Osaka Metropolitan University researchers developed a new protocol for selective and highly sensitive detection, discovering five types of 2-oxo-imidazole-containing dipeptides(2-oxo-IDPs) using mass spectrometry. The 2-oxo-IDPs, present in living organisms, exhibit very high antioxidant activity, and were found to be abundant in meat including, beef, pork, and chicken. CREDIT Hideshi Ihara, Osaka Metropolitan University
Imidazole dipeptides (IDPs), which are abundant in meat and fish, are substances produced in the bodies of various animals, including humans, and have been reported to be effective in relieving fatigue and preventing dementia. However, the physiological mechanism by which IDPs exhibit these activities had not been determined previously.
A research team, led by Professor Hideshi Ihara from the Osaka Metropolitan University Graduate School of Science, was the first to discover 2-oxo-imidazole-containing dipeptides (2-oxo-IDPs)—which have one more oxygen atom than normal IDPs—and found that they are the most common variety of IDPs derivatives in the body. The researchers also found that they have remarkably high antioxidant activity.
In their study, the researchers established a method for selective and highly sensitive detection of five types of 2-oxo-IDPs using mass spectrometry, which enables quantitative detection of trace 2-oxo-IDPs in living organisms. Using this method, they revealed for the first time that beef, pork, chicken, and other meats contain antioxidants, not only IDPs but a variety of 2-oxo-IDPs. Their findings were published in Antioxidants.
“We hope that this research method, which enables advanced analysis of 2-oxo-IDPs, will be applied to basic biology and medicine, agriculture, and pharmacy, where it will help improve peoples’ health and prevent diseases,” concluded Professor Ihara.
Results of a new study led by Roberto Araya, a Canadian neuroscientist, biophysicist and researcher at the CHU Sainte-Justine Research Centre, in Montreal, show that in Fragile X syndrome (FXS), the most common cause of autism, sensory signals from the outside world are integrated differently, causing them to be underrepresented by cortical pyramidal neurons in the brain.
This phenomenon could provide important clues to the underlying cause of the symptoms of this syndrome. The research team’s work not only provides insight into the mechanism at the cellular level, but also opens the door to new targets for therapeutic strategies.
The study was published on January 3 in the prestigious journal Proceedings of the National Academy of Sciences.
Autism is characterized by a wide range of symptoms that may stem from differences in brain development. With advanced imaging tools and the genetic manipulation of neurons, the team of researchers at the CHU Sainte-Justine Research Center was able to observe the functioning of individual neurons – specifically pyramidal neurons of cortical layer 5 – one of the main information output neurons of the cortex (the thin layer of tissue found on the surface of the brain).
The researchers found a difference in how sensory signals are processed in these neurons.
“Previous work has suggested that FXS and autism spectrum disorders are characterized by a hyperexcitable cortex, which is considered to be the main contributor to the hypersensitivity to sensory stimuli observed in autistic individuals,” said Araya, also a professor in the Department of Neurosciences at Université de Montréal.
“To our surprise, our experimental results challenge this generalized view that there is a global hypersensitivity in the neocortex associated with FXS. They show that the integration of sensory signals in cortical neurons is underrepresented in a murine model of FXS,” added Diana E. Michell, first co-author of the study.
A protein, FMRP, that is absent in the brains of people with FXS modulates the activity of a type of potassium channel in the brain. According to the research group’s work, it is the absence of this protein that alters the way sensory inputs are combined, causing them to be underrepresented by the signals coming out of the cortical pyramidal neurons in the brain.
Soledad Miranda-Rottmann, also first co-author of the study, attempted to rectify the situation with genetic and molecular biology techniques. “Even in the absence of the FMRP protein, which has several functions in the brain, we were able to demonstrate how the representation of sensory signals can be restored in cortical neurons by reducing the expression of a single molecule,” she said.
“This finding opens the door to new strategies to offer support to those with FXS and possibly other autism spectrum disorders to correctly perceive sensory signals from the outside world at the level of pyramidal neurons in the cortex,” concluded Araya.
“Even if the over-representation of internal brain signals causing hyperactivity is not addressed, the correct representation of sensory signals may be sufficient to allow better processing of signals from the outside world and of learning that is better suited to decision making and engagement in action.”
UVA Health neuroscientists have discovered a potential way to disrupt the chronic inflammation responsible for multiple sclerosis.
UVA’s new study identifies a vital contributor to the hyperactive autoimmune response and neuroinflammation that are the hallmarks of MS. Blocking this lynchpin in a research model of MS alleviated the harmful inflammation, giving researchers a prime target in their efforts to develop new treatments for multiple sclerosis and other autoimmune diseases.
The research was conducted by Andrea Merchak, a doctoral candidate in neuroscience, and her colleagues in the lab of Alban Gaultier, PhD, of the University of Virginia School of Medicine’s Department of Neuroscience and its Center for Brain Immunology and Glia (BIG).
“We are approaching the search for multiple sclerosis therapeutics from a new direction,” Merchak said. “By modulating the microbiome [the collection of microorganisms that naturally live inside us], we are making inroads in understanding how the immune response can end up out of control in autoimmunity. We can use this information to find early interventions.”
Inflammation in Multiple Sclerosis
Multiple sclerosis affects nearly a million Americans. Symptoms can include muscle spasms, stiffness, weakness, difficulty moving, depression, pain and more. There is no cure, so treatments focus on helping patients manage their symptoms, control flareups and slow disease progression.
Scientists have struggled to understand the causes of MS, but recent research suggests a vital role for the gut microbiome. UVA’s new findings bolster that, determining that an immune system controller found in “barrier tissues” such as the intestine plays a vital role in the disease. The researchers found that this regulator can reprogram the gut microbiome to promote harmful, chronic inflammation.
Gaultier and his collaborators blocked the activity of the regulator, called “aryl hydrocarbon receptor,” in immune cells called T cells and found that doing so dramatically affected the production of bile acids and other metabolites in the microbiomes of lab mice. With this receptor out of commission, inflammation decreased and the mice recovered.
The findings suggest that doctors may one day be able to take a similar approach to interrupt the harmful inflammation in people with MS, though that will take much more research. Before that can happen, scientists will need a much better understanding of the interactions between the immune system and the microbiome, the UVA researchers say.
Ultimately, UVA’s new research lays an important foundation for future efforts to target the microbiome to reduce the inflammation responsible for multiple sclerosis and other autoimmune diseases.
“Due to the complexity of the gut flora, probiotics are difficult to use clinically. This receptor can easily be targeted with medications, so we may have found a more reliable route to promote a healthy gut microbiome,” Merchak said. “Ultimately, fine-tuning the immune response using the microbiome could save patients from dealing with the harsh side effects of immunosuppressant drugs.”
This microscope image of the brain region called the hippocampus shows the protein targeted by cannabis-derived CBD, GPR55 (red), and brain cells (blue) that send their extensions out to form the layers seen in the image. The interconnected nature of the hippocampus makes it a significant site for the initiation and spread of seizures. Tsien et al, Courtesy of Cell Press
A study reveals a previously unknown way in which cannabidiol (CBD), a substance found in cannabis, reduces seizures in many treatment-resistant forms of pediatric epilepsy.
Led by researchers at NYU Grossman School of Medicine, the new study found that CBD blocked signals carried by a molecule called lysophosphatidylinositol (LPI). Found in brain cells called neurons, LPI is thought to amplify nerve signals as part of normal function but can be hijacked by disease to promote seizures.
Published online February 13 in Neuron, the work confirmed a previous finding that CBD blocks the ability of LPI to amplify nerve signals in a brain region called the hippocampus. The current findings argue for the first time that LPI also weakens signals that counter seizures, further explaining the value of CBD treatment.
“Our results deepen the field’s understanding of a central seizure-inducing mechanism, with many implications for the pursuit of new treatment approaches,” said corresponding author Richard W. Tsien, chair of the Department of Physiology and Neuroscience at NYU Langone Health.
“The study also clarified, not just how CBD counters seizures, but more broadly, how circuits are balanced in the brain,” added Tsien. “Related imbalances are present in autism and schizophrenia so that the paper may have a broader impact.”
Disease-Causing Loop
The study results build on how each neuron “fires” to send an electrical pulse down an extension of itself until it reaches a synapse, the gap that connects it to the next cell in a neuronal pathway. When it reaches the cell’s end before the synapse, the pulse triggers the release of compounds called neurotransmitters that float across the gap to affect the next cell in line. Upon crossing, such signals either encourage the cell to fire (excitation), or apply the brakes on firing (inhibition). Balance between the two are essential to brain function; too much excitation promotes seizures.
The new study looked at several rodent models to explore mechanisms behind seizures, often by measuring information-carrying electrical current flows with fine-tipped electrodes. Other experiments looked at the effect of LPI by genetically removing its main signaling partner, or by measuring the release of LPI following seizures.
The tests confirmed past findings that LPI influences nerve signals by binding to a protein called G-coupled receptor 55 (GPR55), on neuron cell surfaces. This LPI-GPR55 presynaptic interaction was found to cause the release of calcium ions within the cell, which encouraged cells to release glutamate, the main excitatory neurotransmitter. Further, when LPI activated GPR55 on the other side of the synapse, it weakened inhibition, by decreasing the supply and proper arrangement of proteins necessary for inhibition. Collectively, this creates a “dangerous” two-pronged mechanism to increase excitability, say the authors.
The research team found that either genetically engineering mice to lack GPR55, or treating mice with plant-derived CBD prior to seizure-inducing stimuli, blocked LPI-mediated effects on both excitatory and inhibitory synaptic transmission. While prior studies had implicated GPR55 as a seizure-reducing target of CBD, the current work provided a more detailed, proposed mechanism of action.
Purple vegetables and tubers have antidiabetic properties
The red, purple and blue pigments in fruits, vegetables, and tubers called anthocyanins can reduce the risk of diabetes by affecting energy metabolism, gut microbiota, and inflammation. A new review article comparing the research results shows that anthocyanins’ beneficial effect on type 2 diabetes is increased if the anthocyanin is acylated, meaning that an acyl group is added to the sugar moieties of anthocyanin.
A significant amount of acylated anthocyanins can be found in purple potatoes, purple sweet potatoes, radishes, purple carrots and red cabbages, whereas bilberries and mulberries contain mostly nonacylated anthocyanins. Acylated anthocyanins are poorly absorbed in digestion, but they have probiotic properties and reduce the risk of diabetes more efficiently than nonacylated anthocyanins.
“The studies have shown that, in addition to changing physical and chemical properties, the acylation affects how the anthocyanins are absorbed and metabolised,” says Postdoctoral Researcher Kang Chen at Food Sciences Unit, University of Turku, Finland.
The acylated anthocyanins are more effective antioxidants than the nonacylated anthocyanins, and they can also improve the intestinal barrier that enables the absorption of necessary nutrients. Furthermore, the acylated anthocyanins maintain gut microbiota homeostasis, suppress pro-inflammatory pathways, and modulate glucose and lipid metabolisms.
“The plant’s genotype defines what kind of anthocyanins they produce. In general, purple vegetables contain many acylated anthocyanins. Also, purple potatoes, especially the Finnish variety called ‘Synkeä Sakari’, is abundant in acylated anthocyanins,” says Chen.
Acylated anthocyanins travel through our bodies from the upper gastrointestinal tract to the colon where they are metabolised by the gut microbiota. Glucose transporters are involved in anthocyanin absorption, but different glucose transporters are responsible for the absorption of acylated and nonacylated anthocyanins. The acylated and nonacylated anthocyanins also have different impacts on the enzymes involved in metabolism.
“The latest research has shown that the acylated and nonacylated anthocyanins can impact type 2 diabetes in different ways,” Chen summarises.
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