TIGAR's promiscuity

Commentary.TIGAR [TP53 (tumour protein 53)-induced glycolysis and apoptosis regulator] protein is known for its ability to inhibit glycolysis, shifting glucose consumption towards the pentose phosphate pathway to promote antioxidant protection of cancer cells. According to sequence homology and activity analyses, TIGAR was initially considered to be a fructose-2,6- bisphosphatase; it has thus received much attention in cancer cell metabolism, given its dependence on p53 and the key role of F26BP (fructose 2,6-bisphosphate) at modulating glycolysis and gluconeogenesis. However, in a rigorous study published in this issue of the Biochemical Journal, Gerin and colleagues report that recombinant TIGAR is a 23BPG (2,3-bisphosphoglycerate) phosphatase, although it also dephosphorylates other carboxylic acid-phosphate esters and, weakly, F26BP. As such, inhibition of endogenous TIGAR leads to a dramatic increase in cellular 23BPG, influencing F26BP to a lower extent that depends on the cellular context. These results challenge the currently held notion that TIGAR modulates glycolysis through decreasing F26BP, and opens a yet unrecognized function(s) for TIGAR-mediated 23BPG control of cellular metabolism in health and disease. © The Authors Journal compilation © 2014 Biochemical Society.My laboratory is funded by the Spanish Ministry of Economy and Competitiveness [grant numbers SAF2013-41177-R and RETICEF-RD12/0043/0021], the Junta de Castilla y León [grant number SA003U13] and the European FEDER Fund.Peer Reviewe

Dichloroacetate prevents restenosis in preclinical animal models of vessel injury

PMCID: PMC4323184.-- et al.Despite the introduction of antiproliferative drug-eluting stents, coronary heart disease remains the leading cause of death in the United States. In-stent restenosis and bypass graft failure are characterized by excessive smooth muscle cell (SMC) proliferation and concomitant myointima formation with luminal obliteration. Here we show that during the development of myointimal hyperplasia in human arteries, SMCs show hyperpolarization of their mitochondrial membrane potential (Δ Ψ m) and acquire a temporary state with a high proliferative rate and resistance to apoptosis. Pyruvate dehydrogenase kinase isoform 2 (PDK2) was identified as a key regulatory protein, and its activation proved necessary for relevant myointima formation. Pharmacologic PDK2 blockade with dichloroacetate or lentiviral PDK2 knockdown prevented Δ Ψ m hyperpolarization, facilitated apoptosis and reduced myointima formation in injured human mammary and coronary arteries, rat aortas, rabbit iliac arteries and swine (pig) coronary arteries. In contrast to several commonly used antiproliferative drugs, dichloroacetate did not prevent vessel re-endothelialization. Targeting myointimal Δ Ψ m and alleviating apoptosis resistance is a novel strategy for the prevention of proliferative vascular diseases. © 2014 Macmillan Publishers Limited.This study was funded by the German Research Foundation (Deutsche Forschungsgemeinschaft (DFG), SCHR992/3-1 and SCHR992/4-1 to S.S.), the International Society for Heart and Lung Transplantation (ISHLT, to S.S.), the Förderverein des Universitären Herzzentrums Hamburg (to S.S.), the Hermann and Lilly Schilling Foundation (to C.K.), the MINECO (SAF2013-41177-R, to J.P.B.) and the NIH (NIH 1R01HL105299, to P.S.T.).Peer Reviewe

Mitochondrial control of cell bioenergetics in Parkinson's disease

PMCID: PMC5065935Parkinson disease (PD) is a neurodegenerative disorder characterized by a selective loss of dopaminergic neurons in the substantia nigra. The earliest biochemical signs of the disease involve failure in mitochondrial-endoplasmic reticulum cross talk and lysosomal function, mitochondrial electron chain impairment, mitochondrial dynamics alterations, and calcium and iron homeostasis abnormalities. These changes are associated with increased mitochondrial reactive oxygen species (mROS) and energy deficiency. Recently, it has been reported that, as an attempt to compensate for the mitochondrial dysfunction, neurons invoke glycolysis as a low-efficient mode of energy production in models of PD. Here, we review how mitochondria orchestrate the maintenance of cellular energetic status in PD, with special focus on the switch from oxidative phosphorylation to glycolysis, as well as the implication of endoplasmic reticulum and lysosomes in the control of bioenergetics.J.P.B. is funded by the MINECO (SAF2013-41177-R; RTC-2015-3237-1), the ISCIII (RD12/0043/0021), the EU SP3-People-MC-ITN program (608381), the EU BATCure grant (666918), the NIH/NIDA (1R21DA037678-01).Peer Reviewe

Design and Synthesis of CNS-targeted Flavones and Analogues with Neuroprotective Potential Against H2O2- and Aβ1-42-Induced Toxicity in SH-SY5Y Human Neuroblastoma Cells

With the lack of available drugs able to prevent the progression of Alzheimer’s disease (AD), the discovery of new neuroprotective treatments able to rescue neurons from cell injury is presently a matter of extreme importance and urgency. Here, we were inspired by the widely reported potential of natural flavonoids to build a library of novel flavones, chromen-4-ones and their C-glucosyl derivatives, and to explore their ability as neuroprotective agents with suitable pharmacokinetic profiles. All compounds were firstly evaluated in a parallel artificial membrane permeability assay (PAMPA) to assess their effective permeability across biological membranes, namely the blood-brain barrier (BBB). With this test, we aimed not only at assessing if our candidates would be well-distributed, but also at rationalizing the influence of the sugar moiety on the physicochemical properties. To complement our analysis, logD7.4 was determined. From all screened compounds, the p-morpholinyl flavones stood out for their ability to fully rescue SH-SY5Y human neuroblastoma cells against both H2O2- and Aβ1-42-induced cell death. Cholinesterase inhibition was also evaluated, and modest inhibitory activities were found. This work highlights the potential of C-glucosylflavones as neuroprotective agents, and presents the p-morpholinyl C-glucosylflavone 37, which did not show any cytotoxicity towards HepG2 and Caco-2 cells at 100 μM, as a new lead structure for further development against AD.Fundação para a Ciência e a Tecnologia-UID/Multi/0612/2019Unión Europea-D3i4AD), FP7-PEOPLE-2013-IAPP, GA 61234

Encapsulation of gold nanostructures and oil-in-water nanocarriers in microgels with biomedical potential

Indexación: Scopus.Funding: This research was funded by FONDECYT 1161450, 1150744, 11130494 and 1170929, FONDEQUIP EQM160157, EQM170111, CONICYT-FONDAP 15130011, and CONICYT PhD Scholarship 21141137.Here we report the incorporation of gold nanostructures (nanospheres or nanorods, functionalized with carboxylate-end PEG) and curcumin oil-in-water (O/W) nanoemulsions (CurNem) into alginate microgels using the dripping technique. While gold nanostructures are promising nanomaterials for photothermal therapy applications, CurNem possess important pharmacological activities as reported here. In this sense, we evaluated the effect of CurNem on cell viability of both cancerous and non-cancerous cell lines (AGS and HEK293T, respectively), demonstrating preferential toxicity in cancer cells and safety for the non-cancerous cells. After incorporating gold nanostructures and CurNem together into the microgels, microstructures with diameters of 220 and 540 µm were obtained. When stimulating microgels with a laser, the plasmon effect promoted a significant rise in the temperature of the medium; the temperature increase was higher for those containing gold nanorods (11–12 ◦ C) than nanospheres (1–2 ◦ C). Interestingly, the incorporation of both nanosystems in the microgels maintains the photothermal properties of the gold nanostructures unmodified and retains with high efficiency the curcumin nanocarriers. We conclude that these results will be of interest to design hydrogel formulations with therapeutic applications. © 2018 by the authors.https://www.mdpi.com/1420-3049/23/5/120

The HABP2 G534E polymorphism does not increase nonmedullary thyroid cancer risk in Hispanics.

Familial nonmedullary thyroid cancer (NMTC) has not been clearly linked to causal germline variants, despite the large role that genetic factors play in risk. Recently, HABP2 G534E (rs7080536A) has been implicated as a causal variant in NMTC. We have previously shown that the HABP2 G534E variant is not associated with TC risk in patients from the British Isles. Hispanics are the largest and the youngest minority in the United States and NMTC is now the second most common malignancy in women from this population. In order to determine if the HABP2 G534E variant played a role in NMTC risk among Hispanic populations, we analyzed 281 cases and 1105 population-matched controls from a multicenter study in Colombia, evaluating the association through logistic regression. We found that the HABP2 G534E variant was not significantly associated with NMTC risk (P=0.843) in this Hispanic group. We also stratified available clinical data by multiple available clinicopathological variables and further analyzed the effect of HABP2 on NMTC presentation. However, we failed to detect associations between HABP2 G534E and NMTC risk, regardless of disease presentation (P≥0.273 for all cases). Therefore, without any significant associations between the HABP2 G534E variant and NMTC risk, we conclude that the variant is not causal of NMTC in this Hispanic population

Unparticle physics and neutrino phenomenology

We have constrained unparticle interactions with neutrinos and electrons using available data on neutrino-electron elastic scattering and the four CERN LEP experiments data on mono photon production. We have found that, for neutrino-electron elastic scattering, the MUNU experiment gives better constraints than previous reported limits in the region d>1.5. The results are compared with the current astrophysical limits, pointing out the cases where these limits may or may not apply. We also discuss the sensitivity of future experiments to unparticle physics. In particular, we show that the measurement of coherent reactor neutrino scattering off nuclei could provide a good sensitivity to the couplings of unparticle interaction with neutrinos and quarks. We also discuss the case of future neutrino-electron experiments as well as the International Linear Collider.Comment: 20 pages, 5 figures. Minor changes, final versio

APC/C-Cdh1-targeted substrates as potential therapies for Alzheimer’s disease

Alzheimer’s disease (AD) is the most prevalent neurodegenerative disorder and the main cause of dementia in the elderly. The disease has a high impact on individuals and their families and represents a growing public health and socio-economic burden. Despite this, there is no effective treatment options to cure or modify the disease progression, highlighting the need to identify new therapeutic targets. Synapse dysfunction and loss are early pathological features of Alzheimer’s disease, correlate with cognitive decline and proceed with neuronal death. In the last years, the E3 ubiquitin ligase anaphase promoting complex/cyclosome (APC/C) has emerged as a key regulator of synaptic plasticity and neuronal survival. To this end, the ligase binds Cdh1, its main activator in the brain. However, inactivation of the anaphase promoting complex/cyclosome-Cdh1 complex triggers dendrite disruption, synapse loss and neurodegeneration, leading to memory and learning impairment. Interestingly, oligomerized amyloid-β (Aβ) peptide, which is involved in Alzheimer’s disease onset and progression, induces Cdh1 phosphorylation leading to anaphase promoting complex/cyclosome-Cdh1 complex disassembly and inactivation. This causes the aberrant accumulation of several anaphase promoting complex/cyclosome-Cdh1 targets in the damaged areas of Alzheimer’s disease brains, including Rock2 and Cyclin B1. Here we review the function of anaphase promoting complex/cyclosome-Cdh1 dysregulation in the pathogenesis of Alzheimer’s disease, paying particular attention in the neurotoxicity induced by its molecular targets. Understanding the role of anaphase promoting complex/cyclosome-Cdh1-targeted substrates in Alzheimer’s disease may be useful in the development of new effective disease-modifying treatments for this neurological disorder

Nuevo registro y ampliación de distribución del búho bicolor (Aegolius harrisii) en Colombia

The Buff-fronted Owl (Aegolius harrisii) is a rare nocturnal raptorial species with a wide distribution in South America. We report a new distribution record in the Regional Natural Park Cerro Páramo de Miraflores, in the department of Huila, Colombia. This is an expansion of its geographical range towards the south along the eastern Andes mountain range, confirming a continuous distribution along the Andes and increasing the upper limit of its altitudinal range by 464 meters.El búho bicolor (Aegolius harrisii) es un ave rapaz nocturna poco conocida, con distribución amplia y discontinua en Suramérica. Reportamos un nuevo registro de distribución de A. harrisii para Colombia, en el Parque Natural Regional Cerro Páramo de Miraflores, departamento del Huila. Este registro constituye una ampliación geográfica de la distribución conocida para esta especie hacia el sur de la cordillera Oriental. Corrobora la continuidad de su distribución a lo largo de los Andes, y también amplía 464 metros el límite superior de su rango altitudinal

Nuevo registro y ampliación de distribución del búho bicolor (<i>Aegolius harrisii</i>) en Colombia

El búho bicolor (Aegolius harrisii) es un ave rapaz nocturna poco conocida, con distribución amplia y discontinua en Suramérica. Reportamos un nuevo registro de distribución de A. harrisii para Colombia, en el Parque Natural Regional Cerro Páramo de Miraflores, departamento del Huila. Este registro constituye una ampliación geográfica de la distribución conocida para esta especie hacia el sur de la cordillera Oriental. Corrobora la continuidad de su distribución a lo largo de los Andes, y también amplía 464 metros el límite superior de su rango altitudinal