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Ghosh S.,Natural Radiation Response Mechanisms Group | Kumar A.,Natural Radiation Response Mechanisms Group | Tripathi R.P.,Institute of Nuclear Medicine and Allied Sciences | Chandna S.,Natural Radiation Response Mechanisms Group
Carcinogenesis | Year: 2014

Radiotherapy exposes certain regions of solid tumours to low sublethal doses of γ-radiation that may cause secondary malignancies. Therefore, evaluating low-dose-γ-radiation-induced alterations in tumorigenic potential and understanding their mechanisms could help in improving radiotherapy outcome. Limited studies have indicated connexin (Cx) up-regulation by low doses, whereas Cxs are independently shown to alter cell migration in unirradiated cells. We investigated low-dose-γ-radiation-induced alterations in Cx43 expression and cell prol iferation/migration/invasion in various tumour cell lines, along with the putative molecular pathways such as p38 and extracellular signal-regulated kinase-1/2 (ERK-1/2)-mitogen-activated protein kinases (MAPKs). Interestingly, a narrow range of low doses (10-20 cGy) enhanced Cx43 expression and also selectively induced glioma cell migration without altering cell proliferation, accompanied by sustained activation of p38 and up-regulation of p21waf1/cip1, whereas the lowest (5 cGy) dose induced cell proliferation coupled with enhanced p-ERK1/2, proliferating cell nuclear antigen and p-H3 levels without inducing cell migration. Most importantly, low-dose-γ-radiation-induced cell migration and p38 activation was strongly inhibited by knocking down Cx43 expression, thereby demonstrating latter's upstream role, whereas the knock-down had no effect on ERK-1/2 or cell proliferation. Silencing Cx43 caused near-complete inhibition of radiation-induced cell migration/invasion in all tumour cell lines (U87, BMG-1, A549 and HeLa), whereas no cell migration/invasiveness was induced in the γ-irradiated primary VH10 or transformed AA8 fibroblasts. Our study demonstrates for the first time that low-dose γ-radiation induces p38-MAPK mediated cell migration selectively in tumour cells. Further, this effect is regulated by Cx43, which could thus be an important mediator in radiation-induced secondary malignancies and/or metastasis. © The Author 2013. Published by Oxford University Press. All rights reserved.


Gupta H.,Institute of Nuclear Medicine and Allied Sciences | Velpandian T.,All India Institute of Medical Sciences | Jain S.,National Institute of Pharmaceutical Education and Research
Journal of Drug Targeting | Year: 2010

Poor bioavailability (<1%) of drugs from conventional eye drops is mainly due to the various precorneal loss factors which include rapid tear turnover, systemic drug absorption through naso-lachrymal duct, transient residence time of the drug solution in the cul-de-sac and the relative impermeability of the drugs to corneal epithelial membrane. The present study describes the formulation and evaluation of chitosan and gellan gum based novel in-situ gel system activated by dual physiological mechanisms. Chitosan (a pH-sensitive polymer) in combination with gellan gum (an ion-activated polymer) were used as gelling agent. Timolol maleate, the drug which is frequently used for glaucoma therapy was used as model drug to check the efficacy of the formulation. The developed formulation was characterized for various in vitro parameters, for example, clarity, gelation pH, isotonicity, sterility, viscosity, transcorneal permeation profile, and ocular irritation. Ocular retention was studied by gamma scintigraphy and a significant increase in retention time was observed. The formulation was also found to be nonirritant and well tolerable. The developed system can be a viable alternative to conventional eye drops for the treatment of various ocular diseases and is suitable for clinical application. © 2010 Informa UK Ltd.


Anuranjani,Institute of Nuclear Medicine and Allied Sciences | Bala M.,Institute of Nuclear Medicine and Allied Sciences
Redox Biology | Year: 2014

Whole body exposure to low linear energy transfer (LET) ionizing radiations (IRs) damages vital intracellular bio-molecules leading to multiple cellular and tissue injuries as well as pathophysiologies such as inflammation, immunosuppression etc. Nearly 70% of damage is caused indirectly by radiolysis of intracellular water leading to formation of reactive oxygen species (ROS) and free radicals and producing a state of oxidative stress. The damage is also caused by direct ionization of biomolecules. The type of radiation injuries is dependent on the absorbed radiation dose. Sub-lethal IR dose produces more of DNA base damages, whereas higher doses produce more DNA single strand break (SSBs), and double strand breaks (DSBs). The Nrf2-ARE pathway is an important oxidative stress regulating pathway. The DNA DSBs repair regulated by MRN complex, immunomodulation and inflammation regulated by HMGB1 and various types of cytokines are some of the key pathways which interact with each other in a complex manner and modify the radiation response. Because the majority of radiation damage is via oxidative stress, it is essential to gain in depth understanding of the mechanisms of Nrf2-ARE pathway and understand its interactions with MRN complex, HMGB1 and cytokines to increase our understanding on the radiation responses. Such information is of tremendous help in development of medical radiation countermeasures, radioprotective drugs and therapeutics. Till date no approved and safe countermeasure is available for human use. This study reviews the Nrf2-ARE pathway and its crosstalk with MRN-complex, HMGB1 and cytokines (TNF-α, IL-6, IFN-γ etc.). An attempt is also made to review the modification of some of these pathways in presence of selected antioxidant radioprotective compounds or herbal extracts. © 2014 The Authors.


Dutta A.,Institute of Nuclear Medicine and Allied Sciences
Cellular and molecular biology (Noisy-le-Grand, France) | Year: 2012

The current study was aimed to determine the stability, serum protein binding ability, biodistribution, antioxidant potential and tissue toxicity status of a novel radioprotective formulation (G-002M) from Podophyllum hexandrum. G-002M is the combination of a flavonoid, a lignan and its glucoside isolated from P. hexandrum rhizome that exhibit high radioprotective potential. Stability of G-002M tagged with 99mTc was observed in vitro and with mice serum till 24 hr of incubation. The formulation was investigated for its antioxidant status and its bioavailability and toxicity in different organs of mice. Biodistribution study of 99mTc-G-002M revealed its uptake by all the vital organs of mice. Higher absorbed dose was observed in lungs, liver, jejunum and kidney. Maximum retention of G-002M in kidney revealed that G-002M was excreted predominantly through renal route. G-002M was also observed to have high free radical scavenging and total reducing properties. Histopathological observations showed no significant alterations in tissue morphology of lungs, liver, jejunum and kidney by G-002M administration. The data conclusively demonstrate that high stability, multi organ availability, longer retention and non-toxic behavior of G-002M might help in exhibiting strong protective potential against lethal radiation.


Mishra K.,Institute of Nuclear Medicine and Allied Sciences | Ojha H.,Institute of Nuclear Medicine and Allied Sciences | Chaudhury N.K.,Institute of Nuclear Medicine and Allied Sciences
Food Chemistry | Year: 2012

Applications of antioxidants are increasing due to their multiple roles in minimising harmful effects of oxidative stress. 2,2-diphenyl-1-picrylhydrazyl (DPPH -) radical scavenging assay is routinely practiced for the assessment of antiradical properties of different compounds. A detailed literature survey revealed use of different materials and methods for DPPH - assay by different investigators resulted in variation in the values of reference standards and measured parameters of new antioxidants. In the present work a detailed kinetic study of antioxidants has been performed and comprehensive results in terms of effective concentration which scavenges 50% radical (EC 50), antioxidant reducing power (ARP), stoichiometry and second order rate constant (k 2) values have been reported with DPPH - assay. Importance of selection of appropriate reference compounds and kinetic calculations are suggested. Few case studies of standard antioxidants have been discussed to emphasise the utilisation of appropriate methodology and reference compounds. © 2011 Elsevier Ltd. All rights reserved.


Walia B.,Institute of Nuclear Medicine and Allied Sciences | Satija N.,Institute of Nuclear Medicine and Allied Sciences | Tripathi R.P.,Institute of Nuclear Medicine and Allied Sciences | Gangenahalli G.U.,Institute of Nuclear Medicine and Allied Sciences
Stem Cell Reviews and Reports | Year: 2012

Objective: To provide a comprehensive source of information about the reprogramming process and induced pluripotency. Background: The ability of stem cells to renew their own population and to differentiate into specialized cell types has always attracted researchers looking to exploit this potential for cellular replacement therapies, pharmaceutical testing and studying developmental pathways. While adult stem cell therapy has already been brought to the clinic, embryonic stem cell research has been beset with legal and ethical impediments. Focus: The conversion of human somatic cells to human induced pluripotent stem cells (hiPSCs), which are equivalent to human embryonic stem cells (hESCs), provides a system to sidestep these barriers and expedite pluripotent stem cell research for the aforementioned purposes. However, being a very recent discovery, iPSCs have yet to overcome many other obstacles and criticism to be proven safe and feasible for clinical use. Methodology: This review introduces iPSC, the various methods that have been used to generate them and their pros and cons. It also covers in detail the pluripotency factors responsible for iPSC generation as well as the signaling pathways, epigenetic modifications and miRNA regulation implicated in the reprogramming process. The known molecular crosstalk between these reprogramming regulators is also illuminated. We will also mention the molecular compounds which have been shown to either replace one or more genetic factors or improve overall efficiency and kinetics of iPSC induction. Conclusion: To conclude, we will briefly discuss the current problems that hinder bench to bedside translation of iPSC research as well as the possible steps that can bring iPSC therapy and other potential applications closer to fruition. © 2011 Springer Science+Business Media, LLC.


D'Souza M.M.,Institute of Nuclear Medicine and Allied Sciences
Nuclear Medicine Communications | Year: 2012

BACKGROUND: 18F-fluorodeoxyglucose ( 18F-FDG) has limited specificity in the evaluation of intracranial lesions as it is taken up by inflammatory and granulomatous lesions as well. C-methionine is known to have a higher specificity in tumor detection, delineation, and differentiation of benign from malignant lesions. However, its uptake in granulomatous lesions remains unclarified. OBJECTIVE: The aim of this study was to explore the value of C-methionine PET/CT and 18F-FDG in the evaluation of intracranial tuberculomas. METHODS: C-methionine PET/CT followed by 18F-FDG PET/CT study was performed on 12 patients with intracranial tuberculomas. The diagnosis was confirmed for all cases on histopathological evaluation and/or follow-up. Quantitative analysis was performed for all cases by measuring the lesion-to-normal gray matter uptake ratio. RESULTS: A high lesion-to-normal gray matter uptake ratio was observed on both C-methionine (1.8±0.38) and 18F-FDG scans (1.64±0.26) in all newly diagnosed cases. Lesion detection and delineation was superior on C-methionine PET/CT. In addition, C-methionine appeared to be a more sensitive indicator for assessing early therapeutic response and incomplete therapeutic response in intracranial tuberculomas. There was complete concordance in the number and sites of lesions detected on C-methionine PET/CT and radiological imaging modalities (namely, CT and MRI). CONCLUSION: This preliminary study suggests that in newly diagnosed, untreated intracranial tuberculomas, C-methionine, like 18F-FDG, may have limited specificity in distinguishing it from a neoplastic lesion. However, it may play an important role in assessing the response to antitubercular treatment. Further studies are warranted to explore the potential of C-methionine in this regard. Copyright © Lippincott Williams & Wilkins.


Tripathi M.,Institute of Nuclear Medicine and Allied Sciences
Clinical nuclear medicine | Year: 2011

We report a case of a 60-year-old woman, diagnosed as a case of non Hodgkins lymphoma (NHL), referred for F-18 fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) following 6 cycles of chemotherapy to evaluate response to therapy. The scan revealed a curvilinear pattern of FDG accumulation in the midline extending anteroposteriorly, just adjacent to the inner table of the skull on the fused PET/CT images with no corresponding abnormality on the low-dose CT. Because this site anatomically corresponded to that of the sagittal sinus, an MRI and magnetic resonance venography was advised which confirmed the presence of sagittal sinus tumor deposits. This case highlights the pattern of sagittal sinus tumor thrombosis on FDG PET/CT and the possibility of its occurrence in NHL.


Dutta S.,Institute of Nuclear Medicine and Allied Sciences | Gupta M.L.,Institute of Nuclear Medicine and Allied Sciences
Mutagenesis | Year: 2014

This study was aimed to evaluate the protection against radiation of human peripheral blood lymphocytic DNA by a formulation of three isolated active principles of Podophyllum hexandrum (G-002M). G-002M in various concentrations was administered 1h prior to irradiation in culture media containing blood. Radioprotective efficacy of G-002M to lymphocytic DNA was estimated using various parameters such as dicentrics, micronuclei (MN), nucleoplasmic bridges (NPB) and nuclear buds (NuB) in binucleated cells. Certain experiments to ascertain the G2/M arrest potential of G-002M were also conducted. It was effective in arresting the cells even at half of the concentration of colchicine used. Observations demonstrated a radiation-dose-dependent increase in dicentric chromosomes (DC), acentric fragments, MN, NPB and NuB upto 5Gy. These changes were found significantly decreased by pre-administration of G-002M. A highly significant dose modifying factor (DMF) 1.43 and 1.39 based on dicentric assay and cytokinesis block micronuclei assay, respectively, was observed against 5Gy exposure in the current experiments. G-002M alone in its effective dose did not induct any change in any of the parameters mentioned above. Observations on cell cycle arrest by G-002M showed that the formulation has potential in arresting cells at G2/M, compared with colchicine. Based on significant DMF at highest radiation dose (5Gy) studied currently and meaningful reduction in radiation-induced chromosomal aberrations, we express that G-002M has a potential of minimising radiation-induced DNA (cytogenetic) damage. © 2014 © The Author 2014. Published by Oxford University Press on behalf of the UK Environmental Mutagen Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.


Ghosh S.,Institute of Nuclear Medicine and Allied Sciences | Kumar A.,Institute of Nuclear Medicine and Allied Sciences | Chandna S.,Institute of Nuclear Medicine and Allied Sciences
Cancer Letters | Year: 2015

Enrichment of tumour cells in G2/M phases in vitro is known to be associated with low-dose hyper-radiosensitivity (HRS). These cell cycle phases also involve reduced expression of adhesion protein connexin-43 (Cx43). Therefore, we investigated the role of Cx43 in HRS. Asynchronous or G2/M enriched tumour cells (U87, BMG-1, HeLa) and normal primary fibroblasts (HDFn) were γ-irradiated at varying doses, with an asynchronous group separately subjected to Cx43-knockdown prior to irradiation. Cx43 level, gap junctional activity, clonogenic cell survival, cell growth/viability, mitochondrial alterations and other apoptosis-regulating events were studied. G2/M enrichment reduced Cx43 level by ~50% and caused considerable HRS at doses 10 cGy-30 cGy in all tumour cell lines. Cx43-knockdown to the same level (60%) also elicited prominent HRS response in these cells. Quite important, radiosensitivity of primary HDFn cells remained unaltered by all these treatments. In Cx43-knockdown tumour cells, low-dose irradiation caused significant growth inhibition and apoptosis involving loss of MMP, cytochrome-c release and caspase-3 activation, thereby demonstrating the important cytoprotective role of Cx43. Therefore, this study significantly shows that Cx43 downregulation (a constitutive feature of G2/M phase) selectively renders tumour cells hypersensitive to low-dose radiation, and presents connexins as potential therapeutic targets. © 2015 Elsevier Ireland Ltd.

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