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Exosomes Carry Dopamine into Brains of Mice in Parkinson’s Study

According to an article written by Alice Melao and published on September 5, 2018 in Parkinson’s Disease Today, tiny fatty vesicles that naturally circulate in the blood can effectively carry medications into the central nervous system, including into the brain, an early study in mice suggests. These blood vesicles, called exosomes, were able to successfully deliver dopamine directly to specific areas of the brain affected by Parkinson’s disease. The research study, “Dopamine-Loaded Blood Exosomes Targeted to Brain for Better Treatment of Parkinson’s Disease,” was published in the October 10, 2018 issue of Journal of Controlled Release. Parkinson’s disease is characterized by the progressive degeneration and death of nerve cells in the brain that produce dopamine (called dopaminergic neurons). Dopamine is a critical signaling molecule that regulates brain cell activity and function. Melao noted that, given the disease’s progressive nature researchers have focused on finding ways to prevent the death of dopaminergic neurons or to restore brain levels of dopamine. But a major challenge has been getting potential therapeutic agents across the blood-brain barrier — a semi-permeable membrane that protects the brain — and reach targeted areas. Researchers at Sichuan University in China explored the possibility of using exosomes as a vehicle for dopamine transport. The team isolated and purified exosomes from blood of mice, and labeled them with a green fluorescent tag to be able to track them easily. When researchers used these exosomes in mouse brain cells grown in the laboratory, they confirmed that the vesicles merged with cell membranes, and their content was released inside the cell, turning it green.

Protein Aggregates Appear to Be Driving Force in Development of ALS (Lou Gehrig’s Disease)

A mechanism for how the disease ALS (amyotrophic lateral sclerosis, also called Lou Gehrig’s disease) evolves has been illuminated at Umeå University, Sweden. This was reported in a September 4, 2018 release from Umeå University, Sweden. The discovery concerns how proteins with a defective structure spread the deformation to other proteins. This according to results in a new thesis. The findings can open up for novel pharmaceutical developments in the future. "We've been able to identify two different types of protein aggregates with different structures and propagation abilities. One type gave rise to a more aggressive disease progression, which shows that these aggregates are the driving force in the development of ALS," says Johan Bergh, MD, doctoral student at the Department of Medical Biosciences at Umeå University, Sweden. Together with the ALS group at Umeå University, Bergh has developed a method of investigating protein aggregates formed in ALS. With this new method, it has then been possible to identify the particular protein aggregates that are driving in the emergence of ALS. The protein that has been targeted is superoxide dismutase-1 (SOD1). It has long been known that mutations in that protein can cause ALS. The goal of the research team was to investigate the way in which the protein contributes to the disease. In several diseases afflicting the nervous system, such as in Alzheimer's and Parkinson's Disease, new studies show that some proteins assume an aberrant structure. Misfolded proteins aggregate and provoke other proteins of the same kind to assume the same structure. In this way, the disease spreads step by step into the nervous system. "Using the new method, we have shown and confirmed through animal models that the development of ALS follows the same principle as for other severe nervous disorders.

Neutrophil Nanosponges Soak Up Proteins That Promote Rheumatoid Arthritis

Engineers at the University of California San Diego have developed neutrophil "nanosponges" that can safely absorb and neutralize a variety of proteins that play a role in the progression of rheumatoid arthritis. Injections of these nanosponges effectively treated severe rheumatoid arthritis in two mouse models. Administering the nanosponges early on also prevented the disease from developing. The work was published online on September 3, 2018 in Nature Nanotechnology. The article is titled “Neutrophil Membrane-Coated Nanoparticles Inhibit Synovial Inflammation and Alleviate Joint Damage in Inflammatory Arthritis.” "Nanosponges are a new paradigm of treatment to block pathological molecules from triggering disease in the body," said senior author Dr. Liangfang Zhang, a nanoengineering professor at the UC San Diego Jacobs School of Engineering. "Rather than creating treatments to block a few specific types of pathological molecules, we are developing a platform that can block a broad spectrum of them, and this way we can treat and prevent disease more effectively and efficiently." This work is one of the latest examples of therapeutic nanosponges developed by Dr. Zhang's lab. Dr. Zhang, who is affiliated with the Institute of Engineering in Medicine and Moores Cancer Center at UC San Diego, and his team previously developed red blood cell nanosponges (http://jacobsschool.ucsd.edu/news/news_releases/release.sfe?id=1350) to combat and prevent MRSA (methicillin-resistant Staphylococcus aureus) infections and macrophage nanosponges (http://jacobsschool.ucsd.edu/news/news_releases/release.sfe?id=2400) to treat and manage sepsis. The new nanosponges are nanoparticles of biodegradable polymer coated with the cell membranes of neutrophils, a type of white blood cell.

Insights into Evolutionary Biology of Deadly Venoms May Lead to Drug Advances

Venomous reptiles, bugs, and marine life have notorious reputations as dangerous, sometimes life-threatening creatures. But in a paper published in the August 31, 2018 issue of Science, first author Dr. Mandë Holford, an Associate Professor of Chemistry and Biochemistry at The Graduate Center of The City University of New York (GC/CUNY) and Hunter College, details how technology and a growing understanding of the evolution of venoms are pointing the way toward entirely new classes of drugs capable of treating diabetes, autoimmune diseases, chronic pain, and other conditions. According to Dr. Holford and her colleagues, venomous species account for more than 15 percent of the Earth's documented biodiversity, and they can be found in virtually all marine and terrestrial habitats. Still, researchers have studied very few venoms because, until recently, scientists lacked the appropriate technology for analyzing the tiny amounts of venom that can be extracted from these mostly small species. But innovations in omics (technologies that map the roles, relationships, and actions of an organism's molecular structure) are allowing researchers to uncover evolutionary changes and diversification among specific venomous species that could prove useful in developing new drugs capable of precisely targeting and binding to molecules that are active in certain human diseases. "Knowing more about the evolutionary history of venomous species can help us make more targeted decisions about the potential use of venom compounds in treating illnesses," said Dr. Holford. "New environments, the development of venom resistance in its prey, and other factors can cause a species to evolve in order to survive.

Rutgers Scientists Model 12-Amino-Acid Protein That May Have Existed When Life Began 4 Billion Years Ago

How did life arise on Earth? Rutgers researchers in New Jersey have found among the first and perhaps only hard evidence that simple protein catalysts - essential for cells, the building blocks of life, to function - may have existed when life began. Their study of a primordial peptide, or short protein, is published in the Journal of the American Chemical Society. The article is titled “Minimal Heterochiral de Novo Designed 4Fe–4S Binding Peptide Capable of Robust Electron Transfer.” In the late 1980s and early 1990s, the chemist Günter Wächtershäuser postulated that life began on iron- and sulfur-containing rocks in the ocean. Wächtershäuser and others predicted that short peptides would have bound metals and served as catalysts of life-producing chemistry, according to Rutgers study co-author Dr. Vikas Nanda, an Associate Professor at Rutgers' Robert Wood Johnson Medical School. Human DNA consists of genes that code for proteins that are a few hundred to a few thousand amino acids long. These complex proteins - needed to make all living things function properly - are the result of billions of years of evolution. When life began, proteins were likely much simpler, perhaps just 10 to 20 amino acids long. With computer modeling, Rutgers scientists have been exploring what early peptides may have looked like and their possible chemical functions, according to Dr. Nanda. The scientists used computers to model a short, 12-amino acid protein (ambidoxin) and tested it in the laboratory. This peptide has several impressive and important features. It contains only two types of amino acids (rather than the estimated 20 amino acids that synthesize millions of different proteins needed for specific body functions), it is very short, and it could have emerged spontaneously on the early Earth in the right conditions.

Evox Therapeutics, an Exosome Therapeutics Company, Completes $45.4 Million Series B Financing for Progressing Exosome-Based Assets Toward the Clinic and for Continued Expansion of Its Exosome Platform for Drug Delivery

Evox Therapeutics Ltd, a leading exosome therapeutics company, announced, on September 3, 2018, that it has raised £35.5 million ($45.4 million) of new capital in a Series B financing round. Redmile Group led the financing with significant new investments from GV (formerly Google Ventures) and Cowen Healthcare Investments, alongside investments from Panacea Healthcare Venture, Borealis Ventures, and a small number of private investors. Existing investors, Oxford Sciences Innovation (OSI) and Oxford University, also participated in this financing round. Evox had previously secured £10 million ($12.9 million) as part of a Series A seed financing from OSI. Proceeds from this financing will support the advancement of Evox’s exosome-based therapeutics pipeline, including progression of several proprietary rare disease assets towards the clinic, and continued development of its world-leading exosome drug platform. Evox is engineering exosomes, the body’s natural vesicular delivery system, to enable a wide variety of drugs to reach previously inaccessible tissues and compartments, such as crossing the blood brain barrier to deliver drugs to the central nervous system, intracellular delivery of biologics, and extra-hepatic delivery of RNA therapeutics. Evox is developing its own proprietary pipeline of exosome-based therapeutics for the treatment of rare, life-threatening diseases with significant unmet need. Evox also continues to form partnerships with major pharmaceutical companies to fully exploit the use of exosome-based therapeutics for the treatment of a wide variety of other diseases. Dr.

Breakthrough in Understanding Warsaw Breakage Syndrome and Function of Key DNA Repair Enzyme DDX11 Helicase

Researchers from Tokyo Metropolitan University and the FIRC Institute of Molecular Oncology (IFOM) in Italy have uncovered a previously unknown function of the DDX11 helicase enzyme. Mutations in the gene which codes for DDX11 are known to be implicated in Warsaw breakage syndrome. The scientists showed that DDX11 plays an important role in DNA repair, and functions as a backup to the Fanconi anemia (FA) pathway, whose malfunction is associated with another life-debilitating condition. DNA plays a central role in the biological function of the cell, but it is constantly being damaged, both spontaneously and through environmental factors. Failure to successfully repair these lesions can lead to malignant tumors. Understanding how damaged DNA is repaired is of the utmost importance; in fact, pioneering work on the subject was recognized with the 2015 Nobel Prize for Chemistry (https://www.nobelprize.org/prizes/chemistry/2015/summary/). The new work was published online on August 14, 2018 in PNAS. The open-access article is titled “Warsaw Breakage Syndrome DDX11 Helicase Acts Jointly with RAD17 in the Repair of Bulky Lesions and Replication Through Abasic Sites.” Warsaw breakage syndrome (WABS) is a genetic disorder; afflicted individuals suffer from mild to severe intellectual disability and growth impairment amongst other potential abnormalities. It was known that mutations in the DDX11 gene in chromosome 12 in the human genome and the enzyme it codes for, the DDX11 helicase, were responsible for the onset of WABS, yet the mechanism by which DDX11 acted remained unclear. Thus, a collaboration led by Dr. Dana Branzei of IFOM, Italy, and Professor Kouji Hirota of Tokyo Metropolitan University set out to investigate the role played by DDX11 using avian cells, particularly noting similarities in the cells of WABS patients to those of Fanconi anemia (FA).

Altered Timing in Growth Signaling May Be Key in Many Cancers; Novel Optogenetics Approach Reveals Importance of Precise Timing in Cellular Signaling Circuits

Genetic mutations in a form of non-small cell lung cancer (NSCLC) may drive tumor formation by blurring cells' perception of key growth signals, according to a new laboratory study published online on August 29, 2018 in Science. The article is titled “Cancer Mutations and Targeted Drugs Can Disrupt Dynamic Signal Encoding by the Ras-Erk Pathway.” The research, led by UC San Francisco (UCSF) researchers, could have important implications for understanding and ultimately targeting the defective mechanisms underlying many human cancers. Healthy cells rely on the central Ras/Erk growth signaling pathway (also known as the Ras/MAPK pathway) to interpret external cues about how and when to grow, divide, and migrate, but defects in how these messages are communicated can cause cells to grow out of control and aggressively invade other parts of the body. Such mutations are found in the majority of human cancers, making treatments for Ras/Erk defects a "holy grail" of cancer research. Decades of study have led scientists to believe that Ras/Erk-driven cancers occur when mutations cause one or more components of the pathway to get stuck in a pro-growth state. Researchers have labored to develop targeted treatments that flip these broken switches back off, but so far most have failed to make it through clinical trials. Now, using a high-throughput technique developed at UCSF that allows scientists to take control of Ras/Erk signaling using pulses of light, and then quickly read out resulting genomic activity, researchers have made a surprising discovery about this extensively studied pathway.

Marijuana Plant Component (Cannabidiol) Shows Rapid and Sustained Anti-Depressive Effects in Rats & Mice

Commercial antidepressants typically take two to four weeks to have a significant effect on a depressed patient. They are also inneffective in approximately 40% of the cases. Finding new drugs for depression that are fast-acting and have more lasting effects is the goal of research conducted by Brazilian scientists in São Paulo State in collaboration with Danish colleagues. Their recent study found that a single dose of cannabidiol in rats with symptoms of depression was highly effective, eliminating the symptoms on the same day and maintaining the beneficial effects for a week. The findings reinforce those of prior research showing that cannabidiol, a component of Cannabis sativa, the plant most commonly used to make marijuana, has promising therapeutic potential in the treatment of broad-spectrum depression in preclinical and human models. The results were published online on June 4, 2018 in Molecular Neurobiology by researchers of the group led by Sâmia Regiane Lourenço Joca, a professor in the University of São Paulo's Ribeirão Preto School of Pharmaceutical Sciences (FCFRP-USP) in Brazil. The first author is Amanda Juliana Sales, who has a PhD scholarship from the São Paulo Research Foundation - FAPESP. The research itself was supported by FAPESP via a Thematic Project, by Brazil's National Council for Scientific and Technological Development (CNPq), and by Denmark's Aarhus University Research Foundation. FAPESP Thematic Project coordinator Francisco Silveira Guimarães, who is also a professor at the University of São Paulo's Ribeirão Preto Medical School (FMRP-USP), stresses that cannabidiol produces neither dependence nor psychotropic effects, despite being extracted from marijuana plant.

High-Res Analysis of FAT10 Degradation Protein Reveals Mechanism Completely Different from That of Ubiquitin

FAT10 is a small protein with a huge effect. Its attachment to a target protein is a signal for its degradation. FAT10 is a marking system for degradation that seems to be inefficient. In contrast to its biological competitor, ubiquitin, which is recycled, FAT10 is degraded along with its target protein which appears wasteful at first glance. So, why does this seemingly inefficient FAT10-system exist at all? Professor Marcus Groettrup, head of the immunology working group at the University of Konstanz, and his team have been carrying out research on FAT10 for many years. Now they have achieved a breakthrough that made it possible to determine the high-resolution structure of FAT10. This success was enabled through another achievement. In collaboration with Dr. Annette Aichem from the Biotechnology Institute Thurgau (BITg), Konstanz chemist Professor Christine Peter and structural biologist Dr. Silke Wiesner from the University of Regensburg, the team developed a molecular technique to produce stable and highly-concentrated FAT10 with a high degree of purity. As a consequence, the researchers could carry out a structure analysis of FAT10 via x-ray crystallography and magnetic resonance spectroscopy. The results were published online on August 20, 2018 in Nature Communications. The open-access article is titled “The Structure of the Ubiquitin-Like Modifier FAT10 Reveals an Alternative Targeting Mechanism for Proteasomal Degradation.” "We found a mechanism in FAT10 that is entirely different from ubiquitin. This mechanism is very interesting for the entire ubiquitin field,” says Dr. Groettrup. In contrast to ubiquitin with one domain, FAT10 has two domains, i.e., folds that enable the proteins to function.

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