Researchers at the Francis Crick Institute and University of Dundee have screened thousands of drug and chemical molecules and identified a range of potential antivirals that could be developed into new treatments for COVID-19 or in preparation for future coronavirus outbreaks.
In a series of seven papers, published in the Biochemical Journal, the scientists identified 15 molecules that inhibit the growth of SARS-CoV-2 by blocking different enzymes involved in its replication. While COVID-19 vaccines are being rolled out, there are still few drug options that can be used to treat patients with the virus, reduce symptoms and speed up recovery time. These treatments are especially important for groups where the vaccines are less effective, such as some patients with blood cancers.
The researchers developed and ran tests for around 5,000 molecules provided by Crick’s High Throughput Screening team to see if any of these effectively blocked the functioning of any of seven SARS-CoV-2 enzymes. The tests were based on fluorescent changes with a special imaging tool detecting if enzymes had been affected.They then validated and tested the potential inhibitors against SARS-CoV-2 in the lab, to determine if they effectively slowed viral growth. The team found at least one inhibitor for all seven enzymes. Three of the molecules identified are existing drugs, used to treat other diseases. Lomeguatrib is used in melanoma and has few side effects, suramin is a treatment for African sleeping sickness and river blindness and trifluperidol is used in cases of mania and schizophrenia. As there is existing safety data on these drugs, it may be possible to more quickly develop into SARS-CoV-2 antivirals.
John Diffley, the lead author of the papers and associate research director and head of the Chromosome Replication Laboratory at the Crick, said: “We’ve developed a chemical toolbox of information about potential new COVID-19 drugs. We hope this attracts attention from scientists with the drug development and clinical expertise needed to test these further, and ultimately see if any could become safe and effective treatments for COVID-19 patients.” The 15 molecules were also tested in combination with remdesivir, an antiviral being used to treat patients with COVID-19. Four of these, all of which target the SARS-CoV-2 enzyme Nsp14 mRNA Cap methyltransferase, were found to improve the effectiveness of this antiviral in lab tests. Scientists now plan to run tests to see if any pairing of the 15 molecules they identified decrease the virus’ growth more than if they are used alone. Targeting enzymes involved in virus replication could also help prepare for future viral pandemics. “Proteins on the outside of viruses evolve rapidly but within different classes of viruses are well-conserved proteins that change very little with time,” adds John.
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STRESS LINKED TO CROHN’S DISEASE FLARE-UPS: STUDY
According to new research by McMaster University, it is possible that psychological stress could be associated with Crohn’s disease flare-ups.
The study has been published in the ‘Nature Communications Journal’. Researchers using mouse models found that stress hormones suppressed the innate immune system that normally protected the gut from invasive Enterobacteriaceae, a group of bacteria including E. coli that has been linked to Crohn’s disease.
The key to innate immunity is the protective barrier of epithelial cells in the gut, which rely on molecular signals from immune cells to keep out harmful microbes, repair the cell wall and secrete mucus. Without properly functioning immune cells, the epithelial cellular wall can break down, allowing microbes associated with Crohn’s disease to invade the gut and trigger symptom flare-ups.
“The main takeaway is that psychological stress impedes the body’s ability to fight off gut bacteria that may be implicated in Crohn’s disease. Innate immunity is designed to protect us from microbes that do not belong in the gut, like harmful bacteria,” said senior author Brian Coombes, professor and chair of biochemistry and biomedical sciences at McMaster.
“When our innate immune system functions properly, it prevents harmful bacteria from colonizing us, but when it breaks down, it leaves an opening for pathogens to colonize locations they normally cannot and cause illness,” he added.
Coombes said that removing stress hormones in the mouse models restored proper function to immune cells and epithelial cells, blocking the invasion of harmful microbes.
While this discovery could lead to new treatments for Crohn’s disease, Coombes emphasized these findings are still at the pre-clinical stage and more work needs to be done.
“The more we know about what triggers Crohn’s disease, the closer we come to new treatments and potentially even disease prevention,” said Coombes.
Crohn’s disease is an inflammatory condition that causes inflammation, ulcers and scarring in the digestive system. While its root cause is still not fully understood, Coombes said patients with the disease often have an altered gut microbiome dominated by Enterobacteriaceae like E. coli.
The Coombes lab is a part of the Michael G. DeGroote Institute for Infectious Disease Research and the Farncombe Family Digestive Health Research Institute based at McMaster University. External funding for the study was provided by the Canadian Institutes of Health Research and Crohn’s and Colitis Canada.
COVID-19 LINKED TO HEART INFLAMMATION IN COLLEGE ATHLETES
According to a new study, a small but significant percentage of college athletes with COVID-19 develop myocarditis, a potentially dangerous inflammation of the heart muscle.
The findings of the study were presented at the annual meeting of the Radiological Society of North America (RSNA). Myocarditis, which typically occurs as a result of a bacterial or viral infection, can affect the heart’s rhythm and ability to pump and often leaves behind lasting damage in the form of scarring to the heart muscle. It has been linked to as many as 20 per cent of sudden deaths in young athletes. The COVID-19 pandemic raised concerns over an increased incidence of the condition in student-athletes.
For the new study, clinicians at schools in the highly competitive Big Ten athletic conference collaborated to collect data on the frequency of myocarditis in student-athletes recovering from COVID-19 infection. Conference officials had required all athletes who had COVID-19 to get a series of cardiac tests before returning to play, providing a unique opportunity for researchers to collect data on the athletes’ cardiac status.
Jean Jeudy, MD, professor and radiologist at the University of Maryland School of Medicine in Baltimore, serves as the cardiac MRI core leader for the Big Ten Cardiac Registry. This registry oversaw the collection of all the data from the individual schools of the Big Ten conference.
Dr Jeudy reviewed the results of 1,597 cardiac MRI exams collected at the 13 participating schools. There was no selection bias for cardiac MRI, as all COVID-positive athletes underwent a complete cardiac battery of tests including cardiac MRI, echocardiogram, ECG and blood tests, as well as a complete medical history.
Thirty-seven of the athletes, or 2.3 per cent, were diagnosed with COVID-19 myocarditis, a percentage on par with the incidence of myocarditis in the general population. However, an alarmingly high proportion of myocarditis cases were found in athletes with no clinical symptoms. Twenty of the patients with COVID-19 myocarditis (54 per cent) had neither cardiac symptoms nor cardiac testing abnormalities. Only cardiac MRI identified the problem.
“Testing patients for clinical symptoms of myocarditis only captured a small percentage of all patients who had myocardial inflammation. Cardiac MRI for all athletes yielded a 7.4-fold increase in detection,” Dr Jeudy said.
The implications of post-COVID-19 myocardial injury detected by cardiac MRI are still unknown.
“The main issue is the presence of persistent inflammation and/or myocardial scar. Each of these can be an underlying foundation for additional damage and increased risk of arrhythmia,” Dr Jeudy added.
As part of the study, Dr Jeudy and colleagues continue to add to the Big Ten Cardiac Registry to gain more understanding.
“We still don’t know the long-term effects. Some athletes had issues that were resolved within a month, but we also have athletes with continued abnormalities on their MRI as a result of their initial injury and scarring. There are a lot of chronic issues with COVID-19 that we need to know more about, and hopefully, this registry can be one of the major parts of getting that information,” Dr Jeudy explained.
The registry will allow researchers to look beyond the presence of abnormalities and study things like changes in exercise function over time.
STUDY FINDS WHY MOLES BECOME MELANOMAS
Melanocytes are cells that give colour to the skin to protect it from the sun’s rays. Specific changes to the DNA sequence of melanocytes, called BRAF gene mutations, are found in over 75 per cent of moles. The same change is also found in 50 per cent of melanomas and is common in cancers like colon and lung.
Moles and melanomas, which come from the same cell called melanocytes, are similar in nature as they both are skin tumours. However, moles are harmless while melanomas are cancerous and require treatment or can turn fatal. Robert Judson-Torres, PhD, Huntsman Cancer Institute (HCI) researcher and University of Utah (U of U) assistant professor of dermatology and oncological sciences has explained how common moles and melanomas are and why moles can turn into melanomas. It was thought that when melanocytes only have the BRAFV600E mutation the cell stopped dividing, resulting in a mole. When melanocytes had other mutations with BRAFV600E, they divided uncontrollably, turning into melanoma. This model is called “oncogene-induced senescence.”
“A number of studies have challenged this model in recent years,” said Judson-Torres.
“These studies have provided excellent data to suggest that the oncogene-induced senescence model does not explain mole formation but what they have all lacked is an alternative explanation — which has remained elusive,” he added.
With help from collaborators across HCI and the University of California San Francisco, the study team took moles and melanomas donated by patients and used transcriptomic profiling and digital holographic cytometry. Transcriptomic profiling let researchers determine molecular differences between moles and melanomas. Digital holographic cytometry helped researchers track changes in human cells.
The study showed melanocytes that turn into melanoma didn’t need to have additional mutations but are actually affected by environmental signalling when cells receive signals from the environment in the skin around them that give them direction. Melanocytes expressed genes in different environments, telling them to either divide uncontrollably or stop dividing altogether.
STUDY FINDS MORNING EXPOSURE TO DEEP RED LIGHT IMPROVES DECLINING EYESIGHT
The study showed daily three-minute exposure to longwave deep red light ‘switched on’ energy-producing mitochondria cells in the human retina, helping boost naturally declining vision.
A pioneering study by UCL researchers has found that just three minutes of exposure to deep red light once a week when delivered in the morning, can significantly improve declining eyesight.
Published in the journal Scientific Reports, the study builds on the team’s previous work, which showed daily three-minute exposure to longwave deep red light ‘switched on’ energy-producing mitochondria cells in the human retina, helping boost naturally declining vision.
For this latest study, scientists wanted to establish what effect a single three-minute exposure would have, while also using much lower energy levels than their previous studies. Furthermore, building on separate UCL research in flies that found mitochondria display ‘shifting workloads’ depending on the time of day, the team compared morning exposure to afternoon exposure.
In summary, researchers found there was, on average, a 17 per cent improvement in participants’ colour contrast vision when exposed to three minutes of 670 nanometres (long wavelength) deep red light in the morning and the effects of this single-exposure lasted for at least a week. However, when the same test was conducted in the afternoon, no improvement was seen.
Scientists say the benefits of deep red light, highlighted by the findings, mark a breakthrough for eye health and should lead to affordable home-based eye therapies, helping millions of people globally with naturally declining vision.
Lead author, Professor Glen Jeffery (UCL Institute of Ophthalmology), said: “We demonstrate that one single exposure to long-wave deep red light in the morning can significantly improve declining vision, which is a major health and wellbeing issue, affecting millions of people globally.
“This simple intervention applied at the population level would significantly impact on quality of life as people age and would likely result in reduced social costs that arise from problems associated with reduced vision.”
In humans around 40 years old, cells in the eye’s retina begin to age, and the pace of this ageing is caused, in part, when the cell’s mitochondria, whose role is to produce energy (known as ATP) and boost cell function, also start to decline.
DENTAL CARE FOR DIABETICS NEEDS GREATER ATTENTION
India holds the unfortunate distinction of being the “Diabetes Capital of the World” and it’s a tag the nation would do well to drop. Nearly 80 million Indians are said to be under the disorder’s grip, with 1 in 2 citizens unaware that they even have the condition. Obesity, diets high in fats and sugar, a genetic predisposition towards diabetes and a general lack of awareness are all accepted as factors behind these statistics.
Along with these well-known causes, however, there’s another crucial determinant that needs close attention from both healthcare experts and the general population: the link between diabetes and oral health.
But before getting into the specifics of how this bidirectional relationship works, let’s take a quick look at what diabetes is and how it manifests itself in the body.
Type 2 diabetes is the most common form of diabetes. Simply put, it is when the sugar (glucose) level in your blood rises. This rise takes place when insulin, a hormone made by the pancreas, fails to get the glucose from the blood into the cells for energy. If left uncontrolled, diabetes can harm our nerves, kidneys, eyes, heart, and mouth, leading to symptoms like excessive hunger, blurry vision, tingling feet, uncontrollable urination, and dry mouth etc.
Along with neuropathy, nephropathy, retinopathy, and micro-and macrovascular diseases, experts have deemed periodontal disease the sixth complication of diabetes.
WHAT IS PERIODONTITIS?
Periodontitis is an infection caused by plaque, a sticky film of bacteria and other microorganisms attached to teeth. The complication affects the bones that support our teeth, damaging the tissue and causing gum shrinkage and tooth loss. It is controllable but when left unchecked, can be devastating for our oral health.
It is now known that periodontitis has a bidirectional relationship with diabetes. What does it mean? Basically this: by controlling periodontitis, you can help keep diabetes in check and vice versa. In other words, this two-way link means diabetes increases the risk for periodontitis… and periodontal inflammation negatively affects glycemic (or glucose) control.
Along with diabetes, periodontitis is quite common in India too. As per reports from the Ministry of Health and Family Welfare, it affects up to 85% of the country’s population!
So how can diabetics manage their condition and stay clear of this debilitating gum disease? It isn’t all that complicated. Along with a healthy diet and exercise, efficient dental care can go a long way in helping them keep their blood sugar levels in check.
DENTAL CARE FOR THE FIGHT AGAINST DIABETES
Oral health simply cannot be overlooked in the quest to control diabetes and its effects. There are numerous ways that diabetics can maintain a healthy mouth and prevent plaque from damaging their teeth and gums. Plaque forms when sugary foods like soft drinks, bread, fruit etc interact with the bacteria in our mouth.
Brushing twice a day and rinsing the mouth well after every meal does wonders for our oral health. These are foundational, everyday practices that must be followed by each one of us. For diabetics, flossing the teeth once a day is also recommended. So is the use of anti-microbial and anti-inflammatory toothpaste. Additionally, rinsing teeth every 1-2 hours can also help maintain oral hygiene. And of course, smoking remains a strict no-no.
It has been suggested that diabetics must visit a dentist every 3 months so that any early sign of periodontitis can be detected. The patient must also report any symptom of gum disease as early as possible — something that is recommended for non-diabetics and/or people with such a genetic background too. Reporting symptoms is especially important because there have been numerous instances of dentists diagnosing diabetes!
THE NEED FOR AWARENESS
Along with the general population, India’s healthcare professionals also need to be more aware on this link between diabetes and oral health so that early diagnosis can be done, and precautionary measures may be suggested. Non-dental care specialists must also be trained and educated on the importance of oral hygiene and upkeep.
A 2014 survey reported that around half of all Indians did not use a toothbrush or toothpaste. What India also needs is more outreach programs that inform the millions of citizens residing in remote, rural and other areas about the need for dental care. India would also do well to make affordable dental care products available so that more citizens are able to access them. The fight against diabetes is taking place on many fronts. However, dental care has long been overlooked as a possible contributing solution. It’s time to change that.
The author is a BDS, MDS – Periodontology and Oral Implantology on Dental care for Diabetics.
UNCOMMON FOR UNBORN BABIES TO CONTRACT COVID-19
According to a study led by UCL researchers with Great Ormond Street Hospital for Children and the NIHR Great Ormond Street Biomedical Research Centre, it is only possible for an unborn baby to contract Covid-19 if their gut is exposed to the SARS-CoV-2 virus.
The research was published in the ‘BJOG – An International Journal of Obstetrics & Gynaecology Journal’. Although the study did not look specifically at mothers with Covid-19 and whether their infection was transmitted to an unborn baby, it found that certain fetal organs, such as the intestine, are more susceptible to infection than others.
However, researchers said, that opportunities for the Covid-19 virus infecting the fetus are extremely limited, as the placenta acted as a highly effective and protective shield, and evidence suggested fetal infection, known as vertical transmission, is extremely uncommon.
Researchers set out to understand how newborn babies could have developed Covid-19 antibodies, as it had been reported in a small number of cases.
Specifically, they wanted to know if and how the virus could be passed from an infected mother to the unborn fetus.
To answer this question, researchers examined various fetal organs and placenta tissue to see if there was any presence of the cell surface protein receptors, ACE2 and TMPRSS2. These two receptors sit on the outside of cells and both are needed for the SARS-Cov-2 virus to infect and spread.
Researchers found the only fetal organs to feature both the ACE2 and TMPRSS2 were the intestines (gut) and the kidney; however, the fetal kidney is anatomically protected from exposure to the virus and is, therefore, less at risk of infection.
Therefore, the team concluded that the SARS-CoV-2 virus could only infect the fetus via the gut and through fetal swallowing of amniotic fluid, which the unborn baby does naturally for nutrients.
After birth ACE2 and TMPRSS2 receptors are known to be present in combination on the surface of cells in the human intestine as well as the lung. The gut and lung are suspected to be the main routes for Covid-19 infection, but in younger children, the intestine appeared to be most important for virus infection.
Senior author, Dr Mattia Gerli (UCL Division of Surgery and Interventional Science & the Royal Free Hospital) explained, “The fetus is known to begin swallowing the amniotic fluid in the second half of pregnancy. To cause infection, the SARS-CoV-2 virus would need to be present in significant quantities in the amniotic fluid around the fetus.”
“However, many studies in maternity care have found that the amniotic fluid around the fetus does not usually contain the SARS-CoV2 virus, even if the mother is infected with Covid-19. Our findings, therefore, explain that clinical infection of the fetus during pregnancy is possible but uncommon and that is reassuring for parents-to-be,” Gerli added.
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