Systemic Inflammation Induced Changes in Protein Expression of ABC Transporters and Ionotropic Glutamate Receptor Subunit 1 in the Cerebral Cortex of Familial Alzheimer`s Disease Mouse Model

Alzheimer's disease (AD) is an incurable disease, with complex pathophysiology and a myriad of proteins involved in its development. In this study, we applied quantitative targeted absolute proteomic analysis for investigation of changes in potential AD drug targets, biomarkers, and transporters in cerebral cortices of lipopolysaccharide (LPS)-induced neuroinflammation mouse model, familial AD mice (APdE9) with and without LPS treatment as compared to age-matched wild type (WT) mice. The ABCB1, ABCG2 and GluN1 protein expression ratios between LPS treated APdE9 and WT control mice were 0.58 (95% CI 0.44-0.72), 0.65 (95% CI 0.53-0.77) and 0.61 (95% CI 0.52-0.69), respectively. The protein expression levels of other proteins such as MGLL, COX-2, CytC, ABCC1, ABCC4, SLC2A1 and SLC7A5 did not differ between the study groups. Overall, the study revealed that systemic inflammation can alter ABCB1 and ABCG2 protein expression in brain in AD, which can affect intra-brain drug distribution and play a role in AD development. Moreover, the inflammatory insult caused by peripheral infection in AD may be important factor triggering changes in GluN1 protein expression. However, more studies need to be performed in order to confirm these findings. The quantitative information about the expression of selected proteins provides important knowledge, which may help in the optimal use of the mouse models in AD drug development and better translation of preclinical data to humans. (c) 2021 American Pharmacists Association. Published by Elsevier Inc. All rights reserved.Peer reviewe

Increased Expression and Activity of Brain Cortical cPLA2 Due to Chronic Lipopolysaccharide Administration in Mouse Model of Familial Alzheimer’s Disease

Cytosolic phospholipase A2 (cPLA2) is an enzyme regulating membrane phospholipid homeostasis and the release of arachidonic acid utilized in inflammatory responses. It represents an attractive target for the treatment of Alzheimer’s disease (AD). Previously, we showed that lipopolysaccharide (LPS)-induced systemic inflammation caused abnormal lipid metabolism in the brain of a transgenic AD mouse model (APdE9), which might be associated with potential changes in cPLA2 activity. Here, we investigated changes in cPLA2 expression and activity, as well as the molecular mechanisms underlying these alterations due to chronic LPS administration in the cerebral cortex of female APdE9 mice as compared to saline- and LPS-treated female wild-type mice and saline-treated APdE9 mice. The study revealed the significant effects of genotype LPS treatment on cortical cPLA2 protein expression and activity in APdE9 mice. LPS treatment resulted in nuclear factor kappa-light-chain-enhancer of activated B cells (NFkB) activation in the cortex of APdE9 mice. The gene expressions of inflammation markers Il1b and Tnfa were significantly elevated in the cortex of both APdE9 groups compared to the wild-type groups. The study provides evidence of the elevated expression and activity of cPLA2 in the brain cortex of APdE9 mice after chronic LPS treatment, which could be associated with NFkB activation

The Role of Solute Carrier Transporters in Efficient Anticancer Drug Delivery and Therapy

Transporter-mediated drug resistance is a major obstacle in anticancer drug delivery and a key reason for cancer drug therapy failure. Membrane solute carrier (SLC) transporters play a crucial role in the cellular uptake of drugs. The expression and function of the SLC transporters can be down-regulated in cancer cells, which limits the uptake of drugs into the tumor cells, resulting in the inefficiency of the drug therapy. In this review, we summarize the current understanding of low-SLC-transporter-expression-mediated drug resistance in different types of cancers. Recent advances in SLC-transporter-targeting strategies include the development of transporter-utilizing prodrugs and nanocarriers and the modulation of SLC transporter expression in cancer cells. These strategies will play an important role in the future development of anticancer drug therapies by enabling the efficient delivery of drugs into cancer cells

The Role of Solute Carrier Transporters in Efficient Anticancer Drug Delivery and Therapy

Transporter-mediated drug resistance is a major obstacle in anticancer drug delivery and a key reason for cancer drug therapy failure. Membrane solute carrier (SLC) transporters play a crucial role in the cellular uptake of drugs. The expression and function of the SLC transporters can be down-regulated in cancer cells, which limits the uptake of drugs into the tumor cells, resulting in the inefficiency of the drug therapy. In this review, we summarize the current understanding of low-SLC-transporter-expression-mediated drug resistance in different types of cancers. Recent advances in SLC-transporter-targeting strategies include the development of transporter-utilizing prodrugs and nanocarriers and the modulation of SLC transporter expression in cancer cells. These strategies will play an important role in the future development of anticancer drug therapies by enabling the efficient delivery of drugs into cancer cells

Estrés académico y autoestima en estudiantes de la Escuela de Economía de una Universidad en Pasco 2022

RESUMEN El presente estudio de investigación, tuvo como propósito principal determinar la relación que existe entre estrés académico y autoestima en estudiantes de la Escuela de Formación Profesional de Economía de la Universidad Nacional Daniel Alcides Carrión - Cerro de Pasco 2022. Lo cual tiene un enfoque cualitativo, es una investigación del tipo básica, con un diseño correlacional de corte transversal, así mismo el tipo de muestro que se empleó fue el no probabilística intencionado, estableciéndose la cantidad de 182 participantes, para la evaluación se utilizó el Inventario Sistémico Cognoscitivista de Estrés Académico conocido como (SISCO) cuyo autor es Barraza, teniendo la validez del instrumentos a través de juicio de expertos así como la confiabilidad con un valor de 0.85; y el segundo instrumento fue la Escala de Autoestima de Coopersmith en la versión adulto, contando también con una validez por juicio de expertos y una confiabilidad de 0.83. El procesamiento de datos fue por medio del programa SPSS en la versión 25; y para la contrastación de hipótesis se trabajó con la Rho de Spearman dándonos como resultado un valor de - 0.325, por lo que se concluye afirmando que existe una correlación negativa débil entre las dos variables de estudio; es decir que, entre más elevado sea el estrés académico menor será la autoestima o viceversa en los estudiantes de la Escuela de Formación Profesional de Economía; por tal razón se concluye aceptando la hipótesis de investigación. PALABRAS CLAVE: Estrés Académico, Autoestim

A Selective and Slowly Reversible Inhibitor of l‑Type Amino Acid Transporter 1 (LAT1) Potentiates Antiproliferative Drug Efficacy in Cancer Cells

The l-type amino acid transporter 1 (LAT1) is a transmembrane protein carrying bulky and neutral amino acids into cells. LAT1 is overexpressed in several types of tumors, and its inhibition can result in reduced cancer cell growth. However, known LAT1 inhibitors lack selectivity over other transporters. In the present study, we designed and synthesized a novel selective LAT1 inhibitor (<b>1</b>), which inhibited the uptake of LAT1 substrate, l-leucin as well as cell growth. It also significantly potentiated the efficacy of bestatin and cisplatin even at low concentrations (25 μM). Inhibition was slowly reversible, as the inhibitor was able to be detached from the cell surface and blood–brain barrier. Moreover, the inhibitor was metabolically stable and selective toward LAT1. Since the inhibitor was readily accumulated into the prostate after intraperitoneal injection to the healthy mice, this compound may be a promising agent or adjuvant especially for the treatment of prostate cancer

A Selective and Slowly Reversible Inhibitor of l‑Type Amino Acid Transporter 1 (LAT1) Potentiates Antiproliferative Drug Efficacy in Cancer Cells

The l-type amino acid transporter 1 (LAT1) is a transmembrane protein carrying bulky and neutral amino acids into cells. LAT1 is overexpressed in several types of tumors, and its inhibition can result in reduced cancer cell growth. However, known LAT1 inhibitors lack selectivity over other transporters. In the present study, we designed and synthesized a novel selective LAT1 inhibitor (<b>1</b>), which inhibited the uptake of LAT1 substrate, l-leucin as well as cell growth. It also significantly potentiated the efficacy of bestatin and cisplatin even at low concentrations (25 μM). Inhibition was slowly reversible, as the inhibitor was able to be detached from the cell surface and blood–brain barrier. Moreover, the inhibitor was metabolically stable and selective toward LAT1. Since the inhibitor was readily accumulated into the prostate after intraperitoneal injection to the healthy mice, this compound may be a promising agent or adjuvant especially for the treatment of prostate cancer

Metabolomic, Lipidomic and Proteomic Characterisation of Lipopolysaccharide-induced Inflammation Mouse Model

Neuroinflammation is an important feature in the pathogenesis and progression of central nervous system (CNS) diseases including Alzheimer's disease (AD). One of the widely used animal models of peripherally induced neuroinflammation and neurodegeneration is a lipopolysaccharide (LPS)-induced inflammation mouse model. An acute LPS administration has been widely used for investigation of inflammation-associated disease and testing inflammation-targeting drug candidates. In the present metabolomic, lipidomic and proteomic study, we investigated short-term effects of systemic inflammation induced by LPS administration on the mouse plasma and brain cortical and hippocampal metabolome, lipidome as well as expression of the brain cortical proteins which were shown to be involved in inflammation-associated CNS diseases. From a global perspective, the hippocampus was more vulnerable to the effects of LPS-induced systemic inflammation than the cortex. In addition, the study revealed several brain region-specific changes in metabolic pathways and lipids, such as statistically significant increase in several cortical and hippocampal phosphatidylcholines/phosphatidylethanolamines, and significantly decreased levels of brain cortical betaine after LPS treatment in mice. Moreover, LPS treatment in mice caused significantly increased protein expression of GluN1 receptor in the brain cortex. The revealed perturbations in the LPS-induced inflammation mouse model may give insight into the mechanisms underlying inflammation-associated CNS diseases. In addition, the finding of the study provide important information about the appropriate use of the model during target validation and drug candidate testing.Open access articleThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]