248 CNO Report 22 SEP 2017


CNO Report # 248

Release Date:  22 SEP 2017

Draft Report Compiled by

Ralph Turchiano






In This Issue:

1.       Dark chocolate with olive oil associated with improved cardiovascular risk profile

2.       Melatonin may help treat blood cancers

3.       Cannot sleep due to stress? Here is the cure

4.       Mice on ketogenic diets live longer and healthier in old age

5.       Folic acid may mitigate autism risk from pesticides

6.       Asthma medication may have psychiatric side effects

7.       BU: Resurgence of whooping cough may owe to vaccine’s inability to prevent infections

8.       Whole food diet may help prevent colon cancer, other chronic conditions


Public Release: 29-Aug-2017

Dark chocolate with olive oil associated with improved cardiovascular risk profile

European Society of Cardiology

Barcelona, Spain – 29 Aug 2017: Dark chocolate enriched with extra virgin olive oil is associated with an improved cardiovascular risk profile, according to research presented today at ESC Congress.1

“A healthy diet is known to reduce the risk of cardiovascular disease,” said lead author Dr Rossella Di Stefano, a cardiologist at the University of Pisa, Italy. “Fruits and vegetables exert their protective effects through plant polyphenols, which are found in cocoa, olive oil, and apples. Research has found that the Italian Panaia red apple has very high levels of polyphenols and antioxidants.”

This study tested the association between consumption of dark chocolate enriched with extra virgin olive oil or Panaia red apple (table 1) with atherosclerosis progression in healthy individuals with cardiovascular risk factors.

The randomised crossover study included 26 volunteers (14 men, 12 women) with at least three cardiovascular risk factors (smoking, dyslipidaemia, hypertension, or family history of cardiovascular disease) who received 40 grams of dark chocolate daily for 28 days. For 14 consecutive days it contained 10% extra virgin olive oil and for 14 consecutive days it contained 2.5% Panaia red apple. The two types of chocolate were given in random order.

Progression of atherosclerosis was assessed by metabolic changes (levels of carnitine and hippurate), lipid profile, blood pressure and levels of circulating endothelial progenitor cells (EPCs). EPCs are critical for vascular repair and maintenance of endothelial function.

Urine and blood samples were collected at baseline and after the intervention. Urine samples were analysed by proton nuclear magnetic resonance spectroscopy for endogenous metabolites. Circulating EPC levels were assessed with flow cytometry. Smoking status, body mass index, blood pressure, glycaemia and lipid profile were also monitored.

After 28 days, the researchers found that the chocolate enriched with olive oil was associated with significantly increased EPC levels and decreased carnitine and hippurate levels compared to both baseline and after consumption of apple-enriched chocolate. Olive oil-enriched chocolate was associated with significantly increased high-density lipoprotein (“good”) cholesterol and decreased blood pressure compared to baseline. There was a non-significant decrease in triglyceride levels with apple-enriched chocolate.

Dr Di Stefano said: “We found that small daily portions of dark chocolate with added natural polyphenols from extra virgin olive oil was associated with an improved cardiovascular risk profile. Our study suggests that extra virgin olive oil might be a good food additive to help preserve our ‘repairing cells’, the EPC.”

Public Release: 1-Sep-2017

Melatonin may help treat blood cancers


Researchers have examined the potential benefits of melatonin, a hormone made by a small gland in the brain, for treating blood cancers such as leukemia and lymphoma. They point to evidence that melatonin boosts the immune response against cancer cells, inhibits cancer cell growth, and protects healthy cells from the toxic effects of chemotherapy.

Because melatonin is also involved in regulating circadian rhythms, which help coordinate and synchronize internal body functions, timing of melatonin treatments may be critical to their anticancer effects.

“We hope this information will be helpful in the design of studies related to the therapeutic efficacy of melatonin in blood cancers,” said Dr. Yang Yang, senior author of the British Journal of Pharmacology article. “Also, clarifying the mechanisms of melatonin’s anticancer actions will help facilitate future basic research and clinical applications.”

Public Release: 4-Sep-2017

Cannot sleep due to stress? Here is the cure

University of Tsukuba

Everyone empirically knows that stressful events certainly affect sound sleep. Scientists in the Japanese sleep institute found that the active component rich in sugarcane and other natural products may ameliorate stress and help having sound sleep.

In today’s world ever-changing environment, demanding job works and socio-economic factors enforces sleep deprivation in human population. Sleep deprivation induces tremendous amount of stress, and stress itself is one of the major factors responsible for sleep loss or difficulty in falling into sleep. Currently available sleeping pills does not address stress component and often have severe side effects. Sleep loss is also associated with certain other diseases including obesity, cardiovascular diseases, depression, anxiety, mania deficits etc.

The research group led by Mahesh K. Kaushik and Yoshihiro Urade of the International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, found that octacosanol reduces stress and restores stress-affected sleep back to normal.

Octacosanol is abundantly present in various everyday foods such as sugarcane (thin whitish layer on surface), rice bran, wheat germ oil, bee wax etc. The crude extract is policosanol, where octacosanol is the major constituent. Policosanol and octacosanol have already been used in humans for various other medical conditions.

In the current study, authors made an advancement and investigated the effect of octacosanol on sleep regulation in mildly stressed mice by oral administration. Octacosanol reduced corticosterone level in blood plasma, which is a stress marker. The octacosanol-administered mice also showed normal sleep, which was previously disturbed due to stress. They therefore claim that the octacosanol mitigates stress in mice and restores stress-affected sleep to normal in mice. The sleep induced by octacosanol was similar to natural sleep and physiological in nature. However, authors also claimed that octacosanol does not affect sleep in normal animals. These results clearly demonstrated that octacosanol is an active compound that has potential to reduce stress and to increase sleep, and it could potentially be useful for the therapy of insomnia caused by stress. Octacosanol can be considered safe for human use as a therapy, because it is a food-based compound and believed to show no side effects.

Octacosanol/policosanol supplements are used by humans for functions such as lipid metabolism, cholesterol lowering or to provide strength. However, well-planned clinical studies need to be carried out to confirm its effect on humans for its stress-mitigation and sleep-inducing potentials. “Future studies include the identification of target brain area of octacosanol, its BBB permeability, and the mechanism via which octacosanol lowers stress,” Kaushik says.

Public Release: 5-Sep-2017

Mice on ketogenic diets live longer and healthier in old age

Cell Press

So-called “keto” diets have been gaining public attention for an array of weight loss and health benefit claims. But scientists are still uncovering what exactly happens in ketosis, when carbohydrate intake is so low that the body shifts to producing ketones to help fuel organs.

Two independent mouse studies provide evidence that a ketogenic diet improves memory in older animals, as well as the chances that an animal lives to old age. The findings, published September 5 in the journal Cell Metabolism, raise hopes that ketogenic diets can improve both longevity and health span, or the time someone lives in good health, but further testing in humans is needed.

“The fact that we had such an effect on memory and preservation of brain function is really exciting,” says Eric Verdin (@EricVerdin), President and CEO of the Buck Institute for Research on Aging and senior author of one of the papers (Newman et al.). “The older mice on the ketogenic diet had a better memory than the younger mice. That’s really remarkable.”

Mice in both studies were fed one of three diets starting in mid-life: a ketogenic diet, a control diet, or a low-carb, high-fat diet. The researchers tested the mice at various ages in tasks such as mazes, balance beams, and running wheels. Further testing checked for heart function and gene regulation changes through RNA sequencing analysis, which revealed that the diets influenced insulin signaling and gene expression patterns typically found in fasting.

“The conclusion we draw out of this is that it’s a robust effect,” said Verdin. “The two studies reinforce each other, because they both show the same global effect on healthspan.”

While both studies showed improvements in mid-life lifespan and memory tests, one study also found that a ketogenic diet preserved physical fitness, such as grip strength, in old age.

“The magnitude of the changes surprised me,” said Jon Ramsey, PhD, a professor at the University of California Davis and a senior author on the second paper (Roberts et al.), which found the improved physical strength in mice. “We’ve had the hypothesis that the shift in metabolism induced by a ketogenic diet would have beneficial effects on aging, but I was impressed by the changes we observed.”

The ketogenic diet owes its origins to fasting. People have long recognized that the practice of fasting had the effect of reducing seizures. Starting in the 1920s, doctors found they could mimic the benefits of fasting for epilepsy patients by cutting out carbs, thereby creating a ketogenic diet. When carbohydrate intake is low enough, the liver will produce ketone bodies to provide energy for organs, especially the brain. Both fasting and exercise can kick off this process of ketosis. For a diet to produce ketosis, it must be extremely low carb, or no carb. Both recent studies used diets in which fat made up 89%-90% of total calorie intake.

“When you do a ketogenic diet, you are essentially reorganizing all of metabolism,” said Verdin. This shock to the system can come with health risks. For example, mice allowed to eat a ketogenic diet at will eventually become obese. To prevent this, Verdin and colleagues alternated between a ketogenic diet and a regular diet. Ramsey and colleagues limited the calories given to mice on ketogenic diets to maintain their weight. The difference in approach may explain why mice in one study, but not the other, retained physical capabilities in old age.

“If we have a better idea of the mechanisms by which the ketogenic diet works, it would open a path to develop less-restrictive interventions,” said Ramsey.

In December 2012, Verdin and colleagues published a paper in the journal Science (doi: 10.1126/science.1227166) that showed that the ketone body β-hydroxybutyrate (BHB) not only functioned as fuel, but also produced cell signaling. BHB cell signaling could induce a state in an animal that made it resistant to oxidative stress, which is one of the pathways of aging.

Verdin and his colleagues are now exploring a molecule that can be used as a precursor to BHB to see if simply taking the molecule as a supplement can induce the same benefits of a ketogenic diet.

“The ketogenic diet is a complicated, drastic diet to follow; can we reduce all of this beneficial effect to one molecule?” said Verdin. Researchers don’t yet know, but this type of research will help further understanding of what is, or isn’t, driving the health and aging benefits of the ketogenic diet.

Public Release: 8-Sep-2017

Folic acid may mitigate autism risk from pesticides

University of California – Davis Health System

Researchers at UC Davis and other institutions have shown that mothers who take recommended amounts of folic acid around conception might reduce their children’s pesticide-related autism risk.

In the study, children whose mothers took 800 or more micrograms of folic acid (the amount in most prenatal vitamins) had a significantly lower risk of developing autism spectrum disorder (ASD) – even when their mothers were exposed to household or agricultural pesticides associated with increased risk. The study appears today in the journal Environmental Health Perspectives.

“We found that if the mom was taking folic acid during the window around conception, the risk associated with pesticides seemed to be attenuated,” said Rebecca J. Schmidt, assistant professor in the Department of Public Health Sciences and first author on the paper. “Mothers should try to avoid pesticides. But if they live near agriculture, where pesticides can blow in, this might be a way to counter those effects.”

In the paper, which used data from the Childhood Autism Risks from Genetics and the Environment (CHARGE) study, researchers looked at 296 children between 2 and 5 who had been diagnosed with ASD and 220 who had developed typically. Mothers were interviewed about their household pesticide exposure during pregnancy, as well as their folic acid and B vitamin intake. The team also linked data from California Pesticide Use reports, which provide important details about agricultural spraying, with the mothers’ addresses.

Mothers who took less than 800 micrograms and encountered household pesticides had a much higher estimated risk of having a child who developed an ASD than moms who took 800 micrograms of folic acid or more and were not exposed to pesticides. The associated risk increased for women exposed repeatedly. Women with low folic acid intake who were exposed to agricultural pesticides during a window from three months before conception to three months afterward also were at higher estimated risk.

“Folic acid intake below the median and exposure to pesticides was associated with higher risk of autism than either low intake or exposure alone,” said Schmidt, a UC Davis MIND Institute faculty member. “The mothers who had the highest risk were the ones who were exposed to pesticides regularly.”

While folic acid did reduce the associated risk of a child developing autism, it did not entirely eliminate it.

“It would be better for women to avoid chronic pesticide exposure if they can while pregnant,” Schmidt said.

The authors caution that this is a case-control study that relied heavily on participants’ memories. In addition, they have yet to establish a causal link. However, these results certainly warrant larger studies to validate them. The team is also eager to investigate the mechanisms that contribute to folic acid’s possible protective effects.

“Folate plays a critical role in DNA methylation (a process by which genes are turned off or on), as well as in DNA repair and synthesis,” said Schmidt. “These are all really important during periods of rapid growth when there are lots of cells dividing, as in a developing fetus. Adding folic acid might be helping out in a number of these genomic functions.”

Public Release: 18-Sep-2017

Asthma medication may have psychiatric side effects

In a Pharmacology Research & Perspectives study, the asthma medication montelukast (trade name Singulair) was linked with neuropsychiatric reactions such as depression and aggression, with nightmares being especially frequent in children.

For the study, investigators examined all adverse drug reactions on montelukast in children and adults reported to the Netherlands Pharmacovigilance Center Lareb and the WHO Global database, VigiBase®, until 2016.

“Because of the high incidence of neuropsychiatric symptoms–especially nightmares–after using montelukast in both children and adults, the clinician should discuss the possibility of these adverse events with the patient and parents,” said Meindina Haarman, lead author of the study.

Public Release: 21-Sep-2017

BU: Resurgence of whooping cough may owe to vaccine’s inability to prevent infections

Boston University School of Medicine

The startling global resurgence of pertussis, or whooping cough, in recent years can largely be attributed to the immunological failures of acellular vaccines, Boston University School of Public Health (BUSPH) researchers argue in a new journal article.

The article, published in F1000 Research, points to the differences in mucosal immunity between whole-cell pertussis (wP) vaccines and the newer acellular pertussis (aP) vaccines, first introduced in the 1990s, as playing a pivotal role in the resurgence of the disease.

“This disease is back because we didn’t really understand how our immune defenses against whooping cough worked, and did not understand how the vaccines needed to work to prevent it,” said Christopher J. Gill, associate professor of global health at BUSPH and lead author of the article. “Instead we layered assumptions upon assumptions, and are now find ourselves in the uncomfortable position of admitting that we may made some crucial errors. This is definitely not where we thought we’d be in 2017.”

Up until the 1950s, there were millions of cases of whooping cough around the globe each year, with numerous fatal cases in infants. The introduction of whole-cell pertussis (wP) vaccines led to a 99 percent reduction in cases. Later, as wP vaccines raised concerns of possible rare neurologic adverse events, aP vaccines were licensed and used in a number of countries starting in the early 1990s. Since then, cases of whooping cough have risen sharply. In 2014, there were more than 32,000 cases reported in the US.

“The resurgence of pertussis in the US to its highest levels since the 1940s emphasizes the need for answers to these questions,” the authors wrote.

The researchers examined mathematical models of pertussis transmission, data derived from the aP and wP vaccines responses in animals, and recent insight into the immunology of pertussis and pertussis vaccines. They found that, contrary to existing assumptions, although both vaccines blocked symptomatic disease, wP vaccines blocked also infections in animals while aP vaccines did not. Other differences included wP vaccines’ ability to induce a stronger herd immunity and robust TH17 responses, which confer mucosal immunity, while aP vaccines only induced TH2 responses.

Experimental and immunologic data has shown that aP vaccines do not provide herd immunity, while mathematical models imply otherwise. The researchers proposed a hypothesis to reconcile the contradictory findings: Herd effects from aP vaccines may be the result of modifications in disease presentation that lead to reduced possibility of transmission rather than induced resistance to infection.

The researchers also considered the role of several known factors in the rise of whooping cough cases, including detection bias, waning of immunity, and evolutionary shifts in the bacteria’s genome. They found that, while contributing to the increase in incidence, these factors alone do not fully explain existing epidemiologic data.

Citing the urgency of the growing health crisis, the authors emphasized the need to go beyond the limitations of animal models and provide human data to further examine the arguments put forth in their article.

“The resurgence of pertussis in the aP vaccine era is evolving into a slow-moving global public health crisis,” the researchers wrote. “But, with the public’s trust in vaccines waning, this has also become a public relations crisis.”

Public Release: 21-Sep-2017

Whole food diet may help prevent colon cancer, other chronic conditions

Penn State

A diet that includes plenty of colorful vegetables and fruits may contain compounds that can stop colon cancer and inflammatory bowel diseases in pigs, according to an international team of researchers. Understanding how these compounds work on a molecular level could be an initial step toward finding treatments for people with cancer, they added.

“What we are learning is that food is a double-edge sword — it may promote disease, but it may also help prevent chronic diseases, like colon cancer,” said Jairam K.P. Vanamala, associate professor of food sciences, Penn State. “What we don’t know is, ‘how does this food work on the molecular level?’ This study is a step in that direction.”

In the study, pigs that were served a high calorie diet supplemented with purple-fleshed potatoes had less colonic mucosal interleukin-6 — IL-6 — compared to a control group. IL-6 is a protein that is important in inflammation, and elevated IL-6 levels are correlated with proteins, such as Ki-67, that are linked to the spread and growth of cancer cells, said Vanamala, who also is a faculty member at the Penn State Hershey Cancer Institute.

According to the researchers, who reported their findings in a recent issue of the Journal of Nutritional Biochemistry, eating whole foods that contain macronutrients — substances that humans need in large amounts, such as proteins — as well as micro- and phytonutrients, such as vitamins, carotenoids and flavonoids, may be effective in altering the IL-6 pathway.

Vanamala said these findings reinforce recent research that suggests cultures with plant-based diets tend to have lower colon cancer rates than cultures with meat-based diets. Colon cancer is the second leading cause of cancer related deaths in the United States and a leading killer in many other Western countries, which tend to include more meat and less fruits and vegetables, he added.

While the researchers used purple potatoes in this study, Vanamala said other colorful fruits and vegetables could prompt similar effects. Colorful plants, including the purple potato, contain bioactive compounds, such as anthocyanins and phenolic acids, that have been linked to cancer prevention.

“For example, white potatoes may have helpful compounds, but the purple potatoes have much greater concentrations of these anti-inflammatory, anti-oxidant compounds,” said Vanamala. “We use the purple potato as a model and hope to investigate how other plants can be used in the future.”

Another advantage of using whole foods for cancer treatment is that it would benefit the agriculture industry and likely help small farmers around the world.

“If this model works, we can see what works in other countries,” Vanamala said. “Instead of promoting a pill, we can promote fruits and vegetables that are very rich in anti-inflammatory compounds to counter the growing problem of chronic disease.”

The researchers fed the animals three different diets: a standard diet with 5 percent fat; a high-calorie diet, with 17 percent added dry fat and 3 to 4 percent added endogenous fat; and a high fat diet supplemented with purple-fleshed potatoes.

The expression of IL-6 was six times lower in pigs that ate the purple potato-enhanced feed compared to the control group. Researchers used both uncooked and baked potatoes and found similar effects.

Currently, anti-IL-6 drugs are used against certain type of rheumatoid arthritis? and are being considered to treat? other? ?inflammation-promoted chronic diseases like colon cancer. However, these drugs are expensive and can cause side-effects, including drug tolerance.

Vanamala said that the pig model was used because the digestive system is very similar to the human digestive system, more so than in mice. The diet approach to cancer treatment has also shown similar promise in mice, however, he added.