Aug
12
Mon
2013
Invited Talk: Neuroprotective and neurodestructive effects of Ayurvedic drug constituents: Parkinson’s disease @ Amriteshwari Hall
Aug 12 @ 2:55 pm – 3:20 pm

mohanakumarK. P. Mohanakumar, Ph.D.
Chief Scientist, Cell Biology & Physiology Division, Indian Institute of Chemical Biology, Kolkata


Neuroprotective and neurodestructive effects of Ayurvedic drug constituents: Parkinson’s disease

The present study reports the good and the bad entities in an Indian traditional medicine used for treating Parkinson’s disease (PD). A prospective clinical trial on the effectiveness of Ayurvedic medication in a population of PD patients revealed significant benefits, which has been attributed to L-DOPA present in the herbs [1]. Later studies revealed better benefits with one of the herbs alone, compared to pure L-DOPA in a clinical trial conducted in UK [2], and in several studies conducted on animal models of PD in independent laboratories world over [3-5]. We have adapted strategies to segregate molecules from the herb, and then carefully removed L-DOPA contained therein, and tested each of these sub-fractions for anti-PD activity in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, rotenone and 6-hydroxydopamine -induced parkinsonian animal models, and transgenic mitochondrial cybrids. We report here two classes of molecules contained in the herb, one of which possessed severe pro-parkinsonian (phenolic amine derivatives) and the other having excellent anti-parkinsonian potential (substituted tetrahydroisoquinoline derivatives). The former has been shown to cause severe dopamine depletion in the striatum of rodents, when administered acutely or chronically. It also caused significant behavioral aberrations, leading to anxiety and depression [6]. The latter class of molecules administered in PD animal model [7], caused reversal of behavioral dysfunctions and significant attenuation of striatal dopamine loss. These effects were comparable or better than the effects of the anti-PD drugs, selegiline or L-DOPA. The mechanism of action of the molecule has been found to be novel, at the postsynaptic receptor signaling level, as well as cellular α-synuclein oligomerization and specifically at mitochondria. The molecule helped in maintaining mitochondrial ETC complex activity and stabilized cellular respiration, and mitochondrial fusion-fission machinery with specific effect on the dynamin related protein 1. Although there existed significant medical benefits that could be derived to patients due to the synergistic actions of several molecules present in a traditional preparation, accumulated data in our hands suggest complicated mechanisms of actions of Ayurvedic medication. Our results also provide great hope for extracting, synthesizing and optimizing the activity of anti-parkinsonian molecules present in traditional Ayurvedic herbs, and for designing novel drugs with novel mechanisms of action.

  1. N, Nagashayana, P Sankarankutty, MRV Nampoothiri, PK Mohan and KP Mohanakumar, J Neurol Sci. 176, 124-7, 2000.
  2. Katzenschlager R, Evans A, Manson A, Patsalos PN, Ratnaraj N, Watt H, Timmermann L, Van der Giessen R, Lees AJ. J Neurol Neurosurg Psychiatry.75, 1672-7, 2004.
  3. Manyam BV, Dhanasekaran M, Hare TA. Phytother Res. 18, 706-12, 2004.
  4. Kasture S, Pontis S, Pinna A, Schintu N, Spina L, Longoni R, Simola N, Ballero M, Morelli M. Neurotox Res. 15, 111-22, 2009.
  5. Lieu CA, Kunselman AR, Manyam BV, Venkiteswaran K, Subramanian T. Parkinsonism Relat Disord.16, 458-65, 2010.
  6. T Sengupta and KP Mohanakumar, Neurochem Int. 57, 637-46, 2010.
  7. T Sengupta, J Vinayagam, N Nagashayana, B Gowda, P Jaisankar and KP Mohanakumar, Neurochem Res 36, 177-86, 2011

MOhan (1) MOhan (2)

Aug
13
Tue
2013
Invited Talk: Pertubation of DNA topology in mycobacteria @ Acharya Hall
Aug 13 @ 11:50 am – 12:12 pm

NagarajaV. Nagaraja Ph.D.
Professor, Indian Institute of Science, Bengaluru, India


Perturbation of DNA topology in mycobacteria

To maintain the topological homeostasis of the genome in the cell, DNA topoisomerases catalyse DNA cleavage, strand passage and rejoining of the ends. Thus, although they are essential house- keeping enzymes, they are the most vulnerable targets; arrest of the reaction after the first trans-esterification step leads to breaks in DNA and cell death.  Some of the successful antibacterial or anticancer drugs target the step ie arrest the reaction or stabilize the topo -DNA covalent complex. I will describe our efforts in this direction – to target DNA gyrase and also topoisomerase1 from mycobacteria. The latter, although essential, has no inhibitors described so far. The new inhibitors being characterized are also used to probe topoisomerase control of gene expression.

In the biological warfare between the organisms, a diverse set of molecules encoded by invading genomes target the above mentioned most vulnerable step of topoisomerase  reaction, leading to the accumulation of double strand breaks. Bacteria, on their part appear to have developed defense strategies to protect the cells from genomic double strand breaks. I will describe a mechanism involving three distinct gyrase interacting proteins which inhibit the enzyme in vitro. However, in vivo all these topology modulators protect DNA gyrase from poisoning effect by sequestering the enzyme away from DNA.

Next, we have targeted a topology modulator protein, a nucleoid associated protein(NAP) from Mycobacterium tuberculosis to develop small molecule inhibitors by structure based design. Over expression of HU leads to alteration in the nucleoid architecture. The crystal structure of the N-terminal half of HU reveals a cleft that accommodates duplex DNA. Based on the structural feature, we have designed inhibitors which bind to the protein and affect its interaction with DNA, de-compact the nucleoid and inhibit cell growth. Chemical probing with the inhibitors reveal the importance of HU regulon in M.tuberculosis.

Invited Talk: From Camels to Worms: Novel Approaches for Drug Discovery in Parkinson’s Disease. @ Acharya Hall
Aug 13 @ 3:02 pm – 3:23 pm

TimGuilliamsTim Guilliams, Ph.D.
Junior Associate Fellow at the Centre for Science and Policy, University of Cambridge


From Camels to Worms: Novel Approaches for Drug Discovery in Parkinson’s Disease

The discovery of novel treatments for neurodegenerative diseases, such as Parkinson’s disease, represents one of the biggest scientific challenges of the 21st century. The development of new tools and models to study the mechanisms underlying neurotoxicity is therefore essential. During my talk, I will outline new strategies for drug design and innovation used during my PhD at the University of Cambridge, which include the combination of fluorescent nematode worms, camelid antibody fragment technology and chemical compounds. These novel approaches will help us to gain insights into the key pathogenic steps involved in Parkinson’s disease and potentially lead to new therapeutic strategies.

Delegate Talk: PC based heart sound monitoring system @ Amriteshwari Hall
Aug 13 @ 3:29 pm – 3:53 pm
Delegate Talk: PC based heart sound monitoring system @ Amriteshwari Hall | Vallikavu | Kerala | India

Arathy R and Binoy B Nair


PC based heart sound monitoring system

Heart diseases caused by disorders of the heart and blood vessels, are world’s largest killers. Early detection and monitoring of heart abnormalities is essential for diagnosis and effective treatment of heart diseases. Severalmethodologies are used for screening and diagnosing heart diseases. They are auscultation, electrocardiogram (ECG), echo-cardiogram, ultrasound etc. The effectiveness and applicability of all these diagnostic methods are highly dependent on the equipment cost and size as well as skill of the physician. This paper presents the design and development of a low cost portable wireless/tubeless digital stethoscope which can be used by the physician for monitoring the patient from a distance. The stethoscope system interfaces to a PC and is also capable of analyzing the heart sounds and identifying abnormalities in the heart sound and its classification. Storage of heart sound for later analysis is also possible.This advanced functionality increases the physician’s diagnostic capability, and such a PCG is not still available in most hospitals. Acoustic stethoscope can be changed into a digital stethoscope by inserting an electric capacity microphone into its diaphragm (Wang, Chen and Samjin, 2009).

Aug
14
Wed
2013
Delegate Talk: Intrinsic modulation of cytokine response by mycobacteria @ Acharya Hall
Aug 14 @ 11:35 am – 11:45 am
Delegate Talk: Intrinsic modulation of cytokine response by mycobacteria @ Acharya Hall | Vallikavu | Kerala | India

Sukhithasri V, Nisha N, Vivek V and Raja Biswas


The host innate immune system acts as the first line of defense against invading pathogens. During an infection, the host innate immune cells recognize unique conserved molecules on the pathogen known as Pathogen Associated Molecular Patterns (PAMPs). This recognition of PAMPs helps the host mount an innate immune response leading to the production of cytokines (Akira et al. 2006). Peptidoglycan, one of the most conserved and essential component of the bacterial cell wall is one such PAMP. Peptidoglycan is known to have potent proinflammatory properties (Gust et al. 2007). Host recognize peptidoglycan using Nucleotide oligomerization domain proteins (NODs). This recognition of peptidoglycan activates the NODs and triggers downstream signaling leading to the nuclear translocation of NF-κB and production of cytokines (McDonald et al. 2005). Pathogenic bacteria modify their peptidoglycan as a strategy to evade innate immune recognition, which helps it to establish infection in the host. These peptidoglycan modifications include O-acetylation and N-glycolylation of muramic acid and N-deacetylation of N-acetylglucosamine (Davis et al. 2011). Modification of mycobacterial peptidoglycan by N-glycolylation prevents the catalytic activity of lysozyme (Raymond et al. 2005). Additionally, mycobacterial peptidoglycan is modified by amidation for unknown reasons.

Here, we have investigated the role of amidated peptidoglycan in Mycobacterium sp in modulating the innate immune response. We isolated amidated peptidoglycan from Mycobacterium sp and non-amidated peptidoglycan from Escherichia coli. We made a comparative analysis of the cytokine response produced on stimulation of innate immune cells by peptidoglycan from E. Coli and Mycobacterium sp. Macrophages and whole blood were treated with peptidoglycan and the cytokines secreted into spent medium and plasma respectively were analyzed using ELISA. Our results show that peptidoglycan from Mycobacterium sp is less effective in stimulating innate immune cells to produce cytokines. This intrinsic modulation of the cytokine response suggests that mycobacteria modify their peptidoglycan by amidation to evade innate immune response.