Jerald Kumar - Academia.edu (original) (raw)

Papers by Jerald Kumar

Advanced NanoBiomed Research

Inorganic nanoparticles (NPs) have been used for cancer theranostics application for last several... more Inorganic nanoparticles (NPs) have been used for cancer theranostics application for last several years. [1-3] Among them, noble metal NPs (gold, silver, and platinum NPs [PtNPs]) offer promising opportunity for various biomedical applications, including drug delivery, bioimaging, diagnostics, etc., owing to their distinctive physicochemical properties. [4-8] However, serious toxicological consequences might be observed on interaction of these NPs with the biological moieties at cellular and subcellular level. Based on this, several studies investigated potential toxicity of various nanomaterials, such as carbon nanotubes, graphene oxides, zinc oxides, cerium oxides, quantum dots, and silica NPs. [9-11] In this context, assessment of probable health risks associated with biologically important novel nanomaterials is essential for the safe biomedical application. Recently, PtNPs have gained vast attention in the field of healthcare and medicine. [5,12-17] However, exposure of PtNPs in a biological system might be associated with unanticipated hazards. [18-20] There are numerous reports on nephrotoxicity, hepatotoxicity, and inflammatory responses along with DNA damage induced by Ptbased NPs. [21,22] On the other hand, PtNPs are also reported to inhibit pulmonary inflammation by exerting antioxidants and free radical scavenging activity. [23-28] These conflicting results specify that the biological effects and toxicological behavior of PtNPs remain poorly explained. In our earlier report, we designed a cancer drug delivery system (DDS) using pegylated (polyethylene glycol functionalized

Abdominal aortic aneurysm (AAA) is a common chronic degenerative disease characterized by progres... more Abdominal aortic aneurysm (AAA) is a common chronic degenerative disease characterized by progressive aortic dilation and rupture. The mechanisms underlying the role of a-tocopherol and b-carotene on AAA have not been comprehensively assessed. We investigated if a-tocopherol and b-carotene supplementation could attenuate AAA, and studied the underlying mechanisms utilized by the antioxidants to alleviate AAA. Four-months-old Apoe2/2 mice were used in the induction of aneurysm by infusion of angiotensin II (Ang II), and were orally administered with a-tocopherol and b-carotene enriched diet for 60 days. Significant increase of LDL, cholesterol, triglycerides and circulating inflammatory cells was observed in the Ang II-treated animals, and gene expression studies showed that ICAM-1, VCAM-1, MCP-1, M-CSF, MMP-2, MMP-9 and MMP-12 were upregulated in the aorta of aneurysm-induced mice. Extensive plaques, aneurysm and diffusion of inflammatory cells into the tunica intima were also notic...

International journal of experimental pathology, 2018

Non-alcoholic fatty liver disease (NAFLD)-like conditions enhance the production and action of cl... more Non-alcoholic fatty liver disease (NAFLD)-like conditions enhance the production and action of clotting factors in humans. However, studies examining the effect of NAFLD due to high-fat high-fructose (HFHF) diet in factor VIII-deficient (haemophilia A) animals or patients have not been reported previously. In this study, we investigated the individual role of factor VIII in the progression of diet-induced NAFLD in the factor 8 (F8 ) mouse model system and its consequences on the haemophilic status of the mice. The F8 mice were fed with HFHF diet for 14 weeks. Physiological, biochemical, haematological, molecular, pathological, and immune histochemical analyses were performed to evaluate the effect of this diet. The F8 mice developed hepatic steatosis after 14 weeks HFHF diet and displayed lower energy metabolism, higher myeloid cell infiltration in the liver, decreased platelet count, upregulated de novo fatty acid synthesis, lipid accumulation, and collagen deposition. This study h...

Scientific Reports, 2016

We have earlier shown that Plumbagin (PB) can induce selective cytotoxicity to BRCA1 defective ov... more We have earlier shown that Plumbagin (PB) can induce selective cytotoxicity to BRCA1 defective ovarian cancer cells; however, the effect of this molecule in BRCA1 mutated breast cancers has not been analyzed yet. Here, we report that reactive oxygen species (ROS) induced by PB resulted in DNA DSB and activates downstream signaling by ATR/ATM kinases and subsequent apoptosis. PB reduces DNA- dependent protein kinase (DNA-PK) expression and inhibits NHEJ (Non Homologous End Joining) activity in BRCA1 defective breast cancer cells. Also, PB induces apoptosis in two different BRCA1 conditional knock out murine models: MMTV-Cre; BRCA1Co/Co and WAP-Cre; BRCA1Co/Co, at 2 mg/kg body weight, but 32 mg/kg of carboplatin (CN) was needed to induce apoptosis in them. This is the first study where two different tissue specific promoter driven transgenic mice models with BRCA1 exon 11 deletions are used for preclinical drug testing. The apoptosis induced by PB in HR (Homologous Recombination) defe...

Free Radical Biology and Medicine, 2016

attenuates monocyte-to-macrophage differentiation and associated inflammation via modulation of i... more attenuates monocyte-to-macrophage differentiation and associated inflammation via modulation of intracellular GSH homeostasis: Relevance in atherosclerosis, Free Radical Biology and Medicine,

Scientific Reports, 2016

Mitochondria-targeted compounds are emerging as a new class of drugs that can potentially alter t... more Mitochondria-targeted compounds are emerging as a new class of drugs that can potentially alter the pathophysiology of those diseases where mitochondrial dysfunction plays a critical role. We have synthesized a novel mitochondria-targeted esculetin (Mito-Esc) with an aim to investigate its effect during oxidative stress-induced endothelial cell death and angiotensin (Ang)-II-induced atherosclerosis in ApoE−/− mice. Mito-Esc but not natural esculetin treatment significantly inhibited H2O2- and Ang-II-induced cell death in human aortic endothelial cells by enhancing NO production via AMPK-mediated eNOS phosphorylation. While L-NAME (NOS inhibitor) significantly abrogated Mito-Esc-mediated protective effects, Compound c (inhibitor of AMPK) significantly decreased Mito-Esc-mediated increase in NO production. Notably, Mito-Esc promoted mitochondrial biogenesis by enhancing SIRT3 expression through AMPK activation; and restored H2O2-induced inhibition of mitochondrial respiration. siSIRT3...

PLOS ONE, 2015

Acute renal failure is a serious complication of the anticancer drug cisplatin. The potential rol... more Acute renal failure is a serious complication of the anticancer drug cisplatin. The potential role of baicalein, a naturally occurring bioflavonoid on cisplatin-induced renal injury is unknown. Here, we assessed the effect of baicalein against a murine model of cisplatininduced acute renal failure and investigated the underlying possible mechanisms. Renal function, kidney histology, inflammation, oxidative stress, renal mitochondrial function, proteins involved in apoptosis, nuclear translocation of Nrf2 and effects on intracellular signaling pathways such as MAPKs, and NF-κB were assessed. Pretreatment with baicalein ameliorated the cisplatin-induced renal oxidative stress, apoptosis and inflammation and improved kidney injury and function. Baicalein inhibited the cisplatin-induced expression of iNOS, TNF-α, IL-6 and mononuclear cell infiltration and concealed redox-sensitive transcription factor NF-κB activation via reduced DNA-binding activity, IκBα phosphorylation and p65 nuclear translocation in kidneys. Further studies demonstrated baicalein markedly attenuated cisplatin-induced p38 MAPK, ERK1/2 and JNK phosphorylation in kidneys. Baicalein also restored the renal antioxidants and increased the amount of total and nuclear accumulation of Nrf2 and downstream target protein, HO-1 in kidneys. Moreover, baicalein preserved mitochondrial respiratory enzyme activities and inhibited cisplatin-induced apoptosis by suppressing p53 expression, Bax/Bcl-2 imbalance, cytochrome c release and activation of caspase-9, caspase-3 and PARP. Our findings suggest that baicalein ameliorates cisplatin-induced renal damage through up-regulation of antioxidant defense mechanisms and down regulation of the MAPKs and NF-κB signaling pathways.

Frontiers in microbiology, 2013

Noroviruses cause most cases of acute viral gastroenteritis worldwide. The lack of a cell culture... more Noroviruses cause most cases of acute viral gastroenteritis worldwide. The lack of a cell culture infection model for human norovirus necessitates the use of molecular methods and/or viral surrogate models amenable to cell culture to predict norovirus inactivation. Murine norovirus (MNV) may be used to construct a small animal model for studying the biology and pathogenesis of noroviruses because MNV is the only norovirus that replicates in cell culture and a small animal model. However, recent studies have shown that natural MNV infection is widespread in laboratory mouse colonies. We investigated MNV infection in both conventional and specific pathogen-free (SPF) genetically modified mice from Japan and the US, and commercial mice from several animal breeders in Japan, using serological and molecular techniques. MNV antibodies were detected in 67.3% of conventional mice and 39.1% of SPF mice from Japan and 62.5% of conventional mice from the US. MNV antibodies were also found in 2...

Diabetes, 2014

Monocyte-to-macrophage differentiation is a critical event that accentuates atherosclerosis by pr... more Monocyte-to-macrophage differentiation is a critical event that accentuates atherosclerosis by promoting an inflammatory environment within the vessel wall. In this study, we investigated the molecular mechanisms responsible for monocyte-to-macrophage differentiation and, subsequently, the effect of metformin in regressing angiotensin II (Ang-II)-mediated atheromatous plaque formation in ApoE−/− mice. AMPK activity was dose and time dependently downregulated during phorbol myristate acetate (PMA)-induced monocyte-to-macrophage differentiation, which was accompanied by an upregulation of proinflammatory cytokine production. Of note, AMPK activators metformin and AICAR significantly attenuated PMA-induced monocyte-to-macrophage differentiation and proinflammatory cytokine production. However, inhibition of AMPK activity alone by compound C was ineffective in promoting monocyte-to-macrophage differentiation in the absence of PMA. On the other hand, inhibition of c-Jun N-terminal kinase...

ChemPlusChem, 2014

Two hexacationic pentamethylcyclopentadienyl rhodium(III) and iridium(III) metalla-prisms, [(h 5-... more Two hexacationic pentamethylcyclopentadienyl rhodium(III) and iridium(III) metalla-prisms, [(h 5-C 5 Me 5) 6 M 6 (m 3-tpt-kN) 2 (m 4-C 6 HRO 4-kO) 3 ] 6 + (tpt = 2,4,6-tri-(pyridin-4-yl)-1,3,5-triazine; R = (CH 2) 10 CH 3 ; M= Rh, [3] 6 + ; M= Ir, [4] 6 +) isolated as their triflate salts, have been synthesised from the dinuclear complexes (h 5-C 5 Me 5) 2 M 2 (m 4-C 6 HRO 4-kO)Cl 2 (M = Rh, 1; M= Ir, 2) and AgCF 3 SO 3. The antiproliferative activity of the neutral and cat-ionic complexes has been evaluated in vitro in human cancer cell lines. The positively charged metalla-prisms appear to target mitochondria, which ultimately induce apoptosis in cancer cells. All biological studies suggest that the rhodium derivative [3][CF 3 SO 3 ] 6 possesses excellent activities, not only in vitro but also in vivo in tumour-induced C57L6/J mice.

Molecular Imaging and Biology, 2015

Researchers had developed and characterized transgenic green/red fluorescent protein (GFP/RFP) nu... more Researchers had developed and characterized transgenic green/red fluorescent protein (GFP/RFP) nude mouse with ubiquitous RFP or GFP expression, but none has evaluated the level of immune cells and expression levels of GFP in this model. The nude GFP mice were evaluated by imaging, hematological indices, and flow cytometry to compare the proportion of immune T cells. Quantitative real-time PCR (qRT-PCR) was done for evaluating the relative expression of GFP transcripts in few organs of the nude GFP mice. The hematological and immune cells of nude GFP were within the range of nude mice. However, the gene expression levels were relatively less in various tissues compared with B6 GFP mice. These findings suggest that nude GFP is an ideal model resembling normal nude mice; however, GFP expression in various tissues by fluorescence should be considered, as the expression of GFP differs in various organs.

Nucleic Acids Research, 2013

Building molecular correlates of drug resistance in cancer and exploiting them for therapeutic in... more Building molecular correlates of drug resistance in cancer and exploiting them for therapeutic intervention remains a pressing clinical need. To identify factors that impact drug resistance herein we built a model that couples inherent cell-based response toward drugs with transcriptomes of resistant/ sensitive cells. To test this model, we focused on a group of genes called metastasis suppressor genes (MSGs) that influence aggressiveness and metastatic potential of cancers. Interestingly, modeling of 84 000 drug response transcriptome combinations predicted multiple MSGs to be associated with resistance of different cell types and drugs. As a case study, on inducing MSG levels in a drug resistant breast cancer line resistance to anticancer drugs caerulomycin, camptothecin and topotecan decreased by more than 50-60%, in both culture conditions and also in tumors generated in mice, in contrast to control un-induced cells. To our knowledge, this is the first demonstration of engineered reversal of drug resistance in cancer cells based on a model that exploits inherent cellular response profiles.

Molecular Therapy, 2009

Glucocorticoid receptor (GR), an ubiquitously present nuclear hormone receptor protein, regulates... more Glucocorticoid receptor (GR), an ubiquitously present nuclear hormone receptor protein, regulates many important functions in almost all cell types including cancerous and noncancerous cells. Maintenance of glucose homeostasis using noncarbohydrate precursors, regulation of protein and fat metabolism and various anti-inflammatory and immunosuppressive actions are some important functions of GR. 1,2 Since the purification and first cloning of full-length GR, many new isoforms of GR have been discovered. 3,4 One of GR's main isoforms, the α-isoform has both 250 odd amino acid ligand-binding domain (LBD) and 60-70 amino acids DNA-binding domain. GR-α undergoes ligandactivated nuclear localization resulting into transactivation of several genes under diversity of glucocorticoid responses. 5 The GR-β isoform, however, having no LBD resides inside nucleus permanently and functionally competes and associates with GR-α inside the nucleus imparting glucocorticoid resistance to gene transactivation. 6,7 The role of coengaging cytoplasmic proteins such as heat-shock proteins that lend structural and functional stability to LBD for ligand-binding and subsequent steps are well characterized. 8 The phenomenon of GR-mediated transactivation and repression is universal because of high sequence homology of GR among species, and, among all nuclear hormone receptor superfamily members, there is remarkably high homology in GR DNAbinding domain and LBD domains irrespective of species. 9-11 To our knowledge, no study has yet been reported that shows GR LBD in human cancer cells and normal cells exhibit differential affinity toward the same glucocorticoid. Therapeutically, GR is an important target. In association with its synthetic ligand dexamethasone (Dex), it is involved in the control of metabolism. It is not only involved in regulation of development, inflammation, cell growth, proliferation, and differentiation, but also in inhibition of hypoxia-inducible factor-1, leukemia, prostate cancer, etc. 12-17 Hence, Dex is an important and inexpensive drug-like substitute that finds use in various pathological conditions including cancer. Cationic lipid/colipid formulations are excellent nonviral tools for the cellular delivery of DNA (reviewed in ref. 18). Previously, we have shown that estrogen, a natural ligand when covalently hooked to a lipid can be used as a targeting ligand for selective delivery of anticancer gene, p53, to elicit target-specific toxicity in estrogen receptor-implicated breast cancer cells. 19 Herein, we describe a unique way to target another nuclear hormone receptor, GR. Because Dex possesses structural similarity with cholesterol (chol), we directly incorporated Dex alongside the regular colipid chol in the cationic lipid-associated gene The first two authors contributed equally to this work.

The Journal of Nutritional Biochemistry, 2014

Cellular and humoral immunity had been implicated in the pathogenesis of non-alcoholic fatty live... more Cellular and humoral immunity had been implicated in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). This study was designed to assess if T, B and natural killer (NK) cells are involved in the progress of NAFLD in mouse models after chronic fructose treatment. Mouse models that are deficient in either T cells, B cells or NK cells or lacking both T and B cells were fed with 30% fructose solution for 12 weeks. Typical features of NAFLD, including the relative body weight, food and water intake, biochemical analytes, liver histology, NAFLD activity score, and glucose tolerance and insulin tolerance test were characterized. Further, the percentage of CD3, B220 and NK cells in peripheral-blood mononuclear cell, terminal deoxynucleotidyl transferase dUTP nick end labeling assay, immunodetection for hepatic apoptosis (p53) and for inflammation (TNFα) and quantitative real-time polymerase chain reaction for putative and inflammatory genes involved were determined. Our results conclude that mice deficient in T cells or NK cells fail to develop fructose induced NAFLD whereas the immunocompetent mice and mice with B-cell-specific defect developed NAFLD. Taken together, these data support that the onset of fructose-induced NAFLD is associated with involvement of T cells and NK cells in mice.

Inorganic Chemistry, 2013

A series of cationic chalcogenolato-bridged diruthenium complexes [(η 6-p-MeC 6 H 4 Pr i) 2 Ru 2 ... more A series of cationic chalcogenolato-bridged diruthenium complexes [(η 6-p-MeC 6 H 4 Pr i) 2 Ru 2 (μ-EC 6 H 5) 3 ] + (E = S, 1; E = Se, 2; E = Te, 3) has been obtained in ethanol from the reaction of (η 6-p-MeC 6 H 4 Pr i) 2 Ru 2 (μ-Cl) 2 Cl 2 with benzenethiol, benzeneselenol, and sodium tellurophenolate, respectively. The thiolato and selenolato derivatives are isolated in good yield as the chloride salts, while the tellurolato analogue is isolated as the hexafluorophosphate salt. Similarly, the dinuclear pentamethylcyclopentadienyl (C 5 Me 5) rhodium and iridium complexes (η 5-C 5 Me 5) 2 M 2 (μ-Cl) 2 Cl 2 react with benzenethiol, benzeneselenol, and sodium tellurophenolate in ethanol to give the corresponding cationic dinuclear complexes of the general formula [(η 5-C 5 Me 5) 2 M 2 (μ-EC 6 H 5) 3 ] +

Comparative Clinical Pathology, 2011

The aim of the study was to evaluate baseline data of mutant strain of mice and to compare haemat... more The aim of the study was to evaluate baseline data of mutant strain of mice and to compare haematological parameters with their background strains. Almost all mutant strains of either sex had statistically significant changes in relation to their background strains. These findings will be useful for researchers in designing experiments on mutant strains for various disease models and interpreting data obtained from those strains.

Biomaterials, 2013

Chaperone protein Hsp90 maintains functional integrity and maturation of a large number of cellul... more Chaperone protein Hsp90 maintains functional integrity and maturation of a large number of cellular proteins including transcription factors, kinases, etc. It is often over-expressed in cancer cells for simultaneous maintenance of many non-regulated and/or genetically mutated proteins. Small moleculebased regimens inhibiting over-expressing Hsp90 in cancer cells often plagued with improper targeting leading to non-specific toxicity. Recently using a glucocorticoid receptor (GR)-targeted cationic lipoplex, we observed cancer cell-specific GR-transactivation and transgene expression by utilizing an unprecedentedly compromised chaperone-activity of cancer cell-associated Hsp90. In normal cells, GR is expressed ubiquitously and is highly regulated and chaperoned by Hsp90. This does not allow cancer cell-alike GR-mediated transgene expression. As a novel anticancer strategy, we showed that compromising Hsp90 in cancer cells can be utilized to selectively deplete its own level by delivering a specially designed artificial miRNA-plasmid against Hsp90 (amiR-Hsp90). Practically, GR-mediated delivery of amiR-Hsp90 plasmid in tumor-bearing mice, depleted Hsp90, critically down-regulated levels of Akt, VEGFR2 and other Hsp90-client proteins but up-regulated wild-type p53 in tumor. These enforced apoptosis in angiogenic vessels and in tumor mass and significantly shrunk tumor-volume. The present study describes gene therapy strategy against Hsp90 using a new GR-targeted liposome-amiR-Hsp90 lipoplex formulation for treating cancer.

Biomarkers, 2009

Human papillomavirus is considered to be a major aetiological factor but is not sufficient for th... more Human papillomavirus is considered to be a major aetiological factor but is not sufficient for the development of cervical cancer. Other host factors, including altered homocysteine levels, a functional marker of folate inadequacy, might contribute to the carcinogenic process. Herein we investigated the potential association of homocysteine levels and MTHFR polymorphisms with cervical cancer in 203 histologically confirmed cases including 39 precancer cases and 231 healthy controls with normal cervical cytology. Both patients and controls were screened for human papillomavirus infection. We found that homocysteine and consequently cysteine levels were significantly higher in cases, both cancer and precancer (p < 0.001) than controls. However, polymorphisms in the MTHFR gene (677C/T and 1298A/C) that are reported to modulate homocysteine levels were not associated with disease. Thus, our study establishes an association of total homocysteine levels with the risk of developing carcinoma of the uterine cervix.

Acta Histochemica, 2013

Please cite this article in press as: Ragamouni S, et al. Histological analysis of cells and matr... more Please cite this article in press as: Ragamouni S, et al. Histological analysis of cells and matrix mineralization of new bone tissue induced in rabbit femur bones by Mg-Zr based biodegradable implants. Acta Histochemica (2013),

Advanced NanoBiomed Research

Inorganic nanoparticles (NPs) have been used for cancer theranostics application for last several... more Inorganic nanoparticles (NPs) have been used for cancer theranostics application for last several years. [1-3] Among them, noble metal NPs (gold, silver, and platinum NPs [PtNPs]) offer promising opportunity for various biomedical applications, including drug delivery, bioimaging, diagnostics, etc., owing to their distinctive physicochemical properties. [4-8] However, serious toxicological consequences might be observed on interaction of these NPs with the biological moieties at cellular and subcellular level. Based on this, several studies investigated potential toxicity of various nanomaterials, such as carbon nanotubes, graphene oxides, zinc oxides, cerium oxides, quantum dots, and silica NPs. [9-11] In this context, assessment of probable health risks associated with biologically important novel nanomaterials is essential for the safe biomedical application. Recently, PtNPs have gained vast attention in the field of healthcare and medicine. [5,12-17] However, exposure of PtNPs in a biological system might be associated with unanticipated hazards. [18-20] There are numerous reports on nephrotoxicity, hepatotoxicity, and inflammatory responses along with DNA damage induced by Ptbased NPs. [21,22] On the other hand, PtNPs are also reported to inhibit pulmonary inflammation by exerting antioxidants and free radical scavenging activity. [23-28] These conflicting results specify that the biological effects and toxicological behavior of PtNPs remain poorly explained. In our earlier report, we designed a cancer drug delivery system (DDS) using pegylated (polyethylene glycol functionalized

Abdominal aortic aneurysm (AAA) is a common chronic degenerative disease characterized by progres... more Abdominal aortic aneurysm (AAA) is a common chronic degenerative disease characterized by progressive aortic dilation and rupture. The mechanisms underlying the role of a-tocopherol and b-carotene on AAA have not been comprehensively assessed. We investigated if a-tocopherol and b-carotene supplementation could attenuate AAA, and studied the underlying mechanisms utilized by the antioxidants to alleviate AAA. Four-months-old Apoe2/2 mice were used in the induction of aneurysm by infusion of angiotensin II (Ang II), and were orally administered with a-tocopherol and b-carotene enriched diet for 60 days. Significant increase of LDL, cholesterol, triglycerides and circulating inflammatory cells was observed in the Ang II-treated animals, and gene expression studies showed that ICAM-1, VCAM-1, MCP-1, M-CSF, MMP-2, MMP-9 and MMP-12 were upregulated in the aorta of aneurysm-induced mice. Extensive plaques, aneurysm and diffusion of inflammatory cells into the tunica intima were also notic...

International journal of experimental pathology, 2018

Non-alcoholic fatty liver disease (NAFLD)-like conditions enhance the production and action of cl... more Non-alcoholic fatty liver disease (NAFLD)-like conditions enhance the production and action of clotting factors in humans. However, studies examining the effect of NAFLD due to high-fat high-fructose (HFHF) diet in factor VIII-deficient (haemophilia A) animals or patients have not been reported previously. In this study, we investigated the individual role of factor VIII in the progression of diet-induced NAFLD in the factor 8 (F8 ) mouse model system and its consequences on the haemophilic status of the mice. The F8 mice were fed with HFHF diet for 14 weeks. Physiological, biochemical, haematological, molecular, pathological, and immune histochemical analyses were performed to evaluate the effect of this diet. The F8 mice developed hepatic steatosis after 14 weeks HFHF diet and displayed lower energy metabolism, higher myeloid cell infiltration in the liver, decreased platelet count, upregulated de novo fatty acid synthesis, lipid accumulation, and collagen deposition. This study h...

Scientific Reports, 2016

We have earlier shown that Plumbagin (PB) can induce selective cytotoxicity to BRCA1 defective ov... more We have earlier shown that Plumbagin (PB) can induce selective cytotoxicity to BRCA1 defective ovarian cancer cells; however, the effect of this molecule in BRCA1 mutated breast cancers has not been analyzed yet. Here, we report that reactive oxygen species (ROS) induced by PB resulted in DNA DSB and activates downstream signaling by ATR/ATM kinases and subsequent apoptosis. PB reduces DNA- dependent protein kinase (DNA-PK) expression and inhibits NHEJ (Non Homologous End Joining) activity in BRCA1 defective breast cancer cells. Also, PB induces apoptosis in two different BRCA1 conditional knock out murine models: MMTV-Cre; BRCA1Co/Co and WAP-Cre; BRCA1Co/Co, at 2 mg/kg body weight, but 32 mg/kg of carboplatin (CN) was needed to induce apoptosis in them. This is the first study where two different tissue specific promoter driven transgenic mice models with BRCA1 exon 11 deletions are used for preclinical drug testing. The apoptosis induced by PB in HR (Homologous Recombination) defe...

Free Radical Biology and Medicine, 2016

attenuates monocyte-to-macrophage differentiation and associated inflammation via modulation of i... more attenuates monocyte-to-macrophage differentiation and associated inflammation via modulation of intracellular GSH homeostasis: Relevance in atherosclerosis, Free Radical Biology and Medicine,

Scientific Reports, 2016

Mitochondria-targeted compounds are emerging as a new class of drugs that can potentially alter t... more Mitochondria-targeted compounds are emerging as a new class of drugs that can potentially alter the pathophysiology of those diseases where mitochondrial dysfunction plays a critical role. We have synthesized a novel mitochondria-targeted esculetin (Mito-Esc) with an aim to investigate its effect during oxidative stress-induced endothelial cell death and angiotensin (Ang)-II-induced atherosclerosis in ApoE−/− mice. Mito-Esc but not natural esculetin treatment significantly inhibited H2O2- and Ang-II-induced cell death in human aortic endothelial cells by enhancing NO production via AMPK-mediated eNOS phosphorylation. While L-NAME (NOS inhibitor) significantly abrogated Mito-Esc-mediated protective effects, Compound c (inhibitor of AMPK) significantly decreased Mito-Esc-mediated increase in NO production. Notably, Mito-Esc promoted mitochondrial biogenesis by enhancing SIRT3 expression through AMPK activation; and restored H2O2-induced inhibition of mitochondrial respiration. siSIRT3...

PLOS ONE, 2015

Acute renal failure is a serious complication of the anticancer drug cisplatin. The potential rol... more Acute renal failure is a serious complication of the anticancer drug cisplatin. The potential role of baicalein, a naturally occurring bioflavonoid on cisplatin-induced renal injury is unknown. Here, we assessed the effect of baicalein against a murine model of cisplatininduced acute renal failure and investigated the underlying possible mechanisms. Renal function, kidney histology, inflammation, oxidative stress, renal mitochondrial function, proteins involved in apoptosis, nuclear translocation of Nrf2 and effects on intracellular signaling pathways such as MAPKs, and NF-κB were assessed. Pretreatment with baicalein ameliorated the cisplatin-induced renal oxidative stress, apoptosis and inflammation and improved kidney injury and function. Baicalein inhibited the cisplatin-induced expression of iNOS, TNF-α, IL-6 and mononuclear cell infiltration and concealed redox-sensitive transcription factor NF-κB activation via reduced DNA-binding activity, IκBα phosphorylation and p65 nuclear translocation in kidneys. Further studies demonstrated baicalein markedly attenuated cisplatin-induced p38 MAPK, ERK1/2 and JNK phosphorylation in kidneys. Baicalein also restored the renal antioxidants and increased the amount of total and nuclear accumulation of Nrf2 and downstream target protein, HO-1 in kidneys. Moreover, baicalein preserved mitochondrial respiratory enzyme activities and inhibited cisplatin-induced apoptosis by suppressing p53 expression, Bax/Bcl-2 imbalance, cytochrome c release and activation of caspase-9, caspase-3 and PARP. Our findings suggest that baicalein ameliorates cisplatin-induced renal damage through up-regulation of antioxidant defense mechanisms and down regulation of the MAPKs and NF-κB signaling pathways.

Frontiers in microbiology, 2013

Noroviruses cause most cases of acute viral gastroenteritis worldwide. The lack of a cell culture... more Noroviruses cause most cases of acute viral gastroenteritis worldwide. The lack of a cell culture infection model for human norovirus necessitates the use of molecular methods and/or viral surrogate models amenable to cell culture to predict norovirus inactivation. Murine norovirus (MNV) may be used to construct a small animal model for studying the biology and pathogenesis of noroviruses because MNV is the only norovirus that replicates in cell culture and a small animal model. However, recent studies have shown that natural MNV infection is widespread in laboratory mouse colonies. We investigated MNV infection in both conventional and specific pathogen-free (SPF) genetically modified mice from Japan and the US, and commercial mice from several animal breeders in Japan, using serological and molecular techniques. MNV antibodies were detected in 67.3% of conventional mice and 39.1% of SPF mice from Japan and 62.5% of conventional mice from the US. MNV antibodies were also found in 2...

Diabetes, 2014

Monocyte-to-macrophage differentiation is a critical event that accentuates atherosclerosis by pr... more Monocyte-to-macrophage differentiation is a critical event that accentuates atherosclerosis by promoting an inflammatory environment within the vessel wall. In this study, we investigated the molecular mechanisms responsible for monocyte-to-macrophage differentiation and, subsequently, the effect of metformin in regressing angiotensin II (Ang-II)-mediated atheromatous plaque formation in ApoE−/− mice. AMPK activity was dose and time dependently downregulated during phorbol myristate acetate (PMA)-induced monocyte-to-macrophage differentiation, which was accompanied by an upregulation of proinflammatory cytokine production. Of note, AMPK activators metformin and AICAR significantly attenuated PMA-induced monocyte-to-macrophage differentiation and proinflammatory cytokine production. However, inhibition of AMPK activity alone by compound C was ineffective in promoting monocyte-to-macrophage differentiation in the absence of PMA. On the other hand, inhibition of c-Jun N-terminal kinase...

ChemPlusChem, 2014

Two hexacationic pentamethylcyclopentadienyl rhodium(III) and iridium(III) metalla-prisms, [(h 5-... more Two hexacationic pentamethylcyclopentadienyl rhodium(III) and iridium(III) metalla-prisms, [(h 5-C 5 Me 5) 6 M 6 (m 3-tpt-kN) 2 (m 4-C 6 HRO 4-kO) 3 ] 6 + (tpt = 2,4,6-tri-(pyridin-4-yl)-1,3,5-triazine; R = (CH 2) 10 CH 3 ; M= Rh, [3] 6 + ; M= Ir, [4] 6 +) isolated as their triflate salts, have been synthesised from the dinuclear complexes (h 5-C 5 Me 5) 2 M 2 (m 4-C 6 HRO 4-kO)Cl 2 (M = Rh, 1; M= Ir, 2) and AgCF 3 SO 3. The antiproliferative activity of the neutral and cat-ionic complexes has been evaluated in vitro in human cancer cell lines. The positively charged metalla-prisms appear to target mitochondria, which ultimately induce apoptosis in cancer cells. All biological studies suggest that the rhodium derivative [3][CF 3 SO 3 ] 6 possesses excellent activities, not only in vitro but also in vivo in tumour-induced C57L6/J mice.

Molecular Imaging and Biology, 2015

Researchers had developed and characterized transgenic green/red fluorescent protein (GFP/RFP) nu... more Researchers had developed and characterized transgenic green/red fluorescent protein (GFP/RFP) nude mouse with ubiquitous RFP or GFP expression, but none has evaluated the level of immune cells and expression levels of GFP in this model. The nude GFP mice were evaluated by imaging, hematological indices, and flow cytometry to compare the proportion of immune T cells. Quantitative real-time PCR (qRT-PCR) was done for evaluating the relative expression of GFP transcripts in few organs of the nude GFP mice. The hematological and immune cells of nude GFP were within the range of nude mice. However, the gene expression levels were relatively less in various tissues compared with B6 GFP mice. These findings suggest that nude GFP is an ideal model resembling normal nude mice; however, GFP expression in various tissues by fluorescence should be considered, as the expression of GFP differs in various organs.

Nucleic Acids Research, 2013

Building molecular correlates of drug resistance in cancer and exploiting them for therapeutic in... more Building molecular correlates of drug resistance in cancer and exploiting them for therapeutic intervention remains a pressing clinical need. To identify factors that impact drug resistance herein we built a model that couples inherent cell-based response toward drugs with transcriptomes of resistant/ sensitive cells. To test this model, we focused on a group of genes called metastasis suppressor genes (MSGs) that influence aggressiveness and metastatic potential of cancers. Interestingly, modeling of 84 000 drug response transcriptome combinations predicted multiple MSGs to be associated with resistance of different cell types and drugs. As a case study, on inducing MSG levels in a drug resistant breast cancer line resistance to anticancer drugs caerulomycin, camptothecin and topotecan decreased by more than 50-60%, in both culture conditions and also in tumors generated in mice, in contrast to control un-induced cells. To our knowledge, this is the first demonstration of engineered reversal of drug resistance in cancer cells based on a model that exploits inherent cellular response profiles.

Molecular Therapy, 2009

Glucocorticoid receptor (GR), an ubiquitously present nuclear hormone receptor protein, regulates... more Glucocorticoid receptor (GR), an ubiquitously present nuclear hormone receptor protein, regulates many important functions in almost all cell types including cancerous and noncancerous cells. Maintenance of glucose homeostasis using noncarbohydrate precursors, regulation of protein and fat metabolism and various anti-inflammatory and immunosuppressive actions are some important functions of GR. 1,2 Since the purification and first cloning of full-length GR, many new isoforms of GR have been discovered. 3,4 One of GR's main isoforms, the α-isoform has both 250 odd amino acid ligand-binding domain (LBD) and 60-70 amino acids DNA-binding domain. GR-α undergoes ligandactivated nuclear localization resulting into transactivation of several genes under diversity of glucocorticoid responses. 5 The GR-β isoform, however, having no LBD resides inside nucleus permanently and functionally competes and associates with GR-α inside the nucleus imparting glucocorticoid resistance to gene transactivation. 6,7 The role of coengaging cytoplasmic proteins such as heat-shock proteins that lend structural and functional stability to LBD for ligand-binding and subsequent steps are well characterized. 8 The phenomenon of GR-mediated transactivation and repression is universal because of high sequence homology of GR among species, and, among all nuclear hormone receptor superfamily members, there is remarkably high homology in GR DNAbinding domain and LBD domains irrespective of species. 9-11 To our knowledge, no study has yet been reported that shows GR LBD in human cancer cells and normal cells exhibit differential affinity toward the same glucocorticoid. Therapeutically, GR is an important target. In association with its synthetic ligand dexamethasone (Dex), it is involved in the control of metabolism. It is not only involved in regulation of development, inflammation, cell growth, proliferation, and differentiation, but also in inhibition of hypoxia-inducible factor-1, leukemia, prostate cancer, etc. 12-17 Hence, Dex is an important and inexpensive drug-like substitute that finds use in various pathological conditions including cancer. Cationic lipid/colipid formulations are excellent nonviral tools for the cellular delivery of DNA (reviewed in ref. 18). Previously, we have shown that estrogen, a natural ligand when covalently hooked to a lipid can be used as a targeting ligand for selective delivery of anticancer gene, p53, to elicit target-specific toxicity in estrogen receptor-implicated breast cancer cells. 19 Herein, we describe a unique way to target another nuclear hormone receptor, GR. Because Dex possesses structural similarity with cholesterol (chol), we directly incorporated Dex alongside the regular colipid chol in the cationic lipid-associated gene The first two authors contributed equally to this work.

The Journal of Nutritional Biochemistry, 2014

Cellular and humoral immunity had been implicated in the pathogenesis of non-alcoholic fatty live... more Cellular and humoral immunity had been implicated in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). This study was designed to assess if T, B and natural killer (NK) cells are involved in the progress of NAFLD in mouse models after chronic fructose treatment. Mouse models that are deficient in either T cells, B cells or NK cells or lacking both T and B cells were fed with 30% fructose solution for 12 weeks. Typical features of NAFLD, including the relative body weight, food and water intake, biochemical analytes, liver histology, NAFLD activity score, and glucose tolerance and insulin tolerance test were characterized. Further, the percentage of CD3, B220 and NK cells in peripheral-blood mononuclear cell, terminal deoxynucleotidyl transferase dUTP nick end labeling assay, immunodetection for hepatic apoptosis (p53) and for inflammation (TNFα) and quantitative real-time polymerase chain reaction for putative and inflammatory genes involved were determined. Our results conclude that mice deficient in T cells or NK cells fail to develop fructose induced NAFLD whereas the immunocompetent mice and mice with B-cell-specific defect developed NAFLD. Taken together, these data support that the onset of fructose-induced NAFLD is associated with involvement of T cells and NK cells in mice.

Inorganic Chemistry, 2013

A series of cationic chalcogenolato-bridged diruthenium complexes [(η 6-p-MeC 6 H 4 Pr i) 2 Ru 2 ... more A series of cationic chalcogenolato-bridged diruthenium complexes [(η 6-p-MeC 6 H 4 Pr i) 2 Ru 2 (μ-EC 6 H 5) 3 ] + (E = S, 1; E = Se, 2; E = Te, 3) has been obtained in ethanol from the reaction of (η 6-p-MeC 6 H 4 Pr i) 2 Ru 2 (μ-Cl) 2 Cl 2 with benzenethiol, benzeneselenol, and sodium tellurophenolate, respectively. The thiolato and selenolato derivatives are isolated in good yield as the chloride salts, while the tellurolato analogue is isolated as the hexafluorophosphate salt. Similarly, the dinuclear pentamethylcyclopentadienyl (C 5 Me 5) rhodium and iridium complexes (η 5-C 5 Me 5) 2 M 2 (μ-Cl) 2 Cl 2 react with benzenethiol, benzeneselenol, and sodium tellurophenolate in ethanol to give the corresponding cationic dinuclear complexes of the general formula [(η 5-C 5 Me 5) 2 M 2 (μ-EC 6 H 5) 3 ] +

Comparative Clinical Pathology, 2011

The aim of the study was to evaluate baseline data of mutant strain of mice and to compare haemat... more The aim of the study was to evaluate baseline data of mutant strain of mice and to compare haematological parameters with their background strains. Almost all mutant strains of either sex had statistically significant changes in relation to their background strains. These findings will be useful for researchers in designing experiments on mutant strains for various disease models and interpreting data obtained from those strains.

Biomaterials, 2013

Chaperone protein Hsp90 maintains functional integrity and maturation of a large number of cellul... more Chaperone protein Hsp90 maintains functional integrity and maturation of a large number of cellular proteins including transcription factors, kinases, etc. It is often over-expressed in cancer cells for simultaneous maintenance of many non-regulated and/or genetically mutated proteins. Small moleculebased regimens inhibiting over-expressing Hsp90 in cancer cells often plagued with improper targeting leading to non-specific toxicity. Recently using a glucocorticoid receptor (GR)-targeted cationic lipoplex, we observed cancer cell-specific GR-transactivation and transgene expression by utilizing an unprecedentedly compromised chaperone-activity of cancer cell-associated Hsp90. In normal cells, GR is expressed ubiquitously and is highly regulated and chaperoned by Hsp90. This does not allow cancer cell-alike GR-mediated transgene expression. As a novel anticancer strategy, we showed that compromising Hsp90 in cancer cells can be utilized to selectively deplete its own level by delivering a specially designed artificial miRNA-plasmid against Hsp90 (amiR-Hsp90). Practically, GR-mediated delivery of amiR-Hsp90 plasmid in tumor-bearing mice, depleted Hsp90, critically down-regulated levels of Akt, VEGFR2 and other Hsp90-client proteins but up-regulated wild-type p53 in tumor. These enforced apoptosis in angiogenic vessels and in tumor mass and significantly shrunk tumor-volume. The present study describes gene therapy strategy against Hsp90 using a new GR-targeted liposome-amiR-Hsp90 lipoplex formulation for treating cancer.

Biomarkers, 2009

Human papillomavirus is considered to be a major aetiological factor but is not sufficient for th... more Human papillomavirus is considered to be a major aetiological factor but is not sufficient for the development of cervical cancer. Other host factors, including altered homocysteine levels, a functional marker of folate inadequacy, might contribute to the carcinogenic process. Herein we investigated the potential association of homocysteine levels and MTHFR polymorphisms with cervical cancer in 203 histologically confirmed cases including 39 precancer cases and 231 healthy controls with normal cervical cytology. Both patients and controls were screened for human papillomavirus infection. We found that homocysteine and consequently cysteine levels were significantly higher in cases, both cancer and precancer (p < 0.001) than controls. However, polymorphisms in the MTHFR gene (677C/T and 1298A/C) that are reported to modulate homocysteine levels were not associated with disease. Thus, our study establishes an association of total homocysteine levels with the risk of developing carcinoma of the uterine cervix.

Acta Histochemica, 2013

Please cite this article in press as: Ragamouni S, et al. Histological analysis of cells and matr... more Please cite this article in press as: Ragamouni S, et al. Histological analysis of cells and matrix mineralization of new bone tissue induced in rabbit femur bones by Mg-Zr based biodegradable implants. Acta Histochemica (2013),