School Of Basic And Applied Sciences
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Item Investigation of combined genotoxic effect of pesticides on cancer cell lines(Central University of Punjab, 2013) Anju; Bhardwaj, PankajThe use of pesticides in agriculture sector is increasing widely to alleviate crop loss due to pests. To combat problem of pest, various types of pesticides are widely used, out of which insecticide are majorly used. In Malwa region of Punjab lots of insecticides are used. These pesticides when present together they may result in combined response. This combined response can be of three types such as independent, dose addition and interaction (synergism or antagonism). This combined response is very big trouble, such as sometimes even low dose of pesticide which is not toxic individually can result in toxic response in the presence of another pesticide. In the present study, Malathion and Monocrotophos (widely used organophosphorous insecticides) selected for investigation of combined effect. Out of selected pesticide Malathion also detected in water, in present study. Various parameters for genotoxicity evaluation was carried out with exposure of pesticides on HCT-116 WT/ p53 mutant (colon cancer) cell lines. Results of present study suggested that combination of pesticides resulted in more cell death, oxidative stress, membrane instability and imbalanced antioxidative system. It is also evaluated that low dose exposure of pesticides individually and in combination resulted in increased cell survival, may be due to activation of defense mechanism with prior treatment. All parameters evaluated was with short term exposure of 1-2 days, so evaluated long term exposure of ten days and found that this resulted in very less cell number and changed cell morphology. It is observed that both pesticides showed genotoxicity individually as well as in combination. The combined exposure of both pesticides deviate from there expected effect for dose addition towards more toxicity. So it is concluded that there may be some interaction between these pesticides, which may be synergistic in nature, because observed more toxicity.Item Assessment of Extract of Syzygium cumini Against Doxorubicin Induced Cardiotoxicity(Central University of Punjab, 2018) Chayan, Mukherjee; Monisha DhimanFor the past four decades, doxorubicin (DOX) has been used to treat cancer, mainly solid tumours and haematological malignancies. However, clinical community is greatly concerned regarding the administration of this as DOX treatment is commonly associated with dose-dependent cardiotoxicity. Attempts at alleviating drug generated cardiac damage using an extract from different parts of plants with radical scavenging property are a promising area of research. Hydroalcoholic extract derived from fruit pulp of Syzygiumcumini which has a significant antiradical scavenging effect. This study aims to assess the effect of parallel administration of SC fruit pulp extract (SC) on mitigating or preventing DOX induced cardiotoxicity in vitro using H9c2 cardiomyoblast cell lines. Addition of SC fruit pulp extract and DOX were performed for both treatment and control sets on H9c2 cells. SC fruit pulp extract showed strong ABTS cation radical scavenging activity in a dose dependent manner. MTT assay was used to study the cytotoxic effect of SC fruit pulp extract and DOX. ROS levels were estimated using NBT assay and DHE assay. The results showed that DOX has significant cytotoxic effect in a dose dependent manner while SC fruit pulp extract did not display any significant cytotoxicity on H9c2 cells. The DOX induced ROS production was found to be significantly reduced in SC fruit pulp extract treated cells. Results of the current study also suggest that the treatment of SC fruit pulp extract along with DOX, displayed cardioprotective potential in H9c2 cells by: 1) reducing lipid peroxidation; 2) decreasing extracellular nitric oxide (NO); 3) decreasing the expression of the protein p47phox and iNOS/NOS-2. These results clearly suggest that treatment of SC fruit pulp extract along with DOX reduces the DOX induced toxicity and hence can be a promising therapeutic intervention in managing DOX mediated cardiotoxicity.Item Oxidative stress responses to sub-lethal dose of Cry toxin in the larvae of castor semilooper, Achaea janata(Central University of Punjab, 2018) Singh, Kanika; Chaitanya,R.K.Development of synthetic insecticides to reduce the level of infestation led to deleterious effects on environment and human health. This lead to the development of ecofriendly pest management alternatives including Bacillus thuringensis (Bt). Bt produce Crystal (Cry), Cytotoxic (Cyt) and Vegetative (Vip) proteins with insecticidal activity against different orders of lepidoptera. Of late, pest resistance against Bt is reported in countries.The reduced toxicity of Bt formulation from degradation by UV light, wash-off by rain, drying, temperature, and soil acidity as well as its chemistry. Further, insects sense pesticides through odorant receptors and move away quickly, there is always a possibility of a population of larvae to get exposed to sub-lethal doses of toxin which might exhibit variable effects and escape mortality and eventually generate resistance. Sub-lethal dose lead to the generation of oxidative stress in the insect and eventually scavenged by anti-oxidant enzymes. These stress responses would enhance our understanding of adaptations for survival and resistance development. The current study is an attempt to monitor the antioxidative responses at the transcriptional level upon sub-lethal exposure of Cry toxin in the larvae of an polyphagous pest castor semilooper, Achaea janata. prevalent in the Indian subcontinent.Item Role of curcumin on monoamine oxidase(MAO) enzyme expression and activity against Amyloid Beta (A?)-induced oxidative stress in human glioblastoma U-87 MG cell.(Central University of Punjab, 2018) Behera, Nishibala N; Mantha,Anil K.Glioblastoma (GBM) is the most common brain tumor in humans. The major factor responsible for its progression is oxidative stress. Oxidative stress leads to disruption of signaling pathways and damage to cells and tissues. Monoamine oxidase (MAO) is involved in oxidative deamination of endogenous biogenic amine neurotransmitters such as dopamine, serotonin, norepinephrine, and epinephrine. Therefore, MAO plays a key role in initiation and progression of GBM through oxidative stress. In the present study, A?(25-35) peptide treatment was used to induce oxidative stress in human glioblastoma (U-87 MG) cells. A?(25-35) is known to induce oxidative stress through altering the expression and activity of various antioxidant and mitochondrial enzymes. In this study, the expression and activity of MAO was evaluated through induction of oxidative stress by A?(25-35) and antioxidant treatment of Curcumin. It was found that Curcumin decreases the mRNA expression of MAO but its protein expression increases, whereas A?(25-35) showed little decrease in the mRNA expression of MAO and increase in its protein expression, thus pointing towards differential regulation of translation and transcription. The activity of MAO was found to be increased in A?(25-35), Cur and Cur+A?(25-35) . Therefore, Curcumin has little or no antioxidant effect in altering the expression and activity of MAO and A? showed its oxidative potential by increasing the expression and activity of MAO, although not very significant, possibly because it uses other pathways for inducing oxidative stress.Item Effect of amyloid beta (25-35) peptide on mitochondrial respiratiory function in neuroral cells over expressing ape1(Central University of Punjab, 2014) Kaur, Navrattam; Mantha, Anil K.Alzheimer's disease (AD) is an important public health problem which affects millions of people worldwide. The major pathological hallmarks associated with AD are the accumulation of amyloid beta (A?) in senile plaques and neurofibrillary tangles (NFTs) made up of hyperphosphorylated tau proteins. Accumulating evidences point towards the role of oxidative stress and mitochondrial dysfunction in the pathogenesis of AD. Aging is considered as one of the greatest risk factor for AD. In order to maintain genome integrity, base excision repair (BER) pathway is the predominant pathway for repairing oxidized base lesions in neuronal cells. APE1 is the central enzyme of the BER-pathway, having both repair and redox activities and shown to enhance neuronal survival after oxidative stress. In my study, effect of A?(25-35) on mitochondrial ROS/RNS levels and activities of respiratory complexes (I, III, & IV) in neuronal cells was studied with and without ectopic APE1 expression and the neuro- modulatory role of Ginkgolide B (from leaves of G. biloba) was evaluated. It was seen that A?(25-35) increases the ROS/RNS levels in these cells which was decreased when pre-treated with Ginkgolide B (G.B) before treating with A?(25-35). APE1 levels were found to be decreased on treating with A?(25-35) and were increased on pre- treatment with G.B and subsequent treatment with A?(25-35). These results indicate that ectopic APE1 expression in the mitochondria of the neuronal cells might overcome the oxidative damage caused by A?(25-35). Also, phytochemical G.B has shown to modulate the mitochondrial complex activity upon A?(25-35)-induced oxidative stress and modulate the ROS/RNS levels in the presence of APE1. Further studies are needed to understand the mechanism of action of APE1 in relation to the above results, which will be carried out during my Ph.D. work.Item Oxidative Stress in Invertebrate Systems(InTech, 2016) Chaitanya, R. K.; Shashank, Kumar; Sridevi, P.Invertebrates have been valuable research models in the discovery of many scientific principles owing to the numerous advantages they provide. Throughout the life cycle, many of them thrive in pathogen-rich environments, manage harsh weathers, exposed to a number of allochemicals, and adapt well to both terrestrial and marine ecosystems. Their remarkable ability to cope up with the enormous oxidative stress generated in all these circumstances, make them attractive models in this field of research. Endocrine control of oxidative stress in insects is recently emerging. Adipokinetic hormone, glucagon, ecdysteroids and juvenile hormone have been implicated in antioxidative protective role in insects. Drosophila and Caenorhabditis elegans have provided the largest body of evidence addressing the free radical theory of ageing. Oxidative stress is also induced by pesticides/insecticides. In mollusks, pesticides exert their biological effects via generation of ROS. Oxidative stress has been shown to be associated with exposure to several organophosphorous compounds and different classes of pyrethroids. Malathion is a potential hazard to the environment. Adverse effects induced by malathion in earthworms and insects have been reported. Information is now available in great detail on the role of ROS in modulating insect immunity during parasite invasion and bacterial infection. In Drosophila melanogaster ROS are actively produced in the midgut at a basal level in the presence of commensal microbiota and highly generated upon bacterial challenge. The involvement of reactive oxygen species (ROS) in mosquito immunity against bacteria and Plasmodium was investigated in the malaria vector Anopheles gambiae. The concentration of ROS increased in sand fly midguts after they fed on the insect pathogen Serratia marcescens. Elevated oxidative stress was previously reported for a mosquito line experimentally infected with Wolbachia, indicating that oxidative stress may be important for Wolbachia-mediated antiviral protection. In a nutshell, this chapter highlights the current advances of oxidative stress in invertebrate model systems and its implications.Item Ganoderic acid targeting multiple receptors in cancer: in silico and in vitro study(Springer Netherlands, 2016) Gill, Balraj Singh; Navgeet; Kumar, Sanjeev; Gill, B.S.; Navgeet, Kumar, S.Receptor tyrosine kinases (RTKs) are transmembrane high-affinity surface receptors responsible for cell migration, adhesion, apoptosis, metabolism, and cell proliferation activities in various cancers. Minute aberration in the RTK signaling modulates the downstream signaling pathways that results in cancer. Ganoderic acid is a triterpene isolated from Ganoderma lucidum, which is renowned for its therapeutics effect, especially in cancer. The present study discusses receptor-based molecular docking of insulin receptor (IR), insulin-like growth factor receptor 1 (IGFR-1), vascular endothelial growth factor receptor-1 (VEGFR-1), vascular endothelial growth factor receptor-2 (VEGFR-2), and estrogen receptor (ER) with 50 isoforms of ganoderic acid along with natural inhibitors. These receptors were assessed for toxicity (ADMET) by using Maestro 9.6 (Schr?dinger Inc). The calculated docking free energy yielded an excellent dock score for the ganoderic acid when docked with proteins IR, IGFR-1, VEGFR-1, VEGFR-2, and ER, suggesting its potential in combating cancer. Protein?ligand profile highlighted the binding interactions comprising lipophilic, hydrogen bonding, pi-pi stacking interactions, and noncovalent bonding which play a pivotal role in targeting cancer. In silico studies revealed structure of ganoderic acid A as best isoforms among 50 isoforms which exhibits biological activity in liver cancer cells. Ganoderic acids A significantly decrease the viability, proliferation, and oxidative stress in a dose-dependent manner in liver cancer cells. ? 2016, International Society of Oncology and BioMarkers (ISOBM).Item A review on protein–protein interaction network of APE1/Ref-1 and its associated biological functions(Wiley, 2015) Thakur, S.; Dhiman, Monisha; Tell, G.; Mantha, Anil K.Apurinic/apyrimidinic endonuclease 1 (APE1) is a classic example of functionally variable protein. Besides its well-known role in (i) DNA repair of oxidative base damage, APE1 also plays a critical role in (ii) redox regulation of transcription factors controlling gene expression for cell survival pathways, for which it is also known as redox effector factor 1 (Ref-1), and recent evidences advocates for (iii) coordinated control of other non-canonical protein–protein interaction(s) responsible for significant biological functions in mammalian cells. The diverse functions of APE1 can be ascribed to its ability to interact with different protein partners, owing to the attainment of unfolded domains during evolution. Association of dysregulation of APE1 with various human pathologies, such as cancer, cardiovascular diseases and neurodegeneration, is attributable to its multifunctional nature, and this makes APE1 a potential therapeutic target. This review covers the important aspects of APE1 in terms of its significant protein–protein interaction(s), and this knowledge is required to understand the onset and development of human pathologies and to design or improve the strategies to target such interactions for treatment and management of various human diseases. Copyright © 2015 John Wiley & Sons, Ltd.Item Phytochemical Ginkgolide B Attenuates Amyloid- 1 - 42 Induced Oxidative Damage and Altered Cellular Responses in Human Neuroblastoma SH-SY5Y Cells(IOS Press, 2017) Gill, Iqbal; Kaur, Sukhchain; Kaur, Navrattan; Dhiman, Monisha; Mantha, Anil K.Oxidative stress is an upsurge in reactive oxygen/nitrogen species (ROS/RNS), which aggravates damage to cellular components viz. lipids, proteins, and nucleic acids resulting in impaired cellular functions and neurological pathologies including Alzheimer's disease (AD). In the present study, we have examined amyloid-β (Aβ)-induced oxidative stress responses, a major cause for AD, in the undifferentiated and differentiated human neuroblastoma SH-SY5Y cells. Aβ1-42-induced oxidative damage was evaluated on lipids by lipid peroxidation; proteins by protein carbonyls; antioxidant status by SOD and GSH enzyme activities; and DNA and RNA damage levels by evaluating the number of AP sites and 8-OHG base damages produced. In addition, the neuro-protective role of the phytochemical ginkgolide B (GB) in countering Aβ1-42-induced oxidative stress was assessed. We report that the differentiated cells are highly vulnerable to Aβ1-42-induced oxidative stress events as exerted by the deposition of Aβ in AD. Results of the current study suggest that the pre-treatment of GB, followed by Aβ1-42 treatment for 24 h, displayed neuro-protective potential, which countered Aβ1-42-induced oxidative stress responses in both undifferentiated and differentiated SH-SY5Y neuronal cells by: 1) hampering production of ROS and RNS; 2) reducing lipid peroxidation; 3) decreasing protein carbonyl content; 4) restoring antioxidant activities of SOD and GSH enzymes; and 5) maintaining genome integrity by reducing the oxidative DNA and RNA base damages. In conclusion, Aβ1-42 induces oxidative damage to the cellular biomolecules, which are associated with AD pathology, and are protected by the pre-treatment of GB against Aβ-toxicity. Taken together, this study advocates for phytochemical-based therapeutic interventions against AD.