Apoptosis and autophagy have opposite roles on imatinib-induced K562 leukemia cell senescence

Imatinib, the anti-Abl tyrosine kinase inhibitor used as first-line therapy in chronic myeloid leukemia (CML), eliminates CML cells mainly by apoptosis and induces autophagy. Analysis of imatinib-treated K562 cells reveals a cell population with cell cycle arrest, p27 increase and senescence-associated beta galactosidase (SA-β-Gal) staining. Preventing apoptosis by caspase inhibition decreases annexin V-positive cells, caspase-3 cleavage and increases the SA-β-Gal-positive cell population. In addition, a concomitant increase of the cell cycle inhibitors p21 and p27 is detected emphasizing the senescent phenotype. Inhibition of apoptosis by targeting Bim expression or overexpression of Bcl2 potentiates senescence. The inhibition of autophagy by silencing the expression of the proteins ATG7 or Beclin-1 prevents the increase of SA-β-Gal staining in response to imatinib plus Z-Vad. In contrast, in apoptotic-deficient cells (Bim expression or overexpression of Bcl2), the inhibition of autophagy did not significantly modify the SA-β-Gal-positive cell population. Surprisingly, targeting autophagy by inhibiting ATG5 is accompanied by a strong SA-β-Gal staining, suggesting a specific inhibitory role on senescence. These results demonstrate that in addition to apoptosis and autophagy, imatinib induced senescence in K562 CML cells. Moreover, apoptosis is limiting the senescent response to imatinib, whereas autophagy seems to have an opposite role.     

Distribución de la circunferencia de la cintura y de la relación circunferencia de la cintura con respecto a la talla según la categoría del índice de masa corporal en los pacientes atendidos en consultas de endocrinología y nutrición

IntroductionWaist circumference (WC) and the waist-to-height ratio (WHtR) are anthropometric measures widely used in clinical practice to evaluate visceral fat and the consequent cardiovascular risk. However, risk thresholds should be standardized according to body mass index (BMI).ObjectiveTo determine the distribution of WC and WHtR according to the BMI cut-points currently used to describe overweight and obesity.Materials and methodsWC, WHtR and BMI were measured in 3521 adult patients (>18 years) attended in Endocrinology and Nutrition units.ResultsA total of 20.8% (734 patients) were diabetic. Obesity was found in 82.1% of diabetic patients and in 75% of non-diabetic patients. The WC thresholds proposed by the National Institute of Health (102 cm in men, 88 cm in women), Bray (100 cm in men, 90 cm in women) and the International Diabetes Federation (94 cm in men, 80 cm in women) were exceeded by 92.9%, 94.8% and 98.4% of obese men, 96.8%, 95.5% and 99.7% of obese women, 79.1%, 83.1% and 90% of diabetic men and 95.5%, 81.5% and 97.4% of diabetic women, respectively. Thresholds adapted to the degree of obesity (90, 100, 110 and 125 cm in men and 80, 90, 105 and 115 cm in women for normal BMI, overweight, obesity I and obesity greater than I) were exceeded by 58.4% of obese men, 54.2% of obese women, 57.5% of diabetic men and 60.7% of diabetic women. WC was higher in men, and BMI and the WHtR were higher in women. The WC of diabetic women equalled that of men, and WC, WHtR and BMI were higher in diabetic than in non-diabetic women (p<0.001). WC (p<0.005), WHtR (p<0.001) and BMI (p<0.5) were also higher in diabetic than in non-diabetic men.ConclusionWC and WHtR thresholds by BMI discriminated diabetic and obese patients better than single thresholds, and can be represented graphically by the distribution of percentile ranks of WC and WHtR by BMI.ik     

Gene expression profiling of subcutaneous adipose tissue in morbid obesity using a focused microarray: Distinct expression of cell-cycle- and differentiation-related genes

Background

Prevalence of obesity is increasing to pandemic proportions. However, obese subjects differ in insulin resistance, adipokine production and co-morbidities. Based on fasting plasma analysis, obese subjects were grouped as Low Acylation Stimulating protein (ASP) and Triglyceride (TG) (LAT) vs High ASP and TG (HAT). Subcutaneous (SC) and omental (OM) adipose tissues (n = 21) were analysed by microarray, and biologic pathways in lipid metabolism and inflammation were specifically examined.

Methods

LAT and HAT groups were matched in age, obesity, insulin, and glucose, and had similar expression of insulin-related genes (InsR, IRS-1). ASP related genes tended to be increased in the HAT group and were correlated (factor B, adipsin, complement C3, p < 0.01 each). Differences between LAT and HAT group were almost exclusively in SC tissue, with little difference in OM tissue. Increased C5L2 (p < 0.01), an ASP receptor, in HAT suggests a compensatory ASP pathway, associated with increased TG storage.

Results

HAT adipose tissue demonstrated increased lipid related genes for storage (CD36, DGAT1, DGAT2, SCD1, FASN, and LPL), lipolysis (HSL, CES1, perilipin), fatty acid binding proteins (FABP1, FABP3) and adipocyte differentiation markers (CEBPα, CEBPβ, PPARγ). By contrast, oxidation related genes were decreased (AMPK, UCP1, CPT1, FABP7). HAT subjects had increased anti-inflammatory genes TGFB1, TIMP1, TIMP3, and TIMP4 while proinflammatory PIG7 and MMP2 were also significantly increased; all genes, p < 0.025.

Conclusion

Taken together, the profile of C5L2 receptor, ASP gene expression and metabolic factors in adipose tissue from morbidly obese HAT subjects suggests a compensatory response associated with the increased plasma ASP and TG.     

Spoilage microflora in fresh chicken breast stored at 4 °C : influence of packaging methods

Chicken breasts with skin were packaged either in air, under vacuum or in modified atmospheres of (i) 30% CO₂/70% N₂ and (ii) 70% CO₂/30% N₂. After 3, 7, 14 and 21 days of storage at 4 °C, the samples were evaluated for spoilage microbial growth, odour and overall aspect. As expected, pseudomonads grew well in air or under vacuum, but growth was suppressed in both types of modified atmosphere packaging (MAP). However, growth of lactobacilli, Enterobacteriaceae and Brochothrix thermosphacta was not inhibited in MAPs. Modified atmosphere packaging (ii) extended shelf-life up to 21 days compared to 5 days for air-packed samples.