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1.
Cancer Res ; 80(10): 1991-2003, 2020 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-32098780

RESUMO

Perineural invasion is a common feature of pancreatic ductal adenocarcinoma (PDAC). Here, we investigated the effect of perineural invasion on the microenvironment and how this affects PDAC progression. Transcriptome expression profiles of PDAC tissues with different perineural invasion status were compared, and the intratumoral T-cell density and levels of neurotransmitters in these tissues were assessed. Perineural invasion was associated with impaired immune responses characterized by decreased CD8+ T and Th1 cells, and increased Th2 cells. Acetylcholine levels were elevated in severe perineural invasion. Acetylcholine impaired the ability of PDAC cells to recruit CD8+ T cells via HDAC1-mediated suppression of CCL5. Moreover, acetylcholine directly inhibited IFNγ production by CD8+ T cells in a dose-dependent manner and favored Th2 over Th1 differentiation. Furthermore, hyperactivation of cholinergic signaling enhanced tumor growth by suppressing the intratumoral T-cell response in an orthotopic PDAC model. Conversely, blocking perineural invasion with bilateral subdiaphragmatic vagotomy in tumor-bearing mice was associated with an increase in CD8+ T cells, an elevated Th1/Th2 ratio, and improved survival. In conclusion, perineural invasion-triggered cholinergic signaling favors tumor growth by promoting an immune-suppressive microenvironment characterized by impaired CD8+ T-cell infiltration and a reduced Th1/Th2 ratio. SIGNIFICANCE: These findings provide a promising therapeutic strategy to modulate the immunosuppressive microenvironment of pancreatic ductal adenocarcinoma with severe perineural invasion.

2.
Hua Xi Kou Qiang Yi Xue Za Zhi ; 37(6): 577-582, 2019 Dec 01.
Artigo em Chinês | MEDLINE | ID: mdl-31875433

RESUMO

OBJECTIVE: To observe the effect of protein kinase D1 (PKD1) on the growth and metabolism of oral squamous cell carcinoma HSC-4 cells and related molecular mechanisms in the tumor microenvironment. METHODS: HSC-4 cell lines were transfected with shRNA plasmids. Three groups (Wild, control-shRNA, and PKD1-shRNA) were cultured under acidic or hypoxic environment for a certain time. Western blot was used to detect the expression of autophagy-related and glycolytic-related proteins. The proliferation changes were detected by CCK-8 kits. RESULTS: The PKD1-knockdown HSC-4 cell line was established. PKD1 silencing increased autophagy activity. Under hypoxic and acidic conditions, the PKD1-knockdown HSC-4 cells showed lower proliferation than the parental cells. PKD1-knockdown also decreased the expression of hypoxia induciblefactor 1α (HIF-1α) and pyruvate kinase M2 (PKM2). CONCLUSIONS: Under hypoxic and acidic conditions, PKD1 gene silencing can increase apoptotic autophagy activity. Downregulated PKD1 gene expression can reduce the glycolysis of oral squamous cell carcinoma cells and inhibit tumor cell proliferation. This study revealed the important role of PKD1 in the metabolism and growth of oral squamous cell carcinoma, making it a possible target for the treatment of oral squamous cell carcinoma.


Assuntos
Carcinoma de Células Escamosas , Neoplasias Bucais , Linhagem Celular Tumoral , Proliferação de Células , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia , Proteínas Quinases , Microambiente Tumoral
3.
Hua Xi Kou Qiang Yi Xue Za Zhi ; 37(6): 583-588, 2019 Dec 01.
Artigo em Chinês | MEDLINE | ID: mdl-31875434

RESUMO

OBJECTIVE: This study aimed to investigate the role of protein kinase D (PKD)1 in regulating the growth, apop-tosis, and drug sensitivity of the squamous carcinoma cell line SCC-25. METHODS: The SCC-25 cell line was transfected with either the control-shRNA or PKD1-shRNA plasmids. The stable transfected cells were selected, and the efficiency of PKD1 knockdown was detected by Western blot. The growth and apoptosis of SCC-25 were analyzed with a cell counting kit-8 (CCK8) and flow cytometry. The 50% inhibitory concentrations (IC50) of paclitaxel in the control and PKD1 knockdown cell lines were detected by CCK-8. The expression levels of Bax, Bcl-2, and P-gp were detected by Western blot. RESULTS: PKD1 was constitutively expressed and phosphorylated in various cancer cell lines. Inhibiting the expression of PKD1 in SCC-25 cells by RNA interference could inhibit the growth and promote the apoptosis of SCC-25 cells via downregulating Bcl-2 expression. Additionally, inhibiting PKD1 expression could downregulate the expression of P-gp, thereby decreasing both the IC50 and resistance index of paclitaxel. CONCLUSIONS: PKD1 plays an important role in regulating the biobehavior of SCC-25. It is a potential therapeutic target for oral squamous carcinoma.


Assuntos
Carcinoma de Células Escamosas , Neoplasias Bucais , Apoptose , Linhagem Celular Tumoral , Proliferação de Células , Humanos
4.
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.

5.
Syst Appl Microbiol ; 42(4): 488-494, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31204142

RESUMO

Four endophytic bacterial strains were isolated from root, stem and leaf of maize planted in different regions of northern China. The four strains possessed almost identical 16S rRNA gene sequences. However, REP-PCR fingerprint patterns discriminated that they were not from one clonal origin. Furthermore, the average nucleotide identity (ANI) values among them were higher than 95%, suggesting they all belong to one species. Based on 16S rRNA gene phylogeny, the four strains were clustered together with Pantoea rodasii LMG 26273T and Pantoea rwandensis LMG 26275T, but on a separate branch. Multilocus sequence analysis (MLSA) indicated that the four strains form a novel Pantoea species. Authenticity of the novel species was confirmed by ANI comparisons between strain 596T and its closest relatives, since obtained values were considerably below the proposed thresholds for the species delineation. The genome size of 596T was 5.1Mbp, comprising 4896 predicted genes with DNA G+C content of 57.8mol%. The respiratory quinone was ubiquinone-8 (Q-8) and the polar lipid profile consisted of phosphatidylethanolamin, diphosphatidylglycerol, phosphatidylglycerol, unidentified aminophospholipid and unidentified phospholipid. The major fatty acids of strain 596T were C16:0, summed feature 2 (C12:0 aldehyde), summed feature 3 (C16:1ω7c and/or C16:1ω6c) and summed feature 8 (C18:1ω7c and/or C18:1ω6c). Based on phylogenetic, genomic, phenotypic and chemotaxonomic data, the four isolates are considered to represent a novel species of the genus Pantoea, for which the name Pantoea endophytica sp. nov., is proposed, with 596T (=DSM 100,785T=CGMCC 1.15280T) as type strain.


Assuntos
Pantoea/classificação , Pantoea/fisiologia , Filogenia , Zea mays/microbiologia , China , DNA Bacteriano/genética , Endófitos , Ácidos Graxos/química , Genes Bacterianos/genética , Genes Essenciais/genética , Genoma Bacteriano/genética , Pantoea/química , Pantoea/genética , Fenótipo , Fosfolipídeos/química , RNA Ribossômico 16S/genética , Análise de Sequência de DNA , Especificidade da Espécie , Ubiquinona/química
6.
Med Sci Monit ; 25: 4617-4626, 2019 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-31227685

RESUMO

BACKGROUND The association of preexisting neurocognitive impairments with perioperative neurocognitive disorders is not well-established. The objective of this study was to record incidences of perioperative neurocognitive disorders, to record changes in perioperative neurocognition, and to analyze factors of perioperative neurocognitive changes after hip joint replacement surgeries. MATERIAL AND METHODS Patients scheduled for hip joint replacement surgery were included in the test group (n=499) and patients with osteoarthritis but who were not planned for any type of surgeries were included in the control group (n=499). The cognitive tests were evaluated at the time of enrollment and at 1 week, 3 months, 1 year, and 4 years after baseline. Neurocognitive disorders for the individual parameter was defined as more than 2 SD of mean below norms for that parameter. Neurocognitive disorders were defined as a significant worst condition in at least 2 parameters out of all parameters. RESULTS Compared to baseline, after 3 months the numbers of patients with perioperative neurocognitive disorders were increased (55 vs. 81, p=0.021). After 4 years, there was a significant decline in numbers of patients with perioperative neurocognitive disorders in the test group (55 vs. 3, p<0.0001). At the end of the 3-month follow-up period, elderly patients (p=0.002) and patients with preexisting neurocognitive impairments (p=0.005) had a higher incidence of perioperative neurocognitive disorders. CONCLUSIONS Age and preexisting neurocognitive impairments are markers predicting the risk of perioperative neurocognitive disorders.


Assuntos
Artroplastia de Quadril/efeitos adversos , Transtornos Cognitivos/etiologia , Transtornos Neurocognitivos/etiologia , Idoso , Idoso de 80 Anos ou mais , Artroplastia de Quadril/métodos , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Transtornos Neurocognitivos/metabolismo , Complicações Pós-Operatórias/epidemiologia , Estudos Prospectivos
7.
J Pharm Sci ; 108(8): 2542-2551, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30876860

RESUMO

In this study, black phosphorus nanosheets (BPNSs) were incorporated into a hydrogel formed from dibenzaldehyde-functionalized polymer (DF-PEG) and polyaspartylhydrazide (PAHy) polymer to create an injectable and pH-sensitive DF-PEG-PAHy/BPNSs hydrogel, which can be used as a smart depot for synergistic chemo-photothermal cancer therapy. The DF-PEG-PAHy/BPNSs hydrogel exhibited excellent gelation characteristics, pH sensitivity, and near-infrared responsiveness. The nanocomposite hydrogel provided controlled drug release and near-infrared irradiation speeded up release of drug from the hydrogel because of the photothermal effect of the BPNSs. Cytotoxicity tests confirmed that the hydrogel has good biocompatibility and exerts its photothermal effect in vitro. Antitumor tests in mice demonstrated the capacity of DF-PEG-PAHy/BPNSs hydrogel for synergistic chemo-photothermal therapy in vivo. The hydrogel showed reduced adverse effects because of stable drug release in the tumor area and an efficient photothermal effect. Together, these data demonstrated the potential of DF-PEG-PAHy/BPNSs hydrogel containing a chemotherapy drug to serve as a novel smart delivery system for combined chemo-photothermal cancer therapy.

8.
Medicine (Baltimore) ; 98(5): e14037, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30702561

RESUMO

Enhanced inflammation response was increasingly reported in association with postoperative cognitive dysfunction (POCD). Glucocorticoid receptor (GR) signal plays a key role in suppression of inflammation. This prospective cohort study aimed to evaluate GR signaling in elderly patients undergoing selective operation.One hundred twenty-six elderly patients were scheduled for hip fracture surgery with general anesthesia. Plasma cortisol levels and the expression levels of GR and FK506 binding protein 51 (FKBP51) in leukocytes were determined at 1 day preoperatively and 7 days. Postoperatively postoperative pain was assessed following surgery using visual analog pain scale (VAS). Neuropsychological tests were performed before surgery and 1 week postoperation. A decline of 1 or more standard deviations in 2 or more tests was considered to reflect POCD.POCD incidence in participants was 28.3% at 1 week after surgery. POCD patients presented significantly higher cortisol and FKBP51 levels compared with non-POCD patients (P < .05). Compared with non-POCD patients, VAS scores at 12 hours after surgery were higher in POCD patients (P < .05). No significant difference in expression levels of GR was found between groups POCD and non-POCD patients.High expression of FKBP51 in leukocytes and glucocorticoid resistance were associated with POCD in aged patients following hip fracture surgery.


Assuntos
Artroplastia de Quadril/efeitos adversos , Disfunção Cognitiva/epidemiologia , Fraturas do Quadril/cirurgia , Complicações Pós-Operatórias/epidemiologia , Proteínas de Ligação a Tacrolimo/biossíntese , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Hidrocortisona/biossíntese , Masculino , Testes Neuropsicológicos , Dor Pós-Operatória , Estudos Prospectivos , Receptores de Glucocorticoides/biossíntese
9.
Oncogene ; 38(20): 3932-3945, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30692639

RESUMO

Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy with high mortality. Lack of effective treatment makes novel therapeutic discovery an urgent demand in PDAC research. By screening an epigenetic-related compound library, we identified THZ1, a covalent inhibitor of CDK7, as a promising candidate. Multiple long-established and patient-derived PDAC cell lines (PDC) were used to validate the efficacy of THZ1 in vitro. In addition, patient-derived xenograft (PDX) models and animal models of PDAC were utilized for examining THZ1 efficacy in vivo. Furthermore, RNA-Seq analyse was performed to reveal the molecular mechanism of THZ1 treatment. Finally, PDAC cell lines with primary or acquired resistance to THZ1 were investigated to explore the potential mechanism of THZ1 susceptibility. CDK7 inhibition was identified as a selective and potent therapeutic strategy for PDAC progression in multiple preclinical models. Mechanistic analyses revealed that CDK7 inhibition led to a pronounced downregulation of gene transcription, with a preferential repression of mitotic cell cycle and NF-κB signaling-related transcripts. MYC transcriptional was found to be involved in susceptibility of PDAC cells to CDK7 inhibition. In conclusion, Identification of CDK7-dependent transcriptional addiction in PDACs provides a potent therapeutic strategy that targets highly aggressive pancreatic cancer.


Assuntos
Carcinoma Ductal Pancreático/tratamento farmacológico , Quinases Ciclina-Dependentes/genética , Neoplasias Pancreáticas/tratamento farmacológico , Fenilenodiaminas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Animais , Antineoplásicos/farmacologia , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patologia , Linhagem Celular Tumoral , Quinases Ciclina-Dependentes/antagonistas & inibidores , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Genes myc , Humanos , Masculino , Camundongos Endogâmicos BALB C , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/etiologia , Neoplasias Experimentais/genética , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Pancreatite/complicações , Ensaios Antitumorais Modelo de Xenoenxerto
10.
Nat Prod Res ; 33(11): 1550-1555, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29334261

RESUMO

Two lignans including a new one, five flavonoids and five coumarins were isolated from the whole plant of Viola philippica (synonymised as Viola yedoensis Makino). The new compound was structurally determined as (7R,8S,8'S) -3,3'-dimethoxy- 4,4',9-trihydroxy- 7,9'-epoxy-8,8'-lignan 9-O-rutinoside by analysis of its NMR, MS and CD spectroscopic data. The known compounds were characterised by comparing their NMR and MS data with those reported. Among the known compounds, 5-hydroxy-4'-methoxyflavone-7-O- rutinoside, 6,7-di-O-ß-D- glucopyranosylesculetin, and 7R,8S-dihydrodehydrodiconiferyl alcohol 4-O-ß-D- glucopyranoside were isolated and identified from this genus for the first time. Of these compounds, 5-hydroxy-4'-methoxyflavone-7-O-rutinoside and (7R,8S,8'S) -3,3'-dimethoxy- 4,4',9-trihydroxy- 7,9'-epoxy-8,8'-lignan 9-O-rutinoside were potently active against α-glucosidase, while the two dimeric coumarins, 5, 5'-bi (6, 7-dihydroxycoumarin) and 6,6',7,7'-tetrahydroxy-5,8'-bicoumarin potently inhibited HCV protease.


Assuntos
Cumarínicos/farmacologia , Flavonoides/farmacologia , Inibidores de Glicosídeo Hidrolases/farmacologia , Hepatite C/enzimologia , Lignanas/farmacologia , Inibidores de Proteases/farmacologia , Viola/química , Dicroísmo Circular , Cumarínicos/química , Flavonoides/química , Inibidores de Glicosídeo Hidrolases/química , Lignanas/química , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Inibidores de Proteases/química
11.
Hua Xi Kou Qiang Yi Xue Za Zhi ; 36(5): 508-513, 2018 Oct 01.
Artigo em Chinês | MEDLINE | ID: mdl-30465344

RESUMO

OBJECTIVE: The aim of this study was to investigate the effect of saliva of patients with chronic periodontitis (CPD) on the differentiation, activation, and secretion of osteoclast-maturing mediators of macrophages. METHODS: A total of 40 saliva samples were collected from healthy donors (n=20) and severe periodontitis patients (n=20). Peripheral blood mononuclear cells (PBMCs) and THP-1 monocyte line cells were challenged with 15% saliva for 5 days. The phenotype, surface marker, and phagocytosis of macrophages were analyzed by flow cytometry and microscopy. Osteoclast-maturing mediators were assayed by using enzyme-linked immunosorbent assay (ELISA) kits. RESULTS: When PBMCs were treated with CPD saliva for 5 days, 61.25%±11.33% of cells were transformed into large granular cells; 86.78%±13.69% of large granular cells were identified as CD14⁺⁺CD16⁺ macrophages. When THP-1 cells were treated with CPD saliva, most cells attached to the bottom of cell culture plates, thereby exhibiting macrophage morphology and releasing additional osteoclast-maturing mediators. Furthermore, the phagocytosis of THP-1 cells considerably increased in the presence of CPD saliva (66.35%±9.67%) compared with medium control (33.33%±7.52%), or healthy saliva (40.71%±3.52%). CONCLUSIONS: Saliva from patients with CPD can induce macrophage differentiation, activate phagocytose microorganisms, and secrete osteoclast-maturing mediators.


Assuntos
Leucócitos Mononucleares , Macrófagos , Periodontite , Saliva , Diferenciação Celular , Humanos , Monócitos , Periodontite/imunologia
12.
Opt Express ; 26(18): 22793-22800, 2018 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-30184934

RESUMO

Quantum key distribution with polarized qubits has not yet been realized over the aerial fiber, due to rapid polarization changes. Here, we report our recent work towards quantum communication through an aerial fiber channel. We designed a fast polarization feedback module featuring high efficiency, fast speed, and good stability. With this module, we implemented long-distance quantum key distribution over different types of aerial fiber links based on polarization encoding. Our work takes a significant step towards the application of quantum communications in complex environments.

13.
Front Pharmacol ; 9: 575, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29946255

RESUMO

Venous thromboembolism (VTE) is highly prevalent in patients with cancer. Non-vitamin K antagonist oral anticoagulants (NOACs), directly targeting the enzymatic activity of thrombin or factor Xa, have been shown to be as effective as and safer than traditional anticoagulation for VTE prophylaxis in no-cancer patients. However, related studies that focused on the anticoagulation in cancer patients are lacked, and almost no net clinical benefit (NCB) analyses that quantified both VTE events and bleeding events have been addressed in this fragile population. Therefore, we aim to investigate this issue using a systematic review and NCB analysis. A comprehensive search of Medline, Embase, and Cochrane Library were performed for randomized controlled trials (RCTs) that reported the VTE events and major bleeding of NOACs and traditional anticoagulants in patients with or without cancer. Odds ratios (ORs) and 95% confidence intervals (CIs) of VTE and bleeding events were calculated using a random-effects model. The primacy outcome of narrow NCB was calculated by pooling ORs of VTE and major bleeding, with a weighting of 1.0. Similarly, the broad NCB was calculated by pooling ORs of VTE and clinically relevant bleeding. Heterogeneity was assessed through I2 test and Q statistic, and subgroup analyses were performed on the basis of different patients (VTE patients or acutely ill patients), comparators (vitamin-K antagonists or low-molecular-weight heparin), and follow-up duration (≤6 months or >6 months). Overall, 9 RCTs including 41,454 patients were enrolled, of which 2,902 (7%) were cancer patients, and 38,552 (93%) were no-cancer patients; 20,712 (50%) were administrated with NOACs and 20,742 (50%) were administrated with traditional anticoagulants. The use of NOACs had a superior NCB than traditional anticoagulation in both cancer patients (OR: 0.68, 95%CI: 0.50-0.85 for narrow NCB; OR: 0.76, 95%CI: 0.61-0.91 for broad NCB) and no-cancer patients (OR: 0.75, 95%CI: 0.54-0.96 for narrow NCB; OR: 0.85, 95%CI: 0.67-1.04 for broad NCB), with the estimates mainly from VTE patients receiving long-term warfarin treatment. In conclusion, NOACs may represent a better NCB property compared to traditional anticoagulants in cancer patients who need long-term anticoagulation treatment.

14.
J Affect Disord ; 234: 305-310, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29587166

RESUMO

BACKGROUND: Immune activation and suppression in patients with major depressive disorders (MDD) have been both reported in different studies. We assume that these findings may indicate innate immunological tolerance in MDD, with subclinical elevated level of proinflammatory cytokines and the decrease in innate immune response while encountering pathogens. METHODS: Peripheral monocytes of 50 untreated patients with MDD and 40 healthy controls were isolated and cultured, with or without 10 ng/ml lipopolysacchride (LPS) for 6 h (6 h, LPS+/-), and with LPS for 18 h (18, LPS+). The cell culture supernatants were collected to measure concentrations of tumor necrosis factor-alpha (TNF-α), interleukin 6 (IL-6), and interleukin 1 beta (IL-1ß). RESULTS: The baseline concentrations of IL-6 and IL-1ß (6 h, LPS-) were significantly higher in the MDD group than those in the control group. There was no significant difference of TNF-α between the two groups. The fold changes of LPS-induced secretion of IL-6 and TNF-α from monocytes cultured for 6 and 18 h were all lower in the patient groups, and that was true for IL-1ß as monocytes cultured for 18 h. LIMITATIONS: Given the gap between the results of in vitro experiments and the actual response that happens in vivo when the immune system encounters pathogens from the external world, future research should include in vivo methods to test the results of the current study. CONCLUSIONS: Patients with MDD may have subclinical inflammation during a depressive episode, and the reduced response to LPS in monocytes indicates innate immunological tolerance.


Assuntos
Citocinas/metabolismo , Transtorno Depressivo Maior/metabolismo , Monócitos/metabolismo , Adolescente , Adulto , Células Cultivadas , Feminino , Voluntários Saudáveis , Humanos , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Lipopolissacarídeos , Masculino , Pessoa de Meia-Idade , Fator de Necrose Tumoral alfa/metabolismo , Adulto Jovem
15.
Oncol Rep ; 39(1): 264-270, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29115632

RESUMO

Despite increasing advances in the diagnosis and treatment for pancreatic cancer, the mortality rate remains high world-wide. There is an urgent need for new therapies to improve survival and quality of life for pancreatic cancer patient. Epigenetic therapeutic agents such as 5-Aza­CdR and suberoylanilide hydroxamic acid (SAHA) have shown therapeutic effects for human cancers. We evaluated the efficacy of 5-Aza­CdR or SAHA and their combination as potential therapies for pancreatic cancer in vitro. Treatment with 5-Aza­CdR or SAHA inhibited pancreatic cancer cell proliferation, migration and induced cell arrest. However, 5-Aza­CdR alone can not induce cell apoptosis. Combination of the two agents enhanced the proliferation and migration inhibition, and induced more cells to G2 arrest and increased the cell apoptosis proportion. Furthermore, combination treatment with SAHA and 5-Aza­CdR significantly increased expression of TP53 and P16. The possible mechanism might be that the two agents inhibited the PI3K/AKT/PTEN signaling pathway. In conclusion, these data demonstrate a potential role for epigenetic modifier drugs for the management of pancreatic cancer.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Azacitidina/análogos & derivados , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Ácidos Hidroxâmicos/farmacologia , Neoplasias Pancreáticas/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Azacitidina/farmacologia , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Inibidor p16 de Quinase Dependente de Ciclina/genética , Decitabina , Sinergismo Farmacológico , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/genética , Transdução de Sinais/efeitos dos fármacos , Proteína Supressora de Tumor p53/genética , Regulação para Cima , Vorinostat
16.
Asian Pac J Cancer Prev ; 18(10): 2891-2891, 2017 10 27.
Artigo em Inglês | MEDLINE | ID: mdl-29127950

RESUMO

Retraction: Retracted: siRNA mediated silencing of NIN1/RPN12 binding protein 1 homolog inhibits proliferation and growth of breast cancer cells Asian Pacific Journal of Cancer Prevention has retracted the article titled "siRNA mediated silencing of NIN1/RPN12 binding protein 1 homolog inhibits proliferation and growth of breast cancer cells"(1) for reason of similarity with a series of articles identified by Byrne and Labbé (2). 1. Huang WY1, Chen DH, Ning L, Wang LW. siRNA mediated silencing of NIN1/RPN12 binding protein 1 homolog inhibits proliferation and growth of breast cancer cells. Asian Pac J Cancer Prev. 2012;13(5):1823-7. 2. J. A. Byrne and C. Labbé, "Striking similarities between publications from China describing single gene knockdown experiments in human cancer cell lines," Scientometrics, vol. 110, no. 3, pp. 1471­1493, 2017. Authors did not respond to request for comment.

17.
Front Microbiol ; 8: 1251, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28725220

RESUMO

An endophytic fungus, Mycosphaerella nawae ZJLQ129, was isolated from the leaves of the traditional Chinese medicine Smilax china. From the fermentation broth and mycelium, a dibenzofurane compound (-)mycousnine (1) was isolated. Chemical modification of it to the amide derivative (-)mycousnine enamine (2), which is new to science, was found to have high and selective immunosuppressive activity: similar to cyclosporin A, (-)mycousnine enamine (2) selectively inhibited T cell proliferation, suppressed the expression of the surface activation antigens CD25 and CD69 and the formation and expression of the cytokines interleukin-2 as well as interferon γ in activated T cells, but did not show any effect on the proliferation of B cells and cancer cells (PANC-1 and A549) and the activation of macrophages. Furthermore, the cytotoxicity of (-)mycousnine enamine was lower than that of cyclosporin A, and its therapeutic index (TC50/EC50) was 4,463.5, which is five-fold higher than that of cyclosporin A. We conclude that (-)mycousnine enamine (2), the semi-synthestic product prepared from the native product (-)mycousnine (1) of the endophyte M. nawae is a novel effective immunosuppressant showing low toxicity and high selectivity.

18.
PLoS One ; 12(5): e0177335, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28489887

RESUMO

AIM: Regorafenib is an oral small-molecule multi kinase inhibitor. Recently, several clinical trials have revealed that regorafenib has an anti-tumor activity in gastric cancer. However, only part of patients benefit from regorafenib, and the mechanisms of regorafenib's anti-tumor effect need further demonstrating. In this study, we would assess the potential anti-tumor effects and the underlying mechanisms of regorafenib in gastric cancer cells, and explore novel biomarkers for patients selecting of regorafenib. METHODS: The anti-tumor effects of regorafenib on gastric cancer cells were analyzed via cell proliferation and invasion. The underlying mechanisms were demonstrated using molecular biology techniques. RESULTS: We found that regorafenib inhibited cell proliferation and invasion at the concentration of 20µmol/L and in a dose dependent manner. The anti-tumor effects of regorafenib related to the decreased expression of CXCR4, and elevated expression and activation of CXCR4 could reverse the inhibition effect of regorafenib on gastric cancer cells. Further studies revealed that regorafenib reduced the transcriptional activity of Wnt/ß-Catenin pathway and led to decreased expression of Wnt pathway target genes, while overexpression and activation of CXCR4 could attenuate the inhibition effect of regorafenib on Wnt/ß-Catenin pathway. CONCLUSIONS: Our findings demonstrated that regorafenib effectively inhibited cell proliferation and invasion of gastric cancer cells via decreasing the expression of CXCR4 and further reducing the transcriptional activity of Wnt/ß-Catenin pathway.


Assuntos
Antineoplásicos/farmacologia , Compostos de Fenilureia/farmacologia , Piridinas/farmacologia , Receptores CXCR4/metabolismo , Neoplasias Gástricas/tratamento farmacológico , Via de Sinalização Wnt/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Mucosa Gástrica/metabolismo , Humanos , Estômago/efeitos dos fármacos , Estômago/patologia , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia
19.
Oncotarget ; 8(20): 33265-33275, 2017 May 16.
Artigo em Inglês | MEDLINE | ID: mdl-28402278

RESUMO

Bile acids (BAs) was critical in the initiation and progression of various tumors. However, their prognostic significance in pancreatic cancer was still illusive. In the present study, the expression and biological significance of FXR, a major receptor of BAs, in the lethal disease were evaluated in mRNA and protein levels. We found that FXR protein was elevated in the cancerous tissues, which was significantly higher than the adjacent tissues (p < 0.05). Meanwhile, our data showed that FXR was positively correlated with primary tumor location (p = 0.04) and poor survival (p = 0.002). Finally, COX regression model indicated that FXR protein was an independent prognostic factor (p = 0.01; HR = 2.15; 95% CI 1.27-3.63). Consistently, we also found a significant difference of FXR expression between the high and low groups in mRNA level (p < 0.001), and that high FXR expression confers a poor prognosis (p < 0.001). More importantly, the correlation assay showed that FXR was positively correlated Sp1 in both protein (r = 0.351, p = 0.008) and mRNA levels (r = 0.263, p < 0.01), with the simultaneously high expression indicated the worst prognosis on protein (p < 0.001) and mRNA levels (p < 0.001). Additionally, we also showed that FXR was elevated in the pancreatic cancer cells responsible for proliferation and migration. Overall, the data suggested co-high expression of the two factors was an independent prognostic factor (p < 0.001; HR = 3.27; 95% CI 1.86-5.76). Based on these data, we proposed a model to link FXR to Sp1, which included triggered FXR, p38/MAPK and/or PI3K/AKT signaling and phosphorylated Sp1, to illustrate the potential crosstalk between the two factors.


Assuntos
Expressão Gênica , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/mortalidade , Receptores Citoplasmáticos e Nucleares/genética , Fator de Transcrição Sp1/genética , Adulto , Idoso , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células , Biologia Computacional/métodos , Bases de Dados Genéticas , Feminino , Perfilação da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Gradação de Tumores , Estadiamento de Neoplasias , Neoplasias Pancreáticas/patologia , Prognóstico , RNA Mensageiro/genética , Receptores Citoplasmáticos e Nucleares/metabolismo , Fator de Transcrição Sp1/metabolismo , Análise Serial de Tecidos
20.
Sci Rep ; 7(1): 470, 2017 03 28.
Artigo em Inglês | MEDLINE | ID: mdl-28352075

RESUMO

Cyclooxygenase-2 (COX-2) was stated to be overexpression in various human malignancies associating with angiogenesis, metastasis and chemoresistence. Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease displaying many of these characteristics. A common abnormality of PDAC is overexpression of specificity protein-1 (Sp1), which was said to correlate with malignant phenotypes of human cancers. Using RNA-seq data from The Cancer Genome Atlas (TCGA), we found that Sp1 expression was positively correlated with that of COX-2 in PDAC, and that the inhibition or overexpression of Sp1 in PDAC cells leads to decreased or elevated COX-2 expression. Luciferase reporter gene and chromatin immunoprecipitation (ChIP) assays revealed that elevated transcription of COX-2 requires Sp1 binding to sequence positions around -245/-240 of COX-2 promoter. Activated epidermal growth factor receptor (EGFR) and downstream p38 mitogen-activated protein kinase (p38-MAPK) were also profoundly altered in PDAC. The inhibition of EGFR/p38-MAPK signaling resulted in reduced Sp1 activation, decreased COX-2 and vascular endothelial growth factor (VEGF) expression. Thus, Sp1 could transcriptionally activate COX-2 expression in a process relies on activated EGFR/p38-MAPK signaling. Finally, we found that the inhibition of COX-2 leads to decreased angiogenesis in a process dependent on VEGF, which link COX-2 to angiogenesis in PDAC.


Assuntos
Ciclo-Oxigenase 2/genética , Regulação Neoplásica da Expressão Gênica , Neovascularização Patológica/genética , Neovascularização Patológica/metabolismo , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Transdução de Sinais , Fator de Transcrição Sp1/metabolismo , Biomarcadores , Linhagem Celular Tumoral , Biologia Computacional/métodos , Ciclo-Oxigenase 2/metabolismo , Receptores ErbB/metabolismo , Genes Reporter , Humanos , Modelos Biológicos , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , Ativação Transcricional , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
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