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.

 

 

Nerves control the body’s bacterial community

 

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A central aspect of life sciences is to explore the symbiotic cohabitation of animals, plants and humans with their specific bacterial communities. Scientists refer to the full set of microorganisms living on and inside a host organism as the microbiome. Over the past years, evidence has accumulated that the composition and balance of this microbiome contributes to the organism’s health. For instance, alterations in the composition of the bacterial community are implicated in the origin of various so-called environmental diseases. However, it is still largely unknown just how the cooperation between organism and bacteria works at the molecular level and how the microbiome and body exactly act as a functional unit.

An important breakthrough in deciphering these highly complex relationships has now been achieved by a research team from Kiel University’s Zoological Institute. Using the freshwater polyp Hydra as a model organism, the Kiel-based researchers and their international colleagues investigated how the simple nervous system of these animals interacts with the microbiome. They were able to demonstrate, for the first time, that small molecules secreted by nerve cells help to regulate the composition and colonization of specific types of beneficial bacteria along the Hydra’s body column. “Up to now, neuronal factors that influence the body’s bacterial colonization were largely unknown. We have been able to prove that the nervous system plays an important regulatory role here,” emphasizes Professor Thomas Bosch, evolutionary developmental biologist and spokesperson of the Collaborative Research Centre 1182 “Origin and Function of Metaorganisms,” funded by the German Science Foundation (DFG). The scientists published their new findings in Nature Communications (September 2017).

The research team, led by Bosch, used the freshwater polyp Hydra as the model organism to elucidate the fundamental principles of nervous system structure and function. Hydra represent an evolutionary ancient branch of the animal kingdom; they have a simple body plan with a nerve net of only about 3000 neurons. Applying modern experimental technology to these organisms that, despite their simplicity, still share a large molecular similarity with the nervous systems of vertebrates, enabled identification of ancient and therefore fundamental principles of nervous system structure and function. Using this model organism, the researchers from Kiel University addressed the question of how messenger substances produced by the nervous system, known as neuropeptides, control the cooperation and communication between host and microbes. They collected cellular, molecular and genetic evidence to show that neuropeptides have antibacterial activity which affects both the composition and the spatial distribution of the colonizing microbes.

To reveal the connections between neuropeptides and bacterial communities, the Kiel-based researchers first concentrated on the development of the freshwater polyp’s nervous system, from the egg stage to an adult animal. Cnidarians develop a complete nervous system within about three weeks. During this developmental time, the bacterial communities covering the animal’s surface change radically, until a stable composition of the microbiome finally forms. Under the influence of the antimicrobial effect of the neuropeptides, the concentration of so-called Gram-positive bacteria, a subgroup of bacteria, decreases sharply over a period of roughly four weeks. At the end of the maturing process, a typical composition of the microbiome prevails, particularly dominated by Gram-negative Curvibacter bacteria. Since the neuropeptides are particularly produced in certain areas of the body only, they also control the spatial localization of the bacteria along the body column. Therefore, in the head region, for example, there is a strong concentration of antimicrobial peptides, resulting in six times fewer Curvibacter bacteria than on the tentacles.

Based on these observations, the scientists concluded that throughout the course of evolution the nervous system also participated in a controlling role for the microbiome, in addition to its sensory and motor tasks. “The findings are also important in an evolutionary context. Since the ancestors of these animals have invented the nervous system, it seems that the interaction between the nervous system and the microbiome is an ancient feature of multicellular animals. Since the simple design of Hydra has great basic and translational relevance and promises to reveal new and unexpected basic features of nervous systems, further research into the interaction between body and bacteria will therefore concentrate more on the neuronal aspects,” said Bosch, to summarize the significance of the work.

Adapted from: Kiel University. (2017, September 26). Nerves control the body’s bacterial community: Research team proves, for the first time, that there is close cooperation between the nervous system and the microbial population of the body. ScienceDaily. Retrieved December 20, 2017 from http://www.sciencedaily.com/releases/2017/09/170926105425.htm

Nutrition Tip of the Day

Keep a food diary! Most people don’t realize how much they really consume in a day. If you write it down, the amount you eat may surprise you.

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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