New wonder compound offers strong protection against harmful effects of UVA rays

A new wonder compound developed by University of Bath scientists in collaboration with King's College London offers unprecedented protection against the harmful effects of UVA radiation in sunlight, which include photo-ageing, cell damage and cancer.

Most sunscreens on the market protect well against solar UVB radiation but have limited effectiveness against UVA-induced damage, relying on the reflective properties of creams to defend against dangerous UVA rays.

However this compound, called the 'mitoiron claw' by the team, offers strong protection within our cells precisely where the greatest damage from UVA occurs, and doesn't interfere with rest of the cell.

The researchers from the University of Bath, working with colleagues at Kings College London, hope to see the mitoiron claw compound added to sunscreens and skin care products within 3-4 years.

Free iron concentration is particularly high within mitochondria, the batteries of the cell, where it is needed for several vital functions. However upon exposure to UVA in sunlight, excess free iron acts as a catalyst for the production of toxic reactive oxygen species (ROS), damaging cell components such as DNA, fat and proteins thereby increasing the risk of cell death and cancer.

However this custom-designed iron chelator (a molecule that binds to an iron atom like a claw) moves directly to mitochondria where it safely binds the excess free iron, preventing it from reacting upon exposure to UVA rays.

Tests with human skin fibroblast cells exposed to UVA radiation equivalent to 140 min of uninterrupted sun exposure at sea level, showed cells treated with the mitoiron claw were completely protected against cell death. Untreated cells suffered significant cell death.

The research is published in the Journal of Investigative Dermatology.

Dr Charareh Pourzand, from the Department of Pharmacy and Pharmacology at the University of Bath, said: "The role of iron-mediated damage induced upon exposure of skin cells to UVA has been underestimated for many years. For efficient protection against UVA-induced iron damage of skin strong chelators are needed, but until now these risked toxic effects caused by non-targeted iron starvation of cells.

"Our mitochondria-targeted compound provides a solution to this problem and can address an unmet need in the skincare and sunscreen fields. This mitoiron claw is a highly effective compound, offering unprecedented protection against UVA-induced mitochondrial damage."

Now that the protective effects of the compound have been demonstrated the team, Dr Charareh Pourzand and Dr Olivier Reelfs from University of Bath and Prof Robert Hider and Dr Vincenzo Abbate at Kings College London, plans further work to explore the potential of this new type of compound.

This includes the possibility of developing therapies for diseases involving mitochondrial iron overload, such as Friedreich's ataxia.


Ref:

1. http://www.bath.ac.uk/news/2016/07/20/sun-cream-uva/

2. http://www.jidonline.org/article/S0022-202X(16)31053-3/fulltext

New wonder compound offers strong protection against harmful effects of UVA rays

Combinations of three antibiotics could help combat drug-resistant bacterial infections

Each year, approximately 700,000 people die from drug-resistant bacterial infections. A study by UCLA life scientists could be a major step toward combating drug-resistant infections.

The research, reported in the journal Royal Society Interface, found that combinations of three different antibiotics can often overcome bacteria's resistance to antibiotics, even when none of the three antibiotics on their own -- or even two of the three together -- is effective.

The researchers grew E. coli bacteria in a laboratory and treated the samples with combinations of one, two and three antibiotics from a group of 14 drugs. The biologists studied how effectively every single possible combination of drugs worked to kill the bacteria.

Some combinations killed 100 percent of the bacteria, including 94 of the 364 three-drug groupings the researchers tested. According to said Pamela Yeh, the paper's senior author and a UCLA assistant professor of ecology and evolutionary biology, the success rate might have been even greater if the researchers tested higher doses of the drugs.

Elif Tekin, the paper's lead author and a UCLA graduate student, helped create a sophisticated framework that enabled the scientists to determine when adding a third antibiotic was producing new effects that combinations of just two drugs couldn't achieve.

"Three antibiotics can change the dynamic," she said. "Not many scientists realize that three-drug combinations can have really beneficial effects that they would not have predicted even by studying all pairs of the antibiotics together."

Different classes of antibiotics use different mechanisms to fight bacteria. One class, which includes amoxicillin, kill bacteria by preventing them from making cell walls. Another disrupts their tightly coiled DNA. A third inhibits their ability to make proteins. But there had been little previous research indicating that combinations of three antibiotics might be more potent together than any two of them.

"People tend to think that you don't need to understand interactions beyond pairs," said Van Savage, a co-author of the paper and a UCLA associate professor of ecology and evolutionary biology and of biomathematics. "We found that isn't always so."

The researchers combined techniques from biology and mathematics to determine which groups of antibiotics would be most effective.

"The three antibiotics must be chosen systematically and rationally," Yeh said.

In addition to identifying certain combinations that were more potent than the researchers expected, the analysis revealed that adding a third antibiotic sometimes made the drug combination less potent -- sometimes much less so, she said.

Yeh said the findings could be one weapon to fight what has become a major public health risk, but overcoming drug resistance will require a full arsenal.

"We need sound policy to stop the overuse of antibiotics, doctors to prescribe antibiotics wisely, agriculture to stop overusing antibiotics and researchers to develop new antibiotics," she said. "We need to attack this problem from all sides. We think our contribution will buy time for researchers to better leverage existing drugs and for policymakers to develop better policy about the use of antibiotics."

Another benefit of three-drug combinations is that they could allow doctors to prescribe lower doses of each antibiotic, which could reduce side effects.

The researchers plan to make available open-access software that would let other scientists and clinicians decide which combinations of antibiotics will be most effective.

Yeh said the team's approach could also be used to study how four or more pharmaceuticals interact, and a similar mathematical framework could be used to better understand climate change (for example, to understand how temperature, rainfall, humidity and acidity of the oceans interact) and other scientific questions that have three or more key factors.

Ref : http://rsif.royalsocietypublishing.org/content/13/119/20160332

Combination of two plant compounds holds promise in treating colon cancer

In combination of my update on curcumin

The combination of two plant compounds that have medicinal properties - curcumin and silymarin - holds promise in treating colon cancer, according Saint Louis University research published in the June 23 issue of the Journal of Cancer.

   curcumin

 silymarin

Curcumin is the active ingredient in the spice turmeric, which is present in spicy curry dishes, and silymarin is a component of milk thistle, which has been used to treat liver disease.

The researchers and their students studied a line of colon cancer cells in a laboratory model. They found treating the cells initially with curcumin, then with silymarin was more effective in fighting cancer than treating the cells with either phytochemical alone, said Uthayashanker Ezekiel, Ph.D., corresponding author and associate professor of biomedical laboratory science at Saint Louis University.

"The combination of phytochemicals inhibited colon cancer cells from multiplying and spreading. In addition, when the colon cancer cells were pre-exposed to curcumin and then treated with silymarin, the cells underwent a high amount of cell death," Ezekiel said.

"Phytochemicals may offer alternate therapeutic approaches to cancer treatments and avoid toxicity problems and side effects that chemotherapy can cause."

Ezekiel noted the research is a preliminary cell study, with more research ahead before scientists know if the compounds are an effective treatment for people who have colon cancer. He saw promise in using the phytochemicals to help prevent colon cancer, which frequently is caused by lifestyle factors, such as diet.

Scientists next would need to study how the curcumin and silymarin impact the actions of molecules, such as genetic transcription and expression, that cause cells to change, Ezekiel said. Then the compounds would be studied in an animal model, then in humans.

"Concentrations of curcumin and silymarin that are too high could be harmful to people," he said. "We still have much to learn, and for now, it's so much safer to add a little spice to your diet and get your curcumin from foods that contain turmeric, such as curry, rather than taking high doses of the compound."

Cinnamon treatment turns poor-learning mice into good ones, research shows

If Dr. Kalipada Pahan's research pans out, the standard advice for failing students might one day be: Study harder and eat your cinnamon!

  (sodium benzoate)

Pahan a researcher at Rush University and the Jesse Brown Veterans Affairs Medical Center in Chicago, has found that cinnamon turns poor learners into good ones--among mice, that is. He hopes the same will hold true for people.

His group published their latest findings online June 24, 2016, in the Journal of Neuroimmune Pharmacology.

"The increase in learning in poor-learning mice after cinnamon treatment was significant," says Pahan. "For example, poor-learning mice took about 150 seconds to find the right hole in the Barnes maze test. On the other hand, after one month of cinnamon treatment, poor-learning mice were finding the right hole within 60 seconds."

Pahan's research shows that the effect appears to be due mainly to sodium benzoate--a chemical produced as cinnamon is broken down in the body.

If that chemical sounds familiar, you may have noticed it on the ingredient labels of many processed foods. Food makers use a synthetic form of it as a preservative. It is also an FDA-approved drug used to treat hyperammonemia--too much ammonia in the blood.

Though some health concerns exist regarding sodium benzoate, most experts agree it's perfectly safe in the amounts generally consumed. One reassuring point is that it's water-soluble and easily excreted in the urine.

Cinnamon acts as a slow-release form of sodium benzoate, says Pahan. His lab studies show that different compounds within cinnamon--including cinnamaldehyde, which gives the spice is distinctive flavor and aroma--are "metabolized into sodium benzoate in the liver. Sodium benzoate then becomes the active compound, which readily enters the brain and stimulates hippocampal plasticity."

Those changes in the hippocampus--the brain's main memory center--appear to be the mechanism by which cinnamon and sodium benzoate exert their benefits.

In their study, Pahan's group first tested mice in mazes to separate the good and poor learners. Good learners made fewer wrong turns and took less time to find food.

In analyzing baseline disparities between the good and poor learners, Pahan's team found differences in two brain proteins. The gap was all but erased when cinnamon was given.

"Little is known about the changes that occur in the brains of poor learners," says Pahan. "We saw increases in GABRA5 and a decrease in CREB in the hippocampus of poor learners. Interestingly, these particular changes were reversed by one month of cinnamon treatment."

The researchers also examined brain cells taken from the mice. They found that sodium benzoate enhanced the structural integrity of the cells--namely in the dendrites, the tree-like extensions of neurons that enable them to communicate with other brain cells.

Cinnamon, like many spices, has antioxidant and anti-inflammatory properties. So it could be expected to exert a range of health-boosting actions, and it does have a centuries-long history of medicinal use around the world.

But the U.S. National Center for Complementary and Integrative Health says that "high-quality clinical evidence to support the use of cinnamon for any medical condition is generally lacking." Most of the clinical trials that have taken place have focused on the spice's possible effect on blood sugar for people with diabetes. Little if any clinical research has been done on the spice's possible brain-boosting properties.

Pahan hopes to change that. Based on the promising results from his group's preclinical studies, he believes that "besides general memory improvement, cinnamon may target Alzheimer's disease, mild cognitive impairment [a precursor to Alzheimer's], and Parkinson's disease as well." He is now talking with neurologists about planning a clinical trial on Alzheimer's.

Before you start heaping cinnamon on your oatmeal, keep a few caveats in mind.

First, most cinnamon found in the store is the Chinese variety, which contains a compound called coumarin that may be toxic to the liver in high amounts. A person would likely have to eat tons of cinnamon to run into a problem, but just the same, Pahan recommends the Ceylon or Sri Lanka type, which is coumarin-free.

Even then, don't overdo it. "Anything in excess is toxic," says Pahan.

What about simply inhaling the pleasant-smelling spice? Will that benefit the brain?

"Simply smelling the spice may not help because cinnamaldehyde should be metabolized into cinnamic acid and then sodium benzoate," explains Pahan. "For metabolism [to occur], cinnamaldehyde should be within the cell."

As for himself, Pahan isn't waiting for clinical trials. He takes about a teaspoonful--about 3.5 grams--of cinnamon powder mixed with honey as a supplement every night.

Should the research on cinnamon continue to move forward, he envisions a similar remedy being adopted by struggling students worldwide.

"Individual differences in learning and educational performance is a global issue, he says. "In many cases, we find two students of the same background studying in the same class, and one turns out to be a poor learner and does worse than the other academically. Now we need to find a way to test this approach in poor learners. If these results are replicated in poor-learning students, it would be a remarkable advance. At present, we are not using any other spice or natural substance."

Rare antibiotic compound detected in fungi for first time

In continuation of my update on valproic acid

Besides mushrooms such as truffles or morels, also many yeast and mould fungi, as well as other filamentous fungi belong to the Ascomycota phylum. They produce metabolic products which can act as natural antibiotics to combat bacteria and other pathogens. Penicillin, one of the oldest antibiotic agents, is probably the best known example. Since then, fungi have been regarded as a promising biological source of antibiotic compounds. Researchers expect that there is also remedy for resistant pathogens among these metabolites.

It depends on the stimulus

However, agents like penicillin are only produced when necessary, not permanently. "Fungi can even deactivate the respective parts of their genome if a metabolite is not needed anymore. These compounds can't be detected any longer and are classified as cryptic compounds," explained Christoph Zutz from the Institute for Milk Hygiene, Milk Technology and Food Science of the Vetmeduni Vienna.

The right stimulus can reinduce the production of antibiotic compounds. The researchers used valproic acid which can induce the activation of such deactivated genes in fungi. In the fungus Doratomyces microsporus, valproic acid even induced the production of several antimicrobial compounds.

 1.valproic acid  

2. cyclo-(L-proline-L-methionine)

Rare compound detected in fungi for the first time

The gained metabolites were effective against a "normal", as well as resistantStaphylococcus aureus pathogens. The team succeeded in filtering out the six most active compounds from all metabolites. These six compounds have been regarded as "cryptic" so far. One compound, cyclo-(L-proline-L-methionine) or cPM, could be detected even for the first time in a fungus. The only source of this compound so far has been a bacterium living in an Antarctic sponge.

Boosting effect as an asset in the fight against resistance

The as yet "cryptic" compound cPM has a special function. It boosts the activity of other antimicrobial compounds. The team assumes that particularly this boosting effect constitutes the effect these compounds have on the tested pathogens.

Therefore, the researchers went a step further and tested the newly detected compound cPM together with ampicillin in two ampicillin-resistant bacteria. The combination has proved successful. "The resistance was demonstrably reduced, even at a lower dose of ampicillin than usually," said co-author and corresponding group leader Kathrin Rychli.

New research platform is looking at the big picture

The team is now going to search for novel antibiotic compounds from other microorganisms by applying similar methods. The new research platform "Bioactive Microbial Metabolites" (BiMM) in Tulln (Lower Austria) provides the facility. BiMM represents the detection of bioactive compounds - metabolites - in microorganisms. "Valproic acid is not the only way to gain active compounds from fungi or other microorganisms. You can also make bacteria and fungi grow together. This also leads to a natural stimulus," explained Joseph Strauss from the University of Natural Resources and Life Sciences, Vienna, who heads the platform. For this purpose, researchers from the University of Veterinary Medicine, Vienna and the University of Natural Resources and Life Sciences, Vienna founded this new research core facility.

Christoph Zutz identified a significant advantage of this inter-university research platform. "Unlike industrial enterprises, we investigate all promising metabolites in microorganisms, not only single chemical compounds. Thus, we consider known and cryptic compounds in our analyses."

Ref : http://www.vetmeduni.ac.at/en/infoservice/news/detail/artikel/2016/07/15/fungi/

Antipsychotic drug could help reduce nausea and vomiting caused by chemotherapy

In continuation of my update on Olanzapine

A drug that blocks neurotransmitters could reduce nausea and vomiting caused by chemotherapy, research co-authored by a Sanford Health physician and published in theNew England Journal of Medicine finds.

Sanford oncologist and cancer researcher Steven Powell, M.D., was among a team of researchers who discovered that the drug olanzapine, which is FDA approved for use as an antipsychotic agent, significantly improved nausea prevention in patients who were receiving chemotherapy for cancer treatment. The drug blocks neurotransmitters involved with nausea and vomiting.

"We've long known the nausea and vomiting that come along with chemotherapy are a major problem and affect the quality of life of our patients," said Powell. "The findings of this study, fortunately, provide physicians with a tool to better address the needs of those they are treating for cancer."

Researchers noted that within the first day after treatment, 74 percent of study participants experienced no nausea or vomiting when their chemotherapy was paired with olanzapine. When a placebo was used instead of olanzapine, that figure dropped to 45 percent. This benefit continued for five days after chemotherapy treatment for many patients.

Ref : http://www.sanfordhealth.org/newsroom/2016/07/sanford-physician-assists-in-developing-new-treatment

Antipsychotic drug could help reduce nausea and vomiting caused by chemotherapy

Virgin olive oil helps in preventing and treating hypertension

Oleic acid plus a constellation of minor constituents as a natural antihypertensive.

Consumption of virgin olive oil is good for you, but why? Scientific evidence on this issue has been accumulating for a quarter century. Epidemiological, clinical, and animal studies support that the consumption of virgin olive oil, instead of other sources of dietary fats, has antihypertensive effects.

What contains does virgin olive oil contain that makes it so healthy? Virgin olive oil is an oily fruit whose composition includes large quantities of oleic acid (a monounsaturated fatty acid) and also a variety of compounds present in lower quantities, named minor constituents, such as hydrocarbons, phytosterols, triterpenic compounds, and phenolic compounds. Both oleic acid and these minor constituents confer unique bioactive properties to virgin olive oil.

How do its components protect from hypertension? They influence on factors associated with the pathophysiology of hypertension such as vascular contractibility and protect from heart and kidney cellular loss and functionality, leading to a reduction of blood pressure.

Is it a miraculous ingredient? No, it is just a food. Virgin olive oil helps in preventing and treating hypertension but its full power arises as part of the Mediterranean diet in a global strategy for a healthy and long-lasting life.

Metallic molecule offers real-time monitoring of amyloid plaques in patients with Alzheimer's

  

A metallic molecule being studied at Rice University begins to glow when bound to amyloid protein fibrils of the sort implicated in Alzheimer's disease. When triggered with ultraviolet light, the molecule glows much brighter, which enables real-time monitoring of amyloid fibrils as they aggregate in lab experiments.

Rice chemist Angel Martí said such a powerful probe could be a boon to researchers seeking a way to break up amyloid plaques, which form in the brains of patients with Alzheimer's. Martí's lab reported on the light-switching molecule in the Journal of the American Chemical Society. Rice graduate student Amir Aliyan is lead author of the paper.

Martí and his team study dyes made of metallic complexes that luminesce when attached to amyloid fibrils or DNA. They discovered that when rhenium dipyridophenazine complexes bind with an amyloid fibril in a test tube and are excited with ultraviolet light, the synthetic molecules increase their natural photoluminescence by several orders of magnitude.

"Most dyes decrease their fluorescence upon continuous excitation because they photobleach," Martí said. "This dye does the complete opposite, increasing its emission even more every time you excite it." The effect isn't nearly as strong if the metallic molecule is either floating in a solution or attached to single amyloid strands, he said.

The effect is seen in two stages, he said. The probe incorporates a hydrophobic part that naturally binds to aggregating fibrils and emits light when it does, giving researchers a clear signal that aggregation is happening. Exciting the combined aggregate and probe with ultraviolet light then boosts the light output more than a hundredfold.

The Rice researchers suspect the dramatic increase happens when reactive oxygen species attack the amino acids on the amyloid beta fibril that would normally quench the luminescence of the metal complex.

"Our hypothesis is that upon ultraviolet irradiation, our (rhenium) metal complex produces reactive oxygen species and they're more aggressive than conventional molecular oxygen," Aliyan said. "There are reports that rhenium complexes are capable of activating oxygen from one form to a more aggressive form in solution."

"That's one of our theories," Martí added. "We still don't understand well what is happening. But we know that besides increasing the emission intensity, the complex also chemically modifies the (amyloid) protein."

Martí said experiments that removed as much oxygen as possible eliminated the enhanced fluorescence effect. He said the lab stepped back to test an earlier metallic complex based on ruthenium, which also showed emission when attached to amyloid fibrils. It did not show enhanced emission under ultraviolet light.

"We thought the effect might be happening with ruthenium and we had completely missed it, so we ran a control experiment and nothing happened," he said.

That makes the rhenium complex unique so far. It also gives researchers the opportunity to learn more about amyloid beta proteins and the mechanics of aggregation, Martí said.

"We've always been interested in knowing where these complexes bind," he said. "If they oxidize amyloid beta in the periphery of their binding site, then by tracking the place of oxidation we will know the place of binding. That is called footprinting. It will allow us to specifically explore binding and how chemical modification of the surface of the protein would affect factors like toxicity and aggregation."

Aliyan said the probe allows real-time protein aggregation study as the probe turns on upon aggregation. "To the naked eye, aggregation is not obvious," he said. "You need a probe to follow the process and see if potential drugs can inhibit aggregation or make it faster or slower. Then you can run assays with or without any drug and in a variety of conditions. One would think if there are ways to modify amyloid beta aggregation, maybe there are ways to treat the process." 

Everolimus combined with standard R-CHOP therapy shows promise in treating DLBCL patients

In continuation of my update on everolimus

The targeted therapy everolimus may be safely combined with R-CHOP for new, untreated diffuse large B-cell lymphoma according to the results of a pilot study by Mayo Clinic researchers published in the Lancet Haematology. R-CHOP is a combination of drugs used to treat lymphoma. The combination includes rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone.

"There is an unmet need to develop new therapies based on R-CHOP to try to increase the cure rate for diffuse large B-cell lymphoma," says Patrick Johnston, M.D., Ph.D., a hematologist at Mayo Clinic and lead author. "This pilot study suggests that adding mTOR inhibitors to standard therapy could improve outcomes, though it needs to be validated in a larger clinical trial."

The everolimus, R-CHOP combination was well-tolerated by patients with no dose-limiting toxicity reached within the planned dose escalation. The vast majority of patients (96 percent) achieved an overall response, and all responders achieved a complete metabolic response to the treatment. The findings indicate that drugs targeting the P13K-mTOR pathway — a cascade of molecules involved in cell growth and survival — add benefit when combined with standard R-CHOP therapy.

Lymphoma is the sixth most common cancer in the U.S., and diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma. The standard accepted treatment for DLBCL is a combination R-CHOP delivered in a 21-day cycle for six cycles. However, this regimen typically cures only approximately 60 percent of patients.

Dr. Johnston and his colleagues scoured the scientific literature in search of ways to improve the cure rate. Two lines of evidence pointed toward targeting the P13K-mTOR pathway. First, numerous studies have demonstrated the importance of this pathway in the pathogenesis of DLBCL cells in the laboratory. Second, clinical studies have documented the single-agent efficacy of everolimus (an mTOR inhibitor) in relapsed DLBCL. Therefore, Mayo Clinic researchers decided to test a regimen that combined the standard R-CHOP with everolimus.

They conducted a phase 1 and feasibility study in 24 patients with new, previously untreated DLBCL in the Alliance for Clinical Trials in Oncology, a National Cancer Institute cooperative group. Patients received everolimus for 14 days in combination with R-CHOP-21. A large proportion of patients achieved an overall response (96 percent) and a complete metabolic response as assessed by positron emission tomography imaging (96 percent). No relapses with DLBCL occurred and all patients achieved the predictive milestone of being event-free at 12 months from enrollment. The treatment was well-tolerated, and the most common adverse events were hematological in nature, such as grade 4 neutropenia (75 percent) and grade 3 febrile neutropenia (21 percent).

"This study is the first to integrate a P13K-mTOR agent with standard RCHOP," says Dr. Johnston. "The encouraging outcome results and toxicity profile of this new regimen, along with the worldwide availability of everolimus, make it potentially applicable to the large population of DLBCL patients."

Urolithin A found in pomegranates may improve muscle strength and endurance during aging

In continuation of my update on Urolithin A

Amazentis SA, an innovative life sciences company applying scientific breakthroughs in nutrition to manage health conditions linked to aging, announced today a collaborative publication in Nature Medicine with the École Polytechnique Fédérale de Lausanne (EPFL), demonstrating that the Company's lead product candidate, urolithin A, improves mitochondrial and muscle function, resulting in enhanced muscle strength and endurance during aging. Amazentis is presently evaluating urolithin A in a first human clinical trial with results expected in 2017.

Urolithin A is generated by gut microflora as a natural metabolite of ellagitannins, a class of compounds found in the pomegranate and other fruits and nuts. "We are excited to publish the first data that demonstrate the effects of this gut metabolite on mitochondrial and muscle function," commented Johan Auwerx, Professor at the École Polytechnique Fédérale de Lausanne (EPFL), Switzerland, and lead author. "We believe this research is a milestone in current anti-aging efforts, which have previously focused on traditional pharmaceutical modalities, and illustrates the opportunity of rigorously tested nutritional bioactive agents that we consider to have outstanding potential for human health."

Urolithin A: a potent gut metabolite to rejuvenate mitochondria and reverse muscle aging

Oral administration of urolithin A leads to an improved mitochondrial function by stimulating mitophagy, a process by which damaged mitochondria are recycled to permit a renewal with healthy mitochondria.

"Mitophagy declines in cells as we age, and the reduction in mitochondrial function in the muscles of the elderly is thought to be one of the main causes of age-related muscle impairment. We believe our research, uncovering the health benefits of urolithin A, holds promise in reversing muscle aging," stated Patrick Aebischer, co-author on the article, EPFL President and Chairman and co-founder of Amazentis.

The results are being reported in the current issue of Nature Medicine in an article titled, "Urolithin A induces mitophagy and prolongs lifespan in C. elegans and increases muscle function in rodents".

Age-related muscle decline: a compelling market opportunity for urolithin A

Declining skeletal muscle mass and the resulting loss of strength are hallmarks of aging. These changes can become debilitating and lead to a condition termed sarcopenia, which is thought to affect 30% of those over 60 years old and greater than 50% of individuals over 80 years. Current estimates in the United States project there will be greater than 75 million adults over 60 years by the year 2020.

The resulting reductions in quality of life and independence as a result of muscle decline constitute a growing healthcare issue in the aging population. There are currently no pharmaceutical therapies to treat age-related decline in muscle function and sarcopenia. Nutritional strategies have had limited impact to date, and new scientifically validated solutions are urgently needed.

Upon consumption of pomegranate juice, compounds known as ellagitannins are broken down in the stomach and then transformed by intestinal bacteria into urolithin A. This biotransformation has been shown to vary widely across individuals, with some showing high or low conversion rates, while others have different compositions of microflora and are unable to perform the conversion. Consequently, supplementing individuals with products designed to deliver carefully calibrated doses of urolithin A can overcome this natural diversity in gut microflora found in the general population.

Amazentis has established a technology portfolio and proprietary knowhow around urolithin A, enabling the manufacture and development of advanced nutrition products for oral delivery.

Chris Rinsch, Ph.D., a co-author and CEO and co-founder of Amazentis, commented, "Based on the rigorous science being published in Nature Medicine, we have advanced our lead product delivering urolithin A into clinical trials. We believe that this discovery will open the door to a new approach for managing muscle decline by rejuvenating mitochondria. Our vision is to translate breakthrough scientific discoveries in nutrition into clinically validated consumer health products that address today's unmet needs in an aging population."

Leukemia drug increases brain dopamine, lowers toxic proteins linked to Parkinson's or dementia

My updates on  nilotinib

A small phase I study provides molecular evidence that an FDA-approved drug for leukemia significantly increased brain dopamine and reduced toxic proteins linked to disease progression in patients with Parkinson's disease or dementia with Lewy bodies. Dopamine is the brain chemical (neurotransmitter) lost as a result of death of dopamine-producing neurons in these neurodegenerative diseases.

Researchers from Georgetown University Medical Center (GUMC), say the findings, described in the Journal of Parkinson's Disease, support improved clinical outcomes observed and first reported at the Society for Neuroscience annual meeting in October 2015.

The study tested nilotinib taken daily for six months. A much smaller dose of nilotinib (150 or 300 mg once daily) was used compared to the dose for chronic myelogenous leukemia (300-400 mg twice daily). Twelve patients were enrolled in the clinical trial — one patient withdrew due to an adverse event. Researchers say the drug appears to be safe and well tolerated in the remaining 11 participants who completed the study.

In addition to safety, the researchers also examined biological markers in the blood and cerebral spinal fluid as well as cognitive, motor and non-motor improvement. They found significant signs that nilotinib may provide benefit for patients with these neurodegenerative diseases.

"These results need to be viewed with caution and further validated in larger placebo controlled trials, because this study was small, the patients were very different from each other, and there was no placebo," says the study's senior investigator, Charbel Moussa, MD, PhD, scientific and clinical research director of the GUMC Translational Neurotherpeutics Program.

Among the biomarker findings were that:

•The level of the dopamine metabolite homovanillic acid — an indicator that dopamine is being produced — steadily doubled, even with the loss of most dopamine neurons. Most study participants were able to stop using, or reduce their use of, dopamine replacement therapies;

•The level of the Parkinson's related oxidative stress marker DJ-1 — an indicator that dopamine-producing neurons are dying — was reduced more than 50 percent after niltonib treatment; and

•The levels of cell death markers (NSE, S100B and tau) were significantly reduced in cerebrospinal fluid (CSF) suggesting reduced neuronal cell death.

In addition, Moussa adds that it appears nilotinib attenuated the loss of CSF alpha-synuclein, a toxic protein that accumulates within neurons, resulting in reduced CSF levels in both Parkinson's disease and dementia with Lewy bodies.

The researchers also said that all 11 patients who tolerated the drug reported meaningful clinical improvements. All patients were at mid-advanced stages of Parkinsonism and they all had mild to severe cognitive impairment.

"Patients progressively improved in motor and cognitive functions as long as they were on the drug — despite the decreased use of dopamine replacement therapies in those participants with Parkinson's and dementia with Lewy bodies," says the study's lead author, Fernando Pagan, MD, medical director of the GUMC Translational Neurotherpeutics Program and director of the Movement Disorders Program at MedStar Georgetown University Hospital.

But three months after withdrawal of the drug, participants returned to the same reduced cognitive and motor state they had before the study began, Pagan adds.

Some serious side effects were reported including one patient who withdrew at week four of treatment due to heart attack and three incidents of urinary tract infection or pneumonia. The researchers say these incidents are not uncommon in this patient population, and additional studies are needed to determine if the adverse events are related to use of nilotinib.

"Long term safety of nilotinib is a priority, so it is important that further studies be conducted to determine the safest and most effective dose in Parkinson's, says Pagan.

The researchers designed the clinical trial to translate several notable observations in the laboratory. The preclinical studies, led by Moussa, showed that nilotinib, a tyrosine kinase inhibitor, effectively penetrates the blood-brain barrier and destroys toxic proteins that build up in Parkinson's disease and dementia by turning on the "garbage disposal machinery" inside neurons.

Their published studies also showed nilotinib increases the levels of the dopamine neurotransmitter — the chemical lost as a result of neuronal destruction due to toxic protein accumulation — and improves motor and cognitive outcomes in Parkinson's and Alzheimer's disease animal models.

"Our hope is to clarify the benefits of nilotinib to patients in a much larger and well controlled study. This was a very promising start," Moussa says. "If these data hold out in further studies, nilotinib would be the most important treatment for Parkinsonism since the discovery of Levodopa almost 50 years ago."

He adds, "Additionally, if we can validate nilotinib effects on cognition in upcoming larger and placebo controlled trials, this drug could become one of the first treatments for dementia with Lewy bodies, which has no cure, and possibly other dementias."

Two randomized, placebo-controlled phase II clinical trials are planned for summer/fall in Parkinson's and Alzheimer's diseases. The Translational Neurotherpeutics Program is also planning a small trial in ALS (Lou Gherig's disease).

According to Novartis, the cost (as of Oct. 2015) of nilotinib for the treatment of CML was about $10,360 a month for 800 mg daily. The dose used in this study was lower — 150 and 300 mg daily.

New research shows how cholesterol medicine has beneficial effect on immune defence system

In continuation of my update on simvastatin,  

The cholesterol medicine simvastatin, which is one of the most commonly used pharmaceuticals in the world, also has a beneficial effect on the immune defence system with regard to diseases such as type 1 diabetes, multiple sclerosis and rheumatoid arthritis. Danish researchers have now explored why this is so, and their findings may result in improved treatment.

New research from Aarhus University has demonstrated how simvastatin, one of the most commonly used medicines in the world - typically prescribed to reduce cholesterol - also has a direct effect on the immune defence system. This discovery opens up new opportunities for treating chronic inflammatory diseases.

Sought-after explanation of unexpected effect

The immune defence system, which normally protects the body against infections and foreign bodies, sometimes attacks the body's own tissue. This error in the immune system - whose cause is unknown - results in a chronic state of inflammation which breaks down the tissue. This, in turn, triggers diseases such as rheumatoid arthritis, multiple sclerosis and type 1 diabetes.

In the case of multiple sclerosis, the immune defence system destroys the central nervous system, while the inflammation affects the kidneys, eyes and sense of touch in both type 1 and type 2 diabetes, leading to a variety of complications. However, simvastatin has been shown to reduce the level of inflammation in these diseases, even though it sometimes has to be administered in high concentrations to have any effect. The reason why it does so has eluded researchers thus far.

"Simvastatin - and statins in general - are not designed to have this effect. We have now identified a new mechanism that forms the basis for the effect, and this opens up new opportunities for developing a better substance to combat these inflammatory diseases. It's an interesting line to pursue because a great many people can take statins without significant side effects," relates Thomas Vorup-Jensen, Professor at the Department of Biomedicine at Aarhus University.

The reason for the positive effect is that the pharmaceutical acts as a 'plug' in the proteins that retain the immune cells in the inflammation zones. With the plug in place, the immune cells can no longer contribute to the inflammation, which is therefore reduced, leaving the patient feeling better. In the case of diabetes, for example, it can help reduce the risk of patients developing complications.

"We initially observed this mechanism in the laboratory. Of course, we now need to establish whether it works in the same way in vivo, but we think it's likely," says Thomas Vorup-Jensen.