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Fighting Diseases: Scientists at IISc discover novel methods to regulate molecular imbalances

Ever wondered about the thought that goes into the development of new drug, the teeny-tiny capsules that your doctor sends you home with an assurance of recovery? Has it ever occurred to you that diseases and ailments needn’t always be caused by external factors like a fungi or a virus, but might also be due to a disturbance in certain molecular levels within your body?

No?

Well, then let me introduce you to the research group led by Dr. Patrick D’ Silva of the Department of Biochemistry at Indian Institute of Science Bangalore. The group focuses on a group of highly reactive molecules called Reactive Oxygen Species (ROS), associated disorders and relevant therapeutic approaches. A common example of ROS is hydrogen peroxide, which many of us have encountered as a bubbling, hissing liquid in chemistry labs, and occasionally applied on a wounded knee.

ROS are produced inside the body as a byproduct of daily life metabolism – the breakdown of complex molecules to release energy, and the synthesis of the body's building blocks – releases charged molecules derived from oxygen, like hydrogen peroxide (H2O2)and other free radicals. At normal levels they contribute to communication within cells. However, high concentrations of ROS species lead to a state of 'oxidative stress' during which molecules that sustain life in our bodies, like proteins and DNA, are affected. Such an impairment can result in devastating conditions like diabetes, arthritis, kidney dysfunction, atherosclerosis, aging and even neurodegenerative diseases like Parkinsons (PD) and Alzheimer’s (AD).

Cells with high-energy demands, with more mitochondrial activity (like stem cells, skeletal & heart muscles, neurons)are found to be more vulnerable to oxidative stress. If the picture thus far looks dismal, it would hearten you to know that our body too has a combat system in place, involving enzymes like glutathione peroxidases(GPx), superoxide dismutases (SODs)and catalases,  that deactivate the ROS molecules by converting them to forms like water. Smart huh!

Well , recent research findings in the D’Silva lab reports on a novel ROS regulator ‘MAGMAS’. It was first  identified to play a role in the import of proteins into mitochondria but turns out to be quite the lifeguard by also maintaining the right amount of these ROS levels in our cells, referred to as ROS homeostasis. “Interestingly”, says D'Silva, “MAGMAS is capable of controlling ROS production by preventing electron leakage within the mitochondria as well as enhancing activity of the enzymatic combat machinery, a role it performs quite independent of the other”.

“Surprisingly, enhanced ROS levels assist tumor progression,but abnormally high levels trigger cell death”, puts in Shubhi Srivastava, lead author of a study published in the journal Cell Death & Disease in 2014, explaining that the experiments were conducted on human embryonic kidney cells(HEK293T), prostate cancer cells and even in baker’s yeast.

Another study from D’Silva lab identifies Hsp31/DJ-1, as a novel ROS detoxifier. Hsp31protein enhances the level of natural detoxifiers such as glutathione (GSH) to protect the cells against harmful effects of ROS. “It localizes in the power house of cell (mitochondria) under stress conditions and shields it from the damage” says D’Silva. Genetic alterations in DJ-1 are known to be involved in familial forms of Parkinson’s disease, and its role in ROS detoxification explains the importance of ROS enhancement in such diseases," says K. Bankapalli, the lead author of the study published in the Journal of Biological Chemistry in 2015.

Two other independent sets of research performed in D’Silva lab in collaboration with Dr. G. Mugesh from the Department of Inorganic and Physical Chemistry, Indian Institute of Science, also sheds light on some novel compounds that offer potential therapeutic values.One of them concerns a nano-material, “Vanadium nanowire”, which exhibits an ROS 'policing' nature. Nanomaterials have sizes in the range of 10-9– – smaller than a human hair. The extremely small size allows these novel ‘nano-enzymes' to bore into cells, wherein they mimic natural detoxifiers and scavenge ROS.  Furthermore, these nano-enzymes have been found to selectively-deactivate an ROS species- hydrogen peroxide (H2O2)-to form water(H2O). “They have also proven themselves as potential artificial replacements of the natural H2O2 deactivator in our body,catalase, which may decrease under disease conditions”, explains Devanjan Sinha and Amit  Vernekar , lead authors of the relevant study published in Nature Communications.

Another of these compounds refers to selenium based ones. Experiments performed in the laboratory on mammalian cell lines proved that an induction of the selenium based compounds in conditions of oxidative stress is analogous to a sick man popping pills into his mouth that gets him better. The study also compared the ROS policing activity of the diselenide compounds to that of ‘ebselen’,which is a well-known scavenger of ROS in presence of GSH. “Appreciatively, these selenium compounds displayed a better scavenging potential in comparison with ebselen,” says Shubhi Srivastava and Debasish, authors of a study published in the AngewandteChemie International Edition in 2015.

Life in itself is spectacular. An understanding of various life processes, apart from satiating our curiosity paves a better ground for us to meddle and try to set things right in case of ailments and fighting diseases. Ongoing research in Dr. Patrick’s  lab unearths and brings to the forefront the hidden importance of ROS homeostasis and its role in fighting ailments ranging from diabetes to Alzheimer’s, a subject of grave importance in today’s world.

Dr. Patrick D’ Silva is an Associate Professor in the Department of Biochemistry, Indian Institute of Science, Bengaluru. He can be contacted at +91-80-2293 2821