This month’s science round up features exciting new research findings such as the discovery of novel mechanisms, new drug indications and unconventional research models. We also highlight the latest in research news around replication issues in the scientific community. We hope you will enjoy reading this month’s post as much as we enjoyed writing it. Happy Reading!
Alzheimer’s disease (AD) is the most common cause of dementia. According to the 2015 World Alzheimer’s report, more than 46 million people live with dementia, and this is expected to increase to 131.5 million by 2050. Recent studies have demonstrated that inflammation in the brain exacerbates AD. Studies also show that the NLRP3 inflammasome is central to the development of inflammation and contributes to AD. Building on these findings, a team of scientists led by Dr. David Brough at The University of Manchester, UK investigated the effect of common non-steroidal anti-inflammatory drugs (NSAIDs) on AD symptoms. Using two different mouse models of AD, the researchers showed that mefenamic acid, a common NSAID used to treat mild pain, can completely reverse memory loss and brain inflammation in mice. This protective effect was sustained for up to 21 days post termination of mefenamic acid treatment. The researchers also demonstrated that mefenamic acid is a potent inhibitor of the NLRP3 inflammasome, the first known drug to target this pathway. These studies present for the first time a possible treatment for AD and other inflammatory diseases using an existing drug. Still, further research is needed to identify the impact of mefenamic acid on humans and the long-term implications of its use.
Daniels MJ et al. (2016). Fenamate NSAIDs inhibit the NLRP3 inflammasome and protect against Alzheimer’s disease in rodent models. Nat Commun 7, 12504.
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It is now appreciated that the most common cause of cancer death is not the primary tumor itself, but rather metastases that later form. Metastasis is defined as the process by which separate tumor cells break away from the original tumor and travel through the blood stream to remote areas of the body to form a secondary tumor. Scientists have long known that in order to metastasize, tumor cells need to rapidly and effectively exit the blood stream by passing through the endothelial cell barrier of blood vessels. Yet, how the tumor cells interact with endothelial cells during their escape from the blood stream remained unclear. In a new study published in the journal Nature, a research group led by Prof. Steffan Offermanns, Director of the Department of Pharmacology at the Max Planck Institute for Heart and Lung Research has succeeded in elucidating the underlying mechanism. Using in vitro and in vivo models, they show that tumor cells induce the death of endothelial cells in a process known as necroptosis (programmed necrosis). This ultimately promotes the extravasation and metastasis of tumor cells. To induce necroptosis, tumor cells engage death receptor 6 (DR6) on endothelial cells via interaction with amyloid precursor protein, expressed on tumor cells. This suggests that proteins involved in endothelial DR6 necroptotic signaling pathways could be prospective targets for anti-metastatic therapies.
Strillic B et al. (2016). Tumour cell-induced endothelial cell necroptosis via death receptor 6 promotes metastasis. Nature 536, 215-218.
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From August 21 to 26, over 4000 immunologists from all over the world will be attending the 2016 International Congress of Immunology meeting in Melbourne Australia. There will be over 1200 talks on basic and clinical immunology, and one of them presented by Dr. Jiri Hrdy of the Charles University in Prague, Czech Republic, focuses on long-term allergy protection in a 20 year clinical study. The incidence of allergies has been steadily increasing in recent years, and probiotics are believed to prevent or reduce this effect. However, the inherent mechanism of how probiotics influence allergy development is poorly understood. The findings presented by Dr. Hrdy show decreased allergy incidence 5-20 years after initial supplementation of newborns with the probiotic Colinfant New Born (E. coli O83:K24:H31). To understand the mechanism responsible for this observation, the research team examined the blood of probiotic colonized and non-colonized children of allergic mothers vs. the non-colonized children of healthy mothers. They also investigated the role of immune cells in mediating the response. They hypothesize that the favorable effect of probiotics in newborns can be partially explained by their effect on immune cells. Their research provides momentous insight into how newborns with genetic risk of allergies can be protected through the use of probiotics.
Hrdy J. The effect of early postnatal colonisation of newborns by probiotic vaccine Colinfant New Born on allergy incidence and immune system characteristics. Conference talk presented at: International Congress of Immunology Meeting; 2016 August 21; Melbourne, Australia.
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Several prognostic markers of breast cancer have been identified; yet only a few are in clinical use. One likely reason is the often poor correlation between animal studies and clinical trials. A group of researchers at Asan Medical Center in South Korea has proposed that canine mammary tumors (CMTs) can be a potential alternative model for human breast cancer by showing that the expression of a key oncogene, EZH2, is similar in canine and human mammary tumors. EZH2 is a catalytic subunit of the epigenetic regulator polycomb repressive complex 2. Overexpression or mutation of EZH2 has been observed in human breast cancer, and it has been shown to play a role in tumor initiation, development, progression, metastasis and drug resistance. The researchers set out to determine whether EZH2 is increased in CMTs, similar to human breast cancers. They observed that EZH2 is also overexpressed in clinical samples of CMTs. Although some histomorphological features may differ between human breast cancer and CMTs, they share many similarities such as age at onset, risk factors, molecular marker expression and prognosis. This suggests that further efforts to establish CMTs as a model for human breast cancer should be made in order to provide new insights into cancer biology and therapy development.
Choi HJ et al. (2016). Significance of EZH2 expression in canine mammary tumors. BMC Vet Res 12, 164.
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G proteins are cellular “messengers” that function as molecular switches to induce the activation of specific signaling pathways. They are found on the inside of cell membranes and receive signals from their associated receptor, a G protein coupled receptor (GPCR). When a GPCR is engaged by a ligand such as hormones, neurotransmitters or growth factors, the alpha subunit of G proteins become “switched” on. It then separates from the receptor and other subunits to activate further proteins in the signaling pathway. This is the first step in most signaling cascades; however, until now, scientists had a poor understanding of exactly what happens when the G protein alpha subunit is “switched” on. Scientists led by Prof. Franz Hagn at Technical University of Munich have now shown precisely how the individual amino acids of the G protein move during the switching process. Using nuclear magnetic resonance spectroscopy, the researchers identified all the steps involved in how the individual amino acids move in the alpha subunit upon activation. They also demonstrate that the open form of the G protein is more readily accessible to active agents than the rigid closed form of the protein. Because G protein dysfunction is the cause of a number of diseases, this study opens up the opportunity for the development of therapeutics that act directly on the G protein.
Goricanec D et al. (2016). Conformational dynamics of a G-protein α subunit is tightly regulated by nucleotide binding. Proc Natl Acad Sci USA 113, E3629-3638.
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The HIV virus is skilled at avoiding immune detection. In order to infect cells and survive in the host, the virus has to copy its RNA genome into DNA, a process known as reverse transcription. How HIV acquires the nucleotides needed to carry out this process, while avoiding immune detection, has been a mystery to scientists until recently. Scientists at the Medical Research Council Laboratory of Molecular Biology in Cambridge, and University College London, recently discovered a unique feature of the HIV virus that it uses to infect cells and avoid being noticed by the immune system. It is known that during the early stages of infection, the HIV capsid (protein shell that surrounds the virus) protects viral components from immune sensors. However, the researchers discovered that an arginine ring structure within the capsid creates a positively charged channel that recruits the required nucleotides for DNA synthesis. The researchers also describe a channel inhibitor called hexacarboxybenzene that competes with nucleotides for binding, and thus efficiently blocks the reverse transcription process inside the viral capsid. This indicates that this arginine ring channel can be a novel drug target for counteracting HIV infection.
Jacques DA et al. (2016). HIV-1 uses dynamic capsid pores to import nucleotides and fuel encapsidated DNA synthesis. Nature 536, 349-353.
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In our June science round up, we featured a study describing a new gene-editing tool called NgAgo. It was described as a proposed alternative to the popular CRISPR-Cas9 system. However, attempts to replicate the findings of the study have proven largely futile. An unofficial online survey conducted by a molecular biologist at the MRC Centre for Regenerative Medicine in Edinburgh, UK has found only 9 researchers that report success with NgAgo, versus 97 who say they that the system did not work when tested. On August 8, 2016, the senior author of the NgAgo study, Prof. Han Chunyu, submitted a protocol outlining how to apply the NgAgo system to the online repository Addgene. Initial concerns regarding the irreproducibility of Prof. Chunyu’s work came through the pipeline of the scientific community with one researcher posting details of his attempts to reproduce the study on his blog site, through leaked e-mails between colleagues, as well as reports to the journal that published the study, Nature Biotechnology. Nature reports that Nature Biotechnology is currently investigating the matter. Since NgAgo would be a significant benefit to scientific research, it is hoped that the issues of reproducibility will soon be resolved.
Cyranoski D (2016). Replications, ridicule and a recluse: the controversy over NgAgo gene-editing intensifies. Nature 536, 136-137.
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