13 results on '"Dharanibalan, Kasiviswanathan"'
Search Results
2. Proteasome gene expression is controlled by the coordinated functions of multiple transcription factors
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Jennifer E. Gilda, Asrafun Nahar, Dharanibalan Kasiviswanathan, Nadav Tropp, Tamar Gilinski, Tamar Lahav, Yael Mandel-Gutfreund, Soyeon Park, and Shenhav Cohen
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Article - Abstract
SUMMARYProteasome activity is crucial for cellular integrity, but how tissues adjust proteasome content in response to catabolic stimuli is uncertain. Here, we demonstrate that transcriptional coordination by multiple transcription factors is required to increase proteasome content and activate proteolysis in catabolic states. Using denervated mouse muscle as a model system for accelerated proteolysisin vivo, we reveal that a two-phase transcriptional program activates genes encoding proteasome subunits and assembly chaperones to boost an increase in proteasome content. Initially, gene induction is necessary to maintain basal proteasome levels, and in a more delayed phase (7-10 d after denervation) it stimulates proteasome assembly to meet cellular demand for excessive proteolysis. Intriguingly, the transcription factors PAX4 and α-PALNRF-1control the expression of proteasome among other genes in a combinatorial manner, driving cellular adaptation to muscle denervation. Consequently, PAX4 and α-PALNRF-1represent new therapeutic targets to inhibit proteolysis in catabolic diseases (e.g. type-2 diabetes, cancer).
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- 2023
3. Biodiversity of the Adipocyte-Derived Hormone, Leptin
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Dharanibalan Kasiviswanathan, Reji Manjunathan, and Jayaraman Selvaraj
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chemistry.chemical_compound ,medicine.medical_specialty ,Endocrinology ,chemistry ,Leptin ,Adipocyte ,Internal medicine ,digestive, oral, and skin physiology ,medicine ,Biodiversity ,Biology ,hormones, hormone substitutes, and hormone antagonists ,Hormone - Abstract
The adipocyte derived hormone leptin is known for its pivotal role in the regulation of a variety of physiological functions mainly associated with metabolism and energy homeostasis. One of the major functions of leptin is pertain with its angiogenic induction in support of organ development as well as under pathological conditions such as atherosclerosis and cancer. Leptin is a well-known pro-angiogenic growth factor which exerts its role through Ob-R receptor present on endothelial cells. The therapeutic application of leptin is based on its potential to maintain various functions at pathological conditions. In this book chapter, the multi-diversity potentials of leptin are discussed in detail.
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- 2022
4. Insulin receptor turnover in fasting is dependent on NAGLU-mediated β-dystroglycan deglycosylation
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Sunu Joseph, Sewar Zbidat, Alexandra Volodin, Dharanibalan Kasiviswanathan, Adina I. Fried, Andrea Armani, Jennifer E. Gilda, and Shenhav Cohen
- Abstract
Fasting exerts various physiological effects, most notably, reduced signaling through the insulin receptor. We showed that insulin receptor activity requires association with Dystrophin Glycoprotein Complex (DGC). Here, we demonstrate that insulin receptor turnover by lysosomes during fasting is dependent on deglycosylation of the principal DGC component, β-dystroglycan. We show that the lysosomal enzymes HexA and Man2b1, which specifically remove N-linked glycans, promote β-dystroglycan deglycosylation and consequently insulin receptor-DGC loss. Surprisingly, the lysosomal enzyme NAGLU, which cannot process N-linked glycosylation, also facilitated β-dystroglycan deglycosylation and insulin receptor loss. NAGLU enhances the activity of the transcriptional complex PPAR-γ/RXR-α, which in turn promotes Man2b1 and HexA induction and the resulting β-dystroglycan deglycosylation. Accordingly, downregulation of HexA, Man2b1, NAGLU or RXR-α during fasting blocked β-dystroglycan deglycosylation, and caused accumulation of insulin receptor-DGC assemblies on the membrane. Thus, NAGLU mediates physiological adaptation to fasting by promoting β-dystroglycan deglycosylation.
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- 2022
5. Dietary flavonoid myricetin inhibits invasion and migration of radioresistant lung cancer cells (A549‐IR) by suppressing MMP‐2 and MMP‐9 expressions through inhibition of the FAK‐ERK signaling pathway
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Moonjae Cho, Somi Kim Cho, Jeong Y. Moon, Meran Keshawa Ediriweera, Dharanibalan Kasiviswanathan, Yeon Woo Song, and Hye Rim Kang
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0301 basic medicine ,myricetin ,transcriptome analysis ,FAK signaling pathway ,MMP‐2 and 9 ,Vimentin ,lcsh:TX341-641 ,Focal adhesion ,Transcriptome ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Radioresistance ,Original Research ,A549 cell ,biology ,Chemistry ,respiratory system ,Cell biology ,respiratory tract diseases ,030104 developmental biology ,030220 oncology & carcinogenesis ,biology.protein ,Phosphorylation ,Myricetin ,Signal transduction ,lcsh:Nutrition. Foods and food supply ,Food Science - Abstract
Myricetin is a commonly found dietary flavonoid. In the present study, we investigated the effects of myricetin on migration and invasion of radioresistant lung cancer cells (A549‐IR). Transcriptome analysis of A549‐IR cells identified several differentially expressed genes (DEGs) in A549‐IR cells compared to parental A549 cells. Functional enrichment analysis revealed that most of the DEGs were linked with PI3K‐AKT signaling, proteoglycans, focal adhesion, and ECM–receptor interactions. A549‐IR cells demonstrated enhanced migratory potential with increased expression of vimentin, snail and slug, and reduced expression of E‐cadherin. A549‐IR cells exposed to myricetin displayed reduced migration and suppressed MMP‐2 and MMP‐9 expression. Notably, myricetin inhibited the phosphorylation of focal adhesion kinase (FAK) and altered the F‐actin/G‐actin ratio in A549‐IR cells, without modulation of EMT markers. These findings suggest that myricetin can inhibit migration of A549‐IR cells by suppressing MMP‐2 and MMP‐9 expressions through inhibition of the FAK‐ERK signaling pathway., Transcriptome analysis of radioresistant lung cancer cells (A549‐IR) identified several differentially expressed genes compared to A549 parental cells. Myricetin inhibited invasion and migration of A549‐IR cells by reducing the expression of matrix metalloproteinases (MMP‐2 and MMP‐9) through inhibition of the FAK‐ERK signaling pathway.
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- 2020
6. Human Recombinant Leptin Shows Dose and Time-Dependent Release of Nitric Oxide from Endothelial Nitric Oxide Synthase in Endothelium While on Angiogenesis
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Malathi Ragunathan, Akila Swaminathan, Swaraj Sinha, Reji Manjunathan, Suvro Chatterjee, and Dharanibalan Kasiviswanathan
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chemistry.chemical_compound ,medicine.anatomical_structure ,Endothelium ,Endothelial nitric oxide synthase ,Chemistry ,law ,Angiogenesis ,Leptin ,medicine ,Recombinant DNA ,Pharmacology ,law.invention ,Nitric oxide - Abstract
Nitric Oxide (NO) modulates various assortments of the angiogenic process. The endogenous hormone leptin is able to induce different physiological process such as angiogenesis at low concentration because of its high receptor specific affinity. Various studies speculated leptin’s ability to induce endothelium‐dependent vascular relaxation by stimulating NO through different signaling pathways. So far, no studies have reported the dose and time dependent potential of human recombinant leptin on NO release. Hence, an attempt has been made to understand the optimal concentration and time of incubation of human recombinant leptin for the enzymatic release of NO from endothelial Nitric Oxide Synthase (eNOS). Leptin induced changes in the localization and phosphorylation pattern of eNOS in cultured endothelium under various concentrations and time of incubation is studied. The 5 Nanomolar concentration of human recombinant leptin within 6 minutes of incubation could induce significant levels of NO from the activated eNOS in cultured endothelium through plasma membrane localization and phosphorylation of eNOS. Our findings suggest that human recombinant leptin can modulate NO-dependent new therapeutic avenue for angiogenesis-related disorders such as wound healing if used within the active concentration and time of incubation.
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- 2021
7. Thalidomide and Its Analogs Differentially Target Fibroblast Growth Factor Receptors: Thalidomide Suppresses FGFR Gene Expression while Pomalidomide Dampens FGFR2 Activity
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Jeganathan Manivannan, Uma Maheswari Balaguru, Sharmila Anishetty, Suvro Chatterjee, Vimal Veeriah, Dharanibalan Kasiviswanathan, Lakshmikirupa Sundaresan, and Pavitra Kumar
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animal structures ,Cell Survival ,Chick Embryo ,010501 environmental sciences ,Biology ,Toxicology ,01 natural sciences ,Transcriptome ,Structure-Activity Relationship ,03 medical and health sciences ,medicine ,Animals ,Humans ,E2F1 ,Kinase activity ,Protein Kinase Inhibitors ,Transcription factor ,Cells, Cultured ,030304 developmental biology ,0105 earth and related environmental sciences ,0303 health sciences ,Dose-Response Relationship, Drug ,Molecular Structure ,Gene Expression Profiling ,Fibroblast growth factor receptor 1 ,General Medicine ,Pomalidomide ,Receptors, Fibroblast Growth Factor ,Thalidomide ,Molecular Docking Simulation ,Fibroblast growth factor receptor ,embryonic structures ,Cancer research ,Chickens ,medicine.drug - Abstract
Thalidomide is an infamous teratogen and it is continuously being explored for its anticancer properties. Fibroblast growth factor receptors (FGFRs) are implicated in embryo development and cancer pathophysiology. With striking similarities observed between FGFR implicated conditions and thalidomide embryopathy, we hypothesized thalidomide targets FGFRs. We utilized three different cell lines and chicken embryo model to investigate the effects of thalidomide and analogs on FGFR expression. We performed molecular docking, KINOMEscan analysis, and kinase activity assays to study the drug-protein interactions. The expression of FGFR1 and FGFR2 was differentially regulated by all the three drugs in cells as well as in developing organs. Transcriptome analysis of thalidomide-treated chick embryo strongly suggests the modulation of FGFR signaling and key transcription factors. Corroboration with previous studies suggests that thalidomide might affect FGFR expression through the transcription factor, E2F1. At the protein level, molecular docking predicted all three analogs to interact with lysine residue at 517th and 508th positions of FGFR2 and FGFR3, respectively. This lysine coordinates the ATP binding site of FGFR, thus hinting at the possible perturbation of FGFR activity by thalidomide. Kinome analysis revealed that kinase activities of FGFR2 and FGFR3 (G697C) reduced by 31% and 65%, respectively, in the presence of 10 μM thalidomide. Further, we checked and confirmed that the analogs inhibited the FGFR2 kinase activity in a dose-dependent manner. This study suggests that FGFRs could be potential targets of thalidomide and the two analogs, and also endorses the link between the teratogenicity and antitumor activities of the drugs.
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- 2019
8. Interactome of miRNAs and transcriptome of human umbilical cord endothelial cells exposed to short-term simulated microgravity
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Lakshmikirupa Sundaresan, Manuel Philip, Srinivasan Bhuvaneswari, Rajadurai Chinnasamy Perumal, Suvro Chatterjee, Pavitra Kumar, Dharanibalan Kasiviswanathan, and Sajesh Puthenpurackal Krishnankutty
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0301 basic medicine ,Physics and Astronomy (miscellaneous) ,Angiogenesis ,lcsh:Biotechnology ,Materials Science (miscellaneous) ,Medicine (miscellaneous) ,Biology ,Biochemistry, Genetics and Molecular Biology (miscellaneous) ,Interactome ,Article ,lcsh:Physiology ,Transcriptome ,Databases ,03 medical and health sciences ,0302 clinical medicine ,Downregulation and upregulation ,lcsh:TP248.13-248.65 ,microRNA ,Molecular medicine ,lcsh:QP1-981 ,Cell growth ,Translational research ,Cell cycle ,Agricultural and Biological Sciences (miscellaneous) ,Cell biology ,body regions ,030104 developmental biology ,Space and Planetary Science ,030220 oncology & carcinogenesis ,embryonic structures ,Clinostat - Abstract
Adaptation of humans in low gravity conditions is a matter of utmost importance when efforts are on to a gigantic leap in human space expeditions for tourism and formation of space colonies. In this connection, cardiovascular adaptation in low gravity is a critical component of human space exploration. Deep high-throughput sequencing approach allowed us to analyze the miRNA and mRNA expression profiles in human umbilical cord vein endothelial cells (HUVEC), cultured under gravity (G), and stimulated microgravity (MG) achieved with a clinostat. The present study identified totally 1870 miRNAs differentially expressed in HUVEC under MG condition when compared to the cells subjected to unitary G conditions. The functional association of identified miRNAs targeting specific mRNAs revealed that miRNAs, hsa-mir-496, hsa-mir-151a, hsa-miR-296-3p, hsa-mir-148a, hsa-miR-365b-5p, hsa-miR-3687, hsa-mir-454, hsa-miR-155-5p, and hsa-miR-145-5p differentially regulated the genes involved in cell adhesion, angiogenesis, cell cycle, JAK-STAT signaling, MAPK signaling, nitric oxide signaling, VEGF signaling, and wound healing pathways. Further, the q-PCR based experimental studies of upregulated and downregulated miRNA and mRNAs demonstrate that the above reported miRNAs influence the cell proliferation and vascular functions of the HUVEC in MG conditions effectively. Consensus on the interactome results indicates restricted fluctuations in the transcriptome of the HUVEC exposed to short-term MG that could lead to higher levels of endothelial functions like angiogenesis and vascular patterning.
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- 2020
9. Live Imaging and Analysis of Vasoactive Properties of Drugs Using an in-ovo Chicken Embryo Model: Replacing and Reducing Animal Testing
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Akila Swaminathan, Bandi Sirishakalyani, Dharanibalan Kasiviswanathan, Prasunpriya Nayak, Uma Maheswari Balaguru, Reji Manjunathan, Srinivasan Bhuvaneswari, and Suvro Chatterjee
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0303 health sciences ,animal structures ,Intravital Microscopy ,Calcium channel ,Vasodilator Agents ,Drug Evaluation, Preclinical ,Embryo ,Vasodilation ,Chick Embryo ,Pharmacology ,Biology ,In ovo ,030226 pharmacology & pharmacy ,03 medical and health sciences ,0302 clinical medicine ,Live cell imaging ,Vasoactive ,embryonic structures ,Animals ,Vasoconstrictor Agents ,Animal testing ,Vitelline arteries ,Instrumentation ,030304 developmental biology - Abstract
Vasodilation occurs as a result of the relaxation of the smooth muscle cells present in the walls of blood vessels. Various suitable models are available for the analysis of the vasoactive properties of drugs with therapeutic applications. But all these models have limitations, such as ethical issues and high cost. The purpose of this study is to develop an alternative model for studying the vasoactive properties of drugs using an in-ovo chicken embryo model. In the preliminary experiment, we used a well-known vasoconstrictor (adrenaline) and a vasodilator (spermine NoNoate) in the chick embryo area vasculosa and evaluated their concentration-response curve. Adrenaline (10 µM) and spermine NoNoate (10 µM) were administered in different arteries and veins and different positions of the right vitelline artery of the chick embryo. Results showed the middle of the vessel bed of the right vitelline artery having the best vasoactive effect compared to others. Finally, anti-hypertensive drugs, calcium channel blockers, and NOS agonists were administered in the chick embryo area vasculosa to validate the model. Results demonstrate that the chick embryo area vasculosa can be an alternative, robust, and unique in-ovo model for screening of anti-hypertensive drugs in real time.
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- 2019
10. Nitric oxide regulates intussusceptive-like angiogenesis in wound repair in chicken embryo and transgenic zebrafish models
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Vimalraj, Selvaraj, primary, Pichu, Sivakamasundari, additional, Pankajam, Thyagarajan, additional, Dharanibalan, Kasiviswanathan, additional, Djonov, Valentin, additional, and Chatterjee, Suvro, additional
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- 2019
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11. Hypoxia perturbs endothelium by re-organizing cellular actin architecture: Nitric oxide offers limited protection
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Akila Swaminathan, Uma Maheswari Balaguru, Geetha Suryakumar, Suvro Chatterjee, Gopi K. Kolluru, and Dharanibalan Kasiviswanathan
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0301 basic medicine ,Cell Membrane Permeability ,Endothelium ,Phalloidin ,macromolecular substances ,Chick Embryo ,030204 cardiovascular system & hematology ,Biology ,Nitric Oxide ,Cell Line ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,medicine ,Animals ,Humans ,Cytoskeleton ,Cellular localization ,Actin remodeling ,Endothelial Cells ,Cell Biology ,General Medicine ,Actin cytoskeleton ,Actins ,Cell Hypoxia ,Cell biology ,Endothelial stem cell ,Actin Cytoskeleton ,030104 developmental biology ,medicine.anatomical_structure ,chemistry ,Paracellular transport ,Endothelium, Vascular ,Developmental Biology - Abstract
Exposure to hypoxia causes structural changes in the endothelial cell (EC) monolayer that alter its permeability. There was a report earlier of impairment of nitric oxide (NO) production in endothelium. The intervention of NO in the altered cellular arrangements of actin cytoskeleton in endothelium for rectification of paracellular gaps in endothelium under hypoxia was observed. The present study demonstrates hypoxia inducing paracellular gaps in hypoxia-exposed blood capillaries in chick embryo extravascular model. Phalloidin staining confirmed significant polymerization of actin and unique cellular localization of the F-actin bands under hypoxia treatments. Addition of spermine NONOate (SPNO), a NO donor, or reoxygenation to endothelial monolayer attenuated hypoxia-mediated effects on endothelial permeability with partial recovery of endothelial integrity through actin remodeling. The present study indicates link of hypoxia-induced actin-associated cytoskeletal rearrangements and paracellular gaps in the endothelium with a low NO availability in the hypoxia milieu. The author concludes that NO confers protection against hypoxia-mediated cytoskeletal remodeling and endothelial leakiness.
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- 2017
12. Disturbed flow mediated modulation of shear forces on endothelial plane: A proposed model for studying endothelium around atherosclerotic plaques
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Uma Maheswari Balaguru, Jeganathan Manivannan, Reji Majunathan, Krishna Priya Mani, Lakshmikirupa Sundaresan, Dharanibalan Kasiviswanathan, Saravanakumar Venkatesan, Suvro Chatterjee, and Akila Swaminathan
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0301 basic medicine ,Pathology ,medicine.medical_specialty ,Multidisciplinary ,Endothelium ,business.industry ,Chemistry ,Shear force ,Computational fluid dynamics ,Cell morphology ,Article ,Plaque, Atherosclerotic ,Stress (mechanics) ,03 medical and health sciences ,030104 developmental biology ,medicine.anatomical_structure ,Fluid dynamics ,medicine ,Biophysics ,Shear stress ,Computer Simulation ,Endothelium, Vascular ,Stress, Mechanical ,Current (fluid) ,business - Abstract
Disturbed fluid flow or modulated shear stress is associated with vascular conditions such as atherosclerosis, thrombosis and aneurysm. In vitro simulation of the fluid flow around the plaque micro-environment remains a challenging approach. Currently available models have limitations such as complications in protocols, high cost, incompetence of co-culture and not being suitable for massive expression studies. Hence, the present study aimed to develop a simple, versatile model based on Computational Fluid Dynamics (CFD) simulation. Current observations of CFD have shown the regions of modulated shear stress by the disturbed fluid flow. To execute and validate the model in real sense, cell morphology, cytoskeletal arrangement, cell death, reactive oxygen species (ROS) profile, nitric oxide production and disturbed flow markers under the above condition were assessed. Endothelium at disturbed flow region which had been exposed to low shear stress and swirling flow pattern showed morphological and expression similarities with the pathological disturbed flow environment reported previously. Altogether, the proposed model can serve as a platform to simulate the real time micro-environment of disturbed flow associated with eccentric plaque shapes and the possibilities of studying its downstream events.
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- 2016
13. Harvesting clues from genome wide transcriptome analysis for exploring thalidomide mediated anomalies in eye development of chick embryo: Nitric oxide rectifies the thalidomide mediated anomalies by swinging back the system to normal transcriptome pattern
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Kavitha Sankaranarayanan, Pavitra Kumar, Vimal Veeriah, Priya Dutta, Ravi Gupta, Dharanibalan Kasiviswanathan, Priyadarshan Kathirvel, Suvro Chatterjee, and Lakshmikirupa Sundaresan
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0301 basic medicine ,genetic structures ,Chick Embryo ,Eye ,Nitric Oxide ,Biochemistry ,Transcriptome ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Animals ,Nitric Oxide Donors ,Eye Abnormalities ,Zebrafish ,Cells, Cultured ,Genetics ,biology ,Gene Expression Profiling ,Embryo ,General Medicine ,biology.organism_classification ,eye diseases ,Cell biology ,Thalidomide ,Gene expression profiling ,030104 developmental biology ,embryonic structures ,Eye development ,Retinal metabolic process ,sense organs ,PAX6 ,Chickens ,030217 neurology & neurosurgery ,medicine.drug - Abstract
Thalidomide, the notorious teratogen is known to cause various developmental abnormalities, among which a range of eye deformations are very common. From the clinical point of view, it is necessary to pinpoint the mechanisms of teratogens that tune the gene expression. However, to our knowledge, the molecular basis of eye deformities under thalidomide treatmenthas not been reported so far. Present study focuses on the possible mechanism by which thalidomide affects eye development and the role of Nitric Oxide in recovering thalidomide-mediated anomalies of eye development using chick embryo and zebrafish models with transcriptome analysis. Transcriptome analysis showed that 403 genes were up-regulated and 223 genes were down-regulated significantly in thalidomide pre-treated embryos. 8% of the significantly modulated genes have been implicated in eye development including Pax6, OTX2, Dkk1 and Shh. A wide range of biological process and molecular function was affected by thalidomide exposure. Biological Processes including structural constituent of eye lens and Molecular functions such as visual perception and retinal metabolic process formed strong annotation clustersindicating the adverse effects of thalidomide on eye development and function. Here, we have discussed the whole embryo transcriptome with the expression of PAX6, SOX2, and CRYAAgenes from developing eyes. Our experimental data showing structural and functional aspects includingeye size, lens transparency and optic nerve activity and bioinformatics analyses of transcriptome suggest that NO could partially protect thalidomide treated embryos from its devastating effects on eye development and function.
- Published
- 2015
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