TNF-α antagonist etanercept reverses age-related increases in constipation in mice

In an exciting new paper led by STRAND Researchers Dr Bhavik Patel, Dr Mel Flint and Dr Mark Yeoman, alongside colleagues from The Open University examining a potential novel treatment class for chronic constipation has been published in the prestigious  Nature Scientific Reports. The paper examines the use of 5-HT, an important pro-kinetic agent in the colon, to see if alterations in colonic 5-HT signalling underlie age–related changes in faecal output in mice and whether these changes were due to an increase in TNF-α. The researchers observed reduced faecal output and water content in aged animals, as well as increased mucosal 5-HT availability and TNF-α expression and decreased mucosal SERT expression and 5-HIAA. The treatment of old mice with Etanercept reversed these changes, suggesting that age-related changes in TNFα expression are an important regulator of mucosal 5-HT signalling and pellet output and water content in old mice. This study points to “anti-TNFα” drugs as potential treatments for age-related chronic constipation.

Patel, BA, Fidalgo, S, Wang, C, Parmar, L, Mandona, K, Panossian, A, Flint, MS, Ranson, RN, Saffrey, MJ  & Yeoman, MS (2017) The TNF-α antagonist etanercept reverses age-related decreases in colonic SERT expression and faecal output in mice. Sci. Rep. 7, 42754; doi: 10.1038/srep42754

Mapping G-protein coupled receptor signalling pathways

Recent work by STRAND Member Kok Choi Kong has been published in the prestigious Proceedings of the National Academy of Sciences of the United States of America. The paper is important as studies in transfected cells have established that G protein-coupled receptors (GPCRs) activate a number of intracellular signaling pathways; however, which of these pathways are physiologically important is unclear. The authors use a genetically engineered mouse to demonstrate a novel role for M3-muscarinic acetylcholine receptor (M3-mAChR) phosphorylation in airway constriction, with implications for human respiratory disease, including asthma and chronic obstructive pulmonary disease. Combining this finding with other M3-mAChR physiological responses, the authors also generate a map of responses that are downstream of G protein-dependent signaling or receptor phosphorylation-dependent signaling. This map predicts the outcome of biased GPCR drugs designed to drive receptor signaling preferentially toward pathways that improve therapeutic efficacy while minimizing toxic/adverse outcomes and providing a fundamental approach to the rational design of next-generation GPCR-based therapies.

If you are interested in the paper, the reference can be found below:

Bradley, SJ, Wiegman CHC, Iglesias, MM, Kong KC, Butcher AJ, Goupil E, Bourgognon JM, Macedo-Hatch T, Russell K, Laporte SA, Kostenis E, Bouvier M, Chung KF, Amrani Y, Tobin AB (2016): Mapping physiological G protein-coupled receptor signalling pathways reveals role for receptor phosphorylation in airway contraction. Proc Natl Acad Sci U S A 113 (16), 4524-4529

MPharm Student awarded Welcome Trust Vacation Scholarship

Congratulations to MPharm Year 3 student, Prijay Bakrania, who has been awarded a Vacation Scholarship entitled ‘Does the expression of Nrf2 change with age in humans?’

The project, under the supervision of STRAND member Dr Greg Scutt, examines Nrf2 an important protein which controls a cells ability to breakdown toxins, poisons and some drugs. Research conducted over the past 10 years has found that the levels of this protein in animals declines with age. This may make older animals more susceptible to harm from these substances.

Dr Scutt said “We are not sure what happens to the levels of Nrf2 in humans, but if it also declines with age, then it could make older individuals more susceptible to the harmful effects of prescribed medications. The aim of this research is to establish whether the age effects the levels of Nrf2 in human white blood cells. We plan do this by taking a small sample of blood from volunteers of different ages and then measuring in white blood cells 1) the level of Nrf2 protein and 2) the level of messenger RNA which contains the code for the Nrf2 protein. There are several known factors which can affect Nrf2 levels, and we want to take these into account when analyzing the data. These include medical history and medication. Some individuals also have a slightly different genetic form Nrf2, or an associated protein called Keap-1 which can affect the activity of Nrf2 found in cells. We also plan to check which genetic form of these proteins volunteers possess so that they can be taken into consideration during the analysis. We also plan to measure the levels of Keap-1 messenger RNA and protein in white blood cells to determine if they change with age.”

Discovering New Antibiotics

Just weeks after Prime Minister David Cameron called for a worldwide cut in the unnecessary use of antibiotics and rewards for drug companies which develop new medicines to fight drug-resistant superbugs, STRAND scientists have been studying soil bacteria which, they say, have the genetic potential to “produce tens of thousands of novel antibiotics”.

The South Korean-led study has been supported by STRAND members Professor Colin Smith and Dr Giselda Bucca, who have undertaken a detailed study of the activity of genes that are responsible for antibiotic production in a soil bacterium called Streptomyces. These bacteria are the major producers of antibiotics that are used worldwide to treat infections. Their study reveals how the activity of the genes for antibiotic production are controlled in the particular species of bacterium they studied – Streptomyces coelicolor– and this new knowledge, they say “suggests new ways for scientists to increase production of known antibiotics and, perhaps more importantly, to discover new antibiotics”.

Professor Colin Smith

Professor Colin Smith

Professor Smith said: “There is a critical need for developing new antibiotics because of the global rise in antibiotic resistance. Soil bacteria such as Streptomyces have the genetic potential to produce tens of thousands of novel antibiotics. However, it can be very difficult to coax them to produce these antibiotics in detectable quantities under laboratory conditions.

“The results from our study suggest how we could manipulate these bacteria to switch on production of antibiotics. This could allow us to ‘awaken’ genetic pathways for antibiotics that are not usually active outside of their natural soil environment. This, in turn, could enable us to study their properties and to scale up their production in the laboratory if they look promising as new antibiotics.”

Professor Smith and Dr Bucca are now embarking on a proof-of-concept study with the global pharmaceutical company GlaxoSmithKline to establish whether the same genetic controls operate in other Streptomyces bacteria. Professor Smith said: “If they do then this will open up new possibilities for increasing production of clinically-important antibiotics.”

Student work published in Autonomic Neuroscience

STRAND Researchers have published a recent paper in Autonomic Neuroscience, with some of  the work being done by BSc Pharamceutical Science students. The paper entitled “Acute paraquat exposure impairs colonic motility by selectively attenuating nitrergic signalling in the mouse” examined the effects of acute paraquat administration on colonic motility in the C57BL/6 mouse.

The study summarised that acute paraquat exposure attenuates colonic transit. These changes may facilitate the absorption of paraquat into the circulation and so facilitate its toxicity.

Top review award for article from STRAND Member

The Lancet Infectious Diseases article was selected for the Elsevier Atlas award, given to a single article every month from the thousands of papers published across Elsevier’s 1,800 journals. The award recognises research with the potential to impact people’s lives around the world.

Dr Jones, Reader in Molecular and Medical Microbiology at the university’s College of Life, Health and Physical Sciences, and Head of Research Development for Queen Victoria Hospital, East Grinstead, was a member of the joint Wellcome Trust and Department of Health working party set-up to review the current alternatives to antibiotics portfolio, and recommend priorities for future funding.

The working party included academics, clinicians and industry representatives, and was chaired by Dr Lloyd Czaplewski (Chemical Biology Ventures Ltd) who led the review process, and development of the report. The Lancet ID article provides a high-level overview of the main working party findings, and has contributed to the governments ongoing review of antimicrobial resistance chaired by economist Jim O’Neill.

Dr Brian Jones in lab

Dr Jones recently featured in the media for his groundbreaking research showing how bacteriophage – viruses that kill bacteria and one of the alternatives recognised in the review – may be used to combat common infections related to the use of medical devices such as catheters.

 

Dr Jones said: “I’m delighted that our work has received this recognition and feel privileged to have taken part in this review. In responding to the threat of antimicrobial resistance (AMR) it is vital that we consider all available strategies, including the use of alternatives to antibiotics where feasible, and how long these may take to develop. I hope this work will contribute to the delivery of an effective approach to tackle AMR.”

 

STRAND hosting International Researchers

STRAND is delighted to be hosting a series of talks, at 3pm on Wednesday 25th November in Watts House, by researchers from the Institute of Neuroscience a Physiology, at The Sahlgrenska AcademyUniversity of Gothenburg. The talks will be given by Prof. Gunnar Tobin, and his research team from the Department of Pharmacology:

Prof. Gunnar Tobin: “Research at the Dept of Pharmacology – an overview”

Dr Michael Winder: “Regulation of nitric oxide in bladder epithelial cells”

Dr Thomas Carlsson: “Bladder dysfunction in animal models of Parkinson´s disease”

Dr Marie Kalm: “How can we prevent cognitive decline after brain tumour treatment?”

The Sahlgrenska Academy consists of 6 institutes, 2 units and 1 national centre  that have attracted more than €90 million in external research funds.  The 22 research centres that form the Academy are inter-disciplinary venues for Research, Training, the Private Sector and the General Community.

For more information please contact us here

Dr Annamaria Gal to talk at Brighton and Sussex Cancer Network

STRAND researcher Dr Annamaria Gal is giving a talk to the Brighton and Sussex Cancer Network on Thursday 26th November.  The seminar, entitled Plasticity and recruitent of tumour associated macrophages in murine metastatic melanoma” will run from 4-6pm in the Medical Research Building, University of Sussex and involve a 50-minute talk followed by discussion and networking.

If you are interested in this seminar please contact Dr Gal, Sarah Newbury (S.Newbury@bsms.ac.uk) or Dr Melanie Flint.

PowerPoint Presentation

New wound dressing to detect infection?

The STRAND microbiology research team, led by Dr Brian Jones, have played a key role in developing a new “intelligent” wound dressing that responds to infection. Dr Jones and his team (from Univeristy of Brighton, Queen Victoria Hospital, and the Blond McIndoe Research Foundation) have been working as part of a group Universities and NHS Trusts across the South of England, led by Prof Toby Jenkins at the University of Bath, to develop this dressing technology. This will tell clinicians when a wound is infected through a simple colour change, and this initial study provides proof-of-concept for an advanced infection detecting dressing for wound care, which could allow the targeted treatment of infections at the bedside and reduce the unnecessary use of antibiotics.  Dr Jones said: “This new dressing technology will not only help clinicians provide the best possible treatment for patients with burns, but could also tell us a lot about how wound infections begin and how they affect the normal healing process. This could in turn lead to even further advances in treating these infections” 

For more information about this project please contact Dr Brian Jones or click here

non-infected dressing

The newly developed dressing

"infected" (simulated) dressing

The dressing when a simulated infection is present