Melatonin as a potential anti-fibrotic drug ?

Melatonin, N-(2-(5-methoxy-1H- indol-3-yl)ethyl)acetamide) is a hormone found in all living creatures. It is naturally synthesized from the amino acid tryptophan, via synthesis of serotonin, by the enzyme 5-hydroxyindole-O-methyl transferase.

Nobel Prize laureate Julius Axelrod performed many of the seminal experiments that elucidated the role of melatonin and the pineal gland in regulating sleep-wake cycles (circadian rhythms). In humans, melatonin is produced by the pineal gland, (a gland located in the center of the brain). Normally, the production of melatonin by the pineal gland is inhibited by light and permitted by darkness.

For this reason melatonin has been called "the hormone of darkness". The secretion of melatonin peaks in the middle of the night, and gradually falls during the second half of the night. Until recent history, humans in temperate climates were exposed to up to eighteen hours of darkness in the winter. In this modern world, artificial lighting typically reduces this to eight hours or less per day all year round.

And also we know that, in animal models, melatonin has been demonstrated to prevent the damage to DNA by some carcinogens. The antioxidant activity of melatonin may reduce damage caused by some types of Parkinson's disease, may play a role in preventing cardiac arrhythmia and may increase longevity; it has been shown to increase the average life span of mice by 20% in some studies. Melatonin appears to have some use against circadian rhythm sleep disorders, such as jet lag and delayed sleep phase syndrome. The primary motivation for the use of melatonin as a supplement is as a natural aid to better sleep, with other incidental benefits to health and well-being due to its role as an antioxidant and its stimulation of the immune system and several components of the endocrine system.

Now something interesting, melatonin has been tested as a potential anti-fibrotic drug. Congrats Professor. Jian-Ming Xu, (of Hospital of Anhui Medical University, China) and group.

The results suggested that treatment with melatonin (10 mg/kg) could decrease the scores of hepatic fibrosis grading, reduced the contents of hyaluronic acid (HA), laminin(LN) in serum and Hydroxyproline (HYP) in liver, treatment with melatonin (5,10 mg/kg ) could decrease serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and blocked the increase in malondialdehyde (MDA) in rats with hepatic injury caused by CCl4.

More over, the authors attribute this property of anti-fibrotic to the Antioxidant activity of melatonin..really interesting......

Reduced melatonin levels linked to greater diabetes risk - Life Extension Update

In continuation of my update on Melatonin....

"Melatonin receptors have been found throughout the body in many tissues including pancreatic islet cells, reflecting the widespread effects of melatonin on physiological functions such as energy metabolism and the regulation of body weight," Ciaran McMullan and colleagues at Brigham and Women's Hospital noted in their introduction to the article. "Loss-of-function mutations in the melatonin receptor are associated with insulin resistance and type 2 diabetes. Additionally, in a cross-sectional analysis of persons without diabetes, lower nocturnal melatonin secretion was associated with increased insulin resistance."

The researchers matched 370 women who developed diabetes while enrolled in the Nurses' Health Study with 370 nondiabetic participants. Morning urine samples obtained upon enrollment in 2000 were analyzed for the ratio of 6-sulfoxymelatonin (the major metabolite of melatonin) to creatinine in order to estimate overnight melatonin secretion.

Women with diabetes had a 6-sulfatoxymelatonin to creatinine ratio that was significantly lower than that of the control group. Among those whose ratio was among the lowest of the participants, the adjusted risk of developing diabetes was more than twice that of women whose ratio was among the highest group.

"This is the first time that an independent association has been established between nocturnal melatonin secretion and type 2 diabetes risk," announced Dr McMullan, who is a researcher in the Renal Division and Kidney Clinical Research Institute at BWH. "Hopefully this study will prompt future research to examine what influences a person's melatonin secretion and what is melatonin's role in altering a person's glucose metabolism and risk of diabetes."

"It is interesting to postulate from these data, in combination with prior literature, whether there is a causal role for reduced melatonin secretion in diabetes risk," the authors remark. "Further studies are needed to determine whether increasing melatonin levels (endogenously via prolonged nighttime dark exposure or exogenously via supplementation) can increase insulin sensitivity and decrease the incidence of type 2 diabetes."

Ref : http://jama.jamanetwork.com/article.aspx?articleid=1674239

Reduced melatonin levels linked to greater diabetes risk - Life Extension Update

Melatonin shown to protect kidney damage caused by obesity with diabetes

In continuation of my update on Melatonin

Scientists from the University of Granada (UGR), the Hospital Universitario La Paz (Madrid), and the University of Texas (U.S.) have taken an important step in the fight against kidney damage and its progression toward kidney failure, which is closely related to diabesity (obesity with type 2 diabetes) and its complications.

Specifically, in two new studies recently published in the Journal of Clinical Medicine and Pharmaceuticals, researchers have developed an obese and diabetic rodent model and have shown that melatonin protects from kidney damage caused by diabesity.

The scientists have shown that chronic administration of melatonin at doses (10 mg/kg body weight/day) prevents mitochondrial and endoplasmic reticulum disruption, which play a critical role in the development and pathogenesis of kidney cell (nephron) damage, and its progression to renal failure.

Thus, it has been shown that melatonin prevents the impairment of the function and dynamics of cellular mitochondria, decreasing the increased production of oxygen free radicals (responsible for oxidative stress). It also prevents pathological alteration in the function of the endoplasmic reticulum (another cell cytoplasmic organelle), which, in conditions of abnormally high oxidative stress, is related to an increase in programmed cell death (of the nephron) leading to the loss of renal functionality, as a preliminary step to the development of renal failure and the need for hemodialysis or transplantation.

The studies coordinated by the UGR show the efficacy of melatonin in halting the progression of renal damage mediated by mitochondrial damage and excess endoplasmic reticulum stress.

As the lead author of this study, Ahmad Agil, a researcher at the Department of Pharmacology of the UGR, says, "Kidney damage is caused by metabolic complications of obesity, such as diabetes, hypertension, blood lipid disorders or fatty liver disease. Given that the prevalence of these pathologies (collectively recognized as metabolic syndrome) continues to increase, kidney damage and its progression over time to kidney failure has become a health problem that affects millions of people worldwide, with a great socioeconomic cost, requiring hemodialysis facilities and/or kidney transplant services, with the corresponding compatibility studies required."

The importance of the work lies not only in the efficacy of melatonin in counteracting the two proposed mechanisms of renal damage (based on the alteration of mitochondrial function and dynamics and the function of the endoplasmic reticulum (ER)), but they also propose an alternative preventive treatment that would improve this renal function with a well-studied drug with a very high safety profile such as melatonin, which is a drug that in the EU must be prescribed by a doctor and is already administered in the treatment of insomnia.

The new findings have also been associated with an improvement in glomerular filtration rate and renal damage of the nephron, manifested in a decrease in creatinine clearance levels (the best marker of renal function), proteinuria, and in the improvement of renal structure, observed after histopathological study of the kidney.

These results are in line with those previously published by these researchers in the last 10 years, demonstrating that the pharmacological administration of melatonin constitutes another new strategy in the therapeutic approach to diabesity (central obesity and its type 2 diabetes) and its complications (such as hepatic steatosis, hypertension, lipid alteration, etc.).

"Our main challenge is the application of melatonin and other strategies such as intermittent fasting in the field of medicine, especially to address the possibility of a treatment perspective for the aforementioned pathologies (diabesity and its complications) that involve an increase in oxidative stress, and mitochondrial damage and associated meta-inflammation (inflammation of metabolic origin)," Agil says.

According to the results, melatonin could help treat kidney damage, which establishes the need to develop new clinical trials to test its effectiveness in humans. The next step is to investigate how it helps in the maintenance of mitochondrial and endoplasmic reticulum homeostasis, and to a greater extent, if melatonin therapy would allow delaying or stopping progressive renal damage by promoting its chronic pharmacological use in kidney repair and regeneration.

https://en.wikipedia.org/wiki/Melatonin

Melatonin shown to protect kidney damage caused by obesity with diabetes

Melatonin appears to suppress growth of breast cancer stem cells

In continuation of my update on Melatonin

Melatonin, a hormone produced in the human brain, appears to suppress the growth of breast cancer tumors.

Researchers at Michigan State University published this finding in the current issue ofGenes and Cancer. While treatments based on this key discovery are still years away, the results give scientists a key foundation on which to build future research.

"You can watch bears in the zoo, but you only understand bear behavior by seeing them in the wild," said David Arnosti, MSU biochemistry professor, director of MSU's Gene Expression in Development and Disease Initiative and co-author of the study. "Similarly, understanding the expression of genes in their natural environment reveals how they interact in disease settings. That's what is so special about this work."

The brain manufactures melatonin only at night to regulate sleep cycles. Epidemiologists and experimentalists have speculated that the lack of melatonin, due in part to our sleep-deprived modern society, put women at higher risk for breast cancer. The latest MSU study showed that melatonin suppresses the growth of breast cancer stem cells, providing scientific proof to support the growing body of anecdotal evidence on sleep deprivation.

The research team was led by Juliana Lopes, a visiting researcher from Sao Paolo, Brazil. Before the team could test its theory, the scientists had to grow tumors from stem cells, known as "mammospheres," a method perfected in the laboratory of James Trosko at MSU.

The growth of these mammospheres was enhanced with chemicals known to fuel tumor growth, namely, the natural hormone estrogen, and estrogen-like chemical Bisphenol A, or BPA, found in many types of plastic food packages.

Melatonin treatment significantly decreased the number and size of mammospheres when compared with the control group. Furthermore, when the cells were stimulated by estrogen or BPA and treated with melatonin at the same time, there was a greater reduction in the number and size of mammospheres.

"This work establishes the principal by which cancer stem cell growth may be regulated by natural hormones, and provides an important new technique to screen chemicals for cancer-promoting effects, as well as identify potential new drugs for use in the clinic," Trosko said.

Melatonin appears to suppress growth of breast cancer stem cells

In continuation of my update on Melatonin

Melatonin, a hormone produced in the human brain, appears to suppress the growth of breast cancer tumors.

Researchers at Michigan State University published this finding in the current issue ofGenes and Cancer. While treatments based on this key discovery are still years away, the results give scientists a key foundation on which to build future research.

"You can watch bears in the zoo, but you only understand bear behavior by seeing them in the wild," said David Arnosti, MSU biochemistry professor, director of MSU's Gene Expression in Development and Disease Initiative and co-author of the study. "Similarly, understanding the expression of genes in their natural environment reveals how they interact in disease settings. That's what is so special about this work."

The brain manufactures melatonin only at night to regulate sleep cycles. Epidemiologists and experimentalists have speculated that the lack of melatonin, due in part to our sleep-deprived modern society, put women at higher risk for breast cancer. The latest MSU study showed that melatonin suppresses the growth of breast cancer stem cells, providing scientific proof to support the growing body of anecdotal evidence on sleep deprivation.

The research team was led by Juliana Lopes, a visiting researcher from Sao Paolo, Brazil. Before the team could test its theory, the scientists had to grow tumors from stem cells, known as "mammospheres," a method perfected in the laboratory of James Trosko at MSU.

The growth of these mammospheres was enhanced with chemicals known to fuel tumor growth, namely, the natural hormone estrogen, and estrogen-like chemical Bisphenol A, or BPA, found in many types of plastic food packages.

Melatonin treatment significantly decreased the number and size of mammospheres when compared with the control group. Furthermore, when the cells were stimulated by estrogen or BPA and treated with melatonin at the same time, there was a greater reduction in the number and size of mammospheres.

"This work establishes the principal by which cancer stem cell growth may be regulated by natural hormones, and provides an important new technique to screen chemicals for cancer-promoting effects, as well as identify potential new drugs for use in the clinic," Trosko said.

Melatonin shows potential to slow tumor growth in certain breast cancers

An  early stage study shows melatonin   a hormone that regulates the body's sleep and awake cycles  may have the potential to help slow the growth of certain breast cancer tumors, according to researchers from Henry Ford Hospital in Detroit and Foundation for Research Support of the State of São Paulo.

Melatonin shows potential to slow tumor growth in certain breast cancers  

Melatonin can help fight obesity and risks associated with it

Melatonin can help fight obesity and risks associated with it

Top-line results from Vanda's tasimelteon Phase IIb/III study on major depressive disorder

We know that, Tasimelteon (BMS-214,778) is a drug which is under development for the treatment of insomnia and other sleep disorders. It is a selective agonist for the melatonin receptors MT₁ and MT₂ in the suprachiasmatic nucleus of the brain, similar to older drugs such as ramelteon. It has been through Phase III trials successfully and was shown to improve both onset and maintenance of sleep, with few side effects.

A year-long (2011-2012) study at Harvard is testing the use of tasimelteon in blind subjects with non-24-hour sleep-wake disorder.

Now Vanda Pharmaceuticals Inc. (NASDAQ: VNDA),  announced top-line results of the Phase IIb/III clinical study (MAGELLAN) in Major Depressive Disorder (MDD), investigating the efficacy and safety of tasimelteon as a monotherapy in the treatment of patients with MDD.  The clinical study did not meet the primary endpoint of change from baseline in the Hamilton Depression Scale (HAMD-17) after 8 weeks of treatment as compared to placebo.  Both tasimelteon and placebo treated patients had an approximately 40% reduction of their MDD symptoms from baseline.  Tasimelteon was shown to be safe and well-tolerated, consistent with observations in prior studies.  Given these current proof of concept clinical study results, Vanda has decided to discontinue all activities in this indication.

"These results are disappointing, as there is still a significant unmet medical need for patients with Major Depression," said Mihael H. Polymeropoulos , M.D., President and CEO of Vanda.  "Tasimelteon's application in the treatment of blind individuals with Non-24 remains our top priority as we pursue our planned NDA submission this year."     

Vanda has recently reported positive results in two phase III clinical studies of tasimelteon in Non-24-Hour Disorder (Non-24) and plans to submit a New Drug Application to the U.S. Food and Drug Administration in mid-2013......

Top-line results from Vanda's tasimelteon Phase IIb/III study on major depressive disorder

Walnuts could be key to happier state-of-mind in young healthy men

In continuation of my update on walnuts

College can be a stressful time for young adults as they figure out how to manage intense daily routines that include work, study and play. Eat well, exercise and get plenty of sleep is a familiar mantra to alleviate this stress, but now with the results of his latest study, UNM Nutrition Professor Peter Pribis is able to tell college students that walnuts could be a key to a happier state-of-mind. 

In this first intervention study in humans, Pribis measured the effect of walnut consumption on mood.

"In the past, studies on walnuts have shown beneficial effects on many health outcomes like heart disease, diabetes and obesity," said Pribis. "Our study was different because we focused on cognition, and in this controlled randomized trial (CRT) we measured mood outcomes in males and females."

The participants of the study were 64 students between the ages of 18-25. They represented most ethnic groups: Caucasian, African American, Hispanic and Asian.

The participants were asked to eat three slices of banana bread every day for sixteen weeks--eight weeks of banana bread with walnuts and eight weeks of banana bread without walnuts. The nuts were finely ground into the dough so the two banana breads were similar in taste and appearance. While eating banana bread with walnuts the participants consumed half a cup of walnuts daily.

The mood of the students was measured at the end of each eight-week period.

"We used a validated questionnaire called Profiles of Mood States (POMS)," says Pribis. "It is one of the most widely used and accepted mood scales in studies on cognition. The test has six mood domains: tension, depression, anger, fatigue, vigor, confusion and also provides a Total Mood Disturbance score (TMD). The lower the TMD score the better the mood."

In this double-blind, randomized, placebo controlled, cross-over feeding trial with walnuts for eight weeks, Pribis observed a significant improvement in mood in young, healthy males.

"There was a meaningful, 28 percent improvement of mood in young men," said Pribis. "However we did not observe any improvement of mood in females. Why this is we do not know."

There are several nutrients in walnuts that could be responsible for the improved mood like alpha-Linolenic acid, vitamin E, folate, polyphenols or melatonin. However, this was a whole food study, so in the end it was the synergy and interaction of all the nutrients in the walnuts combined.

For Pribis, the lesson learned from this food study is clear, "Eat more walnuts. This is an easy intervention. They're not only good for your mood, but overall health as well. The recommended amount is one handful per day."

With this knowledge in hand--and hopefully walnuts in the other--young men can happily tackle life's daily stress.

Ref: http://news.unm.edu/news/the-key-to-a-better-mood-for-young-men-is-a-nut




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