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V O LU M E 2 , I SSU E 4

1st July, 2010


Bharathiar University, Coimbatore—641046, Tamilnadu, India

Journal Clu b, Department of Biote chnology,

Inside this issue: Alexander—The great, why? - Sujatha. P


Why hot peppers are slimming…? - Swapna Merlin David


Shock and Age - Bhuvaneswari Subramanian


Edited By: Lakshmi Venkatachalam E-mail: Contributions, comments and suggestions are highly expected from the readers

Alexander—The great, why? - Sujatha. P

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Why hot peppers are slimming…? - Swapna Merlin David

There seems little doubt that chemicals responsible for the peppery bite of chili peppers can inhibit the accumulation of body fat. It’s not only been illustrated rather convincingly in rodents, but also reported a few months back to operate in people. The question has been how peppers do this. Korean researchers now describe peppery changes in genes that appear to underlie fat-shunning properties — ones that point to how chili’s fiery chemistry might be harnessed to fight obesity. The researchers, all from Daegu University in Kyungsan, fed high fat diets to five-week-old rats for two months. Some got a daily oral injection of dilute capsaicin, the fiery chemical in chili peppers, or just a control — the liquid that had been used to dilute the capsaicin. Throughout the course of the trial, animals getting capsaicin gained 8 percent less weight than untreated animals, and just a fraction more weight than animals eating a normal diet. Capsaicin-treated animals also developed less body fat and accumulated smaller fat droplets within fat cells. These findings would seem to indicate that capsaicin can have a significant inhibitory effect against fat accumulation.

The research team identified the genes that are selectively up- or down-regulated by consumption of dietary fat or by capsaicin. They found that a high fat diet upregulated genes producing 17 proteins, including NQO1, heat shock protein 27, vimentin and preoxiredoxin. Some 10 of which were normalized or almost returned to normal in the animals treated with capsaicin. Another 10 of the bunch were down regulated in animals eating high-fat chow. Unless, that is, they also got capsaicin. Then the production of these proteins also came back to normal, or nearly so. In addition, the activity of several genes that control the production of fat cells were ratcheted down by capsaicin. Meanwhile, this dietary additive boosted the activity of genes associated with turning on the body’s furnace, by accelerating the burning of fat — both the normal white fat and the beneficial brown fat. Altogether, the new findings suggest there may be dietary routes to slowing or even reversing obesity and related diseases. And for those of us who can’t handle much of the mouth-burning capsaicin, it’s good to know that it has a peppery cousin that may work as well — with no fiery effects on the mouth or gut. Source:

VO L U M E 2, IS SU E 4

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Shock and Age - Bhuvaneswari Subramanian The accumulation of misfolded protein marks the accrual of years as the body ages. Could heat shock proteins be used to reduce the effects of aging and diminish the risk of disease by untangling improperly folded proteins?

What does a molecular thermometer look like? This seemed to be a simple question, not much different from the many science fair projects I had done in grade school and high school in Chicago. But rather than the simple solutions I’d present on triptych posterboards, the answer to this question has kept me fascinated for my entire career. The cell’s thermometer appears to be a network of stress-sensing transcription factors and specialized proteins—molecular chaperones—that function as the guardian of the proteome, sensing damage and keeping the cell’s proteins properly folded as they roll off the production line of ribosomes. Exciting as that was, none of us working on this question at the time could have predicted that this thermometer might also control the body’s fountain of youth and provide new ways of thinking about disease. Proteins are fundamental building blocks for the cell; they are the predominant Page 4

products of the genome that provide much of the shape and functionality of cells, tissues, and organisms. The proper synthesis, folding, assembly, translocation, and clearance of proteins is essential for the health of the cell and the organism. Proteins also provide the essential parts to replenish molecular machines for biosynthetic processes and ensure their efficient functioning in the adult cell, a process critical for longevity. At the root of the problem is a fundamental process: protein folding. When quality control—as overseen by heat shock proteins and molecular chaperones—slips, errors occur and persist. This interferes with molecular processes, which can lead to disease. When these events occur in neurons, the consequences can be devastating, leading to major classes of neurological disorders, like multiple sclerosis, Huntington’s disease, Parkinson’s disease, and Alzheimer’s disease. Discovered in 1962 by Ferruccio Ritossa, the heat shock response was described as the temperature-induced change in the organization of the tightly packed Drosophila salivary gland chromosome, leading to the appearance of puffs. Ritossa’s “heat shock” puffs, which by light microscopy looked like cotton balls compressed between sections of tightly packed chromosomes, were also induced by exposure to dinitrophenol, ethanol, and salicylate. However, it was the demonstration that these puffs were new sites of transcription that was most impressive— Ritossa could detect newly synthesized RNA within minutes of puffing. B IO T AL K

The significance of this was soon revealed by Lindquist and Steven Henikoff in the Meselson lab and Allan Spradling with Mary-Lou Pardue at MIT. These heat shock–induced messenger RNAs encoded a set of proteins, now widely known as the heat shock proteins. These are widely studied as Hsp90, Hsp70, and a family of proteins that guide conformation and folding, and prevent misfolding in cells of all species. Using a clever trick of cellular biochemistry to enrich for heat shock messenger RNA, the laboratories of David Hogness at Stanford, Walter Gehring at University of Basel, Brian McCarthy at UCSF, Alfred Tissieres at the University of Geneva, and Meselson all cloned the first heat shock genes from Drosophila in the late 1970s and early 1980s.

Heat shock: Exposure of cells to heat shock or other forms of physiological stress elevates the level of misfolded proteins. Accumulation of damaged proteins is prevented by induction of the heat shock response and the expression of heat shock proteins (Hsp90, Hsp70, and Hsp27). Cells at normal temperature have mostly native proteins and heat shock transcription factors in an inactive state. Upon heat shock, proteins misfold and heat shock factors are activated and result in the elevated expression of heat shock genes. In the stressprotected cell, heat shock proteins stabilize misfolded proteins, prevent the formation of aggregates, and enhance the levels of native functional proteins.

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Heat shock factors in aging: As the cells in an organism age, proteins lose their integrity and appear as misfolded molecules that can aggregate. In the young cell, proteins are mostly in the native folded state. During aging, misfolded proteins appear and can form protein aggregates that interfere with cellular function. The youth recovered state can be attained by enhanced activity of heat shock transcription factor to elevate the levels of heat shock proteins in the cell, thus reducing the appearance of damaged proteins.

Additional insights on the molecular thermometer came from studies showing that the heat shock proteins were regulating the very transcription factor that initiated their production in the nucleus. The function of heat shock proteins as molecular chaperones to guide folding, to ensure alternate conformational states, and to recognize and suppress misfolding was becoming well established. Therefore, the cellular thermometer wasn’t just measuring temperature, it also monitored for the appearance of damaged proteins. Heat shock and other stressors would lead to a flux of misfolded and damaged proteins, shifting the chaperone equilibrium in the cell toward capturing these damaged proteins and releasing Hsf1 to self-associate and form trimers capable of binding to the heat shock elements in the genome. The chaperones, therefore, had yet another role: to repress the transcriptional activity of Hsf1, providing a feedback loop for the heat shock response when sufficient levels of heat shock proteins were available.

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Many human diseases thought to be unrelated may share commonalities of defects in protein folding homeostasis. If this mechanism also occurs in humans, we may be able to find the neuronal signature that controls protein misfolding in cells and activate the heat shock proteins in the skeletal muscle system to help restore function in muscular dystrophy and other motor neuron diseases. The findings also tease the possibility that there might be a way to control, stall, or regulate the misfolding associated with aging via a neurological mechanism. However, the story with neurons seems to be more nuanced. We observed that two neurons in C. elegans control the regulation of the heat shock response in all adult somatic cells. The role of active neuronal signalling and feedback control would seem to provide a basis by which cells and tissues activate a heat shock response according to need. This makes sense, as different tissues will have varied protein biosynthetic needs and environmental exposures. A “one-size-fits-all” approach to the heat shock response would not work. The heat shock response is a good story. It has humble beginnings of pure curiosity. Starting with a small band of “heat shockers,” the field has grown immensely and encompasses a multitude of disciplines and approaches fundamental to biology. In it are all of the elements of intrigue and surprise, with a remarkable cast of characters. Who would have predicted the chance observation of Ritossa’s that chromosomal puffs in Drosophila, induced by elevated temperature, would lead to discoveries across all of biology? Well beyond the satisfaction of these observations alone has been the recognition that many human diseases thought to be unrelated may share commonalities of defects in protein folding homeostasis and that the correction of these defects could have broadreaching global effects on proteome stability and the health of the cell. Read more: Shock and Age - The Scientist - Magazine of the Life Sciences

Forget about the consequences of failure. Failure is only a temporary change in direction to set you straight for your next Success.

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Biotalk vol. 2 issue 4