Biologist engaged in teaching and research at the School of life Sciences, University of Hyderabad. The main focus of research is on eicosanoid signaling in health and disease, with special reference of inflammation and cancer. Polyunsaturated fatty acids such as arachidonic acid, is oxygenated by lipoxygenase and cyclooxygenase pathways to generate eicosanoids such as leukotrienes and prostanoids respectively. These eicosanoids regulate variety of physiological processes but their uncontrolled production is associate with many inflammatory disorders, including cancer. While understanding the role of eicosanoids in normal physiological processes such as reproduction, efforts are being made in the lab to develop isozyme specific inhibitors by employing molecular modelling and drug design approaches.
Biochemistry and cell biology = Biochimie et biologie cellulaire, Oct 1, 2017
Inhibition of angiogenesis is a useful strategy to prevent cancer growth by targeting new vessels... more Inhibition of angiogenesis is a useful strategy to prevent cancer growth by targeting new vessels that grow to nourish actively proliferating tumor cells. Endothelial cells can use a number of different pathways to cause angiogenesis, and each step in these pathways can be targeted. The use of multi-targeted drugs is gaining much importance in this scenario. Our previous results have shown that chebulagic acid (a benzopyran tannin present in the fruits of Terminalia chebula) has anti-angiogenic properties. Thus, this study was designed to examine the molecular mechanism for the anti-angiogenic effects of chebulagic acid. Results from our investigations using molecular docking studies and human umbilical vein endothelial cells in culture suggested that chebulagic acid inhibits both GSK-3β-dependent β-catenin phosphorylation (an important mediator of VE-cadherin-β-catenin signaling) and VEGFR2 phosphorylation, which is an important step in VEGF signaling. Chebulagic acid inhibits angi...
Background: The accurate ranking of analogs of lead molecules with respect to their estimated bin... more Background: The accurate ranking of analogs of lead molecules with respect to their estimated binding free energies to drug targets remains highly challenging in molecular docking due to small relative differences in their free energy values. Methods: Free energy perturbation (FEP) method, which provides the most accurate relative binding free energy values were earlier used to calculate free energies of many ligands for several important drug targets including Fructose-1,6-BisphosPhatase (FBPase). The availability of abundant structural and experimental binding affinity data for FBPase inhibitors provided an ideal system to evaluate four widely used docking programs, AutoDock, Glide, GOLD and SurflexDock, distinct from earlier comparative evaluation studies. Results: The analyses suggested that, considering various parameters such as docking pose, scoring and ranking accuracy, sensitivity analysis and newly introduced relative ranking score, Glide provided reasonably consistent res...
Arachidonic acid 5-lipoxygenase (ALOX5) is the key enzyme in the biosynthesis of pro-inflammatory... more Arachidonic acid 5-lipoxygenase (ALOX5) is the key enzyme in the biosynthesis of pro-inflammatory leukotrienes. We recently created knock-in mice (Alox5-KI) which express an arachidonic acid 15-lipoxygenating Alox5 mutant instead of the 5-lipoxygenating wildtype enzyme. These mice were leukotriene deficient but exhibited an elevated linoleic acid oxygenase activity. Here we characterized the polyenoic fatty acid metabolism of these mice in more detail and tested the animals in three different experimental inflammation models. In experimental autoimmune encephalomyelitis (EAE), Alox5-KI mice displayed an earlier disease onset and a significantly higher cumulative incidence rate than wildtype controls but the clinical score kinetics were not significantly different. In dextran sodium sulfate-induced colitis (DSS) and in the chronic constriction nerve injury model (CCI), Alox5-KI mice performed like wildtype controls with similar genetic background. These results were somewhat surprisi...
Initially, the aim is to provide the big picture illustrating the as is situation in the pharmace... more Initially, the aim is to provide the big picture illustrating the as is situation in the pharmaceutical industry: a lack of productivity resulting in too few products reaching the market; a loss of billions in revenue over the next few years as some of the major megabrands go off patent; a spiraling cost for developing new drugs and taking them through clinical and safety studies. Following on, a look deeper into the organization will offer an insight into the state-of-the-art in a technical function accountable for chemical Process R&D (with a remit to develop scalable, robust, and cost efficient processes for small molecules). The vast majority of compounds already launched in the form of drug products on the market or still being pursued through the phases of discovery and development, fall within the category of small molecules (as opposed to biopharmaceuticals, e.g., proteins, monoclonal antibodies). This typically means molecular weights of <1000Da and puts organic synthesis in the widest sense of the word at the forefront of technologies needed to support R&D programs in the pharma industry. Understandably, the demands on Medicinal Chemistry are quite different to what applies in a Process R&D (PR&D) organization. In the former, making large numbers of potentially interesting molecules, many of which are discarded after testing, is a key driver and for this virtually any synthetic methodology will suffice. For PR&D, however, homing in on selected compounds there is an expectation that the best synthetic routes will be delivered that meet a number of tough criteria, for instance from an environmental and safety point of view, allowing operation on large scale, offering cost competitiveness, avoiding patent infringements, showing sustainability for long-term production, etc. The intention is to focus on issues to be addressed during this transition by providing examples of changes that had to be put in place in order to make the supply of larger amounts of material feasible. At the end some forward looking conclusions will be shared.
Asiatic lions (Panthera leo persica), whose only natural habitat in the world is the Gir forest s... more Asiatic lions (Panthera leo persica), whose only natural habitat in the world is the Gir forest sanctuary of Gujarat State in India, are highly endangered and are considered to be highly inbred with narrow genetic diversity. An objective assessment of genetic diversity in their immune loci will help in assessing their survivability and may provide vital clues in designing strategies for their scientific management and conservation. We analyzed the comparative sequence polymorphism at exon 2 and exon 3 of major histocompatibility complex (MHC) class I in three groups of lions, i.e. wild Asiatic (from Gir forest), captive-bred Asiatic (from zoological parks in India), and Afro-Asiatic hybrid groups (from zoological parks in India) through polymorphism chain reaction-assisted sequence-based typing. The two exons were amplified, cloned, sequenced, and analyzed for polymorphism at nucleotide and putative translated product level. The analysis revealed extensive sequence polymorphism not only between clones derived from different lions but also the clones derived from a single lion. Furthermore, the wild Asiatic lions of Gir forest exhibited abundant sequence polymorphism at MHC class I comparable with that of Afro-Asiatic hybrid lions and significantly higher than that of captive-bred Asiatic lions. We hypothesize that Asiatic lions of Gir forest are not highly inbred as thought earlier and they possess abundant sequence polymorphism at MHC class I loci. During this study, 52 new sequences of the multigene MHC class I family were also identified among Asiatic lions.
Asiatic lions (Panthera leo persica), whose only natural habitat in the world is the Gir forest s... more Asiatic lions (Panthera leo persica), whose only natural habitat in the world is the Gir forest sanctuary of Gujarat State in India, are highly endangered and are considered to be highly inbred with narrow genetic diversity. An objective assessment of genetic diversity in their immune loci will help in assessing their survivability and may provide vital clues in designing strategies for their scientific management and conservation. We analyzed the comparative sequence polymorphism at exon 2 and exon 3 of major histocompatibility complex (MHC) class I in three groups of lions, i.e. wild Asiatic (from Gir forest), captive-bred Asiatic (from zoological parks in India), and Afro-Asiatic hybrid groups (from zoological parks in India) through polymorphism chain reaction-assisted sequence-based typing. The two exons were amplified, cloned, sequenced, and analyzed for polymorphism at nucleotide and putative translated product level. The analysis revealed extensive sequence polymorphism not only between clones derived from different lions but also the clones derived from a single lion. Furthermore, the wild Asiatic lions of Gir forest exhibited abundant sequence polymorphism at MHC class I comparable with that of Afro-Asiatic hybrid lions and significantly higher than that of captive-bred Asiatic lions. We hypothesize that Asiatic lions of Gir forest are not highly inbred as thought earlier and they possess abundant sequence polymorphism at MHC class I loci. During this study, 52 new sequences of the multigene MHC class I family were also identified among Asiatic lions.
The profile of primary dioxygenation products of arachidonic acid catalyzed by lipoxygenase isola... more The profile of primary dioxygenation products of arachidonic acid catalyzed by lipoxygenase isolated from hairy root cultures of Solanum tuberosum treated with a fungal elicitor was compared to that obtained for the enzyme from potato tubers. 11-Hydroperoxyeicosatetraenoic acid ...
12R-LOX over-expression has been reported in various pathologies such as psoriasis, proliferative... more 12R-LOX over-expression has been reported in various pathologies such as psoriasis, proliferative dermatitis as well as pulmonary obstructive diseases indicating that this enzyme plays significant role in pathogenesis of inflammatory diseases. 12R-LOX, therefore, is a suitable target for therapeutic intervention with potential application of its inhibitors in the treatment of skin and other inflammatory disorders. Identification of such inhibitors requires sufficient quantity of active enzyme to be produced by an easy and cost effective expression systems and further development of a robust assay system to screen inhibitors against the 12R-LOX enzyme. Therefore, in the present study, a prokaryotic expression system was developed to over-express and purify active human 12R-LOX enzyme by a single step purification process. We have further standardized an HPLC based assay system to assess the activity of purified human 12R-LOX enzyme. We show here that purified 12R-LOX preferentially u...
Journal of Ayurveda and integrative medicine, Jan 24, 2017
Aegle marmelos (Bilva) is being used in Ayurveda for the treatment of several inflammatory disord... more Aegle marmelos (Bilva) is being used in Ayurveda for the treatment of several inflammatory disorders. The plant is a member of a fixed dose combination of Dashamoola in Ayurveda. However, the usage of roots/root bark or stems is associated with sustainability concerns. The present study is aimed to compare the anti-inflammatory properties of different extracts of young roots (year wise) and mature parts of Bilva plants collected from different geographical locations in India, so as to identify a sustainable source for Ayurvedic formulation. A total of 191 extracts (petroleum ether, ethyl acetate, ethanol and aqueous) of roots, stems and leaves of A. marmelos (collected from Gujarat, Maharashtra, Odisha, Chhattisgarh, Karnataka and Andhra Pradesh region) were tested for anti-inflammatory effects in vitro on isolated target enzymes cyclooxygenase-1 (COX-1), cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LOX), lymphocyte proliferation assay (LPA), cytokine profiling in LPS induced mous...
Lipid signaling network was proposed as a potential target for cancer prevention and treatment. S... more Lipid signaling network was proposed as a potential target for cancer prevention and treatment. Several recent studies revealed that phospholipid metabolising enzyme, phospholipase A2 (PLA), is a critical regulator of cancer accelerating pathologies and apoptosis in several types of cancers. In addition to functioning as an enzyme, PLAcan activate a phospholipase A2 receptor (PLA2R1) in plasma membrane. While the list of PLAtargets extends to glucose homeostasis, intracellular energy balance, adipocyte development, and hepatic lipogenesis, the PLA2R1 downstream effectors are few and scarcely investigated. Among the most addressed PLA2R1 effects are regulation of pro-inflammatory signaling, autoimmunity, apoptosis, and senescence. Localized in glomeruli podocytes, the receptor can be identified by circulating anti-PLA2R1 autoantibodies leading to development of membranous nephropathy, a strong autoimmune inflammatory cascade. PLA2R1 was shown to induce activation of Janus-kinase 2 (J...
Biochemistry and cell biology = Biochimie et biologie cellulaire, Oct 1, 2017
Inhibition of angiogenesis is a useful strategy to prevent cancer growth by targeting new vessels... more Inhibition of angiogenesis is a useful strategy to prevent cancer growth by targeting new vessels that grow to nourish actively proliferating tumor cells. Endothelial cells can use a number of different pathways to cause angiogenesis, and each step in these pathways can be targeted. The use of multi-targeted drugs is gaining much importance in this scenario. Our previous results have shown that chebulagic acid (a benzopyran tannin present in the fruits of Terminalia chebula) has anti-angiogenic properties. Thus, this study was designed to examine the molecular mechanism for the anti-angiogenic effects of chebulagic acid. Results from our investigations using molecular docking studies and human umbilical vein endothelial cells in culture suggested that chebulagic acid inhibits both GSK-3β-dependent β-catenin phosphorylation (an important mediator of VE-cadherin-β-catenin signaling) and VEGFR2 phosphorylation, which is an important step in VEGF signaling. Chebulagic acid inhibits angi...
Background: The accurate ranking of analogs of lead molecules with respect to their estimated bin... more Background: The accurate ranking of analogs of lead molecules with respect to their estimated binding free energies to drug targets remains highly challenging in molecular docking due to small relative differences in their free energy values. Methods: Free energy perturbation (FEP) method, which provides the most accurate relative binding free energy values were earlier used to calculate free energies of many ligands for several important drug targets including Fructose-1,6-BisphosPhatase (FBPase). The availability of abundant structural and experimental binding affinity data for FBPase inhibitors provided an ideal system to evaluate four widely used docking programs, AutoDock, Glide, GOLD and SurflexDock, distinct from earlier comparative evaluation studies. Results: The analyses suggested that, considering various parameters such as docking pose, scoring and ranking accuracy, sensitivity analysis and newly introduced relative ranking score, Glide provided reasonably consistent res...
Arachidonic acid 5-lipoxygenase (ALOX5) is the key enzyme in the biosynthesis of pro-inflammatory... more Arachidonic acid 5-lipoxygenase (ALOX5) is the key enzyme in the biosynthesis of pro-inflammatory leukotrienes. We recently created knock-in mice (Alox5-KI) which express an arachidonic acid 15-lipoxygenating Alox5 mutant instead of the 5-lipoxygenating wildtype enzyme. These mice were leukotriene deficient but exhibited an elevated linoleic acid oxygenase activity. Here we characterized the polyenoic fatty acid metabolism of these mice in more detail and tested the animals in three different experimental inflammation models. In experimental autoimmune encephalomyelitis (EAE), Alox5-KI mice displayed an earlier disease onset and a significantly higher cumulative incidence rate than wildtype controls but the clinical score kinetics were not significantly different. In dextran sodium sulfate-induced colitis (DSS) and in the chronic constriction nerve injury model (CCI), Alox5-KI mice performed like wildtype controls with similar genetic background. These results were somewhat surprisi...
Initially, the aim is to provide the big picture illustrating the as is situation in the pharmace... more Initially, the aim is to provide the big picture illustrating the as is situation in the pharmaceutical industry: a lack of productivity resulting in too few products reaching the market; a loss of billions in revenue over the next few years as some of the major megabrands go off patent; a spiraling cost for developing new drugs and taking them through clinical and safety studies. Following on, a look deeper into the organization will offer an insight into the state-of-the-art in a technical function accountable for chemical Process R&D (with a remit to develop scalable, robust, and cost efficient processes for small molecules). The vast majority of compounds already launched in the form of drug products on the market or still being pursued through the phases of discovery and development, fall within the category of small molecules (as opposed to biopharmaceuticals, e.g., proteins, monoclonal antibodies). This typically means molecular weights of <1000Da and puts organic synthesis in the widest sense of the word at the forefront of technologies needed to support R&D programs in the pharma industry. Understandably, the demands on Medicinal Chemistry are quite different to what applies in a Process R&D (PR&D) organization. In the former, making large numbers of potentially interesting molecules, many of which are discarded after testing, is a key driver and for this virtually any synthetic methodology will suffice. For PR&D, however, homing in on selected compounds there is an expectation that the best synthetic routes will be delivered that meet a number of tough criteria, for instance from an environmental and safety point of view, allowing operation on large scale, offering cost competitiveness, avoiding patent infringements, showing sustainability for long-term production, etc. The intention is to focus on issues to be addressed during this transition by providing examples of changes that had to be put in place in order to make the supply of larger amounts of material feasible. At the end some forward looking conclusions will be shared.
Asiatic lions (Panthera leo persica), whose only natural habitat in the world is the Gir forest s... more Asiatic lions (Panthera leo persica), whose only natural habitat in the world is the Gir forest sanctuary of Gujarat State in India, are highly endangered and are considered to be highly inbred with narrow genetic diversity. An objective assessment of genetic diversity in their immune loci will help in assessing their survivability and may provide vital clues in designing strategies for their scientific management and conservation. We analyzed the comparative sequence polymorphism at exon 2 and exon 3 of major histocompatibility complex (MHC) class I in three groups of lions, i.e. wild Asiatic (from Gir forest), captive-bred Asiatic (from zoological parks in India), and Afro-Asiatic hybrid groups (from zoological parks in India) through polymorphism chain reaction-assisted sequence-based typing. The two exons were amplified, cloned, sequenced, and analyzed for polymorphism at nucleotide and putative translated product level. The analysis revealed extensive sequence polymorphism not only between clones derived from different lions but also the clones derived from a single lion. Furthermore, the wild Asiatic lions of Gir forest exhibited abundant sequence polymorphism at MHC class I comparable with that of Afro-Asiatic hybrid lions and significantly higher than that of captive-bred Asiatic lions. We hypothesize that Asiatic lions of Gir forest are not highly inbred as thought earlier and they possess abundant sequence polymorphism at MHC class I loci. During this study, 52 new sequences of the multigene MHC class I family were also identified among Asiatic lions.
Asiatic lions (Panthera leo persica), whose only natural habitat in the world is the Gir forest s... more Asiatic lions (Panthera leo persica), whose only natural habitat in the world is the Gir forest sanctuary of Gujarat State in India, are highly endangered and are considered to be highly inbred with narrow genetic diversity. An objective assessment of genetic diversity in their immune loci will help in assessing their survivability and may provide vital clues in designing strategies for their scientific management and conservation. We analyzed the comparative sequence polymorphism at exon 2 and exon 3 of major histocompatibility complex (MHC) class I in three groups of lions, i.e. wild Asiatic (from Gir forest), captive-bred Asiatic (from zoological parks in India), and Afro-Asiatic hybrid groups (from zoological parks in India) through polymorphism chain reaction-assisted sequence-based typing. The two exons were amplified, cloned, sequenced, and analyzed for polymorphism at nucleotide and putative translated product level. The analysis revealed extensive sequence polymorphism not only between clones derived from different lions but also the clones derived from a single lion. Furthermore, the wild Asiatic lions of Gir forest exhibited abundant sequence polymorphism at MHC class I comparable with that of Afro-Asiatic hybrid lions and significantly higher than that of captive-bred Asiatic lions. We hypothesize that Asiatic lions of Gir forest are not highly inbred as thought earlier and they possess abundant sequence polymorphism at MHC class I loci. During this study, 52 new sequences of the multigene MHC class I family were also identified among Asiatic lions.
The profile of primary dioxygenation products of arachidonic acid catalyzed by lipoxygenase isola... more The profile of primary dioxygenation products of arachidonic acid catalyzed by lipoxygenase isolated from hairy root cultures of Solanum tuberosum treated with a fungal elicitor was compared to that obtained for the enzyme from potato tubers. 11-Hydroperoxyeicosatetraenoic acid ...
12R-LOX over-expression has been reported in various pathologies such as psoriasis, proliferative... more 12R-LOX over-expression has been reported in various pathologies such as psoriasis, proliferative dermatitis as well as pulmonary obstructive diseases indicating that this enzyme plays significant role in pathogenesis of inflammatory diseases. 12R-LOX, therefore, is a suitable target for therapeutic intervention with potential application of its inhibitors in the treatment of skin and other inflammatory disorders. Identification of such inhibitors requires sufficient quantity of active enzyme to be produced by an easy and cost effective expression systems and further development of a robust assay system to screen inhibitors against the 12R-LOX enzyme. Therefore, in the present study, a prokaryotic expression system was developed to over-express and purify active human 12R-LOX enzyme by a single step purification process. We have further standardized an HPLC based assay system to assess the activity of purified human 12R-LOX enzyme. We show here that purified 12R-LOX preferentially u...
Journal of Ayurveda and integrative medicine, Jan 24, 2017
Aegle marmelos (Bilva) is being used in Ayurveda for the treatment of several inflammatory disord... more Aegle marmelos (Bilva) is being used in Ayurveda for the treatment of several inflammatory disorders. The plant is a member of a fixed dose combination of Dashamoola in Ayurveda. However, the usage of roots/root bark or stems is associated with sustainability concerns. The present study is aimed to compare the anti-inflammatory properties of different extracts of young roots (year wise) and mature parts of Bilva plants collected from different geographical locations in India, so as to identify a sustainable source for Ayurvedic formulation. A total of 191 extracts (petroleum ether, ethyl acetate, ethanol and aqueous) of roots, stems and leaves of A. marmelos (collected from Gujarat, Maharashtra, Odisha, Chhattisgarh, Karnataka and Andhra Pradesh region) were tested for anti-inflammatory effects in vitro on isolated target enzymes cyclooxygenase-1 (COX-1), cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LOX), lymphocyte proliferation assay (LPA), cytokine profiling in LPS induced mous...
Lipid signaling network was proposed as a potential target for cancer prevention and treatment. S... more Lipid signaling network was proposed as a potential target for cancer prevention and treatment. Several recent studies revealed that phospholipid metabolising enzyme, phospholipase A2 (PLA), is a critical regulator of cancer accelerating pathologies and apoptosis in several types of cancers. In addition to functioning as an enzyme, PLAcan activate a phospholipase A2 receptor (PLA2R1) in plasma membrane. While the list of PLAtargets extends to glucose homeostasis, intracellular energy balance, adipocyte development, and hepatic lipogenesis, the PLA2R1 downstream effectors are few and scarcely investigated. Among the most addressed PLA2R1 effects are regulation of pro-inflammatory signaling, autoimmunity, apoptosis, and senescence. Localized in glomeruli podocytes, the receptor can be identified by circulating anti-PLA2R1 autoantibodies leading to development of membranous nephropathy, a strong autoimmune inflammatory cascade. PLA2R1 was shown to induce activation of Janus-kinase 2 (J...
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