삼당류: 두 판 사이의 차이

뷰티르산
일반적인 성질
IUPAC 이름	Butanoic acid
화학식	C4H8O2
CAS 번호	107-92-6
물리적 성질
분자량	88.11 g/mol
녹는점	268.05 K; -5.1 °C; 22.82 °F
끓는점	436.9 K; 163.75 °C; 326.75 °F
밀도	0.9528 g/cm3
형태	무색 유성 액체
열화학적 성질
안전성

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2018년 2월 26일 (월) 17:02 판

뷰티르산(영어: butyric acid) (그리스어 "βούτῡρον"에서 유래, "butter"를 의미함)은 계통명은 부탄산(butanoic acid)이고, BTA로 약칭되며,^[1] 화학식이 C H₃CH₂CH₂-COOH 인 카복실산이다. 뷰티르산의 염 및 에스터(에스테르)는 뷰티레이트(butyrate) 또는 부타노에이트(butanoate)로 알려져 있다. 뷰티르산은 우유 특히 염소, 양 및 아메리카 들소의 젖, 버터, 파마산 치즈 및 혐기성 발효 산물(결장 및 액취증 포함)에서 발견된다. 또한 뷰티르산은 허쉬 공정에 의해 생산된 밀크 초콜릿에서 발견되거나, 허쉬 초콜릿의 맛을 모방하기 위해 첨가된 것으로 추측된다.^[2] 뷰티르산은 사람의 구토물에 존재하며, 불쾌한 냄새를 낸다.^[3] 뷰티르산은 불쾌한 냄새와 콕 쏘는 맛을 가지며, 에테르와 유사한 약간 감미로운 뒷맛을 가진다. 개와 같은 좋은 냄새 탐지 능력이 있는 포유류는 뷰티르산을 10ppb(parts per billion)로 탐지할 수 있는 반면에 사람은 10ppm(parts per million)이상의 농도에서 뷰티르산을 탐지할 수 있다.

뷰티르산은 1814년 프랑스의 화학자 미셀 외젠 슈프뢰이(Michel Eugène Chevreul)에 의해 불순한 형태로 처음 관찰되었다. 1818년까지 슈브외이는 뷰티르산을 특징짓기 위해 충분하게 정제했다. 그러나 슈브뢰이는 뷰티르산에 대한 초기 연구를 발표하지 않았고, 대신 프랑스 파리에 있는 과학 아카데미에 원고 형태로 연구 결과물을 맡겼다. 또한 프랑스의 화학자인 앙리 브라코노(Henri Braconnot)도 버터의 성분을 연구하고 연구 결과를 발표했는데 이것이 우선권에 대한 논쟁으로 이어졌다. 1815년 초에 슈브뢰이는 버터 냄새의 원인이 되는 물질을 발견했다고 주장했다.^[4] 1817년에 슈브뢰이는 뷰티르산의 성질에 관한 연구 결과를 발표하고, 뷰티르산의 이름을 지었다.^[5] 그러나, 1823년에 이르러서야 뷰티르산의 특성이 자세히 밝혀졌다.^[6] 뷰티르산이란 이름은 처음 발견된 물질인 butyrum (또는 buturum)이라는 버터의 라틴어 단어에서 유래되었다.

화학

뷰티르산은 동물성 지방에서 에스터의 형태로 발견되는 지방산이다. 뷰티르산의 트라이글리세라이드는 버터의 3~4%를 차지한다. 버터가 산패할 때, 가수분해에 의해 글리세라이드로부터 뷰티르산이 유리되어 불쾌한 냄새가 난다. 뷰티르산은 짧은 사슬 지방산이라고 불리는 지방산 하위 그룹의 주요 구성원이다. 뷰티르산은 염기와 강력한 산화제와 반응하여 많은 금속을 공격하는 중-강산이다.^[7]

뷰티르산은 물, 에탄올 및 에테르에 쉽게 용해되는 유성의 무색 액체이며 염화 칼슘과 같은 염으로 포화되어 액상으로부터 분리될 수 있다. It is oxidized to carbon dioxide and acetic acid using potassium dichromate and sulfuric acid, while alkaline potassium permanganate oxidizes it to carbon dioxide. The calcium salt, Ca(C₄H₇O₂)₂·H₂O, is less soluble in hot water than in cold.

Butyric acid has a structural isomer called isobutyric acid (2-methylpropanoic acid).

Safety

Personal protective equipment such as rubber or PVC gloves, protective eye goggles, and chemical-resistant clothing and shoes are used to minimize risks when handling butyric acid.

Inhalation of butyric acid may result in soreness of throat, coughing, a burning sensation, and laboured breathing. Ingestion of the acid may result in abdominal pain, shock, and collapse. Physical exposure to the acid may result in pain, blistering and skin burns, while exposure to the eyes may result in pain, severe deep burns and loss of vision.^[7]

Production

It is industrially prepared by the fermentation of sugar or starch, brought about by the addition of putrefying cheese, with calcium carbonate added to neutralize the acids formed in the process. The butyric fermentation of starch is aided by the direct addition of Bacillus subtilis. Salts and esters of the acid are called butyrates or butanoates.

Butyric acid or fermentation butyric acid is also found as a hexyl ester hexyl butyrate in the oil of Heracleum giganteum (a type of hogweed) and as the octyl ester octyl butyrate in parsnip (Pastinaca sativa); it has also been noticed in skin flora and perspiration.

Uses

Butyric acid is used in the preparation of various butyrate esters. Low-molecular-weight esters of butyric acid, such as methyl butyrate, have mostly pleasant aromas or tastes. As a consequence, they are used as food and perfume additives. It is also used as an animal feed supplement due to the ability to reduce pathogenic bacterial colonization.^[8] It is an approved food flavoring in the EU FLAVIS database (number 08.005).

Due to its powerful odor, it has also been used as a fishing bait additive.^[9] Many of the commercially available flavors used in carp (Cyprinus carpio) baits use butyric acid as their ester base; however, it is not clear whether fish are attracted by the butyric acid itself or the substances added to it. Butyric acid was, however, one of the few organic acids shown to be palatable for both tench and bitterling.^[10]

The substance has also been used as a stink bomb by Sea Shepherd Conservation Society to disrupt Japanese whaling crews,^[11] as well as by anti-abortion protesters to disrupt abortion clinics.^[12]

Butyric acid, along with acetic acid, can be reacted with cellulose to produce the organic ester cellulose acetate butyrate (CAB), which is used in a wide variety of tools, parts, and coatings and is more resistant to degradation than cellulose acetate.^[13] However, CAB can degrade with exposure to heat and moisture, releasing butyric acid.^[14] This process is sometimes observed in the unpleasant, vomit-like odor of aging screwdrivers and other hand tools.^[15]

Biochemistry

Microbial biosynthesis

틀:Missing information Butyrate is produced as end-product of a fermentation process solely performed by obligate anaerobic bacteria. Fermented Kombucha "tea" includes butyric acid as a result of the fermentation. This fermentation pathway was discovered by Louis Pasteur in 1861. Examples of butyrate-producing species of bacteria:

Clostridium butyricum
Clostridium kluyveri
Clostridium pasteurianum
Faecalibacterium prausnitzii
Fusobacterium nucleatum
Butyrivibrio fibrisolvens
Eubacterium limosum

The pathway starts with the glycolytic cleavage of glucose to two molecules of pyruvate, as happens in most organisms. Pyruvate is then oxidized into acetyl coenzyme A using a unique mechanism that involves an enzyme system called pyruvate:ferredoxin oxidoreductase. Two molecules of carbon dioxide (CO₂) and two molecules of elemental hydrogen (H₂) are formed as waste products from the cell. Then,

Action	Responsible enzyme
Acetyl coenzyme A converts into acetoacetyl coenzyme A	acetyl-CoA-acetyl transferase
Acetoacetyl coenzyme A converts into β-hydroxybutyryl CoA	β-hydroxybutyryl-CoA dehydrogenase
β-hydroxybutyryl CoA converts into crotonyl CoA	crotonase
Crotonyl CoA converts into butyryl CoA (CH₃CH₂CH₂C=O-CoA)	butyryl CoA dehydrogenase
A phosphate group replaces CoA to form butyryl phosphate	phosphobutyrylase
The phosphate group joins ADP to form ATP and butyrate	butyrate kinase

ATP is produced, as can be seen, in the last step of the fermentation. Three molecules of ATP are produced for each glucose molecule, a relatively high yield. The balanced equation for this fermentation is

C₆H₁₂O₆ → C₄H₈O₂ + 2 CO₂ + 2 H₂

Several species form acetone and n-butanol in an alternative pathway, which starts as butyrate fermentation. Some of these species are:

Clostridium acetobutylicum, the most prominent acetone and propianol producer, used also in industry
Clostridium beijerinckii
Clostridium tetanomorphum
Clostridium aurantibutyricum

These bacteria begin with butyrate fermentation, as described above, but, when the pH drops below 5, they switch into butanol and acetone production to prevent further lowering of the pH. Two molecules of butanol are formed for each molecule of acetone.

The change in the pathway occurs after acetoacetyl CoA formation. This intermediate then takes two possible pathways:

acetoacetyl CoA → acetoacetate → acetone
acetoacetyl CoA → butyryl CoA → butyraldehyde → butanol

Highly-fermentable fiber residues, such as those from resistant starch, oat bran, pectin, and guar are transformed by colonic bacteria into short-chain fatty acids (SCFA) including butyrate, producing more SCFA than less fermentable fibers such as celluloses.^[16] One study found that resistant starch consistently produces more butyrate than other types of dietary fiber.^[17] The production of SCFA from fibers in ruminant animals such as cattle is responsible for the butyrate content of milk and butter.^[18]

Fructans are another source of prebiotic soluble dietary fibers. They are often found in the soluble fibers of foods which are high in sulfur, such as the Allium and Cruciferous vegetables. Sources of fructans include wheat (although some wheat strains such as spelt contain lower amounts),^[19] rye, barley, onion, garlic, Jerusalem and globe artichoke, asparagus, beetroot, chicory, dandelion leaves, leek, radicchio, the white part of spring onion, broccoli, brussels sprouts, cabbage, fennel and prebiotics such as fructooligosaccharides (FOS), oligofructose and inulin.^[20]^[21] While many of these foods lack in butyrate production compared to resistant starch, they do have a number of benefits. They generally possess a low glycemic index which appeals well to diabetics. They also appeal to those on the ketogenic diet who benefit from beta-hydroxybutyric acid, which is a HDAC inhibitor which can cross the blood brain barrier and be used as fuel in the mitochondria of brain cells.^[22] Other HDAC inhibitors in these butyrate producing foods are sulforaphane,^[23] which has promise in inhibiting human breast cancer cells.^[24] Sulforaphane has also been shown to promote hair growth in mice,^[25] it contains compounds which prevent ulcers,^[26] and helps with cognitive function in rats.^[27] It is good to note that sulforaphane in broccoli is destroyed if prepared improperly.^[28] Diallyl disulfide found in the fructans containing garlic has been shown to reduce chemical toxicity and carcinogenesis in rodents,^[29] and shows synergestic benefits with butyrate when it comes to inhibiting the growth of human cancer tumor cells in the colon.^[30]

Pharmacology

Human enzyme and GPCR binding^[31]^[32]
Inhibited enzyme	IC₅₀ (nM)	Entry note
HDAC1	16,000
HDAC2	12,000
HDAC3	9,000
HDAC4	2,000,000	Lower bound
HDAC5	2,000,000	Lower bound
HDAC6	2,000,000	Lower bound
HDAC7	2,000,000	Lower bound
HDAC8	15,000
HDAC9	2,000,000	Lower bound
CA1	511,000
CA2	1,032,000
GPCR target	pEC₅₀	Entry note
FFAR2	2.9–4.6	Full agonist
FFAR3	3.8–4.9	Full agonist
NIACR1	missing data	Full agonist

Pharmacodynamics

Like other short-chain fatty acids (SCFAs), butyrate is an agonist at the free fatty acid receptors FFAR2 and FFAR3, which function as nutrient sensors which help regulate energy balance;^[33]^[34]^[35] unlike the other SCFAs,^[35] butyrate is also an agonist of niacin receptor 1 (NIACR1, aka GPR109A).^[33]^[34]^[35] Butyric acid is utilized by mitochondria, particularly in colonocytes and by the liver, to generate adenosine triphosphate (ATP) during fatty acid metabolism.^[33] Butyric acid is also an HDAC inhibitor (specifically, HDAC1, HDAC2, HDAC3, and HDAC8),^[31]^[32] a drug that inhibits the function of histone deacetylase enzymes, thereby favoring an acetylated state of histones in cells.^[33] Histone acetylation loosens the structure of chromatin by reducing the electrostatic attraction between histones and DNA.^[33] In general, it is thought that transcription factors will be unable to access regions where histones are tightly associated with DNA (i.e., non-acetylated, e.g., heterochromatin).틀:Mcn Therefore, butyric acid is thought to enhance the transcriptional activity at promoters,^[33] which are typically silenced or downregulated due to histone deacetylase activity.

Pharmacokinetics

Butyrate that is produced in the colon through microbial fermentation of dietary fiber is primarily absorbed and utilized by colonocytes and the liver^{[note 1]} for the generation of ATP during energy metabolism;^[33] however, some butyrate is absorbed in the distal colon, which is not connected to the portal vein, thereby allowing for the systemic distribution of butyrate to multiple organ systems through the circulatory system.^[33] Butyrate that has reached systemic circulation can readily cross the blood-brain barrier via monocarboxylate transporters (i.e., certain members of the SLC16A group of transporters).^[36]^[37] Other transporters that mediate the passage of butyrate across lipid membranes include SLC5A8 (SMCT1), SLC27A1 (FATP1), and SLC27A4 (FATP4).^[31]^[37]

Metabolism

Butyric acid is metabolized by various human XM-ligases (ACSM1, ACSM2B, ASCM3, ACSM4, ACSM5, and ACSM6), also known as butyrate–CoA ligase.^[3] The metabolite produced by this reaction is butyryl–CoA, and is produced as follows:^[3]

Adenosine triphosphate + Butyric acid + Coenzyme A → Adenosine monophosphate + Pyrophosphate + Butyryl-CoA

As a short-chain fatty acid, butyrate is utilized by mitochondria as an energy (i.e., adenosine triphosphate or ATP) source through fatty acid metabolism.

In humans, the butyrate prodrug tributyrin is metabolized by triacylglycerol lipase into dibutyrin and butyrate through the reaction:^[38]

Tributyrin + H20 = Dibutyrin + Butyrate

Research

Peripheral therapeutic effects

Butyrate has numerous beneficial effects in humans on energy homeostasis and related diseases (diabetes and obesity), inflammation, and immune function (e.g., it has pronounced antimicrobial and anticarcinogenic effects).^[34]^[39] These effects occur through its utilization by mitochondria to generate ATP during fatty acid metabolism or through one or more of its histone-modifying enzyme targets (i.e., the class I histone deacetylases) and G-protein coupled receptor targets (i.e., FFAR2, FFAR3, and NIACR1).^[34]

Immunomodulation and inflammation

Butyrate's effects on the immune system are mediated through the inhibition of class I histone deacetylases and activation of its G-protein coupled receptor targets: NIACR1 (GPR109A), FFAR2 (GPR43), and FFAR3 (GPR41).^[35]^[40] Among the short-chain fatty acids, butyrate is the most potent promoter of intestinal regulatory T cells in vitro and the only one among the group that is an NIACR1 ligand.^[35] It has been shown to be a critical mediator of the colonic inflammatory response. It possesses both preventive and therapeutic potential to counteract inflammation-mediated ulcerative colitis and colorectal cancer.

Butyrate has established antimicrobial properties in humans that are mediated through the antimicrobial peptide LL-37, which it induces via HDAC inhibition on histone H3.^[40]^[41]^[42] Butyrate increases gene expression of FOXP3 (the transcription regulator for Tregs) and promotes colonic regulatory T cells (Tregs) through the inhibition of class I histone deacetylases;^[35]^[40] through these actions, it increases the expression of interleukin 10, an anti-inflammatory cytokine.^[40]^[35] Butyrate also suppresses colonic inflammation by inhibiting the IFN-γ–STAT1 signaling pathways, which is mediated partially through histone deacetylase inhibition. While transient IFN-γ signaling is generally associated with normal host immune response, chronic IFN-γ signaling is often associated with chronic inflammation. It has been shown that butyrate inhibits activity of HDAC1 that is bound to the Fas gene promoter in T cells, resulting in hyperacetylation of the Fas promoter and up-regulation of Fas receptor on the T-cell surface.^[43] It is thus suggested that butyrate enhances apoptosis of T cells in the colonic tissue and thereby eliminates the source of inflammation (IFN-γ production).^[43]

Similar to other NIACR1 agonists, butyrate also produces marked anti-inflammatory effects in a variety of tissues, including the brain, gastrointestinal tract, skin, and vascular tissue.^[44]^[45]^[46]^[47] Butyrate binding at FFAR3 induces neuropeptide Y release and promotes the functional homeostasis of colonic mucosa and the enteric immune system.^[48]

Butyric acid is important as an energy (ATP) source for cells lining the mammalian colon (colonocytes). Without butyric acid for energy, colon cells undergo upregulated autophagy (i.e., self-digestion).^[49]

Cancer

Butyrate produces different effects in healthy and cancerous cells; this is known as the "butyrate paradox". In particular, butyrate inhibits colonic tumor cells and promotes healthy colonic epithelial cells.^[50] The signaling mechanism is not well understood.^[51] A review suggested that the chemopreventive benefits of butyrate depend in part on the amount, time of exposure with respect to the tumorigenic process, and type of fat in the diet.^[16] The production of volatile fatty acids such as butyrate from fermentable fibers may contribute to the role of dietary fiber in colon cancer.^[16] Short-chain fatty acids, which include butyric acid, are produced by beneficial colonic bacteria (probiotics) that feed on, or ferment prebiotics, which are plant products that contain adequate amounts of dietary fiber. These short-chain fatty acids benefit the colonocytes by increasing energy production and cell proliferation, and may protect against colon cancer.^[52]

Conversely, some researchers have sought to eliminate butyrate and consider it a potential cancer driver.^[53] Studies in mice indicate it drives transformation of MSH2-deficient colon epithelial cells.^[54] It is important to note that these are related to a gene deficiency. Niacin, beta-hydroxybutyrate, and curcumin may be effective adjunct treatments if genetic issues are present.^[55]틀:Ums

Diabetes

A review on the relationship between the microbiome and diabetes asserted that butyrate can induce "profound immunometabolic effects" in animal models and humans with type 2 diabetes;^[39] it also noted a relationship between the presence of obesity or diabetes and a state of marked dysbiosis in a host, which is not yet completely understood.^[39] While acknowledging that there is strong evidence for the use of butyrate in such disorders, the review called for more research into the pathophysiology (i.e., biomolecular mechanisms) of these diseases, so as to improve therapeutic approaches to these diseases.^[39]

Neuroepigenetic effects

Addiction

틀:Psychostimulant addiction The observation of a large number of downregulated genes after methamphetamine withdrawal is consistent with previous results showing that methamphetamine can cause increased expression of histone deacetylases (HDACs) in the nucleus accumbens and the dorsal striatum. Butyric acid is a HDAC inhibitor.^[56] HDACs are enzymes that can cause histone deacetylation and repression of gene expression. HDACs are important regulators of synaptic formation, synaptic plasticity, and long-term memory formation. Several HDACs also appear to play significant roles in various models of drug abuse and addiction.^[57] The local knockout of HDAC1, as well as chronic and continuous infusion of MS-275, a pharmacological inhibitor highly selective in vitro for HDAC1, has been found with NAc suppressed cocaine-induced locomotor sensitization in mice.^[58] HDAC3 inhibitor RGFP966 has been shown to facilitate the extinction of cocaine-seeking behavior and prevent reinstatement of cocaine-conditioned place preference in mice.^[59] Histone deacetylase inhibitors have been shown to decrease cocaine, but not sucrose, self-administration in rats.^[60] The beneficial bacteria that ferment probiotics and prebiotics to produce butyric acid have been shown to regulate behavior by means of the vagus nerve.^[61]

Cognitive deficits and memory

Studies in rodents have found that the environment exerts an influence on epigenetic changes related to cognition, in terms of learning and memory;^[62] environmental enrichment is correlated with increased histone acetylation, and verification by administering histone deacetylase inhibitors induced the sprouting of dendrites, an increased number of synapses, and reinstated learning behaviour and access to long-term memories.^[63]^[64] Research has also linked learning and long-term memory formation to reversible epigenetic changes in the hippocampus and cortex in animals with normal-functioning, undamaged brains.^[64]^[65] In human studies, post-mortem brains from Alzheimer's patients show increased histone de-acetylase levels.^[66]^[67]

Notes

↑ Most of the butyrate that is absorbed into blood plasma from the colon enters the circulatory system via the portal vein;^[33] most of the butyrate that enters the circulatory system by this route is taken up by the liver.^[33]

References

본 문서에는 현재 퍼블릭 도메인에 속한 브리태니커 백과사전 제11판의 내용을 기초로 작성된 내용이 포함되어 있습니다.

↑ “Butanoic Acid”. ALS Environmental. 2014년 6월 13일에 확인함.
↑ Moskin, Julia (2008년 2월 13일). “Dark may be king, but milk chocolate makes a move”. 《The New York Times》. 2016년 1월 1일에 확인함.
↑ ^가 ^나 ^다 〈Butyric acid〉. 《Human Metabolome Database》. University of Alberta. 2015년 8월 15일에 확인함.
↑ Chevreul (1815) "Lettre de M. Chevreul à MM. les rédacteurs des Annales de chimie" (Letter from Mr. Chevreul to the editors of the Annals of Chemistry), Annales de chimie, 94 : 73–79; in a footnote spanning pages 75–76, he mentions that he had found a substance that is responsible for the smell of butter.
↑ Chevreul (1817) "Extrait d'une lettre de M. Chevreul à MM. les Rédacteurs du Journal de Pharmacie" (Extract of a letter from Mr. Chevreul to the editors of the Journal of Pharmacy), Journal de Pharmacie et des sciences accessoires, 3 : 79–81. On p. 81, he named butyric acid: "Ce principe, que j'ai appelé depuis acid butérique, … " (This principle [i.e., constituent], which I have since named "butyric acid", … )
↑ E. Chevreul, Recherches chimiques sur les corps gras d'origine animale [Chemical researches on fatty substances of animal origin] (Paris, France: F.G. Levrault, 1823), pages 115–133.
↑ ^가 ^나 ICSC 1334 – BUTYRIC ACID. Inchem.org (23 November 1998). Retrieved on 2014-03-31.
↑ Supplementation of Coated Butyric Acid in the Feed Reduces Colonization and Shedding of Salmonella in Poultry. Ps.fass.org. Retrieved on 31 March 2014.
↑ Freezer Baits, nutrabaits.net
↑ Kasumyan AO, Døving KB (2003). “Taste preferences in fishes”. 《Fish and Fisheries》 4 (4): 289–347. doi:10.1046/j.1467-2979.2003.00121.x.
↑ Japanese Whalers Injured by Acid-Firing Activists, newser.com, 10 February 2010
↑ National Abortion Federation, HISTORY OF VIOLENCE Butyric Acid Attacks 보관됨 13 6월 2010 - 웨이백 머신. Prochoice.org. Retrieved on 31 March 2014.
↑ Lokensgard, Erik (2015). 《Industrial Plastics: Theory and Applications》 6판. Cengage Learning.
↑ Williams, R. Scott. “Care of Plastics: Malignant plastics”. 《WAAC Newsletter》 (Vol. 24, No. 1) (Conservation OnLine). 2017년 5월 29일에 확인함.
↑ “Why screwdriver handles smell like vomit and make your tongue numb.”. 《The Garage Journal》. 2017년 5월 29일에 확인함.
↑ ^가 ^나 ^다 Lupton JR (February 2004). “Microbial degradation products influence colon cancer risk: the butyrate controversy”. 《The Journal of Nutrition》 134 (2): 479–82. PMID 14747692.
↑ Cummings JH, Macfarlane GT, Englyst HN (February 2001). “Prebiotic digestion and fermentation”. 《The American Journal of Clinical Nutrition》 73 (2 Suppl): 415S–420S. PMID 11157351.
↑ Grummer RR (September 1991). “Effect of feed on the composition of milk fat” (PDF). 《Journal of Dairy Science》 74 (9): 3244–57. doi:10.3168/jds.S0022-0302(91)78510-X. PMID 1779073.
↑ webmed. “Frequently asked questions in the area of diet and IBS”. 《www.med.monash.edu》. 2016년 3월 24일에 확인함.
↑ Gibson, Peter R.; Shepherd, Susan J. (2010년 2월 1일). “Evidence-based dietary management of functional gastrointestinal symptoms: The FODMAP approach”. 《Journal of Gastroenterology and Hepatology》 25 (2): 252–258. doi:10.1111/j.1440-1746.2009.06149.x. ISSN 1440-1746. PMID 20136989.
↑ Gibson, Peter R.; Varney, Jane; Malakar, Sreepurna; Muir, Jane G. (2015년 5월 1일). “Food components and irritable bowel syndrome”. 《Gastroenterology》 148 (6): 1158–1174.e4. doi:10.1053/j.gastro.2015.02.005. ISSN 1528-0012. PMID 25680668.
↑ Owen, O. E.; Morgan, A. P.; Kemp, H. G.; Sullivan, J. M.; Herrera, M. G.; Cahill, G. F. (1967년 10월 1일). “Brain metabolism during fasting”. 《The Journal of Clinical Investigation》 46 (10): 1589–1595. doi:10.1172/JCI105650. ISSN 0021-9738. PMC 292907. PMID 6061736.
↑ Ho, Emily; Clarke, John D.; Dashwood, Roderick H. (2009년 12월 1일). “Dietary Sulforaphane, a Histone Deacetylase Inhibitor for Cancer Prevention”. 《The Journal of Nutrition》 139 (12): 2393–2396. doi:10.3945/jn.109.113332. ISSN 0022-3166. PMC 2777483. PMID 19812222.
↑ Pledgie-Tracy, Allison; Sobolewski, Michele D.; Davidson, Nancy E. (2007년 3월 1일). “Sulforaphane induces cell type–specific apoptosis in human breast cancer cell lines”. 《Molecular Cancer Therapeutics》 (영어) 6 (3): 1013–1021. doi:10.1158/1535-7163.MCT-06-0494. ISSN 1535-7163. PMID 17339367.
↑ Sasaki, Mari; Shinozaki, Shohei; Shimokado, Kentaro (2016년 3월 25일). “Sulforaphane promotes murine hair growth by accelerating the degradation of dihydrotestosterone”. 《Biochemical and Biophysical Research Communications》 472 (1): 250–254. doi:10.1016/j.bbrc.2016.02.099. ISSN 1090-2104. PMID 26923074.
↑ Moon, Joon-Kwan; Kim, Jun-Ran; Ahn, Young-Joon; Shibamoto, Takayuki (2010년 6월 9일). “Analysis and anti-Helicobacter activity of sulforaphane and related compounds present in broccoli ( Brassica oleracea L.) sprouts”. 《Journal of Agricultural and Food Chemistry》 58 (11): 6672–6677. doi:10.1021/jf1003573. ISSN 1520-5118. PMID 20459098.
↑ Dash, Pramod K.; Zhao, Jing; Orsi, Sara A.; Zhang, Min; Moore, Anthony N. (2009년 8월 28일). “Sulforaphane improves cognitive function administered following traumatic brain injury”. 《Neuroscience Letters》 460 (2): 103–107. doi:10.1016/j.neulet.2009.04.028. ISSN 1872-7972. PMC 2700200. PMID 19515491.
↑ Ghawi, Sameer Khalil; Methven, Lisa; Niranjan, Keshavan. “The potential to intensify sulforaphane formation in cooked broccoli (Brassica oleracea var. italica) using mustard seeds (Sinapis alba)”. 《Food Chemistry》 138 (2–3): 1734–1741. doi:10.1016/j.foodchem.2012.10.119.
↑ Yang, C. S.; Chhabra, S. K.; Hong, J. Y.; Smith, T. J. (2001년 3월 1일). “Mechanisms of inhibition of chemical toxicity and carcinogenesis by diallyl sulfide (DAS) and related compounds from garlic”. 《The Journal of Nutrition》 131 (3s): 1041S–5S. ISSN 0022-3166. PMID 11238812.
↑ Sundaram, Sujatha G.; Milner, John A. (1996년 4월 1일). “Diallyl disulfide induces apoptosis of human colon tumor cells”. 《Carcinogenesis》 (영어) 17 (4): 669–673. doi:10.1093/carcin/17.4.669. ISSN 0143-3334. PMID 8625476.
↑ ^가 ^나 ^다 “Butyric acid”. 《IUPHAR》. IUPHAR/BPS Guide to PHARMACOLOGY. 2015년 5월 23일에 확인함.
↑ ^가 ^나 “butanoic acid, 4 and Sodium; butyrate”. 《BindingDB》. The Binding Database. 2015년 5월 23일에 확인함.
↑ ^가 ^나 ^다 ^라 ^마 ^바 ^사 ^아 ^자 ^차 Bourassa MW, Alim I, Bultman SJ, Ratan RR (June 2016). “Butyrate, neuroepigenetics and the gut microbiome: Can a high fiber diet improve brain health?”. 《Neurosci. Lett.》 625: 56–63. doi:10.1016/j.neulet.2016.02.009. PMID 26868600. Butyrate is an attractive therapeutic molecule because of its wide array of biological functions, such as its ability to serve as a histone deacetylase (HDAC) inhibitor, an energy metabolite to produce ATP and a G protein-coupled receptor (GPCR) activator. ... Histone acetylation is a post-translational modification by an epigenetic protein, which are proteins that bind to chromatin and influence chromatin structure to change the propensity that a gene is transcribed or repressed. Acetylated histones cause the chromatin structure to loosen by weakening electrostatic attraction between the histone proteins and the DNA backbone. This process enables transcription factors and the basal transcriptional machinery to bind and increases transcription. ... However, many studies have shown that at least some of these beneficial effects can be attributed NaB’s ability to increase acetylation around the promoters of neurotrophic factors, such as BDNF, GDNF and NGF and thus increasing their transcription [41], [42], [43], [44], [45], [46], [47] and [48]. ... Butyrate also signals through GPR109a ... Much of the butyrate produced in the colon is used as an energy source by the colonocytes, but some butyrate can also exit the colon through the portal vein, where the liver absorbs another large portion [74] and [75]. However, the distal colon is not connected to the portal vein, allowing for some systemic butyrate to be circulated. Indeed, there are many reports of high fiber diets increasing blood levels of circulating butyrate [75], [76] and [77]. These later reports raise the possibility that increases in circulating butyrate could affect CNS function directly.
↑ ^가 ^나 ^다 ^라 Kasubuchi M, Hasegawa S, Hiramatsu T, Ichimura A, Kimura I (2015). “Dietary gut microbial metabolites, short-chain fatty acids, and host metabolic regulation”. 《Nutrients》 7 (4): 2839–49. doi:10.3390/nu7042839. PMC 4425176. PMID 25875123. Short-chain fatty acids (SCFAs) such as acetate, butyrate, and propionate, which are produced by gut microbial fermentation of dietary fiber, are recognized as essential host energy sources and act as signal transduction molecules via G-protein coupled receptors (FFAR2, FFAR3, OLFR78, GPR109A) and as epigenetic regulators of gene expression by the inhibition of histone deacetylase (HDAC). Recent evidence suggests that dietary fiber and the gut microbial-derived SCFAs exert multiple beneficial effects on the host energy metabolism not only by improving the intestinal environment, but also by directly affecting various host peripheral tissues.
↑ ^가 ^나 ^다 ^라 ^마 ^바 ^사 Hoeppli RE, Wu D, Cook L, Levings MK (February 2015). “The environment of regulatory T cell biology: cytokines, metabolites, and the microbiome”. 《Front Immunol》 6: 61. doi:10.3389/fimmu.2015.00061. PMC 4332351. PMID 25741338. Specific species that have been recognized by their high levels of butyrate production include Faecalibacterium prausnitzii and the cluster IV and XIVa of genus Clostridium ... Administration of acetate, propionate, and butyrate in drinking water mimics the effect of Clostridium colonization in germ-free mice, resulting in an elevated Treg frequency in the colonic lamina propria and increased IL-10 production by these Tregs (180, 182). Of the three main SCFAs, butyrate has been found to be the most potent inducer of colonic Tregs. Mice fed a diet enriched in butyrylated starches have more colonic Tregs than those fed a diet containing propinylated or acetylated starches (181). Arpaia et al. tested an array of SCFAs purified from commensal bacteria and confirmed butyrate was the strongest SCFA-inducer of Tregs in vitro (180). Mechanistically, it has been proposed that butyrate, and possibly propionate, promote Tregs through inhibiting histone deacetylase (HDAC), causing increased acetylation of histone H3 in the Foxp3 CNS1 region, and thereby enhancing FOXP3 expression (180, 181). Short-chain fatty acids partially mediate their effects through G-protein coupled receptors (GPR), including GPR41, GPR43, and GPR109A. GPR41 and GPR43 are stimulated by all three major SCFAs (191), whereas GPR109A only interacts with butyrate (192).
Figure 1: Microbial-derived molecules promote colonic Treg differentiation.
↑ Tsuji A (2005). “Small molecular drug transfer across the blood-brain barrier via carrier-mediated transport systems”. 《NeuroRx》 2 (1): 54–62. doi:10.1602/neurorx.2.1.54. PMC 539320. PMID 15717057. Other in vivo studies in our laboratories indicated that several compounds including acetate, propionate, butyrate, benzoic acid, salicylic acid, nicotinic acid, and some β-lactam antibiotics may be transported by the MCT at the BBB.²¹ ... Uptake of valproic acid was reduced in the presence of medium-chain fatty acids such as hexanoate, octanoate, and decanoate, but not propionate or butyrate, indicating that valproic acid is taken up into the brain via a transport system for medium-chain fatty acids, not short-chain fatty acids.
↑ ^가 ^나 Vijay N, Morris ME (2014). “Role of monocarboxylate transporters in drug delivery to the brain”. 《Curr. Pharm. Des.》 20 (10): 1487–98. doi:10.2174/13816128113199990462. PMC 4084603. PMID 23789956. Monocarboxylate transporters (MCTs) are known to mediate the transport of short chain monocarboxylates such as lactate, pyruvate and butyrate. ... MCT1 and MCT4 have also been associated with the transport of short chain fatty acids such as acetate and formate which are then metabolized in the astrocytes [78]. ... SLC5A8 is expressed in normal colon tissue, and it functions as a tumor suppressor in human colon with silencing of this gene occurring in colon carcinoma. This transporter is involved in the concentrative uptake of butyrate and pyruvate produced as a product of fermentation by colonic bacteria.
↑ “triacylglycerol lipase – Homo sapiens”. 《BRENDA》. Technische Universität Braunschweig. 2015년 5월 25일에 확인함.
↑ ^가 ^나 ^다 ^라 Tilg H, Moschen AR (September 2014). “Microbiota and diabetes: an evolving relationship”. 《Gut》 63 (9): 1513–1521. doi:10.1136/gutjnl-2014-306928. PMID 24833634. Recent studies have suggested that gut bacteria play a fundamental role in diseases such as obesity, diabetes and cardiovascular disease. Data are accumulating in animal models and humans suggesting that obesity and type 2 diabetes (T2D) are associated with a profound dysbiosis. First human metagenome-wide association studies demonstrated highly significant correlations of specific intestinal bacteria, certain bacterial genes and respective metabolic pathways with T2D. Importantly, especially butyrate-producing bacteria such as Roseburia intestinalis and Faecalibacterium prausnitzii concentrations were lower in T2D subjects. This supports the increasing evidence, that butyrate and other short-chain fatty acids are able to exert profound immunometabolic effects.
↑ ^가 ^나 ^다 ^라 Wang G (2014). “Human antimicrobial peptides and proteins”. 《Pharmaceuticals (Basel)》 7 (5): 545–94. doi:10.3390/ph7050545. PMC 4035769. PMID 24828484. The establishment of a link between light therapy, vitamin D and human cathelicidin LL-37 expression provides a completely different way for infection treatment. Instead of treating patients with traditional antibiotics, doctors may be able to use light or vitamin D [291,292]. Indeed using narrow-band UV B light, the level of vitamin D was increased in psoriasis patients (psoriasis is a common autoimmune disease on skin) [293]. In addition, other small molecules such as butyrate can induce LL-37 expression [294]. Components from Traditional Chinese Medicine may regulate the AMP expression as well [295]. These factors may induce the expression of a single peptide or multiple AMPs [296]. It is also possible that certain factors can work together to induce AMP expression. While cyclic AMP and butyrate synergistically stimulate the expression of chicken β-defensin 9 [297], 4-phenylbutyrate (PBA) and 1,25-dihydroxyvitamin D3 (or lactose) can induce AMP gene expression synergistically [294,298]. It appears that stimulation of LL-37 expression by histone deacetylase (HDAC) inhibitors is cell dependent. Trichostatin and sodium butyrate increased the peptide expression in human NCI-H292 airway epithelial cells but not in the primary cultures of normal nasal epithelial cells [299]. However, the induction of the human LL-37 expression may not be a general approach for bacterial clearance. During Salmonella enterica infection of human monocyte-derived macrophages, LL-37 is neither induced nor required for bacterial clearance [300].
Table 3: Select human antimicrobial peptides and their proposed targets
Table 4: Some known factors that induce antimicrobial peptide expression
↑ Yonezawa H, Osaki T, Hanawa T, Kurata S, Zaman C, Woo TD, Takahashi M, Matsubara S, Kawakami H, Ochiai K, Kamiya S (2012). “Destructive effects of butyrate on the cell envelope of Helicobacter pylori”. 《J. Med. Microbiol.》 61 (Pt 4): 582–9. doi:10.1099/jmm.0.039040-0. PMID 22194341.
↑ McGee DJ, George AE, Trainor EA, Horton KE, Hildebrandt E, Testerman TL (2011). “Cholesterol enhances Helicobacter pylori resistance to antibiotics and LL-37”. 《Antimicrob. Agents Chemother.》 55 (6): 2897–904. doi:10.1128/AAC.00016-11. PMC 3101455. PMID 21464244.
↑ ^가 ^나 Zimmerman MA, Singh N, Martin PM, Thangaraju M, Ganapathy V, Waller JL, Shi H, Robertson KD, Munn DH, Liu K (2012). “Butyrate suppresses colonic inflammation through HDAC1-dependent Fas upregulation and Fas-mediated apoptosis of T cells”. 《Am. J. Physiol. Gastrointest. Liver Physiol.》 302 (12): G1405–15. doi:10.1152/ajpgi.00543.2011. PMC 3378095. PMID 22517765.
↑ Offermanns S, Schwaninger M (2015). “Nutritional or pharmacological activation of HCA(2) ameliorates neuroinflammation”. 《Trends Mol Med》 21 (4): 245–255. doi:10.1016/j.molmed.2015.02.002. PMID 25766751. Neuroinflammatory cells express HCA2, a receptor for the endogenous neuroprotective ketone body β-hydroxybutyrate (BHB) as well as for the drugs dimethyl fumarate (DMF) and nicotinic acid, which have established efficacy in the treatment of MS and experimental stroke, respectively. This review summarizes the evidence that HCA2 is involved in the therapeutic effects of DMF, nicotinic acid, and ketone bodies in reducing neuroinflammation.
↑ Chai JT, Digby JE, Choudhury RP (May 2013). “GPR109A and vascular inflammation”. 《Curr Atheroscler Rep》 15 (5): 325. doi:10.1007/s11883-013-0325-9. PMC 3631117. PMID 23526298. As GPR109A's primary pharmacological ligand in clinical use, niacin has been used for over 50 years in the treatment of cardiovascular disease, mainly due to its favourable effects on plasma lipoproteins. However, it has become apparent that niacin also possesses lipoprotein-independent effects that influence inflammatory pathways mediated through GPR109A.
↑ Graff EC, Fang H, Wanders D, Judd RL (February 2016). “Anti-inflammatory effects of the hydroxycarboxylic acid receptor 2”. 《Metab. Clin. Exp.》 65 (2): 102–113. doi:10.1016/j.metabol.2015.10.001. PMID 26773933. HCA2 is highly expressed on immune cells, including macrophages, monocytes, neutrophils and dermal dendritic cells, among other cell types. ... Recent studies demonstrate that HCA2 mediates profound anti-inflammatory effects in a variety of tissues, indicating that HCA2 may be an important therapeutic target for treating inflammatory disease processes.
↑ Wakade C, Chong R (December 2014). “A novel treatment target for Parkinson's disease”. 《J. Neurol. Sci.》 347 (1-2): 34–38. doi:10.1016/j.jns.2014.10.024. PMID 25455298. GPR109A and its agonists are known to exert anti-inflammatory actions in the skin, gut and retina.
↑ Farzi A, Reichmann F, Holzer P (2015). “The homeostatic role of neuropeptide Y in immune function and its impact on mood and behaviour”. 《Acta Physiol (Oxf)》 213 (3): 603–27. doi:10.1111/apha.12445. PMC 4353849. PMID 25545642. In the context of this review it is particularly worth noting that short chain fatty acids such as butyrate, which the colonic microbiota generates by fermentation of otherwise indigestible dietary fibre (Cherbut et al. 1998), stimulate L cells to release PYY via the G-protein coupled receptor Gpr41 (Samuel et al. 2008). In this way, short chain fatty acids can indirectly attenuate gastrointestinal motility as well as electrolyte and water secretion (Cox 2007b). More importantly, short chain fatty acids exert homeostatic actions on the function of the colonic mucosa and immune system (Hamer et al. 2008, Tazoe et al. 2008, Guilloteau et al. 2010, Macia et al. 2012a, Smith et al. 2013). Whether PYY plays a role in these effects of short chain fatty acids awaits to be investigated, but may be envisaged from the finding that PYY promotes mucosal cell differentiation (Hallden & Aponte 1997).
↑ Donohoe, Dallas R.; Garge, Nikhil; Zhang, Xinxin; Sun, Wei; O’Connell, Thomas M.; Bunger, Maureen K.; Bultman, Scott J. (2011년 5월 4일). “The Microbiome and Butyrate Regulate Energy Metabolism and Autophagy in the Mammalian Colon”. 《Cell Metabolism》 13 (5): 517–526. doi:10.1016/j.cmet.2011.02.018. ISSN 1550-4131. PMC 3099420. PMID 21531334.
↑ Vanhoutvin SA, Troost FJ, Hamer HM, Lindsey PJ, Koek GH, Jonkers DM, Kodde A, Venema K, Brummer RJ (2009). Bereswill S, 편집. “Butyrate-induced transcriptional changes in human colonic mucosa”. 《PLOS ONE》 4 (8): e6759. doi:10.1371/journal.pone.0006759. PMC 2727000. PMID 19707587. ^{[깨진 링크]}
↑ Klampfer L, Huang J, Sasazuki T, Shirasawa S, Augenlicht L (August 2004). “Oncogenic Ras promotes butyrate-induced apoptosis through inhibition of gelsolin expression” (PDF). 《The Journal of Biological Chemistry》 279 (35): 36680–8. doi:10.1074/jbc.M405197200. PMID 15213223.
↑ Lupton, Joanne R. (2004). 《Microbial Degradation Products Influence Colon Cancer Risk: the Butyrate Controversy》. vol. 134 no. 2: J. Nutr. 479–482쪽.
↑ “Low-carb diet cuts risk of colon cancer, study finds | University of Toronto Media Room”. 《media.utoronto.ca》. 2016년 5월 4일에 확인함.
↑ Belcheva, Antoaneta; Irrazabal, Thergiory; Robertson, Susan J.; Streutker, Catherine; Maughan, Heather; Rubino, Stephen; Moriyama, Eduardo H.; Copeland, Julia K.; Kumar, Sachin (2014년 7월 17일). “Gut microbial metabolism drives transformation of MSH2-deficient colon epithelial cells”. 《Cell》 158 (2): 288–299. doi:10.1016/j.cell.2014.04.051. ISSN 1097-4172. PMID 25036629.
↑ “Colon Cancer Shuts Down Receptor That Could Shut It Down”. 《ScienceDaily》. 2016년 5월 4일에 확인함.
↑ Davie, James R. (2003년 7월 1일). “Inhibition of Histone Deacetylase Activity by Butyrate”. 《The Journal of Nutrition》 (영어) 133 (7): 2485S–2493S. ISSN 0022-3166. PMID 12840228.
↑ Cadet, Jean Lud; Brannock, Christie; Jayanthi, Subramaniam; Krasnova, Irina N. (2015년 1월 1일). “Transcriptional and Epigenetic Substrates of Methamphetamine Addiction and Withdrawal: Evidence from a Long-Access Self-Administration Model in the Rat”. 《Molecular Neurobiology》 51 (2): 696–717. doi:10.1007/s12035-014-8776-8. ISSN 0893-7648. PMC 4359351. PMID 24939695.
↑ Kennedy, Pamela J.; Feng, Jian; Robison, A.J.; Maze, Ian; Badimon, Ana; Mouzon, Ezekiell; Chaudhury, Dipesh; Damez-Werno, Diane M.; Haggarty, Stephen J. (2013년 4월 1일). “Class I HDAC Inhibition Blocks Cocaine-Induced Plasticity Through Targeted Changes in Histone Methylation”. 《Nature Neuroscience》 16 (4): 434–440. doi:10.1038/nn.3354. ISSN 1097-6256. PMC 3609040. PMID 23475113.
↑ Malvaez, Melissa; McQuown, Susan C.; Rogge, George A.; Astarabadi, Mariam; Jacques, Vincent; Carreiro, Samantha; Rusche, James R.; Wood, Marcelo A. (2013년 2월 12일). “HDAC3-selective inhibitor enhances extinction of cocaine-seeking behavior in a persistent manner”. 《Proceedings of the National Academy of Sciences of the United States of America》 110 (7): 2647–2652. doi:10.1073/pnas.1213364110. ISSN 0027-8424. PMC 3574934. PMID 23297220.
↑ Romieu, Pascal; Host, Lionel; Gobaille, Serge; Sandner, Guy; Aunis, Dominique; Zwiller, Jean (2008년 9월 17일). “Histone deacetylase inhibitors decrease cocaine but not sucrose self-administration in rats”. 《The Journal of Neuroscience》 28 (38): 9342–9348. doi:10.1523/JNEUROSCI.0379-08.2008. ISSN 1529-2401. PMID 18799668.
↑ Bravo, Javier A.; Forsythe, Paul; Chew, Marianne V.; Escaravage, Emily; Savignac, Hélène M.; Dinan, Timothy G.; Bienenstock, John; Cryan, John F. (2011년 9월 20일). “Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve”. 《Proceedings of the National Academy of Sciences》 (영어) 108 (38): 16050–16055. doi:10.1073/pnas.1102999108. ISSN 0027-8424. PMC 3179073. PMID 21876150.
↑ 《The Developing Genome: An Introduction to Behavioral Epigenetics》 (영어) 1판. Oxford University Press. 2015년 3월 2일. ISBN 9780199922345.
↑ Fischer, Andre; Sananbenesi, Farahnaz; Wang, Xinyu; Dobbin, Matthew; Tsai, Li-Huei (2007년 5월 10일). “Recovery of learning and memory is associated with chromatin remodelling”. 《Nature》 447 (7141): 178–182. doi:10.1038/nature05772. ISSN 1476-4687. PMID 17468743.
↑ ^가 ^나 Miller, Greg (2010년 7월 2일). “Epigenetics. The seductive allure of behavioral epigenetics”. 《Science》 329 (5987): 24–27. doi:10.1126/science.329.5987.24. ISSN 1095-9203. PMID 20595592.
↑ Gupta, Swati; Kim, Se Y.; Artis, Sonja; Molfese, David L.; Schumacher, Armin; Sweatt, J. David; Paylor, Richard E.; Lubin, Farah D. (2010년 3월 10일). “Histone methylation regulates memory formation”. 《The Journal of Neuroscience》 30 (10): 3589–3599. doi:10.1523/JNEUROSCI.3732-09.2010. ISSN 1529-2401. PMC 2859898. PMID 20219993.
↑ Peleg, Shahaf; Sananbenesi, Farahnaz; Zovoilis, Athanasios; Burkhardt, Susanne; Bahari-Javan, Sanaz; Agis-Balboa, Roberto Carlos; Cota, Perla; Wittnam, Jessica Lee; Gogol-Doering, Andreas (2010년 5월 7일). “Altered histone acetylation is associated with age-dependent memory impairment in mice”. 《Science》 328 (5979): 753–756. doi:10.1126/science.1186088. ISSN 1095-9203. PMID 20448184.
↑ Gräff, Johannes; Rei, Damien; Guan, Ji-Song; Wang, Wen-Yuan; Seo, Jinsoo; Hennig, Krista M.; Nieland, Thomas J. F.; Fass, Daniel M.; Kao, Patricia F. (2012년 3월 8일). “An epigenetic blockade of cognitive functions in the neurodegenerating brain”. 《Nature》 483 (7388): 222–226. doi:10.1038/nature10849. ISSN 1476-4687. PMC 3498952. PMID 22388814.

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각주

[36] Most of the butyrate that is absorbed into blood plasma from the colon enters the circulatory system via the portal vein;^[33] most of the butyrate that enters the circulatory system by this route is taken up by the liver.^[33]

[caslab-1] “Butanoic Acid”. ALS Environmental. 2014년 6월 13일에 확인함.

[2] Moskin, Julia (2008년 2월 13일). “Dark may be king, but milk chocolate makes a move”. 《The New York Times》. 2016년 1월 1일에 확인함.

[HMDB-3] 가 ^나 ^다 〈Butyric acid〉. 《Human Metabolome Database》. University of Alberta. 2015년 8월 15일에 확인함.

[4] Chevreul (1815) "Lettre de M. Chevreul à MM. les rédacteurs des Annales de chimie" (Letter from Mr. Chevreul to the editors of the Annals of Chemistry), Annales de chimie, 94 : 73–79; in a footnote spanning pages 75–76, he mentions that he had found a substance that is responsible for the smell of butter.

[5] Chevreul (1817) "Extrait d'une lettre de M. Chevreul à MM. les Rédacteurs du Journal de Pharmacie" (Extract of a letter from Mr. Chevreul to the editors of the Journal of Pharmacy), Journal de Pharmacie et des sciences accessoires, 3 : 79–81. On p. 81, he named butyric acid: "Ce principe, que j'ai appelé depuis acid butérique, … " (This principle [i.e., constituent], which I have since named "butyric acid", … )

[6] E. Chevreul, Recherches chimiques sur les corps gras d'origine animale [Chemical researches on fatty substances of animal origin] (Paris, France: F.G. Levrault, 1823), pages 115–133.

[inchem1-7] 가 ^나 ICSC 1334 – BUTYRIC ACID. Inchem.org (23 November 1998). Retrieved on 2014-03-31.

[8] Supplementation of Coated Butyric Acid in the Feed Reduces Colonization and Shedding of Salmonella in Poultry. Ps.fass.org. Retrieved on 31 March 2014.

[9] Freezer Baits, nutrabaits.net

[10] Kasumyan AO, Døving KB (2003). “Taste preferences in fishes”. 《Fish and Fisheries》 4 (4): 289–347. doi:10.1046/j.1467-2979.2003.00121.x.

[11] Japanese Whalers Injured by Acid-Firing Activists, newser.com, 10 February 2010

[12] National Abortion Federation, HISTORY OF VIOLENCE Butyric Acid Attacks 보관됨 13 6월 2010 - 웨이백 머신. Prochoice.org. Retrieved on 31 March 2014.

[13] Lokensgard, Erik (2015). 《Industrial Plastics: Theory and Applications》 6판. Cengage Learning.

[14] Williams, R. Scott. “Care of Plastics: Malignant plastics”. 《WAAC Newsletter》 (Vol. 24, No. 1) (Conservation OnLine). 2017년 5월 29일에 확인함.

[15] “Why screwdriver handles smell like vomit and make your tongue numb.”. 《The Garage Journal》. 2017년 5월 29일에 확인함.

[lupton-16] 가 ^나 ^다 Lupton JR (February 2004). “Microbial degradation products influence colon cancer risk: the butyrate controversy”. 《The Journal of Nutrition》 134 (2): 479–82. PMID 14747692.

[17] Cummings JH, Macfarlane GT, Englyst HN (February 2001). “Prebiotic digestion and fermentation”. 《The American Journal of Clinical Nutrition》 73 (2 Suppl): 415S–420S. PMID 11157351.

[18] Grummer RR (September 1991). “Effect of feed on the composition of milk fat” (PDF). 《Journal of Dairy Science》 74 (9): 3244–57. doi:10.3168/jds.S0022-0302(91)78510-X. PMID 1779073.

[19] webmed. “Frequently asked questions in the area of diet and IBS”. 《www.med.monash.edu》. 2016년 3월 24일에 확인함.

[20] Gibson, Peter R.; Shepherd, Susan J. (2010년 2월 1일). “Evidence-based dietary management of functional gastrointestinal symptoms: The FODMAP approach”. 《Journal of Gastroenterology and Hepatology》 25 (2): 252–258. doi:10.1111/j.1440-1746.2009.06149.x. ISSN 1440-1746. PMID 20136989.

[21] Gibson, Peter R.; Varney, Jane; Malakar, Sreepurna; Muir, Jane G. (2015년 5월 1일). “Food components and irritable bowel syndrome”. 《Gastroenterology》 148 (6): 1158–1174.e4. doi:10.1053/j.gastro.2015.02.005. ISSN 1528-0012. PMID 25680668.

[22] Owen, O. E.; Morgan, A. P.; Kemp, H. G.; Sullivan, J. M.; Herrera, M. G.; Cahill, G. F. (1967년 10월 1일). “Brain metabolism during fasting”. 《The Journal of Clinical Investigation》 46 (10): 1589–1595. doi:10.1172/JCI105650. ISSN 0021-9738. PMC 292907. PMID 6061736.

[23] Ho, Emily; Clarke, John D.; Dashwood, Roderick H. (2009년 12월 1일). “Dietary Sulforaphane, a Histone Deacetylase Inhibitor for Cancer Prevention”. 《The Journal of Nutrition》 139 (12): 2393–2396. doi:10.3945/jn.109.113332. ISSN 0022-3166. PMC 2777483. PMID 19812222.

[24] Pledgie-Tracy, Allison; Sobolewski, Michele D.; Davidson, Nancy E. (2007년 3월 1일). “Sulforaphane induces cell type–specific apoptosis in human breast cancer cell lines”. 《Molecular Cancer Therapeutics》 (영어) 6 (3): 1013–1021. doi:10.1158/1535-7163.MCT-06-0494. ISSN 1535-7163. PMID 17339367.

[25] Sasaki, Mari; Shinozaki, Shohei; Shimokado, Kentaro (2016년 3월 25일). “Sulforaphane promotes murine hair growth by accelerating the degradation of dihydrotestosterone”. 《Biochemical and Biophysical Research Communications》 472 (1): 250–254. doi:10.1016/j.bbrc.2016.02.099. ISSN 1090-2104. PMID 26923074.

[26] Moon, Joon-Kwan; Kim, Jun-Ran; Ahn, Young-Joon; Shibamoto, Takayuki (2010년 6월 9일). “Analysis and anti-Helicobacter activity of sulforaphane and related compounds present in broccoli ( Brassica oleracea L.) sprouts”. 《Journal of Agricultural and Food Chemistry》 58 (11): 6672–6677. doi:10.1021/jf1003573. ISSN 1520-5118. PMID 20459098.

[27] Dash, Pramod K.; Zhao, Jing; Orsi, Sara A.; Zhang, Min; Moore, Anthony N. (2009년 8월 28일). “Sulforaphane improves cognitive function administered following traumatic brain injury”. 《Neuroscience Letters》 460 (2): 103–107. doi:10.1016/j.neulet.2009.04.028. ISSN 1872-7972. PMC 2700200. PMID 19515491.

[28] Ghawi, Sameer Khalil; Methven, Lisa; Niranjan, Keshavan. “The potential to intensify sulforaphane formation in cooked broccoli (Brassica oleracea var. italica) using mustard seeds (Sinapis alba)”. 《Food Chemistry》 138 (2–3): 1734–1741. doi:10.1016/j.foodchem.2012.10.119.

[29] Yang, C. S.; Chhabra, S. K.; Hong, J. Y.; Smith, T. J. (2001년 3월 1일). “Mechanisms of inhibition of chemical toxicity and carcinogenesis by diallyl sulfide (DAS) and related compounds from garlic”. 《The Journal of Nutrition》 131 (3s): 1041S–5S. ISSN 0022-3166. PMID 11238812.

[30] Sundaram, Sujatha G.; Milner, John A. (1996년 4월 1일). “Diallyl disulfide induces apoptosis of human colon tumor cells”. 《Carcinogenesis》 (영어) 17 (4): 669–673. doi:10.1093/carcin/17.4.669. ISSN 0143-3334. PMID 8625476.

[IUPHAR-31] 가 ^나 ^다 “Butyric acid”. 《IUPHAR》. IUPHAR/BPS Guide to PHARMACOLOGY. 2015년 5월 23일에 확인함.

[BindingDB-32] 가 ^나 “butanoic acid, 4 and Sodium; butyrate”. 《BindingDB》. The Binding Database. 2015년 5월 23일에 확인함.

[Butyrate_pharmacodynamics_and_neuroepigenetic_effects_2016_review-33] 가 ^나 ^다 ^라 ^마 ^바 ^사 ^아 ^자 ^차 Bourassa MW, Alim I, Bultman SJ, Ratan RR (June 2016). “Butyrate, neuroepigenetics and the gut microbiome: Can a high fiber diet improve brain health?”. 《Neurosci. Lett.》 625: 56–63. doi:10.1016/j.neulet.2016.02.009. PMID 26868600. Butyrate is an attractive therapeutic molecule because of its wide array of biological functions, such as its ability to serve as a histone deacetylase (HDAC) inhibitor, an energy metabolite to produce ATP and a G protein-coupled receptor (GPCR) activator. ... Histone acetylation is a post-translational modification by an epigenetic protein, which are proteins that bind to chromatin and influence chromatin structure to change the propensity that a gene is transcribed or repressed. Acetylated histones cause the chromatin structure to loosen by weakening electrostatic attraction between the histone proteins and the DNA backbone. This process enables transcription factors and the basal transcriptional machinery to bind and increases transcription. ... However, many studies have shown that at least some of these beneficial effects can be attributed NaB’s ability to increase acetylation around the promoters of neurotrophic factors, such as BDNF, GDNF and NGF and thus increasing their transcription [41], [42], [43], [44], [45], [46], [47] and [48]. ... Butyrate also signals through GPR109a ... Much of the butyrate produced in the colon is used as an energy source by the colonocytes, but some butyrate can also exit the colon through the portal vein, where the liver absorbs another large portion [74] and [75]. However, the distal colon is not connected to the portal vein, allowing for some systemic butyrate to be circulated. Indeed, there are many reports of high fiber diets increasing blood levels of circulating butyrate [75], [76] and [77]. These later reports raise the possibility that increases in circulating butyrate could affect CNS function directly.

[Review_-_General_summary_as_of_April_2015,_excluding_neuroepigenetic_research-34] 가 ^나 ^다 ^라 Kasubuchi M, Hasegawa S, Hiramatsu T, Ichimura A, Kimura I (2015). “Dietary gut microbial metabolites, short-chain fatty acids, and host metabolic regulation”. 《Nutrients》 7 (4): 2839–49. doi:10.3390/nu7042839. PMC 4425176. PMID 25875123. Short-chain fatty acids (SCFAs) such as acetate, butyrate, and propionate, which are produced by gut microbial fermentation of dietary fiber, are recognized as essential host energy sources and act as signal transduction molecules via G-protein coupled receptors (FFAR2, FFAR3, OLFR78, GPR109A) and as epigenetic regulators of gene expression by the inhibition of histone deacetylase (HDAC). Recent evidence suggests that dietary fiber and the gut microbial-derived SCFAs exert multiple beneficial effects on the host energy metabolism not only by improving the intestinal environment, but also by directly affecting various host peripheral tissues.

[Review_butyrate_human_T-cell_HDACs-35] 가 ^나 ^다 ^라 ^마 ^바 ^사 Hoeppli RE, Wu D, Cook L, Levings MK (February 2015). “The environment of regulatory T cell biology: cytokines, metabolites, and the microbiome”. 《Front Immunol》 6: 61. doi:10.3389/fimmu.2015.00061. PMC 4332351. PMID 25741338. Specific species that have been recognized by their high levels of butyrate production include Faecalibacterium prausnitzii and the cluster IV and XIVa of genus Clostridium ... Administration of acetate, propionate, and butyrate in drinking water mimics the effect of Clostridium colonization in germ-free mice, resulting in an elevated Treg frequency in the colonic lamina propria and increased IL-10 production by these Tregs (180, 182). Of the three main SCFAs, butyrate has been found to be the most potent inducer of colonic Tregs. Mice fed a diet enriched in butyrylated starches have more colonic Tregs than those fed a diet containing propinylated or acetylated starches (181). Arpaia et al. tested an array of SCFAs purified from commensal bacteria and confirmed butyrate was the strongest SCFA-inducer of Tregs in vitro (180). Mechanistically, it has been proposed that butyrate, and possibly propionate, promote Tregs through inhibiting histone deacetylase (HDAC), causing increased acetylation of histone H3 in the Foxp3 CNS1 region, and thereby enhancing FOXP3 expression (180, 181). Short-chain fatty acids partially mediate their effects through G-protein coupled receptors (GPR), including GPR41, GPR43, and GPR109A. GPR41 and GPR43 are stimulated by all three major SCFAs (191), whereas GPR109A only interacts with butyrate (192).
Figure 1: Microbial-derived molecules promote colonic Treg differentiation.

[SCFA_MCT-mediated_BBB_passage_-_2005_review-37] Tsuji A (2005). “Small molecular drug transfer across the blood-brain barrier via carrier-mediated transport systems”. 《NeuroRx》 2 (1): 54–62. doi:10.1602/neurorx.2.1.54. PMC 539320. PMID 15717057. Other in vivo studies in our laboratories indicated that several compounds including acetate, propionate, butyrate, benzoic acid, salicylic acid, nicotinic acid, and some β-lactam antibiotics may be transported by the MCT at the BBB.²¹ ... Uptake of valproic acid was reduced in the presence of medium-chain fatty acids such as hexanoate, octanoate, and decanoate, but not propionate or butyrate, indicating that valproic acid is taken up into the brain via a transport system for medium-chain fatty acids, not short-chain fatty acids.

[SCFA_MCT-mediated_BBB_passage_-_2014_review-38] 가 ^나 Vijay N, Morris ME (2014). “Role of monocarboxylate transporters in drug delivery to the brain”. 《Curr. Pharm. Des.》 20 (10): 1487–98. doi:10.2174/13816128113199990462. PMC 4084603. PMID 23789956. Monocarboxylate transporters (MCTs) are known to mediate the transport of short chain monocarboxylates such as lactate, pyruvate and butyrate. ... MCT1 and MCT4 have also been associated with the transport of short chain fatty acids such as acetate and formate which are then metabolized in the astrocytes [78]. ... SLC5A8 is expressed in normal colon tissue, and it functions as a tumor suppressor in human colon with silencing of this gene occurring in colon carcinoma. This transporter is involved in the concentrative uptake of butyrate and pyruvate produced as a product of fermentation by colonic bacteria.

[BRENDA_tributyrin-39] “triacylglycerol lipase – Homo sapiens”. 《BRENDA》. Technische Universität Braunschweig. 2015년 5월 25일에 확인함.

[Review_for_diabetes-40] 가 ^나 ^다 ^라 Tilg H, Moschen AR (September 2014). “Microbiota and diabetes: an evolving relationship”. 《Gut》 63 (9): 1513–1521. doi:10.1136/gutjnl-2014-306928. PMID 24833634. Recent studies have suggested that gut bacteria play a fundamental role in diseases such as obesity, diabetes and cardiovascular disease. Data are accumulating in animal models and humans suggesting that obesity and type 2 diabetes (T2D) are associated with a profound dysbiosis. First human metagenome-wide association studies demonstrated highly significant correlations of specific intestinal bacteria, certain bacterial genes and respective metabolic pathways with T2D. Importantly, especially butyrate-producing bacteria such as Roseburia intestinalis and Faecalibacterium prausnitzii concentrations were lower in T2D subjects. This supports the increasing evidence, that butyrate and other short-chain fatty acids are able to exert profound immunometabolic effects.

[REVIEW_butyrate_human_LL-37-41] 가 ^나 ^다 ^라 Wang G (2014). “Human antimicrobial peptides and proteins”. 《Pharmaceuticals (Basel)》 7 (5): 545–94. doi:10.3390/ph7050545. PMC 4035769. PMID 24828484. The establishment of a link between light therapy, vitamin D and human cathelicidin LL-37 expression provides a completely different way for infection treatment. Instead of treating patients with traditional antibiotics, doctors may be able to use light or vitamin D [291,292]. Indeed using narrow-band UV B light, the level of vitamin D was increased in psoriasis patients (psoriasis is a common autoimmune disease on skin) [293]. In addition, other small molecules such as butyrate can induce LL-37 expression [294]. Components from Traditional Chinese Medicine may regulate the AMP expression as well [295]. These factors may induce the expression of a single peptide or multiple AMPs [296]. It is also possible that certain factors can work together to induce AMP expression. While cyclic AMP and butyrate synergistically stimulate the expression of chicken β-defensin 9 [297], 4-phenylbutyrate (PBA) and 1,25-dihydroxyvitamin D3 (or lactose) can induce AMP gene expression synergistically [294,298]. It appears that stimulation of LL-37 expression by histone deacetylase (HDAC) inhibitors is cell dependent. Trichostatin and sodium butyrate increased the peptide expression in human NCI-H292 airway epithelial cells but not in the primary cultures of normal nasal epithelial cells [299]. However, the induction of the human LL-37 expression may not be a general approach for bacterial clearance. During Salmonella enterica infection of human monocyte-derived macrophages, LL-37 is neither induced nor required for bacterial clearance [300].
Table 3: Select human antimicrobial peptides and their proposed targets
Table 4: Some known factors that induce antimicrobial peptide expression

[Primary_-_Butyrate_and_LL-37_target-42] Yonezawa H, Osaki T, Hanawa T, Kurata S, Zaman C, Woo TD, Takahashi M, Matsubara S, Kawakami H, Ochiai K, Kamiya S (2012). “Destructive effects of butyrate on the cell envelope of Helicobacter pylori”. 《J. Med. Microbiol.》 61 (Pt 4): 582–9. doi:10.1099/jmm.0.039040-0. PMID 22194341.

[Primary_-_LL-37_human_pylori-43] McGee DJ, George AE, Trainor EA, Horton KE, Hildebrandt E, Testerman TL (2011). “Cholesterol enhances Helicobacter pylori resistance to antibiotics and LL-37”. 《Antimicrob. Agents Chemother.》 55 (6): 2897–904. doi:10.1128/AAC.00016-11. PMC 3101455. PMID 21464244.

[pmid22517765-44] 가 ^나 Zimmerman MA, Singh N, Martin PM, Thangaraju M, Ganapathy V, Waller JL, Shi H, Robertson KD, Munn DH, Liu K (2012). “Butyrate suppresses colonic inflammation through HDAC1-dependent Fas upregulation and Fas-mediated apoptosis of T cells”. 《Am. J. Physiol. Gastrointest. Liver Physiol.》 302 (12): G1405–15. doi:10.1152/ajpgi.00543.2011. PMC 3378095. PMID 22517765.

[Niacin_neuroinflammation-45] Offermanns S, Schwaninger M (2015). “Nutritional or pharmacological activation of HCA(2) ameliorates neuroinflammation”. 《Trends Mol Med》 21 (4): 245–255. doi:10.1016/j.molmed.2015.02.002. PMID 25766751. Neuroinflammatory cells express HCA2, a receptor for the endogenous neuroprotective ketone body β-hydroxybutyrate (BHB) as well as for the drugs dimethyl fumarate (DMF) and nicotinic acid, which have established efficacy in the treatment of MS and experimental stroke, respectively. This review summarizes the evidence that HCA2 is involved in the therapeutic effects of DMF, nicotinic acid, and ketone bodies in reducing neuroinflammation.

[Niacin_vascular_inflammation-46] Chai JT, Digby JE, Choudhury RP (May 2013). “GPR109A and vascular inflammation”. 《Curr Atheroscler Rep》 15 (5): 325. doi:10.1007/s11883-013-0325-9. PMC 3631117. PMID 23526298. As GPR109A's primary pharmacological ligand in clinical use, niacin has been used for over 50 years in the treatment of cardiovascular disease, mainly due to its favourable effects on plasma lipoproteins. However, it has become apparent that niacin also possesses lipoprotein-independent effects that influence inflammatory pathways mediated through GPR109A.

[NIACR1_anti-inflammatory_effects-47] Graff EC, Fang H, Wanders D, Judd RL (February 2016). “Anti-inflammatory effects of the hydroxycarboxylic acid receptor 2”. 《Metab. Clin. Exp.》 65 (2): 102–113. doi:10.1016/j.metabol.2015.10.001. PMID 26773933. HCA2 is highly expressed on immune cells, including macrophages, monocytes, neutrophils and dermal dendritic cells, among other cell types. ... Recent studies demonstrate that HCA2 mediates profound anti-inflammatory effects in a variety of tissues, indicating that HCA2 may be an important therapeutic target for treating inflammatory disease processes.

[Niacin-NIACR1_in_PD-48] Wakade C, Chong R (December 2014). “A novel treatment target for Parkinson's disease”. 《J. Neurol. Sci.》 347 (1-2): 34–38. doi:10.1016/j.jns.2014.10.024. PMID 25455298. GPR109A and its agonists are known to exert anti-inflammatory actions in the skin, gut and retina.

[Butyrate_NPY_review-49] Farzi A, Reichmann F, Holzer P (2015). “The homeostatic role of neuropeptide Y in immune function and its impact on mood and behaviour”. 《Acta Physiol (Oxf)》 213 (3): 603–27. doi:10.1111/apha.12445. PMC 4353849. PMID 25545642. In the context of this review it is particularly worth noting that short chain fatty acids such as butyrate, which the colonic microbiota generates by fermentation of otherwise indigestible dietary fibre (Cherbut et al. 1998), stimulate L cells to release PYY via the G-protein coupled receptor Gpr41 (Samuel et al. 2008). In this way, short chain fatty acids can indirectly attenuate gastrointestinal motility as well as electrolyte and water secretion (Cox 2007b). More importantly, short chain fatty acids exert homeostatic actions on the function of the colonic mucosa and immune system (Hamer et al. 2008, Tazoe et al. 2008, Guilloteau et al. 2010, Macia et al. 2012a, Smith et al. 2013). Whether PYY plays a role in these effects of short chain fatty acids awaits to be investigated, but may be envisaged from the finding that PYY promotes mucosal cell differentiation (Hallden & Aponte 1997).

[50] Donohoe, Dallas R.; Garge, Nikhil; Zhang, Xinxin; Sun, Wei; O’Connell, Thomas M.; Bunger, Maureen K.; Bultman, Scott J. (2011년 5월 4일). “The Microbiome and Butyrate Regulate Energy Metabolism and Autophagy in the Mammalian Colon”. 《Cell Metabolism》 13 (5): 517–526. doi:10.1016/j.cmet.2011.02.018. ISSN 1550-4131. PMC 3099420. PMID 21531334.

[51] Vanhoutvin SA, Troost FJ, Hamer HM, Lindsey PJ, Koek GH, Jonkers DM, Kodde A, Venema K, Brummer RJ (2009). Bereswill S, 편집. “Butyrate-induced transcriptional changes in human colonic mucosa”. 《PLOS ONE》 4 (8): e6759. doi:10.1371/journal.pone.0006759. PMC 2727000. PMID 19707587. ^{[깨진 링크]}

[52] Klampfer L, Huang J, Sasazuki T, Shirasawa S, Augenlicht L (August 2004). “Oncogenic Ras promotes butyrate-induced apoptosis through inhibition of gelsolin expression” (PDF). 《The Journal of Biological Chemistry》 279 (35): 36680–8. doi:10.1074/jbc.M405197200. PMID 15213223.

[53] Lupton, Joanne R. (2004). 《Microbial Degradation Products Influence Colon Cancer Risk: the Butyrate Controversy》. vol. 134 no. 2: J. Nutr. 479–482쪽.

[54] “Low-carb diet cuts risk of colon cancer, study finds | University of Toronto Media Room”. 《media.utoronto.ca》. 2016년 5월 4일에 확인함.

[55] Belcheva, Antoaneta; Irrazabal, Thergiory; Robertson, Susan J.; Streutker, Catherine; Maughan, Heather; Rubino, Stephen; Moriyama, Eduardo H.; Copeland, Julia K.; Kumar, Sachin (2014년 7월 17일). “Gut microbial metabolism drives transformation of MSH2-deficient colon epithelial cells”. 《Cell》 158 (2): 288–299. doi:10.1016/j.cell.2014.04.051. ISSN 1097-4172. PMID 25036629.

[56] “Colon Cancer Shuts Down Receptor That Could Shut It Down”. 《ScienceDaily》. 2016년 5월 4일에 확인함.

[57] Davie, James R. (2003년 7월 1일). “Inhibition of Histone Deacetylase Activity by Butyrate”. 《The Journal of Nutrition》 (영어) 133 (7): 2485S–2493S. ISSN 0022-3166. PMID 12840228.

[58] Cadet, Jean Lud; Brannock, Christie; Jayanthi, Subramaniam; Krasnova, Irina N. (2015년 1월 1일). “Transcriptional and Epigenetic Substrates of Methamphetamine Addiction and Withdrawal: Evidence from a Long-Access Self-Administration Model in the Rat”. 《Molecular Neurobiology》 51 (2): 696–717. doi:10.1007/s12035-014-8776-8. ISSN 0893-7648. PMC 4359351. PMID 24939695.

[59] Kennedy, Pamela J.; Feng, Jian; Robison, A.J.; Maze, Ian; Badimon, Ana; Mouzon, Ezekiell; Chaudhury, Dipesh; Damez-Werno, Diane M.; Haggarty, Stephen J. (2013년 4월 1일). “Class I HDAC Inhibition Blocks Cocaine-Induced Plasticity Through Targeted Changes in Histone Methylation”. 《Nature Neuroscience》 16 (4): 434–440. doi:10.1038/nn.3354. ISSN 1097-6256. PMC 3609040. PMID 23475113.

[60] Malvaez, Melissa; McQuown, Susan C.; Rogge, George A.; Astarabadi, Mariam; Jacques, Vincent; Carreiro, Samantha; Rusche, James R.; Wood, Marcelo A. (2013년 2월 12일). “HDAC3-selective inhibitor enhances extinction of cocaine-seeking behavior in a persistent manner”. 《Proceedings of the National Academy of Sciences of the United States of America》 110 (7): 2647–2652. doi:10.1073/pnas.1213364110. ISSN 0027-8424. PMC 3574934. PMID 23297220.

[61] Romieu, Pascal; Host, Lionel; Gobaille, Serge; Sandner, Guy; Aunis, Dominique; Zwiller, Jean (2008년 9월 17일). “Histone deacetylase inhibitors decrease cocaine but not sucrose self-administration in rats”. 《The Journal of Neuroscience》 28 (38): 9342–9348. doi:10.1523/JNEUROSCI.0379-08.2008. ISSN 1529-2401. PMID 18799668.

[62] Bravo, Javier A.; Forsythe, Paul; Chew, Marianne V.; Escaravage, Emily; Savignac, Hélène M.; Dinan, Timothy G.; Bienenstock, John; Cryan, John F. (2011년 9월 20일). “Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve”. 《Proceedings of the National Academy of Sciences》 (영어) 108 (38): 16050–16055. doi:10.1073/pnas.1102999108. ISSN 0027-8424. PMC 3179073. PMID 21876150.

[63] 《The Developing Genome: An Introduction to Behavioral Epigenetics》 (영어) 1판. Oxford University Press. 2015년 3월 2일. ISBN 9780199922345.

[64] Fischer, Andre; Sananbenesi, Farahnaz; Wang, Xinyu; Dobbin, Matthew; Tsai, Li-Huei (2007년 5월 10일). “Recovery of learning and memory is associated with chromatin remodelling”. 《Nature》 447 (7141): 178–182. doi:10.1038/nature05772. ISSN 1476-4687. PMID 17468743.

[Miller_24–27-65] 가 ^나 Miller, Greg (2010년 7월 2일). “Epigenetics. The seductive allure of behavioral epigenetics”. 《Science》 329 (5987): 24–27. doi:10.1126/science.329.5987.24. ISSN 1095-9203. PMID 20595592.

[66] Gupta, Swati; Kim, Se Y.; Artis, Sonja; Molfese, David L.; Schumacher, Armin; Sweatt, J. David; Paylor, Richard E.; Lubin, Farah D. (2010년 3월 10일). “Histone methylation regulates memory formation”. 《The Journal of Neuroscience》 30 (10): 3589–3599. doi:10.1523/JNEUROSCI.3732-09.2010. ISSN 1529-2401. PMC 2859898. PMID 20219993.

[67] Peleg, Shahaf; Sananbenesi, Farahnaz; Zovoilis, Athanasios; Burkhardt, Susanne; Bahari-Javan, Sanaz; Agis-Balboa, Roberto Carlos; Cota, Perla; Wittnam, Jessica Lee; Gogol-Doering, Andreas (2010년 5월 7일). “Altered histone acetylation is associated with age-dependent memory impairment in mice”. 《Science》 328 (5979): 753–756. doi:10.1126/science.1186088. ISSN 1095-9203. PMID 20448184.

[68] Gräff, Johannes; Rei, Damien; Guan, Ji-Song; Wang, Wen-Yuan; Seo, Jinsoo; Hennig, Krista M.; Nieland, Thomas J. F.; Fass, Daniel M.; Kao, Patricia F. (2012년 3월 8일). “An epigenetic blockade of cognitive functions in the neurodegenerating brain”. 《Nature》 483 (7388): 222–226. doi:10.1038/nature10849. ISSN 1476-4687. PMC 3498952. PMID 22388814.

[1]

[2]

[3]

[4]

[5]

[6]

[7]

[8]

[9]

[10]

[11]

[12]

[13]

[14]

[15]

[16]

[17]

[18]

[19]

[20]

[21]

[22]

[23]

[24]

[25]

[26]

[27]

[28]

[29]

[30]

[31]

[32]

[33]

[34]

[35]

[note 1]

[36]

[37]

[38]

[39]

[40]

[41]

[42]

[43]

[44]

[45]

[46]

[47]

[48]

[49]

[50]

[51]

[52]

[53]

[54]

[55]

[56]

[57]

[58]

[59]

[60]

[61]

[62]

[63]

[64]

[65]

[66]

[67]