Wednesday, October 19, 2011

Blocking the channel: A pharmacologically active antagonist of the two-pore-domain potassium ion channel K2P9.1 (TASK-3)

 Treatment of neurological conditions such as sleep–wake control, cognition, and depression could be possible by modulation of the TWIK-related acid-sensitive K+ ion channel (TASK-3, or K2P9.1).

A collaborative effort involving scientists at Merck Research Laboratories (USA) and WuXi AppTec (Shanghai, China) led by Craig A. Coburn has identified a new class of potent small-molecule TASK-3 channel blockers through hypothesis-driven screening and a medicinal chemistry lead optimization program, and their results are reported in ChemMedChem.

The team profiled one compound in detail and demonstrated central nervous system (CNS) target engagement in rodent electroencephalogram (EEG) telemetry models where compound-induced modulation of quantitative EEG power and architecture appeared absent in knock-out animals that lack this channel subunit. This promising lead compound could prove valuable for further exploration in the challenging field of modulators.

More information: Craig A. Coburn, Discovery of a Pharmacologically Active Antagonist of the Two-Pore-Domain Potassium Channel K2P9.1 (TASK-3), ChemMedChem 2012, 7, No. 1, Permalink to the article: … dc.201100351

Provided by Wiley (news : web)

Study discovers amazing electrical properties in polymers

 Crystals and ceramics pale when compared to a material researchers at Oak Ridge National Laboratory discovered that has 10 times their piezoelectric effect, making it suitable for perhaps hundreds of everyday uses.

ORNL's Volker Urban and colleagues at Technical University Aachen in Germany noticed the reverse piezoelectric effect - defined as creating a by applying an -- while conducting fundamental research on polymers. At first they didn't think about their observations in terms of classic , but then they became more curious.

"We thought about comparing the effects that we observed to more 'classic' piezoelectric materials and were surprised by how large the effects were by comparison," said Urban, a member of the Department of Energy lab's Neutron Scattering Science Division.

Until now, scientists did not believe that non-polar polymers were capable of exhibiting any piezoelectric effect, which occurs only in non-conductive materials. This research, however, shows up to 10 times the measured electro-active response as compared to the strongest known piezoelectric materials, typically crystals and ceramics.

"We observed this effect when two different like polystyrene and rubber are coupled as two blocks in a di-block copolymer," Urban said.

Temperature-dependent studies of the molecular structure revealed an intricate balance of the repulsion between the unlike blocks and an elastic restoring force found in rubber. The electric field adds a third force that can shift the intricate balance, leading to the piezoelectric effect.

"The extraordinarily large response could revolutionize the field of electro-active devices," said Urban, who listed a number of examples, including sensors, actuators, , power sources and . Urban also noted that additional potential uses are likely as word of this discovery gets out and additional research is performed.

"Ultimately, we're not sure where this finding will take us, but at the very least it provides a fundamentally new perspective in polymer science," Urban said.

The paper, titled "Piezoelectric Properties of Non-Polar Block Copolymers," was published recently as the cover article in Advanced Materials.

Provided by Oak Ridge National Laboratory (news : web)

Self-cleaning cotton breaks down pesticides, bacteria

UC Davis scientists have developed a self-cleaning cotton fabric that can kill bacteria and break down toxic chemicals such as pesticide residues when exposed to light.

“The new fabric has potential applications in biological and chemical protective clothing for health care, food processing and farmworkers, as well as military personnel,” said Ning Liu, who conducted the work as a doctoral student in Professor Gang Sun’s group in the UC Davis Division of Textiles of Clothing.

A paper describing the work was published Sept. 1 in the Journal of Materials Chemistry.

Liu developed a method to incorporate a compound known as 2-anthraquinone carboxylic acid, or 2-AQC, into fabrics. This chemical bonds strongly to the cellulose in cotton, making it difficult to wash off, unlike current self-cleaning agents. Unlike some other experimental agents that have been applied to cotton, it does not affect the properties of the fabric.

When exposed to light, 2-AQC produces so-called reactive oxygen species, such as hydroxyl radicals and hydrogen peroxide, which kill and break down organic compounds such as pesticides and other toxins.

Although 2-AQC is more expensive than other compounds, the researchers say that cheaper equivalents are available.

Provided by UC Davis (news : web)

Gene may be good target for tough-to-kill prostate cancer cells


Purdue University scientists believe they have found an effective target for killing late-stage, metastatic prostate cancer cells.

Xiaoqi Liu, an assistant professor of biochemistry and member of Purdue's Center for Cancer Research, and graduate student Shawn Liu are focusing on the function of a gene called Polo-like kinase (Plk1), a critical regulator of the cell cycle. Plk1 is also an oncogene, which tends to mutate and can cause cancer.

The researchers found that later-stage are missing Pten, a tumor-suppressor gene. The loss of Pten causes problems during cell division. Instead of the parent cell giving equal copies of DNA to two , those new cells receive disproportionate amounts, causing mutations.

"This turns out to be a major driving factor in future cancer," said Xiaoqi Liu, whose findings were published in the . "Without Pten, there is huge potential to become a cancer cell."

When Pten is diminished, the cells become stressed. To compensate, they increase production of Plk1, which causes rapid cell division.

"That's usually a hallmark of ," Xiaoqi Liu said.

This particular type of later-stage is troublesome because the cells do not respond to drugs aimed at stopping cell division and spread to other areas. When Pten is missing, Xiaoqi Liu said, those drugs actually increase the production of more Plk1.

To test the theory that Plk1 is a key to cancer formation, the researchers tested a Plk1 inhibitor called BI 2356 on both human and mice. In both tests, some cancer cells had Pten present while others had lost it.

In both cases, the cells without Pten responded to the drug.

"In later stages of prostate cancer, cells have lost Pten," Xiaoqi Liu said. "This means the Plk1 inhibitor can be a good drug for treatment of those tumors."

Xiaoqi Liu said tests also showed that BI 2536 could also be effective at low dosages, meaning side effects might be less severe.

Next, the researchers will try to replicate the findings in another mouse model. The National Institutes of Health funded the research.

Contributing to the research were: Timothy Ratliff, the Robert Wallace Miller Director of the Purdue Center for ; Stephen Konieczny, a Purdue professor of biological sciences; Bennett Elzey, a Purdue assistant research professor in comparative pathobiology; Bing Song, a Purdue graduate student in biological sciences; Liang Cheng, an Indiana University professor of pathology; and Nihal Ahmad, a University of Wisconsin professor of dermatology.

More information: Polo-like Kinase 1 Facilitates Loss of pten-induced Prostate Cancer Formation, Journal of Biological Chemistry.

Loss of the tumor suppressor Pten (phosphatase and tensin homolog deleted on chromosome 10) is thought to mediate the majority of prostate cancers, but the molecular mechanism remains elusive. In this study, we demonstrate that Pten-depleted cells suffer from mitotic stress, and that nuclear function of Pten, but not its phosphastase activity, is required to reverse this stress phenotype. Further, depletion of Pten results in elevated expression of Polo-like kinase 1 (Plk1), a critical regulator of the cell cycle. We show that overexpression of Plk1 correlates with genetic inactivation of Pten during prostate neoplasia formation. Significantly, we find that elevated Plk1 is critical for Pten-depleted cells to adapt to mitotic stress for survival, and that re-introduction of wild-type Pten into Pten-null prostate cancer cells reduces the survival dependence on Plk1. We further show that Plk1 confers the tumorigenic competence of Pten-deleted prostate cancer cells in a mouse xenograft model. These findings identify a role of Plk1 in facilitating loss of Pten-induced prostate cancer formation, which suggests that Plk1 might be a promising target for prostate cancer patients with inactivating Pten mutations.

Provided by Purdue University (news : web)