Nanoparticle-and liposome-carried drugs: New strategies for active targeting and drug delivery across blood-brain barrier

The blood-brain barrier (BBB), the unusual microvascular endothelial interface between the central nervous system (CNS) and the circulatory system, is a major hindrance to drug delivery in the brain parenchyma. Besides the absence of fenestrations and the abundance of tight junctions, ATP-binding cassette (ABC) transporters critically reduce drug entry within the CNS, as they carry many drugs back into the bloodstream. Nanoparticle-and liposome-carried drugs, because of their increased cellular uptake and reduced efflux through ABC transporters, have been developed in recent times to circumvent the low drug permeability of the BBB. This review discusses the role of ABC transporters in controlling drug penetration into the brain parenchyma, the rationale for using nanoparticle-and liposome-based strategies to increase drug delivery across the BBB and new therapeutic strategies for using nanoparticle-and liposome-carried drugs in different conditions, ranging from CNS tumors and neurodegenerative diseases to viral infections and epilepsy. © 2013 Bentham Science Publishers

Nanoparticle-and liposome-carried drugs: New strategies for active targeting and drug delivery across blood-brain barrier

The blood-brain barrier (BBB), the unusual microvascular endothelial interface between the central nervous system (CNS) and the circulatory system, is a major hindrance to drug delivery in the brain parenchyma. Besides the absence of fenestrations and the abundance of tight junctions, ATP-binding cassette (ABC) transporters critically reduce drug entry within the CNS, as they carry many drugs back into the bloodstream. Nanoparticle-and liposome-carried drugs, because of their increased cellular uptake and reduced efflux through ABC transporters, have been developed in recent times to circumvent the low drug permeability of the BBB. This review discusses the role of ABC transporters in controlling drug penetration into the brain parenchyma, the rationale for using nanoparticle-and liposome-based strategies to increase drug delivery across the BBB and new therapeutic strategies for using nanoparticle-and liposome-carried drugs in different conditions, ranging from CNS tumors and neurodegenerative diseases to viral infections and epilepsy. © 2013 Bentham Science Publishers

Recursos para la enseñanza-aprendizaje de temas complejos de Bioquímica en la educación médica

Introduction: Information and communication technologies (ICTs) have modified the way knowledge is transmitted and assimilated. In medical education, they are considered fundamental for the optimization of the teaching-learning process, to favor the appropriation and integration of knowledge, and to support classroom activities. An effective application of these tools requires the identification of the most difficult topics for students, allowing to precisely address their use for the solution of learning problems. Methods: The Biochemistry topic with more difficulties was identified and a virtual tool was designed with animated slides, drawings and graphs that would address it. Students received conceptual guidance that they prepared and discussed with the professor. Later on, they accessed the tool to reinforce homework. The efficacy of the tool was evaluated on comparing the results of the evaluations before and after applying it and evaluated the students’ attitude towards their use. Results: The global difficulty index identified the metabolism of nitrogen compounds as a critical issue. The implementation of the tool increased the success in the intra- and inter-semester quizzes. The students’ attitude towards the use of the tool was favorable, they considered it useful to reinforce their knowledge and to improve their academic training. Conclusion: The use of the information and communication technologies in higher education favors the process of self-learning and raises the need for a greater integration or structured and adapted implementation of this type of tools to the students’ environment. © 2017, Editorial Ciencias Medicas. All rights reserved

Recursos para la enseñanza-aprendizaje de temas complejos de Bioquímica en la educación médica

Introduction: Information and communication technologies (ICTs) have modified the way knowledge is transmitted and assimilated. In medical education, they are considered fundamental for the optimization of the teaching-learning process, to favor the appropriation and integration of knowledge, and to support classroom activities. An effective application of these tools requires the identification of the most difficult topics for students, allowing to precisely address their use for the solution of learning problems. Methods: The Biochemistry topic with more difficulties was identified and a virtual tool was designed with animated slides, drawings and graphs that would address it. Students received conceptual guidance that they prepared and discussed with the professor. Later on, they accessed the tool to reinforce homework. The efficacy of the tool was evaluated on comparing the results of the evaluations before and after applying it and evaluated the students’ attitude towards their use. Results: The global difficulty index identified the metabolism of nitrogen compounds as a critical issue. The implementation of the tool increased the success in the intra- and inter-semester quizzes. The students’ attitude towards the use of the tool was favorable, they considered it useful to reinforce their knowledge and to improve their academic training. Conclusion: The use of the information and communication technologies in higher education favors the process of self-learning and raises the need for a greater integration or structured and adapted implementation of this type of tools to the students’ environment. © 2017, Editorial Ciencias Medicas. All rights reserved

Factor inducible por hipoxia HIF-1? modula la resistencia a drogas en células de cáncer de colon

Introduction: Drug resistance mechanisms may be associated with decreased cell death and its induction may depend on the response to oxidative stress caused by hypoxia. The correlation between hypoxia-inducible factor HIF-1?, the number of reactive oxygen species and their effect on cell survival has not yet been evaluated. Objective: The purpose of this study was to evaluate the effect of HIF-1? activity and reactive oxygen species (ROS) accumulation in apoptosis of colon cancer cells. Materials and methods: HT29 colon cancer cells were treated with Cobalt(II) chloride (CoCl2) or doxorubicin and the activity of HIF-1? was determined by ELISA assay. ROS were determined using fluorescence probe carboxy-H2DFFDA. Apoptosis was assessed by caspase-3 activation analysis, and PUMA and BAX mRNA levels by qRT-PCR. The reduction of the antiapoptotic effect due to hypoxia was attenuated by use of the endonuclease APE-1 (E3330) inhibitor. The endonuclease E3330 APE-1 inhibitor allowed evaluating the effect of ROS generated by doxorubicin and CoCl2 on apoptosis. Results: Chemical hypoxia in combination with doxorubicin is an oxidative stressor in HT29 cells and induces a reduction in the apoptotic process in a time-dependent manner. Conclusion: Resistance to hypoxia and doxorubicin-mediated cell death could be controlled by a mechanism related to the activity of HIF-1? and the amount of reactive oxygen species generated. © 2018, Universidad Nacional de Colombia. All rights reserved

Oxidative Stress Promotes Doxorubicin-Induced Pgp and BCRP Expression in Colon Cancer Cells Under Hypoxic Conditions

P-glycoprotein (Pgp) and breast cancer resistance protein (BCRP) are ATP binding cassette (ABC) transporters that are overexpressed in different drug-resistant cancer cell lines. In this study, we investigated whether doxorubicin promotes Pgp and/or BCRP expression to induce drug resistance in colon cancer cells under hypoxic conditions. We analyzed HIF-1? activity via ELISA, Pgp, and BCRP expression by qRT-PCR and the relationship between doxorubicin uptake and ABC transporter expression via confocal microscopy in HT-29WT and HT-29 doxorubicin-resistant colon cancer cells (HT-29DxR). These cells were treated with doxorubicin and/or CoCl2 (chemical hypoxia), and reactive oxygen species inductors. We found that the combination of chemically induced hypoxia and doxorubicin promoted Pgp mRNA expression within 24 h in HT-29WT and HT-29DxR cells. Both doxorubicin and CoCl2 alone or in combination induced Pgp and BCRP expression, as demonstrated via confocal microscopy in each of the above two cell lines. Thus, we surmised that Pgp and BCRP expression may result from synergistic effects exerted by the combination of doxorubicin-induced ROS production and HIF-1? activity under hypoxic conditions. However, HIF-1? activity disruption via the administration of E3330, an APE-1 inhibitor, downregulated Pgp expression and increased doxorubicin delivery to HT-29 cells, where it served as a substrate for Pgp, indicating the existence of an indirect relationship between Pgp expression and doxorubicin accumulation. Thus, we concluded that Pgp and BCRP expression can be regulated via cross-talk between doxorubicin and hypoxia, promoting drug resistance in HT-29 WT, and HT-29DxR cells and that this process may be ROS dependent. J. Cell. Biochem. 118: 1868–1878, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc

Factor inducible por hipoxia HIF-1? modula la resistencia a drogas en células de cáncer de colon

Introduction: Drug resistance mechanisms may be associated with decreased cell death and its induction may depend on the response to oxidative stress caused by hypoxia. The correlation between hypoxia-inducible factor HIF-1?, the number of reactive oxygen species and their effect on cell survival has not yet been evaluated. Objective: The purpose of this study was to evaluate the effect of HIF-1? activity and reactive oxygen species (ROS) accumulation in apoptosis of colon cancer cells. Materials and methods: HT29 colon cancer cells were treated with Cobalt(II) chloride (CoCl2) or doxorubicin and the activity of HIF-1? was determined by ELISA assay. ROS were determined using fluorescence probe carboxy-H2DFFDA. Apoptosis was assessed by caspase-3 activation analysis, and PUMA and BAX mRNA levels by qRT-PCR. The reduction of the antiapoptotic effect due to hypoxia was attenuated by use of the endonuclease APE-1 (E3330) inhibitor. The endonuclease E3330 APE-1 inhibitor allowed evaluating the effect of ROS generated by doxorubicin and CoCl2 on apoptosis. Results: Chemical hypoxia in combination with doxorubicin is an oxidative stressor in HT29 cells and induces a reduction in the apoptotic process in a time-dependent manner. Conclusion: Resistance to hypoxia and doxorubicin-mediated cell death could be controlled by a mechanism related to the activity of HIF-1? and the amount of reactive oxygen species generated. © 2018, Universidad Nacional de Colombia. All rights reserved

Oxidative Stress Promotes Doxorubicin-Induced Pgp and BCRP Expression in Colon Cancer Cells Under Hypoxic Conditions

P-glycoprotein (Pgp) and breast cancer resistance protein (BCRP) are ATP binding cassette (ABC) transporters that are overexpressed in different drug-resistant cancer cell lines. In this study, we investigated whether doxorubicin promotes Pgp and/or BCRP expression to induce drug resistance in colon cancer cells under hypoxic conditions. We analyzed HIF-1? activity via ELISA, Pgp, and BCRP expression by qRT-PCR and the relationship between doxorubicin uptake and ABC transporter expression via confocal microscopy in HT-29WT and HT-29 doxorubicin-resistant colon cancer cells (HT-29DxR). These cells were treated with doxorubicin and/or CoCl2 (chemical hypoxia), and reactive oxygen species inductors. We found that the combination of chemically induced hypoxia and doxorubicin promoted Pgp mRNA expression within 24 h in HT-29WT and HT-29DxR cells. Both doxorubicin and CoCl2 alone or in combination induced Pgp and BCRP expression, as demonstrated via confocal microscopy in each of the above two cell lines. Thus, we surmised that Pgp and BCRP expression may result from synergistic effects exerted by the combination of doxorubicin-induced ROS production and HIF-1? activity under hypoxic conditions. However, HIF-1? activity disruption via the administration of E3330, an APE-1 inhibitor, downregulated Pgp expression and increased doxorubicin delivery to HT-29 cells, where it served as a substrate for Pgp, indicating the existence of an indirect relationship between Pgp expression and doxorubicin accumulation. Thus, we concluded that Pgp and BCRP expression can be regulated via cross-talk between doxorubicin and hypoxia, promoting drug resistance in HT-29 WT, and HT-29DxR cells and that this process may be ROS dependent. J. Cell. Biochem. 118: 1868–1878, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc