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duminică, 5 august 2012

A Better Understanding Of Rhomboid Proteases May Lead To New Therapies For Malaria And Other Parasitic Diseases

Johns Hopkins scientists have decoded for the first time the "stability blueprint" of an enzyme that resides in a cell's membrane, mapping which parts of the enzyme are important for its shape and function. These studies, published in advance online in Structure and in Nature Chemical Biology, could eventually lead to the development of drugs to treat malaria and other parasitic diseases.

"[It's] the first time we really understand the architectural logic behind the structure of the enzyme," says Sinisa Urban, Ph.D., an associate professor of molecular biology and genetics at the Johns Hopkins University School of Medicine and an investigator at the Howard Hughes Medical Institute, who with his team has unlocked the mysteries of a special class of enzymes called rhomboid proteases.

Rhomboid proteases are present in many different organisms, and are a unique type of enzyme that resides in the cell's membrane where they cut proteins. Previously Urban and his colleagues demonstrated that the rhomboid enzyme is critical for Plasmodium falciparum, the parasite that causes malaria, to successfully invade red blood cells, a step that ultimately leads to infection. Urban says understanding the stability of rhomboid protease shape may impact the design of enzyme inhibitors - potential drugs. "These enzymes have no selective inhibitors," says Urban. "We really need to understand how [the enzyme] works - is it as stiff as a rock, or is it more gummy, like Jell-O?"

One challenge of studying rhomboid enzymes is that they are surrounded by membranes, making them more difficult to manipulate and work with. To address this, Urban's research team turned to a technique known as thermal light scattering, which heats enzyme samples to progressively higher temperatures while measuring the amount of light bouncing back off of the molecules. Enzymes that have broken from their normal shape will scatter light differently, and the temperature at which this occurs (in effect, the breaking point of the enzyme) indicates the inherent stability of the enzyme.

The researchers first precisely measured the stability of the rhomboid enzyme from E. coli bacteria. Surprisingly, says Urban, the rhomboid enzyme was more "Jell-O-like" than other membrane proteins with similar shapes. He guesses that this "jiggly shape" may help rhomboid proteases interact with other proteins that it cuts. To find which parts of the enzyme are most important for maintaining shape and which parts are more crucial for function, the researchers then made and tested 150 differently altered versions of the enzyme. They found four main regions important for maintaining shape and at least two regions important for function.

The researchers also took advantage of computer simulations to test their ideas about how the enzyme functions. Using a computer program model of the enzyme, they programmed in features of its natural membrane environment, which consists mostly of fats and is very limited in water. The computer program then simulated how this environment might influence the enzyme. Researchers found that the enzyme contains a special internal pocket for holding water molecules - a great advantage in its natural, water-limiting environment.

"We're very excited about our findings and are especially curious about the versions of the enzyme that lost function despite no obvious change in stability or shape," says Urban. Ultimately he hopes that a better understanding of rhomboid proteases will lead to new therapies for treating malaria and other parasitic diseases.

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
Visit our tropical diseases section for the latest news on this subject. These studies were supported by the Howard Hughes Medical Institute, a National Institute of General Medical Sciences grant (GM079223), a National Institute of Allergy and Infectious Diseases grant (AI066025), the National Science Foundation (NSF) and the David and Lucile Packard Foundation.
Other researchers who participated in this study include Rosanna Baker, Yanzi Zhou, Syed Moin and Yingkai Zhang.
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joi, 15 decembrie 2011

Further Study Necessary To Better Utilize Nature's Medicine Cabinet

Main Category: Pharma Industry / Biotech Industry
Also Included In: Cancer / Oncology
Article Date: 15 Dec 2011 - 0:00 PST

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There are probably at least 500 medically useful chemicals awaiting discovery in plant species whose chemical constituents have not yet been evaluated for their potential to cure or treat disease, according to a new analysis by a New York Botanical Garden scientist who has more than 15 years of experience in collecting plants for natural-products discovery programs.

Currently, 135 drugs on the market are derived directly from plants; the analysis indicates that at least three times as many disease-fighting substances have yet to be found that could be developed into drugs or used as the basis for further drug research.

"Clearly, plant diversity has not been exhausted, and there is still great potential in the plant world," said James S. Miller, Ph.D., Dean and Vice President for Science at the Botanical Garden.

Dr. Miller's analysis, "The Discovery of Medicines from Plants: A Current Biological Perspective," is published in the December issue of the peer-reviewed journal Economic Botany.

To arrive at his estimate, Dr. Miller used a formula based on the ratio of the number of drugs that have been developed from plants to the number of plants that were screened to find those drugs. He then applied that ratio to the number of plant species that have not yet been screened.

Because of uncertainties in some of those numbers, the formula yields a range of potential drug discoveries. While there is no general agreement among botanists about the number of plant species that are likely to exist, Dr. Miller concluded that there are 300,000 to 350,000 species of plants. Of those, he determined that the chemistry of only 2,000 species has been thoroughly studied, and perhaps only 60,000 species have been evaluated even partially for medicinally useful chemicals.

Working with those numbers, Dr. Miller calculated that there are likely to be a minimum of 540 to 653 new drugs waiting to be discovered from plants; the actual number could be much greater.

"These calculations indicate that there is significant value in continuing to screen plants for the discovery of novel bioactive medicinally useful compounds," concludes Dr. Miller, who has run natural-products discovery programs that have collected specimens in North America, Central and Southeast Asia, and Africa for government agencies, pharmaceutical companies, and academic programs.

As part of his Economic Botany paper, Dr. Miller reviews the disappointing history of past plant-screening efforts and evaluates the potential for future programs.

Technological advances in the 1970s and 1980s gave medical researchers the capacity to evaluate large numbers of plant samples. That prompted the federal government and large pharmaceutical companies to institute aggressive plant collecting and screening programs. Those programs led to the development of several important drugs such as Taxol from Taxus brevifolia (used in cancer treatment) and Camptothecin from Camptotheca acuminata (derivatives of which are used to treat cancer). Other drugs indirectly trace their discovery to natural-products research, including the anti-viral Oseltamivir, which derives from Illicium anisatum and is marketed in the United States as Tamiflu.

The number of drug discoveries, however, was substantially less than anticipated. By the early 2000s, many of the large pharmaceutical companies had abandoned their efforts.

Dr. Miller argues that one possible explanation for the low yield is the relatively crude way in which plant extracts were tested for their pharmaceutical potential. Plants may contain as many as 500 to 800 different chemical compounds, but the screening programs of the late 20th century used extracts made from a whole plant or at best extracts that contained many hundreds of compounds.

Under those circumstances, one compound may interfere with the action of another, or the amount of one compound may be too small to register in a mix of hundreds of chemicals.

To correct this problem, new technologies now allow researchers to separate complex mixtures of natural products into a "library" of relatively pure compounds that can be tested individually. A 2002 study demonstrated that testing such libraries dramatically improves discovery rates.

Bringing these advances together with refinements in collecting strategies could lead to what Dr. Miller calls a "second renaissance" of natural-products discovery.

Miller undertook his analysis to highlight the fact that despite past collecting programs, the plant world represents a poorly explored source of potentially lifesaving drugs. That adds urgency, he said, to efforts to conserve natural habitats so that species are not driven to extinction before they can be studied.

"The natural world has a great and diverse array of interesting chemicals that have been only minimally studied and still hold considerable potential," he writes.

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
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Orangutans That Have Survived Extreme Food Scarcity May Provide Better Understand Of Obesity And Eating Disorders In Humans

Main Category: Obesity / Weight Loss / Fitness
Also Included In: Eating Disorders; Veterinary
Article Date: 15 Dec 2011 - 0:00 PST

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Rutgers Evolutionary Anthropologist Erin Vogel thinks new research published in Biology Letters, a Journal of the Royal Society, examining how endangered Indonesian orangutans - considered a close relative to humans - survive during times of extreme food scarcity might help scientists better understand eating disorders and obesity in humans.

"There is such a large obesity epidemic today and yet we don't really understand the basis of the obesity condition or how these high-protein or low-protein diets work," said Vogel, whose research, Bornean orangutans on the brink of protein bankruptcy, represents the first time scientists have looked at how these long-haired, orange-colored apes - that depend on low-protein fruit to survive - endure protein cycling, or period bouts of protein deprivation. "I think studying the diets of some of our closest living relatives, the great apes; may help us understand issues with our own modern day diets," she said.

According to Vogel, an assistant professor of anthropology in Department of Anthropology and Center for Human Evolutionary Studies, in the School of Arts and Sciences, the research shows that it is only during high periods of high caloric and protein intake that orangutans put on fat, a scientific fact that is sometimes ignored by those who believe that high protein, low carbohydrate diets are the best way to lose weight. She said it is only when caloric intake is restricted that orangutans use these fat reserves for energy and eventually dip into their protein (muscle) reserves - a condition that is seen with eating disorders like anorexia.

Orangutans in particular are interesting to study, Vogel said, because they are the only documented species of non-human ape to store fat when food is abundant in the wild and use these fat reserves when preferred fruits become scarce, presumably something done by our early hominin ancestors.

Vogel and her research team, analyzed samples collected over a five-year period to study the effects of protein recycling, which included examining urinary metabolites and nitrogen stable isotopes - compounds and byproducts in Orangutan urine. What they determined is that these primates are able to endure prolonged protein deficits without starving to death by consuming higher protein leaves and inner bark and obtaining energy from their stored body fat and even muscles for an extended period of time when low-protein fruit is unavailable.

"We discovered through this research that the daily amount of protein the orangutans take in when fruit is not available is inadequate for humans and one-tenth of the intake of mountain gorillas. But it is sufficient to avert a severe protein deficit," said Vogel. The Bornean orangutan population has fallen drastically in the last 50 years in Indonesia to less than 55,000 and on the island of Sumatra to less than 5,000 due to a massive amount of illegal logging and further clearing of the land to develop palm oil plantations in their now impoverished rainforest habitat. Vogel says that although some palm oil companies argue that clearing partially logged areas of the rainforest for palm oil plantations is not detrimental to the existence of the orangutan because their natural habitat has already been taken away, this research on protein cycling indicates that even areas that have been partially stripped of trees are better for orangutan survival than no forest area at all.

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
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Rutgers University. (2011, December 15). "Orangutans That Have Survived Extreme Food Scarcity May Provide Better Understand Of Obesity And Eating Disorders In Humans." Medical News Today. Retrieved from
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duminică, 11 decembrie 2011

Breast Cancer Prevention - Part Time Low Carb Diet Better Than Standard Full Time Diets

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Main Category: Breast Cancer
Also Included In: Nutrition / Diet; Diabetes
Article Date: 10 Dec 2011 - 10:00 PST

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Women who go on a low carb diet just two days per week have a lower risk of developing breast cancer compared to those who follow a standard calorie-restricted diet every day of the week, in order to lose weight and lower their insulin blood levels. Long-term high blood insulin levels are known to raise cancer risk. These findings were presented by scientists from Genesis Prevention Center at University Hospital in South Manchester, England, at the 2011 CTRC-AACR San Antonio Breast Cancer Symposium.

The researchers stressed that a larger, longer-term additional study is required.

Michelle Harvie, Ph.D., SRD, a research dietician at the Genesis Prevention Center, who presented the study said:

"Weight loss and reduced insulin levels are required for breast cancer prevention, but [these levels] are difficult to achieve and maintain with conventional dietary approaches."

Harvie and her team set out to compare three different 4-month-long diets to assess the effects on weight loss and blood markers of breast cancer risk in 115 women who had a family history of breast cancer. The researchers randomly assigned patients into three groups:The low cal/carb group - they followed a calorie-restricted, low-carbohydrate dietThe part-time low-carb group - they followed an "ad lib" low-carbohydrate diet whereby patients were allowed to consume unlimited proteins and healthy fats, like lean meats, olives and nuts for 2 days per weekThe Mediterranean diet group - a standard, calorie-restricted daily Mediterranean diet for seven days per weekBoth low-carb diets were found to be more effective than the Mediterranean diet in achieving weight loss, reducing body fat, and lowering insulin resistance.Weight loss - in the two low-carb groups the participants lost an average of 4kg (approx. 9 pounds) compared to 2.4kg (approx 5 pounds) in the Mediterranean diet group.Insulin resistance - this went down 22% in the low cal/carb group, 14% in the part-time low-carb group, and 4% in the Mediterranean diet group.Harvie said:

"It is interesting that the diet that only restricts carbohydrates but allows protein and fats is as effective as the calorie-restricted, low-carbohydrate diet."

Harvie and her team are planning on studying carbohydrate intake and breast cancer.

Written by Petra Rattue
Copyright: Medical News Today
Not to be reproduced without permission of Medical News Today

Additional References Citations Visit our breast cancer section for the latest news on this subject. "The Intermittent Diet" Please use one of the following formats to cite this article in your essay, paper or report:

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Visitor Opinions In Chronological Order (2)"Calorie Restricted" low carb diet? What?posted by Bob Bramel on 10 Dec 2011 at 3:56 pm

I think it is well past time for diet researchers to adopt some standards for defining a diet. "Calorie restricted low carb" is as ambiguous as "Mediterranean". Since fuel only comes in three forms, carbs, protein and fat, how about specifying "XX calories, YY gram carb, ZZ gram fat, and AA protein". I know it isn't as glamorous as (trumpet fanfare, please) "Mediterranean" or "South Park", but come on, let's at least try to be a little scientific.
As for the selected diet protocols, where is the diet so many of us use. Every day eat as little (for precision, less than XX grams) of carbs as possible and don't worry about calories or fat.
It doesn't pass the sniff test (i.e., it doesn't make any sense) that a two-day per week eating protocol works better than a seven day per week protocol. I'm guessing that the first, calorie restricted, low carb diet was more calorie restriction and only somewhat carb restricted. Folks, cutting carbs from 90% to 50% doesn't help a lot. Carbs gotta go! (40 pounds lost in 18 months over six years ago and keeping it off takes no effort at all, just stay away from carbs)

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Alright alreadyposted by Susan on 10 Dec 2011 at 6:03 pm

Blah, blah, blah. Every day a new study on what does or does not cause/prevent/treat/cure breast cancer. Obviously, to many breast-cancer grants being given out and too many budding PhD candidates in the field. Eventually, if you tried to follow every theory that's been thrown out there, you'd end up bumping into yourself running over yourself or chasing you own tail.
Give a gal a break, please.

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joi, 8 decembrie 2011

How To Better Predict Success In HIV Prevention Clinical Trials

Main Category: HIV / AIDS
Also Included In: Preventive Medicine; Clinical Trials / Drug Trials
Article Date: 08 Dec 2011 - 3:00 PST

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New research from the University of North Carolina at Chapel Hill schools of medicine and pharmacy may help explain the failure of some recent clinical trials of prevention of HIV infection, compared to the success of others that used the same drugs.

The study published online December 7, 2011 in the journal Science Translational Medicine, also suggests how to improve the chances for success, even before the research begins. These suggestions are reinforced in an editorial by several of the UNC authors writing in The Lancet, also published online December 7, 2011.

Over the past two years, results from several clinical trials involving pre-exposure prophylaxis (PrEP) for HIV infection have been a mixed bag of successful prevention and futility. Reports described varying degrees of successful HIV infection prevention in four trials and failure in two others. In all the PrEP trials, the drugs used were tenofovir (TFV) and emtricitabine (FTC) in daily oral and/or gel combinations.

These drugs have been shown to be protective against HIV infection in animal PrEP studies and are now being used clinically, and tenofovir is considered the backbone of HIV therapy, both used orally and topically.

The new UNC study looked at drug concentrations in the mucus membrane tissues that are most susceptible to HIV infection: the tissue lining the vagina, cervix and rectum.

The study was led by Angela D.M. Kashuba, PharmD, professor in the UNC Eshelman School of Pharmacy and director of the UNC Center for AIDS Research Clinical Pharmacology and Analytic Chemistry Core. She also is a member of the UNC Institute for Global Health & Infectious Diseases.

"We did this study to understand how much drug got into these tissues and how long they lasted over two weeks," Kashuba said. And after giving normal, healthy volunteers a single pill combination of TFV/FTC, "What we found over the next 14 days was somewhat surprising. When a person takes a drug, it doesn't end up in the same concentration in different tissues."

Indeed, concentrations of tenofovir were 100 times higher in rectal tissue than in vaginal or cervical tissue. "And FTC achieved concentrations 10 to 15 times higher in vaginal and cervical tissue than they were in rectal tissue," Kashuba said.

"And this raised some questions: because of these discrepancies can the two drugs be used equally well in both populations women at risk for HIV infection and men at risk for HIV infection? And are the concentrations achieved even after a single dose high enough to prevent HIV infections?"

According to Kashuba, it's clear from the recent clinical studies that drug concentration in tissue may make a difference in effectiveness. For example, in one of the placebo-controlled PrEP clinical trials involving men who have sex with men, the combination of these drugs provided about 44 percent effectiveness overall.

But the half the men given the active form of the drugs had no detectable drug in their system when they were sampled during the study and, therefore, were not taking it consistently every day. Thus, the high tenofovir concentrations in rectal tissue could explain the relatively high efficacy of 44 percent.

Results of a PrEP clinical trial (VOICE) conducted in heterosexual women in Uganda, South Africa and Zimbabwe, also paralleled the UNC findings. The daily tenofovir arm was stopped because no protection was seen for the drug taken daily. "If these women did not take the drug every single day, we think our study supports the fact there would not be good efficacy because tenofovir drug concentrations in the vagina and cervix are so much lower than what we see in rectal tissue, Kashuba said."

The authors of the study and the editorial say adherence to taking the drug as prescribed is crucial. They lament that the only prospective means of measuring adherence now available is what the patient reports. "And so if you ask someone did you take all your doses, most will say yes," Kashuba said "People want to be considered good study participants, and sometimes they just can't remember how many doses they took last week, or in the last month, be it almost all of the doses or half of them."

The UNC researcher points to lessons learned: "Before delving into a clinical trial, we need to keep in mind that when someone takes a pill, you can't assume that the drug gets in all places at the same amount. And before we can select the drugs and the right doses for a clinical trial, we need to know what concentrations in tissue prevent HIV infection. They could be different."

And along with the above, the authors emphasize the need to develop ways to objectively measure drug-taking behavior in clinical studies so that the research can be designed and interpreted correctly.

The study was funded in part from the National Institutes of Health, the UNC Center for AIDS Research, the UNC TraCS Clinical Translational Research Center, and the Gilead Sciences Investigator Initiated Research Program.

Article adapted by Medical News Today from original press release. Source: University of North Carolina
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