RESUMO
Holometabolous insects stop feeding at the final larval instar stage and then undergo metamorphosis; however, the mechanism is unclear. In the present study, using the serious lepidopteran agricultural pest Helicoverpa armigera as a model, we revealed that 20-hydroxyecdysone (20E) binds to the dopamine receptor (DopEcR), a G protein-coupled receptor, to stop larval feeding and promote pupation. DopEcR was expressed in various tissues and its level increased during metamorphic molting under 20E regulation. The 20E titer was low during larval feeding stages and high during wandering stages. By contrast, the dopamine (DA) titer was high during larval feeding stages and low during the wandering stages. Injection of 20E or blocking dopamine receptors using the inhibitor flupentixol decreased larval food consumption and body weight. Knockdown of DopEcR repressed larval feeding, growth, and pupation. 20E, via DopEcR, promoted apoptosis; and DA, via DopEcR, induced cell proliferation. 20E opposed DA function by repressing DA-induced cell proliferation and AKT phosphorylation. 20E, via DopEcR, induced gene expression and a rapid increase in intracellular calcium ions and cAMP. 20E induced the interaction of DopEcR with G proteins αs and αq. 20E, via DopEcR, induced protein phosphorylation and binding of the EcRB1-USP1 transcription complex to the ecdysone response element. DopEcR could bind 20E inside the cell membrane or after being isolated from the cell membrane. Mutation of DopEcR decreased 20E binding levels and related cellular responses. 20E competed with DA to bind to DopEcR. The results of the present study suggested that 20E, via binding to DopEcR, arrests larval feeding and promotes pupation.
Assuntos
Ecdisterona/metabolismo , Proteínas de Insetos/metabolismo , Mariposas/fisiologia , Receptores Dopaminérgicos/metabolismo , Animais , Dopamina/metabolismo , Antagonistas de Dopamina/farmacologia , Comportamento Alimentar/efeitos dos fármacos , Comportamento Alimentar/fisiologia , Flupentixol/farmacologia , Técnicas de Silenciamento de Genes , Proteínas de Insetos/genética , Larva/efeitos dos fármacos , Larva/fisiologia , Muda/efeitos dos fármacos , Muda/fisiologia , Mariposas/efeitos dos fármacos , Interferência de RNA , Receptores Dopaminérgicos/genética , Células Sf9RESUMO
Animal steroid hormones regulate gene transcription through genomic pathways by binding to nuclear receptors. These steroid hormones also rapidly increase intracellular calcium and cyclic adenosine monophosphate (cAMP) levels and activate the protein kinase C (PKC) and protein kinase A (PKA) nongenomic pathways. However, the function and mechanism of the nongenomic pathways of the steroid hormones are unclear, and the relationship between the PKC and PKA pathways is also unclear. We propose that the steroid hormone 20-hydroxyecdysone (20E) activates the PKA pathway to enhance 20E-induced gene transcription in the lepidopteran insect Helicoverpa armigera The expression of the catalytic subunit 1 of PKA (PKAC1) increased during metamorphosis, and PKAC1 knockdown blocked pupation and repressed 20E-responsive gene expression. 20E regulated PKAC1 phosphorylation at threonine 200 and nuclear translocation through an ecdysone-responsive G-protein-coupled receptor 2. PKAC1 induced cAMP response element-binding protein (CREB) phosphorylation at serine 143, which bound to the cAMP response element on DNA to enhance 20E-responsive gene transcription. Through ecdysone-responsive G-protein-coupled receptor 2, 20E increased cAMP levels, which induced CREB PKA phosphorylation and 20E-responsive gene expression. This study demonstrates that the PKA/CREB pathway tightly and critically regulates 20E-induced gene transcription as well as its relationship with the 20E-induced PKC pathway.
Assuntos
Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Ecdisterona/farmacologia , Proteínas de Insetos/genética , Transdução de Sinais/genética , Transcrição Gênica/efeitos dos fármacos , Animais , Western Blotting , Linhagem Celular , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/genética , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Proteínas de Insetos/metabolismo , Larva/genética , Larva/crescimento & desenvolvimento , Larva/metabolismo , Metamorfose Biológica/genética , Mariposas/genética , Mariposas/crescimento & desenvolvimento , Mariposas/metabolismo , Fosforilação/efeitos dos fármacos , Ligação Proteica , Proteína Quinase C/genética , Proteína Quinase C/metabolismo , Interferência de RNA , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
OBJECTIVE: To study the chemical constituents in the seeds of Datura metel from Xinjiang Province. METHODS: The constituents were isolated and purified by silica gel, ODS and Sephadex LH-20 column chromatographic methods. Their chemical structures were analyzed and identified on the basis of physical and chemical properties and spectral data. RESULTS: Ten compounds were isolated and identified as Isofraxidin (1), Scopatone (2), Daturadiol (3),1,4-Benzenediol (4), Arenarine D (5), Vanillin (6), N-trans-Feruloyl-tyramine (7), Scopoletin (8), G-Sitosterol (9) and Hyoscyamilactol (10). CONCLUSION: Compounds 1 and 2 are firstly isolated from the plants in Solanaceae, compounds 3-8 are firstly isolated from this plant.
Assuntos
Datura metel/química , Compostos Fitoquímicos/análise , Sementes/química , Escopoletina , Sitosteroides , TriterpenosRESUMO
The cadherin epidermal growth factor (EGF) laminin G (LAG) seven-pass G-type receptors (CELSRs) are a special subgroup of adhesion G protein-coupled receptors, which are pivotal regulators of many biologic processes such as neuronal/endocrine cell differentiation, vessel valve formation, and the control of planar cell polarity during embryonic development. All three members of the CELSR family (CELSR1-3) have large ecto-domains that form homophilic interactions and encompass more than 2000 amino acids. Mutations in the ecto-domain or other gene locations of CELSRs are associated with neural tube defects and other diseases in humans. Celsr knockout (KO) animals have many developmental defects. Therefore, specific agonists or antagonists of CELSR members may have therapeutic potential. Although significant progress has been made regarding the functions and biochemical properties of CELSRs, our knowledge of these receptors is still lacking, especially considering that they are broadly distributed but have few characterized functions in a limited number of tissues. The dynamic activation and inactivation of CELSRs and the presence of endogenous ligands beyond homophilic interactions remain elusive, as do the regulatory mechanisms and downstream signaling of these receptors. Given this motivation, future studies with more advanced cell biology or biochemical tools, such as conditional KO mice, may provide further insights into the mechanisms underlying CELSR function, laying the foundation for the design of new CELSR-targeted therapeutic reagents. The cadherin EGF LAG seven-pass G-type receptors (CELSRs) are a special subgroup of adhesion G protein-coupled receptors (GPCRs), which have large ecto-domains that form homophilic interactions and encompass more than 2000 amino acids. Recent studies have revealed that CELSRs are pivotal regulators of many biological processes, such as neuronal/endocrine cell differentiation, vessel valve formation and the control of planar cell polarity during embryonic development.
Assuntos
Caderinas/metabolismo , Diferenciação Celular/fisiologia , Polaridade Celular/fisiologia , Laminina/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Animais , Humanos , Transdução de Sinais/fisiologiaRESUMO
From the angle of sensitivity of the long period fiber grating (LPFG) resonant transmission spectrum, we demonstrate the sensitivity of LPFG resonance peak amplitude changing with transverse loads. The design of a resonant peak modulation-based LPFG rebar corrosion sensor is described by combining the spectral characteristics of LPFG with the expansion state monitoring of rebar corrosion. LPFG spectrum curves corresponding with different rebar corrosion status of the environment under test are captured by the monitoring technique of LPFG transmission spectra, and the relationship between the resonance peak amplitude change and the state of rebar corrosion is obtained, that is, the variation of LPFG resonance peak amplitude increases with the intensifying of the degree of rebar corrosion. The experimental results numerically show that the sensor response has good regularity for a wide range of travel.
RESUMO
In the title compound, C(10)H(10)N(4)O, the dihedral angle between the pyridine ring and the -C=O(CH(2))CN group is 24.08â (12)°. In the crystal, inversion dimers linked by pairs of N-Hâ¯N hydrogen bonds generate R(2) (2)(8) loops.
RESUMO
OBJECTIVE: To evaluate the efficacy and adverse effect of valproic acid (VPA) in combination with low dose chemotherapy on intermediate and high-risk myelodysplastic syndrome. METHODS: A total of 41 patients with intermediate (34) and high-risk (7) myelodysplastic syndrome were retrospectively analyzed. Among them, 19 patients received low dose chemotherapy regimen and 22 received low dose chemotherapy plus VPA. Low dose chemotherapy regimen included: homoharringtonine, 1 - 2 mg×m(-2)×d(-1) intravenously, 14 - 28 d; aclarubicin, 5 - 7 mg×m(-2)×d(-1) intravenously, 1 - 8 d, 15 - 23 d; cytarabine 15 mg/m(2) subcutaneously once every 12 h, 14 - 21 d; and subcutaneously use of granulocyte colony-stimulating factor 200 µg·m(-2)×d(-1) when neutrophil deficiency. The outcome and adverse effect were recorded after the treatment. RESULTS: The overall response rate in the low dose chemotherapy regimen group was 47.4% (9/19), 6 patients (31.6%) achieved complete response (CR). The overall response rate in the VPA group was 77.2% (17/22), 9 patients (40.9%) achieved CR. The overall response rate of the low dose chemotherapy in combination with VPA group was significantly higher than that in the low dose chemotherapy group (P < 0.05) while no difference was found in CR rate. The adverse effect of the low dose chemotherapy in combination with VPA regimen was tolerated. CONCLUSION: With acceptable adverse effect, the low dose chemotherapy in combination with VPA regimen is effective for the treatment of intermediate and high-risk myelodysplastic syndrome. Long-term outcome needs further investigation.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Síndromes Mielodisplásicas/tratamento farmacológico , Ácido Valproico/administração & dosagem , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Ácido Valproico/efeitos adversos , Ácido Valproico/uso terapêuticoRESUMO
CTSD/CathD/CATD (cathepsin D) is a lysosomal aspartic protease. A distinguishing characteristic of CTSD is its dual functions of promoting cell proliferation via secreting a pro-enzyme outside the cells as a ligand, and promoting apoptosis via the mature form of this enzyme inside cells; however, the regulation of its secretion, expression, and maturation is undetermined. Using the lepidopteran insect Helicoverpa armigera, a serious agricultural pest, as a model, we revealed the dual functions and regulatory mechanisms of CTSD secretion, expression, and maturation. Glycosylation of asparagine 233 (N233) determined pro-CTSD secretion. The steroid hormone 20-hydroxyecdysone (20E) promoted CTSD expression. Macroautophagy/autophagy triggered CTSD maturation and localization inside midgut cells to activate CASP3 (caspase 3) and promote apoptosis. Pro-CTSD was expressed in the pupal epidermis and was secreted into the hemolymph to promote adult fat body endoreplication/endoreduplication, cell proliferation, and association. Our study revealed that the differential expression and autophagy-mediated maturation of CTSD in tissues determine its roles in apoptosis and cell proliferation, thereby determining the cell fates of tissues during lepidopteran metamorphosis.Abbreviations: 20E: 20-hydroxyecdysone; 3-MA: 3-methyladenine; ACTB/ß-actin: actin beta; AKT: protein kinase B; ATG1: autophagy-related 1; ATG4: autophagy-related 4; ATG5: autophagy-related 5; ATG7: autophagy-related 7; ATG14: autophagy-related 14; BSA: bovine serum albumin; CASP3: caspase 3; CQ: choroquine; CTSD: cathepsin D; DAPI: 4',6-diamidino-2-phenylindole; DMSO: dimethyl sulfoxide; DPBS: dulbecco's phosphate-buffered saline; DsRNA: double-stranded RNA; EcR: ecdysone receptor; EcRE: ecdysone response element; EdU: 5-ethynyl-2´-deoxyuridine; G-m-CTSD: glycosylated-mautre-CTSD; G-pro-CTSD: glycosylated-pro-CTSD; HaEpi: Helicoverpa armigera epidermal cell line; HE staining: hematoxylin and eosin staining; IgG: immunoglobin G; IM: imaginal midgut; JH: juvenile hormone; Kr-h1: krueppel homologous protein 1; LM: larval midgut; M6P: mannose-6-phosphate; PBS: phosphate-buffered saline; PCD: programmed cell death; PNGase: peptide-N-glycosidase F; RFP: red fluorescent protein; RNAi: RNA interference; SDS-PAGE: sodium dodecyl sulfate-polyacrylamide gel electrophoresis; SYX17: syntaxin 17; USP1: ultraspiracle isoform 1.
Assuntos
Apoptose/fisiologia , Autofagia/fisiologia , Catepsina D/metabolismo , Animais , Autofagia/genética , Proliferação de Células/fisiologia , Ecdisterona/metabolismo , Técnicas de Silenciamento de Genes , Lisossomos/metabolismo , Receptores de Esteroides/metabolismoRESUMO
OBJECTIVE: To explore the efficacy and safety of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in the treatment of relapsed or refractory peripheral T-cell lymphoma(PTCL). METHODS: The clinical data of 6 patients with relapsed or refractory PTCL undergoing allo-HSCT from Sep. 2014 to Sep. 2018 in the department of hematology, aerospace center hospital were retrospectively analyzed. Complications and disease-free survival after HSCT were observed. RESULTS: All the patients could well tolerate the conditioning regimen and acquired hematopoietic recon-struction. Following up till December 2018, with a median time of 11.5 months (1-51); acute GVHD developed in 2 cases and chronic GVHD developed in 5 cases, Among 6 cases one case died of viral pheumonia and the other 5 patients remained disease-free survival. The longest disease-free survival time has reached 51 months. CONCLUSION: allo-HSCT is a safe and effective method for relapsed or refractory peripheral T-cell lymphoma, which can be chosen as salvage treatment method for patients with primary resistance. Optimization of the conditioning regimen may result in better efficacy of allo-HSCT.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , DNA (Citosina-5-)-Metiltransferases , DNA Metiltransferase 3A , Humanos , Mutação , Estudos Retrospectivos , Condicionamento Pré-Transplante , Tirosina Quinase 3 Semelhante a fmsRESUMO
OBJECTIVE: To analyze the change of neutrophil/lymphocyte ratio (NLR) in patients with diffuse large B cell lymphoma (DLBCL) patients before and after CHOP or R-CHOP chemotherapy and its effect on survival of patients. METHODS: Clinical data of 60 patients with DLBCL were collected and were retrospectively analyzed. According to median NLR, 60 patients were divided into the group L in 33 cases (NLR< 2.27) and group H in 27 cases (NLR≥ 2.27). The curative effect and survival rate by using CHOP or R-CHOP after chemotherapy were compared between the two groups. RESULTS: In the group H, the total effective rate after chemotherapy (55.56%) was significantly lower than that of group L (87.88%), which showed that the difference were statistically significant (P<0.05); the cumulative survival rate of 1,2,3 years in the group H (70.37%, 59.26%, 37.04%) were significantly lower than that in the group L (93.94%, 87.88%, 60.61%) (P<0.05). The NLR≥ 2.27 before chemotherapy was the factor influencing the prognosis of patients with DLBCL (P<0.05). CONCLUSION: The NLR≥ 2.27 before chemotherapy may be used as a factor influencing the prognosis of patients with DLBCL, and the high NLR may indicate poor clinical efficacy and worse prognosis.
Assuntos
Linfoma Difuso de Grandes Células B , Anticorpos Monoclonais Murinos , Protocolos de Quimioterapia Combinada Antineoplásica , Ciclofosfamida , Doxorrubicina , Humanos , Linfócitos , Neutrófilos , Prednisona , Prognóstico , Estudos Retrospectivos , Rituximab , VincristinaRESUMO
Chronic pancreatitis (CP) is a serious disease that characterized by the progressive replacement of functional pancreas tissue by fibrotic tissue. Vitamin D receptor (VDR) plays a critical role in the development of CP, since it inhibits excessive deposition of extracellular matrix (ECM) in activated pancreatic stellate cells (PSCs). Herein, a novel series of non-secosteriodal VDR ligands were designed and synthesized, and their VDR affinity and anti-fibrosis activity were evaluated. The identification of the potent compound 9c was found over structural optimization, which inhibited ECM deposition and fibrotic gene expression in the western blot and qPCR assays, respectively. Further investigation revealed that compound 9c inhibited pancreatic fibrosis in vivo without increase on serum calcium, which could cause hypercalcemia. These results provide novel insight in possible drug discovery for the treatment of CP using non-secosteroidal VDR modulators.
Assuntos
Desenho de Fármacos , Pancreatite Crônica/tratamento farmacológico , Receptores de Calcitriol/agonistas , Esteroides/farmacologia , Animais , Relação Dose-Resposta a Droga , Células HEK293 , Humanos , Ligantes , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Estrutura Molecular , Esteroides/síntese química , Esteroides/química , Relação Estrutura-AtividadeRESUMO
Modulating the vitamin D receptor (VDR) is an effective way to treat for cancer. We previously reported a potent non-secosteroidal VDR modulator (sw-22) with modest anti-tumor activity, which could be due to its undesirable physicochemical and pharmacokinetic properties. In this study, we investigated the structure-activity and structure-property relationships around the 2'-hydroxyl group of sw-22 to improve the physicochemical properties, pharmacokinetic properties and anti-tumor activity. Compounds 19a and 27b, the potent non-secosteroidal VDR modulators, were identified as the most effective molecules in inhibiting the proliferation of three cancer cell lines, particularly breast cancer cells, with a low IC50 via the distribution of cell cycle and induction of apoptosis by stimulating the expression of p21, p27 and Bax. Further investigation revealed that 19a and 27b possessed favorable rat microsomal metabolic stability (2.22 and 2.3 times, respectively, more stable than sw-22), solubility (43.9 and 50.2 times, respectively, more soluble than sw-22) and in vivo pharmacokinetic properties. In addition, 19a and 27b showed excellent in vivo anti-tumor activity without cause hypercalcemia, which is the main side effect of marketed VDR modulators. In summary, the favorable physicochemical properties, pharmacokinetic properties and anti-tumor activity of 19a and 27b highlight their potential therapeutic applications in cancer treatment.
Assuntos
Antineoplásicos/farmacologia , Pentanos/farmacologia , Receptores de Calcitriol/metabolismo , Moduladores Seletivos de Receptor Estrogênico/farmacologia , Animais , Antineoplásicos/síntese química , 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 , Humanos , Células MCF-7 , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/patologia , Pentanos/síntese química , Pentanos/química , Receptores de Calcitriol/agonistas , Receptores de Calcitriol/antagonistas & inibidores , Moduladores Seletivos de Receptor Estrogênico/síntese química , Moduladores Seletivos de Receptor Estrogênico/química , Relação Estrutura-AtividadeRESUMO
Recently, wearable devices have been attracting significantly increased interest in human motion detection and human physiological signal monitoring. Currently, it is still a great challenge to fabricate strain sensors with high performance and good fit to the human body. In this work, we fabricated a close-fitting and wearable graphene textile strain sensor based on a graphene textile without polymer encapsulation. Graphene oxide acts as a colorant to dye the polyester fabric and is reduced at high temperature, which endows the graphene textile strain sensor with excellent performance. Compared with the previously reported strain sensors, our strain sensor exhibits a distinctive negative resistance variation with increasing strain. In addition, the sensor also demonstrates fascinating performance, including high sensitivity, long-term stability, and great comfort. Based on its superior performance, the graphene textile strain sensor can be knitted on clothing for detecting both subtle and large human motions, showing the tremendous potential for applications in wearable electronics.
Assuntos
Grafite/química , Movimento (Física) , Têxteis , Dispositivos Eletrônicos Vestíveis , HumanosRESUMO
BACKGROUND: Both p16(INK4) and p21(Waf1) are tumor suppressors with similar biological functions in the regulation of cellular senescence. Previous reports showed that p16(INK4) could be activated by p21(Waf1) through transcriptional factor Sp1 in HeLa cells. This study was undertaken to determine the effects of p16(INK4) on the expression and functions of p21(Waf1). METHODS: Human diploid fibroblast 2BS cells were stably transfected with sense (2BS/p16(INK4)), antisense p16(INK4) (2BS/asp16(INK4)) or empty vector (2BS/neo). Then they were assayed by reverse-transcription polymerase chain reaction (RT-PCR), fluorescence activated cell sorting (FACS) and Western blot. RESULTS: 2BS/p16(INK4) cells exhibited cell cycle arrest in both G1 and G2/M phases. Endogenous p21(Waf1) protein levels increased twofold in the 2BS/p16(INK4) cells, but not decreased in the 2BS/asp16(INK4) cells. p21(Waf1) mRNA levels were not affected in neither 2BS/p16(INK4) nor 2BS/asp16(INK4) cells. CONCLUSION: p16(INK4) may play an important role in the regulation of cellular senescence by modulating the p21(Waf1) protein level via the posttranscriptional mechanism.
Assuntos
Inibidor p16 de Quinase Dependente de Ciclina/fisiologia , Inibidor de Quinase Dependente de Ciclina p21/fisiologia , Ciclo Celular , Células Cultivadas , Senescência Celular , Fibroblastos/metabolismo , Humanos , Transcrição GênicaRESUMO
OBJECTIVE: To explore the expression and clinical significance of B cell lymphocyte stimulating factor (BLyS) in B cell-derived malignant hematological diseases. METHODS: Fifty-seven cases of newly diagnosed B cell-derived hematologic malignancies were admitted and treated in our hospital from March 2015 to 2016 July. including 17 cases of multiple myeloma(MM) (A group) and 40 cases of B cell non-Hodgkin's lymphoma(B-NHL) (B group), 30 healthy volunteers were enrolled in control group(C group). The BLyS level in peripheral blood of A,B and C groups was detected by ELISA kit; for patient with hematologic malignancies, the BLyS level was detected again after chemotherapy and was compared with level before chemotherapy. RESULTS: The BLyS level in patients with B cell-derived hematologic malignancies significantly increased, as compared with healthy volanteers(P<0.05). After chemotherapy, the BLyS level in patients all significantly dicreased (P<0.05); the BLyS level in peripheral blood of DLBCL and FL patients was significantly higher than that in patients with B-NHL of other types(P<0.05); the BLyS level in peripheral blood of patients at III-IV stage was significantly higher than that in patients at I-II stage. CONCLUSION: The BLyS expression in B cell derived hematologic malignancies significantly increases, moreover the its expression level in B-NHL patients at different stages and histologic types is different, suggesting that detection of BLyS expression level in patients in vivo possesses a certain guiding role for diagnosis, staging and treatment of B cell-derived hematologic malignancies.
Assuntos
Linfócitos B , Neoplasias Hematológicas/imunologia , Linfoma Difuso de Grandes Células B/imunologia , Fator Ativador de Células B , Neoplasias Hematológicas/metabolismo , Humanos , Linfoma Difuso de Grandes Células B/metabolismoRESUMO
Acute myeloid leukemia (AML), characterized by extremely heterogeneous molecular and biologic abnormalities, is an aggressive hematologic malignancy, hampering the research and development of effective targeted treatment modalities. Sweroside (SWE), an iridoid glycoside, is isolated from Lonicera japonIca. It has diverse biological activities, but little is known in human leukemia. Here, our study showed the potential of sweroside as an effective agent against human leukemia using in vitro and in vivo approaches. Sweroside treatment obviously reduced the cell viability in human leukemia cell lines and primary human leukemia cells. S and G2/M cell-cycle arrest were induced by sweroside, associated with the down-regulation of Cyclin D1, cyclin-dependent kinase 4 (CDK4), CDC2 and CDC25 as well as the up-regulation of p53 and p21. In addition, apoptosis was highly induced by sweroside both in vitro and in vivo through enhancement of cleaved Caspase-3 and poly (ADP-ribosyl) transferase (PARP). Consistently, anti-apoptotic molecule of B cell CLL/lymphoma 2 (Bcl-2) was impeded by sweroside, while pro-apoptotic signal of Bcl-2-associated X protein (Bax) was elevated. In vivo, HL-60-bearing tumor growth was considerably inhibited by sweroside, which was related to proliferation suppression and apoptosis induction. Our study highlighted the therapeutic potential of sweroside, and provided new insights into the molecular mechanism of sweroside chemosensitization in human leukemia.
Assuntos
Apoptose , Glucosídeos Iridoides/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Caspases/metabolismo , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Células HEK293 , Humanos , Glucosídeos Iridoides/química , Glucosídeos Iridoides/farmacologia , Leucemia Mieloide Aguda/patologia , Camundongos Nus , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The aim of this study was to investigate whether polymorphisms of - 938C/A and Thr43Ala in the BCL-2 gene and G - 248A in the BAX gene are associated with the risk of developing non-Hodgkin lymphoma (NHL). We genotyped polymorphisms of - 938C/A and Thr43Ala in the BCL-2 gene and G-248A in the BAX gene among 424 patients with NHL and 446 controls. We found that the - 938AA genotype of the BCL2 gene was significantly associated with the risk of developing NHL (p < 0.001) and this genotype was associated with advanced stage (p = 0.01). Meanwhile, individuals having - 248AG + AA genotypes were significantly associated with an increased risk of NHL (p = 0.01), and these genotypes were associated with larger tumor size (p = 0.02). The present study demonstrated that the - 938AA genotype of the BCL-2 gene and - 248AG + AA genotype of the BAX gene may be susceptible genotypes for NHL. There appeared to be an impact of the BCL2 - 938AA genotype on advanced stage and - 248AG + AA genotypes on tumor size in NHL.
Assuntos
Transformação Celular Neoplásica/genética , Linfoma não Hodgkin/genética , Polimorfismo Genético , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteína X Associada a bcl-2/genética , Adulto , Idoso , Alelos , Estudos de Casos e Controles , Feminino , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Humanos , Linfoma não Hodgkin/diagnóstico , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Fenótipo , Polimorfismo de Nucleotídeo Único , Risco , Fatores de Risco , Carga TumoralRESUMO
It has been demonstrated that aberrant expression of microRNAs (miRNAs) is strongly associated with carcinogenesis. Recently, specific miRNAs may serve as potential biomarkers for the diagnosis and prognosis of various types of tumor. MiR-23a is known to play important role in the development of cancers and deregulated in various hematological malignancies. The aim of the present study is to explore miR-23a as potential diagnostic and/or prognostic marker of diffuse large B-cell lymphoma (DLBCL). We compared the expression level of miR-23a in DLBCL patients (n = 104) and reactive lymph nodes as controls (n = 28) from formalin-fixed, paraffin-embedded tissues using quantitative reverse transcription-polymerase chain reaction. The expression level of miR-23a was significantly higher in DLBCL patients than in controls (P = 0.001). No significant association was observed between the miR-23a expression level and clinical features such as age, gender, Ann Arbor stage, performance status, lactate dehydrogenase, extranodal sites and International Prognostic Index score (IPI). Kaplan-Meier analysis showed that higher expression level of miR-23a was significantly associated with a poor overall survival (OS) in DLBCL patients (log-rank test, P = 0.029), and multivariable Cox regression revealed the expression of miR-23a (adjusted P = 0.034) and IPI (adjusted P = 0.021) was independently associated with OS. To our knowledge, we provide here the first evidence that miR-23a may represent a diagnostic and prognostic marker for DLBCL. DLBCL patients with a high expression level of miR-23a had a shorter OS than patients with a lower expression level. Further investigation of the changes may be of prognostic significance in clinical practice.
Assuntos
Regulação Neoplásica da Expressão Gênica , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/mortalidade , MicroRNAs/genética , MicroRNAs/metabolismo , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais , Feminino , Perfilação da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Prognóstico , Modelos de Riscos Proporcionais , Sensibilidade e Especificidade , Resultado do Tratamento , Adulto JovemRESUMO
The aim of this study was to explore the effect of recombinant human interleukin 11 (rhIL-11) on platelet recovery after peripheral blood hematopoietic stem cell transplantation and its side-effects. 20 patients with hematologic malignancies treated by allogeneic peripheral blood stem cell transplantation (PBSCT) were randomly divided into test and control groups. The patients in test group were treated with rhIL-11 since the day 6 after PBSCT, while the patients in control group were given supporting treatment. The results showed that the average time of the platelet to recover to 20 x 10(9)/L was 22.8 days in test group and 27.3 days in control group (p < 0.01). The average time for platelet to recover to 50 x 10(9)/L was 25.7 days in test group, and 32.3 days in control group (p < 0.01). The average number of megakaryocytes was 15.6 in test group, and 7.8 in control group on day 30 after PBSCT (p < 0.01). In conclusion, the rhIL-11 is able to accelerate platelet recovery after peripheral blood hematopoietic stem cell transplantation.