Publications by authors named "Prabha Tiwari"

12 Publications

  • Page 1 of 1

ω3 fatty acid metabolite, 12-hydroxyeicosapentaenoic acid, alleviates contact hypersensitivity by downregulation of CXCL1 and CXCL2 gene expression in keratinocytes via retinoid X receptor α.

FASEB J 2021 Apr;35(4):e21354

Laboratory of Vaccine Materials, Center for Vaccine and Adjuvant Research and Laboratory of Gut Environmental System, National Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN), Osaka, Japan.

ω3 fatty acids show potent bioactivities via conversion into lipid mediators; therefore, metabolism of dietary lipids is a critical determinant in the properties of ω3 fatty acids in the control of allergic inflammatory diseases. However, metabolic progression of ω3 fatty acids in the skin and their roles in the regulation of skin inflammation remains to be clarified. In this study, we found that 12-hydroxyeicosapentaenoic acid (12-HEPE), which is a 12-lipoxygenase metabolite of eicosapentaenoic acid, was the prominent metabolite accumulated in the skin of mice fed ω3 fatty acid-rich linseed oil. Consistently, the gene expression levels of Alox12 and Alox12b, which encode proteins involved in the generation of 12-HEPE, were much higher in the skin than in the other tissues (eg, gut). We also found that the topical application of 12-HEPE inhibited the inflammation associated with contact hypersensitivity by inhibiting neutrophil infiltration into the skin. In human keratinocytes in vitro, 12-HEPE inhibited the expression of two genes encoding neutrophil chemoattractants, CXCL1 and CXCL2, via retinoid X receptor α. Together, the present results demonstrate that the metabolic progression of dietary ω3 fatty acids differs in different organs, and identify 12-HEPE as the dominant ω3 fatty acid metabolite in the skin.
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http://dx.doi.org/10.1096/fj.202001687RDOI Listing
April 2021

17(),18()-epoxyeicosatetraenoic acid generated by cytochrome P450 BM-3 from inhibits the development of contact hypersensitivity via G-protein-coupled receptor 40-mediated neutrophil suppression.

FASEB Bioadv 2020 Jan 24;2(1):59-71. Epub 2019 Dec 24.

Laboratory of Vaccine Materials Center for Vaccine and Adjuvant Research Laboratory of Gut Environmental System National Institutes of Biomedical Innovation Health and Nutrition (NIBIOHN) Osaka Japan.

Dietary intake of ω3 polyunsaturated fatty acids such as eicosapentaenoic acid and docosahexaenoic acid is beneficial for health control. We recently identified 17,18-epoxyeicosatetraenoic acid (17,18-EpETE) as a lipid metabolite endogenously generated from eicosapentaenoic acid that exhibits potent anti-allergic and anti-inflammatory properties. However, chemically synthesized 17,18-EpETE is enantiomeric due to its epoxy group-17(),18()-EpETE and 17(),18()-EpETE. In this study, we demonstrated stereoselective differences of 17(),18()-EpETE and 17(),18()-EpETE in amelioration of skin contact hypersensitivity and found that anti-inflammatory activity was detected in 17(),18()-EpETE, but not in 17(),18()-EpETE. In addition, we found that cytochrome P450 BM-3 derived from stereoselectively converts EPA into 17(),18()-EpETE, which effectively inhibited the development of skin contact hypersensitivity by inhibiting neutrophil migration in a G protein-coupled receptor 40-dependent manner. These results suggest the new availability of a bacterial enzyme to produce a beneficial lipid mediator, 17(),18()-EpETE, in a stereoselective manner. Our findings highlight that bacterial enzymatic conversion of fatty acid is a promising strategy for mass production of bioactive lipid metabolites.
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http://dx.doi.org/10.1096/fba.2019-00061DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6996328PMC
January 2020

Flavonoids sensitize tumor cells to radiation: molecular mechanisms and relevance to cancer radiotherapy.

Int J Radiat Biol 2020 03 2;96(3):360-369. Epub 2019 Dec 2.

Foundation for Education and Research, Ex Bhabha Atomic Research Center, Mumbai, Maharashtra, India.

Radiobiological research continues to focus on finding newer strategies for enhanced killing of tumor cells by ionizing radiation. In recent years, chemotherapeutic drugs have been found to possess the capabilities to sensitize tumor cells without affecting the normal cells. There have been increasing research efforts to identify novel and nontoxic compounds which cause minimal or no harm to normal cells but maximize tumor toxicity response to radiation exposure. Extensive researches on flavonoids that are compounds derived from plants have shown that these have promising abilities as radioprotectors and radiosensitizers. In this review, we examine the role of flavonoids as potential radiosensitizers, review the underlying molecular mechanisms and discuss their potential usefulness in improving cancer radiotherapy. It is emphasized that obtaining a deeper insight into the molecular mechanisms underlying the combined action of flavonoids and ionizing radiation may provide new directions for radiobiological research applicable to the much needed enhanced selective tumor cytotoxicity to treatment agents.
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http://dx.doi.org/10.1080/09553002.2020.1694193DOI Listing
March 2020

Dietary coconut oil ameliorates skin contact hypersensitivity through mead acid production in mice.

Allergy 2019 08 10;74(8):1522-1532. Epub 2019 Apr 10.

Laboratory of Vaccine Materials, Center for Vaccine and Adjuvant Research and Laboratory of Gut Environmental System, National Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN), Ibaraki-city, Osaka, Japan.

Coconut oil is used as a dietary oil worldwide, and its healthy effects are recognized by the fact that coconut oil is easy to digest, helps in weight management, increases healthy cholesterol, and provides instant energy. Although topical application of coconut oil is known to reduce skin infection and inflammation, whether dietary coconut oil has any role in decreasing skin inflammation is unknown. In this study, we showed the impact of dietary coconut oil in allergic skin inflammation by using a mouse model of contact hypersensitivity (CHS). Mice maintained on coconut oil showed amelioration of skin inflammation and increased levels of cis-5, 8, 11-eicosatrienoic acid (mead acid) in serum. Intraperitoneal injection of mead acid inhibited CHS and reduced the number of neutrophils infiltrating to the skin. Detailed mechanistic studies unveiled that mead acid inhibited the directional migration of neutrophils by inhibiting the filamentous actin polymerization and leukotriene B production required for secondary recruitment of neutrophils. Our findings provide valuable insights into the preventive roles of coconut oil and mead acid against skin inflammation, thereby offering attractive therapeutic possibilities.
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http://dx.doi.org/10.1111/all.13762DOI Listing
August 2019

The 17,18-epoxyeicosatetraenoic acid-G protein-coupled receptor 40 axis ameliorates contact hypersensitivity by inhibiting neutrophil mobility in mice and cynomolgus macaques.

J Allergy Clin Immunol 2018 08 27;142(2):470-484.e12. Epub 2017 Dec 27.

Laboratory of Vaccine Materials, Center for Vaccine and Adjuvant Research, and Laboratory of Gut Environmental System, National Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN), Ibaraki, Japan; Department of Microbiology and Immunology, Kobe University Graduate School of Medicine, Kobe, Japan; Division of Mucosal Immunology, Department of Microbiology and Immunology and International Research and Development Center for Mucosal Vaccines, Institute of Medical Science, University of Tokyo, Tokyo, Japan; Graduate School of Medicine, Graduate School of Pharmaceutical Sciences, Graduate School of Dentistry, Osaka University, Suita, Japan. Electronic address:

Background: Metabolites of eicosapentaenoic acid exert various physiologic actions. 17,18-Epoxyeicosatetraenoic acid (17,18-EpETE) is a recently identified new class of antiallergic and anti-inflammatory lipid metabolite of eicosapentaenoic acid, but its effects on skin inflammation and the underlying mechanisms remain to be investigated.

Objective: We evaluated the effectiveness of 17,18-EpETE for control of contact hypersensitivity in mice and cynomolgus macaques. We further sought to reveal underlying mechanisms by identifying the responsible receptor and cellular target of 17,18-EpETE.

Methods: Contact hypersensitivity was induced by topical application of 2,4-dinitrofluorobenzene. Skin inflammation and immune cell populations were analyzed by using flow cytometric, immunohistologic, and quantitative RT-PCR analyses. Neutrophil mobility was examined by means of imaging analysis in vivo and neutrophil culture in vitro. The receptor for 17,18-EpETE was identified by using the TGF-α shedding assay, and the receptor's involvement in the anti-inflammatory effects of 17,18-EpETE was examined by using KO mice and specific inhibitor treatment.

Results: We found that preventive or therapeutic treatment with 17,18-EpETE ameliorated contact hypersensitivity by inhibiting neutrophil mobility in mice and cynomolgus macaques. 17,18-EpETE was recognized by G protein-coupled receptor (GPR) 40 (also known as free fatty acid receptor 1) and inhibited chemoattractant-induced Rac activation and pseudopod formation in neutrophils. Indeed, the antiallergic inflammatory effect of 17,18-EpETE was abolished in the absence or inhibition of GPR40.

Conclusion: 17,18-EpETE inhibits neutrophil mobility through GPR40 activation, which is a potential therapeutic target to control allergic inflammatory diseases.
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http://dx.doi.org/10.1016/j.jaci.2017.09.053DOI Listing
August 2018

Activation-induced cytidine deaminase auto-activates and triggers aberrant gene expression.

FEBS Lett 2013 Aug 29;587(16):2487-92. Epub 2013 Jun 29.

Immuno-Medical Science, Division of Applied Chemistry, Graduate School of Engineering, Osaka University, 2-1 Yamadaoka, Suita, Osaka 565-0871, Japan.

DNA methylation is a well-characterized epigenetic landmark involved in transcriptional regulation; however, mechanisms underlying its regulation remain poorly characterized. Recent studies demonstrate that activation-induced cytidine deaminase (AID) is involved in active DNA demethylation. AID is aberrantly expressed in inflammation-associated cancers and generates point mutations; however, cellular disorders attributed to its demethylation function are largely unexplored. Here we demonstrate that ectopic AID expression perturbs tumor-related gene expression. AID (with Gadd45) activated a methylated paired box gene 5 (Pax5) reporter construct, and induced expression and association of endogenous Pax5 with the AID promoter, suggesting that aberrant AID expression triggers an auto-activation circuit to consolidate self-expression.
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http://dx.doi.org/10.1016/j.febslet.2013.06.028DOI Listing
August 2013

Prediction and experimental validation of a putative non-consensus binding site for transcription factor STAT3 in serum amyloid A gene promoter.

Biochim Biophys Acta 2013 Jun 5;1830(6):3650-5. Epub 2013 Feb 5.

Graduate School of Engineering, Osaka University, Suita, Osaka, Japan.

We previously demonstrated that though the human SAA1 gene shows no typical STAT3 response element (STAT3-RE) in its promoter region, STAT3 and the nuclear factor (NF-κB) p65 first form a complex following interleukin IL-1 and IL-6 (IL-1+6) stimulation, after which STAT3 interacts with a region downstream of the NF-κB RE in the SAA1 promoter. In this study, we employed a computational approach based on indirect read outs of protein-DNA contacts to identify a set of candidates for non-consensus STAT3 transcription factor binding sites (TFBSs). The binding of STAT3 to one of the predicted non-consensus TFBSs was experimentally confirmed through a dual luciferase assay and DNA affinity chromatography. The present study defines a novel STAT3 non-consensus TFBS at nt -75/-66 downstream of the NF-κB RE in the SAA1 promoter region that is required for NF-κB p65 and STAT3 to activate SAA1 transcription in human HepG2 liver cells. Our analysis builds upon the current understanding of STAT3 function, suggesting a wider array of mechanisms of STAT3 function in inflammatory response, and provides a useful framework for investigating novel TF-target associations with potential therapeutic implications.
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http://dx.doi.org/10.1016/j.bbagen.2013.01.024DOI Listing
June 2013

Silibinin-induced apoptosis in MCF7 and T47D human breast carcinoma cells involves caspase-8 activation and mitochondrial pathway.

Cancer Invest 2011 Jan;29(1):12-20

Radiological Physics and Advisory Division, Bhabha Atomic Research Centre, Trombay, Mumbai 400 085, India.

Silibinin, a natural flavonoid, under phase I/II clinical trial in prostate cancer patients was aimed to evaluate its chemotherapeutic potential in human breast cancer cell MCF7 and T47D. Results showed that T47D cells were found to be more sensitive to silibinin than MCF7 as observed by proliferation, clonogenic, and apoptotic assays, which was abrogated by pan-caspase inhibitor but remained unaffected by p53 inhibitor. Apoptotic events in both cell types differ temporally and also by magnitude that involved mitochondrial and caspase-8 activation pathway. These results have relevance in understanding silibinin treatment to breast tumor.
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http://dx.doi.org/10.3109/07357907.2010.535053DOI Listing
January 2011

Radiobiological basis in management of accidental radiation exposure.

Int J Radiat Biol 2010 Aug;86(8):613-35

Radiation Biology and Health Sciences Division, Bhabha Atomic Research Centre, Mumbai, India.

Purpose: With increasing utilisation of nuclear technologies in power production, medical and industrial applications, and in a scenario of nuclear terrorism/war, there is an enhanced likelihood of accidental radiation exposure to occupational workers, patients and public. The consequent health effects of the radiation exposure are resultant of interaction of radiation with biological systems and subsequent radiation injury. The present review discusses the knowledge gained in radiation biology that can be exploited for better treatment and management of radiation accident victims.

Results: In comparison with planned radiation exposure during diagnosis/therapy, the management of accidental radiation exposure is quite complicated due to uncertainties in dose, duration, organs involved and radionuclides internalised, and hence, require multi-faceted approaches. However, the options available for dosimetry, decorporation of radionuclides and therapeutic protocols of patients are limited, which provides substantial scope in these areas of research. Moreover, there is a need to fill the gaps in knowledge of radiation action in different dose ranges and post-irradiation windows, which would help in improving therapeutic approaches. Cytogenetic approaches are 'gold standard' for biodosimetry but with limited applications in mass casualty scenario. State-of-the-art technological advancement and high throughput in metabolomics, proteomics and genomics could be employed successfully in developing better biodosimetry for triage in accidental radiation exposure. Furthermore, identification of targets at organs/organelles level of internalised radionuclides would be helpful to develop effective decorporation strategies. Despite substantial research investigating several agents, which could modify radiation effects, only a few could reach up to practical application due to poor bioavailability or toxicity.

Conclusions: Deeper insight into the mechanisms of radiation injury under accidental radiation conditions would be helpful in achieving better biodosimetry, decorporation strategies and improvement in prevention/post-irradiation management of radiation accident patients.
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http://dx.doi.org/10.3109/09553001003746059DOI Listing
August 2010

Radioprotection of plasmid and cellular DNA and Swiss mice by silibinin.

Mutat Res 2010 Jan 27;695(1-2):55-60. Epub 2009 Nov 27.

Radiological Physics and Advisory Division, Bhabha Atomic Research Centre, Mumbai 400 085, India.

The radioprotective effect of a non-toxic bioactive component in plant milk thistle, silibinin against genotoxicity induced by gamma-irradiation was investigated in vivo/in vitro. Under in vitro conditions of irradiation, silibinin protected plasmid pBR322 DNA against gamma-radiation-induced strand breaks in a concentration dependent manner (0-200microM). Under cellular conditions of radiation exposure (3Gy), silibinin offered protection to lymphocyte DNA as evidenced from reduction in DNA damage and micronuclei formation, which showed correlation to the extent of intracellular reactive oxygen species reduction. Our extended animal studies suggest that oral administration of silibinin (70mg/kg for 3 days) to mice prior to whole-body gamma-exposure (7.5Gy) resulted in significant protection to radiation-induced mortality and DNA damage in blood leukocytes. However, silibinin treatment after irradiation was not as effective as pre-administration. In conclusion, present study indicated that silibinin has a strong potential to prevent radiation-induced DNA damage under both in vitro and in vivo.
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http://dx.doi.org/10.1016/j.mrgentox.2009.11.007DOI Listing
January 2010

Radiation-induced micronucleus formation and DNA damage in human lymphocytes and their prevention by antioxidant thiols.

Mutat Res 2009 May 5;676(1-2):62-8. Epub 2009 Apr 5.

Radiological Physics and Advisory Division, Bhabha Atomic Research Centre, Mumbai 400 085, India.

Thiol family of antioxidants has been considered to be the most effective class of radio protective agents. Present study reports a comparative evaluation of antioxidant thiols, namely N-acetyl cysteine (NAC), glutathione (GSH) and thioproline (TP), on gamma radiation-induced damage to human lymphocytes DNA as assessed by micronucleus (MN) formation and comet assay parameters. Pretreatment of cells with NAC, GSH and TP showed significant protection against DNA damage and MN frequency in irradiated lymphocytes (2-4 Gy). The magnitude of DNA damage protection was found to be concentration dependent (100-300 microM) which followed the order GSH>NAC>TP. Further, antioxidant thiols mediated protection against DNA damage in irradiated lymphocyte showed significant correlation with their ability to decrease intracellular ROS but not to the increase in intracellular GSH. Experiments on the effect of antioxidant thiols on plasmid DNA irradiated under cell free aqueous conditions showed that NAC exerts greater protection than GSH against radiation damage. TP showed similar responses in cellular and plasmid DNA. Greater protection of plasmid DNA by NAC is ascribable to its more potential hydrogen donor ability as revealed by radical chromogen 2,2-diphenyl-1-picrylhydrazyl (DPPH) photometric assay. Thus, present study indicated that radioprotection of lymphocytes DNA by antioxidant thiols are closely correlated to the reduction of cellular oxidative stress, which seems to involve multiple mechanisms.
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http://dx.doi.org/10.1016/j.mrgentox.2009.03.007DOI Listing
May 2009

Correlation of FBX dosimeter and micronucleus assay in radiation dosimetry of gamma chambers.

J Environ Pathol Toxicol Oncol 2009 ;28(1):63-73

Radiation Biology and Health Sciences Division, Bhabha Atomic Research Centre, Mumbai - 400085, India.

The aim of the present study is to determine the dose distribution in gamma irradiation chambers by chemical dosimetry and to establish its correlation with biological dosimetry. The dose-distribution studies of these two gamma chambers show that compared to the center point of the chambers, the dose rate was 17%-22% higher at the circumference. Moreover, the dose rate was 12%-18% lower at the bottom and top positions compared to the center point. It was interesting to observe that the dose rate determined by chemical dosimetry was well correlated with the number of micro-nucleus (MN) formations at different positions of the chamber. Our results suggest that the formation of the single MN/cell was better correlated with the dose rate than the double MN/cell, suggesting that the number of single MN/cells could be better biomarkers for determining the dose rate. These results provide a correlation between chemical and biological dosimetry, which may have relevance in the development of better bioassay techniques for radiation exposure.
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http://dx.doi.org/10.1615/jenvironpatholtoxicoloncol.v28.i1.70DOI Listing
July 2009