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BACKGROUND: Sarcomas is a group of heterogeneous malignant tumors originated from mesenchymal tissue and different types of sarcomas have disparate outcomes. The present study aims to identify the prognostic value of immune-related genes (IRGs) in sarcoma and establish a prognostic signature based on IRGs. METHODS: We collected the expression profile and clinical information of 255 soft tissue sarcoma samples from The Cancer Genome Atlas (TCGA) database and 2498 IRGs from the ImmPort database. The LASSO algorithm and Cox regression analysis were used to identify the best candidate genes and construct a signature. The prognostic ability of the signature was evaluated by ROC curves and Kaplan-Meier survival curves and validated in an independent cohort. Besides, a nomogram based on the IRGs and independent prognostic clinical variables was developed. RESULTS: A total of 19 IRGs were incorporated into the signature. In the training cohort, the AUC values of signature at 1-, 2-, and 3-years were 0.938, 0.937 and 0.935, respectively. The Kaplan-Meier survival curve indicated that high-risk patients were significantly worse prognosis (P < 0.001). In the validation cohort, the AUC values of signature at 1-, 2-, and 3-years were 0.730, 0.717 and 0.647, respectively. The Kaplan-Meier survival curve also showed significant distinct survival outcome between two risk groups. Furthermore, a nomogram based on the signature and four prognostic variables showed great accuracy in whole sarcoma patients and subgroup analyses. More importantly, the results of the TF regulatory network and immune infiltration analysis revealed the potential molecular mechanism of IRGs. CONCLUSIONS: In general, we identified and validated an IRG-based signature, which can be used as an independent prognostic signature in evaluating the prognosis of sarcoma patients and provide potential novel immunotherapy targets.
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Biomarcadores Tumorais/genética , Biomarcadores Tumorais/imunologia , Regulação Neoplásica da Expressão Gênica , Nomogramas , Sarcoma/patologia , Transcriptoma , Feminino , Seguimentos , Perfilação da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Prognóstico , Curva ROC , Estudos Retrospectivos , Fatores de Risco , Sarcoma/genética , Sarcoma/imunologiaRESUMO
Cellular senescence represents the state of irreversible cell cycle arrest during cell division. Cellular senescence not only plays a role in diverse biological events such as embryogenesis, tissue regeneration and repair, ageing and tumour occurrence prevention, but it is also involved in many cardiovascular, renal and liver diseases through the senescence-associated secretory phenotype (SASP). This review summarizes the molecular mechanisms underlying cellular senescence and its possible effects on a variety of renal diseases. We will also discuss the therapeutic approaches based on the regulation of senescent and SASP blockade, which is considered as a promising strategy for the management of renal diseases.
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Senescência Celular/fisiologia , Nefropatias/patologia , Rim/patologia , Animais , Humanos , FenótipoRESUMO
BACKGROUND: Flavokawain B (FKB) has been identified from kava root extracts as a potent apoptosis inducer for inhibiting the growth of various cancer cell lines, including prostate cancer. However, the molecular targets of FKB in prostate cancer cells remain unknown. METHODS: An in vitro NEDD8 Initiation Conjugation Assay was used to evaluate the neddylation inhibitory activity of FKB. Molecular docking and a cellular thermal shift assay were performed to assess the direct interaction between FKB and the NEDD8 activating enzyme (NAE) complex. Protein neddylation, ubiqutination, stability and expression in cells were assessed with immunoprecipitation and Western blotting methods using specific antibodies. Deletion and site specific mutants and siRNAs were used to evaluate deep mechanisms by which FKB induces Skp2 degradation. Cell growth inhibition and apoptosis induction were measured by MTT, ELISA and Western blotting methods. RESULTS: FKB inhibits NEDD8 conjugations to both Cullin1 and Ubc12 in prostate cancer cell lines and Ubc12 neddylation in an in vitro assay. Molecular docking study and a cellular thermal shift assay reveal that FKB interacts with the regulatory subunit (i.e. APP-BP1) of the NAE. In addition, FKB causes Skp2 degradation in an ubiquitin and proteasome dependent manner. Overexpression of dominant-negative cullin1 (1-452), K720R mutant (the neddylation site) Cullin1 or the F-box deleted Skp2 that losses its binding to the Skp1/Cullin1 complex causes the resistance to FKB-induced Skp2 degradation, whereas siRNA knock-down of Cdh1, a known E3 ligase of Skp2 for targeted degradation, didn't attenuate the effect of FKB on Skp2 degradation. These results suggest that degradation of Skp2 by FKB is involved in a functional Cullin1. Furthermore, proteasome inhibitors Bortezomib and MG132 transcriptionally down-regulate the expression of Skp2, and their combinations with FKB result in enhanced inhibitory effects on the growth of prostate cancer cell lines via synergistic down-regulation of Skp2 and up-regulation of p27/Kip1 and p21/WAF1 protein expression. FKB also selectively inhibits the growth of RB deficient cells with high expression of Skp2. CONCLUSION: These findings provide a rationale for further investigating combination of FKB and Bortezomib for treatment of RB deficient, castration-resistant prostate cancer.
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Antineoplásicos/farmacologia , Bortezomib/farmacologia , Flavonoides/farmacologia , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Proteínas Quinases Associadas a Fase S/metabolismo , Antígenos CD/metabolismo , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Bortezomib/uso terapêutico , Caderinas/metabolismo , Proliferação de Células/efeitos dos fármacos , Proteínas Culina/metabolismo , Flavonoides/uso terapêutico , Humanos , Leupeptinas/farmacologia , Leupeptinas/uso terapêutico , Masculino , Proteína NEDD8/metabolismo , Células PC-3 , Enzimas Ativadoras de Ubiquitina/metabolismo , Enzimas de Conjugação de Ubiquitina/metabolismoRESUMO
BACKGROUND: Although ductal carcinoma in situ (DCIS) is a non-invasive breast cancer, many DCIS lesions may progress to invasive cancer and the genes and pathways responsible for its progression are largely unknown. FGFR1 plays an important role in cell proliferation, differentiation and carcinogenesis. The purpose of this study is to examine the roles of FGFR1 signaling in gene expression, cell proliferation, tumor growth and progression in a non-invasive DCIS model. METHODS: DCIS.COM cells were transfected with an empty vector to generate DCIS-Ctrl cells. DCIS-iFGFR1 cells were transfected with an AP20187-inducible iFGFR1 vector to generate DCIS-iFGFR1 cells. iFGFR1 consists of the v-Src myristoylation membrane-targeting sequence, FGFR1 cytoplasmic domain and the AP20187-inducible FKBP12 dimerization domain, which simulates FGFR1 signaling. The CRISPR/Cas9 system was employed to knockout ERK1, ERK2 or TNFAIP3 in DCIS-iFGFR1 cells. Established cell lines were treated with/without AP20187 and with/without FGFR1, MEK, or ERK1/2 inhibitor. The effects of these treatments were determined by Western blot, RNA-Seq, real-time RT-PCR, cell proliferation, mammosphere growth, xenograft tumor growth, and tumor histopathological assays. RESULTS: Activation of iFGFR1 signaling in DCIS-iFGFR1 cells enhanced ERK1/2 activities, induced partial epithelial-to-mesenchymal transition (EMT) and increased cell proliferation. Activation of iFGFR1 signaling promoted DCIS growth and progression to invasive cancer derived from DCIS-iFGFR1 cells in mice. Activation of iFGFR1 signaling also altered expression levels of 946 genes involved in cell proliferation, migration, cancer pathways, and other molecular and cellular functions. TNFAIP3, a ubiquitin-editing enzyme, is upregulated by iFGFR1 signaling in a FGFR1 kinase activity and in an ERK2-dependent manner. Importantly, TNFAIP3 knockout not only inhibited the AP20187-induced proliferation and tumor growth of DCIS-iFGFR1 cells, but also further reduced baseline proliferation and tumor growth of DCIS-iFGFR1 cells without AP20187 treatment. CONCLUSIONS: Activation of iFGFR1 promotes ERK1/2 activity, EMT, cell proliferation, tumor growth, DCIS progression to invasive cancer, and altered the gene expression profile of DCIS-iFGFR1 cells. Activation of iFGFR1 upregulated TNFAIP3 in an ERK2-dependent manner and TNFAIP3 is required for iFGFR1 activation-promoted DCIS.COM cell proliferation, mammosphere growth, tumor growth and progression. These results suggest that TNFAIP3 may be a potential target for inhibiting DCIS growth and progression promoted by FGFR1 signaling.
Assuntos
Neoplasias da Mama/patologia , Carcinoma Intraductal não Infiltrante/patologia , Transformação Celular Neoplásica/patologia , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/metabolismo , Proteína 3 Induzida por Fator de Necrose Tumoral alfa/metabolismo , Animais , Mama/citologia , Mama/patologia , Neoplasias da Mama/genética , Sistemas CRISPR-Cas , Carcinoma Intraductal não Infiltrante/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Transformação Celular Neoplásica/genética , Células Epiteliais , Feminino , Regulação Neoplásica da Expressão Gênica , Técnicas de Inativação de Genes , Humanos , Sistema de Sinalização das MAP Quinases , Camundongos Endogâmicos BALB C , Camundongos Nus , Invasividade Neoplásica/patologia , Esferoides Celulares , Proteína 3 Induzida por Fator de Necrose Tumoral alfa/genética , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
There is a correlation between tumors and immunity with the degree of immune cell infiltration in tumors being closely related to tumor growth and progression. Therefore, the present study identified immune-related prognostic genes and evaluated the immune infiltration level in lung adenocarcinoma (LUAD). This study performed Kyoto Encyclopedia of Genes and Genomes, Gene Ontology, and Gene Set Enrichment Analysis (GSEA) enrichment analyses on differential immune-associated genes. A risk model was created and validated using six immune-related prognostic genes. Reverse transcription-quantitative PCR was used to assess the prognostic gene expression in non-small cell lung cancer cells. Immune cell infiltration in LUAD was analyzed using the CIBERSORT method. Single sample GSEA was used to compare Tumor Immune Dysfunction and Exclusion (TIDE) scores between high and low-risk groups and to assess the activation of thirteen immune-related pathways. Multifactor Cox proportional hazards model analysis identified six prognostic risk genes (S100A16, FURIN, FGF2, LGR4, TNFRSF11A and VIPR1) to construct a risk model. The survival and receiver operating characteristic curves indicated that patients with higher risk scores had lower overall survival rates. The expression levels of prognostic genes S100A16, FURIN, LGR4, TNFRSF11A and VIPR1 were significantly increased in LUAD. B cells naive, plasma cells, T cells CD4 memory activated, T cells follicular helper, T cells regulatory, NK cells activated, macrophages M1, macrophages M2, and Dendritic cells resting cells showed elevated expression in LUAD. The prognostic genes were differentially associated with individual immune cells. Immune-related function scores, such as those for antigen presenting cell (APC) co-stimulation, APC co-inhibition, check-point, Cytolytic-activity, chemokine receptor, parainflammation, major histocompatibility complex-class-I, type-I-IFN-reponse and T-cell-co-inhibition, were higher in the high-risk group compared with the low-risk group. Furthermore, the TIDE score of the high-risk group was significantly lower than the low-risk group. This immune-related gene prognostic model has the potential to predict the prognosis of LUAD patients, supporting the development of a personalized clinical diagnosis and treatment plan.
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Breast cancer is currently the most commonly occurring cancer globally. Among breast cancer cases, the human epidermal growth factor receptor 2 (HER2)-positive breast cancer accounts for 15% to 20% and is a crucial focus in the treatment of breast cancer. Common HER2-targeted drugs approved for treating early and/or advanced breast cancer include trastuzumab and pertuzumab, which effectively improve patient prognosis. However, despite treatment, most patients with terminal HER2-positive breast cancer ultimately suffer death from the disease due to primary or acquired drug resistance. The prevalence of aberrantly activated the protein kinase B (AKT) signaling in HER2-positive breast cancer was already observed in previous studies. It is well known that p-AKT expression is linked to an unfavorable prognosis, and the phosphatidylinositol-3-kinase (PI3K)/AKT pathway, as the most common mutated pathway in breast cancer, plays a major role in the mechanism of drug resistance. Therefore, in the current review, we summarize the molecular alterations present in HER2-positive breast cancer, elucidate the relationships between HER2 overexpression and alterations in the PI3K/AKT signaling pathway and the pathways of the alterations in breast cancer, and summarize the resistant mechanism of drugs targeting the HER2-AKT pathway, which will provide an adjunctive therapeutic rationale for subsequent resistance to directed therapy in the future.
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Neoplasias da Mama , Resistencia a Medicamentos Antineoplásicos , Proteínas Proto-Oncogênicas c-akt , Receptor ErbB-2 , Transdução de Sinais , Humanos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Receptor ErbB-2/metabolismo , Receptor ErbB-2/genética , Feminino , Proteínas Proto-Oncogênicas c-akt/metabolismo , Resistencia a Medicamentos Antineoplásicos/genética , Fosfatidilinositol 3-Quinases/metabolismo , Antineoplásicos/uso terapêutico , Fosfatidilinositol 3-Quinase/metabolismoRESUMO
BACKGROUND: Nucleus pulposus cell (NPC) senescence in intervertebral disc (IVD) tissue is the major pathological cause of intervertebral disc degeneration (IDD). N6-methyladenosine (m6A) methylation and gut microbiota play important roles in the progression of IDD. This study investigated whether methyltransferase-like 3 (METTL3) regulates TLR2 m6A modification and gut microbiota to influence NPC senescence. METHODS: An IDD rat model was established by lumbar IVD puncture and NPCs were challenged with IL-1ß to mimic IVD injury. IDD rats and IL-1ß-exposed NPCs were treated with METTL3-interfering lentivirus and the TLR2 agonist Pam3CSK4. Compositional changes in the rat gut microbiota were analyzed and fecal microbiota transplantation procedures were used. NPC senescence, cell cycle, and the expression of senescence-associated secretory phenotype (SASP) factors were assessed. The m6A enrichment of TLR2 and the binding of IGF2BP1 to TLR2 mRNA were examined. RESULTS: METTL3 and TLR2 were highly expressed in IDD rats. METTL3 silencing attenuated senescent phenotypes and reduced secretion of SASP factors. Pam3CSK4 reversed the beneficial effects of METTL3 silencing on NPC senescence and IVD injury. METTL3 stabilized TLR2 mRNA in an IGF2BP1-dependent manner. METTL3 silencing restored specific gut microbiota levels in IDD rats, which was further reversed by administration of Pam3CSK4. Fecal microbiota from METTL3 silenced IDD rats altered the pathological phenotypes of IDD rats. CONCLUSIONS: These results demonstrate the beneficial effects of METTL3 silencing on NPC senescence and amelioration of IVD injury, involving modulation of TLR2 m6A modification and gut microbiota. These findings support METTL3 silencing as a potential therapeutic target for IDD.
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Senescência Celular , Microbioma Gastrointestinal , Degeneração do Disco Intervertebral , Metiltransferases , Núcleo Pulposo , Ratos Sprague-Dawley , Receptor 2 Toll-Like , Animais , Receptor 2 Toll-Like/metabolismo , Receptor 2 Toll-Like/genética , Ratos , Metiltransferases/metabolismo , Metiltransferases/genética , Núcleo Pulposo/metabolismo , Núcleo Pulposo/patologia , Degeneração do Disco Intervertebral/metabolismo , Degeneração do Disco Intervertebral/patologia , Degeneração do Disco Intervertebral/microbiologia , Masculino , Modelos Animais de Doenças , Metilação , Adenosina/análogos & derivados , Adenosina/metabolismoRESUMO
Garcinia mangostana, often referred to as mangosteen, is a fruit grown in Southeast Asia and has been used for centuries as a local beverage and natural medicine. Its bioactive compounds, xanthones (i.e., gartanin, α-mangostin, etc), have reported effects on ailments ranging from skin infections and inflammation to urinary tract infections. We demonstrate that mangosteen xanthones (i.e., gartanin and α-mangostin) at pharmacologically achievable concentrations inhibit the growth of cancer cell lines from different stages of human urinary bladder cancer. The growth inhibitory effects of gartanin in mouse embryonic fibroblasts are at least in part dependent on the existence of p53 or TSC1. Indeed, further studies have shown that gartanin treatment of bladder cancer cell lines T24 and RT4 resulted in a marked suppression of p70S6 and 4E-BP1 expression and induction of autophagy, suggesting the inhibition of the mTOR pathway. In addition, gartanin downregulated the expression of Bcl-2 and activated the p53 pathway leading to apoptosis induction. Together, these results suggested that gartanin is a multiple targeting agent that is suitable for further study into its chemopreventive properties for human urinary bladder cancer.
Assuntos
Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Bebidas/análise , Garcinia mangostana/química , Serina-Treonina Quinases TOR/metabolismo , Xantonas/farmacologia , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Antineoplásicos/farmacologia , Proteínas Reguladoras de Apoptose/genética , Proteínas Reguladoras de Apoptose/metabolismo , Proteínas de Ciclo Celular , Linhagem Celular Tumoral , Regulação para Baixo , Frutas/química , Humanos , Camundongos , Microscopia de Fluorescência , Fosfoproteínas/genética , Fosfoproteínas/metabolismo , Proteínas Proto-Oncogênicas/genética , Serina-Treonina Quinases TOR/genética , Proteína 1 do Complexo Esclerose Tuberosa , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo , Regulação para Cima , Neoplasias da Bexiga Urinária/patologiaRESUMO
FGFR1 is a receptor tyrosine kinase deregulated in certain breast cancers (BCs) with a poor prognosis. Although FGFR1-activated phosphorylation cascades have been mapped, the key genes regulated by FGFR1 in BC are largely unclear. FOXQ1 is an oncogenic transcription factor. Although we found that activation of FGFR1 robustly upregulated FOXQ1 mRNA, how FGFR1 regulates FOXQ1 gene expression and whether FOXQ1 is essential for FGFR1-stimulated cell proliferation are unknown. Herein, we confirmed that activation of FGFR1 robustly upregulated FOXQ1 mRNA and protein in BC cells. Knockdown of FOXQ1 blocked the FGFR1 signaling-stimulated BC cell proliferation, colony formation, and xenograft tumor growth. Inhibition of MEK or ERK1/2 activities, or knockout of ERK2 but not ERK1 suppressed the FGFR1 signaling-promoted FOXQ1 gene expression. Inhibition of ERK2 in ERK1 knockout cells blocked, while ectopic expression of FOXQ1 in ERK2 knockout cells rescued the FGFR1-signaling-promoted cell growth. Mechanistically, c-FOS, an early response transcription factor upregulated by the FGFR1-MEK-ERK2 pathway, bound to the FOXQ1 promoter to mediate the FGFR1 signaling-promoted FOXQ1 expression. These results indicate that the FGFR1-ERK2-c-FOS-FOXQ1 regulatory axis plays an essential role in the FGFR1 signaling-promoted BC growth. Targeting ERK2 and FOXQ1 should block BC growth caused by a deregulated FGFR1 signaling.
Assuntos
Neoplasias da Mama , Humanos , Feminino , Neoplasias da Mama/metabolismo , Transdução de Sinais/genética , Mama/metabolismo , Proteínas Proto-Oncogênicas c-fos/metabolismo , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Linhagem Celular Tumoral , Fatores de Transcrição Forkhead/metabolismo , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/metabolismoRESUMO
The incidence of human urinary bladder cancer increases markedly with age, suggesting a mechanistic connection between aging and bladder carcinogenesis and a potential use of anti-aging agents in bladder cancer chemoprevention. Rhodiola rosea, growing in high altitude or cold regions of the world, has been reported to have anti-aging effects in Drosophila. We demonstrated that a R. rosea extract and one of its bioactive components, salidroside, inhibited the growth of bladder cancer cell lines with a minimal effect on nonmalignant bladder epithelial cells TEU-2. Interestingly, the R. rosea extract and salidroside component exhibited a selective ability to inhibit the growth of p53 knockout primary mouse embryo fibroblasts (p53-/- MEFs) compared to their wild-type counterparts. The growth inhibitory effects of the R. rosea extract and salidroside were, however, attenuated in TSC2 and p53 double knock MEFs (TSC2-/-, p53-/- MEFs), suggesting that TSC2 protein is, at least in part, required for the growth inhibitory effects of the R. rosea extract and salidroside. The R. rosea extract and salidroside treatment of UMUC3 cells resulted in an increase of AMP-activated protein kinase (AMPK)-α phosphorylation and a decrease of 4E-BP1 phosphorylation, leading to increased binding of 4E-BP1 to m7 GTP. These results indicate that the R. rosea extract and salidroside inhibit translation initiation. Furthermore, both the R. rosea extract and salidroside treatment of UMUC3 cells caused a significant percentage of cells undergoing autophagy. Therefore, the R. rosea extract and salidroside deserve further study as novel agents for chemoprevention of bladder carcinogenesis.
Assuntos
Autofagia/efeitos dos fármacos , Glucosídeos/farmacologia , Fenóis/farmacologia , Extratos Vegetais/farmacologia , Rhodiola/química , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/antagonistas & inibidores , Neoplasias da Bexiga Urinária/enzimologia , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Camundongos , Fosforilação/efeitos dos fármacos , Proteína 2 do Complexo Esclerose Tuberosa , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo , Neoplasias da Bexiga Urinária/genéticaRESUMO
Three new phenolic compounds, nicotphenols A-C (1-3), together with 14 known phenols (4-17), were isolated from the leaves of Nicotiana tabacum. Their structures were established by means of spectroscopic methods, including extensive 1D and 2D NMR techniques. Compounds 1-3 were tested for their anti-HIV-1 activities and cytotoxicities. They all showed significant cytotoxic abilities and modest anti-HIV-1 activities, respectively.
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Fármacos Anti-HIV/isolamento & purificação , Fármacos Anti-HIV/farmacologia , Medicamentos de Ervas Chinesas/isolamento & purificação , Medicamentos de Ervas Chinesas/farmacologia , Nicotiana/química , Fenóis/isolamento & purificação , Fenóis/farmacologia , Fármacos Anti-HIV/química , Medicamentos de Ervas Chinesas/química , Testes de Sensibilidade Microbiana , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , Fenóis/química , Folhas de Planta/químicaRESUMO
BACKGROUND: Recent studies have shown that polysaccharides from Anoectochilus roxburghii (Wall.) Lindl. (ARPs) can reduce blood glucose levels, ameliorate oxidative stress and inflammation. However, whether ARPs have a beneficial effect on diet-induced obesity remain to be determined. PURPOSE: This study aims to investigate the effect and mechanism of ARPs in improving obesity and metabolic disorders induced by high-fat diet (HFD). METHODS: In this study, 6-week-old male mice were fed with HFD or chow diet for 13 weeks, and a dietary supplementation with ARPs was carried out. Glucose tolerance test and insulin tolerance test were performed to measure the glucose tolerance and insulin sensitivity. Adipose tissue and liver were isolated for analysis by qRT-PCR, Western blotting, hematoxylin-eosin staining and immunostaining. RESULTS: At week 13, body weight and fat mass were significantly increased by HFD, but ARPs supplementation abolished these phenotypes. Compared with HFD group, thermogenic genes including Ucp-1, Pgc-1α, Prdm16 and Dio2 in adipose tissue were up-regulated in ARPs-treated mice. In addition, ARPs decreased liver lipid accumulation by reducing lipid synthesis and increasing oxidation. Meanwhile, dyslipidemia and insulin resistance induced by HFD were improved by ARPs. Mechanistically, ARPs can promote fat thermogenesis via AMPK/SIRT1/PGC-1α signaling pathway. CONCLUSION: Dietary supplementation of ARPs can protect mice against diet-induced obesity, fatty liver and insulin resistance. Our study reveals a potential therapeutic effect for ARPs in regulating energy homeostasis.
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Two new dibenzocyclooctadiene lignans, rubrilignans A and B (1, 2), together with 17 known ones, were isolated from the fruits of Schisandra rubriflora. The structures of 1 and 2 were elucidated by spectroscopic methods including extensive 1D and 2D NMR techniques. Compounds 1 and 2 were also evaluated for their anti-HIV-1 activities and showed weak anti-HIV-1 activity with EC(50) values of 2.26 and 1.82 µg/ml, and therapeutic index values of 35.5 and 18.6, respectively.
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Fármacos Anti-HIV/isolamento & purificação , Fármacos Anti-HIV/farmacologia , Medicamentos de Ervas Chinesas/isolamento & purificação , Medicamentos de Ervas Chinesas/farmacologia , HIV-1/efeitos dos fármacos , Lignanas/isolamento & purificação , Lignanas/farmacologia , Schisandra/química , Fármacos Anti-HIV/química , Medicamentos de Ervas Chinesas/química , Frutas/química , Lignanas/química , Estrutura Molecular , Ressonância Magnética Nuclear BiomolecularRESUMO
PURPOSE: Nonalcoholic fatty liver disease (NAFLD) is closely related to lipid metabolism and insulin resistance. The current research mainly attempted to verify the clinical value of LncRNA plasmacytoma variant translocation 1 (PVT1), and whether microRNA regulates lipid metabolism and insulin resistance to participate in NAFLD. PATIENTS AND METHODS: 81 patients with NAFLD and 78 healthy individuals were enrolled in this study. In addition, C57BL/6 mice were fed a high-fat diet to establish NAFLD model in vivo. Serum PVT1 and miR-20a-5p expression in NAFLD patients and mice were assessed by RT-qPCR. ROC curves determine the diagnostic value of PVT1 and miR-20a-5p. NAFLD mice were subjected to IPGTT to detect changes in insulin sensitivity, and the common indicators of lipid metabolism and insulin resistance were also evaluated. Dual-luciferase reporter assay verified the regulation mechanism of PVT1 and miR-20a-5p. RESULTS: PVT1 was upregulated in NAFLD patients and mice, while miR-20a-5p was decreased. Their expression trends were similar in patients with HOMA-IR ≥2.5. What's more, miR-20a-5p, FBG, ALT, and HOMA-IR were independently correlated with PVT1. And PVT1 and miR-20a-5p show high clinical diagnostic value. Bodyweight, insulin sensitivity, lipid metabolism inductors were increased in NAFLD mice, but these increases were attenuated by PVT1 elimination. Finally, miR-20a-5p might function as the possible miRNA target of PVT1 via the binding sites at 3'-UTR and negatively regulated by it. CONCLUSION: PVT1 and miR-20a-5p are potential clinical biomarkers of NAFLD, and PVT1 promotes the occurrence of NAFLD by regulating insulin sensitivity and lipid metabolism, which may be achieved by targeting miR-20a-5p.
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AIM: Here, we aim to evaluate the chemopreventive efficacy of kava root extracts (KRE) in transgenic adenocarcinoma of the mouse prostate (TRAMP) mice and investigate potential molecular targets of kavalactones, the main components of kava. METHODS: TRAMP mice were administrated with KRE formulated food for different periods of time, and then the incidences of high-grade prostatic intraepithelial neoplasia (HG-PIN) and adenocarcinomas and tumor burdens were compared between vehicle control and KRE food fed groups. In addition, the inhibitory effect of the KRE and kavalactones on monoamine oxidase A (MAO-A) and lysine-specific demethylase 1 (LSD1) enzyme activities were examined by commercially available inhibitor screening kits. Histone H3 lysine 9 dimethylation was also evaluated in prostate cancer cells and tumor tissues using Western blotting analysis. RESULTS: Dietary feeding of 0.3% and 0.6% KRE to TRAMP mice from ages of 6 weeks to 12 weeks inhibited HG-PIN by 43.5% and 59.7%, respectively, and prostate adenocarcinoma by 53.5% and 66.4%, respectively. In addition, 0.6% KRE fed TRAMP mice from ages of 6 weeks to 24 weeks exhibited a significant reduction of genitourinary weight (a surrogate of tumor burden) by 54.5% and reduced body weight gain. Furthermore, the KRE and kavalactones showed a significant inhibition of LSD1 and MAO-A enzyme activities. CONCLUSION: Our results suggest that consumption of kava products through diet can delay prostate cancer development and progression and that kavalactones may be a new structure model for developing a potent dual inhibitor of LSD1 and MAO-A.
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Cytokinin oxidase/dehydrogenases (CKXs) play a key role in the irreversible degradation of phytohormone cytokinin that is necessary for various plant growth and development processes. However, thus far, detailed investigations of the CKX gene family in the model legume Medicago truncatula are limited. In this study, we identified 9 putative CKX homologues with conserved FAD- and cytokinin-binding domains in the M. truncatula genome. We analyzed their phylogenetic relationship, gene structure, conserved domain, expression pattern, protein subcellular locations and other properties. The tissue-specific expression profiles of the MtCKX genes are different among different members and these MtCKXs also displayed different patterns in response to synthetic cytokinin 6-benzylaminopurine (6-BA) and indole-3-acetic acid (IAA), suggesting their diverse roles in M. truncatula development. To further understand the biological function of MtCKXs, we identified and characterized mutants of each MtCKX by taking advantage of the Tnt1 mutant population in M. truncatula. Results indicated that M. truncatula plants harboring Tnt1 insertions in each single MtCKX genes showed no morphological changes in aerial parts, suggesting functional redundancy of MtCKXs in M. truncatula shoot development. However, disruption of Medtr4g126160, which is predominantly expressed in roots, leads to an obvious reduced primary root length and increased lateral root number, indicating the specific roles of cytokinin in regulating root architecture. We systematically analyzed the MtCKX gene family at the genome-wide level and revealed their possible roles in M. truncatula shoot and root development, which shed lights on understanding the biological function of CKX family genes in related legume plants.
Assuntos
Citocininas/genética , Citocininas/metabolismo , Genes de Plantas , Medicago truncatula/genética , Medicago truncatula/metabolismo , Oxirredutases/genética , Oxirredutases/metabolismo , Regulação da Expressão Gênica de Plantas , Estudo de Associação Genômica Ampla , FilogeniaRESUMO
BACKGROUND: Aberrations in the Wnt pathway have been reported to be involved in the metastasis of prostate cancer (PCa) to bone. We investigated the effect and underlying mechanism of a naturally-occurring Wnt inhibitor, WIF1, on the growth and cellular invasiveness of a bone metastatic PCa cell line, PC3. RESULTS: The WIF1 gene promoter was hypermethylated and its expression down-regulated in the majority (7 of 8) of PCa cell lines. Restoration of WIF1 expression in PC-3 cells resulted in a decreased cell motility and invasiveness via up-regulation of epithelial markers (E-cadherin, Keratin-8 and-18), down-regulation of mesenchymal markers (N-cadherin, Fibronectin and Vimentin) and decreased activity of MMP-2 and -9. PC3 cells transfected with WIF1 consistently demonstrated reduced expression of Epithelial-to-Mesenchymal Transition (EMT) transcription factors, Slug and Twist, and a change in morphology from mesenchymal to epithelial. Moreover, WIF1 expression significantly reduced tumor growth by approximately 63% in a xenograft mouse model. This was accompanied by an increased expression of E-cadherin and Keratin-18 and a decreased expression of vimentin in tumor tissues. CONCLUSION: These data suggest that WIF1 regulates tumor invasion through EMT process and thus, may play an important role in controlling metastatic disease in PCa patients. Blocking Wnt signaling in PCa by WIF1 may represent a novel strategy in the future to reduce metastatic disease burden in PCa patients.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/fisiologia , Divisão Celular/fisiologia , Movimento Celular/fisiologia , Transição Epitelial-Mesenquimal , Invasividade Neoplásica , Neoplasias da Próstata/patologia , Proteínas Repressoras/fisiologia , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Sequência de Bases , Linhagem Celular Tumoral , Metilação de DNA , Primers do DNA , Imunofluorescência , Humanos , Masculino , Camundongos , Camundongos Nus , Reação em Cadeia da Polimerase , Regiões Promotoras Genéticas , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Proteínas Repressoras/genéticaRESUMO
Limited success has been achieved in extending the survival of patients with metastatic and hormone-refractory prostate cancer (HRPC). There is a strong need for novel agents in the treatment and prevention of HRPC. We have shown that flavokawain B (FKB), a kava chalcone, is about 4- to 12-fold more effective in reducing the cell viabilities of androgen receptor (AR)-negative, HRPC cell lines DU145 and PC-3 than AR-positive, hormone-sensitive prostate cancer cell lines LAPC4 and LNCaP, with minimal effect on normal prostatic epithelial and stromal cells. FKB induces apoptosis with an associated increased expression of proapoptotic proteins: death receptor-5, Bim and Puma and a decreased expression of inhibitors of apoptosis protein: XIAP and survivin. Among them, Bim expression was significantly induced by FKB as early as 4 hr of the treatment. Knockdown of Bim expression by short-hairpin RNAs attenuates the inhibitory effect on anchorage-dependent and -independent growth and caspase cleavages induced by FKB. These findings suggest that the effect of FKB, at least in part, requires Bim expression. In addition, FKB synergizes with TRAIL for markedly enhanced induction of apoptosis. Furthermore, FKB treatment of mice bearing DU145 xenograft tumors results in tumor growth inhibition and increases Bim expression in tumor tissues. Together, these results suggest robust mechanisms for FKB induction of apoptosis preferentially for HRPC and the potential usefulness of FKB for prevention and treatment of HRPC in an adjuvant setting.
Assuntos
Proteínas Reguladoras de Apoptose/metabolismo , Apoptose/efeitos dos fármacos , Flavonoides/farmacologia , Proteínas de Membrana/metabolismo , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Proteínas Proto-Oncogênicas/metabolismo , Receptores Androgênicos/metabolismo , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/metabolismo , Animais , Proteínas Reguladoras de Apoptose/genética , Proteína 11 Semelhante a Bcl-2 , Western Blotting , Proliferação de Células , Ensaio de Imunoadsorção Enzimática , Humanos , Imunoprecipitação , Masculino , Proteínas de Membrana/genética , Camundongos , Neoplasias da Próstata/tratamento farmacológico , Proteínas Proto-Oncogênicas/genética , RNA Mensageiro/genética , Receptores Androgênicos/genética , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Células Tumorais CultivadasRESUMO
Lycium barbarum (Fructus Lycii, Wolfberry, or Gouqi) belongs to the Solanaceae. The red-colored fruits of L. barbarum have been used for a long time as an ingredient in Chinese cuisine and brewing, and also in traditional Chinese herbal medicine for improving health. However, its effects on cognitive function have not been well studied. In the present study, prevention of a milk-based wolfberry preparation (WP) on cognitive dysfunction was tested in a prenatal stress model with rats and the antioxidant mechanism was tested by in vitro experiments. We found that prenatal stress caused a significant decrease in cognitive function (Morris water maze test) in female offspring. Pretreatment of the mother rats with WP significantly prevented the prenatal stress-induced cognitive dysfunction. In vitro studies showed that WP dose-dependently scavenged hydroxyl and superoxide radicals (determined by an electron spin resonance spectrometric assay), and inhibited FeCl(2)/ascorbic acid-induced dysfunction in brain tissue and tissue mitochondria, including increases in reactive oxygen species and lipid peroxidation and decreases in the activities of complex I, complex II, and glutamate cysteine ligase. These results suggest that dietary supplementation with WP may be an effective strategy for preventing the brain oxidative mitochondrial damage and cognitive dysfunction associated with prenatal stress.
Assuntos
Antioxidantes/farmacologia , Transtornos Cognitivos/prevenção & controle , Lycium/química , Mitocôndrias/efeitos dos fármacos , Extratos Vegetais/farmacologia , Efeitos Tardios da Exposição Pré-Natal , Animais , Ácido Ascórbico/farmacologia , Feminino , Compostos Ferrosos/farmacologia , Sequestradores de Radicais Livres/metabolismo , Glutamato-Cisteína Ligase/antagonistas & inibidores , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Leite , Mitocôndrias/metabolismo , Estresse Oxidativo , Gravidez , Ratos , Ratos Sprague-Dawley , Restrição Física , Estresse Psicológico/complicaçõesRESUMO
PURPOSE: Osteosarcoma (OS) is an invasive bone tumor that primarily affects children and adolescents. MicroRNA-629 (miR-629) acts as an oncogene involved in the development of various cancers. This study aims to reveal the clinical significance and biological function of miR-629 in OS. PATIENTS AND METHODS: The levels of miR-629 expression in tissues and cells were detected through quantitative real-time polymerase chain reaction (qRT-PCR). Chi-square test was used to evaluate the relationship between miR-621 expression and clinical parameters in patients with OS. Survival analysis was performed by the Kaplan-Meier method. Cox regression analysis of the effect of miR-629 expression on the prognosis of OS patients. CCK-8 and Transwell experiments were used to demonstrate the effect of miR-629 on OS cell function. RESULTS: Compared with the controls, miR-629 levels were significantly elevated in patients with OS (P < 0.001), Furthermore, miR-629 upregulation showed significantly associated with clinical stage (P = 0.011), distant metastasis (P = 0.003) and poor survival (log rank test, P = 0.013) in OS patients. miR-629 might be a potential prognostic biomarker for OS (HR = 2.890, 95% CI = 1.126-7.416, P = 0.027). Cell function experiments proved that the high expression of miR-629 promoted cell proliferation, migration, and invasion of OS. CONCLUSION: All experimental results demonstrated that miR-629 as an oncogene promotes the tumor cell growth, migration and invasion of OS, and miR-629 may act as a novel prognostic biomarker and therapeutic target for patients with this malignant tumor.