TET3-mediated DNA oxidation is essential for intestinal epithelial cell response to stressors.

DNA methylation functions as a repressive epigenetic mark that can be reversed by the Ten-eleven translocation (TET) family of DNA dioxygenases that sequentially oxidize 5-methylcytosine into 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC), and 5-carboxylcytosine (5caC). Both 5fC and 5caC can be excised by DNA base-excision repair factors leading to unmodified cytosines. TET enzymes were recently implicated as potential risk factors for inflammatory bowel disease (IBD), but the contribution of TET-mediated DNA oxidation to intestinal homeostasis and response to environmental stressors are unknown. Here, we show prominent roles of TET3 in regulating mouse intestinal epithelial differentiation and response to luminal stressors. Compared with wild-type littermates, mice with intestinal epithelial cell-specific ablation of Tet3 (Tet3ΔIEC) demonstrated a decreased transcriptome involved in innate immune response, Paneth cell differentiation, and epithelial regeneration. Tet3IEC mice exhibited an elevated susceptibility to enteric pathogen infection that is correlated with a decreased epithelial 5hmC abundance. Infection of human enterocytes or mice with the pathogenic bacteria acutely increased 5hmC abundance. Genome-wide 5hmC profiling revealed a shift of genomic enrichment of 5hmC toward genes involved in activating Notch, Wnt, and autophagy pathways. Furthermore, chemical stressor dextran sulfate sodium (DSS) represses epithelial 5hmC abundance in a temporal fashion, and Tet3IEC mice exhibited increased susceptibility to DSS experimental colitis with reduced regenerative capacity. TET3 is a critical regulator of gut epithelial DNA methylome and transcriptome, especially in response to luminal stressors, for the maintenance of tissue homeostasis.

Efficacy and safety of sitagliptin in patients with type 2 diabetes and ESRD receiving dialysis: a 54-week randomized trial.

BACKGROUND: Treatment with oral antihyperglycemic agents has not been well characterized in patients with type 2 diabetes and end-stage renal disease (ESRD). The efficacy and safety of sitagliptin and glipizide monotherapy in patients with type 2 diabetes and ESRD on dialysis therapy were assessed in this study. STUDY DESIGN: 54-week, randomized, double-blind, parallel-arm study. SETTING & PARTICIPANTS: From 31 clinical sites in 12 countries, 129 patients 30 years or older with type 2 diabetes and ESRD who were on dialysis therapy and had a hemoglobin A1c (HbA1c) level of 7%-9% were randomly assigned 1:1 to treatment. INTERVENTION: Monotherapy with sitagliptin, 25 mg daily or glipizide (initiated with 2.5 mg daily and titrated up to a potential maximum dose of 10 mg twice daily or down to avoid hypoglycemia). OUTCOMES: Primary end points were 54-week change in HbA1c level from baseline and tolerability with sitagliptin. A secondary end point was the comparison of sitagliptin versus glipizide on the incidence of symptomatic hypoglycemia. RESULTS: Of 129 patients randomly assigned, 64 were in the sitagliptin group (mean baseline age, 61 years; HbA1c, 7.9%) and 65 were in the glipizide group (mean baseline age, 59 years; HbA1c, 7.8%). After 54 weeks, the least squares mean change from baseline in HbA1c level was -0.72% (95% CI, -0.95% to -0.48%) with sitagliptin and -0.87% (95% CI, -1.11% to -0.63%) with glipizide, for a difference of 0.15% (95% CI, -0.18% to 0.49%). The incidences of symptomatic hypoglycemia and severe hypoglycemia were 6.3% versus 10.8% (between-group difference, -4.8% [95% CI, -15.7% to 5.6%]) and 0% versus 7.7% (between-group difference, -7.8% [95% CI, -17.1% to -1.9%]) in the sitagliptin and glipizide groups, respectively. Higher incidences (ie, 95% CI around between-treatment difference excluded 0) of cellulitis and headache were found with sitagliptin compared to glipizide (6.3% vs 0%, respectively, for both). LIMITATIONS: Small sample size limits between-group comparisons. CONCLUSIONS: Treatment with sitagliptin or glipizide monotherapy was effective and well tolerated over 54 weeks in patients with type 2 diabetes and ESRD who were receiving dialysis.

Hypomethylating Chemotherapeutic Agents as Therapy for Myelodysplastic Syndromes and Prevention of Acute Myeloid Leukemia.

Myelodysplastic Syndromes (MDSs) affect the elderly and can progress to Acute Myeloid Leukemia (AML). Epigenetic alterations including DNA methylation and chromatin modification may contribute to the initiation and progression of these malignancies. DNA hypomethylating agents such as decitabine and azacitidine are used as therapeutic treatments and have shown to promote expression of genes involved in tumor suppression, apoptosis, and immune response. Another anti-cancer drug, the proteasome inhibitor bortezomib, is used as a chemotherapeutic treatment for multiple myeloma (MM). Phase III clinical trials of decitabine and azacitidine used alone and in combination with other chemotherapeutics demonstrated their capacity to treat hematological malignancies and prolong the survival of MDS and AML patients. Although phase III clinical trials examining bortezomib's role in MDS and AML patients are limited, its underlying mechanisms in MM highlight its potential as a chemotherapeutic for such malignancies. Further research is needed to better understand how the epigenetic mechanisms mediated by these chemotherapeutic agents and their targeted gene networks are associated with the development and progression of MDS into AML. This review discusses the mechanisms by which decitabine, azacitidine, and bortezomib alter epigenetic programs and their results from phase III clinical trials.

SIRT6 transcriptionally regulates fatty acid transport by suppressing PPARγ.

Pathological lipid accumulation is often associated with enhanced uptake of free fatty acids via specific transporters in cardiomyocytes. Here, we identify SIRT6 as a critical transcriptional regulator of fatty acid transporters in cardiomyocytes. We find that SIRT6 deficiency enhances the expression of fatty acid transporters, leading to enhanced fatty acid uptake and lipid accumulation. Interestingly, the haploinsufficiency of SIRT6 is sufficient to induce the expression of fatty acid transporters and cause lipid accumulation in murine hearts. Mechanistically, SIRT6 depletion enhances the occupancy of the transcription factor PPARγ on the promoters of critical fatty acid transporters without modulating the acetylation of histone 3 at Lys 9 and Lys 56. Notably, the binding of SIRT6 to the DNA-binding domain of PPARγ is critical for regulating the expression of fatty acid transporters in cardiomyocytes. Our data suggest exploiting SIRT6 as a potential therapeutic target for protecting the heart from metabolic diseases.

Non-Coding RNAs as Mediators of Epigenetic Changes in Malignancies.

Non-coding RNAs (ncRNAs) are untranslated RNA molecules that regulate gene expressions. NcRNAs include small nuclear RNAs (snRNAs), small nucleolar RNAs (snoRNAs), ribosomal RNAs (rRNAs), transfer RNAs (tRNAs), circular RNAs (cRNAs) and piwi-interacting RNAs (piRNAs). This review focuses on two types of ncRNAs: microRNAs (miRNAs) or short interfering RNAs (siRNAs) and long non-coding RNAs (lncRNAs). We highlight the mechanisms by which miRNAs and lncRNAs impact the epigenome in the context of cancer. Both miRNAs and lncRNAs have the ability to interact with numerous epigenetic modifiers and transcription factors to influence gene expression. The aberrant expression of these ncRNAs is associated with the development and progression of tumors. The primary reason for their deregulated expression can be attributed to epigenetic alterations. Epigenetic alterations can cause the misregulation of ncRNAs. The experimental evidence indicated that most abnormally expressed ncRNAs impact cellular proliferation and apoptotic pathways, and such changes are cancer-dependent. In vitro and in vivo experiments show that, depending on the cancer type, either the upregulation or downregulation of ncRNAs can prevent the proliferation and progression of cancer. Therefore, a better understanding on how ncRNAs impact tumorigenesis could serve to develop new therapeutic treatments. Here, we review the involvement of ncRNAs in cancer epigenetics and highlight their use in clinical therapy.

Nivel de conocimiento respecto a la planificación familiar en gestantes que acudieron al Hospital Universitario San José, Popayán, Colombia, 2014-2015 / Knowledge about contraception among pregnant women coming to San José University Hospital in Popayán, Colombia, 2014-2015

Objetivos: determinar el nivel de conocimiento mínimo aceptable existente sobre planificación familiar que tienen las pacientes obstétricas que acuden al Hospital Universitario San José (HUSJ), e n Popayán. Materiales y métodos: estudio transversal en gestantes que acudieron a un hospital público universitario de referencia, de tercer nivel de complejidad, ubicado en el suroccidente de Colombia en los años 2014-2015. Se excluyeron aquellas con información inconsistente, las que por su situación de salud física o mental no pudieran contestar la encuesta y aquellas que no firmaron el consentimiento informado. Se definió como nivel de conocimiento mínimo aceptable aquellas encuestas con más de un 90 % de ítems correctos. Tamaño de muestra: 361 pacientes. Se realizó muestreo aleatorio sistemático; se evaluaron las variables biológicas, sociales y demográficas. Respecto al conocimiento del método se indagó sobre aspectos relacionados con su uso, reacciones adversas y riesgo de falla. Se realizó análisis descriptivo. Resultados: se evaluaron 361 mujeres, 94,46 % manifestaron conocer al menos un método de planificación. El 70,09 % de los embarazos no fueron planeados. Cerca de un cuarto de las pacientes estaban usando algún método de planificación familiar al momento del embarazo. Se encontró en un nivel de conocimiento mínimo del 90 % en el 26,23 % de las pacientes, siendo el más bajo para anticonceptivos (11,85 %). Conclusiones: a pesar de que el 94 % de las gestantes entrevistadas conocían la existencia de métodos de planificación, en cuanto al conocimiento de cómo usarlos y las reacciones adversas asociadas, el 26 % tuvo un nivel mayor al 90 % en ambos aspectos.

Objectives: To determine the level of basic acceptable knowledge on contraception among obstetric patients coming to the Hospital Universitario San José (HUSJ) in Popayán. Materials and methods: Cross-sectional study in pregnant women coming to a Level III referral public university hospital in Southwestern Colombia during 2014 and 2015. Patients with inconsistent information, or who could not complete the survey because of their mental or physical conditions, or those who did not sign inform consent, were excluded. Basic level of knowledge was defined as more than 90 % correct items on the questionnaire. A systematic random sampling was performed, and the biological, social and demographic variables were analysed. In terms of knowledge of the contraception method, there were questions regarding use, adverse reactions and risk of failure. A descriptive analysis was performed. Results: Of a total of 361 women included in the assessment, 94.46 % reported having knowledge of at least one contraception method. Of the pregnancies, 70.09 % were unplanned. Close to one-fourth of the patients were using some form of contraception at the time of pregnancy. A basic level of knowledge of 90 % was found in 26.23 % of the patients, the lowest level being related to the knowledge about oral contraceptives (11,85%). Conclusions: Despite the fact that 94% of the pregnant women interviewed knew of the existence of contraception methods, only 26% of them were found to have a level of knowledge greater than 90% concerning their use and associated adverse reactions.

Fibrodisplasia osificante progresiva. Presentación de un caso / Fibrodysplasia Ossificans Progressive. A Case Report

Se presenta el caso de una niña de 3 años de edad llevada al Servicio de Imágenes Diagnósticas del Hospital de la Universidad del Norte (Barranquilla, Colombia) para una radiografía de tórax. Los hallazgos sugieren una formación de hueso inusual con Hallux Valgus bilateral al examen físico. Se hace también una revisión breve de la literatura de fibrodisplasia osificante progresiva (FOP).

3 year old female patient, who was admitted to Hospital de la Universidad Del Norte diagnostic imaging service, for a chest radiography. Findings were highly suggestive of the formation of unusual bones, with deformed big toes when undergoing physical examination. A brief review of the literature of Fibrodysplasia ossificans progressiva (FOP) is also performed.

Benzazepinone Nav1.7 blockers: potential treatments for neuropathic pain.

A series of benzazepinones were synthesized and evaluated as hNa(v)1.7 sodium channel blockers. Several compounds from this series displayed good oral bioavailability and exposure and were efficacious in a rat model of neuropathic pain.

Discovery of potent and selective beta-homophenylalanine based dipeptidyl peptidase IV inhibitors.

Modification of in-house screening lead beta-aminoacyl proline 8 gave an equipotent thiazolidide 9. Extensive SAR studies on the phenyl ring of 9 led to the discovery of a novel series of potent and selective DP-IV inhibitors. Introduction of a fluorine at the 2-position proved to be crucial for the potency of this series. The 2,5-difluoro (22q) and 2,4,5-trifluoro (22t) analogues were potent inhibitors of DP-IV (IC(50)=270, 119nM, respectively).