RESUMO
Alzheimer's disease (AD) is a serious public health issue but few drugs are currently available for the disease, and these only target the symptoms. It is well established that oxidative stress plays a crucial role in AD, and there is compelling evidence linking oxidative stress to ß-amyloid (Aß). An exciting source of potential new AD therapeutic medication possibilities is medicinal plants. Ginsenoside Rd (GS-Rd) is one of the main bioactive substances in ginseng extracts. In our study, we used a network pharmacology analysis to identify overlapping GS-Rd (therapeutic) and AD (disease)-relevant protein targets, gene ontology (GO) and bio-process annotation, and the KEGG pathway analysis data predicted that GS-Rd impacts multiple targets and pathways, such as the MAPK signal pathway and the JAT-STAT3 signaling pathway. We then assessed the role of GS-Rd in C. elegans and found that GS-Rd prolongs lifespan, improves resistance to heat stress, delays physical paralysis and increases oxidative stress responses. Overall, these results suggest that GS-Rd protects against the toxicity of Aß. The RNA-seq analysis revealed that GS-Rd achieves its effects by regulating gene expressions like daf-16 and skn-1, as well as by participating in many AD-related pathways like the MAPK signaling pathway. In addition, in CL4176 worms, GS-Rd decreased reactive oxygen species (ROS) levels and increased SOD activity. Additional research with transgenic worms showed that GS-Rd aided in the movement of DAF-16 from the cytoplasm to the nucleus. Taken together, the results indicate that GS-Rd significantly reduces Aß aggregation by targeting the MAPK signal pathway, induces nuclear translocation of DAF-16 to activate downstream signaling pathways and increases resistance to oxidative stress in C. elegans to protect against Aß-induced toxicity.
RESUMO
The importance of BET protein BRD4 in gene transcription is well recognized through the study of chemical modulation of its characteristic tandem bromodomain (BrD) binding to lysine-acetylated histones and transcription factors. However, while monovalent inhibition of BRD4 by BET BrD inhibitors such as JQ1 blocks growth of hematopoietic cancers, it is much less effective generally in solid tumors. Here, we report a thienodiazepine-based bivalent BrD inhibitor, MS645, that affords spatially constrained tandem BrD inhibition and consequently sustained repression of BRD4 transcriptional activity in blocking proliferation of solid-tumor cells including a panel of triple-negative breast cancer (TNBC) cells. MS645 blocks BRD4 binding to transcription enhancer/mediator proteins MED1 and YY1 with potency superior to monovalent BET inhibitors, resulting in down-regulation of proinflammatory cytokines and genes for cell-cycle control and DNA damage repair that are largely unaffected by monovalent BrD inhibition. Our study suggests a therapeutic strategy to maximally control BRD4 activity for rapid growth of solid-tumor TNBC cells.
Assuntos
Antineoplásicos/farmacologia , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas Nucleares/antagonistas & inibidores , Fatores de Transcrição/antagonistas & inibidores , Transcrição Gênica/efeitos dos fármacos , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Proteínas de Ciclo Celular , Linhagem Celular Tumoral , Feminino , Humanos , Subunidade 1 do Complexo Mediador/genética , Subunidade 1 do Complexo Mediador/metabolismo , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologia , Fator de Transcrição YY1/genética , Fator de Transcrição YY1/metabolismoRESUMO
The BCCIP (BRCA2- and CDKN1A-interacting protein) is an important cofactor for BRCA2 in tumor suppression. Although the low expression of BCCIP is observed in multiple clinically diagnosed primary tumor tissues such as ovarian cancer, renal cell carcinoma and colorectal carcinoma, the mechanism of how BCCIP is regulated in cells is still unclear. The human INO80/YY1 chromatin remodeling complex composed of 15 subunits catalyzes ATP-dependent sliding of nucleosomes along DNA. Here, we first report that BCCIP is a novel target gene of the INO80/YY1 complex by presenting a series of experimental evidence. Gene expression studies combined with siRNA knockdown data locked candidate genes including BCCIP of the INO80/YY1 complex. Silencing or over-expressing the subunits of the INO80/YY1 complex regulates the expression level of BCCIP both in mRNA and proteins in cells. Also, the functions of INO80/YY1 complex in regulating the transactivation of BCCIP were confirmed by luciferase reporter assays. Chromatin immunoprecipitation (ChIP) experiments clarify the enrichment of INO80 and YY1 at +0.17 kb downstream of the BCCIP transcriptional start site. However, this enrichment is significantly inhibited by either knocking down INO80 or YY1, suggesting the existence of both INO80 and YY1 is required for recruiting the INO80/YY1 complex to BCCIP promoter region. Our findings strongly indicate that BCCIP is a potential target gene of the INO80/YY1 complex.
Assuntos
Proteínas de Ligação ao Cálcio/metabolismo , Proteínas de Ciclo Celular/metabolismo , Montagem e Desmontagem da Cromatina/fisiologia , DNA Helicases/metabolismo , Complexos Multiproteicos/metabolismo , Proteínas Nucleares/metabolismo , Transcrição Gênica/fisiologia , Fator de Transcrição YY1/metabolismo , ATPases Associadas a Diversas Atividades Celulares , Proteínas de Ligação ao Cálcio/genética , Proteínas de Ciclo Celular/genética , DNA Helicases/genética , Proteínas de Ligação a DNA , Células HeLa , Humanos , Complexos Multiproteicos/genética , Proteínas Nucleares/genética , Regiões Promotoras Genéticas/fisiologia , Fator de Transcrição YY1/genéticaRESUMO
OBJECTIVE: To study the protective effect of astragaloside IV (AS IV) on H2O2 induced human mesangial cells (HMC), and further explore its molecular mechanism. METHOD: The cultured mesangial cells were divided into 5 groups: the normal control group, the H2O2 model group, the AS IV (12.5, 100 nmol x L(-1)) group and the Tempol (1 x 10(5) nmol x L(-1)) group. The MTT method was used to observe cell viability. Hoechst 33258 staining was used to observe the HMC apoptosis and DHE staining was used to detect the generation of reactive oxygen species (ROS). The flow cytometry was used to detect the changes in cell cycle. Western blot was used to detect the expression of Cyclin D1, CyclinA, p38, and T-p38. RESULT: H2O2 (1 x 10(5), 2 x 10(5), 3 x 10(5), and 4 x 10(5) nmol x L(-1)) could induce HMC oxidative stress injury, with significant decrease in the cell survival rate. AS IV (100 nmol x L(-1)) could significantly inhibit HMC oxidative stress injury induced by H2O2 (3 x 10(5) nmol x L(-1)), increase the survival rate of HMC cells, inhibit cell apoptosis, and decrease intracellular ROS production. AS IV could also increase the expression of Cyclin D1, recover normal cell proliferation, and decrease the expression of p38. CONCLUSION: AS IV can protect H2O2 induced oxidative stress injury in mesangial cells. Its mechanisms may be related to inhibiting the p38/MAPK signaling pathway, increasing the expression of Cyclin D1 and decreasing the intracellular ROS oxidative stress injury.
Assuntos
Células Mesangiais/efeitos dos fármacos , Células Mesangiais/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Saponinas/farmacologia , Triterpenos/farmacologia , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Ciclina A/metabolismo , Ciclina D1/metabolismo , Relação Dose-Resposta a Droga , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Peróxido de Hidrogênio/farmacologia , Células Mesangiais/citologia , Espécies Reativas de Oxigênio/metabolismoRESUMO
The sporogenesis and development of gametophytes in Tetracentron sinense Oliv. were studied with light microscopy. The anther has four microsporangia; its primary anther wall consists of an epidermis, an endothecium, one or two middle layers and one glandular tapetum. Simultaneous cytokinesis follows meiosis, forming a tetrahedral tetrad. Mature pollen grains are two-celled at the time of anther dehiscence. Its ovule is anatropous, bitegmic and crassinucellate; the development of the female gametophyte is of the monosporic 8-nucleate Polygonum type. Significantly, some striking features were first found in T. sinense: (1) anther dehiscence occurs soon after the endothecium fibrously thickens and the intersporangial septum degenerates; (2) tapetum degeneration is retarded, persisting up to the stage of two-celled pollen grain; (3) a few cellular events such as the vacuolization and the contraction and deformation of the pollen mother cell (PMC) and microspore are not normal at the PMC, dyad and tetrad stages. The abnormalities during male reproduction might be one of important factors resulting in the poor natural regeneration of T. sinense.
Assuntos
Gametogênese Vegetal/fisiologia , Células Germinativas Vegetais/crescimento & desenvolvimento , Magnoliopsida/embriologia , Pólen/embriologia , Células Germinativas Vegetais/citologia , Magnoliopsida/citologia , Reprodução/fisiologiaRESUMO
The sporogenesis and development of gametophytes in Tetracentron sinense Oliv. were studied with light microscopy. The anther has four microsporangia; its primary anther wall consists of an epidermis, an endothecium, one or two middle layers and one glandular tapetum. Simultaneous cytokinesis follows meiosis, forming a tetrahedral tetrad. Mature pollen grains are two-celled at the time of anther dehiscence. Its ovule is anatropous, bitegmic and crassinucellate; the development of the female gametophyte is of the monosporic 8-nucleate Polygonum type. Significantly, some striking features were first found in T. sinense: (1) anther dehiscence occurs soon after the endothecium fibrously thickens and the intersporangial septum degenerates; (2) tapetum degeneration is retarded, persisting up to the stage of two-celled pollen grain; (3) a few cellular events such as the vacuolization and the contraction and deformation of the pollen mother cell (PMC) and microspore are not normal at the PMC, dyad and tetrad stages. The abnormalities during male reproduction might be one of important factors resulting in the poor natural regeneration of T. sinense.
Assuntos
Magnoliopsida/embriologia , Gametogênese Vegetal/fisiologia , Células Germinativas Vegetais/crescimento & desenvolvimento , Pólen/embriologia , Magnoliopsida/citologia , Células Germinativas Vegetais/citologia , Reprodução/fisiologiaRESUMO
Four new fatty acid esters have been isolated from Feces Trogopterus. Their structures were determined by spectroscopic and chemical methods to be bis(7-hydroxyheptyl) icosanedioate (1), bis(7-hydroxyheptyl) heptadecanedioate (2), bis(7-hydroxyheptyl) decanedioate (3), and bis(7-hydroxyheptyl) octanedioate (4). In the anticoagulative assay, compounds 3 and 4 had significant antithrombin activity.