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Combination treatment can increase human insulin-producing cells in vivo

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Combination treatment can increase human insulin-producing cells in vivo


In preclinical studies, a team of researchers from Mount Sinai Health System in New York City and City of Hope in Los Angeles report new findings on a therapeutic combination that regenerated human insulin-producing beta cells, providing a possible new treatment for diabetes. The findings were published today in Science Translational Medicine.

This work, led by Andrew F. Stewart, MD, Irene and Dr. Arthur M. Fishberg Professor of Medicine and Director of the Mount Sinai Diabetes, Obesity and Metabolism Institute, began at the Icahn School of Medicine at Mount Sinai in 2015. The studies were a team effort. Adolfo Garcia-Ocaña, PhD, formerly a professor at Mount Sinai and who is now at City of Hope, a leading research center for diabetes and one of the largest cancer research and treatment organizations in the United States, and is the Ruth B. and Robert K. Lanman Chair in Gene Regulation and Drug Discovery Research and chair of the Department of Molecular & Cellular Endocrinology, and his research team designed the studies and performed the novel, extensive and detailed animal transplant and drug treatment models using beta cells from donors. Final studies took place at City of Hope in 2023.

For the study, the natural product harmine, which is found in some plants, was combined with a widely used class of type 2 diabetes therapy called GLP1 receptor agonists. Researchers transplanted a small number of human beta cells into mice that had no immune system and that also served as a standard model of type 1 and type 2 diabetes; these mice were treated with the combination therapy and their diabetes was rapidly reversed. Strikingly, human beta cell numbers increased by 700 percent over three months with this drug combination.

“This is the first time scientists have developed a drug treatment that is proven to increase adult human beta cell numbers in vivo. This research brings hope for the use of future regenerative therapies to potentially treat the hundreds of millions of people with diabetes,” said Dr. Garcia-Ocaña, the paper’s corresponding author.

“It has been remarkable to watch this story unfold over the past 15 years,” said Dr. Stewart, who, along with Peng Wang, PhD, Professor of Medicine (Endocrinology, Diabetes and Bone Disease) at Icahn Mount Sinai, conceived of and performed the initial high-throughput drug screen that led to the discovery of harmine described in Nature Medicine in 2015. “The steady progression from the most basic human beta cell biology, through robotic drug screening and now moving to human studies, illustrates the essential role for physician-scientists in academia and pharma.”

Growing New Beta Cells

More than 10 percent of the world’s adult population has diabetes, a disease defined by high blood sugar levels. In both type 1 and type 2 diabetes, a reduction in both the quantity and quality of insulin-producing beta cells causes high blood sugar. Unfortunately, none of the many commonly used diabetes therapies are able to increase human beta cell numbers, and therefore cannot completely reverse diabetes.

Fortunately, most people with diabetes have some residual beta cells, which is what inspired the research team to search for ways to restore their numbers. The team had previously shown that several different inhibitors of an enzyme in beta cells called DYRK1A can induce the proliferation of adult human beta cells in a tissue culture dish for a few days. But prior to this study, no one had shown the ability to expand human beta cells numbers in vivo in human islet grafts used in an animal model over many months.

To accurately measure the mass of human beta cells in the islet grafts, the team turned to Sarah A. Stanley, MBBCh, PhD, Associate Professor of Medicine (Endocrinology, Diabetes and Bone Disease), and Neuroscience, at Icahn Mount Sinai. Using an advanced laser microscopy tool called iDISCO+ that effectively makes biological tissue transparent, Dr. Stanley saw that beta cell mass was dramatically increased through mechanisms that included enhanced proliferation, function, and survival of the human beta cells. The technology allowed for accurate and rigorous quantitative assessment of engrafted human beta cells for the first time.

Translating Results to the Clinic

The Mount Sinai team recently completed a phase 1 clinical trial of harmine in healthy volunteers to test its safety and tolerability. At the same time, Robert J. DeVita, PhD, Professor of Pharmacological Sciences and Director of the Marie-Josée and Henry R. Kravis Drug Discovery Institute at Mount Sinai, has developed next-generation DYRK1A inhibitors. Mount Sinai is conducting studies to test these in humans for potential toxicity risks and estimate dosing for clinical trials, and is planning to initiate first-in-human trials with independent research teams next year. Mount Sinai owns an extensive patent portfolio covering these technologies.

Researchers also want to address the fact that in patients with type 1 diabetes, the immune system will continue to kill new beta cells. At City of Hope, Dr. Garcia-Ocaña and colleague Alberto Pugliese, MD, Samuel Rahbar Chair in Diabetes & Drug Discovery, chair of the Department of Diabetes Immunology, and director of The Wanek Family Project for Type 1 Diabetes within the Arthur Riggs Diabetes & Metabolism Research Institute, plan to test inducers of beta cell regeneration together with immunomodulators that regulate the immune system. Their goal is for the combination to allow new beta cells to thrive and improve insulin levels.

“Our studies pave the way for moving DYRK1A inhibitors into human clinical trials and it’s very exciting to be close to seeing this novel treatment used in patients,” Dr. Garcia-Ocaña said. “There is nothing like this available to patients right now.”

The work outlined in the Science Translational Medicine paper was funded by grants from the National Institutes of Health (NIH), the National Institute of Diabetes Digestive and Kidney Disease, and BreakthroughT1D (formerly JDRF); as well as from philanthropic donations to Mount Sinai, support from The Wanek Family Project for Type 1 Diabetes at City of Hope, and additional generous philanthropic gifts.

Other critical members of the team include Mount Sinai’s Carolina Rosselot, PhD; Yansui Li, PhD; and Alexandra Alvarsson, PhD. Additional City of Hope authors on the paper are Geming Lu, MD, assistant research professor, and Randy Kang, BS, senior research associate, who are both members of Dr. Garcia-Ocaña’s lab.

Drs. Stewart and DeVita are named co-inventors on patent applications for DYRK1A inhibitors, such as harmine, for the treatment of diabetes. These patent applications are filed through the Icahn School of Medicine at Mount Sinai and are currently unlicensed.



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Waste Styrofoam can now be converted into polymers for electronics

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University of Delaware and Argonne National Laboratory have come up with a chemical reaction that can convert Styrofoam into a high-value conducting polymer known as PEDOT:PSS. In a new paper published in JACS Au, the study demonstrates how upgraded plastic waste can be successfully incorporated into functional electronic devices, including silicon-based hybrid solar cells and organic electrochemical transistors.

The research group of corresponding author Laure Kayser, assistant professor in the Department of Materials Science and Engineering in UD’s College of Engineering with a joint appointment in the Department of Chemistry and Biochemistry in the College of Arts and Sciences, regularly works with PEDOT:PSS, a polymer that has both electronic and ionic conductivity, and was interested in finding ways to synthesize this material from plastic waste.

After connecting with Argonne chemist David Kaphan during an event hosted by UD’s research office, the research teams at UD and Argonne began evaluating the hypothesis that PEDOT:PSS could be made by sulfonating polystyrene, a synthetic plastic found in many types of disposable containers and packing materials.

Sulfonation is a common chemical reaction where a hydrogen atom is replaced by sulfonic acid; the process is used to create a variety of products such as dyes, drugs and ion exchange resins. These reactions can either be “hard” (with higher conversion efficiency but that require caustic reagents) or “soft” (a less efficient method but one that uses milder materials).

In this paper, the researchers wanted to find something in the middle: “A reagent that is efficient enough to get really high degrees of functionalization but that doesn’t mess up your polymer chain,” Kayser explained.

The researchers first turned to a method described in a previous study for sulfonating small molecules, one that showed promising results in terms of efficiency and yield, using 1,3-Disulfonic acid imidazolium chloride ([Dsim]Cl). But adding functional groups onto a polymer is more challenging than for a small molecule, the researchers explained, because not only are unwanted byproducts harder to separate, any small errors in the polymer chain can change its overall properties.

To address this challenge, the researchers embarked on many months of trial and error to find the optimal conditions that minimized side reactions, said Kelsey Koutsoukos, a materials science doctoral candidate and second author of this paper.

“We screened different organic solvents, different molar ratios of the sulfonating agent, and evaluated different temperatures and times to see which conditions were the best for achieving high degrees of sulfonation,” he said.

The researchers were able to find reaction conditions that resulted in high polymer sulfonation, minimal defects and high efficiency, all while using a mild sulfonating agent. And because the researchers were able to use polystyrene, specifically waste Styrofoam, as a starting material, their method also represents an efficient way to convert plastic waste into PEDOT:PSS.

Once the researchers had PEDOT:PSS in hand, they were able to compare how their waste-derived polymer performed compared to commercially available PEDOT:PSS.

“In this paper, we looked at two devices — an organic electronic transistor and a solar cell,” said Chun-Yuan Lo, a chemistry doctoral candidate and the paper’s first author. “The performance of both types of conductive polymers was comparable, and shows that our method is a very eco-friendly approach for converting polystyrene waste into high-value electronic materials.”

Specific analyses conducted at UD included X-ray photoelectron spectroscopy (XPS) at the surface analysis facility, film thickness analysis at the UD Nanofabrication Facility, and solar cell evaluation at the Institute of Energy Conversion. Argonne’s advanced spectroscopy equipment, such as carbon NMR, was used for detailed polymer characterization. Additional support was provided by materials science and engineering professor Robert Opila for solar cell analysis and by David C. Martin, the Karl W. and Renate Böer Chaired Professor of Materials Science and Engineering, for the electronic device performance analyses.

One unexpected finding related to the chemistry, the researchers added, is the ability to use stoichiometric ratios during the reaction.

“Typically, for sulfonation of polystyrene, you have to use an excess of really harsh reagents. Here, being able to use a stoichiometric ratio means that we can minimize the amount of waste being generated,” Koutsoukos said.

This finding is something the Kayser group will be looking into further as a way to “fine-tune” the degree of sulfonation. So far, they’ve found that by varying the ratio of starting materials, they can change the degree of sulfonation on the polymer. Along with studying how this degree of sulfonation impacts the electrical properties of PEDOT:PSS, the team is interested in seeing how this fine-tuning capability can be used for other applications, such as fuel cells or water filtration devices, where the degree of sulfonation greatly impacts a material’s properties.

“For the electronic devices community, the key takeaway is that you can make electronic materials from trash, and they perform just as well as what you would purchase commercially,” Kayser said. “For the more traditional polymer scientists, the fact that you can very efficiently and precisely control the degree of sulfonation is going to be of interest to a lot of different communities and applications.”

The researchers also see great potential for how this research can contribute to ongoing global sustainability efforts by providing a new way to convert waste products into value-added materials.

“Many scientists and researchers are working hard on upcycling and recycling efforts, either by chemical or mechanical means, and our study provides another example of how we can address this challenge,” Lo said.

The complete list of co-authors includes Chun-Yuan Lo, Kelsey Koutsoukos, Dan My Nguyen, Yuhang Wu, David Angel Trujillo, Tulaja Shrestha, Ethan Mackey, Vidhika Damani, Robert Opila, David Martin, and Laure Kayser from the University of Delaware and Tabitha Miller, Uddhav Kanbur, and David Kaphan from Argonne National Laboratory.



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New snake discovery rewrites history, points to North America’s role in snake evolution

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Combination treatment can increase human insulin-producing cells in vivo


A new species of fossil snake unearthed in Wyoming is rewriting our understanding of snake evolution. The discovery, based on four remarkably well-preserved specimens found curled together in a burrow, reveals a new species named Hibernophis breithaupti. This snake lived in North America 34 million years ago and sheds light on the origin and diversification of boas and pythons.

Hibernophis breithaupti has unique anatomical features, in part because the specimens are articulated — meaning they were found all in one piece with the bones still arranged in the proper order — which is unusual for fossil snakes. Researchers believe it may be an early member of Booidea, a group that includes modern boas and pythons. Modern boas are widespread in the Americas, but their early evolution is not well understood.These new and very complete fossils add important new information, in particular, on the evolution of small, burrowing boas known as rubber boas.

Traditionally, there has been much debate on the evolution of small burrowing boas. Hibernophis breithaupti shows that northern and more central parts of North America might have been a key hub for their development. The discovery of these snakes curled together also hints at the oldest potential evidence for a behavior familiar to us today — hibernation in groups.

“Modern garter snakes are famous for gathering by the thousands to hibernate together in dens and burrows,” says Michael Caldwell, a U of A paleontologist who co-led the research along with his former graduate student Jasmine Croghan, and collaborators from Australia and Brazil. “They do this to conserve heat through the effect created by the ball of hibernating animals. It’s fascinating to see possible evidence of such social behavior or hibernation dating back 34 million years.”



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Good timing: Study unravels how our brains track time

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Ever hear the old adage that time flies when you’re having fun? A new study by a team of UNLV researchers suggests that there’s a lot of truth to the trope.

Many people think of their brains as being intrinsically synced to the human-made clocks on their electronic devices, counting time in very specific, minute-by-minute increments. But the study, published this month in the latest issue of the peer-reviewed Cell Press journal Current Biology, showed that our brains don’t work that way.

By analyzing changes in brain activity patterns, the research team found that we perceive the passage of time based on the number of experiences we have — not some kind of internal clock. What’s more, increasing speed or output during an activity appears to affect how our brains perceive time.

“We tell time in our own experience by things we do, things that happen to us,” said James Hyman, a UNLV associate professor of psychology and the study’s senior author. “When we’re still and we’re bored, time goes very slowly because we’re not doing anything or nothing is happening. On the contrary, when a lot of events happen, each one of those activities is advancing our brains forward. And if this is how our brains objectively tell time, then the more that we do and the more that happens to us, the faster time goes.”

Methodology and Findings

The findings are based on analysis of activity in the anterior cingulate cortex (ACC), a portion of the brain important for monitoring activity and tracking experiences. To do this, rodents were tasked with using their noses to respond to a prompt 200 times.

Scientists already knew that brain patterns are similar, but slightly different, each time you do a repetitive motion, so they set out to answer: Is it possible to detect whether these slight differences in brain pattern changes correspond with doing the first versus 200th motion in series? And does the amount of time it takes to complete a series of motions impact brain wave activity?

By comparing pattern changes throughout the course of the task, researchers observed that there are indeed detectable changes in brain activity that occur as one moves from the beginning to middle to end of carrying out a task. And regardless of how slowly or quickly the animals moved, the brain patterns followed the same path. The patterns were consistent when researchers applied a machine learning-based mathematical model to predict the flow of brain activity, bolstering evidence that it’s experiences — not time, or a prescribed number of minutes, as you would measure it on a clock — that produce changes in our neurons’ activity patterns.

Hyman drove home the crux of the findings by sharing an anecdote of two factory workers tasked with making 100 widgets during their shift, with one worker completing the task in 30 minutes and the other in 90 minutes.

“The length of time it took to complete the task didn’t impact the brain patterns. The brain is not a clock; it acts like a counter,” Hyman explained. “Our brains register a vibe, a feeling about time. …And what that means for our workers making widgets is that you can tell the difference between making widget No. 85 and widget No. 60, but not necessarily between No. 85 and No. 88.”

But exactly “how” does the brain count? Researchers discovered that as the brain progresses through a task involving a series of motions, various small groups of firing cells begin to collaborate — essentially passing off the task to a different group of neurons every few repetitions, similar to runners passing the baton in a relay race.

“So, the cells are working together and over time randomly align to get the job done: one cell will take a few tasks and then another takes a few tasks,” Hyman said. “The cells are tracking motions and, thus, chunks of activities and time over the course of the task.”

And the study’s findings about our brains’ perception of time applies to activities-based actions other than physical motions too.

“This is the part of the brain we use for tracking something like a conversation through dinner,” Hyman said. “Think of the flow of conversation and you can recall things earlier and later in the dinner. But to pick apart one sentence from the next in your memory, it’s impossible. But you know you talked about one topic at the start, another topic during dessert, and another at the end.”

By observing the rodents who worked quickly, scientists also concluded that keeping up a good pace helps influence time perception: “The more we do, the faster time moves. They say that time flies when you’re having fun. As opposed to having fun, maybe it should be ‘time flies when you’re doing a lot’.”

Takeaways

While there’s already a wealth of information on brain processes over very short time scales of less than a second, Hyman said that the UNLV study is groundbreaking in its examination of brain patterns and perception of time over a span of just a few minutes to hours — “which is how we live much of our life: one hour at a time. ”

“This is among the first studies looking at behavioral time scales in this particular part of the brain called the ACC, which we know is so important for our behavior and our emotions,” Hyman said.

The ACC is implicated in most psychiatric and neurodegenerative disorders, and is a concentration area for mood disorders, PTSD, addiction, and anxiety. ACC function is also central to various dementias including Alzheimer’s disease, which is characterized by distortions in time. The ACC has long been linked to helping humans with sequencing events or tasks such as following recipes, and the research team speculates that their findings about time perception might fall within this realm.

While the findings are a breakthrough, more research is needed. Still, Hyman said, the preliminary findings posit some potentially helpful tidbits about time perception and its likely connection to memory processes for everyday citizens’ daily lives. For example, researchers speculate that it could lend insights for navigating things like school assignments or even breakups.

“If we want to remember something, we may want to slow down by studying in short bouts and take time before engaging in the next activity. Give yourself quiet times to not move,” Hyman said. “Conversely, if you want to move on from something quickly, get involved in an activity right away.”

Hyman said there’s also a huge relationship between the ACC, emotion, and cognition. Thinking of the brain as a physical entity that one can take ownership over might help us control our subjective experiences.

“When things move faster, we tend to think it’s more fun — or sometimes overwhelming. But we don’t need to think of it as being a purely psychological experience, as fun or overwhelming; rather, if you view it as a physical process, it can be helpful,” he said. “If it’s overwhelming, slow down or if you’re bored, add activities. People already do this, but it’s empowering to know it’s a way to work your own mental health, since our brains are working like this already.”



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