RESUMO
SUMMARY OBJECTIVE: Obesity is a chronic multisystem disease associated with increased morbidity and mortality. Obesity, which is a complex, multifactorial, and heterogeneous condition, is thought to result from the interaction of environmental, physiological, and genetic factors. In this study, the relationship between serum levels of hemoglobin A1c, mucin-1, and nuclear factor κB in obese and healthy cohorts was evaluated along with biochemical and gene expressions and with demographic and clinical covariates, and their effects on obesity were evaluated. METHODS: This case-control study included a total of 80 individuals, 40 healthy controls and 40 obesity patients, consisting of female and male aged between 18 and 63 years. Hemoglobin A1c, mucin-1, and nuclear factor κB levels were determined by ELISA in serum samples obtained from patients. In addition, aspartate aminotransferase, alanine transaminase, low density lipoprotein, and glucose values were measured. The gene expressions of the same markers were analyzed by quantitative real-time polymerase chain reaction, and their regulation status was defined. RESULTS: Serum levels of hemoglobin A1c, mucin-1, and nuclear factor κB were found to be high in obese individuals (p<0.05). The gene expression of these serum markers was found to be upregulated. Of the anthropometric measurements, waist circumference and body mass index were correlated with both serum markers and gene expressions (p<0.05). CONCLUSION: In addition to the known association of hemoglobin A1c and nuclear factor κB with obesity, serum levels of mucin-1 as well as upregulation of genes point to its modifier effect on obesity. These parameters can be the powerful markers in the diagnosis of obesity.
RESUMO
SUMMARY OBJECTIVE: Breast cancer is the most common malignancy in women. In the treatment of these patients, pathological complete response is defined as the absence of invasive cancer in breast or lymph node tissue after the completion of neoadjuvant chemotherapy. In this study, we aimed to investigate the relationship of enhancer of zeste homolog 2 and mucin 1 expressions with pathological complete response in patients with breast cancer receiving neoadjuvant chemotherapy. METHODS: A total of 151 patients were included in the study. Enhancer of zeste homolog 2 and mucin 1 expressions were evaluated in the biopsy materials pre-neoadjuvant chemotherapy and post-neoadjuvant chemotherapy surgical material, and their relationship with pathological complete response was investigated. RESULTS: The pathological complete response rates were significantly higher among the hormone receptor-negative patients, those with a high Ki-67 score, and patients with HER2-positive. Higher pathological complete response rates were obtained from patients with enhancer of zeste homolog 2 expression positivity pre-neoadjuvant chemotherapy. In addition, after neoadjuvant chemotherapy, enhancer of zeste homolog 2 expression was found to be completely negative in materials with pathological complete response; that is, in breast tissues considered to be tumor-free. While there was no significant relationship between mucin 1 expression and pathological complete response pre-neoadjuvant chemotherapy, mucin 1 expression was determined to significantly differ between the tissues with and without pathological complete response among the surgical materials examined. CONCLUSION: In our study investigating the relationship between enhancer of zeste homolog 2 and mucin 1 expression and pathological complete response in patients who received neoadjuvant chemotherapy, we found that enhancer of zeste homolog 2 expression could be used as a predictive marker for pathological complete response. However, mucin 1 expression was not associated with pathological complete response.
RESUMO
Typical enteroaggregative Escherichia coli (tEAEC) is a diarrheagenic E. coli pathotype associated with pediatric and traveler's diarrhea. Even without diarrhea, EAEC infections in children also lead to increased gut inflammation and growth shortfalls. EAEC strain's defining phenotype is the aggregative adherence pattern on epithelial cells attributable to the aggregative adherence fimbriae (AAF). EAEC only causes diarrhea in humans; therefore, not much is known of the exact intestinal region of infection and damage or its interactions with intestinal enterocytes in vivo and in situ. This study aimed to develop a new tEAEC mouse model of infection, characterize the microbiota of infected mice, and evaluate in situ the expression of host adherence and surface molecules triggering EAEC infection and the role of the EAEC AAF-II in adherence. Six-week-old C57BL/6 mice, without previous antibiotic treatment, were orally challenged with EAEC 042 strain or EAEC 042 AAF-II mutant (ΔAAF/II) strain, or DAEC-MXR strain (diffusely adherent E. coli clinical isolate), and with saline solution (control group). Paraffin sections of the colon and ileum were stained with H&E and periodic acid-Schiff. ZO-1, ß-catenin, MUC1, and bacteria were analyzed by immunofluorescence. EAEC-infected mice, in comparison with DAEC-MXR-infected and control mice, significantly lost weight during the first 3 days. After 7 days post-infection, mucus production was increased in the colon and ileum, ZO-1 localization remained unaltered, and morphological alterations were more pronounced in the ileum since increased expression and apical localization of ß-catenin in ileal enterocytes were observed. EAEC-infected mice developed dysbiosis 21 days post-infection. At 4 days post-infection, EAEC strain 042 formed a biofilm on ileal villi and increased the expression and apical localization of ß-catenin in ileal enterocytes; these effects were not seen in animals infected with the 042 ΔAAF/II strain. At 3 days post-infection, MUC1 expression on ileal enterocytes was mainly detectable among infected mice and colocalized with 042 strains on the enterocyte surface. We developed a novel mouse model of EAEC infection, which mimics human infection, not an illness, revealing that EAEC 042 exerts its pathogenic effects in the mouse ileum and causes dysbiosis. This model is a unique tool to unveil early molecular mechanisms of EAEC infection in vivo and in situ.
Assuntos
Infecções por Escherichia coli , Íleo , Microbiota , Mucina-1 , beta Catenina , Adesinas de Escherichia coli/genética , Animais , Aderência Bacteriana/genética , Diarreia/microbiologia , Modelos Animais de Doenças , Disbiose , Escherichia coli/genética , Escherichia coli/metabolismo , Infecções por Escherichia coli/microbiologia , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Mucina-1/genética , Muco/metabolismo , Viagem , beta Catenina/genéticaRESUMO
Genetic variants are considered risk factors for gastric cancer. To date, 61 polymorphisms have been identified as associated with this disease. The aim of the present study was to analyze the association of some of those polymorphisms with GC in Chile. We performed a case-control study including 310 gastric cancer cases and 311 controls to assess the association of 36 single-nucleotide polymorphisms genotyped by Global Screening Array (GSA). Three polymorphisms was significantly associated: PSCA rs2294008 (allele model, OR = 1.49, 95%CI 1.17-1.88, P = 1.08 × 10-3), IL-4 rs2243250 (allele model, OR = 1.28, 95%CI 1.01-1.62, P = 0.04), and MUC1 rs4072037 (allele model, OR = 0.78, 95%CI 0.61-0.99, P = 0.04).PSCA rs2294008, IL-4 rs2243250 and MUC1 rs4072037 are associated with gastric cancer in Chile. It suggests that those polymorphisms could be used as biomarkers to assess the genetic risk for this cancer outside of the previously studied populations, not only for East Asians and Caucasians populations.
Assuntos
Antígenos de Neoplasias/genética , Predisposição Genética para Doença/genética , Interleucina-4/genética , Mucina-1/genética , Proteínas de Neoplasias/genética , Polimorfismo de Nucleotídeo Único , Neoplasias Gástricas/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Estudos de Casos e Controles , Chile , Feminino , Proteínas Ligadas por GPI/genética , Frequência do Gene , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Adulto JovemRESUMO
The synthesis of MUC1 glycopeptides bearing modified tumor-associated carbohydrate antigens (TACAs) represents an effective strategy to develop potential antitumor vaccines that trigger strong immune response. In this context, we present herein the multistep synthesis of the triazole glycosyl amino acid Neu5Ac-α/ß2-triazole-6-ßGalNAc-ThrOH 1 as STn antigen analog, along with its assembly on the corresponding MUC1 peptide to give NAcProAsp [Neu5Acα/ß2-triazole-6-ßGalNAc]ThrArgProGlyOH 2. Despite interacting differently with SM3 monoclonal antibody, as shown by molecular dynamic simulations, this unnatural triazole glycopeptide may represent a promising candidate for cancer immunotherapy.
Assuntos
Antígenos Glicosídicos Associados a Tumores/química , Glicopeptídeos/química , Glicopeptídeos/síntese química , Mucina-1/química , Triazóis/química , Técnicas de Química SintéticaRESUMO
Hypokalemic periodic paralysis type 1 (OMIM; HOKPP1) and type 2 (OMIM; HOKPP2) are diseases of the muscle characterized by episodes of painless muscle weakness, and is associated with low potassium blood levels. Hyperthyroidism has been associated with thyrotoxic periodic paralysis (TTPP) (OMIM; TTPP1 and TTPP2), and genetic susceptibility has been implicated. In the present study, the clinical and epidemiological characteristics of patients with TTPP are described, together with their association with genetic variants reported previously in other populations. A prospective and a retrospective search of the medical records of patients who attended the emergency department at the Hospital Universitario 'Dr. Jose E. Gonzalez' in Monterrey, Nuevo León, Mexico, and were diagnosed with TTPP was performed. A total of 16 gene variants in the genes MUC1, CACNA1S, KCNE3 and SCN4A, and nine ancestry informative markers (AIMs), were analysed by Multiplex TaqMan™ Open Array assay, and a genetic association study was performed. A total of 11 patients were recruited, comprising nine males and two females (age range, 19-52 years) and 64 control subjects. Only two cases (18%) had a previous diagnosis of hyperthyroidism; the rest were diagnosed subsequently with Graves' disease. Based on the analysis, two DNA variants were found to potentially confer an increased risk for TTPP: S1PR1 rs3737576 [odds ratio (OR), 4.38; 95% confidence interval (CI), 1.08-17.76] and AIM rs2330442 (OR, 4.50; 95% CI, 1.21-16.69), and one variant was suggested to be possibly associated with TTPP, namely MUC1 rs4072037 (OR, 3.08; 95% CI, 0.841-1.38). However, there were no statistically significant associations between any of the 24 DNA variants and TTPP in a population from northeast Mexico.
RESUMO
OBJECTIVES: Xerostomia in SS patients has been associated with low quality and quantity of salivary mucins, which are fundamental for the hydration and protection of the oral mucosa. The aim of this study was to evaluate if cytokines induce aberrant mucin expression and whether tauroursodeoxycholic acid (TUDCA) is able to counteract such an anomaly. METHODS: Labial salivary glands from 16 SS patients and 15 control subjects, as well as 3D acini or human submandibular gland cells stimulated with TNF-α or IFN-γ and co-incubated with TUDCA, were analysed. mRNA and protein levels of Mucin 1 (MUC1) and MUC7 were determined by RT-qPCR and western blot, respectively. Co-immunoprecipitation and immunofluorescence assays for mucins and GRP78 [an endoplasmic reticulum (ER)-resident protein] were also performed. mRNA levels of RelA/p65 (nuclear factor-κB subunit), TNF-α, IL-1ß, IL-6, SEL1L and EDEM1 were determined by RT-qPCR, and RelA/p65 localization was evaluated by immunofluorescence. RESULTS: MUC1 is overexpressed and accumulated in the ER of labial salivary gland from SS patients, while MUC7 accumulates throughout the cytoplasm of acinar cells; however, MUC1, but not MUC7, co-precipitated with GRP78. TUDCA diminished the overexpression and aberrant accumulation of MUC1 induced by TNF-α and IFN-γ, as well as the nuclear translocation of RelA/p65, together with the expression of inflammatory and ER stress markers in 3D acini. CONCLUSION: Chronic inflammation alters the secretory process of MUC1, inducing ER stress and affecting the quality of saliva in SS patients. TUDCA showed anti-inflammatory properties decreasing aberrant MUC1 accumulation. Further studies are necessary to evaluate the potential therapeutic effect of TUDCA in restoring glandular homeostasis in SS patients.
Assuntos
Células Acinares/efeitos dos fármacos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Mucina-1/efeitos dos fármacos , Glândulas Salivares Menores/efeitos dos fármacos , Síndrome de Sjogren/metabolismo , Glândula Submandibular/efeitos dos fármacos , Ácido Tauroquenodesoxicólico/farmacologia , Xerostomia/metabolismo , Células Acinares/metabolismo , Adulto , Idoso , Estudos de Casos e Controles , Células Cultivadas , Chaperona BiP do Retículo Endoplasmático , Estresse do Retículo Endoplasmático/genética , Feminino , Proteínas de Choque Térmico/efeitos dos fármacos , Proteínas de Choque Térmico/genética , Proteínas de Choque Térmico/metabolismo , Humanos , Imunoprecipitação , Técnicas In Vitro , Interferon gama/farmacologia , Interleucina-1beta/efeitos dos fármacos , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Masculino , Proteínas de Membrana/efeitos dos fármacos , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Pessoa de Meia-Idade , Mucina-1/genética , Mucina-1/metabolismo , Mucinas/efeitos dos fármacos , Mucinas/genética , Mucinas/metabolismo , Proteínas/efeitos dos fármacos , Proteínas/genética , Proteínas/metabolismo , RNA Mensageiro/efeitos dos fármacos , RNA Mensageiro/metabolismo , Glândulas Salivares Menores/metabolismo , Proteínas e Peptídeos Salivares/efeitos dos fármacos , Proteínas e Peptídeos Salivares/genética , Proteínas e Peptídeos Salivares/metabolismo , Síndrome de Sjogren/genética , Glândula Submandibular/citologia , Glândula Submandibular/metabolismo , Fator de Transcrição RelA/efeitos dos fármacos , Fator de Transcrição RelA/genética , Fator de Transcrição RelA/metabolismo , Fator de Necrose Tumoral alfa/efeitos dos fármacos , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo , Fator de Necrose Tumoral alfa/farmacologia , Xerostomia/genéticaRESUMO
El adenocarcinoma NOS (no especificado de otra manera) es un tumor salival sin patrón especial poco mencionado en la literatura; su diagnóstico es un desafío porque estructuralmente no se identifica con otros carcinomas salivales más definidos. Por otro lado, Ki67 es un marcador de proliferación celular que brinda información pronóstica de las neoplasias. En cuanto a la mucina humana transmembrana MUC-1 se sobre-expresa en las neoplasias malignas perdiendo su localización exclusivamente apical. Presentamos dos casos de adenocarcinoma NOS diagnosticados con H/E y correlacionamos la expresión de Ki67 y la localización y sobreexpresión de MUC-1 con su grado histológico y pronóstico. Cortes histológicos de dos adenocarcinomas NOS de parótida en mujeres de 62 y 63 años respectivamente se colorearon con H/E e inmunomarcaron para Ki67 y MUC-1. En ambos tumores predominaban estructuras ductales, algunas quísticas, cordones celulares ramificados e islotes sólidos. Las formaciones glandulares presentaban células claras y algunas de aspecto oncocítico. Había importante atipia celular, comedonecrosis, invasión perineural, áreas hemorrágicas y compromiso de los márgenes quirúrgicos. La marcación nuclear con Ki67 fue importante; MUC-1 presentó una fuerte coloración en membranas y citoplasmas. Las dos lesiones se diagnosticaron como de alto grado de malignidad. Nuestros resultados demuestran que existe una importante proliferación marcada con Ki67 y una sobre-expresión de MUC-1 asociadas a atipia celular, infiltración perineural, necrosis y compromiso de márgenes quirúrgicos, factores asociados a un peor pronóstico. El reconocimiento de este tumor es trascendente para médicos y odontólogos ya que por la ausencia de rasgos distintivos que sí presentan otros carcinomas más específicos es fundamental el diagnóstico de exclusión.
Adenocarcinoma NOS (not otherwise specified) is a no special pattern salivary tumor briefly mentioned in the literature; its diagnosis is a challenge because structurally it is not identified with other more definite salivary carcinomas. On the other hand, Ki67 is a marker of cellular proliferation that provides prognostic information of neoplasms. As for human transmembrane mucin, MUC-1 is overexpressed in malignant neoplasms, losing their exclusively apical location. We present two cases of adenocarcinoma NOS diagnosed with H/E and correlate the expression of Ki67 and the location and over-expression of MUC-1 with its histological grade and prognosis. Histological sections of two NOS adenocarcinomas of parotid in women of 62 and 63 ages respectively were stained with H/E and immunolabelled for Ki67 and MUC-1. Both are predominated by ductal structures, some cystic, branched cell cords and solid islets. The glandular formations presented clear cells and some of oncocytic appearance. There was important cellular atypia, comedonecrosis, perineural growth, haemorrhagic areas and compromise of surgical margins. Nuclear marking with Ki67 was important; MUC-1 presented a strong staining in membranes and cytoplasms. They were diagnosed as high-grade malignancy. Our results show that there is an important proliferation marked with Ki67 and overexpression of MUC-1 associated with cellular atypia, perineural growth, necrosis and compromise of surgical margins, factorsassociated with a poor prognosis. The recognition of this tumor is transcendent for physicians and dentists since, due to the absence of distinctive features that other more specific carcinomas present, the diagnosis of exclusion is essential.
Assuntos
Humanos , Feminino , Pessoa de Meia-Idade , Neoplasias Parotídeas/diagnóstico , Neoplasias Parotídeas/metabolismo , Neoplasias Parotídeas/patologia , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Prognóstico , Neoplasias das Glândulas Salivares , Imuno-Histoquímica , Adenocarcinoma/diagnóstico , Biomarcadores Tumorais , Mucina-1/metabolismo , Antígeno Ki-67/metabolismo , Proliferação de CélulasRESUMO
BACKGROUND: Proteins overexpressed in malignant tissues form important targets in the development of targeted therapeutics, and aptamers comprise an important affinity agent for therapy and drug delivery. In this study, aberrantly expressed mucin 1 glycoprotein was investigated as a therapeutic target in a breast cancer model. MATERIALS AND METHODS: In order to determine the feasibility of using an aptamer against mucin 1 (aptA) as carrier of the cytotoxic compound 1,10-phenanthroline to MCF-7 cells, as a potential radiosensitizer, was studied in experiments using circular dichroism and rhodamine labelling by fluorescent microscopy and flow cytometry. RESULTS: 1,10-Phenanthroline can be intercalated within aptA when complexed with Fe(II) ions, with dissociation constant (Kd) of 30 µM. The complex was subsequently capable of binding to and being internalised in MCF-7 breast cancer cells. CONCLUSION: aptA can carry 1,10-phenanthroline to cancer cells specifically and this complex represents a potential target-directed anticancer therapy.
Assuntos
Aptâmeros de Nucleotídeos/metabolismo , Neoplasias da Mama/metabolismo , Portadores de Fármacos , Endocitose , Mucina-1/metabolismo , Fenantrolinas/metabolismo , Radiossensibilizantes/metabolismo , Aptâmeros de Nucleotídeos/química , Aptâmeros de Nucleotídeos/genética , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Neoplasias da Mama/radioterapia , Estudos de Viabilidade , Feminino , Compostos Ferrosos/química , Humanos , Células MCF-7 , Mucina-1/genética , Fenantrolinas/química , Fenantrolinas/farmacologia , Radiossensibilizantes/farmacologiaRESUMO
Enteroaggregative Escherichia coli (EAEC) is a recognized cause of acute diarrhea among both children and adults worldwide. EAEC strains are characterized by the presence of aggregative adherence fimbriae (AAF), which play a key role in pathogenesis by mediating attachment to the intestinal mucosa and by triggering host inflammatory responses. The aggregative adherence fimbria II (AAF/II) is the most important adherence factor of EAEC prototype strain 042 (EAEC042) to intestinal cells. Multiple receptors for AAF/II on epithelial cells have been identified including the transmembrane signaling mucin Muc1. This protocol describes a method to measure adherence of EAEC strains to HEK293 cells expressing the Muc1 glycoprotein.