55 results on '"Elavarasan, Subramani"'
Search Results
2. Editorial: Metabolic regulation under oxidative stress in cancer
- Author
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Elavarasan Subramani, Abishai Dominic, Pratip K. Bhattacharya, Daniel E. Frigo, Ilya Bederman, and Ali Vaziri-Gohar
- Subjects
oxidative stress ,metabolism ,cancer ,therapy ,biomarker ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Published
- 2023
- Full Text
- View/download PDF
3. Nanoencapsulation as a Promising Platform for the Delivery of the Morin-Cu(II) Complex: Antibacterial and Anticancer Potential
- Author
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Pooja Ghosh, Sudipta Bag, Sultana Parveen, Elavarasan Subramani, Koel Chaudhury, and Swagata Dasgupta
- Subjects
Chemistry ,QD1-999 - Published
- 2022
- Full Text
- View/download PDF
4. Imaging 6-Phosphogluconolactonase Activity in Brain Tumors In Vivo Using Hyperpolarized δ-[1-13C]gluconolactone
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Georgios Batsios, Céline Taglang, Peng Cao, Anne Marie Gillespie, Chloé Najac, Elavarasan Subramani, David M. Wilson, Robert R. Flavell, Peder E. Z. Larson, Sabrina M. Ronen, and Pavithra Viswanath
- Subjects
magnetic resonance spectroscopy/imaging (MRS/I) ,hyperpolarized 13C MRS ,dynamic nuclear polarization (DNP) ,pentose phosphate pathway (PPP) ,glioblastoma ,brain tumors ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
IntroductionThe pentose phosphate pathway (PPP) is essential for NADPH generation and redox homeostasis in cancer, including glioblastomas. However, the precise contribution to redox and tumor proliferation of the second PPP enzyme 6-phosphogluconolactonase (PGLS), which converts 6-phospho-δ-gluconolactone to 6-phosphogluconate (6PG), remains unclear. Furthermore, non-invasive methods of assessing PGLS activity are lacking. The goal of this study was to examine the role of PGLS in glioblastomas and assess the utility of probing PGLS activity using hyperpolarized δ-[1-13C]gluconolactone for non-invasive imaging.MethodsTo interrogate the function of PGLS in redox, PGLS expression was silenced in U87, U251 and GS2 glioblastoma cells by RNA interference and levels of NADPH and reduced glutathione (GSH) measured. Clonogenicity assays were used to assess the effect of PGLS silencing on glioblastoma proliferation. Hyperpolarized δ-[1-13C]gluconolactone metabolism to 6PG was assessed in live cells treated with the chemotherapeutic agent temozolomide (TMZ) or with vehicle control. 13C 2D echo-planar spectroscopic imaging (EPSI) studies of hyperpolarized δ-[1-13C]gluconolactone metabolism were performed on rats bearing orthotopic glioblastoma tumors or tumor-free controls on a 3T spectrometer. Longitudinal 2D EPSI studies of hyperpolarized δ-[1-13C]gluconolactone metabolism and T2-weighted magnetic resonance imaging (MRI) were performed in rats bearing orthotopic U251 tumors following treatment with TMZ to examine the ability of hyperpolarized δ-[1-13C]gluconolactone to report on treatment response.ResultsPGLS knockdown downregulated NADPH and GSH, elevated oxidative stress and inhibited clonogenicity in all models. Conversely, PGLS expression and activity and steady-state NADPH and GSH were higher in tumor tissues from rats bearing orthotopic glioblastoma xenografts relative to contralateral brain and tumor-free brain. Importantly, [1-13C]6PG production from hyperpolarized δ-[1-13C]gluconolactone was observed in live glioblastoma cells and was significantly reduced by treatment with TMZ. Furthermore, hyperpolarized δ-[1-13C]gluconolactone metabolism to [1-13C]6PG could differentiate tumor from contralateral normal brain in vivo. Notably, TMZ significantly reduced 6PG production from hyperpolarized δ-[1-13C]gluconolactone at an early timepoint prior to volumetric alterations as assessed by anatomical imaging.ConclusionsCollectively, we have, for the first time, identified a role for PGLS activity in glioblastoma proliferation and validated the utility of probing PGLS activity using hyperpolarized δ-[1-13C]gluconolactone for non-invasive in vivo imaging of glioblastomas and their response to therapy.
- Published
- 2021
- Full Text
- View/download PDF
5. Discovery of novel metabolic signatures for early identification of women at risk of developing gestational hypertension
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Sanjukta Dasgupta, Elavarasan Subramani, Imon Mitra, Anindita Bhattacharya, Da Doma Sherpa, Mamata Joshi, Pratip Chakraborty, Chaitali Datta Ray, and Koel Chaudhury
- Subjects
Endocrinology, Diabetes and Metabolism ,Clinical Biochemistry ,Biochemistry - Published
- 2023
6. Mycobacterial heat shock protein 65 mediated metabolic shift in decidualization of human endometrial stromal cells
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Elavarasan Subramani, Arun Prabhu Rameshbabu, Manivannan Jothiramajayam, Bhuvaneshwaran Subramanian, Debangana Chakravorty, Gunja Bose, Mamata Joshi, Chaitali Datta Ray, Indrani Lodh, Ratna Chattopadhyay, Sudipto Saha, Anita Mukherjee, Santanu Dhara, Baidyanath Chakravarty, and Koel Chaudhury
- Subjects
Medicine ,Science - Abstract
Abstract Successful implantation is dependent on the appropriate decidualization of endometrial stromal cells for the establishment of pregnancy in women. Mycobacterial heat shock protein 65 (HSP65) is involved in pathogenesis of the genital tuberculosis (GTB), one of the common causes of infertility in emerging countries. Though implantation failure appears to be the major cause, understanding the status of decidualizaiton process in women diagnosed with GTB has not been thoroughly addressed. We, therefore, explored the effect of HSP65 protein on the endometrial cell metabolism during in vitro decidualization. In order to identify the cellular metabolism of decidual cells with and without HSP65 treatment, proton NMR based characterization of metabolites extracted from cells and culture media were performed. In presence of HSP65, significant reduction in the decidual phenotype of endometrial stromal cells and prolactin expression is suggestive of impairment in decidualization. The intracellular and extracellular metabolic changes in HSP65 treated endometrial stromal cells produced a distinct pattern, reflecting the interaction between the protein and cellular metabolism. HSP65 mediated dysregulation in cellular metabolism is associated with poor decidualization. Besides enriching the present knowledge on metabolic changes underlying stromal cells decidualization, these findings assist in identifying potential molecular causes for decidualization failure in GTB women.
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- 2017
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7. Supplementary Data from Glutamate Is a Noninvasive Metabolic Biomarker of IDH1-Mutant Glioma Response to Temozolomide Treatment
- Author
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Sabrina M. Ronen, Russell O. Pieper, Joseph F. Costello, Pavithra Viswanath, Romelyn Delos Santos, Anne Marie Gillespie, Donghyun Hong, Abigail R. Molloy, Georgios Batsios, Chloe Najac, Marina Radoul, and Elavarasan Subramani
- Abstract
Supplementary Figures S1-S9 and tables S1-S6
- Published
- 2023
8. Data from Glutamate Is a Noninvasive Metabolic Biomarker of IDH1-Mutant Glioma Response to Temozolomide Treatment
- Author
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Sabrina M. Ronen, Russell O. Pieper, Joseph F. Costello, Pavithra Viswanath, Romelyn Delos Santos, Anne Marie Gillespie, Donghyun Hong, Abigail R. Molloy, Georgios Batsios, Chloe Najac, Marina Radoul, and Elavarasan Subramani
- Abstract
Although lower grade gliomas are driven by mutations in the isocitrate dehydrogenase 1 (IDH1) gene and are less aggressive than primary glioblastoma, they nonetheless generally recur. IDH1-mutant patients are increasingly being treated with temozolomide, but early detection of response remains a challenge and there is a need for complementary imaging methods to assess response to therapy prior to tumor shrinkage. The goal of this study was to determine the value of magnetic resonance spectroscopy (MRS)–based metabolic changes for detection of response to temozolomide in both genetically engineered and patient-derived mutant IDH1 models. Using 1H MRS in combination with chemometrics identified several metabolic alterations in temozolomide-treated cells, including a significant increase in steady-state glutamate levels. This was confirmed in vivo, where the observed 1H MRS increase in glutamate/glutamine occurred prior to tumor shrinkage. Cells labeled with [1–13C]glucose and [3–13C]glutamine, the principal sources of cellular glutamate, showed that flux to glutamate both from glucose via the tricarboxylic acid cycle and from glutamine were increased following temozolomide treatment. In line with these results, hyperpolarized [5–13C]glutamate produced from [2–13C]pyruvate and hyperpolarized [1–13C]glutamate produced from [1–13C]α-ketoglutarate were significantly higher in temozolomide-treated cells compared with controls. Collectively, our findings identify 1H MRS-detectable elevation of glutamate and hyperpolarized 13C MRS-detectable glutamate production from either pyruvate or α-ketoglutarate as potential translatable metabolic biomarkers of response to temozolomide treatment in mutant IDH1 glioma.Significance:These findings show that glutamate can be used as a noninvasive, imageable metabolic marker for early assessment of tumor response to temozolomide, with the potential to improve treatment strategies for mutant IDH1 patients.
- Published
- 2023
9. Adipose triglyceride lipase is regulated by CAMKK2-AMPK signaling and drives advanced prostate cancer
- Author
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Dominik Awad, Thomas L. Pulliam, Meredith Spradlin, Pham Hong-Anh Cao, Elavarasan Subramani, Tristen V. Tellman, Caroline F. Ribeiro, Hubert Pakula, Jeffrey J. Ackroyd, Mollianne M. Murray, Jenny J. Han, Badrajee Piyarathna, Justin M. Drake, Michael M. Ittmann, Cristian Coarfa, Mary C. Farach-Carson, Massimo Loda, Livia S. Eberlin, and Daniel E. Frigo
- Abstract
SummaryLipid metabolism plays a central role in prostate cancer. To date, the major focus on prostate cancer lipid metabolism has centered onde novolipogenesis and lipid uptake with little consideration for how cancer cells access these lipids once they are created or taken up and stored. Patient-derived phosphoproteomics identified adipose triglyceride lipase (ATGL), a previously suspected tumor suppressor, as a CAMKK2-AMPK signaling target that, conversely, promotes castration-resistant prostate cancer (CRPC) progression. Phosphorylation of ATGL increased its lipase activity, cancer cell proliferation, migration, and invasion. Shotgun lipidomics and mass spectrometry imaging demonstrated ATGL’s profound regulation of lipid metabolismin vitroandin vivo, remodeling membrane composition. Inhibition of ATGL induced metabolic plasticity, causing a glycolytic shift that could be exploited therapeutically by co-targeting both metabolic pathways. Together, these data nominate ATGL and intracellular lipolysis as potential therapeutic targets for the treatment of CRPC and provide insights for future combination therapies.
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- 2022
10. Mass spectrometry and bioinformatics analysis data
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Mainak Dutta, Elavarasan Subramani, Khushman Taunk, Akshada Gajbhiye, Shubhendu Seal, Namita Pendharkar, Snigdha Dhali, Chaitali Datta Ray, Indrani Lodh, Baidyanath Chakravarty, Swagata Dasgupta, Srikanth Rapole, and Koel Chaudhury
- Subjects
Computer applications to medicine. Medical informatics ,R858-859.7 ,Science (General) ,Q1-390 - Abstract
2DE and 2D-DIGE based proteomics analysis of serum from women with endometriosis revealed several proteins to be dysregulated. A complete list of these proteins along with their mass spectrometry data and subsequent bioinformatics analysis are presented here. The data is related to “Investigation of serum proteome alterations in human endometriosis” by Dutta et al. [1].
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- 2015
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11. MR-detectable metabolic biomarkers of response to mutant IDH inhibition in low-grade glioma
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Russell O. Pieper, Anne Marie Gillespie, Chloé Najac, Elavarasan Subramani, Abigail R. Molloy, Aliya Lakhani, Pavithra Viswanath, Sabrina M. Ronen, Marina Radoul, and Georgios Batsios
- Subjects
0301 basic medicine ,hyperpolarized C-13 magnetic resonance spectroscopy ,Pyridines ,Proton Magnetic Resonance Spectroscopy ,Mutant ,Medicine (miscellaneous) ,medicine.disease_cause ,0302 clinical medicine ,Pharmacology, Toxicology and Pharmaceutics (miscellaneous) ,Cancer ,screening and diagnosis ,Tumor ,biology ,Chemistry ,Brain Neoplasms ,Glutamate receptor ,Glioma ,Isocitrate Dehydrogenase ,Detection ,Isocitrate dehydrogenase ,Research Paper ,Oncology and Carcinogenesis ,Glycine ,Glutamic Acid ,Antineoplastic Agents ,Diamines ,IDH1 mutation ,Cell Line ,Glutarates ,03 medical and health sciences ,hyperpolarized 13C magnetic resonance spectroscopy ,AG-120 ,Rare Diseases ,AG-881 ,In vivo ,Cell Line, Tumor ,medicine ,Biomarkers, Tumor ,Humans ,Carbon-13 Magnetic Resonance Spectroscopy ,Neurosciences ,Enzyme assay ,Brain Disorders ,4.1 Discovery and preclinical testing of markers and technologies ,Glutamine ,Brain Cancer ,030104 developmental biology ,Cell culture ,Mutation ,Cancer research ,biology.protein ,Carcinogenesis ,low grade glioma ,030217 neurology & neurosurgery ,Biomarkers - Abstract
Author(s): Molloy, Abigail R; Najac, Chloe; Viswanath, Pavithra; Lakhani, Aliya; Subramani, Elavarasan; Batsios, Georgios; Radoul, Marina; Gillespie, Anne Marie; Pieper, Russell O; Ronen, Sabrina M | Abstract: Mutations in isocitrate dehydrogenase 1 (IDH1mut) are reported in 70-90% of low-grade gliomas and secondary glioblastomas. IDH1mut catalyzes the reduction of α-ketoglutarate (α-KG) to 2-hydroxyglutarate (2-HG), an oncometabolite which drives tumorigenesis. Inhibition of IDH1mut is therefore an emerging therapeutic approach, and inhibitors such as AG-120 and AG-881 have shown promising results in phase 1 and 2 clinical studies. However, detection of response to these therapies prior to changes in tumor growth can be challenging. The goal of this study was to identify non-invasive clinically translatable metabolic imaging biomarkers of IDH1mut inhibition that can serve to assess response. Methods: IDH1mut inhibition was confirmed using an enzyme assay and 1H- and 13C- magnetic resonance spectroscopy (MRS) were used to investigate the metabolic effects of AG-120 and AG-881 on two genetically engineered IDH1mut-expressing cell lines, NHAIDH1mut and U87IDH1mut. Results: 1H-MRS indicated a significant decrease in steady-state 2-HG following treatment, as expected. This was accompanied by a significant 1H-MRS-detectable increase in glutamate. However, other metabolites previously linked to 2-HG were not altered. 13C-MRS also showed that the steady-state changes in glutamate were associated with a modulation in the flux of glutamine to both glutamate and 2-HG. Finally, hyperpolarized 13C-MRS was used to show that the flux of α-KG to both glutamate and 2-HG was modulated by treatment. Conclusion: In this study, we identified potential 1H- and 13C-MRS-detectable biomarkers of response to IDH1mut inhibition in gliomas. Although further studies are needed to evaluate the utility of these biomarkers in vivo, we expect that in addition to a 1H-MRS-detectable drop in 2-HG, a 1H-MRS-detectable increase in glutamate, as well as a hyperpolarized 13C-MRS-detectable change in [1-13C] α-KG flux, could serve as metabolic imaging biomarkers of response to treatment.
- Published
- 2020
12. Nanoencapsulation as a Promising Platform for the Delivery of the Morin-Cu(II) Complex: Antibacterial and Anticancer Potential
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Pooja Ghosh, Sudipta Bag, Sultana Parveen, Elavarasan Subramani, Koel Chaudhury, and Swagata Dasgupta
- Subjects
General Chemical Engineering ,General Chemistry - Abstract
Nanoencapsulation has emerged as a promising approach for the effective delivery of poorly aqueous soluble compounds. The current study focuses on the preparation of human serum albumin (HSA)-based nanoparticles (NPs) and poly lactic
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- 2021
13. Rotational Dynamics of Optically Trapped Human Spermatozoa
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Elavarasan Subramani, Himanish Basu, Shyam Thangaraju, Sucheta Dandekar, Deepak Mathur, and Koel Chaudhury
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Technology ,Medicine ,Science - Abstract
Introduction. Optical trapping is a laser-based method for probing the physiological and mechanical properties of cells in a noninvasive manner. As sperm motility is an important criterion for assessing the male fertility potential, this technique is used to study sperm cell motility behavior and rotational dynamics. Methods and Patients. An integrated optical system with near-infrared laser beam has been used to analyze rotational dynamics of live sperm cells from oligozoospermic and asthenozoospermic cases and compared with controls. Results. The linear, translational motion of the sperm is converted into rotational motion on being optically trapped, without causing any adverse effect on spermatozoa. The rotational speed of sperm cells from infertile men is observed to be significantly less as compared to controls. Conclusions. Distinguishing normal and abnormal sperm cells on the basis of beat frequency above 5.6 Hz may be an important step in modern reproductive biology to sort and select good quality spermatozoa. The application of laser-assisted technique in biology has the potential to be a valuable tool for assessment of sperm fertilization capacity for improving assisted reproductive technology.
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- 2014
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14. Imaging 6-Phosphogluconolactonase Activity in Brain Tumors In Vivo Using Hyperpolarized δ-[1-13C]gluconolactone
- Author
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Peng Cao, Georgios Batsios, Chloé Najac, Peder E. Z. Larson, Elavarasan Subramani, Céline Taglang, Sabrina M. Ronen, Robert R. Flavell, Pavithra Viswanath, Anne Marie Gillespie, and David M. Wilson
- Subjects
Cancer Research ,Oncology and Carcinogenesis ,pentose phosphate pathway ,Pentose phosphate pathway ,medicine.disease_cause ,I) ,lcsh:RC254-282 ,Gluconolactone ,6-phosphogluconolactonase ,dynamic nuclear polarization ,chemistry.chemical_compound ,pentose phosphate pathway (PPP) ,dynamic nuclear polarization (DNP) ,Rare Diseases ,In vivo ,magnetic resonance spectroscopy/imaging ,medicine ,hyperpolarized 13C MRS ,magnetic resonance spectroscopy/imaging (MRS/I) ,Cancer ,Gene knockdown ,Temozolomide ,Chemistry ,glioblastoma ,Neurosciences ,Glutathione ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,magnetic resonance spectroscopy ,metabolic therapy ,Brain Disorders ,Brain Cancer ,Oncology ,Cancer research ,brain tumors ,Biomedical Imaging ,imaging (MRS ,hyperpolarized C-13 MRS ,Preclinical imaging ,Oxidative stress ,medicine.drug - Abstract
IntroductionThe pentose phosphate pathway (PPP) is essential for NADPH generation and redox homeostasis in cancer, including glioblastomas. However, the precise contribution to redox and tumor proliferation of the second PPP enzyme 6-phosphogluconolactonase (PGLS), which converts 6-phospho-δ-gluconolactone to 6-phosphogluconate (6PG), remains unclear. Furthermore, non-invasive methods of assessing PGLS activity are lacking. The goal of this study was to examine the role of PGLS in glioblastomas and assess the utility of probing PGLS activity using hyperpolarized δ-[1-13C]gluconolactone for non-invasive imaging.MethodsTo interrogate the function of PGLS in redox, PGLS expression was silenced in U87, U251 and GS2 glioblastoma cells by RNA interference and levels of NADPH and reduced glutathione (GSH) measured. Clonogenicity assays were used to assess the effect of PGLS silencing on glioblastoma proliferation. Hyperpolarized δ-[1-13C]gluconolactone metabolism to 6PG was assessed in live cells treated with the chemotherapeutic agent temozolomide (TMZ) or with vehicle control. 13C 2D echo-planar spectroscopic imaging (EPSI) studies of hyperpolarized δ-[1-13C]gluconolactone metabolism were performed on rats bearing orthotopic glioblastoma tumors or tumor-free controls on a 3T spectrometer. Longitudinal 2D EPSI studies of hyperpolarized δ-[1-13C]gluconolactone metabolism and T2-weighted magnetic resonance imaging (MRI) were performed in rats bearing orthotopic U251 tumors following treatment with TMZ to examine the ability of hyperpolarized δ-[1-13C]gluconolactone to report on treatment response.ResultsPGLS knockdown downregulated NADPH and GSH, elevated oxidative stress and inhibited clonogenicity in all models. Conversely, PGLS expression and activity and steady-state NADPH and GSH were higher in tumor tissues from rats bearing orthotopic glioblastoma xenografts relative to contralateral brain and tumor-free brain. Importantly, [1-13C]6PG production from hyperpolarized δ-[1-13C]gluconolactone was observed in live glioblastoma cells and was significantly reduced by treatment with TMZ. Furthermore, hyperpolarized δ-[1-13C]gluconolactone metabolism to [1-13C]6PG could differentiate tumor from contralateral normal brain in vivo. Notably, TMZ significantly reduced 6PG production from hyperpolarized δ-[1-13C]gluconolactone at an early timepoint prior to volumetric alterations as assessed by anatomical imaging.ConclusionsCollectively, we have, for the first time, identified a role for PGLS activity in glioblastoma proliferation and validated the utility of probing PGLS activity using hyperpolarized δ-[1-13C]gluconolactone for non-invasive in vivo imaging of glioblastomas and their response to therapy.
- Published
- 2021
15. Mitochondria in Metabolic Syndrome, Reproduction and Transgenerational Inheritance—Ongoing Debates and Emerging Links
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Daniel E Frigo and Elavarasan Subramani
- Subjects
medicine.medical_specialty ,Mitochondrial Diseases ,media_common.quotation_subject ,Mitochondrion ,Biology ,DNA, Mitochondrial ,Endocrinology ,Transgenerational epigenetics ,Commentaries ,Internal medicine ,medicine ,Humans ,Genetic Predisposition to Disease ,media_common ,Metabolic Syndrome ,Genetics ,Ovary ,Inheritance (genetic algorithm) ,medicine.disease ,Mitochondria ,Mutation ,Female ,Metabolic syndrome ,Reproduction ,Reactive Oxygen Species ,Infertility, Female - Published
- 2020
16. Identification of key contributory factors responsible for vascular dysfunction in idiopathic recurrent spontaneous miscarriage.
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Priyanka Banerjee, Sanghamitra Ghosh, Mainak Dutta, Elavarasan Subramani, Jaydeep Khalpada, Sourav Roychoudhury, Baidyanath Chakravarty, and Koel Chaudhury
- Subjects
Medicine ,Science - Abstract
Poor endometrial perfusion during implantation window is reported to be one of the possible causes of idiopathic recurrent spontaneous miscarriage (IRSM). We have tested the hypothesis that certain angiogenic and vasoactive factors are associated with vascular dysfunction during implantation window in IRSM and, therefore, could play a contributory role in making the endometrium unreceptive in these women. This is a prospective case-controlled study carried out on 66 women with IRSM and age and BMI matched 50 fertile women serving as controls. Endometrial expression of pro-inflammatory (IL-1β, TNF-α, IFN-γ, TGF-β1), anti-inflammatory (IL-4, -10), angiogenesis-associated cytokines (IL-2, -6, -8), angiogenic and vasoactive factors including prostaglandin E2 (PGE2), vascular endothelial growth factor (VEGF), endothelial nitric oxide synthase (eNOS), nitric oxide (NO) and adrenomedullin (ADM) were measured during implantation window by ELISA. Subendometrial blood flow (SEBF) was assessed by color Doppler ultrasonography. Multivariate analysis was used to identify the significant factor(s) responsible for vascular dysfunction in IRSM women during window of implantation and further correlated with vascular dysfunction. Endometrial expression of pro-inflammatory cytokines and PGE2 were up-regulated and anti-inflammatory and angiogenesis-associated cytokines down-regulated in IRSM women as compared with controls. Further, the angiogenic and vasoactive factors including VEGF, eNOS, NO and ADM were found to be down-regulated and SEBF grossly affected in these women. Multivariate analysis identified IL-10, followed by VEGF and eNOS as the major factors contributing towards vascular dysfunction in IRSM women. Moreover, these factors strongly correlated with blood flow impairment. This study provides an understanding that IL-10, VEGF and eNOS are the principal key components having a contributory role in endometrial vascular dysfunction in women with IRSM. Down-regulation of these factors is also associated with impaired endometrial perfusion which possibly makes the endometrium unreceptive that may eventually cause early pregnancy loss.
- Published
- 2013
- Full Text
- View/download PDF
17. Glutamate is a non-invasive metabolic biomarker of IDH1 mutant glioma response to temozolomide treatment
- Author
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Chloé Najac, Elavarasan Subramani, Georgios Batsios, Russell O. Pieper, Joseph F. Costello, Marina Radoul, Donghyun Hong, Pavithra Viswanath, Anne Marie Gillespie, Abigail R. Molloy, Romelyn Delos Santos, and Sabrina M. Ronen
- Subjects
0301 basic medicine ,Cancer Research ,Magnetic Resonance Spectroscopy ,Glutamine ,Nude ,Protein Engineering ,Mice ,Random Allocation ,0302 clinical medicine ,Pyruvic Acid ,Cancer ,Carbon Isotopes ,Tumor ,Chemistry ,Brain Neoplasms ,Glutamate receptor ,Glioma ,Alkylating ,Isocitrate Dehydrogenase ,Isocitrate dehydrogenase ,Treatment Outcome ,Oncology ,030220 oncology & carcinogenesis ,Biomedical Imaging ,Ketoglutaric Acids ,Female ,medicine.drug ,IDH1 ,Oncology and Carcinogenesis ,Glutamic Acid ,Mice, Nude ,Antineoplastic Agents ,Article ,03 medical and health sciences ,Rare Diseases ,In vivo ,medicine ,Biomarkers, Tumor ,Temozolomide ,Animals ,Humans ,Oncology & Carcinogenesis ,Antineoplastic Agents, Alkylating ,Prevention ,Neurosciences ,medicine.disease ,Brain Disorders ,Brain Cancer ,Citric acid cycle ,030104 developmental biology ,Glucose ,Mutation ,Cancer research ,Biomarkers - Abstract
Although lower grade gliomas are driven by mutations in the isocitrate dehydrogenase 1 (IDH1) gene and are less aggressive than primary glioblastoma, they nonetheless generally recur. IDH1-mutant patients are increasingly being treated with temozolomide, but early detection of response remains a challenge and there is a need for complementary imaging methods to assess response to therapy prior to tumor shrinkage. The goal of this study was to determine the value of magnetic resonance spectroscopy (MRS)–based metabolic changes for detection of response to temozolomide in both genetically engineered and patient-derived mutant IDH1 models. Using 1H MRS in combination with chemometrics identified several metabolic alterations in temozolomide-treated cells, including a significant increase in steady-state glutamate levels. This was confirmed in vivo, where the observed 1H MRS increase in glutamate/glutamine occurred prior to tumor shrinkage. Cells labeled with [1–13C]glucose and [3–13C]glutamine, the principal sources of cellular glutamate, showed that flux to glutamate both from glucose via the tricarboxylic acid cycle and from glutamine were increased following temozolomide treatment. In line with these results, hyperpolarized [5–13C]glutamate produced from [2–13C]pyruvate and hyperpolarized [1–13C]glutamate produced from [1–13C]α-ketoglutarate were significantly higher in temozolomide-treated cells compared with controls. Collectively, our findings identify 1H MRS-detectable elevation of glutamate and hyperpolarized 13C MRS-detectable glutamate production from either pyruvate or α-ketoglutarate as potential translatable metabolic biomarkers of response to temozolomide treatment in mutant IDH1 glioma. Significance: These findings show that glutamate can be used as a noninvasive, imageable metabolic marker for early assessment of tumor response to temozolomide, with the potential to improve treatment strategies for mutant IDH1 patients.
- Published
- 2020
18. Imaging 6-Phosphogluconolactonase Activity in Brain Tumors
- Author
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Georgios, Batsios, Céline, Taglang, Peng, Cao, Anne Marie, Gillespie, Chloé, Najac, Elavarasan, Subramani, David M, Wilson, Robert R, Flavell, Peder E Z, Larson, Sabrina M, Ronen, and Pavithra, Viswanath
- Subjects
pentose phosphate pathway (PPP) ,dynamic nuclear polarization (DNP) ,Oncology ,glioblastoma ,brain tumors ,hyperpolarized 13C MRS ,6-phosphogluconolactonase (PGLS) ,metabolic therapy ,Original Research ,magnetic resonance spectroscopy/imaging (MRS/I) - Abstract
Introduction The pentose phosphate pathway (PPP) is essential for NADPH generation and redox homeostasis in cancer, including glioblastomas. However, the precise contribution to redox and tumor proliferation of the second PPP enzyme 6-phosphogluconolactonase (PGLS), which converts 6-phospho-δ-gluconolactone to 6-phosphogluconate (6PG), remains unclear. Furthermore, non-invasive methods of assessing PGLS activity are lacking. The goal of this study was to examine the role of PGLS in glioblastomas and assess the utility of probing PGLS activity using hyperpolarized δ-[1-13C]gluconolactone for non-invasive imaging. Methods To interrogate the function of PGLS in redox, PGLS expression was silenced in U87, U251 and GS2 glioblastoma cells by RNA interference and levels of NADPH and reduced glutathione (GSH) measured. Clonogenicity assays were used to assess the effect of PGLS silencing on glioblastoma proliferation. Hyperpolarized δ-[1-13C]gluconolactone metabolism to 6PG was assessed in live cells treated with the chemotherapeutic agent temozolomide (TMZ) or with vehicle control. 13C 2D echo-planar spectroscopic imaging (EPSI) studies of hyperpolarized δ-[1-13C]gluconolactone metabolism were performed on rats bearing orthotopic glioblastoma tumors or tumor-free controls on a 3T spectrometer. Longitudinal 2D EPSI studies of hyperpolarized δ-[1-13C]gluconolactone metabolism and T2-weighted magnetic resonance imaging (MRI) were performed in rats bearing orthotopic U251 tumors following treatment with TMZ to examine the ability of hyperpolarized δ-[1-13C]gluconolactone to report on treatment response. Results PGLS knockdown downregulated NADPH and GSH, elevated oxidative stress and inhibited clonogenicity in all models. Conversely, PGLS expression and activity and steady-state NADPH and GSH were higher in tumor tissues from rats bearing orthotopic glioblastoma xenografts relative to contralateral brain and tumor-free brain. Importantly, [1-13C]6PG production from hyperpolarized δ-[1-13C]gluconolactone was observed in live glioblastoma cells and was significantly reduced by treatment with TMZ. Furthermore, hyperpolarized δ-[1-13C]gluconolactone metabolism to [1-13C]6PG could differentiate tumor from contralateral normal brain in vivo. Notably, TMZ significantly reduced 6PG production from hyperpolarized δ-[1-13C]gluconolactone at an early timepoint prior to volumetric alterations as assessed by anatomical imaging. Conclusions Collectively, we have, for the first time, identified a role for PGLS activity in glioblastoma proliferation and validated the utility of probing PGLS activity using hyperpolarized δ-[1-13C]gluconolactone for non-invasive in vivo imaging of glioblastomas and their response to therapy.
- Published
- 2020
19. In vivo detection of γ-glutamyl-transferase up-regulation in glioma using hyperpolarized γ-glutamyl-[1-13C]glycine
- Author
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Peder E. Z. Larson, Hikari A. I. Yoshihara, Shinsuke Sando, Chloé Najac, Anne Marie Gillespie, Pavithra Viswanath, Elavarasan Subramani, Yutaro Saito, Georgios Batsios, Sabrina M. Ronen, and Peng Cao
- Subjects
0301 basic medicine ,Male ,lcsh:Medicine ,medicine.disease_cause ,chemistry.chemical_compound ,0302 clinical medicine ,lcsh:Science ,Cancer ,Carbon Isotopes ,Multidisciplinary ,Tumor ,Chemistry ,Brain ,gamma-Glutamyltransferase ,Dipeptides ,Magnetic Resonance Imaging ,Up-Regulation ,Molecular Imaging ,Biomedical Imaging ,digestive system ,Cell Line ,03 medical and health sciences ,Rare Diseases ,Downregulation and upregulation ,In vivo ,Glioma ,medicine ,Animals ,Humans ,Neoplastic ,lcsh:R ,Neurosciences ,Glutathione ,medicine.disease ,Molecular biology ,Xenograft Model Antitumor Assays ,digestive system diseases ,Brain Disorders ,Rats ,Brain Cancer ,030104 developmental biology ,Gene Expression Regulation ,Cell culture ,Molecular Probes ,Glycine ,Feasibility Studies ,lcsh:Q ,Glioblastoma ,030217 neurology & neurosurgery ,Homeostasis ,Oxidative stress - Abstract
Glutathione (GSH) is often upregulated in cancer, where it serves to mitigate oxidative stress. γ-glutamyl-transferase (GGT) is a key enzyme in GSH homeostasis, and compared to normal brain its expression is elevated in tumors, including in primary glioblastoma. GGT is therefore an attractive imaging target for detection of glioblastoma. The goal of our study was to assess the value of hyperpolarized (HP) γ-glutamyl-[1-13C]glycine for non-invasive imaging of glioblastoma. Nude rats bearing orthotopic U87 glioblastoma and healthy controls were investigated. Imaging was performed by injecting HP γ-glutamyl-[1-13C]glycine and acquiring dynamic 13C data on a preclinical 3T MR scanner. The signal-to-noise (SNR) ratios of γ-glutamyl-[1-13C]glycine and its product [1-13C]glycine were evaluated. Comparison of control and tumor-bearing rats showed no difference in γ-glutamyl-[1-13C]glycine SNR, pointing to similar delivery to tumor and normal brain. In contrast, [1-13C]glycine SNR was significantly higher in tumor-bearing rats compared to controls, and in tumor regions compared to normal-appearing brain. Importantly, higher [1-13C]glycine was associated with higher GGT expression and higher GSH levels in tumor tissue compared to normal brain. Collectively, this study demonstrates, to our knowledge for the first time, the feasibility of using HP γ-glutamyl-[1-13C]glycine to monitor GGT expression in the brain and thus to detect glioblastoma.
- Published
- 2020
20. Investigating the potential of human placenta-derived extracellular matrix sponges coupled with amniotic membrane-derived stem cells for osteochondral tissue engineering
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Sabyasachi Roy, Bhuvaneshwaran Subramanian, Paulomi Ghosh, Santanu Dhara, Priti Prasanna Maity, Arun Prabhu Rameshbabu, Sayanti Datta, Kamakshi Bankoti, Kausik Kapat, Elavarasan Subramani, and Koel Chaudhury
- Subjects
0301 basic medicine ,Scaffold ,Decellularization ,Materials science ,Regeneration (biology) ,Cartilage ,Biomedical Engineering ,02 engineering and technology ,General Chemistry ,General Medicine ,Anatomy ,021001 nanoscience & nanotechnology ,Chondrogenesis ,Cell biology ,Extracellular matrix ,03 medical and health sciences ,030104 developmental biology ,medicine.anatomical_structure ,Tissue engineering ,medicine ,General Materials Science ,Stem cell ,0210 nano-technology - Abstract
Osteochondral injuries are challenging to repair due to their complex tissue anatomy and restricted self-repairing ability associated with a limited blood supply. Osteochondral tissue engineering is an important clinical aspect of the management and treatment of cartilage and underlying bone. In the present study, we fabricated human placenta-derived extracellular matrix sponges (PEMS) for repair of osteochondral tissue through a decellularization process. There were no significant cellular components present in the PEMS; hematoxylin & eosin/DAPI staining, DNA quantification and agarose gel electrophoresis were used to evaluate the extent of decellularization. Moreover, no significant alteration to the collagen and glycosaminoglycan (native extracellular matrix) content of the PEMS was observed. PEMS in vitro provided a non-cytotoxic environment rich in bioactive cues for human amniotic membrane-derived stem cells (HAMSCs) to proliferate in and differentiate into chondrogenic and osteogenic lineages under induction. Histological analysis at 28 days after the PEMS were subcutaneously implanted demonstrated no severe immune response in the host and supported the formation of blood vessels. To assess the osteochondral tissue repair ability of PEMS, cell-free PEMS (CFP) and cell-seeded PEMS (CSP) were implanted at osteochondral defect sites in a rabbit model. Histological scores indicated that osteochondral regeneration was more successful in the defects filled with CSP compared to those filled with CFP and empty defects (ED) after 60 days of implantation. In summary, a naturally derived biocompatible scaffold composed of extracellular matrix from human placenta has been successfully developed for osteochondral tissue engineering.
- Published
- 2020
21. CBMT-02. UP-REGULATION OF Γ-GLUTAMYL-TRANSFERASE CAN BE USED TO IMAGE GLIOBLASTOMA USING HYPERPOLARIZED Γ-GLUTAMYL-[1-(13)C]GLYCINE MRS
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Yutaro Saito, Shinsuke Sando, Anne Marie Gillespie, Peder E. Z. Larson, Peng Cao, Georgios Batsios, Pavithra Viswanath, Hikari A. I. Yoshihara, Sabrina M. Ronen, Chloé Najac, and Elavarasan Subramani
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Cancer Research ,Oncology ,Biochemistry ,Downregulation and upregulation ,Chemistry ,Glycine ,medicine ,Neurology (clinical) ,medicine.disease ,γ glutamyl transferase ,Cell Biology and Metabolism ,Glioblastoma - Abstract
γ-glutamyl-transferase (GGT) is a key enzyme in the γ-glutamyl cycle, which regulates glutathione homeostasis. The enzyme is localized on the outer cell membrane and cleaves glutathione to glutamate and cysteinylglycine. As such, it facilitates uptake of the amino acids essential for intracellular synthesis of glutathione (GSH), which is the major thiol anti-oxidant. GGT is upregulated in glioblastoma, but remains low in normal brain. It is therefore an attractive molecular imaging target for specific detection of glioblastoma. The goal of our study was therefore to assess for the first time the value of hyperpolarized (HP) γ-glutamyl-[1-13C]glycine (γ-Glu-[1-13C]Gly) for imaging glioblastoma in orthotopic tumor-bearing rats. Athymic nude rats with U87 glioblastoma tumors or tumor-free controls were investigated. First, we confirmed that GGT expression was significantly higher in U87 tumors compared to normal rat brain tissue. GSH levels were also higher. Imaging studies were then performed by injecting HP γ-Glu-[1-13C]Gly and acquiring dynamic 13C MR spectra using a flyback spectral-spatial slab sequence on a preclinical Bruker 3T MR system. The dynamic data were analyzed by measuring the signal-to-noise (SNR) ratios of the substrate (γ-Glu-[1-13C]Gly) and the product ([1-13C]Glycine). Comparison of control and tumor-bearing rats showed no statistically significant difference in the SNR of the substrate. In contrast, the SNR of the product demonstrated a significantly higher level of HP [1-13C]Glycine in the tumor-bearing rats compared to controls. Consistent with the higher levels of HP [1-13C]Glycine, the [1-13C]Gly-to-γ-Glu-[1-13C]Glycine ratio was also significantly higher in tumor-bearing animals relative to controls (0.046±0.004 vs 0.021±0.008 respectively; p=0.03). Further studies are needed to assess the generality of our findings. Nonetheless, this study demonstrates for the first time the feasibility of using γ-Glu-[1-13C]Gly to monitor GGT activity and thus could serve as a new approach for monitoring the presence of tumor.
- Published
- 2019
22. EXTH-20. HYPERPOLARIZED [2-(13)C] PYRUVATE TO [5-(13)C] GLUTAMATE AS BIOMARKERS OF IDH1 MUTANT GLIOMA RESPONSE TO TEMOZOLOMIDE THERAPY
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Sabrina M. Ronen, Russell O. Pieper, Anne Marie Gillespie, Pavithra Viswanath, Chloé Najac, Elavarasan Subramani, Marina Radoul, and Georgios Batsios
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Cancer Research ,IDH1 ,Temozolomide ,Chemistry ,Mutant ,Glutamate receptor ,medicine.disease ,Glutamine ,Citric acid cycle ,Isocitrate dehydrogenase ,Oncology ,Glioma ,medicine ,Cancer research ,Experimental Therapeutics ,Neurology (clinical) ,medicine.drug - Abstract
Low-grade gliomas, driven by mutations in the cytosolic isocitrate dehydrogenase 1 (IDH1) gene, are less aggressive than primary glioblastoma, but nonetheless always recur and ultimately lead to patient death. The treatment of IDH1 mutant patients with Temozolomide (TMZ) improves survival, but there remains a need for complementary imaging methods to assess response to therapy at an early time point. The goal of this study was, therefore, to determine the value of magnetic resonance spectroscopy (MRS)-based metabolic imaging biomarkers for detection of response to treatment. To this end we investigated NHA and U87 cells expressing IDH1 R132H mutant gene (NHAIDHmut and U87IDHmut) and first used 1H MRS combined with chemometrics to examined the metabolic alterations that occurred following treatment with the IC50 value of TMZ. We observed a significant increase in 2-hydroxyglutarate (2-HG), glutamate, and glutamine, and metabolic pathway analysis showed tricarboxylic acid (TCA) cycle and pyruvate metabolism to be significantly altered pathways following TMZ treatment compared to DMSO control. To confirm changes in TCA cycle flux and to assess the metabolic pathways contributing to the increase in 2-HG and glutamate/glutamine, cells were then labelled with [1-13C] glucose and [3-13C] glutamine. Our data indicated that both glucose flux via the TCA to glutamate and 2HG, and the contribution of glutamine to glutamate and 2HG were increased following TMZ treatment. Finally, we used hyperpolarized 13C-MRS to dynamically probe the metabolism of hyperpolarized [2-13C] pyruvate and its conversion to hyperpolarized [5-13C] glutamate via the TCA cycle. Consistent with our previous findings, we observed that hyperpolarized [5-13C] glutamate synthesis was significantly higher in TMZ-treated cells compared to controls. Collectively, our findings identify 1H MRS-detectable elevation of 2-HG and glutamate/glutamine as well as hyperpolarized 13C-MRS-detectable [5-13C] glutamate production from [2-13C] pyruvate as potentially translatable metabolic biomarkers of response to TMZ therapy in mutant IDH1 glioma.
- Published
- 2019
23. Polycaprolactone nanofibers functionalized with placental derived extracellular matrix for stimulating wound healing activity
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Elavarasan Subramani, Kamakshi Bankoti, Santanu Dhara, V. Lalzawmliana, Arun Prabhu Rameshbabu, Sayanti Datta, Koel Chaudhury, and Samit Kumar Nandi
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0301 basic medicine ,integumentary system ,Angiogenesis ,Chemistry ,technology, industry, and agriculture ,Biomedical Engineering ,Cell migration ,General Chemistry ,General Medicine ,In vitro ,Cell biology ,Extracellular matrix ,03 medical and health sciences ,Foreskin ,030104 developmental biology ,medicine.anatomical_structure ,Dermis ,Nanofiber ,medicine ,General Materials Science ,Wound healing - Abstract
Impaired wound healing is primarily associated with inadequate angiogenesis, repressed cell migration, deficient synthesis of extracellular matrix (ECM) component/growth factors, and altered inflammatory responses in the wound bed environment. Herein, we report a simple process for the fabrication of PCL nanofiber mats embedded with placental-derived bioactive molecules (PCL–sPEM) rich in growth factors for full-thickness cutaneous wound healing. The physicochemical attributes and biological composition of PCL–sPEM nanofiber mats delivered a nontoxic environment in vitro and significantly promoted the adhesion, infiltration, and proliferation of human fibroblasts/keratinocytes. Conditioned media extracted from PCL–sPEM nanofiber mats enhanced the migration potential of the cells (fibroblasts/keratinocytes) involved in wound healing due to the release of growth factors embedded in it. Further, PCL–sPEM nanofiber mats attracted, stimulated and supported vascularization as determined by the Chick Chorioallantoic Membrane (CAM) assay. Interestingly, critical skin wounds of rats treated with PCL–sPEM nanofiber mats facilitated improved wound closure with well-organized dermis and epidermis, which could be ascribed to prominent vascularization, augmented migration of human foreskin fibroblasts (HFFs) & human epidermal keratinocytes (HEKs), increased collagen synthesis and early re-epithelialization. Collectively, our results suggest that PCL–sPEM nanofiber mats embedded with growth factors could be a suitable matrix for treating critical full-thickness wounds.
- Published
- 2018
24. BIOM-19. METABOLIC ALTERATION INDUCED BY SELECTIVE KNOCK DOWN OF GABPB1L IN U251 CELLS
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Pavithra Viswanath, Elavarasan Subramani, Anne Marie Gillespie, Georgios Batsios, Donghyun Hong, Noriaki Minami, Vinay Ayyappan, Nick Stevers, Joseph F. Costello, Marina Radoul, Sabrina M. Ronen, and Abigail R. Molloy
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Cancer Research ,medicine.diagnostic_test ,Magnetic resonance imaging ,Nuclear magnetic resonance spectroscopy ,Glutathione ,Molecular biology ,Glutamine ,chemistry.chemical_compound ,Oncology ,chemistry ,Plasmid Vector ,Metabolic disturbance ,Mutation (genetic algorithm) ,medicine ,CRISPR ,Neurology (clinical) ,Biomarkers - Abstract
BACKGROUND TERT promoter mutations that result in TERT expression are observed in over 80% of GBM and upstream inhibition of TERT expression by targeting GABPB1L is currently under investigation. In that context, non-invasive reliable biomarkers that can help detect TERT expression are needed. The aim of this research was to assess the value of magnetic resonance spectroscopy (MRS)-detectable metabolic changes as biomarkers of TERT expression in GBM. METHODS GABPB1L knock down clones (GABPB1LKD) were established by introducing Crispr Cas9 plasmid vector targeting GABPB1L into U251 cells. Two representative clones with different knock down efficiency were chosen and compared to control cells. Tumor forming capacity was evaluated by colony formation assay and magnetic resonance imaging of orthotopically implanted tumors in mice. Cells were extracted using the dual phase extraction method and 1H-MRS data of cell extracts acquired using a Bruker 500 scanner. The data was analyzed using Mnova software. Multivariate analysis was performed using the SIMCA software. RESULTS TERT expression was significantly reduced in GABPB1LKD compared to control cells depending on the GABPB1L knock down efficiency. Colony forming capacity was impaired in GABPB1LKD compared to control cells. In vivo MRI data showed significantly smaller tumor volumes in GABPB1LKD compared to control. Unbiased PCA analysis of 1H-MRS data showed separation of GABPB1LKD and control extracts and VIP scores derived from the OPLS-DA analysis, demonstrated that the common metabolites leading to separation of GABPB1LKD and control cells were aspartate, glutathione, glycerophosphocholine, glutamine, NAD(P)+, AXP. This data was confirmed by univariate analysis that revealed that aspartate, glutathione, glutamine, NAD(P)+, AXP level was significantly reduced in GABPB1LKD. CONCLUSIONS GABPB1L knock down cells that show reduced TERT expression demonstrate MRS-detectable metabolic changes. These could be translated into clinical applications, improve the monitoring of GBM patients and advance precision medicine.
- Published
- 2020
25. Mycobacterial heat shock protein 65 mediated metabolic shift in decidualization of human endometrial stromal cells
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Bhuvaneshwaran Subramanian, Indrani Lodh, Manivannan Jothiramajayam, Anita Mukherjee, Santanu Dhara, Ratna Chattopadhyay, Chaitali Datta Ray, Sudipto Saha, Elavarasan Subramani, Arun Prabhu Rameshbabu, Mamata Joshi, Koel Chaudhury, Debangana Chakravorty, Baidyanath Chakravarty, and Gunja Bose
- Subjects
0301 basic medicine ,Adult ,medicine.medical_specialty ,Stromal cell ,Science ,Biology ,Endometrium ,Article ,Pathogenesis ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,Bacterial Proteins ,Internal medicine ,Heat shock protein ,medicine ,Extracellular ,Humans ,Decidual cells ,Embryo Implantation ,Cells, Cultured ,030219 obstetrics & reproductive medicine ,Multidisciplinary ,Decidualization ,Chaperonin 60 ,Tuberculosis, Female Genital ,030104 developmental biology ,medicine.anatomical_structure ,Endocrinology ,Cancer research ,Medicine ,Female ,Stromal Cells ,Intracellular - Abstract
Successful implantation is dependent on the appropriate decidualization of endometrial stromal cells for the establishment of pregnancy in women. Mycobacterial heat shock protein 65 (HSP65) is involved in pathogenesis of the genital tuberculosis (GTB), one of the common causes of infertility in emerging countries. Though implantation failure appears to be the major cause, understanding the status of decidualizaiton process in women diagnosed with GTB has not been thoroughly addressed. We, therefore, explored the effect of HSP65 protein on the endometrial cell metabolism during in vitro decidualization. In order to identify the cellular metabolism of decidual cells with and without HSP65 treatment, proton NMR based characterization of metabolites extracted from cells and culture media were performed. In presence of HSP65, significant reduction in the decidual phenotype of endometrial stromal cells and prolactin expression is suggestive of impairment in decidualization. The intracellular and extracellular metabolic changes in HSP65 treated endometrial stromal cells produced a distinct pattern, reflecting the interaction between the protein and cellular metabolism. HSP65 mediated dysregulation in cellular metabolism is associated with poor decidualization. Besides enriching the present knowledge on metabolic changes underlying stromal cells decidualization, these findings assist in identifying potential molecular causes for decidualization failure in GTB women.
- Published
- 2017
26. In vivo detection of γ-glutamyl-transferase up-regulation in glioma using hyperpolarized γ-glutamyl-[1
- Author
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Georgios, Batsios, Chloé, Najac, Peng, Cao, Pavithra, Viswanath, Elavarasan, Subramani, Yutaro, Saito, Anne Marie, Gillespie, Hikari A I, Yoshihara, Peder, Larson, Shinsuke, Sando, and Sabrina M, Ronen
- Subjects
Male ,Carbon Isotopes ,Brain ,Dipeptides ,gamma-Glutamyltransferase ,digestive system ,Magnetic Resonance Imaging ,Xenograft Model Antitumor Assays ,Cancer metabolism ,digestive system diseases ,Article ,Molecular Imaging ,Rats ,Up-Regulation ,Gene Expression Regulation, Neoplastic ,Tumour biomarkers ,Cell Line, Tumor ,Molecular Probes ,Animals ,Feasibility Studies ,Humans ,Cancer imaging ,Glioblastoma ,Cancer - Abstract
Glutathione (GSH) is often upregulated in cancer, where it serves to mitigate oxidative stress. γ-glutamyl-transferase (GGT) is a key enzyme in GSH homeostasis, and compared to normal brain its expression is elevated in tumors, including in primary glioblastoma. GGT is therefore an attractive imaging target for detection of glioblastoma. The goal of our study was to assess the value of hyperpolarized (HP) γ-glutamyl-[1-13C]glycine for non-invasive imaging of glioblastoma. Nude rats bearing orthotopic U87 glioblastoma and healthy controls were investigated. Imaging was performed by injecting HP γ-glutamyl-[1-13C]glycine and acquiring dynamic 13C data on a preclinical 3T MR scanner. The signal-to-noise (SNR) ratios of γ-glutamyl-[1-13C]glycine and its product [1-13C]glycine were evaluated. Comparison of control and tumor-bearing rats showed no difference in γ-glutamyl-[1-13C]glycine SNR, pointing to similar delivery to tumor and normal brain. In contrast, [1-13C]glycine SNR was significantly higher in tumor-bearing rats compared to controls, and in tumor regions compared to normal-appearing brain. Importantly, higher [1-13C]glycine was associated with higher GGT expression and higher GSH levels in tumor tissue compared to normal brain. Collectively, this study demonstrates, to our knowledge for the first time, the feasibility of using HP γ-glutamyl-[1-13C]glycine to monitor GGT expression in the brain and thus to detect glioblastoma.
- Published
- 2019
27. PI3K/mTOR inhibition of IDH1 mutant glioma leads to reduced 2HG production that is associated with increased survival
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Chloé Najac, Elavarasan Subramani, Anne Marie Gillespie, Abigail R. Molloy, Romelyn Delos Santos, Pavithra Viswanath, Georgios Batsios, Sabrina M. Ronen, and Russell O. Pieper
- Subjects
0301 basic medicine ,Glutamine ,lcsh:Medicine ,Cell Cycle Proteins ,Kaplan-Meier Estimate ,medicine.disease_cause ,Mice ,Phosphatidylinositol 3-Kinases ,0302 clinical medicine ,Phosphorylation ,lcsh:Science ,Cell Line, Transformed ,Cancer ,Sulfonamides ,Multidisciplinary ,Chemistry ,Brain Neoplasms ,TOR Serine-Threonine Kinases ,Adaptor Proteins ,Glioma ,Cancer metabolism ,Isocitrate Dehydrogenase ,Neoplasm Proteins ,Isocitrate dehydrogenase ,Biomarker (medicine) ,Signal transduction ,Signal Transduction ,IDH1 ,Nuclear Magnetic Resonance ,Article ,Cell Line ,Glutarates ,03 medical and health sciences ,Targeted therapies ,Rare Diseases ,In vivo ,Quinoxalines ,medicine ,Animals ,Humans ,Nuclear Magnetic Resonance, Biomolecular ,PI3K/AKT/mTOR pathway ,Protein Processing ,Adaptor Proteins, Signal Transducing ,Ribosomal Protein S6 Kinases ,lcsh:R ,Signal Transducing ,Post-Translational ,Neurosciences ,medicine.disease ,Xenograft Model Antitumor Assays ,Brain Disorders ,CNS cancer ,Brain Cancer ,030104 developmental biology ,Glucose ,Orphan Drug ,Transformed ,Astrocytes ,Cancer research ,lcsh:Q ,Cancer imaging ,Carcinogenesis ,Protein Processing, Post-Translational ,030217 neurology & neurosurgery ,Biomolecular - Abstract
70–90% of low-grade gliomas and secondary glioblastomas are characterized by mutations in isocitrate dehydrogenase 1 (IDHmut). IDHmut produces the oncometabolite 2-hydroxyglutarate (2HG), which drives tumorigenesis in these tumors. The phosphoinositide-3-kinase (PI3K)/mammalian target of rapamycin (mTOR) pathway represents an attractive therapeutic target for IDHmut gliomas, but noninvasive indicators of drug target modulation are lacking. The goal of this study was therefore to identify magnetic resonance spectroscopy (MRS)-detectable metabolic biomarkers associated with IDHmut glioma response to the dual PI3K/(mTOR) inhibitor XL765. 1H-MRS of two cell lines genetically modified to express IDHmut showed that XL765 induced a significant reduction in several intracellular metabolites including 2HG. Importantly, examination of an orthotopic IDHmut tumor model showed that enhanced animal survival following XL765 treatment was associated with a significant in vivo1H-MRS detectable reduction in 2HG but not with significant inhibition in tumor growth. Further validation is required, but our results indicate that 2HG could serve as a potential noninvasive MRS-detectable metabolic biomarker of IDHmut glioma response to PI3K/mTOR inhibition.
- Published
- 2019
28. In vivo investigation of hyperpolarized [1,3-13C2]acetoacetate as a metabolic probe in normal brain and in glioma
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Chloé Najac, Sabrina M. Ronen, Anne Marie Gillespie, Lydia M. Le Page, Georgios Batsios, Elavarasan Subramani, Pavithra Viswanath, and Marina Radoul
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Magnetic Resonance Spectroscopy ,lcsh:Medicine ,Dehydrogenase ,Blood–brain barrier ,Acetoacetates ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Rare Diseases ,In vivo ,Glioma ,Internal medicine ,medicine ,Animals ,lcsh:Science ,Cancer ,chemistry.chemical_classification ,Reactive oxygen species ,Multidisciplinary ,Chemistry ,lcsh:R ,Neurosciences ,Brain ,medicine.disease ,3. Good health ,Mitochondria ,Brain Disorders ,Brain Cancer ,030104 developmental biology ,Endocrinology ,medicine.anatomical_structure ,Spectrophotometry ,Cancer cell ,Neurological ,Ketone bodies ,lcsh:Q ,Female ,NAD+ kinase ,Oxidation-Reduction ,030217 neurology & neurosurgery - Abstract
Dysregulation in NAD+/NADH levels is associated with increased cell division and elevated levels of reactive oxygen species in rapidly proliferating cancer cells. Conversion of the ketone body acetoacetate (AcAc) to β-hydroxybutyrate (β-HB) by the mitochondrial enzyme β-hydroxybutyrate dehydrogenase (BDH) depends upon NADH availability. The β-HB-to-AcAc ratio is therefore expected to reflect mitochondrial redox. Previous studies reported the potential of hyperpolarized 13C-AcAc to monitor mitochondrial redox in cells, perfused organs and in vivo. However, the ability of hyperpolarized 13C-AcAc to cross the blood brain barrier (BBB) and its potential to monitor brain metabolism remained unknown. Our goal was to assess the value of hyperpolarized [1,3-13C2]AcAc in healthy and tumor-bearing mice in vivo. Following hyperpolarized [1,3-13C2]AcAc injection, production of [1,3-13C2]β-HB was detected in normal and tumor-bearing mice. Significantly higher levels of [1-13C]AcAc and lower [1-13C]β-HB-to-[1-13C]AcAc ratios were observed in tumor-bearing mice. These results were consistent with decreased BDH activity in tumors and associated with increased total cellular NAD+/NADH. Our study confirmed that AcAc crosses the BBB and can be used for monitoring metabolism in the brain. It highlights the potential of AcAc for future clinical translation and its potential utility for monitoring metabolic changes associated with glioma, and other neurological disorders.
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- 2019
29. Metabolomic signatures of asthma-COPD overlap (ACO) are different from asthma and COPD
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Parthasarathi Bhattacharyya, Koel Chaudhury, Priyanka Choudhury, Mamata Joshi, Elavarasan Subramani, Dipanjan Saha, Nilanjana Ghosh, Sayoni Sengupta, Sushmita Roychowdhury, and Rintu Banerjee
- Subjects
Adult ,Male ,medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,Clinical Biochemistry ,Disease ,Asthma-Chronic Obstructive Pulmonary Disease Overlap Syndrome ,01 natural sciences ,Biochemistry ,Cohort Studies ,03 medical and health sciences ,Pulmonary Disease, Chronic Obstructive ,Quality of life ,Internal medicine ,medicine ,Humans ,Metabolomics ,030304 developmental biology ,Asthma ,0303 health sciences ,COPD ,Univariate analysis ,business.industry ,010401 analytical chemistry ,Middle Aged ,medicine.disease ,Molecular medicine ,Pathophysiology ,respiratory tract diseases ,0104 chemical sciences ,Cohort ,Metabolome ,Female ,business - Abstract
Asthma-chronic obstructive pulmonary disease (COPD) overlap, termed as ACO, is a complex heterogeneous disease without any clear diagnostic or therapeutic guidelines. The pathophysiology of the disease, its characteristic features, and existence as a unique disease entity remains unclear. Individuals with ACO have a faster lung function decline, more frequent exacerbations, and worse quality of life than those with COPD or asthma alone. The present study aims to determine whether ACO has a distinct metabolic profile in comparison to asthma and COPD. Two different groups of patients were recruited as discovery (D) and validation (V) cohorts. Serum samples obtained from moderate and severe asthma patients diagnosed as per GINA guidelines [n = 34(D); n = 32(V)], moderate and severe COPD cases identified by GOLD guidelines [n = 30(D); 32(V)], ACO patients diagnosed by joint GOLD and GINA guidelines [n = 35(D); 40(V)] and healthy controls [n = 33(D)] were characterized using nuclear magnetic resonance (NMR) spectrometry. Multivariate and univariate analysis indicated that 12 metabolites [lipid, isoleucine, N-acetylglycoproteins (NAG), valine, glutamate, citric acid, glucose, l-leucine, lysine, asparagine, phenylalanine and histidine] were dysregulated in ACO patients when compared with both asthma and COPD. These metabolites were further validated in a fresh cohort of patients, which again exhibited a similar expression pattern. Our findings suggest that ACO has an enhanced energy and metabolic burden associated with it as compared to asthma and COPD. It is anticipated that our results will stimulate researchers to further explore ACO and unravel the pathophysiological complexities associated with the disease.
- Published
- 2019
30. Bioinspired 3D porous human placental derived extracellular matrix/silk fibroin sponges for accelerated bone regeneration
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Sabyasachi Roy, Elavarasan Subramani, Sayanti Datta, Paulomi Ghosh, Santanu Dhara, Arun Prabhu Rameshbabu, Padmavati Manchikanti, Kamakshi Bankoti, Anupam Apoorva, Koel Chaudhury, and Subhodeep Jana
- Subjects
Materials science ,Bone Regeneration ,Compressive Strength ,medicine.medical_treatment ,Placenta ,Neovascularization, Physiologic ,Bioengineering ,Biocompatible Materials ,02 engineering and technology ,Matrix (biology) ,010402 general chemistry ,Bone tissue ,01 natural sciences ,Hemolysis ,Biomaterials ,Extracellular matrix ,Osteogenesis ,Pregnancy ,medicine ,Animals ,Humans ,Bone regeneration ,Tissue Scaffolds ,Growth factor ,Regeneration (biology) ,Mesenchymal stem cell ,Cell Differentiation ,Mesenchymal Stem Cells ,021001 nanoscience & nanotechnology ,Bandages ,0104 chemical sciences ,Cell biology ,Extracellular Matrix ,medicine.anatomical_structure ,Mechanics of Materials ,Female ,Rabbits ,Bone Diseases ,0210 nano-technology ,Fibroins ,Porosity ,Ex vivo - Abstract
Critical bone defects arising from traumatic injury and diseases are of major health concern since they are unable to heal spontaneously without clinical intervention. In this context, bone tissue engineering provides an attractive approach to treat bone defects by providing a bioactive template which has the potential to guide osseous tissue regeneration. In this study, porous hybrid placental extracellular matrix sponge (PIMS) was fabricated by a combinatorial method using silk fibroin (SF)/placental derived extracellular matrix and subsequently evaluated its efficacy towards bone tissue regeneration. The presence of intrinsic growth factors was evidenced by immunoblotting of the extracted proteins derived from the placental derived extracellular matrix. This growth factor rich PIMS lends a unique bioactive scaffolding to human amniotic mesenchymal stem cells (HAMSCs) which supported enhanced proliferation as well as superior osteogenic differentiation. Gene expression studies demonstrated significant up-regulation of osteogenic related genes in the PIMS group. PIMS when implanted in the chick chorioallantoic membrane, significantly attracted allantoic vessels revealing its potential to stimulate angiogenesis ex vivo. Furthermore, no severe immune response to the host was observed on subcutaneous implantation of PIMS in vivo. Instead, it supported the formation of blood vessels, revealing its outstanding biocompatibility. Additionally, critical tibial defects treated with PIMS demonstrated higher bone volume after six weeks when analyzed by micro-CT, which was accompanied by high mineral density. Histological and immunofluorescence studies validated the results and revealed enhanced osseous tissue regeneration after six weeks of surgery. All these findings recapitulated that the growth factors incorporated bioactive PIMS could perform as an appropriate matrix for osteogenic differentiation and efficient bone regeneration.
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- 2018
31. In vivo investigation of hyperpolarized [1,3
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Chloé, Najac, Marina, Radoul, Lydia M, Le Page, Georgios, Batsios, Elavarasan, Subramani, Pavithra, Viswanath, Anne Marie, Gillespie, and Sabrina M, Ronen
- Subjects
Mice ,Magnetic Resonance Spectroscopy ,Spectrophotometry ,Animals ,Brain ,Female ,Glioma ,Oxidation-Reduction ,Article ,Acetoacetates ,Mitochondria - Abstract
Dysregulation in NAD+/NADH levels is associated with increased cell division and elevated levels of reactive oxygen species in rapidly proliferating cancer cells. Conversion of the ketone body acetoacetate (AcAc) to β-hydroxybutyrate (β-HB) by the mitochondrial enzyme β-hydroxybutyrate dehydrogenase (BDH) depends upon NADH availability. The β-HB-to-AcAc ratio is therefore expected to reflect mitochondrial redox. Previous studies reported the potential of hyperpolarized 13C-AcAc to monitor mitochondrial redox in cells, perfused organs and in vivo. However, the ability of hyperpolarized 13C-AcAc to cross the blood brain barrier (BBB) and its potential to monitor brain metabolism remained unknown. Our goal was to assess the value of hyperpolarized [1,3-13C2]AcAc in healthy and tumor-bearing mice in vivo. Following hyperpolarized [1,3-13C2]AcAc injection, production of [1,3-13C2]β-HB was detected in normal and tumor-bearing mice. Significantly higher levels of [1-13C]AcAc and lower [1-13C]β-HB-to-[1-13C]AcAc ratios were observed in tumor-bearing mice. These results were consistent with decreased BDH activity in tumors and associated with increased total cellular NAD+/NADH. Our study confirmed that AcAc crosses the BBB and can be used for monitoring metabolism in the brain. It highlights the potential of AcAc for future clinical translation and its potential utility for monitoring metabolic changes associated with glioma, and other neurological disorders.
- Published
- 2018
32. EXTH-76. (1)H AND HYPERPOLARIZED (13)C MRS BIOMARKERS OF IDH1 MUTANT GLIOMA RESPONSE TO TEMOZOLOMIDE THERAPY
- Author
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Russell O. Pieper, Pavithra Viswanath, Marina Radoul, Chloé Najac, Elavarasan Subramani, Sabrina M. Ronen, Georgios Batsios, and Anne Marie Gillespie
- Subjects
Cancer Research ,Temozolomide ,IDH1 ,business.industry ,Mutant ,Hyperpolarized 13c ,medicine.disease ,Abstracts ,Isocitrate dehydrogenase ,Oncology ,Metabolic disturbance ,Glioma ,medicine ,Cancer research ,Neurology (clinical) ,business ,medicine.drug ,Glioblastoma - Abstract
The alkylating agent temozolomide (TMZ), previously reserved for treatment of glioblastoma, is now being considered for the treatment of low-grade glioma that are driven by mutations in the isocitrate dehydrogenase 1 (IDH1) gene. Though the treatment of IDH1 mutant patients with TMZ improves survival, there is a need for metabolic imaging to help in assessing early response to therapy. The goal of this study was, therefore, to determine the value of magnetic resonance spectroscopy (MRS)-based biomarkers for detection of response to treatment. To address this, we examined the global metabolic alterations that occurred following TMZ treatment in a genetically engineered IDH1 mutant immortalized normal human astrocyte cell line (NHAIDHmut) using (1)H and (13)C MRS combined with chemometrics. Cells were treated either with the IC50 of TMZ (100 μM; N=5), or with DMSO (0.2%; N=5) for 72 hours. Then, metabolites were extracted from cells and (1)H spectra acquired. Data were analyzed using SIMCA and the most significant metabolites contributing to class separation were identified using multivariate and univariate analyses. Alternatively, live cells were exposed to hyperpolarized 2-(13)C-pyruvate and dynamic sets of (13)C-MRS spectra recorded to monitor the production of 5-(13)C-glutamate over time. (1)H MRS showed that glutamine, glutamate, pyruvate, succinate, glucose, phosphocholine, isoleucine, valine, lysine, phenylalanine, NAD+/NADP+ and ATP/ADP/AMP were significantly higher in TMZ-treated cells as compared to controls. Accordingly, the tricarboxylic acid (TCA) cycle was identified as a significantly altered pathway following TMZ treatment. Consistent with this finding, dynamically probing the metabolism of hyperpolarized 2-(13)C-pyruvate revealed that build-up of 5-(13)C-glutamate, which is associated with flux to the TCA cycle, was significantly higher in TMZ-treated cells as compared to controls. Further studies are warranted for validation of our findings in other mutant IDH1 models. Nonetheless, our findings identify potential MRS-detectable early biomarkers of response to TMZ therapy in mutant IDH1 glioma.
- Published
- 2018
33. EXTH-35. IN VIVO (1)H MRS DETECTS REDUCED 2HG PRODUCTION IN IDH1 MUTANT GLIOMAS TREATED WITH A DUAL PI3K/MTOR INHIBITOR
- Author
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Joanna J. Phillips, Pavithra Viswanath, Elavarasan Subramani, Sabrina M. Ronen, Anne Marie Gillespie, Georgios Batsios, and Russell O. Pieper
- Subjects
Cancer Research ,Phosphoinositide 3-kinase ,IDH1 ,biology ,Chemistry ,Mutant ,medicine.disease ,medicine.disease_cause ,Abstracts ,Isocitrate dehydrogenase ,Oncology ,In vivo ,Glioma ,medicine ,biology.protein ,Cancer research ,Neurology (clinical) ,Carcinogenesis ,PI3K/AKT/mTOR pathway - Abstract
70–90% of low-grade gliomas and secondary glioblastomas are characterized by mutations in isocitrate dehydrogenase (IDH1mut). Mutant IDH produces the oncometabolite 2-hydroxyglutarate (2HG), which drives tumorigenesis. Inhibitors of phosphoinositide-3-kinase (PI3K) pathway are currently under clinical investigation for IDH1mut gliomas with positive outcome results, but early response imaging biomarkers are missing. The goal of this study was to identify potential magnetic resonance (MR) detectable biomarkers of IDH1mut glioma response to the dual PI3K/mammalian target of rapamycin (mTOR) inhibitor XL765. We used two genetically-engineered IDH1mut models: a U87 glioblastoma-based model (U87IDHmut) and an immortalized normal human astrocyte-based model (NHAIDHmut), as well as a patient derived IDH1mut model (BT142). The reduction of PI3K/mTOR pathway signaling was validated with western blots of p4E-BP1 for all models. We then used MR spectroscopy (MRS) to investigate the impact of treatment on cell metabolism. Using (1)H-MRS, we observed that XL765 induced a significant ~70% and ~50% reduction in steady-state levels of 2HG and glutamate in U87IDHmut while in NHAIDHmut the drop was ~90% and ~70% for 2HG and glutamate respectively. In the case of BT142 there was a ~35% drop in glutamate levels while 2HG was MRS undetectable in both groups. The translatability of our findings was evaluated in mice bearing orthotropic U87IDHmut xerographs treated with XL765 orally twice a day. XL765-treatment of mice led to an apparent slower tumor growth, which was associated with significantly increased animal survival. Importantly, in vivo (1)H-MRS spectroscopy showed a significant reduction in 2HG levels. The results were verified by (1)H-MRS of tumor extracts. Collectively, our results indicate that treatment with XL765 is associated with response in IDH1mut models. To our knowledge, this is the first time in vivo (1)H-MRS detected reduction in 2HG in gliomas undergoing treatment with a non-IDH1mut-specific inhibitor. Thus, 2HG could potentially be used as a response biomarker.
- Published
- 2018
34. Solubility enhancement of morin and epicatechin through encapsulation in an albumin based nanoparticulate system and their anticancer activity against the MDA-MB-468 breast cancer cell line
- Author
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Atanu Singha Roy, Pooja Ghosh, Koel Chaudhury, Swagata Dasgupta, Elavarasan Subramani, and Sudipta Bag
- Subjects
0301 basic medicine ,MDA-MB-468 ,Chemistry ,General Chemical Engineering ,02 engineering and technology ,General Chemistry ,Morin ,021001 nanoscience & nanotechnology ,Human serum albumin ,body regions ,03 medical and health sciences ,chemistry.chemical_compound ,030104 developmental biology ,Polyphenol ,mental disorders ,embryonic structures ,medicine ,Organic chemistry ,MTT assay ,Nanocarriers ,Solubility ,0210 nano-technology ,Cytotoxicity ,Nuclear chemistry ,medicine.drug - Abstract
The polyphenols morin and epicatechin exhibit properties that include antioxidant, anticancer, and anti-inflammatory activities, etc. However, their clinical application is hampered by their poor aqueous solubility and bioavailability. In the present study an attempt has been made to overcome these drawbacks by encapsulating morin and epicatechin separately into a suitable nanocarrier. We have prepared morin loaded human serum albumin (HSA) nanoparticles (Mor-HSA-NPs) and epicatechin loaded HSA nanoparticles (EC-HSA-NPs) using a desolvation technique, which have been further characterised for particle size, morphology, morin/epicatechin content in nanoparticles, and their in vitro release. The particle size of the prepared formulation was ∼170 ± 6 nm for Mor-HSA-NPs and ∼200 ± 12 nm for EC-HSA-NPs with an almost spherical shape and smooth surface. The release profile exhibited an initial burst release followed by a sustained release. The cytotoxicity of Mor-HSA-NPs and EC-HSA-NPs against the MDA-MB-468 breast cancer cell line has been investigated by MTT assay and the results show that the nanoparticles are capable of destroying the cancer cells more potently than morin/epicatechin alone. This is also supported by fluorescence microscopy images. This result is likely to facilitate an understanding of how to enhance the delivery of flavonoids like morin and epicatechin by encapsulation.
- Published
- 2016
35. Author Correction: Metabolomics reveals perturbations in endometrium and serum of minimal and mild endometriosis
- Author
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Debanjan Das, Uma Sharma, Brajesh Singh, Chaitali Datta Ray, Meenu Maan, Mainak Dutta, Baidyanath Chakravarty, Saikat Jana, Elavarasan Subramani, Swagata Dasgupta, Mamata Joshi, Soumen Das, and Koel Chaudhury
- Subjects
Pathology ,medicine.medical_specialty ,Multidisciplinary ,business.industry ,lcsh:R ,Endometriosis ,lcsh:Medicine ,medicine.disease ,Endometrium ,Metabolomics ,medicine.anatomical_structure ,Medicine ,lcsh:Q ,business ,lcsh:Science - Abstract
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
- Published
- 2020
36. CBMT-08. IN VIVO EVALUATION OF PENTOSE PHOSPHATE PATHWAY ACTIVITY IN ORTHOTOPIC GLIOMA USING HYPERPOLARIZED δ-[1-13C]GLUCONOLACTONE
- Author
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Céline Taglang, Elavarasan Subramani, Robert R. Flavell, Peder E. Z. Larson, Peng Cao, Sabrina M. Ronen, Georgios Batsios, and Pavithra Viswanath
- Subjects
chemistry.chemical_classification ,Cancer Research ,Metabolism ,Pentose phosphate pathway ,medicine.disease ,Cell Biology and Metabolism ,Gluconolactone ,chemistry.chemical_compound ,Oncology ,Biochemistry ,chemistry ,In vivo ,Glioma ,Ribose ,medicine ,Phosphorylation ,Nucleotide ,Neurology (clinical) - Abstract
The pentose phosphate pathway (PPP) generates NADPH and ribose 5-phosphate, which are involved in the scavenging of reactive oxygen species and the synthesis of nucleotides. As such, the PPP is typically upregulated in cancer cells to address the metabolic needs of rapid cell proliferation. Imaging PPP upregulation could therefore be useful in tumor assessment. One intermediate of the pathway is 6-phospho-δ-gluconolactone (6P-δ-GL), which is produced by phosphorylation of δ-gluconolactone. 6P-δ-GL is further metabolized to 6-phospho-gluconate (6PG). The goal of our study was to evaluate, for the first time, whether hyperpolarized (HP) δ-[1-13C]gluconolactone can be used to assess PPP flux and detect the presence of tumor in an orthotopic glioma rat model. Athymic nude rats bearing orthotropic U87 tumors or age-matched tumor-free controls were investigated. HP studies were performed following intravenous injection of HP δ-[1-13C]gluconolactone and metabolic images using a flyback spectral-spatial echo-planar spectroscopic imaging pulse were acquired. The data were processed using in-house Matlab code. 6P-δ-GL and 6-phospho-γ-[1-13C]gluconolactone were observed in all rats ~10 seconds after HP δ-[1-13C]gluconolactone injection, followed ~5 seconds later by production of 6PG observed at 179.3ppm. These data indicate that HP δ-[1-13C]gluconolactone likely crosses the blood-brain barrier, consistent with its transport via glucose transporters, and is rapidly metabolized. Importantly, 6PG was significantly higher in tumor voxels. The ratio of 6PG-to-6P-δ-GL was comparable in normal brain and in normal-appearing contralateral brain of tumor-bearing rats at 0.43±0.09 and 0.45±0.06 respectively (p=0.85), but significant higher in the tumor regions at 0.70±0.11 (p=0.04 and p=0.02 respectively), consistent with the elevated PPP flux that typically occurs in tumor cells. Our results indicate, to our knowledge for the first time, that metabolism of HP δ-[1-13C]gluconolactone can be assessed in the brain and that elevated 6PG production in glioma provides a potential metabolic imaging approach to probe tumor development, recurrence and response to therapy.
- Published
- 2019
37. Silk Sponges Ornamented with a Placenta-Derived Extracellular Matrix Augment Full-Thickness Cutaneous Wound Healing by Stimulating Neovascularization and Cellular Migration
- Author
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Anupam Apoorva, Padmavati Manchikanti, Priti Prasanna Maity, Paulomi Ghosh, Santanu Dhara, Elavarasan Subramani, Sayanti Datta, Koel Chaudhury, Kamakshi Bankoti, and Arun Prabhu Rameshbabu
- Subjects
Materials science ,Placenta ,Silk ,Fibroin ,Neovascularization, Physiologic ,02 engineering and technology ,010402 general chemistry ,01 natural sciences ,Neovascularization ,Extracellular matrix ,Foreskin ,Cell Movement ,Pregnancy ,medicine ,Animals ,Humans ,General Materials Science ,Skin ,Wound Healing ,integumentary system ,Regeneration (biology) ,Cell migration ,021001 nanoscience & nanotechnology ,0104 chemical sciences ,Cell biology ,Extracellular Matrix ,Rats ,medicine.anatomical_structure ,Female ,medicine.symptom ,Stem cell ,0210 nano-technology ,Wound healing - Abstract
Regeneration of full-thickness wounds without scar formation is a multifaceted process, which depends on in situ dynamic interactions between the tissue-engineered skin substitutes and a newly formed reparative tissue. However, the majority of the tissue-engineered skin substitutes used so far in full-thickness wound healing cannot mimic the natural extracellular matrix (ECM) complexity and thus are incapable of providing a suitable niche for endogenous tissue repair. Herein, we demonstrated a simple approach to fabricate porous hybrid ECM sponges (HEMS) using a placental ECM and silk fibroin for full-thickness wound healing. HEMS with retained cytokines/growth factors provided a noncytotoxic environment in vitro for human foreskin fibroblasts (HFFs), human epidermal keratinocytes (HEKs), and human amniotic membrane-derived stem cells to adhere, infiltrate, and proliferate. Interestingly, HEMS-conditioned media accelerated the migration of HFFs and HEKs owing to the presence of cytokines/growth factors. Also, the ex vivo chick chorioallantoic membrane assay of HEMS demonstrated its excellent vascularization potential by inducing and supporting blood vessels. Additionally, HEMS when subcutaneously implanted demonstrated no severe immune response to the host. Furthermore, HEMS implanted in full-thickness wounds in a rat model showed augmented healing progression with well-organized epidermal-dermal junctions via pronounced angiogenesis, accelerated migration of HFFs/HEKs, enhanced granulation tissue formation, and early re-epithelialization. Taken together, these findings show that porous HEMS ornamented with cytokines/growth factors having superior physicomechanical properties may be an appropriate skin substitute for full-thickness cutaneous wounds.
- Published
- 2018
38. Metabolomics reveals perturbations in endometrium and serum of minimal and mild endometriosis
- Author
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Swagata Dasgupta, Koel Chaudhury, Chaitali Datta Ray, Meenu Maan, Elavarasan Subramani, Soumen Das, Debanjan Das, Brajesh Singh, Mainak Dutta, Uma Sharma, Baidyanath Chakravarty, Saikat Jana, and Mamata Joshi
- Subjects
Adult ,Serum ,0301 basic medicine ,medicine.medical_specialty ,Endometriosis ,Uterus ,lcsh:Medicine ,Phenylalanine ,Endometrium ,Sensitivity and Specificity ,Article ,03 medical and health sciences ,Metabolomics ,Stroma ,Internal medicine ,Metabolome ,Humans ,Medicine ,Author Correction ,lcsh:Science ,Multidisciplinary ,business.industry ,lcsh:R ,medicine.disease ,030104 developmental biology ,Endocrinology ,medicine.anatomical_structure ,Female ,lcsh:Q ,Leucine ,business ,Biomarkers - Abstract
Endometriosis is a common benign gynecological disease, characterized by growth and proliferation of endometrial glands and stroma outside the uterus. With studies showing metabolic changes in various biofluids of endometriosis women, we have set upon to investigate whether endometrial tissue show differences in their metabolic profiles. 1H NMR analysis was performed on eutopic endometrial tissue of women with endometriosis and controls. Analysis was performed on spectral data and on relative concentrations of metabolites obtained from spectra using multivariate and univariate data analysis. Analysis shows that various energy, ketogenic and glucogenic metabolites have significant altered concentrations in various stages of endometriosis. In addition, altered tissue metabolites in minimal and mild stages of endometriosis were explored in serum of these patients to assess their role in disease diagnosis. For Stage I diagnosis alanine was found to have 90% sensitivity (true positives) and 58% specificity (true negatives). For Stage II diagnosis alanine, leucine, lysine, proline and phenylalanine showed significant altered levels in serum. While sensitivity of these serum metabolites varied between 69.2–100% the specificity values ranged between 58.3–91.7%. Further, a regression model generated with this panel of serum markers showed an improved sensitivity and specificity of 100% and 83%, respectively for Stage II diagnosis.
- Published
- 2018
39. Proteomic-driven biomarker discovery in gestational diabetes mellitus: A review
- Author
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Chaitali Datta Ray, Apoorva Singh, Srikanth Rapole, Elavarasan Subramani, and Koel Chaudhury
- Subjects
Proteomics ,Pregnancy ,Proteomic Profile ,business.industry ,Biophysics ,Disease ,medicine.disease ,Bioinformatics ,Biochemistry ,Preeclampsia ,Gestational diabetes ,Diabetes, Gestational ,Pre-Eclampsia ,Diabetes mellitus ,medicine ,Humans ,Female ,Biomarker discovery ,business ,Biomarkers - Abstract
Gestational diabetes mellitus (GDM) is defined as any degree of glucose intolerance with onset or first recognition during pregnancy and it affects 18% of pregnant women worldwide. GDM is considered a high-risk state which may lead to type II diabetes which is associated with an increase in a number of interrelated adverse perinatal outcomes. Given the fact that the progress of a successful pregnancy is dependent on the intricate communication between several biological molecules, identification of the proteomic profile perturbations in women with GDM is expected to help in understanding the disease pathogenesis and also discovery of clinical biomarker(s). In recent years, both gel-free and gel-based proteomics have been extensively investigated for improving maternal and child health. Although there are several reports integrating various aspects of proteomics in pregnancy related diseases such as preeclampsia, extensive Pubmed search shows no review so far on the application of proteomics in gestational diabetes. In this review, we focus on various high-throughput proteomic technologies for the identification of unique biosignatures and biomarkers responsible for the early prediction of GDM. Further, different analytical strategies and biological samples involved in proteomic analysis of this pregnancy-related disease are discussed.This article is part of a Special Issue entitled: Proteomics in India.
- Published
- 2015
40. Investigation of serum proteome alterations in human endometriosis
- Author
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Akshada Gajbhiye, Snigdha Dhali, Mainak Dutta, Namita Pendharkar, Khushman Taunk, Chaitali Datta Ray, Indrani Lodh, Srikanth Rapole, Koel Chaudhury, Baidyanath Chakravarty, Shubhendu Seal, Elavarasan Subramani, and Swagata Dasgupta
- Subjects
Adult ,Pathology ,medicine.medical_specialty ,Proteome ,Endometriosis ,Biophysics ,Bioinformatics ,Biochemistry ,Two-Dimensional Difference Gel Electrophoresis ,Pathogenesis ,medicine ,Humans ,Electrophoresis, Gel, Two-Dimensional ,Screening procedures ,biology ,business.industry ,Haptoglobin ,Case-control study ,Blood Proteins ,medicine.disease ,Blood proteins ,Blot ,Case-Control Studies ,Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization ,biology.protein ,Female ,business ,Biomarkers - Abstract
Endometriosis is a common benign gynecological disease, characterized by proliferation of functional endometrial glands and stroma outside the uterine cavity. The present study involves investigation of alterations in the serum proteome of endometriosis patients compared to healthy controls using 2DE and 2D-DIGE combined with MALDI TOF/TOF-MS. Comparison of serum proteome of endometriosis patients and healthy subjects revealed 25 significant differentially expressed proteins. Gene ontology and network analysis, performed using PANTHER, DAVID, WebGestalt and STRING, revealed that the differentially expressed proteins are majorly involved in response to stimulus, immune system, metabolic, localization and cellular processes. For serum diagnostic marker identification, several robust statistical screening procedures were applied to identify the set of the most significant proteins responsible for successful diagnosis of different endometriosis stages. Partial least squares (PLS) based marker selection tool and orthogonal partial least squares-discriminant analysis (OPLS-DA) were used to identify the most significant proteins for disease prediction. Western blotting validation in a separate cohort of patients revealed that haptoglobin (HP), Ig kappa chain C region (IGKC), alpha-1B-glycoprotein (A1BG) can be considered effective serum protein markers for the diagnosis of Stage II, III and IV endometriosis. For diagnosis of Stage I, only IGKC and HP seemed promising.Globally, about 12 in 100 women of reproductive age are diagnosed with endometriosis. The pathogenesis of the disease still remains unclear, leading to non-specific therapeutic approaches for disease management. Moreover, there is a delay of 8-12years in correct diagnosis after the initial onset of symptoms leading to a considerable impact on the woman's lifestyle. Also, the gold standard for diagnosis of endometriosis, laparoscopy, is an invasive procedure. The value of a noninvasive or semi-invasive diagnostic test for endometriosis with easily accessible fluids such as plasma, serum, urine, and saliva is, therefore, rightfully recognized. The present study is expected to considerably improve the understanding of the disease pathogenesis along with improved diagnostics and therapeutic approaches leading to better management of the disease.
- Published
- 2015
41. Mass spectrometry and bioinformatics analysis data
- Author
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Baidyanath Chakravarty, Shubhendu Seal, Snigdha Dhali, Khushman Taunk, Elavarasan Subramani, Swagata Dasgupta, Akshada Gajbhiye, Mainak Dutta, Chaitali Datta Ray, Srikanth Rapole, Namita Pendharkar, Koel Chaudhury, and Indrani Lodh
- Subjects
Multidisciplinary ,Bioinformatics analysis ,business.industry ,Computational biology ,Bioinformatics ,Mass spectrometry ,Proteomics ,lcsh:Computer applications to medicine. Medical informatics ,Text mining ,Serum proteome ,Medicine ,lcsh:R858-859.7 ,business ,lcsh:Science (General) ,lcsh:Q1-390 ,Data Article - Abstract
2DE and 2D-DIGE based proteomics analysis of serum from women with endometriosis revealed several proteins to be dysregulated. A complete list of these proteins along with their mass spectrometry data and subsequent bioinformatics analysis are presented here. The data is related to “Investigation of serum proteome alterations in human endometriosis” by Dutta et al. [1].
- Published
- 2014
42. Abstract 5263: 1H and 13C MRS-based metabolic markers of IDH1 mutant glioma response to temozolomide therapy
- Author
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Anne Marie Gillespie, Chloé Najac, Pavithra Viswanath, Elavarasan Subramani, Sabrina M. Ronen, Marina Radoul, Georgios Batsios, and Russell O. Pieper
- Subjects
Cancer Research ,IDH1 ,Temozolomide ,Chemistry ,medicine.disease ,Glutamine ,chemistry.chemical_compound ,Isocitrate dehydrogenase ,medicine.anatomical_structure ,Oncology ,Glioma ,medicine ,Cancer research ,Isoleucine ,Astrocyte ,Phosphocholine ,medicine.drug - Abstract
Low-grade gliomas, driven by mutations in the isocitrate dehydrogenase 1 (IDH1) gene, are less aggressive than primary glioblastoma (GBM), but nonetheless always recur and ultimately lead to patient death. To improve patient survival, one therapeutic strategy is treatment with the alkylating chemotherapeutic agent Temozolomide (TMZ), previously reserved for the treatment of primary GBM. Though the treatment of IDH1 mutant patients with TMZ improves survival, early detection of treatment-associated effects remains challenging. The goal of this study was, therefore, to determine the value of magnetic resonance spectroscopy (MRS)-based biomarkers for detection of response to treatment. To this end, we examined the global metabolic alterations that occurred following TMZ treatment in a genetically engineered IDH1 mutant immortalized Normal Human Astrocyte (NHAIDHmut)-based cell model using 1H MRS combined with chemometrics and 13C MRS combined with labeling of cells with [1-13C]-glucose and [3-13C]-glutamine. Cells were treated either with the IC50 value of TMZ (100 μM; N=5), or with DMSO (0.2%; N=5) for 72 hours. Then, metabolites were extracted from cells using the dual-phase extraction method. 1H-MRS and proton-decoupled 13C-MRS spectra were acquired using a 500 MHz Bruker Avance spectrometer. 1H MRS data was subjected to multivariate analysis using SIMCA. Specific metabolites were also quantified using Mnova7, integrals normalized to TSP and to cell number and statistical significance of differences determined using unpaired Student’s t-test. Pathway enrichment analysis of dysregulated metabolites was performed using MetPA. principal component analysis score plot showed separation of TMZ-treated from DMSO-treated control cells. Further, improved separation between the groups was obtained by orthogonal-partial least squares discriminant analysis. Most significant metabolites contributing to class separation were identified using correlation ≥0.6 and variable importance in projection score ≥1. Glutamine, glutamate, 2-hydroxyglutarate (2-HG), pyruvate, succinate, glucose, phosphocholine, isoleucine, valine, lysine, phenylalanine, NAD(P)+ and AMP/ADP/ATP were observed to be significantly higher in TMZ-treated cells as compared to controls. Based on pathway impact score, tricarboxylic acid (TCA) cycle was identified to be the significantly altered pathway following treatment Further, there was a significant increases in glucose- and glutamine-derived glutamate and 2-HG, indicating an increase in flux to the TCA cycle following treatment. These findings demonstrate that IDH1 mutant glioma show a clear metabolomic fingerprint in response to TMZ therapy, which, combined with complementary hyperpolarized 13C MRS approaches, may help assess early response to TMZ therapy in mutant IDH1 glioma. Note: This abstract was not presented at the meeting. Citation Format: Elavarasan Subramani, Chloe Najac, Georgios Batsios, Pavithra Viswanath, Marina Radoul, Anne Marie Gillespie, Russell O. Pieper, Sabrina M. Ronen. 1H and 13C MRS-based metabolic markers of IDH1 mutant glioma response to temozolomide therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5263.
- Published
- 2019
43. Profiling non-polar terpenes of rhizomes for distinguishing some Indian Curcuma species
- Author
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Sainiara Begum, Ipsita De Pradhan, Susmita Das, Koel Choudhury, Elavarasan Subramani, Swagata Karak, Poulami Gupta, Bratati De, and Jayashree Acharya
- Subjects
0106 biological sciences ,Caesia ,biology ,Traditional medicine ,Dendrogram ,Curzerene ,Plant Science ,biology.organism_classification ,01 natural sciences ,0104 chemical sciences ,Rhizome ,Terpene ,010404 medicinal & biomolecular chemistry ,chemistry.chemical_compound ,chemistry ,Drug Discovery ,Non polar ,Curcuma ,010606 plant biology & botany ,Germacrene D - Abstract
Identification of the genus Curcuma is poorly understood. The objective of the study is to find biomarker compound(s) in some Indian Curcuma species with the aim to identify, through metabolite profiling and chemometric approach. Total 45 terpenes, including 19 monoterpenes and 16 sesquiterpenes could be detected in the hexane extract of five species of Curcuma e.g. C. amada, C. aromatica, C. caesia, C. longa, and C. zedoaria. Based on terpene profile, dendrogram and OPLSDA separated all the five species from each other. Multivariate analysis carried out considering C. longa as one group and the other species as another group revealed that sesquiterpenes and a few monoterpenes played important role to distinguish species particularly C. longa. Ar-Curcumene, beta-sesquiphellandrene, and alpha-zingiberene were detected in only C. longa. Curzerene, isoborneol, germacrene D could not be detected from C. longa and C. amada. C. caesia is characterized by the presence of delta-cadinene.
- Published
- 2019
44. Identification of serum metabolic markers for diagnosis of women with dormant genital tuberculosis
- Author
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Anita Mukherjee, Elavarasan Subramani, Mainak Dutta, Mamata Joshi, Manivannan Jothiramajayam, Baidyanath Chakravarty, Sudha Srivastava, and Koel Chaudhury
- Subjects
0301 basic medicine ,Infertility ,biology ,Endocrinology, Diabetes and Metabolism ,Clinical Biochemistry ,Physiology ,Genital tuberculosis ,Endometrium ,biology.organism_classification ,medicine.disease ,Biochemistry ,Molecular medicine ,Mycobacterium tuberculosis ,03 medical and health sciences ,030104 developmental biology ,medicine.anatomical_structure ,Metabolic markers ,Immunology ,Correlation analysis ,medicine ,Metabolic profile - Abstract
Genital tuberculosis (GTB) in women is one of the common causes of infertility in emerging countries. As an intracellular pathogen, Mycobacterium tuberculosis in the endometrium significantly alters the host metabolism in dormant GTB cases. Nuclear magnetic resonance (NMR) based metabolic profiling has emerged as a useful tool for identification of biomarkers in biological fluids. To investigate NMR based serum metabolic profile of dormant GTB women as compared to controls. Dormant GTB women (n = 26) and unexplained infertile women (controls; n = 26), healthy proven fertile women undergoing voluntary sterilization (n = 25) and women undergoing recurrent spontaneous miscarriage (RSM) (n = 27) were included in the study. 700 MHz proton NMR spectra of serum collected from these patients were recorded. Multivariate analysis including principal component analysis, partial least squares discriminant analysis and orthogonal projection to latent structure-discriminant analysis was applied to all the spectra. Association of dysregulated serum metabolites with our earlier findings related to altered endometrial tissue metabolites in dormant GTB women was studied using multiple correlation analysis. This study indicates a clear metabolic differentiation between women with dormant GTB and controls. Metabolites including 3-hydroxybutyrate, succinate, citrate, acetate, l-glutamine, l-lysine, glutamate, l-threonine and 1-methyl histidine were found to be significantly upregulated in serum of women with dormant GTB compared with controls. Pearson’s correlation analysis showed a significant correlation between the expression of endometrial tissue and serum metabolites. The set of identified metabolites may be considered as candidate markers for the diagnosis of dormant GTB and help clinicians in early therapeutic management.
- Published
- 2016
45. NMR-based metabonomics for understanding the influence of dormant female genital tuberculosis on metabolism of the human endometrium
- Author
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C. Datta Ray, Anita Mukherjee, Koel Chaudhury, Elavarasan Subramani, Sanjeev Kumar Srivastava, D. Chakravorty, Baidyanath Chakravarty, Mamata Joshi, Manivannan Jothiramajayam, and Mainak Dutta
- Subjects
0301 basic medicine ,Infertility ,Adult ,medicine.medical_specialty ,media_common.quotation_subject ,Biopsy ,Physiology ,India ,Biology ,Creatine ,Endometrium ,Tertiary Care Centers ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Internal medicine ,medicine ,Choline ,Humans ,Metabolomics ,Amino Acids ,Ovulation ,Asymptomatic Infections ,Nuclear Magnetic Resonance, Biomolecular ,media_common ,030219 obstetrics & reproductive medicine ,medicine.diagnostic_test ,Rehabilitation ,Female infertility ,Obstetrics and Gynecology ,Mycobacterium tuberculosis ,medicine.disease ,Tuberculosis, Female Genital ,Glutamine ,030104 developmental biology ,medicine.anatomical_structure ,Endocrinology ,Reproductive Medicine ,chemistry ,Host-Pathogen Interactions ,Female ,Energy Metabolism ,Infertility, Female ,Biomarkers - Abstract
STUDY QUESTION Does investigation of metabolic perturbations in endometrial tissue of women with dormant genital tuberculosis (GTB) during the window of implantation (WOI) assist in improving the understanding of endometrial receptivity? SUMMARY ANSWER In dormant GTB cases significant alterations in endometrial tissue metabolites occur, largely related to energy metabolism and amino acid biosynthesis in dormant GTB cases. WHAT IS KNOWN ALREADY As an intracellular pathogen, Mycobacterium tuberculosis strongly influences the metabolism of host cells causing metabolic dysregulation. It is also accepted that dormant GTB impairs the receptive status of the endometrium. Global metabolic profiling is useful for an understanding of disease progression and distinguishing between diseased and non-diseased groups. STUDY DESIGN, SIZE, DURATION Endometrial tissue samples were collected from patients reporting at the tertiary infertility care center during the period September 2011-March 2013. Women having tested positive for GTB were considered as the study group (n = 24). Normal healthy women undergoing sterilization (n = 26) and unexplained infertile women with repeated IVF failure (n = 21) volunteered to participate as controls. PARTICIPANTS/MATERIALS, SETTING, METHODS Endometrial tissue samples were collected 6-10 days after confirmation of ovulation. PCR and BACTEC-460 culture were used for diagnosing GTB. Proton nuclear magnetic resonance (1H NMR) spectra of tissue were recorded using a 700 MHz Bruker Avance AV III spectrometer. Following phase and baseline correction of all NMR spectra by Bruker Topspin 2.1 software, spectral peak alignment of the data was performed. Multivariate analysis was applied to all spectra and individual metabolites identified and multiple correlation analysis was performed. MAIN RESULTS AND THE ROLE OF CHANCE Leucine, isoleucine, acetate, lactate, glutamate, glutamine, methionine, lysine, creatine, glycogen, glycine, proline and choline were found to be significantly increased (P < 0.05) in endometrial tissue of women with dormant GTB compared with unexplained infertile women with repeated implantation failure. Valine, citrate, succinate and aspartate were also observed to be significantly up-regulated (P < 0.01). Furthermore, a significant decrease in glucose (P < 0.05), threonine (P < 0.05), tyrosine (P < 0.01) and phenylalanine (P < 0.0001) was observed in women with dormant GTB. Pearson's correlation analysis between the expression of various endometrial receptivity markers and metabolites showed a significant negative correlation (-0.236 to -0.545, P < 0.05). Also, the metabolites were positively correlated with endometrial receptivity markers (0.207 to 0.618, P < 0.05). LIMITATIONS, REASONS FOR CAUTION It is often difficult to diagnose dormant GTB because it tends to exist without any clinical signs or symptoms. In addition, the diagnosis of GTB by culture remains a challenge due to low detection rates and its paucibacillary nature. Testing for prostate-specific antigen or the Y chromosome in order to account for the possible influences of recent exposure to semen on endometrial metabolism would be important. WIDER IMPLICATIONS OF THE FINDINGS The metabolic changes associated with the dormant tubercle infection are of potential relevance to clinicians for the treatment of dormant GTB-related infertility. STUDY FUNDING/COMPETING INTERESTS Government of India, Indian Council of Medical Research. There are no conflicts of interest.
- Published
- 2015
46. Dysregulated leukemia inhibitory factor and its receptor regulated signal transducers and activators of transcription 3 pathway: a possible cause for repeated implantation failure in women with dormant genital tuberculosis?
- Author
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Vilceu Bordignon, Elavarasan Subramani, Ejimedo Madogwe, Raj Duggavathi, Koel Chaudhury, Subir Kumar Dutta, Baidyanath Chakravarty, and Chaitali Datta Ray
- Subjects
0301 basic medicine ,Adult ,STAT3 Transcription Factor ,medicine.medical_specialty ,Cell signaling ,Stromal cell ,Leukemia Inhibitory Factor Receptor alpha Subunit ,Leukemia inhibitory factor receptor ,Biology ,Endometrium ,Leukemia Inhibitory Factor ,Andrology ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,Humans ,Embryo Implantation ,Prospective Studies ,STAT3 ,reproductive and urinary physiology ,Cell Line, Transformed ,030219 obstetrics & reproductive medicine ,Obstetrics and Gynecology ,Decidualization ,Tuberculosis, Female Genital ,030104 developmental biology ,medicine.anatomical_structure ,Endocrinology ,Reproductive Medicine ,embryonic structures ,biology.protein ,Female ,Signal transduction ,Leukemia inhibitory factor ,Infertility, Female - Abstract
Objective To investigate the influence of dormant Mycobacterium tuberculosis on the expression of various endometrial receptivity markers and leukemia inhibitory factor (LIF)-signal transducers and activators of transcription 3 (STAT3) signaling pathway. Expression of endometrial receptivity markers and LIF-STAT3 signaling in in vitro decidualized human endometrial stromal cells (hESC) treated with 65 kDa mycobacterial heat shock protein (HSP65) is also explored. Design A prospective study. Setting Tertiary care hospital and reproductive health research unit. Patient(s) Endometrial tissue samples were collected from 38 women who tested positive for Mycobacterium tuberculosis and 30 normal women with proven fertility undergoing sterilization. In vitro decidualization of hESC was performed. Intervention(s) Endometrial biopsies collected from all women during implantation window and treatment of hESC with HSP65. Main Outcome Measure(s) Measurement of various endometrial receptivity markers including αvβ3 integrin, E-cadherin, MECA-79, mucin-1, and pinopodes and LIF/LIFR-STAT3 signaling molecules expressed in the endometrium of women with dormant genital tuberculosis (GTB) during implantation window and measured also in HSP65-treated hESC. Result(s) Significantly reduced levels of endometrial receptivity markers LIF, LIFR, and pSTAT3 were observed in endometrium of women with dormant GTB as compared with controls. A similar trend was observed under in vitro conditions with decreased level of phosphorylated STAT3 in HSP65-treated hESC. However, no change in the expression of endometrial receptivity markers under in vitro conditions was observed. Conclusion(s) Our findings suggest that endometrium of women with dormant GTB is associated with poor receptivity, as evidenced by reduced receptivity markers and aberrant LIF-STAT3 signaling. In vitro treatment of hESC with HSP65 also confirms compromised endometrial decidualization.
- Published
- 2015
47. SESSION 72: CLINICAL AND BASIC ANDROLOGY 2
- Author
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R. Rivera, J. Delaroche, L. Romany, José Remohí, Ratna Chattopadhyay, Emre Seli, O. Ilbay, Karin Pernet-Gallay, Saffet Ozturk, P.C.N. Chiu, B. Breznik, Deepak Mathur, Sylviane Hennebicq, Koel Chaudhury, D.M. Lalioti, W. Hamad, Elavarasan Subramani, A. Khatib, B. Sozen, K.K.W. Lam, Christophe Arnoult, W. Zhao, Marcos Meseguer, B. Kovacic, M. Khalaf, N. Demir, Pierre F. Ray, O. Kayisli-Guzeloglu, Nicolás Garrido, Antonio Pellicer, S. Samawi, P.C. Ho, C. Novella, Charles Coutton, Marwan Alhalabi, A. Othman, W.S.B. Yeung, V. Pierre, J. Sharif, B. Vlaisavljevic, Himanish Basu, Guillaume Martinez, C.L. Lee, Baidyanath Chakravarty, and V.W.X. Huang
- Subjects
Medical education ,medicine.medical_specialty ,Reproductive Medicine ,Obstetrics and gynaecology ,business.industry ,Rehabilitation ,Obstetrics and Gynecology ,Medicine ,Medical physics ,Session (computer science) ,business - Published
- 2012
48. Analysis of implantation and clinical pregnancy in repeated implantation failure undergoing frozen transfer using transfer media with granulocyte macrophage colony stimulating factor or hyaluronan
- Author
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Sanjib Kumar Sharma, Ratna Chattopadhyay, S. Ghosh, Baidyanath Chakravarty, Elavarasan Subramani, S. Wasim, S.K. Goswami, and S. Bathwal
- Subjects
business.industry ,Clinical pregnancy ,Obstetrics and Gynecology ,Andrology ,03 medical and health sciences ,0302 clinical medicine ,Granulocyte macrophage colony-stimulating factor ,Implantation failure ,Reproductive Medicine ,Immunology ,medicine ,030212 general & internal medicine ,business ,030217 neurology & neurosurgery ,medicine.drug - Published
- 2017
49. Therapeutic targeting of the TNF superfamily: a promising treatment for advanced endometrial adenocarcinoma
- Author
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Shyam Thangaraju, Koel Chaudhury, Elavarasan Subramani, and Baidyanath Chakravarty
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Lexatumumab ,medicine.medical_treatment ,Antineoplastic Agents ,Adenocarcinoma ,Receptors, Tumor Necrosis Factor ,Targeted therapy ,Etanercept ,Conatumumab ,chemistry.chemical_compound ,Adalimumab ,Biomarkers, Tumor ,Medicine ,Humans ,Molecular Targeted Therapy ,Neoplasm Staging ,business.industry ,Bortezomib ,NF-kappa B ,Obstetrics and Gynecology ,Antibodies, Monoclonal ,Infliximab ,Temsirolimus ,Endometrial Neoplasms ,Oncology ,chemistry ,Chemotherapy, Adjuvant ,Immunology ,Tumor Necrosis Factors ,Cancer research ,Female ,Tumor Necrosis Factor Inhibitors ,business ,medicine.drug - Abstract
Surgical treatment including total abdominal hysterectomy+bilateral salpingo oopherectomy (TAH+BSO) with pelvic and para‐aortic lymphadenectomy may not be sufficient to treat cases with advanced endometrial adenocarcinoma (EAC), and in these cases, adjuvant treatments including radiotherapy and/or chemotherapy, are employed based upon the tumor location, type and stage of the disease. These treatment modalities have high incidence of systemic toxicity, thereby compelling clinicians to look for targeted therapy aiming specifically at the malignant cells. Bevacizumab (anti-VEGF), temsirolimus (mTOR inhibitor) and aflibercept (VEGF trap) are already under clinical trials in women with EAC. Targeting the ligands and receptors of the tumor necrosis factor (TNF) superfamily holds promise in this regard. The objective of this review is to provide an overview of the various mechanisms and pathways related to the TNF superfamily involved in advanced EAC and to identify the new therapeutic strategies for specifically targeting these impaired pathways. In addition, the development of treatments for EAC is also discussed. The possible therapeutic treatments include targeting TNFα and its receptors using monoclonal antibodies (MAbs) such as infliximab, adalimumab, etanercept, and certolizumab. Proteosome inhibitors including bortezomib and the anti CD-20 agent rituximab are used to inhibit the NF-κB pathway. Other options include targeting the FAS (CD95) pathway and the TNF-related apoptosis-inducing ligand (TRAIL) pathway using agents such as mapatumab, lexatumumab, and conatumumab. These pathways are known to be involved in the pathogenesis of EAC. Moreover, there is adequate evidence to warrant the use of drugs that target the TNF superfamily for the treatment of advanced EAC.
- Published
- 2012
50. Detrimental effects of oxidative stress on sperm membrane and DNA integrity in normozoospermic infertile men
- Author
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Koel Chaudhury and Elavarasan Subramani
- Subjects
business.industry ,DNA damage ,Acrosome reaction ,Semen ,medicine.disease ,medicine.disease_cause ,Male infertility ,Andrology ,Lipid peroxidation ,chemistry.chemical_compound ,chemistry ,medicine ,DNA fragmentation ,business ,Acrosome ,Oxidative stress - Abstract
Oxidative stress (OS) indicates an imbalance between the generation of reactive oxygen species (ROS) and total antioxidant capacity (TAC). ROS and TAC levels, lipid peroxidation (LPO), acrosome reaction status and OS induced DNA damage were assessed in normozoospermic infertile men (Group I) and compared with proven fertile men (Group II; controls). Forty men with normal semen parameters were grouped into normozoospermic infertile men (n=30) and proven fertile men (n=10). ROS and TAC levels were measured by chemiluminescence assay. LPO, acrosome reaction and DNA fragmentation were assessed and compared with ROS generation. Differences between these groups was calculated using two tailed Students t-test and statistical significance assessed at P value
- Published
- 2010
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