Tag Archives: cells

Self-Assembling Nanofibers Prevent Damage from Inflammation

Biomedical engineers at Duke University have developed a self-assembling nanomaterial that can help limit damage caused by inflammatory diseases by activating key cells in the immune system. In mouse models of psoriasis, the nanofiber-based drug has been shown to mitigate damaging inflammation as effectively as a gold-standard therapy. One of the hallmarks of inflammatory diseases, like rheumatoid arthritis, Crohn’s disease and psoriasis, is the overproduction of signaling proteins, called cytokines, that cause inflammation. One of the most significant inflammatory cytokines is a protein called TNF. Currently, the best treatment for these diseases involves the use of manufactured antibodies, called monoclonal antibodies, which are designed to target and destroy TNF and reduce inflammation.

Although monoclonal antibodies have enabled better treatment of inflammatory diseases, the therapy is not without its drawbacks, including a high cost and the need for patients to regularly inject themselves. Most significantly, the drugs also have uneven efficacy, as they may sometimes not work at all or eventually stop working as the body learns to make antibodies that can destroy the manufactured drug. To circumvent these issues, researchers have been exploring how immunotherapies can help teach the immune system how to generate its own therapeutic antibodies that can specifically limit inflammation.

The graphic shows the peptide nanofiber bearing complement protein C3dg (blue) and key components of the TNF protein, which include B-cell epitopes (green), and T-cell epitopes (purple)

We’re essentially looking for ways to use nanomaterials to induce the body’s immune system to become an anti-inflammatory antibody factory,” said Joel Collier, a professor of biomedical engineering at Duke University. “If these therapies are successful, patients need fewer doses of the therapy, which would ideally improve patient compliance and tolerance. It would be a whole new way of treating inflammatory disease.”

In their new paper, which appeared online in the Proceedings of the National Academy of Sciences (PNAS), Collier and Kelly Hainline, a graduate student in the Collier lab, describe how novel nanomaterials could assemble into long nanofibers that include a specialized protein, called C3dg. These fibers then were able to activate immune system B-cells to generate antibodies. “C3dg is a protein that you’d normally find in your body,” said Hainline. “The protein helps the innate immune system and the adaptive immune system communicate, so it can activate specific white blood cells and antibodies to clear out damaged cells and destroy antigens.”

Due to the protein’s ability to interface between different cells in the immune system and activate the creation of antibodies without causing inflammation, researchers have been exploring how C3dg could be used as a vaccine adjuvant, which is a protein that can help boost the immune response to a desired target or pathogen.

Source: https://pratt.duke.edu/

How to Clear Brain Plaques with Light and Oxygen to Prevent Alzheimer’s

A small, light-activated molecule recently tested in mice represents a new approach to eliminating clumps of amyloid protein found in the brains of Alzheimer’s disease patients. If perfected in humans, the technique could be used as an alternative approach to immunotherapy and used to treat other diseases caused by similar amyloids. Researchers injected the molecule directly into the brains of live mice with Alzheimer’s disease and then used a specialized probe to shine light into their brains for 30 minutes each day for one week. Chemical analysis of the mouse brain tissue showed that the treatment significantly reduced amyloid protein. Results from additional experiments using human brain samples donated by Alzheimer’s disease patients supported the possibility of future use in humans.

The importance of our study is developing this technique to target the amyloid protein to enhance clearance of it by the immune system,” said Yukiko Hori, a lecturer at the University of Tokyo and co-first author of the research recently published in Brain. The small molecule that the research team developed is known as a photo-oxygenation catalyst. It appears to treat Alzheimer’s disease via a two-step process.

First, the catalyst destabilizes the amyloid plaques. Oxygenation, or adding oxygen atoms, can make a molecule unstable by changing the chemical bonds holding it together. Laundry detergents or other cleaners known as “oxygen bleach” use a similar chemical principle. The catalyst is designed to target the folded structure of amyloid and likely works by cross-linking specific portions called histidine residues. The catalyst is inert until it is activated with near-infrared light, so in the future, researchers imagine that the catalyst could be delivered throughout the body by injection into the bloodstream and targeted to specific areas using light.

Second, the destabilized amyloid is then removed by microglia, immune cells of the brain that clear away damaged cells and debris outside healthy cells. Using mouse cells growing in a dish, researchers observed microglia engulfing oxygenated amyloid and then breaking it down in acidic compartments inside the cells. “Our catalyst binds to the amyloid-specific structure, not to a unique genetic or amino acid sequence, so this same catalyst can be applied to other amyloid depositions,” said Professor Taisuke Tomita, who led the project at the University of Tokyo.

The American Society of Clinical Oncology estimates that each year in the U.S., 4,000 people are diagnosed with diseases caused by amyloid outside of the brain, collectively known as amyloidosis. The photo-oxygenation catalyst should be capable of removing amyloid protein, regardless of when or where it formed in the body. Although some existing Alzheimer’s disease treatments can slow the formation of new amyloid plaques, eliminating existing plaques is especially important in Alzheimer’s disease because amyloid begins aggregating years before symptoms appear.

Source: https://www.u-tokyo.ac.jp/

Intravenous Immunoglobulins Could Stop Thrombosis after Astrazeneca Vaccination

Some people have developed dangerous blood clots in the brain after receiving the corona vaccination with the AstraZeneca preparation The University Medical Center Greifswald in Germany has now broken down the likely cause of the blood clots. According to Andreas Greinacher, he and his team found special antibodies in the blood of those affected, which are directed against the body’s own blood platelets. These cells play an important role in blood clotting. The antibodies activate the platelets: they clump together, as they normally do to close a wound, and thus form blood clots. The basic problem is therefore an autoimmune reaction.

In Germany, 13 cases of sinus vein thrombosis were reported shortly after an AstraZeneca vaccination, all of which were associated with a lack of blood platelets, i.e. a so-called thrombocytopenia. Around 1.6 million people in Germany were vaccinated. According to Greinacher, the problems that arose shortly after the vaccination are similar to a long-known complication with the administration of another agent, heparin-induced thrombocytopenia, or HIT for short. There, too, antibodies activate platelets so that clots form. In both cases the symptoms appear within 5 to 14 days after administration of the preparation. Greinacher therefore emphasized that the flu-like symptoms that often occur on the day after the vaccination are not a warning signal that a blood clot is developing. But anyone who has a painful leg about five days after the vaccination – as a sign of a deep vein thrombosis – or a severe headache should see a doctor immediately.

The Society for Thrombosis and Hemostasis Research has already published recommendations for doctors based on the Greifswald findings. She assumes that the formation of clots in people with sinus vein thrombosis and thrombocytopenia can be stopped by giving high doses of intravenous immunoglobulins. Greinacher could not answer how reliably this therapy helps those affected. That is not his area of expertise, he said.

Source: https://www.uni-greifswald.de/
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A Cannabis Molecule Reduces Plaque, Improves Cognition in Alzheimer’s

A two-week course of high doses of CBD helps restore the function of two proteins key to reducing the accumulation of beta-amyloid plaque, a hallmark of Alzheimer’s disease, and improves cognition in an experimental model of early onset familial Alzheimer’s, investigators report. The proteins TREM2 and IL-33 are important to the ability of the brain’s immune cells to literally consume dead cells and other debris like the beta-amyloid plaque that piles up in patients’ brains, and levels of both are decreased in Alzheimer’s.

The investigators report for the first time that CBD normalizes levels and function, improving cognition as it also reduces levels of the immune protein IL-6, which is associated with the high inflammation levels found in Alzheimer’s, says Dr. Babak Baban, immunologist and associate dean for research in the Dental College of Georgia (DCG) and the study’s corresponding author. There is a dire need for novel therapies to improve outcomes for patients with this condition, which is considered one of the fastest-growing health threats in the United States, DCG and Medical College of Georgia (MCG) investigators write in the Journal of Alzheimer’s Disease.

Right now we have two classes of drugs to treat Alzheimer’s,” says Dr. John Morgan, neurologist and director of the Movement and Memory Disorder Programs in the MCG Department of Neurology. “One class increases levels of the neurotransmitter acetylcholine, which also are decreased in Alzheimer’s, and another works through the NMDA receptors involved in communication between neurons and important to memory. But we have nothing that gets to the pathophysiology of the disease,” says Morgan, a study coauthor.

The DCG and MCG investigators decided to look at CBD’s ability to address some of the key brain systems that go awry in Alzheimer’s.

They found CBD appears to normalize levels of IL-33, a protein whose highest expression in humans is normally in the brain, where it helps sound the alarm that there is an invader like the beta-amyloid accumulation. There is emerging evidence of its role as a regulatory protein as well, whose function of either turning up or down the immune response depends on the environment, Baban says. In Alzheimer’s, that includes turning down inflammation and trying to restore balance to the immune system, he says.

CBD also improved expression of triggering receptor expressed on myeloid cells 2, or TREM2, which is found on the cell surface where it combines with another protein to transmit signals that activate cells, including immune cells. In the brain, its expression is on the microglial cells, a special population of immune cells found only in the brain where they are key to eliminating invaders like a virus and irrevocably damaged neurons.

Source: https://jagwire.augusta.edu/

How to Reverse Parkinson’s Symptoms

Grafting neurons grown from monkeys’ own cells into their brains relieved the debilitating movement and depression symptoms associated with Parkinson’s disease, researchers at the University of Wisconsin–Madison (UW) reported today.

In a study published in the journal Nature Medicine, the UW team describes its success with neurons made from induced pluripotent stem cells from the monkeys’ own bodies. This approach avoided complications with the primates’ immune systems and takes an important step toward a treatment for millions of human Parkinson’s patients.

This result in primates is extremely powerful, particularly for translating our discoveries to the clinic,” says UW–Madison neuroscientist Su-Chun Zhang, whose lab grew the brain cells.

Parkinson’s disease damages neurons in the brain that produce dopamine, a brain chemical that transmits signals between nerve cells. The disrupted signals make it progressively harder to coordinate muscles for even simple movements and cause rigidity, slowness and tremors that are the disease’s hallmark symptoms. Patients — especially those in earlier stages of Parkinson’s — are typically treated with drugs like L-DOPA to increase dopamine production.

Those drugs work well for many patients, but the effect doesn’t last,” says Marina Emborg, a Parkinson’s researcher at UW–Madison’s Wisconsin National Primate Research Center. “Eventually, as the disease progresses and their motor symptoms get worse, they are back to not having enough dopamine, and side effects of the drugs appear.”

Scientists have tried with some success to treat later-stage Parkinson’s in patients by implanting cells from fetal tissue, but research and outcomes were limited by the availability of useful cells and interference from patients’. Zhang’s lab has spent years learning how to dial donor cells from a patient back into a stem cell state, in which they have the power to grow into nearly any kind of cell in the body, and then redirect that development to create neurons.

The idea is very simple,” Zhang says. “When you have stem cells, you can generate the right type of target cells in a consistent manner. And when they come from the individual you want to graft them into, the body recognizes and welcomes them as their own.

Source: https://news.wisc.edu/

New Variant of SARS-CoV-2 Spreading Fast

A coronavirus variant called B1525 has become one of the most recent additions to the global variant watch list and has been included in the list of variants under investigation by Public Health England.

Scientists are keeping a watchful eye on this variant because it has several mutations in the gene that makes the spike protein – the part of the virus that latches onto human cells. These changes include the presence of the increasingly well-known mutation called E484K, which allows the virus to partly evade the immune system, and is found in the variants first identified in South Africa (B1351) and Brazil (P1).

While there is no information on what this means for B1525, there is growing evidence that E484K may impact how effective COVID vaccines are. But there is no suggestion so far that B1525 is more transmissible or that it leads to more severe disease.

There are other mutations in B1525 that are also noteworthy, such as Q677H. Scientists have repeatedly detected this changeat least six times in different lineages in the US, suggesting that it gives the virus an advantage, although the nature of any benefit has not been identified yet.

The B1525 variant also has several deletions – where “letters” (G, U, A and C) of the virus’s RNA are missing from its genome. These letters are also missing in B117, the variant first detected in Kent, England. Research by Ravindra Gupta, a clinical microbiologist at the University of Cambridge, found that these deletions may increase infectivity twofold in laboratory experiments.

As with many variants, B1525 appears to have emerged quite recently. The earliest example in the shared global database of coronavirus genomes, called Gisaid, dates from 15 December 2020. It was identified in a person in the UK. And like many variants, B1525 had already travelled the world before it came to global attention. A total of 204 sequences of this variant in Gisaid can be traced to 18 countries as of 20 February 2021.

New Blood Test Could Replace Biopsies

No one enjoys getting a biopsy, in which a tissue sample is surgically taken and analyzed in a lab for signs of disease, such as cancer. It’s not only unpleasant for the patient, but has clinical drawbacks: A biopsy doesn’t always extract the diseased tissue and isn’t helpful in detecting disease at early stages. These concerns have encouraged researchers to find less invasive and more accurate diagnostic methods. Prof. Nir Friedman and Ronen Sadeh of the Hebrew University of Jerusalem have developed a blood test that enables lab technicians to diagnose cancer and diseases of the heart and liver by identifying and determining the state of the dead cells throughout the body.

Millions of cells die every day and are replaced by new cells. When cells die, their DNA is fragmented. Some of these DNA fragments reach the blood and can be “read” by advanced DNA sequencing methods.

As a result of these scientific advancements, we understood that if this information is maintained within the DNA structure in the blood, we could use that data to determine the tissue source of dead cells and the genes that were active in those very cells. Based on those findings, we can uncover key details about the patient’s health,” Friedman said.

We are able to better understand why the cells died — whether it’s an infection or cancer — and based on that, be better positioned to determine how the disease is developing,” he said. Co-author Israa Sharkia added the simple blood test could “be administered often and quickly, allowing the medical staff involved to follow the presence or development of a disease more closely.”

A startup company, Senseera, has been established to pursue clinical testing of this innovative approach in partnership with major pharmaceutical companies.

The multi-author study published in Nature Biotechnology explains the test can even identify markers that may differentiate between patients with similar tumors, which could help physicians develop personalized treatments.

Source: https://www.zenger.news/

Katalin Kariko, RNA Hero, Future Nobel Prize

The development of the Pfizer-BioNTech coronavirus vaccine, the first approved jab in the West, is the crowning achievement of decades of work for Hungarian biochemist Katalin Kariko, who fled to the US from communist rule in the 1980s.

When trials found the Pfizer-BioNTech coronavirus vaccine to be safe and 95 percent effective in November, it was the crowning achievement of Katalin Kariko’s 40 years of research on the genetic code RNA (ribonucleic acid). Her first reaction was a sense of “redemption,” Kariko told The Daily Telegraph.

I was grabbing the air, I got so excited I was afraid that I might die or something,” she said from her home in Philadelphia. “When I am knocked down I know how to pick myself up, but I always enjoyed working… I imagined all of the diseases I could treat.”

Born in January 1955 in a Christian family in the town of Szolnok in central Hungary – a year before the doomed heroism of the uprising against the Soviet-backed communist regimeKariko grew up in nearby Kisujszellas on the Great Hungarian Plain, where her father was a butcher. Fascinated by science from a young age, Kariko began her career at the age of 23 at the University of Szeged’s Biological Research Centre, where she obtained her PhD.

It was there that she first developed her interest in RNA. But communist Hungary’s laboratories lacked resources, and in 1985 the university sacked her. Consequently, Kariko looked for work abroad, getting a job at Temple University in Philadelphia the same year. Hungarians were forbidden from taking money out of the country, so she sold the family car and hid the proceeds in her 2-year-old daughter’s teddy bear. “It was a one-way ticket,” she told Business Insider. “We didn’t know anybody.”

Not everything went as planned after Kariko’s escape from communism. At the end of the 1980s, the scientific community was focused on DNA, which was seen as the key to understanding how to develop treatments for diseases such as cancer. But Kariko’s main interest was RNA, the genetic code that gives cells instructions on how to make proteins.

At the time, research into RNA attracted criticism because the body’s immune system sees it as an intruder, meaning that it often provokes strong inflammatory reactions. In 1995, Kariko was about to be made a professor at the University of Pennsylvania, but instead she was consigned to the rank of researcher.

Usually, at that point, people just say goodbye and leave because it’s so horrible,” Kariko told medical publication Stat. She went through a cancer scare at the time, while her husband was stuck in Hungary trying to sort out visa issues. “I tried to imagine: Everything is here, and I just have to do better experiments,” she continued. Kariko was also on the receiving end of sexism, with colleagues asking her the name of her supervisor when she was running her own lab.

Kariko persisted in the face of these difficulties. “From outside, it seemed crazy, struggling, but I was happy in the lab,” she told Business Insider. “My husband always, even today, says, ‘This is entertainment for you.’ I don’t say that I go to work. It is like play.” Thanks to Kariko’s position at the University of Pennsylvania, she was able to send her daughter Susan Francia there for a quarter of the tuition costs. Francia won gold on the US rowing team in the 2008 and 2012 Olympics.

It was a serendipitous meeting in front of a photocopier in 1997 that turbocharged Kariko’s career. She met immunologist Drew Weissman, who was working on an HIV vaccine. They decided to collaborate to develop a way of allowing synthetic RNA to go unrecognised by the body’s immune system – an endeavour that succeeded to widespread acclaim in 2005. The duo continued their research and succeeded in placing RNA in lipid nanoparticles, a coating that prevents them from degrading too quickly and facilitates their entry into cells.

The researchers behind the Pfizer-BioNTech and Moderna jabs used these techniques to develop their vaccines.

Source: https://www.france24.com/

A Protein that Can Melt Tumors Discovered

For the second time, cancer researchers at Vanderbilt have discovered a protein that—when genetically manipulated to impede it from interacting with a gene responsible for cancer genesis—effectively melts tumors in days. 

William Tansey, professor of cell and developmental biology, is dedicated to understanding how the oncogene MYC, an  highly conserved, noodle-like protein, works. It performs important functions in normal human development, and it often becomes reactivated in the deadliest and most difficult to treat cancers. 

Conducted experiment shows six tumor sizes grow for 15 days, at which point the MYC–HCF1 interaction is broken. After day 15, the tumors shrink and are gone. Cancer cells are dead by four days. 

MYC becomes the nitro in the tank, driving relentless rounds of cell duplication and division,” Tansey said. “The faster the cells grow and divide, they accumulate mutations, which give rise to cancer growth.” 

MYC has been an elusive drug target for at least 30 years, Tansey says, and has been considered “undruggable” because of its lack of structure. To work around this roadblock, Tansey set out to identify MYC’s more structured partner proteins with the goal of engineering mutations that disrupt the partners’ interactions with MYC that cause cancer growth. “If we can validate the physical contact between MYC and a protein, we can go after it therapeutically,” Tansey explained.  

Tansey and his collaborators have identified the protein Host Cell Factor-1 (HCF1) as a definite candidate for this type of therapeutic development. HCF1 is touched by MYC and is important for stimulating protein synthesis. When a cancer cell with MYC is genetically engineered to no longer interact with HCF1, the cancer cell begins to self-destruct. Developing a therapy that limits this interaction is a hugely promising step in cancer treatment 

The article, “MYC regulates ribosome biogenesis and mitochondrial gene expression programs through interaction with Host Cell Factor-1,” was published in the journal eLIFE on Jan. 8. 

Source: https://news.vanderbilt.edu/

COVID: the Risk of Death is 70% Higher for Male than for Female Patients

Evidence increasingly indicates that male sex is a risk factor for more severe disease and death from COVID-19. Male bias in COVID-19 mortality is observed in nearly all countries with available sex-disaggregated data, and the risk of death in males is ∼1.7 times higher than in females. Aging is strongly associated with higher risk of death in both sexes, but at all ages above 30 years, males have a significantly higher mortality risk, rendering older males the most vulnerable group. Sex differences are intertwined with differences in gender roles socially and with behavioral factors, which also influence COVID-19 incidence and outcomes. However, there are also possible biological mechanisms of male sex bias that affect the severity of COVID-19, particularly with respect to immune responses.

Sex differences beyond sex organs are present across species and extend to physiological systems, including the immune system. Infection by different pathogens results in differential immune responses and disease outcomes by sex, and although the pattern depends on age and other host factors, male sex is more often associated with lower immune responses and higher susceptibility and/or vulnerability to infections in animals. This is generally also the case in humans: Male patients have higher viral loads for hepatitis B virus (HBV) and HIV. Conversely, females generally mount a more robust immune response to vaccines, such as influenza vaccines. However, the heightened immune responses in females can also lead to detrimental immunopathology in infections.

The physiological response to virus infection is initiated when virus replication is detected by pattern recognition receptors. This leads to two antiviral programs by the infected cells.
Source: https://science.sciencemag.org/