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1.
Gut ; 2019 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-31300513

RESUMO

OBJECTIVE: SETD2, the sole histone H3K36 trimethyltransferase, is frequently mutated or deleted in human cancer, including pancreatic ductal adenocarcinoma (PDAC). However, whether SETD2/H3K36me3 alteration results in PDAC remains largely unknown. DESIGN: TCGA(PAAD) public database and PDAC tissue array with SETD2/H3K36me3 staining were used to investigate the clinical relevance of SETD2 in PDAC. Furthermore, to define the role of SETD2 in the carcinogenesis of PDAC, we crossed conditional Setd2 knockout mice (Pdx cre Setd2 flox/flox) together with Kras G12D mice. Moreover, to examine the role of SETD2 after ductal metaplasia, Crisp/cas9 was used to deplete Setd2 in PDAC cells. RNA-seq and H3K36me3 ChIP-seq were performed to uncover the mechanism. RESULTS: SETD2 mutant/low expression was correlated with poor prognosis in patients with PDAC. Next, we found that Setd2 acted as a putative tumour suppressor in Kras-driven pancreatic carcinogenesis. Mechanistically, Setd2 loss in acinar cells facilitated Kras-induced acinar-to-ductal reprogramming, mainly through epigenetic dysregulation of Fbxw7. Moreover, Setd2 ablation in pancreatic cancer cells enhanced epithelia-mesenchymal transition (EMT) through impaired epigenetic regulation of Ctnna1. In addition, Setd2 deficiency led to sustained Akt activation via inherent extracellular matrix (ECM) production, which would favour their metastasis. CONCLUSION: Together, our findings highlight the function of SETD2 during pancreatic carcinogenesis, which would advance our understanding of epigenetic dysregulation in PDAC. Moreover, it may also pave the way for development of targeted, patients-tailored therapies for PDAC patients with SETD2 deficiency.

2.
Pancreas ; 48(5): 629-635, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31091208

RESUMO

OBJECTIVE: The aim of this study was to investigate the role of LONP1 in the progression of pancreatic cancer. METHODS: Lentivirus was used to silence LONP1 in PANC-1 cells. Colony formation assay, cell counting kit (CCK8) assay, cell scratch-wound assay, and transwell assay were used to assess the effects of our strategy on inhibiting cancer growth, migration, and invasion. Protein expression was detected by Western blot analysis. RESULTS: The expression of LONP1 in pancreatic carcinoma tissues was higher than that in adjacent normal pancreatic tissues. Downregulation of LONP1 suppressed the proliferation, migration, and invasion of PANC-1 cells. Knockdown of LONP1 in PANC-1 cells inhibited epithelial-mesenchymal transition and matrix metalloprotein (MMP) 2/9 by downregulation of vimentin, snail, slug, MMP2, and MMP9 and upregulation of claudin-1. The c-Jun N-terminal kinase pathway was inactivated in LONP1 knockdown PANC-1 cells. Activation of the c-Jun N-terminal kinase pathway by anisomycin treatment significantly reversed the changes in epithelial-mesenchymal transition markers and MMP2/9 induced by ablation of LONP1 in PANC-1 cells. CONCLUSIONS: LONP1 plays a vital role in the proliferation and metastasis of pancreatic cancer, which provides a potential therapeutic target for the treatment of pancreatic cancer.

3.
Clin Cancer Res ; 2018 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-30420446

RESUMO

PURPOSE: Extensive research has reported that the tumor microenvironment components play crucial roles in tumor progression. Thus, blocking the supports of tumor microenvironment is a promising approach to prevent cancer progression. We aimed to determine whether blocking extracellular ATP-P2RY2 axis could be a potential therapeutic approach for PDAC treatment. EXPERIMENTAL DESIGN: Expression of P2RY2 was determined in 264 human PDAC samples, and correlated to patient survival. P2RY2 was inhibited in human PDAC cell lines by antagonist and shRNA, respectively, and cell viability, clonogenicity and glycolysis were determined. RNA sequencing of PDAC cell line was applied to reveal underlying molecular mechanisms. Multiple PDAC mouse models were used to assess the effects of the P2RY2 inhibition on PDAC progression. RESULTS: P2RY2 was upregulated and associated with poor prognosis in PDAC. Activated P2RY2 by increased extracellular ATP in tumor microenvironment promoted PDAC growth and glycolysis. Further studies showed that the agonist-activated P2RY2 triggered PI3K/AKT-mTOR signaling by crosstalk with PDGFR mediated by Yes1, resulting in elevating expression of c-Myc and HIF1a, which subsequently enhanced cancer cell glycolysis. Genetic and pharmacological inhibition of P2RY2 impaired tumor cell growth in subcutaneous and orthotopic xenograft model, as well as delayed tumor progression in inflammation-driven PDAC model. Additionally, synergy was observed when AR-C118925XX, the selective antagonist of P2RY2 receptor, and gemcitabine were combined, resulting in prolonged survival of xenografted PDAC mice. CONCLUSIONS: These findings revealed the roles of the P2RY2 in PDAC metabolic reprogramming, suggesting that P2RY2 might be a potential metabolic therapeutic target for PDAC.

4.
Exp Ther Med ; 16(5): 3939-3950, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30344672

RESUMO

The present study assessed the changes in long non-coding (lnc)RNA and mRNA expression profiles when diosgenin (DIO) exerted a potential osteoprotective effect on the alveolar bone of ovariectomized (OVX) rats. Female Wistar rats underwent a sham operation (SHAM group) or ovariectomy. OVX rats were treated using vehicle (OVX group), DIO (DIO group) or estradiol valerate (EV group) for 12 weeks. After treatment, the biomarkers of bone turnover in plasma and the microstructure of alveolar bone were assessed. lncRNA microarrays were applied to assess lncRNA and mRNA expression profiles in alveolar bone in the OVX and DIO group rats. Subsequently, the differentially expressed mRNAs associated with the comprehensive bone metabolism pathway in Ingenuity Pathway Analysis (IPA) were identified and regarded as key mRNAs. Based on some of the key mRNAs and all the differentially expressed lncRNAs, a coexpression network was established and this network was further analyzed to identify the top 6 lncRNAs with the highest closeness scores (pivotal lncRNAs). Finally, 6 modules showing interactions between pivotal lncRNAs and key mRNAs were constructed. All of the pivotal lncRNAs and key mRNAs were validated with reverse transcription-quantitative polymerase chain reaction. The present findings demonstrated that DIO suppressed the loss of alveolar bone in OVX rats, and the changes to the expression of some lncRNAs or mRNAs occurred in the alveolar bone of the rats in the DIO group. Twenty-four key mRNAs were identified during pathway analysis. Furthermore, 8/24 key mRNAs (Ctnnb1, Smad4, Tcf2, Sp7, Il1b, Il1r1, Tnf and Tnfrsf1a) were used to establish a coexpression network, which included 1,656 nodes and 5,341 edges. During network analysis, 6 pivotal lncRNAs (XR_008346, MRuc007iji, MRAK157089, MRAK076413, MRAK143591 and AB036696) were obtained, and 6 modules illustrating pivotal lncRNA-key mRNA interactions were identified. These results revealed that the anti-osteoporotic effect of DIO on alveolar bone may be associated with the promotion of a bone formation process through increasing the signaling of the Wnt and BMPs pathways and the inhibition of the bone resorption process through decreasing stimulators of osteoclastogenesis. To conclude, several pivotal lncRNAs may serve important roles in these processes via regulating some key mRNAs in the bone metabolism pathway.

6.
Clin Oral Investig ; 22(2): 571-581, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29299731

RESUMO

BACKGROUND: Oral squamous cell carcinomas (OC) are life-threatening diseases emerging as major international health concerns. OBJECTIVE: Development of an efficient clinical strategy for early diagnosis of the disease is a key for reducing the death rate. Biomarkers are proven to be an effective approach for clinical diagnosis of cancer. Although mechanisms underlying regulation of oral malignancy are still unclear, microRNAs (miRNAs) as a group of small non-coded RNAs may be developed as the effective biomarkers used for early detection of oral cancer. METHODS: A literature search was conducted using the databases of PubMed, Web of Science, and the Cochrane Library. The following search terms were used: miRNAs and oral cancer or oral carcinoma. A critical appraisal of the included studies was performed with upregulated miRNAs and downregulated miRNAs in oral cancer. RESULTS: In this review, we summarize the research progress made in miRNAs for diagnosis of oral cancer. The involvement of miRNAs identified in signal transduction pathways in OC, including Ras/MAPK signaling, PI3K/AKT signaling, JAK/STAT signaling, Wnt/ß-catenin signaling, Notch signaling, and TGF-ß/SMAD signaling pathway. CONCLUSIONS: A number of studies demonstrated that miRNAs may be developed as an ideal set of biomarkers used for early diagnosis and prognosis of cancers because of the stability in human peripheral blood and body fluids and availability of non-invasive approaches being developed for clinical utility. CLINICAL RELEVANCE: These findings suggest that miRNAs as biomarkers may be useful for diagnosis of OC.


Assuntos
Biomarcadores Tumorais/metabolismo , MicroRNAs/metabolismo , Neoplasias Bucais/diagnóstico , Neoplasias Bucais/metabolismo , Detecção Precoce de Câncer , Humanos
7.
Adv Exp Med Biol ; 1038: 149-171, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29178075

RESUMO

Mitochondria are generally considered as a powerhouse in a cell where the majority of the cellular ATP and metabolite productions occur. Metabolic rewiring and reprogramming may be initiated and regulated by mitochondrial enzymes. The hypothesis that cellular metabolic rewiring and reprogramming processes may occur as cellular microenvironment is disturbed, resulting in alteration of cell phenotype, such as cancer cells resistant to therapeutics seems to be now acceptable. Cancer metabolic reprogramming regulated by mitochondrial enzymes is now one of the hallmarks of cancer. This chapter provides an overview of cancer metabolism and summarizes progress made in mitochondria-mediated metabolic regulation in cancer drug resistance.


Assuntos
Trifosfato de Adenosina , Resistencia a Medicamentos Antineoplásicos/genética , Mitocôndrias , Neoplasias , Trifosfato de Adenosina/genética , Trifosfato de Adenosina/metabolismo , Animais , Humanos , Mitocôndrias/genética , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Neoplasias/tratamento farmacológico , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patologia
8.
Nutrients ; 9(10)2017 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-29048369

RESUMO

Curcumin has been proven to have a weight-loss effect in a menopausal rat model induced by ovariectomy. However, the effects of curcumin on gut microfloral communities of ovariectomized (OVX) rats remains unclear. Here, we used high-throughput 16S rDNA sequencing to explore the effects of curcumin on microbial diversity in the gut of OVX rats. Female Wistar rats were subjected to either ovariectomy or a sham operation (SHAM group). The OVX rats were treated with vehicle (OVX group) or curcumin (CUR group) by oral gavage. After 12-week treatments, the weights of the bodies and uteri of rats were recorded, the levels of estradiol in the serum were assayed by electrochemiluminescence immunoassay (ECLIA). Then, the fragments encompassing V3-V4 16S rDNA hypervariable regions were PCR amplified from fecal samples, and the PCR products of V3-V4 were sequenced on an Illumina MiSeq for characterization of the gut microbiota. Our results showed that, compared to rats in the SHAM group, rats in the OVX group had more weight gain and lower levels of estradiol in the serum, and curcumin could cause significant weight loss in OVX rats but did not increase the levels of estradiol. Sequencing results revealed the presence of 1120, 1114, and 1119 operational taxonomic units (OTUs) found in the SHAM, OVX, and CUR groups, respectively. The percentage of shared OTUs was 86.1603%. Gut microbiota of rats from the SHAM or CUR group had higher levels of biodiversity and unevenness estimations than those from the OVX group. At the phyla level, compared to rats in SHAM group, rats in the OVX group had a higher ratio of phyla Firmicutes and Bacteroidetes in the gut; at the genus level, four differential gut microbiota (Incertae_Sedis, Anaerovorax, Anaerotruncus, and Helicobacter) between SHAM and OVX groups were found, whereas seven differential gut microbiota (Serratia, Anaerotruncus, Shewanella, Pseudomonas, Papillibacter, Exiguobacterium, and Helicobacter) between OVX and CUR groups were found. In conclusion, estrogen deficiency induced by ovariectomy caused changes in the distribution and structure of intestinal microflora in rats, and curcumin could partially reverse changes in the diversity of gut microbiota.


Assuntos
Bactérias/classificação , Curcumina/farmacologia , Microbioma Gastrointestinal/efeitos dos fármacos , Animais , Bactérias/isolamento & purificação , DNA Bacteriano/isolamento & purificação , Estradiol/sangue , Fezes/química , Fezes/microbiologia , Feminino , Modelos Animais , Tamanho do Órgão/efeitos dos fármacos , Ovariectomia , RNA Ribossômico 16S/isolamento & purificação , Ratos , Ratos Wistar , Análise de Sequência de DNA , Útero/metabolismo , Ganho de Peso/efeitos dos fármacos
9.
Int J Mol Med ; 40(5): 1602-1610, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28901385

RESUMO

The aim of the present study was to assess the effectiveness of Rhizoma Dioscoreae extract (RDE) on preventing rat alveolar bone loss induced by ovariectomy (OVX), and to determine the role of interleukin-6 (IL-6)/signal transducer and activator of transcription 3 (STAT3) signaling pathway in this effect. Female Wistar rats were subjected to OVX or sham surgery. The rats that had undergone OVX were treated with RDE (RDE group), vehicle (OVX group) or 17ß-estradiol subcutaneous injection (E2 group). Subsequently, bone metabolic activity was assessed by analyzing 3-D alveolar bone construction, bone mineral density, as well as the plasma biomarkers of bone turnover. The gene expression of alveolar bone in the OVX and RDE groups was evaluated by IL-6/STAT3 signaling pathway polymerase chain reaction (PCR) arrays, and differentially expressed genes were determined through reverse transcription-quantitative PCR. The inhibitory effect of RDE on alveolar bone loss in the OVX group was demonstrated in the study. In comparison with the OVX group, the RDE group exhibited 19 downregulated genes and 1 upregulated gene associated with the IL-6/STAT3 signaling pathway in alveolar bone. Thus, RDE was shown to relieve OVX-induced alveolar bone loss in rats, an effect which was likely associated with decreased abnormal bone remodeling via regulation of the IL-6/STAT3 signaling pathway.


Assuntos
Perda do Osso Alveolar/etiologia , Perda do Osso Alveolar/metabolismo , Araceae/química , Interleucina-6/metabolismo , Extratos Vegetais/farmacologia , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/efeitos dos fármacos , Perda do Osso Alveolar/diagnóstico , Perda do Osso Alveolar/tratamento farmacológico , Animais , Biomarcadores , Peso Corporal/efeitos dos fármacos , Densidade Óssea/efeitos dos fármacos , Modelos Animais de Doenças , Feminino , Expressão Gênica , Perfilação da Expressão Gênica , Tamanho do Órgão/efeitos dos fármacos , Ovariectomia/efeitos adversos , Extratos Vegetais/química , Ratos , Transcriptoma , Microtomografia por Raio-X
11.
Oncotarget ; 8(18): 30039-30049, 2017 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-28404907

RESUMO

Primary Sjögren's syndrome (pSS) is a chronic autoimmune disease which might progress to mucosal-associated lymphoid tissue lymphoma (pSS/MALT). Diagnosis of pSS requires an invasive tissue biopsy and a delay in diagnosis of pSS has been frequently reported. In this study, four proteins including cofilin-1, alpha-enolase, annexin A2 and Rho GDP-dissociation inhibitor 2 (RGI2) were found to be over-expressed in pSS and pSS/MALT by 2D gel electrophoresis/mass spectrometry, and the finding was verified by the microarray analysis and western blotting results. We then developed enzyme-linked immunosorbent assays for autoantibodies including anti-cofilin-1, anti-alpha-enolase and anti-RGI2 with good quantitative ability. The expression levels of salivary anti-cofilin-1, anti-alpha-enolase and anti-RGI2 were found to be the highest in pSS/MALT patients and lowest in healthy controls. The combination of these three antiantibodies yielded an "area under the curve" (AUC) value of 0.94 with an 86% sensitivity and 93% specificity in distinguishing patients with pSS from healthy controls, an AUC value of 0.99 with a 95% sensitivity and 94% specificity in distinguishing patients with pSS/MALT from healthy controls and an AUC value of 0.86 with a 75% sensitivity and 94% specificity in distinguishing pSS/MALT patients from pSS patients. Collectively, we have successfully identified a panel of potential autoantigens that are progressively up-regulated during the development of pSS and its progression to MALT lymphoma. The autoantibody biomarkers may be used to help diagnose pSS and predict its progression to MALT lymphoma.


Assuntos
Autoanticorpos/imunologia , Linfoma de Zona Marginal Tipo Células B/etiologia , Síndrome de Sjogren/complicações , Síndrome de Sjogren/imunologia , Autoantígenos/imunologia , Biomarcadores , Estudos de Casos e Controles , Eletroforese em Gel Bidimensional , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Linfoma de Zona Marginal Tipo Células B/diagnóstico , Masculino , Espectrometria de Massas , Prognóstico , Proteômica/métodos , Curva ROC , Reprodutibilidade dos Testes , Saliva/imunologia , Síndrome de Sjogren/sangue , Síndrome de Sjogren/diagnóstico
12.
Biomark Res ; 4: 20, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27795830

RESUMO

Pancreatic cancer is characterized as a disease with low survival and high mortality because of no effective diagnostic and therapeutic strategies available in clinic. Conventional clinical diagnostic methods including serum markers and radiological imaging (CT, MRI, EUS, etc.) often fail to detect precancerous or early stage lesions. Development of effective biomarkers is unmet for reduction of mortality of pancreatic cancer. MicroRNAs (miRNAs) are a group of small non-protein-coding RNAs playing roles in regulation of cell physiology including tumorigenesis, apoptotic escape, proliferation, invasion, epithelial-mesenchymal transition (EMT), metastasis and chemoresistance. Various altered signaling pathways involving in molecular pathogenesis of pancreatic cancer are mediated by miRNAs as a role of either oncogenes or tumor suppressors. Among biomarkers developed including protein, metabolites, DNA, RNA, epigenetic mutation, miRNAs are superior because of its unique chemical property. Recent study suggests that miRNAs may be promising biomarkers used for early detection of pancreatic cancer. This review will update the progression made in early detection of pancreatic cancer.

13.
Mol Med Rep ; 13(6): 5342-8, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-27122061

RESUMO

Rhizoma Dioscoreae extract (RDE) exhibits a protective effect on alveolar bone loss in ovariectomized (OVX) rats. The aim of this study was to predict the pathways or targets that are regulated by RDE, by re­assessing our previously reported data and conducting a protein­protein interaction (PPI) network analysis. In total, 383 differentially expressed genes (≥3­fold) between alveolar bone samples from the RDE and OVX group rats were identified, and a PPI network was constructed based on these genes. Furthermore, four molecular clusters (A­D) in the PPI network with the smallest P­values were detected by molecular complex detection (MCODE) algorithm. Using Database for Annotation, Visualization and Integrated Discovery (DAVID) and Ingenuity Pathway Analysis (IPA) tools, two molecular clusters (A and B) were enriched for biological process in Gene Ontology (GO). Only cluster A was associated with biological pathways in the IPA database. GO and pathway analysis results showed that cluster A, associated with cell cycle regulation, was the most important molecular cluster in the PPI network. In addition, cyclin­dependent kinase 1 (CDK1) may be a key molecule achieving the cell­cycle­regulatory function of cluster A. From the PPI network analysis, it was predicted that delayed cell cycle progression in excessive alveolar bone remodeling via downregulation of CDK1 may be another mechanism underling the anti­osteopenic effect of RDE on alveolar bone.


Assuntos
Perda do Osso Alveolar/tratamento farmacológico , Perda do Osso Alveolar/metabolismo , Ciclo Celular/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Pinellia/química , Extratos Vegetais/farmacologia , Perda do Osso Alveolar/patologia , Animais , Feminino , Extratos Vegetais/química , Ratos
14.
Pancreas ; 45(7): 1010-7, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27101570

RESUMO

OBJECTIVE: This paper aimed to assess the physiological effects of p53 on glucose homeostasis in vivo. METHODS: A recombinant adenoviral p53 (rAd-p53) vector was administered to insulin-resistant diabetic mice. Intraperitoneal glucose tolerance test was performed in all groups of mice. Changes in fasting blood glucose, serum triglycerides, C-peptide, and insulin concentrations in treated and untreated mice were measured. Analyses of the target genes related to glucose metabolism were performed. RESULTS: Treatment with the rAd-p53 improved glucose control in a dose- and time-dependent manner and lowered significantly the fasting blood glucose, the serum triglycerides, and improved tolerance test of glucose as compared to control. Lowered blood glucose was associated with up-regulation of genes in the glycogenesis pathways, and down-regulation of genes in the gluconeogenesis pathways in the liver. Overexpressions of GLUT2, GK, PPAR-γ, and insulin receptor precursor were also observed in the liver and the pancreas of treated animals. CONCLUSIONS: Activation of p53-mediated glucose metabolism led to insulin-like antidiabetic effect in the mouse model especially by changing hepatic insulin sensitivity in the diabetic mouse model.


Assuntos
Glicemia/análise , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Tipo 2/genética , Resistência à Insulina , Proteína Supressora de Tumor p53/genética , Animais , Western Blotting , Peptídeo C/sangue , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/etiologia , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/etiologia , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Expressão Gênica , Gluconeogênese/genética , Transportador de Glucose Tipo 2/genética , Transportador de Glucose Tipo 2/metabolismo , Humanos , Insulina/sangue , Masculino , Camundongos Endogâmicos BALB C , PPAR gama/genética , PPAR gama/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais/genética , Triglicerídeos/sangue , Proteína Supressora de Tumor p53/metabolismo , Regulação para Cima
15.
Oncotarget ; 6(12): 10432-44, 2015 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-25826085

RESUMO

Enforced expression of miR-34a eliminates cancer stem cells in some malignant tumors. Sirtuin-1 (SIRT1) is a direct target of miR-34a. Here we found low levels of miR-34a and high levels of SIRT1 in CD44+/CD24- breast cancer stem cells (BCSCs). MiR-34a overexpression and knockdown of SIRT1 decreased proportion of BSCSs and mammosphere formation. Expression of CSC markers, ALDH1, BMI1 and Nanog was decreased. In nude mice xenografts, stable expression of miR-34a and silencing of SIRT1 reduced tumor burden. Taken together, our results demonstrated that miR-34a inhibits proliferative potential of BCSCs in vitro and in vivo, at least partially by downregulating SIRT1. The miR-34a-SIRT1 axis may play role in self-renewal of BCSCs.


Assuntos
Neoplasias da Mama/metabolismo , Neoplasias da Mama/terapia , MicroRNAs/administração & dosagem , MicroRNAs/metabolismo , Sirtuína 1/metabolismo , Animais , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Feminino , Humanos , Células MCF-7 , Camundongos , Camundongos Nus , MicroRNAs/genética , RNA Interferente Pequeno/administração & dosagem , RNA Interferente Pequeno/genética , Distribuição Aleatória , Sirtuína 1/genética , Transfecção , Ensaios Antitumorais Modelo de Xenoenxerto
16.
Nutrients ; 7(2): 1333-51, 2015 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-25690421

RESUMO

The aim of this study was to evaluate the osteoprotective effect of aqueous Rhizoma Dioscoreae extract (RDE) on the alveolar bone of rats with ovariectomy-induced bone loss. Female Wistar rats underwent either ovariectomy or sham operation (SHAM). The ovariectomized (OVX) rats were treated with vehicle (OVX), estradiol valerate (EV), or RDE. After treatments, the bone mineral density (BMD) and the three-dimensional microarchitecture of the alveolar bone were analyzed to assess bone mass. Microarrays were used to evaluate microRNA expression profiles in alveolar bone from RDE-treated and OVX rats. The differential expression of microRNAs was validated using real-time quantitative RT-PCR (qRT-PCR), and the target genes of validated microRNAs were predicted and further analyzed using Ingenuity Pathway Analysis (IPA). The key findings were verified using qRT-PCR. Our results show that RDE inhibits alveolar bone loss in OVX rats. Compared to the OVX rats, the RDE-treated rats showed upregulated expression levels of 8 microRNAs and downregulated expression levels of 8 microRNAs in the alveolar bone in the microarray analysis. qRT-PCR helped validate 13 of 16 differentially expressed microRNAs, and 114 putative target genes of the validated microRNAs were retrieved. The IPA showed that these putative target genes had the potential to code for proteins that were involved in the transforming growth factor (TGF)-ß/bone morphogenetic proteins (BMPs)/Smad signaling pathway (Tgfbr2/Bmpr2, Smad3/4/5, and Bcl-2) and interleukin (IL)-6/oncostatin M (OSM)/Jak1/STAT3 signaling pathway (Jak1, STAT3, and Il6r). These experiments revealed that RDE could inhibit ovariectomy-induced alveolar bone loss in rats. The mechanism of this anti-osteopenic effect in alveolar bone may involve the simultaneous inhibition of bone formation and bone resorption, which is associated with modulation of the TGF-ß/BMPs/Smad and the IL-6/OSM/Jak1/STAT3 signaling pathways via microRNA regulation.


Assuntos
Perda do Osso Alveolar/dietoterapia , Densidade Óssea/efeitos dos fármacos , Dioscorea , MicroRNAs/efeitos dos fármacos , Fitoterapia/métodos , Preparações de Plantas/farmacologia , Perda do Osso Alveolar/metabolismo , Animais , Proteínas Morfogenéticas Ósseas/metabolismo , Estradiol/administração & dosagem , Estradiol/análogos & derivados , Estradiol/farmacologia , Feminino , Interleucina-6/metabolismo , Janus Quinase 1/metabolismo , MicroRNAs/metabolismo , Oncostatina M/metabolismo , Ovariectomia/efeitos adversos , Preparações de Plantas/administração & dosagem , Ratos , Ratos Wistar , Fator de Transcrição STAT3/metabolismo , Fator de Crescimento Transformador beta/metabolismo
17.
Chin J Integr Med ; 21(2): 115-22, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24155070

RESUMO

OBJECTIVE: To re-analyze the data published in order to explore plausible biological pathways that can be used to explain the anti-aging effect of curcumin. METHODS: Microarray data generated from other study aiming to investigate effect of curcumin on extending lifespan of Drosophila melanogaster were further used for pathway prediction analysis. The differentially expressed genes were identified by using GeneSpring GX with a criterion of 3.0-fold change. Two Cytoscape plugins including BisoGenet and molecular complex detection (MCODE) were used to establish the protein-protein interaction (PPI) network based upon differential genes in order to detect highly connected regions. The function annotation clustering tool of Database for Annotation, Visualization and Integrated Discovery (DAVID) was used for pathway analysis. RESULTS: A total of 87 genes expressed differentially in D. melanogaster melanogaster treated with curcumin were identified, among which 50 were up-regulated significantly and 37 were remarkably down-regulated in D. melanogaster melanogaster treated with curcumin. Based upon these differential genes, PPI network was constructed with 1,082 nodes and 2,412 edges. Five highly connected regions in PPI networks were detected by MCODE algorithm, suggesting anti-aging effect of curcumin may be underlined through five different pathways including Notch signaling pathway, basal transcription factors, cell cycle regulation, ribosome, Wnt signaling pathway, and p53 pathway. CONCLUSION: Genes and their associated pathways in D. melanogaster melanogaster treated with anti-aging agent curcumin were identified using PPI network and MCODE algorithm, suggesting that curcumin may be developed as an alternative therapeutic medicine for treating aging-associated diseases.


Assuntos
Envelhecimento/efeitos dos fármacos , Curcumina/farmacologia , Drosophila melanogaster/efeitos dos fármacos , Drosophila melanogaster/genética , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Envelhecimento/genética , Animais , Ciclo Celular/efeitos dos fármacos , Ciclo Celular/genética , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Redes Reguladoras de Genes/efeitos dos fármacos , Genes de Insetos , Biossíntese de Proteínas/efeitos dos fármacos , Biossíntese de Proteínas/genética , Mapas de Interação de Proteínas/efeitos dos fármacos , Mapas de Interação de Proteínas/genética , Receptores Notch/genética , Receptores Notch/metabolismo , Ribossomos/efeitos dos fármacos , Ribossomos/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Via de Sinalização Wnt/efeitos dos fármacos , Via de Sinalização Wnt/genética
18.
Nutrients ; 6(12): 5853-70, 2014 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-25514564

RESUMO

AIM: The aim of this study was to evaluate the osteoprotective effect of aqueous Rhizoma Dioscoreae extract (RDE) on the alveolar bone of rats with ovariectomy-induced bone loss. METHODS: Female Wistar rats were subjected to either ovariectomy or a sham operation (SHAM). The ovariectomized (OVX) rats were treated with vehicle (OVX) or RDE by oral gavage or with 17ß-estradiol (E2) subcutaneously. After treatments, the bone mineral density (BMD), the three-dimensional bone architecture of the alveolar bone and the plasma biomarkers of bone turnover were analyzed to assess bone metabolism, and the histomorphometry of the alveolar bone was observed. Microarrays were used to evaluate gene expression profiles in alveolar bone from RDE-treated and OVX rats. The differential expression of genes was further analyzed using Ingenuity Pathway Analysis (IPA). The key findings were verified using real-time quantitative RT-PCR (qRT-PCR). RESULTS: Our results showed that RDE inhibited alveolar bone loss in OVX rats. Compared to the OVX rats, the RDE-treated rats showed upregulated expression levels of 207 genes and downregulated expression levels of 176 genes in the alveolar bone. The IPA showed that several genes had the potential to code for proteins that were involved in the Wnt/ß-catenin signaling pathway (Wnt7a, Fzd2, Tcf3, Spp1, Frzb, Sfrp2 and Sfrp4) and the p38 MAPK signaling pathway (Il1rn and Mapk14). CONCLUSION: These experiments revealed that RDE could inhibit ovariectomy-induced alveolar bone loss in rats. The mechanism of this anti-osteopenic effect in alveolar bone may be involved in the reduced abnormal bone remodeling, which is associated with the modulation of the Wnt/ß-catenin and the p38 MAPK signaling pathways via gene regulation.


Assuntos
Perda do Osso Alveolar/tratamento farmacológico , Dioscorea/química , Sistema de Sinalização das MAP Quinases , Extratos Vegetais/farmacologia , Via de Sinalização Wnt , Animais , Biomarcadores/sangue , Densidade Óssea/efeitos dos fármacos , Doenças Ósseas Metabólicas/tratamento farmacológico , Doenças Ósseas Metabólicas/etiologia , Remodelação Óssea/efeitos dos fármacos , Colágeno Tipo I/sangue , Regulação para Baixo , Estradiol/sangue , Estradiol/farmacologia , Feminino , Ovariectomia , Fragmentos de Peptídeos/sangue , Pró-Colágeno/sangue , Ratos , Ratos Wistar , Rizoma/química , Transdução de Sinais , Regulação para Cima , Proteínas Wnt/genética , Proteínas Wnt/metabolismo , beta Catenina/genética , beta Catenina/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/genética , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
19.
Int J Mol Sci ; 15(9): 17130-47, 2014 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-25257532

RESUMO

The aim of this study was to evaluate effect of diosgenin (DG) on rats that had osteoporosis-like features induced by ovariectomy (OVX). Seventy-two six-month-old female Wistar rats were subjected to either ovariectomy (n = 60) or Sham operation (SHAM group, n = 12). Beginning at one week post-ovariectomy, the OVX rats were treated with vehicle (OVX group, n = 12), estradiol valerate (EV group, n = 12), or DG at three doses (DG-L, -M, -H group, n = 12, respectively). After a 12-week treatment, administration of EV or DG-H inhibited OVX-induced weight gain, and administration of EV or DG-H or DG-M had a significantly uterotrophic effect. Bone mineral density (BMD) and indices of bone histomorphometry of tibia were measured. Levels of protein and mRNA expression of osteoprotegerin (OPG) and receptor activator of nuclear factor kappa-B ligand (RANKL) in tibia were evaluated by immunohistochemistry and in situ hybridization. Our results show that DG at a high dose (DG-H) had a significant anti-osteoporotic effect compared to OVX control. DG-H treatment down-regulated expression of RANKL and up-regulated expression of OPG significantly in tibia from OVX rats compared to control, and thus lowered the RANKL/OPG ratio. This suggests that the anti-osteoporotic effect of DG might be associated with modulating the RANKL/OPG ratio and DG had potential to be developed as alternative therapeutic agents of osteoporosis induced by postmenopause.


Assuntos
Conservadores da Densidade Óssea/uso terapêutico , Densidade Óssea/efeitos dos fármacos , Diosgenina/uso terapêutico , Osteoporose Pós-Menopausa/tratamento farmacológico , Osteoprotegerina/biossíntese , Ligante RANK/biossíntese , Animais , Peso Corporal/efeitos dos fármacos , Conservadores da Densidade Óssea/administração & dosagem , Diosgenina/administração & dosagem , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Estradiol/análogos & derivados , Estradiol/uso terapêutico , Terapia de Reposição de Estrogênios , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Tamanho do Órgão/efeitos dos fármacos , Osteoprotegerina/genética , Ovariectomia/efeitos adversos , Ligante RANK/genética , Ratos , Ratos Wistar , Tíbia/metabolismo , Tíbia/patologia , Útero/efeitos dos fármacos , Útero/patologia
20.
ScientificWorldJournal ; 2014: 645975, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24526913

RESUMO

The aims of this study were to evaluate the osteoprotective effect of aqueous extract from Rhizoma Dioscoreae (RDE) on rats with ovariectomy- (OVX-) induced osteopenia. Our results show that RDE could inhibit bone loss of OVX rats after a 12-week treatment. The microarray analysis showed that 68 genes were upregulated and that 100 genes were downregulated in femurs of the RDE group rats compared to those in the OVX group. The Ingenuity Pathway Analysis (IPA) showed that several downregulated genes had the potential to code for proteins that were involved in the Wnt/ ß -catenin signaling pathway (Sost, Lrp6, Tcf7l2, and Alpl) and the RANKL/RANK signaling pathway (Map2k6 and Nfatc4). These results revealed that the mechanism for an antiosteopenic effect of RDE might lie in the synchronous inhibitory effects on both the bone formation and the bone resorption, which is associated with modulating the Wnt/ ß -catenin signaling and the RANKL/RANK signaling.


Assuntos
Doenças Ósseas Metabólicas/prevenção & controle , Dioscorea , Medicamentos de Ervas Chinesas/uso terapêutico , Ovariectomia/efeitos adversos , Rizoma , Animais , Densidade Óssea/efeitos dos fármacos , Densidade Óssea/fisiologia , Doenças Ósseas Metabólicas/patologia , Medicamentos de Ervas Chinesas/isolamento & purificação , Medicamentos de Ervas Chinesas/farmacologia , Feminino , Distribuição Aleatória , Ratos , Ratos Wistar , Resultado do Tratamento
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