How excessive salt consumption is linked to cognitive disorders and high blood pressure

Japanese researchers identify two key physiological systems involved in high-salt-induced hypertension and emotional/cognitive impairment

Peer-Reviewed Publication

FUJITA HEALTH UNIVERSITY

Dementia is defined as the loss of cognitive functioning—including thinking, remembering, and reasoning—and is very prevalent in Japan. Currently, the treatment satisfaction for dementia is among the lowest and no drug therapy is available to cure the disease. With a rapidly ageing global population, the development of dementia preventive and therapeutic drugs is critical.

Cognitive impairment has been linked to the consumption of excess table salt, a ubiquitous food seasoning. High salt (HS) intake can also lead to hypertension. To prevent adverse health outcomes, the World Health Organization recommends limiting salt intake to less than 5 g per day. The involvement of angiotensin II (Ang II)—a hormone that plays a key role in regulating blood pressure and fluid balance—and its receptor “AT1”, as well as that of the physiologically important lipid molecule prostaglandin E2 (PGE2 and its receptor “EP1” in hypertension and neurotoxicity is well-recognized. However, the involvement of these systems in HS-mediated hypertension and emotional/cognitive impairment remains elusive.

To this end, a recent study published in the British Journal of Pharmacology thoroughly evaluated the aspects of HS-mediated hypertension and emotional/cognitive impairment. The study was performed by a team of collaborating researchers from Japan, and has shown how hypertension, mediated by the crosstalk between Ang II-AT1 and PGE2-EP1 causes emotional and cognitive dysfunction.

Author Hisayoshi Kubota from Fujita Health University’s Graduate School of Health Science comments, “Excessive salt intake is considered a risk factor for hypertension, cognitive dysfunction, and dementia. However, studies focusing on the interaction between the peripheral and central nervous system have not sufficiently investigated this association.”

According to the published data, the addition of excessive phosphates to the protein “tau” is primarily responsible for this emotional and cognitive consequences. The findings are particularly noteworthy because tau is a key protein of the Alzheimer's disease.

The team first loaded laboratory mice with an HS solution (2% NaCl in drinking water) for 12 weeks and monitored their blood pressure. “The effects of HS intake on emotional/cognitive function and tau phosphorylation were also examined in two key areas of the mouse brain—the prefrontal cortex  and the hippocampus,” explains Prof. Mouri. Next, they also studied the involvement of the Ang II-AT1 and PGE2-EP1 systems in the HS-induced hypertension and neuronal/behavioral impairment.

The results were remarkable and encouraging:  The brains of the experimental mice had several biochemical alternations. At the molecular level, besides the addition of phosphates to tau, the researchers also observed a decrease in the phosphate groups linked to a key enzyme called “CaMKII”—a protein involved in brain signaling. Moreover, changes in the levels of “PSD95”—a protein that plays a vital role in the organization and function of brain synapses (connection between brain cells)—were also evident. Interestingly, the biochemical changes were reversed after the administration of the antihypertensive drug “losartan.” A similar reversal was observed after knocking out the EP1 gene.         

Overall, these findings suggest that angiotensin II-AT1 and prostaglandin E2-EP1 systems could be novel therapeutic targets for hypertension-induced dementia.

Prof. Mouri concludes by saying, “This study is of particular social and economic importance because the annual social cost of dementia treatment in Japan is surging like never before”. Therefore, developing preventive and therapeutic drugs for dementia seems critical for Japan’s rapidly aging population.”

 

***

 

Reference

 

DOI: https://doi.org/10.1111/bph.16093

 

About Fujita Health University
Fujita Health University is a private university situated in Toyoake, Aichi, Japan. It was founded in 1964 and houses one of the largest teaching university hospitals in Japan in terms of the number of beds. With over 900 faculty members, the university is committed to providing various academic opportunities to students internationally. Fujita Health University has been ranked eighth among all universities and second among all private universities in Japan in the 2020 Times Higher Education (THE) World University Rankings. THE University Impact Rankings 2019 visualized university initiatives for sustainable development goals (SDGs). For the “good health and well-being” SDG, Fujita Health University was ranked second among all universities and number one among private universities in Japan. The university became the first Japanese university to host the "THE Asia Universities Summit" in June 2021. The university’s founding philosophy is “Our creativity for the people (DOKUSOU-ICHIRI),” which reflects the belief that, as with the university’s alumni and alumnae, current students also unlock their future by leveraging their creativity.

Website: https://www.fujita-hu.ac.jp/en/index.html

 

About Professor Akihiro Mouri from Fujita Health University
Dr. Akihiro Mouri serves as a Professor at Fujita Health University’s School of Health Sciences. He has over 100 well-cited publications and multiple patents to his credit. Prof. Mouri’s research group primarily focuses on epidemiological and genetic findings in humans and creates animal models of psychiatric and neurological disorders to explore various pathological and pathogenic mechanisms. The group conducts behavioral and neurochemical experiments to develop new therapeutic agents, phytochemicals, and diagnostic biomarkers. Prof. Mouri has won several distinguished awards for his outstanding research contributions.  

 

Funding information
This work was supported by Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (17H04252, 20K07931, and 20K16679) and by the Japan Science and Technology Agency (JST) FOREST Program (JPMJFR215H). In addition, this work was supported by a grant from the Education and Research Facility of Animal Models for Human Diseases at Fujita Health University, a research grant from the Smoking Research Foundation, and the Takeda Science Foundation.

---

JOURNAL

British Journal of Pharmacology

DOI

10.1111/bph.16093 

METHOD OF RESEARCH

Experimental study

SUBJECT OF RESEARCH

Animals

ARTICLE TITLE

High salt induces cognitive impairment via the interaction of angiotensin II-AT1 and prostaglandin E2-EP1 systems

Groundbreaking study reveals sympatric sloths have developed diverse strategies to adapt to their surroundings, enhancing their chances of survival in the face of environmental fluctuations

Peer-Reviewed Publication

PEERJ

 

IMAGE: SLOTH view more 

CREDIT: THE SLOTH CONSERVATION FOUNDATION

Researchers have shed light on the activity patterns and behavioral adaptations of two sympatric sloth species, Bradypus variegatus and Choloepus hoffmanni. This groundbreaking study, conducted in the lowland rainforests of the Caribbean coast of Costa Rica, offers valuable insights into the ecological dynamics of sloths and their ability to thrive in diverse environmental conditions. 

Faced with the challenge of studying the elusive nature of sloths, Dr. Rebecca Cliffe Founder and Executive Director of The Sloth Conservation Foundation and colleagues employed micro data loggers to continuously monitor the behavior of both three-toed sloths (Bradypus) and two-toed sloths (Choloepus) over extended periods, ranging from days to weeks. By doing so, they were able to explore the influence of fluctuating environmental conditions on sloth activity and its correlation with their unique low-energy lifestyle. 

The findings, published in PeerJ Life & Environment, indicate that both Bradypus and Choloepus sloths exhibit cathemeral activity patterns, characterized by irregular and variable periods of activity throughout the 24-hour cycle. This behavior allows sloths to take advantage of favorable environmental conditions while minimizing the risk of predation. 

One of the key revelations of the study was the substantial variability observed in activity levels both between individuals and within individuals. This flexibility suggests that sloths have developed diverse strategies to adapt to their surroundings, enhancing their chances of survival in the face of environmental fluctuations.

Contrary to expectations, daily temperature did not significantly influence sloth activity. However, Bradypus sloths exhibited increased nocturnal activity on colder nights and the nights following colder days, indicating a potential correlation between temperature variations and their behavior. 

Dr. Cliffe, the lead scientist on the project, emphasized the importance of this research for conservation efforts and understanding the impact of anthropogenic activities and climate change on tropical ecosystems in South and Central America. With the vulnerability of these ecosystems on the rise, unraveling the behavioral ecology of wild sloths becomes crucial for developing effective conservation measures. 

The cryptic nature of sloths has traditionally made long-term observational research challenging. However, the use of micro data loggers has provided unprecedented insights into their behavioral patterns and adaptations. This breakthrough paves the way for further studies and encourages the scientific community to explore the behavioral ecology of other elusive species with innovative approaches. 

The results of this study not only contribute to our understanding of sloth ecology but also highlight the importance of preserving and protecting tropical rainforests and their unique inhabitants. As the global climate changes and human activities continue to impact these fragile ecosystems, the knowledge gained from this research will aid in the development of strategies to safeguard their biodiversity and promote sustainable practices.

 

---

JOURNAL

PeerJ

DOI

10.7717/peerj.15430 

SUBJECT OF RESEARCH

Animals

ARTICLE TITLE

The behaviour and activity budgets of two sympatric sloths; Bradypus variegatus and Choloepus hoffmanni

ARTICLE PUBLICATION DATE

29-May-2023

KRISS ushers in era of green hydrogen

KRISS demonstrated carrier transport mechanism of photoanode with protective film to optimize green hydrogen production, The development can contribute to the realization of carbon-free green hydrogen and artificial photosynthesis

Peer-Reviewed Publication

NATIONAL RESEARCH COUNCIL OF SCIENCE & TECHNOLOGY

 

IMAGE: HIGHLIGHTING A STUDY ON A MECHANISM OF PHOTOELECTROCHEMICAL WATER SPLITTING ON SI PHOTOANODE PASSIVATED WITH TIOX LAYER WITH VARIOUS DEFECT DENSITY FROM THE LABORATORIES OF DR. ANSOON KIM AT KOREA RESEARCH INSTITUTE OF STANDARDS & SCIENCE (KRISS). view more 

CREDIT: KOREA RESEARCH INSTITUTE OF STANDARDS AND SCIENCE (KRISS)

Hydrogen has been gaining attention as a clean and efficient energy source. However, is hydrogen really environmentally friendly? Most hydrogen commonly used now is “grey hydrogen” derived from fossil fuels. Since its production process accompanies generation of green house gas, it can be said that grey hydrogen is not environmentally friendly in the strict sense. The era of “green hydrogen” without carbon emissions has not yet begun.

The Korea Research Institute of Standards and Science (KRISS, President Hyun-min Park) has demonstrated the key to the longevous and efficient photoanode with protective film, which is used to produce hydrogen via water splitting using solar energy. This is expected to bring forward the era of environment-friendly “green hydrogen.”

Green hydrogen is produced without carbon emissions by using renewable energy sources. A representative method to produce green hydrogen is photoelectrochemical water splitting using photoanode which is directly immersed in electrolyte and can absorb sunlight. As a result, the photoanode directly splits contacting water into hydrogen and oxygen using absorbed solar energy. However, as the photoanode is in direct contact with electrolyte, it is prone to surface corrosion. Surface protective coatings were deposited on the surface to prevent surface corrosion.

Typically, oxide materials such as titanium dioxide (TiO2) are used as protective films for photoanodes. Although oxide materials are poor conductors of electricity, their conductivity can be modulated when oxygen defects, serving as a channel for charge transport, are formed. The key to extending the lifespan of photoanodes is to develop a protective film durable enough to prevent electrode corrosion and capable of maintaining optimal electrical conductivity.

KRISS has developed the world’s first technology for systematically modulating the levels of oxygen defects in a titanium dioxide (TiO2) protective film of photoanode to maximize hydrogen production efficiency. In order to explore the role of oxygen defects in the charge transfer mechanism, the research team determined the optimal levels of defects that maximize photoanode lifespan and hydrogen production by using X-ray photoelectron spectroscopy and electrochemical analysis

Unlike past studies that relied on spontaneously formed oxygen defects in the protective film during manufacturing process, this research proposes a direct method of production that controls the levels of oxygen defects, enabling mass production. According to the experimental results, the photoanode without a protective film showed a rapid degradation in lifespan within an hour, causing the hydrogen production efficiency to fall below 20 % compared to the initial state. On the other hand, the photoanode with optimized protective film maintained a hydrogen production efficiency of over 85 % even after 100 hours.

This achievement has the potential to enhance the efficiency and lifespan of photoanodes and can be applied to other clean technologies that rely on photoanodes. The artificial photosynthesis technology that captures carbon dioxide and converts it to a chemical energy source using solar energy is one of the examples.

Dr. Ansoon Kim, a principal researcher at KRISS Interdisciplinary Materials Measurement Institute, said, “This approach can improve photoanode lifespan by approximately 10 times and significantly contribute to the commercialization of green hydrogen.”

 

KRISS plans to conduct further research to unveil the optimal levels of oxygen defects and underlying principles that maximize the lifespan of photoanodes.

For the efficient PEC water splitting, it is crucial to balance two factors by systematically controlling the defect density in TiOx passivation layer of n-Si photoanode, which are (1) accessible density of state for carrier transportation in forbidden gap and (2) favorable interface energetics.

CREDIT

Korea Research Institute of Standards and Science (KRISS)

As the national metrology institute (NMI) of Korea founded in 1975, KRISS (Korea Research Institute of Standards and Science) has developed measurement standards technology and played a pivotal role in upgrading Korea’s main industries to the global level.

Supported by mainly KRISS and partly the Technology Innovation Program of NRF (National Research Foundation of Korea), the study was published on the back cover of Journal of Materials Chemistry A (IF=14.511), an international journal in the field of materials chemistry, on 28th February 2023.

---

JOURNAL

Journal of Materials Chemistry A

DOI

10.1039/D2TA07082K 

ARTICLE TITLE

Role of defect density in TiOx protective layer of n-Si photoanode for efficient photoelectrochemical water splitting

X-ray emissions from black hole jets vary unexpectedly, challenging leading model of particle acceleration

Peer-Reviewed Publication

UNIVERSITY OF MARYLAND BALTIMORE COUNTY

 

IMAGE: EILEEN MEYER IS THE LEAD AUTHOR ON A NEW SURPRISING STUDY IN NATURE ASTRONOMY. THE PAPER APPEARS TO RULE OUT A LEADING THEORY FOR HOW BLACK HOLE JETS FORM X-RAYS. BLACK HOLE JETS ARE KNOWN TO EMIT X-RAYS, BUT HOW THEY ACCELERATE PARTICLES TO THIS HIGH-ENERGY STATE IS STILL A MYSTERY. ONE MODEL OF HOW JETS GENERATE X-RAYS EXPECTS THE JETS’ X-RAY EMISSIONS TO REMAIN STABLE OVER LONG TIME SCALES. HOWEVER, THE NEW PAPER FOUND THAT THE X-RAY EMISSIONS OF A STATISTICALLY SIGNIFICANT NUMBER OF JETS VARIED OVER JUST A FEW YEARS. THE FINDINGS OPEN THE DOOR TO REIMAGINING HOW PARTICLE ACCELERATION WORKS. “HOPEFULLY THIS WILL BE A REAL CALL TO THE THEORISTS,” MEYER SAYS, “TO BASICALLY TAKE A LOOK AT THIS RESULT AND COME UP WITH JET MODELS THAT ARE CONSISTENT WITH WHAT WE’RE FINDING.” view more 

CREDIT: MARLAYNA DEMOND/UMBC

Researchers discovered only relatively recently that black hole jets emit x-rays, and how the jets accelerate particles to this high-energy state is still a mystery. Surprising new findings in Nature Astronomy appear to rule out one leading theory, opening the door to reimagining how particle acceleration works in the jets—and possibly also elsewhere in the universe.

One leading model of how jets generate x-rays expects the jets’ x-ray emissions to remain stable over long time scales (millions of years). However, the new paper found that the x-ray emissions of a statistically significant number of jets varied over just a few years.

“One of the reasons we’re excited about the variability is that there are two main models for how x-rays are produced in these jets, and they’re completely different,” explains lead author Eileen Meyer, an astronomer at University of Maryland, Baltimore County. “One model invokes very low-energy electrons and one has very high-energy electrons. And one of those models is completely incompatible with any kind of variability.”

For the study, the authors analyzed archival data from the Chandra X-ray Observatory, the highest-resolution x-ray observatory available. The research team looked at nearly all of the black hole jets for which Chandra had multiple observations, which amounted to 155 unique regions within 53 jets.

Discovering relatively frequent variability on such short time scales “is revolutionary in the context of these jets, because that was not expected at all,” Meyer says.

Rethinking particle acceleration

In addition to assuming stability in x-ray emissions over time, the simplest theory for how jets generate x-rays assumes particle acceleration occurs at the center of the galaxy in the black hole “engine” that drives the jet. However, the new study found rapid changes in x-ray emissions all along the length of the jets. That suggests particle acceleration is occurring all along the jet, at vast distances from the jet’s origin at the black hole.       

“There are theories out there for how this could work, but a lot of what we’ve been working with is now clearly incompatible with our observations,” Meyer says.

Interestingly, the results also hinted that jets closer to Earth had more variability than those much farther away. The latter are so far away, that by the time the light coming from them reaches the telescope, it is like looking back in time. It makes sense to Meyer that older jets would have less variability. Earlier in the universe’s history, the universe was smaller and ambient radiation was greater, which researchers believe could lead to greater stability of x-rays in the jets.

Critical collaboration

Despite Chandra’s outstanding imaging resolution, the data set posed significant challenges. Chandra observed some of the pockets of variability with only a handful of x-ray photons. And the variability in x-ray production in a given jet was typically tens of percent or so. To avoid unintentionally counting randomness as real variability, Meyer collaborated with statisticians at the University of Toronto and the Imperial College of London.

“Pulling this result out of the data was almost like a miracle, because the observations were not designed to detect it,” Meyer says. The team’s analysis suggests that between 30 and 100 percent of the jets in the study showed variability over short time scales. “While we would like better constraints,” she says, “the variability is notably not zero.”

The new findings poke significant holes in one of the major theories for x-ray production in black hole jets, and Meyer hopes the paper spurs future work. “Hopefully this will be a real call to the theorists,” she says, “to basically take a look at this result and come up with jet models that are consistent with what we’re finding.”

---

JOURNAL

Nature Astronomy

DOI

10.1038/s41550-023-01983-1 

METHOD OF RESEARCH

Data/statistical analysis

SUBJECT OF RESEARCH

Not applicable

ARTICLE TITLE

Variability of extragalactic X-ray jets on kiloparsec scales

ARTICLE PUBLICATION DATE

29-May-2023

Medical "microrobots" could one day treat bladder disease, other human illnesses

Peer-Reviewed Publication

UNIVERSITY OF COLORADO AT BOULDER

 

IMAGE: MEDICAL "MICROROBOTS" COULD ONE DAY DELIVER PRESCRIPTION DRUGS THROUGHOUT THE HUMAN BODY. view more 

CREDIT: SHIELDS LAB

A team of engineers at the University of Colorado Boulder has designed a new class of tiny, self-propelled robots that can zip through liquid at incredible speeds—and may one day even deliver prescription drugs to hard-to-reach places inside the human body.

The researchers describe their mini healthcare providers in a paper published last month in the journal Small.

“Imagine if microrobots could perform certain tasks in the body, such as non-invasive surgeries,” said Jin Lee, lead author of the study and a postdoctoral researcher in the Department of Chemical and Biological Engineering. “Instead of cutting into the patient, we can simply introduce the robots to the body through a pill or an injection, and they would perform the procedure themselves.”

Lee and his colleagues aren’t there yet, but the new research is big step forward for tiny robots. 

The group’s microrobots are really small. Each one measures only 20 micrometers wide, several times smaller than the width of a human hair. They’re also really fast, capable of traveling at speeds of about 3 millimeters per second, or roughly 9,000 times their own length per minute. That’s many times faster than a cheetah in relative terms. 

They have a lot of potential, too. In the new study, the group deployed fleets of these machines to transport doses of dexamethasone, a common steroid medication, to the bladders of lab mice. The results suggest that microrobots may be a useful tool for treating bladder diseases and other illnesses in people.

“Microscale robots have garnered a lot of excitement in scientific circles, but what makes them interesting to us is that we can design them to perform useful tasks in the body,” said C. Wyatt Shields, a co-author of the new study and assistant professor of chemical and biological engineering.

Fantastic Voyage

If that sounds like something ripped from science fiction, that’s because it is. In the classic film Fantastic Voyage, a group of adventurers travels via a shrunken-down submarine into the body of a man in a coma.

“The movie was released in 1966. Today, we are living in an era of micrometer- and nanometer-scale robots,” Lee said.

He imagines that, just like in the movie, microrobots could swirl through a person’s blood stream, seeking out targeted areas to treat for various ailments.

The team makes its microrobots out of materials called biocompatible polymers using a technology similar to 3D printing. The machines look a bit like small rockets and come complete with three tiny fins. They also include a little something extra: Each of the robots carries a small bubble of trapped air, similar to what happens when you dunk a glass upside-down in water. If you expose the machines to an acoustic field, like the kind used in ultrasound, the bubbles will begin to vibrate wildly, pushing water away and shooting the robots forward. 

Other CU Boulder co-authors of the new study include Nick Bottenus, assistant professor of mechanical engineering; Ankur Gupta, assistant professor of chemical and biological engineering; and engineering graduate students Ritu Raj, Cooper Thome, Nicole Day and Payton Martinez.

To take their microrobots for a test drive, the researchers set their sights on a common problem for humans: bladder disease.

Microrobot seen under a scanning electron microscope.

CREDIT

Shields Lab

Bringing relief

Interstitial cystitis, also known as painful bladder syndrome, affects millions of Americans and, as its name suggests, can cause severe pelvic pain. Treating the disease can be equally uncomfortable. Often, patients have to come into a clinic several times over a period of weeks where a doctor injects a harsh solution of dexamethasone into the bladder through a catheter. 

Lee believes that microrobots may be able to provide some relief.

In laboratory experiments, the researchers fabricated schools of microrobots encapsulating high concentrations of dexamethasone. They then introduced thousands of those bots into the bladders of lab mice. The result was a real-life Fantastic Voyage: The microrobots dispersed through the organs before sticking onto the bladder walls, which would likely make them difficult to pee out.

Once there, the machines slowly released their dexamethasone over the course of about two days. Such a steady flow of medicine could allow patients to receive more drugs over a longer span of time, Lee said, improving outcomes for patients. 

He added that the team has a lot of work to do before microrobots can travel through real human bodies. For a start, the group wants to make the machines fully biodegradable so that they would eventually dissolve in the body. 

“If we can make these particles work in the bladder,” Lee said, “then we can achieve a more sustained drug release, and maybe patients wouldn’t have to come into the clinic as often.”

---

JOURNAL

Small

DOI

10.1002/smll.202300409 

ARTICLE TITLE

Bubble-Based Microrobots with Rapid Circular Motions for Epithelial Pinning and Drug Delivery

Use of AI: Placebo effect increases risk-taking

Peer-Reviewed Publication

LUDWIG-MAXIMILIANS-UNIVERSITÄT MÜNCHEN

Human augmentation technologies refer to technological aids that enhance human abilities. They include things like exoskeletons, but also augmented reality headsets. A study at the Chair of Human-Centered Ubiquitous Media at LMU has now shown that users have high expectations of the effects of these technologies. As soon as they believe that AI is enhancing their cognitive abilities, they increase their risk-taking. And they do this independently of whether the AI is actually assisting them.

 

“The hype around AI applications affects the expectations of users. This can lead to riskier behavior,” says Steeven Villa, doctoral researcher at the Chair of Human-Centered Ubiquitous Media and lead author of the study.

 

Ruling out placebo effects

 

In the study, participants were informed they would be assisted by an AI application that augments their cognitive abilities during a virtual card game. In reality, there was no such AI enhancement. Nevertheless, the participants exhibited higher risk-taking as soon as they believed they were benefiting from AI.

 

The study points to the possible existence of a placebo effect in technical applications of this nature, akin to the well-established placebo effect for medication. “At a time when people are increasingly interacting with intelligent systems, it’s important to understand a possible placebo effect so that we can build systems that offer genuine support,” says Albrecht Schmidt, Professor of Computer Science at LMU. The researchers recommend assessing the actual benefit of AI applications before releasing them, taking possible placebo effects into account. In addition, they advise tech companies to involve users and their expectations to a greater extent in the development process.

---

JOURNAL

Computers in Human Behavior

DOI

10.1016/j.chb.2023.107787 

ARTICLE TITLE

The placebo effect of human augmentation: Anticipating cognitive augmentation increases risk-taking behavior

New research finds dramatic increase in illegal ketamine seized by authorities, sparking concern about potential dangers of rising recreational use

Peer-Reviewed Publication

NYU LANGONE HEALTH / NYU GROSSMAN SCHOOL OF MEDICINE

A new analysis led by NYU Grossman School of Medicine and the National Drug Early Warning System (NDEWS) at the University of Florida found a 349 percent rise in seizures of illicit ketamine by drug enforcement throughout the United States from 2017 through 2022.

The study findings suggest that rising use of ketamine, a short-acting dissociative anesthetic commonly prescribed off-label to treat chronic pain and depression, can increase the likelihood that people who use recreationally or who use inadvertently may encounter an adulterated and potentially harmful version of the drug. The study publishes online May 24 in JAMA Psychiatry.

“This dramatic rise in ketamine seizures by law enforcement may be indicative of rising nonmedical and recreational use,” said study author Joseph J. Palamar, PhD, MPH, an associate professor in the Department of Population Health at NYU Langone Health and a researcher in the Center for Drug Use and HIV/HCV Research at NYU School of Global Public Health. “Unlike illegal ketamine years ago, most illegally obtained ketamine today is not pharmaceutical grade and is sold in powder form which may increase the risk that it contains other drugs such as fentanyl.” He further added, “Unintentional exposure to fentanyl can lead to overdose.”

During the COVID-19 pandemic, the U.S. government eased prescribing practices for controlled substances so that more patients could use telemedicine and retain access to vital medications. While many patients benefited, the loosened restrictions also gave rise to an industry of pop-up clinics prescribing ketamine online and off label for a variety of mental health conditions, with little oversight of side effects.

“Though the risk of overdose from ketamine alone is low, some people who use the drug report negative dissociative side effects, such as feeling dizzy or nauseous.” In addition, Palamar, who has published extensively on the use of “club drugs” such as ketamine, MDMA (commonly known as ecstasy), and gamma-hydroxybutyric acid (GHB), among others, warns that people who use ketamine recreationally should be concerned about more than the drug’s dissociative side effects.

The fear, according to Palamar, is that any illegal powder in the U.S. may be contaminated with fentanyl, just as it is now turning up in heroin and cocaine. He also warns that media and medical promotion of prescription ketamine in recent years is fueling black-market use and availability.  

In addition to describing the rapid rise in ketamine seizures from 2017 to 2022, Palamar and colleagues found that the total weight of ketamine seized in the U.S. increased from 127 pounds in 2017 to about 1,550 pounds in 2022, an increase of more than 1,100 percent. The highest numbers of seizures were reported in Tennessee, Florida, and California, but it is unclear if these states have the highest usage since the location of seizures does not necessarily reflect the final destination of the drug shipments.

Palamar hopes these latest findings will better inform prevention and harm reduction strategies to protect the public from increased exposure to illegal ketamine and possible adverse effects from use. NDEWS continues to monitor the use and effects of ketamine and many novel drugs to alert the public about alarming trends in a timely manner.

In addition to Palamar, co-investigators include senior author Linda B. Cottler, PhD, MPH, at the University of Florida in Gainesville; Samuel T. Wilkinson, at Yale University in New Haven, Conn.; Thomas H. Carr, at the University of Baltimore in Maryland; and Caroline Rutherford, at Columbia University in New York City.

Research reported in this publication was supported by the National Institute on Drug Abuse of the National Institutes of Health under grant numbers U01DA051126 and R01DA044207. The content of this research is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

 

---

JOURNAL

JAMA Psychiatry

METHOD OF RESEARCH

Observational study

SUBJECT OF RESEARCH

Not applicable

ARTICLE TITLE

Trends in Illicit Ketamine Seizures in the U.S. from 2017 to 2022

ARTICLE PUBLICATION DATE

24-May-2023

A look into the heart of cellular waste disposal

Researchers reveal how a nanomachine takes care of cleaning up inside the cell

Peer-Reviewed Publication

MAX-PLANCK-GESELLSCHAFT

 

IMAGE: FLUORESCENT LIPIDS SHOW HOW THE NANOMACHINE ACCELERATES LIPID TRANSFER WHEN NECESSARY. view more 

CREDIT: ANH NGUYEN / MAX PLANCK INSTITUTE FOR MULTIDISCIPLINARY SCIENCES & POUYA HOSNANI / UNIVERSITY MEDICAL CENTRE GÖTTINGEN

To prevent our body’s cells from overflowing with garbage and to keep them healthy, the waste inside them is constantly being disposed of. This cleaning process is called autophagy. Scientists have now, for the first time, rebuilt the complex nanomachine in the laboratory that starts this process – and it works quite differently from other cellular machines. The researchers’ new insights could help open up new approaches for the treatment of cancer, immune disorders, and neurodegenerative diseases in the future, and possibly even delay aging.

Have you ever put off cleaning the house or decluttering the overflowing basement? Living cells cannot afford this procrastination when it comes to clearing the decks. Tiny garbage chutes are constantly active there to capture worn-out proteins, faulty cell components, or defective organelles. These garbage chutes, called autophagosomes, pick out the discarded components before they accumulate in the cell and cause damage. The cellular waste is then passed on to the cell’s own recycling machinery, the lysosome, where it is digested and recycled. Thus, building blocks for new cellular components are quickly available again. The autophagy process, literally self-eating, thus also helps cells to survive stress or periods of starvation.

Autophagy also serves another important purpose. It renders harmless viruses and bacteria that successfully bypass the immune system’s defenses and reach the cell plasma. The consequences are correspondingly fatal if the autophagy process is faulty, too slow, or too fast. Neurodegenerative diseases and cancer can develop or disorders of the immune system may occur. Aging processes also appear to accelerate.

“Autophagy is a highly complex process involving many different proteins and protein complexes. We know many of them, but there are still fundamental gaps in our knowledge,” reports Alex Faesen, research group leader at the Max Planck Institute for Multidisciplinary Sciences in Göttingen. “How do the protein components work together? How is the process of autophagy started and stopped? When and where is the autophagosome assembled? That is what we want to find out.”

Nanomachine at work

His team has now succeeded, for the first time, in producing all the proteins involved in the autophagy process in the laboratory and observing them directly as the autophagosomes assemble. This was a mammoth task for the entire research group, taking several years, for which they cooperated with the teams led by Björn Stork from the University of Düsseldorf and Michael Meinecke, previously at the University Medical Center Göttingen now at the Heidelberg University Biochemistry Center. “There were many challenges,” recalls Faesen. In the first step, the scientists produced each individual protein component in the laboratory. The standard approach is to use bacteria that are genetically reprogrammed to produce the desired protein in large quantities. “But protein production with bacteria did not work for any of our proteins,” the Göttingen biochemist says. Instead, the researchers switched to insect cells as molecular helpers – the breakthrough.

In the next step, the team brought the individual protein complexes together. “The complexes self-assembled into a protein supercomplex, the autophagy initiation complex. In fact, autophagy involves a sophisticated cellular nanomachine – and it works quite differently than previously thought,” the group leader says.

To make autophagosomes, the autophagy initiation complex first creates a junction between a particular structure of the cell, the endoplasmic reticulum, and the autophagosome that forms. Under stress or in times of starvation, such as during endurance sports, this occurs within just a few minutes. “From this point on, there is no turning back: The waste disposal is assembled and collects the cellular waste,” explains Anh Nguyen, one of the two first authors of the study. Co-first author Fancesca Lugarini adds, “Via the contact site, fat-like molecules called lipids are transported to a precursor stage of autophagosomes, where they are incorporated.” These grow and, in the process, enclose the cell material to be disposed of – the finished mini-organelle is formed. Within barely 20 minutes of its formation, the autophagosome is already delivering its waste to the lysosome by fusing with it.

Protein origami for “on” and “off”

But what starts the assembly of the autophagy machine, what starts it and what stops it? The researchers did not find a molecular “on” and “off” switch as in other molecular machines. Instead, the switch uses a highly unusual behavior of proteins: metamorphosis. ” Certain molecules, called ATG13 and ATG101, have the ability to fold in different 3D structures, thereby changing its ability to bind to proteins in the machine. “This protein metamorphosis also gives the go-ahead for the assembly of the autophagy initiation complex at the right time and in the right place,” says Faesen, describing the special features of the nanomachine. Without metamorphosis, the initiation machine does not assemble.

The scientists hope that the new findings will advance the development of future drugs that can be used to treat diseases that are based on a faulty autophagy process.

---

JOURNAL

Molecular Cell

DOI

10.1016/j.molcel.2023.04.026 

METHOD OF RESEARCH

Experimental study

SUBJECT OF RESEARCH

Cells

ARTICLE TITLE

Metamorphic proteins at the basis of human autophagy initiation and lipid transfer.