Uniformed Services University of the Health Sciences
Department of Pathology
4301 Jones Bridge Road, C1094
Bethesda, Maryland 20814-4799
Phone: (301) 295-3450
fax: (301) 295-1640
Current research in our laboratory is focused on the mechanism of the viral pathogenesis and identification of the potential therapeutic targets/ compounds for treatment of Venezuelan equine encephalitis virus (VEEV). VEEV causes a highly virulent disease of central nervous system in equines and humans. VEEV can spread through aerosol and has been developed as a bio-warfare agent. This work is of special military significance as VEEV can be used as a bio-warfare agent and troops can be exposed when deployed on field. This virus can potentially infect a large population in very short period of time and therefore also carries a civilian significance in case of an epidemic outbreak or bio-terrorism. There is currently no FDA approved vaccine and no antiviral drug against the VEEV. We are engaged in development of a novel strategy for the inactivation of VEEV with an aim of developing a vaccine candidate against VEEV. Inactivation of viruses in a way which does not alter the immunological epitopes important for protection should result in a safe vaccine that generates more durable and longer lived immunity. A hydrophobic photoactivatable alkylating compound, 1, 5 iodonaphthyl-azide (INA) inactivates membrane proteins but preserves the structural integrity and immunogenic properties of these proteins. This approach selectively inactivates the envelope glycoproteins of VEEV that are required for its pathogenesis. Other projects include testing of siRNA for inhibiting VEEV replication in-vitro and in-vivo and testing of various antiviral and anti-inflammatory compounds for treatment of VEEV infection.
Role of Cytokines and Natural Products in Angiogenesis and Wound Healing
We reported that Interferon (IFN), Poly I:C, a potent inducer of IFN and immune enhancer, Curcumin, an active ingredient derived from the root of the Curcuma longa plant; Arnebin-2, derived from the Arnebia nobilis plant and Picroliv, a root extract from Picrorhiza kurrooa resulted in faster restoration of tissue integrity in both full skin punch biopsy and skin incision models. Using in situ hybridization and PCR, results indicated that several growth factors like TGF- 1, PDGF and the levels of mRNAs of laminin (LMN), B1, collagen I, III, and IV were highly increased in wound tissues of rats, rabbits, and guinea pigs treated with these substances. In in- vitro model of angiogenesis using human umbilical vein endothelial cells, we have shown IFN- and curcumin significantly inhibited the tube formation. We are studying the mechanisms and role of angiogenesis in wound healing as well as in cancer chemoprevention.
Role of Natural products in chemoprevention of cancer
Numerous phytochemicals may have a potential to develop into a cancer chemopreventive agent. We are exploring the mechanisms of cancer chemopreventive effects of novel phytochemicals like Green tea, Curcumin, and Brahma Rasayana in hormone-dependent and independent cancer of prostate gland and breast. These photochemical are capable of delaying the tumor incidence as well as reducing the tumor burden in vivo using MDA-MB-231 human breast carcinoma xenografts in athymic nude mice as well as rescues tumor incidence, tumor growth and metastatic spread caused by MAT-LyLu cells in Copenhagen rats. We have also analysed the molecular targets using state of art techniques such as high-density oligonucleotide Affymetrix human genome array GeneChip HG U133 Plus 2.0. We performed a temporal gene expression analysis of the Curcumin-Gene Expression Response (Cu-GER) using hormone-responsive and non responsive human prostate cancer cell line, LNCaP and C4-2B respectively. Hierarchical clustering methods and functional classification of the Cu-GER showed temporal co-regulation of genes involved in specific biochemical pathways involved in the cellular stress response pathways. These studies established novel features of Cu-GER in prostate cancer cells of varying tumorigenic phenotypes and provides potentially novel read-outs for assessing effectiveness of curcumin in prostate cancer and likely in other cancers.
Sharma A, Raviv, Y., Puri, A., Viard, M, Blumenthal, R., and Maheshwari, R (2007). Complete Inactivation of Venezuelan Equine Encephalitis Virus by 1,5 Iodonapthylazide.Biophysical Biochemical Research CommunicationsApr 26; [Epub ahead of print].
Anoop K. Singh, Anuj Sharma, James Warren, Subhashree Madhavan, Keith Steele, N.V. Rajesh Kumar, Thangapazham R. L., Shekhar C. Sharma, Dinesh K Kulshreshtha, Jaya Gaddipati, and Radha K. Maheshwari (2007).Picroliv accelerates epithelialization and angiogenesis in rat wounds. Planta Medica, 73;251-256.
Thangapazham, R., Singh, A.K., Sharma, A., Warren, J., Gaddipati, J., and Maheshwari, R.K. (2007). Green Tea Polyphenols and its constituent Epigallocatechin Gallate Inhibits Proliferation of Human Breast Cancer Cells in vitro and in vivo. Cancer Letters 245, 232-241.
Sharma A., Singh, A.K., Warren J., Thangapazham, R.L, and Maheshwari, R.K. (2006) Differential Expression of Angiogenic Genes in diabetic Wound Healing. Journal of Investigative Dermatology. 126:2323-31.
Thangapazham R., Sharma, A., Gaddipati, J.P., Singh, A.K., and Maheshwari, R.K. (2006). Inhibition of Tumor Angiogenesis by Brahma Rasayana (BR). Journal of Experimental Therapeutics and Oncology 6, 13-21.
Steele, K, Seth, P., Catlin, K., Schoneboom, BA., Husain, M., Grieder, F., and Maheshwari, R.K., (2006). Tunicamycin Enhances Neuroinvasion and neurodegeneration in mice with Venezuelan Equine Encephalitis virus. Veterinerary Pathology 43: 904-913.