The glucose transporter GLUT12, a new actor in obesity and cancer.

Obesity constitutes a global health epidemic which worsens the main leading death causes such as type 2 diabetes, cardiovascular diseases, and cancer. Changes in the metabolism in patients with obesity frequently lead to insulin resistance, along with hyperglycemia, dyslipidemia and low-grade inflammation, favoring a more aggressive tumor microenvironment. One of the hallmarks of cancer is the reprogramming of the energy metabolism, in which tumor cells change oxidative phosphorylation to aerobic glycolysis or "Warburg effect". Aerobic glycolysis is faster than oxidative phosphorylation, but less efficient in terms of ATP production. To obtain sufficient ATP, tumor cells increase glucose uptake by the glucose transporters of the GLUT/SLC2 family. The human glucose transporter GLUT12 was isolated from the breast cancer cell line MCF7. It is expressed in adipose tissue, skeletal muscle and small intestine, where insulin promotes its translocation to the plasma membrane. Moreover, GLUT12 over-expression in mice increases the whole-body insulin sensitivity. Thus, GLUT12 has been proposed as a second insulin-responsive glucose transporter. In obesity, GLUT12 is downregulated and does not respond to insulin. In contrast, GLUT12 is overexpressed in human solid tumors such as breast, prostate, gastric, liver and colon. High glucose concentration, insulin, and hypoxia upregulate GLUT12 both in adipocytes and tumor cells. Inhibition of GLUT12 mediated Warburg effect suppresses proliferation, migration, and invasion of cancer cells and xenografted tumors. This review summarizes the up-to-date information about GLUT12 physiological role and its implication in obesity and cancer, opening new perspectives to consider this transporter as a therapeutic target.

Comparative Study of the Effectiveness of Vedolizumab Versus Ustekinumab After Anti-TNF Failure in Crohn's Disease (Versus-CD): Data from the ENEIDA Registry.

BACKGROUND: Both vedolizumab and ustekinumab are approved for the management of Crohn's disease [CD]. Data on which one would be the most beneficial option when anti-tumour necrosis factor [anti-TNF] agents fail are limited. AIMS: To compare the durability, effectiveness, and safety of vedolizumab and ustekinumab after anti-TNF failure or intolerance in CD. METHODS: CD patients from the ENEIDA registry who received vedolizumab or ustekinumab after anti-TNF failure or intolerance were included. Durability and effectiveness were evaluated in both the short and the long term. Effectiveness was defined according to the Harvey-Bradshaw index [HBI]. The safety profile was compared between the two treatments. The propensity score was calculated by the inverse probability weighting method to balance confounder factors. RESULTS: A total of 835 patients from 30 centres were included, 207 treated with vedolizumab and 628 with ustekinumab. Dose intensification was performed in 295 patients. Vedolizumab [vs ustekinumab] was associated with a higher risk of treatment discontinuation (hazard ratio [HR] 2.55, 95% confidence interval [CI]: 2.02-3.21), adjusted by corticosteroids at baseline [HR 1.27; 95% CI: 1.00-1.62], moderate-severe activity in HBI [HR 1.79; 95% CI: 1.20-2.48], and high levels of C-reactive protein at baseline [HR 1.06; 95% CI: 1.02-1.10]. The inverse probability weighting method confirmed these results. Clinical response, remission, and corticosteroid-free clinical remission were higher with ustekinumab than with vedolizumab. Both drugs had a low risk of adverse events with no differences between them. CONCLUSION: In CD patients who have failed anti-TNF agents, ustekinumab seems to be superior to vedolizumab in terms of durability and effectiveness in clinical practice. The safety profile is good and similar for both treatments.

Differential remodeling of subcutaneous white and interscapular brown adipose tissue by long-term exercise training in aged obese female mice.

Obesity exacerbates aging-induced adipose tissue dysfunction. This study aimed to investigate the effects of long-term exercise on inguinal white adipose tissue (iWAT) and interscapular brown adipose tissue (iBAT) of aged obese mice. Two-month-old female mice received a high-fat diet for 4 months. Then, six-month-old diet-induced obese animals were allocated to sedentarism (DIO) or to a long-term treadmill training (DIOEX) up to 18 months of age. In exercised mice, iWAT depot revealed more adaptability, with an increase in the expression of fatty acid oxidation genes (Cpt1a, Acox1), and an amelioration of the inflammatory status, with a favorable modulation of pro/antiinflammatory genes and lower macrophage infiltration. Additionally, iWAT of trained animals showed an increment in the expression of mitochondrial biogenesis (Pgc1a, Tfam, Nrf1), thermogenesis (Ucp1), and beige adipocytes genes (Cd137, Tbx1). In contrast, iBAT of aged obese mice was less responsive to exercise. Indeed, although an increase in functional brown adipocytes genes and proteins (Pgc1a, Prdm16 and UCP1) was observed, few changes were found on inflammation-related and fatty acid metabolism genes. The remodeling of iWAT and iBAT depots occurred along with an improvement in the HOMA index for insulin resistance and in glucose tolerance. In conclusion, long-term exercise effectively prevented the loss of iWAT and iBAT thermogenic properties during aging and obesity. In iWAT, the long-term exercise program also reduced the inflammatory status and stimulated a fat-oxidative gene profile. These exercise-induced adipose tissue adaptations could contribute to the beneficial effects on glucose homeostasis in aged obese mice.

Differential remodeling of subcutaneous white and interscapular brown adipose tissue by long-term exercise training in aged obese female mice

Obesity exacerbates aging-induced adipose tissue dysfunction. This study aimed to investigate the effects of long-term exercise on inguinal white adipose tissue (iWAT) and interscapular brown adipose tissue (iBAT) of aged obese mice. Two-month-old female mice received a high-fat diet for 4 months. Then, six-month-old diet-induced obese animals were allocated to sedentarism (DIO) or to a long-term treadmill training (DIOEX) up to 18 months of age. In exercised mice, iWAT depot revealed more adaptability, with an increase in the expression of fatty acid oxidation genes (Cpt1a, Acox1), and an amelioration of the inflammatory status, with a favorable modulation of pro/antiinflammatory genes and lower macrophage infiltration. Additionally, iWAT of trained animals showed an increment in the expression of mitochondrial biogenesis (Pgc1a, Tfam, Nrf1), thermogenesis (Ucp1), and beige adipocytes genes (Cd137, Tbx1). In contrast, iBAT of aged obese mice was less responsive to exercise. Indeed, although an increase in functional brown adipocytes genes and proteins (Pgc1a, Prdm16 and UCP1) was observed, few changes were found on inflammation-related and fatty acid metabolism genes. The remodeling of iWAT and iBAT depots occurred along with an improvement in the HOMA index for insulin resistance and in glucose tolerance. In conclusion, long-term exercise effectively prevented the loss of iWAT and iBAT thermogenic properties during aging and obesity. In iWAT, the long-term exercise program also reduced the inflammatory status and stimulated a fat-oxidative gene profile. These exercise-induced adipose tissue adaptations could contribute to the beneficial effects on glucose homeostasis in aged obese mice. (AU)

Mesiodens en dentición temporal y mixta: informe de casos / Mesiodens in primary and mixed dentition: case reports

Objetivo: Presentar una serie de casos clínicos de me- siodens en niños con dentición temporal y mixta, su trata- miento y seguimiento. Casos clínicos: Se muestra el manejo clínico de tres casos de mesiodens en dentición temporal y un caso en den- tición mixta, los cuales fueron diagnosticados en un examen radiográfico de rutina (AU)

Aim: To present a series of clinical cases of mesiodens in children with primary and mixed dentition, their treatment and follow-up. Clinical cases: This paper describes the clinical man- agement of three cases of mesiodens in primary dentition and one case in mixed dentition which were diagnosed in routine radiographic examinations (AU)

Changes in brown adipose tissue lipid mediator signatures with aging, obesity, and DHA supplementation in female mice.

Brown adipose tissue (BAT) dysfunction in aging and obesity has been related to chronic unresolved inflammation, which could be mediated by an impaired production of specialized proresolving lipid mediators (SPMs), such as Lipoxins-LXs, Resolvins-Rvs, Protectins-PDs, and Maresins-MaRs. Our aim was to characterize the changes in BAT SPMs signatures and their association with BAT dysfunction during aging, especially under obesogenic conditions, and their modulation by a docosahexaenoic acid (DHA)-rich diet. Lipidomic, functional, and molecular studies were performed in BAT of 2- and 18-month-old lean (CT) female mice and in 18-month-old diet-induced obese (DIO) mice fed with a high-fat diet (HFD), or a DHA-enriched HFD. Aging downregulated Prdm16 and UCP1 levels, especially in DIO mice, while DHA partially restored them. Arachidonic acid (AA)-derived LXs and DHA-derived MaRs and PDs were the most abundant SPMs in BAT of young CT mice. Interestingly, the sum of LXs and of PDs were significantly lower in aged DIO mice compared to young CT mice. Some of the SPMs most significantly reduced in obese-aged mice included LXB4 , MaR2, 4S,14S-diHDHA, 10S,17S-diHDHA (a.k.a. PDX), and RvD6. In contrast, DHA increased DHA-derived SPMs, without modifying LXs. However, MicroPET studies showed that DHA was not able to counteract the impaired cold exposure response in BAT of obese-aged mice. Our data suggest that a defective SPMs production could underlie the decrease of BAT activity observed in obese-aged mice, and highlight the relevance to further characterize the physiological role and therapeutic potential of specific SPMs on BAT development and function.

Secondary school students' perceptions of a mobile application design for smoking prevention.

INTRODUCTION: Our research was based on the BUS model, which provides guidelines for developing mobile applications for health. This model is supported by theories of behavior change, user-centered design, and social marketing. This study aimed to determine secondary school students' perceptions of a mobile application design for smoking prevention. METHODS: In 2018, qualitative research was conducted in three secondary schools located in the central part of the state of Veracruz, Mexico. Focus groups were established to explore beliefs about smoking and mobile phone use. The sketch technique was used to identify the characteristics for the mobile application. RESULTS: The students' perception of smoking allowed us to determine behaviors that can be changed: 1) associating cigarettes with a distraction from problems can be prevented; 2) peer and family pressure as a trigger to starting smoking can be avoided; and 3) tobacco use can be disassociated from being popular. Regarding the design of the mobile application prototype, an entertaining game with levels to help teenagers stay active was proposed. CONCLUSIONS: Games for health can help modify user behavior and even positively influence their values. The final product was the prototype for the 'No le entres' (don't jump in) application. An important finding was that adolescents living in both urban and rural settings use mobile phones similarly.

Effects of Long-Term DHA Supplementation and Physical Exercise on Non-Alcoholic Fatty Liver Development in Obese Aged Female Mice.

Obesity and aging are associated to non-alcoholic fatty liver disease (NAFLD) development. Here, we investigate whether long-term feeding with a docosahexaenoic acid (DHA)-enriched diet and aerobic exercise, alone or in combination, are effective in ameliorating NAFLD in aged obese mice. Two-month-old female C57BL/6J mice received control or high fat diet (HFD) for 4 months. Then, the diet-induced obese (DIO) mice were distributed into four groups: DIO, DIO + DHA (15% dietary lipids replaced by a DHA-rich concentrate), DIO + EX (treadmill running), and DIO + DHA + EX up to 18 months. The DHA-rich diet reduced liver steatosis in DIO mice, decreasing lipogenic genes (Dgat2, Scd1, Srebp1c), and upregulated lipid catabolism genes (Hsl/Acox) expression. A similar pattern was observed in the DIO + EX group. The combination of DHA + exercise potentiated an increase in Cpt1a and Ppara genes, and AMPK activation, key regulators of fatty acid oxidation. Exercise, alone or in combination with DHA, significantly reversed the induction of proinflammatory genes (Mcp1, Il6, Tnfα, Tlr4) in DIO mice. DHA supplementation was effective in preventing the alterations induced by the HFD in endoplasmic reticulum stress-related genes (Ern1/Xbp1) and autophagy markers (LC3II/I ratio, p62, Atg7). In summary, long-term DHA supplementation and/or exercise could be helpful to delay NAFLD progression during aging in obesity.

Effect of aging and obesity on GLUT12 expression in small intestine, adipose tissue, muscle, and kidney and its regulation by docosahexaenoic acid and exercise in mice.

Obesity is characterized by excessive fat accumulation and inflammation. Aging has also been characterized as an inflammatory condition, frequently accompanied by accumulation of visceral fat. Beneficial effects of exercise and n-3 long-chain polyunsaturated fatty acids in metabolic disorders have been described. Glucose transporter 12 (GLUT12) is one of the less investigated members of the GLUT family. Glucose, insulin, and tumor necrosis factor alpha (TNF-α) induce GLUT12 translocation to the membrane in muscle, adipose tissue, and intestine. We aimed to investigate GLUT12 expression in obesity and aging, and under diet supplementation with docosahexaenoic acid (DHA) alone or in combination with physical exercise in mice. Aging increased GLUT12 expression in intestine, kidney, and adipose tissue, whereas obesity reduced it. No changes on the transporter occurred in skeletal muscle. In obese 18-month-old mice, DHA further decreased GLUT12 in the 4 organs. Aerobic exercise alone did not modify GLUT12, but the changes triggered by exercise were able to prevent the DHA-diminishing effect, and almost restored GLUT12 basal levels. In conclusion, the downregulation of metabolism in aging would be a stimulus to upregulate GLUT12 expression. Contrary, obesity, an excessive energy condition, would induce GLUT12 downregulation. The combination of exercise and DHA would contribute to restore basal function of GLUT12. Novelty In small intestine, kidney and adipose tissue aging increases GLUT12 protein expression whereas obesity reduces it. Dietary DHA decreases GLUT12 in small intestine, kidney, adipose tissue and skeletal muscle. Exercise alone does not modify GLUT12 expression, nevertheless exercise prevents the DHA-diminishing effect on GLUT12.

DHA and its derived lipid mediators MaR1, RvD1 and RvD2 block TNF-α inhibition of intestinal sugar and glutamine uptake in Caco-2 cells.

Tumor necrosis factor-alfa (TNF-α) is a pro-inflammatory cytokine highly-involved in intestinal inflammation. Omega-3 polyunsaturated fatty acids (n3-PUFAs) show anti-inflammatory actions. We previously demonstrated that the n3-PUFA EPA prevents TNF-α inhibition of sugar uptake in Caco-2 cells. Here, we investigated whether the n3-PUFA DHA and its derived specialized pro-resolving lipid mediators (SPMs) MaR1, RvD1 and RvD2, could block TNF-α inhibition of intestinal sugar and glutamine uptake. DHA blocked TNF-α-induced inhibition of α-methyl-D-glucose (αMG) uptake and SGLT1 expression in the apical membrane of Caco-2 cells, through a pathway independent of GPR120. SPMs showed the same preventive effect but acting at concentrations 1000 times lower. In diet-induced obese (DIO) mice, oral gavage of MaR1 reversed the up-regulation of pro-inflammatory cytokines found in intestinal mucosa of these mice. However, MaR1 treatment was not able to counteract the reduced intestinal transport of αMG and SGLT1 expression in the DIO mice. In Caco-2 cells, TNF-α also inhibited glutamine uptake being this inhibition prevented by EPA, DHA and the DHA-derived SPMs. Interestingly, TNF-α increased the expression in the apical membrane of the glutamine transporter B0AT1. This increase was partially blocked by the n-3 PUFAs. These data reveal DHA and its SPMs as promising biomolecules to restore intestinal nutrients transport during intestinal inflammation.

Basolateral presence of the proinflammatory cytokine tumor necrosis factor -α and secretions from adipocytes and macrophages reduce intestinal sugar transport.

We have previously demonstrated in Caco-2 cells that tumor necrosis factor-α (TNF-α) inhibits sugar uptake, acting from the apical membrane, by decreasing the expression of the Na+ -glucose cotransporter SGLT1 in the brush border membrane. The goal was to investigate the hypothesis that TNF-α from abdominal adipose tissue (adipocytes and macrophages) would decrease sugar and amino acid transport acting from the basolateral membrane of the enterocytes. TNF-α placed in the basal compartment of Caco-2 cells decreased α-methyl- d-glucose (αMG) and glutamine uptake. The apical medium derived from these Caco-2 cells apically placed in another set of cells, also reduced sugar and glutamine transport. Reverse-transcription polymerase chain reaction analysis demonstrated upregulation of TNF-α, IL-1ß, and MCP1 expression in Caco-2 cells exposed to basal TNF-α. Similarly, αMG uptake was inhibited after Caco-2 cells were incubated, in the basal compartment, with medium from visceral human mesenchymal stem cells-derived adipocytes of overweight individuals. The apical medium collected from those Caco-2 cells, and placed in the upper side of other set of cells, also decreased sugar uptake. Basal presence of medium derived from lipopolysaccharide-activated macrophages and nonactivated macrophages decreased αMG uptake as well. Diet-induced obese mice showed an increase in the visceral adipose tissue surrounding the intestine. In this physiological condition, there was a reduction on αMG uptake in jejunal everted rings. Altogether, these results suggest that basolateral TNF-α, which can be produced by adipocytes and macrophages during obesity, would be able to activate TNF-α and other proinflammatory proteins expression in the small intestine and diminish intestinal sugar and amino acids transport.

GLUT12 expression and regulation in murine small intestine and human Caco-2 cells.

GLUT12 was cloned from the mammary cancer cell line MCF-7, but its physiological role still needs to be elucidated. To gain more knowledge of GLUT12 function in the intestine, we investigated GLUT12 subcellular localization in the small intestine and its regulation by sugars, hormones, and intracellular mediators in Caco-2 cells and mice. Immunohistochemical methods were used to determine GLUT12 subcellular localization in human and murine small intestine. Brush border membrane vesicles were isolated for western blot analyses. Functional studies were performed in Caco-2 cells by measuring α-methyl-d-glucose (αMG) uptake in the absence of sodium. GLUT12 is located in the apical cytoplasm, below the brush border membrane, and in the perinuclear region of murine and human enterocytes. In Caco-2 cells, GLUT12 translocation to the apical membrane and α-methyl- d-glucose uptake by the transporter are stimulated by protons, glucose, insulin, tumor necrosis factor-α (TNF-α), protein kinase C, and AMP-activated protein kinase. In contrast, hypoxia decreases GLUT12 expression in the apical membrane. Upregulation of TNF-α and hypoxia-inducible factor-1α ( HIF-1α) genes is found in the jejunal mucosa of diet-induced obese mice. In these animals, GLUT12 expression in the brush border membrane is slightly decreased compared with lean animals. Moreover, an intraperitoneal injection of insulin does not induce GLUT12 translocation to the membrane, as it occurs in lean animals. GLUT12 rapid translocation to the enterocytes' apical membrane in response to glucose and insulin could be related to GLUT12 participation in sugar absorption during postprandial periods. In obesity, in which insulin sensitivity is reduced, the contribution of GLUT12 to sugar absorption is affected.

Short and long-term effectiveness and safety of vedolizumab in inflammatory bowel disease: results from the ENEIDA registry.

BACKGROUND: Effectiveness of vedolizumab in real world clinical practice is unknown. AIM: To evaluate the short and long-term effectiveness of vedolizumab in patients with inflammatory bowel disease (IBD). METHODS: Patients who received at least 1 induction dose of vedolizumab were included. Effectiveness was defined based on Harvey-Bradshaw index (HBI) in Crohn's disease (CD) and Partial Mayo Score (PMS) in ulcerative colitis (UC). Short-term response was assessed at week 14. Variables associated with short-term remission were identified by logistic regression analysis. The Kaplan-Meier method was used to evaluate the long-term durability of vedolizumab treatment. Cox model was used to identify factors associated with discontinuation of treatment and loss of response. RESULTS: 521 patients were included (median follow-up 10 months [interquartile range 5-18 months]). At week 14, 46.8% had remission and 15.7% clinical response. CD (vs UC), previous surgery, higher CRP concentration and disease severity at baseline were significantly associated with impaired response. The rate of vedolizumab discontinuation was 37% per patient-year of follow-up (27.6% in UC and 45.3% in CD, P < 0.01). CD (vs UC), anaemia at baseline, steroids during induction and CRP concentration were associated with lower durability of treatment. Seven per cent of patients developed adverse events, infections being the most frequent. CONCLUSIONS: Over 60% of IBD patients respond to vedolizumab. Many patients discontinue treatment over time. CD and disease burden impair both short- and long-term response. Vedolizumab seems to be safe in clinical practice.

Complicaciones cardio-respiratorias graves derivadas de la sedación con propofol controlado por endoscopista / Severe cardiorespiratory complications derived from propofol sedation monitored by an endoscopist

Introducción: la sedación profunda con propofol controlada por endoscopista en las diferentes unidades de endoscopia ha sido un tema de continua controversia a lo largo de los últimos años, origen de conflictos de intereses entre las distintas sociedades científicas de Anestesiología y Gastroenterología. Numerosos estudios han demostrado ya la eficacia, eficiencia y escasa aparición de complicaciones en la sedación controlada por un endoscopista formado frente al anestesiólogo. Material y métodos: hemos revisado en nuestra base de datos el porcentaje de complicaciones cardio-respiratorias graves en nuestra unidad, en el periodo comprendido entre 2011 y 2016, en las distintas exploraciones endoscópicas que realizamos (gastroscopia, colonoscopia, colangiopancreatografía retrógrada endoscópica [CPRE] y ecoendoscopia [USE]) y cuya sedación es controlada por un endoscopista. Resultados: se llevó a cabo el análisis de 33.195 exploraciones durante el periodo de estudio. Obtuvimos un 0,13% de complicaciones cardio-respiratorias, la mayor parte de ellas desaturaciones graves (la mayoría respondieron a la apertura de la vía aérea asociada a la interrupción de la infusión del fármaco, precisando la necesidad de ambú en contadas ocasiones). No existieron diferencias estadísticamente significativas entre los diferentes grupos excepto en edad media, riesgo por tipo de exploración y riesgo ASA, donde la CPRE presentó una p < 0,01 frente al resto de exploraciones. Conclusión: con los datos de los que disponemos hasta la actualidad, existen numerosas evidencias en la literatura científica para divulgar que la sedación de las endoscopias controlada por un endoscopista formado es segura, eficaz y eficiente. No obstante, deben realizarse más estudios prospectivos que confirmen estas suposiciones, ya que hasta el momento la mayoría de los estudios son retrospectivos

Introduction: deep sedation with propofol monitored by an endoscopist in different endoscopy units is a controversial subject and the source of conflicts of interest between the various scientific societies of Anesthesiology and Gastroenterology. Many studies have already demonstrated the efficacy, efficiency and low incidence of complications associated with sedation when under the control of a trained endoscopist vs an anesthesiologist. Material and methods: the rate of severe cardiorespiratory complications during various endoscopic examinations (gastroscopy, colonoscopy, endoscopic retrograde cholangiopancreatography [ERCP] and endoscopic ultrasound [EUS]) where sedation was controlled by an endoscopist within our unit, from 2011 to 2016, was reviewed. Results: during the study period, 33,195 examinations were analyzed. The rate of cardiorespiratory complications was 0.13% and the majority were severe desaturations. Most cases responded to an opening in the airway associated with the interruption of drug infusion and an ambu bag was required in a few cases. There were no statistically significant differences between the different groups, except for mean age, risk by type of examination and ASA risk, where the difference between ERCP and the rest of examinations was statistically significant. Conclusion: there is a high level of evidence in the scientific literature suggesting that sedation controlled by a trained endoscopist is safe, effective and efficient. However, further prospective studies are required in order to confirm this conclusion due to the fact that the majority of studies to date are retrospective

Severe cardiorespiratory complications derived from propofol sedation monitored by an endoscopist.

INTRODUCTION: deep sedation with propofol monitored by an endoscopist in different endoscopy units is a controversial subject and the source of conflicts of interest between the various scientific societies of Anesthesiology and Gastroenterology. Many studies have already demonstrated the efficacy, efficiency and low incidence of complications associated with sedation when under the control of a trained endoscopist vs an anesthesiologist. MATERIAL AND METHODS: the rate of severe cardiorespiratory complications during various endoscopic examinations (gastroscopy, colonoscopy, endoscopic retrograde cholangiopancreatography [ERCP] and endoscopic ultrasound [EUS]) where sedation was controlled by an endoscopist within our unit, from 2011 to 2016, was reviewed. RESULTS: during the study period, 33,195 examinations were analyzed. The rate of cardiorespiratory complications was 0.13% and the majority were severe desaturations. Most cases responded to an opening in the airway associated with the interruption of drug infusion and an ambu bag was required in a few cases. There were no statistically significant differences between the different groups, except for mean age, risk by type of examination and ASA risk, where the difference between ERCP and the rest of examinations was statistically significant. CONCLUSION: there is a high level of evidence in the scientific literature suggesting that sedation controlled by a trained endoscopist is safe, effective and efficient. However, further prospective studies are required in order to confirm this conclusion due to the fact that the majority of studies to date are retrospective.

EPA blocks TNF-α-induced inhibition of sugar uptake in Caco-2 cells via GPR120 and AMPK.

The aim of the present work was to investigate in Caco-2 cells whether eicosapentaenoic acid (EPA), an omega-3 polyunsaturated fatty acid, could block the inhibitory effect of tumor necrosis factor-α (TNF-α) on sugar transport, and identify the intracellular signaling pathways involved. After pre-incubation of the Caco-2 cells with TNF-α and EPA for 1 hr, EPA prevented the inhibitory effect of the cytokine on α-methyl-d-glucose (αMG) uptake (15 min) and on SGLT1 expression at the brush border membrane, measured by Western blot. The ERK1/2 inhibitor PD98059 and the AMPK activator AICAR also prevented the inhibitory effect of TNF-α on both αMG uptake and SGLT1 expression. Interestingly, the AMPK inhibitor, Compound C, abolished the ability of EPA to prevent TNF-α-induced reduction of sugar uptake and transporter expression. The GPR120 antagonist, AH7614, also blocked the preventive effect of EPA on TNF-α-induced decrease of αMG uptake and AMPK phosphorylation. In summary, TNF-α inhibits αMG uptake by decreasing SGLT1 expression in the brush border membrane through the activation of ERK1/2 pathway. EPA prevents the inhibitory effect of TNF-α through the involvement of GPR120 and AMPK activation.

CDX2 upregulates SLC26A3 gene expression in intestinal epithelial cells.

SLC26A3 [downregulated in adenoma (DRA)] plays a key role in mammalian intestinal NaCl absorption, in that it mediates apical membrane Cl-/[Formula: see text] exchange. DRA function and expression are significantly decreased in diarrhea associated with inflammatory bowel disease. DRA is also considered to be a marker of cellular differentiation and is predominantly expressed in differentiated epithelial cells. Caudal-type homeobox protein-2 (CDX2) is known to regulate genes involved in intestinal epithelial differentiation and proliferation. Reduced expression of both DRA and CDX2 in intestinal inflammation prompted us to study whether the DRA gene is directly regulated by CDX2. Our initial studies utilizing CDX2 knockout (CDX2fV/fV;Cre+) mice showed a marked reduction in DRA mRNA and protein levels in proximal and distal colon. In silico analysis of the DRA promoter showed two consensus sites for CDX2 binding. Therefore, we utilized Caco-2 cells as an in vitro model to examine if DRA is a direct target of CDX2 regulation. siRNA-mediated silencing of CDX2 in Caco-2 cells resulted in a marked (~50%) decrease in DRA mRNA and protein levels, whereas ectopic overexpression of CDX2 upregulated DRA expression and also stimulated DRA promoter activity, suggesting transcriptional regulation. Electrophoretic mobility shift and chromatin immunoprecipitation assays demonstrated direct binding of CDX2 to one of the two putative CDX2 binding sites in the DRA promoter (+645/+663). In summary, our studies, for the first time, demonstrate transcriptional regulation of DRA expression by CDX2, implying that reduced expression of DRA in inflammatory bowel disease-associated diarrhea may, in part, be due to downregulation of CDX2 in the inflamed mucosa.NEW & NOTEWORTHY SLC26A3 [downregulated in adenoma (DRA)] mediates intestinal luminal NaCl absorption and is downregulated in inflammatory bowel disease-associated diarrhea. Since both DRA and caudal-type homeobox protein-2 (CDX2) are reduced in intestinal inflammation and the DRA promoter harbors CDX2 binding sites, we examined whether the DRA gene is regulated by CDX2. Our studies, for the first time, demonstrate transcriptional regulation of DRA expression by CDX2 via direct binding to the DRA promoter, suggesting that reduced expression of DRA in inflammatory bowel disease-associated diarrhea could, in part, be attributed to downregulation of CDX2.

Cassane diterpenes from Caesalpinia platyloba.

The dichloromethane extract from the leaves of Caesalpinia platyloba provided cassane diterpenes whose structures were determined as (-)-(5S,6R,8S,9S,10R,14R)-6-acetoxyvouacapane (1), (-)-(5S,6R,8S,9S,10R,12Z,14R)-6-acetoxycassa-12,15-diene (3), and (-)-(5S,6R,8S,9S,10R,13E)-6-acetoxycassa-13,15-diene (4). Compound 1 was chemically correlated with (-)-(5S,6R,8S,9S,10R,14R)-6-hydroxyvouacapane (2), (+)-(5S,8S,9S,10R,14R)-6-oxovouacapane (5), and (+)-(5S,6S,8S,9S,10R,14R)-6-acetoxyvouacapane (6), the last one previously isolated from Dipteryx lacunifera. The absolute configurations of all six diterpenes 1-6 were established by comparison of DFT calculated vibrational circular dicroism spectra of 1, 2 and 5 with those obtained experimentally. In addition, several reported chemical shifts for 2 and 5 were reassigned based on two-dimensional NMR measurements.

Fístula gastrocólica por adenocarcinoma gástrico / Gastrocolonic fistula due to gastric adenocarcinoma

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