30 results on '"Nikunj, Sharma"'
Search Results
2. Diatoms Biotechnology: Various Industrial Applications for a Greener Tomorrow
- Author
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Nikunj Sharma, Daris Pazhukkunnel Simon, Aracely Maribel Diaz-Garza, Elisa Fantino, Anis Messaabi, Fatma Meddeb-Mouelhi, Hugo Germain, and Isabel Desgagné-Penix
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diatoms ,microalgae biotechnology ,metabolic engineering ,metabarcoding ,sustainable economy ,biofuel ,Science ,General. Including nature conservation, geographical distribution ,QH1-199.5 - Abstract
The benefits of the complex microscopic and industrially important group of microalgae such as diatoms is not hidden and have lately surprised the scientific community with their industrial potential. The ability to survive in harsh conditions and the presence of different pore structures and defined cell walls have made diatoms ideal cell machinery to produce a variety of industrial products. The prospect of using a diatom cell for industrial application has increased significantly in synch with the advances in microscopy, metabarcoding, analytical and genetic tools. Furthermore, it is well noted that the approach of industry and academia to the use of genetic tools has changed significantly, resulting in a well-defined characterization of various molecular components of diatoms. It is possible to conduct the primary culturing, harvesting, and further downstream processing of diatom culture in a cost-effective manner. Diatoms hold all the qualities to become the alternative raw material for pharmaceutical, nanotechnology, and energy sources leading to a sustainable economy. In this review, an attempt has been made to gather important progress in the different industrial applications of diatoms such as biotechnology, biomedical, nanotechnology, and environmental technologies.
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- 2021
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3. Challenges and Opportunities Associated with Food and Agricultural Waste Management Across the Globe
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Drishti Kadian, Syed Mansha Rafiq, Nikunj Sharma, Syed Insha Rafiq, Syed Anam Ul Haq, R. M. Shukla, Faizan Masoudi, and Insha Nazir
- Published
- 2023
4. Red Light Variation an Effective Alternative to Regulate Biomass and Lipid Profiles in Phaeodactylum tricornutum
- Author
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Nikunj Sharma, Gabriel Fleurent, Fatima Awwad, Michael Cheng, Fatma Meddeb-Mouelhi, Suzanne M. Budge, Hugo Germain, and Isabel Desgagné-Penix
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light shift ,Phaeodactylum tricornutum ,biomass ,microalgae ,lipids ,autotrophy ,Technology ,Engineering (General). Civil engineering (General) ,TA1-2040 ,Biology (General) ,QH301-705.5 ,Physics ,QC1-999 ,Chemistry ,QD1-999 - Abstract
Marine water diatom Phaeodactylum tricornutum is a photosynthetic organism that is known to respond to the changing light environment and adapt to different temperatures to prevent photoinhibition and maintain its metabolic functions. The objective of the present study was to test whether light shift variations in different growth phases impact the growth and lipid metabolism of P. tricornutum. Thus, we investigated R exposure in different growth phases to find the most effective light shift condition. The results showed that substituting white light (W) by red light (R) under autotrophic conditions, a condition called red shift (RS), increased biomass and lipid content compared to levels found under continuous W or R exposure alone. We observed an increase by 2-fold biomass and 2.3-fold lipid content in RS as compared to W. No significant change was observed in the morphology of lipid droplets, but the fatty acid (FA) composition was altered. Specifically, polyunsaturated FAs were increased, whereas monounsaturated FAs decreased in P. tricornutum grown in RS compared to W control. Therefore, we propose that a light shift during the beginning of the stationary phase is a low-cost cultivation strategy to boost the total biomass and lipids in P. tricornutum.
- Published
- 2020
- Full Text
- View/download PDF
5. Myeloid Krüppel-like factor 2 is a critical regulator of metabolic inflammation
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Nikunj Sharma, David R Sweet, Panjamaporn Sangwung, Yoichi Takami, Neelakantan T Vasudevan, Anthony Wynshaw-Boris, Paul Holvoet, Yuan Lu, Liyan Fan, Xudong Liao, Stanton L. Gerson, E. Ricky Chan, Chen Fu, Chloe E Booth, Vinesh Vinayachandran, Guangjin Zhou, Lilei Zhang, Keiichiro Matoba, Yulan Qing, Komal S Keerthy, Mukesh K. Jain, Lalitha Nayak, and Derin Tugal
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0301 basic medicine ,Central Nervous System ,Male ,Myeloid ,Regulator ,General Physics and Astronomy ,Eating ,Mice ,0302 clinical medicine ,Myeloid Cells ,lcsh:Science ,Mice, Knockout ,INSULIN-RESISTANCE ,Multidisciplinary ,KLF2 ,Type 2 diabetes ,Metabolic syndrome ,Multidisciplinary Sciences ,medicine.anatomical_structure ,OBESITY ,Knockout mouse ,Science & Technology - Other Topics ,medicine.symptom ,EXPRESSION ,Science ,Kruppel-Like Transcription Factors ,Inflammation ,Diet, High-Fat ,General Biochemistry, Genetics and Molecular Biology ,Article ,03 medical and health sciences ,Insulin resistance ,Immune system ,Metabolic Diseases ,Peripheral Nervous System ,medicine ,Animals ,Humans ,Obesity ,Science & Technology ,business.industry ,General Chemistry ,medicine.disease ,030104 developmental biology ,Cancer research ,lcsh:Q ,JNK ,Insulin Resistance ,business ,030217 neurology & neurosurgery ,Microglial cells - Abstract
Substantial evidence implicates crosstalk between metabolic tissues and the immune system in the inception and progression of obesity. However, molecular regulators that orchestrate metaflammation both centrally and peripherally remains incompletely understood. Here, we identify myeloid Krüppel-like factor 2 (KLF2) as an essential regulator of obesity and its sequelae. In mice and humans, consumption of a fatty diet downregulates myeloid KLF2 levels. Under basal conditions, myeloid-specific KLF2 knockout mice (K2KO) exhibit increased feeding and weight gain. High-fat diet (HFD) feeding further exacerbates the K2KO metabolic disease phenotype. Mechanistically, loss of myeloid KLF2 increases metaflammation in peripheral and central tissues. A combination of pair-feeding, bone marrow-transplant, and microglial ablation implicate central and peripheral contributions to K2KO-induced metabolic dysfunction observed. Finally, overexpression of myeloid KLF2 protects mice from HFD-induced obesity and insulin resistance. Together, these data establish myeloid KLF2 as a nodal regulator of central and peripheral metabolic inflammation in homeostasis and disease., Inflammation contributes to the development of metabolic disease through incompletely understood mechanisms. Here the authors report that deletion of the transcription factor KLF2 in myeloid cells leads to increased feeding and weight gain in mice with concomitant peripheral and central tissue inflammation, while overexpression protects against diet-induced metabolic disease.
- Published
- 2020
6. Food Spoilage and Safety
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Sourav Garg, Syed Mansha Rafiq, G Balaji, Sristi Mundhada, Syed Insha Rafiq, and Nikunj Sharma
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- 2022
7. The SNARE Protein Syntaxin 3 Confers Specificity for Polarized Axonal Trafficking in Neurons.
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Linda Soo Hoo, Chris D Banna, Carolyn M Radeke, Nikunj Sharma, Mary E Albertolle, Seng Hui Low, Thomas Weimbs, and Carol A Vandenberg
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Medicine ,Science - Abstract
Cell polarity and precise subcellular protein localization are pivotal to neuronal function. The SNARE machinery underlies intracellular membrane fusion events, but its role in neuronal polarity and selective protein targeting remain unclear. Here we report that syntaxin 3 is involved in orchestrating polarized trafficking in cultured rat hippocampal neurons. We show that syntaxin 3 localizes to the axonal plasma membrane, particularly to axonal tips, whereas syntaxin 4 localizes to the somatodendritic plasma membrane. Disruption of a conserved N-terminal targeting motif, which causes mislocalization of syntaxin 3, results in coincident mistargeting of the axonal cargos neuron-glia cell adhesion molecule (NgCAM) and neurexin, but not transferrin receptor, a somatodendritic cargo. Similarly, RNAi-mediated knockdown of endogenous syntaxin 3 leads to partial mistargeting of NgCAM, demonstrating that syntaxin 3 plays an important role in its targeting. Additionally, overexpression of syntaxin 3 results in increased axonal growth. Our findings suggest an important role for syntaxin 3 in maintaining neuronal polarity and in the critical task of selective trafficking of membrane protein to axons.
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- 2016
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8. Cattle urine increases lipid content in Chlorella pyrenoidosa: A low cost medium for bioenergy application
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Nikunj Sharma and Monika Prakash Rai (India)
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Environmental sciences ,GE1-350 - Published
- 2015
9. S27 of IFNα1 Contributes to Its Low Affinity for IFNAR2 and Weak Antiviral Activity
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Ronald L. Rabin, Nikunj Sharma, Saurav Misra, Alexey Khalenkov, Erisa Gjinaj, Anya J O'Neal, Lisa M. Parsons, Christian Gonzalez, Dorothy E. Scott, Megen Wittling, and Debasis Panda
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Models, Molecular ,0301 basic medicine ,Dimer ,Immunology ,Interferon-alpha ,Microbial Sensitivity Tests ,Receptor, Interferon alpha-beta ,Vesiculovirus ,Cell Biology ,03 medical and health sciences ,chemistry.chemical_compound ,030104 developmental biology ,0302 clinical medicine ,Low affinity ,chemistry ,030220 oncology & carcinogenesis ,Virology ,Serine ,Tumor Cells, Cultured ,Biophysics ,Humans ,Stat signaling ,Hydrophobic and Hydrophilic Interactions ,Ternary complex - Abstract
Type I interferons (IFNs) signal by forming a high affinity IFN-IFNAR2 dimer, which subsequently recruits IFNAR1 to form a ternary complex that initiates JAK/STAT signaling. Among the 12 IFNα subtypes, IFNα1 has a uniquely low affinity for IFNAR2 (100 × of the other IFNα subtypes) and commensurately weak antiviral activity, suggesting an undefined function distinct from suppression of viral infections. Also unique in IFNα1 is substitution of a serine for phenylalanine at position 27, a contact point that stabilizes the IFNα:IFNAR2 hydrophobic interface. To determine whether IFNα1-S27 contributes to the low affinity for IFNAR2, we created an IFNα1 mutein, IFNα1-S27F, and compared it to wild-type IFNα1 and IFNα2. Substitution of phenylalanine for serine increased affinity for IFNAR2 ∼4-fold and commensurately enhanced activation of STAT1, STAT3, and STAT5, transcription of a subset of interferon stimulated genes, and restriction of vesicular stomatitis virus infection
- Published
- 2019
10. Basolateral sorting of syntaxin 4 is dependent on its N-terminal domain and the AP1B clathrin adaptor, and required for the epithelial cell polarity.
- Author
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Elena Reales, Nikunj Sharma, Seng Hui Low, Heike Fölsch, and Thomas Weimbs
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Medicine ,Science - Abstract
Generation of epithelial cell polarity requires mechanisms to sort plasma membrane proteins to the apical and basolateral domains. Sorting involves incorporation into specific vesicular carriers and subsequent fusion to the correct target membranes mediated by specific SNARE proteins. In polarized epithelial cells, the SNARE protein syntaxin 4 localizes exclusively to the basolateral plasma membrane and plays an important role in basolateral trafficking pathways. However, the mechanism of basolateral targeting of syntaxin 4 itself has remained poorly understood. Here we show that newly synthesized syntaxin 4 is directly targeted to the basolateral plasma membrane in polarized Madin-Darby canine kidney (MDCK) cells. Basolateral targeting depends on a signal that is centered around residues 24-29 in the N-terminal domain of syntaxin 4. Furthermore, basolateral targeting of syntaxin 4 is dependent on the epithelial cell-specific clathrin adaptor AP1B. Disruption of the basolateral targeting signal of syntaxin 4 leads to non-polarized delivery to both the apical and basolateral surface, as well as partial intercellular retention in the trans-Golgi network. Importantly, disruption of the basolateral targeting signal of syntaxin 4 leads to the inability of MDCK cells to establish a polarized morphology which suggests that restriction of syntaxin 4 to the basolateral domain is required for epithelial cell polarity.
- Published
- 2011
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11. SUN-LB019 Myeloid Krüppel-like Factor 2 is a Critical Regulator of Metabolic Inflammation
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Liyan Fan, David R Sweet, Yoichi Takami, Panjamaporn Sangwung, E. Ricky Chan, Lilei Zhang, Nikunj Sharma, Chen Fu, Keiichiro Matoba, Mukesh K. Jain, Neelakantan T Vasudevan, Yuan Lu, Paul Holvoet, Anthony Wynshaw-Boris, Lalitha Nayak, and Derin Tugal
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Myeloid ,medicine.anatomical_structure ,Metabolic inflammation ,Adipose Tissue, Appetite, and Obesity ,Krüppel ,Endocrinology, Diabetes and Metabolism ,medicine ,Cancer research ,Regulator ,Impact of Obesity on Metabolic Target Organs ,Biology - Abstract
Substantial evidence implicates crosstalk between metabolic tissues and the immune system, both centrally and peripherally, in the inception and progression of obesity. Nodal factors that orchestrate systemic “metaflammation” remain very incompletely understood. Here, we identify myeloid Krüppel-like factor 2 (KLF2) as an essential regulator of obesity and its sequelae. Macrophages with KLF2 deletion enrich transcriptional networks associated with metabolic syndrome. In mice and humans, consumption of a fatty diet is associated with downregulation of KLF2 in myeloid cells. Mice with myeloid specific deletion of KLF2 (K2KO) exhibited basal metabolic disturbances including increased feeding contributing to rapid weight gain. Stimulating K2KO mice with metaflammatory stress (high fat diet) caused genotype-dependent increases in insulin resistance and non-alcoholic steatohepatitis. Mechanistically, loss of myeloid KLF2 increased metaflammation in peripheral (white adipose, liver) and central (hypothalamus) metabolic tissues, demonstrating the widespread regulation that KLF2 poses on metabolic homeostasis. This regulation occurs, in part, through KLF2’s attenuation of inflammasome activation, a major pathogenic mechanism of metabolic disease. Critically, overexpression of KLF2 in the myeloid compartment protected mice from long-term HFD-induced obesity and insulin resistance. Together, these data establish myeloid KLF2 as a decisive regulator of central and peripheral metabolic inflammation in homeostasis and disease. Funding: This work was funded by the American Heart Association and National Institutes of Health from the NHLBI and NIGMS. Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. Abstracts presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.
- Published
- 2019
12. Red Light Variation an Effective Alternative to Regulate Biomass and Lipid Profiles in Phaeodactylum tricornutum
- Author
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Suzanne M. Budge, Isabel Desgagné-Penix, Michael Cheng, Fatma Meddeb-Mouelhi, Hugo Germain, Nikunj Sharma, Fatima Awwad, and Gabriel Fleurent
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0106 biological sciences ,Photoinhibition ,light shift ,Biomass ,lcsh:Technology ,01 natural sciences ,lcsh:Chemistry ,lipids ,03 medical and health sciences ,Lipid droplet ,General Materials Science ,Phaeodactylum tricornutum ,Food science ,Autotroph ,lcsh:QH301-705.5 ,Instrumentation ,metabolites ,030304 developmental biology ,Fluid Flow and Transfer Processes ,chemistry.chemical_classification ,0303 health sciences ,biomass ,biology ,lcsh:T ,microalgae ,Process Chemistry and Technology ,General Engineering ,Fatty acid ,Lipid metabolism ,biology.organism_classification ,lcsh:QC1-999 ,Computer Science Applications ,lcsh:Biology (General) ,lcsh:QD1-999 ,chemistry ,lcsh:TA1-2040 ,autotrophy ,Composition (visual arts) ,lcsh:Engineering (General). Civil engineering (General) ,lcsh:Physics ,010606 plant biology & botany - Abstract
Marine water diatom Phaeodactylum tricornutum is a photosynthetic organism that is known to respond to the changing light environment and adapt to different temperatures to prevent photoinhibition and maintain its metabolic functions. The objective of the present study was to test whether light shift variations in different growth phases impact the growth and lipid metabolism of P. tricornutum. Thus, we investigated R exposure in different growth phases to find the most effective light shift condition. The results showed that substituting white light (W) by red light (R) under autotrophic conditions, a condition called red shift (RS), increased biomass and lipid content compared to levels found under continuous W or R exposure alone. We observed an increase by 2-fold biomass and 2.3-fold lipid content in RS as compared to W. No significant change was observed in the morphology of lipid droplets, but the fatty acid (FA) composition was altered. Specifically, polyunsaturated FAs were increased, whereas monounsaturated FAs decreased in P. tricornutum grown in RS compared to W control. Therefore, we propose that a light shift during the beginning of the stationary phase is a low-cost cultivation strategy to boost the total biomass and lipids in P. tricornutum.
- Published
- 2020
13. Effect of Salinity, pH, Light Intensity on Growth and Lipid Production of Microalgae for Bioenergy Application
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Monika Prakash Rai, Nikunj Sharma, and Trishnamoni Gautom
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Biodiesel ,biology ,food and beverages ,Biomass ,biology.organism_classification ,General Biochemistry, Genetics and Molecular Biology ,Salinity ,Chlorella ,Light intensity ,Biofuel ,Bioenergy ,Biodiesel production ,Botany ,Food science ,General Agricultural and Biological Sciences - Abstract
The crisis of energy producing molecules (fuels) is expected to increase in future, which is currently produced from crude mineral oil. Biodiesel is most reliable, non-toxic, biocompatible liquid fuel that can replace the existing unsustainable sources of energy. Among all the known sources, microalgae display high potential for the production of biodiesel owing to their numerous benefits like higher biomass productivities than plants, no agricultural land requirement, cultivation in waste water and accumulation of 20-50% triacylglycerols. Microalgae biomass and lipid content plays an important role in commercial production of biodiesel. The present work was carried out to develop an axenic culture of a potential microalga Chlorella sp. for high biomass and enhanced lipid accumulation. The important growth parameters like pH, light colour, light intensity and photoperiod were studied for better production of Chlorella biomass. The effect of salinity on cell growth was also studied and compared with normal Fogg’s medium grown cells. The main biomolecules like carbohydrate, protein, lipid and chlorophyll content were also estimated with the help of standard biochemical methods in salt supplemented and without salt Fogg’s medium. The cellular lipid content was increased by growing the cells under different salt concentrations. The micro algal strain showed highest growth of 0.822 g L-1 and 1.021g L-1 in Fogg’s medium and under 0.2 M NaCl supplemented medium respectively. However, the maximum lipid production of 0.1842 g L-1 was estimated by growing the cells in Fogg’s medium including 0.5 M NaCl with slight compromise in cell growth (0.858 g L-1). The lipid content of Chlorella sp. was found to be 26.84% as compared to 14% obtained under normal culture condition. Thus, growing Chlorella sp. under salt supplemented medium and optimizing light requirement will produce high biomass and oil for biodiesel production.
- Published
- 2015
14. Phycoremediation of municipal wastewater by microalgae to produce biofuel
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Shashi Kumar, Nikunj Sharma, Malik Zainul Abdin, Amit Singh, Thomas Mock, and Humaira Farooqi
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Environmental remediation ,020209 energy ,Biomass ,02 engineering and technology ,Plant Science ,Chlorella ,010501 environmental sciences ,Wastewater ,complex mixtures ,01 natural sciences ,Nutrient ,Botany ,0202 electrical engineering, electronic engineering, information engineering ,Microalgae ,Environmental Chemistry ,0105 earth and related environmental sciences ,biology ,food and beverages ,biology.organism_classification ,Pulp and paper industry ,Pollution ,Biodegradation, Environmental ,Biofuel ,Biodiesel production ,Biofuels ,Environmental science ,Eutrophication - Abstract
Municipal wastewater (WW), if not properly remediated, poses a threat to the environment and human health by carrying significant loads of nutrients and pathogens. These contaminants pollute rivers, lakes, and natural reservoirs where they cause eutrophication and pathogen-mediated diseases. However, the high nutrient content of WW makes it an ideal environment for remediation with microalgae that require high nutrient concentrations for growth and are not susceptible to toxins and pathogens. Given that an appropriate algal strain is used for remediation, the incurred biomass can be refined for the production of biofuel. Four microalgal species (Chlamydomonas reinhardtii, Chlorella sp., Parachlorella kessleri-I, and Nannochloropsis gaditana) were screened for efficient phycoremediation of municipal WW and potential use for biodiesel production. Among the four strains tested, P. kessleri-I showed the highest growth rate and biomass production in 100% WW. It efficiently removed all major nutrients with a removal rate of up to 98% for phosphate after 10 days of growth in 100% municipal WW collected from Delhi. The growth of P. kessleri-I in WW resulted in a 50% increase of biomass and a 115% increase of lipid yield in comparison to growth in control media. The Fatty acid methyl ester (FAME), and fuel properties of lipids isolated from cells grown in WW complied with international standards. The present study provides evidence that the green alga P. kessleri-I effectively remediates municipal WW and can be used to produce biodiesel.
- Published
- 2017
15. Potential Applications of Antioxidants from Algae in Human Health
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Anwesha Khanra, Monika Prakash Rai, and Nikunj Sharma
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0301 basic medicine ,chemistry.chemical_classification ,Reactive oxygen species ,biology ,business.industry ,Glutathione ,Disease ,medicine.disease_cause ,Bioinformatics ,Malondialdehyde ,Biotechnology ,Superoxide dismutase ,03 medical and health sciences ,chemistry.chemical_compound ,030104 developmental biology ,0302 clinical medicine ,chemistry ,Ageing ,030220 oncology & carcinogenesis ,biology.protein ,medicine ,business ,Reactive nitrogen species ,Oxidative stress - Abstract
Ageing is a very complex process that leads to various physiological changes due to multiple environmental and lifestyle changes. Initially it is harmless as our body is trained to tackle all these small damages, but it does not have the potential to handle these impacts for infinite period. Oxidative stress and production of reactive oxygen species (ROS) and reactive nitrogen species (RNS) are the major reasons for various age-related disorders such as neurodegenerative disorders, types of cancers and diabetes (Collier et al. 1990; Boynes 1991). Oxidative stress plays a significant function in their pathogenesis, and this may bring about certain changes in the oxidative stress biomarkers such as malondialdehyde (MDA), superoxide dismutase (SOD), glutathione, etc. These biomarkers are excellent tool that can be used as an indicator to analyse the pathological or control conditions. Different biomarkers have varied characteristics according to disease state, disease trait and rate of the disease. As per global ageing index, approximately 22% of the total population will be 60+, i.e. 2031 million (http://www.helpage.org/global-agewatch/population-ageing-data/global-ageing-data/). This will have a huge impact on healthcare and needed infrastructure cost (http://www.nia.nih.gov/sites/default/files/global_health_and_aging.pdf).
- Published
- 2017
16. Kruppel-Like Factor 2 Is a Transcriptional Regulator of Chronic and Acute Inflammation
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Yoichi Takami, Nikunj Sharma, Mukesh K. Jain, Ganapati H. Mahabeleshwar, Lalitha Nayak, Parul Kapil, and Lediana Goduni
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Lipopolysaccharides ,Myeloid ,Transcription, Genetic ,Kruppel-Like Transcription Factors ,Regulator ,Inflammation ,Biology ,Carrageenan ,Cell Line ,Proinflammatory cytokine ,Pathology and Forensic Medicine ,Mice ,Sepsis ,medicine ,Transcriptional regulation ,Animals ,Edema ,Humans ,Skin ,Hemizygote ,Innate immune system ,NF-kappa B ,Regular Article ,NFKB1 ,Disease Models, Animal ,medicine.anatomical_structure ,Gene Expression Regulation ,Acute Disease ,Chronic Disease ,KLF2 ,Immunology ,Disease Progression ,medicine.symptom - Abstract
Although myeloid cell activation is requisite for an optimal innate immune response, this process must be tightly controlled to prevent collateral host tissue damage. Kruppel-like factor 2 (KLF2) is a potent regulator of myeloid cell proinflammatory activation. As an approximately 30% to 50% reduction in KLF2 levels has been observed in human subjects with acute or chronic inflammatory disorders, we studied the biological response to inflammation in KLF2(+/-) mice. Herein, we show that partial deficiency of KLF2 modulates the in vivo response to acute (sepsis) and subacute (skin) inflammatory challenge. Mechanistically, we link the anti-inflammatory effects of KLF2 to the inhibition of NF-κB transcriptional activity. Collectively, the observations provide biologically relevant insights into KLF2-mediated modulation of these inflammatory processes that could potentially be manipulated for therapeutic gain.
- Published
- 2013
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17. Syntaxins 3 and 4 Are Concentrated in Separate Clusters on the Plasma Membrane before the Establishment of Cell Polarity
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Jayasri Nanduri, Min He, Amit Vasanji, Judith A. Drazba, Seng Hui Low, Nikunj Sharma, Thomas Weimbs, and Michelle Koo
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endocrine system ,Vesicle fusion ,Syntaxin 1 ,Biology ,Caveolae ,Microtubules ,environment and public health ,Exocytosis ,Cell Line ,Jurkat Cells ,Mice ,Dogs ,Cell polarity ,Animals ,Humans ,Syntaxin ,Qc-SNARE Proteins ,Molecular Biology ,Sequence Deletion ,Qa-SNARE Proteins ,urogenital system ,Cell Membrane ,Cell Polarity ,Lipid bilayer fusion ,Coated Pits, Cell-Membrane ,Articles ,Cell Biology ,Basolateral plasma membrane ,Fibroblasts ,Qb-SNARE Proteins ,Actins ,Syntaxin 3 ,Cell biology ,Cholesterol ,nervous system ,biological phenomena, cell phenomena, and immunity - Abstract
Syntaxins 3 and 4 localize to the apical and basolateral plasma membrane, respectively, of epithelial cells where they mediate vesicle fusion. Here, we report that before establishment of cell polarity, syntaxins 3 and 4 are confined to mutually exclusive, submicron-sized clusters. Syntaxin clusters are remarkably uniform in size, independent of expression levels, and are distinct from caveolae and clathrin-coated pits. SNAP-23 partially colocalizes with both syntaxin 3 and 4 clusters. Deletion of the apical targeting signal of syntaxin 3 does not prevent sorting into clusters away from syntaxin 4. Syntaxin 3 and 4 cluster formation depends on different mechanisms because the integrity of syntaxin 3 clusters depends on intact microtubules, whereas syntaxin 4 clusters depend on intact actin filaments. Cholesterol depletion causes dispersion of syntaxin 3 but not syntaxin 4 clusters. In migrating cells, syntaxin clusters polarize to the leading edge, suggesting a role in polarized exocytosis. These results suggest that exocytosis occurs at small fusion sites exhibiting high local concentrations of SNARE proteins that may be required for efficient membrane fusion. The establishment of separate clusters for each syntaxin suggests that the plasma membrane is inherently polarized on an ultrastructural level even before the establishment of true cell polarity.
- Published
- 2006
18. Apical targeting of syntaxin 3 is essential for epithelial cell polarity
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Thomas Weimbs, Nikunj Sharma, Bhattaram Pallavi, Seng Hui Low, and Saurav Misra
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Munc18 Proteins ,endocrine system ,Amino Acid Motifs ,Syntaxin 1 ,Biology ,environment and public health ,Cell Membrane Structures ,Article ,03 medical and health sciences ,0302 clinical medicine ,Dogs ,Cell polarity ,Animals ,Research Articles ,Cells, Cultured ,030304 developmental biology ,Epithelial polarity ,0303 health sciences ,urogenital system ,Qa-SNARE Proteins ,Cell Polarity ,Epithelial Cells ,Cell Biology ,Apical membrane ,Syntaxin 3 ,Transport protein ,Cell biology ,Protein Transport ,Membrane protein ,nervous system ,Mutation ,biological phenomena, cell phenomena, and immunity ,SNARE Proteins ,030217 neurology & neurosurgery - Abstract
In polarized epithelial cells, syntaxin 3 localizes to the apical plasma membrane and is involved in membrane fusion of apical trafficking pathways. We show that syntaxin 3 contains a necessary and sufficient apical targeting signal centered around a conserved FMDE motif. Mutation of any of three critical residues within this motif leads to loss of specific apical targeting. Modeling based on the known structure of syntaxin 1 revealed that these residues are exposed on the surface of a three-helix bundle. Syntaxin 3 targeting does not require binding to Munc18b. Instead, syntaxin 3 recruits Munc18b to the plasma membrane. Expression of mislocalized mutant syntaxin 3 in Madin-Darby canine kidney cells leads to basolateral mistargeting of apical membrane proteins, disturbance of tight junction formation, and loss of ability to form an organized polarized epithelium. These results indicate that SNARE proteins contribute to the overall specificity of membrane trafficking in vivo, and that the polarity of syntaxin 3 is essential for epithelial cell polarization.
- Published
- 2006
19. Awareness to action through multi-channel advocacy for effective tobacco control in India: a case study from Bihar
- Author
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Amit, Yadav, Sanjay, Kumar, Manjusha, Chaterjee, Nikunj, Sharma, Radhika, Shrivastav, Abhinav, Bassi, Deepak, Mishra, and Monika, Arora
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Tobacco Use ,Capacity Building ,Law Enforcement ,Health Policy ,Humans ,India ,Health Promotion ,Mass Media ,Program Development ,Public-Private Sector Partnerships ,Needs Assessment - Abstract
Developing a synergistic relationship between the government machinery and civil society is crucial for advancing the tobacco control movement in India. With diverse patterns of tobacco use and far reach of the tobacco industry, stringent enforcement mechanisms along with innovative and culturally appropriate advocacy efforts are imperative. In this paper, we evaluate multi- level tobacco control interventions undertaken in the Indian state of Bihar and the subsequent success achieved in strengthening government-non-government partnerships and commitment towards tobacco control in the state. Our experience shows that sustained advocacy at the policy and grassroots levels, along with willingness of the administrative machinery, can present result- oriented tobacco control initiatives at the state and grassroots levels.
- Published
- 2014
20. PP024 YOUTH FOR HEALTH: TOWARDS A TOBACCO FREE WORLD
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Nikunj Sharma, Monika Arora, and Radhika Shrivastav
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Pulmonary and Respiratory Medicine ,Health promotion ,business.industry ,Environmental health ,Medicine ,Free world ,business - Published
- 2013
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21. The SNARE Protein Syntaxin 3 Confers Specificity for Polarized Axonal Trafficking in Neurons
- Author
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Chris D. Banna, Linda Soo Hoo, Nikunj Sharma, Seng Hui Low, Carol A. Vandenberg, Thomas Weimbs, Carolyn M. Radeke, Mary E. Albertolle, and Donaldson, Julie G
- Subjects
0301 basic medicine ,Cell Membranes ,Neurexin ,lcsh:Medicine ,medicine.disease_cause ,Membrane Fusion ,Mechanical Treatment of Specimens ,environment and public health ,Nerve Fibers ,0302 clinical medicine ,Animal Cells ,Cell polarity ,Protein targeting ,lcsh:Science ,Neurons ,Multidisciplinary ,Chemistry ,Cell adhesion molecule ,Protein subcellular localization prediction ,Cell biology ,Specimen Disruption ,Cellular Types ,Cellular Structures and Organelles ,biological phenomena, cell phenomena, and immunity ,Research Article ,endocrine system ,General Science & Technology ,1.1 Normal biological development and functioning ,Vesicle Fusion ,Research and Analysis Methods ,03 medical and health sciences ,Underpinning research ,medicine ,Vesicles ,urogenital system ,lcsh:R ,Neurosciences ,Biology and Life Sciences ,Membrane Proteins ,Lipid bilayer fusion ,Cell Biology ,Neuronal Dendrites ,Axons ,Syntaxin 3 ,030104 developmental biology ,nervous system ,Membrane protein ,Specimen Preparation and Treatment ,Cellular Neuroscience ,lcsh:Q ,Generic health relevance ,030217 neurology & neurosurgery ,Neuroscience - Abstract
Cell polarity and precise subcellular protein localization are pivotal to neuronal function. The SNARE machinery underlies intracellular membrane fusion events, but its role in neuronal polarity and selective protein targeting remain unclear. Here we report that syntaxin 3 is involved in orchestrating polarized trafficking in cultured rat hippocampal neurons. We show that syntaxin 3 localizes to the axonal plasma membrane, particularly to axonal tips, whereas syntaxin 4 localizes to the somatodendritic plasma membrane. Disruption of a conserved N-terminal targeting motif, which causes mislocalization of syntaxin 3, results in coincident mistargeting of the axonal cargos neuron-glia cell adhesion molecule (NgCAM) and neurexin, but not transferrin receptor, a somatodendritic cargo. Similarly, RNAi-mediated knockdown of endogenous syntaxin 3 leads to partial mistargeting of NgCAM, demonstrating that syntaxin 3 plays an important role in its targeting. Additionally, overexpression of syntaxin 3 results in increased axonal growth. Our findings suggest an important role for syntaxin 3 in maintaining neuronal polarity and in the critical task of selective trafficking of membrane protein to axons.
- Published
- 2016
22. Myeloid Krüppel-like factor 4 deficiency augments atherogenesis in ApoE-/- mice--brief report
- Author
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Jonathan S. Stamler, Mukesh K. Jain, Xudong Liao, Guangjin Zhou, Nikunj Sharma, Yuan Lu, Parul Kapil, Ganapati H. Mahabeleshwar, and Puneet Anand
- Subjects
Myeloid ,Macrophage polarization ,Kruppel-Like Transcription Factors ,Inflammation ,Biology ,Article ,Pathogenesis ,Kruppel-Like Factor 4 ,Mice ,Apolipoproteins E ,Transcriptional regulation ,medicine ,Macrophage ,Animals ,Mice, Knockout ,Macrophages ,Atherosclerosis ,Disease Models, Animal ,medicine.anatomical_structure ,Phenotype ,KLF4 ,Immunology ,medicine.symptom ,Cardiology and Cardiovascular Medicine ,Platelet factor 4 ,Foam Cells - Abstract
Objective— To investigate the role of Krüppel-like factor 4 (KLF4), an essential transcriptional regulator of macrophage polarization (M1/M2), in the pathogenesis of atherosclerosis. Methods and Results— Despite the acknowledged importance of macrophages in atherosclerosis, the role of M1 (classically activated or proinflammatory) versus M2 (alternatively activated or anti-inflammatory) macrophages in this process remains incompletely understood. We recently identified KLF4 as a regulator of macrophage subset specification; that is, KLF4 promotes M2 and inhibits M1 phenotype. Here, we provide evidence that KLF4-deficient macrophages exhibit enhanced proinflammatory activation and foam cell formation in response to oxidized lipids. In vivo, myeloid KLF4-deficient mice (ApoE −/− background) develop significantly more vascular inflammation and atherosclerotic lesion formation. Conclusion— Our findings identify myeloid KLF4 as an essential regulator of vascular inflammation and experimental atherogenesis.
- Published
- 2012
23. Endothelial Kruppel-like factor 4 protects against atherothrombosis in mice
- Author
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Mukesh K. Jain, Alvin H. Schmaier, Yunmei Wang, Lalitha Nayak, Hong Shi, Anne Hamik, Lauren M Boerboom, Andrew T. Hale, Xudong Liao, Brett R. Blackman, Yuan Lu, Ryan E. Feaver, Daniel I. Simon, Huiyun Gao, Amar Desai, Guangjin Zhou, G. Brandon Atkins, Stanton L. Gerson, Hongmei Tian, and Nikunj Sharma
- Subjects
Vasculitis ,Endothelium ,Kruppel-Like Transcription Factors ,Mice, Transgenic ,P300-CBP Transcription Factors ,Biology ,Proinflammatory cytokine ,Kruppel-Like Factor 4 ,Mice ,Coactivator ,medicine ,Human Umbilical Vein Endothelial Cells ,Animals ,Humans ,Protein Interaction Domains and Motifs ,p300-CBP Transcription Factors ,Endothelial dysfunction ,Cells, Cultured ,Brief Report ,Thrombosis ,General Medicine ,medicine.disease ,Atherosclerosis ,Cell biology ,Vascular endothelial growth factor B ,Mice, Inbred C57BL ,Vascular endothelial growth factor A ,medicine.anatomical_structure ,Vascular endothelial growth factor C ,Gene Expression Regulation ,Immunology ,Protein Binding - Abstract
The endothelium regulates vascular homeostasis, and endothelial dysfunction is a proximate event in the pathogenesis of atherothrombosis. Stimulation of the endothelium with proinflammatory cytokines or exposure to hemodynamic-induced disturbed flow leads to a proadhesive and prothrombotic phenotype that promotes atherothrombosis. In contrast, exposure to arterial laminar flow induces a gene program that confers a largely antiadhesive, antithrombotic effect. The molecular basis for this differential effect on endothelial function remains poorly understood. While recent insights implicate Kruppel-like factors (KLFs) as important regulators of vascular homeostasis, the in vivo role of these factors in endothelial biology remains unproven. Here, we show that endothelial KLF4 is an essential determinant of atherogenesis and thrombosis. Using in vivo EC-specific KLF4 overexpression and knockdown murine models, we found that KLF4 induced an antiadhesive, antithrombotic state. Mechanistically, we demonstrated that KLF4 differentially regulated pertinent endothelial targets via competition for the coactivator p300. These observations provide cogent evidence implicating endothelial KLFs as essential in vivo regulators of vascular function in the adult animal.
- Published
- 2012
24. Circadian rhythms govern cardiac repolarization and arrhythmogenesis
- Author
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Juergen Ripperger, Kun Hu, Saptarsi M. Haldar, Eckhard Ficker, Betty L. Eapen, Xiaoping Wan, Xander H.T. Wehrens, Yuan Lu, Mark McCauley, Sophie Demolombe, Atsushi Sanbe, James Gulick, Jeffrey M. Robbins, Nikunj Sharma, Steven Shea, Michael J. Cutler, Urs Albrecht, Mukesh K. Jain, David S. Rosenbaum, Roman V. Kondratov, and Darwin Jeyaraj
- Subjects
Male ,medicine.medical_specialty ,Time Factors ,Cardiac rhythmicity ,Heart disease ,Heart Ventricles ,Kruppel-Like Transcription Factors ,030204 cardiovascular system & hematology ,Biology ,Sudden cardiac death ,Electrocardiography ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Heart Conduction System ,Heart Rate ,Internal medicine ,medicine ,Animals ,Repolarization ,Circadian rhythm ,cardiovascular diseases ,Promoter Regions, Genetic ,Cells, Cultured ,030304 developmental biology ,Muscle Cells ,0303 health sciences ,Multidisciplinary ,medicine.diagnostic_test ,Arrhythmias, Cardiac ,Kv Channel-Interacting Proteins ,medicine.disease ,Circadian Rhythm ,Rats ,DNA-Binding Proteins ,Mice, Inbred C57BL ,Death, Sudden, Cardiac ,Endocrinology ,Gene Expression Regulation ,Heart failure ,Cardiology ,cardiovascular system ,Electrical conduction system of the heart ,Transcription Factors - Abstract
Sudden cardiac death exhibits diurnal variation in both acquired and hereditary forms of heart disease, but the molecular basis of this variation is unknown. A common mechanism that underlies susceptibility to ventricular arrhythmias is abnormalities in the duration (for example, short or long QT syndromes and heart failure) or pattern (for example, Brugada’s syndrome)6 of myocardial repolarization. Here we provide molecular evidence that links circadian rhythms to vulnerability in ventricular arrhythmias in mice. Specifically, we show that cardiac ion-channel expression and QT-interval duration (an index of myocardial repolarization) exhibit endogenous circadian rhythmicity under the control of a clock-dependent oscillator, krüppel-like factor 15 (Klf15). Klf15 transcriptionally controls rhythmic expression of Kv channel- interacting protein 2 (KChIP2), a critical subunit required for generating the transient outward potassium current. Deficiency or excess of Klf15 causes loss of rhythmic QT variation, abnormal repolarization and enhanced susceptibility to ventricular arrhythmias. These findings identify circadian transcription of ion channels as a mechanism for cardiac arrhythmogenesis.
- Published
- 2012
25. Basolateral sorting of syntaxin 4 is dependent on its N-terminal domain and the AP1B clathrin adaptor, and required for the epithelial cell polarity
- Author
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Nikunj Sharma, Heike Fölsch, Elena Reales, Thomas Weimbs, and Seng Hui Low
- Subjects
lcsh:Medicine ,Biochemistry ,Clathrin ,Transmembrane Transport Proteins ,03 medical and health sciences ,Dogs ,0302 clinical medicine ,Molecular Cell Biology ,Animals ,lcsh:Science ,Biology ,030304 developmental biology ,Epithelial polarity ,0303 health sciences ,Multidisciplinary ,biology ,Qa-SNARE Proteins ,urogenital system ,Cell Membrane ,lcsh:R ,Proteins ,Cell Polarity ,Epithelial Cells ,Basolateral plasma membrane ,Syntaxin 3 ,Syntaxin 4 ,Cell biology ,Adaptor Proteins, Vesicular Transport ,Membrane ,Membrane protein ,nervous system ,Cytochemistry ,biology.protein ,Membranes and Sorting ,lcsh:Q ,biological phenomena, cell phenomena, and immunity ,030217 neurology & neurosurgery ,Intracellular ,Research Article ,Signal Transduction - Abstract
Generation of epithelial cell polarity requires mechanisms to sort plasma membrane proteins to the apical and basolateral domains. Sorting involves incorporation into specific vesicular carriers and subsequent fusion to the correct target membranes mediated by specific SNARE proteins. In polarized epithelial cells, the SNARE protein syntaxin 4 localizes exclusively to the basolateral plasma membrane and plays an important role in basolateral trafficking pathways. However, the mechanism of basolateral targeting of syntaxin 4 itself has remained poorly understood. Here we show that newly synthesized syntaxin 4 is directly targeted to the basolateral plasma membrane in polarized Madin-Darby canine kidney (MDCK) cells. Basolateral targeting depends on a signal that is centered around residues 24-29 in the N-terminal domain of syntaxin 4. Furthermore, basolateral targeting of syntaxin 4 is dependent on the epithelial cell-specific clathrin adaptor AP1B. Disruption of the basolateral targeting signal of syntaxin 4 leads to non-polarized delivery to both the apical and basolateral surface, as well as partial intercellular retention in the trans-Golgi network. Importantly, disruption of the basolateral targeting signal of syntaxin 4 leads to the inability of MDCK cells to establish a polarized morphology which suggests that restriction of syntaxin 4 to the basolateral domain is required for epithelial cell polarity.
- Published
- 2011
26. Krüppel-like factor 4 regulates macrophage polarization
- Author
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Xudong Liao, Anne Hamik, Fehmida Kapadia, Elise Dalmas, Nikunj Sharma, Bryan Doreian, Guangjin Zhou, Karine Clément, Kurt Q. Lu, Klaus H. Kaestner, Julian A Kim, Mukesh K. Jain, Christopher A Flask, Yuan Lu, Hong Hong, Kaavya Paruchuri, Ganapati H. Mahabeleshwar, and Nicolas Venteclef
- Subjects
Lipopolysaccharides ,Macrophage polarization ,Regulator ,Kruppel-Like Transcription Factors ,Gene Expression ,Inflammation ,Biology ,Proinflammatory cytokine ,Cell Line ,Kruppel-Like Factor 4 ,Mice ,medicine ,Escherichia coli ,Macrophage ,Animals ,Humans ,Obesity ,Macrophage inflammatory protein ,Mice, Knockout ,Wound Healing ,Macrophages ,NF-kappa B ,Cell Polarity ,General Medicine ,Macrophage Activation ,NFKB1 ,Cell biology ,Adipose Tissue ,KLF4 ,Immunology ,medicine.symptom ,Insulin Resistance ,STAT6 Transcription Factor ,Research Article - Abstract
Current paradigms suggest that two macrophage subsets, termed M1 and M2, are involved in inflammation and host defense. While the distinct functions of M1 and M2 macrophages have been intensively studied - the former are considered proinflammatory and the latter antiinflammatory - the determinants of their speciation are incompletely understood. Here we report our studies that identify Kruppel-like factor 4 (KLF4) as a critical regulator of macrophage polarization. Macrophage KLF4 expression was robustly induced in M2 macrophages and strongly reduced in M1 macrophages, observations that were recapitulated in human inflammatory paradigms in vivo. Mechanistically, KLF4 was found to cooperate with Stat6 to induce an M2 genetic program and inhibit M1 targets via sequestration of coactivators required for NF-κB activation. KLF4-deficient macrophages demonstrated increased proinflammatory gene expression, enhanced bactericidal activity, and altered metabolism. Furthermore, mice bearing myeloid-specific deletion of KLF4 exhibited delayed wound healing and were predisposed to developing diet-induced obesity, glucose intolerance, and insulin resistance. Collectively, these data identify KLF4 as what we believe to be a novel regulator of macrophage polarization.
- Published
- 2010
27. Polycystin-1, STAT6, and P100 function in a pathway that transduces ciliary mechanosensation and is activated in polycystic kidney disease
- Author
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Claire H. Larson, Shivakumar Vasanth, Tomoko Obara, Sambuddho Mukherjee, Seng Hui Low, Nikunj Sharma, Michelle E. Kane, Michael Kinter, and Thomas Weimbs
- Subjects
Embryo, Nonmammalian ,HUMDISEASE ,Fluorescent Antibody Technique ,Gene Expression ,urologic and male genital diseases ,Kidney ,Mechanotransduction, Cellular ,Epithelium ,Translocation, Genetic ,0302 clinical medicine ,Gene expression ,Polycystic kidney disease ,Luciferases ,Zebrafish ,STAT6 ,Polycystin-1 ,0303 health sciences ,integumentary system ,Cilium ,Nuclear Proteins ,respiratory system ,Polycystic Kidney, Autosomal Dominant ,Cell biology ,SIGNALING ,Protein Binding ,endocrine system ,medicine.medical_specialty ,TRPP Cation Channels ,Blotting, Western ,Biology ,Transfection ,Models, Biological ,General Biochemistry, Genetics and Molecular Biology ,Cell Line ,03 medical and health sciences ,Internal medicine ,parasitic diseases ,Coactivator ,medicine ,Animals ,Humans ,Immunoprecipitation ,Amino Acid Sequence ,Cilia ,Transcription factor ,Molecular Biology ,030304 developmental biology ,Mechanosensation ,Dose-Response Relationship, Drug ,Proteins ,Cell Biology ,medicine.disease ,Blotting, Northern ,Embryo, Mammalian ,Endonucleases ,Protein Structure, Tertiary ,Enzyme Activation ,Endocrinology ,Gene Expression Regulation ,Mutagenesis ,Trans-Activators ,Interleukin-4 ,STAT6 Transcription Factor ,030217 neurology & neurosurgery ,Developmental Biology - Abstract
SummaryPrimary cilia are implicated in the pathogenesis of autosomal-dominant polycystic kidney disease (ADPKD), which results from defects in polycystin-1 (PC1), but the function of PC1 remains poorly understood. Here, we show that PC1 undergoes proteolytic cleavage that results in nuclear translocation of its cytoplasmic tail. The PC1 tail interacts with the transcription factor STAT6 and the coactivator P100, and it stimulates STAT6-dependent gene expression. Under normal conditions, STAT6 localizes to primary cilia of renal epithelial cells. Cessation of apical fluid flow results in nuclear translocation of STAT6. Cyst-lining cells in ADPKD exhibit elevated levels of nuclear STAT6, P100, and the PC1 tail. Exogenous expression of the human PC1 tail results in renal cyst formation in zebrafish embryos. These results identify a novel mechanism of cilia function in the transduction of a mechanical signal to changes of gene expression involving PC1 and show that this pathway is inappropriately activated in ADPKD.
- Published
- 2005
28. O064 Mobilizing Youth for a Tobacco-Free Society: NMT 21C (No More Tobacco in the 21st Century)
- Author
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Amit Yadav, Monika Arora, Radhika Shrivastav, K. Srinath Reddy, Manjusha Chatterjee, and Nikunj Sharma
- Subjects
Community and Home Care ,Economic growth ,Epidemiology ,business.industry ,Environmental health ,Medicine ,Cardiology and Cardiovascular Medicine ,business - Published
- 2014
29. PT314 Motivating Indian youth to embrace walking – the Ground Miles Challenge
- Author
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Monika Arora, Radhika Shrivastav, Ima Chopra, Nikunj Sharma, Manjusha Chatterjee, and Prerna Bharadwaj
- Subjects
Community and Home Care ,Epidemiology ,business.industry ,Medicine ,Public relations ,Cardiology and Cardiovascular Medicine ,business ,Simulation - Published
- 2014
30. The Myeloid Transcription Factor KLF2 Regulates the Host Response to Polymicrobial Infection and Endotoxic Shock
- Author
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Nikunj Sharma, Thomas J. Ryan, Hector R. Wong, Yoichi Takami, Robert Grealy, Ganapati H. Mahabeleshwar, Lalitha Nayak, Jerry B. Lingrel, Daiji Kawanami, Patrick Leahy, Saptarsi M. Haldar, G. Brandon Atkins, Hong Shi, Zhiyong Lin, Ross McManus, Darwin Jeyaraj, Guangjin Zhou, Mary C. White, and Mukesh K. Jain
- Subjects
Lipopolysaccharides ,Male ,Myeloid ,Immunology ,Regulator ,Kruppel-Like Transcription Factors ,Inflammation ,Mice, Transgenic ,Biology ,Article ,Cell Line ,Mice ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Animals ,Immunology and Allergy ,Myeloid Cells ,Transcription factor ,030304 developmental biology ,0303 health sciences ,Innate immune system ,NF-kappa B ,Bacterial Infections ,NFKB1 ,Hypoxia-Inducible Factor 1, alpha Subunit ,Shock, Septic ,Immunity, Innate ,3. Good health ,medicine.anatomical_structure ,Infectious Diseases ,030220 oncology & carcinogenesis ,KLF2 ,Cancer research ,Female ,medicine.symptom ,IRF8 ,030215 immunology - Abstract
SummaryPrecise control of myeloid cell activation is required for optimal host defense. However, this activation process must be under exquisite control to prevent uncontrolled inflammation. Herein, we identify the Kruppel-like transcription factor 2 (KLF2) as a potent regulator of myeloid cell activation in vivo. Exposure of myeloid cells to hypoxia and/or bacterial products reduced KLF2 expression while inducing hypoxia inducible factor-1α (HIF-1α), findings that were recapitulated in human septic patients. Myeloid KLF2 was found to be a potent inhibitor of nuclear factor-kappaB (NF-κB)-dependent HIF-1α transcription and, consequently, a critical determinant of outcome in models of polymicrobial infection and endotoxemia. Collectively, these observations identify KLF2 as a tonic repressor of myeloid cell activation in vivo and an essential regulator of the innate immune system.
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