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These bioactive lipid amides are generated by the membrane enzyme [[NAPE-PLD]], and natural [[bile acids]] regulate this essential process.<ref name="Garau">{{cite journal | vauthors = Magotti P, Bauer I, Igarashi M, Babagoli M, Marotta R, Piomelli D, Garau G | title = Structure of Human N-Acylphosphatidylethanolamine-Hydrolyzing Phospholipase D: Regulation of Fatty Acid Ethanolamide Biosynthesis by Bile Acids | journal = Structure | volume = 23 | issue = 3 | date = Dec 2014 | doi = 10.1016/j.str.2014.12.018 | pmid=25684574 | pages=598–604 | pmc=4351732}}</ref> A LEI-401 enzyme is found to be a [[Central nervous system|CNS]]-active NAPE-PLD inhibitor, that modulate NAE [[biosynthesis]], and with similar effect like a cannabinoid [[Cannabinoid receptor type 1|CB1]] receptor [[Cannabinoid receptor antagonist|antagonist]], which could be reversed by a [[Fatty acid amide hydrolase|FAAH]] inhibitor.<ref name=":7">{{Cite journal|last=Mock|first=Elliot D.|last2=Mustafa|first2=Mohammed|last3=Gunduz-Cinar|first3=Ozge|last4=Cinar|first4=Resat|last5=Petrie|first5=Gavin N.|last6=Kantae|first6=Vasudev|last7=Di|first7=Xinyu|last8=Ogasawara|first8=Daisuke|last9=Varga|first9=Zoltan V.|last10=Paloczi|first10=Janos|last11=Miliano|first11=Cristina|date=June 2020|title=Discovery of a NAPE-PLD inhibitor that modulates emotional behavior in mice|url=https://www.nature.com/articles/s41589-020-0528-7|journal=Nature Chemical Biology|language=en|volume=16|issue=6|pages=667–675|doi=10.1038/s41589-020-0528-7|issn=1552-4469}}</ref>
These bioactive lipid amides are generated by the membrane enzyme [[NAPE-PLD]], and natural [[bile acids]] regulate this essential process.<ref name="Garau">{{cite journal | vauthors = Magotti P, Bauer I, Igarashi M, Babagoli M, Marotta R, Piomelli D, Garau G | title = Structure of Human N-Acylphosphatidylethanolamine-Hydrolyzing Phospholipase D: Regulation of Fatty Acid Ethanolamide Biosynthesis by Bile Acids | journal = Structure | volume = 23 | issue = 3 | date = Dec 2014 | doi = 10.1016/j.str.2014.12.018 | pmid=25684574 | pages=598–604 | pmc=4351732}}</ref> A LEI-401 enzyme is found to be a [[Central nervous system|CNS]]-active NAPE-PLD inhibitor, that modulate NAE [[biosynthesis]], and with similar effect like a cannabinoid [[Cannabinoid receptor type 1|CB1]] receptor [[Cannabinoid receptor antagonist|antagonist]], which could be reversed by a [[Fatty acid amide hydrolase|FAAH]] inhibitor.<ref name=":7">{{Cite journal|last=Mock|first=Elliot D.|last2=Mustafa|first2=Mohammed|last3=Gunduz-Cinar|first3=Ozge|last4=Cinar|first4=Resat|last5=Petrie|first5=Gavin N.|last6=Kantae|first6=Vasudev|last7=Di|first7=Xinyu|last8=Ogasawara|first8=Daisuke|last9=Varga|first9=Zoltan V.|last10=Paloczi|first10=Janos|last11=Miliano|first11=Cristina|date=June 2020|title=Discovery of a NAPE-PLD inhibitor that modulates emotional behavior in mice|url=https://www.nature.com/articles/s41589-020-0528-7|journal=Nature Chemical Biology|language=en|volume=16|issue=6|pages=667–675|doi=10.1038/s41589-020-0528-7|issn=1552-4469}}</ref>


All are members of the endocannabinoidome, a complex [[lipid]] signaling system composed of more than 100 of fatty acid-derived mediators and their receptors, its [[Anabolism|anabolic]] and [[Catabolism|catabolic]] [[enzyme]]s of more than 50 [[protein]]s, which are deeply involved in the control of [[Bioenergetics|energy metabolism]] and its [[Pathology|pathological]] deviations,<ref>{{Cite journal|last1=Silvestri|first1=Cristoforo|last2=Di Marzo|first2=Vincenzo|date=2019-08-20|title=Lifestyle and Metabolic Syndrome: Contribution of the Endocannabinoidome|journal=Nutrients|volume=11|issue=8|at=1956|doi=10.3390/nu11081956|pmid=31434293|pmc=6722643}}</ref> as well as [[immunosuppression]].<ref name=":5">{{Cite journal|last1=Surowiec|first1=Izabella|last2=Gouveia-Figueira|first2=Sandra|last3=Orikiiriza|first3=Judy|last4=Lindquist|first4=Elisabeth|last5=Bonde|first5=Mari|last6=Magambo|first6=Jimmy|last7=Muhinda|first7=Charles|last8=Bergström|first8=Sven|last9=Normark|first9=Johan|date=2017-09-08|title=The oxylipin and endocannabidome responses in acute phase Plasmodium falciparum malaria in children|journal=Malaria Journal|volume=16|issue=1|pages=358|doi=10.1186/s12936-017-2001-y|issn=1475-2875|pmc=5591560|pmid=28886714}}</ref> NAE's are also involved in modulation of different physiological processes such as [[pain]], [[Stress (biology)|stress]], [[anxiety]], [[appetite]], [[Circulatory system|cardiovascular]] function and [[inflammation]]. A study suggest the presence of an endogenous NAE tone control emotional behavior, and perhaps the difference in personalities.<ref name=":7" />
All are members of the endocannabinoidome, a complex [[lipid]] signaling system composed of more than 100 of fatty acid-derived mediators and their receptors, its [[Anabolism|anabolic]] and [[Catabolism|catabolic]] [[enzyme]]s of more than 50 [[protein]]s, which are deeply involved in the control of [[Bioenergetics|energy metabolism]] and its [[Pathology|pathological]] deviations,<ref>{{Cite journal|last1=Silvestri|first1=Cristoforo|last2=Di Marzo|first2=Vincenzo|date=2019-08-20|title=Lifestyle and Metabolic Syndrome: Contribution of the Endocannabinoidome|journal=Nutrients|volume=11|issue=8|at=1956|doi=10.3390/nu11081956|pmid=31434293|pmc=6722643}}</ref> as well as [[immunosuppression]].<ref name=":5">{{Cite journal|last1=Surowiec|first1=Izabella|last2=Gouveia-Figueira|first2=Sandra|last3=Orikiiriza|first3=Judy|last4=Lindquist|first4=Elisabeth|last5=Bonde|first5=Mari|last6=Magambo|first6=Jimmy|last7=Muhinda|first7=Charles|last8=Bergström|first8=Sven|last9=Normark|first9=Johan|date=2017-09-08|title=The oxylipin and endocannabidome responses in acute phase Plasmodium falciparum malaria in children|journal=Malaria Journal|volume=16|issue=1|pages=358|doi=10.1186/s12936-017-2001-y|issn=1475-2875|pmc=5591560|pmid=28886714}}</ref> NAE's are also involved in modulation of different physiological processes such as [[pain]], [[Stress (biology)|stress]], [[anxiety]], [[appetite]], [[Circulatory system|cardiovascular]] function and [[inflammation]]. A study suggest the presence of an endogenous NAE tone control [[Emotion|emotional]] [[behavior]], and perhaps the difference in [[Personality|personalities]].<ref name=":7" />


''"One way of explaining it is there are several hundred compounds, endocannabinoid-like compounds. They are like anandamide in their chemical structure, that are present in the brain, and it is quite possible that each one of us, has a different, slightly different level of these compounds. And it is quite possible that differences in the endocannabinoid system, endocannabinoid-like system, can have something to do with the different personalities, and that ratios of 10 of these to 10 of others and so on will cause that"'', said by [[Raphael Mechoulam]], that described and named Anandamide in 1992, in the [[YouTube]] video The Scientist, released in 2015.<ref>{{Citation|title=The Scientist|url=https://www.youtube.com/watch?v=csbJnBKqwIw|language=en|access-date=2021-03-14}}</ref>
''"One way of explaining it is there are several hundred compounds, endocannabinoid-like compounds. They are like anandamide in their chemical structure, that are present in the brain, and it is quite possible that each one of us, has a different, slightly different level of these compounds. And it is quite possible that differences in the endocannabinoid system, endocannabinoid-like system, can have something to do with the different personalities, and that ratios of 10 of these to 10 of others and so on will cause that"'', said by [[Raphael Mechoulam]], that described and named Anandamide in 1992, in the [[YouTube]] video The Scientist, released in 2015.<ref>{{Citation|title=The Scientist|url=https://www.youtube.com/watch?v=csbJnBKqwIw|language=en|access-date=2021-03-14}}</ref>


Beyond [[vertebrate]]s NAEs are also found to have signaling roles in more primitive [[organism]], implicated as [[Metabolism|metabolic]] signals that coordinate [[nutrient]] status and [[Life expectancy|lifespan]] determination in ''[[Caenorhabditis elegans]]'', and detected in organisms as diverse as [[yeast]] (''[[Saccharomyces cerevisiae]]''), [[freshwater fish]] (''[[Esox lucius]]'' and ''[[Common carp|Cyprinus carpio]]''), [[Bivalvia|bivalve mollusc]] (''[[Mediterranean mussel|Mytilus galloprovincialis]]''), [[protist]]s (''[[Tetrahymena|Tetrahymena thermophila]]''), [[slime mold]] (''[[Dictyostelium discoideum]]''), [[Microorganism|microbes]] such as [[bacteria]], [[Fungus|fungi]], and [[virus]]es, are all organisms that appear to regulate their endogenous NAE levels via similar enzymatic machinery as [[mammal]]ian vertebrates, show a widespread occurrence of NAEs, from [[Unicellular organism|single-celled]] organisms to humans, and a highly conserved role for this group of [[Lipid signaling|lipids]] in [[cell signaling]].<ref>{{Cite journal|last1=Blancaflor|first1=Elison B.|last2=Kilaru|first2=Aruna|last3=Keereetaweep|first3=Jantana|last4=Khan|first4=Bibi Rafeiza|last5=Faure|first5=Lionel|last6=Chapman|first6=Kent D.|date=2014|title=N-Acylethanolamines: lipid metabolites with functions in plant growth and development|journal=The Plant Journal|language=en|volume=79|issue=4|pages=568–583|doi=10.1111/tpj.12427|pmid=24397856|issn=1365-313X|doi-access=free}}</ref><ref name=":4" />
Beyond [[vertebrate]]s NAEs are also found to have signaling roles in more primitive [[organism]], implicated as [[Metabolism|metabolic]] signals that coordinate [[nutrient]] status and [[Life expectancy|lifespan]] determination in ''[[Caenorhabditis elegans]]'', and detected in organisms as diverse as [[yeast]] (''[[Saccharomyces cerevisiae]]''), [[freshwater fish]] (''[[Esox lucius]]'' and ''[[Common carp|Cyprinus carpio]]''), [[Bivalvia|bivalve mollusc]] (''[[Mediterranean mussel|Mytilus galloprovincialis]]''), [[protist]]s (''[[Tetrahymena|Tetrahymena thermophila]]''), [[slime mold]] (''[[Dictyostelium discoideum]]''), [[Microorganism|microbes]] such as [[bacteria]], [[Fungus|fungi]], and [[virus]]es, are all organisms that appear to regulate their endogenous NAE levels via similar enzymatic machinery as [[mammal]]ian vertebrates, show a widespread occurrence of NAEs, from [[Unicellular organism|single-celled]] organisms to humans, and a highly conserved role for this group of [[Lipid signaling|lipids]] in [[cell signaling]].<ref>{{Cite journal|last1=Blancaflor|first1=Elison B.|last2=Kilaru|first2=Aruna|last3=Keereetaweep|first3=Jantana|last4=Khan|first4=Bibi Rafeiza|last5=Faure|first5=Lionel|last6=Chapman|first6=Kent D.|date=2014|title=N-Acylethanolamines: lipid metabolites with functions in plant growth and development|journal=The Plant Journal|language=en|volume=79|issue=4|pages=568–583|doi=10.1111/tpj.12427|pmid=24397856|issn=1365-313X|doi-access=free}}</ref><ref name=":4" />

== NAE and the reproductive system ==
Several researches have found, that NAE, and especially 20:4 anandamide (AEA: [[Carbon|C]]<sub>22</sub>[[Hydrogen|H]]<sub>37</sub>[[Biological functions of nitric oxide|NO]]<sub>2</sub>; 20:[[Double bond|4]], [[Omega-6 fatty acid|ω-6]]), is a part of the [[reproductive system]],<ref>{{Cite journal|last=Melamede|first=Robert|date=2005-09-22|title=Harm reduction-the cannabis paradox|url=https://doi.org/10.1186/1477-7517-2-17|journal=Harm Reduction Journal|volume=2|issue=1|pages=17|doi=10.1186/1477-7517-2-17|issn=1477-7517|pmc=PMC1261530|pmid=16179090}}</ref> and play a fundamental role for a healthy and successful [[pregnancy]].

A 2006 report from the Pediatrics Department at [[Vanderbilt University]] characterized NAE 20:4 (AEA) as “an emerging concept in [[Female reproductive system|female reproduction]]”, because they found a “cannabinoid sensor” mechanism to influence several crucial steps during early pregnancy.

The Vanderbilt research team termed this “endocannabinoid signaling in preimplantation embryo development and activation”, because, one of the first things the [[Fertilisation|fertilized]] [[embryo]] must do, is to attach itself to the lining of the [[uterus]], and without becoming attached to the [[Uterus#Layers|uterine wall]], which forms the [[umbilical cord]], there will be no pregnancy. NAE 20:4 AEA play a key role, because, for the embryo to become attached to the lining of the uterus, a particular amount (temporary reduction) of NAE 20:4 AEA, present at the uterine lining, is necessary for the fertilized embryo can attach itself to the uterine wall. NAE 20:4 (AEA) uses the CB1 receptors, that are at high levels on the [[blastocyst]] (fertilized egg), to this attachment. So the amount of NAE 20:4 AEA directs the outcome of the attachment to the uterine wall via CB1, and thereby, the outcome of pregnancy,<ref>{{Cite journal|last=Wang|first=Haibin|last2=Xie|first2=Huirong|last3=Dey|first3=Sudhansu K.|date=2006|title=Endocannabinoid signaling directs periimplantation events|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3231559/|journal=The AAPS Journal|volume=8|issue=2|pages=E425–E432|doi=10.1007/BF02854916|issn=1550-7416|pmc=3231559|pmid=16808046}}</ref> and a later possible [[miscarriage]]. <ref name=":8">{{Cite journal|last=Fride|first=Ester|date=2004-10-01|title=The endocannabinoid-CB1 receptor system in pre- and postnatal life|url=https://www.sciencedirect.com/science/article/pii/S0014299904007423|journal=European Journal of Pharmacology|series=SPECIAL CELEBRATORY VOLUME 500 Dedicated to Professor David de Wied Honorary and Founding Editor|language=en|volume=500|issue=1|pages=289–297|doi=10.1016/j.ejphar.2004.07.033|issn=0014-2999}}</ref>

An earlier 2004 research in to the course of [[ectopic pregnancy]], a result of embryo retention in the [[fallopian tube]], found that decoupled cannabinoid receptor CB1, can cause retention of embryos in the mouse [[Oviducal|oviduct]], and lead to pregnancy failure. The report estimates that aberrant cannabinoid signaling impedes coordinated oviductal [[smooth muscle]] [[Muscle contraction|contraction]] and relaxation, which are crucial to normal oviductal embryo transport. This was also seen in wild-type mice treated with [[methanandamide]] (AM-356; C<sub>23</sub>H<sub>39</sub>NO<sub>2</sub>, 20:4, n6), and thereby concluded, that a colocalization of CB1 in the oviduct muscularis implicate a basal endocannabinoid tone of NAE 20:4 (AEA) is needed for oviductal [[motility]] and for normal journey of embryos into the uterus.<ref>{{Cite journal|last=Wang|first=Haibin|last2=Guo|first2=Yong|last3=Wang|first3=Dingzhi|last4=Kingsley|first4=Philip J.|last5=Marnett|first5=Lawrence J.|last6=Das|first6=Sanjoy K.|last7=DuBois|first7=Raymond N.|last8=Dey|first8=Sudhansu K.|date=2004|title=Aberrant cannabinoid signaling impairs oviductal transport of embryos|url=https://www.nature.com/articles/nm1104|journal=Nature Medicine|language=en|volume=10|issue=10|pages=1074–1080|doi=10.1038/nm1104|issn=1546-170X}}</ref>

Another 2004 study published in the ''[[American Journal of Obstetrics and Gynecology]]'' find NAE 20:4 (AEA) and the [[phytocannabinoid]] [[Tetrahydrocannabinol|Δ<sup>9</sup>-tetrahydrocannabinol]] (THC: [[Carbon|C]]<sub>21</sub>[[Hydrogen|H]]<sub>30</sub>[[Oxygen|O]]<sub>2</sub>), that can mimic NAE 20:4 (AEA) activation at CB1 and [[Cannabinoid receptor type 2|CB2]] receptors, to exert a direct relaxant effect on human pregnant [[myometrium]] [[in vitro]], with equal potency for both compounds, which was mediated through the CB1 receptor. This means that the middle layer of the uterine wall is modulated by NAE 20:4 (AEA) as well.<ref>{{Cite journal|last=Dennedy|first=Michael C.|last2=Friel|first2=Ann M.|last3=Houlihan|first3=Diarmaid D.|last4=Broderick|first4=Venita M.|last5=Smith|first5=Terry|last6=Morrison|first6=John J.|date=2004-01-01|title=Cannabinoids and the human uterus during pregnancy|url=https://www.ajog.org/article/S0002-9378(03)00988-8/abstract|journal=American Journal of Obstetrics & Gynecology|language=English|volume=190|issue=1|pages=2–9|doi=10.1016/j.ajog.2003.07.013|issn=0002-9378}}</ref>


== Mood ==
== Mood ==
Line 56: Line 67:


== Medical values ==
== Medical values ==
N-acylethanolamines (NAEs), with its cell-protective and [[Stress (biology)|stress]]-[[Stress management|combating]] action-response of organisms, have showed promise as therapeutic potential in treating [[Bacterial infection|bacterial]], [[Mycosis|fungal]], and [[Viral disease|viral]] [[infection]]s, as NAEs also exhibit [[anti-inflammatory]], [[Antibiotic|antibacterial]], and [[Antiviral drug|antiviral]] properties, which have considerable application potential.<ref name=":4" />
N-acylethanolamines (NAEs), with its cell-protective and [[Stress (biology)|stress]]-[[Stress management|combating]] action-response of organisms, have showed promise as therapeutic potential in treating [[Bacterial infection|bacterial]], [[Mycosis|fungal]], and [[Viral disease|viral]] [[infection]]s, as NAEs also exhibit [[anti-inflammatory]], [[Antibiotic|antibacterial]], and [[Antiviral drug|antiviral]] properties, which have considerable application potential.<ref name=":4" />


In [[Pediatrics|pediatric medicine]] for conditions including “non-organic [[Failure to thrive|failure-to-thrive]]” and [[cystic fibrosis]].<ref name=":8" /> A dysfunction of the endocannabinoid system is researched for a possible determining factor for causing [[infertility]] in cystic fibrosis (CF), as the [[illness]] is associated with an imbalance of [[Fatty acid|fatty acids]], show that mild stimulation of the endocannabinoid system (CB1 and CB2) in [[Infant|infancy]] and [[adolescence]], appears to normalize many reproductive processes and prevent infertility in CF males. The mild stimulated, were fully fertile, producing offspring comparable by the number of litters and the number of pups as the wild-type mice, and there counterparts, not treated, were shown completely infertile.<ref>{{Cite journal|last=Bregman|first=Tatiana|last2=Fride|first2=Ester|date=2011-06-17|title=Treatment with tetrahydrocannabinol (THC) prevents infertility in male cystic fibrosis mice|url=https://pubmed.ncbi.nlm.nih.gov/22865360/|journal=Journal of Basic and Clinical Physiology and Pharmacology|volume=22|issue=1-2|pages=29–32|doi=10.1515/jbcpp.2011.004|issn=0792-6855|pmid=22865360}}</ref>
== See also ==


* [[Pain in amphibians]]
* [[Pain in amphibians]]
*[[Retrograde signaling]]
*[[Retrograde signaling]]
*[[Endocannabinoid system]]
*[[Endocannabinoid system]]
*[[Cannabis in pregnancy]]
*[[Evolutionary history of life]]
*[[Evolutionary history of life]]
*[[Evolutionary history of plants]]
*[[Evolutionary history of plants]]

Revision as of 17:01, 16 March 2021

General chemical structure of N-acylethanolamines

An N-acylethanolamine (NAE) is a type of fatty acid amide formed when one of several types of acyl group is linked to the nitrogen atom of ethanolamine. These amides conceptually can be formed from a fatty acid and ethanolamine with the release of a molecule of water, but the known biological synthesis uses a specific phospholipase D to cleave the phospholipid unit from N-acylphosphatidylethanolamines.[1] Another route relies on the transesterification of acyl groups from phosphatidylcholine by an N-acyltransferase (NAT) activity.[citation needed] The suffixes -amine and -amide in these names each refer to the single nitrogen atom of ethanolamine that links the compound together: it is termed "amine" in ethanolamine because it is considered as a free terminal nitrogen in that subunit, while it is termed "amide" when it is considered in association with the adjacent carbonyl group of the acyl subunit. Names for these compounds may be encountered with either "amide" or "amine" varying by author.[2]

Examples of N-acylethanolamines include:[3]

These bioactive lipid amides are generated by the membrane enzyme NAPE-PLD, and natural bile acids regulate this essential process.[24] A LEI-401 enzyme is found to be a CNS-active NAPE-PLD inhibitor, that modulate NAE biosynthesis, and with similar effect like a cannabinoid CB1 receptor antagonist, which could be reversed by a FAAH inhibitor.[25]

All are members of the endocannabinoidome, a complex lipid signaling system composed of more than 100 of fatty acid-derived mediators and their receptors, its anabolic and catabolic enzymes of more than 50 proteins, which are deeply involved in the control of energy metabolism and its pathological deviations,[26] as well as immunosuppression.[27] NAE's are also involved in modulation of different physiological processes such as pain, stress, anxiety, appetite, cardiovascular function and inflammation. A study suggest the presence of an endogenous NAE tone control emotional behavior, and perhaps the difference in personalities.[25]

"One way of explaining it is there are several hundred compounds, endocannabinoid-like compounds. They are like anandamide in their chemical structure, that are present in the brain, and it is quite possible that each one of us, has a different, slightly different level of these compounds. And it is quite possible that differences in the endocannabinoid system, endocannabinoid-like system, can have something to do with the different personalities, and that ratios of 10 of these to 10 of others and so on will cause that", said by Raphael Mechoulam, that described and named Anandamide in 1992, in the YouTube video The Scientist, released in 2015.[28]

Beyond vertebrates NAEs are also found to have signaling roles in more primitive organism, implicated as metabolic signals that coordinate nutrient status and lifespan determination in Caenorhabditis elegans, and detected in organisms as diverse as yeast (Saccharomyces cerevisiae), freshwater fish (Esox lucius and Cyprinus carpio), bivalve mollusc (Mytilus galloprovincialis), protists (Tetrahymena thermophila), slime mold (Dictyostelium discoideum), microbes such as bacteria, fungi, and viruses, are all organisms that appear to regulate their endogenous NAE levels via similar enzymatic machinery as mammalian vertebrates, show a widespread occurrence of NAEs, from single-celled organisms to humans, and a highly conserved role for this group of lipids in cell signaling.[29][9]

NAE and the reproductive system

Several researches have found, that NAE, and especially 20:4 anandamide (AEA: C22H37NO2; 20:4, ω-6), is a part of the reproductive system,[30] and play a fundamental role for a healthy and successful pregnancy.

A 2006 report from the Pediatrics Department at Vanderbilt University characterized NAE 20:4 (AEA) as “an emerging concept in female reproduction”, because they found a “cannabinoid sensor” mechanism to influence several crucial steps during early pregnancy.

The Vanderbilt research team termed this “endocannabinoid signaling in preimplantation embryo development and activation”, because, one of the first things the fertilized embryo must do, is to attach itself to the lining of the uterus, and without becoming attached to the uterine wall, which forms the umbilical cord, there will be no pregnancy. NAE 20:4 AEA play a key role, because, for the embryo to become attached to the lining of the uterus, a particular amount (temporary reduction) of NAE 20:4 AEA, present at the uterine lining, is necessary for the fertilized embryo can attach itself to the uterine wall. NAE 20:4 (AEA) uses the CB1 receptors, that are at high levels on the blastocyst (fertilized egg), to this attachment. So the amount of NAE 20:4 AEA directs the outcome of the attachment to the uterine wall via CB1, and thereby, the outcome of pregnancy,[31] and a later possible miscarriage. [32]

An earlier 2004 research in to the course of ectopic pregnancy, a result of embryo retention in the fallopian tube, found that decoupled cannabinoid receptor CB1, can cause retention of embryos in the mouse oviduct, and lead to pregnancy failure. The report estimates that aberrant cannabinoid signaling impedes coordinated oviductal smooth muscle contraction and relaxation, which are crucial to normal oviductal embryo transport. This was also seen in wild-type mice treated with methanandamide (AM-356; C23H39NO2, 20:4, n6), and thereby concluded, that a colocalization of CB1 in the oviduct muscularis implicate a basal endocannabinoid tone of NAE 20:4 (AEA) is needed for oviductal motility and for normal journey of embryos into the uterus.[33]

Another 2004 study published in the American Journal of Obstetrics and Gynecology find NAE 20:4 (AEA) and the phytocannabinoid Δ9-tetrahydrocannabinol (THC: C21H30O2), that can mimic NAE 20:4 (AEA) activation at CB1 and CB2 receptors, to exert a direct relaxant effect on human pregnant myometrium in vitro, with equal potency for both compounds, which was mediated through the CB1 receptor. This means that the middle layer of the uterine wall is modulated by NAE 20:4 (AEA) as well.[34]

Mood

As the euphoric feeling described after running, called the "runners high" is, at least in part, due to increased circulating endocannabinoids (eCBs), and these lipid signaling molecules are involved in reward, appetite, mood, memory and neuroprotection, an analysis of endocannabinoid concentrations and moods after singing, dancing, exercise and reading in healthy volunteers, showed that singing increased plasma levels of anandamide (AEA) by 42%, palmitoylethanolamine (PEA) by 53% and oleoylethanolamine (OEA) by 34%, and improved positive mood and emotions. Dancing did not affect eCB levels, but decreased negative mood and emotions. Cycling increased OEA levels by 26%, and reading increased OEA levels by 28%. All the ethanolamines were positively correlated with heart rate. As so, the plasma OEA levels were positively correlated with positive mood and emotions, and AEA levels were seen positively correlated with satiation.[16]

Metabolic production of NAEs

Diets in mammals, containing 20:4,n−6 and 22:6,n−3, are found to increase several biologically active NAEs in brain homogenates as metabolic products, like 20:4,n−6 NAE (4-fold), 20:5,n−3 NAE (5-fold), and 22:5,n−3 and 22:6,n−3 NAE (9- to 10-fold). The increase in all of the metabolic NAEs is regarded biologically important, because NAEs having fatty acids with at least 20 carbons and three double bonds bind to CB1 receptors,[35] and endogenously released NAE 20:4 and 2-arachidonylglycerol (2-AG: C23H38O4; 20:4,n-6) are also found to activate CB2 receptors in addition.[17]

The hydrolysis of NAE to free fatty acid (FFA) and ethanolamine (MEA) in animals, is catalyzed by fatty acid amide hydrolase (FAAH) or by a N-acylethanolamine-hydrolyzing acid amidase (NAAA), and the polyunsaturated NAEs such as NAE 18:2, NAE 18:3, or NAE 20:4 can also be oxygenated via lipoxygenase (LOX) or cyclooxygenase (COX), to produce ethanolamide oxylipins, like prostaglandin ethanolamides (prostamide) by COX-2, with various potential bioactivities that may have enhanced affinity with cannabinoid receptors in comparison to their respective non-oxygenated NAEs,[36][27][37] as well as to oxygenated eicosanoid ethanolamides, prostaglandins, and leukotrienes, all believed to be important signaling compounds.[38]

The major COX-2 derived prostanoid product from NAE 20:4 (AEA) are prostaglandin E2 (PGE2) ethanolamide (PGE2-EA; prostamide E2) and PGD2 ethanolamide (PGD2-EA; prostamide D2), might have many important functions,[39] as PGE2 and PGD2 are pro-inflammatory mediators responsible for the induction of inflammation,[36] PGE2-EA and PGD2-EA are contrary both growth inhibitory and can induce apoptosis,[40] as well as that NAE 20:4 (AEA) and/or its prostamide metabolites in the renal medulla, may represent medullipin and function as a regulator of body fluid and the mean arterial pressure (MAP).[41]

In addition to metabolism by FAAH, COX-2 and LOXs, NAE 20:4 (AEA) can also undergo oxidation by several of human cytochrome P450 (CYPs) enzymes, resulting in various oxidized lipid species, some of which have biological relevance as CYP-derived epoxides, that can act as a potent agonist of CB2 receptors.[38]

Similar pathways of hydrolysis or oxidation of NAEs are also found in plant cells.[42][43]

NAEs in plants

N-acylethanolamines (NAEs), constitute a class of lipid compounds naturally present in both animal and plant membranes, as constituents of the membrane-bound phospholipid, N-acylphosphatidylethanolamine (NAPE). NAPE is composed of a third fatty acid moiety linked to the amino head group of the commonly occurring membrane phospholipid, phosphatidylethanolamine.[17]

It is found, that the levels of NAEs increases 10- to 50-fold in tobacco (Nicotiana tabacum) leaves treated with fungal elicitors, as a protection against it, by producing the N-myristoylethanolamine (Myristamide-MEA: C16H33NO2; NAE 14:0), that specific binds to a protein in tobacco membranes with biochemical properties appropriate for the physiological responses, and it do not show identical binding properties to NAE-binding proteins in intact tobacco microsomes, compared to non-intact microsomes. In addition to this, antagonists of mammalian CB receptors was seen to block both of the biological activities previously attributed to NAE 14:0, this endogenous NAE that is accumulated in tobacco cell suspensions and leaves after pathogen elicitor perception, is why it is proposed, that plants possess an NAE-signaling pathway with functional similarities to the “endocannabinoid” pathway of animal systems, and this pathway, in part, participates in xylanase elicitor perception in the tobacco plant, as well as in the Arabidopsis and Medicago truncatula plant tissues.[17]

Medical values

N-acylethanolamines (NAEs), with its cell-protective and stress-combating action-response of organisms, have showed promise as therapeutic potential in treating bacterial, fungal, and viral infections, as NAEs also exhibit anti-inflammatory, antibacterial, and antiviral properties, which have considerable application potential.[9]

In pediatric medicine for conditions including “non-organic failure-to-thrive” and cystic fibrosis.[32] A dysfunction of the endocannabinoid system is researched for a possible determining factor for causing infertility in cystic fibrosis (CF), as the illness is associated with an imbalance of fatty acids, show that mild stimulation of the endocannabinoid system (CB1 and CB2) in infancy and adolescence, appears to normalize many reproductive processes and prevent infertility in CF males. The mild stimulated, were fully fertile, producing offspring comparable by the number of litters and the number of pups as the wild-type mice, and there counterparts, not treated, were shown completely infertile.[44]

References

  1. ^ Okamoto, Y.; Morishita, J.; Tsuboi, K.; Tonai, T.; Ueda, N. (2004). "Molecular characterization of a phospholipase D generating anandamide and its congeners". The Journal of Biological Chemistry. 279 (7): 5298–5305. doi:10.1074/jbc.M306642200. PMID 14634025.
  2. ^ For example, note synonyms in PubChem for oleoylethanolamine.
  3. ^ The list and references provided are based on background discussion in Okamoto Y, Morishita J, Tsuboi K, Tonai T, Ueda N (February 2004). "Molecular characterization of a phospholipase D generating anandamide and its congeners". J. Biol. Chem. 279 (7): 5298–305. doi:10.1074/jbc.M306642200. PMID 14634025.
  4. ^ WA Devane, L Hanus, A Breuer, RG Pertwee, LA Stevenson, G Griffin, D Gibson, A Mandelbaum, A Etinger, and R Mechoulam; Hanus; Breuer; Pertwee; Stevenson; Griffin; Gibson; Mandelbaum; Etinger; Mechoulam (1992). "Isolation and structure of a brain constituent that binds to the cannabinoid receptor". Science. 258 (5090): 1946–1949. Bibcode:1992Sci...258.1946D. doi:10.1126/science.1470919. PMID 1470919.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  5. ^ Di Marzo (1998). "'Endocannabinoids' and other fatty acid derivatives with cannabimimetic properties: biochemistry and possible physiopathological relevance". Biochimica et Biophysica Acta (BBA) - Lipids and Lipid Metabolism. 1392 (2–3): 153–75. doi:10.1016/s0005-2760(98)00042-3. PMID 9630590.
  6. ^ Di Marzo; De Petrocellis, L; Fezza, F; Ligresti, A; Bisogno, T (2002). "Anandamide receptors". Prostaglandins, Leukotrienes, and Essential Fatty Acids. 66 (2–3): 377–91. doi:10.1054/plef.2001.0349. PMID 12052051.
  7. ^ a b Calignano; La Rana, G; Giuffrida, A; Piomelli, D (1998). "Control of pain initiation by endogenous cannabinoids". Nature. 394 (6690): 277–81. Bibcode:1998Natur.394..277C. doi:10.1038/28393. PMID 9685157. S2CID 4418082.
  8. ^ a b Stella, Nephi; Möller, Thomas; Witting, Anke; Franklin, Allyn; Walter, Lisa (2002-06-07). "Astrocytes in Culture Produce Anandamide and Other Acylethanolamides". Journal of Biological Chemistry. 277 (23): 20869–20876. doi:10.1074/jbc.M110813200. ISSN 0021-9258. PMID 11916961.
  9. ^ a b c Swamy, Musti J.; Kamlekar, Ravi Kanth (2006-07-01). "Molecular packing and intermolecular interactions in two structural polymorphs of N-palmitoylethanolamine, a type 2 cannabinoid receptor agonist". Journal of Lipid Research. 47 (7): 1424–1433. doi:10.1194/jlr.M600043-JLR200. ISSN 0022-2275. PMID 16609146.
  10. ^ Lambert; Vandevoorde, S; Jonsson, KO; Fowler, CJ (2002). "The palmitoylethanolamide family: a new class of anti-inflammatory agents?". Current Medicinal Chemistry. 9 (6): 663–74. doi:10.2174/0929867023370707. PMID 11945130.
  11. ^ Rahman, Iffat Ara Sonia; Tsuboi, Kazuhito; Uyama, Toru; Ueda, Natsuo (2014-08-01). "New players in the fatty acyl ethanolamide metabolism". Pharmacological Research. Lipid amide signaling: regulation, physiological roles and pathological implications. 86: 1–10. doi:10.1016/j.phrs.2014.04.001. PMID 24747663.
  12. ^ a b Chapman, Kent; Venables, Barney; Markovic, Robert; Blair Jr, Raymond; Bettinger, Chris (1999). "N-Acylethanolamines in Seeds. Quantification of Molecular Species and Their Degradation upon Imbibition". Plant Physiology. 120 (4): 1157–1164. doi:10.1104/pp.120.4.1157. PMC 59349. PMID 10444099.
  13. ^ Motes, Christy M.; Pechter, Priit; Yoo, Cheol Min; Wang, Yuh-Shuh; Chapman, Kent D.; Blancaflor, Elison B. (2005-12-12). "Differential effects of two phospholipase D inhibitors, 1-butanol and N-acylethanolamine, on in vivo cytoskeletal organization and Arabidopsis seedling growth". Protoplasma. 226 (3–4): 109–123. doi:10.1007/s00709-005-0124-4. ISSN 0033-183X. PMID 16333570. S2CID 19838345.
  14. ^ a b Rodríguez De Fonseca; Navarro, M; Gómez, R; Escuredo, L; Nava, F; Fu, J; Murillo-Rodríguez, E; Giuffrida, A; Loverme, J (2001). "An anorexic lipid mediator regulated by feeding". Nature. 414 (6860): 209–12. Bibcode:2001Natur.414..209R. doi:10.1038/35102582. PMID 11700558. S2CID 4430005.
  15. ^ Kilaru, Aruna; Tamura, Pamela; Isaac, Giorgis; Welti, Ruth; Venables, Barney J.; Seier, Edith; Chapman, Kent D. (2012-06-07). "Lipidomic analysis of N-acylphosphatidylethanolamine molecular species in Arabidopsis suggests feedback regulation by N-acylethanolamines". Planta. 236 (3): 809–824. doi:10.1007/s00425-012-1669-z. ISSN 0032-0935. PMC 3579225. PMID 22673881.
  16. ^ a b Stone, Nicole L.; Millar, Sophie A.; Herrod, Philip J. J.; Barrett, David A.; Ortori, Catharine A.; Mellon, Valerie A.; O’Sullivan, Saoirse E. (2018-11-26). "An Analysis of Endocannabinoid Concentrations and Mood Following Singing and Exercise in Healthy Volunteers". Frontiers in Behavioral Neuroscience. 12: 269. doi:10.3389/fnbeh.2018.00269. ISSN 1662-5153. PMC 6275239. PMID 30534062.{{cite journal}}: CS1 maint: unflagged free DOI (link) Material was copied from this source, which is available under a Creative Commons Attribution 4.0 International License.
  17. ^ a b c d e Tripathy, Swati; Kleppinger-Sparace, Kathryn; Dixon, Richard A.; Chapman, Kent D. (2003). "N-Acylethanolamine Signaling in Tobacco Is Mediated by a Membrane-Associated, High-Affinity Binding Protein". Plant Physiology. 131 (4): 1781–1791. doi:10.1104/pp.102.014936. ISSN 0032-0889. PMC 166934. PMID 12692337.
  18. ^ Hofmann, Ulrich; Domeier, Erik; Frantz, Stefan; Laser, Martin; Weckler, Barbara; Kuhlencordt, Peter; Heuer, Stefan; Keweloh, Boris; Ertl, Georg (2003-06-01). "Increased myocardial oxygen consumption by TNF-α is mediated by a sphingosine signaling pathway". American Journal of Physiology. Heart and Circulatory Physiology. 284 (6): H2100–H2105. doi:10.1152/ajpheart.00888.2002. ISSN 0363-6135. PMID 12560208.
  19. ^ Amadou, Aïssata; Nawrocki, Artur; Best-Belpomme, Martin; Pavoine, Catherine; Pecker, Françoise (2002-06-01). "Arachidonic acid mediates dual effect of TNF-α on Ca2+ transients and contraction of adult rat cardiomyocytes". American Journal of Physiology. Cell Physiology. 282 (6): C1339–C1347. doi:10.1152/ajpcell.00471.2001. ISSN 0363-6143. PMID 11997249.
  20. ^ Brown I, Cascio MG, Wahle KW, Smoum R, Mechoulam R, Ross RA, et al. (2010). "Cannabinoid receptor-dependent and -independent anti-proliferative effects of omega-3 ethanolamides in androgen receptor-positive and -negative prostate cancer cell lines". Carcinogenesis. 31 (9): 1584–91. doi:10.1093/carcin/bgq151. PMC 2930808. PMID 20660502.
  21. ^ Kim HY, Spector AA, Xiong ZM (2011). "A synaptogenic amide N-docosahexaenoylethanolamide promotes hippocampal development". Prostaglandins Other Lipid Mediat. 96 (1–4): 114–20. doi:10.1016/j.prostaglandins.2011.07.002. PMC 3215906. PMID 21810478.
  22. ^ Lee, Ji-Won; Huang, Bill X.; Kwon, HeungSun; Rashid, Md Abdur; Kharebava, Giorgi; Desai, Abhishek; Patnaik, Samarjit; Marugan, Juan; Kim, Hee-Yong (2016-10-19). "Orphan GPR110 (ADGRF1) targeted by N-docosahexaenoylethanolamine in development of neurons and cognitive function". Nature Communications. 7: 13123. doi:10.1038/ncomms13123. ISSN 2041-1723. PMC 5075789. PMID 27759003.
  23. ^ Stella, Nephi; Mackie, Ken; Kunos, George; Xie, Yiheng; Wade, Christian; Witting, Anke; Franklin, Allyn; Walter, Lisa (2003-02-15). "Nonpsychotropic Cannabinoid Receptors Regulate Microglial Cell Migration". Journal of Neuroscience. 23 (4): 1398–1405. doi:10.1523/JNEUROSCI.23-04-01398.2003. ISSN 0270-6474. PMC 6742252. PMID 12598628.
  24. ^ Magotti P, Bauer I, Igarashi M, Babagoli M, Marotta R, Piomelli D, Garau G (Dec 2014). "Structure of Human N-Acylphosphatidylethanolamine-Hydrolyzing Phospholipase D: Regulation of Fatty Acid Ethanolamide Biosynthesis by Bile Acids". Structure. 23 (3): 598–604. doi:10.1016/j.str.2014.12.018. PMC 4351732. PMID 25684574.
  25. ^ a b Mock, Elliot D.; Mustafa, Mohammed; Gunduz-Cinar, Ozge; Cinar, Resat; Petrie, Gavin N.; Kantae, Vasudev; Di, Xinyu; Ogasawara, Daisuke; Varga, Zoltan V.; Paloczi, Janos; Miliano, Cristina (June 2020). "Discovery of a NAPE-PLD inhibitor that modulates emotional behavior in mice". Nature Chemical Biology. 16 (6): 667–675. doi:10.1038/s41589-020-0528-7. ISSN 1552-4469.
  26. ^ Silvestri, Cristoforo; Di Marzo, Vincenzo (2019-08-20). "Lifestyle and Metabolic Syndrome: Contribution of the Endocannabinoidome". Nutrients. 11 (8). 1956. doi:10.3390/nu11081956. PMC 6722643. PMID 31434293.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  27. ^ a b Surowiec, Izabella; Gouveia-Figueira, Sandra; Orikiiriza, Judy; Lindquist, Elisabeth; Bonde, Mari; Magambo, Jimmy; Muhinda, Charles; Bergström, Sven; Normark, Johan (2017-09-08). "The oxylipin and endocannabidome responses in acute phase Plasmodium falciparum malaria in children". Malaria Journal. 16 (1): 358. doi:10.1186/s12936-017-2001-y. ISSN 1475-2875. PMC 5591560. PMID 28886714.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  28. ^ The Scientist, retrieved 2021-03-14
  29. ^ Blancaflor, Elison B.; Kilaru, Aruna; Keereetaweep, Jantana; Khan, Bibi Rafeiza; Faure, Lionel; Chapman, Kent D. (2014). "N-Acylethanolamines: lipid metabolites with functions in plant growth and development". The Plant Journal. 79 (4): 568–583. doi:10.1111/tpj.12427. ISSN 1365-313X. PMID 24397856.
  30. ^ Melamede, Robert (2005-09-22). "Harm reduction-the cannabis paradox". Harm Reduction Journal. 2 (1): 17. doi:10.1186/1477-7517-2-17. ISSN 1477-7517. PMC 1261530. PMID 16179090.{{cite journal}}: CS1 maint: PMC format (link) CS1 maint: unflagged free DOI (link)
  31. ^ Wang, Haibin; Xie, Huirong; Dey, Sudhansu K. (2006). "Endocannabinoid signaling directs periimplantation events". The AAPS Journal. 8 (2): E425–E432. doi:10.1007/BF02854916. ISSN 1550-7416. PMC 3231559. PMID 16808046.
  32. ^ a b Fride, Ester (2004-10-01). "The endocannabinoid-CB1 receptor system in pre- and postnatal life". European Journal of Pharmacology. SPECIAL CELEBRATORY VOLUME 500 Dedicated to Professor David de Wied Honorary and Founding Editor. 500 (1): 289–297. doi:10.1016/j.ejphar.2004.07.033. ISSN 0014-2999.
  33. ^ Wang, Haibin; Guo, Yong; Wang, Dingzhi; Kingsley, Philip J.; Marnett, Lawrence J.; Das, Sanjoy K.; DuBois, Raymond N.; Dey, Sudhansu K. (2004). "Aberrant cannabinoid signaling impairs oviductal transport of embryos". Nature Medicine. 10 (10): 1074–1080. doi:10.1038/nm1104. ISSN 1546-170X.
  34. ^ Dennedy, Michael C.; Friel, Ann M.; Houlihan, Diarmaid D.; Broderick, Venita M.; Smith, Terry; Morrison, John J. (2004-01-01). "Cannabinoids and the human uterus during pregnancy". American Journal of Obstetrics & Gynecology. 190 (1): 2–9. doi:10.1016/j.ajog.2003.07.013. ISSN 0002-9378.
  35. ^ Berger, Alvin; Crozier, Gayle; Bisogno, Tiziana; Cavaliere, Paolo; Innis, Sheila; Di Marzo, Vincenzo (2001-05-22). "Anandamide and diet: Inclusion of dietary arachidonate and docosahexaenoate leads to increased brain levels of the corresponding N-acylethanolamines in piglets". Proceedings of the National Academy of Sciences of the United States of America. 98 (11): 6402–6406. doi:10.1073/pnas.101119098. ISSN 0027-8424. PMC 33480. PMID 11353819.
  36. ^ a b Dyall, Simon C. (2017). "Interplay Between n-3 and n-6 Long-Chain Polyunsaturated Fatty Acids and the Endocannabinoid System in Brain Protection and Repair". Lipids. 52 (11): 885–900. doi:10.1007/s11745-017-4292-8. ISSN 0024-4201. PMC 5656721. PMID 28875399.
  37. ^ Gaitán, Adriana V; Wood, JodiAnne T; Solomons, Noel W; Donohue, Juliana A; Ji, Lipin; Liu, Yingpeng; Nikas, Spyros P; Zhang, Fan; Allen, Lindsay H (2019-03-27). "Endocannabinoid Metabolome Characterization of Milk from Guatemalan Women Living in the Western Highlands". Current Developments in Nutrition. 3 (6): nzz018. doi:10.1093/cdn/nzz018. ISSN 2475-2991. PMC 6517780. PMID 31111118.
  38. ^ a b Keereetaweep, Jantana; Chapman, Kent D. (2016). "Lipidomic Analysis of Endocannabinoid Signaling: Targeted Metabolite Identification and Quantification". Neural Plasticity. 2016: 2426398. doi:10.1155/2016/2426398. ISSN 2090-5904. PMC 4709765. PMID 26839710.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  39. ^ Ramesha, Chakkodabylu S.; Ives, Danial; Yu, Ming (1997-08-22). "Synthesis of Prostaglandin E2 Ethanolamide from Anandamide by Cyclooxygenase-2". Journal of Biological Chemistry. 272 (34): 21181–21186. doi:10.1074/jbc.272.34.21181. ISSN 0021-9258. PMID 9261124.
  40. ^ Patsos, H A; Hicks, D J; Dobson, R R H; Greenhough, A; Woodman, N; Lane, J D; Williams, A C; Paraskeva, C (2005). "The endogenous cannabinoid, anandamide, induces cell death in colorectal carcinoma cells: a possible role for cyclooxygenase 2". Gut. 54 (12): 1741–1750. doi:10.1136/gut.2005.073403. ISSN 0017-5749. PMC 1774787. PMID 16099783.
  41. ^ Ritter, Joseph K.; Li, Cao; Xia, Min; Poklis, Justin L.; Lichtman, Aron H.; Abdullah, Rehab A.; Dewey, William L.; Li, Pin-Lan (2012). "Production and Actions of the Anandamide Metabolite Prostamide E2 in the Renal Medulla". The Journal of Pharmacology and Experimental Therapeutics. 342 (3): 770–779. doi:10.1124/jpet.112.196451. ISSN 0022-3565. PMC 3422528. PMID 22685343.
  42. ^ Stelt, Marcelis van der; Noordermeer, Minke A.; Kiss, Tünde; Zadelhoff, Guus van; Merghart, Ben; Veldink, Gerrit A.; Vliegenthart, Johannes F. G. (2000). "Formation of a new class of oxylipins from N-acyl(ethanol)amines by the lipoxygenase pathway". European Journal of Biochemistry. 267 (7): 2000–2007. doi:10.1046/j.1432-1327.2000.01203.x. hdl:1874/5348. ISSN 1432-1033. PMID 10727939.
  43. ^ Gachet, María Salomé; Schubert, Alexandra; Calarco, Serafina; Boccard, Julien; Gertsch, Jürg (2017-01-25). "Targeted metabolomics shows plasticity in the evolution of signaling lipids and uncovers old and new endocannabinoids in the plant kingdom". Scientific Reports. 7: 41177. doi:10.1038/srep41177. ISSN 2045-2322. PMC 5264637. PMID 28120902.
  44. ^ Bregman, Tatiana; Fride, Ester (2011-06-17). "Treatment with tetrahydrocannabinol (THC) prevents infertility in male cystic fibrosis mice". Journal of Basic and Clinical Physiology and Pharmacology. 22 (1–2): 29–32. doi:10.1515/jbcpp.2011.004. ISSN 0792-6855. PMID 22865360.

External links

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