Department Of Zoology
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Item ORGANOPHOSPHATE PESTICIDES PESTER Aβ- INDUCED GENOTOXIC RESPONSES IN CULTURED NEURONAL CELLS: APE1/Ref-1 MEDIATED INTERVENTION(Central University of Punjab, 2018) Sarkar, Bibekananda; Mantha, Anil K. and Mittal, SunilAmyloid beta ( ) peptide deposition is the primary cause of neurodegeneration in reasons deposition, but the actual cause is not apparent. Several reports point towards the role of pesticides in the AD pathogenesis, especially organophosphate pesticides (OPPs) that also act as acetylcholinesterase inhibitors (AChEIs) and are reported to be neurotoxic in nature at sub-lethal doses. Monocrotophos (MCP) and Chlorpyrifos (CP) are the most widely used OPPs with highest production and consumption throughout the world. - induced oxidative stress associated with the neurodegeneration in AD has been assessed -35) peptide. Natural compounds like curcumin have been well documented for their ameliorating powers against various neurodegenerative disease models. The cell survival assay showed that MCP and CP kill the neuronal cells in both dose- and time-dependently. Nitro blue tetrazolium (NBT) based assay for determination of intracellular reactive oxygen species (ROS) demonstrated that MCP and CP produce significant oxidative stress in IMR-32 and SH-SY -35) increased oxidative stress in IMR-32 and SH-SY5Y cells, whereas curcumin reduced ROS levels significantly (pItem Curcumin revitalizes Amyloid beta (25–35)-induced and organophosphate pesticides pestered neurotoxicity in SH-SY5Y and IMR-32 cells via activation of APE1 and Nrf2(Springer, 2017) Sarkar, Bibekananda; Dhiman, Monisha; Mittal, Sunil; Mantha, Anil K.Amyloid beta (Aβ) peptide deposition is the primary cause of neurodegeneration in Alzheimer’s disease (AD) pathogenesis. Several reports point towards the role of pesticides in the AD pathogenesis, especially organophosphate pesticides (OPPs). Monocrotophos (MCP) and Chlorpyrifos (CP) are the most widely used OPPs. In this study, the role of MCP and CP in augmenting the Aβ-induced oxidative stress associated with the neurodegeneration in AD has been assessed in human neuroblastoma IMR-32 and SH-SY5Y cell lines. From the cell survival assay, it was observed that MCP and CP reduced cell survival both dose- and time-dependently. Nitro blue tetrazolium (NBT) based assay for determination of intracellular reactive oxygen species (ROS) demonstrated that Aβ(25–35), MCP or CP produce significant oxidative stress alone or synergistically in IMR-32 and SH-SY5Y cells, while pretreatment of curcumin reduced ROS levels significantly in all treatment combinations. In this study, we also demonstrate that treatment of Aβ(25–35) and MCP upregulated inducible nitric oxide synthase (iNOS/NOS2) whereas, no change was observed in neuronal nitric oxide synthase (nNOS/NOS1), but down-regulation of the nuclear factor erythroid 2-related factor 2 (Nrf2) level was observed. While curcumin pretreatment resulted in upregulation of iNOS and Nrf2 proteins. Also, the expression of key DNA repair enzymes APE1, DNA polymerase beta (Pol β), and PARP1 were found to be downregulated upon treatment with MCP, Aβ(25–35) and their combinations at 24 h and 48 h time points. In this study, pretreatment of curcumin to the SH-SY5Y cells enhanced the expression of DNA repair enzymes APE1, pol β, and PARP1 enzymes to counter the oxidative DNA base damage via base excision repair (BER) pathway, and also activated the antioxidant element (ARE) via Nrf2 upregulation. Furthermore, the immunofluorescent confocal imaging studies in SH-SY5Y and IMR-32 cells treated with Aβ(25–35) and MCP-mediated oxidative stress and their combinations at different time periods suggesting for cross-talk between the two proteins APE1 and Nrf2. The APE1’s association with Nrf2 might be associated with the redox function of APE1 that might be directly regulating the ARE-mediated neuronal survival mechanisms.Item APE1/Ref-1 as an emerging therapeutic target for various human diseases: Phytochemical modulation of its functions(Nature Publishing Group, 2014) Thakur, Shweta; Sarkar, Bibekananda; Cholia, Ravi P.; Gautam, Nandini; Dhiman, Monisha; Mantha, Anil K.Apurinic/apyrimidinic endonuclease 1 (APE1) is a multifunctional enzyme involved in the base excision repair (BER) pathway, which repairs oxidative base damage caused by endogenous and exogenous agents. APE1 acts as a reductive activator of many transcription factors (TFs) and has also been named redox effector factor 1, Ref-1. For example, APE1 activates activator protein-1, nuclear factor kappa B, hypoxia-inducible factor 1a, paired box gene 8, signal transducer activator of transcription 3 and p53, which are involved in apoptosis, inflammation, angiogenesis and survival pathways. APE1/Ref-1 maintains cellular homeostasis (redox) via the activation of TFs that regulate various physiological processes and that crosstalk with redox balancing agents (for example, thioredoxin, catalase and superoxide dismutase) by controlling levels of reactive oxygen and nitrogen species. The efficiency of APE1/Ref-1's function(s) depends on pairwise interaction with participant protein(s), the functions regulated by APE1/Ref-1 include the BER pathway, TFs, energy metabolism, cytoskeletal elements and stress-dependent responses. Thus, APE1/Ref-1 acts as a 'hub-protein' that controls pathways that are important for cell survival. In this review, we will discuss APE1/Ref-1's versatile nature in various human etiologies, including neurodegeneration, cancer, cardiovascular and other diseases that have been linked with alterations in the expression, subcellular localization and activities of APE/Ref-1. APE1/Ref-1 can be targeted for therapeutic intervention using natural plant products that modulate the expression and functions of APE1/Ref-1. In addition, studies focusing on translational applications based on APE1/Ref-1-mediated therapeutic interventions are discussed. ? 2014 KSBMB.Item Understanding human thiol dioxygenase enzymes: structure to function and biology to pathology(Wiley, 2017) Sarkar, Bibekananda; Kulharia, Mahesh; Mantha, Anil K.Amino acid metabolism is a significant metabolic activity in humans, especially of sulphur-containing amino acids, methionine and cysteine (Cys). Cys is cytotoxic and neurotoxic in nature; hence, mammalian cells maintain a constant intracellular level of Cys. Metabolism of Cys is mainly regulated by two thiol dioxygenases: cysteine dioxygenase (CDO) and 2-aminoethanethiol dioxygenase (ADO). CDO and ADO are the only human thiol dioxygenases reported with a role in Cys metabolism and localized to mitochondria. This metabolic pathway is important in various human disorders, as it is responsible for the synthesis of antioxidant glutathione and is also for the synthesis of hypotaurine and taurine. CDO is the most extensively studied protein, whose high-resolution crystallographic structures have been solved. As compared to CDO, ADO is less studied, even though it has a key role in cysteamine metabolism. To further understand ADO’s structure and function, the three-dimensional structures have been predicted from I-TASSER and SWISS-MODEL servers and validated with PROCHECK software. Structural superimposition approach using iPBA web server further confirmed near-identical structures (including active sites) for the predicted protein models of ADO as compared to CDO. In addition, protein–protein interaction and their association in patho-physiology are crucial in understanding protein functions. Both ADO and CDO interacting partner profiles have been presented using STRING database. In this study, we have predicted a 3Dmodel structure for ADO and summarized the biological roles and the pathological consequences which are associated with the altered expression and functioning of ADO and CDO in case of cancer, neurodegenerative disorders and other human diseases.Item A short review on the implications of base excision repair pathway for neurons: Relevance to neurodegenerative diseases(Elsevier, 2014) Mantha, Anil K.; Sarkar, Bibekananda; Tell, GianlucaOxidative DNA damage results from the attack by reactive oxygen and nitrogen species (ROS/RNS) on human genome. This includes base modifications such as oxidized bases, abasic (AP) sites, and single-strand breaks (SSBs), all of which are repaired by the base excision repair (BER) pathway, one among the six known repair pathways. BER-pathway in mammalian cells involves several evolutionarily conserved proteins and is also linked to genome replication and transcription. The BER-pathway enzymes, namely, DNA glycosylases (DGs) and the end-processing proteins such as abasic endonuclease (APE1), form complexes with downstream repair enzymes via protein-protein and DNA-protein interactions. An emerging concept for BER proteins is their involvement in non-canonical functions associated to RNA metabolism, which is opening new interesting perspectives. Various mechanisms that are underlined in maintaining neuronal cell genome integrity are identified, but are inconclusive in providing protection against oxidative damage in neurodegenerative disorders, main emphasis is given towards the role played by the proteins of BER-pathway that is discussed. In addition, mechanisms of action of BER-pathway in nuclear vs. mitochondria as well as the non-canonical functions are discussed in connection to human neurodegenerative diseases. ? 2013 ? Elsevier B.V. and Mitochondria Research Society. All rights reserved.Item Indian Herbs and their Therapeutic Potential against Alzheimer’s Disease and other Neurological Disorders(Wiley, 2017) Kaur, Navrattan; Sarkar, Bibekananda; Gill, Iqbal; Kaur, Sukhchain; Mittal, Sunil; Dhiman, Monisha; Padala, Prasad R.; Perez-Polo, Regino; Mantha, Anil K.Many present-day diseases are caused by disruption of the delicate balance between the reactive oxygen/nitrogen species (ROS/RNS) produced by oxidants and their scavenging by the antioxidants in the body. Chief among them is Alzheimer's disease (AD), an age-related neurodegenerative disease caused by the accumulation in the brain of amyloid beta (Aβ) plaques and of neurofibrillary tangles made up of the protein tau. Various theories for the pathogenesis of AD have been given, but no precise mechanism of its pathogenesis has been elucidated to date. A number of scientists are currently focusing on developing therapeutics for the prevention and treatment of AD. Natural plant-based products, which have been known traditionally in the treatment of brain disorders, could be a great help. Traditional herbal formulations developed for brain disorders are known as “Medhya drugs” in the Indian system of medicine called “Ayurveda” – a disease-preventive and health-promotive approach dating back to 5000 BC. This review focuses on the traditional use of some common Indian herbs in relation to AD, alongside recent advances in our understanding of their modes of action.