Thursday, 2 August 2018

Scientists Develop New Method to Synthesize Bio-Conjugates

Antibody-drug conjugates combine drugs with antibodies that specifically target tumour markers in cancer cells.



(Drs. Neetu Kalra, Vishal Rai, Sanjeev Shukla, M. Chilamari (Left to Right))

In a promising development in the area of targeted treatment of cancer, a team of researchers at the Indian Institute of Science Education and Research (IISER), Bhopal, have developed a new method to synthesize antibody-drug conjugates (ADC) using the chemical route.

Antibody-drug conjugates combine drugs with antibodies that specifically target tumor markers in cancer cells. When administered to patients, antibodies in conjugate track tumor markers and attach themselves to the surface of cancer cells. The antibody-market reaction triggers a signal in tumor cells which absorbs antibodies together with the drug.

However, the difficulty is that several amino acid residues in antibodies like lysine, tyrosine, tryptophan, cysteine, and histidine compete during installation of drugs. Amino acid residues also have multiple copies, each having a different level of reactivity making it difficult to identify the right one.

The researchers at IISER have now demonstrated that it was possible to synthesize an effective conjugate with lysine without much of a problem. The process makes use of 4-acetyl benzaldehyde, an electron-rich aromatic aldehyde, and triethyl phosphate, which is an organo-phosphorous compound used as a reagent.

“We had earlier demonstrated that it was possible to differentiate various copies of lysine for a level of reactivity and to selectively pick up the desired one, but we still could not develop a conjugate as we had used a metal-complex. Now the reaction is metal-free. A sequential formation of C-N bond and a C-P bond results in the labeling of lysine which is followed by installation of the drug,” explained Dr. Vishal Rai, leader of the team, while speaking to India Science Wire.

The team has developed conjugate of breast cancer drug, Trastuzumab, and anti-cancer drug Doxorubicin and tested its anti-proliferative effect on a HER2 over-expressing cancer cell line. After two days of treatment, the conjugate showed significant inhibition of SKBR3 breast cancer cell proliferation.

For evaluating selectivity of the conjugate, the researchers compared its anti-proliferative effect against a direct dose of Doxorubicin for effect on SKBR3 breast cancer cells and on the non-pathogenic HER2 negative MDA-MB-231 cells.

“The anti-proliferative activity towards breast cancer cells holds promise for further pre-clinical evaluation,” commented Dr. S. Chandrasekaran from Indian Institute of Science, Bangalore, who was not associated with this study. Dr.T. Govindaraju from Jawaharlal Nehru Centre for Advanced Scientific Research, Bangalore, said, “specific advantage of this bio-conjugation technique is that it is metal-free.”

The technology is being transferred for commercial use through the IISER Bhopal based startup, Plabeltech. The research team included M. Chilamari, Neetu Kalra, and Sanjeev Shukla besides Dr. Vishal Rai.

The results of the study, funded by the Science and Engineering Research Board (SERB), have been published in journal Chemical Communications.

Journal Reference: 
Single-site labeling of lysine in proteins through a metal-free multicomponent approach

Tuesday, 17 July 2018

Scientists Provide New Insight Into Basophils Activation

Researchers have uncovered that Tregs can instead stimulate the activation of a particular immune cell, which has a role in several inflammatory conditions, particularly in allergy.


By Ratneshwar Thakur  Appeared in BiotechTimes, ResearchStash

(Meenu Sharma and Jagadeesh Bayry )

Human body naturally produces a different type of white blood cells (leukocytes). Of them, basophils share around 0.5% of total leukocytes in the blood- which provides protection against helminth parasites. Despite basophils are known since ages for their role in allergic and inflammatory diseases, how their activities are regulated and are kept in check still not understood. 

Normally immune system guards our body against pathogens like bacteria and virus, and cleans them regularly. However, under certain conditions, immune system attacks our own body and those results in autoimmune and inflammatory diseases like diabetes, arthritis, and others. Therefore, there are peacekeepers in the body to make sure that our immune system does not attack our own body, organs and tissues. These peacekeepers are regulatory T cells or “Tregs” that block hyperactivation of immune system and thus prevent autoimmune diseases and inflammation. For that matter, Tregs-derived molecules are currently used in clinic for the immunotherapy of several diseases.

Thus by default, Tregs are known in the scientific community as ‘immunosuppressor’ cells, which ensure that autoimmune responses and inflammation are kept in check and hence safeguard our body. Now, researchers for the first time have uncovered that Tregs can instead stimulate the activation of a particular immune cell, which has role in several inflammatory conditions, particularly in allergy.

Dr. Jagadeesh Bayry’s team at Institut National de la Santé et de la Recherche Médicale (French National Institute of Health and Medical Research, INSERM), Paris, France- have discovered that Tregs instead of suppressing the activities of basophils, they trigger these cells to express activation markers, to secrete cytokines and support their allergic responses. These findings also explain why Tregs are unable to control allergic responses when we encounter various environmental allergens in our daily life.

“We have discovered that Tregs forget that they are supposed to be suppressors when mesmerized by basophils. Our findings revealed that Tregs instead of suppressive, they activate the basophils and thus highlights a ‘secret’ life and a special relationship of basophils with Tregs,” said Dr. Jagadeesh Bayry, study leader and co-author in this study.

Meenu Sharma, First author in this study, says, “this is the first ever study that revealed previously unknown aspect of Tregs. We have found unusual relationship between basophils and Tregs.”

“Ours is a fundamental immunology finding and has broad implication for the therapy of allergic diseases. In view of our current findings, we strongly urge the scientific community to target both Tregs and basophils in order to obtain maximum efficacy of immunotherapy,” said Dr. Bayry.

“This report will completely change our current default view on Tregs as immune suppressors. Because of these unexpected findings, the concept of Treg-based therapeutic approaches may need to be revisited for allergy and asthma, where basophils are one of the major players that drive the inflammation”, commented Prof. K. N. Balaji from Indian Institute of Science, India. He is not involved in this study.

The research team included Meenu Sharma, Mrinmoy Das, Emmanuel Stephen-Victor, Caroline Galeotti, Anupama Karnam, Mohan S. Maddur, Patrick Bruneval, Srini V. Kaveri, and Jagadeesh Bayry. These results were published in the journal “Science Immunology.” The study was funded by French National Institute of Health and Medical Research, European Commission collaborative Grant and Sorbonne University.

Journal Reference: 

Friday, 22 June 2018

Scientists Figure Out Why HIV-1C Subtype Replicates Faster

Scientists from India and America have figured out why HIV-1C subtype is more prevalent than other subtypes of the virus.


(Dr. Udaykumar Ranga with the research team)
A team of scientists from India and America have figured out why HIV-1C subtype is more prevalent than other subtypes of the virus.

The human immunodeficiency virus consists of two types HIV 1 and 2 and each one of them has many subtypes. Of them, HIV-1C alone causes half of all the HIV infections globally and nearly all in India.

Researchers have found that HIV-1C can efficiently duplicate an important region of its genome to replicate faster unlike other subtypes. HIV-1C duplicates a region of its Gag protein called PTAP domain to make two copies of this domain.

The study was conducted in a group of HIV positive persons in India. It was found that viral strains of HIV-1C containing two PTAP domains could dominate viral strains containing only one PTAP domain in the blood of eight persons during follow up.

“This molecular trick may have given HIV-1C a big replication advantage over others. Given the dynamic nature of viral evolution, this trick may be transmitted to other slow-witted cousins through ‘viral recombination’ and may make this new molecular trick a universal problem,” explained Dr. Udaykumar Ranga, a scientist at Jawaharlal Nehru Centre for Advanced Scientific Research (JNCASR), Bangalore, who led the study.

Dr. Shahid Jameel, a virologist and CEO of Wellcome Trust DBT India Alliance, who was not associated with this study, pointed out that “HIV shows high degree of sequence variation, making it both an interesting virus to study and a difficult one to control through vaccines and drugs.” 

Dr. Akhil C. Banerjea, Emeritus Professor at the National Institute of Immunology commented that “the researchers have found a new motif in HIV that may explain why subtype C can multiply at a faster rate. This study will also allow targeting this motif to control viral replication.”

The research team included Shilpee Sharma, P.S. Arunachalam, Malini Menon, J. Jebaraj, Shambhu G., Chaitra Rao, Sreshtha Pal and Udaykumar Ranga (JNCASR); V. Ragupathy, I. Hewlett (Center for Biologics Evaluation and Research, USA); Ravi Vijaya Satya (GRAIL Inc, USA); S. Saravanan, K. G Murugavel, P. Balakrishnan and (late) S. Solomon (Y.R. Gaitonde Centre for AIDS Research and Education, Chennai). 

This work was supported by Department of Science and Technology (DST). The researchers have published their findings in the Journal of Biological Chemistry.

Journal Reference:



Wednesday, 13 June 2018

New Route To Synthesize Bioplastics Developed

Researchers have developed a new strategy that promises to help expand the scope for production of bioplastics.




A group of researchers has developed a new strategy that promises to help expand the scope for production of bioplastics.

In recent years, scientists and industry have focused on developing bioplastics as a replacement for synthetic ones to help protect the environment. However, bio-polymers produced from materials like starch have found limited applications and their production processes are expensive and generate pollution.

The strategy — developed by researchers from National Institute of Technology (Warangal), SASTRA Deemed University (Thanjavur) and Central University of Jammu — promises to overcome this problem. The process involves use of natural monomers and a bio-catalyst called Novozyme 435. It is a lipase obtained from the yeast called Candida Antarctica.

While preparing oligoesters as part of regular experiments, researchers observed formation of a viscous solution which was behaving very similar to molecular self-assembly: disordered molecules were adopting a defined structure on their own. “This observation motivated us to understand the concept of self-assembly assisted polymerization,” said K. Muthusamy from Sastra University, Thanjavur, co-author in the study.

The new protocol involves two steps. First, bio-based monomers, C-glycosylfuran and diacids, were subject to poly-condensation to form high molecular weight compound in the presence of bio-catalyst. The output was then made to undergo self-assembly assisted polymerization to realize the desired product. Conventionally, vegetable oils, carbohydrates, lignin and cardanol are used for producing bio-based polymers. The process is, however, expensive and not environment-friendly.

“We have used environmental friendly bio-based monomers, C-glycosylfuran derived from monosaccharides and a bio-catalyst. With this approach, we can generate cross-linked polymers and different products with varying properties can be produced by manipulating the design of oligoester. The products may find use for a range of applications in medical and food sectors,” explained study leader Dr. S. Nagarajan of NIT, Warangal, while speaking to India Science Wire.

Converting bio-based monomers into value-added materials is important in sustainable chemistry. “The group has prepared bifunctional monomers and which were converted into polymers using an enzyme-catalyzed reaction. It is an efficient way of generating materials which have potential to make soft materials, and may find applications in near future," commented Dr. Praveen Kumar Vemula from Institute for Stem Cell Biology and Regenerative Medicine, Bangalore who is not a part of this study.

The research team included K. Muthusamy, K. Lalitha, Y. Siva Prasad, A. Thamizhanban, C. Uma Maheswari (SASTRA Deemed University),V. Sridharan (Central University of Jammu) and S. Nagarajan from NIT Warangal. The study, financially supported by the Department of Science and Technology (DST), has been published in journal ChemSusChem.

Reference:

Monday, 28 May 2018

Artificial Membrane Inspired By Fish Scales May Help In Cleaning Oil Spills

IIT Guwahati based researchers have developed a stretchable underwater superoleophobic membrane that can separate water from various forms of oil contamination.


(Dr. Uttam Manna and Dibyangana Parbat )

Fish scales have a typical structure and chemistry that makes them naturally capable of repelling oil. Scientists are trying to exploit this property to develop novel materials that can find application in addressing oil pollution. The objective is to synthesise artificial interfaces that have oil-repelling properties or underwater superoleophobicity.

In this direction, a group of researchers at the Indian Institute of Technology (IIT), Guwahati, have developed a stretchable underwater superoleophobic membrane that can separate water from various forms of oil contamination. The membrane can work in complex scenarios, including extreme pH and temperatures, surfactant-contaminated water, river water, and seawater. It is able to separate oil repetitively from water even after 1,000 cycles of physical deformations.

The material has been designed by depositing a polymeric nano-complex on a polyurethane-based stretchable fibrous substrate. The polymeric nano-complex was prepared by mixing a branched polyethylene polymer with penta-acrylate molecules. The polymeric nano-complex coated fibrous substrate was then modified with glucamine molecules to mimic fish-scale wettability, explained Dr. Uttam Manna, leader of the research team, while speaking to India Science Wire.

Dibyangana Parbat, co-researcher, said the new material could help in taking care of wastewater discharge from refineries and other oil-based industrial units and accidental oil spills. In addition, it could also have biomedical applications. For instance, it could be used as an anti-biofouling coating on substrates such as catheter balloons.

The existing general approaches for synthesis of fish-scale mimicked interfaces are mostly based on depositions of polymeric hydrogels and metal oxides, both of which are not durable in severe conditions.

“This work can find immense applications, and potentially create economic value,” commented,” Dr. Thalappil Pradeep, Professor of Chemistry, from the Indian Institute of Technology Madras, who was not connected with the study.

This study was financially supported by Science and Engineering Research Board (SERB), Department of Science and Technology. The results of this study have been published in Journal of Materials Chemistry A.

Journal ref.: 

Wednesday, 23 May 2018

Scientist Uncover A Piece In The Puzzle Of Macrophage Activation

Scientists at the Institute of Microbial Technology (IMTECH), Chandigarh have found that a protein called Arf-like (Arl) GTPase-11(Arl11) activates macrophages in response to pathogenic stimuli.




(Scientists at the Institute of Microbial Technology (IMTECH), Chandigarh)


Macrophages - derived from the Greek word meaning large eaters’ - are one of the sentinels of human immune system that engulf pathogens and degrade them and also alert other sentinels about presence of foreign pathogens. However, in some cases there is uncontrolled or hyperactivation of macrophages such as in cancer or autoimmune disorders.

Researchers are trying to shed light on how macrophages get activated so as to help control such problems. Scientists at the Institute of Microbial Technology (IMTECH), Chandigarh have found that a protein called Arf-like (Arl) GTPase-11(Arl11) activates macrophages in response to pathogenic stimuli. In a paper published in Journal of Biological Chemistry, they have reported that the protein is essential for macrophages to kill foreign pathogens.

"We worked on this particular protein as previous studies had found it to be missing in tumour cells but its function was not known. We were surprised to know that it is expressed in many immune cells including macrophages, and therefore set out to know what would be the function of Arl11 in macrophages," Dr. Amit Tuli, who led the research team, told India Science Wire.

The study throws light on cellular function of Arl11, which is an evolutionarily conserved protein. "We found that the expression of Arl11 increases when macrophages encounter pathogens and that this is required to initiate a cascade of events that finally result in activation of macrophage," explained Subhash B. Arya, a member of the research team.

Understanding how immune system functions is crucial not only for immunotherapy, such as, against cancer but also to understand inflammation that damages normal tissues. The study found that by increasing Arl11 expression in macrophages can activate them. "It will be highly relevant to study Arl11 expression changes in diseases such as autoimmune disorders, atherosclerosis and obesity", added Dr. Tuli.

Commenting on the work, Prof. Somdatta Sinha from Indian Institute of Science Education and Research (IISER), Mohali, who was not associated with the study, said, "the study has found a novel and interesting relation between a gene that is known to be related to familial risk of different types of cancers, to its role in responding to bacterial pathogen in certain immune cells. The molecular elucidation of pathways of interactions of this gene can, in the long run, tell us ways that immune system functions in handling different types of diseases."

The research team included Subhash B. Arya, Gaurav Kumar, Harmeet Kaur and Amandeep Kaur. This work was supported by the Wellcome Trust/Department of Biotechnology (DBT) India Alliance and CSIR-IMTECH intramural funding.

Journal reference: 

Wednesday, 16 May 2018

Metal-Organic Nanosheets May Help Develop Novel Lens Material

The new photochromic 2D metal-organic nanosheets (MONs) are envisaged to be applicable not only in ophthalmic lenses, but also in other related applications, where light-induced switching between two or more species with different optical properties must occur smoothly.



(Prof. J.N. Moorthy and his team members)

Photochromic materials can change colour under stimulation of light. They are of high commercial importance for ophthalmic lens industry as also in sectors like optoelectronic switching devices, data storage and optical transmission.

Photochromic materials change colours on account of changes in the arrangement of atoms in materials. Atoms in photochromic materials are arranged in a certain manner and change when exposed to sunlight or UV light. We can observe this reversible behaviour in sunglasses. However, there are challenges associated with polymers. It is restricted by what features are desired in polymers in terms of rigidity, hardness and scratch resistance. Presently, researchers achieve photoswitching by linking photochromes covalently to soft low-molecular weight polymers.

A team of researchers at Indian Institute of Technology (IIT), Kanpur have demonstrated that porous 2-dimensional metal-organic nanosheets (MONs) constructed from photochromic building blocks can also be employed as agents or dopants in polymers to bring out the desired optical properties in photochromic polymers.

Three dimensional porous metal-organic framework materials (MOFs) have been used for various applications like photo-controlled gas storage, separations, sensing, and catalysis in recent years. However, they are not suitable for use in thin films and polymeric matrices to develop photo-responsive materials, as they pose problems like leaching and poor photoswitching.

The new photochromic 2D metal-organic nanosheets (MONs) are envisaged to be applicable not only in ophthalmic lenses, but also in other related applications, where light-induced switching between two or more species with different optical properties must occur smoothly.

Speaking to India Science Wire, leader of the team Prof. J. N. Moorthy said, “Photo-responsive MONs can find applications in ophthalmic industry. As photo-chromes distributed in polymeric 2D nanosheets can be impregnated in rigid polymeric matrices, leaching of photo-chromes can be overcome, besides providing practical simplicity in terms of fabrication. The concept can also be exploited for photo-controlled sieving of organic molecules.”

Commenting on the work, Prof. Rahul Banerjee from Indian Institute of Science Education and Research (IISER), Kolkata, who was not involved in this study, said, “this is an interesting finding in which researchers could show that exfoliation of layered porous metal-organic frameworks (MOFs) using a top-down approach can help produce 2D metal-organic nanosheets (MONs). This type of crystal engineering approach is quite novel and could bring in novel and new applications in the field of MOFs.”

Prof. Gautam R. Desiraju, Indian Institute of Science, Bangalore, who too was not involved in the study, said, “MOFs as a field is getting saturated and plateauing out. It may require a new vision over the next five to ten years. This subject is not associated with organic chemistry alone. Multi-disciplinary study of MOFs may move in advantageous directions in the future. Chemistry is looking for new paradigms, where the essence of the old is clubbed with a whole new superstructure, combining vertical and horizontal ways of thinking.”

The study has been published in the latest issue of journal CHEM. Besides Prof. Moorthy, the research team included Arindam Mukhopadhyay, Vijay Kumar Maka, and Govardhan Savitha. The study was funded by Science and Engineering Research Board (SERB) of the Department of Science and Technology (DST).

Reference: Photochromic 2D Metal-Organic Framework Nanosheets (MONs): Design, Synthesis, and Functional MON-Ormosil Composite

Wednesday, 9 May 2018

Scientists Find Synthetic Mimic For Critical Biomolecule

The researchers have mimicked ATP-selective actin- like self-assembly in the laboratory very similar to what happens in the natural conditions inside the cells.





(The research team at Jawaharlal Nehru Centre for Advanced Scientific Research (JNCASR), Bengaluru.)

Biological assemblies are thousands of tiny pieces of machinery which play collectively important roles towards maintaining the cellular structure and functions, and many of them even play very critical roles. Self-assembly of these tiny machines requires biological fuel to become operational. Scientists have been trying to figure out how these tiny machines are controlled. This could help in controlling engineered organic designs comparable to natural frameworks.

A research team led by Dr. Subi J. George and Dr. S. Balasubramanian at Jawaharlal Nehru Centre for Advanced Scientific Research (JNCASR), Bengaluru, have shown that synthetic molecules can grow and be controlled on similar stimuli such as biological systems.

In this study, researchers worked on Actin, a protein which frames the contractile fibers of muscle cells. In a living system, Actin assembles on its own using its monomer components under the influence of biological fuel Adenosine Triphosphate (ATP). Actin as the tiny machine works like a treadmill to support cellular movements.

The researchers have mimicked ATP-selective actin- like self-assembly in the laboratory very similar to what happens in the natural conditions inside the cells. They could observe monomer subunits undergoing ATP-fuel-driven elongation resembling natural actin self-assembly. Interestingly, when researchers used ATP-hydrolysing enzymes, it prompts actin dissociation. The results of this study have been published in the journal Nature Communications.

Speaking to India Science Wire, Dr. George said “since the stimulus in our case is ATP, which is one of the most universally present chemicals, this makes our work a benchmark in what can be achieved synthetically. Also, our study has come closest in synthetically mimicking natural protein Actin’s assembly, a protein which plays an important role in various biological functions. These outcomes will guide investigators to search for more synthetic analogs of important biological self-assembly”.

“Using biological cues like ATP opens up routes for bio-adaptable systems. A step even further perhaps is the possibility of an organic electronic device in the interface with biological live feed. Such a system would be highly efficient and uniquely adaptive in reporting live biological changes in a body,” he added.

Commenting on the research findings, Prof. E. W. Meijer from the Eindhoven University of Technology, The Netherlands- who is not involved in the work, said, “Researchers have tackled one of the main challenges in mimicking natural systems. Where chemists normally can control the assembly of small molecules in large one-dimensional aggregates only by solvent or temperature, Nature assembles and disassembles these structures by chemical fuels – chemical reactions that take care of the growth. This study is an important next step in the development of functional life-like materials and systems.”

The research team also included Ananya Mishra, D. B. Korlepara, Mohit Kumar, Ankit Jain, N.Jonnalagadda, and K.K. Bejagam. The study was funded by the Department of Science and Technology.

Reference:
Biomimetic temporal self-assembly via fuel-driven controlled supramolecular polymerization

Monday, 23 April 2018

Tinkering With Root Hair May Help Boost Crop Yields

Once roots sense low availability of phosphate in the soil, the information is communicated to the plant which then signals back use of auxin to roots, in order to stimulate root hairs to grow longer and capture phosphate.

(Dr. Jitender Giri and Bipin K. Pandey)

Have you ever wondered how a plant is able to sense nutrients in the soil. The answer lies in the root design. Plants have the capability to change angle and length of their roots as well as hair-like extensions on roots for absorbing nutrients from soil. 

Now researchers are exploring mechanisms adopted by plants to survive in low phosphate soils and figuring out if they can develop better strategies for plants to deal with poor water availability and low soil minerals. 

In a collaborative study, researchers at the National Institute of Plant Genome Research (NIPGR) here have discovered in rice plant that production and transport of a hormone, auxin, in root hair zone triggers elongation of root hair under low phosphate conditions. The results of the study have been published in journal Nature Communications.

Phosphate is an important nutrient for plant growth and development. Researchers say once roots sense low availability of phosphate in the soil, the information is communicated to the plant which then signals back use of auxin to roots, in order to stimulate root hairs to grow longer and capture phosphate. 

The study explains how auxin serves as an important signal for phosphate status in the root. A specific gene, OsAUX1, mobilizes auxin in the region of root where it signals hair elongation when roots encounter low soil phosphate. 

Root hairs help to absorb phosphate and water from soil. The root hairs elongate to increase surface area to capture scarce nutrients such as phosphate under low soil phosphate conditions. 

“Green revolution helped almost triple yields of major crops like rice and wheat. However, it was highly dependent on chemical fertilizers like phosphate and urea. India imports almost 90 percent of raw material for producing phosphate fertilizers. This inspired us to engineer plant roots for better nutrient acquisition,” Dr. Jitender Giri told India Science Wire. Bipin K. Pandey, a member of the team, explained that the study had revealed big role of tiny cellular extensions - root hairs- in nutrient acquisition from poor soils.

In another study published in the same journal, the research group has used Arabidopsis, a model plant, to further explore the phenomenon. It has been seen that when auxin synthesis or its transport to root tissues is disrupted, plant shows poor root hair elongation in response to low external phosphate conditions.

This research teams included members from NIPGR (India) , University of Nottingham (UK), Shanghai Jiao Tong University, (China), CIRAD (France), Swedish University of Agricultural Sciences (Sweden), University of Aberdeen (UK), JIRCAS (Japan), James Hutton Institute (UK), Rothamsted Research (UK), The Pennsylvania State University, (USA) and University of Adelaide (Australia). The research work at NIPGR was funded by the Department of Biotechnology (DBT).

Reference:
https://www.nature.com/articles/s41467-018-03850-4
https://www.nature.com/articles/s41467-018-03851-3

Wednesday, 18 April 2018

Glycogen In Neurons Of Degenerating Brains Is Beneficial: Study

A team of Indian scientists has figured out that glycogen in neurons actually has a protective role in patients with neurodegenerative disorders like Alzheimer’s and Huntington’s.




(Dr. S. Ganesh and his team members)


Healthy neurons do not store glycogen – the main source of energy storage for cells – while they do possess the machinery for glycogen synthesis in an inactive state. At the same time, neurons in degenerating brains are known to accumulate glycogen. A team of Indian scientists has figured out that glycogen in neurons actually has a protective role in patients with neurodegenerative disorders like Alzheimer’s and Huntington’s.

For long, scientists have been trying to find the specific role of glycogen in neurons, especially in brain diseases like Huntington’s, Lafora, Alzheimer’s etc. with some believing it be neurotoxic. The new study led by Prof. Subramaniam Ganesh of Indian Institute of Technology, Kanpur (IIT-K) suggests that glycogen has a protective role in neurons of patients suffering from neurodegenerative disorders.

Glycogen synthetic machinery in healthy neurons usually remains in an inactive state. In this machinery, an enzyme called glycogen synthase catalyzes the formation of glycogen. Using cellular and animal models of Huntington’s disease, the researchers have shown that high level of cytotoxic mutant Huntingtin protein triggers more glycogen synthesis in neurons by activating glycogen synthase. They observed that increased level of glycogen synthase protects neurons from the cytotoxicity of the mutant Huntingtin protein.

“Our findings establish that glycogen synthase is required for neurons to survive during stress. We also show that glycogen thus synthesized prevents aggregation of abnormal proteins, and helps in their clearance. These findings might open up new avenues of therapeutic interventions,” explained Dr. Ganesh.

The activation of glycogen synthase is harmful to healthy and happy neurons, and this may explain why glycogen granules are not seen in normal neurons. This means glycogen accumulation in degenerating brain could possibly represent a failed attempt of neurons to survive during the stress. “Our work establishes the neuroprotective role of glycogen synthase in Huntington’s disease models and thus discovers a previously unknown function of glycogen synthase in neuronal physiology”, he added.

“It is an important finding on the protective role of glycogen synthase in neurodegenerative diseases which may have translational relevance,” commented Prof. Sathees C. Raghavan from Indian Institute of Science, who is not connected with this study.

“These findings may open exciting possibilities for developing new therapeutic approaches for the neurodegenerative diseases which are becoming serious health issues in human populations in recent times,” said Prof. S. C. Lakhotia from Banaras Hindu University, who is not a part of this study.

The study has been published in journal Cell Death and Disease. The research team included Anupama Rai, Pankaj K. Singh, Virender Singh, Rohit Mishra, Ashwani K. Thakur, and Subramaniam Ganesh (IIT-Kanpur); Vipendra Kumar, Nihar R. Jana (National Brain Research Centre, Manesar); Anita Mahadevan, Susarla K. Shankar, (NIMHANS, Bengaluru). This research work was funded by Department of Biotechnology. (India Science Wire)

Journal Ref.: 

Thursday, 12 April 2018

Scientists Shed Light On Cancer Risk Associated With Epigenetic Changes During Aging

To be able to predict aging-related cancer risks, researchers are trying to identify those genes which undergo the most epigenetic changes during normal aging and in early tumor development.


(Research team members)


The new science of Epigenetics has enabled us to track, how our lifestyle and surroundings affect the behavior of genes in our body, without altering the underlying DNA sequence (commonly called ‘mutations’).These epigenetic changes may stop aged cells and damaged cells from forming any new cells–akin to forced retirement, scientifically known as senescence, thereby preventing chances of cancer. However unusual epigenetic changes might help rogue cells to escape senescence and steer towards formation of tumors.

Now, to be able to predict aging-related cancer risks, researchers are trying to identify those genes which undergo the most epigenetic changes during normal aging and in early tumor development.

In a collaborative study, a team of researchers from India and USA (Dr.Subhojit Sen of University of Mumbai and Dr. Hariharan Easwaran of John Hopkins University, USA) have identified two sets of genes: one that may help human cancer cells to progress by rejecting forced retirement or senescence due to unusual DNA methylation, while a different set which might be responsible for cancers from normally aging cells. The results of this study have been published in the Journal ‘Cancer Cell’.

In this study, researchers have performed experiments on mice and cells from human skin samples. To analyze epigenetic changes, they observed patterns of DNA methylation, a process by which cells add tiny methyl chemical groups to a beginning region of a gene's DNA sequence, thereby dictating how that gene is used.

“Some groups have suggested that epigenetic changes may promote tumour formation. It was puzzling us-- how epigenetic changes occurring in the tumour-protective process of senescence may also promote formation of tumours ?. Hence we investigated the differences in epigenetic changes that occur in both events,”said Dr. Hariharan Easwaran.

The authors observed that although the process of DNA methylation appeared similar for both senescent and tumours cells, the genes that got methylated and the way it occurred were different between the two. They found that DNA methylation in senescent cells occurred in metabolic process related genes and appeared to be programmed and reproducible. On the other hand, in tumour cells, methylation occurred in growth related genes and appeared to be relatively random.

Classically, environmental stresses like smoking, harmful diets or lifestyle choices were thought to cause cancer mainly through DNA mutations. Recent studies have suggested that environmental stresses and carcinogens can also induce these types of unusual epigenetic changes. “Thus it is important to realize that these exposures impact our genomes in multiple ways - both genetic and epigenetic - all of which may synergize in inducing tumour formation,” added Dr. Easwaran.

“Next, we will explore strategies for determining age-associated risk of tumor development. It may eventually lead to biomarker development which might help us detect these changes very early on, even in healthy individuals,” said Dr. Easwaran

“This happens to be the first or at least initial evidence to clearly demonstrate differences in DNA methylations in terms of target genes. Successful replication of these results may help in deciding whether well-defined methylated genes can be developed as biomarkers for cancer risk assessment,” said Prof. Girish B. Maru, ACTREC, Mumbai, a cancer researcher who is not connected with this study.

Besides Dr. Easwaran and Dr. Subhojit Sen, the research team included many researchers from Johns Hopkins University and the USA’s National Institutes of Health.

Journal Ref.: DNA Methylation Patterns Separate Senescence from Transformation Potential and Indicate Cancer Risk