RESUMO
Dengue vaccine candidates have been shown to improve vaccine safety and efficacy by altering the residues or accessibility of the fusion loop on the virus envelope protein domain II (DIIFL) in an ex vivo animal study. The current study aimed to comprehensively investigate the impact of DIIFL mutations on the antigenicity, immunogenicity, and protective efficacy of Japanese encephalitis virus (JEV) virus-like particles (VLPs) in mice. We found the DIIFL G106K/L107D (KD) and W101G/G106K/L107D (GKD) mutations altered the binding activity of JEV VLP to cross-reactive monoclonal antibodies but had no effect on their ability to elicit total IgG antibodies in mice. However, JEV VLPs with KD or GKD mutations induced significantly less neutralizing antibodies against JEV. Only 46% and 31% of the KD and GKD VLPs-immunized mice survived compared to 100% of the wild-type (WT) VLP-immunized mice after a lethal JEV challenge. In passive protection experiments, naïve mice that received sera from WT VLP-immunized mice exhibited a significantly higher survival rate of 46.7% compared to those receiving sera from KD VLP- and GKD VLP-immunized mice (6.7% and 0%, respectively). This study demonstrated that JEV DIIFL is crucial for eliciting potently neutralizing antibodies and protective immunity against JEV. IMPORTANCE: Introduction of mutations into the fusion loop is one potential strategy for generating safe dengue and Zika vaccines by reducing the risk of severe dengue following subsequent infections, and for constructing live-attenuated vaccine candidates against newly emerging Japanese encephalitis virus (JEV) or Japanese encephalitis (JE) serocomplex virus. The monoclonal antibody studies indicated the fusion loop of JE serocomplex viruses primarily comprised non-neutralizing epitopes. However, the present study demonstrates that the JEV fusion loop plays a critical role in eliciting protective immunity in mice. Modifications to the fusion loop of JE serocomplex viruses might negatively affect vaccine efficacy compared to dengue and zika serocomplex viruses. Further studies are required to assess the impact of mutant fusion loop encoded by commonly used JEV vaccine strains on vaccine efficacy or safety after subsequent dengue virus infection.
Assuntos
Vírus da Encefalite Japonesa (Espécie) , Encefalite Japonesa , Vacinas contra Encefalite Japonesa , Animais , Camundongos , Aminoácidos , Anticorpos Neutralizantes , Anticorpos Antivirais , Dengue , Vírus da Encefalite Japonesa (Espécie)/fisiologia , Encefalite Japonesa/imunologia , Encefalite Japonesa/prevenção & controle , Epitopos , Vacinas contra Encefalite Japonesa/genética , Proteínas do Envelope Viral/genética , Zika virus , Infecção por Zika virusRESUMO
Fms-like tyrosine kinase 3 (FLT3) is considered a promising therapeutic target for acute myeloid leukemia (AML) in the clinical. However, monotherapy with FLT3 inhibitor is usually accompanied by drug resistance. Dual inhibitors might be therapeutically beneficial to patients with AML due to their ability to overcome drug resistance. Mitogen-activated protein kinase (MAPK)-interacting kinases (MNKs) phosphorylate eukaryotic translation initiation factor 4E (eIF4E), which brings together the RAS/RAF/ERK and PI3K/AKT/mTOR oncogenic pathways. Therefore, dual inhibition of FLT3 and MNK2 might have an additive effect against AML. Herein, a structure-based virtual screening approach was performed to identify dual inhibitors of FLT3 and MNK2 from the ChemDiv database. Compound K783-0308 was identified as a dual inhibitor of FLT3 and MNK2 with IC50 values of 680 and 406 nM, respectively. In addition, the compound showed selectivity for both FLT3 and MNK2 in a panel of 82 kinases. The structure-activity relationship analysis and common interactions revealed interactions between K783-0308 analogs and FLT3 and MNK2. Furthermore, K783-0308 inhibited MV-4-11 and MOLM-13 AML cell growth and induced G0/G1 cell cycle arrest. Taken together, the dual inhibitor K783-0308 showed promising results and can be potentially optimized as a lead compound for AML treatment.
Assuntos
Leucemia Mieloide Aguda , Tirosina Quinase 3 Semelhante a fms , Apoptose , Linhagem Celular Tumoral , Proliferação de Células , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Leucemia Mieloide Aguda/tratamento farmacológico , Mutação , Fosfatidilinositol 3-Quinases , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Serina-Treonina QuinasesRESUMO
There is interest in whether nicotine could enhance attention in sporting performance, but evidence on the acute effect of nicotine on physical response and sports performance in baseball players remains scant. This was an observational study to examine whether nicotine gum chewed before exercise could provide acute effects on physiological responses and sport performance. Accordingly, heart rate variability (HRV), saliva cotinine concentration and α-amylase activity, cognitive function, muscle strength, and baseball-hitting performance were measured. Thirteen healthy male non-smoker baseball players were recruited. Conducting two sequences with 7-day intervals, they chewed nicotine gum (nicotine group) or flavor-matched placebo gum (placebo group) for 30 min. HRV and saliva analyses were conducted before gum consumption (S1), after gum consumption (S2), and after test completion (S3). Cognitive, muscle strength, and baseball-hitting performance tests were performed after nicotine or placebo gum chewing. The outcomes of all assessed variables were compared within and between the groups. Significant changes in HRV, α-amylase, testosterone, and cortisol were observed in the nicotine group at S2 and S3 (p < 0.05). Compared with the placebo group, the nicotine group exhibited enhanced motor reaction times, grooved pegboard test (GPT) results on cognitive function, and baseball-hitting performance, and small effect sizes were noted (d = 0.47, 0.46 and 0.41, respectively). Nicotine could induce changes in endocrine and sympathetic nerve activity and enhance cognitive function and baseball-hitting performance. However, no increase in muscle strength was observed after nicotine intake.
Assuntos
Desempenho Atlético , Beisebol , Atenção , Goma de Mascar , Humanos , Masculino , NicotinaRESUMO
Human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) were shown to have potential for immunoregulation and tissue repair. The objective of this study was to investigate the effects of hUC-MSCs on emphysema in chronic obstructive pulmonary disease (COPD). The C57BL/6JNarl mice were exposed to cigarette smoke (CS) for 4 months followed by administration of hUC-MSCs at 3 × 106 (low dose), 1 × 107 (medium dose), and 3 × 107 cells/kg body weight (high dose). The hUC-MSCs caused significant decreases in emphysema severity by measuring the mean linear intercept (MLI) and destructive index (DI). A decrease in neutrophils (%) and an increase in lymphocytes (%) in bronchoalveolar lavage fluid (BALF) were observed in emphysematous mice after hUC-MSC treatment. Lung levels of interleukin (IL)-1ß, C-X-C motif chemokine ligand 1 (CXCL1)/keratinocyte chemoattractant (KC), and matrix metalloproteinase (MMP)-12 significantly decreased after hUC-MSC administration. Significant reductions in tumor necrosis factor (TNF)-α, IL-1ß, and IL-17A in serum occurred after hUC-MSC administration. Notably, the cell viability of lung fibroblasts improved with hUC-MSCs after being treated with CS extract (CSE). Furthermore, the hUC-MSCs-conditioned medium (hUC-MSCs-CM) restored the contractile force, and increased messenger RNA expressions of elastin and fibronectin by lung fibroblasts. In conclusion, hUC-MSCs reduced inflammatory responses and emphysema severity in CS-induced emphysematous mice.
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Aberrant alteration of epigenetic information disturbs chromatin structure and gene function, thereby facilitating cancer development. Several drugs targeting histone deacetylases (HDACs), a group of epigenetic enzymes, have been approved for treating hematologic malignancies in the clinic. However, patients who suffer from solid tumors often respond poorly to these drugs. In this study, we report a selective entinostat derivative, MPT0L184, with potent cancer-killing activity in both cell-based and mouse xenograft models. A time-course analysis of cell-cycle progression revealed that MPT0L184 treatment elicited an early onset of mitosis but prevented the division of cells with duplicated chromosomes. We show that MPT0L184 possessed potent inhibitory activity toward HDAC1 and 2, and its HDAC-inhibitory activity was required for initiating premature mitotic signaling. HDAC inhibition by MPT0L184 reduced WEE1 expression at the transcription level. In addition, MPT0L184 treatment also downregulated ATR-mediated CHK1 phosphorylation independent of HDAC inhibition. Furthermore, gastric cancer cells resistant to HDAC inhibitors were vulnerable to MPT0L184. Taken together, our study discovers MPT0L184 as a novel HDAC inhibitor that can trigger premature mitosis and potentially counteract drug resistance of cancers.
Assuntos
Benzamidas/farmacologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Inibidores de Histona Desacetilases/farmacologia , Piridinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Animais , Benzamidas/química , Pontos de Checagem do Ciclo Celular/fisiologia , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Feminino , Inibidores de Histona Desacetilases/química , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Mitose/efeitos dos fármacos , Mitose/fisiologia , Piridinas/química , Transdução de Sinais/fisiologia , Carga Tumoral/efeitos dos fármacos , Carga Tumoral/fisiologia , Ensaios Antitumorais Modelo de Xenoenxerto/métodosRESUMO
BACKGROUND: Nicotine is beneficial to mood, arousal and cognition in humans. Due to the importance of cognitive functioning for archery athletes, we investigated the effects of nicotine supplementation on the cognitive abilities, heart rate variability (HRV), and sport performance of professional archers. METHODS: Eleven college archers were recruited and given 2 mg of nicotine supplementation (NIC group) and placebo (PLA group) in a crossover design. RESULTS: The results showed that at 30 min after the intake of nicotine gum, the "correct rejection" time in the NIC group was significantly lower than that of the PLA group (7.29 ± 0.87 vs. 8.23 ± 0.98 msec, p < 0.05). In addition, the NIC group completed the grooved pegboard test in a shorter time than the PLA group (48.76 ± 3.18 vs. 53.41 ± 4.05 s, p < 0.05), whereas motor reaction times were not different between the two groups. Saliva α-amylase activity was significantly lower after nicotine supplementation (p < 0.01) but increased immediately after the archery test in the NIC group (p < 0.05). In addition, nicotine supplementation significantly decreased HRV and increased the archery score (290.58 ± 10.09 vs. 298.05 ± 8.56, p < 0.01). CONCLUSIONS: Nicotine enhances the performance of archery athletes by increasing cognitive function and stimulating the sympathetic adrenergic system.
Assuntos
Atletas , Desempenho Atlético , Cognição/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Nicotina/farmacologia , Agonistas Nicotínicos/farmacologia , Estudos Cross-Over , Humanos , Masculino , Nicotina/administração & dosagem , Goma de Mascar de Nicotina , Agonistas Nicotínicos/administração & dosagem , Placebos/administração & dosagem , Placebos/farmacologia , Tempo de Reação/efeitos dos fármacos , alfa-Amilases Salivares/análise , alfa-Amilases Salivares/efeitos dos fármacos , Taiwan , Fatores de TempoRESUMO
Cigarette smoke (CS) has been reported to induce oxidative stress and inflammatory process in the lungs. However, the role of human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) in the regulation of pulmonary inflammation remains unclear. The objective of this study is to investigate the effects of hUC-MSCs on lung inflammation in the acute CS-induced pulmonary inflammation animal model. Eight-week-old male C57BL/6 mice were intravenously administered 3 × 106, 1 × 107, and 3 × 107 cells/kg of hUC-MSCs as well as normal saline alone (control) after 3 days of CS exposure. Mice exposed to high-efficiency particulate air (HEPA)-filtered room air served as the CS control group. High-dose (3 × 107 cells/kg) hUC-MSC administration significantly decreased tumor necrosis factor (TNF)-α in the bronchoalveolar lavage fluid (BALF) of CS-exposed mice (p < 0.05). The chemokine (CXC motif) ligand 1/keratinocyte chemoattractant (CXCL1/KC) in BALF were significantly reduced by low-dose (3 × 106 cells/kg) and high-dose (3 × 107 cells/kg) hUC-MSC (p < 0.05). Medium-dose hUC-MSC administration decreased interleukin (IL)-1ß in lung of mice, and TNF-α and caspase-3 were decreased in the lung of CS-exposed mice by medium- and high-dose MSC (p < 0.05). Low-dose hUC-MSCs significantly elevated serum CXCL1/KC and IL-1ß in CS-exposed mice (p < 0.05). Our results suggest that high-dose hUC-MSCs reduced pulmonary inflammation and had antiapoptotic effects in acute pulmonary inflammation.
RESUMO
Multitarget agents simultaneously trigger molecules in functionally complementary pathways, and are therefore considered to have potential in effectively treating Alzheimer's disease (AD), which has a complex pathogenetic mechanism. In this study, the HDAC inhibitor core is incorporated into the acetylcholine esterase (ACE) inhibitor acridine-derived moiety and resulted in compounds that exhibited higher class IIa HDAC (4, 5, 7, and 9)- and class IIb HDAC6-inhibiting activity when compared to the pan-HDAC inhibitor SAHA in clinical practice. One of these compounds, 11b, displayed greater selectivity toward HDAC6 than other isoform enzymes. In contrast, the activity of compound 6a was selective toward class IIa HDAC and HDAC6. These two compounds exhibited strong activity against Aß-aggregation as well as significantly disrupted Aß-oligomer. Additionally, 11b and 6a strongly inhibited AChE. These experimental findings demonstrate that compounds 11b and 6a are HDAC-Aß-aggregation-AChE inhibitors. Notably, they can enhance neurite outgrowth, but with no significant neurotoxicity. Further biological evaluation revealed the various cellular effects of multitarget compounds 11b and 6a, which have the potential to treat AD.
Assuntos
Acridinas/farmacologia , Doença de Alzheimer/tratamento farmacológico , Inibidores de Histona Desacetilases/farmacologia , Histona Desacetilases/metabolismo , Acetilcolinesterase/metabolismo , Acridinas/síntese química , Acridinas/química , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/metabolismo , Animais , Sobrevivência Celular/efeitos dos fármacos , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Relação Dose-Resposta a Droga , Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/química , Humanos , Camundongos , Estrutura Molecular , Fragmentos de Peptídeos/antagonistas & inibidores , Fragmentos de Peptídeos/metabolismo , Agregados Proteicos/efeitos dos fármacos , Relação Estrutura-Atividade , Células Tumorais CultivadasRESUMO
Novel dual inhibitors of histone deacetylase (HDAC) and heat-shock protein 90 (HSP90) are synthesized and evaluated. These compounds are endowed with potent HDAC and HSP90 inhibitory activities with IC50 values in nanomolar range with Compound 20 (HDAC IC50â¯=â¯194â¯nM; HSP90α IC50â¯=â¯153â¯nM) and compound 26 (HDAC IC50â¯=â¯360â¯nM; HSP90α IC50â¯=â¯77â¯nM) displaying most potent HDAC and HSP90α inhibitory activities. Both of these compounds induce HSP70 expression and down regulate HSP90 client proteins which play important roles in the regulation of survival and invasiveness in cancer cells. In addition, compounds 20 and 26 induce acetylation of α-tubulin and histone H3. Significantly, compounds 20 and 26 could effectively reduce programmed death-ligand 1 (PD-L1) expression in IFN-γ treated lung H1975â¯cells in a dose dependent manner. These findings suggest that dual inhibition of HDAC and HSP90 that can modulate immunosuppressive ability of tumor area may provide a better therapeutic strategy for cancer treatment in the future.
Assuntos
Anilidas/farmacologia , Antineoplásicos/farmacologia , Inibidores Enzimáticos/farmacologia , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Histona Desacetilases/metabolismo , Ácidos Hidroxâmicos/farmacologia , Anilidas/síntese química , Anilidas/química , Antineoplásicos/síntese química , Antineoplásicos/química , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/biossíntese , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Regulação para Baixo/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Proteínas de Choque Térmico HSP90/metabolismo , Humanos , Ácidos Hidroxâmicos/síntese química , Ácidos Hidroxâmicos/química , Interferon gama/antagonistas & inibidores , Interferon gama/biossíntese , Estrutura Molecular , Relação Estrutura-Atividade , Células Tumorais CultivadasRESUMO
BACKGROUND: Oncogenic K-Ras signaling highly relies on the canonical Ras/MEK/ERK pathway to contribute to pancreatic cancer progression. However, numerous efforts of MEK inhibitors have failed to provide an optimal antitumor effect for pancreatic cancer in practice. The aim of the present work was to develop a more efficacious therapeutic intervention for MEK inhibitors through combination with histone deacetylase (HDAC) inhibitor MPT0E028. METHODS: The effects of combined therapy on cell viability, apoptosis, protein, and RNA expressions were determined by MTT assay, flow cytometry, western blotting, and quantitative PCR analysis. The AsPC-1 xenograft was used to assess antitumor effects in vivo. RESULTS: The co-administration of MPT0E028 and MEK inhibitor yielded synergistic effects on cell viability suppression both in K-Ras mutated and wild-type pancreatic cancer cells and also markedly triggered cell apoptosis. Surprisingly, ERK and epidermal growth factor receptor (EGFR) were activated by the long-term and low-concentration treatment of MPT0E028 or another HDAC inhibitor alone. Whereas, the pharmacological attenuation of ERK signaling dramatically abolished the MPTE028-induced p-ERK and EGFR expression. Overexpression of HDAC4, HDAC6, and MEK, respectively, reversed the cell death induced by the combined treatment. Finally, the combined treatment decreased the tumor volume in an AsPC-1 xenograft model compared to each individual treatment alone. CONCLUSIONS: The synergistic anti-survival effect of the combination was suggested to occur via compensation of the MEK inhibitor for activated ERK. Our results indicate that this combination strategy could benefit patients with pancreatic cancer beyond K-Ras status.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Inibidores de Histona Desacetilases/administração & dosagem , Ácidos Hidroxâmicos/administração & dosagem , Indóis/administração & dosagem , Neoplasias Pancreáticas/tratamento farmacológico , Inibidores de Proteínas Quinases/administração & dosagem , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Sinergismo Farmacológico , Epigênese Genética/efeitos dos fármacos , Receptores ErbB/genética , Flavonoides/administração & dosagem , Flavonoides/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Inibidores de Histona Desacetilases/farmacologia , Humanos , Ácidos Hidroxâmicos/farmacologia , Indóis/farmacologia , Masculino , Camundongos , Neoplasias Pancreáticas/genética , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas p21(ras)/genética , Piridonas/administração & dosagem , Piridonas/farmacologia , Pirimidinonas/administração & dosagem , Pirimidinonas/farmacologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The JAK2/STAT signaling pathway mediates cytokine receptor signals that are involved in cell growth, survival and homeostasis. JAK2 is a member of the Janus kinase (JAK) family and aberrant JAK2/STAT is involved with various diseases, making the pathway a therapeutic target. The similarity between the ATP binding site of protein kinases has made development of specific inhibitors difficult. Current JAK2 inhibitors are not selective and produce unwanted side effects. It is thought that increasing selectivity of kinase inhibitors may reduce the side effects seen with current treatment options. Thus, there is a great need for a selective JAK inhibitor. In this study, we identified a JAK2 specific inhibitor. We first identified key pharmacological interactions in the JAK2 binding site by analyzing known JAK2 inhibitors. Then, we performed structure-based virtual screening and filtered compounds based on their pharmacological interactions and identified compound NSC13626 as a potential JAK2 inhibitor. Results of enzymatic assays revealed that against a panel of kinases, compound NSC13626 is a JAK2 inhibitor and has high selectivity toward the JAK2 and JAK3 isozymes. Our cellular assays revealed that compound NSC13626 inhibits colorectal cancer cell (CRC) growth by downregulating phosphorylation of STAT3 and arresting the cell cycle in the S phase. Thus, we believe that compound NSC13626 has potential to be further optimized as a selective JAK2 drug.
RESUMO
BACKGROUND: There are some limitations of standard chemotherapy for acute leukemia. Vincristine and doxorubicin are commonly used for acute leukemia, but they may induce serious side effects such as cardiomyopathy and neurotoxicity. Furthermore, chemotherapy resistance occurs more and more frequently. Therefore, effective treatment strategies are needed. Histone deacetylase 6 inhibition is considered as a potential therapeutic strategy for acute leukemia, since it is observed that HDAC6 is overexpressed in acute leukemia and regulates tumor survival. Combination therapy for cancer is used to minimize adverse drug effects, reduce drug dosage, enhance efficacy, and prevent drug resistance. In order to improve efficacy of chemotherapy agents of acute leukemia, this study will investigate the effects of combination MPT0G211, a novel histone deacetylase 6 inhibitor, with doxorubicin or vincristine on human acute leukemia cells. RESULTS: MPT0G211 combined with doxorubicin induces DNA damage response on human acute myeloid leukemia cells. MPT0G211 can additionally increase Ku70 acetylation and release BAX to mitochondria. Ectopic expression of HDAC6 successively reversed the apoptosis triggered by the combined treatment. Moreover, co-treatment of MPT0G211 and vincristine may alter microtubule dynamics, triggering acute lymphoblastic leukemia cells arrest in mitotic phase followed by induction of the apoptotic pathway. Finally, MPT0G211 plus doxorubicin or vincristine can significantly improve the tumor growth delay in a tumor xenograft model. CONCLUSIONS: Collectively, our data highlighted that MPT0G211 in combination with chemotherapy drugs has significant anticancer activity, suggesting a novel strategy for the treatment of acute leukemia.
Assuntos
Benzamidas/administração & dosagem , Doxorrubicina/administração & dosagem , Inibidores de Histona Desacetilases/administração & dosagem , Leucemia Mieloide Aguda/tratamento farmacológico , Vincristina/administração & dosagem , Animais , Benzamidas/farmacologia , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Doxorrubicina/farmacologia , Sinergismo Farmacológico , Células HL-60 , Desacetilase 6 de Histona/antagonistas & inibidores , Inibidores de Histona Desacetilases/farmacologia , Humanos , Leucemia Mieloide Aguda/metabolismo , Camundongos , Vincristina/farmacologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Long-term administration of luteinizing hormone-releasing hormone analogs (LHRHa) is the main type of androgen-deprivation therapy (ADT) for lethal prostate cancer. A fully insertable microneedle system, composed of embeddable chitosan microneedles and a dissolvable polyvinyl alcohol/polyvinyl pyrrolidone supporting array, was developed for sustained delivery of LHRHa to the skin. A porcine cadaver skin test showed that chitosan microneedles can be fully embedded within the skin and microneedle-created micropores reseal within 7 days. The measured LHRHa loading amount was 73.3±2.8 µg per microneedle patch. After applying goserelin-containing microneedles to mice, serum LH levels increased initially and then declined below baseline at day 7. In contrast, serum testosterone levels increased to reach a peak at day 14 and then declined to a castration level at day 21. Additionally, such a castration level was maintained for 2 weeks. Therefore, transdermal delivery of goserelin with embeddable chitosan microneedles can produce a castrated state in mice. Such a system is a promising, feasible means of delivering ADT.
Assuntos
Antagonistas de Androgênios/administração & dosagem , Quitosana/química , Sistemas de Liberação de Medicamentos/métodos , Hormônio Liberador de Gonadotropina/administração & dosagem , Agulhas , Administração Cutânea , Antagonistas de Androgênios/química , Antagonistas de Androgênios/farmacocinética , Animais , Antineoplásicos Hormonais/administração & dosagem , Antineoplásicos Hormonais/química , Antineoplásicos Hormonais/farmacocinética , Hormônio Liberador de Gonadotropina/química , Hormônio Liberador de Gonadotropina/farmacocinética , Gosserrelina/administração & dosagem , Gosserrelina/química , Gosserrelina/farmacocinética , Humanos , Hormônio Luteinizante/sangue , Masculino , Camundongos Endogâmicos ICR , Pele/metabolismo , Suínos , Testosterona/sangueRESUMO
Heat shock protein 90 (Hsp90) is a molecular chaperone that facilitates the correct folding and functionality of its client protein. Numerous Hsp90-client proteins are involved in cancer development. Thus, Hsp90 inhibitors have potential applications as anti-cancer drugs. We previously discovered that Hsp90α expression increased in breast cancer stem cells (BCSCs), which can initiate tumorigenesis and metastasis and resist treatment. In the present study, we further demonstrated that 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG), an inhibitor of Hsp90, could suppress the self-renewal of BCSCs by downregulating B lymphoma Mo-MLV insertion region 1 homolog (BMI1), a polycomb family member with oncogenic activity in breast cancer. Through immunoprecipitation analysis, we found that BMI1 did not interact with Hsp90α and that the downregulation of BMI1 by 17-DMAG was mediated by the inhibition of c-Myc and enhancement of zeste homolog 2 (EZH2) expression. The transcriptional and BMI1 promoter-binding activities of c-Myc in BCSCs were inhibited by 17-DMAG treatment. The overexpression of EZH2 attenuated the inhibitory effect of 17-DMAG on BMI1 and c-Myc expression. Furthermore, Hsp90α could be co-immunoprecipitated with c-Myc and EZH2 and bind to the BMI1 promoter. Treatment with 17-DMAG decreased the nuclear expression of EZH2 and c-Myc but not that of Hsp90α. In conclusion, our data suggested that Hsp90α could positively regulate the self-renewal of BCSCs by facilitating the nuclear translocation of c-Myc and EZH2 to maintain BMI1 expression.
Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Proteínas de Choque Térmico HSP90/metabolismo , Células-Tronco Neoplásicas/metabolismo , Complexo Repressor Polycomb 1/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Benzoquinonas/farmacologia , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Autorrenovação Celular/genética , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Lactamas Macrocíclicas/farmacologia , Ligação Proteica , Transporte Proteico , Proteínas Proto-Oncogênicas c-myc/genética , Transcrição GênicaRESUMO
Bruton's tyrosine kinase (Btk) is expressed in a variety of immune cells and previous work has demonstrated that blocking Btk is a promising strategy for treating autoimmune diseases. Herein, we utilized a tool Btk inhibitor, M7583, to determine the therapeutic efficacy of Btk inhibition in two mouse lupus models driven by TLR7 activation and type I interferon. In BXSB-Yaa lupus mice, Btk inhibition reduced autoantibodies, nephritis, and mortality. In the pristane-induced DBA/1 lupus model, Btk inhibition suppressed arthritis, but autoantibodies and the IFN gene signature were not significantly affected; suggesting efficacy was mediated through inhibition of Fc receptors. In vitro studies using primary human macrophages revealed that Btk inhibition can block activation by immune complexes and TLR7 which contributes to tissue damage in SLE. Overall, our results provide translational insight into how Btk inhibition may provide benefit to a variety of SLE patients by affecting both BCR and FcR signaling.
Assuntos
Lúpus Eritematoso Sistêmico/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Tirosina Quinases/antagonistas & inibidores , Tirosina Quinase da Agamaglobulinemia , Animais , Artrite/tratamento farmacológico , Artrite/patologia , Autoanticorpos/sangue , Modelos Animais de Doenças , Feminino , Articulações do Pé/efeitos dos fármacos , Articulações do Pé/patologia , Humanos , Imunossupressores , Interferon Tipo I/imunologia , Rim/efeitos dos fármacos , Rim/patologia , Lúpus Eritematoso Sistêmico/induzido quimicamente , Lúpus Eritematoso Sistêmico/imunologia , Lúpus Eritematoso Sistêmico/patologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Nefrite/tratamento farmacológico , Nefrite/patologia , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/farmacologia , Proteinúria/tratamento farmacológico , Proteinúria/patologia , Terpenos , Receptor 7 Toll-Like/imunologiaRESUMO
Cutaneous endocrine mucin-producing sweat gland carcinoma (EMPSGC) is a very rare low-grade malignant neoplasm analogous to the mammary solid-papillary carcinoma. It frequently expresses neuroendocrine markers and may show mucinous differentiation. Although the nodules are circumscribed, myoepithelial cells cannot be showed in most cases and about half of the cases are associated with invasive mucinous carcinoma. Hence, it has been suggested to be invasive and the precursor lesion of some primary cutaneous mucinous carcinomas. After being recognized as a distinct entity, all cases reported to date occurred either in the periocular region or on the cheek. Two thirds of the patients were female. Herein we present an unusual case of in situ EMPSGC on the chest wall skin of a middle-aged man.
Assuntos
Adenocarcinoma Mucinoso/patologia , Neoplasias das Glândulas Sudoríparas/patologia , Tórax/patologia , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND: The epidemiological patterns of cancer incidence have been investigated widely in western countries. Nevertheless, information is quite limited in Jiangxi province, southern China. MATERIALS AND METHODS: All data were reported by 6 population-based cancer registries in Jiangxi Province. The results were presented as incidence rates of cases by site (ICD-10), sex, crude rate (CR), age-standardized rates (ASRs) and truncated incidence rate (TR) per 100,000 person-years, using the direct method of standardization to the world population. RESULTS: 8,765 new cancer cases were registered in our study during the period 2009-2011. Diagnosis of cancer was based on histopathology in 61.0%, clinical or radiology findings in 4.87% and death certificate only (DCO) in 3.0% of the cases. The median age at diagnosis was 62.0 years (mean, 61; standard deviation, 15). The ASRs were 170.8 per 100,000 for men and 111.2 for women. The ASRs for all invasive cancers from the urban areas (145.7 per 100,000) was higher than that of rural areas (137.1). Incidence rates for lung cancer were higher in rural (35.8) than in urban areas (27.0). Similarly, relatively high rates were observed for stomach cancer in rural (20.1) relative to urban areas (15.5). CONCLUSIONS: Our results reveal that the most common cancers were breast and lung in women and lung and liver in men. Interestingly, this study suggested a higher incidence rates for lung and stomach cancer in rural males than in urban population, which may suggest other potential causes, such as over-consumption of smoked meats and high prevalence of Helicobacter pylori infection, respectively. Public education and the promotion of healthy lifestyles should be actively carried out.
Assuntos
Neoplasias/epidemiologia , Neoplasias/mortalidade , Adulto , Distribuição por Idade , China/epidemiologia , Feminino , Geografia , Infecções por Helicobacter/epidemiologia , Helicobacter pylori , Humanos , Classificação Internacional de Doenças , Estilo de Vida , Masculino , Carne , Pessoa de Meia-Idade , Sistema de Registros , Distribuição por SexoRESUMO
Four previously unreported chemical entities, boydone A (1), boydone B (2), botryorhodine F (3), and botryorhodine G (4), along with five known compounds, fusidilactone A (5), (R)-(-)-mevalonolactone (6), (R)-(-)-lactic acid (7), ovalicin (8), and botryorhodine C (9), were isolated from the ethyl acetate extracts of the fermented broths of the fungal strain Pseudallescheria boydii NTOU2362. The structures of 1-9 were characterized on the basis of their spectroscopic data analyses. The absolute configurations of 1 and 2 were established by comparison with the literature and the modified Mosher's method. The growth inhibitory activities of 1-9 against the A549 non-small-cell lung cancer cell line were evaluated, and 2 and 8 exhibited moderate to potent bioactivities with GI50 values of 41.3 and 4.1 µM, respectively, in comparison with fluorouracil (GI50 = 3.6 µM).
Assuntos
Aizoaceae/microbiologia , Antineoplásicos/isolamento & purificação , Policetídeos/isolamento & purificação , Pseudallescheria/química , Antineoplásicos/química , Antineoplásicos/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Fluoruracila/farmacologia , Humanos , Concentração Inibidora 50 , Estrutura Molecular , Folhas de Planta/química , Policetídeos/química , Policetídeos/farmacologia , ScedosporiumRESUMO
Ellagic acid (EA) is able to inhibit the growth of several cancer cells; however, its effect on human ovarian carcinoma cells has not yet been investigated. Ovarian carcinoma ES-2 and PA-1 cells were treated with EA (10~100 µ M) and assessed for viability, cell cycle, apoptosis, anoikis, autophagy, and chemosensitivity to doxorubicin and their molecular mechanisms. EA inhibited cell proliferation in a dose- and time-dependent manner by arresting both cell lines at the G1 phase of the cell cycle, which were from elevating p53 and Cip1/p21 and decreasing cyclin D1 and E levels. EA also induced caspase-3-mediated apoptosis by increasing the Bax : Bcl-2 ratio and restored anoikis in both cell lines. The enhancement of apoptosis and/or inhibition of autophagy in these cells by EA assisted the chemotherapy efficacy. The results indicated that EA is a potential novel chemoprevention and treatment assistant agent for human ovarian carcinoma.
RESUMO
A shift in prevalence from Japanese encephalitis virus (JEV) genotype III (GIII) to GI virus has been observed in several Asian countries. Genotype I virus was first detected in Taiwan in 2008, and became the dominant JEV island-wide within a year. We conducted a serosurvey using swine serum specimens from multiple counties in Taiwan following the transmission season in 2009 and results showed 67-100% of JEV seropositive swine showed evidence of GI virus infection. The envelope (E) protein is a structural protein that elicits protective neutralizing antibodies (Nt Ab). The GIII at222 (a live-attenuated swine vaccine) virus E protein differs at eight amino acid residues (E-123, E-129, E-138, E-176, E-209, E-222, E-327 and E-366) from that of the GI TC2009-1 strain (isolated in Taiwan in 2009). Twenty piglets were vaccinated with two doses of at222 vaccine, and serum specimens were collected to evaluate the strain-specific Nt Ab titer against GIII at222, GIII CJN, and GI TC2009-1 viruses. Seropositivity rates (Nt Ab titer≥1:10) and geometric mean titers (GMT) were similar against at222 and CJN viruses. However, sera from swine vaccinated with at222 were least potently neutralizing against GI TC2009-1 virus. The estimated protective threshold against GI virus was observed only when the PRNT50 against at222 virus was ≥1:320. Thus, our current study indicates that the live-attenuated at222 swine vaccine can be partially protective against GI virus, and suggests that the efficacy of GIII swine vaccines currently used may require a comprehensive reevaluation in the field.