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Rana P.,Institute of Nuclear Medicine and Allied Sciences | Gupta M.,Institute of Nuclear Medicine and Allied Sciences | Khan A.R.,Institute of Nuclear Medicine and Allied Sciences | Hemanth Kumar B.S.,Institute of Nuclear Medicine and Allied Sciences | And 2 more authors.
Neurochemistry International | Year: 2014

Cranial irradiation is widely used as a treatment modality or prophylactic treatment in cancer patients, but it is frequently related to neurocognitive impairment in cancer survivors. Though most of radiation-induced changes occur during early and late delayed phase of radiation sickness, recent reports have supported the evidence of impaired neurogenesis within 24-48 h of radiation exposure that may implicate changes in acute phase as well. Inspection of these acute changes could be considered important as they may have long lasting effect on cognitive development and functions. In the present study, 1H NMR spectroscopy based metabolomic approach was used to obtain comprehensive information of hippocampus metabolic physiology during acute phase of radiation sickness in a mouse model for single dose 8 Gy cranial irradiation. The analysis demonstrated reduced metabolic activity in irradiated animals compared to controls, typically evident in citric acid cycle intermediates, glutamine/glutamate and ketone bodies metabolism thus providing strong indication that the hippocampus is metabolically responsive to radiation exposure. The data suggested reduced glucose utilization, altered intermediary and neurotransmitter metabolism in hippocampus tissue extract. To the best of our knowledge this is the first metabolomic study to document cranial irradiation induced acute metabolic changes using in vitro 1H NMR spectroscopy. © 2014 Elsevier Ltd. All rights reserved.

Singh D.V.,Indian Institute of Information Technology Allahabad | Singh D.V.,Central University of Bihar | Agarwal S.,Indian Institute of Information Technology Allahabad | Singh P.,SGPGIMS Campus | And 2 more authors.
Asian Pacific Journal of Cancer Prevention | Year: 2013

In order to enhance the bioavailability of curcumin its conjugates with piperic acid and glycine were synthesized by esterifying the 4 and 4' phenolic hydroxyls, the sites of metabolic conjugation. Antiproliferative and apoptotic efficacy of synthesized conjugates was investigated in MCF-7 and MDA-MB-231 cell lines. IC50 values of di-O-glycinoyl (CDG) and di-O-piperoyl (CDP) esters of curcumin were found to be comparable with that of curcumin. Both conjugates induced chromatin condensation fragmentation and apoptotic body formation. CDP exposure to MCF-7 cells induced apoptosis initiating loss of mitochondrial membrane potential (Ψm) followed by inhibition of translocation of transcription factor NF-kB and release of Cytochrome-C. Reactive oxygen species (ROS) production was evaluated by fluorescent activated cell sorter. Change in ratio of Bcl2/Bclxl was observed, suggesting permeablization of mitochondrial membrane leading to the release of AIF, Smac and other apoptogenic molecules. DNA fragmentation as a hallmark for apoptosis was monitored by TUNEL as well as agrose gel electrophoresis. Thus, it was proven that conjugation does not affect the therapeutic potential of parent molecule in vitro, while these could work in vivo as prodrugs with enhanced pharmacokinetic profile. P harmacokinetics of these molecules under in vivo conditions is a further scope of this study.

Singh A.K.,Center for Biomedical Magnetic Resonance | Misra K.,Center for Biomedical Magnetic Resonance
Proceedings of the National Academy of Sciences India Section B - Biological Sciences | Year: 2012

A 759 amino acid long sequence of polymerase PB2 [Influenza A virus {A/Mexico/47N/2009(H1N1)}] was taken to build the model of the protein which was validated by different tools of SAVS (structural analysis and verification server). The modeled protein was interacted with four different drugs available in the market viz. oseltaminivir, amantadine, zanasmivir, rimantadine (RS) and some naturally occurring compounds i.e. curcuminoids (curcumin, demethoxy curcumin, bis-demethoxy curcumin and cyclocurcumin) along with two synthetic bioconjugates of curcumin viz. dipiperoyl and disalicyloyl esters. The analysis parameters including docking score, reranking score and number of H-bonds indicate cyclocurcumin as the most favoured. © The National Academy of Sciences, India 2012.

Singh A.K.,Center for Biomedical Magnetic Resonance | Misra K.,Center for Biomedical Magnetic Resonance
Interdisciplinary Sciences: Computational Life Sciences | Year: 2013

Curcumin (diferuloyl methane) and its naturally occurring analogs viz. demethoxy, bisdemethoxy and cyclocurcumin, present in rhizomes of curcuma species turmeric, have been shown to inhibit the proliferation of a wide variety of tumor cells. Target nuclear protein HPV 16 E6 (PDB ID: 2fk4) is the major protein actively participating in oral and cervical cancers. In silico studies indicate that curcumin and its natural analogs have effective binding with different active sites on HPV 16 E6 protein, ideal target for restoring the tumor suppressor function of p53 and thus allowing the apoptosis of infected cells. The main limitation in the use of curcuminoids as therapeutic agents is their low bioavailability. Since piperine is known to enhance curcumin bioavailability to more than two thousand times by inhibiting its efflux, a conjugate of curcumin-piperic acid was also used. Although curcumin has been found to have strongest binding with this target and the two curcuminoids, demethoxy and bisdemethoxy curcumin have lower but comparable affinity, chlorogenic acid amongst the naturally occurring analogs has been found to have best binding affinity amongst all the analogs. Although curcumin-piperoyl conjugate does not show very encouraging results, it is likely to have potential activity in vitro and in vivo. These results throw light on the SAR of curcuminoids, leading to future designing of potent, non-toxic drugs for oral and cervical cancers. © 2013 International Association of Scientists in the Interdisciplinary Areas and Springer-Verlag Berlin Heidelberg.

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