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Madhulika Dixit
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Madhulika Dixit
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Madhulika Dixit
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Dixit, M.
Dixit, Madhulika
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29 results
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- PublicationAnalysis and modelling of septic shock microarray data using Singular Value Decomposition(01-06-2017)
;Allanki, Srinivas; ;Thangaraj, PaulBeing a high throughput technique, enormous amounts of microarray data has been generated and there arises a need for more efficient techniques of analysis, in terms of speed and accuracy. Finding the differentially expressed genes based on just fold change and p-value might not extract all the vital biological signals that occur at a lower gene expression level. Besides this, numerous mathematical models have been generated to predict the clinical outcome from microarray data, while very few, if not none, aim at predicting the vital genes that are important in a disease progression. Such models help a basic researcher narrow down and concentrate on a promising set of genes which leads to the discovery of gene-based therapies. In this article, as a first objective, we have used the lesser known and used Singular Value Decomposition (SVD) technique to build a microarray data analysis tool that works with gene expression patterns and intrinsic structure of the data in an unsupervised manner. We have re-analysed a microarray data over the clinical course of Septic shock from Cazalis et al. (2014) and have shown that our proposed analysis provides additional information compared to the conventional method. As a second objective, we developed a novel mathematical model that predicts a set of vital genes in the disease progression that works by generating samples in the continuum between health and disease, using a simple normal-distribution-based random number generator. We also verify that most of the predicted genes are indeed related to septic shock. - PublicationConstriction based microfluidic device for the cell phenotyping(01-01-2016)
;Raj, A.; We report a constriction based microfluidic device for characterization of mechanical properties of single cells. The device is capable of measuring the effect of size ratio, entry angle as well as external pressure applied across the constrictions on cell movement. Multiple cells can be processed through the constrictions at a single stretch. The device can give much higher throughput than the single constriction device normally used for all the experiments. It was observed, the entry time increase with the decrease in the cone angle (entry angle). Experimentally, the velocity of the cell was found to increase along the constriction length. - PublicationAngiopoietin-2 mediates thrombin-induced monocyte adhesion and endothelial permeability(01-08-2016)
;Rathnakumar, K. ;Savant, S. ;Giri, H. ;Ghosh, A. ;Fisslthaler, B. ;Fleming, I. ;Ram, U.; ;Augustin, H. G.Essentials Mechanism of thrombin–induced inflammation is not fully understood. Thrombin induced monocyte adhesion and barrier loss require Angiopoietin-2 (Ang-2). Ang-2 mediates vessel leakage and monocyte adhesion through SHP-2/p38MAPK pathway. Calcium dependent SHP2/p38MAPK activation regulates Ang-2 expression through a feedback loop. Summary: Background Thrombin imparts an inflammatory phenotype to the endothelium by promoting increased monocyte adhesion and vascular permeability. However, the molecular players that govern these events are incompletely understood. Objective The aim of this study was to determine whether Angiopoietin-2 (Ang-2) has a role, if any, in regulating inflammatory signals initiated by thrombin. Methods Assessment of vascular leakage by Miles assay was performed by intra-dermal injection on the foot paw. Surface levels of intercellular adhesion molecule-1 (ICAM-1) were determined by flow cytometry. Overexpression, knockdown and phosphorylation of proteins were determined by Western blotting. Results In time-course experiments, thrombin-stimulated Ang-2 up-regulation, peaked prior to the expression of adhesion molecule ICAM-1 in human umbilical vein-derived endothelial cells (HUVECs). Knockdown of Ang-2 blocked both thrombin-induced monocyte adhesion and ICAM-1 expression. In addition, Ang-2−/− mice displayed defective vascular leakage when treated with thrombin. Introducing Ang-2 protein in Ang-2−/− mice failed to recover a wild-type phenotype. Mechanistically, Ang-2 appears to regulate the thrombin-activated calcium spike that is required for tyrosine phosphatase SHP2 and p38 MAPK activation. Further, down-regulation of SHP2 attenuated both thrombin-induced Ang-2 expression and monocyte adhesion. Down-regulation of the adaptor protein Gab1, a co-activator of SHP2, as well as overexpression of the Gab1 mutant incapable of interacting with SHP2 (YFGab1), inhibited thrombin-mediated effects, including downstream activation of p38 MAPK, which in turn was required for Ang-2 expression. Conclusions The data establish an essential role of the Gab1/SHP2/p38MAPK signaling pathway and Ang-2 in regulating thrombin-induced monocyte adhesion and vascular leakage. - PublicationIncreased endothelial inflammation, sTie-2 and arginase activity in umbilical cords obtained from gestational diabetic mothers(20-12-2013)
;Giri, Hemant ;Chandel, Shivam ;Dwarakanath, Linga S. ;Sreekumar, SooriyakalaObjective: The aim of this study was to determine subclinical inflammation in umbilical vein derived endothelial cells (HUVECs) obtained from Asian Indian subjects with gestational diabetes (GDM) and to determine levels of angiogenic factors and arginase activity in their cord blood. Methods: This case-control study included 38 control and 30 GDM subjects. Subjects were confirmed as GDM based on 75g oral glucose tolerance test (OGTT) conducted in the second trimester of pregnancy. Angiogenic markers and arginase activity were measured in cord blood by ELISA and colorimetric methods respectively. Endothelial inflammation was assessed through adhesion of PKH26-labelled leukocytes onto HUVEC monolayer obtained from the study groups. Gene and surface expression of adhesion molecules were confirmed via reverse transcription polymerase chain reaction (RT-PCR) and flow cytometry respectively. Results: The study revealed increased adhesion of leukocytes to HUVECs isolated from GDM subjects compared to controls. HUVECs of babies born to GDM mothers had increased surface and mRNA expression of E-selectin. sTie2 levels were significantly higher in the cord blood for GDM subjects (3869 ± 370 ng/L) compared to controls (3045 ± 296 ng/L). Furthermore, arginase activity was higher in cord blood of GDM mothers as opposed to the control group (7.75 ± 2.4 μmoles of urea/ml/hour vs 2.88 ±0.49 μmoles of urea/ml/hour; p-value= 0.019). Spearman's correlation analysis revealed positive correlation of cord blood arginase activity with glucose intolerance (ρ=0.596, p=0.004) and post load glucose values (ρ=0.472, p=0.031) of mothers observed during the second trimester of pregnancy. Conclusions: HUVECs derived from Asian Indian GDM mothers, exhibit signs of sub-clinical endothelial inflammation along with increased levels of sTie2 and arginase activity in their cord blood serum. © 2013 Giri et al. - PublicationComparison and functional characterisation of peripheral blood mononuclear cells isolated from filarial lymphoedema and endemic normals of a South Indian population(01-11-2017)
;Nathan, Abel Arul; ;Babu, SubashBalakrishnan, Anand SettyObjective: The underlying problem in lymphatic filariasis is irreversible swelling of the limbs (lymphoedema), which is a unique feature of lymphatic insufficiency. It is still unclear whether the natural ability of lymphatics to form functional lymphatic vasculature is achieved or attenuated in the lymphoedemal pathology. Clinical studies have clearly shown that circulating lymphatic progenitors (CLPs), a subset of bone marrow-derived mononuclear cells (PBMCs), contribute to post-natal lymph vasculogenesis. CLP-based revascularisation could be a promising strategy to bypass the endothelial disruption and damage incurred by the filarial parasites. Thus our aim was to compare and characterise the functional prowess of PBMCs in physiological and lymphoedemal pathology. Methods: PBMCs were isolated from venous blood sample from drug-naive endemic normals (EN) and drug-deprived filarial lymphoedema (FL) individuals using density gradient centrifugation. Adhesion, transwell migration and in vitro matrigel assays were employed to characterise the lymphvasculogenic potential of PBMCs. CLPs were phenotypically characterised using flow cytometry; expression levels of lymphatic markers and inflammatory cytokines were quantified using qRT-PCR and ELISA, respectively. Results: PBMCs from FL group display poor adherence to fibronectin (P = 0.040), reduced migration towards SDF-1α (P = 0.035), impaired tubular network (P = 0.004) and branching point (P = 0.048) formation. The PBMC mRNA expression of VEGFR3 (P = 0.039) and podoplanin (P = 0.050) was elevated, whereas integrin α9 (P = 0.046) was inhibited in FL individuals; additionally, the surface expression of CD34 (P = 0.048) was significantly reduced in the FL group compared to the EN group. Conclusion: PBMCs from filarial lymphoedema show defective and dysregulated lymphvasculogenic function compared to endemic normals. - PublicationGlucose challenge increases circulating progenitor cells in Asian Indian male subjects with normal glucose tolerance which is compromised in subjects with pre-diabetes: A pilot study(11-01-2011)
;Nathan, Abel A. ;Mohan, Viswanathan ;Babu, Subash S. ;Bairagi, SoumiBackground: Haematopoietic stem cells undergo mobilization from bone marrow to blood in response to physiological stimuli such as ischemia and tissue injury. The aim of study was to determine the kinetics of circulating CD34+ and CD133+CD34+ progenitor cells in response to 75 g glucose load in subjects with normal and impaired glucose metabolism.Methods: Asian Indian male subjects (n = 50) with no prior history of glucose imbalance were subjected to 2 hour oral glucose tolerance test (OGTT). 24 subjects had normal glucose tolerance (NGT), 17 subjects had impaired glucose tolerance (IGT) and 9 had impaired fasting glucose (IFG). The IGT and IFG subjects were grouped together as pre-diabetes group (n = 26). Progenitor cell counts in peripheral circulation at fasting and 2 hour post glucose challenge were measured using direct two-color flow cytometry.Results: The pre-diabetes group was more insulin resistant (p < 0.0001) as measured by homeostasis assessment model (HOMA-IR) compared to NGT group. A 2.5-fold increase in CD34+ cells (p = 0.003) and CD133+CD34+ (p = 0.019) cells was seen 2 hours post glucose challenge in the NGT group. This increase for both the cell types was attenuated in subjects with IGT. CD34+ cell counts in response to glucose challenge inversely correlated with neutrophil counts (ρ = -0.330, p = 0.019), while post load counts of CD133+CD34+ cells inversely correlated with serum creatinine (ρ = -0.312, p = 0.023).Conclusion: There is a 2.5-fold increase in the circulating levels of haematopoietic stem cells in response to glucose challenge in healthy Asian Indian male subjects which is attenuated in subjects with pre-diabetes. © 2011 Nathan et al; licensee BioMed Central Ltd. - PublicationHyperinsulinemia-induced vascular smooth muscle cell (VSMC) migration and proliferation is mediated by converging mechanisms of mitochondrial dysfunction and oxidative stress(01-01-2013)
;Abhijit, Shiny ;Bhaskaran, Regin ;Narayanasamy, Abirami ;Chakroborty, Anand ;Manickam, Nagaraj; ;Mohan, ViswanathanBalasubramanyam, MuthuswamyAtherosclerosis is one of the major complications of diabetes and involves endothelial dysfunction, matrix alteration, and most importantly migration and proliferation of vascular smooth muscle cells (VSMCs). Although hyperglycemia and hyperinsulinemia are known to contribute to atherosclerosis, little is known about the specific cellular signaling pathways that mediate the detrimental hyperinsulinemic effects in VSMCs. Therefore, we investigated the cellular mechanisms of hyperinsulinemia-induced migration and proliferation of VSMCs. VSMCs were treated with insulin (100 nM) for 6 days and subjected to various physiological and molecular investigations. VSMCs subjected to hyperinsulinemia exhibited increased migration and proliferation, and this is paralleled by oxidative stress [increased NADPH oxidase activity, NADPH oxidase 1 mRNA expression, and reactive oxygen species (ROS) generation], alterations in mitochondrial physiology (membrane depolarization, decreased mitochondrial mass, and increased mitochondrial ROS), changes in mitochondrial biogenesis-related genes (mitofusin 1, mitofusin 2, dynamin-related protein 1, peroxisome proliferator-activated receptor gamma coactivator 1-alpha, peroxisome proliferator-activated receptor gamma coactivator 1-beta, nuclear respiratory factor 1, and uncoupling protein 2), and increased Akt phosphorylation. Diphenyleneiodonium, a known NADPH oxidase inhibitor significantly inhibited migration and proliferation of VSMCs and normalized all the above physiological and molecular perturbations. This study suggests a plausible crosstalk between mitochondrial dysfunction and oxidative stress under hyperinsulinemia and emphasizes counteracting mitochondrial dysfunction and oxidative stress as a novel therapeutic strategy for atherosclerosis. © 2012 Springer Science+Business Media New York. - PublicationGlucose-induced increase in circulating progenitor cells is blunted in polycystic amenorrhoeic subjects(01-01-2012)
;Bairagi, Soumi ;Gopal, Jayashree ;Nathan, Abel A. ;Babu, Subash S. ;Kumar, N. PavanBackground Glucose-induced kinetics of bone marrow-derived stem cells in healthy females is presently unknown. The objectives of this study were to determine whether circulating levels of CD133, CD34 and CD133CD34 cells increase in response to glucose load in healthy females and whether the kinetics is altered in amenorrhoeic women. The other objective of the work was to compare the endothelial differentiation potential of peripheral blood-derived endothelial progenitor cells (EPCs) from healthy versus amenorrhoeic women.Methods In this casecontrol study, 44 amenorrhoeic subjects and 36 age-matched females with no menstrual disturbance were recruited at Apollo Hospitals, a Tertiary health care center in Chennai, India. Circulating bone marrow-derived stem cells were measured by two color direct flow cytometry. Cultured progenitor cells were characterized at Day 7 and 14 for expression of endothelial markers and production of nitric oxide (NO) via immunofluoroscence. Results The amenorrhoeic subjects were insulin resistant with homeostatic model of assessment of insulin resistance values of 3.33 ± 0.3 versus 1.75 ± 0.148 observed for controls (P< 0.0001). Among the amenorrhoeic subjects, 38 subjects had polycystic ovaries with no signs of hyperandrogenism. Fasting levels of CD133, CD34 and CD133CD34 cells were reduced in amenorrhoeic subjects (P< 0.001). There was a 1.5 to 2-fold increase in the circulating levels of these cells in response to 75 g oral glucose challenge at 1 and 2 h post-load conditions in controls, which was significantly blunted for CD133 (P< 0.001) and CD133CD34 (P< 0.001) cells in amenorrhoeic subjects. A positive correlation was observed between estrogen and fasting CD133 (r 0.205, P 0.070), CD34 (r 0.249, P 0.027) and CD133CD34 (r 0.217, P 0.055) cell counts. Additionally, fasting counts for CD34 and CD133CD34 cells positively correlated with FSH and inversely correlated with LH and C-peptide in the polycystic group. Cultured cells from polycystic subjects exhibited reduced adherence to fibronectin and expressed lower levels of endothelial nitric-oxide synthase and NO. Conclusions Oral glucose-induced increase in circulating numbers of CD133 and CD133CD34 cells and endothelial differentiation potential of peripheral blood-derived EPCs is attenuated in insulin resistant amenorrhoeic subjects. © 2012 The Author. - PublicationAstaxanthin inhibits JAK/STAT-3 signaling to abrogate cell proliferation, invasion and angiogenesis in a hamster model of oral cancer(08-10-2014)
;Kowshik, J. ;Baba, Abdul Basit ;Giri, Hemant ;Reddy, G. Deepak; Nagini, SiddavaramIdentifying agents that inhibit STAT-3, a cytosolic transcription factor involved in the activation of various genes implicated in tumour progression is a promising strategy for cancer chemoprevention. In the present study, we investigated the effect of dietary astaxanthin on JAK-2/STAT-3 signaling in the 7,12-dimethylbenz[a]anthracene (DMBA)-induced hamster buccal pouch (HBP) carcinogenesis model by examining the mRNA and protein expression of JAK/STAT-3 and its target genes. Quantitative RT-PCR, immunoblotting and immunohistochemical analyses revealed that astaxanthin supplementation inhibits key events in JAK/STAT signaling especially STAT-3 phosphorylation and subsequent nuclear translocation of STAT- 3. Furthermore, astaxanthin downregulated the expression of STAT-3 target genes involved in cell proliferation, invasion and angiogenesis, and reduced microvascular density, thereby preventing tumour progression. Molecular docking analysis confirmed inhibitory effects of astaxanthin on STAT signaling and angiogenesis. Cell culture experiments with the endothelial cell line ECV304 substantiated the role of astaxanthin in suppressing angiogenesis. Taken together, our data provide substantial evidence that dietary astaxanthin prevents the development and progression of HBP carcinomas through the inhibition of JAK-2/STAT-3 signaling and its downstream events. Thus, astaxanthin that functions as a potent inhibitor of tumour development and progression by targeting JAK/STAT signaling may be an ideal candidate for cancer chemoprevention. - PublicationEffect of fermentation parameters, elicitors and precursors on camptothecin production from the endophyte Fusarium solani(01-04-2016)
;Venugopalan, Aarthi ;Potunuru, Uma Rani; Volumetric productivity of camptothecin from the suspension culture of the endophyte Fusarium solani was enhanced up to ~152 fold (from 0.19 μg l-1 d-1 to 28.9 μg l-1 d-1) under optimized fermentation conditions including initial pH (6.0), temperature (32 °C) and agitation speed (80 rpm) with (5% (v/v)) ethanol as medium component. Among various elicitors and precursors studied, tryptamine (0.5 mM) as precursor and bovine serum albumin (BSA) (0.075 mM) as an elicitor added on day 6 of the cultivation period resulted in maximum enhancement of camptothecin concentration (up to 4.5 and 3.4-fold, respectively). These leads provide immense scope for further enhancement in camptothecin productivity at bioreactor level. The cytotoxicity analysis of the crude camptothecin extract from the fungal biomass revealed its high effectiveness against colon and mammary gland cancer cell lines.
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