Effect of sitagliptin on down-regulation of KAT7 and SIRT1 gene expression in breast cancer cell line MCF7.

BACKGROUND: To date, the main clinical interest in DPP4 is focused on its inhibition in diabetic patients to prolong the half-life of incretins. Epigenetic alterations resulting from DPP4 inhibition have been poorly explored. OBJECTIVE: The objective of this study was to determine, whether sitagliptin, a DPP4 inhibitor, has effects on the expression of KAT7 and SIRT1 (genes encoding a histone acetyltransferase and a histone deacetylase, respectively) in MCF7 breast cancer cells, which play an essential role in modulating the epigenetic landscape of chromatin. MATERIAL AND METHODS: MCF7 cells were incubated for 20 h with sitagliptin at concentrations of 0.5, 1.0 and 2.0 µM. Total RNA was isolated and the relative mRNA expression of KAT7 and SIRT1 was determined by RT-qPCR. RESULTS: There was downregulation in the relative expression of both genes; for KAT7, downregulation reached up to 0.49 (p = 0.027) and for SIRT1, it reached up to 0.55 (p = 0.037). CONCLUSIONS: These results suggest that sitagliptin has effects on the histone epigenetic landscape. This topic deserves further study due to the current sample use of DPP4 inhibitors in diabetic patients.

ANTECEDENTES: Hasta la fecha, el principal interés clínico de la DPP4 se centra en su inhibición en pacientes diabéticos para prolongar la vida media de las incretinas. Las alteraciones epigenéticas resultantes de la inhibición de DPP4 han sido poco exploradas. OBJETIVO: Determinar si la sitagliptina, un inhibidor de DPP4, tiene efectos sobre la expresión de KAT7 y SIRT1 (genes que codifican una histona acetiltransferasa y una histona desacetilasa, respectivamente) en células de cáncer de mama MCF7, que desempeñan un papel esencial en la modulación del paisaje epigenético de la cromatina. MÉTODO: Las células MCF7 se incubaron durante 20 h con sitagliptina a concentraciones de 0.5, 1.0 y 2.0 µM. Se aisló el ARN total y se determinó la expresión relativa de ARNm de KAT7 y SIRT1 mediante RT-qPCR. RESULTADOS: Hubo una regulación a la baja en la expresión relativa de ambos genes; para KAT7, la regulación negativa alcanzó hasta 0.49 (p = 0.027) y para SIRT1 alcanzó hasta 0.55 (p = 0.037). CONCLUSIONES: Estos resultados sugieren que la sitagliptina tiene efectos sobre el paisaje epigenético de las histonas. Este tema merece más estudios debido al uso actual de inhibidores de DPP4 en pacientes diabéticos.

Effect of oral magnesium supplementation on the transcription of TRPM6, TRPM7, and SLC41A1 in individuals newly diagnosed of pre-hypertension. A randomized, double-blind, placebo-controlled trial.

A stringent regulation of influx and efflux of magnesium by cation transporters seems to play an important role in the regulation of blood pressure (BP). With this regard, we evaluate the effect of oral magnesium supplementation on the transcription of TRPM6, TRPM7, and SLC41A1, in individuals with incident pre-hypertension (preHTN). For such purpose, we conducted a randomized, double-blind, placebo-controlled trial that compared 18 individuals who received oral magnesium lactate (360 mg elemental magnesium) versus 18 individuals who received placebo, during 4 months. Diagnosis of hypertension or normal BP, diabetes, alcohol intake, chronic diarrhea, use of diuretics, intake of magnesium supplementation, and reduced renal function were exclusion criteria. Regarding the transcription analysis of TRPM6, TRPM7, and SLC41A1 using RT-qPCR, leukocyte-rich plasma was obtained and total RNA was isolated with the kit Direct-zol™ RNA MiniPrep (Zymo). The leukocyte TRPM6 mRNA relative expression showed a significant increase (2.1 ± 1.37 and 0.8 ± 0.4, P<0.05), whereas the mRNA relative expression of both leukocyte TRPM7 (0.8 ± 1.1 and 0.9 ± 0.6, pNS) and SLC41A1 (0.9 ± 1.0 and 0.7 ± 0.6, pNS) showed no significant differences, between the magnesium and placebo groups, respectively. Oral magnesium supplementation increases the leukocyte TRPM6 mRNA relative expression, in subjects with new diagnosis of preHTN.

Risk of microalbuminuria in relatives of subjects with diabetic nephropathy: a predictive model based on multivariable dimensionality reduction approach.

AIM: To evaluate a predictive model of microalbuminuria by using anthropometric, clinical and genetic variables in relatives of subjects with diabetic nephropathy. METHODS: Eligible subjects, aged 18-63 years with body mass index<35 kg/m2, and first degree relatives of patients with type 2 diabetes and diabetic nephropathy were enrolled in a cross-sectional study. A total of 70 individuals with microalbuminuria were compared with 60 individuals without microalbuminuria. Based on a morning urinary sample, microalbuminuria was defined as albumin≥30<300 mg/dL. Genotyping of single nucleotide polymorphisms (SNPs) G-174C of IL6 (rs1800795), G-308A of TNF (rs1800629), and Pro12Ala of PPARγ2 (rs1801282) genes were determined. The multivariable dimensionality reduction analysis was performed using the software multifactor dimensionality reduction package. RESULTS: The multivariable dimensionality reduction analysis showed that obesity and SNP G-308A of TNF gene exhibited main effects with 1.10 and 1.98% of information gain (IG), respectively. The IL6 showed synergy (interaction) with HDL-c (IG 1.27%) and sex (IG 1.02%); also high-sensitivity C-reactive protein and triglycerides levels showed synergy (IG 1.08%). The consistency of the cross-validation for this model was 0.6836, with sensitivity and specificity of 0.58 and 0.76 (odds ratio 4.64; 95% CI 4.0-10.0, p<0.0001). CONCLUSION: Our results indicate that obesity and/or high blood pressure, in synergism with high-sensitivity C-reactive protein and high-density lipoprotein cholesterol levels, is the main predictive risk factor of diabetic nephropathy in healthy subjects, relatives of patients with type 2 diabetes and diabetic nephropathy.

Obesity and inflammation: epidemiology, risk factors, and markers of inflammation.

Obesity is a public health problem that has reached epidemic proportions with an increasing worldwide prevalence. The global emergence of obesity increases the risk of developing chronic metabolic disorders. Thus, it is an economic issue that increased the costs of the comorbidities associated. Moreover, in recent years, it has been demonstrated that obesity is associated with chronic systemic inflammation, this status is conditioned by the innate immune system activation in adipose tissue that promotes an increase in the production and release of pro-inflammatory cytokines that contribute to the triggering of the systemic acute-phase response which is characterized by elevation of acute-phase protein levels. On this regard, low-grade chronic inflammation is a characteristic of various chronic diseases such as metabolic syndrome, cardiovascular disease, diabetes, hypertension, non-alcoholic fatty liver disease, and some cancers, among others, which are also characterized by obesity condition. Thus, a growing body of evidence supports the important role that is played by the inflammatory response in obesity condition and the pathogenesis of chronic diseases related.

No positive effect of oral magnesium supplementation in the decreases of inflammation in subjects with prediabetes: a pilot study.

To determine whether oral magnesium supplementation modifies serum levels of high-sensitivity C-reactive protein (hsCRP), TNF-alpha, IL-6, and IL-10 in subjects with prediabetes, inflammation, and hypomagnesemia, a total of 26 subjects men and non-pregnant women were included and randomly allocated to receive 30 ml of MgCl(2) 5% solution (equivalent to 382 mg of magnesium) or placebo, daily during three months. At baseline conditions, there were not significant statistical differences between the groups. At end of the study, hsCRP levels were significantly lower in the intervention group (3.3 ± 2.5 vs 8.0 ± 5.9 mg/L, p = 0.03), as compared with the control group. However, the intra-group analysis of the individuals who received magnesium, did not shows significant statistical differences between baseline and final conditions (4.1 ± 3.0 and 3.3 ± 2.5, p = 0.45). In addition, TNF-alpha (1.2 ± 0.3 vs 1.1 ± 0.3 pg/mL, p = 0.69), IL-6 (0.3 ± 0.3 vs 5.0 ± 7.7 pg/mL, p = 0.08), and IL-10 (1.8 ± 0.4 vs 1.8 ± 0.5 pg/mL, p = 0.89) serum levels were not significantly different between the groups. Our results do not show a beneficial effect of oral magnesium supplementation on hsCRP, IL-6, TNF-alpha, and IL-10 levels in prediabetic subjects with hypomagnesemia and inflammation. Further studies with large sample sizes and longer time of follow-up are necessaries to verify the results of our pilot study.

C-reactive protein is directly associated with urinary albumin-to-creatinine ratio.

BACKGROUND AND AIMS: There are no studies that elucidate whether the role of inflammation in the increase of urinary albumin is independent, mediated by family history or by risk factors acquired during life in the offspring of subjects with type 2 diabetes. We undertook this study to evaluate whether elevated C-reactive protein (CRP) levels are independently associated with urinary albumin-to-creatinine ratio (UACR) in the offspring of subjects with diabetic nephropathy. METHODS: A total of 64 healthy males and healthy nonpregnant females, offspring of subjects with diabetic nephropathy, aged 18-69 years, and with body mass index ≤35 kg/m(2) were enrolled in a cross-sectional study. Hypertension, glucose metabolic disorders, metabolic syndrome, smoking, alcohol intake, chronic or acute infections, renal disease, neoplasm, cardiovascular disease, degenerative disease, intake of anti-inflammatory drugs, exercise, or sexual intercourse in the previous 72 h were exclusion criteria. Subjects with high-sensitivity CRP (hsCRP) levels ≥3.0 mg/dL were compared with a gender- and age-matched control group of subjects with hsCRP levels <3.0 mg/dL. RESULTS: The multivariate linear regression analysis showed that hsCRP (B = 0.50, ß = 0.583, p = 0.02), total body fat (B = -2.80, ß = 0.473, p = 0.03), BMI (B = -1.45, ß = 0.390, p = 0.04) and waist circumference (B = 0.89, ß = 0.407, p = 0.04) are predictors for elevation of UACR (Table 2). However, in the stepwise model only hsCRP (B = 0.674; ß = 0.314; p = 0.04) remained significantly associated with UACR. CONCLUSIONS: Our results show that independent of the primary risk factors, elevated hsCRP levels are associated with UACR.

Las hormonas esteroides y la etiopatogénesis de padecimientos hepáticos de naturaleza fibrótica / Fibrotic liver disease and steroid hormones

Existen hipótesis en el sentido de que el estatus hormonal está involucrado en la distinta susceptibilidad entre el hombre y la mujer en el desarrollo de enfermedad hepatobiliar, ya que el hígado es órgano blanco para hormonas esteroides. En el desarrollo del fenómeno fibrogénico durante la cirrosis hepática de diversa etiología están involucradas las células de Ito, los miofibroblastos y diversas citocinas como factor transformador de crecimiento-ß, interleucina-6 y factor de necrosis tumoral-alfa. Se sabe que en el organismo existen asas de regulación mutua entre citocinas, glucocorticoides y esteroides sexuales; en el hígado, esta interacción pudiera afectar el proceso fibrogénico a través de diferenciación de células de Ito. El conocimiento del papel preciso de los glucocorticoides y las hormonas esteroides sexuales sobre los mecanismos fibrogénicos, permitiría sustentar racionalmente la viabilidad de la manipulación hormonal en el tratamiento de padecimiento hepático de natulareza fibrótica