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Type of sugar may treat atherosclerosis, mouse study shows

Type of sugar may treat atherosclerosis, mouse study shows

Researchers have long sought ways to harness the body’s immune system to treat disease, especially cancer. Now, scientists have found that the immune system may be triggered to treat atherosclerosis and possibly other metabolic conditions, including fatty liver disease and type 2 diabetes.

Studying mice, researchers at Washington University School of Medicine in St. Louis have shown that a natural sugar called trehalose revs up the immune system’s cellular housekeeping abilities. These souped-up housecleaners then are able to reduce atherosclerotic plaque that has built up inside arteries. Such plaques are a hallmark of cardiovascular disease and lead to an increased risk of heart attack.

“We are interested in enhancing the ability of these immune cells, called macrophages, to degrade cellular garbage — making them super-macrophages,” said senior author Babak Razani, MD, PhD, an assistant professor of medicine.

Macrophages are immune cells responsible for cleaning up many types of cellular waste, including misshapen proteins, excess fat droplets and dysfunctional organelles — specialized structures within cells.

“In atherosclerosis, macrophages try to fix damage to the artery by cleaning up the area, but they get overwhelmed by the inflammatory nature of the plaques,” Razani explained. “Their housekeeping process gets gummed up. So their friends rush in to try to clean up the bigger mess and also become part of the problem. A soup starts building up — dying cells, more lipids. The plaque grows and grows.”

In the study, Razani and his colleagues showed that mice prone to atherosclerosis had reduced plaque in their arteries after being injected with trehalose. The sizes of the plaques measured in the aortic root were variable, but on average, the plaques measured 0.35 square millimeters in control mice compared with 0.25 square millimeters in the mice receiving trehalose, which translated into a roughly 30 percent decrease in plaque size. The difference was statistically significant, according to the study.

The effect disappeared when the mice were given trehalose orally or when they were injected with other types of sugar, even those with similar structures.

Found in plants and insects, trehalose is a natural sugar that consists of two glucose molecules bound together. It is approved by the Food and Drug Administration for human consumption and often is used as an ingredient in pharmaceuticals. Past work by many research groups has shown trehalose triggers an important cellular process called autophagy, or self-eating. But just how it boosts autophagy has been unknown.

In this study, Razani and his colleagues show that trehalose operates by activating a molecule called TFEB. Activated TFEB goes into the nucleus of macrophages and binds to DNA. That binding turns on specific genes, setting off a chain of events that results in the assembly of additional housekeeping machinery — more of the organelles that function as garbage collectors and incinerators.

“Trehalose is not just enhancing the housekeeping machinery that’s already there,” Razani said. “It’s triggering the cell to make new machinery. This results in more autophagy — the cell starts a degradation fest. Is this the only way that trehalose works to enhance autophagy by macrophages? We can’t say that for sure — we’re still testing that. But is it a predominant process? Yes.”

The researchers are continuing to study trehalose as a potential therapy for atherosclerosis, especially since it is not only safe for human consumption but is also a mild sweetener. One obstacle the scientists would like to overcome, however, is the need for injections. Trehalose likely loses its effectiveness when taken orally because of an enzyme in the digestive tract that breaks trehalose into its constituent glucose molecules. Razani said the research team is looking for ways to block that enzyme so that trehalose retains its structure, and presumably its function, when taken by mouth.

This article was published in Science Daily dated ‘Jun. 07, 2017’

Understanding antibiotic resistance

Understanding antibiotic resistance

Central to understanding why bacteria become antibiotic resistant is knowing how bacteria respond to the drugs trying to kill them. In a new study, Boston College researchers report that antibiotics disrupt the genetic defensive responses in lethal bacteria.

When facing a common — or historic — threat such as deprivation of nutrients, the deadly bacterium Streptococcus pneumonia exerts a highly organized response — one influenced by the bacteria’s genetic evolution and powered by genes that respond cooperatively to stress, the researchers found. But when confronted with antibiotics — a relatively new form of stress — the bacterium mounts a confused defense, according to the study “Antibiotics Disrupt Coordination between Transcriptional and Phenotypic Stress Responses in Pathogenic Bacteria,” published today in the journal Cell Reports.

“We show that nutrient stress results in a highly organized response from the bacterium,” said Associate Professor of Biology Tim van Opijnen, the study’s principal investigator. “It basically seems to recognize the stress and knows how to deal with it.

“But the response to antibiotics was highly disorganized, showing that the organism has difficulties with this stress, trying out all kinds of unrelated things to come to a solution and overcome the stress,” he said. “This shows that the bacterium is far less familiar with antibiotics, not ‘knowing’ how to respond appropriately.”

Van Opijnen, whose data-driven research has helped to establish an understanding of how bacteria rely on underlying genetic networks to function, said the findings may advance the development of new drugs and also help predict how bacteria evolve, adapt and become resistant to antibiotics.

Van Opijnen and co-authors Karen Zhu, a BC doctoral student, and former post-doctoral researcher Paul Jensen, now at the University of Illinois, combined large quantities of experimental data with a new, large-scale computational model they developed to produce new insights and challenge some long-held assumptions about the interplay between bacteria and the drugs designed to treat them.

S. pneumoniae kills approximately 1.5 million people annually. In prior research, van Opijnen and colleagues have revealed that different strains of the bacterium respond uniquely to antibiotics. This time, the research team looked at how strains respond to different stressors. The team employed two analytical approaches — one in use for many years and one developed in the van Opijnen lab.

The team used a process known as RNA sequencing, or RNA-Seq, to assess bacterial genes that are provoked to change, a process known as transcription. This activity has long been viewed as central to understanding how bacteria combat antibiotics and other stressors.

The team paired that analysis with its own technique: transposon insertion sequencing, or Tn-Seq. Developed by van Opijnen, Tn-Seq combs through millions of genetic sequences and singles-out gene functions in bacteria. The advantage of Tn-Seq is that it is able to begin to pinpoint which genes play the most important defensive roles.

During the course of more than two years, the team’s RNA-Seq experiments analyzed 800 million genetic sequences and produced 150,000 data points. Tn-Seq analyzed 1.2 billion sequences and produced 300 million data points, Zhu said.

“RNA-Seq looks at the activity of every gene in the genome of the organism,” said van Opijnen. “The activity of every gene has always been associated with importance. The assumption for nearly three decades has been if you take an organism and stress it out, and a gene’s activity changes, it must be important.”

That assumption has been difficult to test, said van Opijnen. But with Tn-Seq, van Opijnen has the ability to assess the importance of a gene in a specific condition.

“We found that you cannot assume that change in the activity of a gene means the gene is important,” said van Opijnen. It was a surprising finding, he said. After all, why would a change in gene activity take place if it was not important to the organism’s survival?

Part of the answer may be in the collaborative nature of the way genes work across the entire genome of a bacterial strain, van Opijnen said. “They collaborate and corroborate to perform functions, to resolve into a specific phenotype,” he said. “So there is a relationship as genes all work with each other in pathways, or networks; they cooperate with each other.”

The researchers constructed a metabolic model of the coordinated response to deprivation, which placed the responding genes in close proximity to each other. When challenged with antibiotics, the model shows that the response of the physical network breaks down in disorganization and those genes are no longer in close proximity.

“Bacteria use these types of regulation to fight against stress,” Zhu said. “In terms of nutritional depletion, because they have responded to this type of stress over the course of their evolution, the bacteria ‘know’ how to coordinate this activity. But with a relatively new invasive stressor, like an antibiotic, bacteria may not be able to figure out a way to produce a coordinated response.”

In a search for reasons why certain types of bacteria become resistant to antibiotics, the researchers have established a new approach to understanding why antibiotics succeed in combatting bacterial infections.

“By combining computational and large-scale experimental work, we’ve built a model to get the first, basic understanding of how known and unknown stress is processed by bacteria,” said van Opijnen. “That’s critical because it makes it a stepping stone to a new intervention at some point in the future. If we can understand how stress is processed, we can come up with a better way to develop a new stressor to break an organism, or eradicate it.”

This article was published in Science Daily dated ‘Aug. 15, 2017’