Astronomers Discover Largest Peptide-like Molecule In Space (Planetary Science)

A team of international astronomers reported the discovery of the propionamide, the largest peptide-like molecule, in space toward Sagittarius B2(N1) at a position called N1E that is slightly offset from the continuum peak. Their study recently appeared in Arxiv.

Proteins are polymers of amino acids joined together by the peptide bond, -NHCO-. Due to the high molecular weight and extremely low gas-phase abundance, detection of proteins in the interstellar medium (ISM) at the current stage of development of observation facilities looks like a formidable task. Therefore, molecules with peptide-like bonds are of particular interest for our understanding of possible routes of protein formation in space. However, the number of peptide-like molecules found so far in space is quite limited.

Now, using the high sensitivity and high angular resolution of the ReMoCA spectral line survey conducted with ALMA toward Sgr B2(N), Chinese astronomers for the first time detected propionamide, C2H5CONH2, the next member of the interstellar amide chemical family after formamide and acetamide.

© Juan Li et al.

They performed a new laboratory measurements of the propionamide spectrum in the 9-461 GHz range, which provide them an opportunity to check directly for the transition frequencies of detected interstellar lines of propionamide.

“By mapping propionamide versus CH13CN, they selected a position 1.5ʹʹ to the east of the hot core Sgr B2(N1) (referred to as Sgr B2(N1E)) where they found propionamide is relatively strong while other molecular emissions are relatively weak.”

— they wrote.

Their observational results indicated that propionamide emission comes from the warm, compact cores in Sagittarius B2, in which massive protostellars are forming. The column density of propionamide toward Sgr B2(N1E) was derived to be 1.5×1016 cm¯2, which is three-fifths of that of acetamide, and one-nineteenth of that of formamide.

“The detection of propionamide in Sgr B2(N) demonstrates that interstellar chemistry can reach sufficient levels of complexity to form relatively large peptide molecules and shows the possible growth of larger amide molecules from smaller ones in a massive star-forming process. It is probable that propionamide might also exist in massive star-forming regions in the Galactic disk, such as Orion KL and NGC 6334.”

— they concluded.

Featured image: Generalized structure and model of propionamide © Juan Li et al.

Reference: Juan Li, Junzhi Wang, Xing Lu, Vadim Ilyushin, Roman A. Motiyenko, Qian Gou, Eugene A. Alekseev, Donghui Quan, Laurent Margules, Feng Gao, Frank J. Lovas, Yajun Wu, Edwin Bergin, Shanghuo Li, Zhiqiang Shen, Fujun Du, Meng Li, Siqi Zheng, Xingwu Zheng, “Propionamide (C2H5CONH2): The largest peptide-like molecule in space”, Arxiv, pp. 1-49, 2021.

Note for editors of other websites: To reuse this article fully or partially kindly give credit either to our author/editor S. Aman or provide a link of our article

Ultrasound Remotely Triggers Immune Cells to Attack Tumors in Mice Without Toxic Side Effects (Medicine)

Bioengineers at the University of California San Diego have developed a cancer immunotherapy that pairs ultrasound with cancer-killing immune cells to destroy malignant tumors while sparing normal tissue.

The new experimental therapy significantly slowed down the growth of solid cancerous tumors in mice.

The team, led by the labs of UC San Diego bioengineering professor Peter Yingxiao Wang and bioengineering professor emeritus Shu Chien, detailed their work in a paper published Aug. 12 in Nature Biomedical Engineering.

The work addresses a longstanding problem in the field of cancer immunotherapy: how to make chimeric antigen receptor (CAR) T-cell therapy safe and effective at treating solid tumors.  

CAR T-cell therapy is a promising new approach to treat cancer. It involves collecting a patient’s T cells and genetically engineering them to express special receptors, called CAR, on their surface that recognize specific antigens on cancer cells. The resulting CAR T cells are then infused back into the patient to find and attack cells that have the cancer antigens on their surface.

This therapy has worked well for the treatment of some blood cancers and lymphoma, but not against solid tumors. That’s because many of the target antigens on these tumors are also expressed on normal tissues and organs. This can cause toxic side effects that can kills cells—these effects are known as on-target, off-tumor toxicity.

“CAR T cells are so potent that they may also attack normal tissues that are expressing the target antigens at low levels,” said first author Yiqian (Shirley) Wu, a project scientist in Wang’s lab.

“The problem with standard CAR T cells is that they are always on—they are always expressing the CAR protein, so you cannot control their activation,” explained Wu.

To combat this issue, the team took standard CAR T cells and re-engineered them so that they only express the CAR protein when ultrasound energy is applied. This allowed the researchers to choose where and when the genes of CAR T cells get switched on.

“We use ultrasound to successfully control CAR T cells directly in vivo for cancer immunotherapy,” said Wang, who is a faculty member of the Institute of Engineering in Medicine and the Center for Nano-ImmunoEngineering, both at UC San Diego. What’s exciting about the use of ultrasound, noted Wang, is that it can penetrate tens of centimeters beneath the skin, so this type of therapy has the potential to non-invasively treat tumors that are buried deep inside the body.

The team’s approach involves injecting the re-engineered CAR T cells into tumors in mice and then placing a small ultrasound transducer on an area of the skin that’s on top of the tumor to activate the CAR T cells. The transducer uses what’s called focused ultrasound beams to focus or concentrate short pulses of ultrasound energy at the tumor. This causes the tumor to heat up moderately—in this case, to a temperature of 43 degrees Celsius (109 degrees Fahrenheit)—without affecting the surrounding tissue. The CAR T cells in this study are equipped with a gene that produces the CAR protein only when exposed to heat. As a result, the CAR T cells only switch on where ultrasound is applied.

The researchers put their CAR T cells to the test against standard CAR T cells. In mice that were treated with the new CAR T cells, only the tumors that were exposed to ultrasound were attacked, while other tissues in the body were left alone. But in mice that were treated with the standard CAR T cells, all tumors and tissue expressing the target antigen were attacked.

“This shows our CAR T-cell therapy is not only effective, but also safer,” said Wu. “It has minimal on-target, off-tumor side effects.”

The work is still in the early stages. The team will be performing more preclinical tests and toxicity studies before it can reach clinical trials.

Paper: “Control of the activity of CAR-T cells within tumours via focused ultrasound.” Co-authors include Yahan Liu, Ziliang Huang, Xin Wang, Jiayi Li, Linshan Zhu, Molly Allen, Yijia Pan, Robert Bussell, Aaron Jacobson, Thomas Liu and Shu Chien, UC San Diego; Zhen Jin, Shanghai Jiao Tong University, China; and Praopim Limsakul, Prince of Songkla University, Thailand.

This work was supported in part by the National Institutes of Health (grants HL121365, GM125379, GM126016, CA204704 and CA209629).

Disclosure: Peter Yingxiao Wang is scientific co-founder of and has financial interest in Cell E&G Inc. and in Acoustic Cell Therapy Inc., a company that aims to license the technology for further development. These financial interests do not affect the design, conduct or reporting of this research.

Reference: Wu, Y. et al, Control of the activity of CAR-T cells within tumours via focused ultrasound, Nat Biomed Eng (2021).

Provided by University of California – San Diego

Novel Nanotechnology Found To Enhance Fight Against Colorectal Cancer and Melanoma (Medicine)

A first-of-its-kind nanotherapeutic delivery system demonstrated remarkable efficacy against both early-stage and difficult-to-treat late-stage metastatic tumors.

University of Arizona Health Sciences researchers recently completed a study that has the potential to improve cancer treatment for colorectal cancer and melanoma by using nanotechnology to deliver chemotherapy in a way that makes it more effective against aggressive tumors. The findings were published today in Nature Nanotechnology.

“I’ve always been interested in harnessing the intrinsic immunity to fight against cancer,” said Jianqin Lu, BPharm, PhD, assistant professor of pharmaceutics and pharmacokinetics in the UArizona College of Pharmacy’s Department of Pharmacology and Toxicology and associate member of the UArizona Cancer Center. “To do this in a safe and effective way, nanotechnology comes into play because of its ability to improve drug movement and therapeutic efficacy, as well as the potential to reduce systemic toxicities. My hope is that these innovative nanotherapeutics and therapeutic regimens eventually will help cancer patients combat cancers more effectively and safely.”

Immunotherapies help boost the immune system’s ability to fight off cancer cells. Immune checkpoints are regulators of the immune system, which are pivotal in preventing the body from attacking healthy cells indiscriminately. Some types of cancer circumvent these checkpoints, allowing cancerous cells to avoid detection and continue to spread. Immune checkpoint blockade (ICB) is a newer therapy that can essentially “release the brakes” on the immune system and help the body fight back. 

ICB therapies are effective for some types of cancer, but they don’t work for every patient. For example, only approximately 4% of patients with colorectal cancer, the second leading cause of cancer-related deaths in U.S., will respond to ICB therapy, Dr. Lu said.

Recent research has focused on ways to enhance the power of ICB therapies by combining them with chemotherapeutic agents such as camptothecin. Though camptothecin is potent, it is also unstable, has poor solubility in water and can have serious side effects for healthy cells.

Dr. Lu and the research team created the first nanotherapeutic platform of its kind to overcome these hurdles. Using a nanotechnology delivery method, researchers enhanced camptothecin’s ability to synergize with ICB therapies, making them more effective against aggressive tumors. 

“To render a more effective ICB therapy, we have developed a nanotherapeutic platform that can switch the tumors from ‘immune-cold’ to ‘immune-hot,’” said Dr. Lu, who is also a member of the BIO5 Institute and the Southwest Environmental Health Sciences Center. “As a result, this nanotherapeutic platform was able to increase the effectiveness of the ICB therapy to eradicate a large portion of early-stage colorectal cancer tumors while concurrently activating the body’s memory immunity, preventing tumor recurrence.”   

The team attached camptothecin to sphingomyelin, a naturally occuring lipid found on the surface of cells. The combination of the two molecules into a nanovesicle called camptothesome stabilized camptothecin, improving its efficacy and diminishing systemic toxicities. The nanotech delivery method also improved the tumor uptake of the camptothesome in a rodent model, where it deeply penetrated the tumour with efficient release of the chemotherapy.

Dr. Lu and the research team then created a way to load an immune checkpoint inhibitor targeting one of the key checkpoints, indoleamine 2,3-dioxygenase (IDO1), inside of the camptothesomes. When combined with inhibitors targeting other immune checkpoints known as PD-L1 and PD-1, this nanotherapeutic strategy eliminated a significant portion of clinically difficult-to-treat late-stage metastatic colorectal cancer and melanoma tumors, paving the pathway for further studies.   

The researchers note that their nanotechnology platform can be used to deliver a range of cancer therapeutics, and it has a significant head start in the drug development pipeline as it is derived from sphingomyelin, a lipid that is already approved by the U.S. Food and Drug Administration.

Dr. Lu hopes to collaborate with oncologists at the UArizona Cancer Center to further optimize the nanotherapeutic system to make it suitable for an early phase clinical trial.

Co-authors include: Aaron James Scott, MD, associate professor in the UArizona College of Medicine – Tucson and member of the UArizona Cancer Center; and from the Department of Pharmacology and Toxicology, Zhiren Wang, PhD, a postdoctoral research associate; Weiguo Han, PhD, an assistant research professor; former PharmD student Nicholas Little; and former undergraduate students, Jiawei Chen, Kevin Tyler Lambesis, Kimberly Thi Le.

This research was supported in part by the National Institute of Environmental Health Sciences (P30 ES006694), a division of the National Institutes of Health, the National Cancer Institute (R01CA092596 and P30 CA023074), also a division of the National Institutes of Health, and the UArizona BIO5 Institute and Arizona’s Technology and Research Initiative Fund.

Reference: Wang, Z., Little, N., Chen, J. et al. Immunogenic camptothesome nanovesicles comprising sphingomyelin-derived camptothecin bilayers for safe and synergistic cancer immunochemotherapy. Nat. Nanotechnol. (2021).

Provided by University of Arizona Health Sciences

Scientists Discover New Mechanisms of Activity Improvement On Bimetallic Catalysts For Hydrogen Generation & Fuel Cells (Chemistry)

A group of researchers at the Hong Kong University of Science and Technology (HKUST) and Xiamen University has revealed new understandings of how surface ruthenium atoms can improve the hydrogen evolution and oxidation activities of platinum. This discovery opens a new venue for rational design of more advanced catalysts for electrolyzer and fuel cell applications. 

Hydrogen is a clean energy carrier that does not contain carbon. It is believed to play an essential role in our future sustainable society. Hydrogen can be produced from water via the hydrogen evolution reaction (HER) in an electrolyzer by using renewable energies, and consumed via a hydrogen oxidation reaction (HOR) in a fuel cell to generate electricity. Unfortunately, these two reactions are well-known kinetically sluggish in alkaline media, even on the most active platinum catalysts. The slow reaction rates limit the efficiencies of these two electrochemical devices and hinder their wide adoption. It has been known that the reaction rates of HER/HOR on platinum can be improved by surface modification or alloying with ruthenium. However, the mechanisms for this promotion have been under debate for over decades. Part of the reasons is a lack of direct observation of behaviors of hydrogen atoms on the surfaces of catalysts.

To reveal the enigma of high HER/HOR activities on platinum-ruthenium bimetallic catalysts, a research team led by Prof. Minhua ShaoDepartment of Chemical and Biological Engineering and Energy Institute at HKUST, recently applied the powerful surface-enhanced infrared absorption spectroscopy (SEIRAS) to directly monitor the binding strength of the important reaction intermediate, hydrogen atoms on various surfaces. Through the combined electrochemical, spectroscopic, and theoretical studies they confirmed the surface ruthenium atoms interacted with the sub-surface platinum is one order of magnitude more active than platinum, i.e., the ruthenium rather than platinum atoms are main active sites in this system. 

“Previous works mainly used conventional electrochemical and characterization techniques, which cannot directly monitor the adsorption behavior of hydrogen reaction intermediates. In this work, we use the powerful surface-enhanced infrared absorption spectroscopy, which is among the very few techniques that can directly “see” surface hydrogen atoms, and provides us more straightforward information on how ruthenium improves the activity” said Prof. Shao. “This work rules out the most widespread theory that the bifunctional effect on the interface between platinum and ruthenium is the cause of increased activities, and opens new directions on future design of more advanced HER/HOR catalysts, which can consequently reduce the usage of precious metals in both water electrolyzers and hydrogen fuel cells.”

This work is part of the newly founded Collaborative Research Fund project led by Prof. Shao “Development of high-performance and long-life alkaline membrane fuel cells”, and constitutes an important subsection of fundamental research to this whole project. Following works on the development of practical and high-performance bimetallic platinum-ruthenium electrocatalysts based on these findings is in progress.

This study was recently published in Nature Catalysis entitled “The Role of Ruthenium in Improving the Kinetics of Hydrogen Oxidation and Evolution Reactions of Platinum”.

Featured image: Ruthenium atoms supported on platinum are extremely active to produce hydrogen © HKUST

Provided by HKUST

People in the Philippines have the most Denisovan DNA (Biology)

Researchers have known from several lines of evidence that the ancient hominins known as the Denisovans interbred with modern humans in the distant past. Now researchers reporting in the journal Current Biology on August 12 have discovered that the Philippine Negrito ethnic group known as the Ayta Magbukon have the highest level of Denisovan ancestry in the world. In fact, they carry considerably more Denisovan DNA than the Papuan Highlanders, who were previously known as the present-day population with the highest level of Denisovan ancestry.

“We made this observation despite the fact that Philippine Negritos were recently admixed with East Asian-related groups—who carry little Denisovan ancestry, and which consequently diluted their levels of Denisovan ancestry,” said Maximilian Larena (@maxlarena) of Uppsala University. “If we account for and masked away the East Asian-related ancestry in Philippine Negritos, their Denisovan ancestry can be up to 46 percent greater than that of Australians and Papuans.”

In the new study, Larena and colleagues, including Mattias Jakobsson, aimed to establish the demographic history of the Philippines. Through a partnership between Uppsala University of Sweden and the National Commission for Culture and the Arts of the Philippines (NCCA), aided by collaboration with indigenous cultural communities, local universities, local government units, non-governmental organizations, and/or regional offices of the National Commission for Indigenous Peoples, they analyzed about 2.3 million genotypes from 118 ethnic groups of the Philippines including diverse self-identified Negrito populations. The sample also included high-coverage genomes of AustraloPapuans and Ayta Magbukon Negritos.

The study shows that Ayta Magbukon possess the highest level of Denisovan ancestry in the world, consistent with an independent admixture event into Negritos from Denisovans. Together with the recent discovery of a small-bodied hominin, called Homo luzonensis, the data suggest that there were multiple archaic species that inhabited the Philippines prior to the arrival of modern humans, and that these archaic groups may have been genetically related.

Altogether, the researchers say that the findings unveil a complex intertwined history of modern and archaic humans in the Asia-Pacific region, where distinct Islander Denisovan populations differentially admixed with incoming Australasians across multiple locations and at various points in time.

“This admixture led to variable levels of Denisovan ancestry in the genomes of Philippine Negritos and Papuans,” Jakobsson said. “In Island Southeast Asia, Philippine Negritos later admixed with East Asian migrants who possess little Denisovan ancestry, which subsequently diluted their archaic ancestry. Some groups, though, such as the Ayta Magbukon, minimally admixed with the more recent incoming migrants. For this reason, the Ayta Magbukon retained most of their inherited archaic tracts and were left with the highest level of Denisovan ancestry in the world.”

“By sequencing more genomes in the future, we will have better resolution in addressing multiple questions, including how the inherited archaic tracts influenced our biology and how it contributed to our adaptation as a species,” Larena said.

This work was supported by the Swedish Research Council and the Knut and Alice Wallenberg Foundation.

Current Biology, Larena et al.: “Philippine Ayta possess the highest level of Denisovan ancestry in the world”

Provided by Cell Press

Palaeontology: Three Fossils Shed Light on Dinosaurs in China

Three dinosaurs from Northwest China represent two new species and are some of the first vertebrates uncovered in the region, according to a study published in Scientific Reports. The findings shed light on sauropods in China.   

Dr. Xiaolin Wang and colleagues analysed fossil fragments (spinal vertebrae and rib cage) previously discovered in the Turpan-Hami Basin (Xinjiang, China) and dated to the Early Cretaceous (around 130 to 120 million years ago). They compared specific features of the remains (vertebrae and rib structure) to other sauropod dinosaurs from China and other localities. 

The authors identified the first specimen as a new species and named it Silutitan sinensis. The authors found that some characteristics of the neck vertebrae indicate that it belonged to a family of sauropods known as Euhelopodidae, which so far have been found only in East Asia. They compared the specimen with what they believe was a closely related group of dinosaurs, or genus, (Euhelopus) and estimated that the specimen was originally over 20 metres long.   

The authors named the second specimen, which they also identify as a new species, Hamititan xinjiangensis. The specimen consists of seven vertebrae from the tail, which the authors believe are the fourth to tenth in the spine. The authors conclude the shape and ridges along vertebrae suggest that it belonged to a family of sauropods known as Titanosaurs, abundant in both Asia and South America. They estimate the full specimen was 17 meters long by comparing it to what they believe to be closely related genera (Rapetosaurus and Opisthocoelicaudia).

The third specimen was limited to four vertebrae and rib fragments. The authors’ analysis suggests it may be a somphospondylan sauropod, a group of dinosaurs who lived from the late Jurassic, 160.3 million years ago to the late Cretaceous, 66 million years ago.

These samples are some of the first dinosaurs reported in the Turpan-Hami Basin, increasing the known diversity of the Mesozoic reptiles found in the area. The findings also shed light on which sauropods were present in China. 

Featured image: Map showing the fossil site where the new sauropod dinosaur specimens were collected (A,B), and the relative positions of these three specimens (C). Credit: Nature Publishing Group

Reference: Wang, X. et al, The first dinosaurs from the Early Cretaceous Hami Pterosaur Fauna, China, Sci Rep (2021). DOI: 10.1038/s41598-021-94273-7

Provided by Nature Publishing Group

Study Reveals Structure Of Receptor Implicated In Type 2 Diabetes And More (Biology)

Researchers from the University of Southern California, Merck & Co., Skoltech, MIPT, UCLA, and the Université de Sherbrooke have determined the structure of the human leukotriene B4 receptor 1, involved in inflammatory, infectious, allergic, and tumorigenic diseases. Published in Nature Communications, the analysis of the structure reveals how the receptor recognizes its binding partners and interacts with them. This opens up avenues for designing better drugs that would target the receptor to treat Type 2 diabetes and other pathologies.

Receptors are the protein-based equipment cells use to receive and transmit signals. A receptor becomes activated when it binds a messenger molecule called an agonist, whereupon it relays the signal, which regulates some biological function. Antagonists, by contrast, shut down the receptor when bound. Agonists and antagonists are collectively known as ligands.

The human leukotriene B4 receptor 1, or hBLT1, regulates inflammation-related processes — such as the recruitment of T cells — as well as the proliferation and migration of smooth muscle cells. That receptor has been associated with diseases, including asthma, influenza, arthritis, atherosclerosis, diabetes, and cancer.

Since its discovery in 1997, there have been a number of attempts to develop hBLT1 ligands for use as drugs, but they had many side effects, low efficacy, and the body took comparatively long to eliminate them. A likely explanation for this is that the hBLT1 ligands used are not specific to that receptor and engage in other unwanted interactions. Learning more about the structure of the receptor and how it binds ligands can allow pharmacologists to design better, more selective drugs.

A recent study by a Russian-U.S.-Canadian collaboration sheds light on the makeup and functioning of hBLT1. Vadim Cherezov, professor of Chemistry at USC and the head of the MIPT Laboratory for Structural Biology of GPCRs, commented: “We have determined the 2.9-angstrom-resolution crystal structure of the hBLT1 receptor in complex with a selective antagonist, MK-D-046, developed by Merck & Co. This structure should help to rationally design better therapeutics to treat type 2 diabetes and other inflammatory conditions.”

Structure determination was complemented by site-directed mutagenesis and docking studies — an experimental and a computational method, respectively. According to Skoltech Assistant Professor Petr Popov, “this made it possible to reveal the key determinants of intermolecular interactions between the receptor and the ligands.”

The analysis of hBLT1 structure reveals how the receptor recognizes and binds ligands, suggesting a putative ligand access channel buried in the receptor’s membrane. More specifically, the findings hint at the possible ways the receptor might bind its endogenous agonists. That is, compounds naturally produced by the body to bind to that receptor and activate it.

By improving our understanding of hBLT1 structure and functioning, the study opens up possibilities for structure-based drug design.

Featured image: Structure and binding site of hBLT1. © Michaelian, N., et al. Nature Communications (

Reference: Michaelian, N., Sadybekov, A., Besserer-Offroy, É. et al. Structural insights on ligand recognition at the human leukotriene B4 receptor 1. Nat Commun 12, 2971 (2021).

Provided by Skoltech

Discovery Raises Possibility Of New Medication For Alzheimer’s, Parkinson’s (Neuroscience)

OHSU study reveals that synthetic compound regulates gene implicated in neurodegenerative diseases

Researchers from Oregon Health & Science University have for the first time demonstrated it’s possible to use a synthetic thyroid hormone to regulate a gene implicated in neurodegenerative diseases like Alzheimer’s, Parkinson’s and multiple sclerosis.

The findings from tests in cells and mice, published today in the journal Cell Chemical Biology, raise the possibility of development of new medication to treat debilitating diseases.

Close-in headshot of Tom Scanlan, Ph.D., a smiling white adult.
Tom Scanlan, Ph.D. © OHSU

“This is the first example reported that shows it’s possible to increase the expression of the TREM2 gene in a way that will lead to healing in certain diseases,” said senior author Tom Scanlan, Ph.D., professor of physiology and pharmacology in the OHSU School of Medicine. “This will generate a lot of excitement.”

The paper’s first author is Skylar J. Ferrara, Ph.D., a postdoctoral fellow in the OHSU School of Medicine’s chemical physiology and biochemistry department. 

Portrait of Sky Ferrara, Ph.D., a short-haired, brunette adult in a suit and tie.
Sky Ferrara, Ph.D. © OHSU

The discovery builds on a 2013 publication linking genetic variants of TREM2 to risk of Alzheimer’s disease.

The new research from OHSU builds on that work by showing that it’s possible to turn on TREM2 expression and the TREM2 pathway using a compound originally developed more than two decades ago to lower cholesterol.

Researchers administered an analog of the compound that penetrates into the central nervous system of mice. They discovered they were able to increase the expression of TREM2 and reduce damage to myelin. Myelin is the insulation-like protective sheath covering nerve fibers that’s damaged in disorders like multiple sclerosis.

The pathway activated by the TREM2 gene is also implicated in neurodegenerative diseases, including Alzheimer’s and Parkinson’s.

“TREM2 is a receptor,” Scanlan said. “It senses damaged cellular debris from disease and responds in a healing, productive way. The thought is, if you can simply turn up its expression, then that’s going to lead to a therapeutic effect in most neurodegenerative diseases.”

Joseph Quinn, M.D., professor of neurology in the OHSU School of Medicine, who treats patients with Parkinson’s and Alzheimer’s, said the findings are promising. Quinn wasn’t involved in the research.

“TREM2 is a viable ‘target’ for treatment in Alzheimer’s disease, based on genetics and other studies,” Quinn said. “This new report has important implications for testing a new therapeutic approach for Alzheimer’s, including raising the potential for developing a new medication to regulate TREM2.”

The synthetic thyroid hormone compound, known as sobetirome and similar analogs, is already licensed by an OHSU spinoff company to conduct clinical trials for central nervous system diseases, including multiple sclerosis. In contrast to other basic science discoveries in mice, Scanlan said this latest discovery connects this class of compounds to Alzheimer’s, Parkinson’s and other neurodegenerative diseases, advancing the science that much closer to clinical trials in people with debilitating disease.  

“The possibility of doing clinical trials is not millions of miles away,” Scanlan said. “It would be an achievable thing.”

REFERENCE: Skylar J. Ferrara, Priya Chaudhary, Margaret J. DeBell, Gail Marracci, Hannah Miller, Evan Calkins, Edvinas Pocius, Brooke A. Napier, Ben Emergy, Dennis Bourdette, Thomas S. Scanlan, TREM2 is thyroid hormone regulated making the TREM2 pathway druggable with ligands for thyroid hormone receptor, Cell Chemical Biology, Aug. 9, 2021, DOI:

This research was supported by the National Institutes of Health, awards DK52798 and GM133804; the National Multiple Sclerosis Society, awards RG5199A4 and RG 1607-25053, RG5106A1/1 and RG 2001-35775; the Race to Erase MS, and the OHSU Laura Fund for Innovation in Multiple Sclerosis.

Featured image: Researchers from Oregon Health & Science University have for the first time demonstrated it’s possible to use a synthetic thyroid hormone to regulate a gene implicated in neurodegenerative diseases like Alzheimer’s, Parkinson’s and multiple sclerosis. (Getty Images)

Provided by OHSU

UCI Study Finds Targeting Mitochondria Shows Promise in Treating Obesity (Medicine)

Molecule that changes the shape of mitochondria corrects obesity

 A team of University of California, Irvine, scientists have discovered a novel pharmacological approach to attenuate the mitochondrial dysfunction that drives diet-induced obesity. The results of their study were published recently in the journal, EMBO Molecular Medicine.

Consuming a high-fat diet can lead to obesity and metabolic disorders such as diabetes and fatty liver. Palmitate, a fat abundant in a Western diet, triggers metabolic dysfunction by causing excessive mitochondrial fission within cells. Mitochondria play a crucial role in a cell’s energy production, but also coordinate cell stress responses. Too much mitochondrial fission impairs their function, undermining metabolism and increasing toxic by-products associated with insulin resistance in some tissue types.

“Elegant genetic studies in mice show that maintaining mitochondrial networks in a fused state can overcome high fat diet-induced obesity. Our study uses a small molecule to re-shape mitochondria in multiple tissues simultaneously, reversing obesity and correcting metabolic disease even though mice continue to consume the unhealthy diet,” said senior author Aimee Edinger, UCI Chancellor’s Fellow and professor of developmental & cell biology.

In their new study, Professor Edinger and her team utilized their patented water-soluble, orally bioavailable, synthetic sphingolipid SH-BC-893 to inhibit endolysosomal trafficking proteins required for mitochondrial fission. The study was conducted using in vitro experiments and a high-fat diet-induced obesity mouse model. The researchers observed that SH-BC-893 prevented mitochondrial dysfunction in the liver, brain, and white adipose tissue of mice consuming a Western diet. As a result, circulating levels of critical metabolic hormones, leptin and adiponectin, were normalized leading to weight loss, improved glucose handling, and reversal of fatty liver disease despite continued access to high-fat food.

“Imbalances in the hormones leptin and adiponectin that accompany obesity create an uphill battle for people trying to lose weight. Having too much leptin can increase appetite while too little adiponectin activity is linked to many metabolic diseases. How or why is not really clear, but the state of the mitochondria may be an important link between these hormones and obesity,” said Elizabeth Selwan, a former graduate student researcher in UCI’s Department of Developmental and Cell Biology and co-lead author of the study.

The study’s findings suggest that SH-BC-893 could be a promising therapy for managing diet-induced obesity. The authors found the drug to be safe and effective in the mouse model and plan on further investigating the compound for possible use in human patients. 

“This compound works through a novel mode of action – if it is safe and effective in humans, it would offer a new weight loss strategy that could also be combined with other treatments,” said Professor Edinger.

Researchers who contributed to this work were: Vaishali Jayashankar, Amandine Verlande, Maggie Goodson, Kazumi Eckenstein, Giedre Milinkeviciute, Brianna Hoover, Angela Fleischman, Karina Cramer and Selma Masri from the University of California, Irvine; Sarah Hancock and Nigel Turner from the University of New South Wales; and Bin Chen and Stephen Hanessian from the Université de Montréal. 

The study was supported by the University of California, Irvine, the National Institutes of Health, UCI Beall Applied Innovation, the National Health and Medical Research Council of Australia, the Concern Foundation for Cancer Research, the V Foundation for Cancer Research, and the U.S. Department of Education.  

The study, “Drug-like sphingolipid SH-BC-893 opposes ceramide-induced mitochondrial fission and corrects diet-induced obesity”, EMBO Mol Med (2021)13:e13086

Provided by University of Columbia Irvine