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Carrier-mediated blood-brain barrier transport of short-chain monocarboxylic organic acids
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“The abundant expression of MCTs in endothelial cells (75, 92) might facilitate crossing of the BBB by SCFAs since brain uptake of SCFAs has previously been demonstrated in rats following injection of 14C-SCFAs into the carotid artery (93).”
From The Role of Short-Chain Fatty Acids From Gut Microbiota in Gut-Brain Communication (2020) · cites this paper as [93]
In the citing paper
“A small fraction reaches the systemic circulation and can cross the tightly regulated BBB using their own transporters located on brain vascular epithelial cells (100, 101).”
From The gut-brain axis: how microbiota and host inflammasome influence brain physiology and pathology (2020) · cites this paper as [100]
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The role of short-chain fatty acids in microbiota–gut–brain communication
Dalile, B., Van Oudenhove, L., Vervliet, B., & Verbeke, K. (2019) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-019-0157-3 · Cited by 3,357
The Role of Short-Chain Fatty Acids From Gut Microbiota in Gut-Brain Communication
Silva, Y. P., Bernardi, A., & Frozza, R. L. (2020) · Frontiers in Endocrinology · doi:10.3389/fendo.2020.00025 · Cited by 3,043
“The abundant expression of MCTs in endothelial cells (75, 92) might facilitate crossing of the BBB by SCFAs since brain uptake of SCFAs has previously been demonstrated in rats following injection of 14C-SCFAs into the carotid artery (93).”
BackgroundThe neuropharmacology of butyrate: the bread and butter of the microbiota-gut-brain axis
Stilling, R. M., van de Wouw, M., Clarke, G., Stanton, C., Dinan, T. G., & Cryan, J. F. (2016) · Neurochemistry International · doi:10.1016/j.neuint.2016.06.011 · Cited by 891
“Studies using isotope-labelled butyrate were able to demonstrate carrier-mediated uptake of butyrate and other monocarboxylates into the brain as far back as the 1970s (Oldendorf, 1973; Sarna et al., 1979), although more”
Brain Glucose Metabolism: Integration of Energetics with Function
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Helms, H. C., Abbott, N. J., Burek, M., Cecchelli, R., Couraud, P.-O., Deli, M. A., Förster, C., Galla, H. J., Romero, I. A., Shusta, E. V., et al. (2016) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1177/0271678x16630991 · Cited by 843
The gut-brain axis: how microbiota and host inflammasome influence brain physiology and pathology
Rutsch, A., Kantsjö, J. B., & Ronchi, F. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.604179 · Cited by 821
“A small fraction reaches the systemic circulation and can cross the tightly regulated BBB using their own transporters located on brain vascular epithelial cells (100, 101).”
BackgroundShort chain fatty acids: Microbial metabolites for gut-brain axis signalling
O’Riordan, K. J., Collins, M., Moloney, G. M., Knox, E. G., Aburto, M. R., Fülling, C., Morley, S. J., Clarke, G. A., Schellekens, H., & Cryan, J. F. (2022) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2022.111572 · Cited by 788
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Regulation of retinal blood flow in health and disease
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TRANSPORT OF METABOLIC SUBSTRATES THROUGH THE BLOOD‐BRAIN BARRIER1
Pardridge, W. M., & Oldendorf, W. H. (1977) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.1977.tb07702.x · Cited by 535
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“The higher proportion may be explained by differences in transport rates and mechanisms of the two substrates (Oldendorf, 1971, 1973), or it could be a consequence of anesthesia, fasting, or species differences.”
BackgroundInfluentialMechanisms of Blood–Brain Barrier Protection by Microbiota-Derived Short-Chain Fatty Acids
Fock, E. M., & Parnova, R. G. (2023) · Cells · doi:10.3390/cells12040657 · Cited by 435
“Its uptake by the brain was 6 times lower but was at the same level as in the heart [62].”
BackgroundMonographs on fragrance raw materials
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Preferential Utilization of Acetate by Astrocytes Is Attributable to Transport
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“Research on acetate transport in the nervous system has focused primarily on movement across the blood–brain barrier; previous studies suggest that uptake occurs by passive diffusion (Oldendorf, 1973; Terasaki et al., 1991).”
BackgroundPyruvate Protects Neurons against Hydrogen Peroxide-Induced Toxicity
Desagher, S., Glowinski, J., & Prémont, J. (1997) · Journal of Neuroscience · doi:10.1523/jneurosci.17-23-09060.1997 · Cited by 370
“Unlike exogenous catalase, pyruvate and other a-ketoacids can cross the blood–brain barrier (Oldendorf, 1973; Conn et al., 1983).”
BackgroundButyrate in Energy Metabolism: There Is Still More to Learn
Zhang, L., Liu, C.-D., Jiang, Q., & Yin, Y. (2021) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2020.12.003 · Cited by 379
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“However, lactate can cross the blood– brain barrier through monocarboxylate transporters (MCTs) (Oldendorf, 1973; Simpson et al., 2007), and recent studies have provided evidence that lactate can become a significant fuel source when elevated in the blood (Smith et al.”
BackgroundHu, Y., & Wilson, G. S. (1997) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.1997.69041484.x · Cited by 337
Cerebral metabolism of [1,2-13C2]acetate as detected by in vivo and in vitro 13C NMR.
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Regulation of Ketone Body Metabolism and the Role of PPARα
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“The difficulties in crossing BBB are no concern for ketone bodies, which are efficiently absorbed through monocarboxylate transporters (MCT1, MCT2), the expression of which increases significantly during fasting [100,101].”
BackgroundWidner, H., & Brundin, P. (1988) · Brain Research Reviews · doi:10.1016/0165-0173(88)90010-0 · Cited by 287
Effect of aging on the blood-brain barrier
Mooradian, A. D. (1988) · Neurobiology of Aging · doi:10.1016/s0197-4580(88)80013-7 · Cited by 296
Hladky, S. B., & Barrand, M. A. (2016) · Fluids and Barriers of the CNS · doi:10.1186/s12987-016-0040-3 · Cited by 304
Delivery of peptide and protein drugs over the blood–brain barrier
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Transport of small molecules through the blood-brain barrier: biology and methodology
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Glucose and ketone body utilization by the brain of neonatal rats
Nehlig, A., & de Vasconcelos, A. P. (1993) · Progress in Neurobiology · doi:10.1016/0301-0082(93)90022-k · Cited by 282
Pathways for Small Molecule Delivery to the Central Nervous System across the Blood-Brain Barrier
Mikitsh, J. L., & Chacko, A. (2014) · Perspectives in Medicinal Chemistry · doi:10.4137/pmc.s13384 · Cited by 284
Peptides and the blood–brain barrier
Banks, W. A. (2015) · Peptides · doi:10.1016/j.peptides.2015.03.010 · Cited by 267
Cremer, J. E., Cunningham, V. J., Pardridge, W. M., Braun, L. D., & Oldendorf, W. H. (1979) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.1979.tb05173.x · Cited by 263
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Blood-brain barrier transport machineries and targeted therapy of brain diseases
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“Although it is likely that SCFA pass across the blood– brain barrier via a carrier-mediated mechanism((96)), there is little or no apparent expression of FFA2 in the hypothalamus((59)).”
BackgroundKinetics of blood-brain barrier transport of hexoses
Pardridge, W. M., & Oldendorf, W. H. (1975) · Biochimica et Biophysica Acta (BBA) - Biomembranes · doi:10.1016/0005-2736(75)90279-5 · Cited by 244
Self-citationMolecular Anatomy of the Blood-Brain Barrier as Defined by Immunocytochemistry
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Fatty Acid Oxidation and Ketogenesis by Astrocytes in Primary Culture
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Independent blood-brain barrier transport systems for nucleic acid precursors
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Self-citationSeizure control by decanoic acid through direct AMPA receptor inhibition
Chang, P., Augustin, K., Boddum, K., Williams, S., Sun, M., Terschak, J. A., Hardege, J. D., Chen, P. E., Walker, M. C., & Williams, R. S. B. (2015) · Brain · doi:10.1093/brain/awv325 · Cited by 234
“…2013; Wlaz et al., 2015) but octanoic acid does not, and with previous in vivo pharmacokinetic data indicating that decanoic acid penetrates the blood–brain barrier (Oldendorf, 1973), these data suggest that decanoic acid directly contributes to the therapeutic effect of the MCT ketogenic diet.”
BackgroundA Historical Review of Brain Drug Delivery
Pardridge, W. M. (2022) · Pharmaceutics · doi:10.3390/pharmaceutics14061283 · Cited by 219
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Methods for quantifying the transport of drugs across brain barrier systems
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Mechanisms of Short-Chain Fatty Acids Derived from Gut Microbiota in Alzheimer's Disease
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Small molecular drug transfer across the blood-brain barrier via carrier-mediated transport systems
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Microbial-derived metabolites as a risk factor of age-related cognitive decline and dementia
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“In fact, the uptake of SCFAs into the brain has formerly been exhibited in rodents following the injection of 14C-SCFAs into the carotid artery [293].”
BackgroundThe energetic brain—A review from students to students
Bordone, M. P., Salman, M. M., Titus, H. E., Amini, E., Andersen, J. V., Chakraborti, B., Diuba, A. V., Dubouskaya, T. G., Ehrke, E., Espindola de Freitas, A., et al. (2019) · Journal of Neurochemistry · doi:10.1111/jnc.14829 · Cited by 205
Changes during development in transport processes of the blood-brain barrier
Cremer, J. E., Braun, L. D., & Oldendorf, W. H. (1976) · Biochimica et Biophysica Acta (BBA) - Biomembranes · doi:10.1016/0005-2736(76)90120-6 · Cited by 197
Self-citationPhysiology and pathophysiology of organic acids in cerebrospinal fluid
Hoffmann, G. F., Meier‐Augenstein, W., Stöckler, S., Surtees, R. A. H., Rating, D., & Nyhan, W. L. (1993) · Journal of Inherited Metabolic Disease · doi:10.1007/bf00711898 · Cited by 191
Functional expression and localization of P‐glycoprotein at the blood brain barrier
Bendayan, R., Lee, G. S., & Bendayan, M. (2002) · Microscopy Research and Technique · doi:10.1002/jemt.10090 · Cited by 186
“…information into the transport properties of amino acids (Betz and Goldstein, 1978), glucose (Pardridge et al., 1990), monocarboxylic acids (Oldendorf, 1973), choline (Estrada et al., 1990), nucleosides (Cornford and Oldendorf, 1975), neurotransmitters (Hardebo et al., 1979), as well as a…”
BackgroundFellows, L. K., Boutelle, M. G., & Fillenz, M. (1993) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.1993.tb03285.x · Cited by 176
“Abbreviations used: aCSF, artificial cerebrospinal fluid; AP-5, 2- amino-5-phosphonopentanoic acid; AP-7, 2-amino-7-phosphono- heptanoic acid; BBB, blood-brain barrier; HRP, horseradish peroxidase ; MK-801, (+)-”
BackgroundInfluentialSubstrate Utilization and Brain Development
Cremer, J. E. (1982) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1038/jcbfm.1982.45 · Cited by 173
Snigdha, S., Ha, K., Tsai, P., Dinan, T. G., Bartos, J. D., & Shahid, M. (2021) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2021.107978 · Cited by 173
Ketone Bodies Are Selectively Used by Individual Brain Regions
Hawkins, R. A., & Biebuyck, J. F. (1979) · Science · doi:10.1126/science.451608 · Cited by 168
The Role of Compartmentation in the Control of Glycolysis
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Kalyanaraman, B., Cheng, G., & Hardy, M. (2024) · Redox Biology · doi:10.1016/j.redox.2024.103092 · Cited by 185
“SCFAs — the byproducts of bacterial fermentation of dietary fiber-— get into the systemic circulation, cross the blood – brain barrier, and exert their effects on microglia in the brain [57,58].”
BackgroundMori, S., Takanaga, H., Ohtsuki, S., Deguchi, T., Kang, Y., Hosoya, K., & Terasaki, T. (2003) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1097/01.wcb.0000050062.57184.75 · Cited by 172
“In patients with Reye’s syndrome and medium-chain acyl-CoA dehydrogenase deficiency, octanoic acid concentrations in the blood increase dramatically with concomitant increases in the brain because of the transport of octanoic acid across the BBB (Oldendorf, 1973).”
BackgroundPardridge, W. M. (2015) · Expert Opinion on Therapeutic Targets · doi:10.1517/14728222.2015.1042364 · Cited by 159
“The STP of BBB MCT was defined in vivo in the rat [29-31], and is:”
BackgroundChanges in the Blood-Brain Barrier in Hepatic Coma After Hepatectomy in the Rat
Livingstone, A. S., Potvin, M.-J., Goresky, C. A., Finlayson, M. H., & Hinchey, E. J. (1977) · Gastroenterology · doi:10.1016/s0016-5085(19)31768-8 · Cited by 155
Blood-brain barrier transport of caffeine: Dose-related restriction of adenine transport
McCall, A. L., Millington, W. R., & Wurtman, R. J. (1982) · Life Sciences · doi:10.1016/0024-3205(82)90715-9 · Cited by 158
Fatty Acid Transport Through the Blood‐Brain Barrier
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Deficiency in short-chain fatty acid β-oxidation affects theta oscillations during sleep
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Vector-mediated drug delivery to the brain
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Shank, R. P., & Campbell, G. L. M. (1984) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.1984.tb12724.x · Cited by 144
Specialized Properties and Solute Transport in Brain Capillaries
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Oldendorf, W. H., & Braun, L. D. (1976) · Brain Research · doi:10.1016/0006-8993(76)90024-x · Cited by 141
Self-citationPekmeability Changes in the Blood-Brain Barrier: Causes and Consequences
Pardridge, W. M., Connor, J. D., Crawford, I. L., & Oldendorf, W. H. (1975) · Critical Reviews in Toxicology · doi:10.3109/10408447509079857 · Cited by 138
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Pyruvate Administered After Severe Hypoglycemia Reduces Neuronal Death and Cognitive Impairment
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“Because pyruvate crosses the blood-brain barrier by both facilitated transport and diffusion (25,26), this increase in plasma concentration should substantially increase pyruvate transport into brain.”
13C MR Spectroscopy Study of Lactate as Substrate for Rat Brain
Qu, H., Haberg, A. K., Haraldseth, O., Unsgård, G., & Sonnewald, U. (2000) · Developmental Neuroscience · doi:10.1159/000017472 · Cited by 132
“Earlier studies with 14C-labeled lactate indicated that the bloodbrain barrier contains a saturable lactate carrier with Lstereospecificity [Oldendorf, 1973; Nemoto and Severinghaus, 1974].”
BackgroundShort chain fatty acids: the messengers from down below
Mansuy‐Aubert, V., & Ravussin, Y. (2023) · Frontiers in Neuroscience · doi:10.3389/fnins.2023.1197759 · Cited by 144
“Some SCFA have been demonstrated to cross the blood brain barrier in rats (Oldendorf, 1973) and in humans (Bachmann et al., 1979), possibly due to high expression of their transporter, monocarboxylate transporters (MCTs) in blood cells and astrocytes (Bachmann et al., 1979; Dalile et al., 2019).”
BackgroundDeüticke, B., Beyer, E. C., & Forst, B. (1982) · Biochimica et Biophysica Acta (BBA) - Biomembranes · doi:10.1016/0005-2736(82)90053-0 · Cited by 128
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“short-chain fatty acids are transported across the BBB (12).”
BackgroundMethodDietary Cholesterol and the Origin of Cholesterol in the Brain of Developing Rats
Edmond, J., Korsak, R. A., Morrow, J. W., Torok-Both, G. A., & Catlin, D. H. (1991) · Journal of Nutrition · doi:10.1093/jn/121.9.1323 · Cited by 125
Short-chain fatty acids and gut microbiota in multiple sclerosis
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Stereoselective, SH-dependent transfer of lactate in mammalian erythrocytes
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Age-related changes in the blood-brain barrier
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Human Serum Metabolites Associate With Severity and Patient Outcomes in Traumatic Brain Injury
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“Several other metabolites, which are present at high concentrations in cerebrospinal fluid (Hartonen et al., 2013) and BMD,were also upregulated in serum of the TBI patients, indicative of disruption of the BBB.”
BackgroundInfluentialBlood–Brain Barrier Transport of Valproic Acid
Cornford, E. M., Diep, C. P., & Pardridge, W. M. (1985) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.1985.tb08793.x · Cited by 113
Butyrate ameliorates quinolinic acid–induced cognitive decline in obesity models
Ge, X., Zheng, M., Hu, M., Fang, X., Geng, D., Liu, S., Wang, L., Zhang, J., Guan, L., Zheng, P., et al. (2023) · Journal of Clinical Investigation · doi:10.1172/jci154612 · Cited by 122
“…in the frontal cortex (Figure 2E) as a result of a decrease in the sum and maximum number of dendritic inter-sections ( P < 0.01; P < 0.01; Figure 2, F and G), but no alteration is the SCFA most abundantly uptaken by the brain (22) compared with other SCFAs, including acetate and propionate.”
InfluentialGJEDDE, A. H., & Marrett, S. (2001) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1097/00004647-200112000-00002 · Cited by 112
“Third, although the lactate dehydrogenase and monocarboxylate transporter proteins have been presented as recently discovered key elements in the operation of the shuttle, neither protein, as catalyst of a near-equilibrium reaction, can be claimed to indicate a net direction of flux in vivo, nor is the discovery of th…”
BackgroundGut microbiota-derived metabolites and their importance in neurological disorders
Swer, N. M., Venkidesh, B. S., Murali, T. S., & Mumbrekar, K. D. (2022) · Molecular Biology Reports · doi:10.1007/s11033-022-08038-0 · Cited by 120
“[39], where SCFAs were injected into the common carotid artery of Wistar rats, and all the three significant SCFAs were detected in the Cerebrospinal fluid (CSF) in varying ratios.”
MethodBoundaries and integration between microbiota, the nervous system, and immunity
Macpherson, A. J., Pachnis, V., & Prinz, M. (2023) · Immunity · doi:10.1016/j.immuni.2023.07.011 · Cited by 118
Quantitative assessment of dynamic PET imaging data in cancer imaging
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Kuhr, W. G., den Berg, C. J. V., & Korf, J. (1988) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1038/jcbfm.1988.142 · Cited by 106
Standardized method for high-resolution 1H-NMR of cerebrospinal fluid
Wevers, R. A., Engelke, U. F. H., Wendel, U., et al. (1995) · Clinical Chemistry · doi:10.1093/clinchem/41.5.744 · Cited by 103
Sympathetic influence on cerebral blood flow and metabolism during exercise in humans
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“Lactate is transported across the BBB via MCTs and the transport is specific for L-lactate that demonstrates Michaelis-Menten kinetics (Oldendorf, 1971, 1973).”
BackgroundEDLUND, G. L., & Halestrap, A. P. (1988) · Biochemical Journal · doi:10.1042/bj2490117 · Cited by 102
Drug delivery through the blood-brain barrier
Tamai, I., & Tsuji, A. (1996) · Advanced Drug Delivery Reviews · doi:10.1016/0169-409x(96)00011-7 · Cited by 101
Ischemic stroke and intestinal flora: an insight into brain–gut axis
Hu, W., Kong, X., Wang, H., Li, Y., & Luo, Y. (2022) · European journal of medical research · doi:10.1186/s40001-022-00691-2 · Cited by 102
Lactulose, Disaccharides and Colonic Flora
Clausen, M. R., & Mortensen, P. B. (1997) · Drugs · doi:10.2165/00003495-199753060-00003 · Cited by 98
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“SCFAs can reach the brain, as they were shown to cross the BBB in a cell culture model and in rats following injection of SCFAs [51,52].”
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“Circulating levels of SCFA are able to cross the blood brain barrier, and the primary SCFA uptake by the brain is for butyrate, followed by propionate and acetate (Oldendorf, 1973).”
BackgroundOhtsuki, S. (2004) · Biological and Pharmaceutical Bulletin · doi:10.1248/bpb.27.1489 · Cited by 94
Inhibition of brain energy metabolism by the α-keto acids accumulating in maple syrup urine disease
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Applications of Medium-Chain Triglycerides in Foods
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“There are in vivo data supporting this hypothesis that decanoic acid crosses the blood-brain barrier (54).”
Background
Metadata
- Authors
- Oldendorf, W.
- Corresponding author
- Oldendorf, WH
- Venue
- American Journal of Physiology-Legacy Content
- Publisher
- American Physiological Society
- Published
- 1973-06-01
- Volume
- 224
- Issue
- 6
- Pages
- 1450-1453
- ISSN
- 0002-9513 (ISSN-L)
- OpenAlex
- W2294335852
- Cited by
- 463
- References
- 0
- Citations by year
- 2026: 16 · 2025: 17 · 2024: 21 · 2023: 20 · 2022: 32 · 2021: 13 · 2020: 7 · 2019: 5 · 2018: 9 · 2017: 2 · 2016: 9 · 2015: 4 · 2014: 4 · 2013: 9 · 2012: 6
- FWCI
- 4.23
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- American Journal of Physiology-Legacy Content (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Keywords
- blood-brain barrier, carrier-mediated transport, organic acids, brain uptake, monocarboxylate transporters
- MeSH terms
- Acetates, Amino Acids, Animals, Biological Transport, Blood-Brain Barrier, Brain, Butyrates, Carbon Isotopes, Carboxylic Acids, Dicarboxylic Acids, Female, Glucose, Lactates, Male, Propionates, Pyruvates, Tricarboxylic Acids, Tritium, Rats
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