Publications by authors named "Ajay K Yadav"

30 Publications

  • Page 1 of 1

Subterahertz collective dynamics of polar vortices.

Nature 2021 Apr 14;592(7854):376-380. Epub 2021 Apr 14.

Advanced Photon Source, Argonne National Laboratory, Lemont, IL, USA.

The collective dynamics of topological structures are of interest from both fundamental and applied perspectives. For example, studies of dynamical properties of magnetic vortices and skyrmions have not only deepened our understanding of many-body physics but also offered potential applications in data processing and storage. Topological structures constructed from electrical polarization, rather than electron spin, have recently been realized in ferroelectric superlattices, and these are promising for ultrafast electric-field control of topological orders. However, little is known about the dynamics underlying the functionality of such complex extended nanostructures. Here, using terahertz-field excitation and femtosecond X-ray diffraction measurements, we observe ultrafast collective polarization dynamics that are unique to polar vortices, with orders-of-magnitude higher frequencies and smaller lateral size than those of experimentally realized magnetic vortices. A previously unseen tunable mode, hereafter referred to as a vortexon, emerges in the form of transient arrays of nanoscale circular patterns of atomic displacements, which reverse their vorticity on picosecond timescales. Its frequency is considerably reduced (softened) at a critical strain, indicating a condensation (freezing) of structural dynamics. We use first-principles-based atomistic calculations and phase-field modelling to reveal the microscopic atomic arrangements and corroborate the frequencies of the vortex modes. The discovery of subterahertz collective dynamics in polar vortices opens opportunities for electric-field-driven data processing in topological structures with ultrahigh speed and density.
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http://dx.doi.org/10.1038/s41586-021-03342-4DOI Listing
April 2021

Depleting deubiquitinating enzymes promotes apoptosis in glioma cell line via RNA binding proteins SF2/ASF1.

Biochem Biophys Rep 2020 Dec 8;24:100846. Epub 2020 Dec 8.

Cancer Genetics Laboratory, Dr. B.R. Ambedkar Center for Biomedical Research, University of Delhi, North Campus, Delhi, 110007, India.

USP5 and USP8 (Deubiquitinating enzyme) are highly overexpressed and more recognized as poor prognosis marker in various cancers. Depleting USP5 or USP8 to assess the synergism with proteasome inhibitor (Bortezomib) were measured. Furthermore, in present finding USP5 cooperates hnRNPA1 & USP8 cooperate SF2/ASF1, therefore gain in expression of either hnRNPA1 or SF2/ASF1 is sufficient to promote cell survival. On the other side, apoptosis markers were more pronounced in U87 or T98G cells devoid of either USP5 or USP8. However, apparent increase in SF2/ASF1 in absence of USP5, providing resistant factor is new. Antiapoptotic activity due to rise in SF2/ASF1 was validated after co-knock down of SF2/ASF1 in addition to USP5 induces more apoptosis comparing to individual knock down of USP5 or SF2/ASF1. This reveals SF2/ASF1 (RNA binding protein) delayed the apoptotic effect due to loss of USP5, lends ubiquitination of hnRNPA1. In presence of USP5, PI3 kinase inhibition promotes even more interaction between USP5 and hnRNPA1, thereby stabilizes hnRNPA1 in U87MG. In that way hnRNPA1 and SF2/ASF1 impart oncogenic activity. In conclusion, siRNA based strategy against USP5 is not enough to inhibit glioma, moreover targeting additionally SF2/ASF1 by knocking down USP8 is suitably more effective to deal with glioma tumour reoccurrence by indirectly targeting both SF2/ASF1 and hnRNPA1 oncogene.
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http://dx.doi.org/10.1016/j.bbrep.2020.100846DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7726668PMC
December 2020

Enhanced ferroelectricity in ultrathin films grown directly on silicon.

Nature 2020 04 22;580(7804):478-482. Epub 2020 Apr 22.

Department of Electrical Engineering and Computer Sciences, University of California, Berkeley, CA, USA.

Ultrathin ferroelectric materials could potentially enable low-power perovskite ferroelectric tetragonality logic and nonvolatile memories. As ferroelectric materials are made thinner, however, the ferroelectricity is usually suppressed. Size effects in ferroelectrics have been thoroughly investigated in perovskite oxides-the archetypal ferroelectric system. Perovskites, however, have so far proved unsuitable for thickness scaling and integration with modern semiconductor processes. Here we report ferroelectricity in ultrathin doped hafnium oxide (HfO), a fluorite-structure oxide grown by atomic layer deposition on silicon. We demonstrate the persistence of inversion symmetry breaking and spontaneous, switchable polarization down to a thickness of one nanometre. Our results indicate not only the absence of a ferroelectric critical thickness but also enhanced polar distortions as film thickness is reduced, unlike in perovskite ferroelectrics. This approach to enhancing ferroelectricity in ultrathin layers could provide a route towards polarization-driven memories and ferroelectric-based advanced transistors. This work shifts the search for the fundamental limits of ferroelectricity to simpler transition-metal oxide systems-that is, from perovskite-derived complex oxides to fluorite-structure binary oxides-in which 'reverse' size effects counterintuitively stabilize polar symmetry in the ultrathin regime.
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http://dx.doi.org/10.1038/s41586-020-2208-xDOI Listing
April 2020

Augmenter of liver regeneration enhances cell proliferation through the microRNA-26a/Akt/cyclin D1 pathway in hepatic cells.

Hepatol Res 2019 Nov 25;49(11):1341-1352. Epub 2019 Jul 25.

Faculty of Life Sciences and Biotechnology, South Asian University, Akbar Bhawan, Chanakyapuri, New Delhi, India.

Aim: Hepatocytes can proliferate and regenerate when injured by toxins, viral infections, and so on. Augmenter of liver regeneration (ALR) is a key regulator of liver regeneration, but the mechanism is unknown. The role of ALR in other cell types is not known. In the present study, we investigated the relationship between microRNA (miRNA)-26a and ALR in the Huh7 cell line and adipose tissue-derived mesenchymal cells from chronic liver disease patients and healthy individuals.

Methods: Huh7 cells were transfected independently with ALR and miRNA-26a expression vectors, and their effects on cell proliferation, the expression of miRNA-26a, and activation of the phosphatase and tensin homolog and Akt signaling pathways were determined. The experiments were repeated on mesenchymal stem cells derived from healthy individuals and chronic liver disease patients to see whether the observations can be replicated in primary cells.

Results: Overexpression of ALR or miRNA-26a resulted in an increase of the phosphorylation of Akt and cyclin D1 expression, whereas it resulted in decreased levels of p-GSK-3β and phosphatase and tensin homolog in Huh7 cells. The inhibition of ALR expression by ALR siRNA or anti-miR-26a decreased the Akt/cyclin D1 signaling pathway, leading to decreased proliferation. Mesenchymal stem cells isolated from the chronic liver disease patients had a higher ALR expression, while the mesenchymal stem cells isolated from healthy volunteers responded to the growth factor treatments for increased ALR expression. It was found that there was a significant increase in miRNA-26a expression and proliferation.

Conclusions: These data clearly showed that ALR induced the expression of miRNA-26a, which downregulated phosphatase and tensin homolog, resulting in an increased p-Akt/cyclin D1 pathway and enhanced proliferation in hepatic cells.
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http://dx.doi.org/10.1111/hepr.13404DOI Listing
November 2019

TGF-β induces liver fibrosis via miRNA-181a-mediated down regulation of augmenter of liver regeneration in hepatic stellate cells.

PLoS One 2019 5;14(6):e0214534. Epub 2019 Jun 5.

Faculty of Life Sciences and Biotechnology, South Asian University, Akbar Bhawan, Chanakyapuri, New Delhi, India.

Objective: To study the role of miRNA-181a and augmenter of liver regeneration in TGF-β-induced fibrosis in hepatic stellate cells.

Methods: LX2 cells were treated with 20 ng/ml TGF-β for 24 h. miRNA-181a, ALR plasmid and empty vectors were transfected using siPORT NeoFx reagent. Cells were harvested after 48 h or 72 h of transfection for protein or RNA analysis. Western blotting was performed for ALR, TGF-β receptor II (TGFβ-RII), collagen 1A1 (COLL1A1), alpha-smooth muscle cell actin (α-SMA), rac1, E-cadherin and β-actin. Quantitative RT-PCR was performed for ALR, GAPDH, miRNA-181a or 5S rRNA.

Results: TGF-β induced the expression of miRNA-181a, which in turn down-regulated ALR thereby induced the fibrosis markers, such as COLL1A1, α-SMA and rac1 in hepatic stellate cells. Over-expression of miRNA-181a down-regulated expression of ALR and up-regulated expression of fibrosis markers. On the other hand, ALR over-expression resulted in a decrease in miRNA-181a expression and fibrosis markers. Over-expression of ALR also inhibited the expression of TGFβ-RII and increased expression E-cadherin.

Conclusion: TGF-β induced miRNA-181a, which in turn induced fibrosis, at least in part, by inhibiting ALR. ALR inhibited TGF-β action by decreasing the expression of TGFβ-RII, thereby inhibiting miRNA-181a expression and fibrosis markers. ALR could serve as a potential molecule to inhibit liver fibrosis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0214534PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6550375PMC
January 2020

Author Correction: Spatially resolved steady-state negative capacitance.

Nature 2019 Apr;568(7753):E13

Department of Electrical Engineering and Computer Sciences, University of California, Berkeley, CA, USA.

In this Letter, the first name of author Bhagwati Prasad was misspelled Bhagawati. This error has been corrected online.
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http://dx.doi.org/10.1038/s41586-019-1106-6DOI Listing
April 2019

Spatially resolved steady-state negative capacitance.

Nature 2019 01 14;565(7740):468-471. Epub 2019 Jan 14.

Department of Electrical Engineering and Computer Sciences, University of California, Berkeley, CA, USA.

Negative capacitance is a newly discovered state of ferroelectric materials that holds promise for electronics applications by exploiting a region of thermodynamic space that is normally not accessible. Although existing reports of negative capacitance substantiate the importance of this phenomenon, they have focused on its macroscale manifestation. These manifestations demonstrate possible uses of steady-state negative capacitance-for example, enhancing the capacitance of a ferroelectric-dielectric heterostructure or improving the subthreshold swing of a transistor. Yet they constitute only indirect measurements of the local state of negative capacitance in which the ferroelectric resides. Spatial mapping of this phenomenon would help its understanding at a microscopic scale and also help to achieve optimal design of devices with potential technological applications. Here we demonstrate a direct measurement of steady-state negative capacitance in a ferroelectric-dielectric heterostructure. We use electron microscopy complemented by phase-field and first-principles-based (second-principles) simulations in SrTiO/PbTiO superlattices to directly determine, with atomic resolution, the local regions in the ferroelectric material where a state of negative capacitance is stabilized. Simultaneous vector mapping of atomic displacements (related to a complex pattern in the polarization field), in conjunction with reconstruction of the local electric field, identify the negative capacitance regions as those with higher energy density and larger polarizability: the domain walls where the polarization is suppressed.
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http://dx.doi.org/10.1038/s41586-018-0855-yDOI Listing
January 2019

Direct N-H/ N-Me Aziridination of Unactivated Olefins Using O-(Sulfonyl)hydroxylamines as Aminating Agents.

J Org Chem 2018 10 17;83(19):12255-12260. Epub 2018 Sep 17.

Department of Chemistry , Baba Saheb Bhim Rao Ambedkar University , Lucknow 226025 , India.

Unactivated aziridines are the core substructures in a plethora of bioactive natural products and serve as building blocks in organic synthesis. Despite this, very limited methods are available to access them directly from olefins, as most of the known methods are devoted to their activated counterparts. Herein, we have developed a highly efficient Rh(II)-catalyzed method for the direct preparation of unactivated aziridines from olefins using O-(sulfonyl)hydroxylamines as the aminating agent. The reactions proceed with a high stereospecificity.
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http://dx.doi.org/10.1021/acs.joc.8b01673DOI Listing
October 2018

Antagonistic role of GSK3 isoforms in glioma survival.

J Cancer 2018 24;9(10):1846-1855. Epub 2018 Apr 24.

Cancer Genetics Laboratory, Dr. B.R. Ambedkar Center for Biomedical Research, University of Delhi (North Campus), Delhi- 110007, India.

GSK3 (Glycogen Synthase Kinase-3) function in brain is contributed by two distinct gene GSK3 alpha and GSK3 beta. Present findings indicate that imbalance in between GSK3 alpha and beta isoform contributes oncogenesis. In gliomas, GSK3 isoform specific functions are different then as reported for melanoma, prostate cancer, lung cancer etc. Both the isoforms of GSK3 are inversely regulating hnRNPA1 (RNA binding protein) expression, subsequently affecting RNA alternative splicing (BIN1, RON, Mcl1, PKM) in gliomas. Elevated expression of c-Myc, hnRNPA1, Phospo-ERK1/2 and Cyclin D1 in GSK3 alpha knock down cells, resembles GSK3 beta isoform overexpressing glioma cells, promotes cell survival. HnRNPA1 dependent survival signaling pathway were elaborated using si RNA approach or by over expressing cloned hnRNPA1 gene in U87 glioma cells. Therefore, performed study empirically support GSK3β inhibition along with restoration of GSK3α would be a good strategy to target gliomas.
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http://dx.doi.org/10.7150/jca.21248DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5968773PMC
April 2018

A drug combination targeting hypoxia induced chemoresistance and stemness in glioma cells.

Oncotarget 2018 Apr 6;9(26):18351-18366. Epub 2018 Apr 6.

National Brain Research Centre, Manesar, Gurgaon-122051, India.

Hypoxia is a characteristic of solid tumors especially Glioblastoma and is critical to chemoresistance. Cancer stem cells present in hypoxic niches are known to be a major cause of the progression, metastasis and relapse. We tried to identify synergistic combinations of drugs effective in both hypoxia and normoxia in tumor cells as well as in cancer stem cells. Since COX-2 is over-expressed in subset of glioblastoma and is also induced in hypoxia, we studied combinations of a prototype Cyclooxygenase (COX-2) inhibitor, NS-398 with various drugs (BCNU, Temozolomide, 2-Deoxy-D-glucose and Cisplatin) for their ability to abrogate chemoresistance under both severe hypoxia (0.2% O) and normoxia (20% O) in glioma cells. The only effective combination was of NS-398 and BCNU which showed a synergistic effect in both hypoxia and normoxia. This synergism was evident at sub-lethal doses for either of the single agent. The effectiveness of the combination resulted from increased pro- apoptotic and decreased anti-apoptotic molecules and increased caspase activity. PGE levels, a manifestation of COX-2 activity were increased during hypoxia, but were reduced by the combination during both hypoxia and normoxia. The combination reduced the levels of epithelial-mesenchymal transition (EMT) markers. It also resulted in a greater reduction of cell migration. While single drugs could reduce the number of gliomaspheres, the combination successfully abrogated their formation. The combination also resulted in a greater reduction of the cancer stem cell marker CD133. This combination could be a prototype of possible therapy in a tumor with a high degree of hypoxia like glioma.
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http://dx.doi.org/10.18632/oncotarget.24839DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5915077PMC
April 2018

Emergent chirality in the electric polarization texture of titanate superlattices.

Proc Natl Acad Sci U S A 2018 01 16;115(5):915-920. Epub 2018 Jan 16.

Department of Materials Science & Engineering, University of California, Berkeley, CA 94720.

Chirality is a geometrical property by which an object is not superimposable onto its mirror image, thereby imparting a handedness. Chirality determines many important properties in nature-from the strength of the weak interactions according to the electroweak theory in particle physics to the binding of enzymes with naturally occurring amino acids or sugars, reactions that are fundamental for life. In condensed matter physics, the prediction of topologically protected magnetic skyrmions and related spin textures in chiral magnets has stimulated significant research. If the magnetic dipoles were replaced by their electrical counterparts, then electrically controllable chiral devices could be designed. Complex oxide BaTiO/SrTiO nanocomposites and PbTiO/SrTiO superlattices are perfect candidates, since "polar vortices," in which a continuous rotation of ferroelectric polarization spontaneously forms, have been recently discovered. Using resonant soft X-ray diffraction, we report the observation of a strong circular dichroism from the interaction between circularly polarized light and the chiral electric polarization texture that emerges in PbTiO/SrTiO superlattices. This hallmark of chirality is explained by a helical rotation of electric polarization that second-principles simulations predict to reside within complex 3D polarization textures comprising ordered topological line defects. The handedness of the texture can be topologically characterized by the sign of the helicity number of the chiral line defects. This coupling between the optical and novel polar properties could be exploited to encode chiral signatures into photon or electron beams for information processing.
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http://dx.doi.org/10.1073/pnas.1711652115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5798329PMC
January 2018

Butyrate induces ROS-mediated apoptosis by modulating miR-22/SIRT-1 pathway in hepatic cancer cells.

Redox Biol 2017 08 7;12:340-349. Epub 2017 Mar 7.

Faculty of Life Sciences and Biotechnology, South Asian University, Chanakyapuri, New Delhi, India. Electronic address:

Butyrate is one of the short chain fatty acids, produced by the gut microbiota during anaerobic fermentation of dietary fibres. It has been shown that it can inhibit tumor progression via suppressing histone deacetylase and can induce apoptosis in cancer cells. However, the comprehensive pathway by which butyrate mediates apoptosis and growth arrest in cancer cells still remains unclear. In this study, the role of miR-22 in butyrate-mediated ROS release and induction of apoptosis was determined in hepatic cells. Intracellular expression of miR-22 was increased when the Huh 7 cells were incubated with sodium butyrate. Over-expression of miR-22 or addition of sodium butyrate inhibited SIRT-1 expression and enhanced the ROS production. Incubation of cells with anti-miR-22 reversed the effects of butyrate. Butyrate induced apoptosis via ROS production, cytochrome c release and activation of caspase-3, whereas addition of N-acetyl cysteine or anti-miR-22 reversed these butyrate-induced effects. Furthermore, sodium butyrate inhibited cell growth and proliferation, whereas anti-miR-22 inhibited these butyrate-mediated changes. The expression of PTEN and gsk-3 was found to be increased while p-akt and β-catenin expression was decreased significantly by butyrate. These data showed that butyrate modulated both apoptosis and proliferation via miR-22 expression in hepatic cells.
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http://dx.doi.org/10.1016/j.redox.2017.03.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5350572PMC
August 2017

Stability of Polar Vortex Lattice in Ferroelectric Superlattices.

Nano Lett 2017 04 8;17(4):2246-2252. Epub 2017 Mar 8.

Department of Materials Science and Engineering, The Pennsylvania State University , University Park, Pennsylvania 16802, United States.

A novel mesoscale state comprising of an ordered polar vortex lattice has been demonstrated in ferroelectric superlattices of PbTiO/SrTiO. Here, we employ phase-field simulations, analytical theory, and experimental observations to evaluate thermodynamic conditions and geometric length scales that are critical for the formation of such exotic vortex states. We show that the stability of these vortex lattices involves an intimate competition between long-range electrostatic, long-range elastic, and short-range polarization gradient-related interactions leading to both an upper and a lower bound to the length scale at which these states can be observed. We found that the critical length is related to the intrinsic domain wall width, which could serve as a simple intuitive design rule for the discovery of novel ultrafine topological structures in ferroic systems.
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http://dx.doi.org/10.1021/acs.nanolett.6b04875DOI Listing
April 2017

Interface Engineering of Domain Structures in BiFeO Thin Films.

Nano Lett 2017 01 9;17(1):486-493. Epub 2016 Dec 9.

Department of Electrical Engineering and Computer Sciences, University of California Berkeley , Berkeley, California 94720, United States.

A wealth of fascinating phenomena have been discovered at the BiFeO domain walls, examples such as domain wall conductivity, photovoltaic effects, and magnetoelectric coupling. Thus, the ability to precisely control the domain structures and accurately study their switching behaviors is critical to realize the next generation of novel devices based on domain wall functionalities. In this work, the introduction of a dielectric layer leads to the tunability of the depolarization field both in the multilayers and superlattices, which provides a novel approach to control the domain patterns of BiFeO films. Moreover, we are able to study the switching behavior of the first time obtained periodic 109° stripe domains with a thick bottom electrode. Besides, the precise controlling of pure 71° and 109° periodic stripe domain walls enable us to make a clear demonstration that the exchange bias in the ferromagnet/BiFeO system originates from 109° domain walls. Our findings provide future directions to study the room temperature electric field control of exchange bias and open a new pathway to explore the room temperature multiferroic vortices in the BiFeO system.
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http://dx.doi.org/10.1021/acs.nanolett.6b04512DOI Listing
January 2017

Synergistic increase in efficacy of a combination of 2-deoxy-D-glucose and cisplatin in normoxia and hypoxia: switch from autophagy to apoptosis.

Tumour Biol 2016 Sep 15;37(9):12347-12358. Epub 2016 Jun 15.

Department of Biochemistry, All India Institute of Medical Sciences, New Delhi, 110029, India.

Resistance to drugs, which is aggravated by hypoxia, is a well-known feature of tumors. The combination of drug exposure and hypoxia can give rise to several survival strategies in the exposed cells. Glioblastoma multiforme (GBM) is among the most hypoxic of solid tumors, and we have used glial cells to identify a drug combination that would be synergistically effective in these cells under both normoxia and hypoxia. Cisplatin (CP) and 2-deoxy-D-glucose (2-DG), which have been used for second-line therapy and for preclinical research, are relatively ineffective as single agents. During in vitro experiments with A172 and LN229 cells, there was increased resistance to both drugs under hypoxia. However, the combination of CP and 2-DG showed a synergistic effect in reducing cell viability under both normoxia and hypoxia, with a combination index of less than 1. Increased autophagy is a distinct feature of the response to 2-DG. However, autophagic markers were reduced, and apoptotic markers were upregulated by the combination, indicating a switch over from autophagic to apoptotic pathways with reduction in endoplasmic reticulum (ER) stress. The combination also resulted in a decrease of pAKT levels. The effect of CP in the combination was replicated by the prototype AKT inhibitor LY294002, further supporting the role of AKT inhibition in the synergism. Combination of 2-DG with CP, or possibly an AKT inhibitor, can prove to be an effective rational combination for reducing chemoresistance under both normoxic and hypoxic conditions in gliomas.
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http://dx.doi.org/10.1007/s13277-016-5089-8DOI Listing
September 2016

Humic acid inhibits HBV-induced autophagosome formation and induces apoptosis in HBV-transfected Hep G2 cells.

Sci Rep 2016 10 6;6:34496. Epub 2016 Oct 6.

Faculty of Life Sciences and Biotechnology, South Asian University, Akbar Bhawan Chanakyapuri New Delhi, India.

Hepatitis B Virus (HBV) utilizes several mechanisms to survive in the host cells and one of the main pathways being autophagosome formation. Humic acid (HA), one of the major components of Mineral pitch, is an Ayurvedic medicinal food, commonly used by the people of the Himalayan regions of Nepal and India for various body ailments. We hypothesized that HA could induce cell death and inhibit HBV-induced autophagy in hepatic cells. Incubation of Hep G2.2.1.5 cells (HepG2 cells stably expressing HBV) with HA (100 μM) inhibited both cell proliferation and autophagosome formation significantly, while apoptosis induction was enhanced. Western blot results showed that HA incubation resulted in decreased levels of beclin-1, SIRT-1 and c-myc, while caspase-3 and β-catenin expression were up-regulated. Western blot results showed that HA significantly inhibited the expression of HBx (3-fold with 50 μM and 5-fold with 100 μM) compared to control cells. When HA was incubated with HBx-transfected Hep G2 cells, HBx-induced autophagosome formation and beclin-1 levels were decreased. These data showed that HA induced apoptosis and inhibited HBV-induced autophagosome formation and proliferation in hepatoma cells.
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http://dx.doi.org/10.1038/srep34496DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5052648PMC
October 2016

Identification of Specific miRNA Signature in Paired Sera and Tissue Samples of Indian Women with Triple Negative Breast Cancer.

PLoS One 2016 12;11(7):e0158946. Epub 2016 Jul 12.

Dr. B.R. Ambedker Centre for Biomedical Research, University of Delhi, New Delhi, India.

Of several subtypes of breast cancer, triple negative breast cancer (TNBC) is a highly aggressive tumor that lacks expression of hormone receptors for estrogen, progesterone and human epidermal growth factor receptor 2 and shows a worst prognosis. The small noncoding RNAs (miRNAs) considered as master regulator of gene expression play a key role in cancer initiation, progression and drug resistance and have emerged as attractive molecular biomarkers for diagnosis, prognosis and treatment targets in cancer. We have done expression profiling of selected miRNAs in paired serum and tissue samples of TNBC patients and corresponding cell lines and compared with that of other subtypes, in order to identify novel serum miRNA biomarkers for early detection and progression of TNBC. A total of 85 paired tumor tissues and sera with an equal number of adjacent normal tissue margins and normal sera from age matched healthy women including tissue and sera samples from 15 benign fibroadenomas were employed for the study. We report for the first time an extremely high prevalence (73.9%) of TNBC in premenopausal women below 35 years of age and a significant altered expression of a panel of three specific oncogenic miRNAs- miR-21, miR-221, miR-210, and three tumor suppressor miRNAs- miR-195, miR-145 and Let-7a in both tissues and corresponding sera of TNBC patients when compared with triple positive breast cancer (TPBC) patients. While miR-21, miR-221 and miR-210 showed significant over-expression, miR-195 and miR-145 were downregulated and well correlated with various clinicopathological and demographic risk factors, tumor grade, clinical stage and hormone receptor status. Interestingly, despite being a known tumor suppressor, Let-7a showed a significant overexpression in TNBCs. It is suggested that this panel of six miRNA signature may serve as a minimally invasive biomarker for an early detection of TNBC patients.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0158946PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4942139PMC
July 2017

Mineral pitch induces apoptosis and inhibits proliferation via modulating reactive oxygen species in hepatic cancer cells.

BMC Complement Altern Med 2016 May 27;16:148. Epub 2016 May 27.

Faculty of Life Sciences and Biotechnology, South Asian University, Akbar Bhawan Chanakyapuri, New Delhi, India.

Background: Mineral Pitch (MP) is a dark brown coloured humic matter originating from high altitude rocks. It is an Ayurvedic medicinal food, commonly used by the people of the Himalayan regions of Nepal and India for various body ailments.

Methods: The Huh-7 cells were treated with different concentrations of MP for 24 h, and both apoptosis and proliferation was determined by the TUNEL and MTT assays respectively. The formation of ROS and nitric oxide was analysed by DCFH-DA and Griess reagent respectively. The expression of miRNA-21 and miRNA-22 were checked by the real time PCR. Effect of miRNA-22 on proliferation and c-myc was studied by over-expressing miRNA-22 premiRs in Huh-7 cells.

Results: We found that MP enhanced anti-cancer effects by inducing apoptosis and inhibiting proliferation. MP induced both ROS and NO, upon neutralizing them, there was a partial recovery of apoptosis and proliferation. MP also induced miRNA-22 expression, while miRNA-21 expression was inhibited. Over-expression of miRNA-22 resulted in a significant inhibition of proliferation. miRNA-22 directly targeted c-myc gene, thereby inhibited proliferation. These results clearly show that MP induces its anti-cancer activity by more than one pathway.

Conclusion: The data clearly indicate that MP induced apoptosis via the production of ROS, and inhibited proliferation by inducing miRNA-22 and inhibiting miRNA-21 in Huh-7 cells.
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http://dx.doi.org/10.1186/s12906-016-1131-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4882837PMC
May 2016

Post Tracheostomy Carotid-Tracheal Fistula.

Indian J Otolaryngol Head Neck Surg 2016 Mar 4;68(1):97-9. Epub 2014 Dec 4.

Department of Radiodiagnosis, All India Institute of Medical Sciences, New Delhi, 110029 India.

Tracheostomy is the life saving procedure in patients presenting with upper airway obstruction. The procedure is also performed in patients on chronic ventilatory support. It is generally considered a safe procedure with a low complication rate. Vascular injuries are the most serious and life threatening complications. Injury to a high lying innominate artery is the most frequent vascular injury in such cases. Injury to other vessels e.g. carotid arteries is less frequent. We are presenting one such rare type of vascular injury with a fistulous communication between trachea and carotid artery leading to massive hemoptysis.
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http://dx.doi.org/10.1007/s12070-014-0813-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4809812PMC
March 2016

Unusual cord transection in a patient with traumatic spondylolisthesis.

Asian J Neurosurg 2016 Jan-Mar;11(1):72

Department of Neurosurgery, All India Institute of Medical Sciences, New Delhi, India.

Spinal cord injury is one of the most debilitating injuries in patients with spinal trauma. Cord injury may range from simple cord edema to frank transection. Cord transection is the most severe form of cord injury as it results in complete and irreversible loss of all neural functions. Generally, it is a result of unstable spinal fractures with associated spondylolisthesis or spondyloptosis. Generally, the level of cord transection corresponds to the level of spinal fracture/spondylolisthesis. However, here we are presenting a case having a traumatic spinal fracture with spondylolisthesis where the level of cord transection was much higher than the level of the spinal fracture. Due to the traumatic traction, the cord distal to transection is displaced inferior leaving behind a long segment of the empty thecal sac.
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http://dx.doi.org/10.4103/1793-5482.165803DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4732254PMC
February 2016

Lineage-specific splicing of a brain-enriched alternative exon promotes glioblastoma progression.

J Clin Invest 2014 Jul 27;124(7):2861-76. Epub 2014 May 27.

Tissue-specific alternative splicing is critical for the emergence of tissue identity during development, yet the role of this process in malignant transformation is undefined. Tissue-specific splicing involves evolutionarily conserved, alternative exons that represent only a minority of the total alternative exons identified. Many of these conserved exons have functional features that influence signaling pathways to profound biological effect. Here, we determined that lineage-specific splicing of a brain-enriched cassette exon in the membrane-binding tumor suppressor annexin A7 (ANXA7) diminishes endosomal targeting of the EGFR oncoprotein, consequently enhancing EGFR signaling during brain tumor progression. ANXA7 exon splicing was mediated by the ribonucleoprotein PTBP1, which is normally repressed during neuronal development. PTBP1 was highly expressed in glioblastomas due to loss of a brain-enriched microRNA (miR-124) and to PTBP1 amplification. The alternative ANXA7 splicing trait was present in precursor cells, suggesting that glioblastoma cells inherit the trait from a potential tumor-initiating ancestor and that these cells exploit this trait through accumulation of mutations that enhance EGFR signaling. Our data illustrate that lineage-specific splicing of a tissue-regulated alternative exon in a constituent of an oncogenic pathway eliminates tumor suppressor functions and promotes glioblastoma progression. This paradigm may offer a general model as to how tissue-specific regulatory mechanisms can reprogram normal developmental processes into oncogenic ones.
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http://dx.doi.org/10.1172/JCI68836DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4071411PMC
July 2014

AR-A 014418 Used against GSK3beta Downregulates Expression of hnRNPA1 and SF2/ASF Splicing Factors.

J Oncol 2014 2;2014:695325. Epub 2014 Jan 2.

Institute of Nuclear Medicine and Allied Sciences, Timarpur, Delhi 110007, India.

Glioblastoma is one of the most aggressive forms of primary brain tumors of glial cells, including aberrant regulation of glycogen synthase kinase 3 β (GSK3 β ) and splicing factors deregulation. Here, we investigate the role of small molecule AR-A014418 and Manzamine A against GSK3 kinase with factual control on splicing regulators. AR-A 014418, 48 hrs posttreatment, caused dose (25-100  μ M) dependent inhibition in U373 and U87 cell viability with also inhibition in activating tyrosine phosphorylation of GSK3alpha (Tyr 279) and beta (Tyr 216). Furthermore, inhibition of GSK3 kinase resulted in significant downregulation of splicing factors (SRSF1, SRSF5, PTPB1, and hnRNP) in U87 cells with downregulation of antiapoptotic genes such as BCL2, BCL-xL, Survivin, MCL1, and BMI1. Similarly, downregulation of splicing factors was also observed in U373 glioma cell after using SiRNA against AKT and GSK3beta kinase. In addition, potential roles of AR-A014418 in downregulation of splicing factors were reflected with decrease in Anxa7 (VA) variant and increase in Anxa7 WT tumor suppressor transcript and protein. The above results suggest that inhibition of GSK3beta kinase activation could be the beneficial strategy to inhibit the occurrence of alternative cancer escape pathway via downregulating the expression of splicing regulators as well as apoptosis.
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http://dx.doi.org/10.1155/2014/695325DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3914408PMC
February 2014

Crossover from incoherent to coherent phonon scattering in epitaxial oxide superlattices.

Nat Mater 2014 Feb 8;13(2):168-72. Epub 2013 Dec 8.

1] Department of Materials Science and Engineering, University of California, Los Angeles, California 90095, USA [2] Western Institute of Nanoelectronics, Department of Electrical Engineering, University of California, Los Angeles, California 90095, USA [3] California NanoSystems Institute, University of California, Los Angeles, California 90095, USA.

Elementary particles such as electrons or photons are frequent subjects of wave-nature-driven investigations, unlike collective excitations such as phonons. The demonstration of wave-particle crossover, in terms of macroscopic properties, is crucial to the understanding and application of the wave behaviour of matter. We present an unambiguous demonstration of the theoretically predicted crossover from diffuse (particle-like) to specular (wave-like) phonon scattering in epitaxial oxide superlattices, manifested by a minimum in lattice thermal conductivity as a function of interface density. We do so by synthesizing superlattices of electrically insulating perovskite oxides and systematically varying the interface density, with unit-cell precision, using two different epitaxial-growth techniques. These observations open up opportunities for studies on the wave nature of phonons, particularly phonon interference effects, using oxide superlattices as model systems, with extensive applications in thermoelectrics and thermal management.
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http://dx.doi.org/10.1038/nmat3826DOI Listing
February 2014

NFKBIA deletion in glioblastomas.

N Engl J Med 2011 Feb 22;364(7):627-37. Epub 2010 Dec 22.

Department of Neurosurgery, Neurocenter, University of Freiburg, Freiburg, Germany.

Background: Amplification and activating mutations of the epidermal growth factor receptor (EGFR) oncogene are molecular hallmarks of glioblastomas. We hypothesized that deletion of NFKBIA (encoding nuclear factor of κ-light polypeptide gene enhancer in B-cells inhibitor-α), an inhibitor of the EGFR-signaling pathway, promotes tumorigenesis in glioblastomas that do not have alterations of EGFR.

Methods: We analyzed 790 human glioblastomas for deletions, mutations, or expression of NFKBIA and EGFR. We studied the tumor-suppressor activity of NFKBIA in tumor-cell culture. We compared the molecular results with the outcome of glioblastoma in 570 affected persons.

Results: NFKBIA is often deleted but not mutated in glioblastomas; most deletions occur in nonclassical subtypes of the disease. Deletion of NFKBIA and amplification of EGFR show a pattern of mutual exclusivity. Restoration of the expression of NFKBIA attenuated the malignant phenotype and increased the vulnerability to chemotherapy of cells cultured from tumors with NFKBIA deletion; it also reduced the viability of cells with EGFR amplification but not of cells with normal gene dosages of both NFKBIA and EGFR. Deletion and low expression of NFKBIA were associated with unfavorable outcomes. Patients who had tumors with NFKBIA deletion had outcomes that were similar to those in patients with tumors harboring EGFR amplification. These outcomes were poor as compared with the outcomes in patients with tumors that had normal gene dosages of NFKBIA and EGFR. A two-gene model that was based on expression of NFKBIA and O(6)-methylguanine DNA methyltransferase was strongly associated with the clinical course of the disease.

Conclusions: Deletion of NFKBIA has an effect that is similar to the effect of EGFR amplification in the pathogenesis of glioblastoma and is associated with comparatively short survival.
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http://dx.doi.org/10.1056/NEJMoa1006312DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3652611PMC
February 2011

Deletion analysis of BMI1 oncoprotein identifies its negative regulatory domain.

Mol Cancer 2010 Jun 22;9:158. Epub 2010 Jun 22.

Department of Medicine, NorthShore University HealthSystem Research Institute, Evanston, IL 60201, USA.

Background: The polycomb group (PcG) protein BMI1 is an important regulator of development. Additionally, aberrant expression of BMI1 has been linked to cancer stem cell phenotype and oncogenesis. In particular, its overexpression has been found in several human malignancies including breast cancer. Despite its established role in stem cell maintenance, cancer and development, at present not much is known about the functional domains of BMI1 oncoprotein. In the present study, we carried out a deletion analysis of BMI1 to identify its negative regulatory domain.

Results: We report that deletion of the C-terminal domain of BMI1, which is rich in proline-serine (PS) residues and previously described as PEST-like domain, increased the stability of BMI1, and promoted its pro-oncogenic activities in human mammary epithelial cells (HMECs). Specifically, overexpression of a PS region deleted mutant of BMI1 increased proliferation of HMECs and promoted an epithelial-mesenchymal transition (EMT) phenotype in the HMECs. Furthermore, when compared to the wild type BMI1, exogenous expression of the mutant BMI1 led to a significant downregulation of p16INK4a and an efficient bypass of cellular senescence in human diploid fibroblasts.

Conclusions: In summary, our data suggest that the PS domain of BMI1 is involved in its stability and that it negatively regulates function of BMI1 oncoprotein. Our results also suggest that the PS domain of BMI1 could be targeted for the treatment of proliferative disorders such as cancer and aging.
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http://dx.doi.org/10.1186/1476-4598-9-158DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2900245PMC
June 2010

Monosomy of chromosome 10 associated with dysregulation of epidermal growth factor signaling in glioblastomas.

JAMA 2009 Jul;302(3):276-89

Department of Neurological Surgery, Northwestern Brain Tumor Institute, Lurie Center for Cancer Genetics Research, Northwestern University Feinberg School of Medicine, Chicago, IL 60611-3015, USA.

Context: Glioblastomas--uniformly fatal brain tumors--often have both monosomy of chromosome 10 and gains of the epidermal growth factor receptor (EGFR) gene locus on chromosome 7, an association for which the mechanism is poorly understood.

Objectives: To assess whether coselection of EGFR gains on 7p12 and monosomy 10 in glioblastomas promotes tumorigenic epidermal growth factor (EGF) signaling through loss of the annexin A7 (ANXA7) gene on 10q21.1-q21.2 and whether ANXA7 acts as a tumor suppressor gene by regulating EGFR in glioblastomas.

Design, Setting, And Patients: Multidimensional analysis of gene, coding sequence, promoter methylation, messenger RNA (mRNA) transcript, protein data for ANXA7 (and EGFR), and clinical patient data profiles of 543 high-grade gliomas from US medical centers and The Cancer Genome Atlas pilot project (made public 2006-2008; and unpublished, tumors collected 2001-2008). Functional analyses using LN229 and U87 glioblastoma cells.

Main Outcome Measures: Associations among ANXA7 gene dosage, coding sequence, promoter methylation, mRNA transcript, and protein expression. Effect of ANXA7 haploinsufficiency on EGFR signaling and patient survival. Joint effects of loss of ANXA7 and gain of EGFR expression on tumorigenesis.

Results: Heterozygous ANXA7 gene deletion is associated with significant loss of ANXA7 mRNA transcript expression (P = 1 x 10(-15); linear regression) and a reduction (mean [SEM]) of 91.5% (2.3%) of ANXA7 protein expression compared with ANXA7 wild-type glioblastomas (P = .004; unpaired t test). ANXA7 loss of function stabilizes the EGFR protein (72%-744% increase in EGFR protein abundance) and augments EGFR transforming signaling in glioblastoma cells. ANXA7 haploinsufficiency doubles tumorigenic potential of glioblastoma cells, and combined ANXA7 knockdown and EGFR overexpression promotes tumorigenicity synergistically. The heterozygous loss of ANXA7 in approximately 75% of glioblastomas in the The Cancer Genome Atlas plus infrequency of ANXA7 mutation (approximately 6% of tumors) indicates its role as a haploinsufficiency gene. ANXA7 mRNA transcript expression, dichotomized at the median, associates with patient survival in 191 glioblastomas (log-rank P = .008; hazard ratio [HR], 0.667; 95% confidence interval [CI], 0.493-0.902; 46.9 vs 74.8 deaths/100 person-years for high vs low ANXA7 mRNA expression) and with a separate group of 180 high-grade gliomas (log-rank P = .00003; HR, 0.476; 95% CI, 0.333-0.680; 21.8 vs 50.0 deaths/100 person-years for high vs low ANXA7 mRNA expression). Deletion of the ANXA7 gene associates with poor patient survival in 189 glioblastomas (log-rank P = .042; HR, 0.686; 95% CI, 0.476-0.989; 54.0 vs 80.1 deaths/100 person-years for wild-type ANXA7 vs ANXA7 deletion).

Conclusion: Haploinsufficiency of the tumor suppressor ANXA7 due to monosomy of chromosome 10 provides a clinically relevant mechanism to augment EGFR signaling in glioblastomas beyond that resulting from amplification of the EGFR gene.
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http://dx.doi.org/10.1001/jama.2009.1022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3089898PMC
July 2009

A network model of a cooperative genetic landscape in brain tumors.

JAMA 2009 Jul;302(3):261-75

Department of Neurological Surgery, Northwestern Brain Tumor Institute and Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611-3015, USA.

Context: Gliomas, particularly glioblastomas, are among the deadliest of human tumors. Gliomas emerge through the accumulation of recurrent chromosomal alterations, some of which target yet-to-be-discovered cancer genes. A persistent question concerns the biological basis for the coselection of these alterations during gliomagenesis.

Objectives: To describe a network model of a cooperative genetic landscape in gliomas and to evaluate its clinical relevance.

Design, Setting, And Patients: Multidimensional genomic profiles and clinical profiles of 501 patients with gliomas (45 tumors in an initial discovery set collected between 2001 and 2004 and 456 tumors in validation sets made public between 2006 and 2008) from multiple academic centers in the United States and The Cancer Genome Atlas Pilot Project (TCGA).

Main Outcome Measures: Identification of genes with coincident genetic alterations, correlated gene dosage and gene expression, and multiple functional interactions; association between those genes and patient survival.

Results: Gliomas select for a nonrandom genetic landscape-a consistent pattern of chromosomal alterations-that involves altered regions ("territories") on chromosomes 1p, 7, 8q, 9p, 10, 12q, 13q, 19q, 20, and 22q (false-discovery rate-corrected P<.05). A network model shows that these territories harbor genes with putative synergistic, tumor-promoting relationships. The coalteration of the most interactive of these genes in glioblastoma is associated with unfavorable patient survival. A multigene risk scoring model based on 7 landscape genes (POLD2, CYCS, MYC, AKR1C3, YME1L1, ANXA7, and PDCD4) is associated with the duration of overall survival in 189 glioblastoma samples from TCGA (global log-rank P = .02 comparing 3 survival curves for patients with 0-2, 3-4, and 5-7 dosage-altered genes). Groups of patients with 0 to 2 (low-risk group) and 5 to 7 (high-risk group) dosage-altered genes experienced 49.24 and 79.56 deaths per 100 person-years (hazard ratio [HR], 1.63; 95% confidence interval [CI], 1.10-2.40; Cox regression model P = .02), respectively. These associations with survival are validated using gene expression data in 3 independent glioma studies, comprising 76 (global log-rank P = .003; 47.89 vs 15.13 deaths per 100 person-years for high risk vs low risk; Cox model HR, 3.04; 95% CI, 1.49-6.20; P = .002) and 70 (global log-rank P = .008; 83.43 vs 16.14 deaths per 100 person-years for high risk vs low risk; HR, 3.86; 95% CI, 1.59-9.35; P = .003) high-grade gliomas and 191 glioblastomas (global log-rank P = .002; 83.23 vs 34.16 deaths per 100 person-years for high risk vs low risk; HR, 2.27; 95% CI, 1.44-3.58; P<.001).

Conclusions: The alteration of multiple networking genes by recurrent chromosomal aberrations in gliomas deregulates critical signaling pathways through multiple, cooperative mechanisms. These mutations, which are likely due to nonrandom selection of a distinct genetic landscape during gliomagenesis, are associated with patient prognosis.
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http://dx.doi.org/10.1001/jama.2009.997DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4447713PMC
July 2009

Human hemoglobin shares bioactivities ascribed to human tumor necrosis factor-alpha.

Immunopharmacol Immunotoxicol 2004 ;26(4):559-72

Immunobiology Laboratory, Industrial Toxicology Research Centre, Lucknow, India.

Hemoglobin mediated cytotoxicity and apoptosis has been evaluated in Tumor necrosis factor-alpha (TNF-alpha) sensitive cell line, U937 and compared with TNF-alpha. Both species of hemoglobin, Hemoglobin A2 and Hemoglobin A0 induced apoptosis and cytotoxicity in U937 cell as measured by flow cytometry and 3-(4,5-dihydro-6-(4-(3,4-dimethoxybenzooyl)-1-piperazinyl)-2(1H)-quinoline (MTT) assay respectively. Different concentration of Hemoglobin A0 (4 ng/mL to 4000 ng/mL) induced apoptosis ranging from 9% to 16% in U937 cells. 4000 ng/mL hemoglobin A0 showed maximal apoptotic cells. TNF-alpha showed 87% apoptotic U937 cells at concentration of 1 pg/mL. HbA0 displayed cytotoxicity in U937 cell line at higher concentration in comparison to TNF-alpha. 4000 ng/mL of hemoglobin A0 showed optimal cytotoxic response in U937 cells. A dose response curve was also observed with varying doses of hemoglobin A0. U937 cells pretreated with serum activated LPS for 1 hr and incubated with different concentration of hemoglobin or human TNF-alpha for 24 h reduced the cytotoxic effect on U937. Dexamethasone treatment of U937 cells helped in protecting the HbA0 and HbA2 mediated cytotoxicity and anti-TNF-alpha antibody neutralized the hemoglobin mediated apoptosis and cytotoxicity. It is therefore apparent that human hemoglobin shares some of the bioactivities previously ascribed to TNF-alpha. Sharing of bioactivities of TNF-alpha by hemoglobin is interesting and suggests that cell free hemoglobin can mimic TNF-alpha functionally.
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http://dx.doi.org/10.1081/iph-200042309DOI Listing
May 2005

Silica induced early fibrogenic reaction in lung of mice ameliorated by Nyctanthes arbortristis extract.

Biomed Environ Sci 2002 Sep;15(3):215-22

Immunobiology Laboratory, Industrial Toxicology Research Centre, M.G. Marg, Lucknow 226001, U.P., India.

Objective: To investigate the pharmacological effect of Nyctanthes arbortristis (NAT) leaf extract in the prevention of lung injury induced by silica particles.

Method: Lung injury was induced in Swiss mice through inhalation exposure to silica particles (< 5 mu) using a Flow Past Nose Only Inhalation Chamber at the rate of -10 mg/m3 respirable mass for 5 h. Lung bronchoalveolar lavage (BAL) fluid collected between 48 and 72 h was subjected to protein profiling by electrophoresis and cytokine evaluation by solid phase sandwich ELISA. Lung histopathology was performed to evaluate lung injury.

Results: Inhalation of silica increased the level of tumor necrosis factor-alpha (TNF-alpha), and of the 66 and 63 kDa peptides in the BAL fluid in comparison to sham-treated control. Pre-treatment of silica exposed mice with NAT leaf extract significantly prevented the accumulation of TNF-alpha in the BAL fluid, but the 66 and 63 kDa peptides remained unchanged. The extract was also effective in the prevention of silica-induced early fibrogenic reactions like congestion, edema and infiltration of nucleated cells in the interstitial alveolar spaces, and thickening of alveolar septa in mouse lung.

Conclusion: NAT leaf extract helps in bypassing silica induced initial lung injury in mice.
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September 2002
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