Melatonin controls cell proliferation and modulates mitochondrial physiology in pancreatic stellate cells

We have investigated the effects of melatonin on major pathways related with cellular proliferation and energetic metabolism in pancreatic stellate cells. In the presence of melatonin (1 mM, 100 µM, 10 µM, or 1 µM), decreases in the phosphorylation of c-Jun N-terminal kinase and of p44/42 and an increase in the phosphorylation of p38 were observed. Cell viability dropped in the presence of melatonin. A rise in the phosphorylation of AMP-activated protein kinase was detected in the presence of 1 mM and 100 µM melatonin. Treatment with 1 mM melatonin decreased the phosphorylation of protein kinase B, whereas 100 µM and 10 µM melatonin increased its phosphorylation. An increase in the generation of mitochondrial reactive oxygen species and a decrease of mitochondrial membrane potential were noted following melatonin treatment. Basal and maximal respiration, ATP production by oxidative phosphorylation, spare capacity, and proton leak dropped in the presence of melatonin. The expression of complex I of the mitochondrial respiratory chain was augmented in the presence of melatonin. Conversely, in the presence of 1 mM melatonin, decreases in the expression of mitofusins 1 and 2 were detected. The glycolysis and the glycolytic capacity were diminished in cells treated with 1 mM or 100 µM melatonin. Increases in the expression of phosphofructokinase-1 and lactate dehydrogenase were noted in cells incubated with 100 µM, 10 µM, or 1 µM melatonin. The expression of glucose transporter 1 was increased in cells incubated with 10 µM or 1 µM melatonin. Conversely, 1 mM melatonin decreased the expression of all three proteins. Our results suggest that melatonin, at pharmacological concentrations, might modulate mitochondrial physiology and energy metabolism in addition to major pathways involved in pancreatic stellate cell proliferation. (AU)

Melatonin controls cell proliferation and modulates mitochondrial physiology in pancreatic stellate cells.

We have investigated the effects of melatonin on major pathways related with cellular proliferation and energetic metabolism in pancreatic stellate cells. In the presence of melatonin (1 mM, 100 µM, 10 µM, or 1 µM), decreases in the phosphorylation of c-Jun N-terminal kinase and of p44/42 and an increase in the phosphorylation of p38 were observed. Cell viability dropped in the presence of melatonin. A rise in the phosphorylation of AMP-activated protein kinase was detected in the presence of 1 mM and 100 µM melatonin. Treatment with 1 mM melatonin decreased the phosphorylation of protein kinase B, whereas 100 µM and 10 µM melatonin increased its phosphorylation. An increase in the generation of mitochondrial reactive oxygen species and a decrease of mitochondrial membrane potential were noted following melatonin treatment. Basal and maximal respiration, ATP production by oxidative phosphorylation, spare capacity, and proton leak dropped in the presence of melatonin. The expression of complex I of the mitochondrial respiratory chain was augmented in the presence of melatonin. Conversely, in the presence of 1 mM melatonin, decreases in the expression of mitofusins 1 and 2 were detected. The glycolysis and the glycolytic capacity were diminished in cells treated with 1 mM or 100 µM melatonin. Increases in the expression of phosphofructokinase-1 and lactate dehydrogenase were noted in cells incubated with 100 µM, 10 µM, or 1 µM melatonin. The expression of glucose transporter 1 was increased in cells incubated with 10 µM or 1 µM melatonin. Conversely, 1 mM melatonin decreased the expression of all three proteins. Our results suggest that melatonin, at pharmacological concentrations, might modulate mitochondrial physiology and energy metabolism in addition to major pathways involved in pancreatic stellate cell proliferation.

Ultra-short celiac disease exhibits differential genetic and immunophenotypic features compared to conventional celiac disease / La enfermedad celiaca ultra corta presenta una expresión genética e inmunológica distinta a la de la enfermedad celiaca convencional

Background: Ultra-short coeliac disease (USCD) is a novel celiac disease (CD) subtype limited to the duodenal bulb (D1). HLA haplotypes and flow cytometry have not been assessed yet. Aims: To compare genetic, clinical, serologic, histopathologic and inmmunophenotypic parameters between USCD and conventional celiac disease (CCD) patients. Methods: Prospective single-center study in children and adult patients undergoing duodenal biopsies on a gluten-containing diet. Biopsies for histology and flow cytometry were taken separately from D1 and distal duodenum. Biopsies in seronegative patients with celiac lymphogram were repeated after 2 years on a gluten-free diet. Results: Among 505 included patients, 127 were diagnosed with CD, of whom 7 (5.5%) showed USCD. HLADQ2 was significantly less common in USCD compared to CCD (71% vs. 95%, p 0.003). Likewise, USCD patients showed more frequent non-significant seronegativity (28% vs. 8%, p 0.07) and significantly lower titrations (7–15IU/ml) of tissue transglutaminase antibodies (tTG-IgA) (60% vs. 13%, p<0.001). Biopsies from D1 revealed significant less NK cells down-expression in USCD patients (1.4 vs. 5, p 0.04). Conclusions: Up to 5.5% of CD patients showed USCD. A lower frequency of HLADQ2, along with less serum tTG-IgA titration and duodenal NK cell suppression, were differential features of USCD.(AU)

Antecedentes: La enfermedad celiaca ultracorta (ECUC) es un nuevo fenotipo de la enfermedad celiaca, que afecta exclusivamente al bulbo duodenal (D1), cuyas características genéticas e inmunológicas no han sido descritas. Objetivos: Comparar las características genéticas, clínicas, serológicas, histológicas e inmunológicas entre ECUC y enfermedad celiaca convencional (ECC). Métodos: Estudio prospectivo, unicéntrico, en el que se realizaron biopsias duodenales a pacientes adultos y pediátricos que seguían una dieta con gluten. Se realizó análisis histológico y por citometría de flujo por separado de duodeno distal y D1. En pacientes seronegativos con histología o linfograma concordante con EC, se repitió la biopsia tras 2 años con dieta sin gluten. Resultados: Se incluyeron 505 pacientes, siendo diagnosticados 127 de enfermedad celiaca, de los cuales 7 (5,5%) tenían ECUC. Los pacientes con ECUC expresaron el haplotipo DQ2 con menor frecuencia que en la ECC (71% vs. 95%, p 0,003) y presentaron mayor seronegatividad (28% vs. 8%, p 0,07) y, de manera significativa, titulaciones bajas de anticuerpos antitransglutaminasa (7-15IU/ml) (60% vs. 13%, p < 0,001). Comparado con la ECC, la citometría de flujo en las biopsias bulbares reveló una reducción atenuada significativa de células NK (1,4 vs. 5, p 0,04) en pacientes con ECUC. Conclusiones: Un 5,5% de los pacientes celiacos presentaron ECUC. Comparada con la ECC, las características diferenciales de la ECUC son menor expresión de HLADQ2, títulos más bajos de anticuerpos antitranglutaminasa y menor supresión de células NK a nivel bulbar.(AU)

Ultra-short celiac disease exhibits differential genetic and immunophenotypic features compared to conventional celiac disease.

BACKGROUND: Ultra-short coeliac disease (USCD) is a novel celiac disease (CD) subtype limited to the duodenal bulb (D1). HLA haplotypes and flow cytometry have not been assessed yet. AIMS: To compare genetic, clinical, serologic, histopathologic and inmmunophenotypic parameters between USCD and conventional celiac disease (CCD) patients. METHODS: Prospective single-center study in children and adult patients undergoing duodenal biopsies on a gluten-containing diet. Biopsies for histology and flow cytometry were taken separately from D1 and distal duodenum. Biopsies in seronegative patients with celiac lymphogram were repeated after 2 years on a gluten-free diet. RESULTS: Among 505 included patients, 127 were diagnosed with CD, of whom 7 (5.5%) showed USCD. HLADQ2 was significantly less common in USCD compared to CCD (71% vs. 95%, p 0.003). Likewise, USCD patients showed more frequent non-significant seronegativity (28% vs. 8%, p 0.07) and significantly lower titrations (7-15IU/ml) of tissue transglutaminase antibodies (tTG-IgA) (60% vs. 13%, p<0.001). Biopsies from D1 revealed significant less NK cells down-expression in USCD patients (1.4 vs. 5, p 0.04). CONCLUSIONS: Up to 5.5% of CD patients showed USCD. A lower frequency of HLADQ2, along with less serum tTG-IgA titration and duodenal NK cell suppression, were differential features of USCD.

Lymphocytic esophagitis: A rare finding in adult patients with dysphagia and food impaction / Esofagitis linfocítica: una observación poco frecuente en pacientes adultos con disfagia e impactación alimentaria

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Step-up empiric elimination diet for pediatric and adult eosinophilic esophagitis: The 2-4-6 study.

BACKGROUND: Numerous dietary restrictions and endoscopies limit the implementation of empiric elimination diets in patients with eosinophilic esophagitis (EoE). Milk and wheat/gluten are the most common food triggers. OBJECTIVE: We sought to assess the effectiveness of a step-up dietary strategy for EoE. METHODS: We performed a prospective study conducted in 14 centers. Patients underwent a 6-week 2-food-group elimination diet (TFGED; milk and gluten-containing cereals). Remission was defined by symptom improvement and less than 15 eosinophils/high-power field. Nonresponders were gradually offered a 4-food-group elimination diet (FFGED; TFGED plus egg and legumes) and a 6-food-group elimination diet (SFGED; FFGED plus nuts and fish/seafood). In responders eliminated food groups were reintroduced individually, followed by endoscopy. RESULTS: One hundred thirty patients (25 pediatric patients) were enrolled, with 97 completing all phases of the study. A TFGED achieved EoE remission in 56 (43%) patients, with no differences between ages. Food triggers in TFGED responders were milk (52%), gluten-containing grains (16%), and both (28%). EoE induced only by milk was present in 18% and 33% of adults and children, respectively. Remission rates with FFGEDs and SFGEDs were 60% and 79%, with increasing food triggers, especially after an SFGED. Overall, 55 (91.6%) of 60 of the TFGED/FFGED responders had 1 or 2 food triggers. Compared with the initial SFGED, a step-up strategy reduced endoscopic procedures and diagnostic process time by 20%. CONCLUSIONS: A TFGED diet achieves EoE remission in 43% of children and adults. A step-up approach results in early identification of a majority of responders to an empiric diet with few food triggers, avoiding unnecessary dietary restrictions, saving endoscopies, and shortening the diagnostic process.

Proton pump inhibitor-responsive esophageal eosinophilia: still a valid diagnosis?

PURPOSE OF REVIEW: To update rapidly evolving concepts regarding the controversial entity of 'proton pump inhibitor (PPI)-responsive esophageal eosinophilia,' referring to patients with clinical, endoscopic and histologic features of eosinophilic esophagitis (EoE) who achieve remission on PPI therapy. RECENT FINDINGS: Up to half of pediatric and adult patients with typical EoE symptoms and histology achieve clinico-pathologic remission on PPI therapy, irrespective of whether esophageal pH monitoring demonstrates abnormal acid reflux. In patients with clinical and histologic features of EoE, genotypic and phenotypic features of PPI responders and nonresponders are virtually indistinguishable, and different from those of patients with gastroesophageal reflux disease. In PPI responders, PPIs effects on esophageal Th2 inflammation and gene expression are similar to those of topical steroids in PPI nonresponders. These therapies, along with diets, recently have been shown to be potentially interchangeable in two small series. SUMMARY: Proton pump inhibitor-responsive esophageal eosinophilia is an inappropriate disease descriptor, arbitrarily based on a response to a single drug, and should be abandoned. Patients who have esophageal eosinophilia and esophageal symptoms that resolve with PPI therapy have phenotypic, molecular, mechanistic, and therapeutic features indistinguishable from similar patients who do not respond to PPIs. These patients with PPI responsiveness should be considered within the spectrum of EoE.