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    • In this study we also profiled the

    2022-06-24

    In this study, we also profiled the expression of the transporters in wild-type RBL-2H3 cells, RBL-2H3 Sc98 cells, and rat peritoneal mast cells. OCT1 and PMAT were expressed at high levels in both RBL-2H3 Sc98 and RBL-2H3 cells. However, OCT2 and OCT3 were weakly or least detected in RBL-2H3 Sc98 cells. The patterns of protein expression in RBL-2H3 Sc98 cells were in parallel with the results obtained in the inhibitor experiments. OCT1 mRNA has also been detected in murine basophils, but its role in histamine uptake was not considered because [3H]-histamine was poorly transported into OCT1-transfected 293 cells (Schneider et al., 2005). Histamine uptake was suppressed by a high concentration of the OCT1 inhibitor desipramine in RBL-2H3 Sc98 cells. Therefore, OCT1 might be involved in histamine uptake at a high concentration. However, because of the low level of OCT3 expression and lack of histamine uptake suppression by corticosterone in RBL-2H3 Sc98 cells, the involvement of OCT3 in histamine uptake may be negligible in RBL-2H3 cells. These findings suggest that PMAT and OCT1 might act as histamine transporters in RBL-2H3 cells.
    Acknowledgments We thank Mrs. M. Shudo, T. Kiyoi (Division of Analytical Bio-medicine, Advanced Research Support Center, Ehime University), and Ms. E. Takemasa (Department of Pharmacology, Ehime University Graduate School of Medicine) for their technical advice and support, and The Directorate General of Higher Education, The Ministry of Research, Technology and Higher Education, Republic of Indonesia, for the Doctoral Scholarship granted to Trivadila. We also thank Mitchell Arico from Edanz Group (www.edanzediting.com/ac) for editing a draft of this manuscript.
    Novel therapeutic strategies are needed for pediatric traumatic 848 injury Traumatic brain injury (TBI) is a major public health problem in the United States with an annual incidence of approximately 1.7 million, of which 50,000 injuries result in death (Coronado et al., 2015; Faul and Coronado, 2015), and is the leading cause of death and injury in children and older adolescents. TBI also has been associated with increased risk of neurodegenerative diseases such as Alzheimer's disease later in life (Gavett et al., 2010), and this aspect may be particularly impactful when injury occurs in a developing brain. Significant progress has been made in understanding the cellular and molecular processes involved in the pathogenesis of TBI. This includes potentially reversible and/or preventable secondary injury mechanisms such as excitotoxicity, oxidative stress, and inflammation that follow the irreversible primary injury phase of TBI which consists of shearing and tearing of the brain tissue (Werner and Engelhard, 2007). Although several pharmacological agents have been studied in clinical trials of TBI, none of them have shown positive results in terms of survival or relevant clinical outcomes (Diaz-Arrastia et al., 2014; Kochanek et al., 2015; Hall, 2016). It is important to note that all clinical trials evaluating outcome after TBI have been done in adult patients and have not included children. There has been a growing interest in incorporating the neurovascular unit in the understanding of pathological mechanisms of TBI, similar to the framework developed for stroke (Lok et al., 2015). This framework emphasizes the dynamic interaction among the different cells that constitute the neurovascular unit, i.e., neurons, endothelial cells and glial cells. A central component of this paradigm is the communication between the different cells that is mediated by proteins, lipids, hormones, amino acids, metabolites, and neurotransmitters (Lok et al., 2015). Since many of these signaling molecules are polar in physiologic conditions, they require transporters –transmembrane proteins which regulate the trafficking of molecules across the lipid bilayer of cellular membranes – to enter the intracellular environment or cross compartmental barriers such as the blood-brain barrier (BBB) (Lee et al., 2001; Ahn and Nigam, 2009; Wu et al., 2011; Piehler et al., 2012; Nigam, 2015; Stieger and Gao, 2015). Thus, membrane transporters are important contributors to the dynamic interplay within the neurovascular unit to regain homeostasis after TBI. Furthermore, lack of understanding of the nature and extent of the distribution of drugs into the brain and within the neurovascular unit, and even more so the developing brain and developing neurovascular unit, represents an unaddressed area of TBI research that has been linked to the failure of clinical drug trials in TBI (Loane and Faden, 2010). Since transporters regulate the distribution of drugs into and within the brain, they could importantly influence the outcome of therapeutics used in TBI.