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Researchers have come close to making insulin pills

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Australian researchers hope that a molecule different from insulin could one day help make insulin pills.People with type 1 diabetes cannot produce insulin and need multiple daily injections of insulin to control their blood glucose levels. This new research confirms that alternative molecules can be used to activate the absorption of blood glucose and bypass the need for insulin altogether.

Researchers at the “Walter and Eliza Hall Medical Institute” (WEHI) in Melbourne answered a 100-year-old question in the field of diabetes research. The question is whether a molecule different from insulin can have the same effect. These findings provide important insights for the development of an oral insulin pills in the future.

Insulin pills

This research group has shown how a molecule other than insulin can mimic the role of insulin, a key hormone for controlling blood sugar levels.

Walter and Eliza Hall Institute of Medicine research is paving new ways to develop drugs that could replace daily insulin injections for people with type 1 diabetes.

People with type 1 diabetes cannot produce insulin and need multiple daily injections of insulin to control their blood glucose levels. This new research confirms that alternative molecules can be used to activate the absorption of blood glucose and bypass the need for insulin altogether.

This research was conducted under the supervision of Dr Nicholas Kirk and Professor Mike Lawrence, researchers of the Walter and Eliza Hall Medical Institute, and in collaboration with the American pharmaceutical company Eli Lilly and Company. has been

Why are there no insulin tablets?

insulin pills and tablets

Scientists have tried to make insulin in pill form because insulin is unstable and is easily broken down by the body after it is digested, Dr Kirk said. Since the discovery of insulin about 100 years ago, making insulin pills has been a dream for diabetes researchers, but after decades of efforts, not much success has been achieved.

This research has now been dramatically accelerated by the development of cryo-electron microscopy (cryo-EM), which can visualize complex molecules in atomic detail, allowing researchers to rapidly produce 3D images of the insulin receptor.

Kirk continued: With cryo-electron microscopy, we can now directly understand how various molecules, including insulin, change the shape of the insulin receptor. Insulin interactions are much more complex than anticipated; so insulin and its receptors change dramatically.

New research shows how an insulin-mimicking molecule acts on the insulin receptor and turns it on. This is the first step in a pathway that directs cells to take up glucose when the body’s sugar levels are too high.

Read more: Why do we get sick in cold weather?

The research team performed complex cryo-electron microscopy reconstructions to obtain a map of several molecules called “peptides” that interact with the insulin receptor and hold it in an active position. Cryo-electron microscopy experiments identified a peptide that can bind to and activate the receptor like that of insulin.

“Insulin has evolved to hold the receptor as carefully as a hand holding a pair of pliers together,” Kirk said. The peptides we used work in pairs to activate the insulin receptor, like two hands holding a pair of pliers.

Although the time to reach therapeutic results is far away, the discovery of this research group can lead to the production of drugs to replace insulin and reduce the need for injections in patients with diabetes.

Scientists have succeeded in replacing these types of mimic molecules with drugs that can be taken as pills, Kirk said. Reaching this destination still has a long way to go, which requires more research, but it is interesting to know that our discovery paves the way for providing oral treatments for type 1 diabetes.

Via :Medicaldialogues

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Making a small version of the intestine in the laboratory

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Making a small version of the intestine in the laboratory

Making a small version of the intestine in the laboratory. A lab-grown small intestine could help provide personalized treatment for Crohn’s disease.

Making a small version of the intestine in the laboratory

Scientists have found a way to reveal the severity of intestinal diseases through epigenetic changes, which could help develop a new treatment plan for patients.

For decades, biomedical researchers have been looking for ways to develop a standard treatment for patients with Crohn’s disease and irritable bowel disease (IBD).

Now, scientists at the University of Cambridge have discovered a way to grow a small intestine in the lab from cells taken from a patient for more precise and personalized treatments.

Professor Matthias Zilbauer, professor of pediatric gastroenterology at the University of Cambridge and Cambridge University Hospitals, explained: “The actual model of this small intestine was made more than a decade ago by a scientist named Hans Clovers. Together with a group of scientists, he discovered structural units called intestinal epithelial stem cells.

He added that the scientists combined this with what is needed for cells to continue growing and dividing after they leave the gut.

Focusing on children with Crohn’s disease

Inspired by this model that grows organoids from humans, researchers in this new study found specific epigenetic findings in patients, especially children and adolescents, with Crohn’s disease.

Crohn’s disease is a chronic inflammatory bowel disease whose cases are increasing worldwide, especially among children. This disease significantly affects the quality of life of patients and can lead to severe complications.

A new pathway called major histocompatibility complex class I (MHC class I) was observed, which appears to be regulated by changes in epigenetic programming.

Scientists have discovered a way to reveal the severity of diseases through epigenetic changes, which could help develop a new treatment plan for patients.

“What we found was that patients with significant epigenetic changes had a more severe disease course,” says Seelbauer.

Drug treatment for the small intestine in vitro before administration to the patient

Scientists hope to develop new drugs that can be tested on this small lab intestine before being given to a patient.

Conventional treatments are only effective 60% of the time, so the vast majority of patients may not respond to them and may even be exposed to severe side effects.

In the future, scientists hope to grow these organoids from patients for drug testing and, if a drug works on the small intestine, administer it to the patient.

The study found that the cells that make up the inner lining of the intestine in patients with Crohn’s disease show increased activity of major histocompatibility complex class I, which are proteins found on the surface of nearly all nucleated cells in the body and are critical for the immune response.

Read more: Artificial intelligence identifies cancer killer cells

This high activity can lead to inflammation by activating immune cells to more easily recognize antigens such as toxins or other foreign substances. Antigens may include molecules from food or gut microbiota that trigger an immune response and contribute to the inflammation characteristic of Crohn’s disease. This is the first time that stable epigenetic changes have been shown to explain intestinal epithelial abnormalities in Crohn’s patients.

The team of researchers is currently working on finding drugs that can modify this pathway.

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How to rejuvenate an aging immune system?

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Scientists succeeded in rejuvenating the immune system of old mice with a new therapeutic approach.

How to rejuvenate an aging immune system?

After scientists reduced abnormal stem cells in old animals, mice’s immune systems became more youthful. This technique enhanced the response of old rodents to viral infection and reduced signs of inflammation. In this method, published March 27 in the journal Nature, old mice are treated with an antibody to reduce a population of stem cells that give rise to other types of cells, such as those involved in inflammation.

Excessive inflammation can wreak havoc on the body, and pro-inflammatory stem cells proliferate during aging in mice and humans.

Imbalanced immune system

For decades, researchers in Irving Weissman’s group at Stanford University in California have closely followed the fate of blood stem cells. These cells replenish the supply of red blood cells (which carry oxygen from the lungs to all parts of the body) and white blood cells (which are key components of the immune system).

Balancing the blood stem cell population can rejuvenate the immune system

In 2005, Weissman and colleagues found that as mice age, their blood stem cell population changes. In young mice, there is a balance between two types of blood stem cells, each contributing to a different branch of the immune system. The adaptive compartment produces antibodies and T cells that target specific pathogens. The innate part produces general responses such as inflammation against infection.

However, in old mice, the balance between the two parts of the immune system is skewed towards the production of more pro-inflammatory innate immune cells. Similar changes have been reported in the blood stem cells of aging humans, and researchers speculate that this could lead to a reduced ability to produce new antibodies and T-cell responses. This may explain why the elderly are more susceptible to serious infections from pathogens such as influenza viruses and SARS-CoV-2, and why their response to vaccination is weaker than that of younger people.

Restore the balance of the immune system

If the researchers’ conclusions are correct, restoring balance to the blood stem cell population could also rejuvenate the immune system.

The researchers tested this hypothesis by producing antibodies that bind to blood stem cells, which mainly produce innate immune cells. They then injected these antibodies into old mice with the hope that their immune systems would destroy the stem cells attached to the antibodies.

Antibody treatment rejuvenated the immune system of treated mice. They showed a stronger reaction to the vaccination than the old mice that did not receive the treatment and were better at warding off the viral infection. The treated mice also had lower levels of proteins associated with inflammation, which the authors say shows how different populations of blood stem cells affect the aging of the immune system.

It is possible that the effect of antibody treatment is more than affecting the blood stem cell population. Antibody therapy may also affect the environment in which blood stem cells can live. On the other hand, the said treatment can clear other old cells from the body or stimulate immune responses, thus affecting how mice respond to vaccines and viruses.

It will be years before Weissman and his colleagues’ approach can be tested in humans, but many aspects of the stem cell biology that underlies the production of immune cells are similar in mice and humans.

Weissman’s team is working on a similar approach to rebalance the blood stem cells of elderly people. He believes that even if there is sufficient funding and no unexpected obstacles arise, it will take at least three to five years before they can test their method on humans. In the meantime, the researchers will continue to study the mice to learn more about other effects of the antibody therapy, such as whether it affects the rate of cancer or inflammatory diseases. “The blood-forming system of young and old blood is very different,” says Weissman. “The difference is not just in the bone marrow, but throughout the body.”

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How can hacking the immune system help slow aging?

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Our immune system weakens over time and this could explain the negative effects of aging. Manipulation of the immune system may alter the aging process.

How can hacking the immune system help slow aging?

Stem cell researcher Carolina Florian couldn’t believe what she was seeing. His old laboratory mice began to look younger. They were more lively and their fur was shinier. However, all he had done was a short treatment a few weeks earlier with a drug that modified the organization of proteins in a type of stem cell.

Stem cell researcher Carolina Florian couldn’t believe what she was seeing. His old laboratory mice began to look younger. They were more lively and their fur was shinier. However, all he had done was a short treatment a few weeks earlier with a drug that modified the organization of proteins in a type of stem cell.

When technicians repeating Florian’s experiment in two other laboratories reached the same conclusion, Florian became more confident that the treatment in question would rejuvenate the animals. In two papers in 2020 and 2022, his team explained how this process extended the lifespan of mice and kept them in good physical condition into old age.

The purpose of Florian Elixir is the immune system. The immune cells he targeted are called hematopoietic stem cells, which give rise to mature immune cells. By circulating the blood, a mixture of these cells enters all the organs and affects all the functions of the body. However the molecular composition of hematopoietic stem cells changes during aging, and this upsets the balance of the immune cells that these stem cells produce.

Florian, who works at the Bleuge Biomedical Research Institute in Barcelona, ​​says reversing the misalignment that occurs over time appears to reverse many of the problems of aging, not only in the immune system but in the rest of the body as well.

Health and agingDescription Researchers think the immune system could be the key to healthy aging.

In a paper published in March in the journal Nature, researchers show that restoring the balance between two key types of immune cells rejuvenates the immune system of aging mice and improves the animals’ ability to respond to vaccines and ward off viral infections.

Other scientists have used different experimental methods to reach a similar conclusion: Rejuvenating the immune system rejuvenates many organs in animals, at least in mice. More interestingly, evidence shows that aging of the immune system may cause aging of those organs.

The potential of the findings to help people stay healthy in old age is tantalizing. But applying this knowledge and using it in clinics will be challenging. Tampering with the immune system can be dangerous. Therefore, researchers initially aimed at low-risk goals such as improving the response of the elderly to vaccination and improving the efficacy of cancer immunotherapy.

Vittorio Sebastiano, a stem cell scientist at the Stanford School of Medicine in California, says the prospect that reversing aging might curb age-related diseases is enticing, but we proceed with caution.

Weakened immunity

The human immune system is a complex system whose many cellular and molecular components work together to help a person grow, protect him from infection, help heal wounds, and destroy cells that are becoming cancerous. But along with aging and changing the composition of the system, its efficiency decreases. In old age, people become susceptible to a wide range of infectious and non-infectious diseases and become more resistant to the protective power of vaccines.

Aging of the immune system may cause aging of different body parts

The immune system has two main components: the innate system, which indiscriminately destroys invading pathogens, and the more precise adaptive immune system, whose components learn to recognize and produce antibodies against specific foreign bacteria and viruses.

Hematopoietic stem cells in the bone marrow produce both arms of the immune system. They differentiate into two main types (lymphoid cells and myeloid cells), which then undergo further differentiation.

Lymphoid cells are primarily responsible for adaptive immunity and include B cells that produce antibodies, T cells that help attack invaders and coordinate immune responses and natural killer cells that kill infectious cells. Myeloid cells comprise a group of cell types that are mainly involved in innate immunity.

protein inside cellsProteins in stem cells that produce immune cells become more symmetrical as they age (right).

One of the first changes in the immune system during aging is the shrinking of the thymus, which begins after puberty. The thymus is where T cells mature, but much of this tissue turns to fat by the third decade of life, reducing the production of new T cells and weakening the immune system.

In addition, the function of T cells changes with age and they are not as specialized in detecting infectious agents as before. The ratio of different types of immune cells in the circulation also changes. The ratio of myeloid to lymphoid cells is significantly skewed toward myeloid cells and this can cause inflammation. In addition, an increasing number of immune cells become senescent, meaning that they stop replicating but do not die.

Aging cells usually occur when they undergo mutations. When cells are in this condition, they begin to release inflammatory signals and mark themselves for destruction.

An important anti-cancer and wound-healing mechanism works best when young. But when too much damage accumulates with age and the immune cells themselves age, this mechanism is disrupted. Senescent immune cells, attracted by inflammatory signals from senescent tissues, secrete their own inflammatory molecules. Therefore, they are not cleared properly but instead, add to the inflammation that also damages the surrounding healthy tissues. This phenomenon is known as inflammatory aging. This turns into a terrible positive feedback loop, says Aran Akbar, an immunologist at University College London. Evidence shows that this feedback loop is initiated by the immune system.

Laura Niedernhofer from the University of Minnesota in Minneapolis has shown in a series of experiments in mice that the aging of immune cells causes the aging of other tissues. He says these cells are very dangerous.

His team used genetic methods to delete an important DNA repair enzyme in the immune system of mice. The animals remained healthy until adulthood, but after that, they were no longer able to correct the accumulated mutations, and different types of immune cells began to age.

A few months later, an increasing number of cells in organs such as the liver and kidney were also senescent, and signs of organ damage appeared. When the scientists gave old mice immune cells from the spleens of young, healthy mice, all of these effects were reversed. All of this suggests that modifying the aging properties of the immune system could help prevent or reduce age-related diseases, Niederenhofer says.

Fight against aging

Many scientists are trying to do this from very different angles. Many approaches suggest that very short treatment of the immune system may have long-term effects and minimize side effects.

One of the ways to deal with aging immune cells is to use drugs to remove or inhibit the inflammatory factors that these cells release. Aging immune cells in humans can be changed, Niederenhofer says. If you smoke, they increase and if you exercise, they decrease.

Modifying the immune system can help prevent or reduce aging-related diseases

Some drugs, such as dasatinib, which is approved for the treatment of certain cancers, and quercetin, which is marketed as an antioxidant dietary supplement but not approved as a drug, slow cellular aging, and several trials are testing their effects on aging-related diseases.

Niederneuhofer is conducting a small clinical trial in elderly people with sepsis. Sepsis is a condition that becomes more deadly with age. His team is also conducting experiments to assess which types of immune cells are most involved in aging in the body, and their results could help design more precise treatments. Two types of cells (T cells and natural killer cells) are emerging as the main contenders, he says. He plans to examine natural products and approved drugs for their ability to interact with these types of immune cells during aging.

Akbar thinks targeting inflammation may be just as effective as targeting senescent cells. He and his colleagues conducted a study in healthy volunteers using the investigational compound lozepimod, which inhibits an enzyme involved in the production of a type of inflammatory molecule called cytokines. They treated volunteers with this drug for four days and then measured their skin’s response to an injection of the chickenpox virus over the course of a week. Most people are exposed to this virus during their life and this virus often stays in the body.

As people age, they lose their immunity to the chicken pox virus, and this time it can appear as shingles. The drug restored the immune response in the skin of older volunteers to a level similar to that of young volunteers. Akbar has found in unpublished studies that the same strong results persist up to three months later. Temporarily inhibiting inflammation in this way to keep the immune system functioning may similarly enhance the response of older patients to flu vaccinations, he says.

Boosting the immune system

The value of priming the elderly immune system prior to vaccination has been demonstrated in a series of clinical trials led by Joanne Mannick, CEO of Boston, Massachusetts-based Tornado Therapeutics. The trials tested analogs of the drug rapamycin and other drugs with similar mechanisms that target the immune system and are approved to prevent organ transplant rejection and to treat certain cancers.

The mentioned drugs inhibit an enzyme called mTOR, which is vital for many physiological functions and whose function is impaired in aging. Participants were treated with doses of the drug that were low enough to avoid side effects for several weeks before receiving the flu vaccine. This treatment regimen improved their response to the vaccine and increased their immune system’s ability to resist viral infections.

vaccinationVaccines are less effective in older people, but new approaches could increase their potency.

However the drug rapamycin can increase susceptibility to infection and affect metabolism, so Manick is planning trials with similar drugs that could be safer. “There are different ways to improve the immune system,” he notes.

Another way is to try to restore thymus function to maintain the production of new T cells. Jarrod Dudakoff, an immunologist at the Fred Hutchinson Cancer Center in Seattle, is studying the basic biology of thymus cells to understand how they regenerate after bouts of stress. Dudakov says it’s a little early to see how our understanding of this can be applied in the clinic. But he thinks it’s important to preserve the ability of the thymus to produce T cells.

Others try to fight aging by producing thymus tissue from powerful stem cells and then transplanting it. But Greg Fahey, chief scientific officer at Intervene Immune in Torrance, Calif., says there’s no need to wait to achieve those long-term prospects because synthetic growth hormone regenerates thymus tissue. He is conducting small studies in healthy volunteers using growth hormones as part of a mixture of compounds.

Preliminary results show that the amount of functional thymus tissue in the participants increased and their epigenetic clock (a biomarker of aging) was reversed by several years. Fahey is conducting further testing to see if the drug combination also improves the physical condition of the participants.

Turn back the clock

Another approach that has yet to reach the clinic is reprogramming immune cells to try to turn back the clock on cells that have aged. This procedure involves temporarily placing the cells in a dish exposed to a combination of transcription factors that induce a pluripotent state in mature cells.

Sebastiano and colleagues have shown in human cells that this corrects the epigenetic changes that accompany aging. He has founded a startup to use this technique to tackle a type of cancer treatment called CAR T, in which T cells are engineered outside the body to target and destroy a person’s cancer. However, the T cells may age before they are returned to the person. Rejuvenating them makes production faster and more powerful, says Sebastiano.

One of the challenges of aging studies is the inability to measure aging accurately

Florian’s approach also aims to produce healthier immune cells within the body. Hematopoietic stem cells in the blood develop epigenetic changes and their environment also changes with age. This causes the proteins to arrange themselves in a more symmetrical way in the cells (a process known as polarization), which shifts the balance of differentiation of stem cells towards myeloid cells.

In his studies, Florian used a four-day treatment with a compound called CASIN, which inhibited part of this process to correct polarization and help the mice live longer. When hematopoietic stem cells from aged mice that had received CASIN were transplanted into aged mice that had not received the treatment, the same life-extending effects were seen. Florian hopes to turn his results into a practical method in the clinic. He thinks his drug may help rebuild the immune system after receiving cancer chemotherapy.

The challenge of measuring aging

Research on immune aging faces major challenges. One of the challenges in aging studies of all organs is the inability to measure aging accurately. “We don’t know in a quantitative, measurable, predictable way what aging means at the molecular level in different cell types,” says Sebastiano. “Without these metrics, it is very difficult to demonstrate rejuvenation.”

Another challenge is the difficulty in determining the characteristics that make an immune cell unique. Until recently, it was difficult to show where each of the immune cell subsets lived and how they changed over time. But technologies such as single-cell RNA sequencing, which quantitatively measures genes expressed in single cells, have made the analysis more challenging. For example, a large study of immune cells in the blood of humans and mice across a range of ages, published last November, revealed 55 subpopulations. Only 12 subpopulations of cells changed with age.

By collaborating with different research areas, scientists hope to prove that the immune system plays an important role in healthy aging. Don’t expect an elixir of youth anytime soon, says Florian. Aging research will take a long time, but it can help design tools that will be transformative.

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