In the months after a heart attack or stroke, patients are more likely to have another attack or stroke. A paper in the Journal of the American College of Cardiology now explains what happens inside blood vessels to increase risk and suggests a new way to treat it. The paper states that heart attacks in mice caused inflammatory cells and platelets to more easily stick to the inner lining of arteries throughout the body and particularly where there was already plaque. As a result, these sticky cells and platelets caused plaque to become unstable and contribute to blood clots that led to another heart attack or stroke.
The study found treating mice that had experienced a heart attack or stroke with the powerful antioxidant apocynin cut plaque buildup in half and lowered inflammation to pre-attack levels. "Knowing that newer forms of antioxidants such as apocynin can lower the risk of a second heart attack or stroke gives us a new treatment to explore and could one day help reduce heart attacks and strokes," says the paper's author, Jonathan R. Lindner, M.D., a professor of cardiovascular medicine at the OHSU School of Medicine.
The researchers discovered the sticky cells and platelets by using unique forms of ultrasound imaging they developed to view molecules on the lining of blood vessels. This research could help explain why the recent Canakinumab Anti-inflammatory Thrombosis Outcomes Study, also known as the CANTOS clinical trial, found an anti-inflammatory drug already approved to treat juvenile arthritis also reduced the risk of a second heart attack in trial participants by 15 percent. Lindner and his colleagues are further studying how the relative stickiness of remote arteries affects the risks for additional heart attacks and strokes and are also evaluating new therapies beyond antioxidants.
Antioxidant Benefits Of Sleep
A new study published in PLOS Biology, found that short-sleeping fruit fly mutants shared the common defect of sensitivity to acute oxidative stress, and thus that sleep supports antioxidant processes. Understanding this ancient bi-directional relationship between sleep and oxidative stress in the humble fruit fly could provide much-needed insight into modern human diseases such as sleep disorders and neurodegenerative diseases.
Despite the cost of sleep behavior, almost all animals sleep, suggesting that sleep fulfills an essential and evolutionarily conserved function from humans to fruit flies. The researchers reasoned that if sleep is required for a core function of health, animals that sleep significantly less than usual should all share a defect in that core function. For this study, they used a diverse group of short-sleeping Drosophila (fruit fly) mutants. They found that these short-sleeping mutants do indeed share a common defect: they are all sensitive to acute oxidative stress.
Oxidative stress results from excess free radicals that can damage cells and lead to organ dysfunction. Toxic free radicals, or reactive oxygen species, build up in cells from normal metabolism and environmental damage. If the function of sleep is to defend against oxidative stress, then increasing sleep should increase resistance to oxidative stress. Vanessa Hill, Mimi Shirasu-Hiza and colleagues at Columbia University, New York, used both pharmacological and genetic methods to show that this is true.
They proposed, if sleep has antioxidant effects, then surely oxidative stress might regulate sleep itself. Consistent with this hypothesis, they found that reducing oxidative stress in the brain by overexpressing antioxidant genes also reduced the amount of sleep. Taken together, these results point to a bi-directional relationship between sleep and oxidative stress - sleep functions to defend the body against oxidative stress and oxidative stress in turn helps to induce sleep.
This work is relevant to human health because sleep disorders are correlated with many diseases that are also associated with oxidative stress, such as Alzheimer's, Parkinson's, and Huntington's diseases. Sleep loss could make individuals more sensitive to oxidative stress and subsequent disease; conversely, pathological disruption of the antioxidant response could also lead to loss of sleep and associated disease pathologies.
Triggering Antioxidant Production
One reason we're supposed to eat a variety of colorful fruits and vegetables is because they contain nutritious compounds called antioxidants. These molecules counteract the damage to our bodies from harmful products of normal cells called reactive oxygen species (ROS). Research published in Science Signaling, and led by a Salk Institute professor along with collaborators from Yale, Appalachian State University and other institutions, found that a protein called ATM - short for ataxia-telangiectasia mutated - can sense the presence of ROS and responds by sounding the alarm to trigger the production of antioxidants.
The work could have implications for a disease in which ATM is dysfunctional and could also help reveal ways to boost cellular health overall. "In ataxia-telangiectasia, the disease caused when the ATM is gene is mutated, people are prone to DNA damage because one of ATM's functions is to repair DNA," says Gerald Shadel, a Salk professor and co-corresponding author. "But we also see signs in this disease of damage caused by ROS, and it hasn't been clear why that would be connected to dysfunctional ATM."
Shadel studies mitochondria, the powerhouses of cells, which convert our food into chemical energy cells use. In the process, mitochondria produce the ROS that not only damage cells but also are danger signals. To better understand the role of ATM, Shadel began by investigating ATM's response to ROS produced by mitochondria. His team exposed laboratory cells in culture dishes to a chemical that encourages mitochondria to produce ROS. As expected, they saw increased ROS, but they also observed ATM molecules pairing up into what scientists call a dimer, which is not what ATM does when responding to DNA damage. These observations corroborate other research suggesting that ATM has two modes for responding to different types of cellular threats - DNA damage and ROS from mitochondria.
Making Sense Of ATMs
Treating the cells with a chemical that causes DNA damage did not induce ATM to form dimers, and the non-dimerized ATM went on to prompt damage-repair mechanisms. The scientists figured ATM's formation of dimers in the presence of ROS represents a type of ROS-sensing function. Dimerized ATMs induced an entirely different mechanism than non-dimerized ATM - the pentose phosphate pathway - which is a series of biochemical steps that generates cellular antioxidants.
ATM is like a smoke detector that also has a carbon monoxide sensor. Either a fire (DNA damage) or carbon monoxide (ROS) will cause the detector (ATM) to sound the alarm to protect your health. "ATM is well known for its role in repair of DNA damage, but why it forms dimers in response to reactive oxygen species has been a mystery," says co-corresponding author Brooke E. Christian of Appalachian State University. "This work is exciting because it reveals a functional consequence of ATM dimerization: to increase cellular antioxidant capacity through activation of the pentose phosphate pathway. It makes sense for ATM to have this function as a way to protect the genome from the damaging effects of reactive oxygen species."
"We went into the study wanting to know the mechanism and function of the ATM-mediated mitochondrial ROS signaling pathway," says Yichong Zhang, a graduate student researcher at Yale University and the paper's first author. "The most exciting moment for me was when we discovered the details of the mechanism by which ROS signaling through ATM regulates cellular antioxidant responses." The revelation how ATM and the production of antioxidants are connected via this pentose phosphate pathway could lead to ways to develop new treatments for the disease ataxia-telangiectasia.
Antioxidant Slows Symptoms Of Human Skin Aging
A study published recently in Scientific Reports suggests that a common, inexpensive and safe chemical could slow the aging of human skin. The researchers at the University of Maryland found evidence that the chemical - an antioxidant called methylene blue - could slow or reverse several well-known signs of aging when tested in cultured human skin cells and simulated skin tissue. "Our work suggests that methylene blue could be a powerful antioxidant for use in skin care products," said Kan Cao, senior author on the study and an associate professor of cell biology and molecular genetics at UMD. "The effects we are seeing are not temporary. Methylene blue appears to make fundamental, long-term changes to skin cells."
The researchers tested methylene blue for four weeks in skin cells from healthy middle-aged donors, as well as those diagnosed with progeria - a rare genetic disease that mimics the normal aging process at an accelerated rate. In addition to methylene blue, the researchers also tested three other known antioxidants: N-Acetyl-L-Cysteine, MitoQ and MitoTEMPO. Methylene blue outperformed the other three antioxidants, improving several age-related symptoms in cells from both healthy donors and progeria patients. The skin cells or fibroblasts - the cells that produce the structural protein collagen - experienced a decrease in damaging molecules known as reactive oxygen species, a reduced rate of cell death and an increase in the rate of cell division throughout the four-week treatment.
Cao and her colleagues tested methylene blue in fibroblasts from older donors again for a period of four weeks. At the end of the treatment, the cells from older donors had experienced a range of improvements, including decreased expression of two genes commonly used as indicators of cellular aging: senescence-associated beta-galactosidase and p16. "I was encouraged and excited to see skin fibroblasts, derived from individuals more than 80 years old, grow much better in methylene blue-containing medium with reduced cellular senescence markers," said Zheng-Mei Xiong, lead author of the study and an assistant research professor of cell biology and molecular genetics at UMD. "Methylene blue demonstrates a great potential to delay skin aging for all ages."
The researchers then used simulated human skin - a system developed by Cao and Xiong - to perform several more experiments. This simulated skin - a three-dimensional model made of living skin cells - includes all the major layers and structures of skin tissue, with the exception of hair follicles and sweat glands. The model skin could also be used in skin irritation tests required by the Food and Drug Administration for the approval of new cosmetic products. "This system allowed us to test a range of aging symptoms that we can't replicate in cultured cells alone," Cao said. "Most surprisingly, we saw that model skin treated with methylene blue retained more water and increased in thickness - both of which are features typical of younger skin."
The researchers also used the model skin to test the safety of cosmetic creams with methylene blue added. The results suggest that methylene blue causes little to no irritation, even at high concentrations. Cao, Xiong and their colleagues hope to develop safe and effective ways for consumers to benefit from the properties of methylene blue. "We have already begun formulating cosmetics that contain methylene blue,” Cao added. “Now we are looking to translate this into marketable products. We are also very excited to develop the three-dimensional skin model system. Perhaps down the road we can customize the system with bioprinting, such that we might be able to use a patient's own cells to provide a tailor-made testing platform specific to their needs."
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