Study shows how caffeine counteracts age-related cognitive deficits in animals

A study published in the journal Scientific Reports from Nature publishing group, describes the mechanism by which caffeine counteracts age-related cognitive deficits in animals.

The study coordinated by Portuguese researchers from Instituto de Medicina Molecular (iMM Lisboa) and collaborators from Inserm in Lille, France, along with teams from Germany and United States, showed that the abnormalexpression of a particular receptor - the adenosine A2A, target for caffeine - in the brain of rats induces an aging-like profile namely memory impairments linked to the loss of stress controlling mechanisms.

"This is part of a larger study initiated 4 years ago in which we identified the role of this receptor in stress, but we did not know whether its activation would be sufficient to trigger all the changes. We now found that by altering the amount of this receptor alone in neurons from hippocampus and cortex - memory related areas - is sufficient to induce a profile that we designate as 'early-aging' combining the memory loss and an increase in stress hormones in plasma (cortisol)" - explains Luisa Lopes, Group Leader at iMM Lisboa and the coordinator of the study.

When the same animals were treated with a caffeine analogue, which blocks the action of adenosine A2A receptors, both memory and stress related deficits were normalized.

David Blum, from Inserm research director, adds: "In elderly people, we know there is an increase of stress hormones that have an impact on memory. Our work supports the view that the procognitive effects of A2AR antagonists, namely caffeine, observed in Alzheimer's and age-related cognitive impairments may rely on this ability to counteract the loss of stress controlling mechanisms that occurs upon aging"

This is important not only to understand the fundamental changes that occur upon aging, but it also identifies the dysfunctions of the adenosine A2A receptor as a key player in triggering these changes. And a very appealing therapeutic target" - concludes Luisa Lopes.

Study shows how caffeine counteracts age-related cognitive deficits in animals: A study published in the journal Scientific Reports from Nature publishing group, describes the mechanism by which caffeine counteracts age-related cognitive deficits in animals.

Novel compound provides safe, effective pain relief with zero abuse potential in animal model

Since the isolation of morphine from opium in the 19th century, scientists have hoped to find a potent opioid analgesic that isn't addictive and doesn't cause respiratory arrest with increased doses.

Now scientists at Wake Forest Baptist Medical Center report that in an animal model a novel pain-killing compound, BU08028, is not addictive and does not have adverse respiratory side effects like other opioids. The research findings are published in the Aug. 29 online edition of the Proceedings of the National Academy of Sciences.

"Based on our research, this compound has almost zero abuse potential and provides safe and effective pain relief," said Mei-Chuan Ko, Ph.D., professor of physiology and pharmacology at Wake Forest Baptist and lead author of the study. "This is a breakthrough for opioid medicinal chemistry that we hope in the future will translate into new and safer, non-addictive pain medications."

Pain, a symptom of numerous clinical disorders, afflicts millions of people worldwide. Despite the remarkable advances in the identification of novel targets as potential analgesics in the last decade, including nociceptin-orphanin FQ peptide (NOP) receptor, mu opioid peptide (MOP) receptor agonists remain the most widely used drugs for pain management even though they are addictive and have a high mortality rate caused by respiratory arrest, Ko said.

This study, which was conducted in 12 non-human primates, targeted a combination of classical (MOP) and non-classical (NOP) opioid receptors. The researchers examined behavioral, physiological and pharmacologic factors and demonstrated that BU08028 blocked the detection of pain without the side effects of respiratory depression, itching or adverse cardiovascular events.

In addition, the study showed pain relief lasted up to 30 hours and repeated administration did not cause physical dependence.

"To our knowledge, this is the only opioid-related analgesic with such a long duration of action in non-human primates," Ko said. "We will investigate whether other NOP/Mop receptor-related compounds have similar safety and tolerability profiles like BU08028, and initiate investigational new drug-enabling studies for one of the compounds for FDA's approval."

Ref : http://www.wakehealth.edu/Search/Results.aspx?st=BU08028&tn=12&sfp=88882

Novel compound provides safe, effective pain relief with zero abuse potential in animal model

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