Let me first express my gratitude towards you for extending all your active support, as without t... more Let me first express my gratitude towards you for extending all your active support, as without that it would not have been possible for me to bring out the International Journal Of Applied Environmental Science And Technology Vol-3- Issue. 1 of the year 2015.
Hope you will be good enough to keep on extending the same so that qualitative improvement can be made after every issue and send another research article for the next issue. The LAST DATE for receiving manuscript is 25th oct 2015, but please do not wait for the LAST DATE. But if your article is ready, please send it immediately as it takes about TWO months time in getting it processed. Soft copy of the present issue is attached herewith for your perusal and with a request to forward the same to your students and colleagues so that they can also submit articles for publication in this journal.
Background: Tumors of the head and neck present aggressive pathological behavior in patients due ... more Background: Tumors of the head and neck present aggressive pathological behavior in patients due to high expression of CDK/CCND1 proteins. P276-00, a novel CDK inhibitor currently being tested in clinic, inhibits growth of several cancers in vitro and in vivo. The pre clinical activity of P276-00 in head and neck cancer and its potential mechanisms of action at molecular level are the focus of the current studies.
Scientists are constantly searching for phytochemical compounds with anti-cancer activity. In thi... more Scientists are constantly searching for phytochemical compounds with anti-cancer activity. In this study, activity of plant extract NPB001-05 from Piper betle was tested on human chronic myelogenous leukemia (CML) xenograft models. NPB001-05 was active when dosed orally (500 mg/kg) once or twice a day in xenograft tumor models. NPB001-05 showed activity to T315I tumor xenograft, where imatinib failed to show antitumor activity. NPB001-05 showed no relevant toxicity in animal models during 2 weeks exposure to drug. Responsive tumor showed inhibition of tyrosine kinase activity with lowered Bcr-Abl protein levels and increased apoptosis. Microarray based transcription profiling studies demonstrated that both imatinib and NPB001-05 dysregulated imatinib- responsive genes. NPB001-05 showed additional genes selectively dysregulated from ER stress, PI3K/AKT, MAPK pathways. Additionally, we tested gene expression of PI3K, AKT1, JUN, CASP3 and DDIT3 in K562, BaF3P210(BCR-ABL) and BaF3 P210(BCR-ABLT315I) cell line treated for 6- and 12- hours with NPB001-05 and imatinib. The data indicates that NPB001-05 mediated cell death in K562 affects the function of ER stress. NPB001-05 shows antitumor activity with favorable toxicity profile.
Medicinal plants have shown great promise as a source of novel drug compounds for the treatment o... more Medicinal plants have shown great promise as a source of novel drug compounds for the treatment of inflammatory disorders. In our search for new entities with anti-inflammatory potential, the extracts of the whole plant of Saussurea heteromalla (family-Asteraceae), collected from Himalayas, were evaluated in the high throughput screen for TNF-␣ and IL-6 inhibitors. The extract blocked TNF-␣ and IL-6 production in LPS stimulated THP-1 cells (human acute monocyte leukemia cell line) completely at 10 and 30 g/ml. The plant has been found as a new source of chlorojanerin, a guaianolide type of sesquiterpene lactone. Chlorojanerin was shown to be significantly effective in inhibiting TNF-␣ and IL-6 production in LPS-stimulated THP-1 cells (IC 50 = 2.3 ± 0.2 M and 1.8 ± 0.7 M respectively). The compound also blocked TNF-␣ and IL-6 production from LPS-stimulated human monocytes (IC 50 = 1.5 ± 0.4 and 0.7 ± 0.2 M respectively) and synovial cells from a patient with rheumatoid arthritis (IC 50 < 0.03 and 0.5 M respectively). Transcriptional profiling of the LPS stimulated THP-1 cells revealed that chlorojanerin exerted its anti-inflammatory effect by inhibiting the expression of 8 genes involved in activating the transcription factor -NF-B. Real time analysis of these genes validated the effect of chlorojanerin on the classical downstream targets of NF-B. Thus, this study clearly delineated 8 genes which were specifically mitigated due to the effect of chlorojanerin on NF-B induced signaling at the mRNA level. Further, chlorojanerin at 5 M also inhibited the binding of NF-B in a GFP reporter assay system by 55.5% thus validating the microarray gene expression data. This work is a step towards the isolation and characterization of lead anti-inflammatory agents from the extract of Saussurea heteromalla, which can be developed into better therapeutic molecules targeted towards some specific inflammatory diseases.
Microarray technology can be used to study the molecular mechanisms of new chemical entities with... more Microarray technology can be used to study the molecular mechanisms of new chemical entities with the aim to develop effective therapeutics. 7-Hydroxyfrullanolide (7HF) is a sesquiterpene lactone that was found to be efficacious in multiple animal models of inflammation by suppression of pro-inflammatory cytokines; however, its molecular mechanism of action remains unclear. We investigated the effects of 7HF on lipopolysaccharide (LPS)-stimulated human peripheral blood mononuclear cells using microarray-based gene expression studies and explored the molecular targets affected. Gene expression profiles and pathway analysis revealed that 7HF potently suppressed multiple inflammatory pathways induced by LPS. More importantly, 7HF was found to inhibit NF-κB related transcripts. These transcripts were further validated using freshly isolated synovial cells from rheumatoid arthritis patients, thus clinically validating our findings. Cell-based imaging and subsequent Western blot analysis demonstrated that 7HF inhibited the translocation of NF-κB into the nucleus by directly inhibiting the phosphorylation of IKK-β. Since the transcription of adhesion molecules is regulated by NF-κB, further investigation showed that 7HF dose-dependently suppressed ICAM-1, VCAM-1 and E-selectin expression on LPS-stimulated endothelial cells as well as inhibited the adhesion of monocytes to LPS-stimulated endothelial cells. Taken together, our results reveal that 7HF possesses NF-κB inhibitory potential and suggest a likely molecular mechanism of its anti-inflammatory activity.
Biochemical and Biophysical Research Communications, 2010
Studying peripheral blood transcriptome in the quest for translational markers of toxicity is con... more Studying peripheral blood transcriptome in the quest for translational markers of toxicity is considered to be an attractive offshoot in the field of toxicogenomics. Moreover, it is acknowledged that, xenobiotics which cause a toxic response through similar mechanisms lead to distinctive gene expression patterns. The current study was undertaken to gauge the response of an accessible surrogate tissue, such as blood, to drug-induced perturbations aimed at deriving gene expression patterns. Human peripheral blood mononuclear cells (hPBMC) were exposed to conventional drugs, with reported kidney and/or liver injury, in order to determine their transcriptomic response. Test drugs were divided into two classes viz., drugs affecting kidney (cyclophosphamide, amphotericin B, gentamicin and cisplatin) and liver (acetaminophen, rosiglitazone, fluconazole and isoniazid). After performing gene expression analysis and hierarchical clustering, signature patterns for the two classes were obtained, with a set of 365 genes that can discriminate the two classes of drugs. Our results imply that transcriptional profile of hPBMC get altered as a consequence of drug exposure and unique patterns indicative of specific organ toxicity can hence be deduced. These signature patterns obtained for drugs could be studied for their qualification to identify drug-induced toxicity.
Several studies have characterized drug-induced toxicity in liver and kidney. However, the majori... more Several studies have characterized drug-induced toxicity in liver and kidney. However, the majority of these studies have been performed with 'individual' organs in isolation. Separately, little is known about the role of whole blood as a surrogate tissue in drug-induced toxicity. Accordingly, we investigated the 'concurrent' response of liver, kidney and whole blood during a toxic assault. Rats were acutely treated with therapeutics (acetaminophen, rosiglitazone, fluconazole, isoniazid, cyclophosphamide, amphotericin B, gentamicin and cisplatin) reported for their liver and/or kidney toxicity. Changes in clinical chemistry parameters (e.g. AST, urea) and/or observed microscopic tissue damage confirmed induced hepatotoxicity and/or nephrotoxicity by all drugs. Drug-induced toxicity was not confined to an 'individual' organ. Not all drugs elicited significant alterations in phenotypic parameters of toxicity (e.g. ALT, creatinine). Accordingly, the transcriptional profile of the organs was studied using a toxicity panel of 30 genes derived from literature. Each of the test drugs generated specific gene expression patterns which were unique for all three organs. Hierarchical cluster analyses of purported hepatotoxicants and nephrotoxicants each led to characteristic 'fingerprints' (e.g. decrease in Cyp3a1 indicative of hepatotoxicity; increase in Spp1 and decrease in Gstp1 indicative of nephrotoxicity). In whole blood cells, a set of genes was derived which closely correlated with individual drug-induced concomitant changes in liver or kidney. Collectively, these data demonstrate drug-induced multi-organ toxicity. Furthermore, our findings underscore the importance of transcriptional profiling during inadequate phenotypic anchorage and suggest that whole blood may be judiciously used as a surrogate for drug-induced extra-hematological organ toxicity.
INTERNATIONAL JOURNAL OF APPLIED ENVIRONMENTAL SCIENCE AND TECHNOLOGY is a biannual an academic a... more INTERNATIONAL JOURNAL OF APPLIED ENVIRONMENTAL SCIENCE AND TECHNOLOGY is a biannual an academic and peer-reviewed Journal published by ACADEMIC AND RESEARCH PUBLICATIONS. It was published from year i.e. 2012. The ISSN of the JOURNAL is 2321-8223. Earlier this journal was known as International Journal Of Environmental Science & Technology(IJEST)with ISSN : 2278-0785.
Let me first express my gratitude towards you for extending all your active support, as without t... more Let me first express my gratitude towards you for extending all your active support, as without that it would not have been possible for me to bring out the International Journal Of Applied Environmental Science And Technology Vol-3- Issue. 1 of the year 2015.
Hope you will be good enough to keep on extending the same so that qualitative improvement can be made after every issue and send another research article for the next issue. The LAST DATE for receiving manuscript is 25th oct 2015, but please do not wait for the LAST DATE. But if your article is ready, please send it immediately as it takes about TWO months time in getting it processed. Soft copy of the present issue is attached herewith for your perusal and with a request to forward the same to your students and colleagues so that they can also submit articles for publication in this journal.
Background: Tumors of the head and neck present aggressive pathological behavior in patients due ... more Background: Tumors of the head and neck present aggressive pathological behavior in patients due to high expression of CDK/CCND1 proteins. P276-00, a novel CDK inhibitor currently being tested in clinic, inhibits growth of several cancers in vitro and in vivo. The pre clinical activity of P276-00 in head and neck cancer and its potential mechanisms of action at molecular level are the focus of the current studies.
Scientists are constantly searching for phytochemical compounds with anti-cancer activity. In thi... more Scientists are constantly searching for phytochemical compounds with anti-cancer activity. In this study, activity of plant extract NPB001-05 from Piper betle was tested on human chronic myelogenous leukemia (CML) xenograft models. NPB001-05 was active when dosed orally (500 mg/kg) once or twice a day in xenograft tumor models. NPB001-05 showed activity to T315I tumor xenograft, where imatinib failed to show antitumor activity. NPB001-05 showed no relevant toxicity in animal models during 2 weeks exposure to drug. Responsive tumor showed inhibition of tyrosine kinase activity with lowered Bcr-Abl protein levels and increased apoptosis. Microarray based transcription profiling studies demonstrated that both imatinib and NPB001-05 dysregulated imatinib- responsive genes. NPB001-05 showed additional genes selectively dysregulated from ER stress, PI3K/AKT, MAPK pathways. Additionally, we tested gene expression of PI3K, AKT1, JUN, CASP3 and DDIT3 in K562, BaF3P210(BCR-ABL) and BaF3 P210(BCR-ABLT315I) cell line treated for 6- and 12- hours with NPB001-05 and imatinib. The data indicates that NPB001-05 mediated cell death in K562 affects the function of ER stress. NPB001-05 shows antitumor activity with favorable toxicity profile.
Medicinal plants have shown great promise as a source of novel drug compounds for the treatment o... more Medicinal plants have shown great promise as a source of novel drug compounds for the treatment of inflammatory disorders. In our search for new entities with anti-inflammatory potential, the extracts of the whole plant of Saussurea heteromalla (family-Asteraceae), collected from Himalayas, were evaluated in the high throughput screen for TNF-␣ and IL-6 inhibitors. The extract blocked TNF-␣ and IL-6 production in LPS stimulated THP-1 cells (human acute monocyte leukemia cell line) completely at 10 and 30 g/ml. The plant has been found as a new source of chlorojanerin, a guaianolide type of sesquiterpene lactone. Chlorojanerin was shown to be significantly effective in inhibiting TNF-␣ and IL-6 production in LPS-stimulated THP-1 cells (IC 50 = 2.3 ± 0.2 M and 1.8 ± 0.7 M respectively). The compound also blocked TNF-␣ and IL-6 production from LPS-stimulated human monocytes (IC 50 = 1.5 ± 0.4 and 0.7 ± 0.2 M respectively) and synovial cells from a patient with rheumatoid arthritis (IC 50 < 0.03 and 0.5 M respectively). Transcriptional profiling of the LPS stimulated THP-1 cells revealed that chlorojanerin exerted its anti-inflammatory effect by inhibiting the expression of 8 genes involved in activating the transcription factor -NF-B. Real time analysis of these genes validated the effect of chlorojanerin on the classical downstream targets of NF-B. Thus, this study clearly delineated 8 genes which were specifically mitigated due to the effect of chlorojanerin on NF-B induced signaling at the mRNA level. Further, chlorojanerin at 5 M also inhibited the binding of NF-B in a GFP reporter assay system by 55.5% thus validating the microarray gene expression data. This work is a step towards the isolation and characterization of lead anti-inflammatory agents from the extract of Saussurea heteromalla, which can be developed into better therapeutic molecules targeted towards some specific inflammatory diseases.
Microarray technology can be used to study the molecular mechanisms of new chemical entities with... more Microarray technology can be used to study the molecular mechanisms of new chemical entities with the aim to develop effective therapeutics. 7-Hydroxyfrullanolide (7HF) is a sesquiterpene lactone that was found to be efficacious in multiple animal models of inflammation by suppression of pro-inflammatory cytokines; however, its molecular mechanism of action remains unclear. We investigated the effects of 7HF on lipopolysaccharide (LPS)-stimulated human peripheral blood mononuclear cells using microarray-based gene expression studies and explored the molecular targets affected. Gene expression profiles and pathway analysis revealed that 7HF potently suppressed multiple inflammatory pathways induced by LPS. More importantly, 7HF was found to inhibit NF-κB related transcripts. These transcripts were further validated using freshly isolated synovial cells from rheumatoid arthritis patients, thus clinically validating our findings. Cell-based imaging and subsequent Western blot analysis demonstrated that 7HF inhibited the translocation of NF-κB into the nucleus by directly inhibiting the phosphorylation of IKK-β. Since the transcription of adhesion molecules is regulated by NF-κB, further investigation showed that 7HF dose-dependently suppressed ICAM-1, VCAM-1 and E-selectin expression on LPS-stimulated endothelial cells as well as inhibited the adhesion of monocytes to LPS-stimulated endothelial cells. Taken together, our results reveal that 7HF possesses NF-κB inhibitory potential and suggest a likely molecular mechanism of its anti-inflammatory activity.
Biochemical and Biophysical Research Communications, 2010
Studying peripheral blood transcriptome in the quest for translational markers of toxicity is con... more Studying peripheral blood transcriptome in the quest for translational markers of toxicity is considered to be an attractive offshoot in the field of toxicogenomics. Moreover, it is acknowledged that, xenobiotics which cause a toxic response through similar mechanisms lead to distinctive gene expression patterns. The current study was undertaken to gauge the response of an accessible surrogate tissue, such as blood, to drug-induced perturbations aimed at deriving gene expression patterns. Human peripheral blood mononuclear cells (hPBMC) were exposed to conventional drugs, with reported kidney and/or liver injury, in order to determine their transcriptomic response. Test drugs were divided into two classes viz., drugs affecting kidney (cyclophosphamide, amphotericin B, gentamicin and cisplatin) and liver (acetaminophen, rosiglitazone, fluconazole and isoniazid). After performing gene expression analysis and hierarchical clustering, signature patterns for the two classes were obtained, with a set of 365 genes that can discriminate the two classes of drugs. Our results imply that transcriptional profile of hPBMC get altered as a consequence of drug exposure and unique patterns indicative of specific organ toxicity can hence be deduced. These signature patterns obtained for drugs could be studied for their qualification to identify drug-induced toxicity.
Several studies have characterized drug-induced toxicity in liver and kidney. However, the majori... more Several studies have characterized drug-induced toxicity in liver and kidney. However, the majority of these studies have been performed with 'individual' organs in isolation. Separately, little is known about the role of whole blood as a surrogate tissue in drug-induced toxicity. Accordingly, we investigated the 'concurrent' response of liver, kidney and whole blood during a toxic assault. Rats were acutely treated with therapeutics (acetaminophen, rosiglitazone, fluconazole, isoniazid, cyclophosphamide, amphotericin B, gentamicin and cisplatin) reported for their liver and/or kidney toxicity. Changes in clinical chemistry parameters (e.g. AST, urea) and/or observed microscopic tissue damage confirmed induced hepatotoxicity and/or nephrotoxicity by all drugs. Drug-induced toxicity was not confined to an 'individual' organ. Not all drugs elicited significant alterations in phenotypic parameters of toxicity (e.g. ALT, creatinine). Accordingly, the transcriptional profile of the organs was studied using a toxicity panel of 30 genes derived from literature. Each of the test drugs generated specific gene expression patterns which were unique for all three organs. Hierarchical cluster analyses of purported hepatotoxicants and nephrotoxicants each led to characteristic 'fingerprints' (e.g. decrease in Cyp3a1 indicative of hepatotoxicity; increase in Spp1 and decrease in Gstp1 indicative of nephrotoxicity). In whole blood cells, a set of genes was derived which closely correlated with individual drug-induced concomitant changes in liver or kidney. Collectively, these data demonstrate drug-induced multi-organ toxicity. Furthermore, our findings underscore the importance of transcriptional profiling during inadequate phenotypic anchorage and suggest that whole blood may be judiciously used as a surrogate for drug-induced extra-hematological organ toxicity.
INTERNATIONAL JOURNAL OF APPLIED ENVIRONMENTAL SCIENCE AND TECHNOLOGY is a biannual an academic a... more INTERNATIONAL JOURNAL OF APPLIED ENVIRONMENTAL SCIENCE AND TECHNOLOGY is a biannual an academic and peer-reviewed Journal published by ACADEMIC AND RESEARCH PUBLICATIONS. It was published from year i.e. 2012. The ISSN of the JOURNAL is 2321-8223. Earlier this journal was known as International Journal Of Environmental Science & Technology(IJEST)with ISSN : 2278-0785.
Uploads
Papers by Prabha Mishra
Hope you will be good enough to keep on extending the same so that qualitative improvement can be made after every issue and send another research article for the next issue. The LAST DATE for receiving manuscript is 25th oct 2015, but please do not wait for the LAST DATE. But if your article is ready, please send it immediately as it takes about TWO months time in getting it processed. Soft copy of the present issue is attached herewith for your perusal and with a request to forward the same to your students and colleagues so that they can also submit articles for publication in this journal.
Hope you will be good enough to keep on extending the same so that qualitative improvement can be made after every issue and send another research article for the next issue. The LAST DATE for receiving manuscript is 25th oct 2015, but please do not wait for the LAST DATE. But if your article is ready, please send it immediately as it takes about TWO months time in getting it processed. Soft copy of the present issue is attached herewith for your perusal and with a request to forward the same to your students and colleagues so that they can also submit articles for publication in this journal.