Scientist Profile

Sandhya. L. Sitasawad, Ph.D.

The broad areas of my research include involvement of free radicals in diabetes and cancer.
Email

ssitaswad@nccs.res.in

Research Areas

Biology of Cancer and chronic Diseases

Professional Experience

Scientist G, National Centre for Cell Science, Pune.

Research

The broad areas of my research include involvement of free radicals in diabetes and cancer.

Diabetes induced cardiovascular complications are a major cause of morbidity and mortality in diabetic patients. Of the various cardiovascular complications, Diabetic cardiomyopathy (DCM) characterized by left ventricle (LV) systolic and diastolic dysfunction carries a substantial risk for heart failure and increased mortality in diabetic patients. Several studies have shown hyperglycemia and cell death such as apoptosis playing an important role leading to diabetic cardiomyopathy. However, the molecular mechanisms behind the pathogenesis remain incompletely understood. Currently, research in my laboratory is focused on elucidating the cellular and molecular mechanisms that underlie the pathogenic processes occurring in the heart leading to diabetic cardiomyopathy. Evidences implicating increased oxidative stress and low antioxidant capacity in the development of diabetic cardiac complications in animals or humans suggest that cellular redox regulation may provide important insights for elucidating the molecular mechanisms underlying altered cardiac function in diabetes.

We are particularly interested in hyperglycemia induced contractile dysfunction and stress signaling changes in diabetic heart. Since the cytotoxic actions of glucose are mediated, in part, through oxidative stress and intracellular Ca2+ overload, the focus of our work is to study the role of oxidative and nitrosative stress and calcium regulation in diabetic cardiomyopathy.

CURRENT PROJECTS

1) Role of Monoamine Oxidase-A (MAO-A) in hyperglycemia-induced oxidative stress in diabetic cardiomyopathy

The mitochondrial apoptotic pathways play an important role in diabetes-induced myocardial cell death. In addition to the respiratory chain, monoamine oxidase (MAO), a flavoprotein localized on the outer mitochondrial membrane, is another important mitochondrial source of ROS. Monoamine oxidases (MAOs) are responsible for oxidation of monoamines. During this process they generate H2O2 and reactive aldehydes as by products and contribute to an increase in concentrations of ROS within the mitochondrial matrix and cytosol. Based on substrate specificity and inhibitor sensitivity two isoforms of MAO have been identified MAO A and MAO B. However, MAO A appears to be the predominant isoform in the myocardium of several species. Recent findings demonstrate the involvement of MAO A in maladaptive remodeling and cardiomyocyte necrosis leading to left ventricular dysfunction. Moreover the important role of MAO A as relevant source of ROS in ischemia/reperfusion (I/R) injury was demonstrated both ex vivo and in vivo. Yet the involvement of MAO A in diabetic cardiomyopathy is not defined.

Therefore, we aimed to investigate whether MAO A can potentially be a relevant source of ROS and contribute to development of diabetic cardiomyopathy.

2) Role of Nrf2 mediated antioxidant mechanisms against hyperglycemia induced oxidative stress in diabetic cardiomyopathy

Against the sustained oxidative stress, cells have evolved endogenous defense mechanisms such as the redox-sensitive transcription factor nuclear factor E2-related factor 2 (Nrf2), which regulates a cis-acting element designated antioxidant response element (ARE/electrophile response element)-mediated expression of detoxifying and antioxidant enzymes. Nrf2 is normally targeted for proteasomal degradation via its cytosolic regulatory protein Kelch-like ECH-associated protein 1 (Keap1). ROS and electrophilic agents lead to spatial alterations in the Nrf2-Keap1 complex, resulting in nuclear accumulation of Nrf2 and upregulation of ARE-linked gene expression.

We are investigating the role and mechanism of Nrf2 in ARE-mediated gene expression and induction of antioxidants in response to hyperglycemia induced oxidative stress in diabetic cardiomyopathy

Peroxiredoxins-Mechanisms of Action

3) Role of Prx-3 through Trx-2 in diabetic cardiomyopathy

Peroxiredoxins (Prx) are a new family of peroxidases, predominantly required under stress conditions to reduce H2O2 and various organic peroxides with use of electron donor thioredoxins or glutathione. In mammals, 6 distinct Prx family members have been identified (Prx-1 through -6). Among the Prxs, Prx-3 is unique because it is localized specifically within the mitochondria and can scavenge H2O2 using mitochondrial Trx-2 as the electron donor. Further studies have shown that overexpression of Prx-3 prevented left ventricular remodeling and failure after myocardial infarction in mice. These beneficial characteristics make Prx-3 a promising candidate for therapy against oxidative stress during diabetic cardiomyopathy.

PLoS One, 2009; 4(4):e5365

4) Investigation of the cellular and molecular mechanisms of AECHL-1 on the breast cancer cells: Role of mitochondria and redox regulation and its anti-angiogenic activity in vitro and in vivo.

We have recently isolated and characterized a novel triterpenoid Ailanthus excelsa chloroform extract-1 (AECHL-1) (C29H36O10) from the root bark of Ailanthus excelsa RoxB (Tree of heaven), a tree belonging to family Simaroubaceae which is widely used in Ayurveda as evidenced by phytotherapy Other species from this family are well known for their anti-cancer activities Chemical constituents of A. excelsa include some triterpenes and alkaloids This compound AECHL-1, was characterized by UV, IR, NMR and mass spectroscopy and the purity was conformed by HPLC. It is a triterpenoid with high polarity and a molecular weight 453.8 and has been shown to possess a broad spectrum of activity against cancer cells in vitro and also in vivo in tumor of mouse melanoma B16F10 implanted in C57BL/6 mice and human breast cancer MCF-7 cells in athymic nude mice.

AECHL-1 inhibited cell proliferation and induced death in B16F10, MDA-MB-231, MCF-7, and PC3 cells in a concentration and time-dependent manner with minimum growth inhibition in normal HEK 293. The antitumor effect of AECHL-1 was comparable with that of the conventional antitumor drugs paclitaxel and cisplatin. The growth inhibition of AECHL-1 treated cells was associated with S/G(2)-M arrests in MDA-MB-231, MCF-7, and PC3 cells and a G(1) arrest in B16F10 cells. Among the above cell lines, the anticancer activity was observed more in MCF-7 cells and microtubule disruption was observed in these cells treated with AECHL-1 in vitro. The anti-cancer activity demonstrated by AECHL-1 can be attributed to its ability to cause apoptosis of cancer cells.

AECHL-1 also targets tumor neo-vasculature and impairs the endothelial cell cytoskeleton. Further, we seek to study the redox regulatory mechanism of AECHL-1 and are also studying if it targets the cancer stem cells (CSCs).

Publications

Dasgupta A, Sawant MA, Kavishwar G, Lavhale M, Sitasawad S. AECHL-1 targets breast cancer progression via inhibition of metastasis, prevention of EMT and suppression of Cancer Stem Cell characteristics. Sci Rep. 2016 Dec 15;6:38045.

Arkat S, Umbarkar P, Singh S, Sitasawad SL. Mitochondrial Peroxiredoxin-3 protects against hyperglycemia induced myocardial damage in Diabetic cardiomyopathy. Free Radic Biol Med. 2016 Aug;97:489-500.

Sawant MA, Dasgupta A, Lavhale MS, Sitasawad SL. Novel triterpenoid AECHL-1 induces apoptosis in breast cancer cells by perturbing the mitochondria-endoplasmic reticulum interactions and targeting diverse apoptotic pathways. Biochim Biophys Acta. 2016 Feb 3;1860(6):1056-1070.

A novel SOD mimic with a redox-modulating mn (II) complex, ML1 attenuates high glucose-induced abnormalities in intracellular Ca2+ transients and prevents cardiac cell death through restoration of mitochondrial function. Kain V., Sawant MA., Dasgupta, A., Jaiswal, G., Vyas, A., Padhye, S., Sitasawad, SL. Biochemistry and Biophysics Reports 5(2016) 296-304.

Monoamine Oxidase-A (MAO-A) is an important source of oxidative stress and promotes Cardiac Dysfunction, Apoptosis, and Fibrosis in Diabetic Cardiomyopathy. Umbarkar P, Singh S, Arkat S, Bodhankar SL, Lohidasan S, Sitasawad SL. Free Radic Biol Med. 2015 Jun 26. pii: S0891-5849(15)00293-2.

AECHL-1, a novel triterpenoid, targets tumor neo-vasculature and impairs the endothelial cell cytoskeleton. Dasgupta A, Sawant MA, Lavhale MS, Krishnapati LS, Ghaskadbi S, Sitasawad SL. Angiogenesis. 2015 Jul;18(3):283-99.

Mimetics Offer Superior Protection Against Oxidative Damages in Hek293 Kidney Cells. Vyas, A., Kain, V., Afrasiabi Z., Sitasawad SL., Khetmalas M, Nivière V. and Padhye P. Novel Mn-SOD Journal of Pharmaceutical Sciences and Pharmacology Vol. 1, 1–8, 2014

Mimetics Offer Superior Protection Against Oxidative Damages in Hek293 Kidney Cells. Vyas, A., Kain, V., Afrasiabi Z., Sitasawad SL., Khetmalas M, Nivière V. and Padhye P. Novel Mn-SOD Journal of Pharmaceutical Sciences and Pharmacology Vol. 1, 1–8, 2014

Prevention of Mitochondrial Membrane Permeabilization and Pancreatic β-Cell Death by an Enantioenriched, Macrocyclic Small Molecule. Jimmidi, R., Shroff, GK,  Satyanarayana, M., Reddy, BR., Reddy,J., Sawant MA, Sitasawad SL,  Arya, P. and Mitra P. Europen Journal of Organic Chemistry Vol.  2014, Issue 6, pages 1151–1156.

Multiple antioxidants improve cardiac complications and inhibit cardiac cell death in streptozotocin-induced diabetic rats. Kumar S, Prasad S, Sitasawad SL. PLoS One. 2013 Jul 2;8(7):e67009.

High glucose-induced Ca2+ overload and oxidative stress contribute to apoptosis of cardiac cells through mitochondrial dependent and independent pathways. Kumar S, Kain V, Sitasawad SL. Biochim Biophys Acta. 2012 Jul;1820(7):907-20.

Azelnidipine prevents cardiac dysfunction in streptozotocin-diabetic rats by reducing intracellular calcium accumulation, oxidative stress and apoptosis. Kain V, Kumar S, Sitasawad S. Cardiovasc Diabetol. 2011 Nov 4; 10(1):97.

Azelnidipine protects myocardium in hyperglycemia-induced cardiac damage. Kain V, Kumar S, Puranik AS, Sitasawad SL. Cardiovasc Diabetol. 2010 Dec 1;9:82.

Antidiabetic effects of scoparic acid D isolated from Scoparia dulcis in rats with streptozotocin-induced diabetes. Latha M, Pari L, Ramkumar KM, Rajaguru P, Suresh T, Dhanabal T, Sitasawad S, Bhonde R. Nat Prod Res. 2009;23(16):1528-40.

Cardiotoxicity of calmidazolium chloride is attributed to calcium aggravation, oxidative and nitrosative stress, and apoptosis. Kumar S, Kain V, Sitasawad SLFree Radic Biol Med. 2009 Sep 15;47(6):699-709.

A novel triterpenoid isolated from the root bark of Ailanthus excelsa Roxb (Tree of Heaven), AECHL-1 as a potential anti-cancer agent. Lavhale MS, Kumar S, Mishra SH, Sitasawad SL. PLoS One. 2009;4(4):e5365. Epub 2009 Apr 28.

N-acetylcysteine prevents glucose/glucose oxidase-induced oxidative stress, mitochondrial damage and apoptosis in H9c2 cells. Kumar S, Sitasawad SL. Life Sci. 2009 Mar 13;84(11-12):328-36

Cytoprotective and antioxidant role of diallyl tetrasulfide on cadmium induced renal injury: An in vivo and in vitro study. Pari L, Murugavel P, Sitasawad SL, Kumar K. Life Sci. 2007 Jan 23;80(7):650-8.

Cadmium induced mitochondrial injury and apoptosis in vero cells: protective effect of diallyl tetrasufide from garlic. Murugavel P, Pari L , Sitasawad SL, Kumar S, Kumar S. Int J Biochem Cell Biol. 2007;39(1):161-70.

Scoparia dulcis, a traditional antidiabetic plant, protects against streptozotocin induced oxidative stress and apoptosis in vitro and in vivo. Latha M, Pari L, Sitasawad S, Bhonde R. J Biochem Mol Toxicol. 2004;18(5):261-72.

Insulin-secretagogue activity and cytoprotective role of the traditional antidiabetic plant Scoparia dulcis (Sweet Broomweed) Muniappan Latha, Leelavinothan Pari, Sandhya Sitasawad, Ramesh Bhonde Life Sciences 75 (2004) 2003-2014.

Decreased antioxidant enzymes and membrane essential polyunsaturated fatty acids in schizophrenic and bipolar mood disorder patients. Prabhakar K Ranjekar, Ashwini Hinge, Mahabaleshwar Hegade, Madhav Ghate M., Anvita Kale, Sandhya Sitasawad , Ulhas Wagh, Vijay Debsikdar, Sahebrao Mahadik (2003) Psychiatry Research, 121(2):109-22.

Essential polyunsaturated fatty acid and lipid peroxide levels in never-medicated and medicated schizophrenia patients. Arvindakshan M, Sitasawad S, Debsikdar V, Ghate M, Evans D, Horrobin DF, Bennett C, Ranjekar PK, Mahadik SP (2003) Biol Psychiatry 53(1):56-64

Beneficial effect of supplementation with Copper Sulfate on STZ-diabetic mice (IDDM). Sandhya Sitasawad, Manisha Deshpande, Mamata Katdare, Suraj Tirth and Pradeep Parab (2001) Diabetes Res Clin Pract 2001 May;52(2):77-84

Inter Individual Differences in Carbamezapine handling. Yardi, N., Divekar D., Sant H., Divate P., Apte C., Singh J.P. and Shiras A.Sitasawad S., Wagh. U. (1997) Epilepsia, 38 (3) : 41-48.

 

Patents

Dr. Sandhya Sitasawad

1) “Anti-tumor activity of AECHL-1, a novel triterpenoid isolated from Ailanthus excelsa in vitro and in vivo”. PCT Application #PCT/INO8/000795 dated 02/12/2008.

Granted: US: 8,519,163 B2; Japan: 5468611; Europe: 2337782

Book Chapter

Mahadik SP, Sitasawad S., Mulchandani M. Membrane Peroxidation and the Neuropathology of Schizophrenia. In: Phospholipid Spectrum Disorder in Psychiatry, Pages 99, 2000, Malcolm Peet, Iain Glen and Horrobin D.F (Eds.), (Maurius Press)

Membership

Council Member and Member of the Advisory Committee for International Academy of Cardiovascular Sciences - IACS (India Section)

Funding

The work in our laboratory is supported by grant from the Department of Biotechnology, New Delhi, India. Aparajita and Mithila are supported by fellowship from the Council of scientific and Industrial research, New Delhi, Prachi, Sarojini, Shilpa and Dinisha are supported by fellowship from the University Grants Commission, New Delhi and the project on AECHL-1 from the Department of Science and Technology, New Delhi.

Current Ph.D Students

  • Ms. Sarojini Singh (Senior Research Fellow)
  • Ms. Dinisha Kamble (Senior Research Fellow)
  • Ms. Deepali Badhane (Junior Research Fellow)
  • Ms. Rohini Dhat (Junior Research Fellow)
  • Ms. Megharani Mahajan (Junior Research Fellow)
  • Ms. Suneeta (Junior Research Fellow)
  • Ms. Vishi Sharma (Junior Research Fellow)

Alumni

  • Santosh Kumar
  • Sandeep Kumar
  • Vasundhara Kain
  • Mithila Sawant
  • Aparjita Dasgupta
  • Prachi Umbarkar
  • A. Silpa

Back
Back to Top