RESUMO
Glioblastoma (GB) is one of the most aggressive and malignant tumors of the central nervous system. Conventional treatment for GB requires surgical resection followed by radiotherapy combined with temozolomide chemotherapy; however, the median survival time is only 12-15 months. Angelica sinensis Radix (AS) is commonly used as a traditional medicinal herb or a food/dietary supplement in Asia, Europe, and North America. This study aimed to investigate the effect of AS-acetone extract (AS-A) on the progression of GB and the potential mechanisms underlying its effects. The results indicated that AS-A used in this study showed potency in growth inhibition of GB cells and reduction of telomerase activity. In addition, AS-A blocked the cell cycle at the G0/G1 phase by regulating the expression of p53 and p16. Furthermore, apoptotic morphology, such as chromatin condensation, DNA fragmentation, and apoptotic bodies, was observed in AS-A-treated cells, induced by the activation of the mitochondria-mediated pathway. In an animal study, AS-A reduced tumor volume and prolonged lifespans of mice, with no significant changes in body weight or obvious organ toxicity. This study confirmed the anticancer effects of AS-A by inhibiting cell proliferation, reducing telomerase activity, altering cell cycle progression, and inducing apoptosis. These findings suggest that AS-A has great potential for development as a novel agent or dietary supplement against GB.
Assuntos
Glioblastoma , Telomerase , Humanos , Camundongos , Animais , Glioblastoma/tratamento farmacológico , Glioblastoma/metabolismo , Glioblastoma/patologia , Telomerase/metabolismo , Telomerase/farmacologia , Telomerase/uso terapêutico , Apoptose , Pontos de Checagem do Ciclo Celular , Ciclo Celular , Proliferação de Células , Telômero/metabolismo , Telômero/patologia , Mitocôndrias , Linhagem Celular TumoralRESUMO
Aging is widely thought to be associated with oxidative stress. Momordica charantia (MC) is a classic vegetable and traditional herbal medicine widely consumed in Asia, and M. charantia polysaccharide (MCP) is the main bioactive ingredient of MC. We previously reported an antioxidative and neuroprotective effect of MCP in models of cerebral ischemia/reperfusion and hemorrhage injury. However, the role played by MCP in neurodegenerative diseases, especially during aging, remains unknown. In this study, we investigated the protective effect of MCP against oxidative stress and brain damage in a D-galactose-induced aging model (DGAM). The Morris water maze test was performed to evaluate the spatial memory function of model rats. The levels of malondialdehyde (MDA), glutathione (GSH), and superoxide dismutase (SOD) were measured and telomerase activity was determined. The results showed that MCP treatment attenuated spatial memory dysfunction induced by D-galactose. In addition, MCP increased antioxidant capacity by decreasing MDA and increasing SOD and GSH levels. MCP treatment also improved telomerase activity in aging rats. Mechanistically, MCP promoted the entry of both Nrf2 and ß-Catenin into the nucleus, which is the hallmark of antioxidation signaling pathway activation. This study highlights a role played by MCP in ameliorating aging-induced oxidative stress injury and reversing the decline in learning and memory capacity. Our work provides evidence that MCP administration might be a potential antiaging strategy.
Assuntos
Momordica charantia , Telomerase , Ratos , Animais , Galactose/toxicidade , Momordica charantia/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , beta Catenina/metabolismo , Telomerase/metabolismo , Telomerase/farmacologia , Envelhecimento/metabolismo , Estresse Oxidativo , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Antioxidantes/metabolismo , Transdução de Sinais , Polissacarídeos/farmacologia , Polissacarídeos/uso terapêutico , Superóxido Dismutase/metabolismo , Malondialdeído/metabolismoRESUMO
OBJECTIVES: Lung ischaemia-reperfusion (IR) injury is one of the major complications following lung transplantation. The novel peptide GV1001, which is derived from human telomerase reverse transcriptase, has been reported to possess both antitumour and anti-inflammatory effects. In this study, we focused on the anti-inflammatory effects of GV1001 to investigate the IR injury prevention effect of GV1001 in a rat lung transplantation model. METHODS: An orthotopic left lung transplantation rat model was established using the modified cuff technique. We applied 50 ml of normal saline (control), Perfadex (low-potassium standard dextran containing perfusion solution), Perfadex with 5 mg GV1001 (5-mg GV, low concentration) and Perfadex with 50 mg GV1001 (50-mg GV, high concentration) as both flushing and preservation solutions. The left lung was stored in the same solution as the flushing solution at 4°C for 3 h. After transplantation, the recipient rats were monitored for 3 h. Arterial blood gas analysis (ABGA), bronchoalveolar lavage (BAL) analysis, wet/dry ratio, histological analysis, apoptotic cell analysis and cytokine [tumour necrosis factor alpha (TNF-α) and interleukin 6 (IL-6)] analysis were performed to determine the reduction or prevention effect of GV1001 regarding lung IR injury. RESULTS: Compared with the control group, the neutrophil count in BAL, reperfusion oedema and cytokine (TNF-α, IL-6) levels of the transplanted lung were significantly decreased in the 5-mg GV group. Compared with the Perfadex group (16.85 ± 2.43), the neutrophil count in BAL was also significantly decreased in the 5-mg GV group (5.39 ± 0.81) (P< 0.001). In addition, the cytokine (TNF-α, IL-6) levels of the transplanted lung were also significantly decreased in the 5-mg GV group (41.99 ± 12.79, 1069.74 ± 98.48 pg/ml) compared with the Perfadex group (90.73 ± 23.87, 2051.92 ± 243.57 pg/ml) (P < 0.05 and P < 0.001, respectively). However, the 50-mg GV group showed less effect than the 5-mg GV group. CONCLUSIONS: Adding a low concentration of GV1001 to the lung preservation solution (Perfadex) provided potential protective effects against IR injury after lung transplantation in rats. Therefore, GV1001 should be considered as a promising anti-inflammatory agent for IR injury.
Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Transplante de Pulmão/métodos , Fragmentos de Peptídeos/uso terapêutico , Traumatismo por Reperfusão/prevenção & controle , Telomerase/uso terapêutico , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/farmacologia , Apoptose/efeitos dos fármacos , Líquido da Lavagem Broncoalveolar/citologia , Dióxido de Carbono/sangue , Citratos , Citocinas/metabolismo , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos/métodos , Cuidados Intraoperatórios/métodos , Contagem de Leucócitos , Pulmão/irrigação sanguínea , Pulmão/patologia , Transplante de Pulmão/efeitos adversos , Masculino , Neutrófilos , Preservação de Órgãos/métodos , Soluções para Preservação de Órgãos , Oxigênio/sangue , Pressão Parcial , Fragmentos de Peptídeos/administração & dosagem , Fragmentos de Peptídeos/farmacologia , Ratos Sprague-Dawley , Reperfusão , Traumatismo por Reperfusão/etiologia , Traumatismo por Reperfusão/patologia , Telomerase/administração & dosagem , Telomerase/farmacologiaRESUMO
The objective of the present study was to investigate the effect of beta-lapachone, a quinone obtained from the bark of the lapacho tree (Tabebuia avellanedae), on the cell growth and apoptosis in human lung carcinoma cell line A549. Exposure of A549 cells to beta-lapachone resulted in growth inhibition and induction of apoptosis in a time- and dose-dependent manner as measured by hemocytometer counts, fluorescence microscopy and flow cytometry analysis. This increase in apoptosis was associated with a decrease in Bcl-2 and expression, an increase of Bax, and an activation of caspase-3 and caspase-9. beta-lapachone treatment markedly inhibited the activity of telomerase in a dose-dependent fashion. Additionally, the levels of human telomerase RNA (hTR) and c-myc expression were progressively down-regulated by beta-lapachone treatment. Taken together, these findings provide important new insights into the possible molecular mechanisms of the anti-cancer activity of beta-lapachone.
Assuntos
Apoptose/efeitos dos fármacos , Carcinoma/patologia , Neoplasias Pulmonares/patologia , Naftoquinonas/farmacologia , Extratos Vegetais/farmacologia , Inibidores da Transcriptase Reversa/farmacologia , Telomerase/farmacologia , Proliferação de Células , Relação Dose-Resposta a Droga , Citometria de Fluxo , Humanos , Tabebuia/química , Telomerase/efeitos dos fármacos , Células Tumorais CultivadasRESUMO
Phytoestrogens are some plant compounds exhibiting estrogen-like activities. However, some studies have shown that they also affect the growth of some nonhormone-dependent diseases. In this study, daidzein--one of the most common phytoestrogens--was used to investigate its effects on human cervical cancer cells HeLa in vitro. First, the cell growth was measured by using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. Then, the distributions of cell cycle and apoptosis were analyzed with the help of flow cytometry. Finally, the telomerase activity was detected by using real-time quantitative reverse transcription-polymerase chain reaction. The results showed that at the concentrations from 6.25 to 100 micro mol/l, daidzein inhibited the growth of HeLa cells. Flow cytometric analysis showed that cancer cells were arrested at G(0)/G(1) or G(2)/M phase with daidzein. The inductive effects of apoptosis were more obviously observed in low-concentration groups. After HeLa cells were treated with daidzein, the expression of human telomerase catalytic subunit mRNA decreased. These meant that daidzein affected human nonhormone-dependent cervical cancer cells in several ways, including cell growth, cell cycle, and telomerase activity in vitro.
Assuntos
Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Isoflavonas/farmacologia , Fitoestrógenos/farmacologia , Telomerase/efeitos dos fármacos , Telomerase/farmacologia , Neoplasias do Colo do Útero/patologia , Apoptose/efeitos dos fármacos , Feminino , Células HeLa , Humanos , Reação em Cadeia da Polimerase Via Transcriptase ReversaAssuntos
Clusia/química , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/farmacologia , DNA Topoisomerases Tipo I/efeitos dos fármacos , DNA Topoisomerases Tipo I/farmacologia , DNA Topoisomerases Tipo II/efeitos dos fármacos , DNA Topoisomerases Tipo II/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Telomerase/efeitos dos fármacos , Telomerase/farmacologia , Células Tumorais CultivadasRESUMO
Conventional solvent fractionation and bioactivity based target assays were used to identify a new anti-cancer molecule from Phyllanthus urinaria, a herbal medicinal plant used in South India. At each step of the purification process the different fractions that were isolated were tested for specific anti-proliferative activity by assays measuring the inhibition of [(3)H]thymidine incorporation, and trypan blue drug exclusion. The ethyl acetate fraction that contained the bioactivity was further purified and resolved by HPLC on a preparative column. The purity of each of the fractions and their bioactivity were checked. Fraction 3 demonstrated a single spot on TLC and showed maximum anti-proliferative activity. This fraction was further purified and the structure was defined as 7'-hydroxy-3',4',5,9,9'-pentamethoxy-3,4-methylene dioxy lignan using NMR and mass spectrometry analysis. The pure compound and the crude ethyl acetate fraction which showed anti-proliferative activities were examined for ability to target specific markers of apoptosis like bcl2, c-myc and caspases and for effects on telomerase. Four specific cancer cell lines HEp2, EL-1 monocytes, HeLa and MCP7 were used in this study. The results indicate that 7'-hydroxy-3',4',5,9,9'-pentamethoxy-3,4-methylene dioxy lignan was capable of inhibiting telomerase activity and also could inhibit bcl2 and activate caspase 3 and caspase 8 whose significance in the induction of apoptosis is well known. We believe that this compound could serve as a valuable chemotherapeutic drug after further evaluations.