237 CNO 11 NOV 2016

237CNO07NOV2016

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Release Date 11 NOV 2016

Draft Report Compiled by

Ralph Turchiano

http://www.clinicalnews.org

 

 

 

 

 

 

 In this Issue:

1.       Anti-cancer effects found in natural compound derived from onions

2.       Trial finds Red Bull additive taurine improves symptoms of young people suffering first episode psychosis

3.       Trial finds Red Bull additive taurine improves symptoms of young people suffering first episode psychosis

4.       Study shows low vitamin D levels are associated with increased negative and depressive symptoms in psychotic disorders

5.       Turns out protein quality matters when it comes to building muscle

6.       Cranberry disrupts harmful bacteria’s ability to communicate, spread and become virulent

7.       A new look at vitamin D challenges the current view of its benefits

8.       Mulberry extract activates brown fat, shows promise as obesity treatment

9.       Early supplementation may help offset early-life stress on the adult brain

10.   Additional benefit of omega-3 fatty acids for the clearance of metabolites from the brain

11.   Iron supplements in the fight against lead

12.   Natural compound reduces signs of aging in healthy mice

13.   UC researchers affirm diet can impact migraines

14.   U-M study bodes well for low-carb eaters

15.   High-protein diets reduce liver fat

16.   Gut microbes linked to immunotherapy response in melanoma patients

17.   Alzheimer’s disease found to be a diabetic disorder of the brain

18.   Expensive new cancer drugs have little effect on survival of many cancers

19.   Huperzine A provides seizure protection in genetic epilepsy models

20.   Probiotics improve cognition in Alzheimer’s patients

 

Public Release: 19-Oct-2016

Anti-cancer effects found in natural compound derived from onions

Kumamoto University

Research from Kumamoto University, Japan has found that a natural compound isolated from onions, onionin A (ONA), has several anti-ovarian cancer properties. This discovery is a result of research on the effects of ONA on a preclinical model of epithelial ovarian cancer (EOC) both in vivo and in vitro. This research comes from the same group that found ONA suppressed pro-tumor activation of host myeloid cells.

According to a 2014 review of cancer medicines from the World Health Organization, EOC is the most common type of ovarian cancer and has a 5-year survival rate of approximately 40%. It has a relatively low lifetime risk that is less than 1%, but that can increase up to 40% if there is a family history of the disease. A majority of patients (80%) experience a relapse after their initial treatment with chemotherapy, therefore a more effective line of treatment is needed.

Kumamoto University researchers found that ONA has several effects on EOC. The group’s in vitro experiments showed that EOCs, which usually proliferate in the presence of pro-tumor M2 macrophages, showed inhibited growth after introduction of ONA. This was thought to be due to ONAs influence on STAT3, a transcription factor known to be involved in both M2 polarization and cancer cell proliferation. Furthermore, the team found that ONA inhibited the pro-tumor functions of myeloid derived suppressor cells (MDSC), which are closely associated with the suppression of the anti-tumor immune response of host lymphocytes, by using preclinical sarcoma model. ONA was also found to enhance the effects of anti-cancer drugs by strengthening their anti-proliferation capabilities. Moreover, experiments on an ovarian cancer murine model that investigated the effects of orally administered ONA resulted in longer lifespans and inhibited ovarian cancer tumor development. This was considered to be a result of ONA’s suppression of M2 polarized macrophages.

The research shows that ONA reduces the progression of malignant ovarian cancer tumors by interfering with the pro-tumor function of myeloid cells. ONA appears to activate anti-tumor immune responses by nullifying the immunosuppressive function of myeloid cells. ONA has the potential to enhance existing anti-cancer drugs while also having little to no cytotoxic effects on normal cells. Additionally, side effects in animals have not been seen. With a little more testing, an oral ONA supplement should greatly benefit cancer patients.

Public Release: 19-Oct-2016

Trial finds Red Bull additive taurine improves symptoms of young people suffering first episode psychosis

International Early Psychosis Association

New research presented at this year’s International Early Psychosis Association (IEPA) meeting in Milan, Italy (20-22 October) shows that supplementation with taurine (well known as an additive found in drinks such as Red Bull) improves symptoms in young people suffering a first episode of psychosis (FEP). The study is by Dr Colin O’Donnell, Donegal Mental Health Service, Letterkenny, County Donegal, Ireland, and Professor Patrick McGorry and Dr Kelly Allott, Orygen, The National Centre of Excellence in Youth Mental Health, Parkville, VIC, Australia, and colleagues.

Taurine is an amino acid naturally occurring in the body that has various functions, including aiding the function of the cardiovascular system. It exhibits an inhibitory neuro-modulatory effect in the nervous system and also functions as a neuroprotective agent. It is also involved in development of the nervous system. For all these reasons, it was chosen as an interesting substance to study for potential treatment of psychosis. In this new study, the authors analysed the efficacy of taurine supplementation in improving both symptoms and cognition in patients with FEP.

A total of 121 patients (aged 18-25 years) with FEP, taking low dose antipsychotic medication, and attending Orygen’s early intervention services in Melbourne agreed to take part in the study. Patients received taurine 4 grams or placebo once daily. A scoring system called BPRS (Brief Psychiatric Rating Scale) was used to assess symptoms, and a different tool called MCCB (MATRICS consensus cognitive battery) was used to assess cognition.

A total of 86 patients (47 receiving taurine and 39 placebo) were included in the final analysis. Taurine was found to be both safe and well tolerated. Taurine significantly improved symptoms on the BPRS scale, both in overall score and the part specifically analysing psychosis. There were also improvements in depression symptoms (rated by the Calgary Depression Scale for Schizophrenia [CDSS]) and general overall functioning (including social and workplace functioning). However, there was no difference between groups regarding cognition.

The authors conclude: “Although taurine supplementation did not improve cognition, it appears to improve core symptoms and depression in patients with FEP. The use of taurine warrants further investigation in larger randomised studies, particularly early in the course of psychosis.”

The authors are planning further studies to examine the potential benefits of taurine both alone and in conjunction with other supplements in the treatment of psychosis.

Public Release: 19-Oct-2016

Study shows low vitamin D levels are associated with increased negative and depressive symptoms in psychotic disorders

International Early Psychosis Association

New research presented at this year’s International Early Psychosis Association (IEPA) meeting in Milan, Italy (20-22 October) shows that low vitamin D status is associated with increased negative and depressive symptoms in psychotic disorders. The research is by Dr Mari Nerhus, NORMENT Research Centre, Institute of Clinical Medicine, University of Oslo, Norway, and colleagues.

There are indications that low vitamin D levels are associated with increased disease severity in psychotic disorders. In these new studies, the authors investigated if low vitamin D status was associated with a specific symptom profile and if vitamin D deficiency was associated with cognitive deficits in young people with a psychotic disorder.

The studies recruited patients from in and outpatient clinics, and healthy controls. In the first study the authors included 358 patients with symptoms assessed by tools called the Positive and Negative Syndrome Scale and by the Calgary Depression Scale for Schizophrenia. In the second study the authors included 225 patients and 159 controls assessed by a cognitive test battery including processing speed, verbal learning, verbal memory and executive function tests.

Advanced statistical modelling was performed to enable control for other factors that could influence the results. Low vitamin D levels were found to be significantly associated with increased negative and depressive symptoms after controlling for gender differences, education level, inpatient status or having ethnic minority background. Season of the year for the assessments and having a diagnosis of schizophrenia versus affective psychosis were also included in the analyses. The authors were also able to show an association between vitamin D deficiency and cognitive impairments in processing speed and verbal fluency that remained significant after controlling for patient versus control status, current IQ levels, gender differences and the participants’ ethnic background.

The authors conclude: “The associations between low vitamin D levels and increased negative and depressive symptoms, and decreased processing speed and verbal fluency are good arguments for planning large scale randomised controlled studies in target populations, in order to reach conclusions about vitamin D’s potential beneficial effect in psychotic disorders.”

They are currently running studies investigating potential associations between vitamin D levels and brain structures as measured by magnetic resonance imaging (MRI).

Public Release: 25-Oct-2016

Turns out protein quality matters when it comes to building muscle

Internationally venerated skeletal muscle scientist takes a critical look at how protein quality impacts muscle mass and strength gains with resistance exercise

Pollock Communications

Rosemont, IL, October 25, 2016 – Attention Crossfit®, HIIT, Orange Theory® and absolutely anyone who cares about maintaining muscle mass – Tier 1 Canada Research Chair in Skeletal Muscle Health, Dr. Stuart M. Phillips of MacMaster University, reasons that the quality of protein you consume for muscle building with resistance training may be more important than you realize. In a recent article in Nutrition and Metabolism, Dr. Phillips reviewed the current science to examine the effects of the quality of supplemental protein on changes in muscle mass, strength and body composition when combined with strength training. His comprehensive inquiry suggests that based on the new proposed method to evaluate protein quality using its indispensable (or essential) amino acid composition and its digestibility, protein sources that provide leucine (an essential amino acid) – such as whey protein – are the strongest determinant of muscle protein synthesis and likely muscle growth.

“My assessment of the data on protein supplementation and resistance exercise reveals that the amount of leucine in a protein supplement has the greatest impact on muscle protein synthesis,” said, Dr. Phillips. “Leucine is not only a building block for protein, but a trigger for working muscles to synthesize more protein. In essence, it turns on muscle protein synthesis like a light switch so that over time, there could be greater gains in lean body mass and strength, and subsequently, body composition improvements.”

Proteins with the greatest content of leucine include whey protein isolate or concentrate. Whey protein is a milk protein that is considered high-quality due to its amino acid profile and high score for digestibility. Based on the culmination of data inspecting protein types and muscle protein synthesis, whey protein rated higher than other protein sources such as soy, pea or rice.

“The outcome of this review isn’t just applicable to strength trainers,” Dr. Phillips notes. “As we age, muscle loss becomes prevalent if we don’t thwart the decline. Leucine-rich whey protein supplementation, combined with resistance exercise, may be one way to help preserve muscle mass throughout the lifespan.”

While more research is warranted to further characterize proteins based on their quality, digestibility and amino acid profile, as well as to identify their impact on the aging population – at this point, consumers should reach for a leucine-containing protein supplement, like whey, to maximize gains from hard workouts.

Public Release: 25-Oct-2016

Cranberry disrupts harmful bacteria’s ability to communicate, spread and become virulent

New study shows promise for blunting the spread of hard-to-fight bacterial infections

Pollock Communications

CARVER, Mass., Oct. 18, 2016 – Scientists from McGill University and INRS-Institut Armand-Frappier in Canada recently released a novel investigation showing that cranberry extract successfully interrupted the communication between bacteria associated with problematic and pervasive infections. The authors of the data published in Nature’s Scientific Reports, Eric Déziel, professor-investigator at INRS-Institut Armand-Frappier and Nathalie Tufenkji, professor at McGill University, state that not only do the results provide insights into how cranberry compounds may work, they also have implications for the development of alternative approaches to control infections.

Previously published work has shown that the American cranberry (Vaccinium macrocarpon L) contains compounds — such as proanthocyanidins (PACs) — that provide meaningful antioxidant, anti-adhesion and anti-microbial properties that help fend off illness. Given this, the scientific team hypothesized that cranberries may also have an anti-virulence potential. They wanted to know if these cranberry compounds could help manage bacterial infections. By feeding fruit flies — a commonly used model for studying human infections — cranberry extract, the team discovered that cranberry provided flies protection from a bacterial infection and they lived longer than their cranberry-free counterparts. In essence, the cranberry extract reduced the severity of the bacterial infection.

Study author, Dr. Tufenkji, elaborates on what this might mean for humans, as opposed to flies, “This means that cranberries could be part of the arsenal used to manage infections and potentially minimize the dependence on antibiotics for the global public.”

To further explain cranberries’ impact on bacteria, Dr. Déziel said, “Cranberry PACs interrupt the ability for bacteria to communicate with each other, spread and become virulent — a process known as quorum sensing. The cranberry extract successfully interferes with the chain of events associated with the spread and severity of chronic bacterial infections.”

Added to the evidence of cranberry’s role in preventing recurrent urinary tract infections by blocking bacteria from sticking to cell walls, the current study suggests that PACs may help control the virulence or spread of potentially dangerous bacterial infections around the world.

Public Release: 25-Oct-2016

A new look at vitamin D challenges the current view of its benefits

Research in C. elegans shows the popular supplement engages longevity genes to increase lifespan and prevent the accumulation of toxic proteins linked to many age-related diseases

Buck Institute for Research on Aging

A simple Google search for “what does vitamin D do?” highlights the widely used dietary supplement’s role in regulating calcium absorption and promoting bone growth. But now it appears that vitamin D has much wider effects — at least in the nematode worm, C. elegans. Research at the Buck Institute shows that vitamin D works through genes known to influence longevity and impacts processes associated with many human age-related diseases. The study, published in Cell Reports, may explain why vitamin D deficiency has been linked to breast, colon and prostate cancer, as well as obesity, heart disease and depression.

“Vitamin D engaged with known longevity genes – it extended median lifespan by 33 percent and slowed the aging-related misfolding of hundreds of proteins in the worm,” said Gordon Lithgow, PhD, senior author and Buck Institute professor. “Our findings provide a real connection between aging and disease and give clinicians and other researchers an opportunity to look at vitamin D in a much larger context.”

Study provides links to human disease

The study shines a light on protein homeostasis, the ability of proteins to maintain their shape and function over time. It’s a balancing act that goes haywire with normal aging — often resulting in the accumulation of toxic insoluble protein aggregates implicated in a number of conditions, including Alzheimer’s, Parkinson’s and Huntington’s diseases, as well as type 2 diabetes and some forms of heart disease. “Vitamin D3, which is converted into the active form of vitamin D, suppressed protein insolubility in the worm and prevented the toxicity caused by human beta-amyloid which is associated with Alzheimer’s disease,” said Lithgow. “Given that aging processes are thought to be similar between the worm and mammals, including humans, it makes sense that the action of vitamin D would be conserved across species as well.”

Postdoctoral fellow Karla Mark, PhD, led the team doing the experiments. She says the pathways and the molecular network targeted in the work (IRE-1/XBP-1/SKN-1) are involved in stress response and cellular detoxification. “Vitamin D3 reduced the age-dependent formation of insoluble proteins across a wide range of predicted functions and cellular compartments, supporting our hypothesis that decreasing protein insolubility can prolong lifespan.”

Clinicians weigh in

“We’ve been looking for a disease to associate with vitamin D other than rickets for many years and we haven’t come up with any strong evidence,” said Clifford Rosen, MD, the director of the Center for Clinical and Translational Research and a senior scientist at the Maine Medical Center Research Institute studying osteoporosis and obesity. “But if it’s a more global marker of health or longevity as this paper suggests, that’s a paradigm shift. Now we’re talking about something very different and exciting.”

“This work is really appealing and challenging to the field,” said Janice M. Schwartz, MD, a professor of medicine and bioengineering and therapeutic sciences the University of California, San Francisco, and a visiting research scientist at the Jewish Home in San Francisco. She has studied vitamin D supplementation in the elderly. “We focus on vitamin D and the bones because that’s where we can measure its impact. I believe that vitamin D is as crucial for total body function and the muscles as it is for bones. Vitamin D influences hundreds of genes – most cells have vitamin D receptors, so it must be very important.”

Current recommendations and controversies

How much vitamin D do humans need and how do they best get it? The issue is confusing with disagreement rampant among experts. The Institute of Medicine’s (IOM) latest recommendations (from 2011) pertain only to vitamin D’s role in bone health and fracture reduction. Experts concluded that evidence for other proposed benefits of vitamin D was inconsistent, inconclusive, or insufficient to set recommended intakes. The IOM recommends a daily intake of 600 International Units (IU) for people between 1 and 70 years old, and 800 IU daily for those older. The upper limit — the levels above which health risks are thought to increase — was set at 4,000 IU per day for adults. Excess vitamin D can raise blood levels of calcium which leads to vascular and tissue calcification, with subsequent damage to the heart, blood vessels and kidneys.

Many vitamin D researchers and some health organizations, including the Endocrine Society and the International Osteoporosis Foundation, disagreed with the IOM’s recommendations for daily intake, instead recommending supplementation of 800 to 2,000 IU per day, at least for people known or likely to have low blood levels. The disagreement highlights another difficulty: measuring blood levels of vitamin D is problematic given a lack of standardization and reliability among labs. Blood levels of the precursor to the active vitamin D are measured in nanograms per milliliter (ng/mL) in the U.S. Many researchers and expert groups have argued that a blood level of at least 30 ng/mL is optimal; some call for optimum levels to be set at 40 or 50 ng/mL. But the IOM report concluded that blood levels starting at 20 ng/mL would be adequate for bone health in the vast majority of people.

Universal supplementation?

Based on problems with laboratory standards and a lack of agreed-upon meaning of results, both Rosen and Schwartz agree that the costs of universal testing for vitamin D levels would outweigh the benefits. Instead, both recommend universal supplementation of between 800 – 1000 IU of vitamin D daily for adults. “It’s safe, there’s no reason for anyone not to take it,” said Schwartz, who has written about vitamin D for the popular press.

Schwartz says older adults may be particularly prone to vitamin D deficiency because the skin’s ability to manufacture vitamin D from sun or UV light exposure declines with age, adding that the elderly are less likely to spend time in the sun, are more likely to have diets lacking in sources of vitamin D, and may suffer from gastrointestinal disorders that make it harder to absorb vitamin D. Others prone to vitamin D deficiency include those with darker skin and those who live in higher latitudes where the sun’s angle is low in the sky.

Bringing it back to aging

Given adequate funding, senior author Lithgow plans to test vitamin D in mice to measure and determine how it affects aging, disease and function — and he hopes that clinical trials in humans will go after the same measurements. “Maybe if you’re deficient in vitamin D, you’re aging faster. Maybe that’s why you’re more susceptible to cancer or Alzheimer’s,” he said. “Given that we had responses to vitamin D in an organism that has no bone suggests that there are other key roles, not related to bone, that it plays in living organisms.”

Lithgow gave a shout out to the tiny, short-lived nematode worms which populated this study. “Working in these simple animals allows us to identify novel molecular pathways that influence how animals age,” he said. “This gives us a solid starting point to ask questions and seek definitive answers for how vitamin D could impact human health. We hope that this work will spur researchers and clinicians to look at vitamin D in a larger, whole-person context that includes the aging process.”

Public Release: 26-Oct-2016

Mulberry extract activates brown fat, shows promise as obesity treatment

New research in The FASEB Journal suggests that rutin extracted from mulberries acts as an activator of brown adipose tissue (BAT) to mimic cold which regulates energy metabolism by enhancing BAT activity

Federation of American Societies for Experimental Biology

Good news for those who want to activate their brown fat (or BAT, brown adipose tissue) without having to be cold: New research, published in The FASEB Journal, suggests that a natural compound in mulberries, called “rutin,” can activate the BAT in our bodies to increase metabolism and facilitate weight loss.

“The beneficial effects of rutin on BAT-mediated metabolic improvement have evoked a substantial interest in the potential treatment for obesity and its related diseases, such as diabetes,” said Wan-Zhu Jin, Ph.D., a researcher involved in the work from the Institute of Zoology at the Chinese Academy of Sciences in Beijing, China. “In line with this idea, discovery of more safe and effective BAT activators is desired to deal with obesity and its related diseases.”

To make their discovery, Jin and colleagues used both genetically obese mice and mice with diet-induced obesity as models. These mice were fed a regular diet, and supplemental rutin (1 mg/ml) was added to their drinking water. Rutin treatment significantly reduced adiposity, increased energy expenditure, and improved glucose homeostasis in both the genetically obese mice and the mice with diet-induced obesity. Specifically, the researchers found that rutin directly binds to and stabilizes SIRT1 (NAD-dependent deacetylase sirtuin-1), leading to hypoacetylation of PGC1α protein, which stimulates Tfam transactivation and eventually augments mitochondrial number and UCP1 activity in BAT. Rutin functions as a cold mimetic through activating a SIRT1-PGC1α-Tfam signaling cascade and increasing mitochondrial number and UCP1 activity in BAT. Rutin also induced brown-like (beige) adipocyte formation in subcutaneous adipose tissue in both obesity mouse models.

“Unlike hibernating animals, we humans have only a small spot of brown fat, and yet its importance in human metabolism has only recently come into view,” said Thoru Pederson, Ph.D., Editor-in-Chief of The FASEB Journal. “In this study, the philosophy of ancient Chinese medicine’s exploitation of plant materials has conjoined in the modern era with a very able physiology research team to evoke a promising lead.”

Public Release: 26-Oct-2016

Early supplementation may help offset early-life stress on the adult brain

New research in The FASEB Journal suggests that short and early dietary supplementation prevents reduced nutrient levels and lasting effects of early-life stress on later learning and memory in adults

Federation of American Societies for Experimental Biology

Early-life stress has been shown to impair learning and memory in later life, but new research, published online in The FASEB Journal, suggests that improved nutrition may help offset the negative effects of this stress. Specifically, using mice, scientists focused on essential micronutrients, including methionine, vitamins B6and B12, and folic acid, none of which are made by the body and need to be ingested through diet. They found that early-life stress reduces the levels of these nutrients in mouse pups, but supplementation prevented the reduction of methionine levels and even prevented some of the lasting negative effects of early-life stress on later learning and memory in adult offspring.

“Today’s children are tomorrow’s future,” said Aniko Korosi, Ph.D., a researcher involved in the work from the Swammerdam Institute for Life Sciences and the Center for Neuroscience at the University of Amsterdam in Amsterdam, The Netherlands. “We hope that this study can contribute to novel nutritional strategies that help prevent lasting consequences of a stressful childhood on later mental health.”

To make their discovery, Korosi and colleagues mimicked a stressful early-life environment during the first week after birth (postnatal days 2-9) for newborn mice and their mothers. Control mice and their mothers were housed in a normal environment. During the stress period, half of the mouse mothers (control and early-life stress) received a standard rodent diet, the other half received a diet that was supplemented with essential micronutrients. The lactating mouse mothers ate the diet and thereby developed elevated micronutrient levels in maternal milk and subsequently in the blood and the brains of their pups. After the initial stress period, all mice received a standard diet and environment. Once the mice became 4 months old, their learning and memory skills were tested in various cognitive/behavioral tasks. Mice that were previously exposed to early-life stress performed worse than control animals and demonstrated poor learning and memory skills. However, stress-exposed mice from mothers that received the supplemented diet performed equally well as the control mice did.

“The field of postnatal nutrition has sometimes taken a back seat to research on the maternal-fetal axis, but of course we cannot ever ignore either,” said Thoru Pederson, Ph.D., Editor-in-Chief of The FASEB Journal. “Here we see strikingly beneficial cognitive effects of a sound postnatal diet. The nutrients tested were familiar ones, but the results speak for themselves.”

Public Release: 26-Oct-2016

Additional benefit of omega-3 fatty acids for the clearance of metabolites from the brain

Research in The FASEB Journal suggests that omega-3 polyunsaturated fatty acids could improve the function of the glymphatic system and promote clearance of amyloid-β peptides from the brain

Federation of American Societies for Experimental Biology

New research published online in The FASEB Journal suggests that omega-3 polyunsaturated fatty acids, which are found in fish oil, could improve the function of the glymphatic system, which facilitates the clearance of waste from the brain, and promote the clearance of metabolites including amyloid-β peptides, a primary culprit in Alzheimer’s disease.

To make this discovery, scientists first used transgenic fat-1 mice, which express high endogenous omega-3 polyunsaturated fatty acids (PUFAs) in the brain, to investigate the effect of omega-3 PUFAs on the clearance function of the glymphatic system. Compared to the wild-type mice, the fat-1 mice with enriched endogenous omega-3 PUFAs significantly promote the clearance function of the lymphatic system, including the Aβ clearance from the brain. Wild-type mice were supplemented with fish oil, which contains high concentrations of omega-3 PUFAs, and found that fish oil-supplemented mice also improved the clearance function of the glymphatic system compared to the control mice without fish oil supplementation. Omega-3 PUFAs help maintain the brain homeostasis, which may provide benefits in a number of neurological diseases, such as Alzheimer’s disease, traumatic brain injury, and sleep impairment, among others.

“These now-famous fatty acids have been the subject of major studies both in academia and industry. Just when we thought we had heard everything, here is something new, and it is provocative indeed,” said Thoru Pederson, Ph.D., Editor-in-Chief of The FASEB Journal. “This study should not turn attention away from the roles of these substances in maintaining vascular health, but neither should they restrict our view. The brain is an extremely vascularized organ, while we might also bear in mind that omega-3 fatty acids may impact neurons, glia, and astrocytes themselves.”

Public Release: 26-Oct-2016

Iron supplements in the fight against lead

ETH Zurich

Lead is a toxic heavy metal that was added to petrol for use in cars until as recently as 25 years ago. It is particularly harmful to the developing brains of infants, children and teenagers, and the damage it does is irreversible.

The situation becomes significantly worse if people are exposed to a high level of lead at the same time as they are suffering from iron deficiency. In the small intestine, lead and iron bind to the same transport protein, which absorbs the metals into the bloodstream. If someone consumes too little iron with their food, the transporter increases its activity, and can carry lead into the bloodstream instead, leading to increased levels of the toxic heavy metal in the body and brain.

450 Moroccan schoolchildren examined

A team of researchers led by ETH professor Michael B. Zimmermann from the Laboratory of Human Nutrition have now shown in a study that fortifying food with iron produces a striking reduction in blood lead concentration in children exposed to high levels of the metal.

This is the result of a trial involving over 450 children carried out by Zimmermann’s former doctoral student Raschida Bouhouch and colleagues in southern Morocco. It is the first controlled prospective study to investigate the connection between iron deficiency and lead poisoning and to demonstrate that iron fortification can reduce blood lead levels. The study came about within the framework of a North-South project conducted by ETH Zurich and the University and University Hospital of Marrakesh.

Mining in the surrounding area meant that children of preschool and school age were exposed to an increased quantity of lead. At the same time, the level of iron in their blood was relatively low, placing them in a high-risk group.

Biscuits with iron

Depending on their weight, the children were given several white-flour biscuits on a daily basis for a period of four and a half months. The biscuits were fortified with different iron preparations: some received biscuits containing a specific quantity of iron sulphate, while others received biscuits with sodium iron EDTA or sodium EDTA without iron. To test the effect of the iron supplements, some children received only placebo biscuits containing no additional iron.

EDTA, which stands for ethylene diamine tetraacetic acid, forms stable complexes with iron, aiding its uptake into the bloodstream from the intestines, but it is not absorbed itself. EDTA can also bind to lead in the intestines, reducing its absorption. In Europe, the compound is approved as food additive E385 in emulsified sauces and foods preserved in tins and jars. Sodium iron EDTA has already been used for iron fortification in foodstuffs for many years.

The researchers measured the children’s blood lead concentration and iron status before and after the trial, as well as conducting tests to determine how well the children could solve cognitive tasks.

A positive effect on lead concentration

The researchers were delighted to find that the biscuits fortified with iron did indeed reduce the level of lead in the blood – specifically, by a third with sodium iron EDTA complexes and by a quarter with EDTA and iron sulphate.

Before the study began, the children’s blood contained on average 4.3 micrograms of lead per decilitre. Biscuits with added sodium iron EDTA facilitated a reduction in blood lead concentration to 2.9 micrograms per decilitre. The biscuits also brought about an improvement in the children’s iron status. On the other hand, the reduction in lead concentration had no effect on cognitive performance, as the researchers discovered during the corresponding tests.

Nevertheless, Zimmermann is very happy with the study’s results: “The finding – that you can reduce blood lead concentration in exposed individuals with just a short intervention – is hugely significant for public health services,” says the ETH professor.

Although, contrary to the researchers’ expectations, the children’s blood lead concentration before supplementation with iron was in line with the worldwide average at 4.3 micrograms per decilitre of blood, it was still possible to achieve a considerable reduction by administering the biscuits.

Zimmermann attributes the lack of improvement in cognitive performance to the fact that lead leaves behind lasting damage that cannot be reversed by administering iron. “Nevertheless, it definitely makes sense to use iron fortification to prevent brain damage in exposed sectors of the population,” says the nutrition specialist. Iron supplementation may even provides foetuses in the womb with effective protection against subsequent brain damage.

As the base level of lead in the schoolchildren in the study corresponds to the worldwide average, Zimmermann says the results offer good transferability to other regions and population groups.

The tool of choice: NaFeEDTA

Based on these findings, he recommends using sodium iron EDTA to fortify foodstuffs in areas where lead poisoning and iron deficiency are common, and iron fortification is already used in food. “This is the most effective way to reduce the level of lead in the bloodstream.” Although it is more expensive than iron sulphate, it also works better.

Lead contamination of food and water is still a serious problem in mining and heavy industry areas in Africa, India and China, but the issue is not yet resolved even in industrialised Western countries. The discussion has flared up in Flint, Michigan (USA), where the drinking water is contaminated with lead because inhabitants are supplied with water that flows through lead pipes. The pipes should have been replaced a long time ago.

Public Release: 27-Oct-2016

Natural compound reduces signs of aging in healthy mice

Safety of NMN being tested in small clinical trial in Japan

Washington University School of Medicine

 

Much of human health hinges on how well the body manufactures and uses energy. For reasons that remain unclear, cells’ ability to produce energy declines with age, prompting scientists to suspect that the steady loss of efficiency in the body’s energy supply chain is a key driver of the aging process.

Now, scientists at Washington University School of Medicine in St. Louis have shown that supplementing healthy mice with a natural compound called NMN can compensate for this loss of energy production, reducing typical signs of aging such as gradual weight gain, loss of insulin sensitivity and declines in physical activity.

The study is published Oct. 27 in the journal Cell Metabolism.

“We have shown a way to slow the physiologic decline that we see in aging mice,” said Shin-ichiro Imai, MD, PhD, a professor of developmental biology and of medicine. “This means older mice have metabolism and energy levels resembling that of younger mice. Since human cells rely on this same energy production process, we are hopeful this will translate into a method to help people remain healthier as they age.”

Imai is working with researchers conducting a clinical trial to test the safety of NMN in healthy people. The phase 1 trial began earlier this year at Keio University School of Medicine in Tokyo.

With age, the body loses its capacity to make a key element of energy production called NAD (nicotinamide adenine dinucleotide). Past work by Imai and co-senior author Jun Yoshino, MD, PhD, an assistant professor of medicine, has shown that NAD levels decrease in multiple tissues as mice age. Past research also has shown that NAD is not effective when given directly to mice so the researchers sought an indirect method to boost its levels. To do so, they only had to look one step earlier in the NAD supply chain to a compound called NMN (nicotinamide mononucleotide).

NMN can be given safely to mice and is found naturally in a number of foods, including broccoli, cabbage, cucumber, edamame and avocado. The new study shows that when NMN is dissolved in drinking water and given to mice, it appears in the bloodstream in less than three minutes. Importantly, the researchers also found that NMN in the blood is quickly converted to NAD in multiple tissues.

“We wanted to make sure that when we give NMN through drinking water, it actually goes into the blood circulation and into tissues,” Imai said. “Our data show that NMN absorption happens very rapidly.”

To determine the long-term effects of giving NMN, Imai, Yoshino and their colleagues studied three groups of healthy male mice fed regular mouse chow diets. Starting at five months of age, one group received a high dose of NMN-supplemented drinking water, another group received a low dose of the NMN drinking water, and a third group served as a control, receiving no NMN. The researchers compared multiple aspects of physiology between the groups, first at 5 months of age and then every three months, until the mice reached 17 months of age. Typical laboratory mice live about two years.

The researchers found a variety of beneficial effects of NMN supplementation, including in skeletal muscle, liver function, bone density, eye function, insulin sensitivity, immune function, body weight and physical activity levels. But these benefits were seen exclusively in older mice.

“When we give NMN to the young mice, they do not become healthier young mice,” Yoshino said. “NMN supplementation has no effect in the young mice because they are still making plenty of their own NMN. We suspect that the increase in inflammation that happens with aging reduces the body’s ability to make NMN and, by extension, NAD.”

In skeletal muscle, the investigators — including the study’s first author, Kathryn Mills, the research supervisor in Imai’s lab — found that NMN administration helps energy metabolism by improving the function of mitochondria, which operate as cellular power plants. They also found that mice given NMN gained less weight with aging even as they consumed more food, likely because their boosted metabolism generated more energy for physical activity. The researchers also found better function of the mouse retina with NMN supplementation, as well as increased tear production, which is often lost with aging. They also found improved insulin sensitivity in the older mice receiving NMN, and this difference remained significant even when they corrected for differences in body weight.

In a paper published earlier this year in Cell Reports, Yoshino and his colleagues revealed more details of how NAD works in influencing glucose metabolism and the body’s fat tissue. In that study, the mice had a defect in the ability to manufacture NAD only in the body’s fat tissue. The rest of their tissues and organs were normal.

“Even though NAD synthesis was stopped only in the fat tissue, we saw metabolic dysfunction throughout the body, including the skeletal muscle, the heart muscle, the liver and in measures of the blood lipids,” Yoshino said. “When we gave NMN to these mice, these dysfunctions were reversed. That means NAD in adipose tissue is a critical regulator of whole body metabolism.”

Added Imai, “This is important because Jun showed that if you mess up NAD synthesis only in fat tissue, you see insulin resistance everywhere. Adipose tissue must be doing something remarkable to control whole body insulin sensitivity.”

During the long-term NMN study in healthy mice, Imai also said they monitored the animals for any potential increase in cancer development as a result of NMN administration.

“Some tumor cells are known to have a higher capability to synthesize NAD, so we were concerned that giving NMN might increase cancer incidence,” Imai said. “But we have not seen any differences in cancer rates between the groups.”

The phase 1 trial in Japan is using NMN manufactured by Oriental Yeast Co., which also provided the NMN used in these mouse studies. Outside of this clinical trial, high-grade NMN for human consumption is not commercially available. But there’s always broccoli.

 

Public Release: 31-Oct-2016

UC researchers affirm diet can impact migraines

University of Cincinnati Academic Health Center

CINCINNATI–Eliminating that morning ‘Cup of Joe,’ consuming processed foods high in nitrites or monosodium glutamate (MSG) and enjoying too much alcohol are potential headache triggers for individuals battling migraines, says Vincent Martin, MD, professor in the Department of Internal Medicine at the University of Cincinnati (UC) College of Medicine.

There are two different approaches to preventing headaches with diet. The first approach would be an elimination diet that avoids foods and beverages known to trigger headaches. The second approach would be follow a comprehensive diet whose very composition may prevent headaches, explains Martin, co-director of the Headache and Facial Pain Center at UC Gardner Neuroscience Institute and an expert in the area of migraine. His conclusions and others for migraineurs come after performing an exhaustive literature review of more than 180 research studies on the subject of migraine and diet.

Martin’s two-part review, “Diet and Headache” is available online in the scholarly publication Headache: The Journal of Head and Face Pain. It is co-authored by Dr. Brinder Vij, associate professor in the UC Department of Neurology and Rehabilitation Medicine.

“One of the most important triggers for headache is the withdrawal of caffeine,” says Martin, who also sees patients at UC Health. “Let’s say you regularly pound down three or four cups of coffee every morning and you decide to skip your morning routine one day, you will likely have full-fledged caffeine withdrawal headache that day.”

That said, too much coffee may also present a risk, no more than 400 milligrams daily–one cup is 125 milligrams–is probably the maximum for migraine patients, says Martin. “Large amounts of caffeine can bring on anxiety and depressive symptoms as well as headaches,” he explains.

Another trigger for migraine is MSG, which is a flavor enhancer used in a variety of processed foods, including frozen or canned foods, soups, international foods, snack foods, salad dressing, seasoning salts, ketchup, barbecue sauce, and heavily in Chinese cooking, says Martin.

“You eliminate it by eating fewer processed foods,” explains Martin. “You eat more natural things such as fresh vegetables, fresh fruits and fresh meats. MSG is most provocative when consumed in liquids such as soups.”

Nitrites are preservatives food in processed meats such as bacon, sausage, ham and lunch meat to preserve color and flavor. Martin says a diary study found that five percent of individuals with migraine were statistically more likely to have an attack on days when they consume nitrites. Use of nitrites in foods has declined with stronger government regulation though checking labels remains a good idea, he explains.

Alcohol is one of the most commonly reported dietary trigger factors for migraine and studies suggest vodka and red wines, especially those with highest histamine content are problematic, says Martin. There is a lot of interest in gluten-free diets, but they are only helpful in lessening headaches if the individuals suffer from celiac disease, which can be established by a positive blood test or intestinal biopsy, he adds.

There have been three comprehensive diets whose very composition may prevent headaches such as low fat and low carbohydrate diets as well as those that increase the amount of omega-3 fatty acids and decrease the amount of omega-6 fatty acids, according to Martin.

Vij says low fat diets restrict the amount of fat in the diet to less than 20 percent of your daily energy requirements. “The beauty of these diets is that they not only reduce headaches, but may produce weight loss and prevent heart disease”, says Vij.

Low carbohydrate diets such as ketogenic diets can reduce headache frequency, but it’s not something to consider without strict physician supervision. The diet limits carbohydrates more than the well-known Atkins diet, Vij explains.

One of the most promising diets for those with more frequent attacks of migraine is one that boosts your omega-3 fats while lessoning your omega-6 levels and that means tossing out polyunsaturated vegetable oils (corn, sunflower, safflower, canola and soy) in favor of flaxseed oil, says Martin. Foods to consume would include flaxseed, salmon, halibut, cod and scallops while those to avoid would be peanuts and cashews.

“Persons with headache and migraine have more dietary options than ever. Ultimately a healthy headache diet excludes processed foods, minimizes caffeine and includes a lot of fruits, vegetables, fish and lean meats”, Martin says. He adds, “After all, you are what you eat.”

Public Release: 1-Nov-2016

U-M study bodes well for low-carb eaters

University of Michigan

ANN ARBOR–Three low-carb meals within 24 hours lowers post-meal insulin resistance by more than 30 percent, but high-carb meals sustain insulin resistance, a condition that leads to high blood pressure, prediabetes and diabetes, according to a University of Michigan study.

The study also found that two hours of moderate-intensity exercise, which is supposed to lower insulin resistance and blood sugar levels, has no impact on these results. To the contrary, blood sugar levels increase after the exercise, said Katarina Borer, professor in the School of Kinesiology and principal investigator in a study done with doctoral student Po-Ju Lin, now at the University of Rochester Medical Center.

Insulin is a hormone critical in metabolism. Insulin sensitivity refers to insulin’s ability to efficiently respond to and regulate glucose in the blood, so that our cells can use it for energy and other functions. If we’re insulin resistant, insulin is less effective in removing glucose from the bloodstream and the pancreas must produce more insulin to help. This can eventually lead to diabetes.

The study sample was small, Borer said, but the results are significant, in part, because they reinforce results in two preceding studies and one 2015 review on high-carbohydrate diets and their negative effects on insulin.

In the U-M study, 32 post-menopausal metabolically healthy women were divided into four groups and given meals of either 30 or 60 percent carbohydrates with or without moderate-intensity exercise before meals. The low-carb group showed a reduction in insulin resistance after the third meal in the evening, but the high-carb group sustained high post-meal insulin, Borer said.

The high-carb group’s diet fell in line with the 45-to-60 percent daily carbohydrate intake the departments of Agriculture and Health and Human Services recommend, Borer said.

“We showed an acute, one-day reduction in insulin resistance after the third low-carbohydrate meal eaten in the evening, so one could argue that this is transient and insignificant,” Borer said. “But at least two other studies where high-carbohydrate meals were fed to volunteers for 5 and for 14 days show that the outcome was worrisome. These subjects developed increased fasting insulin secretion and insulin resistance, increased glucose release by the liver which produced high blood sugar, and dramatically lowered fat oxidation that contributes to obesity. These then were more persistent effects that could be a path to prediabetes and diabetes.

“What is remarkable about our findings is that they show that a simple dietary modification of reducing the carbohydrate content of the meals can, within a day, protect against development of insulin resistance and block the path toward development of prediabetes while sustained intake of high carbohydrate diets as shown in the two mentioned studies lead to increased fasting insulin secretion and resistance. And even more surprising and amazing is that exercise before the meals made the subjects more carbohydrate intolerant–that is, it increased evening blood sugar levels.”

Because exercise did not lower insulin resistance, it suggests that the insulin reaction the subjects experienced after the evening meal was driven by an intestinal response to the carbohydrate, and not by exercise. But this doesn’t mean exercise doesn’t influence insulin, she said.

Going forward, Borer’s lab will examine the timing of meals and whether insulin-lowering effect can be produced in the morning and whether blood sugar will decline when women exercise after low-carbohydrate meals.

Public Release: 2-Nov-2016

High-protein diets reduce liver fat

Deutsches Zentrum fuer Diabetesforschung DZD

According to a new nutritional study conducted by the German Institute of Human Nutrition (DIfE) on individuals with type 2 diabetes, high-protein diets reduced liver fat by up to 48 percent within six weeks. It did not matter whether the diet was mainly based on plant or animal protein.

The team of scientists led by Mariya Markova, Olga Pivovarova, Silke Hornemann and Andreas F. H. Pfeiffer of DIfE, a partner of the German Center for Diabetes Research (DZD), has now published its findings in the journal Gastroenterology (Markova et al. 2016; DOI: http://dx.doi.org/10.1053/j.gastro.2016.10.007).

Nonalcoholic fatty liver disease is the most common chronic liver disease in Europe and the U.S. “When left untreated, fatty liver is an important step progress to type 2 diabetes and can develop into liver cirrhosis, which can have life-threatening effects,” said endocrinologist Andreas F. H. Pfeiffer of DIfE, who led the study. “Since the number of affected persons is increasing, it is therefore more important than ever to work together with our partners to develop effective dietary strategies that prevent the disease,” he added.

Various studies throughout the world have already investigated the effects of high-protein diets on human metabolism. In many of these studies, scientists have observed beneficial effects on body weight, liver fat content, blood lipid levels, long-term blood glucose levels and muscle mass retention. However, some studies have also concluded that high protein intake can reduce insulin activity and affect renal function. Since both positive as well as negative effects have been observed, the researchers at DIfE posed the question whether the protein source was decisive for the respective effect. Therefore, in the current study, they investigated the effects of two high-protein diets* on the metabolism of 37 female and male subjects between the ages of 49 and 78 years suffering from type 2 diabetes and, in most cases, from fatty liver. The two diets differed only in the protein sources, which were either mainly plant or animal origin. To ensure that the weight of the participants remained stable during the entire study and that any weight loss could not influence the result, the scientists individually adjusted the energy content of the diet to each individual. The scientists randomized which of the two diet forms each participant should follow. The main source for the plant protein group were foods such as noodles or bread that were enriched with pea protein and were especially prepared by the company IGV Institut für Getreideverarbeitung GmbH. The animal protein group consumed lean milk products as well as white meat and fish as protein sources.

“As our results show, all study participants benefited from the high-protein diet, whether based on plant or animal protein. Negative effects on renal function or glucose metabolism were not observed,” said first author Markova. “Liver fat content decreased significantly, in half of the study participants by more than 50 percent. In conjunction with this, we observed favorable changes in the liver and lipid metabolism, improved insulin sensitivity of the participants and in addition a significant reduction in the hormone fibroblast growth factor 21 in the blood,” added Olga Pivovarova, who along with Mariya Markova and Silke Hornemann coordinated the current study. The function of the hormone released by the liver into the blood has not yet been adequately clarified and thus the results are not easy to interpret, according to the scientist. However, previous studies have shown that the hormone affects different organs and adipose tissue. Especially in overweight people, high concentrations are found in the blood. According to Silke Hornemann, a physician involved in the study, other studies as well as their own studies suggest that the hormone concentration also depends on the type and quantity of the consumed macronutrients.

“Larger and longer studies are needed to better understand the metabolic mechanisms underlying the observation, to study the long-term effects, and to see whether also younger patients would benefit from the change in diet,” said Pfeiffer. “The favorable effects we observed in the study may also be age-dependent, because the study participants were on average older than sixty years of age. If no renal disease is present, sufficient protein supply plays an important role particularly in this age group. For example, a decrease in muscle mass is often associated with age,” Pfeiffer added. Further research is still needed to elucidate the hormonal regulation mechanisms involved. In conclusion, however, it can be said that from the observations and taking into account environmentally relevant aspects, consumers should preferably rely on plant foods for their protein source.

Background Information:

In both diets, the respective protein content contributed 30 percent to the energy supply. The proportion of carbohydrate intake amounted to 40 percent, and fats amounted to 30 percent of the energy supply. In addition, the nutritionists advised both groups to maintain an equal intake of saturated, mono- and polyunsaturated fatty acids. Prior to the change in diet of the study participants the protein content of their diet contributed an average of 17 percent to the energy supply, the carbohydrate content 42 percent and fat content 41 percent.

Foods such as lean meat, fish, eggs and low-fat dairy products are very rich in protein, as are legumes (e.g. peas, beans, lentils), nuts and almonds. According to the German Nutrient Database (Bundeslebensmittelschlüssel), 100 grams of roast turkey breast contain 25.2 grams of protein, and 100 grams of dried green peas contain 22.9 grams.

The German Society of Nutrition (DGE) recommends for adults a daily intake of 0.8 grams of protein per kilogram of body weight. That means for a body weight of 60 kilograms, for example, 48 grams of protein per day. (Source: DGE).

The German Institute of Human Nutrition Potsdam-Rehbruecke (DIfE) is a member of the Leibniz Association. It investigates the causes of diet-related diseases in order to develop new strategies for prevention and therapy and to provide dietary recommendations. Its research focus includes the causes and consequences of the metabolic syndrome, which is a combination of obesity, high blood pressure, insulin resistance and lipid metabolism disorder, as well as the role of diet in healthy aging and the biological basis of food choices and eating habits. In addition, the DIfE is a partner of the German Center for Diabetes Research (DZD), which has been funded since 2009 by the BMBF. More information on the DZD can be found at http://www.dzd-ev.de

The Leibniz Association is the umbrella organization for 88 independent research institutions whose spectrum encompasses the natural, engineering and environmental sciences, economics and the spatial and social sciences as well as the humanities. Leibniz Institutes address issues of social, economic and ecological relevance. They conduct knowledge-driven and applied basic research, also in the overarching Leibniz research networks, as well as constitute or maintain scientific infrastructures and provide research-based services. The Leibniz Association sets priorities in knowledge transfer, in particular with the Leibniz research museums. It provides advice and information for policymakers, academia, business and industry and the general public. Leibniz Institutes collaborate intensively with universities – e.g. in the form of “Leibniz Science Campi” as well as with industry and other partners in Germany and abroad. They are subject to a transparent and independent review procedure. Due to their importance for Germany as a whole, they are funded jointly by the federal and state governments. Leibniz Institutes employ some 18,100 individuals, including 9,200 scientists. The overall budget of the institutes amounts to more than EUR 1.6 billion. More information can be found at http://www.leibniz-gemeinschaft.de.

Gut microbes linked to immunotherapy response in melanoma patients

Cancer Research UK

Patients with malignant melanoma — whose disease has spread — are more likely to respond to immunotherapy treatment if they had greater diversity in their gut bacteria, according to new research* presented at the National Cancer Research Institute’s (NCRI) Cancer Conference in Liverpool.

Scientists at the University of Texas MD Anderson Cancer Centre studied over 200 mouth and over 100 gut microbiome samples from people who had advanced melanoma.

They discovered that people whose cancer responded to immunotherapy treatment had more diversity in the types of bacteria found in their gut. They also found significant differences in the type of bacteria found in the gut of people whose cancer responded versus those who didn’t. There was no difference in the type of mouth bacteria between patients.

Early studies in mice have shown that changing the type of bacteria that live in the gut can improve the response to immunotherapy, but this is one of the first studies to look at the link in patients.

Immunotherapy, which harness the body’s immune system to target cancer cells, are an exciting avenue of cancer treatment. However, not all patients respond to these treatments, and researchers are trying to understand why.

This research suggests that adapting people’s gut bacteria, such as giving antibiotics, probiotics, or a faecal transplant before immunotherapy, could increase the benefits already achieved with new immunotherapy drugs now being used to treat several different types of cancer. However, this needs to be tested clinical trials.

Melanoma is the fifth most common cancer in the UK with about 14,600 people being diagnosed each year. And each year about 2,300 die from the disease.

Dr Jennifer Wargo, lead researcher at the University of Texas, said: “Our research shows a really interesting link that may mean the immune system is aided by gut bacteria when responding to these drugs. Not all patients respond to immunotherapy drugs and it’s hard to know who will benefit from the treatment prior to it being given.

“The gut microbiome can be changed through a number of different strategies, so there is real potential here to modify the gut microbiome to boost an immunotherapy response.”

Dr Pippa Corrie, Chair of the NCRI’s Skin Cancer Clinical Studies Group, said: “There is growing evidence that gut bacteria play a vital role in warding off disease, absorbing nutrients from the food we eat, and maintaining normal function of our immune systems.

“Gut microbes have been shown to influence the role of conventional chemotherapy, so it’s probably not surprising that they impact on response to new immunotherapies being used in the clinic. Manipulating the gut flora may be a new strategy to enhance activity of immunotherapy drugs, as well as to manage problematic toxicity in the future.”

This research was funded by the Melanoma Research Alliance and by the Melanoma Moon Shot Program at MD Anderson Cancer Center.

Public Release: 8-Nov-2016

Alzheimer’s disease found to be a diabetic disorder of the brain

Tohoku University

Researchers at Tohoku University have found a promising treatment for Alzheimer’s disease, by noticing a similarity in the way insulin signaling works in the brain and in the pancreas of diabetic patients.

“In the pancreas, the Kir6.2 channel blockade increases the insulin signaling, and insulin signaling decreases the blood glucose levels,” says Dr. Shigeki Moriguchi. “In the brain, insulin signaling increases the acquisition of memory through CaM kinase II activation by Kir6.2 channel blockade.”

The research group, led by Dr. Moriguchi and Professor Kohji Fukunaga of the Graduate School of Pharmaceutical Sciences, thus concluded that Alzheimer’s disease can be described as a diabetic disorder of the brain.

Memantine, a drug widely used to treat Alzheimer’s disease, is a well known inhibitor of the N-methyl-D-aspartate (NMDA) receptors that prevent excessive glutamate transmission in the brain. Researchers have now found that memantine also inhibits the ATP-sensitive potassium channel (Kir6.2 channel), improving insulin signal dysfunction in the brain.

In their experiment with mice, the researchers found that memantine treatment improved impaired hippocampal long-term potentiation (LTP) and memory-related behaviors in the mice through the inhibition of KATP channel Kir6.2.

“Since KATP channels Kir6.1 or Kir6.2 are critical components of sulfonylurea receptors (SURs) which is downstream insulin receptor signaling, the KATP channel inhibition by Memantine mediates the anti-diabetic drug action in peripheral tissues,” says Dr. Moriguchi. “And this leads to improved cognitive functions and improved memory retention among Alzheimer’s patients.”

The researchers now hope that results of their study and the parallels drawn with diabetes, will lead to new treatments for Alzheimer’s disease, using the inhibition of Kir6.2 channel.

Public Release: 9-Nov-2016

Expensive new cancer drugs have little effect on survival of many cancers

BMJ

Despite considerable investment and innovation, new cancer drugs approved in the past 10 years may have little effect on survival in adults with cancer, raising a number of concerns, argues an expert in The BMJ today.

Peter Wise, a former consultant at Charing Cross Hospital in London, says spending an annual six figure sum to prolong life by a few weeks or months “may be inappropriate” for many patients. In 2015, global sales of cancer drugs were around $110bn (£85bn; €95bn).

He calls for stricter drug approval criteria and improved consent processes “to achieve ethical treatment and reduce cancer costs.”

Cancer survival has improved in recent decades, he explains. In the US, for example, five year relative survival in adults with solid cancer increased from 49% in to 68% over 40 years.

But how much of the improvement in cancer survival can we attribute to new drugs, he asks? Other factors are more likely to have been responsible. Many new drugs approved in the last decade prolonged life by just one to two months.

“The approval of drugs with such small survival benefits raises ethical questions, including whether recipients are aware of the drugs’ limited benefits, whether the high cost:benefit ratios are justified, and whether trials are providing the right information,” writes Wise, whose major interests lie in the ethical elements of medical research and care.

He draws attention to limitations of cancer drug trials, such as the use of surrogate endpoints that allow earlier approval of new drugs, but are not always true indicators of survival benefit. And he warns that the marginal responses in clinical trials may not even apply to the majority of patients treated outside trials.

He is hopeful that the recent integration of the Cancer Drugs Fund into the National Institute of Health and Care Excellence (NICE) in England might make it possible to monitor the “real world benefit” of these drugs.

He also raises concern over the US Food and Drug Administration (FDA)’s accelerated and “breakthrough” category which, he says, compounds the risk of premature approval on limited evidence.

“The low bar of approval for these expensive drugs ignores the ethical principle of fairness and equity,” he writes. “By promoting marginally better treatment of poorly responsive cancers it diverts valuable resources that might be better employed for other health needs, within and outside cancer care.”

A lack of fully informed consent for cancer treatment is also a concern, often leading to misinformed patients with unrealistic expectations, he adds.

“Good cancer care demands empowerment of patients with accurate, impartial information followed by genuinely informed consent in both the clinical trial and therapeutic settings,” he writes. “Ethical impediments to sound practice need to be addressed and corrected.”

“Above all, the threshold for approval of new and existing cancer drugs needs to be raised – using more meaningful disease specific criteria of risk-benefit and cost-benefit,” he concludes.

Public Release: 10-Nov-2016

Huperzine A provides seizure protection in genetic epilepsy models

Plant compound raises seizure threshold in Dravet, GEFS+ models

Emory Health Sciences

The compound huperzine A can increase resistance to induced seizures in mouse models of genetic epilepsy, scientists at Emory University School of Medicine have found.

In particular, huperzine A shows potential for protecting against febrile seizures, which are a feature of both Dravet syndrome, a severe form of childhood epilepsy, and a related condition, GEFS+ (genetic epilepsy with febrile seizures plus).

The findings were recently published in Frontiers in Pharmacology.

Huperzine A comes from the club moss Huperzia serrata and has been used in traditional Chinese medicine. The compound has been tested for the treatment of inflammation and neurological disorders, including Alzheimer’s disease and schizophrenia.

Children with Dravet syndrome experience early-life seizures due to high fever as well as other types of seizures and developmental delays. Although the condition can be controlled with some antiepileptic drugs, most patients do not achieve adequate seizure control.

Most cases of Dravet syndrome are caused by “de novo” (not inherited) mutations in a sodium channel gene called SCN1A. The channel allows sodium to quickly enter into the cell, and forms part of the molecular machinery that is critical for how an electrical signal forms and travels along a neuron. In Dravet syndrome, the mutations often inactivate the gene, while SCN1A mutations in GEFS+ change properties of the sodium channel without inactivating it completely. Both types of mutations lead to increased neuron excitability.

“We think that huperzine A could normalize the balance between neuronal inhibition and excitation in patients with SCN1A mutations, thereby protecting against seizure generation,” says senior author Andrew Escayg, PhD, associate professor of human genetics at Emory University School of Medicine.

At Emory, Escayg and his colleagues have developed mice in which one copy of the SCN1A gene has been modified as mouse models for the study of Dravet syndrome and GEFS+. Co-first authors of the paper are postdoctoral fellow Jennifer Wong, PhD and Stacey Dutton, PhD, now an assistant professor of biology at Agnes Scott College.

SCN1A mutant mice exhibit increased susceptibility to seizures induced by hyperthermia, which serves as a model of human febrile seizures. In the Frontiers paper, almost all SCN1A mutant mice exhibited a seizure when their core body temperature reached 40°C. In contrast, when the mice were pre-treated with huperzine A, they only experienced a seizure at significantly higher temperatures. Escayg’s team also found that huperzine A can reduce the frequency and severity of electrically and chemically induced seizures, both in normal mice and in SCN1A-mutant mice.

In these experiments, the scientists observed that the protective effect against electricity-induced seizures in normal mice diminishes after 12 days of daily huperzine A administration, but “complete protection” is maintained in the SCN1A-mutant mice.

“The protection observed in normal mice suggest huperzine A might also increase seizure resistance in other forms of treatment-resistant epilepsy. While these results are encouraging, further research will be required to determine suitability of using huperzine A as a clinical treatment for epilepsy,” Escayg says.

Biscayne Pharmaceuticals has plans to begin a phase 1b clinical trial of huperzine A in adults with refractory complex partial epilepsy in 2017. Clinical studies in children with Dravet syndrome are planned after additional toxicology studies are performed, as required by regulatory authorities.

Huperzine A is thought to work, in part, by inhibiting the enzyme acetylcholinesterase, which breaks down the neurotransmitter acetylcholine. Thus, huperzine A can increase the levels of acetylcholine in the brain.

In mice, the scientists observed some transient side effects from huperzine A administration: hypothermia, muscle twitching and lethargy. However, they determined that hypothermia does not contribute to seizure protection. Previous clinical studies have reported side effects such as nausea and vomiting. Wong and Escayg are now testing whether huperzine A can reduce the frequency of spontaneous seizures in their mouse models.

Public Release: 10-Nov-2016

Probiotics improve cognition in Alzheimer’s patients

Frontiers

For the first time, scientists have shown that probiotics — beneficial live bacteria and yeasts taken as dietary supplements — can improve cognitive function in humans. In a new clinical trial, scientists show that a daily dose of probiotic Lactobacillus and Bifidobacterium bacteria taken over a period of just 12 weeks is enough to yield a moderate but significant improvement in the score of elderly Alzheimer’s patients on the Mini-Mental State Examination (MMSE) scale, a standard measure of cognitive impairment.

Probiotics are known to give partial protection against certain infectious diarrheas, irritable bowel syndrome, inflammatory bowel disease, eczema, allergies, colds, tooth decay, and periodontal disease. But scientists have long hypothesized that probiotics might also boost cognition, as there is continuous two-way communication between the intestinal microflora, the gastrointestinal tract, and the brain through the nervous system, the immune system, and hormones (along the so-called “microbiota-gut-brain axis”). In mice, probiotics have indeed been shown to improve learning and memory, and reduce anxiety and depression- and OCD-like symptoms. But prior to the present study there was very limited evidence of any cognitive benefits in humans.

Here, the researchers, from Kashan University of Medical Sciences, Kashan, and Islamic Azad University, Tehran, Iran, present results from a randomized, double-blind, controlled clinical trial on a total of 52 women and men with Alzheimer’s between 60 and 95 years of age. Half of the patients daily received 200 ml milk enriched with four probiotic bacteria Lactobacillus acidophilus, L. casei, L. fermentum, and Bifidobacterium bifidum (approximately 400 billion bacteria per species), while the other half received untreated milk.

At the beginning and the end of the 12-week experimental period, the scientists took blood samples for biochemical analyses and tested the cognitive function of the subjects with the MMSE questionnaire, which includes tasks like giving the current date, counting backwards from 100 by sevens, naming objects, repeating a phrase, and copying a picture.

Over the course of the study, the average score on the MMSE questionnaire significantly increased (from 8.7 to 10.6, out of a maximum of 30) in the group receiving probiotics, but not in the control group (from 8.5 to 8.0). Even though this increase is moderate, and all patients remained severely cognitively impaired, these results are important because they are the first to show that probiotics can improve human cognition. Future research, on more patients and over longer time-scales, is necessary to test if the beneficial effects of probiotics become stronger after longer treatment.

“In a previous study, we showed that probiotic treatment improves the impaired spatial learning and memory in diabetic rats, but this is the first time that probiotic supplementation has been shown to benefit cognition in cognitively impaired humans,” says Professor Mahmoud Salami from Kashan University, the senior author of the study.

Treatment with probiotics also resulted in lower levels of triglycerides, Very Low Density Lipoprotein (VLDL), high-sensitivity C-Reactive Protein (hs-CRP) in the blood of the Alzheimer patients, and likewise a reduction in two common measures (called “Homeostatic Model Assessment”, HOMA-IR and HOMA-B) of insulin resistance and the activity of the insulin-producing cells in the pancreas.

“These findings indicate that change in the metabolic adjustments might be a mechanism by which probiotics affect Alzheimer’s and possibly other neurological disorders,” says Salami. “We plan to look at these mechanisms in greater detail in our next study.”

Walter Lukiw, Professor of Neurology, Neuroscience and Ophthalmology and Bollinger Professor of Alzheimer’s disease at Louisiana State University, who reviewed the study but was not involved in the research, said: “This early study is interesting and important because it provides evidence for gastrointestinal (GI) tract microbiome components playing a role in neurological function, and indicates that probiotics can in principle improve human cognition. This is in line with some of our recent studies which indicate that the GI tract microbiome in Alzheimer’s is significantly altered in composition when compared to age-matched controls, and that both the GI tract and blood-brain barriersbecome significantly more leaky with aging, thus allowing GI tract microbial exudates (e.g. amyloids, lipopolysaccharides, endotoxins and small non-coding RNAs) to access Central Nervous System compartments.”

The study is published in the open-access journal Frontiers in Aging Neuroscience.

 

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