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2.
Int J Mol Sci ; 21(3)2020 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-31991793

RESUMO

Circular RNAs (circRNAs) are endogenous noncoding RNAs with covalently closed continuous loop structures that are formed by 3'-5' ligation during splicing. These molecules are involved in diverse physiological and developmental processes in eukaryotic cells. Jasmonic acid (JA) is a critical hormonal regulator of plant growth and defense. However, the roles of circRNAs in the JA regulatory network are unclear. In this study, we performed high-throughput sequencing of Arabidopsis thaliana at 24 h, 48 h, and 96 h after methyl JA (MeJA) treatment. A total of 8588 circRNAs, which were distributed on almost all chromosomes, were identified, and the majority of circRNAs had lengths between 200 and 800 bp. We identified 385 differentially expressed circRNAs (DEcircRNAs) by comparing data between MeJA-treated and untreated samples. Gene Ontology (GO) enrichment analysis of the host genes that produced the DEcircRNAs showed that the DEcircRNAs are mainly involved in response to stimulation and metabolism. Additionally, some DEcircRNAs were predicted to act as miRNA decoys. Eight DEcircRNAs were validated by qRT-PCR with divergent primers, and the junction sites of five DEcircRNAs were validated by PCR analysis and Sanger sequencing. Our results provide insight into the potential roles of circRNAs in the MeJA regulation network.

4.
Theranostics ; 9(25): 7648-7665, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31695792

RESUMO

Alternative splicing (AS) has emerged as a key event in tumor development and microenvironment formation. However, comprehensive analysis of AS and its clinical significance in head and neck squamous cell carcinoma (HNSC) is urgently required. Methods: Genome-wide profiling of AS events using RNA-Seq data from The Cancer Genome Atlas (TCGA) program was performed in a cohort of 464 patients with HNSC. Cancer-associated AS events (CASEs) were identified between paired HNSC and adjacent normal tissues and evaluated in functional enrichment analysis. Splicing networks and prognostic models were constructed using bioinformatics tools. Unsupervised clustering of the CASEs identified was conducted and associations with clinical, molecular and immune features were analyzed. Results: We detected a total of 32,309 AS events and identified 473 CASEs in HNSC; among these, 91 were validated in an independent cohort (n = 15). Functional protein domains were frequently altered, especially by CASEs affecting cancer drivers, such as PCSK5. CASE parent genes were significantly enriched in pathways related to HNSC and the tumor immune microenvironment, such as the viral carcinogenesis (FDR < 0.001), Human Papillomavirus infection (FDR < 0.001), chemokine (FDR < 0.001) and T cell receptor (FDR < 0.001) signaling pathways. CASEs enriched in immune-related pathways were closely associated with immune cell infiltration and cytolytic activity. AS regulatory networks suggested a significant association between splicing factor (SF) expression and CASEs and might be regulated by SF methylation. Eighteen CASEs were identified as independent prognostic factors for overall and disease-free survival. Unsupervised clustering analysis revealed distinct correlations between AS-based clusters and prognosis, molecular characteristics and immune features. Immunogenic features and immune subgroups cooperatively depict the immune features of AS-based clusters. Conclusion: This comprehensive genome-wide analysis of the AS landscape in HNSC revealed novel AS events related to carcinogenesis and immune microenvironment, with implications for prognosis and therapeutic responses.

5.
Nat Commun ; 10(1): 3941, 2019 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-31477699

RESUMO

Liquid biopsies have the utility for detecting minimal residual disease in several cancer types. Here, we investigate if liquid biopsy tracking on-treatment informs on tumour phenotypes by longitudinally quantifying circulating Epstein-barr virus (EBV) DNA copy number in 673 nasopharyngeal carcinoma patients undergoing radical induction chemotherapy (IC) and chemo-radiotherapy (CRT). We observe significant inter-patient heterogeneity in viral copy number clearance that is classifiable into eight distinct patterns based on clearance kinetics and bounce occurrence, including a substantial proportion of complete responders (≈30%) to only one IC cycle. Using a supervised statistical clustering of disease relapse risks, we further bin these eight subgroups into four prognostic phenotypes (early responders, intermediate responders, late responders, and treatment resistant) that are correlated with efficacy of chemotherapy intensity. Taken together, we show that real-time monitoring of liquid biopsy response adds prognostic information, and has the potential utility for risk-adapted treatment de-intensification/intensification in nasopharyngeal carcinoma.


Assuntos
Infecções por Vírus Epstein-Barr/terapia , Biópsia Líquida/métodos , Carcinoma Nasofaríngeo/terapia , Neoplasias Nasofaríngeas/terapia , Adulto , Quimiorradioterapia , DNA Viral/sangue , DNA Viral/genética , Infecções por Vírus Epstein-Barr/complicações , Infecções por Vírus Epstein-Barr/virologia , Feminino , Herpesvirus Humano 4/efeitos dos fármacos , Herpesvirus Humano 4/genética , Herpesvirus Humano 4/efeitos da radiação , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Carcinoma Nasofaríngeo/complicações , Fenótipo , Prognóstico
6.
Cancer Res ; 79(18): 4612-4626, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31331909

RESUMO

Long noncoding RNAs (lncRNA) play important roles in the tumorigenesis and progression of cancers. However, the clinical significance of lncRNAs and their regulatory mechanisms in nasopharyngeal carcinogenesis (NPC) are largely unknown. Here, based on a microarray analysis, we identified 384 dysregulated lncRNAs, of which, FAM225A was one of the most upregulated lncRNAs in NPC. FAM225A significantly associated with poor survival in NPC. N(6)-Methyladenosine (m6A) was highly enriched within FAM225A and enhanced its RNA stability. FAM225A functioned as an oncogenic lncRNA that promoted NPC cell proliferation, migration, invasion, tumor growth, and metastasis. Mechanistically, FAM225A functioned as a competing endogenous RNA (ceRNA) for sponging miR-590-3p and miR-1275, leading to the upregulation of their target integrin ß3 (ITGB3), and the activation of FAK/PI3K/Akt signaling to promote NPC cell proliferation and invasion. In summary, our study reveals a potential ceRNA regulatory pathway in which FAM225A modulates ITGB3 expression by binding to miR-590-3p and miR-1275, ultimately promoting tumorigenesis and metastasis in NPC. SIGNIFICANCE: These findings demonstrate the clinical significance of the lncRNA FAM225A in nasopharyngeal carcinoma (NPC) and the regulatory mechanism involved in NPC development and progression, providing a novel prognostic indicator and promising therapeutic target.

7.
Eur J Med Chem ; 180: 171-190, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31306905

RESUMO

p300 is an important histone acetyltransferase in epigenetics, and its overexpression is closely related to various diseases such as cancers. C646 is one of the most representative p300 inhibitors and used in various studies of p300. However, its intrinsic drawbacks such as containing potentially toxic groups prevent it from further development. In order to find potent p300 inhibitors with good drug-like properties, C646 was chosen as the lead compound and a series of new p300 inhibitors were designed based on the principle of bioisosterism and reasonable scaffold hopping, and the structure-activity relationship was systematically explored. Ten of them were found to show comparable inhibitory activity as C646. The most potent compound, 1r (IC50 = 0.16 µM), showed better p300 inhibitory activity than C646 with improved drug-like properties. Western blotting experiment confirmed that 1r could reduce the level of H3K27 acetylation more significantly than C646. Further cellular assay indicated that it could inhibit the proliferation of human breast ductal carcinoma cell T47D and human breast cancer cell MCF7 with the IC50 values of 5.08 µM and 22.54 µM, respectively. Docking study of 1r with p300 protein showed the possible reasons for its higher inhibition activity. Thus, compound 1r might be with potential for development as a novel epigenetic agent targeting p300.


Assuntos
Antineoplásicos/farmacologia , Inibidores Enzimáticos/farmacologia , Pirazolonas/farmacologia , Fatores de Transcrição de p300-CBP/antagonistas & inibidores , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Células MCF-7 , Simulação de Acoplamento Molecular , Estrutura Molecular , Pirazolonas/síntese química , Pirazolonas/química , Relação Estrutura-Atividade , Fatores de Transcrição de p300-CBP/metabolismo
8.
Front Microbiol ; 10: 1531, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31354650

RESUMO

Downy mildew is one of the most serious diseases of grapevine (Vitis spp). The causal agent of grapevine downy mildew, Plasmopara viticola, is an obligate biotrophic oomycete. Although oomycete pathogens such as P. viticola are known to secrete RxLR effectors to manipulate host immunity, there have been few studies of the associated mechanisms by which these may act. Here, we show that a candidate P. viticola RxLR effector, PvAvh74, induces cell death in Nicotiana benthamiana leaves. Using agroinfiltration, we found that nuclear localization, two putative N-glycosylation sites, and 427 amino acids of the PvAvh74 carboxyl terminus were necessary for cell-death-inducing activity. Using virus-induced gene silencing (VIGS), we found that PvAvh74-induced cell death in N. benthamiana requires EDS1, NDR1, SGT1, RAR1, and HSP90, but not BAK1. The MAPK cascade components MEK2, WIPK, and SIPK were also involved in PvAvh74-induced cell death in N. benthamiana. Transient expression of PvAvh74 could suppress Phytophthora capsici colonization of N. benthamiana, which suggests that PvAvh74 elicits plant immune responses. Suppression of P. capsici colonization also was dependent on nuclear localization of PvAvh74. Additionally, PvAvh74-triggered cell death could be suppressed by another effector, PvAvh8, from the same isolate. This work provides a framework to further investigate the interactions of PvAvh74 and other RxLR effectors with host immunity.

9.
BMC Genomics ; 20(1): 362, 2019 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-31072302

RESUMO

BACKGROUND: The glyoxalase system usually comprises two enzymes, glyoxalase I (GLYI) and glyoxalase II (GLYII). This system converts cytotoxic methylglyoxal (MG) into non-toxic D-lactate in the presence of reduced glutathione (GSH) in two enzymatic steps. Recently, a novel type of glyoxalase III (GLYIII) activity has observed in Escherichia coli that can detoxify MG into D-lactate directly, in one step, without a cofactor. Investigation of the glyoxalase enzymes of a number of plant species shows the importance of their roles in response both to abiotic and to biotic stresses. Until now, glyoxalase gene families have been identified in the genomes of four plants, Arabidopsis, Oryza sativa, Glycine max and Medicago truncatula but no similar study has been done with the grapevine Vitis vinifera L. RESULTS: In this study, four GLYI-like, two GLYII-like and three GLYIII-like genes are identified from the genome database of grape. All these genes were analysed in detail, including their chromosomal locations, phylogenetic relationships, exon-intron distributions, protein domain organisations and the presence of conserved binding sites. Using quantitative real-time PCR analysis (qRT-PCR), the expression profiles of these genes were analysed in different tissues of grape, and also when under infection stress from downy mildew (Plasmopara viticola). The study reveals that most VvGLY-like genes had higher expressions in stem, leaf, tendril and ovule but lower expressions in the flower. In addition, most of the VvGLY-like gene members were P. viticola responsive with high expressions 6-12 h and 96-120 h after inoculation. However, VvGLYI-like1 was highly expressed 48 h after inoculation, similar to VvPR1 and VvNPR1 which are involved in the defence response. CONCLUSIONS: This study identified the GLYI-like, GLYII-like and GLYIII-like full gene families of the grapevine. Based on a phylogenetic analysis and the presence of conserved binding sites, we speculate that these glyoxalase-like genes in grape encode active glyoxalases. Moreover, our study provides a basis for discussing the roles of VvGLYI-like, VvGLYII-like and VvGLYIII-like genes in grape's response to downy mildew infection. Our results shed light on the selection of candidate genes for downy mildew tolerance in grape and lay the foundation for further functional investigations of these glyoxalase genes.


Assuntos
Perfilação da Expressão Gênica , Regulação da Expressão Gênica de Plantas , Genoma de Planta , Família Multigênica , Doenças das Plantas/microbiologia , Proteínas de Plantas/genética , Vitis/genética , Aldeído Oxirredutases/genética , Resistência à Doença , Lactoilglutationa Liase/genética , Oomicetos/fisiologia , Filogenia , Doenças das Plantas/genética , Tioléster Hidrolases/genética , Vitis/crescimento & desenvolvimento , Vitis/microbiologia
10.
Protoplasma ; 256(5): 1409-1424, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31115695

RESUMO

Downy mildew, resulted from Plasmopara viticola, is one of most severe fungal diseases of grapevine. Since Vitis vinifera is susceptible to downy mildew, much effort has been focused on improving the resistance of V. vinifera. The Chinese wild V. pseudoreticulata accession Baihe-35-1 (BH) shows resistance to P. viticola; however, the molecular mechanism underlying its resistance to P. viticola is largely unknown. In order to better understand the cellular processes, the transcriptomic changes were investigated at 0, 12, 24, 48, 96, and 120 h post infection (hpi). Transcriptome analysis identified a total of 175 differentially expressed genes. Most of them were found to be associated with oxidative stress, cell wall modification, and protein modification. Moreover, the BH resistance to P. viticola was involved in metabolism process, including terpene synthesis and hormone synthesis. In addition, we verified 12 genes to ensure the accuracy of transcriptome data using quantitative real-time PCR (qRT-PCR). This study broadly characterizes a molecular mechanism in which oxidative stress and cell wall biosynthesis and modification play important roles in the response of BH to P. viticola and provides a basis for further analysis of key genes involved in the resistance to P. viticola.


Assuntos
Perfilação da Expressão Gênica/métodos , Regulação da Expressão Gênica de Plantas/genética , Estresse Oxidativo/genética , Doenças das Plantas/genética , Proteínas de Plantas/química , Vitis/química , Grupo com Ancestrais do Continente Asiático , Humanos
11.
Artigo em Inglês | MEDLINE | ID: mdl-31024451

RESUMO

In mammals the melanocortin 4 receptor (Mc4r) signaling system has been mainly associated with the regulation of appetite and energy homeostasis. In fish of the genus Xiphophorus (platyfish and swordtails) puberty onset is genetically determined by a single locus, which encodes the mc4r. Wild populations of Xiphophorus are polymorphic for early and late-maturing individuals. Copy number variation of different mc4r alleles is responsible for the difference in puberty onset. To answer whether this is a special adaptation of the Mc4r signaling system in the lineage of Xiphophorus or a more widely conserved mechanism in teleosts, we studied the role of Mc4r in reproductive biology of medaka (Oryzias latipes), a close relative to Xiphophorus and a well-established model to study gonadal development. To understand the potential role of Mc4r in medaka, we characterized the major features of the Mc4r signaling system (mc4r, mrap2, pomc, agrp1). In medaka, all these genes are expressed before hatching. In adults, they are mainly expressed in the brain. The transcript of the receptor accessory protein mrap2 co-localizes with mc4r in the hypothalamus in adult brains indicating a conserved function of modulating Mc4r signaling. Comparing growth and puberty between wild-type and mc4r knockout medaka revealed that absence of Mc4r does not change puberty timing but significantly delays hatching. Embryonic development of knockout animals is retarded compared to wild-types. In conclusion, the Mc4r system in medaka is involved in regulation of growth rather than puberty.

12.
Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi ; 33(3): 332-336, 2019 Mar 15.
Artigo em Chinês | MEDLINE | ID: mdl-30874391

RESUMO

Objective: To summarize clinical experience and curative effect in applying three-dimensional mechanical equilibrium concept to cartilage scaffold construction in total auricular reconstruction. Methods: Between June 2015 and June 2017, ninety-seven microtia patients (102 ears) were treated with total ear reconstruction by using tissue expanders. The patients included 43 males and 54 females and their age ranged from 7 to 45 years with an average of 14 years. There were 92 unilateral cases (45 in left side and 47 in right side) and 5 bilateral ones. There were 89 congenital cases and 8 secondary cases. According to microtia classification criteria, there were 21 cases of type Ⅱ, 67 cases of type Ⅲ, and 9 cases of type Ⅳ. Tissue expander was implanted in the first stage. In the second stage, autogenous cartilage was used to construct scaffolds which were covered by enlarged flap. According to the three-dimensional mechanical equilibrium concept, the stable ear scaffold was supported by the scaffolds base, the junction of helix and inferior crura of antihelix, and helix rim. The reconstructed ears were repaired in the third stage operation. Results: All patients had undergone ear reconstruction successfully and all incisions healed well. No infection, subcutaneous effusion, or hemorrhage occurred after operation. All skin flaps, grafts, and ear scaffolds survived completely. All patients received 5- to 17-month follow-up time (mean, 11.3 months) and follow-up time was more than 12 months in 61 cases (64 ears). All reconstructed ears stood upright, and subunits structure and sensory localization of reconstructed ears were clear, and the position, shape, size, and height of bilateral ears were basically symmetrical. Mastoid region scar hyperplasia occurred in 3 patients, which was relieved by anti-scar drugs injection. No scaffolds exposure, absorption, or structural deformation occurred during follow-up period. Conclusion: Application of three-dimensional mechanical equilibrium concept in cartilage scaffold construction can reduce the dosage of costal cartilage, obtain more stable scaffold, and acquire better aesthetic outcomes.


Assuntos
Microtia Congênita , Orelha Externa , Procedimentos Cirúrgicos Reconstrutivos , Adolescente , Adulto , Cartilagem , Criança , Microtia Congênita/cirurgia , Orelha Externa/cirurgia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Retalhos Cirúrgicos , Expansão de Tecido , Adulto Jovem
13.
J Burn Care Res ; 40(3): 355-360, 2019 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-30926991

RESUMO

Burn trauma is generally associated with profound inflammation and organ injuries, especially the lung. Damage-associated molecular patterns (DAMPs), such as mitochondrial DNA (mtDNA), released after tissue injuries, play a crucial role in the development of the inflammation. The aim of our study was to investigate the protective profiles of cyclosporine-A (CsA) in murine models with thermal injury. We studied 24 C57BL/6 mice which were randomly subjected to four groups: a sham-operation group (SO group, n = 6), an experiment group (a full-thickness thermal injury covered 30% of the TBSA, n = 6), a low-CsA group (injection of 2.5 mg/kg of CsA 15 min before the thermal injury, n = 6) and a high-CsA group (injection of 25 mg/kg of CsA 15 min before the thermal injury, n = 6). Systemic inflammatory mediators and plasma mtDNA were measured while lung injury was evaluated pathologically and cytosolic cytochrome c and mtDNA were detected. Noticeable increases in concentration of mtDNA and inflammatory mediators were obtained in the experiment group and two CsA groups comparing with the SO group (P < .05). There were significant decreases in the concentrations of mtDNA and inflammatory mediators with increasing doses of CsA (P < .05). Similarly, severity of lung injury was mitigated with increasing doses of CsA. Meanwhile, CsA also attenuated oxidative stress and release of cytochrome c and mtDNA in the lung tissue on a dose-dependent manner (P < .05). Our results suggested mtDNA contributes to the development of thermal injury-induced inflammation and lung injury. CsA might exert dual protective effects, reducing the release of mtDNA and limiting the mtDNA-induced mitochondrial dysfunction in the lung, on the thermal injury-induced acute lung injury.

14.
Int Immunopharmacol ; 69: 257-262, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30743201

RESUMO

Skin lesions are typical clinical manifestations of systemic lupus erythematosus (SLE) and the biomarker for predicting SLE skin injury is not clear. We conducted a hospital-based case-control study with aim to explore the predictive value of the ratio of aryl hydrocarbon receptor (AhR) in T helper 17 (Th17) cells to AhR in regulatory T (Treg) cells (AhR ratio) in SLE skin lesions. The clinical and laboratory data were obtained from their medical records, and the AhR relative expression levels were evaluated by reverse transcription-quantitative polymerase chain reaction. Flow cytometry was applied to determine the proportion of AhR-overexpressing cells in Th17 and Treg cells. Pearson's correlation and logistic regression analyses were used to evaluate the association between AhR ratio risk of skin lesions. Results showed that the expression level of AhR in peripheral blood mononuclear cells was increased >3-fold in patients with SLE compared with that in healthy controls. Compared with control group, the percentage of AhR-overexpressing cells to Th17 cells was statistically higher in patients with SLE, whereas no significant difference was observed in the percentage of AhR-overexpressing cells to Treg cells between patients with SLE and control group. AhR ratio was also higher in SLE, and it was negatively correlated with complement 3 while positively correlated with erythrocyte sedimentation rate. In addition, compared with the low-AhR ratio group, more younger SLE patients with skin lesions, ultraviolet allergies and lower C3 levels were observed in the high-AhR ratio group, implicating that AhR ratio may be a potential biomarker for predicting SLE skin injury.


Assuntos
Lúpus Eritematoso Sistêmico/metabolismo , Receptores de Hidrocarboneto Arílico/metabolismo , Pele/metabolismo , Linfócitos T Reguladores/metabolismo , Células Th17/metabolismo , Adulto , Estudos de Casos e Controles , Complemento C3/metabolismo , Feminino , Humanos , Lúpus Eritematoso Sistêmico/diagnóstico , Lúpus Eritematoso Sistêmico/patologia , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prognóstico , Pele/patologia , Adulto Jovem
15.
Gastroenterology ; 156(8): 2281-2296.e6, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30779922

RESUMO

BACKGROUND & AIMS: Levels of microRNA 31 (MIR31) are increased in intestinal tissues from patients with inflammatory bowel diseases and colitis-associated neoplasias. We investigated the effects of this microRNA on intestinal inflammation by studying mice with colitis. METHODS: We obtained colon biopsy samples from 82 patients with ulcerative colitis (UC), 79 patients with Crohn's disease (CD), and 34 healthy individuals (controls) at Shanghai Tenth People's Hospital. MIR31- knockout mice and mice with conditional disruption of Mir31 specifically in the intestinal epithelium (MIR31 conditional knockouts) were given dextran sulfate sodium (DSS) or 2,4,6-trinitrobenzene sulfonic acid (TNBS) to induce colitis. We performed chromatin immunoprecipitation and luciferase assays to study proteins that regulate expression of MIR31, including STAT3 and p65, in LOVO colorectal cancer cells and organoids derived from mouse colon cells. Partially hydrolyzed alpha-lactalbumin was used to generate peptosome nanoparticles, and MIR31 mimics were loaded onto their surface using electrostatic adsorption. Peptosome-MIR31 mimic particles were encapsulated into oxidized konjac glucomannan (OKGM) microspheres, which were administered by enema into the large intestines of mice with DSS-induced colitis. Intestinal tissues were collected and analyzed by histology and immunohistochemistry. RESULTS: Levels of MIR31 were increased in inflamed mucosa from patients with CD or UC, and from mice with colitis, compared with controls. STAT3 and nuclear factor-κB activated transcription of MIR31 in colorectal cancer cells and organoids in response to tumor necrosis factor and interleukin (IL)6. MIR31-knockout and conditional-knockout mice developed more severe colitis in response to DSS and TNBS, with increased immune responses, compared with control mice. MIR31 bound to 3' untranslated regions of Il17ra and Il7r messenger RNAs (RNAs) (which encode receptors for the inflammatory cytokines IL17 and IL7) and Il6st mRNA (which encodes GP130, a cytokine signaling protein). These mRNAs and proteins were greater in MIR31-knockout mice with colitis, compared with control mice; MIR31 and MIR31 mimics inhibited their expression. MIR31 also promoted epithelial regeneration by regulating the WNT and Hippo signaling pathways. OKGM peptosome-MIR31 mimic microspheres localized to colonic epithelial cells in mice with colitis; they reduced the inflammatory response, increased body weight and colon length, and promoted epithelial cell proliferation. CONCLUSIONS: MIR31, increased in colon tissues from patients with CD or UC, reduces the inflammatory response in colon epithelium of mice by preventing expression of inflammatory cytokine receptors (Il7R and Il17RA) and signaling proteins (GP130). MIR31 also regulates the WNT and Hippo signaling pathways to promote epithelial regeneration following injury. OKGM peptosome-MIR31 microspheres localize to the colon epithelium of mice to reduce features of colitis. Transcript Profiling: GSE123556.


Assuntos
Biomarcadores/metabolismo , Colite Ulcerativa/patologia , Doença de Crohn/patologia , Mucosa Intestinal/metabolismo , MicroRNAs/metabolismo , Regeneração/fisiologia , Animais , Biópsia por Agulha , Estudos de Casos e Controles , China , Modelos Animais de Doenças , Humanos , Imuno-Histoquímica , Mucosa Intestinal/patologia , Camundongos , Camundongos Knockout , Microesferas , RNA Mensageiro/metabolismo , Distribuição Aleatória , Transdução de Sinais
16.
Clin Drug Investig ; 39(3): 331-340, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30684251

RESUMO

BACKGROUND AND OBJECTIVE: Teriflunomide is a once-daily oral immunomodulatory agent approved in 80 countries for the treatment of patients with relapsing multiple sclerosis (RMS). The study objective was to estimate the cost effectiveness of teriflunomide (14 mg tablet, daily) versus interferon beta-1b (250 mcg subcutaneous injection, every other day) among RMS patients from the Chinese healthcare system perspective. METHODS: A Markov model with annual cycles and a lifetime horizon was utilized to assess cost-effectiveness of teriflunomide in comparison with interferon beta-1b in RMS patients. Treatment effects, including 3-month confirmed disability worsening and annualized relapse rate, were derived from a network meta-analysis. Cost inputs included costs related to treatment acquisition, administration, monitoring, natural disease management through Expanded Disability Status Scale states, relapse treatment, and adverse event management. These costs were calculated as the product between unit costs from published sources and healthcare resource utilization patterns identified in a survey conducted among 11 neurologists across different areas in China. Health effects were expressed as quality-adjusted life years (QALYs) with costs in local currency (¥) and US dollars (US$), 2018. RESULTS: Teriflunomide dominated interferon beta-1b and was associated with lower total costs (teriflunomide ¥1,887,144 vs interferon beta-1b ¥2,061,393) and higher QALYs (teriflunomide 9.60 QALYs vs interferon beta-1b 8.88 QALYs). In probabilistic sensitivity analysis, teriflunomide was dominant in 62.2% of model runs. CONCLUSION: Teriflunomide is a cost-effective therapy over a lifetime time horizon compared to interferon beta-1b in the treatment of RMS patients in China. Results should be interpreted with caution as head-to-head comparisons are not available.


Assuntos
Crotonatos/administração & dosagem , Fatores Imunológicos/administração & dosagem , Interferon beta-1b/administração & dosagem , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Toluidinas/administração & dosagem , Adulto , China , Análise Custo-Benefício , Crotonatos/economia , Feminino , Humanos , Fatores Imunológicos/economia , Injeções Subcutâneas , Interferon beta-1b/economia , Masculino , Esclerose Múltipla Recidivante-Remitente/economia , Anos de Vida Ajustados por Qualidade de Vida , Recidiva , Toluidinas/economia
17.
Cancer Lett ; 443: 34-46, 2019 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-30503555

RESUMO

Gankyrin plays important roles in tumorigenicity and metastasis of hepatocellular carcinoma (HCC). We have for the first time investigated the effects of Gankyrin on glycolysis and glutaminolysis both in vitro and in vivo, including in patient-derived xenografts. We reported Gankyrin increases glucose consumption, lactate production, glutamine consumption and glutamate production in HCC through upregulating the expression of the transporters and enzymes involved in glycolysis and glutaminolysis, including HK2, GLUT1, LDHA, PKM2, ASCT2 and GLS1. We further demonstrated that Gankyrin drives glycolysis and glutaminolysis through upregulating c-Myc via activating ß-catenin signaling. Importantly, we found c-Myc mediated metabolic reprogramming might contribute to the tumorigenicity, metastasis and drug resistance induced by Gankyrin. c-Myc inhibitor synergizes with Sorafenib or Regorafenib to suppress HCC PDX tumors with high Gankyrin levels. We detected a significant correlation between Gankyrin and ß-catenin expression levels in a cohort of HCC biopsies, and combination of these two parameters is a more powerful predictor of poor prognosis. Collectively, our results uncovered that Gankyrin functions as an essential regulator in glycolysis and glutaminolysis via activation of ß-catenin/c-Myc to promotes tumorigenesis, metastasis and drug resistance in human HCC.


Assuntos
Carcinoma Hepatocelular/patologia , Resistencia a Medicamentos Antineoplásicos , Neoplasias Hepáticas/patologia , Complexo de Endopeptidases do Proteassoma/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Animais , Carcinoma Hepatocelular/metabolismo , Linhagem Celular Tumoral , Reprogramação Celular , Regulação Neoplásica da Expressão Gênica , Glicólise , Humanos , Neoplasias Hepáticas/metabolismo , Masculino , Camundongos , Metástase Neoplásica , Transplante de Neoplasias , Complexo de Endopeptidases do Proteassoma/genética , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Transdução de Sinais , beta Catenina/metabolismo
18.
Bioorg Med Chem Lett ; 29(1): 51-55, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30448233

RESUMO

Ginsenoside Compound K (CK) showed potent activity against IgE for the treatment of asthma. A series of CK analogues were then synthesized by straightforward procedures. The in vivo anti-IgE activity evaluations using the OVA-induced asthmatic mouse model revealed preliminary SARs of the CK analogues, which showed that the sugar type, modifications on A-ring and the C20 side chain of CK all affected much on the activities. Primary SARs optimization led to the discovery of compounds T1, T2, T3, T8 and T12, which displayed superior or comparable anti-asthmatic effects (IgE value = 1237.11 ±â€¯106.28, 975.82 ±â€¯160.32, 1136.96 ±â€¯121.85, 1191.08 ±â€¯107.59 and 1258.27 ±â€¯148.70 ng/mL, respectively) in comparison with CK (1501.85 ±â€¯184.66 ng/mL). These potent compounds could serve as leads for further development.


Assuntos
Antiasmáticos/farmacologia , Asma/tratamento farmacológico , Ginsenosídeos/farmacologia , Animais , Antiasmáticos/síntese química , Antiasmáticos/química , Asma/induzido quimicamente , Asma/imunologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Ginsenosídeos/síntese química , Ginsenosídeos/química , Imunoglobulina E/imunologia , Camundongos , Conformação Molecular , Ovalbumina/antagonistas & inibidores , Relação Estrutura-Atividade
19.
Cell Physiol Biochem ; 50(2): 768-782, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30308491

RESUMO

BACKGROUND/AIMS: Non-radical primary tumour resection (PTR) of asymptomatic metastatic colorectal cancer (mCRC) can prolong survival time of some patients. Patients with mutated RAS gene have worse survival outcome. This study aimed to investigate the impact of RAS gene mutations on the prognosis of asymptomatic unresectable mCRC patients who underwent PTR. METHODS: A retrospective observational cohort study was deduced among mCRC patients who experienced PTR or had intact primary tumour (IPT). All of them had the primary tumour tissue genotyping tested for RAS (KRAS and NRAS) gene mutations. The tumour-related overall survival (OS) time and progression-free survival (PFS) time was estimated. From January 2011 to June 2014, 421 mCRC patients with asymptomatic, unresectable, metastatic disease were enrolled in this study. Among them, 282 patients underwent PTR and 139 patients had IPT. RESULTS: The mutation rate of RAS was 53.8% (221/411). With a median followed-up time of 46.5 months, the overall survival time of mCRC patients harboring wtRAS or mtRAS was 28.0 versus 22.0 months (p = 0.043) in PTR group and was 21.6 versus 17.8 months (p=0.071) in IPT groups. A Multivariate regression analysis suggested that RAS gene (p=0.039, HR=1.288,95%CI [1.072∼2.911]), metastatic organ number (p=0.033, HR=3.091,95%CI [1.090∼5.755]) and systemic therapy response (p=0.019, HR=0.622,95%CI [0.525∼0.811]) were independent prognostic factors in PTR population. CONCLUSION: We found that wild-type RAS gene was a favorable factor for the asymptomatic unresectable mCRC patients experiencing PTR.


Assuntos
Neoplasias Colorretais/patologia , Proteínas ras/genética , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/mortalidade , Intervalo Livre de Doença , Feminino , Genótipo , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Mutação , Metástase Neoplásica , Prognóstico , Modelos de Riscos Proporcionais , Análise de Regressão , Estudos Retrospectivos
20.
Cell Physiol Biochem ; 50(4): 1496-1509, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30359964

RESUMO

BACKGROUND/AIMS: Colorectal cancer (CRC) is mainly caused by chromosomal instability (CIN) and microsatellite instability (MSI). The RAS and RAF genes are essential components of the CIN pathway, and several studies have found that RAS and RAF mutations are associated with MSI status in CRC. Here, we examined these three factors in CRC in Northeast China and aimed to reveal new details of the relationship between these mutations and MSI status. METHODS: This study involved 290 patients with CRC who had RAS or RAF gene mutation detected using fluorescence-based allele-specific polymerase chain reaction or Sanger sequencing. The majority of the identified patients were found to harbor MSI (MSI status). Accurate molecular detection was carried out using formalin-fixed paraffin-embedded tissue or blood samples. RESULTS: The rates of RAS and RAF mutations were 58.5% and 4.1%, respectively. The prevalence of RAS mutation in CRC was clearly higher and that of RAF mutation was lower in Northeast China compared with previously reported cohorts in other locations. High MSI level (MSI-H status) was more complex, at around 10%. This was consistent with previous data from China. However, compared with data reported from other continents, MSI-H was higher than that of Japan or South Korea in Asia, and lower than that of Europe or the United States. CONCLUSION: RAS/RAF mutations and MSI status in CRC are closely associated with tumor location and ethnicity. Further studies investigating the relationship between these three factors can help in the development of treatment strategies for patients with CRC.


Assuntos
Neoplasias Colorretais/patologia , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas ras/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , China/epidemiologia , Neoplasias Colorretais/epidemiologia , Neoplasias Colorretais/etnologia , Neoplasias Colorretais/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Taxa de Mutação , Prevalência , Proteínas Proto-Oncogênicas B-raf/metabolismo , Proteínas ras/metabolismo
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