Metformin works by lowering glucose production in the liver, reducing blood sugar levels that, in turn, improve the body’s response to insulin. But scientists have also noted that metformin possesses anti-inflammatory properties, though the basis for this activity was not known.

In a study published online June 8, 2021 in the journal Immunity, a multi-institution team led by researchers at University of California San Diego School of Medicine identified the molecular mechanism for the anti-inflammatory activity of metformin and, in mouse studies, found that metformin prevents pulmonary or lung inflammation in animals infected with SARS-CoV-2, the virus that causes COVID-19.

Over the past year, several retrospective clinical studies had reported that metformin use by diabetic and obese patients prior to hospital admission for COVID-19 correlated to reduced severity and mortality. Both diabetes and obesity are recognized risk factors for COVID-19, and are linked to more severe outcomes. Notably, other drugs used to control blood sugar levels do not appear to produce a similar effect.

But while these clinical studies suggested metformin’s anti-inflammatory activity, rather than lowering of blood glucose, could be responsible for reduced COVID-19 severity and mortality, none of the studies offered an explanation or prompted large, randomized clinical trials needed for obtaining conclusive answers.

“The clinical studies were plagued by confounders that made conclusions hard to reach. There was some skepticism in their findings,” said corresponding study author Michael Karin, PhD, Distinguished Professor of Pharmacology and Pathology and Ben and Wanda Hildyard Chair for Mitochondrial and Metabolic Diseases at UC San Diego School of Medicine. “And because metformin is an out-of-patent, low-cost drug, there is little impetus to conduct large-scale trials, which are quite expensive.”

Karin, with co-senior author Elsa Sanchez-Lopez, PhD, an assistant professor at the Department of Orthopedic Surgery, postdoctoral fellow Hongxu Xian, PhD, and others, turned their focus to a mouse model of acute respiratory distress syndrome (ARDS), a life-threatening condition in which fluids leak into the lungs, making breathing difficult and restricting oxygen supply to essential organs.

ARDS is triggered by trauma and by bacterial or viral infections. It is a frequent cause of death in patients hospitalized with COVID-19. The researchers found that metformin administered to mice prior to or after exposure to bacterial endotoxin, a surrogate for bacterial pneumonia, resulted in the inhibition of ARDS onset and lessening of its symptoms. Metformin also produced a marked reduction in mortality in endotoxin-challenged mice and inhibited IL-1? production and inflammasome assembly within alveolar macrophages — immune cells found in the lungs.

IL-1?, along with IL-6, are small proteins called cytokines that cause inflammation as an early immune response. Their amounts are often highly elevated in persons infected by SARS-CoV-2, creating “cytokine storms” in which the body starts attacking its own cells and tissues. They are signs of an acute immune response gone awry.

Production of IL-1? depends on a large protein complex called the inflammasome, whose presence in lung tissue is found to be highly increased in deceased COVID-19 patients, a discovery made by co-authors Moshe Arditi, MD, and Timothy R. Crother, PhD, at Cedars-Sinai Medical Center in Los Angeles.

Working with colleagues at The Scripps Research Institute, the UC San Diego researchers confirmed that metformin inhibited inflammasome activation and prevented SARS-CoV-2-induced pulmonary inflammation in mice.

Cell culture studies using macrophages revealed the underlying mechanism by which metformin exerts its anti-inflammatory activity: reduced production of ATP by mitochondria. ATP is the molecule that mitochondria use to store chemical energy for cells. It is essential to all cellular processes, but blunted ATP production in liver cells is responsible for the glucose lowering effect of metformin.

Lower amounts of ATP in macrophages led to inhibition of mitochondrial DNA synthesis, which had been previously identified by Karin’s lab as a critical step in NLRP3 inflammasome activation. Subsequent research found that clearing away damaged mitochondria reduced NLRP3 inflammasome activity and reduced inflammation.

UC San Diego researchers also confirmed that specific interference with mitochondrial DNA synthesis in macrophages caused by removal of the enzyme CMPK2 (cytidine monophosphate kinase 2) inhibited IL-1? (but not IL-6) production and prevented ARDS onset.

“These experiments strongly suggest that improved delivery of metformin or CMPK2 inhibitors into lung macrophages can provide new treatments for severe COVID-19 and other forms of ARDS,” said Sanchez Lopez.

The authors said the findings suggest metformin may have therapeutic potential for treating a variety of neurodegenerative and cardiovascular diseases in which NLRP3 inflammasome activation is a factor. “Inhibition of inflammasome activation may also account for the poorly explained anti-aging effect of metformin,” said Karin.

Co-authors include: Alexandra Rundberg Nilsson, Raphaella Gatchalian and Sarah Kang, UC San Diego; Warren G. Tourtellote and Yi Zhang, Cedars-Sinai; German R. Aleman-Muench, Gavin Lewis, Weixuan Chen and Pejman Soroosh, Janssen Research & Development; and Melissa Luevanos, Dorit Trudler, Stuart A. Lipton, John Teijaro, and Juan Carlos de la Torre, The Scripps Research Institute.

Disclosure: Michael Karin is founder of Elgia Pharmaceuticals, where he is also an inventor and serves on the advisory board. Karin also receives research support from Gossamer Bio, Janssen Pharmaceuticals and Merck.

“Saliva as a sample type for COVID-19 testing was a game changer in our fight against the pandemic. It helped us with increased compliance from the population for testing along with decreased exposure risk to the healthcare workers during the collection process,” said lead investigator Ravindra Kolhe, MD, PhD, Department of Pathology, Medical College of Georgia, Augusta University, Augusta, GA, USA.

The study included samples from a hospital and nursing home as well as from a drive-through testing site. In the first phase (protocol U), 240 matched NPS and saliva sample pairs were tested prospectively for SARS-CoV-2 RNA by RT-PCR. In the second phase of the study (SalivaAll), 189 matched pairs, including 85 that had been previously evaluated with protocol U, were processed in an Omni bead mill homogenizer before RT-PCR testing. An additional study was conducted with samples with both protocol U and SalivaAll to determine if bead homogenization would affect the clinical sensitivity in NPS samples. Finally, a five-sample pooling strategy was evaluated. Twenty positive pools containing one positive and four negative samples were processed with the Omni bead homogenizer before pooling for SARS-CoV-2 RT-PCR testing and compared to controls.

In Phase I, 28.3 percent of samples tested positive for SARS-CoV-2 from either NPS, saliva, or both. The detection rate was lower in saliva compared to NPS (50.0 percent vs. 89.7 percent). In Phase II, 50.2 percent of samples tested positive for SARS-CoV-2 from either saliva, NPS, or both. The detection rate was higher in saliva compared to NPS samples (97.8 percent vs. 78.9 percent). Of the 85 saliva samples tested with both protocols, the detection rate was 100 percent for samples tested with SalivaAll and 36.7 percent with protocol U.

Dr. Kolhe observed that the underlying issues associated with lower sensitivity of saliva to RT-PCR testing could be attributed to the gel-like consistency of saliva samples, which made it difficult to accurately pipet samples into extraction plates for nucleic acid extraction. Adding the homogenization step rendered the saliva samples to uniform viscosity and consistency, making it easier to pipet for the downstream assay.

Dr. Kolhe and his colleagues also successfully validated saliva samples in the five-sample pooling strategy. The pooled testing results demonstrated a positive agreement of 95 percent, and the negative agreement was found to be 100 percent. Pooled testing will be critical for SARS-CoV-2 mass surveillance as schools reopen, travel and tourism resume, and people return to offices.

“Monitoring SARS-CoV-2 will remain a public health need,” Dr. Kolhe said. “The use of a non-invasive collection method and easily accessible sample such as saliva will enhance screening and surveillance activities and bypass the need for sterile swabs, expensive transport media, and exposure risk, and even the need for skilled healthcare workers for sample collection.”

Story Source:

Materials provided by Elsevier. Note: Content may be edited for style and length.

While plastic products are omnipresent indoors, plastic waste and broken bits now litter the outdoors, too. The smallest of these — microplastics less than 5 mm in size — are hard to pick up and remove. In addition, they can adsorb heavy metals and pollutants, potentially harming humans or animals if accidentally consumed. So, previous researchers proposed a low-energy way to get rid of plastics in the environment by using catalysts that use sunlight to produce highly reactive compounds that break down these types of polymers. However, getting the catalysts and tiny plastic pieces in contact with each other is challenging and usually requires pretreatments or bulky mechanical stirrers, which aren’t easily scaled-up. Martin Pumera and colleagues wanted to create a sunlight-propelled catalyst that moves toward and latches onto microparticles and dismantles them.

To transform a catalytic material into light-driven microrobots, the researchers made star-shaped particles of bismuth vanadate and then evenly coated the 4-8 ?m-wide structures with magnetic iron oxide. The microrobots could swim down a maze of channels and interact with microplastic pieces along their entire lengths. The researchers found that under visible light, microrobots strongly glommed on to four common types of plastics. The team then illuminated pieces of the four plastics covered with the microrobot catalyst for seven days in a dilute hydrogen peroxide solution. They observed that the plastic lost 3% of its weight and that the surface texture for all types changed from smooth to pitted, and small molecules and components of the plastics were found in the left-over solution. The researchers say the self-propelled microrobot catalysts pave the way toward systems that can capture and degrade microplastics in hard-to-reach-locations.

Story Source:

Materials provided by American Chemical Society. Note: Content may be edited for style and length.

The electrification of heavy-duty vehicles and aircraft requires batteries with more energy density. A team of researchers believes a paradigm shift is necessary to make a significant impact in battery technology for these industries. This shift would take advantage of the anionic reduction-oxidation mechanism in lithium-rich cathodes. Findings published in Nature mark the first time direct observation of this anionic redox reaction has been observed in a lithium-rich battery material.

Collaborating institutions included Carnegie Mellon University, Northeastern University, Lappeenranta-Lahti University of Technology (LUT) in Finland, and institutions in Japan including Gunma University, Japan Synchrotron Radiation Research Institute (JASRI), Yokohama National University, Kyoto University, and Ritsumeikan University.

Lithium-rich oxides are promising cathode material classes because they have been shown to have much higher storage capacity. But, there is an ‘AND problem’ that battery materials must satisfy — the material must be capable of fast charging, be stable to extreme temperatures, and cycle reliably for thousands of cycles. Scientists need a clear understanding of how these oxides work at the atomic level, and how their underlying electrochemical mechanisms play a role, to address this.

Normal Li-ion batteries work by cationic redox, when a metal ion changes its oxidation state as lithium is inserted or removed. Within this insertion framework, only one lithium-ion can be stored per metal-ion. Lithium-rich cathodes, however, can store much more. Researchers attribute this to the anionic redox mechanism — in this case, oxygen redox. This is the mechanism credited with the high capacity of the materials, nearly doubling the energy storage compared to conventional cathodes. Although this redox mechanism has emerged as the leading contender among battery technologies, it signifies a pivot in materials chemistry research.

The team set out to provide conclusive evidence for the redox mechanism utilizing Compton scattering, the phenomenon by which a photon deviates from a straight trajectory after interacting with a particle (usually an electron). The researchers performed sophisticated theoretical and experimental studies at SPring-8, the world’s largest third-generation synchrotron radiation facility which is operated by JASRI.

Synchrotron radiation consists of the narrow, powerful beams of electromagnetic radiation that are produced when electron beams are accelerated to (almost) the speed of light and are forced to travel in a curved path by a magnetic field. Compton scattering becomes visible.

The researchers observed how the electronic orbital that lies at the heart of the reversible and stable anionic redox activity can be imaged and visualized, and its character and symmetry determined. This scientific first can be game-changing for future battery technology.

While previous research has proposed alternative explanations of the anionic redox mechanism, it could not provide a clear image of the quantum mechanical electronic orbitals associated with redox reactions because this cannot be measured by standard experiments.

The research team had an “A ha!” moment when they first saw the agreement in redox character between theory and experimental results. “We realized that our analysis could image the oxygen states that are responsible for the redox mechanism, which is something fundamentally important for battery research,” explained Hasnain Hafiz, lead author of the study who carried out this work during his time as a postdoctoral research associate at Carnegie Mellon.

“We have conclusive evidence in support of the anionic redox mechanism in a lithium-rich battery material,” said Venkat Viswanathan, associate professor of mechanical engineering at Carnegie Mellon. “Our study provides a clear picture of the workings of a lithium-rich battery at the atomic scale and suggests pathways for designing next-generation cathodes to enable electric aviation. The design for high-energy density cathodes represents the next-frontier for batteries.”

Story Source:

Materials provided by College of Engineering, Carnegie Mellon University. Original written by Lisa Kulick. Note: Content may be edited for style and length.

In a phase 2 clinical trial, the researchers demonstrated that symptoms of depression improve rapidly following treatment with inhaled nitrous oxide. Further, they reported the benefits can last for several weeks.

The findings are published June 9 in the journal Science Translational Medicine.

“A large percentage of patients don’t respond to standard antidepressant therapies — the patients in this study had failed an average of 4.5 antidepressant trials — and it’s very important to find therapies to help these patients,” said Charles R. Conway, MD, a professor of psychiatry at Washington University and one of the study’s senior investigators. “That we saw rapid improvements in many such patients in the study suggests nitrous oxide may help people with really severe, resistant depression.”

Conway, and the study’s other co-senior investigator, Peter Nagele, MD, professor and chair of the Department of Anesthesia & Critical Care at the University of Chicago, and who previously had an appointment in the Department of Anesthesiology at Washington University School of Medicine, have been studying the potential of nitrous oxide as an antidepressant for the past decade.

Standard antidepressant drugs affect norepinephrine and serotonin receptors in the brain, yet they often take weeks to improve a person’s symptoms. Nitrous oxide, however, interacts with different receptors on brain cells — NMDA glutamate receptors — and tends to improve symptoms within hours when effective.

“Our primary goals in this study were twofold: to determine whether a lower dose of nitrous oxide might be just as effective as doses we’d tested previously — and it was for most patients — and we also wanted to see how long the relief lasted,” Nagele said. “In a proof-of-concept study several years ago, we assessed patients for 24 hours. In this study, we continued to assess them for two weeks, and most continued to feel better.”

The study involved 24 patients. Each one received three treatments about one month apart. In one session, patients breathed gas for an hour that was half nitrous oxide, half oxygen. In a second treatment, the same patients breathed a solution that was 25% nitrous oxide. A third treatment, the placebo, involved breathing only oxygen, with no nitrous oxide.

“You can’t really get a better comparison group than when you compare a person to himself or herself,” Nagele said. “Serving as your own control is ideal. The alternative is studying the effects of a drug in two similar groups of people in which you either get one treatment or another. But the problem with that is that you need much larger numbers of patients before you really can draw conclusions.”

The primary conclusions in this study were that nitrous oxide — both at 25% and in a 50-50 mixture with oxygen — improved depression in 17 of those study participants. The differences between a 25% mix and a 50% mix mainly involved how long the antidepressant effects lasted. Whereas the 50% dosage had greater antidepressant effects two weeks after treatment, the 25% dose was associated with fewer adverse events, the most common of which was feeling nauseated.

“Some patients experience side effects — it’s a small subset, but it’s very real — and the main one is that some people get nauseated,” Conway said. “But in our study, only when people got the 50% dose did they experience nausea. When they received 25% nitrous oxide, no one developed nausea. And that lower dose was just about as effective as the higher dose at relieving depression.”

Of the 20 people who completed all of the study’s treatments and follow-up exams, 55% (11 of 20) experienced a significant improvement in at least half of their depressive symptoms, and 40% (eight of 20) were considered to be in remission — meaning they no longer were clinically depressed — after breathing a nitrous oxide solution for one hour.

Over the course of the entire study, having received both dose levels of nitrous oxide and the placebo treatment, some 85% (17 of 20) of the study participants experienced a significant enough improvement that their clinical classification moved at least one category — for example, from severe to moderate depression.

Many of those in the study also took antidepressant drugs — medications that, for the most part, had failed to relieve their depression — but they were allowed to continue using those drugs while they participated in the study.

As many as one-third of those who take antidepressants don’t improve. Nitrous oxide and ketamine, another anesthetic drug that interacts with NMDA glutamate receptors, recently have shown promise in those with treatment-resistant depression. Conway and Nagele believe both drugs may represent breakthroughs for people with treatment-resistant depression, but they believe nitrous oxide may have some practical advantages.

“One potential advantage to nitrous oxide, compared with ketamine, is that because it’s a volatile gas, its anesthetic effects subside very quickly,” Conway said. “It’s similar to what happens in a dentist’s office when people drive themselves home after getting a tooth pulled. After treatment with ketamine, patients need to be observed for two hours following treatment to make sure they are OK, and then they have to get someone else to drive them.”

Nagele and Conway said it is important for scientists soon to conduct a large, multicenter study comparing the effects of ketamine and nitrous oxide to placebo.

This work was supported by a NARSAD award from the Brain & Behavior Research Foundation and the Taylor Family Institute for Innovative Psychiatric Research at Washington University School of Medicine.

Results show that having trouble falling asleep in 2002 was associated with cognitive impairment in 2016. Specifically, more frequent trouble falling asleep predicted poorer episodic memory, executive function, language, processing speed, and visuospatial performance. Further analysis found that associations between sleep initiation and later cognition were partially explained by both depressive symptoms and vascular diseases in 2014 for all domains except episodic memory, which was only partially explained by depressive symptoms.

“While there is growing evidence for a link between insomnia and cognitive impairment in older adults, it has been difficult to interpret the nature of these associations given how differently both insomnia and cognitive impairment can present across individuals,” said lead author Afsara Zaheed, a graduate student in clinical science within the department of psychology at the University of Michigan. “By investigating associations between specific insomnia complaints and cognition over time using strong measures of cognitive ability, we hoped to gain additional clarity on whether and how these different sleep problems may lead to poor cognitive outcomes.”

Insomnia involves difficulty falling asleep or staying asleep, or regularly waking up earlier than desired, despite allowing enough time in bed for sleep. Daytime symptoms include fatigue or sleepiness; feeling dissatisfied with sleep; having trouble concentrating; feeling depressed, anxious, or irritable; and having low motivation or energy.

The study analyzed data from the Health and Retirement Study, which involved 2,496 adults who were at least 51 years of age. In 2002 they reported the frequency of experiencing insomnia symptoms. In 2016 the participants’ cognition was assessed as part of the Harmonized Cognitive Assessment Protocol and operationalized with a comprehensive neuropsychological battery tapping episodic memory, executive function, language, visuoconstruction, and processing speed. Analyses controlled for sociodemographics and baseline global cognitive performance.

“These results are important given the lack of currently available treatments for late-life cognitive disorders, like Alzheimer’s disease and other dementias,” said Zaheed. “Sleep health and sleep behaviors are often modifiable. These results suggest that regular screening for insomnia symptoms may help with tracking and identifying people with trouble falling asleep in mid-to-late life who might be at risk for developing cognitive impairments later in life. Additional intervention research is needed to determine whether intervening on insomnia symptoms can help prevent or slow the progression of cognitive impairments in later life.”

Story Source:

Materials provided by American Academy of Sleep Medicine. Note: Content may be edited for style and length.