Researchers identify previously unknown step in cholesterol absorption in the gut

Illustration Credit: Scientific Frontline

UCLA researchers have described a previously unknown step in the complex process by which dietary cholesterol is processed in the intestines before being released into the bloodstream – potentially revealing a new pathway to target in cholesterol treatment.

Although an existing drug and statins impact part of the process, an experimental drug being studied in UCLA research labs appears to specifically target the newfound pathway, possibly adding a new approach to the cholesterol management toolbox.

“Our results show that certain proteins in the Aster family play a critical role in moving cholesterol through the absorption and uptake process,” said Dr. Peter Tontonoz, a UCLA professor and researcher in Pathology and Laboratory Medicine and Biological Chemistry, senior author of an article in Science. “The Aster pathway appears to be a potentially attractive target for limiting intestinal cholesterol absorption and reducing levels of plasma cholesterol.”

Cholesterol from food is absorbed by cells that line the inner surface of the intestines – enterocytes – where it is processed into droplets that eventually reach the bloodstream. But this journey involves a multistep process.

New antifungal molecule kills fungi without toxicity in human cells, mice

The mechanism for a critical but highly toxic antifungal is revealed in high resolution. Self-assembled Amphotericin B sponges (depicted in light blue) rapidly extract sterols (depicted in orange and white) from cells. This atomic level understanding yielded a novel kidney-sparing antifungal agent. 
Illustration Credit: Jose Vazquez

A new antifungal molecule, devised by tweaking the structure of prominent antifungal drug Amphotericin B, has the potential to harness the drug’s power against fungal infections while doing away with its toxicity, researchers at the University of Illinois Urbana-Champaign and collaborators at the University of Wisconsin-Madison report in the journal Nature.

Amphotericin B, a naturally occurring small molecule produced by bacteria, is a drug used as a last resort to treat fungal infections. While AmB excels at killing fungi, it is reserved as a last line of defense because it also is toxic to the human patient – particularly the kidneys. 

Ural Scientists Have Synthesized a New Substance for the Treatment of Alzheimer’s Disease

Scientists from the Ural Federal University, the Institute of Organic Synthesis of the Ural Branch of the Russian Academy of Sciences, together with colleagues from India have developed a method for creating safe and non-toxic substances that could become the basis for drugs for Alzheimer's disease. Using the new technology, they synthesized and tested several compounds of tacrine analogues, which toxicity is estimated to be from two to five times lower than that of the known drug. The description of the new method and the compounds obtained was published in the Journal of Heterocyclic Chemistry. 

"We believe that our technology will help to create safe substances that will become the basis for future drugs for Alzheimer's disease. Our studies have shown that the toxicity of the resulting substances is two to five times lower than that of tacrine. At the same time, they are effective as they help to increase the level of acetylcholine in the cerebral cortex, which slows down the destruction of neuronal connections. This allows patients to maintain their cognitive functions and lead an active and fulfilling life for as long as possible," explains Nibin Joy Muthipeedika, Senior Researcher at the UrFU Organic Synthesis Laboratory.

Bowel cancer: aspirin activates protective genes

Photo Credit: günter

Colorectal cancer (bowel cancer) is the third most common form of cancer worldwide, with around 1.9 million newly diagnosed cases and 900,000 deaths every year. Therefore, preventive substances represent an urgent clinical need. Aspirin/acetylsalicylic acid has proven to be one of the most promising candidates for the prevention of colorectal cancer. Among other findings, studies have shown that when patients with cardiovascular diseases took low doses of aspirin over several years, it reduced their risk of colorectal cancer. Furthermore, aspirin can inhibit the progression of colorectal cancer. Now a team led by Heiko Hermeking, Professor of Experimental and Molecular Pathology at LMU, has investigated which molecular mechanisms mediate these effects.

As the researchers report in the journal Cell Death and Disease, aspirin induces the production of two tumor-suppressive microRNA molecules (miRNAs) called miR-34a and miR-34b/c. To do this, aspirin binds to and activates the enzyme AMPK, which in turn alters the transcription factor NRF2 such that it migrates into the cell nucleus and activates the expression of the miR-34 genes. For this activation to succeed, aspirin additionally suppresses the oncogene product c-MYC, which otherwise inhibits NRF2.

Weekly insulin injections have the potential to be as effective

Photo Credit: Peter Stanic

Insulin icodec, a once-weekly basal injection to treat type 1 diabetes, has the potential to be as effective in managing the condition as daily basal insulin treatments, according to research from the University of Surrey. The results of the year-long phase 3 clinical trial could revolutionize the future of diabetes care and help millions of people better manage their condition. 

During this pioneering study, scientists across 12 countries at 99 sites, led by Professor David Russell-Jones from Surrey, tested the efficacy and safety of a weekly basal injection of icodec (a long-lasting type of insulin) and compared it to a daily basal injection of insulin degludec in adults with type 1 diabetes. Short acting insulin to cover meals was used in both groups. 

Professor David Russell-Jones, Professor of Diabetes and Endocrinology at the University of Surrey and a Consultant at the Royal Surrey Foundation Trust, said: 

"Many people find managing a long-term condition such as diabetes very difficult and report missing vital insulin injections. Missed injections can affect glycaemic control, and a lack of consistency in the treatment has been linked to increased rates of diabetic ketoacidosis, a serious complication of the condition that can be life-threatening. Reducing insulin injection frequency could lessen the burden of treatment for some people with the condition and improve their glycaemic control." 

Type 1 diabetes occurs when the body cannot produce enough of the hormone insulin, causing the level of glucose (sugar) in the blood to become too high, leading to an increased risk of developing heart, eye, and kidney disease. 

To learn more about the efficacy of icodec, scientists recruited 582 participants with type 1 diabetes. Participants were split into two groups; the first received once-weekly injections of icodec (700U/ml), and the second received daily injections of degludec (100 U/ml), both in combination with aspart, a short-acting insulin at mealtimes. 

After 26 weeks, scientists identified HbA1C (a protein within red blood cells with glucose attached to it and the universal marker for overall diabetes control) levels in those who had taken icodec had decreased from a mean of 7.59 percent at baseline to an estimated mean of 7.15 percent, and for degludec, the mean had decreased from 7.63 percent to 7.10 percent. The estimated treatment difference between them being 0.05 percent, confirming the non-inferiority of icodec to degludec, but with a significantly reduced injection frequency for patients to manage. 

 Scientists did also identify higher rates of hypoglycemic episodes (abnormally low levels of glucose in the blood) in the icodec group compared to degludec. However, despite the higher levels in the icodec group, scientists noted that incidences were low in both groups, with most episodes only requiring oral carbohydrate administration. For icodec, time below 3.0 mmol/L was at the threshold of the internationally recommended targets during weeks 22-26 and below recommended targets during weeks 48-52.  

 Professor Russell-Jones added: 

 "What we have found is that once-weekly icodec injections showed non inferiority to once-daily injections of degludec in reducing HbA1C after 26 weeks. Although there is a slightly higher rate of hypoglycaemia under this regime, we found this could be easily managed. We’ve concluded this new insulin may have a role in reducing the burden of daily basal injections for patients managing type 1 diabetes. 

 "Our findings are very promising, but further analysis of continuous glucose monitoring data and real-world studies are needed." 

Funding: Provided by Novo Nordisk. 

Published in journal: The Lancet

Source/Credit: University of Surrey

Reference Number: phar103023_01

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New antibody could target breast cancers

A synthetic antibody called RD-43, developed by graduate student Zhe Qian in collaboration with CSHL’s Antibody & Phage Display Shared Resource, may help stop the spread of breast cancer by degrading the PTPRD enzyme.
Image Credit: Courtesy of Cold Spring Harbor Laboratory

An enzyme that may help some breast cancers spread can be stopped with an antibody created in the lab of Cold Spring Harbor Laboratory Professor Nicholas Tonks. With further development, the antibody might offer an effective drug treatment for those same breast cancers.

The new antibody targets an enzyme called PTPRD that is overabundant in some breast cancers. PTPRD belongs to a family of molecules known as protein tyrosine phosphatases (PTPs), which help regulate many cellular processes. They do this by working in concert with enzymes called kinases to control how other proteins inside cells behave. Kinases add small chemical regulators called phosphates to proteins. PTPs take them off.

Disruptions in the addition or removal of phosphates can contribute to inflammation, diabetes, and cancer. Some disruptions can be corrected with kinase-blocking drugs. Tonks explains:

Mechanics of breast cancer metastasis discovered, offering target for treatment

A human breast cancer cell, adenocarcinoma MDA-MB-231, demonstrates metastatic-like adhesion, spreading and migrating in a collagen matrix designed to mimic soft tissue. New research led by Penn State reveals for the first time the mechanics behind how breast cancer cells may invade healthy tissues. The discovery, showing that a motor protein called dynein powers the movement of cancer cells in soft tissue models, offers new clinical targets against metastasis and has the potential to fundamentally change how cancer is treated. 
Image Credit: Erdem Tabdanov / Pennsylvania State University
(CC BY-NC-ND 4.0 DEED)

The most lethal feature of any cancer is metastasis, the spread of cancer cells throughout the body. New research led by Penn State reveals for the first time the mechanics behind how breast cancer cells may invade healthy tissues. The discovery, showing that a motor protein called dynein powers the movement of cancer cells in soft tissue models, offers new clinical targets against metastasis and has the potential to fundamentally change how cancer is treated.

“This discovery marks a paradigm shift in many ways,” said Erdem Tabdanov, assistant professor of pharmacology at Penn State and a lead co-corresponding author on the study, recently published in the journal Advanced Science. “Until now, dynein has never been caught in the business of providing the mechanical force for cancer cell motility, which is their ability to move themselves. Now we can see that if you target dynein, you could effectively stop motility of those cells and, therefore, stop metastatic dissemination.”

The project began as a collaboration between Penn State’s Department of Chemical Engineering and Penn State’s College of Medicine, before growing into a multi-institution partnership with researchers at the University of Rochester Medical Center, Georgia Institute of Technology, Emory University, and the U.S. Food and Drug Administration.

Oregon State researchers uncover mechanism for treating dangerous liver condition

Illustration Credit: Julien Tromeur

A study spearheaded by Oregon State University has shown why certain polyunsaturated fatty acids work to combat a dangerous liver condition, opening a new avenue of drug research for a disease that currently has no FDA-approved medications.

Scientists led by Oregon State’s Natalia Shulzhenko, Andrey Morgun and Donald Jump used a technique known as multi-omic network analysis to identify the mechanism through which dietary omega 3 supplements alleviated nonalcoholic steatohepatitis, usually abbreviated to NASH.

The mechanism involves betacellulin, a protein growth factor that plays multiple positive roles in the body but also contributes to liver fibrosis, or scarring, and the progression to cirrhosis and liver cancer.

“We only succeeded in finding these surprising results because we implemented an entirely unbiased approach that incorporated a diverse type of big data analysis ranging from lipids and metabolites to whole tissue and single-cell RNA sequences,” said Morgun, a researcher in the OSU College of Pharmacy.

Treating the inflamed intestinal wall locally

For their self-forming gel, the researchers chose a lipid that is well tolerated and safe for use in humans. It is a fluid material at room temperature and can be administered as an enema into the inflamed area of the colon. There, at body temperature, it forms a viscous and sticky gel and remains adherent for at least six hours, gradually releasing the active ingredient.
Illustration Credit: © University of Bern, Marianna Carone

Treatment of the chronic inflammatory bowel disease ulcerative colitis often produces unsatisfactory results. Researchers at the University of Bern have now developed a lipid gel that is administered directly to the inflamed part of the intestine, where it remains and releases its active substance evenly. This could result in a new, targeted therapy approach with fewer side effects.

For diseases that affect a specific organ or tissue, a drug is usually most effective and well-tolerated if it is administered exactly where it is supposed to work in the body. If it is swallowed or injected, it distributes throughout the body, thus increasing the risk of side effects.

Researchers from the Department of Chemistry, Biochemistry and Pharmaceutical Sciences and the Institute of Tissue Medicine and Pathology at the University of Bern, together with colleagues from the University Hospital Zurich, have developed a self-forming, viscous lipid gel to deliver anti-inflammatory drugs directly to the wall of the colon or rectum. Thanks to this innovation, patients with ulcerative colitis, a chronic inflammation of the terminal part of the intestine, could be helped in a more targeted way and with fewer side effects.

Amitriptyline helps relieve IBS symptoms

Generic image of amitriptyline tablets

A cheap and widely available prescription drug can improve symptoms of irritable bowel syndrome in patients seen in GP surgeries, new research presented at UEG Week 2023 has found.

Amitriptyline, which is commonly used at low doses for a range of health concerns, has been found to improve irritable bowel syndrome (IBS) symptoms too, according to the results of the ATLANTIS trial.

Led by researchers at the Universities of Leeds, Bristol and Southampton, and funded by the National Institute for Health and Care Research (NIHR), the study was conducted in primary care. GPs prescribed the drug and patients managed their own dose based on the severity of their symptoms, using an adjustment document designed for the trial. Most people with IBS are seen and managed in primary care by their GP, which means that the results of this trial are likely to be applicable to many people with the condition.

The results showed that patients taking amitriptyline were almost twice as likely to report an overall improvement in symptoms as those taking a placebo.

Now the trial team is recommending that GPs support their patients with IBS to use amitriptyline to manage their symptoms – and has made the dose adjustment document available for clinicians and patients.

Targeting a coronavirus ion channel could yield new Covid-19 drugs

MIT chemists found that the SARS-CoV-2 E protein, which acts as an ion channel, has a broad opening at the bottom when in the closed state and a narrower opening in the open state.
Image Credits: Courtesy of the researchers, MIT News, and iStock
(CC BY-NC-ND 3.0 DEED)

The genome of the SARS-CoV-2 virus encodes 29 proteins, one of which is an ion channel called E. This channel, which transports protons and calcium ions, induces infected cells to launch an inflammatory response that damages tissues and contributes to the symptoms of Covid-19.

MIT chemists have now discovered the structure of the “open” state of this channel, which allows ions to flow through. This structure, combined with the “closed” state structure that was reported by the same lab in 2020, could help scientists figure out what triggers the channel to open and close. These structures could also guide researchers in developing antiviral drugs that block the channel and help prevent inflammation.

“The E channel is an antiviral drug target. If you can stop the channel from sending calcium into the cytoplasm, then you have a way to reduce the cytotoxic effects of the virus,” says Mei Hong, an MIT professor of chemistry and the senior author of the study.

MIT postdoc Joao Medeiros-Silva is the lead author of the study, which appears today in Science Advances. MIT postdocs Aurelio Dregni and Pu Duan and graduate student Noah Somberg are also authors of the paper.

New Study Points to New Possibilities for Treating Lung Cancer Patients

Illustration Credit: Rawpixel

Currently, researchers from different institutions in the world are testing a drug against obesity and diabetes, and now a Danish research team reports that the same substance has had a beneficial effect on mice with experimental lung cancer.

The substance is the short-chain fatty acid propionate, which is naturally produced by bacteria in our gut. From there, it is distributed throughout the body, and this new research study shows that treating mice with lung cancer with propionate can reduce the occurrence of metastases.

The study also demonstrates a role for propionate in increasing the effectiveness of Cisplatin, a commonly used drug for lung cancer patients. This was shown by lab experiments carried out in cancer cells derived from patients.

Common diabetes drug could treat gum disease and help you age healthier

Photo Credit: Cedric Fauntleroy

In their latest publication in the Journal of Translational Medicine, a team of researchers at the Faculty of Dentistry, Oral & Craniofacial Sciences have found new ways of stopping periodontal (gum) disease and potentially reducing the incidence of diabetes and obesity. This new approach focuses on controlling inflammation and sugar levels in both the mouth and body with a common type 2 diabetes drug, Metformin.

Periodontal (gum) diseases are strikingly common across the globe and are strongly associated with systemic conditions such as diabetes and obesity. Lifestyle choices such as increased sugar intake are a common cause of gum disease, as well as diabetes and obesity. Diabetes, obesity and gum disease all develop over our lifetime, but gum disease has the potential to be picked up first as it can start at as early as 30 years old.

The only treatment strategy currently available to tackle gum disease is to deep clean the teeth to rid the mouth of bacteria, as well as prescribing antibiotics. But this treatment does not protect against the continuation and development of systemic associated diseases, such as diabetes and obesity.

Red Algae Could Be Used to Create a Drug for Coronavirus

Chemical research on Laurencia red algae began in 1965.
Photo Credit: 🇸🇮 Janko Ferlič

Laurencia red algae can be used as a basis for new drugs against the SARS-CoV-2 virus, biochemists have found. A team of scientists from the Ural Federal University, the Institute of Organic Synthesis of the Ural Branch of the Russian Academy of Sciences, together with colleagues from Australia and Germany, carried out molecular docking of 300 bioactive components (ligands) of red algae and found seven compounds with the required activity. The scientists published a description of the experiments and results in the journal Microbiology Research. 

"Laurencia belongs to the family Rhodomelaceae, which is considered one of the largest families of marine red algae, with an estimated 125 genera and 700 species worldwide. Laurencia has recently been the subject of active research. Since 2015, a total of 1,047 secondary metabolites with various useful properties have been isolated from Laurencia species alone," explains Grigory Zyryanov, Chief Researcher of the UrFU Laboratory of Advanced Materials, Green Methods and Biotechnology.

Evolutionary history of three-finger snake toxins decoded

Burkhard Rost, a professor of bioinformatics
Photo Credit: Julia Eberle / ediundsepp / TUM

Snakebites cause around 100,000 deaths worldwide every year. Researchers at the Technical University of Munich (TUM) have investigated how the toxin emerged between 50 and 120 million years ago through the modification of a gene that also occurs in mammals and other reptiles. The results could help with the development of better snakebite treatments and lead to new knowledge for the treatment of illnesses such as type 2 diabetes and hypertension.

When venom passes into a snakebite victim, it binds onto receptors on nerve and muscle cells and interrupts communication pathways between them. This initially causes paralysis and, without an antidote, can cause death within a matter of minutes or hours. A team of researchers has studied how the protein structure of snake venoms known as three-finger toxins (3FTxs) has changed over the course of evolution.

Antiviral drugs could preserve capacity to produce insulin in type 1 diabetes patients

People with diabetes type 1 must administer insulin hormone for the rest of their lives.
Photo Credit: PhotoMIX-Company

Antiviral drug treatment could preserve the remaining capacity to release insulin in children recently diagnosed with type 1 diabetes, according to a new study by Scandinavian researchers. Johnny Ludvigsson, senior professor at LiU, was involved in the planning of the study, published in Nature Medicine.

The association between type 1 diabetes and viral infection was evidenced long ago. In their present study, the researchers have given antiviral drugs to children and young people newly diagnosed with type 1 diabetes. According to the study, this treatment partially slowed down the loss of insulin production. This is the first study testing antiviral treatment at the onset of diabetes.

The study was led by Knut Dahl-Jørgensen, senior professor at Oslo University Hospital and the University of Oslo.

“This result is an important step in showing that viruses could trigger diabetes. This means that it may be possible to treat and slow down type 1 diabetes with medication. Maybe eventually it will also prevent the disease,” says Knut Dahl-Jørgensen in a press release.

Psychedelics improve mental health, cognition in special ops veterans

The Colorado River toad (Incilius alvarius), also known as the Sonoran Desert toad, is a toad species found in northwestern Mexico and the southwestern United States. It is well known for its ability to exude toxins from glands within its skin that have psychoactive properties.
Photo Credit: Alan Schmierer
(CC0 1.0 DEED)

One treatment each of two psychedelic drugs lowered depression and anxiety and improved cognitive functioning in a sample of U.S. special operations forces veterans who sought care at a clinic in Mexico, according to a new analysis of the participants’ charts. 

The treatment included a combination of ibogaine hydrochloride, derived from the West African shrub iboga, and 5-MeO-DMT, a psychedelic substance secreted by the Colorado River toad. Both are designated as Schedule I drugs under the U.S. Controlled Substances Act.

In addition to relieving symptoms of post-traumatic stress disorder (PTSD), the combined treatment also alleviated cognitive impairment linked to traumatic brain injury – which stood out to researchers from The Ohio State University who led the chart-review analysis. Many special operations forces veterans seeking treatment for complex psychiatric symptoms do not respond to more traditional therapies. 

“What sets this group apart from some other veterans and civilians is that often, they are exposed to repeated traumatic events as a routine part of their jobs. This build-up of exposure to these difficulties seems to produce a cluster of challenges that include traumatic brain injury, which we know in and of itself predisposes people to mental health problems,” said lead author Alan Davis, associate professor and director of the Center for Psychedelic Drug Research and Education (CPDRE) in Ohio State’s College of Social Work. 

“So, the fact that we saw that there were improvements in cognitive functioning linked to brain injury were probably the most striking results, because that’s something we didn’t predict and it’s very new and novel in terms of how psychedelics might help in so many different domains.” 

New strategy for eye condition could replace injections with eyedrops

Yulia Komarova, UIC associate professor in the department of pharmacology and regenerative medicine at the College of Medicine
Photo Credit: Komarova

A new compound developed at the University of Illinois Chicago could potentially offer an alternative to injections for the millions of people who suffer from an eye condition that causes blindness.

Wet age-related macular degeneration causes vision loss due to the uncontrolled growth and leakage of blood vessels in the back of the eye. A new paper in Cell Reports Medicine led by UIC researcher Yulia Komarova finds that a small-molecule inhibitor can reverse damage from AMD and promote regenerative and healing processes. 

The drug can also be delivered via eyedrops — an improvement over current treatments for AMD, which require repeated injections into the eye. 

“The idea was to develop something that can be more patient-friendly and doesn’t require a visit to the doctor’s office,” said Komarova, associate professor of pharmacology at the College of Medicine. 

“Anti-tangle” molecule could aid search for new dementia treatments, say scientists

Scientists at Bath have found a way of blocking the protein tangles that are associated with dementia diseases
Photo Credit: NCI

Scientists have identified a molecule that can prevent tangling of a brain protein that is linked to diseases such as Parkinson’s. The findings may provide insights into new ways of treating or diagnosing the early stages of dementia.

Alpha-synuclein, a protein found in brain cells, is commonly associated with neurodegenerative diseases such as Parkinson's, a debilitating neurological disorder affecting millions worldwide.

Like all proteins, it is made up of a long strand of molecules called amino acids. When it’s made, this strand folds in on itself to form a complex but precise 3D shape, made up of sub-structures and loops.

In healthy individuals, alpha-synuclein interacts with cell membranes where it plays a role in how brain cells (neurons) communicate with each other, but as a person ages, the 3D shape of the protein can malformed, or “misfolded”, causing it to start sticking together to form toxic clumps in the brain.

Over time these clumps continue to stack, forming fibers that can interfere with the protein’s normal role, eventually killing brain cells, contributing to the development of Parkinson's and related dementia diseases.

Pharmacy researcher develops intervention for metabolic diseases like diabetes, stroke and heart disease

Photo Credit: Michal Jarmoluk

An investigator with the University of Kansas School of Pharmacy has filed an invention disclosure, part of a provisional patent application with the United States Patent and Trademark Office, for a treatment that could apply to heart disease, stroke and a host of other human diseases related to metabolism.

Liqin Zhao, KU associate professor of pharmacology & toxicology and investigator at the Life Span Institute2, has researched the human ApoE gene for years. A major focus of her work centers on how the ApoE2 variant — one of three major isoforms of ApoE gene — might protect people from Alzheimer’s disease3.

Now, based upon a discovery made during her Alzheimer’s-disease work, Zhao is patenting a way to leverage rhApoE2 to regulate blood lipids. Lipids, like fats and oils, are building materials of life at the cellular level that also are tied to heart disease and other metabolic diseases.

“In essence, we found that rhApoE2 significantly lowered blood levels of a number of ceramides,” Zhao said. “Moreover, rhApoE2 increased blood levels of a variety of ‘good triglycerides’ — triglycerides that contain health-promoting, long-chain polyunsaturated fatty acids such as alpha-linolenic acid, EPA and DHA, and lowered levels of ‘bad triglycerides,’ or triglycerides that contain saturated or monosaturated fatty acids that can impose a cardiovascular risk.”