Terfenadine induces apoptosis and autophagy in melanoma cells through ROS-dependent and -independent mechanisms

Previously we found that terfenadine, an H1 histamine receptor antagonist, acts as a potent apoptosis inducer in melanoma cells through modulation of Ca2+ homeostasis. In this report, focusing our attention on the apoptotic mechanisms activated by terfenadine, we show that this drug can potentially activate distinct intrinsic signaling pathways depending on culture conditions. Serum-deprived conditions enhance the cytotoxic effect of terfenadine and caspase-4 and -2 are activated upstream of caspase-9. Moreover, although we found an increase in ROS levels, the apoptosis was ROS independent. Conversely, terfenadine treatment in complete medium induced ROS-dependent apoptosis. Caspase-4, -2, and -9 were simultaneously activated and p73 and Noxa induction were involved. ROS inhibition prevented p73 and Noxa expression but not p53 and p21 expression, suggesting a role for Noxa in p53-independent apoptosis in melanoma cells. Finally, we found that terfenadine induced autophagy, that can promote apoptosis. These findings demonstrate the great potential of terfenadine to kill melanoma cells through different cellular signaling pathways and could contribute to define new therapeutic strategies in melanoma

Consumption of caffeinated beverages and kidney function decline in an elderly Mediterranean population with metabolic syndrome

It remains unclear whether caffeinated beverages could have deleterious renal effects in elderly population with underlying comorbid conditions. We investigated the associations between coffee, tea, or caffeine intake and 1-year changes in glomerular filtration rate (eGFR) in a large Spanish cohort of overweight/obese elderly with metabolic syndrome (MetS). This prospective analysis includes 5851 overweight/obese adults (55-75 years) with MetS from the PREDIMED-Plus study. We assessed coffee, tea, and caffeine consumption from a validated food-frequency questionnaire and creatinine-based eGFR using the Chronic Kidney Disease Epidemiology Collaboration equation. Multivariate-adjusted regression models were applied to test associations between baseline coffee, tea, or caffeine intake and 1-year eGFR changes. Caffeinated coffee (> 2 cups/day) and tea (at least 1 cup/day) drinkers had 0.88 and 0.93 mL/min/1.73 m2 greater eGFR decrease respectively, compared to those with less than 1 cup/day of coffee consumption or non-tea drinkers. Furthermore, caffeinated coffee consumption of > 2 cups/day was associated with 1.19-fold increased risk of rapid eGFR decline > 3 mL/min/1.73 m2 (95% CI 1.01-1.41). Similarly, individuals in the highest (median, 51.2 mg/day) tertile of caffeine intake had a 0.87 mL/min/1.73 m2 greater eGFR decrease. Decaffeinated coffee was not associated with eGFR changes. In conclusion, higher consumption of caffeinated coffee, tea, and caffeine was associated with a greater 1-year eGFR decline in overweight/obese adults with MetS.The authors also thank the PREDIMED-Plus Biobank Network as a part of the National Biobank Platform of the ISCIII for storing and managing the PREDIMED-Plus biological samples. This work was supported by the official Spanish Institutions for funding scientific biomedical research, CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN) and Instituto de Salud Carlos III (ISCIII), through the Fondo de Investigación para la Salud (FIS), which is co-funded by the European Regional Development Fund (five coordinated FIS projects leaded by JS-S and JVi, including the following projects: PI13/00673, PI13/00492, PI13/00272, PI13/01123, PI13/00462, PI13/00233, PI13/02184, PI13/00728, PI13/01090, PI13/01056, PI14/01722, PI14/00636, PI14/00618, PI14/00696, PI14/01206, PI14/01919, PI14/00853, PI14/01374, PI14/00972, PI14/00728, PI14/01471, PI16/00473, PI16/00662, PI16/01873, PI16/01094, PI16/00501, PI16/00533, PI16/00381, PI16/00366, PI16/01522, PI16/01120, PI17/00764, PI17/01183, PI17/00855, PI17/01347, PI17/00525, PI17/01827, PI17/00532, PI17/00215, PI17/01441, PI17/00508, PI17/01732, PI17/00926, PI19/00957, PI19/00386, PI19/00309, PI19/01032, PI19/00576, PI19/00017, PI19/01226, PI19/00781, PI19/01560, PI19/01332, PI20/01802, PI20/00138, PI20/01532, PI20/00456, PI20/00339, PI20/00557, PI20/00886, PI20/01158); the Especial Action Project entitled: Implementación y evaluación de una intervención intensiva sobre la actividad física Cohorte PREDIMED-Plus Grant to JS-S; the European Research Council (Advanced Research Grant 2014–2019; Agreement #340918) granted to MÁM-G.; the Recercaixa (Number 2013ACUP00194) grant to JS-S; grants from the Consejería de Salud de la Junta de Andalucía (PI0458/2013, PS0358/2016, PI0137/2018); the PROMETEO/2017/017 grant from the Generalitat Valenciana; the SEMERGEN grant; funds from the European Regional Development Fund (CB06/03); International Nut & Dried Fruit Council – FESNAD (Long-term effects of an energy-restricted Mediterranean diet on mortality and cardiovascular disease 2014 –2015, No. 201302) (PI: MÁM-G); the AstraZeneca Young Investigators Award in Category of Obesity and T2D 2017 (PI: DR); grant of support to research groups no. 35/2011 (Balearic Islands Gov.; FEDER funds) (JAT and CB); the JR17/00022 (ISCIII) grant to OC; the Boosting young talent call grant program for the development of IISPV research projects 2019–2021 (Ref.: 2019/IISPV/03 grant to AD-L); the Societat Catalana d'Endocrinologia i Nutrició (SCEN) Clinical-Research Grant 2019 (IPs: JS-S and AD-L)