Publications by authors named "Andres Jimenez"

31 Publications

Diabetes Second-Line Medication Prescription Patterns in Costa Rica and Panama: Evidence From the DISCOVER Registry.

Cureus 2021 Jun 30;13(6):e16060. Epub 2021 Jun 30.

Internal Medicine, Private Practice, Penonomé, PAN.

Aim: This study aimed to describe the prescription patterns of second-line medications for patients with diabetes from selected centers in Costa Rica and Panama.

Methods: DISCOVER is a registry of patients with type 2 diabetes switching from first- to second-line medications. We analyzed medication choice and the reasons to switch for each country.  Results: A total of 219 patients were included during 2014-2016, 127 in Costa Rica and 92 in Panama. The most frequently prescribed first-line medication was metformin, followed by sulphonylureas in Panama, and a combination of metformin and dipeptidyl peptidase-4 inhibitor (iDPP4) in Costa Rica. DPP4 inhibitors plus metformin was the most commonly prescribed second-line medication, followed by metformin combined with sodium-glucose transport protein-2 inhibitor (iSGLT2) in Costa Rica and iDPP4 in monotherapy in Panama. The main reason to switch being efficacy. When choosing the second-line medication, the main reasons behind the switch were efficacy, weight loss, and hypoglycemia risk in both countries (tolerability being also common in Panama).

Conclusions: According to the DISCOVER registry, in Costa Rica and Panama, efficacy is the most common reason to switch to second-line medication. Metformin plus iDPP4 was the most commonly prescribed agent.
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http://dx.doi.org/10.7759/cureus.16060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8328805PMC
June 2021

Sclerosing angiomatoid nodular transformation (SANT) of the spleen: a rare cause of acute abdomen.

J Surg Case Rep 2021 Apr 9;2021(4):rjab126. Epub 2021 Apr 9.

Instituto Ecuatoriano de Seguridad Social, Department of Internal Medicine at Hospital IESS Quito Sur, Quito, Ecuador.

Sclerosing angiomatoid nodular transformation (SANT) of the spleen is an extremely rare benign lesion. It originates from the spleen's red pulp; however, its pathogenesis is not clearly defined. These tumors are usually asymptomatic or cause nonspecific abdominal symptoms. Most SANTs are found incidentally on radiographic examination or during surgery for an unrelated condition. The differential diagnosis from other splenic tumors or malignant lesions can be challenging due to the risk for a possible malignancy of the suspicious lesion. As more SANTs are being discovered and treated, they should always be considered in the differential. We present the case of an otherwise healthy 30-year-old female; she presented with abdominal pain and a mass in her spleen. Surgery was performed, and an SANT was discovered. The patient underwent full recovery, and on follow-up is doing well.
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http://dx.doi.org/10.1093/jscr/rjab126DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8034883PMC
April 2021

Emergency CABG for a migrated stent in a COVID-19 positive patient.

J Card Surg 2021 Aug 25;36(8):2933-2934. Epub 2021 Mar 25.

Division of Cardiovascular Surgery, Fundación Clínica Shaio, Bogotá, Colombia.

Percutaneous coronary interventions (PCI) have become a standard of treatment worldwide. Despite high safety rates, iatrogenic complications caused by stent dislodgements do exist in 0.21% of cases and most require emergency coronary artery by-pass grafting (CABG). Here we present a case of a coronavirus disease 2019 positive 40-year-old male patient presenting with STEMI due to thrombotic lesions in his left coronary trunk. The patient is taken to PCI and stent placement. Stent dislodgement results in the need for emergency CABG and stent removal. Informed consent and ethics approval were obtained.
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http://dx.doi.org/10.1111/jocs.15523DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8251245PMC
August 2021

Sulphur mustard induces progressive toxicity and demyelination in brain cell aggregate culture.

Neurotoxicology 2021 05 19;84:114-124. Epub 2021 Mar 19.

Defence Research & Development Canada, Suffield Research Centre, Box 4000, Medicine Hat, Alberta, T1A 8K6, Canada.

Sulphur mustard (H; bis(2-chloroethyl) sulphide) is a vesicant chemical warfare (CW) agent that has been well documented as causing acute injury to the skin, eyes and respiratory system. Although a great deal of research effort has been expended to understand how H exerts these effects, its mechanism of action is still poorly understood. At high exposures, H also causes systemic toxicity with chronic and long-term effects to the immune, cardiovascular and central nervous systems, and these aspects of H poisoning are much less studied and comprehended. Rat aggregate cultures comprised of multiple brain cell types were exposed to H and followed for four weeks post-exposure to assess neurotoxicity. Toxicity (LDH, caspase-3 and aggregate diameter) was progressive with time post-exposure. In addition, statistically significant changes in neurofilament heavy chain (NFH), glial fibrillary acidic protein (GFAP), Akt phosphorylation, IL-6, GRO-KC and TNF-α were noted that were time- and concentration-dependent. Myelin basic protein, CNPase and vascular endothelial growth factor (VEGF) were found to be especially sensitive to H exposure in a time- and concentration-dependent fashion, with levels falling to ∼50 % of control values at ∼10 μM H by 8 days post-exposure. Demyelination and VEGF inhibition may be causal in the long-term neuropsychological illnesses that have been documented in casualties exposed to high concentrations of H, and may also play a role in the peripheral neuropathy that has been observed in some of these individuals.
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http://dx.doi.org/10.1016/j.neuro.2021.03.004DOI Listing
May 2021

PyDSLRep: A domain-specific language for robotic simulation in V-Rep.

PLoS One 2020 1;15(7):e0235271. Epub 2020 Jul 1.

Department of Computer Science, University of Manchester, Manchester, United Kingdom.

Calculating forward and inverse kinematics for robotic agents is one of the most time-intensive tasks when controlling the robot movement in any environment. This calculation is then encoded to control the motors and validated in a simulator. The feedback produced by the simulation can be used to correct the code or to implement the code can be implemented directly in the robotic agent. However, the simulation process executes instructions that are not native to the robotic agents, extending development time or making it preferable to validate the code directly on the robot, which in some cases might result in severe damage to it. The use of Domain-Specific Languages help reduce development time in simulation tasks. These languages simplify code generation by describing tasks through an easy-to-understand language and free the user to use a framework or programming API directly for testing purposes. This article presents the language PyDSLRep, which is characterized by the connection and manipulation of movement in mobile robotic agents in the V-Rep simulation environment. This language is tested in three different environments by twenty people, against the framework given by V-Rep, demonstrating that PyDSLRep reduces the average development time by 45.22%, and the lines of code by 76.40% against the Python framework of V-Rep.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0235271PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7329094PMC
September 2020

Pedestrian counting estimation based on fractal dimension.

Heliyon 2019 Apr 8;5(4):e01449. Epub 2019 Apr 8.

Department of Electronic Engineering, Fundación Universitaria Los Libertadores, Carrera 16 No. 63 A - 68, Bogotá, Colombia.

Counting the number of pedestrians in urban environments has become an area of interest over the past few years. Its applications include studies to control vehicular traffic lights, urban planning, market studies, and detection of abnormal behaviors. However, these tasks require the use of intelligent algorithms of high computational demand that need to be trained in the environment being studied. This article presents a novel method to estimate pedestrian flow in uncontrolled environments by using the fractal dimension measured through the box-counting algorithm, which does not require the use of image pre-processing and intelligent algorithms. Four scenarios were used to validate the method presented in this article, of which the last scene was a low-light surveillance video, showing experimental results with a mean relative error of 4.92% when counting pedestrians. After comparing the results with other techniques that depend on intelligent algorithms, we can confirm that this method achieves improved performance in the estimation of pedestrian traffic.
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http://dx.doi.org/10.1016/j.heliyon.2019.e01449DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6458473PMC
April 2019

Vitamin D binding protein, but not vitamin D or vitamin D-related peptides, is associated with septic shock mortality.

Enferm Infecc Microbiol Clin (Engl Ed) 2019 Apr 20;37(4):239-243. Epub 2018 Nov 20.

Health Research Institute Valdecilla-IDIVAL, University of Cantabria, School of Nursing, Avenida de Valdecilla s/n 39008, Santander, Spain.

Background: The aim of this study was to assess the prognostic value of vitamin D, vitamin D binding protein (VDBP) and vitamin D-related peptides in septic shock patients in relation to hospital mortality.

Methods: This is a single-center, prospective, observational study that included all consecutive patients meeting criteria for septic shock who were admitted to the ICU. VDBP, 25-hydroxy vitamin D, 1,25-dihydroxy vitamin D, cathelicidin and beta-defensin levels were determined in blood samples obtained on admission to the ICU.

Results: Seventy-five patients were studied. The best area under the curve (AUC) for prediction of in-hospital mortality was for VDBP (0.78), with a negative predictive value of 85.45% for the optimal cut-off point. VDBP was also the only variable that had a statistically significant association with a higher risk of in-hospital mortality, regardless of other assessed variables and pre-determined confounders: adjusted odds ratio of 5.20 (95% confidence interval: 1.21-22.36). When restricted to patients with vitamin D insufficiency (n=54), the AUC was 0.77, and the adjusted OR 12.22 (95% CI: 1.46-102.14; p=0.021) for in-hospital mortality.

Conclusions: VDBP levels showed a statistically significant association with in-hospital mortality, supporting the clinical utility of VDBP as a good prognostic marker in septic shock patients. Vitamin D and vitamin D-related peptides are not associated with in-hospital mortality. These results should be confirmed in a multicentre study with a larger sample size.
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http://dx.doi.org/10.1016/j.eimc.2018.06.011DOI Listing
April 2019

Decentralized Online Simultaneous Localization and Mapping for Multi-Agent Systems.

Sensors (Basel) 2018 Aug 9;18(8). Epub 2018 Aug 9.

Department of Engineering, Distrital University Francisco José de Caldas, 110221 Bogotá, Colombia.

Planning tasks performed by a robotic agent require previous access to a map of the environment and the position where the agent is located. This creates a problem when the agent is placed in a new environment. To solve it, the RA must execute the task known as Simultaneous Location and Mapping (SLAM) which locates the agent in the new environment while generating the map at the same time, geometrically or topologically. One of the big problems in SLAM is the amount of memory required for the RA to store the details of the environment map. In addition, environment data capture needs a robust processing unit to handle data representation, which in turn is reflected in a bigger RA unit with higher energy use and production costs. This article presents a design for a system capable of a decentralized implementation of SLAM that is based on the use of a system comprised of wireless agents capable of storing and distributing the map as it is being generated by the RA. The proposed system was validated in an environment with a surface area of 25 m 2 , in which it was capable of generating the topological map online, and without relying on external units connected to the system.
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http://dx.doi.org/10.3390/s18082612DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6111967PMC
August 2018

A Decentralized Framework for Multi-Agent Robotic Systems.

Sensors (Basel) 2018 Feb 1;18(2). Epub 2018 Feb 1.

Department of Engineering, Distrital University Francisco José de Caldas, Cr.7#40B-53 Bogotá, Colombia.

Over the past few years, decentralization of multi-agent robotic systems has become an important research area. These systems do not depend on a central control unit, which enables the control and assignment of distributed, asynchronous and robust tasks. However, in some cases, the network communication process between robotic agents is overlooked, and this creates a dependency for each agent to maintain a permanent link with nearby units to be able to fulfill its goals. This article describes a communication framework, where each agent in the system can leave the network or accept new connections, sending its information based on the transfer history of all nodes in the network. To this end, each agent needs to comply with four processes to participate in the system, plus a fifth process for data transfer to the nearest nodes that is based on Received Signal Strength Indicator (RSSI) and data history. To validate this framework, we use differential robotic agents and a monitoring agent to generate a topological map of an environment with the presence of obstacles.
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http://dx.doi.org/10.3390/s18020417DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5855891PMC
February 2018

[Psychosocial risk factors and work satisfaction in female seasonal workers in Chile].

Rev Panam Salud Publica 2015 May;37(4-5):301-7

Facultad de Psicología, Universidad de Talca, Talca, Chile.

Objective: Characterize the relationship between psychosocial risk factors and work satisfaction in female seasonal agricultural workers in central Chile.

Methods: Cross-sectional study in a non-probability sample of 106 female workers for a fruit trading and export company in the region of Maule, Chile. The interviews were conducted in September and October 2013. The SUSESO ISTA-21 questionnaire was used to evaluate five areas of psychosocial risk in the workplace (psychological requirements, active work and opportunities for development, social support in the company and quality of leadership, compensation, and "double presence"). Questionnaire S10/12 was used to measure labor satisfaction in three areas (satisfaction with benefits received, satisfaction with the company's physical environment, and satisfaction with supervision) and satisfaction in general.

Results: The level of psychosocial risk was high in two areas (double presence, and active work and possibilities of development) and medium in the other areas; the level of satisfaction was high in all three areas. The perception of psychosocial risk factors was negatively associated with work satisfaction in three areas: active work and opportunities for development, social support in the company and quality of leadership, and compensation (compensation was negatively associated except for satisfaction with the company's physical environment).

Conclusions: Risks associated with seasonal work and the main issues that workers consider to affect their satisfaction with work and, by extension, their general well-being, are concentrated mainly in the three areas identified.
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May 2015

Neuronal cell cycle re-entry markers are altered in the senescence accelerated mouse P8 (SAMP8).

J Alzheimers Dis 2012 ;30(3):573-83

Departments of Neurosciences, Case Western Reserve University School of Medicine, Cleveland, OH, USA.

Senescence-accelerated mice 8 (SAMP8), a model of aging, display many established pathological features of Alzheimer's disease (AD); however, whether cell cycle alterations exist in these animals remains unknown. Given that these animals present changes such as tau phosphorylation and redox imbalance, both associated with cell cycle alterations, we determined whether changes in cell cycle markers were present in SAMP8 and SAMR1 (control strain) at 3, 6, and 9 months-old brains. As expected, an increase in tau hyperphosphorylation and its associated machinery, i.e., cdk5 and GSK3β, was observed both between strains and also with aging. Particularly, significant differences in cyclin A, cyclin D1, cyclin E, Cdk2, cyclin B, pR, and E2F1 were found when comparing SAMP8 to SAMR1. More interestingly, a partial correlation with several cell cycle markers described in AD brain is found in SAMP8, indicating that some specific hallmarks of AD are also present in this strain, which has been postulated as an early switch model of the disease.
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http://dx.doi.org/10.3233/JAD-2012-120112DOI Listing
October 2012

Evaluation of potential pro-survival pathways regulated by melatonin in a murine senescence model.

J Pineal Res 2008 Nov 13;45(4):497-505. Epub 2008 Aug 13.

Unitat de Farmacologia i Farmacognòsia Facultat de Farmàcia, Institut de Biomedicina (IBUB), Centros de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, Universitat de Barcelona, Nucli Universitari de Pedralbes, Barcelona, Spain.

We examined the effect of melatonin on pro-survival processes in three groups of mice. Untreated senescence-accelerated mice (SAMP8), melatonin-treated SAMP8 and untreated senescence-accelerated resistant mice (SAMR1) of 10 months old were studied. Melatonin (10 mg/kg) or vehicle (ethanol at 0.066%) was supplied in the drinking water from the end of the first month until the end of the ninth month of life. Differences in the Akt/Erk1-2 pathway and downstream targets were examined and no significant changes were observed, except for beta-catenin. However, sirtuin 1 expression was significantly lower in SAMP8 than in SAMR1. In addition, acetylated p53 and NFkappaB expression were lower in SAMP8 than in SAMR1. These changes were prevented by melatonin. Moreover, the concentration/expression of alpha-secretase was lower and that of amyloid beta aggregates (Abeta) was higher in untreated SAMP8 than in SAMR1. Likewise, the levels of Bid were higher, whereas Bcl-2(XL) levels were lower in SAMP8 than in SAMR1. Melatonin reduced all these changes. We conclude that melatonin improves pro-survival signals and reduces pro-death signals in age-related impairments of neural processes.
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http://dx.doi.org/10.1111/j.1600-079X.2008.00626.xDOI Listing
November 2008

GSK-3 beta inhibition and prevention of mitochondrial apoptosis inducing factor release are not involved in the antioxidant properties of SB-415286.

Eur J Pharmacol 2008 Jul 11;588(2-3):239-43. Epub 2008 Apr 11.

Unitat de Farmacologia i Farmacognòsia and Institut de Biomedicina (IBUB), Facultat de Farmàcia, Universitat de Barcelona, Nucli Universitari de Pedralbes, 08028 Barcelona, Spain.

The antioxidant effects of lithium and SB-415286, two glycogen synthase kinase-3 beta (GSK-3 beta) inhibitors, were studied in cerebellar granule neurons by measuring changes in 2, 7-dichlorodihydrofluorescein diacetate (H2DCFDA) fluorescence. GSK-3 beta inhibitors inhibit apoptosis mediated by serum and potassium withdrawal (S/K withdrawal) and GSK-3 beta activation, as measured by beta-catenin degradation. Furthermore, as both drugs prevent mitochondrial apoptosis inducing factor (AIF) release, these data indicate that GSK-3 beta inhibitors prevent caspase-independent apoptosis in cerebellar granule neurons induced by S/K withdrawal. While the most specific GSK-3 beta inhibitor, SB-415286, demonstrated antioxidant effects, Li+ 10 mM did not. These results indicate that lithium 10 mM and SB-415286 20 microM exert anti-apoptotic effects in cases of S/K withdrawal mediated by GSK-3 beta inhibition. However, these antioxidant properties are independent of GSK-3 beta inhibition and prevention of mitochondrial AIF release.
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http://dx.doi.org/10.1016/j.ejphar.2008.04.019DOI Listing
July 2008

Improving spatial perception in 5-yr.-old Spanish children.

Percept Mot Skills 2007 Jun;104(3 Pt 2):1223-35

Departamento de Didáctica de la Expresión Musical, Plastica y Corporal Facultad de Educación y Humanidades, Universidad de Granada, Campus Melilla, Spain.

Assimilation of distance perception was studied in 70 Spanish primary school children. This assimilation involves the generation of projective images which are acquired through two mechanisms. One mechanism is spatial perception, wherein perceptual processes develop ensuring successful immersion in space and the acquisition of visual cues which a person may use to interpret images seen in the distance. The other mechanism is movement through space so that these images are produced. The present study evaluated the influence on improvements in spatial perception of using increasingly larger spaces for training sessions within a motor skills program. Visual parameters were measured in relation to the capture and tracking of moving objects or ocular motility and speed of detection or visual reaction time. Analysis showed that for the group trained in increasingly larger spaces, ocular motility and visual reaction time were significantly improved during. different phases of the program.
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http://dx.doi.org/10.2466/pms.104.4.1223-1235DOI Listing
June 2007

[Waist circumference as a predictor of insulin resistance in young men].

Med Clin (Barc) 2005 Jun;125(2):46-50

Departamento de Medicina, Universidad de Cádiz, Cádiz, Spain.

Background And Objective: Waist circumference (WC) is a measure of upper body fat and so should be useful for identifying overweight and obese men at risk of developing metabolic complications. The objective was to determine the relations of WC to cardiovascular risk factors in a sample of young men and to assess the clinical relevance of WC in identifying insulin resistance.

Subjects And Method: This study included 194 male Spanish subjects aged 26 (5) years who were divided in 3 groups according to the WC: Normal (< 94 cm), moderate risk (> or = 94 cm) and elevated risk (> or = 102 cm). Body mass index (BMI), WC, blood pressure, serum levels of total cholesterol, triglycerides (TG), HDL-cholesterol, LDL-cholesterol, glucose, uric acid and insulin were measured by standard methods. The homeostasis model assessment was applied to estimate the degree of insulin resistance (HOMAIR).

Results: The prevalence of overweight and obesity was 46.9% and 6.7% respectively. Men with moderate and elevated risk showed higher concentrations of glucose (p < 0.004), uric acid (p < 0.001), TG (p < 0.001), LDL-cholesterol/HDL-cholesterol index (p < 0.001), insulin (p < 0.001) and HOMAIR (p < 0.001). WC was significantly correlated with age (r = 0,282; p < 0.001), TG (r = 0.308; p < 0,001), insulin (r = 0.282; p < 0.001) and HOMAIR (r = 0.281; p < 0.001). A multivariate linear correlation analysis showed that HOMAIR was significantly associated with WC (p < 0.009) and TG (p < 0.003; r2 = 0.13).

Conclusions: WC of these young men was independently associated with certain cardiovascular risk factors, in particular insulin resistance. This suggests that WC may be reasonably included in clinical practice as a simple tool that may help identify sub-groups of overweight or obese young men at higher metabolic risk.
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http://dx.doi.org/10.1157/13076462DOI Listing
June 2005

Inhibition of multiple pathways accounts for the antiapoptotic effects of flavopiridol on potassium withdrawal-induced apoptosis in neurons.

J Mol Neurosci 2005 ;26(1):71-84

Unitat de Farmacologia i Farmacognòsia, Facultat de Farmàcia, Universitat de Barcelona, Nucli Universitari de Pedralbes, E-08028 Barcelona, Spain.

Serum and potassium (S/K) deprivation is a well-known apoptotic model in cerebellar granule neurons (CGNs), used to study the efficacy of potential neuroprotective drugs. The objective of this study was to determine the pathways involved in the neuroprotective role of flavopiridol, a pan-inhibitor of cyclin-dependent kinases (CDKs), upon S/K withdrawal-induced apoptosis in CGNs. Cell death in primary cultures of rat CGNs was accompanied by chromatin condensation and activation of caspases-3, -6, and -9. Caspase-3 activity was also evaluated by cleavage of 120-kDa alpha-spectrin. Flavopiridol (1 microM) prevented caspase activation and abolished apoptotic features mediated by S/K withdrawal. Re-entry in the cell cycle is also involved in apoptotic neuronal cell death. Flavopiridol (1 microM) inhibited DNA synthesis as measured by BrdU incorporation, thus enhancing proliferating cell nuclear antigen expression. Serum/potassium (S/K) deprivation induced apoptotic cell death mediated by the activation of several kinases such as glycogen synthase kinase-3beta and CDK5, as well as the breakdown of p35 in the neurotoxic fragment p25; inactivation of myocyte enhancer factor-2 (MEF2) was also found. Pretreatment with flavopiridol prevented these biochemical and molecular alterations. Taken together, these findings suggest an apoptotic route in CGNs after S/K withdrawal mediated by the activation of several kinases involved in cell cycle deregulation and MEF2 inactivation. We propose that the antiapoptotic properties of flavopiridol are mediated through kinase pathway inhibition.
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http://dx.doi.org/10.1385/JMN:26:1:071DOI Listing
October 2005

Evaluation of the neuronal apoptotic pathways involved in cytoskeletal disruption-induced apoptosis.

Biochem Pharmacol 2005 Aug;70(3):470-80

Unitat de Farmacologia i Farmacognòsia, Facultat de Farmàcia, Universitat de Barcelona, Nucli Universitari de Pedralbes, E-08028 Barcelona, Spain.

The cytoskeleton is critical to neuronal functioning and survival. Cytoskeletal alterations are involved in several neurodegenerative diseases such as Alzheimer's and Parkinson's diseases. We studied the possible pathways involved in colchicine-induced apoptosis in cerebellar granule neurons (CGNs). Although colchicine evoked an increase in caspase-3, caspase-6 and caspase-9 activation, selective caspase inhibitors did not attenuate apoptosis. Inhibitors of other cysteine proteases such as PD150606 (a calpain-specific inhibitor), Z-Phe-Ala fluoromethyl ketone (a cathepsins-inhibitors) and N(alpha)-p-tosyl-l-lysine chloromethyl ketone (serine-proteases inhibitor) also had no effect on cell death/apoptosis induced by colchicine. However, BAPTA-AM 10 microM (intracellular calcium chelator) prevented apoptosis mediated by cytoskeletal alteration. These data indicate that calcium modulates colchicine-induced apoptosis in CGNs. PARP-1 inhibitors did not prevent apoptosis mediated by colchicine. Finally, colchicine-induced apoptosis in CGNs was attenuated by kenpaullone, a cdk5 inhibitor. Kenpaullone and indirubin also prevented cdk5/p25 activation mediated by colchicine. These findings indicate that cytoskeletal alteration can compromise cdk5 activation, regulating p25 formation and suggest that cdk5 inhibitors attenuate apoptosis mediated by cytoskeletal alteration. The present data indicate the potential therapeutic value of drugs that prevent the formation of p25 for the treatment of neurodegenerative disorders.
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http://dx.doi.org/10.1016/j.bcp.2005.04.036DOI Listing
August 2005

Inhibition of the cdk5/MEF2 pathway is involved in the antiapoptotic properties of calpain inhibitors in cerebellar neurons.

Br J Pharmacol 2005 Aug;145(8):1103-11

Rudolf-Boehm-Institut für Pharmakologie und Toxikologie, Universität Leipzig, Härtelstrasse, 16-18, 04107 Leipzig, Germany.

Experimental data implicate calpain activation in the pathways involved in neuronal apoptosis. Indeed, calpain inhibitors confer neuroprotection in response to various neurotoxic stimuli. However, the pathways involved in calpain activation-induced apoptosis are not well known. We demonstrate that apoptosis (40%) induced by serum/potassium (S/K) withdrawal on cerebellar granule cells (CGNs) is inhibited by selective calpain inhibitors PD150606 (up to 15%) and PD151746 (up to 29%), but not PD145305 in CGNs. zVAD-fmk, a broad spectrum inhibitor of caspases, attenuates apoptosis (up to 20%) mediated by S/K deprivation and protects against cell death, as measured by MTT ([3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium]) assay. PD150606 and PD151746 prevented apoptosis mediated by S/K withdrawal through inhibition of calpain. Furthermore, PD151746 was able to inhibit caspase-3 activity. After S/K withdrawal, we observed an increase in cdk5/p25 formation and MEF2 phosphorylation that was prevented by 40 microM PD150606 and PD151746. This indicates that calpain inhibition may be an upstream molecular target that prevents neuronal apoptosis in vitro. Taken together, these data suggest an apoptotic route in S/K withdrawal in CGNs mediated by calpain activation, cdk5/p25 formation and MEF2 inhibition. Calpain inhibitors may attenuate S/K withdrawal-induced apoptosis and may provide a potential therapeutic target for drug treatment in a neurodegenerative process.
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http://dx.doi.org/10.1038/sj.bjp.0706280DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1576230PMC
August 2005

p21(WAF1/Cip1) is not involved in kainic acid-induced apoptosis in murine cerebellar granule cells.

Brain Res 2004 Dec;1030(2):297-302

Unitat de Farmacologia i Farmacognòsia, Facultat de Farmàcia, Universitat de Barcelona, Nucli Universitari de Pedralbes, E-08028 Barcelona, Spain.

Kainic acid (KA) treatment induced neuronal death and apoptosis in murine cerebellar granule cells (CGNs) cultures from both wild-type and knockout p21(-/-) mice. There was not statistically significant difference in the percentage of neuronal apoptosis among strains. KA-induced neurotoxicity was prevented in the presence of NBQX (20 microM) and GYKI 52446 (20 microM), but not by z-VAD-fmk, suggesting that caspases are not involved in the apoptotic process. Data suggest that p21(WAF/Cip) was unable to modulate KA-induced apoptosis in murine CGNs.
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http://dx.doi.org/10.1016/j.brainres.2004.09.052DOI Listing
December 2004

Neurotoxicity of amphetamine derivatives is mediated by caspase pathway activation in rat cerebellar granule cells.

Toxicol Appl Pharmacol 2004 Apr;196(2):223-34

Unitat de Farmacologia i Farmacognòsia, Facultat de Farmàcia, Universitat de Barcelona, Barcelona 08028, Spain.

The neurotoxic action of the abuse drugs methamphetamine (METH) and 3,4-methylenedioxymethamphetamine (MDMA) on cerebellar granule neurones (CGNs) culture was examined. Treatment for 48 h with METH or MDMA (1-5 mM) induced a higher decrease in viability than 24 h treatment. z.VAD.fmk (100 microM) but not MK-801 nor NBQX recovered control viability values. In both cases, cell death was characterised as apoptotic rather than necrotic by morphology cell observation. Apoptosis measured by flow cytometry indicated an increase in the hypodiploid population after 48 h treatment with METH and MDMA. Apoptosis was reverted by the presence of z.VAD.fmk (100 microM) but not by 10 microM MK-801 or NBQX. Similar results were obtained by analysing nuclear chromatine condensation. These results ruled out excitotoxic participation in amphetamine derivative-induced neurotoxicity in CGNs. Participation of radical oxygen species (ROS) was evaluated using alpha-tocopherol (1-15 microM) and cytometric studies. The co-treatment with 4 mM METH or MDMA for 48 h partially reverted neurotoxic action and apoptotic features, indicating ROS implication in CGNs death by amphetamine derivatives. Alteration of mitochondrial function induced cytochrome C (Cyt C) release after 48-h treatment with METH and MDMA (4 mM). There was also indication of caspase-3-like activation, measured by immunoanalysis and biochemically. Finally, neurodegenerative action caused by amphetamine derivatives may be prevented by using caspase inhibitors.
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http://dx.doi.org/10.1016/j.taap.2003.12.017DOI Listing
April 2004

Inhibition of CDKs: a strategy for preventing kainic acid-induced apoptosis in neurons.

Ann N Y Acad Sci 2003 Dec;1010:671-4

Unitat de Farmacologia i Farmacognòsia, Facultat de Farmàcia, Universitat de Barcelona, Barcelona, Spain.

Stimulation of ionotropic glutamate receptors are implicated in neurodegenerative diseases such as Alzheimer's and Parkinson's diseases. Recently this has been demonstrated in the expression of cell cycle proteins in vulnerable neurons in Alzheimer's disease. Thus, the aim of the present study was to evaluate the expression of cell cycle proteins in cerebellar granule cells after stimulation of AMPA/KA receptors and likewise to study the neuroprotective effects of CDK inhibitors. Our results demonstrated that after a treatment with CDK inhibitors, a significant decrease in apoptotic nuclei induced by kainic acid was found in the presence of flavopiridol and 3-ATA. We concluded that CDK activation is involved, at least, in part, in the pro-apoptotic effects of kainic acid.
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http://dx.doi.org/10.1196/annals.1299.122DOI Listing
December 2003

Cyclosporin A enhances colchicine-induced apoptosis in rat cerebellar granule neurons.

Br J Pharmacol 2004 Feb;141(4):661-9

Unitat de Farmacologia i Farmacognòsia, Facultat de Farmàcia, Universitat de Barcelona, Nucli Universitari de Pedralbes, Barcelona E-08028, Spain.

1. Cyclosporin A (CsA, 1-50 microM), an immunosuppressive drug with known neurotoxic effects, did not decrease the viability of primary cultures of rat cerebellar granule neurons (CGN) or induce apoptotic features. However, CsA specifically enhanced the cytotoxicity and apoptosis induced by colchicine (1 microM). 2. Flavopiridol, an inhibitor of cyclin-dependent kinases (CDKs), prevented the neurotoxic effects of colchicine plus CsA. At 0.1-5 microM, it also showed antiapoptotic effects, as revealed by propidium iodide staining, flow cytometry and counting of cell nuclei. 3. Roscovitine (25-50 microM), a selective cdk1, 2 and 5 inhibitor, showed an antiapoptotic effect against colchicine- and colchicine plus CsA-induced apoptosis. 4. CsA increased the expression of cdk5 and cdk5/p25 mediated by colchicine, a CDK involved in neuronal apoptosis. After treatment of CGN with colchicine plus CsA, the changes in the p25/p35 ratio pointed to cdk5 activation. 5. Immunohistochemical results showed a nuclear localization of cdk5 after neurotoxic treatment, which was prevented by cdk inhibitors. Thus, we propose a new mechanism of modulation of CsA neurotoxicity mediated by cdk5.
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http://dx.doi.org/10.1038/sj.bjp.0705664DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1574246PMC
February 2004

Inhibition of cell cycle pathway by flavopiridol promotes survival of cerebellar granule cells after an excitotoxic treatment.

J Pharmacol Exp Ther 2004 Feb 10;308(2):609-16. Epub 2003 Nov 10.

Unitat de Farmacologia i Farmacognòsia, Facultat de Farmàcia, Universitat de Barcelona, Nucli Universitari de Pedralbes, Barcelona, Spain.

Kainic acid (KA)-induced neuronal damage and the protective effects of flavopiridol were studied in primary cultures of rat cerebellar granule cells (CGNs). When neurons were treated with 500 microM KA, the percentage of cells with condensed nuclei measured by nuclear counting increased by up to 55%. After flavopiridol treatment, an antitumoral drug that is a broad inhibitor of cyclin-dependent kinases, the percentage of condensed nuclei decreased by up to 26%. Furthermore, this KA-mediated cell death was only partially dependent on the activation of the initiator caspase-9 and the effector caspases-3 and -6. This argues for a minor role of caspases in the intracellular pathway leading to KA-induced programmed cell death in CGNs. We examined the possible implication of cell cycle proteins in KA-induced neurotoxicity. We found an increase in the expression of proliferating cell nuclear antigen and E2F-1, two proteins implicated in S-phase, by Western blot. KA increased bromodeoxyuridine incorporation in CGNs, a marker of cell proliferation, and flavopiridol attenuated this effect. These results indicated that flavopiridol decreased the expression of cell cycle markers in CGNs after KA treatment. Flavopiridol might thus be used as a preventive agent against neurodegenerative diseases associated with cell cycle activation.
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http://dx.doi.org/10.1124/jpet.103.057497DOI Listing
February 2004

Antiapoptotic effects of roscovitine in cerebellar granule cells deprived of serum and potassium: a cell cycle-related mechanism.

Neurochem Int 2004 Mar;44(4):251-61

Unitat de Farmacologia i Farmacognòsia, Facultat de Farmàcia, Universitat de Barcelona, Nucli Universitari de Pedralbes, E-08028 Barcelona, Spain.

Neuronal apoptosis may be partly due to inappropriate control of the cell cycle. We used serum deprivation as stimulus and reduced potassium from 25 to 5mM (S/K deprivation), which induces apoptosis in cerebellar granule neurons (CGNs), to evaluate the direct correlation between re-entry in the cell cycle and apoptosis. Roscovitine (10 microM), an antitumoral drug that inhibits cyclin-dependent kinase 1 (cdk1), cdk2 and cdk5, showed a significant neuroprotective effect on CGNs deprived of S/K. S/K deprivation induced the expression of cell cycle proteins such as cyclin E, cyclin A, cdk2, cdk4 and E2F-1. It also caused CGNs to enter the S phase of the cell cycle, measured by a significant incorporation of BrdU (30% increase over control cells), which was reduced in the presence of roscovitine (10 microM). On the other hand, roscovitine modified the expression of cytochrome c (Cyt c), Bcl-2 and Bax, which are involved in the apoptotic intrinsic pathway induced by S/K deprivation. We suggest that the antiapoptotic effects of roscovitine on CGNs are due to its anti-proliferative efficacy and to an action on the mitochondrial apoptotic mechanism.
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http://dx.doi.org/10.1016/s0197-0186(03)00147-5DOI Listing
March 2004

Neuroprotective action of flavopiridol, a cyclin-dependent kinase inhibitor, in colchicine-induced apoptosis.

Neuropharmacology 2003 Oct;45(5):672-83

Unitat de Farmacologia i Farmacognòsia, Facultat de Farmàcia, Universitat de Barcelona, Nucli Universitari de Pedralbes, 08028 Barcelona, Spain.

Flavopiridol was developed as a drug for cancer therapy due to its ability to inhibit cell cycle progression by targeting cyclin-dependent kinases (CDKs). In this study, we show that flavopiridol may also have a neuroprotective action. We show that at therapeutic dosage (or at micromolar range), flavopiridol almost completely prevents colchicine-induced apoptosis in cerebellar granule neurones. In agreement with this, flavopiridol inhibits both the release of cyt c and the activation of caspase-3 induced in response to colchicine treatment. We demonstrate that in this cellular model for neurotoxicity, neither re-entry in the cell cycle nor activation of stress-activated protein kinases, such as c-Jun N-terminal kinase (JNK) or p38 MAP kinase, is involved. In contrast, we show that colchicine-induced apoptosis correlates with a substantial increase in the expression of cdk5 and Par-4, which is efficiently prevented by flavopiridol. Accordingly, a cdk5 inhibitor such as roscovitine, but not a cdk4 inhibitor such as 3-ATA, was also able to protect neurons from apoptosis as well as prevent accumulation of cdk5 and Par-4 in response to colchicine. Our data suggest a potential therapeutic use of flavopiridol in disorders of the central nervous system in which cytoskeleton alteration mediated by cdk5 activation and Par-4 expression has been demonstrated, such as Alzheimer's disease.
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http://dx.doi.org/10.1016/s0028-3908(03)00204-1DOI Listing
October 2003

Neuroprotective effects of (+/-)-huprine Y on in vitro and in vivo models of excitoxicity damage.

Exp Neurol 2003 Apr;180(2):123-30

Unitat de Farmacologia i Farmacognòsia, Facultat de Farmàcia, Universitat de Barcelona, Barcelona, Spain.

We have investigated the neuroprotective effects of (+/-)-huprine Y on excitotoxic lesions in rat cerebellar granule cells (CGCs). (+/-)-Huprine Y prevented cell death induced by 100 microM glutamate, as well as, 10 microM MK-801, a NMDA receptor antagonist, in a significant manner. On the other hand, intracellular calcium increase induced by NMDA (200 microM), measured by fura-2 fluorescence, was prevented by (+/-)-huprine Y with an EC(50) of 12.44 microM, which evidences the modulatory action of this compound on NMDA-induced calcium currents. In vivo, we have studied (+/-)-huprine Y neuroprotective effects on striatal lesions induced by the subacute administration of the mitochondrial toxin 3-nitropropionic acid (3-NP, 30 mg/kg, ip, for 10 days). We have assessed that both the behavioral and the morphological consequences of the lesion were prevented by pretreatment with (+/-)-huprine Y (2.5 mg/kg/twice a day, ip). Striatal gliosis induced by 3-NP treatment was prevented by (+/-)-huprine Y pretreatment, as demonstrated by the attenuation of both the increase in [(3)H]PK 11195 specific binding indicative of microgliosis and the expression of hsp27 kDa, a chaperone expressed mainly in astrocytes. In conclusion, (+/-)-huprine Y attenuated excitotoxic-induced lesions, both in vitro and in vivo, and further evidence is provided for the potential use of this compound in the prevention of neurodegenerative disorders.
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http://dx.doi.org/10.1016/s0014-4886(02)00029-8DOI Listing
April 2003

Kainic acid-induced apoptosis in cerebellar granule neurons: an attempt at cell cycle re-entry.

Neuroreport 2002 Mar;13(4):413-6

Unitat de Farmacologia i Farmacognósia, Facultat de Farmàcia, Universitat de Barcelona, Nucli Universitari de Pedralbes, E-08028 Barcelona, Spain.

This study was undertaken to investigate whether kainic acid (KA) may regulate the expression of several proteins which plays an important role in cell-cycle progression in cerebellar granule neurons (CGNs). KA induced decrease in MTT values in a concentration dependent way. Flow cytometric analysis showed that KA was able to induce 30% apoptosis in CGNs. Apoptotic nuclear condensation were detected 24 h of exposure to KA (200 microM). An associated marked increase in DNA synthesis, measured by BrdU incorporation, was observed. Western blot analysis showed that KA induced an increase in the expression of Cdk2, cyclin E and E2F-1. It is proposed that, in post-mitotic cells like CGNs, re-entry cell cycle could be responsible for the apoptotic effect of KA.
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http://dx.doi.org/10.1097/00001756-200203250-00010DOI Listing
March 2002

Kainic acid-induced neuronal cell death in cerebellar granule cells is not prevented by caspase inhibitors.

Br J Pharmacol 2002 Mar;135(5):1297-307

Unitat de Farmacologia i Farmacognòsia, Facultat de Farmàcia, Universitat de Barcelona, Nucli Universitari de Pedralbes, E-08028 Barcelona, Spain.

1. We examined the role of non-NMDA receptors in kainic acid (KA)-induced apoptosis in cultures of rat cerebellar granule cells (CGCs). KA (1 - 500 microM) induced cell death in a concentration-dependent manner, which was prevented by NBQX and GYKI 52466, non-NMDA receptor antagonists. Moreover, AMPA blocked KA-induced excitotoxicity, through desensitization of AMPA receptors. 2. Similarly, KA raised the intracellular calcium concentration of CGCs, which was inhibited by NBQX and GYKI 52466. Again, AMPA (100 microM) abolished the KA (100 microM)-induced increase in intracellular calcium concentration. 3. KA-induced cell death in CGCs had apoptotic features, which were determined morphologically, by DNA fragmentation, and by expression of the prostate apoptosis response-4 protein (Par-4). 5. KA (500 microM) slightly (18%) increased caspase-3 activity, which was strongly enhanced by colchicine (1 microM), an apoptotic stimulus. However, neither Z-VAD.fmk, a pan-caspase inhibitor, nor the more specific caspase-3 inhibitor, Ac-DEVD-CHO, prevented KA-induced cell death or apoptosis. In contrast, both drugs inhibited colchicine-induced apoptosis. 5. The calpain inhibitor ALLN had no effect on KA or colchicine-induced neurotoxicity. 6. Our findings indicate that colchicine-induced apoptosis in CGCs is mediated by caspase-3 activation, unlike KA-induced apoptosis.
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http://dx.doi.org/10.1038/sj.bjp.0704581DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1573245PMC
March 2002
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