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1.
Clin Psychopharmacol Neurosci ; 17(4): 487-494, 2019 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-31671485

RESUMO

Objective: Loneliness is a specific risk factor for depressive symptoms and suicidal behavior. The present study examined whether the serum oxytocin level would interact with social support and buffers loneliness and hypothalamic-pituitary-adrenal (HPA)-axis activity in drug-naïve patients with major depressive disorder (MDD). Methods: Twenty-six patients with MDD (male:female = 3:23; mean age, 45.54 ± 12.97 years) were recruited. The 17-item Hamilton Depression Rating Scale, UCLA Loneliness Scale and self-reported Measurement of Support Function Questionnaire were administered. Serum oxytocin and cortisol levels were assessed using a commercial immunoassay kits. Results: In MDD patients, a negative association was found between degrees of social support and loneliness (ß= -0.39, p = 0.04). The interaction between social support and serum oxytocin level was negatively associated with loneliness (ß= -0.50, p = 0.017) and serum cortisol level (ß= -0.55, p = 0.020) after adjusting for age. Follow-up analyses showed that the association between higher social support and lower loneliness was observed only in the higher-oxytocin group (r = -0.75, p = 0.003) but not in the lower group (r = -0.19, p = 0.53). The significance remained after further adjusting for sex and depression severity. Conclusion: Low oxytocin level is a vulnerability factor for the buffering effect of social support for loneliness and aberrant HPA-axis activity in MDD patients.

2.
Am J Physiol Gastrointest Liver Physiol ; 317(6): G763-G772, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31545922

RESUMO

Pancreatic ductal adenocarcinoma (PDAC)'s growing incidence has been linked to the rise in obesity and type 2 diabetes mellitus. In previous work, we have shown that metformin can prevent the increased incidence of PDAC in a KrasG12D mouse model subjected to a diet high in fat and calories (HFCD). One potential way that metformin can affect the host is through alterations in the gut microbiome. Therefore, we investigated microbial associations with PDAC development and metformin use in the same mouse model. Lox-Stop-Lox Kras G12D/+ (LSL-Kras G12D/+); p48-Cre (KC) mice were given control diet, HFCD, or HFCD with 5 mg/mL metformin in drinking water for 3 mo. At the end of the 3 mo, 16S rRNA sequencing was performed to characterize microbiome composition of duodenal mucosal, duodenal luminal, and cecal luminal samples. KC mice on an HFCD demonstrated depletion of intact acini and formation of advanced pancreatic intraepithelial neoplasia. This effect was completely abrogated by metformin treatment. HFCD was associated with significant changes in microbial composition and diversity in the duodenal mucosa and lumen, much of which was prevented by metformin. In particular, Clostridium sensu stricto was negatively correlated with percent intact acini and seemed to be inhibited by the addition of metformin while on an HFCD. Administration of metformin eliminated PDAC formation in KC mice. This change was associated with significant microbial changes in both the mucosal and luminal microbiome of the duodenum. This suggests that the microbiome may be a potential mediator of the chemopreventive effects of metformin.NEW & NOTEWORTHY Pancreatic ductal adenocarcinoma (PDAC)'s growing incidence has been linked to the rise in obesity and type 2 diabetes mellitus. Administration of metformin eliminated PDAC formation in KC mice with diet-induced obesity. This change was associated with significant microbial changes in both the mucosal and luminal microbiome of the duodenum. This suggests that the microbiome may be a potential mediator of the chemopreventive effects of metformin.

3.
Oncogene ; 38(38): 6550-6565, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31363162

RESUMO

Gastrointestinal stromal tumors (GISTs) are frequently driven by auto-activated, mutant KIT and have durable response to KIT tyrosine kinase inhibitor. However, acquired resistance is an increasing clinical issue in GIST patients receiving front-line imatinib therapy. Our previous studies showed the colocalization of KIT with DAPI-stained nuclei in GIST cells without knowing the role of nuclear KIT in GIST tumorigenesis. In this article, we first identified the binding of nuclear KIT to the promoter of NFKB inhibitor beta (NFKBIB) by chromatin immunoprecipitation (ChIP) sequencing and ChIP assays, which was accompanied with enhanced NFKBIB protein expression in GIST cells. Clinically, high NCCN risk GISTs had significantly higher mean expression levels of nuclear phospho-KIT and NFKBIB as compared with those of intermediate or low/very low-risk GISTs. Conversely, downregulation of NFKBIB by siRNA led to RELA nuclear translocation that could bind to the KIT promoter region and subsequently reduced KIT transcription/expression and the viability of GIST cells. These findings were further confirmed by either RELA overexpression or NFKB/RELA inducer, valproic acid, treatment to result in reduced KIT expression and relative cell viability of imatinib-resistant GIST cells. Combining valproic acid with imatinib showed significantly better growth inhibitory effects on imatinib-resistant GIST48 and GIST430 cells in vitro, and in the GIST430 animal xenograft model. Taken together, these results demonstrate the existence of a nuclear KIT-driven NFKBIB-RELA-KIT autoregulatory loop in GIST tumorigenesis, which are potential targets for developing combination therapy to overcome imatinib-resistant of KIT-expressing GISTs.


Assuntos
Resistencia a Medicamentos Antineoplásicos , Neoplasias Gastrointestinais , Tumores do Estroma Gastrointestinal , Proteínas I-kappa B/metabolismo , Mesilato de Imatinib/uso terapêutico , Proteínas Proto-Oncogênicas c-kit/fisiologia , Fator de Transcrição RelA/metabolismo , Animais , Células COS , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Retroalimentação Fisiológica/efeitos dos fármacos , Retroalimentação Fisiológica/fisiologia , Neoplasias Gastrointestinais/tratamento farmacológico , Neoplasias Gastrointestinais/genética , Neoplasias Gastrointestinais/metabolismo , Neoplasias Gastrointestinais/patologia , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Tumores do Estroma Gastrointestinal/genética , Tumores do Estroma Gastrointestinal/metabolismo , Tumores do Estroma Gastrointestinal/patologia , Homeostase/efeitos dos fármacos , Homeostase/genética , Humanos , Mesilato de Imatinib/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Proteínas Proto-Oncogênicas c-kit/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/genética
4.
Cells ; 8(7)2019 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-31277269

RESUMO

Pancreatic ductal adenocarcinoma (PDAC) is expected to soon become the second leading cause of cancer related deaths in the United States. This may be due to the rising obesity prevalence, which is a recognized risk factor for PDAC. There is great interest in deciphering the underlying driving mechanisms of the obesity-PDAC link. Visceral adiposity has a strong correlation to certain metabolic diseases and gastrointestinal cancers, including PDAC. In fact, our own data strongly suggest that visceral adipose tissue inflammation is a strong promoter for PDAC growth and progression in a genetically engineered mouse model of PDAC and diet-induced obesity. In this review, we will discuss the relationship between obesity-associated adipose tissue inflammation and PDAC development, with a focus on the key molecular and cellular components in the dysfunctional visceral adipose tissue, which provides a tumor permissive environment.


Assuntos
Adiposidade/imunologia , Carcinoma Ductal Pancreático/imunologia , Inflamação/imunologia , Obesidade/imunologia , Neoplasias Pancreáticas/imunologia , Animais , Carcinoma Ductal Pancreático/metabolismo , Modelos Animais de Doenças , Humanos , Inflamação/metabolismo , Gordura Intra-Abdominal/imunologia , Gordura Intra-Abdominal/metabolismo , Camundongos , Obesidade/complicações , Obesidade/metabolismo , Neoplasias Pancreáticas/metabolismo , Fatores de Risco
5.
PLoS One ; 14(5): e0216603, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31100067

RESUMO

We examined the impact of statins on Yes-associated Protein (YAP) localization, phosphorylation and transcriptional activity in human and mouse pancreatic ductal adenocarcinoma (PDAC) cells. Exposure of sparse cultures of PANC-1 and MiaPaCa-2 cells to cerivastatin or simvastatin induced a striking re-localization of YAP from the nucleus to the cytoplasm and inhibited the expression of the YAP/TEAD-regulated genes Connective Tissue Growth Factor (CTGF) and Cysteine-rich angiogenic inducer 61 (CYR61). Statins also prevented YAP nuclear import and expression of CTGF and CYR61 stimulated by the mitogenic combination of insulin and neurotensin in dense culture of these PDAC cells. Cerivastatin, simvastatin, atorvastatin and fluvastatin also inhibited colony formation by PANC-1 and MiaPaCa-2 cells in a dose-dependent manner. In contrast, the hydrophilic statin pravastatin did not exert any inhibitory effect even at a high concentration (10 µM). Mechanistically, cerivastatin did not alter the phosphorylation of YAP at Ser127 in either PANC-1 or MiaPaCa-2 cells incubated without or with neurotensin and insulin but blunted the assembly of actin stress fiber in these cells. We extended these findings with human PDAC cells using primary KC and KPC cells, (expressing KrasG12D or both KrasG12D and mutant p53, respectively) isolated from KC or KPC mice. Using cultures of these murine cells, we show that lipophilic statins induced striking YAP translocation from the nucleus to the cytoplasm, inhibited the expression of Ctgf, Cyr61 and Birc5 and profoundly inhibited colony formation of these cells. Administration of simvastatin to KC mice subjected to diet-induced obesity prevented early pancreatic acini depletion and PanIN formation. Collectively, our results show that lipophilic statins restrain YAP activity and proliferation in pancreatic cancer cell models in vitro and attenuates early lesions leading to PDAC in vivo.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/antagonistas & inibidores , Carcinoma Ductal Pancreático/prevenção & controle , Núcleo Celular/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Neoplasias Pancreáticas/prevenção & controle , Proteínas Proto-Oncogênicas p21(ras)/genética , Fatores de Transcrição/antagonistas & inibidores , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patologia , Proliferação de Células , Ensaio de Unidades Formadoras de Colônias , Humanos , Camundongos , Mutação , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Fosforilação , Transporte Proteico , Fatores de Transcrição/metabolismo , Células Tumorais Cultivadas
6.
Int J Mol Sci ; 20(7)2019 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-30959948

RESUMO

Insulin-sensitizer treatment with metformin is widely used in polycystic ovary syndrome (PCOS). However, the treatment effectiveness shows individual differences in PCOS patients. Organic cation transporter (OCT) 1 and 2 have been reported to mediate metformin transport in the liver and kidney, respectively. In this study, we investigated the association between the polymorphisms of OCT1 and OCT2 and the treatment effectiveness of metformin in PCOS patients. The single nucleotide polymorphisms (SNPs) of OCT1 (rs683369 and rs628031) and OCT2 (rs316019) were analyzed in 87 PCOS and 113 control women. Oral glucose tolerance tests (OGTTs), which represented metformin treatment response, were conducted at the start of treatment and after six-month treatment. The results demonstrated that the SNP frequencies of OCT1 and OCT2 were not associated with PCOS pathophysiology, and that the polymorphisms of OCT1 and OCT2 were not associated with the OGTT parameters at baseline. However, PCOS patients with the G allele of OCT1 rs683369 and/or with the A allele of OCT1 rs628031 had increased insulin sensitivity compared to those with wild-type genotype after receiving metformin treatment. Moreover, the interactions of metformin*SNP were significant in both OCT1 rs683369 (p < 0.001) and rs628031 (p = 0.001) during the treatment period. Taken together, genetic polymorphisms of OCT1 contributed to different metformin treatment responses, and further study is needed to establish personalized treatment programs using a pharmacogenomic algorithm approach in PCOS patients.


Assuntos
Metformina/uso terapêutico , Transportador 1 de Cátions Orgânicos/genética , Transportador 1 de Cátions Orgânicos/metabolismo , Síndrome do Ovário Policístico/tratamento farmacológico , Síndrome do Ovário Policístico/genética , Polimorfismo de Nucleotídeo Único/genética , Adulto , Alelos , Feminino , Genótipo , Teste de Tolerância a Glucose , Humanos , Hipoglicemiantes/uso terapêutico , Resistência à Insulina , Masculino , Transportador 2 de Cátion Orgânico/genética , Estudos Prospectivos
7.
BMC Cancer ; 18(1): 797, 2018 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-30086728

RESUMO

BACKGROUND: Hormone sensitive lipase (HSL) is a neutral lipase that preferentially catalyzes the hydrolysis of diacylglycerol contributing to triacylglycerol breakdown in the adipose tissue. HSL has been implicated to play a role in tumor cachexia, a debilitating syndrome characterized by progressive loss of adipose tissue. Consequently, pharmacological inhibitors of HSL have been proposed for the treatment of cancer-associated cachexia. In the present study we used the conditional KrasG12D (KC) mouse model of pancreatic ductal adenocarcinoma (PDAC) with a deficiency in HSL to determine the impact of HSL suppression on the development of PDAC. METHODS: KC;Hsl+/+ and KC;Hsl-/- mice were fed standard rodent chow for 20 weeks. At sacrifice, the incidence of PDAC was determined and inflammation in the mesenteric adipose tissue and pancreas was assessed histologically and by immunofluorescence. To determine statistical significance, ANOVA and two-tailed Student's t-tests were performed. To compare PDAC incidence, a two-sided Fisher's exact test was used. RESULTS: Compared to KC;Hsl+/+ mice, KC;Hsl-/- mice gained similar weight and displayed adipose tissue and pancreatic inflammation. In addition, KC;Hsl-/- mice had reduced levels of plasma insulin and leptin. Importantly, the increased adipose tissue and pancreatic inflammation was associated with a significant increase in PDAC incidence in KC;Hsl-/- mice. CONCLUSIONS: HSL deficiency is associated with adipose tissue and pancreatic inflammation and accelerates PDAC development in the KC mouse model.


Assuntos
Neoplasias Pancreáticas , Esterol Esterase , Animais , Feminino , Inflamação/metabolismo , Inflamação/patologia , Masculino , Camundongos , Camundongos Transgênicos , Pâncreas/metabolismo , Pâncreas/patologia , Neoplasias Pancreáticas/enzimologia , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Esterol Esterase/deficiência , Esterol Esterase/genética , Esterol Esterase/metabolismo
8.
Psychiatry Res ; 268: 28-33, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29986174

RESUMO

The aim of this study was to examine the metabolic parameters, including body mass index (BMI), homeostasis model assessment-estimated insulin resistance (HOMA-IR), homeostasis model assessment-estimated pancreatic ß-cell function (HOMA-ß), and lipid plasma level, in medicated patients with major depressive disorder (MDD) and to assess factors related to metabolic parameters in patients with MDD. 121 patients with MDD and 63 controls were recruited. The Hamilton Depression Rating Scale (HDRS), Wisconsin Card Sorting Test (WCST), Continuous Performance Test (CPT), and Finger-Tapping Test (FTT), were administered. BMI, HOMA-IR, and HOMA-ß were calculated as modifiable metabolic parameters. The FTT results and BMI in depressed patients were significantly poorer and lower, respectively, than those of the controls. However, no significant differences were noted between MDD patients and controls included metabolic parameters and other neuropsychological tests. Among depressed patients, higher BMI is significantly related with lower education, no tobacco use, and male. The result demonstrated metabolic parameters could be neutral among medicated patients with MDD, particularly in non-elderly Asian individuals. The deficits of psychomotor speed could be more prominent than other cognitive alterations in patient with MDD.


Assuntos
Antidepressivos/uso terapêutico , Índice de Massa Corporal , Transtorno Depressivo Maior/metabolismo , Transtorno Depressivo Maior/psicologia , Testes Neuropsicológicos , Adulto , Idoso , Transtorno Depressivo Maior/tratamento farmacológico , Feminino , Humanos , Resistência à Insulina/fisiologia , Masculino , Pessoa de Meia-Idade , Fatores de Risco
9.
Front Immunol ; 9: 1229, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29977235

RESUMO

The combined/synergistic effect of genetic mutation of KRAS in the pancreas and obesity, a life-style factor on suppression of natural killer (NK) cells at the pre-neoplastic stage of pancreatic cancer has not been investigated and is the subject of this report. Obese mice with KRAS (KC) mutation in the pancreas fed with high-fat calorie diet (HFCD) exhibit severe deficiencies in the NK cell expansion and function at the pre-neoplastic stage of pancreatic cancer. Decreased NK cell-mediated cytotoxicity is observed in the peripheral blood, spleen, pancreas, and peri-pancreatic adipose tissue in obese KC mice, whereas in bone marrow an increased NK cell-mediated cytotoxicity is observed when compared to lean WT mice fed with control diet (CD). Obese KC mice on HFCD demonstrated the least ability to expand NK cells or induce NK cell-mediated cytotoxicity when compared to the other groups of mice. Indeed, the following profile WT/CD > WT/HFCD > KC/CD > KC/HFCD was seen for the ability to expand NK cells or mediate cytotoxicity among four groups of mice in spleen, peripheral blood, pancreas, and peri-pancreatic adipose tissue. Sorted NK cells from the splenocytes of four groups of mice also exhibited the same profiles for the cytotoxicity as the unsorted splenocytes, and a decreased IFN-γ secretion could be seen in cultures of NK cells from KC mice fed with either CD or HFCD. Cultures of NK cells with autologous monocytes from obese KC mice fed with HFCD exhibited decreased cytotoxicity and IFN-γ secretion, whereas cultures of allogeneic NK cells from WT mice fed with CD with osteoclasts of obese mice fed with HFCD demonstrated decreased cytotoxicity but augmented IFN-γ secretion. Increased IL-6 along with decreased IFN-γ and cell-mediated cytotoxicity by the NK cells, within NK-adipose tissue of KC/HFCD mice, may provide safe microenvironment for the expansion of pancreatic tumors.


Assuntos
Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Mutação , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Lesões Pré-Cancerosas , Proteínas Proto-Oncogênicas p21(ras)/genética , Tecido Adiposo/imunologia , Tecido Adiposo/metabolismo , Animais , Biomarcadores , Citocinas/metabolismo , Citotoxicidade Imunológica , Modelos Animais de Doenças , Imunofenotipagem , Contagem de Leucócitos , Camundongos , Camundongos Knockout , Camundongos Obesos , Osteoclastos/metabolismo , Baço/imunologia , Baço/metabolismo
10.
Int J Neuropsychopharmacol ; 21(4): 319-324, 2018 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-29618013

RESUMO

Background: Patients with bipolar disorder are at high risk of metabolic disturbance after mood stabilizer treatment. However, the mediators linking the two conditions remain unknown. In this study, we investigated whether fibroblast growth factor-21 (FGF21) was associated with metabolic effects and treatment response in depressed bipolar disorder patients. Methods: We recruited 78 community-dwelling controls and 137 bipolar disorder patients; the latter were interviewed using the Chinese Version of the Modified Schedule of Affective Disorder and Schizophrenia-Life Time. Upon study entry, the bipolar disorder patients were all in a major depressive status, with 17-item Hamilton Depression Rating Scale (HDRS) scores >15. They received valproate (500-1000 mg daily) for 12 weeks, and fluoxetine 20 mg daily was permitted to treat depressive symptoms. Fasting plasma level of FGF21, lipid profiles, and body weight were collected at baseline and after 12 weeks of treatment. Results: At baseline, the demographic characteristics, FGF21 level, and metabolic indices did not differ significantly between the controls and bipolar disorder patients. After 12 weeks of treatment, the FGF21 level (167.7±122.0 to 207.1±162.3 pg/mL, P=.001), body weight and waist circumference had increased significantly (P<.001 and P=.028, respectively). Moreover, the change in FGF21 level was significantly correlated with the changes in HDRS score (r=0.393, P=.002), total cholesterol (r=-0.344, P=.008), and low-density lipoprotein (r=-0.347, P=.007). Conclusions: The central and peripheral mediating effects of FGF21 on bipolar disorder depression treatment might be opposite. High peripheral FGF21 levels might link regulation of metabolic effect and resistance to treatment in bipolar disorder.


Assuntos
Antimaníacos/farmacologia , Transtorno Bipolar , Peso Corporal/efeitos dos fármacos , Transtorno Depressivo Maior , Fatores de Crescimento de Fibroblastos/sangue , Fatores de Crescimento de Fibroblastos/efeitos dos fármacos , Inibidores de Captação de Serotonina/farmacologia , Ácido Valproico/farmacologia , Circunferência da Cintura/efeitos dos fármacos , Adulto , Antimaníacos/administração & dosagem , Transtorno Bipolar/sangue , Transtorno Bipolar/tratamento farmacológico , Transtorno Bipolar/fisiopatologia , Transtorno Depressivo Maior/sangue , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Maior/fisiopatologia , Quimioterapia Combinada , Feminino , Fluoxetina/farmacologia , Humanos , Masculino , Pessoa de Meia-Idade , Inibidores de Captação de Serotonina/administração & dosagem , Ácido Valproico/administração & dosagem , Adulto Jovem
11.
Sci Rep ; 8(1): 5899, 2018 04 12.
Artigo em Inglês | MEDLINE | ID: mdl-29651002

RESUMO

Pancreatic ductal adenocarcinoma (PDAC) is a particularly deadly disease. Chronic conditions, including obesity and type-2 diabetes are risk factors, thus making PDAC amenable to preventive strategies. We aimed to characterize the chemo-preventive effects of metformin, a widely used anti-diabetic drug, on PDAC development using the KrasG12D mouse model subjected to a diet high in fats and calories (HFCD). LSL-KrasG12D/+;p48-Cre (KC) mice were given control diet (CD), HFCD, or HFCD with 5 mg/ml metformin in drinking water for 3 or 9 months. After 3 months, metformin prevented HFCD-induced weight gain, hepatic steatosis, depletion of intact acini, formation of advanced PanIN lesions, and stimulation of ERK and mTORC1 in pancreas. In addition to reversing hepatic and pancreatic histopathology, metformin normalized HFCD-induced hyperinsulinemia and hyperleptinemia among the 9-month cohort. Importantly, the HFCD-increased PDAC incidence was completely abrogated by metformin (p < 0.01). The obesogenic diet also induced a marked increase in the expression of TAZ in pancreas, an effect abrogated by metformin. In conclusion, administration of metformin improved the metabolic profile and eliminated the promoting effects of diet-induced obesity on PDAC formation in KC mice. Given the established safety profile of metformin, our findings have a strong translational potential for novel chemo-preventive strategies for PDAC.


Assuntos
Carcinogênese/efeitos dos fármacos , Carcinoma Ductal Pancreático/prevenção & controle , Fígado Gorduroso/prevenção & controle , Hiperinsulinismo/prevenção & controle , Metformina/farmacologia , Obesidade/prevenção & controle , Neoplasias Pancreáticas/prevenção & controle , Administração Oral , Animais , Carcinogênese/genética , Carcinogênese/metabolismo , Carcinogênese/patologia , Carcinoma Ductal Pancreático/etiologia , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patologia , Quimioprevenção/métodos , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Água Potável , Fígado Gorduroso/etiologia , Fígado Gorduroso/genética , Fígado Gorduroso/patologia , Feminino , Regulação da Expressão Gênica , Humanos , Hiperinsulinismo/etiologia , Hiperinsulinismo/genética , Hiperinsulinismo/patologia , Masculino , Alvo Mecanístico do Complexo 1 de Rapamicina/genética , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Camundongos , Camundongos Transgênicos , Proteína Quinase 1 Ativada por Mitógeno/genética , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/genética , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Obesidade/etiologia , Obesidade/genética , Obesidade/patologia , Neoplasias Pancreáticas/etiologia , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Proteínas Proto-Oncogênicas p21(ras)/deficiência , Proteínas Proto-Oncogênicas p21(ras)/genética , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Ganho de Peso/efeitos dos fármacos
12.
Front Immunol ; 8: 1606, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29255459

RESUMO

The aim of our studies is to determine the dynamics of natural killer (NK) cell modulation in gingivae in precancerous and cancerous stages of pancreatic and oral cancers in P48+/Cre;LSL-KRASG12D (KC) mice carrying a pancreas-specific oncogenic Kras mutation and BLT-humanized mice. Wild type and KC mice fed with control diet (CD) or high-fat calorie diet (HFCD), and the pancreatic and oral tumor-bearing humanized BLT (hu-BLT) mice were used to determine precancerous and cancer induced changes in numbers and function of gingival NK cells. Increased numbers of PanIN lesions and the greatest score of inflammation in pancreas of KC mice fed with CD and HFCD co-related with significant decline in percentages of circulating and gingival NK cells, lack of DX5+ NK expansion and increased secretion of IFN-γ and IL-6 after culture. At the malignant stage of pancreatic cancer, hu-BLT tumor-bearing mice had the lowest secretion of IFN-γ from cells dissociated from the gingival tissues as compared to those from non-tumor-bearing mice. Injection of NK cells into tumor-bearing mice increased IFN-γ secretion, and the secretion was similar or higher than those obtained by gingival cells from non-tumor-bearing hu-BLT control mice. The highest increase in IFN-γ secretion was observed when tumor-bearing mice were fed with AJ2 probiotic bacteria and injected with the NK cells. Along with an increase in secretion of IFN-γ, injection of NK cells in the presence and absence of feeding with AJ2 in pancreatic tumor-bearing mice increased percentages of CD45+ and CD3+ T cells in oral gingival cells. Similar results were observed with oral tumors. In conclusion, these results indicated that oral cavity may mirror systemic disease and provide a rationale for why cancer patients may be prone to suffer from diverse oral pathologies.

13.
Oncotarget ; 8(38): 64180-64190, 2017 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-28969061

RESUMO

Rheumatoid arthritis (RA) is one of the most common autoimmune diseases, can lead to long-term joint damage, chronic pain, and loss of motor function in the hands, and may share some common genetic factors with other autoimmune disorders, such as ankylosing spondylitis (AS). Many single-nucleotide polymorphisms (SNPs) were reported by genome-wide association studies (GWASs) of RA, but some of them have not been examined in the Taiwanese population. In this study, for 15 SNPs reported in previous RA and AS GWASs, we investigated their association with RA in a Taiwanese population. Based on 334 RA patients recruited from the Taichung Veterans General Hospital and 16,036 healthy subjects from the Taiwan Biobank (TWB) project, we observed that subjects having minor allele C at rs2841277 (phospholipase D family, member 4 (PLD4)) have lower susceptibility of RA, compare to those having genotype TT (Odds ratio (OR) = 0.6, p = 3.0 × 10-6). Among the RA patients, we observed that subjects having GG at rs4672495 have a lower proportion of severe RA, compare to other subjects (OR = 0.09, p = 5.6 × 10-3). Results of a bioinformatics approach showed that rs2841277 is able to influence expression of LINC00638 and AHNAK2 and rs4672495 is able to influence the expression of B3GNT2. In summary, this study replicated an association of rs2841277 with RA susceptibility and showed an AS-associated SNP, rs4672495, is associated with RA activity in the Taiwanese population.

14.
Psychiatry Res ; 258: 402-406, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28865715

RESUMO

Oxytocin may play a role in mood regulation. Research has shown the plasma oxytocin level of patients with bipolar I disorder (BD I) during a manic episode was significantly higher than that of BD I patients of other statuses, and also that of healthy subjects. However, whether or not a difference in the level of oxytocin exists between patients with major depressive disorder (MDD) and those with BD II is unclear. This study aimed to investigate the plasma oxytocin levels in MDD and BD II patients in a depressive episode. 119 healthy controls, 135 BD II patients, and 97 MDD patients were enrolled. All of the BD II and MDD patients were drug-naïve, with baseline depressive status 17-item Hamilton Depression Rating Scale scores >15. The plasma oxytocin level of the BD II patients was significantly higher than that of the MDD patients and controls at baseline. After treatment, the plasma oxytocin level of the BD II patients increased significantly; however, in the MDD group, the oxytocin level decreased slightly after treatment. Our findings suggested more significant plasma oxytocin dysregulation in the patients in the BD II group than in the MDD patients and controls, both before and after treatment.


Assuntos
Transtorno Bipolar/sangue , Transtorno Depressivo Maior/sangue , Ocitocina/sangue , Adulto , Afeto , Depressão/sangue , Feminino , Humanos , Masculino , Escalas de Graduação Psiquiátrica
15.
PLoS One ; 12(9): e0184455, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28886117

RESUMO

Epidemiologic data has linked obesity to a higher risk of pancreatic cancer, but the underlying mechanisms are poorly understood. To allow for detailed mechanistic studies in a relevant model mimicking diet-induced obesity and pancreatic cancer, a high-fat, high-calorie diet (HFCD) was given to P48+/Cre;LSL-KRASG12D (KC) mice carrying a pancreas-specific oncogenic Kras mutation. The mice were randomly allocated to a HFCD or control diet (CD). Cohorts were sacrificed at 3, 6, and 9 months and tissues were harvested for further analysis. Compared to CD-fed mice, HFCD-fed animals gained significantly more weight. Importantly, the cancer incidence was remarkably increased in HFCD-fed KC mice, particularly in male KC mice. In addition, KC mice fed the HFCD showed more extensive inflammation and fibrosis, and more advanced PanIN lesions in the pancreas, compared to age-matched CD-fed animals. Interestingly, we found that the HFCD reduced autophagic flux in PanIN lesions in KC mice. Further, exome sequencing of isolated murine PanIN lesions identified numerous genetic variants unique to the HFCD. These data underscore the role of sustained inflammation and dysregulated autophagy in diet-induced pancreatic cancer development and suggest that diet-induced genetic alterations may contribute to this process. Our findings provide a better understanding of the mechanisms underlying the obesity-cancer link in males and females, and will facilitate the development of interventions targeting obesity-associated pancreatic cancer.


Assuntos
Dieta Hiperlipídica/efeitos adversos , Ingestão de Energia , Mutação , Neoplasias Pancreáticas/etiologia , Proteínas Proto-Oncogênicas p21(ras)/genética , Substituição de Aminoácidos , Animais , Autofagia/genética , Peso Corporal , Códon , Biologia Computacional/métodos , Modelos Animais de Doenças , Exoma , Matriz Extracelular/metabolismo , Feminino , Fibrose , Variação Genética , Sequenciamento de Nucleotídeos em Larga Escala , Inflamação/etiologia , Inflamação/patologia , Masculino , Camundongos , Neoplasias Pancreáticas/patologia
16.
J Affect Disord ; 221: 151-157, 2017 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-28646711

RESUMO

BACKGROUND: Balance in the immune system plays roles in bipolar disorder (BD) and its metabolic co-morbidities. Memantine is an NMDA receptor antagonist with anti-inflammatory effects. However, the effects of memantine adjunct treatment on metabolic status of BD are unclear. METHODS: During the 12 weeks period, a total of 191 BD patients were enrolled and split into valproate (VPA) + placebo and VPA + memantine (5mg/day) arms. The fasting plasma levels of high-sensitivity C-reactive protein (CRP) and metabolic indices were assessed. BD patients were stratified according to their initial CRP level. RESULTS: A cut-off value of initial CRP level of 2322ng/mL discriminated the waist circumference in these BD patients after 12-week VPA treatment. In the high CRP (> 2322ng/mL) group, patients in the VPA + memantine arm had a significantly decreased in their CRP (p= 0.009), total cholesterol (p= 0.002), LDL (p= 0.002) levels, BMI (p= 0.001), and waist circumference (p< 0.001), compared to those in the VPA + placebo arm. However, analysis of the low CRP group did not showed the effect. LIMITATIONS: We recruited BD patients in depressed states and the sample size was relative small. The effects of the fixed dose of memantine on metabolic indices were 12-week follow up in BD patients treated with VPA. CONCLUSIONS: BD patients with high initial CRP levels receiving memantine adjunct treatment have a reduced risk of inflammation and metabolic imbalance. Prospective studies are needed to confirm the long-term outcome for memantine adjunct therapy in BD patients.


Assuntos
Antimaníacos/farmacologia , Transtorno Bipolar/tratamento farmacológico , Proteína C-Reativa/efeitos dos fármacos , Lipídeos/sangue , Memantina/farmacologia , Adulto , Transtorno Bipolar/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Ácido Valproico/farmacologia
17.
Surgery ; 161(6): 1570-1578, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28222855

RESUMO

BACKGROUND: There is strong evidence linking inflammation and the development of pancreatic ductal adenocarcinoma. Cyclooxygenase-2 (COX-2) and COX-2-derived PGE2 are overexpressed in human and murine pancreatic ductal adenocarcinoma. Several studies have demonstrated an important role of COX-2-derived PGE2 in tumor-stroma interactions; however, the direct growth effects of prostaglandin E2 (PGE2) on pancreatic ductal adenocarcinoma cells is less well defined. Our aim was to investigate the effects of PGE2 on pancreatic ductal adenocarcinoma cell growth and to characterize the underlying mechanisms. METHODS: Human pancreatic ductal adenocarcinoma cell lines, Panc-1 and MIA PaCa-2, were treated with PGE2 in varying doses (0-10 µM). Effects on the phosphorylation of ERK1/2 were evaluated by Western blot. Colony formation was observed for cells treated with PGE2 for 11 days. DNA synthesis was determined by (3H)-thymidine incorporation assay. Gene expression of E-type prostaglandin (EP)2/EP4 receptors and their correlation with survival in patients with pancreatic ductal adenocarcinoma were assessed using the RNA-Seq data set from The Cancer Genome Atlas Research Network. RESULTS: PGE2 decreased the size and number of colonies in Panc-1 but not MIA PaCa-2 cells. In the Panc-1 cells, PGE2 activated PKA/CREB and decreased phosphorylation of ERK1/2, which was reversed by an EP4 receptor antagonist, while an EP2 receptor antagonist had no effect. In contrast, in MIA PaCa-2 cells, PGE2 had no effect on ERK1/2 phosphorylation. Treatment of both Panc-1 and MIA PaCa-2 cells with forskolin/IBMX decreased ERK1/2 phosphorylation. Finally, PGE2 decreased DNA synthesis only in Panc-1 cells, which was reversed by an EP4 receptor antagonist. In human pancreatic ductal adenocarcinoma, high EP2 and low EP4 gene expression was correlated to worse median overall survival (15.6 vs 20.8 months, log-rank P = .017). CONCLUSION: Our study provides evidence that PGE2 can inhibit directly pancreatic ductal adenocarcinoma cell growth through an EP4-mediated mechanism. Together with our gene expression and survival analysis, this observation suggests a protective role of EP4 receptors in human pancreatic ductal adenocarcinoma that expresses E-type prostaglandin receptors.


Assuntos
Linhagem Celular Tumoral/efeitos dos fármacos , Ciclo-Oxigenase 2/metabolismo , Dinoprostona/farmacologia , Receptores de Prostaglandina E Subtipo EP1/genética , Receptores de Prostaglandina E Subtipo EP2/metabolismo , Idoso , Western Blotting , Carcinoma Ductal Pancreático/patologia , Proliferação de Células/efeitos dos fármacos , Ciclo-Oxigenase 2/efeitos dos fármacos , Feminino , Regulação da Expressão Gênica , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/farmacologia , Masculino , Pessoa de Meia-Idade , Pâncreas/citologia , Neoplasias Pancreáticas/patologia , Fosforilação/efeitos dos fármacos , Fosforilação/genética , Receptores de Prostaglandina E Subtipo EP2/efeitos dos fármacos , Receptores de Prostaglandina E Subtipo EP4/efeitos dos fármacos , Receptores de Prostaglandina E Subtipo EP4/metabolismo , Sensibilidade e Especificidade
19.
World J Biol Psychiatry ; 18(1): 63-70, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-26895280

RESUMO

Objectives We aimed to examine whether the C-reactive protein (CRP) level could be used to differentiate between major depressive disorder (MDD) and bipolar II disorder (BD II). Methods Ninety-six healthy controls, 88 BD II and 72 MDD drug-naïve patients in their major depressive episodes were enrolled. The fasting plasma level of high-sensitivity CRP was assessed at baseline and after treatment. Results The BD II patients presented significantly higher 17-item Hamilton Depression Rating Scale (HDRS) scores and CRP levels at baseline when adjustment for age, gender, and body mass index (P < 0.001 and P < 0.001, respectively). After treatment the CRP levels remained significantly different (P < 0.001), although the HDRS score was not significantly different between the BD II and MDD patients. A receiver-operating characteristic analysis showed that a baseline CRP level of 621.6 ng/mL could discriminate between BD II and MDD, with an area under the curve of 0.816 and a sensitivity and specificity of 0.699 and 0.882, respectively. Furthermore, the baseline CRP level greater than 621.6 ng/ml had 28.2 higher odds of a diagnosis of BD II (P < 0.001, 95% confidence interval: 10.96-72.35). Conclusions The level of CRP plays a role of biomarker to differentiate between MDD and BD II depression in both their depressed and euthymic state.


Assuntos
Transtorno Bipolar/sangue , Proteína C-Reativa/análise , Transtorno Depressivo Maior/sangue , Adulto , Biomarcadores/sangue , Transtorno Bipolar/diagnóstico , Estudos de Casos e Controles , Transtorno Depressivo Maior/diagnóstico , Feminino , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Curva ROC , Sensibilidade e Especificidade , Taiwan , Adulto Jovem
20.
Am J Physiol Gastrointest Liver Physiol ; 311(4): G675-G687, 2016 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-27609771

RESUMO

Epidemiological studies support strong links between obesity, diabetes, and pancreatic disorders including pancreatitis and pancreatic adenocarcinoma (PDAC). Type 2 diabetes (T2DM) is associated with insulin resistance, hyperglycemia, and hyperinsulinemia, the latter due to increased insulin secretion by pancreatic beta-cells. We reported that high-fat diet-induced PDAC progression in mice is associated with hyperglycemia, hyperinsulinemia, and activation of pancreatic stellate cells (PaSC). We investigated here the effects of high concentrations of insulin and glucose on mouse and human PaSC growth and fibrosing responses. We found that compared with normal, pancreata from T2DM patients displayed extensive collagen deposition and activated PaSC in islet and peri-islet exocrine pancreas. Mice fed a high-fat diet for up to 12 mo similarly displayed increasing peri-islet fibrosis compared with mice fed control diet. Both quiescent and activated PaSC coexpress insulin (IR; mainly A type) and IGF (IGF-1R) receptors, and both insulin and glucose modulate receptor expression. In cultured PaSC, insulin induced rapid tyrosine autophosphorylation of IR/IGF-1R at specific kinase domain activation loop sites, activated Akt/mTOR/p70S6K signaling, and inactivated FoxO1, a transcription factor that restrains cell growth. Insulin did not promote activation of quiescent PaSC in either 5 mM or 25 mM glucose containing media. However, in activated PaSC, insulin enhanced cell proliferation and augmented production of extracellular matrix proteins, and these effects were abolished by specific inhibition of mTORC1 and mTORC2. In conclusion, our data support the concept that increased local glucose and insulin concentrations associated with obesity and T2DM promote PaSC growth and fibrosing responses.


Assuntos
Proliferação de Células/efeitos dos fármacos , Diabetes Mellitus Tipo 2/patologia , Fibrose/patologia , Glucose/farmacologia , Insulina/farmacologia , Células Estreladas do Pâncreas/efeitos dos fármacos , Animais , Células Cultivadas , Colágeno/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Dieta Hiperlipídica , Feminino , Fibrose/metabolismo , Humanos , Camundongos , Pessoa de Meia-Idade , Pâncreas Exócrino/metabolismo , Pâncreas Exócrino/patologia , Células Estreladas do Pâncreas/metabolismo , Células Estreladas do Pâncreas/patologia , Fosforilação/efeitos dos fármacos , Receptor IGF Tipo 1/metabolismo
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