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Article: Donepezil, tacrine and alpha-phenyl-n-tert-butyl nitrone (PBN) inhibit choline transport by conditionally immortalized rat brain capillary endothelial cell lines (TR-BBB).

Kang, Young-Sook / Lee, Kyeong-Eun / Lee, Na-Young / Terasaki, Tetsuya

2005 Volume 28, Issue 4, Page(s) 443–450

Abstract: ... hydrochloride, tacrine and alpha-phenyl-n-tert-butyl nitrone (PBN), respectively. These characteristics ... In the present study, we have characterized the choline transport system and examined the influence ... of various amine drugs on the choline transporter using a conditionally immortalized rat brain ...

Abstract	In the present study, we have characterized the choline transport system and examined the influence of various amine drugs on the choline transporter using a conditionally immortalized rat brain capillary endothelial cell line (TR-BBB) in vitro. The cell-to-medium (C/M) ratio of [3H]choline in TR-BBB cells increased time-dependently. The initial uptake rate of [3H]choline was concentration-dependent with a Michaelis-Menten value, Km, of 26.2 +/- 2.7 microM. The [3H]choline uptake into TR-BBB was Na+-independent, but was membrane potential-dependent. The [3H]choline uptake was susceptible to inhibition by hemicholinium-3, and tetraethylammonium (TEA), which are organic cation transporter substrates. Also, the uptake of [3H]choline was competitively inhibited with Ki values of 274 microM, 251 microM and 180 microM in the presence of donepezil hydrochloride, tacrine and alpha-phenyl-n-tert-butyl nitrone (PBN), respectively. These characteristics of choline transport are consistent with those of the organic cation transporter (OCT). OCT2 mRNA was expressed in TR-BBB cells, while the expression of OCT3 or choline transporter (CHT) was not detected. Accordingly, these results suggest that OCT2 is a candidate for choline transport at the BBB and may influence the BBB permeability of amine drugs.
MeSH term(s)	Animals ; Biological Transport/drug effects ; Blood-Brain Barrier/drug effects ; Blood-Brain Barrier/metabolism ; Brain/blood supply ; Brain/cytology ; Brain/metabolism ; Cell Line, Transformed ; Central Nervous System Agents/pharmacology ; Choline/metabolism ; Cyclic N-Oxides ; Donepezil ; Endothelial Cells/drug effects ; Endothelial Cells/metabolism ; Indans/pharmacology ; Models, Biological ; Nerve Tissue Proteins/biosynthesis ; Nitrogen Oxides/pharmacology ; Organic Cation Transport Proteins/biosynthesis ; Piperidines/pharmacology ; Plasma Membrane Neurotransmitter Transport Proteins ; Rats ; Symporters/biosynthesis ; Tacrine/pharmacology
Chemical Substances	Central Nervous System Agents ; Cyclic N-Oxides ; Indans ; Nerve Tissue Proteins ; Nitrogen Oxides ; Organic Cation Transport Proteins ; Piperidines ; Plasma Membrane Neurotransmitter Transport Proteins ; Symporters ; Slc6a8 protein, rat (147652-48-0) ; phenyl-N-tert-butylnitrone (3I91332OPG) ; Tacrine (4VX7YNB537) ; Donepezil (8SSC91326P) ; Choline (N91BDP6H0X)
Language	English
Publishing date	2005-05-11
Publishing country	Korea (South)
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	447623-2
ISSN	1976-3786 ; 0253-6269
ISSN (online)	1976-3786
ISSN	0253-6269
DOI	10.1007/bf02977674
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Article ; Online: Circumventricular organ-hypothalamic circuit endoplasmic reticulum stress drives hepatic steatosis during obesity.

Kim, Han Rae / Young, Colin N

Obesity (Silver Spring, Md.)

2023 Volume 32, Issue 1, Page(s) 59–69

Abstract: Objective: Nonalcoholic fatty liver disease (NAFLD), characterized by excess liver triglyceride accumulation (hepatic steatosis), leads to an increased risk for cardiometabolic diseases and obesity-related mortality. Emerging evidence points to ... ...

Abstract	Objective: Nonalcoholic fatty liver disease (NAFLD), characterized by excess liver triglyceride accumulation (hepatic steatosis), leads to an increased risk for cardiometabolic diseases and obesity-related mortality. Emerging evidence points to endoplasmic reticulum (ER) stress in the central nervous system as critical in NAFLD pathogenesis. Here, we tested the contribution of ER stress in a circumventricular organ-hypothalamic circuit in NAFLD development during obesity. Methods: C57BL/6J male mice were fed a high-fat diet (HFD) or normal chow. A combination of histological, viral tracing, intersectional viral targeting, and in vivo integrative physiological approaches were used to examine the role of ER stress in subfornical organ to hypothalamic paraventricular nucleus projecting neurons (SFO➔PVN) in NAFLD during diet-induced obesity. Results: Immunohistochemical analysis revealed marked unfolded protein response activation in the SFO, particularly in excitatory SFO➔PVN neurons of HFD-fed animals. Moreover, intersectional viral inhibition of ER stress in SFO➔PVN neurons resulted in a reduction in hepatomegaly, hepatic steatosis, and a blunted increase in body weight gain during diet-induced obesity, independent of changes in food intake, substrate partitioning, energy expenditure, and ambulatory activity. Conclusions: These results indicate that ER stress in an SFO➔PVN neural circuit contributes to hepatic steatosis during obesity.
MeSH term(s)	Mice ; Animals ; Male ; Non-alcoholic Fatty Liver Disease/metabolism ; Mice, Inbred C57BL ; Liver/metabolism ; Obesity/metabolism ; Diet, High-Fat/adverse effects ; Endoplasmic Reticulum Stress ; Circumventricular Organs/metabolism ; Circumventricular Organs/pathology
Language	English
Publishing date	2023-10-04
Publishing country	United States
Document type	Journal Article
ZDB-ID	2230457-5
ISSN	1930-739X ; 1071-7323 ; 1930-7381
ISSN (online)	1930-739X
ISSN	1071-7323 ; 1930-7381
DOI	10.1002/oby.23895
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Article: Central Feminization of Obese Male Mice Reduces Metabolic Syndrome.

Blackmore, Katherine / Young, Colin N

Brain sciences

2022 Volume 12, Issue 10

Abstract: Metabolic syndrome encompasses a spectrum of conditions that increases the risk for cardiovascular and metabolic diseases. It is widely accepted that the sex hormone estrogen plays a protective metabolic role in premenopausal women, in part through ... ...

Abstract	Metabolic syndrome encompasses a spectrum of conditions that increases the risk for cardiovascular and metabolic diseases. It is widely accepted that the sex hormone estrogen plays a protective metabolic role in premenopausal women, in part through central nervous system (CNS) mechanisms. However, most work to date has focused on the loss of estrogen in females (e.g., menopause). Interestingly, transgender individuals receiving feminizing gender affirming therapy (i.e., estrogen) are relatively protected from metabolic syndrome conditions, pointing to a role for CNS estrogen in the development of metabolic syndrome in men. Here, we show that estrogen signaling in the brain protects males from metabolic syndrome and obesity related complications. First, short-term CNS specific supplementation of low-dose 17-β-estradiol in diet-induced obese male mice resulted in a significant reduction in body weight in parallel with a decrease in food intake without alterations in energy expenditure. In conjunction, central supplementation of estrogen reduced visceral adiposity, including epididymal and abdominal regions, with slighter decreases in subcutaneous inguinal and thermogenic brown adipose tissue. Furthermore, central estrogen administration reduced the liver manifestation of metabolic syndrome including hepatomegaly and hepatic steatosis. Collectively, these findings indicate that a lack of estrogen action in the brain may predispose males to metabolic syndrome pathogenesis.
Language	English
Publishing date	2022-09-30
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2651993-8
ISSN	2076-3425
ISSN	2076-3425
DOI	10.3390/brainsci12101324
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Article: Donepezil, tacrine and Î±-phenyl-n-tert-butyl nitrone (PBN) inhibit choline transport by conditionally immortalized rat brain capillary endothelial cell lines (TR-BBB)

Kang, Young-Sook / Kyeong-Eun Lee / Na-Young Lee / Tetsuya Terasaki

Archives of pharmacal research. 2005 Apr., v. 28, no. 4

2005

Abstract: ... hydrochloride, tacrine and Î±-phenyl-n-tert-butyl nitrone (PBN), respectively. These characteristics of choline ... In the present study, we have characterized the choline transport system and examined the influence ... of various amine drugs on the choline transporter using a conditionally immortalized rat brain ...

Abstract	In the present study, we have characterized the choline transport system and examined the influence of various amine drugs on the choline transporter using a conditionally immortalized rat brain capillary endothelial cell line (TR-BBB)in vitro. The cell-to-medium (C/M) ratio of [Â³H]choline in TR-BBB cells increased time-dependently. The initial uptake rate of [Â³H]choline was concentration-dependent with a Michaelis-Menten value, Kâ, of 26.2 Â± 2.7 Î¼M. The [Â³H]choline uptake into TR-BBB was Naâº-independent, but was membrane potential-dependent. The [Â³H]choline uptake was susceptible to inhibition by hemicholinium-3, and tetraethy-lammonium (TEA), which are organic cation transporter substrates. Also, the uptake of [Â³H]choline was competitively inhibited withK áµ¢ values of 274 Î¼M, 251 Î¼M and 180 Î¼M in the presence of donepezil hydrochloride, tacrine and Î±-phenyl-n-tert-butyl nitrone (PBN), respectively. These characteristics of choline transport are consistent with those of the organic cation transporter (OCT). OCT2 mRNA was expressed in TR-BBB cells, while the expression of OCT3 or choline transporter (CHT) was not detected. Accordingly, these results suggest that OCT2 is a candidate for choline transport at the BBB and may influence the BBB permeability of amine drugs.
Keywords	brain ; cations ; choline ; drugs ; endothelial cells ; messenger RNA ; permeability ; rats ; tritium
Language	English
Dates of publication	2005-04
Size	p. 443.
Publishing place	Pharmaceutical Society of Korea
Document type	Article
ZDB-ID	447623-2
ISSN	1976-3786 ; 0253-6269
ISSN (online)	1976-3786
ISSN	0253-6269
DOI	10.1007/BF02977674
Database	NAL-Catalogue (AGRICOLA)

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Article: Spatial-extent inference for testing variance components in reliability and heritability studies.

Pan, Ruyi / Dickie, Erin W / Hawco, Colin / Reid, Nancy / Voineskos, Aristotle N / Park, Jun Young

bioRxiv : the preprint server for biology

2023

Abstract: Clusterwise inference is a popular approach in neuroimaging to increase sensitivity, but most existing methods are currently restricted to the General Linear Model (GLM) for testing mean parameters. Statistical methods for ... ...

Abstract	Clusterwise inference is a popular approach in neuroimaging to increase sensitivity, but most existing methods are currently restricted to the General Linear Model (GLM) for testing mean parameters. Statistical methods for testing
Language	English
Publishing date	2023-10-08
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.04.19.537270
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Article ; Online: Antibodies elicited by Plasmodium falciparum circumsporozoite proteins lacking sequentially deleted C-terminal amino acids reveal mouse strain and epitopes specific differences.

Hayashi, Clifford T H / Cao, Yi / Zavala, Fidel / Simonyan, Hayk / Young, Colin N / Kumar, Nirbhay

Vaccine

2023

Abstract: ... within the central repeat region and at the junction of the repeat and N-terminal domain are well documented as major ...

Abstract	Malaria affects ∼ ¼ billion people globally and requires the development of additional tools to aid in elimination efforts. The recently approved RTS,S/AS01 vaccine represents a positive step, however, the moderate efficacy necessitates the development of more efficacious vaccines. PfCSP is a key target antigen for pre-erythrocytic vaccines aimed at preventing Plasmodium falciparum malaria infections. Epitopes within the central repeat region and at the junction of the repeat and N-terminal domain are well documented as major protective B cell epitopes. On the other hand, a majority of antibodies against the epitopes in the C-terminal domain, have been shown to be non-protective against sporozoite challenge. The C-terminal domain, however, contains CD4
Language	English
Publishing date	2023-10-10
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	605674-x
ISSN	1873-2518 ; 0264-410X
ISSN (online)	1873-2518
ISSN	0264-410X
DOI	10.1016/j.vaccine.2023.10.009
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Zs.MO 458: Show issues

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Article ; Online: Endoplasmic reticulum stress in the pathogenesis of hypertension.

Young, Colin N

Experimental physiology

2017 Volume 102, Issue 8, Page(s) 869–884

Abstract: New findings: What is the topic of this review? This review highlights the emerging role of disruptions in endoplasmic reticulum (ER) function, namely ER stress, as a contributor to hypertension. What advances does it highlight? This review presents an ... ...

Abstract	New findings: What is the topic of this review? This review highlights the emerging role of disruptions in endoplasmic reticulum (ER) function, namely ER stress, as a contributor to hypertension. What advances does it highlight? This review presents an integrative view of ER stress in cardiovascular control systems, including systems within the brain, kidney and peripheral vasculature, as related to development of hypertension. The endoplasmic reticulum (ER) is a cellular organelle specialized in the synthesis, folding, assembly and modification of proteins. In situations of increased protein demand, complex signalling pathways, termed the unfolded protein response, influence a series of cellular feedback loops to control ER function strictly. Although this is initially a compensatory attempt to maintain cellular homeostasis, chronic activation of the unfolded protein response, known as ER stress, leads to sustained changes in cellular function. A growing body of literature points to ER stress in diverse cardioregulatory systems, including the brain, kidney and vasculature, as central to the development of hypertension. Here, these recent findings from essential and obesity-related forms of hypertension are highlighted in an integrative manner, with discussion of the potential upstream causes and downstream consequences of ER stress. Given that hypertension is a leading medical and socio-economic global challenge, emerging findings suggest that targeting ER stress might represent a viable strategy for the treatment of hypertensive disease.
MeSH term(s)	Animals ; Endoplasmic Reticulum/physiology ; Endoplasmic Reticulum Stress/physiology ; Humans ; Hypertension/physiopathology ; Signal Transduction/physiology ; Unfolded Protein Response/physiology
Language	English
Publishing date	2017-06-09
Publishing country	England
Document type	Journal Article ; Review ; Research Support, N.I.H., Extramural
ZDB-ID	1016295-1
ISSN	1469-445X ; 0958-0670
ISSN (online)	1469-445X
ISSN	0958-0670
DOI	10.1113/EP086274
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Article ; Online: Large-field-of-view scanning electron microscopy of the paraventricular nucleus of the hypothalamus during diet-induced obesity.

Arestakesyan, Hovhannes / Blackmore, Katherine / Smith, Hannah C / Popratiloff, Anastas / Young, Colin N

Journal of neurophysiology

2023 Volume 130, Issue 2, Page(s) 345–352

Abstract: Dysregulation in the paraventricular nucleus of the hypothalamus (PVN) is associated with a variety of diseases including those related to obesity. Although most investigations have focused on molecular changes, structural alterations in PVN neurons can ... ...

Abstract	Dysregulation in the paraventricular nucleus of the hypothalamus (PVN) is associated with a variety of diseases including those related to obesity. Although most investigations have focused on molecular changes, structural alterations in PVN neurons can reveal underlying functional disruptions. Although electron microscopy (EM) can provide nanometer resolution of brain structures, an inherent limitation of traditional transmission EM is the single field of view nature of data collection. To overcome this, we used large-field-of-view high-resolution backscatter scanning electron microscopy (bSEM) of the PVN. By stitching high-resolution bSEM images, taken from normal chow and high-fat diet mice, we achieved interactive, zoomable maps that allow for low-magnification screening of the entire PVN and high-resolution analyses of ultrastructure at the level of the smallest cellular organelle. Using this approach, quantitative analysis across the PVN revealed marked electron-dense regions within neuronal nucleoplasm following high-fat diet feeding, with an increase in kurtosis, indicative of a shift away from a normal distribution. Furthermore, measures of skewness indicated a shift toward darker clustered electron-dense regions, potentially indicative of heterochromatin clusters. We further demonstrate the utility to map out healthy and altered neurons throughout the PVN and the ability to remotely perform bSEM imaging in situations that require social distancing, such as the COVID-19 pandemic. Collectively, these findings present an approach that allows for the precise placement of PVN cells within an overall structural and functional map of the PVN. Moreover, they suggest that obesity may disrupt PVN neuronal chromatin structure.
MeSH term(s)	Mice ; Animals ; Humans ; Paraventricular Hypothalamic Nucleus ; Microscopy, Electron, Scanning ; Pandemics ; COVID-19 ; Hypothalamus ; Obesity ; Diet, High-Fat/adverse effects
Language	English
Publishing date	2023-07-12
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	80161-6
ISSN	1522-1598 ; 0022-3077
ISSN (online)	1522-1598
ISSN	0022-3077
DOI	10.1152/jn.00208.2023
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Article: Sensory Circumventricular Organs, Neuroendocrine Control, and Metabolic Regulation.

Jeong, Jin Kwon / Dow, Samantha A / Young, Colin N

Metabolites

2021 Volume 11, Issue 8

Abstract: The central nervous system is critical in metabolic regulation, and accumulating evidence points to a distributed network of brain regions involved in energy homeostasis. This is accomplished, in part, by integrating peripheral and central metabolic ... ...

Abstract	The central nervous system is critical in metabolic regulation, and accumulating evidence points to a distributed network of brain regions involved in energy homeostasis. This is accomplished, in part, by integrating peripheral and central metabolic information and subsequently modulating neuroendocrine outputs through the paraventricular and supraoptic nucleus of the hypothalamus. However, these hypothalamic nuclei are generally protected by a blood-brain-barrier limiting their ability to directly sense circulating metabolic signals-pointing to possible involvement of upstream brain nuclei. In this regard, sensory circumventricular organs (CVOs), brain sites traditionally recognized in thirst/fluid and cardiovascular regulation, are emerging as potential sites through which circulating metabolic substances influence neuroendocrine control. The sensory CVOs, including the subfornical organ, organum vasculosum of the lamina terminalis, and area postrema, are located outside the blood-brain-barrier, possess cellular machinery to sense the metabolic interior milieu, and establish complex neural networks to hypothalamic neuroendocrine nuclei. Here, evidence for a potential role of sensory CVO-hypothalamic neuroendocrine networks in energy homeostasis is presented.
Language	English
Publishing date	2021-07-29
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2662251-8
ISSN	2218-1989
ISSN	2218-1989
DOI	10.3390/metabo11080494
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Article: Dose-response effect of egg-phosphatidylcholine on maze-learning ability and fatty acid composition of plasma and brain in aged mice fed an n-3 fatty acid-deficient diet.

Lim, Sun-Young / Suzuki, Hiramitsu

Annals of nutrition & metabolism

2002 Volume 46, Issue 5, Page(s) 215–221

Abstract: ... months were fed the following diets for 4 months: (i) 5 g palm oil/100 g diet (n-3-deficient ... All animals were maintained on the n-3 fatty acid-deficient diets to examine the direct effect of egg-PC ... maze-learning ability in aged mice fed n-3 fatty acid-deficient diets but it does not influence the percentage ...

Abstract	Background/aims: We investigated the dose-response effect of egg-phosphatidylcholine (PC) on the maze-learning ability and brain fatty acid composition in aged mice. Method: Male Crj:CD-1 mice aged 18 months were fed the following diets for 4 months: (i) 5 g palm oil/100 g diet (n-3-deficient control group); (ii) 1 g egg-PC/100 g diet plus 4 g palm oil/100 g diet (egg-PC 1% group); (iii) 2.5 g egg-PC/100 g diet plus 2.5 g palm oil/100 g diet (egg-PC 2.5% group), and (iv) 5 g egg-PC/100 g diet (egg-PC 5% group). Maze-learning ability was assessed 3 months after the start of the experiment. All animals were maintained on the n-3 fatty acid-deficient diets to examine the direct effect of egg-PC on maze behavior. The time required to reach the maze exit and the number of times that a mouse strayed into blind alleys in the maze were measured in 3 trials every 4 days. Results: Our results showed that the 2.5 and 5% egg-PC groups needed less (p < 0.05) time to find the exit and strayed into blind alleys fewer times (p < 0.05) than the control group. In order to determine the relationship between maze-behavior and brain docosahexaenoic acid (DHA) and arachidonic acid (AA) levels in aged mice fed various doses of egg-PC, the plasma and brain fatty acid composition was examined. Dose-response increases in the percentage of DHA were found in plasma lipids. However, based on our data on the brain fatty acid composition of mice fed various doses of egg-PC, no significant differences in the percentages of DHA and AA among the dietary groups were observed. Conclusion: These results suggest that the intake of egg-PC improves maze-learning ability in aged mice fed n-3 fatty acid-deficient diets but it does not influence the percentage of brain DHA and AA.
MeSH term(s)	Aging/metabolism ; Animals ; Behavior, Animal/drug effects ; Brain/drug effects ; Brain/metabolism ; Dose-Response Relationship, Drug ; Fatty Acids/metabolism ; Fatty Acids, Omega-3/administration & dosage ; Lipids/blood ; Male ; Maze Learning/drug effects ; Mice ; Phosphatidylcholines/administration & dosage ; Time Factors
Chemical Substances	Fatty Acids ; Fatty Acids, Omega-3 ; Lipids ; Phosphatidylcholines
Language	English
Publishing date	2002
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	392341-1
ISSN	1421-9697 ; 0250-6807 ; 1018-9688
ISSN (online)	1421-9697
ISSN	0250-6807 ; 1018-9688
DOI	10.1159/000065410
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