The Cannabis Papers: A citizen’s guide to cannabinoids (2011)
By Publius

 
July’s science roundup looks at ten articles on how the cannabinoid system (CS) modulates our health and homeostasis. The line-up links to 2014 CS PubMed articles: three directly on homeostasis, two each on the central nervous, circulatory, and digestive systems, and one on the respiratory system and its natural cancer killer cells.

I. Respiratory System (Lung Cancer) and the CS
“Cannabinoids have been shown to promote the expression of the intercellular adhesion molecule 1 (ICAM-1) on lung cancer cells as part of their anti-invasive and antimetastatic action. … These findings provide proof for a novel antitumorigenic mechanism of cannabinoids.”
Cannabinoids Increase Lung Cancer Cell Lysis by Lymphokine-Activated Killer Cells Via Upregulation of ICAM-1.
Haustein M, Ramer R, Linnebacher M, Manda K, Hinz B.
Biochem Pharmacol. 2014 Jul 25. pii: S0006-2952(14)00420-1. doi: 10.1016/j.bcp.2014.07.014. [Epub ahead of print]
PMID: 25069049 [PubMed - as supplied by publisher]
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II. Homeostasis (PTSD-related Insomnia/Nightmares/Chronic Pain) and the CS
“Nabilone is a synthetic cannabinoid that has shown promise for the treatment of posttraumatic stress disorder (PTSD)-related insomnia and nightmares as well as efficacy in the management of chronic pain. … This retrospective study of 104 male inmates with serious mental illness prescribed nabilone analyzes the indications, efficacy, and safety of its use. … This study supports the promise of nabilone as a safe, effective treatment for concurrent disorders in seriously mentally ill correctional populations.”
Use of a Synthetic Cannabinoid in a Correctional Population for Posttraumatic Stress Disorder-Related Insomnia and Nightmares, Chronic Pain, Harm Reduction, and Other Indications: A Retrospective Evaluation.
Cameron C, Watson D, Robinson J.
J Clin Psychopharmacol. 2014 Jul 1. [Epub ahead of print]
PMID: 24987795 [PubMed - as supplied by publisher]
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III. Homeostasis (Strength Training and Pain Relief) and the CS
“Resistance exercise (RE) is also known as strength training, and it is performed to increase the strength and mass of muscles, bone strength, and metabolism. RE has been increasingly prescribed for pain relief. … The present study suggests that a single session of RE activates the endocannabinoid system to induce antinociception.”
Acute Resistance Exercise Induces Antinociception by Activation of the Endocannabinoid System in Rats.
Galdino G, Romero T, da Silva JF, Aguiar D, de Paula AM, Cruz J, Parrella C, Piscitelli F, Duarte I, Di Marzo V, Perez A.
Anesth Analg. 2014 Jun 26. [Epub ahead of print]
PMID: 24977916 [PubMed - as supplied by publisher]
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IV. Circulatory System (Tumor-to-Endothelial Cells) and the CS
“Cannabinoids inhibit tumor neovascularisation as part of their tumorregressive action. However, the underlying mechanism is still under debate. In the present study the impact of cannabinoids on potential tumor-to-endothelial cell communication conferring anti-angiogenesis was studied. … Collectively, our data suggest a pivotal role of the anti-angiogenic factor TIMP-1 in intercellular tumor-endothelial cell communication resulting in anti-angiogenic features of endothelial cells.”
Cannabinoids inhibit angiogenic capacities of Endothelial cells via release of Tissue inhibitor of matrix metalloproteinases-1 from lung cancer cells.
Ramer R, Fischer S, Haustein M, Manda K, Hinz B.
Biochem Pharmacol. 2014 Jun 26. pii: S0006-2952(14)00360-8. doi: 10.1016/j.bcp.2014.06.017. [Epub ahead of print]
PMID: 24976505 [PubMed - as supplied by publisher]
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V. Digestive System (Obesity, Diabetes) and GPR55 and the CS
“Cannabinoids are known to be important in controlling appetite and metabolic balance, and it is now emerging that GPR55 may have a role to play in energy homeostasis through the regulation of food intake, fuel storage in adipocytes, gut motility and insulin secretion. … Understanding the role of GPR55 in energy homeostasis may provide a novel target for therapeutic intervention in obesity and type 2 diabetes mellitus.”
GPR55: From orphan to metabolic regulator?
Liu B, Song S, Jones PM, Persaud SJ.
Pharmacol Ther. 2014 Jun 24. pii: S0163-7258(14)00124-7. doi: 10.1016/j.pharmthera.2014.06.007. [Epub ahead of print] Review.
PMID: 24972076 [PubMed - as supplied by publisher]
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VI. CNS, Heteromers(CB1-GPR55 this time) and the CS
“A further aim of the present paper was to check for cannabinoid CB1-GPR55 receptor heteromers in the central nervous system (CNS), specifically in striatum. … The results indicate not only that GPR55 is expressed in striatum but also that CB1 and GPR55 receptors form heteromers in this specific CNS region.”
CB1 and GPR55 receptors are co-expressed and form heteromers in rat and monkey striatum.
Martínez-Pinilla E, Reyes-Resina I, Oñatibia-Astibia A, Zamarbide M, Ricobaraza A, Navarro G, Moreno E, Dopeso-Reyes IG, Sierra S, Rico AJ, Roda E, Lanciego JL, Franco R.
Exp Neurol. 2014 Jun 23. pii: S0014-4886(14)00204-0. doi: 10.1016/j.expneurol.2014.06.017. [Epub ahead of print]
PMID: 24967683 [PubMed - as supplied by publisher]
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VII. Digestive System (Liver Cirrhosis / Ascites) and the CS
“Our study suggests that CB2R agonist have the potential to treat BT [bacterial translocation] and various relevant abnormalities through the inhibition of systemic/intestinal oxidative stress, inflammatory cytokines and TNFα releases in cirrhosis. Overall, chronic CB2R agonist treatment affects multiple approach mechanisms, and the direct effect on hyperdynamic circulation is only minor.”
Long-term cannabinoid type 2 receptor agonist therapy decreases Bacterial Translocation In Rats with cirrhosis and ascites.
Yang YY, Hsieh SL, Lee PC, Yeh YC, Lee KC, Hsieh YC, Wang YW, Lee TY, Huang YH, Chan CC, Lin HC.
J Hepatol. 2014 Jun 19. pii: S0168-8278(14)00411-5. doi: 10.1016/j.jhep.2014.05.049. [Epub ahead of print]
PMID: 24953022 [PubMed - as supplied by publisher]
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VIII. CNS (Alzheimer’s disease) and CS CB1
“The activity of CB1 cannabinoid receptors was studied in postmortem brain samples of Alzheimer's disease (AD) patients during clinical deterioration. CB1 activity was higher at earlier AD stages in limited hippocampal areas and internal layers of frontal cortex, but a decrease was observed at the advanced stages. The pattern of modification appears to indicate initial hyperactivity of the endocannabinoid system in brain areas that lack of classical histopathological markers at earlier stages of AD, indicating an attempt to compensate for the initial synaptic impairment, which is then surpassed by disease progression. These results suggest that initial CB1 stimulation might have therapeutic relevance.”
Type-1 Cannabinoid Receptor Activity During Alzheimer's Disease Progression.
Manuel I, de San Román EG, Giralt MT, Ferrer I, Rodríguez-Puertas R.
J Alzheimers Dis. 2014 Jun 19. [Epub ahead of print]
PMID: 24946872 [PubMed - as supplied by publisher]
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IX. Homeostasis Heterodimers: Bivalency of Orexin OX1 and CS CB1
“Cannabinoid CB1 and orexin OX1 receptors have been suggested to form heterodimers and oligomers. … Bivalent ligands targeting CB1-OX1 receptor dimers could be potentially useful as a tool for further exploring the roles of such heterodimers in vitro and in vivo.”
Toward the Development of Bivalent Ligand Probes of Cannabinoid CB1 and Orexin OX1 Receptor Heterodimers.
Perrey DA, Gilmour BP, Thomas BF, Zhang Y.
ACS Med Chem Lett. 2014 Mar 25;5(6):634-8. doi: 10.1021/ml4004759. eCollection 2014 Jun 12.
PMID: 24944734 [PubMed]
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X. Circulatory System (Anti-inflammation) and the CS CB2
“To observe a PPAR-alpha agonist effect of N-oleoylethanolamine (OEA) on CB2 (cannabinoid receptor 2), an anti-inflammatory receptor in vascular endothelial cell, healthy HUVECs and TNF-alpha induced HUVECs were used to establish a human vascular endothelial cell inflammatory model. … The anti-inflammation effect of OEA is induced by PPAR-alpha and CB2, suggesting that CB2 signaling could be a target for anti-atherosclerosis, OEA have wide effect in anti-inflammation, it may have better therapeutic potential in anti-inflammation in HUVECs, thus achieving anti-atherosclerosis effect.”
[Anti-atherosclerosis role of N-oleoylethanolamine in CB2].
Gai YT, Shu Q, Chen CX, Lai YL, Li WJ, Peng L, Lin LM, Jin X.
Yao Xue Xue Bao. 2014 Mar;49(3):316-21. Chinese.
PMID: 24961101 [PubMed - in process]
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~
Posted by Bryan W. Brickner

War Cry Heal Union: The series (6th of 10)


American exceptionalism: immigrants and constitutions.

Factions heard not silenced is today’s topic with Henry Lee III defending the First Amendment and the Unrepresented.

Henry Lee III is “Light-Horse Harry” Lee. He was famous in is own time, way before his son Robert was born. Lee served with distinction in the Revolutionary War, receiving recognition from the Second Continental Congress for his leadership at Paulus Hook (19 August 1779). Lee then followed through and supported the new Constitution through acts; as Governor of Virginia, he led the federalized state militias (during President Washington’s first-term) over the mountains and into western Pennsylvania in 1794 during the Whiskey Rebellion; he also took a beating for the First Amendment … more on that in a moment.

The Lee family is a founding American family ~ perhaps even “the” founding family ~ and thereby part of what makes us exceptional.

So what is that? ~ What makes us exceptional?

Well, a nation of immigrants is one thing; the first Lee in the colonies was early on at Jamestown, 1639, one Richard Lee I (1617-1664). He’s pictured right and is known as The Immigrant. He made his fortune in the early days of Virginia; he was involved in the fur trade with the aborigine and scooped up land from the King and turned it into working farms and plantations; to do so he exported tobacco, imported indentured workers, and was in the “business” of slavery. Richard Lee, at the time of his death in 1664, was a wealthy well-connected colonial immigrant.

Henry Lee III provides us another example of American exceptionalism: our Constitution, specifically, the First Amendment’s freedom of speech.

Henry Lee did lots of things ~ both good and bad. He didn’t do so well in business; he speculated on land and lost. That’s the bad mostly. The good is what others like George Washington noticed: his ability to lead.

Which brings us to Lee’s Baltimore beating, 27 July 1812. In a biography of his son, Douglas Southall Freeman’s Pulitzer Prize winning Lee (1934: Abridgment 1997), the author tells the story of Henry Lee’s First Amendment defense to illustrate a penchant for being in the thick of things (sounds like a Lee). This time though Henry is a citizen and not a soldier. He finds himself in a mob fracas; he defends a publisher, Alexander C. Hanson, who had published an antiwar (the US shouldn’t go to war) editorial and had his business and friends attacked by a mob; Freeman describes the brutality (page 8):

“When it was over, half of Hanson’s friends had escaped, but one had been killed and eleven frightfully beaten. Eight were thought to be dead and were piled together in front of the building, where they were subjected to continued mutilation. Henry Lee was among this number. Drunken brutes thrust penknives into his flesh, and waited to see whether there was a flicker when hot candle grease was poured into his eyes. One fiend tried to cut off his nose. After a while, some of the town physicians succeeded in carrying him to a hospital.”

Henry Lee never recovered from his Baltimore beating ~ he was never the same; what he did though, honoring his revolutionary arts in peace as well as war, is recoverable: it’s an American experience and evidence of exception ~ even the not so pretty kind.

“Be not unmindful of the future” is the translation of the Latin motto “Ne Incautus Futuri” found on the Lee coat of arms ~ and that’s exceptional too.

Next up is the seventh essay in the War Cry Heal Union series: Monday 11 August and the 150th anniversary of a Civil War day in Georgia, 1864 ~ Johnny Reb and Gus Kotka discuss Robert E. Lee.

Posted by Bryan W. Brickner

War Cry Heal Union: The series (5th of 10)


Honor and Death were present when Van de Graaff met Buckley.

Imagine a hot Georgia mid-afternoon 150 years ago today; about 1,000 soldiers, mostly Mississippians, hear the fate of Atlanta (and thus the Confederacy) is in their hands.

Now imagine another moment, one less than an hour from the other one, of a Mississippian (Van de Graaff / a name implying Germany) and a New Yorker (Buckley / who was born in Canada) meet and try to kill each other.

Here, I’ll explain …

The commander of the Mississippi brigade, Brigadier General Winfield Scott Featherston, a veteran who fought in the eastern theater (Virginia and Maryland) under the command of Robert E. Lee (at Antietam in 1862, for example), and then was transferred west (also by Lee) later that year. On this day, 20 July 1864, Featherston is leading an aspect of Confederate General John B. Hood’s plan of attack on the Federal approach to Atlanta. Hood was put in command by Jefferson Davis (President of the Confederacy) and brought an “I’ll attack” strategy to the defense of Atlanta; the battle at Peachtree Creek was his first effort.

Hood told General Stewart, who told General Loring, who told Featherston who then told the 1,000 Mississippians (including Van de Graaff) of their moment. So off they go in attack, six Confederate/MS battalions forward into six Federal battalions ~ two from Ohio and one each from Connecticut, Massachusetts, Wisconsin and New York. The Federal line falls back; at first the charge succeeds with the Mississippi brigade taking the ridge; then the Federals’ fire cannon into the breached line (into the Mississippians) and counter-assault.

The 26th Wisconsin captured the battle flag pictured here from one of Featherston’s battalions, the 33rd Mississippi, and its loss (capture) would have taken place during this phase of the battle; in total, Featherston’s brigade would lose seven battle flags at Peachtree Creek.

Which brings us to the meeting of Van de Graaff and Buckley.  

Private Dennis B. Buckley of the 136th New York battalion struggles with the battalion Adjutant of the 31st Mississippi, W.J. Van de Graaff. Various reports note a hand-to-hand struggle for the flag of the 31st; it would have looked like the one pictured above, the 33rd’s. Van de Graaff, who was carrying the flag only because the other bearers had been shot, lost the flag to Buckley; Buckley, after wresting control of the flag, was then shot and killed. Private Dennis B. Buckley was awarded the US Medal of Honor for capturing the 31st’s battle flag and is buried in Marietta National Cemetery.

Being from Illinois, I usually see our Civil War more or less from the Federal perspective; today, having been myself an Adjutant (battalion staff officer/personnel, US Army, Saudi Arabia 1991), it’s Van de Graaff that I’m feeling. In his report of the battle, Featherston made special mention of the 31st’s leaders who died on 20 July 1864, specifically, their commander Lt. Col. J. W. Drane and executive officer Major F. M. Gillespie. The 31st suffered 164 casualties from 215 men sent into battle; here’s what  Featherston wrote in his report of Van de Graaff, followed by the names of the unit’s leaders killed or reported missing: “Adjt. W.L. Van de Graaff, of the 31st Mississippi Regiment, a gallant and accomplished officer, a young man of promise and great moral worth, seized the colors of his regiment and bore them to the front after two or three color bearers had been shot down, and following their example shared their fate. He fell with the colors in his hand.”


Killed:
Lt. Col. J. W. Drane, Major F. M. Gillespie, Capt. John B. Ketchum, Adjutant W. J. Van de Graaff , Lt. W. D. Carradine, Lt. J. C. Morrow, Sgt. J. M. Johnson.
Missing:
Capt. G. W. Lewdon, Capt. C. W. Richards, Lt. S. M. Bobbs, Lt. J. C. Hallum, Lt. Thomas Lyles, Lt. P. G. McGraw, Sgt. J. S. Bridges, Sgt. J. J. Cudley.

Representing all our citizens in a new constitutional House of Representatives, one for every 30,000, is something we have to look forward to; while doing so, let’s look back and perhaps think again ~ of the individual citizen-soldiers of our Civil War ~ as well.

Next time, July 27th, is the sixth essay in the War Cry Heal Union series ~ Henry Lee III, father of Robert E. Lee, defends the First Amendment and the Unrepresented.

Posted by Bryan W. Brickner

War Cry Heal Union: The series (4th of 10)


Empires crumble in willy-nilly ways.

That’s Hannah Arendt (1906-1975) and her mother in 1912. They are Jews in Kaiser Wilhelm’s German Empire ~ and Emperor “Willy” didn’t like Jews.

In Russia and cousin Tsar Nicholas’ empire, the world of Emperor “Nicky,” Jews weren’t liked much either. Examples: the 1891 Ukase (executive order) expelling 20,000 Jews from Moscow and the Russian language gave us the word pogrom ~ an organized, sanctioned and violent assault on a Jewish community.

In Germany the clearest example is Emperor Wilhem.  John Röhl, in The Kaiser and His Court: Wilhelm II and the Government of Germany (1994: p. 210), provides some choice 1919 anti-semitic Willy words. First, the former Emperor calls his abdication: “the deepest, most disgusting shame ever perpetrated by a person in history, the Germans have done to themselves... egged on and misled by the tribe of Judah ... Let no German ever forget this, nor rest until these parasites have been destroyed and exterminated from German soil!” Second, Willy praises Russia’s pogroms and, chillingly, said the Jews were a nuisance and should be gotten rid of; in 1919, the fallen German Emperor Kaiser Wilhelm even stated how: “I believe the best thing would be gas!”

War cries.

From 28 July to 1 August 1914, the two Emperors exchanged telegrams with the intention of avoiding “bloodshed” ~ the Willy-Nicky Telegrams. The telegrams are ego-empiric (it is 1914 and Sigmund Freud is nearby in Vienna, Austria); they read nice at the beginning, both talking of peace and accommodation. In the end, on the eve of catastrophe, the letters expose the underlying insecurity and paranoia inherent to empire; Willy and Nicky boxed themselves into their hubristic minds, and in that state one never hears the cries of Others ~ emperor or Jew.

Willy and Nicky’s failure produced 15 million dead, the Soviet Union and Hitler's Third Reich (two more empires really), and sowed the harvest we call World War II. Kaiser Wilhelm abdicates in 1918 and is exiled to the Netherlands; he blames his “Hebrew subjects” and “the tribe of Judah” for his fall and writes Hitler congratulatory notes (on the 1939 invasion of Poland, for example). Tsar Nicholas’ fate is fatal: he abdicates in 1917, is imprisoned and then murdered on the orders of the new Others.

In October 1964, Gunter Gaus interviewed Hannah Arendt on “Zur Person” (The Person); the show was taped for a West German audience and she answers questions about heritage, growing up in Konigsberg and her mother’s influence. The interview highlights Arendt as a political theorist; when asked about 1933 Germany, the year the Nazis came into power, and what that was like, Arendt describes the motivating will of the Unrepresented ~ of the Other ~ that speaks in all ages: “Indifference was no longer possible in 1933. It was impossible even before that.”

Tomorrow on the War Cry Heal Union series ~ Civil War Battle Flags, Medals of Honor and Soldiers Unknown.
Posted by Bryan W. Brickner

The Cannabis Papers: A citizen’s guide to cannabinoids (2011)
By Publius


A World (Cup) of Cannabinoids: Fielders Edition

Today’s science roundup looks at ten articles on how the cannabinoid system (CS) modulates our health and homeostasis; the line-up links to 2014 CS PubMed articles: four directly on homeostasis, two on the circulatory system, two on the central nervous system, and one each on our digestive and respiratory systems.

I. CNS (Pediatric Brain Injury) and the CS
“Paediatric traumatic brain injury (TBI) is a leading cause of death and disability. Previous studies showed neuroprotection after TBI by (endo)cannabinoid mechanisms, suggesting involvement of cannabinoid receptors (CBR). … The results may provide explanation for the neuroprotective properties of cannabinoid ligands and future therapeutic strategies of TBI.”
Early increase of cannabinoid receptor density after experimental traumatic brain injury in the newborn piglet.
Donat CK, Fischer F, Walter B, Deuther-Conrad W, Brodhun M, Bauer R, Brust P.
Acta Neurobiol Exp (Wars). 2014;74(2):197-210.
PMID: 24993629 [PubMed - in process]
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II. Digestive System (Irritable Bowel Syndrome) and the CS
“The activation of the ATP ion-gated channels, voltage-gated sodium (Nav) and calcium (Cav) channels, as well as the activation of protease-activated receptors (PAR2), transient receptor potential vanilloide-1, serotonin, cannabinoids and cholecystokinin are involved in the genesis of visceral hypersensitivity in IBS.”
Main ion channels and receptors associated with visceral hypersensitivity in irritable bowel syndrome.
de Carvalho Rocha HA, Dantas BP, Rolim TL, Costa BA, de Medeiros AC.
Ann Gastroenterol. 2014;27(3):200-206. Review.
PMID: 24976114 [PubMed - as supplied by publisher] Free PMC Article
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III. Respiratory System (Paraquat and Acute Lung Injury) and the CS
“Paraquat [PQ], a widely used herbicide, is well known to exhibit oxidative stress and lung injury. … The results suggested that activating CB2 receptor exerted protective activity against PQ-induced ALI [Acute Lung Injury], and it potentially contributed to the suppression of the activation of MAPKs and NF- κ B pathways.”
CB2 Receptor Activation Ameliorates the Proinflammatory Activity in Acute Lung Injury Induced by Paraquat.
Liu Z, Wang Y, Zhao H, Zheng Q, Xiao L, Zhao M.
Biomed Res Int. 2014;2014:971750. doi: 10.1155/2014/971750. Epub 2014 May 22.
PMID: 24963491 [PubMed - in process] Free PMC Article
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IV. Homeostasis (Indole Quinuclidine Analogs) and the CS
“Therefore, indole quinuclidines are a novel structural class of compounds exhibiting high affinity and a range of intrinsic activity at cannabinoid type-1 and type-2 receptors.”
Characterization of the intrinsic activity for a novel class of cannabinoid receptor ligands: Indole quinuclidine analogs.
Franks LN, Ford BM, Madadi NR, Penthala NR, Crooks PA, Prather PL.
Eur J Pharmacol. 2014 Aug 15;737:140-8. doi: 10.1016/j.ejphar.2014.05.007. Epub 2014 May 20.
PMID: 24858620 [PubMed - in process]
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V. Circulatory System (Ischemic Heart Disease) and the CS
“Ischemic heart disease is associated with inflammation, interstitial fibrosis and ventricular dysfunction prior to the development of heart failure. … Therefore, the endocannabinoid-CB2 receptor axis plays a key role in cardioprotection during the initial phase of ischemic cardiomyopathy development.”
The endocannabinoid-CB2 receptor axis protects the ischemic heart at the early stage of cardiomyopathy.
Duerr GD, Heinemann JC, Suchan G, Kolobara E, Wenzel D, Geisen C, Matthey M, Passe-Tietjen K, Mahmud W, Ghanem A, Tiemann K, Alferink J, Burgdorf S, Buchalla R, Zimmer A, Lutz B, Welz A, Fleischmann BK, Dewald O.
Basic Res Cardiol. 2014 Jul;109(4):425. doi: 10.1007/s00395-014-0425-x. Epub 2014 Jul 1.
PMID: 24980781 [PubMed - in process]
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VI. Homeostasis, Endocannabinoid Deficiencies and the CS
“Subsequent research has confirmed that underlying endocannabinoid deficiencies indeed play a role in migraine, fibromyalgia, irritable bowel syndrome and a growing list of other medical conditions. Clinical experience is bearing this out. Further research and especially, clinical trials will further demonstrate the usefulness of medical cannabis. As legal barriers fall and scientific bias fades this will become more apparent.”
Clinical endocannabinoid deficiency (CECD) revisited: Can this concept explain the therapeutic benefits of cannabis in migraine, fibromyalgia, irritable bowel syndrome and other treatment-resistant conditions?
Smith SC, Wagner MS.
Neuro Endocrinol Lett. 2014 Jun 30;35(3):198-201. [Epub ahead of print]
PMID: 24977967 [PubMed - as supplied by publisher]
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VII. Homeostasis (Epilepsy, Neuronal Plasticity) and the CS
“Synaptic communication requires constant adjustments of pre- and postsynaptic efficacies. In addition to synaptic long-term plasticity, the presynaptic machinery underlies homeostatic regulations which prevent out of range transmitter release. In this mini-review we will discuss the relevance of selected presynaptic mechanisms to epilepsy including voltage- and ligand-gated ion channels as well as cannabinoid and adenosine receptor signaling.”
Presynaptic mechanisms of neuronal plasticity and their role in epilepsy.
Meier J, Semtner M, Winkelmann A, Wolfart J.
Front Cell Neurosci. 2014 Jun 17;8:164. doi: 10.3389/fncel.2014.00164. eCollection 2014. Review.
PMID: 24987332 [PubMed]
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VIII. Homeostasis (Turning Agonists into Antagonists) and the CS
“However, we discovered that bivalency has an influence on the effect at both cannabinoid receptors. Moreover, we found out that the spacer length and the attachment position altered the efficacy of the bivalent ligands at the receptors by turning agonists into antagonists and inverse agonists.”
Synthesis and biological evaluation of bivalent cannabinoid receptor ligands based on hCB2R selective benzimidazoles reveal unexpected intrinsic properties.
Nimczick M, Pemp D, Darras FH, Chen X, Heilmann J, Decker M.
Bioorg Med Chem. 2014 Jun 13. pii: S0968-0896(14)00454-4. doi: 10.1016/j.bmc.2014.06.008. [Epub ahead of print]
PMID: 24984935 [PubMed - as supplied by publisher]
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IX. Circulatory System (Blood Vessels-Heart) and the CS
“2-Arachidonoylglycerol [2-AG] plays an important role in the regulation of the circulatory system via direct and/or indirect, through their metabolites, effects on blood vessels and/or heart. Accumulating evidence reveals that 2-AG is involved in the pathogenesis of various shocks and atherosclerosis.”
Role of endocannabinoid 2-arachidonoylglycerol in the physiology and pathophysiology of the cardiovascular system.
Karabowicz P, Grzęda E, Baranowska-Kuczko M, Malinowska B.
Postepy Hig Med Dosw (Online). 2014 Jun 12;68(0):814-27.
PMID: 24934539 [PubMed - in process]
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X. CNS (Brain Mitochondria) and the CS
“Our results show that the use of appropriate controls and quantifications allows detecting mtCB1 receptor with CB1 receptor antibodies, and that, if mitochondrial fractions are enriched and purified, CB1 receptor agonists reliably decrease respiration in brain mitochondria.”
Cannabinoid control of brain bioenergetics: Exploring the subcellular localization of the CB1 receptor.
Hebert-Chatelain E, Reguero L, Puente N, Lutz B, Chaouloff F, Rossignol R, Piazza PV, Benard G, Grandes P, Marsicano G.
Mol Metab. 2014 Apr 2;3(4):495-504. doi: 10.1016/j.molmet.2014.03.007. eCollection 2014 Jul.
PMID: 24944910 [PubMed] Free PMC Article
Related citations

See also: Alzheimer’s, Cancer and Homeostatic Cannabinoid Science

Bonus Video: Homeostasis

Posted by Bryan W. Brickner

The Cannabis Papers: A citizen’s guide to cannabinoids (2011)
By Publius

The CS World Cup: Goaltender Edition

Today, tending to the goals of mediating Alzheimer’s and preventing carcinogenesis, Publius spotlights two June abstracts from PubMed on the homeostatic cannabinoid system (CS). For Alzheimer’s disease it is CS modulation of cognitive decline; for preventing carcinogenesis the findings unveil a previously unknown CS signaling platform: CB2-GPR55 receptor heteromers.



I. CS Mediates Cognitive Decline In Alzheimer's Disease

Set: “It has been widely reported that β-amyloid peptide (Aβ) blocks long-term potentiation (LTP) of hippocampal synapses. Here, we show evidence that Aβ more potently blocks the potentiation of excitatory postsynaptic potential (EPSP)-spike coupling (E-S potentiation). This occurs, not by direct effect on excitatory synapses or postsynaptic neurons, but rather through an indirect mechanism: reduction of endocannabinoid-mediated peritetanic disinhibition.”

Setting: “During high-frequency (tetanic) stimulation, somatic synaptic inhibition is suppressed by endocannabinoids. We find that Aβ prevents this endocannabinoid-mediated disinhibition, thus leaving synaptic inhibition more intact during tetanic stimulation.”

Science: “This intact inhibition opposes the normal depolarization of hippocampal pyramidal neurons that occurs during tetanus, thus opposing the induction of synaptic plasticity. Thus, a pathway through which Aβ can act to modulate neural activity is identified, relevant to learning and memory and how it may mediate aspects of the cognitive decline seen in Alzheimer's disease.”
β-Amyloid Inhibits E-S Potentiation through Suppression of Cannabinoid Receptor 1-Dependent Synaptic Disinhibition.
Orr AL, Hanson JE, Li D, Klotz A, Wright S, Schenk D, Seubert P, Madison DV.
Neuron. 2014 Jun 18;82(6):1334-45. doi: 10.1016/j.neuron.2014.04.039.
PMID: 24945775 [PubMed - in process]
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II. CS Oncology Signaling Unveiled: Evidence of Previously Unknown Platforms

Set: “The G protein-coupled receptors CB2 (CB2R) and GPR55 are overexpressed in cancer cells and human tumors. As a modulation of GPR55 activity by cannabinoids has been suggested, we analyzed whether this receptor participates in cannabinoid effects on cancer cells.”

Setting: “Here, we show that CB2R and GPR55 form heteromers in cancer cells, that these structures possess unique signaling properties, and that modulation of these heteromers can modify the antitumoral activity of cannabinoids in vivo.”

Science: “These findings unveil the existence of previously unknown signaling platforms that help explain the complex behavior of cannabinoids and may constitute new targets for therapeutic intervention in oncology.”
Targeting CB2-GPR55 Receptor Heteromers Modulates Cancer Cell Signaling.
Moreno E, Andradas C, Medrano M, Caffarel MM, Pérez-Gómez E, Blasco-Benito S, Gómez-Cañas M, Pazos MR, Irving AJ, Lluís C, Canela EI, Fernández-Ruiz J, Guzmán M, McCormick PJ, Sánchez C.
J Biol Chem. 2014 Jun 18. pii: jbc.M114.561761. [Epub ahead of print]
PMID: 24942731 [PubMed - as supplied by publisher] Free Article
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Video: Homeostasis 1, Physiological Principles ~ Dr. John Campbell

Posted by Bryan W. Brickner

War Cry Heal Union: The series (3rd of 10)

The United States is the Other today: Hannah Arendt cast in lead.

The painting of the assassination on June 28th 1914 portrays the heir to the Austrian-Hungarian Empire, Archduke Franz Ferdinand, and his wife Sophie being shot by 19 year-old Gavrilo Princip on a Sarajevo street corner.

The painting encapsulates an era of endemic militancy that fueled 1914 Europe and the catastrophe called World War I: fired shots, stunned chauffer, blank-wall, sabered rider, plumed officer, soldiers sashed, lurched and rifled, and a grounded headless hat.

Those times and today’s circumstances are nicely summed in the Wall Street Journal article, Scars of World War I Linger in Europe on Eve of Centennial. The author notes war’s carnage is never simple (or just) and 15 million dead also means 15 million destroyed homes, families and relationships. Lyrically apropos war is not: it thrives and embellishes disharmonies in order to live off the discord. War needs Others, that is clear. One take home lesson for today is that Peace needs Others just as much (maybe more).

Hannah Arendt, who found citizenship in America, is today’s representative example of the Other. Born in 1906 in one of the Empires about to fall (the German one), Arendt “moved” to the United States running from the Nazis and their ideas of Otherness: Arendt became a US citizen.

Representative Arendt? ~ Yes, it has a nice sound to it.

Citizens like Hannah Arendt in Congress representing a district of thirty thousand as our constitution commands? That too sounds nice. Geez ~ she wrote The Origins of Totalitarianism (1951) and The Human Condition (1958), and would have added much to any mid-century policy debate.

Maybe that’s one of our political bad habits we can grow away from, this always thinking it can’t matter who’s representing us.

We will learn the constitutional lessons of representing We the People, or, like the generations before us, some will survive the carnage and do what the Others always do – start building again.

Peace Others.

Bryan W. Brickner
Ew Publishing

War Cry Heal Union: The series (2 of 10)

I came upon today’s story by happenstance ~ much like the citizens who fought and died there.

In 2011 I visited Marietta Georgia and its National Cemetery. Most of the federal soldiers interned there are from 1864 and Sherman’s campaign to capture Atlanta; many fought in the Kennesaw Mountain battle and, specifically, at Cheatham Hill, also known as “Dead Angle,” and the map indicated a monument to Illinois ~ my home state.

The above photo’s perspective is from the top of Cheatham Hill; on the morning of battle, 27 June 1864, this would have been the Tennessee/Confederate line (the sun is to the northwest ~ an afternoon photo). The Federals were in the forest background with the hill to their front. They were mostly citizen-soldiers from Illinois, Indiana and Ohio in infantry regiments; they would soon rush across that field and up the hill to assault the Tennesseans.

What are a citizen-soldier’s sentiments at such moments? Prayer for sure … and probably shouts of ~ “There’s Hell boys!” or “Here comes Hell boys!” ~ depending on one’s perspective.

At 9:00 a.m. Federal skirmishers and a human wave of blue moved out of the forest and up the hill to assault the Confederate breastworks …

Because we can, let’s pause the assault for a moment and give some thought to the carnage that is about to take place; let’s even ponder such things as: why are citizens from Illinois, Indiana and Ohio assaulting Tennesseans on a Georgia hilltop? Or, more clearly, what part of our Constitution failed: Madison’s theory of representing We the People according to our numbers or the lack thereof?

Since we just paused war for a moment, we might as well keep going and call in a couple of founding spirits ~ Benjamin Franklin (anti-slaver) and James Madison (slaver) ~ for an imagined-yet-real constitutional dialogue:

Ben Franklin: James, they didn’t use the blueprint and representing We the People at the ratio of one Representative for every thirty Thousand.

James Madison: I know Benjamin ~ they got caught-up in slavery and the three-fifths clause.

Franklin: By 1860, the last Census before the Civil War, the representation ratio had risen to 119,000 citizens per Representative [Brickner: Article the First page 100]. Obviously, that is un-representation and not our design for We the people of the United States Republic.

Madison: I know ~ it’s Plato’s Republic …

Franklin: … Which doesn’t work.

Madison: They’ll learn ~ we had too as well.

Yes, We the People still hold the Unrepresented “not yet” card. It’s the Constitution’s Article 1 Section 2 Clause 3: “The Number of Representatives shall not exceed one for every thirty Thousand, but each State shall have at Least one Representative.”

Okay, back to the assault. If the Illinois, Indiana and Ohio citizens have to charge (orders you know) and the Tennesseans, under the command of Benjamin Franklin Cheatham and Patrick R. Cleburne, have to obey orders and hold the line … you can see what’s about to happen. There’s no room for maneuver ~ nowhere to go. The Illinois citizens want the hill so they can take Atlanta (only 20 miles away) and go back home; the Tennesseans want the hill to save Atlanta and go back to a home.

So the assault happens … now the photo looks different; suddenly it’s a nice picture of a citizen-killing zone. Soldiers often say similar things ~ how peaceful Nature can be and feel … and then Hell breaks out.

On 27 June 1914, the 50th anniversary of the battle, the Illinois Monument was dedicated on Cheatham Hill; it’s on the spot where 15 Illinois Infantry Regiments fought and dug in: they couldn’t dislodge the Tennesseans and they couldn’t retreat down the hill without suffering terrible casualties; “Dig-in” was the command and dig they did. The Battle of Kennesaw Mountain 150th Anniversary group recently highlighted a 100 year-old article from The Marietta Journal and Courier written in preparation for the monument’s unveiling a century ago; the events at Dead Angle are honored:

“Cheatham’s Hill was one of the memorable battles of the war. The Federals and Confederates faced each other there for six days and six nights, their lines being so close that the soldiers were in ordinary speaking distance. They fought from the 27th of June to the 3rd of July, 1864 and on the last day the Confederates withdrew because of a flank movement. It was well they did so, as the Federals had constructed a tunnel far into the hill, had placed explosives under the Confederate position and intended to touch off the mine on the 4th of July.”

The tunnel is still visible today … and war continues its flanking movement.

The day after the monument's dedication, 28 June 1914, the heir to the Austrian throne is assassinated by an “unrepresented” subject of the empire (an anarchist); this singular event, seemingly a world away from Marietta and Cheatham Hill, would lead the European Empires into World War I ~ a war that would soon touch Georgia and all the other states in the Union.

Perhaps stated in terms of We the People of Europe, WW I (like our Civil War) was caused by a failure to represent ~ account for ~ The Unrepresented.

We’ll pick-up there tomorrow with Empires Crumble and Others Build, part 3 in the War Cry Heal Union series.

Video:
Cheatham Hill

Bryan W. Brickner
Ew Publishing

Serotonin activation was our topic on 19 April 2014; it’s serotonin life sciences today with the precursor 5-HTP (5-hydroxytryptophan) in highlight. 

Below are four (brief) science stories from the National Institutes of Health (PubMed). Shortened titles should suffice to suggest the main themes: Therapeutic 5-HTP, Hot Flash and Breast Cancer Reduction, Irritable Bowels, and Morphine’s Efficacy. The links and quotes are from PubMed (1998-2014).

Healthy Solstice Everyone!
~.~
Therapeutic 5-HTP Has Been Shown … (1998)
“5-Hydroxytryptophan (5-HTP) is the intermediate metabolite of the essential amino acid L-tryptophan (LT) in the biosynthesis of serotonin. Intestinal absorption of 5-HTP does not require the presence of a transport molecule, and is not affected by the presence of other amino acids; therefore it may be taken with meals without reducing its effectiveness. … Therapeutic administration of 5-HTP has been shown to be effective in treating a wide variety of conditions, including depression, fibromyalgia, binge eating associated with obesity, chronic headaches, and insomnia.”
5-Hydroxytryptophan: a clinically-effective serotonin precursor.
Birdsall TC.
Altern Med Rev. 1998 Aug;3(4):271-80. Review.
PMID: 9727088 [PubMed - indexed for MEDLINE] Free Article
Related citations

Hot Flash (and Breast Cancer) Reduction: a hypothesis (2005)
“This would be particularly desirable for menopausal women with breast cancer or with risks of breast cancer. This article discusses the background information on hot flashes, SSRIs, tryptophan, and 5HTP, and possible clinical application of 5HTP for menopausal women with breast cancer risk.”
The potential of 5-hydryoxytryptophan for hot flash reduction: a hypothesis.
Curcio JJ, Kim LS, Wollner D, Pockaj BA.
Altern Med Rev. 2005 Sep;10(3):216-21.
PMID: 16164376 [PubMed - indexed for MEDLINE] Free Article
Related citations

A Serotonin-mediated Mechanism in Bowels (2014)
“Oral 5-HTP induced alterations in mucosal 5-HT metabolism. In healthy controls, a reinforcement of the intestinal barrier was seen whereas such reaction was absent in IBS [irritable bowel syndrome] patients. This could indicate the presence of a serotonin-mediated mechanism aimed to reinforce intestinal barrier function, which seems to dysfunction in IBS patients.”
Serotonergic reinforcement of intestinal barrier function is impaired in irritable bowel syndrome.
Keszthelyi D, Troost FJ, Jonkers DM, van Eijk HM, Lindsey PJ, Dekker J, Buurman WA, Masclee AA.
Aliment Pharmacol Ther. 2014 Jun 18. doi: 10.1111/apt.12842. [Epub ahead of print]
PMID: 24943480 [PubMed - as supplied by publisher]
Related citations

Serotonin and Morphine’s Efficacy (2014)
“Systemic administration of morphine increases 5-HT levels in the spinal cord, and the increase in 5-HT contributes to morphine-induced analgesia in the normal state but attenuates that in neuropathic pain through spinal 5-HT3 receptors. The plasticity of the descending serotonergic system may contribute to the reduced efficacy of systemic morphine in neuropathic pain.”
Peripheral Nerve Injury Reduces Analgesic Effects of Systemic Morphine via Spinal 5-Hydroxytryptamine 3 Receptors.
Kimura M, Obata H, Saito S.
Anesthesiology. 2014 Jun 2. [Epub ahead of print]
PMID: 24887968 [PubMed - as supplied by publisher]
Related citations

VIDEO:
5HTP benefit and side effects of 5htp, dosage, anxiety, weight loss, sleep

BONUS VIDEO: Serotonin/Binaural Beats
5-HTP secretion for happiness binaural beats, intensity WARNING

~ Posted by Bryan W. Brickner ~

War Cry Heal Union: The series (1 of 10)

Aesop ~ of Aesop’s Fables fame ~ was a slave.

Like the last slaves freed in the United States on 19 June 1865, Juneteenth, Aesop too had his freedom day. In his life he passed from owner to owner as a slave until his intellect won his freedom. Plutarch, a priest at Delphi, reports that after gaining his freedom Aesop was employed by King Croesus of Lydia. The king sent Aesop to Delphi to negotiate terms regarding Apollo’s oracle. The people of Delphi didn’t like Aesop’s talk ~ his logic ~ and took matters into their own hands. Plutarch reports the people of Delphi killed the famed-fabalist by forcing him over a cliff … more on Aesop in a moment.

A fable is a story with animals talking; civilization is a story with the animal human talking. The civilization story always begins with the same premise: things were once bad and then changed and people (tribes, clans, and nations) called it good; and always within the story of civilization, providing a seemingly visceral and vital role, is the slave. Essentially, civilization was designed by many and built by slaves.

Slavery is usurpation and usurpation is slavery. A citizen without rights is a slave; similar to a subject, they lack agency power to appeal to a higher law than the current sovereign. A (rightful) citizen, however, has agency to appeal to power in the form of written constitutions.

On April 9th, Usurpation Day 2014, it was noted that slavery is the shadow of usurpation (rights taken without right) and couldn’t be dismissed from Greek or American history. Simply, slavery cannot be edited out of the fable known as the United States of America: as part of our heritage it is part of us. To wit: in telling America’s story of slavery, let’s tell it through symbols. There is a version of the Greek Athena atop our acropolis, the US Capitol; her name is Freedom and she was designed with America in mind. That being so, it’s not ironic she was born in 1863 in the middle of our Civil War and great citizenship debacle. It’s also not ironic the foreman (wage-earner) went on strike while building Freedom and would not complete the bronze statue: slaves completed Freedom.

Oh yeah ~ back to Aesop the slave. There are lots of thoughts on where he came from; some say a northern Dorian settlement on the Black Sea, some Phrygia in modern-day Turkey, and even others Ethiopia; most likely it looks like he hailed from the Samos and Miletus area on the Mediterranean coast of Turkey. This eternal debate is easily solved by genetic fiat: according to DNA, we’re all out of Africa.

Ah, there we are ~ Aesop the human.

Bonus Video
Aesop’s The Lion & The Mouse

Next up in the series War Cry Heal Union:
27 June 2014: War Cry ~ Cheatham’s Hill, 27 June 1864.

Posted by Bryan W. Brickner