New compound could reverse loss of muscle mass in cancer, other diseases

Dec. 19, 2013 — A new antibody could dramatically boost strength and muscle mass in patients with cancer, chronic obstructive pulmonary disease (COPD), sporadic inclusion body myositis, and in elderly patients with sarcopenia according to research published ahead of print in the journal Molecular and Cellular Biology.

"Age-related loss of muscle mass is a major contributing factor to falls, broken bones, and the loss of mobility," says co-corresponding author David Glass of Novartis, Cambridge, MA, one of the compound's developers, along with first author Estelle Trifilieff, also of Novartis. "This study illustrates that we may have a powerful tool to prevent muscle wasting and promote growth."

The new compound (BYM338) acts to prevent muscle wasting by blocking a receptor that engages a cellular signaling system that exists to put the brakes on muscle development when appropriate. But sometimes those brakes are activated inappropriately, or are stuck on.

"Our goal was to release the brakes," says Glass.

A variety of signals can activate the receptor. Prior to development of BYM338, compounds developed to block these molecules were blunt instruments, either trapping all incoming signals (which stimulated muscle growth but also caused harmful side effects) or blocking just a single receptor activator (providing only tepid growth stimulation.) BYM338 was designed to be in the Goldilocks zone (just right.)

In the study the compound boosted muscle mass 25 to 50 percent and increased strength in animal models. Those gains were significantly superior to those of compounds that blocked a single receptor activator. Clinical trials are currently underway.

The conditions BYM338 is designed to treat are losses of skeletal muscle and fat, which are not reversed by simply eating more, and are known as cachexias when associated with certain chronic illnesses. Cancer cachexia develops in a majority of patients with advanced malignancy, and can interfere with the ability to undergo chemotherapy, says Glass. COPD afflicts an estimated 65 million people worldwide, and is predicted to become the third leading cause of death by 2020. As many as a quarter of COPD patients suffer from cachexia, which can worsen already dire respiratory difficulties.

Sarcopenia -- age-related loss of muscle and physical function -- afflicts 5-13% of 60-70 year olds, rising to 11-50% in individuals over 80 years old. These individuals become especially vulnerable to falling. Among older adults, falls are the leading cause of both fatal and non-fatal injuries, according to the Centers for Disease Control and Prevention.

Preliminary data on the antibody was promising enough to have it designated a breakthrough therapy by the US Food and Drug Administration for sporadic inclusion body myositis, a rare muscle wasting disease with no approved therapies.

"We need to be able to help people maintain productive and meaningful lives, and muscle function is a major part of the equation," says Glass. "It could be the difference between independent living and having to move into a nursing home."

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Treat the fungus among us with nontoxic medicinal compound

Sep. 12, 2013 — A Kansas State University microbiologist has found a breakthrough herbal medicine treatment for a common human fungal pathogen that lives in almost 80 percent of people.

Govindsamy Vediyappan, assistant professor of biology, noticed that diabetic people in developing countries use a medicinal herb called Gymnema slyvestre to help control sugar levels. He decided to study the microbiological use of Gymnema slyvestre -- a tropical vine plant found in India, China and Australia -- to see if it could treat a common human fungal pathogen called Candida albicans.

The investigation was successful on two levels: Vediyappan's research team found the medicinal compound is both nontoxic and blocks the virulence properties of the fungus so that it is more treatable. The results are important for human health, biomedical applications and potential drug development.

"We have shown that this compound is safe to use because it doesn't hurt our body cells, yet it blocks the virulence of this fungus under in vitro conditions," Vediyappan said. "Taking the medicine could potentially help patients control the invasive growth of the fungus and also help bring their sugar levels down."

Candida albicans is one of the major fungal pathogens in humans because it lives in oral and intestinal areas as a normal flora, Vediyappan said. But the fungus can overgrow and can cause oral, intestinal and genital infections. The fungus kills almost 30 percent of people who have it and it is a concern among cancer patients -- especially patients with neck or oral cancer -- HIV patients, organ transplant patients and other people with compromised immune systems.

The fungus can grow in two forms: a treatable yeast and a difficult-to-treat hyphal form. Once the fungus transforms from a yeast to a hyphal growth it becomes difficult to treat because the hyphal growth has long filament-like structures that can spread into various organs. Vediyappan's study aimed to block the hyphal growth form.

"Once it gets into the tissue, it spreads like roots and is difficult to contain by our immune system," Vediyappan said.

If the fungus remains in yeast form, it is easy to manage and does not invade tissues. Vediyappan's research team purified gymnemic acid compounds that prevented the transition stage from occurring and stopped the fungus spread. The gymnemic acids come from the leaves of Gymnema sylvestre, a traditional medicinal plant.

The research appears in the peer-reviewed journal PLOS ONE in an article titled "Gymnemic acids inhibit hyphal growth and virulence in Candida albicans."

Gymnema extract is commonly used to treat diabetes and other ailments because it is a cost-effective treatment, Vediyappan said. Often, people drink the extract to control their sugar levels or to lose weight.

Although Vediyappan's research team is not the first to discover gymnemic acid compounds, the team is the first to discover that the compounds block the fungal transition. The researchers found that the compounds work quickly, too, which was an important characteristic. The treatable fungal yeast can transition to a hyphal growth within 30 minutes of an infection. When the hyphal transition has occurred, it will grow into branched filaments.

The gymnemic acid compounds are nontoxic, which is especially important for cancer patients and other immunocompromised patients. The gymnemic acids can stop the unwanted invasive infection while preserving important healthy cells.

The Candida albicans fungus also makes a biofilm, which is a fungal cell collection that can be difficult to treat. The researchers found that the gymnemic acid compounds converted the biofilm back to treatable yeast cells.

"This compound prevents the biofilm formation because hyphae are the major builders of biofilms and biofilms are resistant to antifungals," Vediyappan said. "Yeast cells by themselves cannot make biofilms and are sensitive to antifungal treatments."

Another interesting aspect: The gymnemic acid compounds also stopped the growth of Aspergillus, another fungal pathogen that can affect heart transplant patients and leukemia patients.

Vediyappan plans future studies to research mode of action, potential drug development, diabetes applications and other ways to improve treatment for Candida albicans and other fungal pathogens.

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Could Compound in Artificial Sweeteners Worsen Crohn's Disease?

AppId is over the quota
AppId is over the quota

MONDAY, May 21 (HealthDay News) -- The food additive maltodextrin, commonly used in some artificial sweeteners, may worsen Crohn's disease by encouraging the growth of E. coli bacteria in the small intestine, a new study suggests.

However, researchers stressed that the findings are preliminary and the tests were conducted in the lab, not in people, so it's too soon to advise those with the inflammatory bowel disease to avoid maltodextrin.

Maltodextrin is a white powder used in many processed foods as a thickener or a filler, including the artificial sweeteners Splenda and Equal, along with cereal, canned fruits, packaged desserts, instant pudding, sauces and salad dressings. Maltodextrin, typically derived from corn or wheat starch, is also used in some medication coatings.

In the study, researchers placed Equal, Splenda and another sweetener, Stevia, in a dish along with E. coli bacteria taken from people with Crohn's disease. While E. coli is commonly found in the digestive tract of humans, it's usually found in the large intestine, explained senior study author Christine McDonald, assistant staff in the pathobiology department at the Cleveland Clinic's Lerner Research Institute. Prior research has found that people with Crohn's tend to have E. coli in their small intestine.

Though the precise role that E. coli plays in Crohn's is unknown, it's thought that the bacteria may contribute to the inflammation that marks the condition.

When grown in the dish with the Equal (which contains aspartame, dextrose and maltodextrin) and the Splenda (which contains sucralose, dextrose and maltodextrin), the E. coli grew stickier, forming a thick biofilm, according to the researchers. The same didn't happen with the Stevia, which is made from the leaves of a South American plant and does not contain maltodextrin.

Researchers then repeated the experiments, culturing E. coli with maltodextrin alone, and the same sticky biofilm formed.

"In the lab, the E. coli becomes stickier, and it sticks to intestinal cells," said McDonald, who conducted the research with graduate student Kourtney Nickerson. "But we haven't tested this in animals to see if there is a particular amount you need to eat to have this effect. It may be that in people who have other risk factors for inflammatory bowel disease, this may tip them over the edge."

The study, which was funded by the U.S. National Institutes of Health, was to be presented Monday at the Digestive Disease Week meeting in San Diego.

Crohn's disease is an inflammation of the digestive tract that can lead to swelling, pain and ulcers. Although the disease can affect any part of the digestive tract from the mouth to the anus, the most common spot is the small intestine.

It's unknown what causes the disease, although it's believed that microbes -- along with genetics and other environmental factors -- play a role, said Dr. Jerrold Turner, an associate chair in the department of pathology at the University of Chicago.

A healthy gut contains a multitude of bacteria that aid in the digestion of food and extraction of nutrients from foods. A healthy intestine has a layer of mucus that keeps the bacteria away from the lining of the intestine itself. Prior studies have found that, in people with Crohn's, the thickness of that mucus layer decreases, meaning there are more bacteria directly on the cells lining the intestine, possibly leading to inflammation, Turner explained.

The sticky biofilm may also mean there are more bacteria on the lining of the intestines, McDonald said.

No specific diet has been shown to prevent or treat Crohn's disease, according to the U.S. National Digestive Diseases Information Clearinghouse. However, the incidence of Crohn's has been rising in the United States in recent decades, leading researchers to suspect that something about the modern American diet is contributing.

In addition, many people with the disease notice that certain foods or types of foods seem to make their symptoms worse.

McDonald said people with Crohn's may want to try avoiding maltodextrin and see if their symptoms improve, but she and Turner both said more needs to be learned before they recommend that people with Crohn's or a susceptibility to Crohn's avoid the additive.

"It's a very interesting and provocative finding, and [it] may tell us something about the bacteria and what is happening in the intestines, but it's really too preliminary to make any recommendations," Turner said.

A group representing the artificial sweetener industry said the finding was too preliminary to prompt any changes in how artificial sweeteners are made or sold.

"This study was done on cells in petri dishes, therefore it is not possible to apply these findings to humans," the Calorie Control Council said in a statement released Monday. "Even the researcher has stated that it is too early to conclude that maltodextrin promotes disease. Further research is needed before any human nutrition recommendations can be made."

Because this study was presented at a medical meeting, the data and conclusions should be viewed as preliminary until published in a peer-reviewed journal.

More information

The U.S. National Digestive Diseases Information Clearinghouse has more on Crohn's.

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