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1.
Cell Death Dis ; 15(4): 292, 2024 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-38658527

RESUMO

Although bevacizumab (BVZ), a representative drug for anti-angiogenesis therapy (AAT), is used as a first-line treatment for patients with glioblastoma (GBM), its efficacy is notably limited. Whereas several mechanisms have been proposed to explain the acquisition of AAT resistance, the specific underlying mechanisms have yet to be sufficiently ascertained. Here, we established that inhibitor of differentiation 1 (ID1)high/activin Ahigh glioblastoma cell confers resistance to BVZ. The bipotent effect of activin A during its active phase was demonstrated to reduce vasculature dependence in tumorigenesis. In response to a temporary exposure to activin A, this cytokine was found to induce endothelial-to-mesenchymal transition via the Smad3/Slug axis, whereas prolonged exposure led to endothelial apoptosis. ID1 tumors showing resistance to BVZ were established to be characterized by a hypovascular structure, hyperpermeability, and scattered hypoxic regions. Using a GBM mouse model, we demonstrated that AAT resistance can be overcome by administering therapy based on a combination of BVZ and SB431542, a Smad2/3 inhibitor, which contributed to enhancing survival. These findings offer valuable insights that could contribute to the development of new strategies for treating AAT-resistant GBM.


Assuntos
Ativinas , Inibidores da Angiogênese , Bevacizumab , Resistencia a Medicamentos Antineoplásicos , Glioblastoma , Proteína 1 Inibidora de Diferenciação , Glioblastoma/tratamento farmacológico , Glioblastoma/patologia , Glioblastoma/metabolismo , Glioblastoma/irrigação sanguínea , Humanos , Animais , Proteína 1 Inibidora de Diferenciação/metabolismo , Proteína 1 Inibidora de Diferenciação/genética , Camundongos , Inibidores da Angiogênese/farmacologia , Inibidores da Angiogênese/uso terapêutico , Ativinas/metabolismo , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Linhagem Celular Tumoral , Bevacizumab/farmacologia , Bevacizumab/uso terapêutico , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia , Camundongos Nus , Apoptose/efeitos dos fármacos
2.
Chemosphere ; 352: 141415, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38336039

RESUMO

This study was to enhance the nitrogen removal efficiency in the sequencing batch reactor (SBR) process by adding sulfur-based carriers. The nitrogen removal efficiency of the control group was compared with that of the experimental group through a two-series operation of SBR1 without carrier and SBR2 with the carrier under the condition of no external carbon source. A total nitrogen (T-N) removal efficiency of 6.6%, 72.6%, and 79.9% was observed in SBR1, SBR2 (5%), and (10%), respectively. The T-N removal efficiency was improved in the system with carriers, which showed an increase in the removal efficiency of approximately 91.7%. The results suggest that the inclusion of the carrier led to an elevation in the sulfur ratio, implying an augmented surface area for sulfur-based denitrifying microorganisms. Additionally, CaCO3 contributed essential alkalinity for sulfur denitrification, thereby preventing a decline in pH. Regardless of the carrier, the efficiency of organic matter removal surpassed 89%, indicating that the sulfur-based carrier did not adversely affect the biological reaction associated with organic matter. Therefore, autotrophic denitrification was successfully performed using a sulfur carrier in the SBR process without an external carbon source, improving the nitrogen removal efficiency.


Assuntos
Desnitrificação , Purificação da Água , Reatores Biológicos , Enxofre , Purificação da Água/métodos , Nitrogênio , Carbono
3.
Chemosphere ; 333: 138929, 2023 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-37207901

RESUMO

In this study, the effect of chlorine, which is used as a chemical cleaning agent or disinfection agent on membrane deterioration, was analyzed under various conditions during the membrane process. Reverse osmosis (RO: ESPA2-LD and RE4040-BE) and nanofiltration (NF: NE4040-70) membranes made of polyamide (PA) thin film composite (TFC) were used for evaluation. Chlorine exposure was performed at doses ranging from 1000 ppm h to 10,000 ppm h using 10 ppm and 100 ppm, and temperatures from 10 °C to 30 °C. Raw water containing NaCl, MgSO4, and dextrose was used to compare the filtration performance after exposure to each of the conditions studied. Reduction in removal performance and enhancement in permeability were observed as chlorine exposure increased. Attenuated total reflectance-Fourier transform infrared (ATR-FTIR) spectroscopy and scanning electron microscope (SEM) were employed to determine the surface characteristics of the decomposed membranes. ATR-FTIR was used to compare the intensity of the peaks related to the TFC membrane. Based on the analysis, the state of membrane degradation was elucidated. SEM was used to confirm visual degradation of the membrane surface. Permeability and correlation analyses were performed on CnT as an index for determining membrane lifetime in order to investigate the power coefficient. The relative influence of the exposure concentration and time on membrane degradation was explored by comparing the power efficiency according to the exposure dose and temperature.


Assuntos
Cloro , Membranas Artificiais , Cloro/análise , Temperatura , Osmose , Filtração/métodos
4.
Cells ; 11(13)2022 06 26.
Artigo em Inglês | MEDLINE | ID: mdl-35805116

RESUMO

The oncogenic role of nuclear LIM domain only 2 (LMO2) as a transcriptional regulator is well established, but its function in the cytoplasm is largely unknown. Here, we identified LMO2 as a cytoplasmic activator for signal transducer and activator of transcription 3 (STAT3) signaling in glioma stem cells (GSCs) through biochemical and bioinformatics analyses. LMO2 increases STAT3 phosphorylation by interacting with glycoprotein 130 (gp130) and Janus kinases (JAKs). LMO2-driven activation of STAT3 signaling requires the LDB1 protein and leads to increased expression of an inhibitor of differentiation 1 (ID1), a master regulator of cancer stemness. Our findings indicate that the cytoplasmic LMO2-LDB1 complex plays a crucial role in the activation of the GSC signaling cascade via interaction with gp130 and JAK1/2. Thus, LMO2-LDB1 is a bona fide oncogenic protein complex that activates either the JAK-STAT signaling cascade in the cytoplasm or direct transcriptional regulation in the nucleus.


Assuntos
Glioma , Fator de Transcrição STAT3 , Proteínas Adaptadoras de Transdução de Sinal , Receptor gp130 de Citocina/metabolismo , Citoplasma/metabolismo , Proteínas de Ligação a DNA/metabolismo , Glioma/genética , Glioma/metabolismo , Glicoproteínas/metabolismo , Humanos , Janus Quinases/metabolismo , Proteínas com Domínio LIM/genética , Proteínas com Domínio LIM/metabolismo , Proteínas com Homeodomínio LIM/metabolismo , Células-Tronco Neoplásicas/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Fator de Transcrição STAT3/metabolismo , Fatores de Transcrição/metabolismo
5.
Cells ; 9(3)2020 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-32183406

RESUMO

Constitutively activated STAT3 plays an essential role in the initiation, progression, maintenance, malignancy, and drug resistance of cancer, including glioblastoma, suggesting that STAT3 is a potential therapeutic target for cancer therapy. We recently identified ODZ10117 as a small molecule inhibitor of STAT3 and suggested that it may have an effective therapeutic utility for the STAT3-targeted cancer therapy. Here, we demonstrated the therapeutic efficacy of ODZ10117 in glioblastoma by targeting STAT3. ODZ10117 inhibited migration and invasion and induced apoptotic cell death by targeting STAT3 in glioblastoma cells and patient-derived primary glioblastoma cells. In addition, ODZ10117 suppressed stem cell properties in glioma stem cells (GSCs). Finally, the administration of ODZ10117 showed significant therapeutic efficacy in mouse xenograft models of GSCs and glioblastoma cells. Collectively, ODZ10117 is a promising therapeutic candidate for glioblastoma by targeting STAT3.


Assuntos
Glioblastoma/genética , Fator de Transcrição STAT3/antagonistas & inibidores , Animais , Linhagem Celular Tumoral , Modelos Animais de Doenças , Glioblastoma/mortalidade , Humanos , Camundongos , Fator de Transcrição STAT3/uso terapêutico , Análise de Sobrevida , Ensaios Antitumorais Modelo de Xenoenxerto
6.
J Ethnopharmacol ; 236: 393-400, 2019 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-30878548

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Korean Red ginseng extract (RG) is one of the most widely used traditional health functional food in Asia, which invigorates immunity and vital energy. RG have been suggested to inhibit proliferation, invasion, and inflammation in several cancer cell lines. Correspondingly, clinical studies have raised the possibility that RG could augment therapeutic efficacy in cancer patients. However, little is known about the anti-cancer effects of RG in glioblastoma (GBM), the most common and aggressive brain tumor for which effective therapeutic regimens need to be developed. AIM OF THIS STUDY: Here, we assessed the in vivo and in vitro anti-cancer properties of RG in a patient-derived xenograft mouse model and GBM stem cell (GSC) line. MATERIALS AND METHODS: We evaluated the anti-cancer effects of RG in patient-derived GBM xenograft mice with and without combined concurrent chemo- and radiation therapy (CCRT). Furthermore, we verified the in vitro effects of RG on the proliferation, cell death, and stem cell-like self-renewal capacity of cancer cells. Finally, we investigated the signaling pathway affected by RG, via which its anti-cancer effects were mediated. RESULTS: When combined with CCRT, RG impeded GBM progression by reducing cancer cell proliferation and ionized calcium-binding adapter molecule 1 (IBA1)-positive immune cell recruitment. The anti-cancer effects of RG were mediated by Rg3 and Rh2 ginsenosides. Rg3 promoted cell death while Rh2 did not. Furthermore, both Rg3 and Rh2 reduced cell viability and self-renewal capacity of GSCs by inhibiting Wnt/ß-catenin signaling. CONCLUSION: Therefore, our observations imply that RG could be applied to the GBM patients in parallel with CCRT to enhance therapeutic efficacy.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Neoplasias Encefálicas/tratamento farmacológico , Glioblastoma/tratamento farmacológico , Panax/química , Extratos Vegetais/farmacologia , Adulto , Animais , Antineoplásicos Fitogênicos/isolamento & purificação , Antineoplásicos Fitogênicos/uso terapêutico , Encéfalo/citologia , Encéfalo/patologia , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Glioblastoma/patologia , Humanos , Medicina Tradicional Coreana , Camundongos , Células-Tronco Neoplásicas , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/uso terapêutico , Via de Sinalização Wnt/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
7.
J Med Food ; 20(9): 838-845, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28792781

RESUMO

Glioblastoma multiforme (GBM) is one of the most aggressive and lethal human brain tumors, and the median survival of patients with GBM is only 14 months. Glioblastoma stem cells (GSCs) are regarded as a main cause of GBM recurrence, because of their self-renewal and drug resistance properties. Therefore, targeting GSCs is an important therapeutic strategy for GBM. In this study, we show the effects of BRM270, a compound from natural plant extracts, on GSCs in vitro and GBM recurrence in vivo. BRM270 induced apoptotic cell death and inhibited cell growth and "stemness" both in vitro and in vivo. Combining BRM270 treatment with concurrent chemoradiotherapy (CCRT) dramatically increased mice survival and tumor growth inhibition. Taken together, our results suggested that BRM270 synergizes with CCRT as a therapeutic agent to target GSCs.


Assuntos
Antineoplásicos Fitogênicos/administração & dosagem , Neoplasias Encefálicas/tratamento farmacológico , Proliferação de Células/efeitos dos fármacos , Glioblastoma/tratamento farmacológico , Células-Tronco Neoplásicas/citologia , Extratos Vegetais/administração & dosagem , Animais , Apoptose/efeitos dos fármacos , Neoplasias Encefálicas/fisiopatologia , Neoplasias Encefálicas/radioterapia , Proliferação de Células/efeitos da radiação , Quimiorradioterapia , Terapia Combinada , Glioblastoma/fisiopatologia , Glioblastoma/radioterapia , Humanos , Camundongos , Camundongos Nus , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/efeitos da radiação
8.
Tumour Biol ; 37(2): 2473-80, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26383528

RESUMO

High-grade gliomas are considered the most malignant of brain tumors and have a poor prognosis. In a previous study, we showed that LIM domain only 2 (LMO2) regulates glioma stem cell properties and tumor angiogenesis and gave rise to highly invasive glioma xenografts. Glioma invasion in the surrounding parenchymal tissues is a major hurdle with respect to eliminating glioma by surgery. Invasive glioma cells are considered one of the main culprits for the recurrence of tumors after therapies. In the current study, we focused on determining the molecular mechanism(s) by which LMO2 regulates glioma cell migration and invasion. Forced expression of LMO2 in human U87MG glioma cells led to glioma invasion, as determined by in vivo xenograft assays and enhanced in vitro migration and invasion. LMO2 was associated with increased levels of cytosolic p27(Kip1) protein. LMO2 possibly induced the stabilization and augmented interactions between p27(Kip1) and RhoA. We knocked down the expression of p27(Kip1), which led to a decrease in LMO2-driven glioma cell migration and invasion. Taken together, our findings indicate that LMO2 promotes glioma cell migration and invasion by increasing the levels of cytosolic p27(Kip1).


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Movimento Celular/fisiologia , Inibidor de Quinase Dependente de Ciclina p27/metabolismo , Citosol/metabolismo , Glioma/metabolismo , Glioma/patologia , Proteínas com Domínio LIM/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Animais , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Linhagem Celular , Linhagem Celular Tumoral , Citosol/patologia , Células HEK293 , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Recidiva Local de Neoplasia/metabolismo , Recidiva Local de Neoplasia/patologia , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia , Proteína rhoA de Ligação ao GTP/metabolismo
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