Category: Uncategorized

„Melatonin’s role in Cancer“ Talk By Russel J. Reiter, PhD

Pupillary reflex to red light and white light

Red monochromatic light going through the eye pupil in the range of 610-760nm causes no pupillary constriction. Hitting eye pupil 7438K CCT white light with peak in blue 444nm causes a rapid contraction of the pupil.

Narrowing and broadening of the pupil is the job of ganglion cells. Besides other functions, their sensitivity is the strongest in the 460-480nm range. On monochromatic red light more than 600nm, ganglion cells do not respond as well as rhodopsin in rods.

Study by George C. Brainarda

2001 study

Action Spectrum for Melatonin Regulation in Humans: Evidence for a Novel Circadian Photoreceptor

George C. Brainard,John P. Hanifin,Jeffrey M. Greenson, Brenda Byrne, Gena Glickman, Edward Gerner, a Mark D. Rollag
Department of Neurology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, and 2Department of Anatomy, Physiology and Genetics, Uniformed Services University of Health Sciences, Bethesda, Maryland 20814

The photopigment in the human eye that transduces light for circadian and neuroendocrine regulation, is unknown. The aim of this study was to establish an action spectrum for lightinduced melatonin suppression that could help elucidate the ocular photoreceptor system for regulating the human pineal gland. Subjects (37 females, 35 males, mean age of 24.5  0.3 years) were healthy and had normal color vision. Full-field, monochromatic light exposures took place between 2:00 and 3:30 A.M. while subjects’ pupils were dilated. Blood samples collected before and after light exposures were quantified for melatonin. Each subject was tested with at least seven different irradiances of one wavelength with a minimum of 1 week between each nighttime exposure. Nighttime melatonin suppression tests (n 627) were completed with wavelengths from 420 to 600 nm. The data were fit to eight univariant, sigmoidal fluence–response curves (R2 0.81–0.95). The action spectrum constructed from these data fit an opsin template (R2 0.91), which identifies 446–477 nm as the most potent wavelength region providing circadian input for regulating melatonin secretion. The results suggest that, in humans, a single photopigment may be primarily responsible for melatonin suppression, and its peak absorbance appears to be distinct from that of rod and cone cell photopigments for vision. The data also suggest that this new photopigment is retinaldehyde based. These findings suggest that there is a novel opsin photopigment in the human eye that mediates circadian photoreception.

Key words: melatonin; action spectrum; circadian; wavelength; light; pineal gland; neuroendocrine; photoreception; photopigment; human




The action spectrum presented here matches a vitamin A1- retinaldehyde photopigment template that supports the hypothesis that one of the new opsin photopigment candidates provides primary photic input for melatonin regulation in humans. The molecular identification of candidate opsin or non-opsin photoreceptors and their localization in the retina and/or neural components of the circadian system make them well suited to act as circadian phototransducers. However, functional data confirming any of these molecules as having a direct role in mammalian circadian photoreception is currently lacking. Furthermore, caution should be exercised in generalizing results from plants, insects, fish, amphibians, and rodents to humans. Are the effects of light on melatonin suppression relevant to general circadian regulation? Studies have shown that hamsters have a higher intensity threshold for light-induced phase-shifts of wheel-running rhythms than for melatonin suppression (Nelson and Takahashi, 1991). Recently, however, a study on humans showed that the 50% response sensitivity for circadian phase shifting (119 lux) was only slightly higher than that for melatonin suppression (106 lux) with white light (Zeitzer et al., 2000). It is possible that there are separate photoreceptors for mediating circadian entrainment versus acute suppression of melatonin. It is reasonable, however, to hypothesize that a variety of nonvisual effects of light, such as melatonin suppression, entrainment of circadian rhythms, and possibly some clinical responses to light, are mediated by a shared photoreceptor system. Additional experiments are needed to test this hypothesis. In general, relatively high light illuminances ranging from 2500 to 12,000 lux are used for treating winter depression, selected sleep disorders, and circadian disruption (Wetterberg, 1993; Lam, 1998). Although these light levels are therapeutically effective, some patients complain that they produce side effects of visual glare, visual fatigue, photophobia, ocular discomfort, and headache. Determining the action spectrum for circadian regulation may lead to improvements in light therapy. Total illuminances for treating a given disorder can be reduced as the wavelength emissions of the therapeutic equipment are optimized. Modern industrialized societies use light extensively in homes, schools, work places, and public facilities to support visual performance, visual comfort, and aesthetic appreciation within the environment. Given that light is also a powerful regulator of the human circadian system, future lighting strategies will need to provide illumination for human visual responses, as well as homeostatic responses. The action spectrum presented here suggests that there are separate photoreceptors for visual and circadian responses to light in humans. Hence, new approaches to architectural lighting may be needed to optimally stimulate both the visual and circadian systems. In conclusion, this study characterizes the wavelength sensitivity of the ocular photoreceptor system for regulating the human pineal gland by establishing an action spectrum for light-induced melatonin suppression. The results identify the 446–477 nm portion of the spectrum as the most potent wavelengths providing circadian input for regulating melatonin secretion. These data suggest that the primary photoreceptor system for melatonin suppression is distinct from the rod and cone photoreceptors for vision. Finally, this action spectrum suggests that there is a novel retinaldehyde photopigment that mediates human circadian photoreception. These findings open the door for optimizing the use of light in both therapeutic and architectural applications


Whole study of the impact of light on the suppression of melatonin secretion can be read here

Effects of LED-backlit Computer Screen and Emotional Selfregulation on Human Melatonin Production

35th Annual International Conference of the IEEE EMBS  2013

Watchara Sroykham, Student Member, IEEE and Yodchanan Wongsawat, Member, IEEE

Abstract— Melatonin is a circadian hormone transmitted via suprachiasmatic nucleus (SCN) in the hypothalamus and sympathetic nervous system to the pineal gland. It is a hormone necessary to many human functions such as immune, cardiovascular, neuron and sleep/awake functions. Since melatonin enhancement or suppression is reported to be closely related to the photic information from retina, in this paper, we aim further to study both the lighting condition and the emotional self-regulation in different lighting conditions together with their effects on the production of human melatonin. In this experiment, five participants are in three light exposure conditions by LED backlit computer screen (No light, Red light (~650nm) and Blue light (~470nm)) for 30 minute (8-8:30pm), then they are collected saliva both before and after the experiments. After the experiment, the participants are also asked to answer the emotional selfregulation questionnaire of PANAS and BRUMS regarding each light exposure condition. These results show that positive mood mean difference of PANAS between no light and red light is significant with p=0.001. Tension, depression, fatigue, confusion and vigor from BRUMS are not significantly changed while we can observe the significant change in anger mood. Finally, we can also report that the blue light of LEDbacklit computer screen significantly suppress melatonin production (91%) more than red light (78%) and no light (44%).

I. INTRODUCTION Melatonin or N-Acetyl-5-methoxytryptamine is a circadian hormone. It is rhythmically produced by the pineal grand in the brain with a low level during daytime and a high level during nighttime. The level of melatonin rises during the evening (8-11pm). It will reach the peak level between 2- 4am and decrease to the baseline level during late morning (8-10am). This mechanism is controlled by the suprachiasmatic nucleus (SCN) which is inhibited by light and is stimulated by darkness. Melatonin is also known as a hormone necessary to many human functions such as immune, cardiovascular, neuron and sleep/awake functions. In recent, technology development has led to energysaving and effective electronic devices. The Light-Emitting Diode (LED) is one of those. It is widely used in display of This project is supported in part by the government funding of Mahidol University. W. Sroykham is with the Department of Biomedical Engineering, Mahidol University, 25/25 Putttamonthon 4, Salaya, Nakornpathom 73170 Thailand and with Center for Biomedical Instrument Research and Development, Institute of Molecular Biosciences,Mahidol University, 25/25 Putttamonthon 4, Salaya, Nakornpathom 73170 Thailand(e-mail: Y. Wongsawat is with the Department of Biomedical Engineering, Mahidol University, 25/25 Putttamonthon 4, Salaya, Nakornpathom 73170 Thailand (corresponding author, phone: 66-82-889-2138 Ext 6361; fax: 66- 82-889-2138 Ext 6366; e-mail: electronic device such as smart mobile phone, television, desktop computer, notebook computer and tablet. However, the light form this device can suppress human melatonin production. Recently Studies, Wood et al (2013) showed that melatonin production can be suppressed after 1-2 hours by tablet with blue LEDs [1]. Cajochen et al (2011) showed that LED-backlit computer screen can significantly suppressed human melatonin production more than a non-LED backlit computer screen [2]. Furthermore, Figueiro et al (2011) showed that light from cathode ray tube computer screen can slightly suppressed human melatonin production and has suggested that the light from electrical devices at nighttime can suppress human melatonin production [3]. Lewy et al also showed that melatonin secretion in human can be suppressed by artificial light [4].

whole study here

Illuminating the deleterious effects of light at night

2011 study

Laura K. Fonken, Randy J. Nelson
Department of Neuroscience and The Institute for Behavioral Medicine Research, The Ohio State University

Technological advances, while providing many benefits, often create circumstances that differ from the conditions in which we evolved. With the wide-spread adoption of electrical lighting during the 20thcentury, humans became exposed to bright and unnatural light at night for the first time in their evolutionary history. Electrical lighting has led to the wide-scale practice of 24-hour shift-work and has meant that what were once just “daytime” activities now run throughout the night; in many ways Western society now functions on a 24-hour schedule. Recent research suggests that this gain in freedom to function throughout the night may also come with significant repercussions. Disruption of our naturally evolved light and dark cycles can result in a wide range of physiological and behavioral changes with potentially serious medical implications. In this article we will discuss several mechanisms through which light at night may exert its effects on cancer, mood, and obesity, as well as potential ways to ameliorate the impact of light at night.

At different times during our respective childhoods, we both toured Carlsbad Caverns in New Mexico. As part of the tour, the lights in the cave were turned off. The darkness was incredible, engulfing absolutely everything. In our society, we rarely experience such profound darkness; every night, our homes, work places, and streets are brightly illuminated by the glow of electric lights. We will of course always be naturally illuminated by the stars and the moon on a clear night, but we can safely say that most of the light we experience at night is unnatural.

Humans are diurnal, that is, we evolved to be active during the day and to sleep at night. As such, we never developed the ability to see well in the dark. Over time, we have, however, developed the desire to do more and more during the time we are awake, be it night or day, and so we have created an environment that corrects for our relative night blindness. Since the advent of electrical lighting around the turn of the 20thcentury, humans have become increasingly exposed to bright and unnatural light at night. Urban development has further exacerbated the issue, with lighting from infrastructure straying into the atmosphere nightly (Figure 1). Today, 99% of the population in the United States and Europe, and 62% of the world’s remaining population, are exposed to this “light pollution” [1]. There is no denying that the invention of electrical lighting was a boon for developing industry and technology, allowing the extension of the workday into the night and boosting economic development. However, the use of light at night continues to rapidly increase (by 6% per year) [1] without thorough (or any) consideration of its biological implications.




A common risk factor in many of the pathologies associated with exposure to light at night is a change in immune function, notably inflammatory responses, and recent research has demonstrated that light at night may detrimentally affect the immune system [18]. Thus, in addition to investigating the influence of melatonin and circadian disruption as mechanisms contributing to the maladaptive affects of light at night, characterization of the inflammatory response is also warranted.

One important population that is often neglected when considering light at night is patients in hospitals. While multiple epidemiological studies have been conducted on nurses, there are no studies on the impact of light at night on the patients with whom they work. Many in-patients are already at high risk of increased inflammation and disrupted physiology, which may be exacerbated by light at night.

Preventing the general population from excessive exposure to light at night can be achieved with relatively low-cost manipulations, such as using curtains to block out street lights, turning off hallway lights, and removing all light sources, including televisions and computers, from bedrooms. However, these methods do not prevent the extension of daytime hours that many of us experience, but by no means do we recommend that everyone go to bed at sunset. Rather, it may be important for people to try to keep a consistent schedule and avoid rapid shifts in their waking hours. This is often unavoidable in shift-working populations, and there are ongoing studies currently comparing visual aids that may alleviate some of the maladaptive effects of exposure to light at night in shift workers. More specifically, not all lighting has an equal effect; the intrinsically photosensitive retinal ganglion cells that project to the master circadian clock in the brain contain melanopsin and are most responsive to the blue region of the visible spectrum (ranging from 450 to 485 nm), with longer wavelengths of lighting minimally impacting the circadian system. Manipulation of wavelength may prove effective in blocking out some of the light-induced physiological changes. Current research investigating the effectiveness of goggles designed to block out blue wavelength lighting on preventing light-induced melatonin suppression is ongoing. Furthermore, work environments could potentially use lighting sources that emit less blue light, which unfortunately is at odds with the push for energy-saving compact fluorescent bulbs.

Modern society now functions on a 24-hour schedule. Although there are many economic and other societal benefits to such a schedule, there is converging evidence from epidemiological and experimental work that light at night has unintended, maladaptive consequences. In many ways, this field of study is just beginning; further characterization of the impact of light at night is needed along with effective interventions to ameliorate the unintended negative effects of light at night on health.

The entire study, the effect of exposure to light at night can be read at this link.

Circadian and Melatonin Disruption by Exposure to Light at Night Drives Intrinsic Resistance to Tamoxifen Therapy in Breast Cancer

July 2014 study

Robert T. Dauchy, Shulin Xiang, Lulu Mao, Samantha Brimer, Melissa A. Wren, Lin Yuan, Muralidharan Anbalagan, Adam Hauch, Tripp Frasch, Brian G. Rowan1, David E. Blask, and Steven M. Hill


Resistance to endocrine therapy is a major impediment to successful treatment of breast cancer. Preclinical and
clinical evidence links resistance to antiestrogen drugs in breast cancer cells with the overexpression and/or
activation of various pro-oncogenic tyrosine kinases. Disruption of circadian rhythms by night shift work or
disturbed sleep-wake cycles may lead to an increased risk of breast cancer and other diseases. Moreover, light
exposure at night (LEN) suppresses the nocturnal production of melatonin that inhibits breast cancer growth. In
this study, we used a rat model of estrogen receptor (ERaþ) MCF-7 tumor xenografts to demonstrate how altering
light/dark cycles with dim LEN (dLEN) speed the development of breast tumors, increasing their metabolism and
growth and conferring an intrinsic resistance to tamoxifen therapy. These characteristics were not observed in
animals in which the circadian melatonin rhythm was not disrupted, or in animals subjected to dLEN if they
received nocturnal melatonin replacement. Strikingly, our results also showed that melatonin acted both as a tumor
metabolic inhibitor and a circadian-regulated kinase inhibitor to reestablish the sensitivity of breast tumors to
tamoxifen and tumor regression. Together, our findings show how dLEN-mediated disturbances in nocturnal
melatonin production can render tumors insensitive to tamoxifen. Cancer Res; 74(15); 1–12. 2014 AACR.



Differential effects of 4OH-TAM on the growth and regression of (ERaþ ) MCF-7 tissue-isolated breast tumor xenografts in female nude rats housed in standard lighting schedule (LD 12:12) or in dLEN lighting schedules with or without melatonin supplementation. A, study I, estimated tumor weight (g/d) of MCF-7 (ERaþ) human breast tumor xenografts from nude rats exposed to a dLEN lighting schedule and treated diluent (red triangles) with 4OH-TAM (blue triangles; 80 mg/kg/d) or a LD 12:12 lighting schedule and treated with diluent (black circles) or 4OH-TAM (green circles). B, study II, estimated tumor weight (g/d) of MCF-7 (ERaþ) human breast tumor xenografts from nude rats exposed to a dLEN lighting schedule and treated with vehicle (red triangles) or 4OH-TAM (blue triangles; 80 mg/kg/d) or in a dLEN lighting schedule supplemented with exogenous melatonin at night and treated vehicle (black circles) or 4OH-TAM (green circles). Tumor weights were estimated daily as described in Materials and Methods. Images of tumor-bearing nude rats in studies I (A, i–iv) and II (B, i–iv) maintained on either experimental (dLEN) or control (LD12:12) lighting schedules, as described in Materials and Methods. A, xengografts from experimental animals 28 days after tumor implant in dLEN (i, top) and LD 12:12 (ii). iii and iv, xenografts from experimental animals 40 days after tumor implant in LD 12:12 and diluent treatment (iii) and LD 12:12 after 28 days of treatment with tamoxifen (iv). Photographs in B are xenografts from experimental animals 28 days after tumor implant in control dLEN lighting schedule (i) and dLEN supplemented with exogenous nighttime melatonin (ii). B, iii, xenografts from experimental animals 40 days after tumor implant in dLEN supplemented with exogenous nighttime melatonin and administered the vehicle for tamoxifen. B, iv, xenografts from experimental animals 40 days after tumor implant in dLEN but supplemented with exogenous nighttime melatonin and after treatment with tamoxifen.

Whole study can be read here.

Article Harvard Health Publications

2012 study

Harvard Health Publications - Harvard Medical School

Blue light has a dark side

Light at night is bad for your health, and exposure to blue light emitted by electronics and energy-efficient lightbulbs may be especially so.

Until the advent of artificial lighting, the sun was the major source of lighting, and people spent their evenings in (relative) darkness. Now, in much of the world, evenings are illuminated, and we take our easy access to all those lumens pretty much for granted.

But we may be paying a price for basking in all that light. At night, light throws the body’s biological clock—the circadian rhythm—out of whack. Sleep suffers. Worse, research shows that it may contribute to the causation of cancer, diabetes, heart disease, and obesity.

But not all colors of light have the same effect. Blue wavelengths—which are beneficial during daylight hours because they boost attention, reaction times, and mood—seem to be the most disruptive at night. And the proliferation of electronics with screens, as well as energy-efficient lighting, is increasing our exposure to blue wavelengths, especially after sundown.


Daily rhythms influenced by light

Everyone has slightly different circadian rhythms, but the average length is 24 and one-quarter hours. The circadian rhythm of people who stay up late is slightly longer, while the rhythms of earlier birds fall short of 24 hours. Dr. Charles Czeisler of Harvard Medical School showed, in 1981, that daylight keeps a person’s internal clock aligned with the environment.




Full article on the influence of blue wavelengths of white light on the human body can be read here


2014 article


Melanopsin is a photopigment found in some retinal ganglion cells in the eyes of humans and other vertebrates. These cells, known as intrinsically photosensitive retinal ganglion cells, perceive light but are much slower to react to visual changes than the better-known rod and cone cells. They have been shown to affect circadian rhythms, the pupillary light reflex, and several other functions related to ambient light.

In structure, melanopsin is an opsin, a retinylidene protein variety of G-protein-coupled receptor. Melanopsin is most sensitive to blue light. A melanopsin based receptor has been linked to the association between light sensitivity and migraine pain.

Melanopsin differs from other opsin photopigments in vertebrates. In fact, it resembles invertebrate opsins in many respects, including its amino acid sequence and downstream signaling cascade. Like invertebrate opsins, melanopsin appears to be a bistable photopigment, with intrinsic photoisomerase activity, and to signal through a G-protein of the Gq family.



Evidence supports prior theories that melanopsin is the photopigment responsible for the entrainment of the central „body clock“, the suprachiasmatic nuclei (SCN), in mammals. Fluorescent immunocytochemistry was used to visualize melanopsin distribution throughout the rat retina and showed that melanopsin was found in approximately 2.5% of the total rat retinal ganglion cells (RGCs) and that these cells were indeed ipRGCs. Using β-galactosidase as a marker for the melanopsin gene, X-gal labeling of these ipRGCs showed that their axons directly target the SCN, providing further evidence that melanopsin is important in entrainment through the retinohypothalamic tract (RHT).

More about melanopsin can be read here.


2013 article

Steven D. Ehrlich, NMD, Solutions Acupuncture, a private practice specializing in complementary and alternative medicine, Phoenix                            z webu: University of Meryland Medical Center


Melatonin is a hormone secreted by the pineal gland in the brain. It helps regulate other hormones and maintains the body’s circadian rhythm. The circadian rhythm is an internal 24-hour “clock” that plays a critical role in when we fall asleep and when we wake up. When it is dark, your body produces more melatonin; when it is light, the production of melatonin drops. Being exposed to bright lights in the evening or too little light during the day can disrupt the body’s normal melatonin cycles. For example, jet lag, shift work, and poor vision can disrupt melatonin cycles.

Melatonin also helps control the timing and release of female reproductive hormones. It helps determine when a woman starts to menstruate, the frequency and duration of menstrual cycles, and when a woman stops menstruating (menopause).

Some researchers also believe that melatonin levels may be related to aging. For example, young children have the highest levels of nighttime melatonin. Researchers believe these levels drop as we age. Some people think lower levels of melatonin may explain why some older adults have sleep problems and tend to go to bed and wake up earlier than when they were younger. However, newer research calls this theory into question.

Melatonin has strong antioxidant effects. Preliminary evidence suggests that it may help strengthen the immune system.




Studies suggest that melatonin supplements may help people with disrupted circadian rhythms (such as people with jet lag or those who work the night shift) and those with low melatonin levels (such as some seniors and people with schizophrenia) to sleep better. A review of clinical studies suggests that melatonin supplements may help prevent jet lag, particularly in people who cross five or more time zones.


Breast Cancer

Prostate Cancer


Benzodiazepine Withdrawal


Irritable Bowel Syndrome



The entire article can be read at this odkaze.

Intrinsically photosensitive retinal ganglion cells

2015 article


Intrinsically photosensitive Retinal Ganglion Cells (ipRGCs), also called photosensitive Retinal Ganglion Cells (pRGC), or melanopsin-containing retinal ganglion cells, are a type of neuron (nerve cell) in the retina of the mammalian eye. They were discovered in 1923, forgotten, rediscovered in the early 1990s, and are, unlike other retinal ganglion cells, intrinsically photosensitive. This means that they are a third class of retinal photoreceptors, excited by light even when all influences from classical photoreceptors (rods and cones) are blocked (either by applying pharmacological agents or by dissociating the ganglion cell from the retina). Photosensitive ganglion cells contain the photopigment melanopsin. The giant retinal ganglion cells of the primate retina are examples of photosensitive ganglion cells.


Research in humans

Attempts were made to hunt down the receptor in humans, but humans posed special challenges and demanded a new model. Unlike in other animals, researchers could not ethically induce rod and cone loss either genetically or with chemicals so as to directly study the ganglion cells. For many years, only inferences could be drawn about the receptor in humans, though these were at times pertinent.

In 2007, Zaidi and colleagues published their work on rodless, coneless humans, showing that these people retain normal responses to nonvisual effects of light. The identity of the non-rod, non-cone photoreceptor in humans was found to be a ganglion cell in the inner retina as shown previously in rodless, coneless models in some other mammals. The work was done using patients with rare diseases that wiped out classic rod and cone photoreceptor function but preserved ganglion cell function. Despite having no rods or cones, the patients continued to exhibit circadian photoentrainment, circadian behavioural patterns, melatonin suppression, and pupil reactions, with peak spectral sensitivities to environmental and experimental light that match the melanopsin photopigment. Their brains could also associate vision with light of this frequency. Clinicians and scientists are now seeking to understand the new receptor’s role in human diseases and, as discussed below, blindness.

Full article on retinal ganglion cells can be read here.