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OBJECTIVE: This study aimed to investigate the clinical characteristics of hemifacial spasm (HFS) after Bell's palsy and to evaluate the therapeutic efficacy of microvascular decompression (MVD). METHODS: A retrospective analysis was conducted on 18 patients who underwent MVD for HFS after Bell's palsy at our institution between January 1, 2017, and December 31, 2021. Clinical presentations, intraoperative findings, postoperative outcomes, and complications were comprehensively assessed. RESULTS: Neurovascular compression (NVC) was identified in all the 18 patients. The offending vessels included anterior inferior cerebellar artery (AICA) in 6 patients (33.3%), posterior inferior cerebellar artery (PICA) in 7 patients (38.9%), vertebral artery (VA) combined with AICA in 3 patients (16.7%), and VA alongside PICA in 2 patients (11.1%). Notably, marked arachnoid membrane adhesion was evident in 11 patients (61.1%). 15(83.3%) patients were cured immediately after MVD, delayed relief was found in 3 (16.7%) patients. During the follow-up period, recurrence was not documented. Surgical complications were limited to facial paralysis in 3 patients and auditory impairment in 1 patient. No additional surgical complications were recorded. CONCLUSIONS: In patients manifesting HFS after Bell's palsy, NVC predominantly underlies the etiology. MVD is a reliably safe and efficacious therapeutic intervention.
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Paralisia de Bell , Paralisia Facial , Espasmo Hemifacial , Cirurgia de Descompressão Microvascular , Humanos , Espasmo Hemifacial/etiologia , Espasmo Hemifacial/cirurgia , Paralisia de Bell/cirurgia , Paralisia de Bell/complicações , Paralisia Facial/etiologia , Paralisia Facial/cirurgia , Estudos Retrospectivos , Cirurgia de Descompressão Microvascular/efeitos adversos , Resultado do TratamentoRESUMO
This study aims to explore the causes of primary young onset trigeminal neuralgia (TN) and the clinical outcomes of these patients. From May 2015 to December 2020, 19 primary TN patients with onset age under 30 years underwent microvascular decompression (MVD) in Nanjing Drum Tower Hospital. In this study, the clinical characteristics, surgical outcomes, and postoperative complications of these patients were analyzed retrospectively. Of the 19 patients, 5 were males and 14 were females, and the pain was located on the right side in 10 cases (52.6%). Vascular compression was observed in 17 patients, including 14 cases of superior cerebellar artery (SCA) alone, 2 cases of superior petrosal vein (SPV) alone, and 1 case of SCA and SPV combined. Two patients had no neurovascular conflict, and nerve combing was performed. After surgery, 18 patients got immediate pain relief; 1 patient improved but still had occasional pain. With a mean follow-up of 42.7 ± 22.3 months, one patient was found to have a relapse 45 months after MVD. Surgical complications including mild facial numbness in two patients and hearing impairment in one patient. Neurovascular compression is the main cause of young onset primary TN, and the most commonly encountered vascular was SCA. MVD is a safe and effective treatment for these patients.
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Cirurgia de Descompressão Microvascular , Neuralgia do Trigêmeo , Masculino , Feminino , Humanos , Adulto , Neuralgia do Trigêmeo/cirurgia , Neuralgia do Trigêmeo/etiologia , Cirurgia de Descompressão Microvascular/efeitos adversos , Estudos Retrospectivos , Resultado do Tratamento , Dor/etiologiaRESUMO
Recently, increasing studies have suggested that miRNAs play a significant role in the occurrence and development of glioma. More researches are needed to explore the role of miRNAs in glioma, which will help to find new therapeutic targets. miR-212-5p has been reported to be involved in the progression in many cancers. However, whether miR-212-5p has a regulative effect on glioma remains un clear. In this study, we aimed to explore the effect of miR-212-5p on glioma development and its mechanism. Here, we demonstrated that miR-212-5p was lowly expressed in glioma cell. miR-212-5p suppressed the glioma cell proliferation, inhibited the migratory and invasive capabilities and promoted apoptosis in glioma cells. Besides, miR-212-5p also inhibited tumor growth in vivo. We found small ubiquitin-like modifier 2 (SUMO2) was the target of miR-212-5p, and miR-212-5p suppressed SUMO2 expression to regulate the proliferation, migration, and apoptosis of glioma cells. These findings indicated that miR-212-5p may be a possible therapeutic target for the treatment for glioma.
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Glioma , MicroRNAs , Humanos , Glioma/genética , MicroRNAs/genética , MicroRNAs/metabolismo , Proliferação de Células , Apoptose , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Proteínas Modificadoras Pequenas Relacionadas à Ubiquitina/metabolismo , Proteínas Modificadoras Pequenas Relacionadas à Ubiquitina/farmacologiaRESUMO
OBJECTIVE: Microvascular decompression (MVD) has become an accepted treatment modality for the vertebral artery (VA)-involved hemifacial spasm (HFS). The aim of this retrospective study was to evaluate clinical and surgical outcomes of HFS patients undergoing MVD and surgical and cranial nerve complications and investigate reasonable transposition procedures for two different anatomic variations of VA. METHODS: Between January and December 2018, 109 patients underwent first MVD for HFS involving VA at Nanjing Drum Tower Hospital. Based on whether the VA could be moved ventrally at the lower cranial nerves (LCNs) level, patients were assigned to Group A (movable VA, n = 72) or B (unmovable VA, n = 37), and clinical and surgical outcomes and complications on the day of post-surgery and during follow-up were assessed. All patients were followed up ranging from 17 to 24 months with a mean follow-up period of 21 months. RESULTS: After a mean follow-up of 21 months, the total cure rate significantly decreased in all patients compared to that achieved on the day of surgery, and Group A patients exhibited a higher cure rate versus Group B (93.1% vs. 75.7%, P = 0.015). Group B patients with unmovable VA revealed both higher incidence of surgical complications (45.9% vs. 15.3%, P = 0.001) and frequency of bilateral VA compression (27% vs. 8.3%, P = 0.009) versus Group A. No significant difference was observed in long-term cranial nerve complications. CONCLUSIONS: VA-involved HFS can benefit from MVD strategies after preoperative assessment of VA compression. HFS patients with movable VA may receive better long-term efficacy and fewer complications. A Teflon bridge wedged between the distal VA and medulla gives rise to adequate space for decompression surgery.
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Espasmo Hemifacial , Cirurgia de Descompressão Microvascular , Nervos Cranianos/cirurgia , Espasmo Hemifacial/etiologia , Espasmo Hemifacial/cirurgia , Humanos , Cirurgia de Descompressão Microvascular/efeitos adversos , Estudos Retrospectivos , Resultado do Tratamento , Artéria Vertebral/diagnóstico por imagem , Artéria Vertebral/cirurgiaRESUMO
OBJECTIVE: The most common cause for trigeminal neuralgia (TN) is vascular compression at the nerve root, and microvascular decompression (MVD) has been proven to be an effective surgical approach for this disease. For some patients, TN is secondary to the intracranial space-occupying lesion, and tumor resection is usually recommended. However, it is not easy to determine proper treatments when craniotomy is infeasible. In this study, we aim to explore the clinical outcomes of percutaneous balloon compression (PBC) for secondary TN caused by cerebellopontine angle (CPA) tumors. METHODS: From June 2016 to December 2019, 15 patients with TN caused by CPA tumors underwent PBC in Nanjing Drum Tower Hospital. The clinical features, surgical outcomes, and complications of these patients were analyzed retrospectively. RESULTS: Fourteen out of the 15 patients had immediate pain relief after successful PBC, while one showed occasional pain, without needing any medication. No patients had a relapse of facial pain within a mean follow-up of 32.5 months. As for surgical complications, 14 patients experienced facial numbness, and six had masseter muscle weakness. No patients experienced serious surgical morbidities. CONCLUSIONS: For the patients with TN caused by CPA tumors, PBC could be considered a useful technique, especially when craniotomy is infeasible.
Assuntos
Cirurgia de Descompressão Microvascular , Neuroma Acústico , Neuralgia do Trigêmeo , Humanos , Neuralgia do Trigêmeo/etiologia , Neuralgia do Trigêmeo/cirurgia , Neuroma Acústico/cirurgia , Estudos Retrospectivos , Recidiva Local de Neoplasia/cirurgia , Cirurgia de Descompressão Microvascular/métodos , Dor/cirurgia , Resultado do TratamentoRESUMO
BACKGROUND: Activation of nuclear factor-kappa B (NF-κΒ) through DNA damage is one of the causes of tumor cell resistance to radiotherapy. Chromosome region 1 (CRM1) regulates tumor cell proliferation, drug resistance, and radiation resistance by regulating the nuclear-cytoplasmic translocation of important tumor suppressor proteins or proto-oncoproteins. A large number of studies have reported that inhibition of CRM1 suppresses the activation of NF-κΒ. Thus, we hypothesize that the reversible CRM1 inhibitor S109 may induce radiosensitivity in glioblastoma (GBM) by regulating the NF-κΒ signaling pathway. METHODS: This study utilized the cell counting kit-8 (CCK-8), 5-ethynyl-2'-deoxyuridine (EdU), and colony formation assay to evaluate the effect of S109 combined with radiotherapy on the proliferation and survival of GBM cells. The therapeutic efficacy of S109 combined with radiotherapy was evaluated in vivo to explore the therapeutic mechanism of S109-induced GBM radiosensitization. RESULTS: We found that S109 combined with radiotherapy significantly inhibited GBM cell proliferation and colony formation. By regulating the levels of multiple cell cycle- and apoptosis-related proteins, the combination therapy induced G1 cell cycle arrest in GBM cells. In vivo studies showed that S109 combined with radiotherapy significantly inhibited the growth of intracranial GBM and prolonged survival. Importantly, we found that S109 combined with radiotherapy promoted the nuclear accumulation of IκΒα, and inhibited phosphorylation of p65 and the transcriptional activation of NF-κΒ. CONCLUSION: Our findings provide a new therapeutic regimen for improving GBM radiosensitivity as well as a scientific basis for further clinical trials to evaluate this combination therapy.
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BACKGROUND: Switch-associated protein 70 (SWAP-70) is a guanine nucleotide exchange factor that is involved in cytoskeletal rearrangement and regulation of migration and invasion of malignant tumors. However, the mechanism by which SWAP-70 regulates the migration and invasion of glioblastoma (GB) cells has not been fully elucidated. METHODS: This study used an online database to analyze the relationship between SWAP-70 expression and prognosis in GB patients. The in vitro wound healing assay and transwell invasion assay were used to determine the role of SWAP-70 in GB cell migration and invasion as well as the underlying mechanism. RESULTS: We found that patients with high SWAP-70 expression in the GB had a poor prognosis. Downregulation of SWAP-70 inhibited GB cell migration and invasion, whereas SWAP-70 overexpression had an opposite effect. Interestingly, SWAP-70 expression was positively correlated with the expression of the standard form of CD44 (CD44s) in GB tissues. Downregulation of SWAP-70 also reduced CD44s protein expression, whereas SWAP-70 overexpression enhanced CD44s protein expression. However, downregulation of SWAP-70 expression did not affect the mRNA expression of CD44s. Reversal experiments showed that overexpressing CD44s in cell lines with downregulated SWAP-70 partially abolished the inhibitory effects of downregulated SWAP-70 on GB cell migration and invasion. CONCLUSIONS: These results suggest that SWAP-70 may promote GB cell migration and invasion by regulating the expression of CD44s. SWAP-70 may serve as a new biomarker and a potential therapeutic target for GB.
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Abnormal localization of tumor suppressor proteins is a common feature of renal cancer. Nuclear export of these tumor suppressor proteins is mediated by chromosome region maintenance-1 (CRM1). Here, we investigated the antitumor eff ects of a novel reversible inhibitor of CRM1 on renal cancer cells. We found that S109 inhibits the CRM1-mediated nuclear export of RanBP1 and reduces protein levels of CRM1. Furthermore, the inhibitory eff ect of S109 on CRM1 is reversible. Our data demonstrated that S109 signifi cantly inhibits proliferation and colony formation of renal cancer cells. Cell cycle assay showed that S109 induced G1-phase arrest, followed by the reduction of Cyclin D1 and increased expression of p53 and p21. We also found that S109 induces nuclear accumulation of tumor suppressor proteins, Foxo1 and p27. Most importantly, mutation of CRM1 at Cys528 position abolished the eff ects of S109. Taken together, our results indicate that CRM1 is a therapeutic target in renal cancer and the novel reversible CRM1 inhibitor S109 can act as a promising candidate for renal cancer therapy.
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Plumbagin, a natural quinonoid constituent isolated from the root of medicinal plant Plumbago zeylanica L, has exhibited anti-tumor and anti-proliferative activities in various tumor cell lines as well as in animal tumor models. However, its anticancer effects and the mechanisms underlying its suppression of glioma cell growth have not been elucidated. Oncogenic transcription factor Forkhead Box M1 (FOXM1) has garnered particular interest in recent years as a potential target for the prevention and/or therapeutic intervention in glioma, nevertheless, less information is currently available regarding FOXM1 inhibitor. Here, we reported that plumbagin could effectively inhibit cell proliferation, migration and invasion and induce apoptosis of glioma cells. Cell cycle assay showed that plumbagin induced G2/M arrest. Interestingly, we found that plumbagin decreased the expression of FOXM1 both at mRNA level and protein level. Plumbagin also inhibited the transactivation ability of FOXM1, resulting in down-regulating the expression of FOXM1 downstream target genes, such as cyclin D1, Cdc25B, survivin, and increasing the expression of p21(CIP1) and p27(KIP1). Most importantly, down-regulation of FOXM1 by siFOXM1 transfection enhanced plumbagin-induced change in viability. On the contrary, over-expression of FOXM1 by cDNA transfection reduced plumbagin-induced glioma cell growth inhibition. These results suggest that plumbagin exhibits its anticancer activity partially by inactivation of FOXM1 signaling pathway in glioma cells. Our findings indicate that plumbagin may be considered as a potential natural FOXM1 inhibitor, which could contribute to the development of new anticancer agent for therapy of gliomas.
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Antineoplásicos Fitogênicos/farmacologia , Fatores de Transcrição Forkhead/biossíntese , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glioma/metabolismo , Naftoquinonas/farmacologia , Apoptose/efeitos dos fármacos , Western Blotting , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/fisiologia , Regulação para Baixo , Proteína Forkhead Box M1 , Humanos , RNA Interferente Pequeno , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , TransfecçãoRESUMO
Plumbagin is a natural compound that is isolated from the root of the medicinal plant Plumbago zeylanica L. Based on a previous in vitro study performed by our group, which demonstrated the effectiveness of plumbagin against glioma cells, we further ascertained whether plumbagin exhibits the same effectiveness against glioma cell xenografts in nude mice. Our results revealed that tumor volume was reduced by 54.48% in the plumbagin-treated group compared with the controls. Furthermore, there were no obvious signs of toxicity as assessed by the organ sizes and cell morphologies of the mice that were treated with plumbagin. Immunoï¬uorescence assays further revealed that plumbagin significantly inhibited glioma cell proliferation and induced cell apoptosis. Importantly, we also determined that the expressions of FOXM1 and its downstream target effectors, including cyclin D1 and Cdc25B, were down-regulated in the treated group, while the expressions of p21 and p27 were increased; the latter findings corroborate the results of our previous in vitro study. Taken together, these findings indicate that plumbagin may be a natural downregulator of FOXM1 with potential therapeutic effectiveness for the treatment of gliomas.
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Antineoplásicos Fitogênicos , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/genética , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Expressão Gênica/efeitos dos fármacos , Glioma/genética , Glioma/patologia , Terapia de Alvo Molecular , Naftoquinonas/farmacologia , Naftoquinonas/uso terapêutico , Fitoterapia , Plumbaginaceae/química , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Feminino , Proteína Forkhead Box M1 , Expressão Gênica/genética , Glioma/tratamento farmacológico , Humanos , Camundongos Nus , Naftoquinonas/isolamento & purificação , Transplante de NeoplasiasRESUMO
BACKGROUND: Increasing evidence highlights the involvement of metabolic disorder and calcium influx mediated by transient receptor potential channels in migraine; however, the relationship between these factors in the pathophysiology of migraine remains unknown. Gastrodin is the major component of the traditional Chinese medicine Tianma, which is extensively used in migraine therapy. PURPOSE: Our work aimed to explore the analgesic action of gastrodin and its regulatory mechanisms from a metabolic perspective. METHODS/RESULTS: After being treated with gastrodin, the mice were given nitroglycerin (NTG) to induce migraine. Gastrodin treatment significantly raised the threshold of sensitivity in response to both mechanical and thermal stimulus evidenced by von Frey and hot plate tests, respectively, and decreased total contact numbers in orofacial operant behavioral assessment. We found that the expression of transient receptor potential melastatin 2 (TRPM2) channel was increased in the trigeminal ganglion (TG) of NTG-induced mice, resulting in a sustained Ca2+ influx to trigger migraine pain. The content of succinate, a metabolic biomarker, was elevated in blood samples of migraineurs, as well as in the serum and TG tissue from NTG-induced migraine mice. Calcium imaging assay indicated that succinate insult elevated TRPM2-mediated calcium flux signal in TG neurons. Mechanistically, accumulated succinate upregulated hypoxia inducible factor-1α (HIF-1α) expression and promoted its translocation into nucleus, where HIF-1α enhanced TRPM2 expression through transcriptional induction in TG neurons, evidenced by luciferase reporter measurement. Gastrodin treatment inhibited TRPM2 expression and TRPM2-dependent Ca2+ influx by attenuating succinate accumulation and downstream HIF-1α signaling, and thereby exhibited analgesic effect. CONCLUSION: This work revealed that succinate was a critical metabolic signaling molecule and the key mediator of migraine pain through triggering TRPM2-mediated calcium overload. Gastrodin alleviated NTG-induced migraine-like pain via inhibiting succinate/HIF-1α/TRPM2 signaling pathway in TG neurons. These findings uncovered the anti-migraine effect of gastrodin and its regulatory mechanisms from a metabolic perspective and provided a novel theoretical basis for the analgesic action of gastrodin.
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Álcoois Benzílicos , Glucosídeos , Transtornos de Enxaqueca , Canais de Cátion TRPM , Camundongos , Animais , Nitroglicerina/efeitos adversos , Nitroglicerina/metabolismo , Ácido Succínico/efeitos adversos , Ácido Succínico/metabolismo , Cálcio/metabolismo , Canais de Cátion TRPM/efeitos adversos , Canais de Cátion TRPM/metabolismo , Gânglio Trigeminal/metabolismo , Dor/tratamento farmacológico , Transtornos de Enxaqueca/induzido quimicamente , Transtornos de Enxaqueca/tratamento farmacológico , Transdução de Sinais , Analgésicos/farmacologiaRESUMO
Microvascular decompression (MVD) is a widely adopted neurosurgery in treating cranial nerve diseases providing long-term pain relief. Improving surgical techniques has been a focus of recent studies. Venous structures such as the sigmoid sinus are essential to protect, and whose risk of destruction during surgery increases with size. The medical records of patients who went through MRI ahead of MVD surgery between Dec 2020 and Dec 2021 were reviewed. Section area of sigmoid sinus calculated from the MRI plane of auditory nerve showed a right dominance of the sinus. The improved method concerning the relationship between affected side and the dominant sigmoid sinus offered a better bone window and surgical field by planning the operation incision in advance. Intraoperative adjustment of the bone flap was avoided, and the risk of destructing the sigmoid sinus was reduced.
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Background: Chitinase-3-like protein 1 (CHI3L1) is overexpressed in various types of tumors, especially in glioma, and contributes to tumor progression. However, the definite role of CHI3L1 and involved pathway in glioma progression are not completely understood. Methods: CHI3L1 expression in human gliomas and its association with patient survival was determined using enzyme-linked immunosorbent assay, western blot, immunohistochemistry, and public databases. Single-cell RNA-seq was used to characterize the landscape of tumor and myeloid cells. Human proteome microarray assay was applied to identify the binding partners of CHI3L1. Protein-protein interactions were analyzed by co-immunoprecipitation and cellular co-localization. The roles of CHI3L1 in glioma proliferation and invasion were investigated in tumor cell lines by gain- and loss- of function, as well as in vivo animal experiments. Results: CHI3L1 was up-regulated in all disease stages of glioma, which was closely related with tumor survival, growth, and invasion. CHI3L1 was primarily expressed in glioma cells, followed by neutrophils. Moreover, glioma cells with high expression of CHI3L1 were significantly enriched in NF-κB pathway. Pseudo-time trajectory analysis revealed a gradual transition from CHI3L1low to CHI3L1high glioma cells, along with the NF-κB pathway gradually reversed from inhibition to activation. Intriguingly, CHI3L1 binds to actinin alpha 4 (ACTN4) and NFKB1, and enhances the NF-κB signaling pathway by promoting the NF-κB subunit nuclear translocation in glioma cells. Further, CHI3L1 were released into the tumor microenvironment (TME) and interacted with CD44 expressed on tumor-associated macrophages to activate AKT pathway, thereby contributing to M2 macrophage polarization. In addition, CHI3L1 positively correlated to the expression of immune checkpoints, such as CD274 (PD-L1) and HAVCR2 (LAG3), which then remodeled the TME to an immunosuppressive phenotype. Conclusion: Our research revealed that CHI3L1 facilitated NF-κB pathway activation within glioma cells and reprogramed the TME, thereby serving as a promising therapeutic target for glioma.
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Proteína 1 Semelhante à Quitinase-3 , Glioma , Transdução de Sinais , Microambiente Tumoral , Animais , Humanos , Actinina/metabolismo , Antígeno B7-H1 , Proteína 1 Semelhante à Quitinase-3/genética , Proteína 1 Semelhante à Quitinase-3/metabolismo , Glioma/patologia , NF-kappa B/metabolismo , Proteoma , Proteínas Proto-Oncogênicas c-akt/metabolismoRESUMO
To explore the causes of persistent abnormal muscle response (AMR) after microvascular decompression (MVD) for hemifacial spasm (HFS) and the clinical outcomes of these patients. MVDs performed in Nanjing Drum Tower Hospital in 2017 were retrospectively studied, and 326 patients with HFS were classified into two groups based on whether AMR disappeared or persisted following MVD. The clinical features, treatment efficacy and postoperative complications were compared between the two groups. 305 patients with disappeared AMR after decompression were classified as Group A. In Group B, the 21 patients exhibited persistent AMR after successful MVD. The preoperative duration of symptoms in Group B was significantly longer than that in Group A (P < 0.001), and no significant difference was identified between the two groups in terms of gender, side, age and offending vessels (P > 0.05). The immediate postoperative cure rate of Group A (88.9%)was significantly higher than that in Group B (28.6%, P < 0.001), furthermore, the two groups were not different in the long-term outcome and the incidence of surgical complications (P > 0.05). The long preoperative duration of HFS patients may account for persistent AMR after successful decompression, and it is more likely for these patients to get delayed cured, the long-term outcomes showed no difference compared to those in patients with disappeared AMR after MVD.
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Músculos Faciais/fisiopatologia , Espasmo Hemifacial/cirurgia , Cirurgia de Descompressão Microvascular/efeitos adversos , Adulto , Idoso , Estimulação Elétrica , Eletromiografia , Nervo Facial , Feminino , Seguimentos , Espasmo Hemifacial/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Monitorização Intraoperatória , Complicações Pós-Operatórias/epidemiologia , Estudos Retrospectivos , Resultado do TratamentoRESUMO
BACKGROUND: Malignant gliomas are associated with a high mortality rate, and effective treatment options are limited. Thus, the development of novel targeted treatments to battle this deadly disease is imperative. METHODS: In this study, we investigated the in vitro effects of the novel reversible chromosomal region maintenance 1 (CRM1) inhibitor S109 on cell proliferation in human gliomas. S109 was also evaluated in an intracranial glioblastoma xenograft model. RESULTS: We found that high expression of CRM1 in glioma is a predictor of short overall survival and poor patient outcome. Our data demonstrate that S109 significantly inhibits the proliferation of human glioma cells by inducing cell cycle arrest at the G1 phase. Notably, we observed that high-grade glioma cells are more sensitive to S109 treatment compared with low-grade glioma cells. In an intracranial mouse model, S109 significantly prolonged the survival of tumor-bearing animals without causing any obvious toxicity. Mechanistically, S109 treatment simultaneously perturbed the three core pathways (the RTK/AKT/Foxos signaling pathway and the p53 and Rb1 tumor-suppressor pathways) implicated in human glioma cells by promoting the nuclear retention of multiple tumor-suppressor proteins. CONCLUSIONS: Taken together, our study highlights the potential role of CRM1 as an attractive molecular target for the treatment of human glioma and indicates that CRM1 inhibition by S109 might represent a novel treatment approach.
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Aminopiridinas/farmacologia , Ciclopentanos/farmacologia , Glioma/patologia , Carioferinas/antagonistas & inibidores , Receptores Citoplasmáticos e Nucleares/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Animais , Proteínas Reguladoras de Apoptose , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Proteínas de Ligação ao GTP , Xenoenxertos , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Camundongos , Prognóstico , Proteínas de Ligação a Retinoblastoma/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Proteína Exportina 1RESUMO
Colorectal cancer arises via a multistep carcinogenic process and the deregulation of multiple pathways. Thus, the simultaneous targeting of multiple pathways may be a promising therapeutic approach for colorectal treatment. CRM1 is an attractive cancer drug target, because it can regulate multiple pathways and tumor suppressor proteins. In this study, we investigated the anti-tumor activity of a novel reversible CRM1 inhibitor S109 in colorectal cancer. Our data demonstrate that S109 inhibits proliferation and induces cell cycle arrest in colorectal cancer cells. Mechanistically, we demonstrate that the activity of S109 is associated with the nuclear retention of major tumor suppress proteins. Furthermore, the Cys528 mutation of CRM1 prevented the ability of S109 to block nuclear export and inhibit the proliferation of colorectal cancer cells. Interestingly, S109 decreased the CRM1 protein level via proteasomal pathway. We argue that reversible CRM1 inhibitors but not irreversible inhibitors can induce the degradation of CRM1, because the dissociation of reversible inhibitors of CRM1 changes the conformation of CRM1. Taken together, these findings demonstrate that CRM1 is a valid target for the treatment of colorectal cancer and provide a basis for the development of S109 therapies for colorectal cancer.
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Antineoplásicos/farmacologia , Núcleo Celular/efeitos dos fármacos , Carioferinas/antagonistas & inibidores , Receptores Citoplasmáticos e Nucleares/antagonistas & inibidores , Transporte Ativo do Núcleo Celular/efeitos dos fármacos , Aminopiridinas/química , Aminopiridinas/farmacologia , Antineoplásicos/química , Western Blotting , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Núcleo Celular/metabolismo , Proliferação de Células/efeitos dos fármacos , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Ciclopentanos/química , Ciclopentanos/farmacologia , Relação Dose-Resposta a Droga , Citometria de Fluxo , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Células HT29 , Humanos , Carioferinas/genética , Carioferinas/metabolismo , Microscopia de Fluorescência , Estrutura Molecular , Mutação , Proteínas Nucleares/metabolismo , Receptores Citoplasmáticos e Nucleares/genética , Receptores Citoplasmáticos e Nucleares/metabolismo , Ensaio Tumoral de Célula-Tronco , Proteína Exportina 1RESUMO
BACKGROUND: Ovarian cancer represents the most fatal type of gynecological malignancies. Unfortunately, there are still no effective targeted treatment strategies for ovarian cancer. Overexpression of CRM1 has been correlated with poor prognosis of patients with ovarian cancer. AIM: In this study, we investigated the antitumor effects of a novel reversible inhibitor of CRM1 in ovarian cancer cells. METHODS: The effects of S109 on proliferation was detected by CCK-8, EdU, clonogenic assay. The protein expression were determined by Western blot. The subcellular localization of RanBP1 was analyzed by immunofluorescence microscopy assay. RESULTS: We demonstrated that S109 could induce nuclear accumulation of RanBP1, a canonical biomarker for CRM1 inhibition. This effect was clearly reversible in the majority of the cells, whereas the inhibitory effect of LMB could not be reversed. Our data reveal that treatment with S109 results in decrease in proliferation and colonogenic capacity of ovarian cancer cells by arresting cell cycle. Mechanistically, S109 treatment increase the expression of the cyclin-dependent kinase inhibitor p21, while it reduced the expression of cell cycle promoting proteins, Cyclin D1 and Cyclin B. CRM1 level itself was also down-regulated following S109 treatment. Furthermore, the nuclei of cells incubated with S109 accumulated tumor suppressor proteins (Foxo1, p27 and IκB-α). More importantly, Cys528 mutation of CRM1 abolished the ability of S109 to block proliferation of ovarian cancer cells. CONCLUSIONS: Together, our study identifies CRM1 as a valid target in ovarian cancer and provides a basis for the development of S109 in ovarian cancer.