Protein that makes local bladder cancer invasive found

Washington, May 15 (ANI): Researchers at the Kimmel Cancer Center at Jefferson have identified a protein, which, according to them, is involved in pushing tumours to become invasive – and deadly.

It is known that bladder cancer often becomes aggressive and spreads in patients despite treatment.

“We have found that IGF-IR is a critical regulator of motility and invasion of bladder cancer cells, and this could offer us a novel molecular target to treat patients with this cancer in order to prevent metastasis,” said the lead investigator, Dr. Andrea Morrione, a research associate professor of Urology at Jefferson Medical College.

The researchers claim that the finding is promising because there are about a dozen agents targeted against the protein, the insulin-like growth factor receptor I (IGF-IR), that are now undergoing clinical testing to treat a variety of patient tumours.

“Testing presence of the protein could also serve as a novel tumour biomarker for diagnosis, and possibly prognosis of bladder tumours,” he added.

Although bladder cancer is common, the molecular mechanisms that push the cancer to become invasive and to spread are still poorly understood, say the researchers.

Although most bladder cancers are caught early and treated, they often come back and become aggressive, despite subsequent therapy with surgery, chemotherapy, or immunotherapy.

In the study, the researchers looked at the role of the protein receptor for the growth factor IGF-I, an important modulator of cell proliferation in bladder cancer cells.

They found that although activation of IGF-IR did not affect growth of bladder cancer cells, it did promote the migration and invasion of these cells.

The researchers showed that IGF-IR activated other molecules in cancer-promoting pathways (Akt and MAPK) that allow cancer cells to break its bond with other cells in a tumor in order to travel to others sites in the body.

“These data seem to indicate that this protein receptor may play a more prominent role in later stages of bladder cancer, not in the initiation of the cancer,” said Morrione.

Additional work is needed to validate the role of IGF-IR in pushing bladder cancer into an invasive form, but if the results continue to be promising, it might be possible to test anti IGF-IR therapies in bladder cancer and to see how effective a test for these proteins in bladder tumor biopsies might predict cancer spread, the researchers say.

The study has been published in the June issue of American Journal of Pathology. (ANI)

How omega-3 fatty acids reduce inflammation

London, May 3 (ANI): Researchers at the University of Pittsburgh School of Medicine have found new mediators that not only can explain how omega-3 fatty acids reduce inflammation, but also hint at novel treatments for a host of diseases linked to inflammatory processes.

Dr. Bruce A. Freeman said that there is strong evidence that eating foods rich in omega-3 fatty acids, such as some fish, plant-derived oils and nuts, or taking omega-3s as a dietary supplement reduces inflammation and lowers the risk of illness and death from cardiovascular and other inflammatory diseases.

“What has been a provocative question for people familiar with these impressive clinical actions is how omega-3 fatty acids actually induce such beneficial pharmacological effects. This study has given us fresh and revealing perspective into that process,” Nature quoted him as saying.

In the study, also led by Dr. Francisco J. Schopfer, the researchers examined metabolic byproducts of omega-3 fatty acids that are produced by activated macrophages, a type of immune cell that is always present in inflamed tissue, and discovered previously unknown biochemical mediators of inflammation.

They used a small molecule called beta-mercaptoethanol (BME) as a reactive bait, and “hooked” several derivatives of omega-3 fatty acids that were produced by immune cells.

These derivatives were chemically modified to become electrophilic fatty acid oxidation products (EFOX), meaning they are attracted to electrons and therefore react with critical molecular targets in many different cell types.

By interacting with certain protein residues that have electrons available for chemical binding, these derivatives stimulate changes in cellular protein function and the genetic expression patterns of cells, resulting in a broad range of antioxidant and anti-inflammatory responses.

The research team found that an enzyme called cyclooxygenase-2 (COX-2), which is the molecular target of common drugs such as aspirin, ibuprofen and acetaminophen, mediates the transformation of omega-3 fatty acids into EFOX.

Notably, cellular EFOX concentrations were significantly increased in the presence of aspirin, suggesting another mechanism for that drug”s beneficial effects.

“There is a lot of evidence that supports minimizing inflammation as a fundamental therapy for many diseases. Our new insights help explain in part the multitude of beneficial actions observed for both omega-3 fatty acids and aspirin, and the discovery of this new class of omega-3 fatty acid-derived anti-inflammatory mediators could point drug development activities in new and fruitful directions,” said Freeman.

For example, drugs that, like aspirin, enhance the production of EFOX could be of value, or new agents might be synthesized that are able to induce anti-inflammatory signals that are similar to those induced by EFOX, he explained.

The findings were published in the online version of Nature Chemical Biology. (ANI)

How insects decide what to eat and what to avoid

Washington, Apr 24 (ANI): A protein in sensory cells on the “tongues” of fruit flies enables them to detect a noxious chemical and, thereby influencing their decision about what to eat and what to avoid, reveals a Johns Hopkins team.

The study raises the possibility that the protein — TRPA1 — is a new molecular target for controlling insect pests.

“We”re interested in how TRPA1 and a whole family of so-called TRP channels affect not just the senses, like taste, but also behaviour,” says Dr. Craig Montell.

He claimed that when his team knocked out the TRPA1 sensor, the behaviour change — an alteration in food preference — was stark.

“This is the first TRP channel in insects that responds to a naturally occurring plant chemical known as an antifeedant, so now we have a target for finding more effective chemicals to protect plants from destruction by insect pests,” he added.

“We already knew that TRP channels have these broad sensory roles, having previously discovered that the insect TRPA1 had a role in helping flies to detect small differences in sub-optimal temperatures within their comfort range. We wondered if it had any other sensory roles, so we went looking,” said Montell.

First, the team genetically altered a normal TRPA1 gene. This experiment let them show that the protein was made in the fly”s major taste organ (called the labellum) and trace its manufacture to a subset of sensory cells that respond to noxious chemicals.

The researchers then conducted a series of behavioural tests comparing the feeding of wild type flies to those of mutants in which the TRPA1 gene was knocked out — unable to manufacture the protein.

The team placed 50 to 100 flies that had been purposely starved for a day in a covered plate with 72 wells full of two concentrations of sugar water. The wells containing the high concentration of sugar water were laced with different bitter compounds, including quinine, caffeine, strychnine and aristolochic acid.

Surprisingly, most of the mutants avoided all but one of the bitter compounds — aristolochic acid, a naturally occurring chemical produced by plants to prevent themselves from being eaten by insects.

“To our surprise, it was looking at first like TRPA1 didn”t have a role in responding to anything. The aristolochic acid was literally the last compound we tried. I certainly wasn”t expecting that the TRPA1 would be so specific in its response,” said Montell.

The team followed up with electrophysiology tests on both wild type flies and those lacking the TRPA1 gene.

They found that TRPA1 was required for aristolochic acid-induced activity by neurons, meaning it”s essential for aristolochic acid avoidance.

“It”s important to make this discovery in insects, not only because it”s interesting to trace the similarities and differences through millions of years of evolution, but also because of the possible practical applications. By targeting this TRP channel, we might be able to prevent insects from causing crop damage,” said Montell.

The study appeared in the online Early Edition of the Proceedings of the National Academy of Sciences (PNAS). (ANI)

Novel way to stop malarial parasite growth found

Washington, May 19 (ANI): Researchers at the Johns Hopkins University School of Medicine have found a novel way to stop malarial parasite growth.

According to researchers, the new finding could guide the development of new malaria treatments.

“Our findings offer both a new potential molecular target for treating malaria and a compound that interacts at that target. These are important steps in discovering drugs that could help to treat malaria,” said Jun O. Liu, Ph.D., a professor of pharmacology and molecular sciences

Liu’s research team has for many years studied MetAP2 proteins, which are found in all organisms – from humans to single-celled bacteria – and essential for cell survival.

They reasoned that if the malaria parasite has its own MetAP2, finding a chemical that disrupts MetAP2 function may lead to a new drug to stop parasite growth and malaria spread.

So they searched a computer database of the sequence of the malaria parasite genome and found one protein very similar to human MetAP2, which they named PfMetAP2 for plasmodium falciparum, the parasite that causes malaria.

Recently other researchers reported that the natural antibiotic fumagillin can stop malaria parasites from growing, possibly by interfering with MetAP2.

But the man-made version of fumagillin causes brain cells to die, so Liu’s team made several compounds chemically related to fumagillin in hopes of finding one less toxic but still effective in interfering with PfMetAP2.

They chose to further study one of these compounds, fumarranol, because it interacts with human MetAP2 and is less toxic to mice.

The team first tested whether fumarranol can stick to and interfere with PfMetAP2 by treating mouse cells containing PfMetAP2 with different amounts of fumarranol and fumagillin and comparing them to untreated cells. In treated cells, fumarranol stuck to PfMetAP2 and stopped it from working.

They next asked whether fumarranol could stop malaria parasites from growing in a culture dish. They treated both drug-resistant and multidrug-resistant strains of Plasmodium falciparum and found that fumarranol could stop the parasite from multiplying.

The researchers then gave mice infected with malaria fumarranol for four days after infection and measured the parasite load in the blood.

They found that after four days, fumarranol worked as well as fumagillin to slow infection. After another 26 days they again measured parasites in the blood, found that some mice carried no observable level of parasites and considered these animals cured.

“The next step for establishing a new treatment for malaria would be to test whether fumarranol is the most optimal treatment or if new compounds that are similar to fumarranol might be even more specific to malaria parasites,” Liu said.

The research was published in the February 27 issue of Chemistry and Biology. (ANI)

Scientists identify promising compound to treat epilepsy

Washington, May 5 (ANI): Scientists have identified a new anticonvulsant compound, called paxilline, which may cease the progression of epilepsy, a neurological disorder marked by abnormal electrical activity in the brain that leads to recurring seizures.

The study by Carnegie Mellon University researchers is based on a previous work in which scientists identified a specific molecular target whose increased activity is linked with seizure disorders- a potassium channel known as the BK channel.
“We have found a new anticonvulsant compound that eliminates seizures in a model of epilepsy,” said Alison Barth, associate professor of biological sciences at Carnegie Mellon’s Mellon College of Science.

She added: “The drug works by inhibiting ion channels whose role in epilepsy was only recently discovered. Understanding how these channels work in seizure disorders, and being able to target them with a simple treatment, represents a significant advance in our ability to understand and treat epilepsy.” he researchers found that after a first seizure, BK channel function was markedly enhanced.

Thus, the neurons became overly excitable and were firing with more speed, intensity and spontaneity, which led the researchers to believe that the abnormal increase in the activity of the channels might play a role in causing subsequent seizures and the emergence of epilepsy. n the current study, the researchers tested this theory by blocking the ion channels using a BK-channel antagonist called paxilline.

Using an experimental model for epilepsy, Barth tested whether paxilline could reduce or prevent experimentally induced seizures, as it could normalize aberrant brain activity induced by previous seizures.

And to their surprise, the researchers discovered that the compound was effective at completely blocking subsequent seizures. The drug is orally available, and works in the low nanomolar range,” said Barth.

As the drug is effective in low concentrations and can be taken as a pill, it could turn out to be an especially promising compound for treatment in epilepsy patients.

The researchers believe that targeting the BK channels and the abnormal brain activity that they induce might one day be used as a way to prevent the progression of seizure disorders over time, thus attacking the root cause of epilepsy.

The findings have been published in the current issue of the journal Epilepsia. (ANI)

Obesity may not lie in the brain

London, Feb 05 (ANI): A team of American researchers has identified a gene that when mutated causes obesity by dampening the body’s ability to burn energy while leaving appetite unaffected.

Researchers at the University of North Carolina at Chapel Hill School of Medicine say that the new study could potentially lead to new pharmacologic approaches to treating obesity in humans that do not target the brain.

The findings also add new knowledge to the growing field of epigenetics, in which heritable changes in gene expression or physical appearance are caused by mechanisms besides changes in the underlying DNA.

The gene in question encodes for a specific epigenetic factor, an enzyme called Jhdm2a.

In 2006, study’s senior author Yi Zhang, Ph.D. showed that Jhdm2a was able to demethylate, or remove, a methyl group from one of four histone proteins bound to all genes.

Because they are so intimately associated with DNA, even slight chemical alterations of histones can have profound effects on nearby genes.

The new study focused on a line of so-called “knockout” mice that lacked the Jhdm2a gene.

Zhang found impairment in two molecular signaling pathways important for normal function in brown fat tissue and muscle cells.

Both pathways exert a major influence on metabolism, the body’s conversion of food to energy. Without the enzyme, the mice had reduced metabolisms, becoming visibly obese.

According to Zhang’, this is the first mouse model to exhibit obese traits that do not resulting from an alteration in appetite, which is largely a brain function.

“Given that this gene is not expressed in the brain, any drug that targets this gene would not have an effect on brain function. Therefore, we are really looking for a pure effect on metabolism,” Nature quoted him, as saying.

With that in mind, Zhang anticipates that the study could be of great interest to pharmaceutical companies eager to develop new anti-obesity drugs aimed at a novel, new molecular target expressed in non-brain tissues.

The study is published online February 4, 2009 in the journal Nature. (ANI)

GVK Biosciences and Crelux set up fragment-based drug discovery platform to deliver lead molecules

Munich, Germany/ Hyderabad Jan 29 (ANI/Business Wire India):GVK Biosciences (GVK BIO) and CRELUX announced today that they have set-up a highly robust fragment-based drug discovery platform proven to deliver rapidly, viable lead molecules.

CRELUX’s high performance structural biology technologies together with GVK BIO’s mature computer-assisted drug design (CADD) tools and other components of its drug discovery and development engine, encompass all steps from challenging targets to novel drug candidates.

CRELUX and GVK BIO will provide seamless integration of all aspects of structure-based drug design for the biopharmaceutical industry and furnishes accelerated timelines for moving molecules from concept into the clinic at an optimal cost. Fragment-based Drug Design (FBDD) helps in visualizing binding modes and hence rationalizes an accelerated SAR allowing efficient lead optimization through CADD.

CRELUX will leverage its capabilities of all aspects of multifaceted structural studies towards X-ray elucidation of fragment or lead target complexes, whereas GVK BIO will perform all discovery chemistry and biology work including in silico, in vitro and in vivo studies as well as activities necessary to ensure pre-clinical candidate nomination.

“Collaborating with a renowned life-sciences service provider like GVK BIO in a fast emerging competitive area like fragment-based drug discovery is a strong appreciation of our high quality services. Together we have generated a truly one-stop-shop from target-to-IND and support our customers with comprehensive drug discovery services”, commented Dr. Michael Schäffer, CEO of CRELUX.

“GVK BIO is committed to further advance the discovery tools and services that are needed to systematically profit from the enhanced understanding of biochemical pathways and important molecular target families”, said Sven Wagner, Ph.D., Vice President, Discovery Business Development for GVK BIO.

“With a strong alliance partner like CRELUX, GVK BIO is moving in the direction of its vision of being a global leader in life-sciences services” said Manni Kantipudi, President, GVK BIO. (ANI)