Underwater banquet!

Cabal, is a term defined in the Merriam-Webster dictionary, as the contrived scheme of a group of persons secretly united in a plot (as to overturn a government, for example). 

But, if you talk in terms of Biology, cabals are also sets of synergistic venom peptides essential for the capture of prey. One animal venom can be a complex mixture of 10-200+ short chains of amino acids linked by amide bonds (peptides), working in a concerted manner to modulate physiological function, with very potent and precise molecular targets1.

Cone snail, a small venomous marine mollusk that hunts fish and worms, has ~850 species identified, with each expressing many thousands of unique peptides that selectively target a diverse range of voltage- and ligand-gated ion-channels, transporters and G-protein couple receptors2

These tiny wonders of nature have the ability to switch between predatory and defensive venom regimes.

For example, if they just want to stunt a predator causing a flaccid paralysis, they will produce venom that has high levels of muscle blockers (motor cabal), and that inhibit sodium channels and nicotinic acetylcholine receptors. 

But, if in the mean time, they change their minds and intend to eat the prey, they use a combination of peptides that cause a rigid paralysis. This lightning-strike cabal, has excitatory peptides that inhibit potassium channels and delay inactivation of sodium channels, causing the prey to lie “dead” until it is happily digested in an underwater banquet!

Cone snail
Cone snail

Reference:

1.         Angell Y, Holford M and Moos WH. Building on Success: A Bright Future for Peptide Therapeutics. Protein Pept Lett. 2018;25:1044-1050.

2.         Himaya SWA, Mari F and Lewis RJ. Accelerated proteomic visualization of individual predatory venoms of Conus purpurascens reveals separately evolved predation-evoked venom cabals. Sci Rep. 2018;8:330.

Alcohol or Melatonin?

In 1958, in the Yale laboratories, A.B. Lerner and colleagues isolated melatonin from the pineal gland of bovines1. They were surprised that after 40 years of research they had finally found the active component that lightened the frog skin color, inhibiting the darkening effect of the Melanocyte Stimulating Hormone (MSH); hence the name, Melatonin1. Disappointingly, the skin lightening properties of melatonin could not be further demonstrated and the project was abandoned2. In the 90’s, melatonin got back on the coolness charts of science, with Reppert and Weaver calling it “Madness” in a Cell article in 1995. During this time, it was discovered its function in regulating the seasonal and circadian rhythms3, the presence of its specific G-coupled receptors in different tissues4; and, its antioxidant properties5. Since then, melatonin has been widely studied and continues to wonder over its broad range of therapeutic effects. From helping on jet-lag relief6, with insomnia7, being an anti-aging agent8, neuro-protective9, and also, improving cardiovascular diseases10: melatonin-madness continues until today.

Melatonin is widely accepted as a nutritional supplement being prescribed for sleep regulation in jetlag and adult sleep disorders; but in 2011 the U.S.A Food and Drug Administration (FDA), issued a warning to a company selling “relaxation brownies”, stating that the synthetic melatonin used in them hasn’t been proved safe as a food additive. Most commercial products are offered at dosages of 1-3mg of melatonin, which causes a spike of melatonin in the blood, reaching much higher levels than those that are naturally produced in the body somewhere between 50 and 200 pg/mL.

But, why use synthetic melatonin when this molecule is present in appetizing plants, nuts, fruits, meats, beverages and other foods11? The levels of melatonin in foods are much lower than those given as a nutritional supplement; but it has been proven that eating such foods drastically increases the circulating melatonin levels in the range of physiological concentrations, which peak at nighttime12, 13.

Maldonado and colleagues have shown that different types of beers are rich in melatonin; and, the more melatonin they have got, the greater is their alcoholic degree14. No wonder some people claim that beer makes them sleepy. But, Molfino15and I have made the same question: if the volunteers were sleepy, was it because of the melatonin or an alcoholic-mediated effect? So far, there’s still no answer to that question.

But, Garcia-Moreno and Maldonado’s group have shown, that Barley, which is malted and grounded in the early brewing process, and Yeast, during the second fermentation, are the largest contributors to the enrichment of beer with melatonin16. From this, we can deduct that not only beer has melatonin, but whatever drink where fermentation occurs, will also be rich in it. Logically, wine was also found to be a rich source of the Madness-molecule. In fact, beer has around 0,09 ng/mL while wine is up to 129,5 ng/mL11. And again, Rodriguez-Naranjo and colleagues showed that melatonin is formed during the alcoholic fermentation, because it is absent in the grapes and musts17.

 

References:

    1. Lerner ABC, J.D.; Takahashi, Y.; Lee, T.H.; Mori, W. Isolation of melatonin, a pineal factor that lightens melanocytes. J Am Chem Soc. 1958;80:2587.
    2. Jiki Z, Lecour S and Nduhirabandi F. Cardiovascular Benefits of Dietary Melatonin: A Myth or a Reality? Front Physiol. 2018;9:528.
    3. Arendt J. Melatonin and the pineal gland: influence on mammalian seasonal and circadian physiology. Rev Reprod. 1998;3:13-22.
    4. Reppert SM, Godson C, Mahle CD, Weaver DR, Slaugenhaupt SA and Gusella JF. Molecular characterization of a second melatonin receptor expressed in human retina and brain: the Mel1b melatonin receptor. Proc Natl Acad Sci U S A. 1995;92:8734-8.
    5. Hardeland R, Reiter RJ, Poeggeler B and Tan DX. The significance of the metabolism of the neurohormone melatonin: antioxidative protection and formation of bioactive substances. Neurosci Biobehav Rev. 1993;17:347-57.
    6. Sletten TL, Magee M, Murray JM, Gordon CJ, Lovato N, Kennaway DJ, Gwini SM, Bartlett DJ, Lockley SW, Lack LC, Grunstein RR, Rajaratnam SMW and Delayed Sleep on Melatonin Study G. Efficacy of melatonin with behavioural sleep-wake scheduling for delayed sleep-wake phase disorder: A double-blind, randomised clinical trial. PLoS Med. 2018;15:e1002587.
    7. Riemann D, Baglioni C, Bassetti C, Bjorvatn B, Dolenc Groselj L, Ellis JG, Espie CA, Garcia-Borreguero D, Gjerstad M, Goncalves M, Hertenstein E, Jansson-Frojmark M, Jennum PJ, Leger D, Nissen C, Parrino L, Paunio T, Pevernagie D, Verbraecken J, Weess HG, Wichniak A, Zavalko I, Arnardottir ES, Deleanu OC, Strazisar B, Zoetmulder M and Spiegelhalder K. European guideline for the diagnosis and treatment of insomnia. J Sleep Res. 2017;26:675-700.
    8. Day D, Burgess CM and Kircik LH. Assessing the Potential Role for Topical Melatonin in an Antiaging Skin Regimen. J Drugs Dermatol. 2018;17:966-969.
    9. Zhao Z, Lu C, Li T, Wang W, Ye W, Zeng R, Ni L, Lai Z, Wang X and Liu C. The protective effect of melatonin on brain ischemia and reperfusion in rats and humans: in vivo assessment and a randomized controlled trial. J Pineal Res. 2018:e12521.
    10. Liu Y, Li LN, Guo S, Zhao XY, Liu YZ, Liang C, Tu S, Wang D, Li L, Dong JZ, Gao L and Yang HB. Melatonin improves cardiac function in a mouse model of heart failure with preserved ejection fraction. Redox Biol. 2018;18:211-221.
    11. Meng X, Li Y, Li S, Zhou Y, Gan RY, Xu DP and Li HB. Dietary Sources and Bioactivities of Melatonin. Nutrients. 2017;9.
    12. Sae-Teaw M, Johns J, Johns NP and Subongkot S. Serum melatonin levels and antioxidant capacities after consumption of pineapple, orange, or banana by healthy male volunteers. J Pineal Res. 2013;55:58-64.
    13. Reiter RJ, Manchester LC and Tan DX. Melatonin in walnuts: influence on levels of melatonin and total antioxidant capacity of blood. Nutrition. 2005;21:920-4.
    14. Maldonado MD, Moreno H and Calvo JR. Melatonin present in beer contributes to increase the levels of melatonin and antioxidant capacity of the human serum. Clin Nutr. 2009;28:188-91.
    15. Molfino A, Laviano A and Rossi Fanelli F. Sleep-inducing effect of beer: a melatonin- or alcohol-mediated effect? Clin Nutr. 2010;29:272.
    16. Garcia-Moreno H, Calvo JR and Maldonado MD. High levels of melatonin generated during the brewing process. J Pineal Res. 2013;55:26-30.
    17. Rodriguez-Naranjo MI, Gil-Izquierdo A, Troncoso AM, Cantos-Villar E and Garcia-Parrilla MC. Melatonin is synthesised by yeast during alcoholic fermentation in wines. Food Chem. 2011;126:1608-13.

 

 

Evolution and melatonin

Since life has emerged on Earth, 3.7. billion years ago, the rising and setting of the Sun has been a constant. Whether it was light or dark, it was day or night. Humans, and all other organisms, have evolved with this imposed biological rhythm; and, human physiology was determined by the light/dark cycle.

Every cell in our bodies exhibits a circadian rhythm, a 24h-cycle synchronized to a light/dark pattern. But, how do cells deep inside in our bodies know when it’s dark outside? The answer to that question is Melatonin (N-acetyl-5-methoxytryptamine), the messenger from our brain to communicate to our cells that it is dark. The master clock of the body, the Suprachiasmatic Nucleus (SCN) receives darkness information from the retina and sends it to the brain. From there it provides an input to the Pineal Gland, to produce melatonin. Melatonin secretion increases in the evening, and is stimulated by darkness; whereas light rapidly suppresses melatonin production.

Melatonin is not unique to humans. It is spread through out the animal kingdom, plants, bacteria, and even unicellular organisms have it. There’s no species that has been identified so far that does not contain Melatonin. This expresses the importance of this molecule to life.