New chemical compound could potentially be used to treat Ebola virus infection

quinoxalin-2-mercapto-acetyl-urea analogs

More at : http://www.sciencedirect.com/science/article/pii/S0960894X16306643

Virus spread can be blocked by attacking Ebola's Achilles' heel.

Scientists have found Ebola's Achilles' heel: a new kind of chemical compound can block the protein Ebola uses to break out of cells and infect new cells. The compounds, revealed in a new paper in Bioorganic & Medicinal Chemistry Letters, could potentially be used to treat the disease after infection.

The outbreak of Ebola virus disease (EVD) in West Africa between 2013 and 2016 claimed more than 11,000 lives. The global public health threat has led to a resurgence in efforts to tackle the virus with scientific discovery and innovation. Many scientists are now developing vaccines, but they need to be given prophylactically and could only protect against Ebola, leaving people at risk of other hemorrhagic viruses.

Viruses replicate by hijacking the machinery in the cells of their host - in the case of Ebola, human cells - and co-opting the cells to help produce more viruses. Once production is complete, particular virus proteins promote release of viruses from the cell surface, which can go on to infect more cells.

The new compounds target an interaction between the virus and the host cell, inhibiting new Ebola viruses from escaping cells once they have been assembled. The team's results show that the compounds block this interaction without being toxic to human cells.

Dr. Harty, one of the authors of the study from the University of Pennsylvania School of Veterinary Medicine in the US, commented: "Positive results showing potent viral inhibition without toxicity to normal healthy cells may lead to a paradigm shift in the search for better antiviral drugs. Importantly, as these virus-host interactions represent a common mechanism used by a range of RNA viruses, we predict that this virus-host interaction may represent an Achilles' heel in the life cycle of RNA viruses."

Dr. Harty and the team wanted to target the virus' mechanism for breaking out of cells, which is similar in many different RNA viruses, including Marburg and Lassa fever virus. The original virus-host interaction they modeled was between Ebola VP40 protein and host protein NEDD4. They had screened 4..8 million compounds in silico to find one that was shown to prevent VP40-NEDD4 interactions, therefore blocking virus egress.

He then worked with Dr. Jay Wrobel of Fox Chase Chemical Diversity Center in the US to evaluate about 20 different commercial chemicals and this led to more potent compounds than the original hit compound. The team prepared and evaluated novel molecules that were even more potent than the original. Their efforts led to a new class of small molecule compounds that target filovirus egress. Dr. Wrobel explained:

"We postulate that emergency administration of such an antiviral therapeutics during an outbreak would inhibit virus dissemination and spread in infected individuals, thus slowing disease progression and allowing the immune system more time to mount a robust response to effectively combat and clear the infection."

The modified compounds were more than 30 times more potent than the original chemicals at inhibiting virus egress. They also showed that they do not interfere with human cell metabolism for breaking down chemicals, and are not toxic to human cells.

The research is still in the early stages. The team is now trying to get additional grants and working on even more potent chemicals with better drug-like properties so they can be tested in animal models. The next step will be for the chemicals to be tested on live viruses, then on animal models and eventually they hope to start human trials.

"This work is exciting to me since it may translate our basic science work into a potential product or therapeutic," concluded Dr. Harty.

Optimal doses of omega-3 fatty acids appear to improve outcomes from traumatic brain injury

In continuation of my update on omega-3 fatty acids

The treatment of concussions and traumatic brain injury (TBI) is a clinical challenge. Clinical studies thus far have failed to identify an effective treatment strategy when a combination of targets controlling aspects of neuroprotection, neuroinflammation, and neuroregeneration is needed. According to emerging science and clinical experience, aggressive intake of omega-3 fatty acids (n-3FA) seems to be beneficial to TBI, concussion, and post-concussion syndrome patients. This research is presented in Concussions, Traumatic Brain Injury, and the Innovative Use of Omega-3s, a review article from the Journal of the American College of Nutrition, official publication of the American College of Nutrition.

Research suggests that early and optimal doses of omega-3 fatty acids (n-3FA) have the potential to improve outcomes from traumatic brain injury. The article reviews preclinical research and cites three brain injury case studies that resulted from a mining accident, a motor vehicle accident, and a drowning accident. Each instance showcased evidence of safety and tolerability, wherein the patients who sustained life-threatening brain injuries recovered brain health with the aid of omega-3 fatty acids (n-3FA).

Growing clinical experience by numerous providers is that the brain needs to be saturated with high doses of n-3FA in order for the brain to have the opportunity to heal. Without an optimal supply of omegas, healing is less likely to happen. It is well recognized that n-3FAs are not a drug and not a cure and every situation is different. Clinically, some patients respond better than others. However, there is no downside to providing optimal levels of nutrition in order to give a patient the best opportunity to regain as much function as possible following a TBI.

Article author Michael D. Lewis, a retired Army Colonel and physician, is the author of the highly anticipated book, When Brains Collide: What Every Athlete and Parent Should Know About the Prevention and Treatment of Concussions and TBI, that will be available on Amazon in September 2016. Dr. Lewis concludes, "n-3FA should be considered mainstream, conventional medicine, if conventional medicine can overcome its inherent bias against nutritional, nonpharmacological therapies."

Essential oils could treat inflammation of lung and liver induced by air pollution

Certain ingredients in essential oils made from plants such as cloves, anise, fennel and ylang-ylang could serve as a natural treatment of lung and liver conditions caused by air pollution. This is according to Miriana Kfoury of the Unité de Chimie Environnementale et Interactions sur le Vivant, Université du Littoral Côte d'Opale in France and the Lebanese University in Lebanon. She is the lead author of a study in Springer's journal Environmental Chemistry Letters. It is the first of its kind to evaluate the value of using certain essential oil compounds to treat inflammation caused by the fine particles that are typical of hazy, polluted air, and that are known to be carcinogenic.

   

[The phenylpropanoids are a diverse family of organic compounds that are synthesized by plants from the amino acid phenylalanine. Their name is derived from the six-carbon, aromatic phenyl group and the three-carbon propene tail of cinnamic acid, which is synthesized from phenylalanine in the first step of phenylpropanoid biosynthesis. Phenylpropanoids are found throughout the plant kingdom, where they serve as essential components of a number of structural polymers, provide protection from ultraviolet light, defend against herbivores and pathogens, and mediate plant-pollinator interactions as floral pigments and scent compounds. Concentrations of phenylpropanoids within plants are also altered by changes in resource availability].
 Isoeugenol   Eugenol

 Estragole   Anethole

Plants naturally contain various essential oils that are made up of different compounds. Some of these have been found to have antioxidant value, and to also be able to fight inflammation. A group of organic compounds called phenylpropanoids are found in the essential oils of some plants, and show promise as possible anti-inflammatory substances. Among these are trans-anethole (a flavor component of anise and fennel), estragole (found in basil), eugenol (which occurs in clove bud oil) and isoeugenol (contained in ylang ylang).

Kfoury and her collaborators first collected air pollutant samples containing fine particles in Beirut, Lebanon. In laboratory tests, the samples were then introduced to human cell cultures of normal bronchial epithelial cells (BEAS-2B) and cancer derived hepatic cells (HepG2). The fine particle matter was found to induce inflammation in the cells - these started to secrete the pro-inflammatory cytokines IL-6 and IL-8 (substances that are secreted during infections and tissue damage). Cytokin levels normally increase when the body's immune system is fighting a specific infection.

Next, the researchers established that the trans-anethole, estragole, eugenol and isoeugenol all have so-called cytotoxicity, which means that they could cause cell death at relatively high concentrations. In this evaluation, they were able to determine the level of cytotoxicity of these oil compounds. This was important in order to establish the maximum dose to be selected in the next step, namely the assessment for anti-inflammatory properties. In the second round of tests, the four compounds were introduced to the combination of cell lines and air pollutants to see whether these could protect liver and lung cells damaged by fine particle air pollutants. It was found that the essential oil compounds tested decrease the levels of the two types of cytokines in the samples. The levels of cytokine IL-6 decreased up to 96 percent, and the levels of cytokine IL-8 by 87 percent.

"The findings provide the first evidence that natural essential oil components counteract the inflammatory effects of particulate matter, such as that contained in polluted air," says Kfoury.

Melatonin appears to suppress growth of breast cancer stem cells

In continuation of my update on Melatonin

Melatonin, a hormone produced in the human brain, appears to suppress the growth of breast cancer tumors.

Researchers at Michigan State University published this finding in the current issue ofGenes and Cancer. While treatments based on this key discovery are still years away, the results give scientists a key foundation on which to build future research.

"You can watch bears in the zoo, but you only understand bear behavior by seeing them in the wild," said David Arnosti, MSU biochemistry professor, director of MSU's Gene Expression in Development and Disease Initiative and co-author of the study. "Similarly, understanding the expression of genes in their natural environment reveals how they interact in disease settings. That's what is so special about this work."

The brain manufactures melatonin only at night to regulate sleep cycles. Epidemiologists and experimentalists have speculated that the lack of melatonin, due in part to our sleep-deprived modern society, put women at higher risk for breast cancer. The latest MSU study showed that melatonin suppresses the growth of breast cancer stem cells, providing scientific proof to support the growing body of anecdotal evidence on sleep deprivation.

The research team was led by Juliana Lopes, a visiting researcher from Sao Paolo, Brazil. Before the team could test its theory, the scientists had to grow tumors from stem cells, known as "mammospheres," a method perfected in the laboratory of James Trosko at MSU.

The growth of these mammospheres was enhanced with chemicals known to fuel tumor growth, namely, the natural hormone estrogen, and estrogen-like chemical Bisphenol A, or BPA, found in many types of plastic food packages.

Melatonin treatment significantly decreased the number and size of mammospheres when compared with the control group. Furthermore, when the cells were stimulated by estrogen or BPA and treated with melatonin at the same time, there was a greater reduction in the number and size of mammospheres.

"This work establishes the principal by which cancer stem cell growth may be regulated by natural hormones, and provides an important new technique to screen chemicals for cancer-promoting effects, as well as identify potential new drugs for use in the clinic," Trosko said.

Ginger-derived nanoparticles may be good medicine for inflammatory bowel disease

A recent study by researchers at the Atlanta Veterans Affairs Medical Center took them to a not-so-likely destination: local farmers markets. They went in search of fresh ginger root.

Back at the lab, the scientists turned the ginger into what they are calling GDNPs, or ginger-derived nanoparticles. The process started simply enough, with your basic kitchen blender. But then it involved super-high-speed centrifuging and ultrasonic dispersion of the ginger juice, to break it up into single pellets. (Don't try this at home!)

The research team, led by Dr. Didier Merlin with VA and the Institute for Biomedical Sciences at Georgia State University, believes the particles may be good medicine for Crohn's disease and ulcerative colitis, the two main forms of inflammatory bowel disease (IBD). The particles may also help fight cancer linked to colitis, the scientists believe.

They report their findings, based on experiments with cells and mice, in the September 2016 issue of Biomaterials.

Each ginger-based nanoparticle was about 230 nanometers in diameter. More than 300 of them could fit across the width of a human hair.

Fed to lab mice, the particles appeared to be nontoxic and had significant therapeutic effects:

• Importantly, they efficiently targeted the colon. They were absorbed mainly by cells in the lining of the intestines, where IBD inflammation occurs.
• The particles reduced acute colitis and prevented chronic colitis and colitis-associated cancer.
• They enhanced intestinal repair. Specifically, they boosted the survival and proliferation of the cells that make up the lining of the colon. They also lowered the production of proteins that promote inflammation, and raised the levels of proteins that fight inflammation.

Part of the therapeutic effect, say the researchers, comes from the high levels of lipids--fatty molecules--in the particles, a result of the natural lipids in the ginger plant. One of the lipids is phosphatidic acid, an important building block of cell membranes.

The particles also retained key active constituents found naturally in ginger, such as 6-gingerol and 6-shogaol. Past lab studies have shown the compounds to be active against oxidation, inflammation, and cancer. They are what make standard ginger an effective remedy for nausea and other digestion problems. Traditional cultures have used ginger medicinally for centuries, and health food stores carry ginger-based supplements--such as chews, or the herb mixed with honey in a syrup--as digestive aids.

Delivering these compounds in a nanoparticle, says Merlin's team, may be a more effective way to target colon tissue than simply providing the herb as a food or supplement.

The idea of fighting IBD with nanoparticles is not new. In recent years, Merlin's lab and others have explored how to deliver conventional drugs via nanotechnology. Some of this research is promising. The approach may allow low doses of drugs to be delivered only where they are needed--inflamed tissue in the colon--and thus avoid unwanted systemic effects.

The advantage of ginger, say the researchers, is that it's nontoxic, and could represent a very cost-effective source of medicine.

The group is looking at ginger, and other plants, as potential "nanofactories for the fabrication of medical nanoparticles."

Merlin and his VA and Georgia State University coauthors elaborated on the idea in a report earlier this year titled "Plant-derived edible nanoparticles as a new therapeutic approach against diseases." They wrote that plants are a "bio-renewable, sustainable, diversified platform for the production of therapeutic nanoparticles."

Ref : http://www.research.va.gov/currents/0816-2.cfm

Ginger-derived nanoparticles may be good medicine for inflammatory bowel disease

New drug prevents vaginal and oral transmission of HIV in pre-clinical animal models

 

HIV remains a major health concern for women and children globally. Worldwide, the majority of new HIV infections occur in young women. Each year, 1.5 million women living with HIV become pregnant. Without effective treatment, up to 45 percent of HIV-infected mothers will transmit the virus to their child, usually through breastfeeding. In an effort to prevent HIV transmission to women and their children, researchers from the University of North Carolina at Chapel Hill demonstrated the effectiveness of a new anti-HIV medication, 4'-Ethynyl-2-fluoro-2'deoxyadenosine or EFdA, in pre-clinical animal models. They found that EFdA can prevent vaginal and oral transmission of HIV. These results were published in the Journal of Antimicrobial Chemotherapy on Monday, August 1.

"Women and children are vulnerable to HIV infection," said Martina Kovarova, PhD, the study's lead author and Assistant Professor of Medicine in the Division of Infectious Diseases at UNC's School of Medicine. "We discovered that EFdA can prevent vaginal transmission of HIV, which would prevent new infections in women. In addition, we were also able to show that EFdA can prevent oral transmission of HIV which would prevent infants who are born to mothers already living with HIV from acquiring the virus during breastfeeding."

Kovarova and her colleagues tested the efficacy of EFdA in vivo using validated pre-clinical humanized mouse models of vaginal and oral HIV transmission. In both studies, a once daily dose of EFdA was able to prevent HIV infection in mice that were exposed multiple times to high doses of HIV.

"Our results are very encouraging," Kovarova said. "We will now try to determine how low of a dose you can give while still providing protection against HIV, and how long the medication will last in your system to see if daily dosing is needed or if it can be administered significantly less frequently."

"The majority of new HIV infections in women and children occur in developing countries with limited resources. The availability of an anti-HIV drug that is potent enough to be used as a preventative agent in both women and infants has the potential to make a significant impact on the global HIV epidemic," said Angela Wahl, PhD, senior author of the study and Assistant Professor of Medicine in the Division of Infectious Diseases at UNC's School of Medicine.

Ref : https://en.wikipedia.org/wiki/4%E2%80%B2-Ethynyl-2-fluoro-2%E2%80%B2-deoxyadenosine

New drug prevents vaginal and oral transmission of HIV in pre-clinical animal models

BCL-2 inhibitor shows promise in AML patients

In continuation of my update on Venetoclax

Patients whose acute myelogenous leukemia (AML) had relapsed or was resistant to chemotherapy and those who were deemed unable to tolerate chemotherapy experienced responses to the selective BCL-2 inhibitor venetoclax (Venclexta), with complete remissions in some, according to phase II clinical trial data.

Journal in Which the Study was Published: Cancer Discovery, a journal of the American Association for Cancer Research.

Authors: Senior author: Anthony Letai, MD, PhD, associate professor of medicine at Harvard Medical School and Dana-Farber Cancer Institute, in Boston, Massachusetts; Lead author: Marina Konopleva, MD, PhD, professor in the Department of Leukemia and the Department of Stem Cell Transplantation at The University of Texas MD Anderson Cancer Center in Houston

Background: Venetoclax is a small molecule that belongs to a class of drugs called BH3 mimetics. It binds with great affinity and selectivity to BCL-2, an antiapoptotic protein that plays a role in many blood cancers, Letai said. BCL-2 proteins keep the AML cells alive by binding to proapoptotic proteins. Venetoclax binds to BCL-2 and frees the proapoptotic proteins, thus rapidly and irreversibly forcing the AML cell to undergo apoptosis, he explained.

In April 2016, venetoclax was approved by the U.S. Food and Drug Administration for the treatment of certain patients with chronic lymphocytic leukemia (CLL).

How the Study Was Conducted: The study investigators recruited 32 patients with AML with a median age of 71 years to this multicenter, single-arm trial evaluating 800 mg daily oral venetoclax. Twenty-six patients received at least four weeks of therapy.

The investigators performed cytogenetic analysis, BH3 profiling, and next-generation sequencing to look for AML-related genetic mutations in the patients' samples collected at study entry and found that 12 patients had mutations in IDH genes, and six had a high BCL-2-sensitive protein index.

Results: The overall response rate was 19 percent; two patients had complete response (CR) and four had complete response with incomplete blood count recovery (CRi). The median duration of therapy in responders was 144.5 days, and the median duration of CR was 48 days. All patients discontinued therapy due to progressive disease or an adverse event, or for other reasons.

The four patients who had CRi had IDH mutations in their cancer cells. Response to the drug correlated with biomarker results, including indices of BCL-2 protein expression and BH3 profiling, Letai said. "This is significant as it supports the mechanism of action of venetoclax as an on-target inhibitor of BCL-2. Moreover, it offers the possibility of using BH3 profiling as a potential predictive biomarker for clinical use of BH3 mimetics," he added.

First investigational treatment for infantile-onset SMA shows promising results in clinical trial

A major milestone was reached when nusinersen, an investigational treatment for spinal muscular atrophy (SMA), was shown to significantly improve achievement of motor milestones in babies with infantile-onset SMA, according to an interim analysis of the double-blind, randomized, placebo controlled Phase 3 clinical trial called ENDEAR. Babies born with SMA, a genetic disorder affecting nerves that control muscle movement, cannot hold up their heads, roll over or sit up independently. They often do not survive beyond 2 years of age. Thirty-six centers around the world participated in the study, including Ann & Robert H. Lurie Children's Hospital of Chicago, which had the highest patient enrollment.

"This landmark study provides the most robust type of evidence that nusinersen, which targets the genetic defect in SMA, safely and effectively helps infants with this condition gain muscle function," said Nancy Kuntz, MD, Principal Investigator (PI) at Lurie Children's, Medical Director of Mazza Foundation Neuromuscular Program and Associate Professor of Pediatrics and Neurology at Northwestern University Feinberg School of Medicine. "This might be a promising therapy for this devastating disorder."

Based on these positive findings and safety profile, the trial will be stopped early and nusinersen will be the first SMA treatment to be filed for FDA approval. Patients in the study will be transitioned into an open label study in which all infants will receive nusinersen. Biogen, the sponsoring company, is working to open a global expanded access program for eligible patients with infantile-onset SMA in the coming months.

"Going forward, we could add SMA to the newborn screening panel and treat infants in the pre-symptomatic phase," said Leon Epstein, MD, Co-PI at Lurie Children's, Division Head of Neurology, Medical Director of the Clinical Research Unit of Stanley Manne Children's Research Institute at Lurie Children's, and Professor of Pediatrics and Neurology at Northwestern University Feinberg School of Medicine.

Due to a genetic defect, infants with SMA do not produce enough survival motor neuron (SMN) protein, which is critical for the maintenance of motor nerve cells. Nusinersen is designed to increase production of fully functional SMN protein by regulating gene expression. The investigational treatment is delivered to the fluid around the spine by lumbar puncture, or spinal tap. Repeated doses are needed.

"The success we saw in the trial is incredibly exciting for families of infants with SMA, as well as for physicians who care for these children," said Kuntz.

Ref : http://www.chemspider.com/Chemical-Structure.34983394.html

Heron Therapeutics Announces FDA Approval of Sustol (granisetron) Extended-Release Injection for the Prevention of Chemotherapy-Induced Nausea and Vomiting

Heron Therapeutics, Inc. (NASDAQ:HRTX), today announced that the U.S. Food and Drug Administration (FDA) has approved Sustol (granisetron) extended-release injection. Sustol is a serotonin-3 (5-HT3) receptor antagonist indicated in combination with other antiemetics in adults for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of moderately emetogenic chemotherapy (MEC) or anthracycline and cyclophosphamide (AC) combination chemotherapy regimens.

Sustol is an extended-release, injectable 5-HT3 receptor antagonist that utilizes Heron’s Biochronomer® polymer-based drug delivery technology to maintain therapeutic levels of granisetron for ≥5 days, covering both the acute and delayed phases of chemotherapy-induced nausea and vomiting (CINV).

“Despite advances in the management of CINV, up to half of patients receiving chemotherapy can still experience CINV, with delayed CINV being particularly challenging to control,” commented Ralph V. Boccia, MD, FACP, Medical Director, Center for Cancer and Blood Disorders. “In our experience, other 5-HT3 receptor antagonists, including palonosetron, are generally effective for 48 hours or less. Sustol, due to its extended-release profile, represents a novel option that can protect patients from CINV for a full 5 days.”

The Sustol global Phase 3 development program was comprised of two, large, guideline-based clinical trials that evaluated Sustol's efficacy and safety in more than 2,000 patients with cancer. Sustol's efficacy in preventing nausea and vomiting was evaluated in both the acute phase (day 1 following chemotherapy) and the delayed phase (days 2-5 following chemotherapy). "The Sustol clinical trial populations and results are highly representative of cancer patients in our real-world clinical practice,” said Jeffrey Vacirca, MD, FACP, Chief Executive Officer and Director of Clinical Research, North Shore Hematology Oncology Associates and Vice President, Community Oncology Alliance. “Use of MEC regimens is widespread, and AC-based regimens are among the most commonly prescribed highly emetogenic chemotherapy regimens. The most significant challenge for my breast cancer patients receiving AC is chemotherapy-induced nausea and vomiting. Sustol represents a better option to manage this devastating side effect of therapy.”

"We would like to thank the investigators, caregivers and most of all the patients who have helped us to achieve this important milestone,” commented Barry D. Quart, PharmD, Chief Executive Officer of Heron Therapeutics. “In addition to bringing an important product to patients, we are extremely pleased to have obtained the first approval of a product utilizing Heron’s Biochronomer polymer-based drug delivery technology.”

"The approval of Sustol is a major step in Heron’s evolution into a fully-integrated biopharmaceutical company with both development and commercial capabilities," said Robert H. Rosen, President of Heron Therapeutics. “Our focus now turns to ensuring patients have access to this important therapy. We look forward to collaborating with the oncology community to make SUSTOL available in the fourth quarter of this year.”

About Sustol (granisetron) extended-release injection

Sustol is indicated in combination with other antiemetics in adults for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of moderately emetogenic chemotherapy (MEC) or anthracycline and cyclophosphamide (AC) combination chemotherapy regimens. Sustol is an extended-release, injectable 5-HT3 receptor antagonist that utilizes Heron’s Biochronomer® polymer-based drug delivery technology to maintain therapeutic levels of granisetron for ≥5 days. The Sustol global Phase 3 development program was comprised of two, large, guideline-based clinical trials that evaluated Sustol's efficacy and safety in more than 2,000 patients with cancer. Sustol's efficacy in preventing nausea and vomiting was evaluated in both the acute phase (day 1 following chemotherapy) and the delayed phase (days 2-5 following chemotherapy).

Drugs designed to target nervous system could control inflammation in the gut, study shows

There's a reason it's called a gut feeling. The brain and the gut are connected by intricate neural networks that signal hunger and satiety, love and fear, even safety and danger. These networks employ myriad chemical signals that include dopamine, a powerful neurotransmitter most famous for its role in reward and addiction.

Duke University researchers have shown that manipulating dopamine signaling in the nervous system of the nematode worm C. elegans can control inflammation in the gut.

The study, which appears Aug. 12 in Current Biology, provides a proof of principle that the immune system can be controlled using drugs originally designed to target the nervous system, such as antipsychotics.

"We are talking about an existing set of drugs and drug targets that could open up the spectrum of potential therapeutic applications by targeting pathways that fine-tune the inflammatory response," said Alejandro Aballay, Ph.D., a professor of molecular genetics and microbiology at Duke School of Medicine.

"It is a big leap from worms to humans, but the idea of targeting the nervous system to control the immune system could potentially be used to treat conditions such as rheumatoid arthritis, autoimmune disease, cancer, inflammatory bowel disease, and Crohn's disease," Aballay said.

Recent research suggests that the wiring between the gut and the brain is involved in many other maladies, including autism, anxiety, depression, Alzheimer's disease, and Parkinson's disease.

Aballay believes that C. elegans provides an excellent model for dissecting this complex cross-talk between the nervous system and the immune system. This tiny, transparent worm has a simple nervous system, consisting of only 302 neurons compared to the roughly 100 billion neurons in the human brain. Yet the worm also has a very basic, rudimentary immune system.

Aballay and his team first stumbled upon the gut-brain connection a few years ago when they were studying the immune system of C. elegans. The worms were subjected to a barrage of chemicals in search of immune activators that could protect against bacterial infections. Out of more than a thousand different chemical compounds, they identified 45 that turned on an immune pathway. Curiously, half of those were involved in the nervous system, and a handful blocked the activity of dopamine.

In this study, Aballay decided to examine the effects of dopamine and dopamine signaling pathways on immunity.

Graduate student Xiou Cao blocked dopamine by treating animals with chlorpromazine, a dopamine antagonist drug used to treat schizophrenia and manic depression in humans. He found that these worms were more resistant to infection by the common pathogen Pseudomonas aeruginosa than counterparts that hadn't received the drug.

When Cao then treated the animals with dopamine, it generated the opposite effect, rendering them more susceptible to infection.

The researchers believe their findings indicate that dopamine signaling acts by putting the brakes on the body's inflammatory response so it doesn't go too far.

"Worms have evolved mechanisms to deal with colonizing bacteria," Aballay said. "That is true for us as well. Humans have trillions of microorganisms in our guts, and we have to be careful when activating antimicrobial defenses so that we mainly target potentially harmful microbes, without damaging our good bacteria -- or even our own cells -- in the process."

"The nervous system appears to be the perfect system for integrating all these different physiological cues to keep the amount of damage in check," Aballay said.

Aballay plans continue his studies in C. elegans to identify the different cues involved in fine-tuning the immune response. He also thinks it is worth looking at different analogues or different doses of dopamine antagonists to see if their effects on psychosis can be separated from their effects on immunity.

Drugs designed to target nervous system could control inflammation in the gut, study shows

New class of anti-cancer agents may be promising treatment for multiple myeloma

Australian researchers have discovered that a new class of anti-cancer agents may be effective in treating multiple myeloma, an incurable bone marrow cancer.

The research revealed that the majority of myelomas rely on a protein called MCL-1 to stay alive. Potential drugs that inhibit MCL-1, which are in pre-clinical development, may be a promising new treatment for multiple myeloma.

Each year more than 1700 Australians are diagnosed with multiple myeloma, which is a cancer of immune cells called plasma cells. Currently available treatments are only able to halt the progression of the disease and relieve symptoms, but cannot cure the disease.

Walter and Eliza Hall Institute researchers Dr Jianan Gong, Dr David Segal, Ms Yuan Yao, Professor Andrew Roberts and Professor David Huang, working with researchers at the Australian Centre for Blood Diseases, Monash University and the Alfred Hospital, investigated the 'survival proteins' that keep myeloma cells alive, allowing the cancer to persist.

The survival of many cancer types relies on a family of related survival proteins called BCL-2 family proteins, Professor Huang said. "In the past decade there has been considerable interest in the using anti-cancer agents called 'BH3-mimetics' to kill cancer cells by blocking the BCL-2 family proteins," he said. "Recent clinical trials have demonstrated that a BH3-mimetic that switches off the protein BCL-2 is an effective treatment for certain forms of leukaemia.

"Our latest research has focused on which BH3-mimetics would be the most effective in treating multiple myeloma, a cancer for which new treatments are urgently needed," Professor Huang said.

Dr Gong said the team discovered that the majority of myeloma samples died when MCL-1 was switched off. "In contrast, only around one-quarter were susceptible to inhibiting BCL-2," she said. "This finding is in keeping with earlier research at the Walter and Eliza Hall Institute that pinpointed MCL-1 as the likely protein that keeps myeloma cells alive.

"Our research shows that switching off MCL-1 has the potential to be effective new treatment approach for the majority of patients with myeloma," Dr Gong said.

Professor Roberts said that there had been considerable interest in developing anti-cancer agents that target MCL-1. "As yet, these inhibitors are still in pre-clinical development," he said. "Our results suggest that, once necessary laboratory testing for safety is completed, clinical trials of their effectiveness in treating patients with multiple myeloma that is no longer responding to current therapies would be well justified."

New class of anti-cancer agents may be promising treatment for multiple myeloma

Commonly used anti-inflammatory drug shows potential to treat Alzheimer's disease

A research project has shown that an experimental model of Alzheimer's disease can be successfully treated with a commonly used anti-inflammatory drug.

A team led by Dr David Brough from The University of Manchester found that the anti-inflammatory drug completely reversed memory loss and brain inflammation in mice.

Nearly everybody will at some point in their lives take non-steroidal anti-inflammatory drugs; mefenamic acid, a common Non-Steroidal Anti Inflammatory Drug (NSAID), is routinely used for period pain.

The findings are published today in a paper authored by Dr Brough and colleagues, in the respected journal Nature Communications. Dr Brough and Dr Catherine Lawrence supervised PhD student Mike Daniels, and postdoc Dr Jack Rivers-Auty who conducted most of the experiments.

Though this is the first time a drug has been shown to target this inflammatory pathway, highlighting its importance in the disease model, Dr Brough cautions that more research is needed to identify its impact on humans, and the long-term implications of its use.

The research, funded by the Medical Research Council and the Alzheimer's Society, paves the way for human trials which the team hope to conduct in the future.

Around 500,000 people in the UK have Alzheimer's disease which gets worse over time, affecting many aspects of their lives, including the ability to remember, think and make decisions.

In the study transgenic mice that develop symptoms of Alzheimer's disease were used. One group of 10 mice was treated with mefenamic acid, and 10 mice were treated in the same way with a placebo.

The mice were treated at a time when they had developed memory problems and the drug was given to them by a mini-pump implanted under the skin for one month.

Memory loss was completely reversed back to the levels seen in mice without the disease.

Dr Brough said: "There is experimental evidence now to strongly suggest that inflammation in the brain makes Alzheimer's disease worse.

"Our research shows for the first time that mefenamic acid, a simple Non-Steroidal Anti Inflammatory Drug can target an important inflammatory pathway called the NLRP3 inflammasome , which damages brain cells."

He added: "Until now, no drug has been available to target this pathway, so we are very excited by this result.

"However, much more work needs to be done until we can say with certainty that it will tackle the disease in humans as mouse models don't always faithfully replicate the human disease."Because this drug is already available and the toxicity and pharmacokinetics of the drug is known, the time for it to reach patients should, in theory, be shorter than if we were developing completely new drugs.

"We are now preparing applications to perform early phase II trials to determine a proof-of-concept that the molecules have an effect on neuroinflammation in humans."

Dr Doug Brown, Director of Research and Development at Alzheimer's Society, said: "Testing drugs already in use for other conditions is a priority for Alzheimer's Society - it could allow us to shortcut the fifteen years or so needed to develop a new dementia drug from scratch.

"These promising lab results identify a class of existing drugs that have potential to treat Alzheimer's disease by blocking a particular part of the immune response. However, these drugs are not without side effects and should not be taken for Alzheimer's disease at this stage - studies in people are needed first."

Commonly used anti-inflammatory drug shows potential to treat Alzheimer's disease

Antioxidant compound could be effective to combat immune rejection after islet transplantation

A team of researchers has found that doses of bilirubin help provide suppression of the immune response following islet transplantation in mouse models. Bilirubin also significantly decreased islet cell death after the cells had been isolated and undergone nutrient deprivation and hypoxic (low oxygen) stress. If applied, the results of the study are expected to improve outcomes after allograft (other donated) islet cell transplantation to treat type 1 diabetes.

Carried out by researchers at North Carolina State University, Ohio State University and the University of California Irvine, the study will be published in a future issue of Cell Transplantation  

"Pancreatic islet transplantation has the potential to provide a potentially curative, non-invasive treatment for type 1 diabetes," said Dr. Christopher A. Adin, associate professor, College of Veterinary Medicine, North Carolina State University. "However, stress and injury can cause up to a 70 percent loss of cells in the first 72 hours after transplantation. We hypothesized that bilirubin, an antioxidant, could be used as a supplement to suppress the immune response to allograft islet transplantation. In this study with mice, we administered bilirubin to the pancreas before procurement or added it to a culture after islet isolation."

Bilirubin, a cytoprotectant, has been shown to improve outcomes in cases of sepsis and in solid organ transplantation, said the researchers. The current study, however, is the first to investigate bilirubin as an islet allograft protectant from the immune response and other cell death-causing injury.

The researchers found that bilirubin supplementation could suppress the damage caused by the release of "damage-associated molecular patterns" (DAMPs) that included types of foreign cell-fighting immune cells.

Their studies also revealed that bilirubin also has a direct effect on the phenotype - the physical appearance - of the antigen cells that fight against engraftment, especially macrophages, a type of cell that engulfs and digests cellular debris and foreign substances.

Taken together, that bilirubin can suppress DAMP release, alter cytokine profiles, and affect macrophages, suggests that the use of this natural antioxidant may provide a method for pre-conditioning to improve outcomes after islet allograft transplantation, concluded the researchers.

"With the increasing age of the population, diabetes will increase in prevalence and the demand for new treatment paradigms will become more pressing," said Dr. Camillo Ricordi, Diabetes Research Institute, University of Miami, Miami, FL. "Use of an anti-oxidant compound to combat immune rejection could be an effective method for overcoming obstacles to the advancement of cell therapy for diabetes."

Ref : http://www.ingentaconnect.com/content/cog/ct/pre-prints/content-ct-1616_adin_et_al

Antioxidant compound could be effective to combat immune rejection after islet transplantation

New compound could kill parasites of three neglected diseases

Scientists have identified a compound that can kill the parasites responsible for three neglected diseases: Chagas disease, leishmaniasis and sleeping sickness. These diseases affect millions of people in Latin America, Asia and Africa, but there are few effective treatments available.

A new study, published today in Nature, suggests that a single class of drugs could be used to treat all three. Wellcome-funded researchers at the Genomics Institute of the Novartis Research Foundation (GNF) have identified a chemical that can cure all of these diseases in mice. It also does not harm human cells in laboratory tests, providing a strong starting point for drug development.

Chagas, leishmaniasis and sleeping sickness have different symptoms, but are all caused by parasites called 'kinetoplastids' - a type of single-celled organism. The parasites share similar biology and genetics, which led scientists to think it might be possible to find a single chemical that could destroy all three.

The team at GNF tested over 3 million different chemicals and identified a compound, GNF6702, which was effective against the parasites but did not damage human cells. They refined this starting compound to make it more potent before testing in it mice.

Senior study author Frantisek Supek from GNF said: "We found that these parasites harbour a common weakness. We hope to exploit this weakness to discover and develop a single class of drugs for all three diseases."

Dr Stephen Caddick, Director of Innovation at Wellcome, said: "These three diseases lead to more than 50,000 deaths annually, yet they receive relatively little funding for research and drug development. We hope that our early stage support for this research will provide a basis for the development of new treatments that could reduce suffering for millions of people in the poorest regions of the world."

Existing treatments for the three diseases are expensive, often have side effects and are not very effective. The fact that GNF6702 does not seem to have any adverse effects in mice suggests that it might have fewer side-effects than existing drugs, although this will need to be explored in human studies. GNF6702 is now being tested for toxicity before it can be moved in to clinical trials.

Ref : https://en.wikipedia.org/wiki/GNF6702

New compound could kill parasites of three neglected diseases

Novel compound holds potential for next-generation prostate cancer treatment

In the search for new ways to attack recurrent prostate cancer, researchers at Duke Health report that a novel compound appears to have a unique way of blocking testosterone from fueling the tumors in mice.

The potential foundation for a next-generation therapy, called tetraaryl cyclobutane, or CB, is being studied as an option for prostate tumors that have grown resistant to current anti-androgen drugs, notably enzalutamide. (see below structure)

"Prostate cancer is the most prevalent form of cancer in men, and the principal driver of tumor growth is the androgen receptor," said John D. Norris, Ph.D., associate research professor in the Department of Pharmacology & Cancer Biology at Duke and senior author of a study published online Aug. 8 in the journal Nature Chemical Biology.

"Suppression of androgen receptor function by anti-endocrine therapies is initially effective, but most tumors develop resistance, resulting in a more aggressive cancer," Norris said. "Our research has been focused on finding a new approach to suppressing androgen receptor activity, because even in situations where tumors are resistant to current therapies, the androgen receptor remains a viable target."

  

Norris and colleagues focused on a group of CB compounds developed in collaboration with scientists at the University of Illinois at Urbana-Champaign. The compounds act as competitive inhibitors of androgen receptors, but are structurally different from current anti-androgens such as enzalutamide.

One of the CB compounds, in particular, inhibits mutant forms of the androgen receptors that promote resistance to enzalutamide. It functions by preventing the androgen receptor from entering the nucleus of the cell where it can promote tumor growth.

"It's encouraging that this compound has a different mechanism of action when compared to current therapies, which gives it a good chance of having efficacy in resistant disease," Norris said. "We have shown in animal models that the compound has activity against prostate tumors where enzalutamide fails."

Norris said additional studies are underway in additional animal models and in tests with other forms of cancer, including breast cancer.

Ref: http://www.nature.com/nchembio/journal/vaop/ncurrent/full/nchembio.2131.html#compounds

Novel compound holds potential for next-generation prostate cancer treatment