New study shows that fasting really does ramp up the human metabolism with verifiable beneficial effects

A study by the G0 Cell Unit and Kyoto University researchers suggests that fasting, which puts the body in “starvation mode,” leads to fuel substitution, antioxidation, increased mitochondrial activation and altered signal transduction.

Fasting may help people lose weight, but new research suggests going without food may also boost human metabolic activity, generate antioxidants, and help reverse some effects of aging.

Scientists at the Okinawa Institute of Science and Technology Graduate University (OIST) and Kyoto University identified 30 previously-unreported substances whose quantity increases during fasting and indicate a variety of health benefits.

“We have been researching aging and metabolism for many years and decided to search for unknown health effects in human fasting,” said Dr. Takayuki Teruya, first author of the paper and a technician in the OIST G0 Cell Unit, led by Prof. Mitsuhiro Yanagida. “Contrary to the original expectation, it turned out that fasting induced metabolic activation rather actively.”

The study, published January 29, 2019 in Scientific Reports, presents an analysis of whole human blood, plasma, and red blood cells drawn from four fasting individuals. The researchers monitored changing levels of metabolites — substances formed during the chemical processes that grant organisms energy and allow them to grow. The results revealed 44 metabolites, including 30 that were previously unrecognized, that increased universally among subjects between 1.5- to 60-fold within just 58 hours of fasting.

In previous research, the G0 Cell Unit identified various metabolites whose quantities decline with age, including three known as leucine, isoleucine, and ophthalmic acid. In fasting individuals, these metabolites increase in level, suggesting a mechanism by which fasting could help increase longevity.

“These are very important metabolites for maintenance of muscle and antioxidant activity, respectively,” said Teruya. “This result suggests the possibility of a rejuvenating effect by fasting, which was not known until now.”

Metabolites Give Clues to Mechanism and Health Effects

The human body tends to utilize carbohydrates for quick energy — when they’re available. When starved of carbs, the body begins looting its alternate energy stores. The act of “energy substitution” leaves a trail of evidence, namely metabolites known as butyrates, carnitines, and branched-chain amino acids. These well-known markers of energy substitution have been shown to accumulate during fasting.

But fasting appears to elicit effects far beyond energy substitution. In their comprehensive analysis of human blood, the researchers noted both established fasting markers and many more. For example, they found a global increase in substances produced by the citric acid cycle, a process by which organisms release energy stored in the chemical bonds of carbohydrates, proteins and lipids. The marked increase suggests that, during fasting, the tiny powerhouses running every cell are thrown into overdrive.

Fasting also appeared to enhance the metabolism of purine and pyrimidine, chemical substances which play key roles in gene expression and protein synthesis. The finding suggests fasting may reprogram which proteins cells build at what time, thus altering their function. The change may promote homeostasis in cells, or serve to edit their gene expression in response to environmental influences.

When metabolized, purine and pyrimidine also boost the body’s production of antioxidants. Several antioxidants, such as ergothioneine and carnosine, were found to increase significantly over the 58-hour study period. Antioxidants serve to protect cells from free radicals produced during metabolism. Products of a metabolic pathway called the “pentose phosphate pathway” also stay the harmful effects of oxidation, and were similarly seen to increase during fasting, but only in plasma.

Newfound Health Benefits of Fasting?

The authors suggest that these antioxidative effects may stand as the body’s principal response to fasting, as starvation can foster a dangerously oxidative internal environment. Their exploratory study provides the first evidence of antioxidants as a fasting marker. In addition, the study introduces the novel notion that fasting might boost production of several age-related metabolites, abundant in young people, but depleted in old.

“Recent aging studies have shown that caloric restriction and fasting have a prolonging effect on lifespan in model animals…but the detailed mechanism has remained a mystery,” said Teruya. “It might be possible to verify the anti-aging effect from various viewpoints by developing exercise programs or drugs capable of causing the metabolic reaction similar to fasting.”

The findings expand on established ideas of what fasting could do for human health. The next step would be to replicate these results in a larger study, or investigate how the metabolic changes might be triggered by other means.

“People are interested in whether human beings can enjoy the effects of prevention of metabolic diseases and prolonging life span by fasting or caloric restriction, as with model animals,” said Teruya. “Understanding the metabolic changes caused by fasting is expected to give us wisdom for maintaining health.”

Learn more: Fasting Ramps Up Human Metabolism, Study Shows

 

 

The Latest on: Fasting

via Google News

 

The Latest on: Fasting

via  Bing News

 

Seneca Valley Virus could be the next breakthrough cancer therapy

via OIST

Seneca Valley Virus sounds like the last bug you’d want to catch, but it could be the next breakthrough cancer therapy.

Now, scientists at the Okinawa Institute of Science and Technology (OIST) and the University of Otago have described exactly how the virus interacts with tumors — and why it leaves healthy tissues alone.

The study, published in the Proceedings of the National Academy of Sciences of the United States of America on October 29, 2018, provides the first detailed images of the complex Seneca Valley Virus forms with its preferred receptor. The researchers used cryo-electron microscopy to capture images of over 7000 particles and render the structure in high-resolution. They predict their results will help scientists develop the virus, and other viral drug candidates, for clinical use.

“If you have a virus that targets cancer cells and nothing else, that’s the ultimate cancer fighting tool,” said Prof. Matthias Wolf, principal investigator of the Molecular Cryo-Electron Microscopy Unit at OIST and co-senior author of the study. “I expect this study will lead to efforts to design viruses for cancer therapy.”

 

An international team of researchers at OIST and University of Otago have used the Nobel-winning cryo-electron microscopy method to reconstruct the structure of Seneca Valley virus, abbreviated SVV, at near-atomic resolution.
The structure shows how the virus binds to its cellular receptor, the Anthrax toxin receptor. Type 1 of this receptor is selectively expressed in up to 60% of human cancer cells and allows the virus to infect and destroy them while not affecting healthy cells. The study, which was published in the journal Proceedings of the National Academy of Sciences USA, reveals how the virus can recognize its target and leave normal tissue alone.

Credit:
Provided by Matthias Wolf, additional edits by Andrew Scott

Targeting two-thirds of human cancers

In the past few years, so-called “virotherapy” has grown up as a new branch of cancer immunotherapy. Anticancer viruses tend to target tumors while sparing the healthy cells around them, and many already exist in nature. Scientists hunt down these cancer-killers, study their attack strategies, and optimize their effectiveness through genetic modification. The U.S. Food and Drug Administration has already approved one viral therapy to treat Stage IV melanoma, and other viral drug candidates appear promising in clinical trials.

Seneca Valley Virus stands out as a potential virotherapy for one key reason: it selectively targets a receptor found coating tumor cells in over 60 percent of human cancers. The receptor, known as ANTXR1, is only expressed on tumors, but it has a cousin that only appears on healthy tissues, called ANTXR2. Seneca Valley Virus doesn’t bind with the similar receptor on healthy cells — it only shows strong affinity for ANTXR1. The study’s authors wanted to know why.

“The differences between the two receptors are subtle, but nonetheless, these subtle differences make one bind the virus with high affinity while the other doesn’t,” said Wolf. The researchers found that the outer shell of the Seneca Valley Virus locks tightly onto specific structural features of ANTXR1 — features that aren’t conserved in ANTXR2. “The components must fit together like a key in a lock — this is a highly evolved system where everything fits perfectly.”

Designing an optimal cancer therapy

Seneca Valley Virus has already demonstrated its cancer-fighting abilities in Phase I clinical trials in pediatric solid tumors and Phase II trials in small-cell lung cancers. But there’s one problem: the body builds up immunity to the virus within three weeks and squashes the bug before its work is done.

“If you give a virus as a vaccine, you want an immune response — there, the goal is the destruction of the virus,” said Wolf. “In this case, you want the opposite. You want the virus to evade the immune system, continue to replicate and kill the cancer cells.”

A cryo-EM map of the receptor decorated capsid in which a single protomer was replaced with the atomic model. Seneca Valley Virus capsid proteins are shown in blue, green, and red, and the ANTXR1 receptor is shown in magenta.
Credit:
OIST Molecular Cryo-Electron Microscopy Unit and University of Otago Centre for Electron Microscopy

“By looking at this structure, we can learn what part of the virus is essential for binding to the receptor and which is not,” said Prof. Mihnea Bostina, the academic director of the Otago Centre for Electron Microscopy at the University of Otago and co-senior author of the study. “If we want to make the virus ‘better,’ we can try to change the non-essential parts in order to escape the action of the immune system while leaving the essential part intact.”

With deeper understanding of how the virus works, scientists may be able to outsmart the body’s immune system and protect their mighty cancer-killer. In principle, Seneca Valley Virus could also be modified to recognize different receptors, Wolf said, rendering it a broadly applicable weapon in the fight against cancer.

“I have always been intrigued by ways how we can make use of naturally occurring microorganisms for our benefit,” said Nadishka Jayawardena, a graduate student at the University of Otago and first author of the study. “Being able to work on a virus that can kill cancers is very rewarding, especially knowing that one day our findings could potentially lead to tackling a major global health issue.”

Learn more: Anti-Cancer Virus Fits Tumor Receptor Like a “Key in a Lock”

 

 

The Latest on: Seneca Valley Virus

via Google News

 

The Latest on: Seneca Valley Virus

via  Bing News

 

Nanomushroom sensors have the potential to revolutionize a wide range of processes from monitoring food quality to diagnosing diseases

via OIST

A small rectangle of pink glass, about the size of a postage stamp, sits on Professor Amy Shen’s desk. Despite its outwardly modest appearance, this little glass slide has the potential to revolutionize a wide range of processes, from monitoring food quality to diagnosing diseases.

The slide is made of a ‘nanoplasmonic’ material — its surface is coated in millions of gold nanostructures, each just a few billionths of a square meter in size. Plasmonic materials absorb and scatter light in interesting ways, giving them unique sensing properties. Nanoplasmonic materials have attracted the attention of biologists, chemists, physicists and material scientists, with possible uses in a diverse array of fields, such as biosensing, data storage, light generation and solar cells.

In several recent papers, Prof. Shen and colleagues at the Micro/Bio/Nanofluidics Unit at the Okinawa Institute of Science and Technology (OIST), described their creation of a new biosensing material that can be used to monitor processes in living cells.

“One of the major goals of nanoplasmonics is to search for better ways to monitor processes in living cells in real time,” says Prof. Shen. Capturing such information can reveal clues about cell behavior, but creating nanomaterials on which cells can survive for long periods of time yet don’t interfere with the cellular processes being measured is a challenge, she explains.

Counting Dividing Cells

One of the team’s new biosensors is made from a nanoplasmonic material that is able to accommodate a large number of cells on a single substrate and to monitor cell proliferation, a fundamental process involving cell growth and division, in real time.  Seeing this process in action can reveal important insights into the health and functions of cells and tissues.

Researchers in OIST’s Micro/Bio/Nanofluidics Unit described the sensor in a study recently published in the journal Advanced Biosystems.

The most attractive feature of the material is that it allows cells to survive over long time periods. “Usually, when you put live cells on a nanomaterial, that material is toxic and it kills the cells,” says Dr. Nikhil Bhalla, a postdoctoral researcher at OIST and first author of the paper.  “However, using our material, cells survived for over seven days.” The nanoplasmonic material is also highly sensitive: It can detect an increase in cells as small as 16 in 1000 cells.

The material looks just like an ordinary pieces of glass. However, the surface is coated in tiny nanoplasmonic mushroom-like structures, known as nanomushrooms, with stems of silicon dioxide and caps of gold. Together, these form a biosensor capable of detecting interactions at the molecular level.

Learn more: Nanomushroom Sensors: One Material, Many Applications

 

The Latest on: Nanoplasmonic materials

via Google News

 

The Latest on: Nanoplasmonic materials

via  Bing News

 

 

Using plentiful manganese to turn carbon dioxide into useful organic chemicals

via Okinawa Institute of Science and Technology

Carbon dioxide (CO2) is known as a greenhouse gas and plays an essential role in climate change; it is no wonder scientists have been looking for solutions to prevent its release in the environment. However, as a cheap, readily available and non-toxic carbon source, in the past few years there have been efforts to turn carbon dioxide into valuable wares, or ‘value-added’ products.

For instance, carbon dioxide enables energy storage by reacting with hydrogen gas – called the hydrogenation process – transforming the mixture into higher energy liquid compounds such as methanol that can be easily transported and used as fuel for cars. Similarly, carbon dioxide hydrogenation in the presence of other chemicals can lead to the formation of various value-added products widely used in industry such as formic acid, formamides, or formaldehyde. These chemicals can also potentially be used for energy storage as, for example, heating formic acid under certain conditions allow for the release of hydrogen gas in a controlled and reversible fashion.

Conversion of carbon dioxide into useful products is complicated by the fact that CO2 is the most oxidized form of carbon and as such a very stable and unreactive molecule. Therefore, the direct reaction of CO2 with hydrogen requires high energy, making the process economically unfavorable. This problem can be overcome using catalysts, which are compounds used in small amounts to accelerate chemicals reactions. For CO2 hydrogenation purposes, most known catalysts are based on precious metals such as iridium, rhodium or ruthenium. While excellent catalysts, the scarcity of these precious metals makes it difficult to use them at industrial scales. They are also hard to recycle and potentially toxic for the environment. Other catalysts use cheaper metals such as iron or cobalt but require a phosphorus-based molecule – called phosphine -surrounding the metal. Phosphines are not always stable around oxygen and sometimes burn violently in an air atmosphere, which presents another problem for the practical applications.

 

Members of the OIST Coordination Chemistry and Catalysis Unit developed a new manganese-based catalyst for CO2 hydrogenation (structure of the catalyst is shown on the computer screen). From left to right back row: Dr. Abhishek Dubey and Dr. Robert Fayzullin. Front row: Prof. Julia Khusnutdinova.

To overcome these issues, the OIST Coordination Chemistry and Catalysis Unit led by Prof. Julia Khusnutdinova reported in ACS Catalysis novel and efficient catalysts based on an inexpensive and abundant metal: manganese. Manganese is the third most abundant metal in Earth’s crust after titanium and iron, and presents much lower toxicity as compared to many other metals used in CO2 hydrogenation.

The scientists initially looked for inspiration within the natural world: hydrogenation is a reaction that occurs in many organisms that would not have access to precious metals or phosphines. They observed the structure of specific enzymes – hydrogenases – to understand how they could accomplish hydrogenation using simple, Earth-abundant materials. To facilitate the hydrogenation, enzymes utilize a ‘smart’ arrangement where the surrounding organic framework cooperates with a metal atom – like iron-  efficiently kick-starting the reaction.

 

Structure of a natural iron-based hydrogenase. The structure of natural enzymes inspired the scientists to design an efficient artificial frame for a manganese-based catalyst. The insert shows the proposed chemical structure responsible for the hydrogen activation.

“After looking at hydrogenases, we wanted to check if we could make artificial molecules that mimics these enzymes using the same type of common materials, like iron and manganese,” explained Dr. Abhishek Dubey, the first author of this study.

The main challenge of this study was to build an adequate frame – called a ligand – around the manganese to induce the hydrogenation. The scientists came up with a surprisingly simple ligand structure resembling natural hydrogenase enzymes with a twist from typical phosphine catalysts.

“In most cases, ligands support the metal without directly taking part in a chemical bond activation. In our case, we believe the ligand directly participates in the reaction,” said Dr. Dubey.

 

Crystal structure of the manganese-based catalyst reported in the study. The manganese atom (in purple) is at the center of the frame – the ligand – which facilitates the hydrogenation of CO2.

In ligand design, the structure of a ligand is tightly linked to its efficiency. The new catalyst – the ligand and the manganese together – can perform more than 6,000 turnovers in a hydrogenation reaction, converting more than 6,000 times CO2molecules before decaying. And this new ligand, the outcome of a collaboration with an international team including Prof. Carlo Nervi and Mr. Luca Nencini from University of Turin in Italy and Dr. Robert Fayzullin from Russia, is simple to manufacture and stable in the air.

For now, the catalyst is able to transform carbon dioxide into formic acid, a widely-used food preservative and tanning agent, and formamide, which has industrial applications. But the versatility of this catalyst opens many other possibilities.

“Our next goal is to utilize such structurally simple, inexpensive manganese catalysts to target other types of reactions in which CO2 and hydrogen can be converted into useful organic chemicals”, concluded Prof. Khusnutdinova.

Learn more:Recruiting Manganese to Upgrade Carbon Dioxide

 

The Latest on: Converting carbon dioxide

via Google News and Bing News

New printing method to create inexpensive and effective disease detection tools

via Okinawa Institute of Science and Technology (OIST) Graduate University

The field of medicine is always on the lookout for better disease diagnostic tools—simpler, faster, and cheaper technologies to enhance patient treatment and outcomes.

Currently, microfluidic bioassay devices are the preferred diagnostic tools that allow clinicians to measure the concentration of disease biomarkers within a patient’s biological sample, such as blood. They can indicate the likelihood of a disease based on a comparison of the biomarker concentration in the sample relative to the normal level. To detect this concentration, the patient’s sample is passed across a surface containing immobilized bioreceptors, or “biomarker-capturing” molecules that have been attached to this surface. A researcher can then record the biomarker abundance, determine whether the level is normal, and reach a diagnosis. Since the efficiency of these devices relies on how intact and functional the attached bioreceptors are, immobilizing these bioreceptors without causing damage has proved daunting.

Over the last two decades, microcontact printing, which uses a rubber stamp to immobilize the bioreceptors, has been established as a robust method to create a variety of assays with multiple applications. Yet this method also has its flaws, particularly when utilized at the nano scale—the scale where proteins and DNA reign. At this scale, the harsh and elaborate techniques currently used compromise the device’s resolution, whether by deforming the stamp or damaging the bioreceptors, thus yielding data somewhat unmanageable for use in diagnostics or other applications. However, in a recent article published in the journal Analyst, researchers at the Okinawa Institute of Science and Technology Graduate University (OIST) describe a new sequence of printing steps that have rectified these issues.

For microcontact printing, “you need a stamp, an ink, and a surface, and then you create your pattern on your surface. It’s as simple as that,” explains Shivani Sathish, OIST PhD student in the Micro/Bio/Nanofluidics Unit, and first author on the paper.

The stamp is made of polydimethylsiloxane, which is a flexible solid similar to the rubber used in everyday stamps. The ink is a solution composed of silicon- and oxide-containing molecules called APTES, and the surface is glass. After coating the stamp with the ink, the stamp is pressed onto the glass, and then removed after a short incubation. The result is a patterned layer of APTES on the glass—a checkerboard of regions with or without APTES (Figure, ii). Next, a microfluidic device, which contains one or more microchannels configured to guide fluid through specified pathways, is sealed over the patterned glass (Figure, iv). Finally, the bioreceptors are chemically linked to the APTES regions within the microfluidic channels. The device as a whole is about the size of a postage stamp.

The system is now ready for use as a diagnostic assay. To carry out the assay, a fluid sample from a patient is delivered through the microfluidic device attached to the glass. If the pertinent disease biomarker is present, the molecule will “stick” to the areas containing the bioreceptors.

What is important about the APTES solution is its convenient chemistry. “Depending on your bioreceptor of interest, you just have to choose the appropriate chemistry to link the molecule with the APTES,” Ms. Sathish explains. Or in other words, one stamp can be used to prepare an assay with the ability to immobilize a variety of different bioreceptors—one stamp allows for multiple tests and diagnoses on a single surface. This feature would be advantageous for diagnosing complex diseases such as cancer, which relies on tests that can detect multiple markers to improve the diagnosis.

In their research, Ms. Sathish and colleagues developed an improved technique to create the most optimal disease diagnostic device for use at the nano scale. Here, they first patterned nanoscale features of APTES using an ink made of APTES in water, as opposed to harsh chemicals, which eliminated the stamp-swelling issue. Then, they immobilized the bioreceptors onto the surface as the very last step of the process, after patterning the APTES and attaching the microfluidic device. By attaching the bioreceptors as the final step, the researchers avoided exposing them to extreme and damaging conditions. They then demonstrated the efficacy of the final device by running an assay to capture the biomarkers interleukin 6 and human c-reactive protein, two substances that are often elevated in the body during inflammation.

“The final goal is to create a point-of-care device,” explains OIST Professor Amy Shen, who headed the research.

“If you get your bioreceptors pre-immobilized within microfluidic devices you can then use them as diagnostic tools as and when required,” Ms. Sathish continues. “[Eventually] instead of having a whole clinical team that processes your sample…we’re hoping that the patients can do it themselves at home.”

Learn more: Miniature Technology, Big Hope for Disease Detection

 

The Latest on: Disease detection

via Google News and Bing News