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Archive - Mar 2016

Date

March 1st

Novel Mechanism Underlies Aldosterone-Induced Heath Damage

When the heart begins to fail, the body does everything in its power to fix the situation. But sometimes, those compensatory mechanisms ultimately do more harm than good. Such is the case with the adrenal hormone aldosterone, which stimulates the heart to pump harder, causing greater damage to the heart muscle. But now, researchers at the Lewis Katz School of Medicine at Temple University (LKSOM) are closer than ever to putting the brakes on that process. With their recent discovery of an unexpected mechanism by which signaling molecules known as G protein-coupled receptor kinases (GRKs) mediate aldosterone-induced heart damage, they have opened the path to an important therapeutic advance. "It turns out that two kinases, GRK2 and GRK5, contribute to the pathology of heart failure by inducing specific changes in myocytes (heart cells) down-stream of mineralocorticoid receptors that bind aldosterone," explained Dr. Walter J. Koch (photo), Ph.D., William Wikoff Smith Endowed Chair in Cardiovascular Medicine, Professor and Chair of the Department of Pharmacology, Director of the Center for Translational Medicine at LKSOM and senior investigator on the new study. The report, published online on March 2, 2016 in the journal Nature Communications, is the first to shed light on the unique interaction. The open-access article is titled “Myocardial Pathology Induced by Aldosterone Is Dependent on Non-Canonical Activities of G Protein-Coupled Receptor Kinases.”"When aldosterone binds to its receptor, GRK2 moves to the mitochondria, where it stimulates pro-death pathways, and GRK5 moves to the cell nucleus, where it activates pathways that cause heart cells to grow, making them less efficient," Dr. Koch said.

Bone Marrow Stromal/Stem Cell-Derived EVs Regulate Osteoblast Activity and Differentiation In Vitro and Promote Bone Regeneration In Vivo

Scientists from Shanghai and Gaungzhou, China have presented evidence that an assay they developed using bone marrow stromal-derived extracellular vesicles (EVs) will become a valuable tool for promoting bone regeneration. In their new work, the scientists isolated bone marrow stromal/stem cell (BMSC)-derived EVs through gradient ultracentrifugation and ultrafiltration, and tested the influence of the EVs on osteogenesis, both in vivo and in vitro. The results indicated that EVs positively regulated osteogenic genes and osteoblastic differentiation, but did not inhibit proliferation in vitro. Furthermore, the scientists constructed an EBV delivery system to stimulate bone formation in Sprague Dawley (SD) rats with calvarial defects. They found that BMSC-derived EVs led to more bone formation in the critical-size calvarial bone defects. Furthermore, the scientists constructed an EV delivery system to stimulate bone formation in Sprague Dawley (SD) rats with calvarial defects. They found that BMSC-derived EVs led to more bone formation in the critical-size calvarial bone defects. Moreover, they found that miR-196a plays an essential role in the regulation of osteoblastic differentiation and the expression of osteogenic genes. This work was published online on February 25, 2016 in Scientific Reports. The open-access article is titled “Bone Marrow Stromal/Stem Cell-Derived Extracellular Vesicles Regulate Osteoblast Activity and Differentiation In Vitro and Promote Bone Regeneration In Vivo.”

[Scientific Reports article]

March 1st

Pheromone Addition Enhances Baiting Technique for Argentine Ant Spreading Across Southern USA

University of California (UC) Riverside researchers may have found a better, more environmentally friendly way to stop the procession of Argentine ants, which have been spreading across the United States for the past few decades, despite pest control efforts. The Argentine ant is an invasive species that has become a major nuisance in California and southern states, including Georgia, South Carolina. Alabama, Mississippi, Louisiana, Florida, Tennessee, and North Carolina. In fact, a 2007 survey found that 85 percent of all urban pest control services in California were focused on the Argentine ant. A common weapon for managing the Argentine ant has been residual insecticide sprays, insecticides that remain effective for a length of time after being sprayed on a surface. However, the downside of this tactic is that the insecticides can find their way into water systems and harm some aquatic species. Another common management technique is baiting, where the ants take food mixed with insecticides back to their colony and then expose other ants to the toxins. This method is more environmentally friendly, but it can be tricky to perfect because the baits need to be palatable, non-repellent, slow-acting, transferable, and inaccessible to non-ants. In an effort to improve the baiting technique, a team from the UC Riverside added ant pheromones to the bait. They found that baits with pheromones reduced ant activity by 74 percent after four weeks. Baits without pheromones reduced ant activity only 42 percent after four weeks. The researchers used the Argentine ant pheromone (Z)-9-hexadecenal, which is inexpensive enough that the researchers believe they could be an economically viable modification to existing bait products. This result came as a bit of a surprise to the authors.

PLK1 Silencing Achieved in Bladder Cancer Cells Via Exosomes Containing PLK1 siRNA

The use of small interfering RNAs (siRNAs) in gene therapy is limited by the lack of safe and efficient delivery vectors. Exosomes are nanovesicles that naturally carry RNA and have the ability to induce transcriptional and translational changes in target cells, thus their use as delivery vectors for siRNA is promising. Polo-like kinase-1 (PLK1) gene is a regulator of mitotic progression and is overexpressed in bladder cancer. Studies show that PLK1 depletion leads to cell cycle arrest and apoptosis in bladder cancer cells. The objective of the current work was to use exosomes as a vector to deliver PLK1 siRNA to bladder cancer cells lines. The work is described in the April 2016 issue of The Journal of Urology. The title of the article is “MP34-16 PLK1 Silencing in Bladder Cancer by siRNA Delivered with Exosomes.” Exosomes were isolated by ultracentrifugation from human embryonic kidney (HEK) cell conditioned media and labeled with PKH-26 membrane dye. Exosomes were then co-cultured with bladder cancer cells as well as normal bladder epithelial cells and imaged on Amnis ImageStreamX to assess for differential uptake. PLK1 siRNA and negative control siRNA were loaded into HEK exosomes using electroporation. An invasive bladder cancer cell line (UMUC3) was co-cultured with electroporated exosomes. Total RNA was isolated 24 and 48 hours following the addition of exosomes and real-time PCR was performed. Bladder cancer cells lines internalize an increased percentage of HEK exosomes when compared to normal bladder epithelial cells. Exosomes electroporated with PLK1 siRNA achieved successful knockdown of PLK1 RNA when compared to the negative control at both 24 and 48 hour timepoints.

Beta-Blockers May Slow Growth of Triple-Negative Breast Tumors

New research published in the March 2016 issue of The FASEB Journal, shows that a commonly prescribed class of high blood pressure drugs may have the potential to slow the growth of triple-negative breast cancer tumors. These drugs, called "beta blockers" work by counteracting the pro-growth effect caused by adrenaline by affecting the beta2-adrenoceptor. "Previous studies have linked increased stress with accelerated onset of metastasis in some forms of breast cancer," said Michelle L. Halls, Ph.D., a researcher involved in the work from the Drug Discovery Biology Theme at Monash Institute of Pharmaceutical Sciences at Monash University in Parkville, Victoria, Australia. "By understanding how stress accelerates invasion in aggressive breast tumor cells, this work will inform future studies into whether beta-blockers could be a useful adjuvant therapy in the treatment of some aggressive breast cancers." The new FASEB Journal article is titled “The β2-Adrenoceptor Activates a Positive cAMP-Calcium Feedforward Loop to Drive Breast Cancer Cell Invasion.” To make their discovery, Dr. Halls and colleagues examined how an aggressive triple-negative breast cancer cell responds to the stress hormone adrenaline. They found that an aggressive breast cancer tumor cell has a cell surface protein called "beta2-adrenoceptor" that can binds both beta-blockers and the stress hormone adrenaline. When bound to adrenaline, the beta2-adrenoceptor on these tumor cells stimulates a positive signaling loop to accelerate invasion. When bound to a beta-blocker, however, the accelerated invasion of these cells was decreased. "This is excellent research that shows us that we still do not know the full potential of many of the drugs sitting in most medicine cabinets," said Thoru Pederson, Ph.D., Editor-in-Chief of The FASEB Journal.

New Mexico Bioinformatics, Science, & Technology (NMBIST) Symposium March 17-18

The New Mexico IDeA Networks of Biomedical Research Excellence (NM-INBRE) and the National Center for Genome Resources (NCGR) has announced announced the 11th annual New Mexico Bioinformatics, Science and Technology (NMBIST) symposium to be held March 17-18, 2016 at the Drury Plaza Hotel in Santa Fe, New Mexico. The symposium will cover cutting-edge advances in epigenomics, RNA machinery, and single-cell omics. Cells use multiple mechanisms to turn genes on and off, allowing an organism to develop, function and respond to its environment. While cells contain the same genetic information they use sophisticated controls to specialize (e.g., as a heart, brain, or eye cell). They can add chemical tags to DNA to influence gene expression without affecting the gene's "code." Studying these tags and the resulting gene expression patterns is termed epigenomics. Another mechanism for regulation is through the machinery that interacts with genes and their expressed copies (messenger RNA). This machinery, itself made primarily from RNA and/or protein, includes the ribosome, which converts messenger RNA into protein, small and long non-coding RNAs that regulate gene expression, the spliceosome, which joins together RNA segments from the same gene in different arrangements to create a variety of proteins, and the exosome that eliminates RNAs that are defective or no longer needed and/or tranfers informational molecules from one region of the body to another. The results of gene regulation include cells that can be highly differentiated despite being in the same tissue or even adjacent to each other. Recent technological advances have enabled the sequencing of tiny amounts of DNA and RNA, allowing researchers to sequence a single cell and elucidate its unique properties.

Certain Anti-Psychotic and Anti-Depression Drugs May Also Be Effective Against Dangerous Bunyaviruses, Study Suggests; Potassium Ion Channel Effects Are Key

A group of drugs already in everyday use to treat psychosis or depression may also be used to defeat deadly and emerging viruses, according to new research led by scientists at the University of Leeds in the UK. Researchers found that common drugs in everyday use were successful in preventing a particular virus from infecting cells, by blocking the ion channels that regulate potassium levels in those cells. Ion channels normally control the balance of chemicals such as potassium, calcium and sodium within our cells. The virus the research focused on was in the Bunyavirus family, which includes lethal human pathogens such as Hantaviruses and Crimean-Congo haemorrhagic fever virus (CCHFV), a widespread disease that is becoming more prevalent in Mediterranean countries and endemic in Africa, the Middle Eas,t and some Asian countries, where outbreaks can kill up to four out of 10 people who contract it. They found that drugs that inhibit potassium ion channels were effective against Bunyamwera virus, which is a model for all of the bunyaviruses. Adding drugs that specifically block the ion channels that regulate potassium levels blocked the ability of all of the bunyaviruses tested to infect cells, but did not have any effect on unrelated viruses. The viruses tested included Hazara virus, used as a model for CCHFV, and Schmallenberg virus, which causes deformities and neurological defects in unborn lambs and calves. The common drugs used in the research included the anti-psychotic haloperidol, the anti-depressant fluoxetine, and a local anaesthetic, bupivacaine.

Exosome Sciences Announces Publication of Preliminary Findings of Exosome-Based Blood Test to Detect Chronic Traumatic Encephalopathy (CTE) During Life

Exosome Sciences, Inc., in collaboration with majority shareholder Aethlon Medical, Inc. (Nasdaq: AEMD) and investigators at Boston University and the University of Washington, announced, on February 25, 2016, the publication of preliminary results of possibly the first blood test to detect the neurodegenerative disease, chronic traumatic encephalopathy (CTE) during life. An early online version of these findings was published on February 10, 2016 in the Journal of Alzheimer's Disease. The openn-access article is titled “Preliminary Study of Plasma Exosomal Tau as a Potential Biomarker for Chronic Traumatic Encephalopathy.” CTE is associated with exposure to repetitive head impacts, such as those experienced by American football players, and can only be diagnosed post-mortem at this time. The researchers developed a method of measuring plasma exosomal tau, also referred to as a TauSome™. Exosomes are very small membrane-bounded vesicles that are released from all types of cells throughout the body, including brain cells. They can be isolated in all body fluids, including plasma, a component of blood. Exosomes carry within them the proteins from their cells of origin. Because exosomes can cross the blood-brain-barrier (a selective barrier that separates the circulating blood from the brain's extracellular fluid), they can provide a unique method of measuring certain aspects of the contents of brain cells through a blood test. That is, if the brain-derived exosomes can be isolated in plasma and then be stained for specific proteins found in the brain cells, researchers can potentially measure brain proteins through a blood test. That was the goal of this preliminary study.