Zinc-binding is vital for regulating pH levels in the brain

Researchers in Oslo, Norway, have discovered that Zinc-binding plays a vital role in the sensing and regulation of pH in the human brain. The findings come as one of the first studies that directly link Zinc-binding with bicarbonate transporters.

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The Morth Group, led by J. Preben Morth, recently published the findings in Scientific Reports. The group is based at the Centre for Molecular Medicine Norway and studies the structure and function of membrane proteins, and their interaction with lipids in the biological membrane.  When we inhale, oxygen is distributed via our red blood cells to every living cell of our body. Human cells use oxygen to produce Adenosine triphosphate (ATP) – the molecule that fuels vital processes in the cells, such as maintaining the electrical potential across the membranes of the cells that allow us to think and feel. In other words, we wouldn’t “work” very efficiently without this process.

ATP generation is directly linked to the citric acid cycle also known as the Krebs cycle, which leads to the complete breakdown of nutrients. This process ultimately generates carbon dioxide (CO2) as the final waste product, which is expelled when we exhale. However, before we can emit the excess CO2, this critical molecule is involved in one of the most important biological functions in our body: It regulates pH in our cells. This process is incredibly important; if the pH in and around our cells is lower than 6.8 or higher than 7.8, then we are in danger of dying due to cell death and tissue damage.

An example of how essential pH levels are to our health is demonstrated by the fact that pH levels in blood from the umbilical cord are always tested in newborn babies. A low pH value is correlated with a low oxygen supply during birth, which can lead to severe brain damage. When in water, CO2 forms bicarbonate (HCO3-) and is transported by specific transport proteins across the cell membrane. How these transport molecules sense what the pH value is inside the cell is still an open question. However, the work performed by Alvadia et al.describes that the transition metal, Zinc, likely interacts with the proteins that facilitate the transport of HCO3– through the membrane.

This Zinc-binding, therefore, plays a vital role in the sensing and regulation of cellular pH, in particular in the transporters found in neurons of the human brain. This is one of the first studies that directly associates Zinc binding with bicarbonate transporters. Preben Morth, Group Leader at NCMM comments, “This is a basic research project, and at this stage, it is difficult to predict what the medical consequences will be. However, it is likely that Zinc may play a key role in the regulation of pH in the brain and therefore has implications for brain function and health.”

The results have recently been published in Scientific Reports from the Nature publishing group. The research group behind the discovery is M.Sc. Carolina Alvadia Dr. Kaare Bjerregaard-Andersen, Dr. Theis Sommer, M.Sc. Michele Montrasio, Asc. Prof. Helle Damkier, Prof. Christian Aalkjaer, Asc. and Nordic EMBL Partnership principal investigator, J. Preben Morth.

Adapted from: Carolina M. Alvadia, Theis Sommer, Kaare Bjerregaard-Andersen, Helle Hasager Damkier, Michele Montrasio, Christian Aalkjaer, J. Preben Morth. The crystal structure of the regulatory domain of the human sodium-driven chloride/bicarbonate exchangerScientific Reports, 2017; 7 (1) DOI: 10.1038/s41598-017-12409-0

Nutrition Nugget

Pre-Pack Your Meals And Snacks! It’s easy to get caught up with work and meetings during the day, leaving a quick fast-food lunch your only option. Spare yourself the empty calories and money by packing your lunch. Whether you meal prep at the beginning of the week or have leftovers from last night’s healthy dinner, you’re guaranteed a healthy option for lunch. Save even more money when you pack your own snacks to avoid any unnecessary trips to the vending machine!

Inspirational Nugget

Don’t forget to Thank God for keeping you safe through the night and every time you awaken to see a beautiful new day.

 

A dietary supplement dampens the brain hyperexcitability seen in seizures or epilepsy

Researchers have found that inducing a biochemical alteration in brain proteins via the dietary supplement glucosamine was able to rapidly dampen that pathological hyperexcitability in rat and mouse models. These results represent a potentially novel therapeutic target for the treatment of seizure disorders, and they show the need to better understand the physiology underlying these neural and brain circuit changes.

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Seizure disorders, including epilepsy, are associated with pathological hyperexcitability in brain neurons. Unfortunately, there are limited available treatments that can prevent this hyperexcitability. However, the *University of Alabama at Birmingham researchers have found that inducing a biochemical alteration in brain proteins via the dietary supplement glucosamine was able to rapidly dampen that pathological hyperexcitability in rat and mouse models.

 

These results represent a potentially novel therapeutic target for the treatment of seizure disorders, and they show the need to better understand the physiology underlying these neural and brain circuit changes. Proteins are the workhorses of living cells, and their activities are tightly and rapidly regulated in responses to changing conditions. Adding or removing a phosphoryl group of proteins is a well-known regulator of many proteins, and it is estimated that human proteins may have as many as 230,000 sites for phosphorylation. A lesser-known regulation comes from the addition or removal of N-acetylglucosamine to proteins, which is usually controlled by glucose, the primary fuel for neurons. Several years ago, neuroscientist Lori McMahon, Ph.D., professor of cell, developmental and integrative biology at UAB, found out from her colleague John Chatham, D.Phil., a UAB professor of pathology and a cardiac physiologist, that brain cells had the second-highest amounts of proteins with N-acetylglucosamine, or O-GlcNAcylation, in the body.

At the time, very little was known about how O-GlcNAcylation might affect brain function, so McMahon and Chatham started working together. In 2014, McMahon and Chatham, in a study led by graduate student Erica Taylor and colleagues, reported that acute increases in protein O-GlcNAcylation caused long-term synaptic depression, a reduction in neuronal synaptic strength, in the hippocampus of the brain. This was the first time acute changes in O-GlcNAcylation of neuronal proteins were shown to directly change synaptic function. Since neural excitability in the hippocampus is a crucial feature of seizures and epilepsy, they hypothesized that acutely increasing protein O-GlcNAcylation might dampen the pathological hyperexcitability associated with these brain disorders.

That turned out to be the case, as reported in the Journal of Neuroscience study, “Acute increases in protein O-GlcNAcylation dampen epileptiform activity in the hippocampus.” The study was led by corresponding author McMahon and first author Luke Stewart, a doctoral student in the Neuroscience Theme of the Graduate Biomedical Sciences Program. Stewart is co-mentored by McMahon and Chatham. “Our findings support the conclusion that protein O-GlcNAcylation is a regulator of neuronal excitability, and it represents a promising target for further research on seizure disorder therapeutics,” they wrote in their research significance statement. The researchers caution that the mechanism underlying the dampening is likely to be complicated.

Research details

Glucose, the primary fuel for neurons, also controls the levels of protein O-GlcNAcylation on proteins. However, high levels of the dietary supplement glucosamine, or an inhibitor of the enzyme that removes O-GlcNAcylation, leads to rapid increases in O-GlcNAc levels. In experiments with hippocampal brain slices treated to induce stable and ongoing hyperexcitability, UAB researchers found that an acute rise in protein O-GlcNAcylation significantly decreased the sudden bursts of electrical activity known as epileptiform activity in area CA1 of the hippocampus. An increased protein O-GlcNAcylation in normal cells also protected against a later induction of drug-induced hyperexcitability.

The effects were seen in slices treated with both glucosamine and an inhibitor of the enzyme that removes O-GlcNAc groups. They also found that treatment with glucosamine alone for as short a time as 10 minutes was able to dampen ongoing drug-induced hyperexcitability. In common with the long-term synaptic depression provoked by increased O-GlcNAcylation, the dampening of hyperexcitability required the GluA2 subunit of the AMPA receptor, which is a glutamate-gated ion channel responsible for fast synaptic transmission in the brain. This finding suggested a conserved mechanism for the two changes provoked by increased O-GlcNAcylation — synaptic depression and dampening of hyperexcitability.

The researchers also found that the spontaneous firing of pyramidal neurons in another region of hippocampus, area CA3, was reduced by increased O-GlcNAcylation in normal brain slices and in slices with drug-induced hyperexcitability. This reduction in spontaneous firing of CA3 pyramidal neurons likely contributes to decreased hyperexcitability in area CA1 since the CA3 neurons directly excite those in CA1. Similar to the findings for brain slices, mice that were treated to increase O-GlcNAcylation before getting drug-induced hyperexcitability had fewer of the brain activity spikes associated with epilepsy that are called interictal spikes. Several drug-induced hyperexcitable mice had convulsive seizures during the experiments, this occurred in both the increased O-GlcNAcylation mice and the control mice. Brain activity during the seizures differed between these two groups: The peak power of the brain activity for the mice with increased O-GlcNAcylation occurred at a lower frequency, as compared with the control mice.

*I am very proud to say UA (though UA Tuscaloosa) is my graduate program home!

Adapted from: Luke T. Stewart, Anas U. Khan, Kai Wang, Diana Pizarro, Sandipan Pati, Susan C. Buckingham, Michelle L. Olsen, John C. Chatham, Lori L. McMahon. Acute Increases in Protein O-GlcNAcylation Dampen Epileptiform Activity in HippocampusThe Journal of Neuroscience, 2017; 37 (34): 8207 DOI: 10.1523/JNEUROSCI.0173-16.2017

Nutrition Daily Nugget…..and a bit of wine! 

Watch out for added sugars! They add extra calories but no helpful nutrients. Sugar-sweetened beverages and soft drinks are the number one source of added sugars for most of us.

AND….if you are looking for some excellent wine selections, check out Bright Cellars. The link is also on the right side of my blog for future reference.

Daily Inspiration Nugget

Never stop believing in hope. Miracles happen everyday.

 

 

Brain cells that control appetite identified for first time

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Dieting could be revolutionized, thanks to the ground-breaking discovery by the University of Warwick on the key brain cells which control our appetite. Professor Nicholas Dale in the School of Life Sciences has identified for the first time that tanycytes, cells found in part of the brain that controls energy levels, detect nutrients in food and tell the brain directly about the food we have eaten. According to the new research, tanycytes in the brain respond to amino acids found in foods, via the same receptors that sense the flavor of amino acids (“umami” taste), which are found in the taste buds of the tongue. Two amino acids that react most with tanycytes, and therefore are likely to make you feel more full, are arginine and lysine.

These amino acids are found in high concentrations in foods such as pork shoulder, beef sirloin steak, chicken, mackerel, plums, apricots, avocadoes, lentils and almonds. Therefore, eating those foods will activate the tanycytes, based on the research, and make you feel less hungry more quickly. The researchers made their discovery by adding concentrated amounts of arginine and lysine into brain cells, which were made fluorescent so that any microscopic reactions would be visible. They observed that within thirty seconds, the tanycytes detected and responded to the amino acids, releasing information to the part of the brain that controls appetite and body weight. They found that signals from amino acids are directly detected by the umami taste receptors by removing or blocking these receptors and observing that the amino acids no longer reacted with tanycytes.

Nicholas Dale, who is Ted Pridgeon Professor of Neuroscience at the University of Warwick, commented: “Amino acid levels in blood and brain following a meal are a very important signal that imparts the sensation of feeling full. Finding that tanycytes, located at the centre of the brain region that controls body weight directly sensing amino acids, has very significant implications for coming up with new ways to help people control their body weight within healthy bounds.” This major discovery opens up new possibilities for creating more effective diets, and even future treatments to suppress one’s appetite by directly activating the brain’s tanycytes, bypassing food and the digestive system. Nearly two thirds of the UK population is overweight or obese and one third of the U.S. population is obese. This excess weight elevates the risk of premature death and a range of illnesses, such as cancer, diabetes, cardiovascular disease and stroke, which greatly reduce quality of life. A new understanding of how appetite functions could curb the growing obesity crisis.

The research, ‘Amino Acid Sensing in Hypothalamic Tanycytes via Umami Taste Receptors’, will be published in Molecular Metabolism and is funded by the Biotechnology and Biological Sciences Research Council.

Adapted from: University of Warwick. (2017, September 27). Brain cells that control appetite identified for first time: Dieting could be revolutionized, thanks to the groundbreaking discovery by the University of Warwick of the key brain cells which control our appetite. ScienceDaily. Retrieved December 21, 2017 from http://www.sciencedaily.com/releases/2017/09/170927093254.htm

Nutrition Tip of the Day

Make snacks count! Be sure your snack consists of protein, whole grains and healthy fat for the trifecta that will keep you feeling fuller longer.

Daily Inspiration 

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Brain cancer growth halted by absence of protein

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The growth of certain aggressive brain tumors can be halted by cutting off their access to a signaling molecule produced by the brain’s nerve cells, according to a new study by researchers at the Stanford University School of Medicine. When the signaling molecule neuroligin-3 was absent, or when its signal was interrupted with medication, human cancers called high-grade gliomas could not spread in the brains of mice, the researchers found. The study will be was published online Sept. 20 in Nature. Graduate student Humsa Venkatesh is the study’s lead author.

“We thought that when we put glioma cells into a mouse brain that was neuroligin-3 deficient, that might decrease tumor growth to some measurable extent. What we found was really startling to us: For several months, these brain tumors simply didn’t grow,” said Michelle Monje, MD, PhD, assistant professor of neurology and senior author of the study. The findings suggest that interrupting the neuroligin-3 signal could be a helpful strategy for controlling high-grade gliomas in human patients, Monje added. High-grade gliomas are a group of deadly brain tumors that include adult glioblastoma, the brain cancer now affecting U.S. Sen. John McCain of Arizona; anaplastic oligodendroglioma; pediatric glioblastoma; and a pediatric tumor called diffuse intrinsic pontine glioma (DIPG). Five-year survival rates are 60 percent for anaplastic oligodendroglioma, around 10 percent for adult and pediatric glioblastomas and virtually nonexistent for DIPG. New treatments are urgently needed.

Hijacking the normal machinery

The new findings build on prior research published by Monje’s team in 2015. At that time, the scientists showed that neuroligin-3 fueled the growth of high-grade gliomas. This was surprising because the protein is a part of the normal machinery of neuroplasticity in a healthy brain, and it is a relatively new concept that cancer can hijack an organ’s healthy function to drive cancer growth. In the new study, Monje’s team examined mice that were genetically engineered to lack neuroligin-3. These mice have nearly normal brain function. However, when their brains were implanted with any of the forms of human high-grade glioma, the cancer cells could not proliferate. The growth stagnation persisted for several months.

“Lack of neuroligin-3 doesn’t kill the cancer cells; the cells that are there remain there, but they do not grow,” Monje said. However, 4½ months after implantation, tumors in some mice circumvented their dependency on neuroligin-3 and began to grow again, she added.

Effect specific to high-grade gliomas

The researchers also tried implanting the brains of mice lacking neuroligin-3 with human breast cancer cells. Lack of neuroligin-3 did not affect breast cancer growth, showing that the effect is specific to high-grade gliomas.The growth-stagnation effects, conserved across different classes of high-grade glioma, were unexpectedly strong. To find out why, the researchers conducted follow-up experiments that examined the cell signals involved in neuroligin-3’s role in the division of glioma cells, which demonstrated that neuroligin-3 activates multiple cancer-promoting signaling pathways and also increases the expression of genes involved in cell proliferation, promotion of malignancy, function of potassium channels and synapse function. The researchers now believe that neuroligin-3 is more than just a gatekeeper of glioma cell division, though further research is needed to clarify its exact role, Monje said.

The team also explored whether blocking neuroligin-3 has therapeutic potential for treating gliomas. Using mice with normal neuroligin-3 brain signaling and human high-grade gliomas, the researchers tested whether two inhibitors of neuroligin-3 secretion could stop the cancers’ growth. One of the inhibitors has never been tested in humans, but the other has already reached phase-2 clinical trials as a potential chemotherapy for other forms of cancer outside the brain. Both inhibitors significantly reduced glioma growth during a short-term trial, suggesting that the strategy of inhibiting neuroligin-3 secretion may help human patients.

‘Clear path forward for therapy’

“We have a really clear path forward for therapy; we are in the process of working with the company that owns the clinically characterized compound in an effort to bring it to a clinical trial for brain tumor patients,” Monje said. Inhibition of neuroligin-3 will not represent a cure for high-grade gliomas, she cautioned, since it does not kill the cancer cells. Ultimately, she hopes to combine it with other treatment strategies against the tumors. “We will have to attack these tumors from many different angles to cure them,” Monje said. However, given how devastating the tumors are, the possibility of using neuroligin-3 inhibition to slow tumor progression is a hopeful development, she added. “Any measurable extension of life and improvement of quality of life is a real win for these patients.”

Adapted from: Stanford University Medical Center. (2017, September 20). Brain cancer growth halted by absence of protein. ScienceDaily. Retrieved December 4, 2017 from http://www.sciencedaily.com/releases/2017/09/170920131658.htm

Nutrition Tip of the Day

Make healthy swaps! For instance, try mashed avocado instead of butter or use whole-wheat pastry flour in place of white, refined types.

Daily Inspiration 

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