of paeoniflorin and demonstrated paeoniflorin downregulated c-Met via K63-linked c-Met polyubiquitination-dependent autophagic degradation. Collectively, these findings indicated that paeoniflorin inhibits EMT and angiogenesis via K63-linked c-Met polyubiquitination-dependent autophagic degradation in human glioblastoma.
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Objective: Glioblastoma is one of the most common and fatal malignancies in adults. Current treatment is still not optimistic. Glioblastoma (GBM) transports RNA to platelets in the blood system via microvesicles, suggesting that platelet RNA can be a potential diagnostic and therapeutic target. The roles of specific platelet RNAs in treatment of GBM are not well understood. Methods: Platelet RNA profiling of 8 GBM and 12 normal samples were downloaded from the GEO database. Differentially expressed genes (DEGs) were identified between tumors and normal samples. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed to elucidate the functions of up- and downregulated genes. miRNA was predicted by miRTarBase, TargetScan, and miRDB databases. circBase and circBank were used for circRNA prediction. ceRNA (circRNA-mRNA-miRNA) network was constructed to investigate the potential interactions. Results: 22 genes were upregulated and 9 genes were downregulated. There are only two genes (CCR7 and FAM102A) that connect to miRNAs (hsa-let-7a-5p, hsa-miR-1-3p). We assessed the overall survival rates by Kaplan-Meier plotter, and relative expression of GBM and subtypes for overlapped mRNA (CCR7 and FAM102A) were evaluated, and further, we obtained circRNAs (has-circ-0015164, hsa-circ-0003243) by circBank and circBase and bind sites through the CSCD database. Finally, a ceRNA network (circRNA-mRNA-miRNA) was constructed based on 2 miRNAs, 2 mRNAs, and 2 circRNAs by Cytoscape. This study focused on potential mRNA and ceRNA biomarkers to targeted treatment of GBM and provided ideas for clinical treatment through the combination of hematology and oncology. Conclusion: The findings of this study contribute to better understand the relationship between GBM and the blood system (platelets) and might lay a solid foundation for improving GBM molecule and gene diagnosis and prognosis.
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Glioblastoma , MicroRNAs , Adulto , Biomarcadores/metabolismo , Biologia Computacional , Redes Reguladoras de Genes/genética , Glioblastoma/genética , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , RNA Circular/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores CCR7/genéticaRESUMO
OBJECTIVE: To explore the predictive value of milk fat globule epidermal growth factor 8 (MFG-E8) in the occurrence of delayed cerebral ischemia (DCI) after an aneurysmal subarachnoid hemorrhage (aSAH). METHODS: We recruited 32 patients with aSAH as the case group and 24 patients with unruptured aneurysms as the control group. Serum MFG-E8 levels were measured by western blot and enzyme-linked immunosorbent assay. We analyzed the relationship between MFG-E8 levels and the risk of DCI. RESULTS: The levels of serum MFG-E8 in the case group (mean = 11160.9 pg/mL) were significantly higher than those in the control group (mean = 3081.0 pg/mL, p < 0.001). MFG-E8 levels highly correlated with the World Federation of Neurosurgical Societies (WFNS) and modified Fisher scores (r = -0.691 and - 0.767, respectively, p < 0.001). In addition, MFG-E8 levels in patients with DCI (5882.7 ± 3162.4 pg/mL) were notably higher than those in patients without DCI (15818.2 ± 3771.6 pg/mL, p < 0.001). A receiver operating characteristic curve showed that the occurrence of DCI could effectively be predicted by MFG-E8 (area under the curve = 0.976, 95%CI = 0.850-1.000). Kaplan-Meier survival analysis showed a remarkable decrease in the incidence of DCI in case group individuals with high levels of MFG-E8 (≥11160.9 pg/mL, p < 0.001). CONCLUSION: MFG-E8 may be a useful predictive marker for DCI after an aSAH and could be a promising surrogate end point.
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Antígenos de Superfície/metabolismo , Isquemia Encefálica/metabolismo , Infarto Cerebral/metabolismo , Proteínas do Leite/metabolismo , Hemorragia Subaracnóidea/metabolismo , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Curva ROCRESUMO
PURPOSE: Arctigenin (ARG) is a natural lignan compound extracted from Arctium lappa and has displayed anticancer function and therapeutic effect in a variety of cancers. Arctigenin is mainly from Arctium lappa extract. It has been shown to induce autophagy in various cancers. However, as for whether arctigenin induces autophagy in gliomas or not, the specific mechanism is still worth exploring. METHODS: Using CCK8, the monoclonal experiment was made to detect the proliferation ability. The scratch experiment and the transwell experiment were applied to the migration and invasion ability. PI/RNase and FITC-conjugated anti-annexin V were used to detect the cell cycle and apoptosis. Western blotting was used to determine the specified protein level, and constructed LC3B-GFP plasmid was used for analysis of autophagy. RESULTS: Our research showed that ARG inhibited the growth and proliferation and invasion and migration of glioma cells in a dose-dependent manner (U87MG and T98G) and arrested the cell cycle and induced apoptosis. Interestingly, ARG induced autophagy in a dose-dependent manner. We applied Western blotting to measure the increase in the key autophagy protein LC3B, as well as some other autophagy-related proteins (increase in Beclin-1 and decrease in P62). In order to further explore the mechanism that ARG passed initiating autophagy to inhibit cell growth, we further found by Western blotting that AKT and mTOR phosphorylation proteins (P-AKT, P-mTOR) were reduced after ARG treatment, and we used AKT agonists to rescue, and the phosphorylated proteins of AKT and mTOR increased, and we found that the autophagy-related proteins were also reversed. And interestingly, the protein of apoptosis was also reversed along with autophagy. CONCLUSIONS: We thought ARG inhibited the proliferation of glioma cells by inducing autophagy and apoptosis through the AKT/mTOR pathway.
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Autofagia/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Furanos/farmacologia , Glioblastoma/tratamento farmacológico , Lignanas/farmacologia , Serina-Treonina Quinases TOR/metabolismo , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Glioblastoma/metabolismo , Glioma/tratamento farmacológico , Glioma/metabolismo , Humanos , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt , Transdução de Sinais/efeitos dos fármacosRESUMO
Cytotoxic CD8(+) T cells are key effectors in the immunotherapy of malignant and viral diseases. However, autologous T cell responses to tumor antigens presented by self-MHC are usually weak and ineffective. Allo-restricted T cells represent a potent source of tumor-specific T cells for adoptive immunotherapy. This study reports in vivo anti-melanoma efficacy of the pTRP2-specific allo-restricted CTLs expanded from the BALB/c splenocytes by multiple stimulations with aAPCs made by coating H-2K(b)-Ig/pTRP2 dimeric complexes, anti-CD28 antibody, 4-1BBL molecules and CD83 molecules to cell-sized latex beads. The induced allo-restricted CTLs exhibited specific lysis against RMA-S cells pulsed with the peptide pTRP2 and H-2K(b+) melanoma cells expressing TRP2, while a murine Lewis lung carcinoma cell line 3LL could not be recognized by the CTLs. The peptide-specific activity was inhibited by anti-H-2K(b) monoclonal antibody Y3. Adoptive transfer of the allo-restricted CTLs specific for malignant melanoma expanded by the aAPCs can mediate effective anti-melanoma response in vivo. These results suggested that the specific allo-restricted CTLs expanded by aAPCs coated with an MHC-Ig/peptide complex, anti-CD28 antibody, 4-1BBL and CD83 could be a potential option of specific immunotherapy for patients with malignant melanoma.
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Melanoma/imunologia , HumanosRESUMO
Paeoniflorin (PF), as one of the important valid natural compounds of the total glucosides of peony, has displayed a potential effect in cancer prevention and treatment. Aggressive migration and invasion, as an important process, can contribute to tumor progression through infiltrating the surround normal tissue. Actin cytoskeleton rearrangement plays a key role in cells migration and invasion, involving multiple signal pathways. HGF/c-Met signal, as an important couple of oncoprotein, has been demonstrated to regulate actin cytoskeleton rearrangement. In our study, we aim to explore whether paeoniflorin can inhibit migration and invasion and actin cytoskeleton rearrangement via regulation of HGF/c-Met/RhoA/ROCK signal. Various approaches were applied to demonstrate the mechanism of paeoniflorin-mediated anticancer effect, including cell wound healing assay, invasion assay, immunofluorescence staining and transfection, and western blotting. We observed that paeoniflorin inhibited HGF-induced migration and invasion and actin cytoskeleton rearrangement in glioblastoma cells. Furthermore, the inhibition of HGF-induced migration and invasion and actin cytoskeleton rearrangement involved c-Met-mediated RhoA/ROCK signaling in glioblastoma. Thus, our study proved that paeoniflorin could inhibit migration and invasion and actin cytoskeleton rearrangement through inhibition of HGF/c-Met/RhoA/ROCK signaling in glioblastoma, suggesting that paeoniflorin might be a candidate compound to treat glioblastoma.
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Glioblastoma/tratamento farmacológico , Glucosídeos/farmacologia , Fator de Crescimento de Hepatócito/genética , Monoterpenos/farmacologia , Proteínas Proto-Oncogênicas c-met/genética , Proteína rhoA de Ligação ao GTP/genética , Citoesqueleto de Actina/genética , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glioblastoma/genética , Glioblastoma/patologia , Humanos , Invasividade Neoplásica/genética , Transdução de Sinais/efeitos dos fármacos , Quinases Associadas a rho/genéticaRESUMO
BACKGROUND: Paeoniflorin, a polyphenolic compound derived from Radix Paeoniae Alba (Paeonia lactiflora), has exhibited anticancer activity in various human cancers, including glioblastoma. However, the mechanisms underlying the effects of this compound have not been fully elucidated. Toll-like receptor 4 (TLR4) plays an important role in the regulation of cancer cell proliferation and progression, and high TLR4 expression in glioblastoma specimens is associated with a poor prognosis. The present study aimed to investigate whether paeoniflorin suppresses glioblastoma via inhibition of TLR4 expression. METHODS: CCK-8 experiments and clone formation assay were performed to detect the cell proliferation. Western blotting was used to analyze protein expression levels. Detection of Triad3A binding with TLR4 was assessed by the immunoprecipitation. Orthotopic xenograft mouse model was used to evaluate the effect of paeoniflorin in vivo. MST was used to analyze the interaction between paeoniflorin and TLR4 protein. RESULTS: In our study, we found that paeoniflorin effectively inhibited glioblastoma growth and suppressed TLR4 protein levels, as well its downstream effectors both in vivo and in vitro. Moreover, when overexpressed TLR4 in glioblastoma abolished the effects of paeoniflorin on cell proliferation, migration, and invasion. Furthermore, we found that paeoniflorin decreased TLR4 protein through ubiquitination proteasome pathway (UPP)-mediated degradation in glioblastoma cells. Mechanistically, paeoniflorin promoted Triad3A to conjugate with TLR4, resulting in degradation. In addition, Triad3A-shRNA abolished paeoniflorin-enhanced UPP-mediated TLR4 degradation. Finally, we found that paeoniflorin could directly bind with TLR4 protein as assessed by MST assay. CONCLUSION: Our study is the first to identify a novel mechanism for the antitumor activity of paeoniflorin, specifically: it decreases tumor growth by directly targeting TLR4 and modulating the TLR4/Triad3A-dependent axis, leading to TLR4 protein degradation and inhibition of glioblastoma cell progression in vitro and in vivo. Our current findings indicate that paeoniflorin is a potential glioblastoma therapeutic agent due to its Triad3A-dependent ubiquitin degradation of TLR4.
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In the present study antitumor effect of 2-(4-aminophenyl) benzothiazole (BTZ) was evaluated against human U251 and rat C6 glioma cell lines using MTT assay. It was observed that BTZ exhibited significant antitumor effect with IC50 of 3.5 and 4 µM against human U251 and rat C6 glioma cells respectively. To gain in-depth insights about the antitumor effect of BTZ, glioma xenograft rat model was prepared. The rats were treated with 10 mg and 15 mg/kg body weight doses of BTZ daily for 21 days after C6 cell administration. Treatment of the rats with BTZ reduced the tumor volume to 12% compared to 100% in the untreated rats. TUNEL assay showed a remarkable increase in the proportion of apoptotic cells in the BTZ treated rats than those in the untreated rats. The increase in the population of apoptotic cells was 23-fold compared to control. Immuno-histological staining revealed marked reduction (16%) in the proportion of CD31-stained vessels in the BTZ treated rats than those of the untreated rats. These changes were accompanied with decreased transcript levels of vascular endothelial growth factor (VEGF) and the VEGF receptor Flt1 as well as ERK1/2 and matrix metalloproteinase-2 (MMP2). Moreover, BTZ altered the expression of several cell cycle control proteins. While as pRb protein expression decreased, E2F1 remained unaltered and cyclin D1 protein and p53 expression was enhanced. Taken together, the results indicate that BTZ is a potent inhibitor of glioma cell proliferation in vivo and exerts its effects on cell cycle control and angiogenesis related proteins.
RESUMO
The interleukin (IL) 13 receptor alpha2 (IL-13Ralpha2) is a glioma-restricted cell-surface epitope not otherwise detected within the central nervous system. This study reported a novel approach for targeting malignant glioma with IL-13Ralpha2-specific allo-restricted cytotoxic T cells (CTLs) induced from the peripheral blood lymphocytes (PBLs) of HLA-A2-negative healthy donors by multiple stimulations with artificial antigen-presenting cells (aAPCs) made by coating HLA-A2/pIL-13Ralpha2(345-354) tetrameric complexes, anti-CD28 antibody and CD83 molecules to cell-sized latex beads. The induced allo-restricted CTLs exhibited specific lysis against T2 cells pulsed with the peptide pIL-13Ralpha2(345-354) and HLA-A2+ glioma cells expressing IL-13Ralpha2(345-354), while HLA-A2- glioma cell lines that express IL-13Ralpha2(345-354) could not be recognized by the CTLs. The peptide-specific activity was inhibited by anti-HLA class I monoclonal antibody. These results suggested the induced allo-restricted CTLs specific for IL-13Ralpha2(345-354) peptide could be a potential target of specific immunotherapy for HLA-A2+ patients with malignant glioma.
Assuntos
Células Apresentadoras de Antígenos/imunologia , Epitopos/imunologia , Glioma/imunologia , Linfócitos T Citotóxicos/imunologia , Ensaio de Imunoadsorção Enzimática , Epitopos/química , Antígeno HLA-A2/imunologia , Humanos , Subunidade alfa2 de Receptor de Interleucina-13/imunologia , Fragmentos de Peptídeos/imunologia , Fragmentos de Peptídeos/farmacologia , Linfócitos T Citotóxicos/efeitos dos fármacos , Células Tumorais Cultivadas/imunologiaRESUMO
In this study, we investigated the potential anticancer effects of calycosin against human glioblastoma cells, including the impacts on cell proliferation, apoptosis, and cell cycle distribution. We further studied its inhibitory activity on migration and invasion in U87 and U251 cells. Furthermore, transforming growth factor beta-mediated reductions of mesenchymal-associated genes/activators, matrix metalloproteinases-2, and -9 were detected in this process. Administration of calycosin in a glioblastoma xenograft model showed that calycosin could not only reduce tumor volume but also suppress transforming growth factor beta as well as its downstream molecules. These results revealed calycosin as a potential antitumor agent in human glioblastoma.
Assuntos
Antineoplásicos/farmacologia , Movimento Celular/efeitos dos fármacos , Glioblastoma/tratamento farmacológico , Glioblastoma/patologia , Isoflavonas/farmacologia , Células-Tronco Mesenquimais/efeitos dos fármacos , Fator de Crescimento Transformador beta/metabolismo , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Glioblastoma/metabolismo , Humanos , Lactente , Isoflavonas/administração & dosagem , Isoflavonas/química , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Células-Tronco Mesenquimais/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Invasividade Neoplásica , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Relação Estrutura-Atividade , Células Tumorais CultivadasRESUMO
OBJECTIVE: To investigate the electrophysiological influences of gamma knife at different doses on the compressed cat optic nerve. METHODS: Model of compressed optic nerve was established in 20 cats. Two months later, the 20 cats were randomly divided into 5 equal groups. Four groups accepted the irradiation of gamma knife at the dose of 10, 11, 12, and 13 Gy respectively. One group was used as controls. Pattern visual evoked potential examination was used 3 days, 1 week, half a month, and 1, 2, 3, 4, and 5 months after the beginning of irradiation. RESULTS: Electrophysiological changes could be observed 1 week later began to recover half a month later and then gradually recovered to normal with the lapse of time. Irreversible electrophysiological changes were observed in the groups undergoing gamma knife at the doses of 11 Gy and over, and these changes aggravated with the lapse of time. CONCLUSION: 10 Gy is the minimum dose of gamma knife that cause beneficial electrophysiological changes in the compressed cat optic nerves. The minimum dose that causes irreversible damage is 11 Gy.