Sleeping, obesity and

metabolic balanceImportance of proper sleeping much higher than just having more

oxygen for fat burning during the night

MUDr. Dana Maňasková

Sleep duration and all-cause mortality: a systematic review and meta-analysis of prospective studies. Cappuccio FP, D'Elia L, Strazzullo P, Miller MA. Sleep. 2010 May;33(5):585-92.http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2864873/

• Systematic search of publications using MEDLINE (1966-2009), EMBASE (from 1980), the Cochrane Library, and manual searches without language restrictions

• Included studies: prospective, follow-up >3 years, duration of sleep at baseline, and all-cause mortality prospectively

• 1,382,999 male and female participants• Follow-up range 4 to 25 years, and 112,566 deaths• Sleep duration was assessed by questionnaire and outcome through death certification. • Short duration of sleep was associated with a greater risk of death (RR: 1.12; 95% CI 1.06 to 1.18; P <

0. 01)• Short sleepers (commonly < 7 h per night, often < 5 h per night) have a 12% greater risk of dying [1]

• Long duration of sleep was also associated with a greater risk of death (1.30; [1.22 to 1.38]; P < 0.0001)

• Long sleepers (commonly > 8 or 9 h per night) a 30% greater risk of dying [1]

• than those sleeping 7 to 8 h per night [1]

• Effect was stronger in older cohorts, sleep of 10 h an more h per night, in follow-ups not longer than 19 years, and in East Asian cohorts.

Meta-analysis of short sleep duration and obesity in children and adults.

Cappuccio FP1, Taggart FM, Kandala NB, Currie A, Peile E, Stranges S, Miller MA.Sleep. 2008 May;31(5):619-26.http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2398753/

Children from 2 to 20 years

• 12 studies from the published articles were included in the pooled analysis.

• 30,002 participants from France, Tunisia, Japan, Germany, USA, Brazil, Portugal, United Kingdom, Canada, Taiwan, and China

• Significant association between short duration of sleep and obesity. • The pooled OR was 1.89 (1.46 to 2.43)

Adults from 15 to 102 years

• 17 studies included 604,509 participants from Spain, Japan, USA, France, Switzerland, Sweden, Brazil, Finland, Norway, Canada, Hong Kong, and United Kingdom

• Significant association between short duration of sleep and obesity. • The pooled OR was 1.55 (1.43 to 1.68)

Sweet/Dessert foods are more appealing to adolescents after sleep restriction.Simon SL, Field J, Miller LE, DiFrancesco M, Beebe DW. PLoS One. 2015 Feb 23;10(2):e0115434. doi: 10.1371/journal.pone.0115434. eCollection 2015.http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4338308/

• 31 typically-developing adolescents aged 14–17 years• The 3-week protocol consisted of:

• a baseline week• randomly 2 groups:

• 5 consecutive nights of SR (6.5 hours in bed) • 5 nights healthy sleep duration (HS; 10 hours in bed)

• a 2-night wash-out period• 5-night cross-over intervention in that 2 groups

• Sleep was monitored via actigraphy• Every morning teens rated their hunger, underwent a 24-hour diet recall interview, and rated the

appeal of a series of pictures of sweet/dessert foods (e.g., ice cream, candy) and non-sweets (meat, eggs, fruits, vegetables)

• Results:• Intake of overall calories was 11% higher • Consumption of sweet/dessert servings was 52% greater during SR than HS

Duration of sleep

Short sleep is associated with:• higher total mortality, poor self-rated health [1]

• hypertension, cardiovascular disease [1]

• metabolic syndrome [5], type 2 diabetes [1, 4]

• obesity in both children and adults and respiratory disorders [1]

• Microarousals during sleep were the best predictors of increased morning cortisol levels and hyperlipidemia [7]

• reduced cognitive function [5]

• unhappiness and symptoms of depression, suicidal ideation and attempts [5]

• burnout syndrome, a syndrome characterized by emotional exhaustion, depersonalization and low personal accomplishment [7]

People reporting consistently sleeping 5 hours or less per night should be regarded as a higher risk group for all-cause mortality. [1]

2007 USA: More than 30% of adult men and women between the ages of 30 and 64 years report sleeping less than 6 hours per night. Has occurred over the same time period as the increase in the prevalence of obesity and diabetes. [4]

Long duration of sleep is associated with:• all different comorbidities and poor general health [1] • depressive symptoms and using antidepressants / sedatives [5] • low socioeconomic status and unemployment [1] • low level of physical activity [1] • undiagnosed health conditions [1] • cancer-related fatigue [1] • recent treatment for cancer [5] • increased total cholesterol [5] • higher total/HDL cholesterol ratio among the elderly [5] • having had a heart attack or angina [5] • poorer cognitive function [5] • cardiovascular mortality and greater carotid intimal medial

thickness [5, 6] • esophageal cancer, pancreatic cancer, increased risk of

urothelial cancer and non-Hodgkins lymphoma in women [6] • decreased risk of prostate cancer [6] • sleep apnea - compensating for the large degree of

fragmentation associated with the disorder by spending more time asleep or excessive amounts of time in bed [6]

Sleeping 9 h or more per night may represent a useful diagnostic tool for detecting subclinical or undiagnosed co-morbidity. [1]

Longer duration as compensation

of poor sleep quality!

Short sleep side effects:• EEG and hormonal changes after acute total and recurrent partial sleep deprivation [4] = depression, emotional lability etc...

• Decrease in cerebral glucose metabolism (PET studies) [4]

• Leptin low, ghrelin high [1]• Increase appetite, caloric intake, reduce energy expenditure, facilitate obesity and impaired glycemic control [1] = problems to keep on any diet and

no real appetite to move

• Sympathetic tone increased [4], elevated catecholamine secretion [6]• Short sleep = stressor in the acute and chronic setting [6] = lead to disease, neuronal damage, earlier aging [6]• Elevated heart rate variability [4]

• Increased cortisol secretion [1] = bad weight reduction... • Insulin resistance etc. = strong hungers at the beginning of the low saccharide diets

• ivGTT protocol: after 5 days of restricted sleep in young people is similar to those in older adults with impaired glucose tolerance [4]• Glycaemia higher after sleep restriction than after sleep recovery, insulin secretion non-significantly higher [4]• HOMA curve for the breakfast meal more than 50% higher after 6 days of sleep restriction [4]• Insulin resistance may develop progressively with increasing exposure to partial sleep loss [4]• Accelerated by sleep-disordered breathing (SDB) (independent risk factor for insulin resistance) [4]

• Altered growth hormone metabolism [1] • GH secretion peaks drop to baseline during recurrent sleep restriction [4] = harder to grow muscles and regenerate

• TSH• total sleep deprivation = TSH over 200% [4] • 3-5 days of partial sleep deprivation = TSH markedly depressed [4] = low heat production, lower energy burning and bad weight reduction

• Lack of melatonin [hormone of youth, strong antioxidant !!!] = accelerated ageing !!!• Low grade inflammation - activated during short sleep [1] • Increased levels of inflammatory cytokines and low grade inflammation [4] esp.: interleukin-6 and tumor necrosis factor alpha [6] • Elevated CRP concentrations have been reported in healthy subjects exposed to total and partial short-term sleep deprivation [6]• Elevations of CRP [can bind leptin and cause it's lower function] [4] = higher taste to eat

Melatonine [N-acetyl-5- methoxytryptamine] - key substance of regeneration

Quality of sleep and morning alertnessMetabolic adaptations - adipose and muscle tissues to physical training [16]Broad-spectrum antioxidant • Scavenges: hydrogen peroxide, hydroxyl radical, nitric oxide, peroxynitrite anion, hypochlorous acid, singlet oxygen, superoxide anion,

peroxyl radical and oxygen radicals [8] • Chain of metabolites effective free radical scavengers [8]

• Elevate concentrations of antioxidating enzymes: superoxid dismutase, glutation peroxidase, glutation reductase and inhibit prooxidative enzymes [10]

• Form several stable end-products which are excreted in the urine [8] = non toxic Antiinflammatory functions • Down-regulates 5-lipooxygenase in B lymphocytes [12]• AFMK (metabolite] inhibits IL-6, adhesion molecules [12], TNF alfa and IL-8 formation caused by LPS in neutrophils and mononuclear

cells. [10] • AFMK and AMK selectively inhibit gene expression of COX-2 [10] Anticancer effects - different pathways• Direct augmentation of NK cells [13 ], stimulates production of IL-2, IL-6, IL-12, and IFN-gamma [13]• Suppress EGFR/MAPK mitogen activity (blocks linoleic acid uptake by tumor cells and its conversion)Neurogenesis, neuroprotection and neuromodulation [12, 13]• Inhibits NOS and dopamine release [12 ], potentiates GABA in CNS [12 ], modulates serotonin receptors, potentiates opioid analgesic

[12], increases REM sleep continuity (dreams), increase CoQ9 in brain mitochondria(precursor to CoQ10) Immunomodulation - infection resistance [12] Intervening in lipid metabolism [12]

Melatonin for every cellIn all living organisms, also vegetables, fruits and herbs • Flowers and seeds (reproductive organs vulnerable to oxidative insults) [8] • In ancient photosynthetic prokaryotes as receptor-independent free radical scavenger [10] • Better growing of the corps [functional food - transgenic rice [17]] Substantial amounts found in: • Tissues exposed to high stress: gut, bile, skin - keratinocytes • Organs with high oxygen consumption: brain, 3rd ventricular fluid, bone marrow [10] Extrapineal production of melatonin ! [no light/dark regulation]: • Retina, ciliary body, lens, Harderian gland, brain, thymus, airway epithelium, bone marrow, gut [two orders greater than

that produced by the pineal gland], ovary, testicle, placenta, lymphocytes, skin [10] • Intracellular melatonin much higher than that of the glutathione level in cells !!! [10] Mitochondria contain high levels of melatonin • Strongly inhibit cytochrome C release from the mitochondria • Suppress the activity of caspase 3 • Stabilizes mitochondrial membrane • part of the neuroprotection in oxygen–glucose–serum deprivation [10] • Elevate ATP production by lowering electron leakage and inhibiting opening of the mitochondrial permeability transition

pores [10] • = Strong protection of mitochondria agg. ox. stress

Proved positive effects of melatonin as an adjuvant therapy in:

• Macular degeneration, glaucoma, gastric ulcer, gastric reflux, irritable bowel syndrome, hemodialysis [11], Smith-Magenis syndrome, Sunburn prevention

• Arterial hypertension, diabetes, androgenetic hair loss• Side effects of chemotherapy and radiation in cancer patients !!

• Anti-aromatase effect of resveratrol and melatonin on hormonal positive breast cancer cells co-cultured with breast adipose fibroblasts.

• Melatonin sensitizes human breast cancer cells to ionizing radiation by downregulating proteins involved in double-strand DNA break repair.

• Sleep deterioration, depression, premenstrual tension and postmenopausal hot flashes and irritability [14]• Agomelatine - new medicament for major depression and bipolar affective disorder

• Alzheimer and other dementias, Parkinson disease, multiple sclerosis, stroke, brain ischemia/reperfusion, traumatic CNS injuries etc. !!! [12], Tinnitus

• Anesthetic procedures [9], some of the glucocorticoid indications [melatonin allows to use lower doses of glucocorticoids = less side effects] [12 ]

• Malaria [10] and other inflammations [12], Septic shock and associated multi organ failure in critically ill patients [13] • Premature infants with severe respiratory distress syndrome and septic shock [13]

• "Oral pulsatile system for potential delivery of melatonin to pediatric population" [2014] [ 20]

Melatonin reduces the severity of disease conditions where free radicals are implicatedAccording to the: • strong antioxidant activity • up to now not known toxic effects of recommended melatonin doses / very rare effects of higher doses• not known side effects of normal duration sleep= PROFIT CAN BE EXPECTED IN EVERY ILNESS AND SITUATION - also in reducing weight !!! [my message]

The most complex therapy of the whole body ever known:

During the day: have fun

in the Sun and during the night:

is the best to sleep and have a rest.

Lower levels of melatonine:Lower production: block of enzymes / lack of cofactors / substrates• Low tryptophan [basic precursor] = low serotonin = also low

melatonin !!!• <300 kcal per day 2-7 days reduces melatonin in the blood by about

20% • Alcohol - dose dependent - decreases TRP and glucose in blood

• 5-hydroxylation • Decarboxylation - necessary coenzyme vitamin B6 (= serotonin)• N-acetylation by arylalkylamin N-acetyltransferase [AA-NAT] - suppressed

by light• Chemical pinealectomy (constant light exposure) [10] • Even a small light exposition [esp. blue light 460-480 nm] at night

stops melatonin secretion !!!• Light from small self-luminous displays [23] • Exposure to room light before Bedtime suppresses melatonin

onset and shortens melatonin duration [24] • Stimulated by adenosin (increases cAMP levels) - blocked by

caffeine, theobromine, xantine• Low Zinc and magnesium - bind to AANAT [activating and

increasing it's affinity to bind serotonin]• O-methylation by hydroxyindol-O metyl transferase = cooperate

with folate, B6, B12 pathway (methylation)• Folate, magnesium and zinc deficiencies have been linked with lower

melatonin levels in rodents

Other causes of lower secretion • Epigallocatechin Gallate (EGCG) - Green Tea -

antagonism • High lesions of cervical spinal cord - miss of

night melatonin peak, some brain tumors • Adrenergic agonists/antagonists

beta1 adrenergic blocators, alpha2 receptors - clonidine

• Stronger electromagnetic field near the head !!!

• Increased level of insuline, proinfalmmatory cytokines, cortisol etc.

• Glucose, sodium, ethanol, caffeine - phase-shifting circadian rhythms

• Older people [pineal calcification etc.] Higher liver metabolism - induction of CYP1A1, CYP1A2, [CYP2C19]: • Cigarette smoking, Carbamazepine, Rifampicin • Consumption higher than synthesis - by

scavenging free radicals = low levels • Intensive oxidative stress [10] -toxic

environmental contaminants [10] etc.

Higher levels of melatonin: Higher production • Catecholamine elevation at the synapsis: • MAO inhibitors and tricyclic

antidepressants • Some brain tumors • Low intensity stressors such as dietary

restriction and exercise, cold, UV-B irradiation etc. activate AA-NAT [10]

• Glucocorticoids • upregulate stress-responsive

transcriptional factor AP1 = upregulate gene expression for melatonin synthesis

• Sources of: tryptophan, serotonin, B6, glycine, phytoestrogenes, folate,...

Higher secretion • Soon after the onset of darkness, peaks

at 0-2-4 am and diminishes during rest of the night

Lower liver and extrahepatal metabolism / lower consumption by oxidative stress • In the elderly • Liver cirrhosis - significantly increased melatonin during daylight

hours • Fluvoxamine - inhibits CYP1A2 and CYP2C19 - [17x increase in blood

[10]] • 5- or 8-methoxypsoralen (5 and 8-MOP) • Cimetidine - CYP2D inhibitor • Estrogens, oral contraceptives - inhibition of CYP1A1 and CYP1A2 • Quinolones • melatonin taken orally with 200 mg caffeine [large cup of coffee] -

bioavailability increases 140% - both are substrates of CYP1A2 [10] • Taken with vitamin E and vitamin C, the bioavailability of melatonin

increased • Folic acid and many other antioxidants from food

• Caffeine, St. John's wort (Hypericum perforatum) Exogenous melatonin • Pills: [Circadine, Melatonex (Sun source); Mela-T (Alacer); Night Rest

(Source Naturals), Regulin etc.] • FOOD [next page]

What to do keep proper melatonine production and 7-8 hours of good quality sleep :

• Morning sun-light exposure, ideal together with physical activity. Work near a window. • Hormetins [low prooxidative stressors that stimulate antioxidative protection of our body] - Moderate sport activity, small doses of alcohol, sauna,

cryosauna, cold training, sun insolation,... • Weak warm light a few hours before going to sleep. Eliminate blue and other disturbing light waves (orange glasses while reading in the evening/working on

PC).• Kayumov et al. showed that light wavelengths greater than 530 nm does not suppress melatonin in bright-light conditions.

• No coffee or real tea [better in the morning] and no cigarettes in the evening. No alcohol - only some products have high melatonin content], meditation instead (25)

• Sleep beginning ideal before 23h !!!• Electro free area near the head!!! = No mobile under the pillow and within 2m, electric cables within 40cm, cook or fridge behind the wall, strong Wi-Fi,... =

Switch it all off.• "Chronic exposures, there are now at least 11 studies in humans showing that magnetic fields as low as 0.2 μ T suppress or otherwise disrupt the

nocturnal production of melatonin in the pineal gland" • Sleep in 100% darkness !!! = Really dark curtains. No light on the way to the toilet etc.• Control of used medicaments according to the quality of sleep and melatonin production:

• Sleep disturbancy: Diuretics, antiasthmatics, stimulating antidepressants, thyroideal hormones, nootropica etc.• Melatonin synthesis lowered by: beta blockers, calcium channel blockers, anti-anxiety drugs, NSAIDs, steroids, some antidepressants, verapamil,

Flumazenil• Therapy of the depression [cave: depression as a symptom of food deficiency], inflammations and chronic pain [night doses more important than during the

day]• Food supplements: B6, Vitamin E [14], C, glycine [14], L-tryptophan, phytoestrogens [resveratrol, soya beans, stevia, ...], B12, folate, melatonin

• Low serotonin may contribute to intense cravings for sugar. Insulin helps tryptophan to reach the brain.• Reduction of the chemicals in your home, food, clothes, cosmetics etc.: [melatonin consumption by oxidative stress due to chemical stress]

• Bedroom - toxic VOCs from matresses, viscofoam pillows, colors from the beddings, phtalates etc. from the floor, formaldehydes etc. from the furniture, dust with contaminants from air and ground pollution,... [prefer natural materials, wash dust and refresh air more often]

• Physics aspects of sleeping hygiene: Room temperature +- 18°C and less, moisture of the air at least 60%

METABOLIC BALANCE and quality of the sleep - involved steps to achieve higher concentrations of melatonin: • Not to eat after 21h - calm for stomach

• low insulin, lower inflammatory signals form gut, higher glucagon for burning fats... • Reduce inflammation and insulin levels on low-saccharide diet

• almost no fructose, restricted doses of coffee during the day• restriction of energy intake - stimulates melatonin production

• Only fresh basic food - no unnecessary food additives and heat pre-preparations with too many preservatives - lower melatonin consumption

• Rich on omega3-rich oils, fiber, vitamins E, A, C, folate and other antioxidants in food - synergic with melatonin = lower melatonin consumption

• n-3 deficient diet reduces nighttime melatonin secretion, which returns to normal with supplemented DHA [seen in rodents]• Individual food list rich on necessary and synergic working substances for melatonin synthesis and its higher levels, especially if

reported sleep or depressive disorders [I'd expected this...] • Tryptophan: turkey, cheese, nuts, sunflower seeds, pumpkin seeds • Vitamin B6: eggs, liver, spinach, turnip greens, garlic, cauliflower, mustard greens, celery, fish (especially tuna, halibut, salmon, cod and

snapper), poultry (chicken and turkey], lean beef tenderloin, Quinoa • Serotonin: plantain,... • Melatonin: Seeds and nuts - walnuts 3–4 ng/g, orange bell peppers, beverages - coffee 40 µg/cup, tea, wine 50–230 pg/ml, beer 52–170

pg/ml, crops - rice and barley 300–1,000 pg/g, corn, wheat, and oats, pineapple, banana and orange [15], Montmorency or tart cherry [Weichsel] [14], vegetable [16], Meats, eggs, colostrum [22] - but for sure as in humans drops by stress [me], Tomato 3–114 ng/g, Strawberry 1–11 ng/g, Olive oil 53–119 pg/ml, Cow's milk (unprocessed) 3–25 pg/ml, Nighttime milk 10–40 ng/ml

• Alcoholic fermentation of grapes, malt and pomegranate [19], yeast production during bear and bread [best 180 min.] fermentation etc. [18] • Germination of lentils (Lens culinaris L.) and kidney beans (Phaseolus vulgaris L.) - max. melatonin 6th day when germinated in the dark [21] • Heat [backing] consumes melatonin - in bread [19]

Sources: • [1] Sleep duration and all-cause mortality: a systematic review and meta-analysis of prospective studies.

Cappuccio FP, D'Elia L, Strazzullo P, Miller MA. Sleep. 2010 May;33(5):585-92. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2864873/

• [2] Meta-analysis of short sleep duration and obesity in children and adults. Cappuccio FP1, Taggart FM, Kandala NB, Currie A, Peile E, Stranges S, Miller MA.Sleep. 2008 May;31(5):619-26. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2398753/

• [3] Sweet/Dessert Foods Are More Appealing to Adolescents after Sleep Restriction, Stacey L. Simon,1,* Julie Field,2 Lauren E. Miller,3 Mark DiFrancesco,2 and Dean W. Beebe2,4, Ralph E Mistlberger, Academic Editor

• [4] The Metabolic Consequences of Sleep Deprivation, Kristen L. Knutson, PhD,1 Karine Spiegel, PhD,2 Plamen Penev, MD, PhD,1 and Eve Van Cauter, PhD1http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1991337/

• [5] Sleep duration and all-cause mortality: a critical review of measurement and associations, Lianne M. Kurina, PhD,a,* Martha K. McClintock, PhD,b Jen-Hao Chen, PhD,a Linda J. Waite, PhD,c Ronald A. Thisted, PhD,a and Diane S. Lauderdale, PhDa

• [6] Mortality Associated with Short Sleep Duration: The Evidence, The Possible Mechanisms, and The Future, Michael A. Grandner, PhD,1 Lauren Hale, PhD,2 Melisa Moore, PhD,1,3 and Nirav P. Patel, MD1,4

• [7] Sleep loss: a novel risk factor for insulin resistance and Type 2 diabetes, Karine Spiegel , Kristen Knutson , Rachel Leproult , Esra Tasali , Eve Van Cauter , Journal of Applied Physiology Published 1 November 2005 Vol. 99 no. 5, 2008-2019 DOI: 10.1152/japplphysiol.00660.2005, http://jap.physiology.org/content/99/5/2008

• [8] Significance of Melatonin in Antioxidative Defense System: Reactions and Products, Tan D.-X.a · Manchester L.C.a · Reiter R.J.a · Qi W.-B.a · Karbownik M.b · Calvo J.R.a, Biol Signals Recept 2000;9:137–159 (DOI:10.1159/000014635), http://www.karger.com/Article/Abstract/14635

• [9] Clinical uses of melatonin: evaluation of human trials. Curr Med Chem. 2010;17(19):2070-95. Sánchez-Barceló EJ1, Mediavilla MD, Tan DX, Reiter RJ.

• [10] One molecule, many derivatives: a never-ending interaction of melatonin with reactive oxygen and nitrogen species? J Pineal Res. 2007 Jan;42(1):28-42. Tan DX1, Manchester LC, Terron MP, Flores LJ, Reiter RJ. http://onlinelibrary.wiley.com/doi/10.1111/j.1600-079X.2006.00407.x/full

• [11] Implications of melatonin therapy in irritable bowel syndrome: a systematic review. Curr Pharm Des. 2010;16(33):3646-55. Mozaffari S1, Rahimi R, Abdollahi M.

• [12] Antiinflammatory Activity of Melatonin in Central Nervous System, Emanuela Esposito1 and Salvatore Cuzzocrea1,2,*

• [13] Melatonin in bacterial and viral infections with focus on sepsis: a review. Srinivasan V1, Mohamed M, Kato H.

• [14] Resveratrol, tryptophanum, glycine and vitamin E: a nutraceutical approach to sleep disturbance and irritability in peri- and post-menopause. Parazzini F1.

• [15] Association of vegetable intake with urinary 6-sulfatoxymelatonin level. Nagata C1, Nagao Y, Shibuya C, Kashiki Y, Shimizu H.

• [16] J Pineal Res. 2013 Oct;55(3):229-39. doi: 10.1111/jpi.12065. Epub 2013 May 28. Adaptations of the aging animal to exercise: role of daily supplementation with melatonin. Mendes C1, Lopes AM, do Amaral FG, Peliciari-Garcia RA, Turati Ade O, Hirabara SM, Scialfa Falcão JH, Cipolla-Neto J.

• [17] J Pineal Res. 2014 Jan;56(1):31-8. doi: 10.1111/jpi.12093. Epub 2013 Sep 30. Alcoholic fermentation induces melatonin synthesis in orange juice. Fernández-Pachón MS1, Medina S, Herrero-Martín G, Cerrillo I, Berná G, Escudero-López B, Ferreres F, Martín F, García-Parrilla MC, Gil-Izquierdo A.

• [18] J Pineal Res. 2014 Apr;56(3):275-82. doi: 10.1111/jpi.12120. Epub 2014 Feb 8. Elevated production of melatonin in transgenic rice seeds expressing rice tryptophan decarboxylase. Byeon Y1, Park S, Lee HY, Kim YS, Back K.

• [19] Formation of Melatonin and Its Isomer during Bread Dough Fermentation and Effect of Baking Cemile Yılmaz , Tolgahan Kocadağlı , and Vural Gökmen * Department of Food Engineering, Hacettepe University, 06800 Beytepe, Ankara, Turkey

• [20] Int J Pharm. 2014 Jul 20;469(1):67-79. doi: 10.1016/j.ijpharm.2014.04.055. Epub 2014 Apr 24. Formulating SLMs as oral pulsatile system for potential delivery of melatonin to pediatric population. Albertini B1, Di Sabatino M2, Melegari C2, Passerini N2.

• [21] J Agric Food Chem. 2014 Nov 5;62(44):10736-43. doi: 10.1021/jf503613w. Epub 2014 Oct 23. Effect of illumination on the content of melatonin, phenolic compounds, and antioxidant activity during germination of lentils (Lens culinaris L.) and kidney beans (Phaseolus vulgaris L.). Aguilera Y1, Liébana R, Herrera T, Rebollo-Hernanz M, Sanchez-Puelles C, Benítez V, Martín-Cabrejas MA.

• [22] J Pineal Res. 2014 Sep;57(2):213-8. doi: 10.1111/jpi.12152. Epub 2014 Jul 8. Melatonin identified in meats and other food stuffs: potentially nutritional impact. Tan DX1, Zanghi BM, Manchester LC, Reiter RJ. http://www.ncbi.nlm.nih.gov/pubmed/24942090

• [23] Light level and duration of exposure determine the impact of self-luminous tablets on melatonin suppression Brittany Wood , Mark S. Rea , Barbara Plitnick , Mariana G. Figueiro,

• [24] J Clin Endocrinol Metab. 2011 Mar; 96(3): E463–E472. Published online 2010 Dec 30. doi: 10.1210/jc.2010-2098 PMCID: PMC3047226 Exposure to Room Light before Bedtime Suppresses Melatonin Onset and Shortens Melatonin Duration in Humans Joshua J. Gooley, Kyle Chamberlain, Kurt A. Smith, Sat Bir S. Khalsa, Shantha M. W. Rajaratnam, Eliza Van Reen, Jamie M. Zeitzer, Charles A. Czeisler, and Steven W. Lockley

• [25] Acute increases in night-time plasma melatonin levels following a period of meditation. Biol Psychol. 2000 May;53(1):69-78. Tooley GA1, Armstrong SM, Norman TR, Sali A.