Road signs for immune defense cells

The mechanism of MHC I assembly, epitope editing and quality control within the peptide loading complex (PLC). The fully assembled PLC machinery of antigen processing is formed by the antigen transport complex TAP1/2, the chaperones calreticulin, ERp57, and tapasin, and the heterodimeric MHC I (heavy and light chain in teal and green, respectively).
Credit: Christoph Thomas & Robert Tampé

How do killer T cells recognize cells in the body that have been infected by viruses? Matter foreign to the body is presented on the surface of these cells as antigens that act as a kind of road sign. A network of accessory proteins – the chaperones – ensure that this sign retains its stability over time. Researchers at Goethe University have now reached a comprehensive understanding of this essential cellular quality control process. Their account of the structural and mechanistic basis of chaperone networks has just appeared in the prestigious science journal Nature Communications. These new findings could be harbingers of progress in areas such as vaccine development.

Organisms are constantly invaded by pathogens such as viruses. Our immune system swings into action to combat these pathogens immediately. The innate non-specific immune response is triggered first, and the adaptive or acquired immune response follows. In this second defense reaction, specialized cytotoxic T lymphocytes known as killer T cells destroy cells in the body that have been infected and thus prevent damage from spreading. Humans possess a repertoire of some 20 million T cell clones with varying specificity to counter the multitude of infectious agents that exist. But how do the killer T cells know where danger is coming from? How do they recognize that something is wrong inside a cell in which viruses are lurking? They can't just have a quick peek inside.

New injectable gel offers promise for tough-to-treat brain tumors

Quanyin Hu, an assistant professor in the University of Wisconsin–Madison School of Pharmacy’s Pharmaceutical Sciences Division
Credit: UWM

Like the hardiest weed, glioblastoma almost always springs back — usually within months after a patient’s initial brain tumor is surgically removed. That is why survival rates for this cancer are just 25 percent in one year and plummet to 5 percent by the five-year mark.

One of the challenges of treating this disease is that surgeons can’t always remove every bit of tumor or glioma stem cells that might linger in the brain.

“One characteristic of glioblastoma is that the tumor cells are very aggressive, and they will infiltrate the surrounding tissues. So, the surgeon can’t clearly feel the boundaries between the tumor and the normal tissue, and you cannot remove as much as possible because all the tissues in the brain are extremely important — you certainly don’t want to remove too much,” explains Quanyin Hu, an assistant professor in the University of Wisconsin–Madison School of Pharmacy’s Pharmaceutical Sciences Division. “So, the tumor will come back again, and that sharply decreases the survival rate after treatment.”

But Hu’s Cell-Inspired Personalized Therapeutic (CIPT) Lab has developed a powerful immunity-boosting postoperative treatment that could transform the odds for patients with glioblastoma. Hu and his collaborators published their research on the treatment’s use in mouse models of human glioblastoma this month in the journal Science Translational Medicine.

New inhaled COVID-19 therapeutic blocks viral replication in the lungs

UC Berkeley postdoctoral scholar Chi Zhu is part of a team of researchers who are developing a new COVID-19 therapeutic that can be administered as a nasal spray. The experimental treatment is effective against all SARS-CoV-2 “variants of concern” and could be readily modified to target other RNA viruses.
UC Berkeley photo by Brittany Hosea-Small

Scientists at the University of California, Berkeley, have created a new COVID-19 therapeutic that could one day make treating SARS-CoV-2 infections as easy as using a nasal spray for allergies.

The therapeutic uses short snippets of synthetic DNA to gum up the genetic machinery that allows SARS-CoV-2 to replicate within the body.

In a new study published online in the journal Nature Communications, the team shows that these short snippets, called antisense oligonucleotides (ASOs), are highly effective at preventing the virus from replicating in human cells. When administered in the nose, these ASOs are also effective at preventing and treating COVID-19 infection in mice and hamsters.

“Vaccines are making a huge difference, but vaccines are not universal, and there is still a tremendous need for other approaches,” said Anders Näär, a professor of metabolic biology in the Department of Nutritional Sciences and Toxicology (NST) at UC Berkeley and senior author of the paper. “A nasal spray that is cheaply available everywhere and that could prevent someone from getting infected or prevent serious disease could be immensely helpful.”

Because the ASO treatment targets a portion of the viral genome that is highly conserved among different variants, it is effective against all SARS-CoV-2 “variants of concern” in human cells and in animal models. It is also chemically stable and relatively inexpensive to produce at large scale, making it ideal for treating COVID-19 infections in areas of the world that do not have access to electricity or refrigeration.

Triazavirin to Be Tested for Effectiveness Against Tick-Borne Encephalitis

Triazavirin was developed by scientists of the Ural Federal University and the Ural Branch of the Russian Academy of Sciences.
Credit: UrFU Press Service

The scientific community has provided research recommendations

The Medsintez plant, the manufacturer of the antiviral drug Triazavirin, plans to conduct studies of the drug for effectiveness against tick-borne encephalitis. Aleksandr Petrov, Chairman of the Board of Directors of the Medsintez Plant LLC, notes that the company has already received recommendations from the scientific community. This was reported by TASS.

"The effectiveness of Triazavirin against tick-borne encephalitis is a very interesting topic to study. Scientists are already saying that the drug can be effective against this virus. Currently we are guided by the opinion of scientists, that is why we are considering the possibility of conducting such studies," said Petrov.

He stressed that this year in some regions there is a high activity of ticks and increased detection of cases of encephalitis, that is why Triazavirin research in this area is relevant.

Reference:
Medsintez plant is located in Novouralsk (Sverdlovsk region). It specializes in the production of pharmaceutical products. The plant produces infusion solutions, ready forms of genetically engineered human insulin, solid and liquid forms of drugs. The plant manufactures licensed products and is engaged in the creation of new drugs.

Source/Credit: Ural Federal University

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Researchers discover new leukemia-killing compounds

Natasha Kirienko (left) and Svetlana Panina in Kirienko’s Rice University laboratory in 2019. Kirienko, associate professor of biosciences, and Panina, a former postdoctoral research associate in Kirienko’s lab, collaborated with researchers at the University of Texas MD Anderson Cancer Center to study potential new mitophagy-inducing drugs that could be paired with other chemotherapies to deliver a potent one-two punch to leukemia.
Photo by Jeff Fitlow/Rice University

Researchers from Rice University and the University of Texas MD Anderson Cancer Center have discovered potential new drugs that work in concert with other drugs to deliver a deadly one-two punch to leukemia.

The potential drugs are still years away from being tested in cancer patients, but a recently published study in the journal Leukemia highlights their promise and the innovative methods that led to their discovery.

In previous studies, the research groups of Rice biochemist Natasha Kirienko and MD Anderson physician-scientist Marina Konopleva screened some 45,000 small-molecule compounds to find a few that targeted mitochondria. In the new study, they chose eight of the most promising compounds, identified between five and 30 closely related analogs for each and conducted tens of thousands of tests to systematically determine how toxic each analog was to leukemia cells, both when administered individually or in combination with existing chemotherapy drugs like doxorubicin.

“One of the big challenges was to establish optimal conditions and doses for testing on both cancer cells and healthy cells,” said study lead author Svetlana Panina , a researcher at the University of Texas at Austin who conducted the research during her postdoctoral studies at Rice. “The results from our previously published cytotoxicity assay were helpful, but very little is known about these small-molecule compounds. None of them had been thoroughly described in other studies, and we had to essentially start from scratch to determine how much to use, what they do in cells, everything. All the doses and treatment conditions had to be adjusted by multiple preliminary experiments.”

Cancer drug shows potential as treatment for muscular dystrophy

Dr. Farshad Babaeijandaghi
Source UBC

Researchers at UBC’s School of Biomedical Engineering have discovered that an existing cancer drug could have potential as a treatment for muscular dystrophy.

The researchers found that the drug — known as a colony-stimulating factor 1 receptor (CSF1R) inhibitor — helped slow the progress of Duchenne muscular dystrophy in mice by increasing the resiliency of muscle fibers.

The findings were published today in Science Translational Medicine.

“This is a class of drug that is already being used in clinical trials to treat rare forms of cancer,” says Dr. Farshad Babaeijandaghi, a postdoctoral fellow at UBC and first author on the study. “To find that it could potentially serve a double purpose as a treatment for muscular dystrophy is incredibly exciting. It shows a lot of promise, and with further testing, could help extend and improve quality of life for patients.”

Duchenne muscular dystrophy (DMD) is a severe genetic disorder that leads to progressive muscle weakness and degeneration due to disruptions to the protein dystrophin, which helps keep muscle cells intact. It is the most common congenital disease in Canada, affecting about one out of every 3,500 males, and in rarer cases, females.

DMD symptoms typically appear in early childhood, with patients facing increased loss of muscle function as they age. As the disease progresses, many patients are forced to rely on mobility aids, such as a wheelchair, with the disease eventually impacting heart and lung function. While improvements in cardiac and respiratory care have increased life expectancy in recent decades, there is currently no cure.

Chemically modified plant substances work against the hepatitis E virus

Chemically modified rocaglamides prevent certain viruses from multiplying.
Credit: Department of Molecular and Medical Virology

Rocaglamides from mahogany plants raise hope for the development of an antiviral drug.

The hepatitis E virus (HEV) is widespread and so far, there is no effective drug. In the search for this, the so-called rocaglamides have come into focus: plant substances that can inhibit the multiplication of viruses. Researchers from the Molecular and Medical Virology Department at the Ruhr University Bochum (RUB) have examined a library of chemically modified rocaglamides for their antiviral effects, which a team from Boston has created. A group of active substances that has a so-called amidino group stood out. It particularly effectively inhibited virus multiplication. The team around Dimas F. Praditya, Mara Klöhn and Prof. Dr. Eike Steinmann reports in the journal Antiviral Research.

Plant substances inhibit the multiplication of cancer cells and viruses

Rocaglamides are a group of plant substances that are produced by various mahogany plants. It is known that they have an inhibitory effect on the multiplication of some cancer cells. It was not until 2008 that findings on their antiviral effects against RNA viruses were published for the first time: for example, they can inhibit the multiplication of Ebolaviruses, HEV, zikaviruses or Sars-Cov-2.

An Experimental Treatment Failed in Mice, and Researchers Did the Right Thing: They Published About It

Treatment of FOP mice with an antibody to ACVR1 greatly exacerbates abnormal bone formation (heterotopic ossification) following muscle injury. This is a 3D-rendered microCT image in which the heterotopic bone has been colorized green.
Source: University of Connecticut

Blocking the mutant protein with an antibody didn’t stop the strange, abnormal bone growths in mice. But the knowledge gained could steer scientists toward more promising approaches, report researchers from UConn and Alexion Pharmaceuticals in the The Journal of Clinical Investigation.

Fewer than 4,000 people worldwide are afflicted with fibrodysplasia ossificans progressiva (FOP), an inherited disease in which small injuries or bruises to skeletal muscle provoke the growth of massive, abnormal bone and cartilage. Gradually much of the body’s soft tissue turns to bone. Now, researchers at UConn and Alexion Pharmaceuticals who were investigating a potential cure instead found a concerning surprise–blocking the protein responsible for the disease with a monoclonal antibody made the abnormal bone growth worse in mice.

Normally, stem cells help repair muscle damaged by injury or disease. But in people with FOP, certain stem cells get the wrong message from a mutant receptor on their surface. Instead of promoting muscle regeneration, the stem cells develop into bone.

UConn Professor of Molecular and Cell Biology David Goldhamer, Alexion Pharmaceuticals researcher Jeffrey Hunter, and colleagues worked for years to discover a potential antibody therapy for FOP using accurate genetic mouse models of the disease developed by the two groups. The idea was that the antibody would block the mutant receptor and prevent the responsible stem cells from making new bone. But the results were exactly the opposite.

New delivery method allows slow-release of broader array of peptide drugs in the body

Schwendeman Lab.
Image credit: Michigan Photography

A new study from the University of Michigan describes one of the first entirely new drug delivery microencapsulation approaches in decades.

Microencapsulation in biodegradable polymers allows drugs such as peptide therapeutics to be released over time in the body.

Peptides are molecules in the body that are composed of short chains of amino acids, and include messengers, growth factors and well-known hormones such as insulin. Because of their larger size and structure, peptide drugs are rarely given by mouth and must be injected. Microencapsulation is one way to decrease the time needed between injections.

One slow-release delivery method for peptide drugs is to encapsulate them within the type of resorbable polymers often used as dissolving sutures, said study co-author Steven Schwendeman, professor of pharmaceutical sciences and biomedical engineering.

However, development of polymer dosage forms for delivery of certain peptide drugs has been difficult because the currently available methods to microencapsulate the peptide molecules in the polymer require organic solvents and complex manufacturing.

Locking Leukemia’s Cellular Escape Hatch

Kris Wood, PhD, associate professor of
Pharmacology and Cancer Biology

Leukemia starts in cells that would normally develop into different types of blood cells. About 61,000 people in the U.S. are diagnosed each year, and depending on the type of leukemia and the age of the patient, five-year survival rates vary between about 20-80%.

After losing a close friend to an aggressive form of leukemia, acute myeloid leukemia (AML), Kris Wood, PhD, associate professor of pharmacology and cancer biology, devoted his research to helping find better treatment options for people with leukemias and lymphomas. He and his colleagues have discovered a potential new drug therapy that is preparing to enter clinical trials.

A new class of drugs called nuclear exportin inhibitors has recently been approved for use to treat cancers. Nuclear exportins are proteins that shuttle other proteins out of the nucleus of a cell. These new drugs stop the shuttle from leaving the station.

“The idea is that if you treat cells with a drug that blocks a nuclear exportin,” Wood said, “its client proteins become trapped in the nucleus.” And while researchers don’t fully understand why this is therapeutic, it works. Wood and his team investigated the mechanisms behind it. Their results were published in Nature Cancer.

First, they treated AML cells with Selinexor, a nuclear exportin inhibitor. At the same time, they used CRISPR screens to knock out thousands of genes across the genome one at a time to identify genes that made the drug work either much better or much worse when knocked out.

Common drug-resistant superbug develops fast resistance to 'last resort' antibiotic

Pseudomonas under a microscope
Credit: Sean Booth

New research has found that Pseudomonas bacterium develops resistance much faster than usual to a common ‘last-resort’ antibiotic.

A study published today in Cell Reports reveals how populations of a bacterium called Pseudomonas respond to being treated with Colistin, a 'last resort' antibiotic for patients who have developed multi-drug resistant infections.

Antibiotics play a key role in human health by helping to combat bacterial infection, but bacteria can evolve resistance to antibiotics patients rely on. Antibiotic-resistant infections now cause >1 million deaths worldwide per year.

With a small number of ‘last-resort’ antibiotics available, researchers from the University of Oxford are investigating the processes that drive the rise, and fall, of resistance in common bacterial pathogen populations, which is key to tackling the increase in antimicrobial resistance (AMR).

Alzheimer’s disease causes cells to overheat and ‘fry like eggs’

Mammalian cell stained with fluorescence polymeric thermometers and falsely-colored based on temperature gradients. 
Credit: Chyi Wei Chung

The researchers, from the University of Cambridge, used sensors small and sensitive enough to detect temperature changes inside individual cells, and found that as amyloid-beta misfolds and clumps together, it causes cells to overheat.

In an experiment using human cell lines, the researchers found the heat released by amyloid-beta aggregation could potentially cause other, healthy amyloid-beta to aggregate, causing more and more aggregates to form.

In the same series of experiments, the researchers also showed that amyloid-beta aggregation can be stopped, and the cell temperature lowered, with the addition of a drug compound. The experiments also suggest that the compound has potential as a therapeutic for Alzheimer’s disease, although extensive tests and clinical trials would first be required.

The researchers say their assay could be used as a diagnostic tool for Alzheimer’s disease, or to screen potential drug candidates. The results are reported in the Journal of the American Chemical Society.

Common drug offers fertility hope for women with obesity

Researchers may have found a solution to improving fertility in women with obesity, following a successful trial in mice using diabetes medication to reduce blood glucose levels.

The University of Queensland study found the common type 2 diabetes medication, Dapagliflozin, altered reproductive hormones in obese mice, and could be the key to improving fertility in humans.

Professor Chen Chen, from UQ’s School of Biomedical Sciences, said the results were a promising sign, as human and mouse reproductive cycles are similar.

“After eight weeks of treatment, blood glucose levels in the mice normalized, body weight reduced, reproductive cycles recovered, and reproductive hormones and ovulation were largely restored, compared with mice that were not treated,” Professor Chen said.

“The drug we used – Dapagliflozin – is known for reducing blood glucose levels and improving other biomarkers of metabolic health, but its effects on reproductive health and fertility have yet to be fully investigated.

“Our findings suggest that normalizing blood glucose metabolism with Dapagliflozin in obesity may be a promising route for restoring reproductive function, at the very least.”

The drug gabapentin may boost functional recovery after a stroke

These 3D images of mouse brain vasculature show normal conditions, top, and after an ischemic stroke, which occurs when a blood vessel clot blocks blood flow in the brain.
Credit: Andrea Tedeschi

The drug gabapentin, currently prescribed to control seizures and reduce nerve pain, may enhance recovery of movement after a stroke by helping neurons on the undamaged side of the brain take up the signaling work of lost cells, new research in mice suggests.

The experiments mimicked ischemic stroke in humans, which occurs when a clot blocks blood flow and neurons die in the affected brain region.

Results showed that daily gabapentin treatment for six weeks after a stroke restored fine motor functions in the animals’ upper extremities. Functional recovery also continued after treatment was stopped, the researchers found.

The Ohio State University team previously found that gabapentin blocks the activity of a protein that, when expressed at elevated levels after an injury to the brain or spinal cord, hinders re-growth of axons, the long, slender extensions of nerve cell bodies that transmit messages.

Experimental COVID-19 vaccine provides mutation-resistant T cell protection in mice

Marulasiddappa Suresh
Credit: UWM

A second line of defense — the immune system’s T cells — may offer protection from COVID-19 even when vaccine-induced antibodies no longer can, according to new research out of the University of Wisconsin School of Veterinary Medicine.

The researchers discovered that a new, protein-based vaccine against the original version of the COVID-19 virus was able to teach mouse T cells how to recognize and kill cells infected with new, mutated versions of the virus. This T cell protection worked even when antibodies lost their ability to recognize and neutralize mutated SARS-CoV-2, the virus that causes COVID-19.

“Antibodies prevent COVID-19 infection, but if new variants escape these antibodies, T cells are there to provide a second line of protection,” explains lead scientist Marulasiddappa Suresh, a professor of immunology and associate dean for research at the School of Veterinary Medicine.

The study, published in the Proceedings of the National Academy of Sciences, investigates the role of T cells, a specialized type of white blood cell, in defending against COVID-19 when antibodies fail.

When you receive a COVID-19 vaccine, your body learns to produce antibodies, proteins in the immune system that bind to and neutralize SARS-CoV-2. These antibodies circulate in the blood stream and protect you from illness by patrolling the nostrils, airways and lungs and wiping out the virus before it can cause infection or disease.

Investigational Mucosal COVID Vaccine Protects Against Disease and Transmission

In animal studies that mimic human exposures, an investigational COVID vaccine designed to be taken orally not only protects the host, but also decreases the airborne spread of the virus to other close contacts.

The study, led by Duke researcher Stephanie N. Langel, Ph.D., medical instructor in the Department of Surgery, demonstrated the potential of a COVID vaccine that works through the mucosal tissue to neutralize the SARS-CoV-2 virus, limiting infections and the spread of active virus in airborne particles.

The findings are published today in the journal Science Translational Medicine.

“Considering most of the world is under-immunized -- and this is especially true of children -- the possibility that a vaccinated person with a breakthrough infection can spread COVID to unimmunized family or community members poses a public health risk,” Langel said. “There would be a substantial benefit to develop vaccines that not only protect against disease, but also reduce transmission to unvaccinated people.”

Langel and colleagues -- including teams from the vaccine developer, Vaxart, and a clinical research non-profit, Lovelace Biomedical Research Institute -- tested a vaccine candidate that uses an adenovirus as a vector to express the spike protein of the SARS-CoV-2 virus. The human vaccine is designed to be taken as a pill.

Promising nose spray could prevent and treat COVID-19

A newly discovered small molecule could be sprayed into people’s noses to prevent COVID-19 illness prior to exposure and provide early treatment if administered soon after infection, according to a study in mice led by Cornell researchers.

The study, published March 28 in the journal Nature, employed experimental mice engineered with human receptors for the SARS-CoV-2 virus on their cell surfaces and found that a molecule, called N-0385, inhibited entry of the virus into cells in the body. At Cornell, N-0385 was shown to protect mice from infection prior to exposure, while also providing effective treatment when administered up to 12 hours after exposure. The molecule was developed in collaboration with investigators at the Université de Sherbrooke in Quebec, Canada.

The treatment holds promise for both preventing disease and reducing severity of and mortality from COVID-19 post-infection with a few single daily doses.

“There are very few, if any, small molecule antivirals that have been discovered that work prophylactically to prevent infection,” said Hector Aguilar-Carreno, associate professor of virology in the Department of Microbiology and Immunology in the College of Veterinary Medicine, and a senior author of the paper, “A TMPRSS2 Inhibitor ACTS as a pan-SARS-CoV-2 prophylactic and therapeutic.” Other senior authors include Francois Jean, associate professor of microbiology and immunology at the University of British Columbia in Vancouver, and Richard Leduc, professor of pharmacology at the Université de Sherbrooke.