A surgical model of short bowel syndrome induces a long-lasting increase in pancreatic beta-cell mass

Several surgical techniques are used nowadays as a severe treatment for obesity and diabetes mellitus type 2. These techniques are aggressive due to drastic changes in the nutrient flow and non-reversible modifications on the digestive tube. In this paper we present the effects of a massive intestinal resection on the pancreas. Results have shown that short bowel technique is less aggressive to normal anatomy and physiology of the intestinal tract than Gastric bypass or biliopancreatic diversion (e.g.). In this paper we reproduce a model of short bowel syndrome (SIC), with similar surgical conditions and clinical complications as seen in human cases. This work was conducted on normal Wistar rats, with no other concurrent factors, in order to determine the effects on normal pancreas islets. We measured pancreatic implications by histomorphometric studies, which included beta-cell mass by immunocytochemistry, and apoptosis/proliferation test with TUNEL technique and Ki-67. Briefly, we reported on an increased relative area of the islets of the pancreas, as well as an increase in the average size of islets in the SIC versus the control group. Furthermore we stated that this increase in size of the pancreatic islets is due to the mechanisms of proliferation of beta cells in animals undergoing SIC. These goals could reveal a direct influence of surgical modification of the digestive tract over the pancreatic beta cell homeostasis. In this sense, there are many potential stimulators of intestinal adaptation, including peptide hormones and growth components which are associated or involved as effectors of the endocrine pancreas

Toxicity Induced by Cytokines, Glucose, and Lipids Increase Apoptosis and Hamper Insulin Secretion in the 1.1E7 Beta Cell-Line

Basic research on types 1 and 2 diabetes mellitus require early stage studies using beta cells or cell lines, ideally of human origin and with preserved insulin secretion in response to glucose. The 1.1E7 cells are a hybrid cell line resulting from the electrofusion of dispersed human islets and PANC-1 cells, capable of secreting insulin in response to glucose, but their survival and function under toxic conditions remains untested. This characterization is the purpose of the present study. We treated these cells with a cytokine mix, high glucose, palmitate, and the latter two combined. Under these conditions, we measured cell viability and apoptosis (MTT, Caspase Glo and TUNEL assays, as well as caspase-8 and -9 levels by Western blotting), endoplasmic reticulum stress markers (EIF2AK3, HSPA4, EIF2a, and HSPA5) by real-time PCR, and insulin secretion with a glucose challenge. All of these stimuli (i) induce apoptosis and ER stress markers expression, (ii) reduce mRNA amounts of 2-5 components of genes involved in the insulin secretory pathway, and (iii) abrogate the insulin release capability of 1.1E7 cells in response to glucose. The most pronounced effects were observed with cytokines and with palmitate and high glucose combined. This characterization may well serve as the starting point for those choosing this cell line for future basic research on certain aspects of diabetes.This research was funded by grants by the Andalusian Department of Health (PI 0765-2011 and PI-0269-2014) to A.M.L.-S. A.D.-G. was funded by an intramural grant from the Foundation for Biomedical Research in Cadiz. No external funding for APC was available

Bariatric Surgery Influences beta-Cell Turnover in Non Obese Rats.

Manuscrito en proceso de revisión editorialThe aim of this study was to investigate the different bariatric surgeries relationship with pancreatic beta-cell turnover. We used healthy adult male Wistar rats to undergo the different techniques. We developed three surgical techniques (malabsorptive, Sleeve gastrectomy and Roux-Y Gastric Bypass-), and two control groups (Sham and fasting control). Pancreatic beta-cell mass was measured, as well as apoptosis, proliferation and neogenesis related to cellular turnover. Otherwise, we measured the functional issues to elucidate the physiological role that these surgical techniques trigger in the carbohydrate metabolism (e.g. food intake, weight gain, intraperitoneal glucose tolerance test, and basal glycaemia). Results included the differences that these parameters underwent in each surgical model. The -cell mass presented modifications that were related with proliferation processes. We reported significant increase of -cell mass in the malabsorptive technique. Other while the peripheral resistance to insulin trended to reduce in rats underwent with malabsorptive and mixed techniques. The goal of the present study was to present how different bariatric surgical techniques affected on pancreatic beta-cell turnover. We considered that these implications of surgery over the endocrine pancreas must be one of the mechanisms related to the improvement of type 2 Diabetes mellitus afterward the bariatric surgery.41 paginas, que recogen toda la documentación enviada a consideración editoria

Synergistic DNA-damaging effect in multiple myeloma with the combination of zalypsis, bor tezomib and dexamethasone

Despite new advances in multiple myeloma treatment and the consequent improvement in overall survival, most patients relapse or become refractory to treatment. This suggests that new molecules and combinations that may further inhibit important survival pathways for these tumor cells are needed. In this context, zalypsis is a novel compound, derived from marine organisms, with a powerful preclinical anti-myeloma effect based on the sensitivity of malignant plasma cells to DNA-damage induction; and it has already been tested in a phase I/II clinical trial in multiple myeloma. We hypothesized that the addition of this compound to the combination of bortezomib plus dexamethasone may improve efficacy with acceptable toxicity. The triple combination demonstrated strong synergy and higher efficacy compared with double combinations; not only in vitro, but also ex vivo and, especially, in in vivo experiments. The triple combination triggers cell death, mainly through a synergistic induction of DNA damage and a decrease in the nuclear localization of nuclear factor kappa B. Our findings support the clinical evaluation of this combination for relapsed and refractory myeloma patients.This work was in part funded by the Spanish ISCIII-FIS (PI 15/0067 and PI15/02156) and FEDER, the Spanish RTICC (RD12/0036/0058), "Asociación Española Contra el Cancer" (AECC, GCB120981SAN), the regional Council from “Castilla y León” (GRS 1175/A/15 and FIC335U14) and a research grant from Pharmamar SAU. MMS were also supported by the Network of Centers for Regenerative Medicine and Cellular Therapy from Castilla y León, Spain. A-A López-Iglesias was supported by a grant from the Spanish Society of Hematology and Hemotherapy.Peer Reviewe

A Multimodal Intervention for Prevention of Overweight and Obesity in Schoolchildren. A Protocol Study "PREVIENE-CADIZ"

This paper describes the protocol for a study designed to address the high prevalence (40%) of childhood overweight and obesity in the province of Cadiz, Spain, as a reflection of what is happening worldwide. It is widely known that children who suffer from childhood obesity have a higher risk of developing chronic diseases in adulthood. This causes a decrease in the quality of life and an increase in health spending. In this context, it is necessary to intervene promoting healthy lifestyle habits from an early stage. The objective of this project will be to evaluate the effectiveness of a multimodal intervention (individual, school and family) called "PREVIENE-CaDIZ" [CADIZ-PREVENT]. The intervention will be focused mainly on diet, physical activity, sedentary lifestyle and sleep, to prevent overweight and obesity in schoolchildren from 8 to 9 years old in the province of Cadiz. It will consist of a 10-session education program carried out in the classroom by the teachers. In addition, children will be assigned two workbooks, one to work on in class and the other at home with parents. A workshop aimed at parents will be included to help teach them how to obtain healthier lifestyle habits. The proposed study will involve a quasi-experimental design with a control group

The kinesin spindle protein inhibitor filanesib enhances the activity of pomalidomide and dexamethasone in multiple myeloma

[EN]Kinesin spindle protein inhibition is known to be an effective therapeutic approach in several malignancies. Filanesib (ARRY-520), an inhibitor of this protein, has demonstrated activity in heavily pre-treated multiple myeloma patients. The aim of the work herein was to investigate the activity of filanesib in combination with pomalidomide plus dexamethasone backbone, and the mechanisms underlying the potential synergistic effect. The ability of filanesib to enhance the activity of pomalidomide plus dexamethasone was studied in several in vitro and in vivo models. Mechanisms of this synergistic combination were dissected by gene expression profiling, immunostaining, cell cycle and short interfering ribonucleic acid studies. Filanesib showed in vitro, ex vivo, and in vivo synergy with pomalidomide plus dexamethasone treatment. Importantly, the in vivo synergy observed in this combination was more evident in large, highly proliferative tumors, and was shown to be mediated by the impairment of mitosis transcriptional control, an increase in monopolar spindles, cell cycle arrest and the induction of apoptosis in cells in proliferative phases. In addition, the triple combination increased the activation of the proapoptotic protein BAX, which has previously been associated with sensitivity to filanesib, and could potentially be used as a predictive biomarker of response to this combination. Our results provide preclinical evidence for the potential benefit of the combination of filanesib with pomalidomide and dexamethasone, and supported the initiation of a recently activated trial being conducted by the Spanish Myeloma group which is investigating this combination in relapsed myeloma patients.Array BioPharma, the Spanish ISCIII-FIS and FEDER, the Spanish RTICC, Spanish Association Against Cancer (AECC) and the Regional Council of Castilla y León (Consejería de Medicina y Educación)

Prevención del sobrepeso y la obesidad infantil en escolares de la provincia de Cádiz. Estudio cuasiexperimental de la efectividad de una intervención multicomponente. PREVIENE-CÁDIZ. Informe de resultados.

En el presente documento se muestran los informes de los principales resultados obtenidos de la evaluación de los escolares participantes en el proyecto "Prevención del sobrepeso y la obesidad infantil en escolares de la provincia de Cádiz. Estudio cuasiexperimental de la efectividad de una intervención multicomponente. PREVIENE-CÁDIZ", mostrándose la comparativa entre el global de la muestra del estudio y segmentando por cada centro escolar participante, con el objetivo de que los centros escolares que han participado en el estudio puedan comprobar el estado de salud en el que se encuentran sus estudiantes con respecto al total de la provincia de Cádiz. De esta forma cada centro puede comprobar en qué aspectos (alimentación, actividad física, sedentarismo y/o descanso) deben hacer hincapié para mejorar el estado de salud de los estudiantes, tanto actuales como futuros.European ITI project PI-0007-2017477 página

Somatic NLRP3 mosaicism in Muckle-Wells syndrome. A genetic mechanism shared by different phenotypes of cryopyrin-associated periodic syndromes

Familial cold autoinflammatory syndrome, Muckle-Wells syndrome (MWS), and chronic, infantile, neurological, cutaneous and articular (CINCA) syndrome are dominantly inherited autoinflammatory diseases associated to gain-of-function NLRP3 mutations and included in the cryopyrin-associated periodic syndromes (CAPS). A variable degree of somatic NLRP3 mosaicism has been detected in ≈35% of patients with CINCA. However, no data are currently available regarding the relevance of this mechanism in other CAPS phenotypes. OBJECTIVE: To evaluate somatic NLRP3 mosaicism as the disease-causing mechanism in patients with clinical CAPS phenotypes other than CINCA and NLRP3 mutation-negative. METHODS: NLRP3 analyses were performed by Sanger sequencing and by massively parallel sequencing. Apoptosis-associated Speck-like protein containing a CARD (ASC)-dependent nuclear factor kappa-light chain-enhancer of activated B cells (NF-κB) activation and transfection-induced THP-1 cell death assays determined the functional consequences of the detected variants. RESULTS: A variable degree (5.5-34.9%) of somatic NLRP3 mosaicism was detected in 12.5% of enrolled patients, all of them with a MWS phenotype. Six different missense variants, three novel (p.D303A, p.K355T and p.L411F), were identified. Bioinformatics and functional analyses confirmed that they were disease-causing, gain-of-function NLRP3 mutations. All patients treated with anti-interleukin1 drugs showed long-lasting positive responses. CONCLUSIONS: We herein show somatic NLRP3 mosaicism underlying MWS, probably representing a shared genetic mechanism in CAPS not restricted to CINCA syndrome. The data here described allowed definitive diagnoses of these patients, which had serious implications for gaining access to anti-interleukin 1 treatments under legal indication and for genetic counselling. The detection of somatic mosaicism is difficult when using conventional methods. Potential candidates should benefit from the use of modern genetic tool

Distribución de materia seca, área foliar y calidad nutricional en dos genotipos de Clitoria ternatea L.

Objective: To evaluate dry matter distribution, leaf area and nutritional quality in two Clitoria ternatea L. genotypes. Materials and Methods: The plants, 30 days old, were established in the field in a vertical trellis training system. A complete randomized experimental design was applied, with thirty replications per genotype and one plant as experimental unit. Ninety days after the experiment was established, growth and nutritional quality variables were evaluated in the blue and white genotypes of C. ternatea. Results: The genotype affected (p < 0,05) the growth and nutritional quality variables, except for the percentages of dry matter, ash, crude fiber, and total digestible nutrients. The blue genotype showed higher dry matter content per plant, leaf/stem ratio, leaf area, crude protein and ethereal extract percentages. The white genotype showed higher percentages of nitrogen-free extract, neutral detergent fiber, acid detergent fiber and acid detergent lignin. Both genotypes had high percentages of dry matter, crude protein and total digestible nutrients, as well as excellent relative forage value. Dry matter intake potential was excellent in the blue genotype, and high in the white genotype. Conclusions: Growth and yield of the genotypes were different; while dry matter distribution was similar, mainly in the leaves. The blue genotype stood out for its higher vegetative growth (leaves, branches and stem). The white genotype stood out for fruit and flower production. The bromatological composition and nutritional quality of both genotypes were excellent

Decrease in Beta -Cell Proliferation Precedes Apoptosis during Diabetes Development in Bio-Breeding/ Worcester Rat: Beneficial Role of Exendin-4

In autoimmune type 1 diabetes mellitus, proinflammatory cytokine-mediated apoptosis of beta-cells has been considered to be the first event directly responsible for beta-cell mass reduction. In the Bio-Breeding (BB) rat, an in vivo model used in the study of autoimmune diabetes, beta-cell apoptosis is observed from 9 wk of age and takes place after an insulitis period that begins at an earlier age. Previous studies by our group have shown an antiproliferative effect of proinflammatory cytokines on cultured beta-cells in Wistar rats, an effect that was partially reversed by Exendin-4, an analogue of glucagon-like peptide-1. In the current study, the changes in beta-cell apoptosis and proliferation during insulitis stage were also determined in pancreatic tissue sections in normal and thymectomized BB rats, as well as in Wistar rats of 5, 7, 9, and 11 wk of age. Although stable beta-cell proliferation in Wistar and thymectomized BB rats was observed along the course of the study, a decrease in beta-cell proliferation and beta-cell mass from the age of 5 wk, and prior to the commencement of apoptosis, was noted in BB rats. Exendin-4, in combination with anti-interferon-gamma antibody, induced a near-total recovery of beta-cell proliferation during the initial stages of insulitis. This highlights the importance of early intervention and, as well, the possibilities of new therapeutic approaches in preventing autoimmune diabetes by acting, initially, in the insulitis stage and, subsequently, on beta-cell regeneration and on beta-cell apoptosis