Science.gov

Sample records for cycle inducing compounds

  1. Inhibition of Vpr-induced cell cycle abnormality by quercetin: a novel strategy for searching compounds targeting Vpr.

    PubMed

    Shimura, M; Zhou, Y; Asada, Y; Yoshikawa, T; Hatake, K; Takaku, F; Ishizaka, Y

    1999-08-01

    Vpr, an accessory gene product of HIV-1 which induces cell cycle abnormality leading to the increased HIV replication, is supposed to be a possible target for anti-AIDS drugs. We recently established a cell line (MIT-23) in which Vpr-induced cell cycle perturbation could be manipulated by a tetracycline promoter. Here, we screened anti-Vpr activity in 27 kinds of herb drugs using MIT-23 cells. One of the extracts prepared from Houttuyniae herba showed an inhibitory activity. Quercetin (QCT), a compound of this crude drug, efficiently inhibited Vpr function without affecting its expression. Furthermore, data suggested that Vpr-induced transcription from HIV-LTR was considerably abrogated by QCT. These data indicate that QCT, a flavonoid previously reported to inhibit HIV replication, also targets Vpr, implicating that MIT-23 cell provides a novel strategy for screening compounds possessing anti-Vpr activity which would be in turn utilized for clarifying the mechanism of Vpr function.

  2. Compound cycle engine program

    NASA Technical Reports Server (NTRS)

    Bobula, G. A.; Wintucky, W. T.; Castor, J. G.

    1987-01-01

    The Compound Cycle Engine (CCE) is a highly turbocharged, power compounded power plant which combines the lightweight pressure rise capability of a gas turbine with the high efficiency of a diesel. When optimized for a rotorcraft, the CCE will reduce fuel burn for a typical 2 hr (plus 30 min reserve) mission by 30 to 40 percent when compared to a conventional advanced technology gas turbine. The CCE can provide a 50 percent increase in range-payload product on this mission. A program to establish the technology base for a Compound Cycle Engine is presented. The goal of this program is to research and develop those technologies which are barriers to demonstrating a multicylinder diesel core in the early 1990's. The major activity underway is a three-phased contract with the Garrett Turbine Engine Company to perform: (1) a light helicopter feasibility study, (2) component technology development, and (3) lubricant and material research and development. Other related activities are also presented.

  3. Compound cycle engine program

    NASA Technical Reports Server (NTRS)

    Bobula, G. A.; Wintucky, W. T.; Castor, J. G.

    1986-01-01

    The Compound Cycle Engine (CCE) is a highly turbocharged, power compounded power plant which combines the lightweight pressure rise capability of a gas turbine with the high efficiency of a diesel. When optimized for a rotorcraft, the CCE will reduce fuel burned for a typical 2 hr (plus 30 min reserve) mission by 30 to 40 percent when compared to a conventional advanced technology gas turbine. The CCE can provide a 50 percent increase in range-payload product on this mission. A program to establish the technology base for a Compound Cycle Engine is presented. The goal of this program is to research and develop those technologies which are barriers to demonstrating a multicylinder diesel core in the early 1990's. The major activity underway is a three-phased contract with the Garrett Turbine Engine Company to perform: (1) a light helicopter feasibility study, (2) component technology development, and (3) lubricant and material research and development. Other related activities are also presented.

  4. Mechanisms of G1 cell cycle arrest and apoptosis in myeloma cells induced by hybrid-compound histone deacetylase inhibitor

    SciTech Connect

    Fujii, Seiko; Okinaga, Toshinori; Ariyoshi, Wataru; Takahashi, Osamu; Iwanaga, Kenjiro; Nishino, Norikazu; Tominaga, Kazuhiro; Nishihara, Tatsuji

    2013-05-10

    Highlights: •Novel histone deacetylase inhibitor Ky-2, remarkably inhibits myeloma cell growth. •Ky-2 demonstrates no cytotoxicity against normal lymphocytic cells. •Ky-2 induces cell cycle arrest through the cell cycle-associated proteins. •Ky-2 induces Bcl-2-inhibitable apoptosis through a caspase-dependent cascade. -- Abstract: Objectives: Histone deacetylase (HDAC) inhibitors are new therapeutic agents, used to treat various types of malignant cancers. In the present study, we investigated the effects of Ky-2, a hybrid-compound HDAC inhibitor, on the growth of mouse myeloma cells. Materials and methods: Myeloma cells, HS-72, P3U1, and mouse normal cells were used in this study. Effect of HDAC inhibitors on cell viability was determined by WST-assay and trypan blue assay. Cell cycle was analyzed using flow cytometer. The expression of cell cycle regulatory and the apoptosis associated proteins were examined by Western blot analysis. Hoechst’s staining was used to detect apoptotic cells. Results: Our findings showed that Ky-2 decreased the levels of HDACs, while it enhanced acetylation of histone H3. Myeloma cell proliferation was inhibited by Ky-2 treatment. Interestingly, Ky-2 had no cytotoxic effects on mouse normal cells. Ky-2 treatment induced G1-phase cell cycle arrest and accumulation of a sub-G1 phase population, while Western blotting analysis revealed that expressions of the cell cycle-associated proteins were up-regulated. Also, Ky-2 enhanced the cleavage of caspase-9 and -3 in myeloma cells, followed by DNA fragmentation. In addition, Ky-2 was not found to induce apoptosis in bcl-2 overexpressing myeloma cells. Conclusion: These findings suggest that Ky-2 induces apoptosis via a caspase-dependent cascade and Bcl-2-inhibitable mechanism in myeloma cells.

  5. A novel platinum compound inhibits constitutive Stat3 signaling and induces cell cycle arrest and apoptosis of malignant cells.

    PubMed

    Turkson, James; Zhang, Shumin; Mora, Linda B; Burns, Audrey; Sebti, Said; Jove, Richard

    2005-09-23

    Previous studies have established constitutive activation of Stat3 protein as one of the molecular changes required for tumorigenesis. To develop novel therapeutics for tumors harboring constitutively active Stat3, compounds from the NCI 2000 diversity set were evaluated for inhibition of Stat3 DNA-binding activity in vitro. Of these, a novel platinum (IV) compound, IS3 295, interacted with Stat3 and inhibited its binding to specific DNA-response elements. Further analysis suggested noncompetitive-type kinetics for the inhibition of Stat3 binding to DNA. In human and mouse tumor cell lines with constitutively active Stat3, IS3 295 selectively attenuated Stat3 signaling, thereby inducing cell growth arrest at G0/G1 phase and apoptosis. Moreover, in transformed cells, IS3 295 repressed expression of cyclin D1 and bcl-xL, two of the known Stat3-regulated genes that are overexpressed in malignant cells, suggesting that IS3 295 mediates anti-tumor cell activity in part by blocking Stat3-mediated sub-version of cell growth and apoptotic signals. Together, our findings provide evidence for the inhibition of Stat3 activity and biological functions by IS3 295 through interaction with Stat3 protein. This study represents a significant advance in small molecule-based approaches to target Stat3 and suggests potential new applications for platinum (IV) complexes as modulators of the Stat3 pathway for cancer therapy.

  6. Potent organometallic osmium compounds induce mitochondria-mediated apoptosis and S-phase cell cycle arrest in A549 non-small cell lung cancer cells.

    PubMed

    van Rijt, Sabine H; Romero-Canelón, Isolda; Fu, Ying; Shnyder, Steve D; Sadler, Peter J

    2014-05-01

    The problems of acquired resistance associated with platinum drugs may be addressed by chemotherapeutics based on other transition metals as they offer the possibility of novel mechanisms of action. In this study, the cellular uptake and induction of apoptosis in A549 human non-small cell lung cancer cells of three promising osmium(II) arene complexes containing azopyridine ligands, [Os(η(6)-arene)(p-R-phenylazopyridine)X]PF6, where arene is p-cymene or biphenyl, R is OH or NMe2, and X is Cl or I, were investigated. These complexes showed time-dependent (4–48 h) potent anticancer activity with highest potency after 24 h (IC50 values ranging from 0.1 to 3.6 μM). Cellular uptake of the three compounds as quantified by ICP-MS, was independent of their logP values (hydrophobicity). Furthermore, maximum cell uptake was observed after 24 h, with evident cell efflux of the osmium after 48 and 72 h of exposure, which correlated with the corresponding IC50 values. The most active compound 2, [Os(η(6)-p-cymene)(NMe2-phenylazopyridine)I]PF6, was taken up by lung cancer cells predominately in a temperature-dependent manner indicating that energy-dependent mechanisms are important in the uptake of 2. Cell fractionation studies showed that all three compounds accumulated mainly in cellular membranes. Furthermore, compound 2 induced apoptosis and caused accumulation in the S-phase of the cell cycle. In addition, 2 induced cytochrome c release and alterations in mitochondrial membrane potential even after short exposure times, indicating that mitochondrial apoptotic pathways are involved. This study represents the first steps towards understanding the mode of action of this promising class of new osmium-based chemotherapeutics.

  7. Microbial cycling of volatile organic sulfur compounds.

    PubMed

    Lomans, B P; van der Drift, C; Pol, A; Op den Camp, H J M

    2002-04-01

    Microbial cycling of volatile organic sulfur compounds (VOSCs), especially dimethyl sulfide (DMS) and methanethiol (MT), is intensively studied because these compounds play an important role in the processes of global warming, acid precipitation, and the global sulfur cycle. VOSC concentrations in freshwater sediments are low due to the balance between the formation and degradation of these compounds. These reactions occur for the greater part at the oxic/anoxic interphase of sediment and water column. In contrast to marine ecosystems, where dimethylsulfoniopropionate is the main precursor of MT and DMS, in freshwater ecosystems, VOSCs are formed mainly by methylation of sulfide and to a lesser extent from the degradation of S-containing amino acids. One of the major routes for DMS and MT formation through sulfide methylation is anaerobic O-demethylation of methoxylated aromatic compounds. Inhibition studies have revealed that the major part of the endogenously produced MT and DMS is degraded anaerobically by methanogens. The major bacterial groups involved in formation and consumption of VOSCs are described. PMID:12022467

  8. Technology developments for a compound cycle engine

    NASA Technical Reports Server (NTRS)

    Bobula, George A.; Wintucky, William T.; Castor, J. G.

    1988-01-01

    The Compound Cycle Engine (CCE) is a highly turbocharged, power compounded power plant which combines the light weight pressure rise capability of a gas turbine with the high efficiency of a diesel. When optimized for a rotorcraft, the CCE will reduce fuel burned for a typical 2 hour (plus 30 min reserve) mission by 30 to 40 percent when compared to a conventional advanced technology gas turbine. The CCE can provide a 50 percent increase in range-payload product on this mission. Results of recent activities in a program to establish the technology base for a CCE are presented. The objective of this program is to research and develop those critical technologies which are necessary for the demonstration of a multicylinder diesel core in the early 1990s. A major accomplishment was the initial screening and identification of a lubricant which has potential for meeting the material wear rate limits of the application. An in-situ wear measurement system also was developed to provide accurate, readily obtainable, real time measurements of ring and liner wear. Wear data, from early single cylinder engine tests, are presented to show correlation of the in-situ measurements and the system's utility in determining parametric wear trends. A plan to demonstrate a compound cycle engine by the mid 1990s is included.

  9. Compound cycle engine for helicopter application

    NASA Technical Reports Server (NTRS)

    Castor, Jere G.

    1986-01-01

    The Compound Cycle Engine (CCE) is a highly turbocharged, power compounded, ultra-high power density, light-weight diesel engine. The turbomachinery is similar to a moderate pressure ratio, free power turbine engine and the diesel core is high speed and a low compression ratio. This engine is considered a potential candidate for future military light helicopter applications. This executive summary presents cycle thermodynamic (SFC) and engine weight analyses performed to establish general engine operating parameters and configuration. An extensive performance and weight analysis based on a typical two hour helicopter (+30 minute reserve) mission determined final conceptual engine design. With this mission, CCE performance was compared to that of a T-800 class gas turbine engine. The CCE had a 31% lower-fuel consumption and resulted in a 16% reduction in engine plus fuel and fuel tank weight. Design SFC of the CCE is 0.33 lb-HP-HR and installed wet weight is 0.43 lbs/HP. The major technology development areas required for the CCE are identified and briefly discussed.

  10. Compound cycle engine for helicopter application

    NASA Technical Reports Server (NTRS)

    Castor, Jere; Martin, John; Bradley, Curtiss

    1987-01-01

    The compound cycle engine (CCE) is a highly turbocharged, power-compounded, ultra-high-power-density, lightweight diesel engine. The turbomachinery is similar to a moderate-pressure-ratio, free-power-turbine gas turbine engine and the diesel core is high speed and a low compression ratio. This engine is considered a potential candidate for future military helicopter applications. Cycle thermodynamic specific fuel consumption (SFC) and engine weight analyses performed to establish general engine operating parameters and configurations are presented. An extensive performance and weight analysis based on a typical 2-hour helicopter (+30 minute reserve) mission determined final conceptual engine design. With this mission, CCE performance was compared to that of a contemporary gas turbine engine. The CCE had a 31 percent lower-fuel consumption and resulted in a 16 percent reduction in engine plus fuel and fuel tank weight. Design SFC of the CCE is 0.33 lb/hp-hr and installed wet weight is 0.43 lb/hp. The major technology development areas required for the CCE are identified and briefly discussed.

  11. Sparstolonin B, a novel plant derived compound, arrests cell cycle and induces apoptosis in N-myc amplified and N-myc nonamplified neuroblastoma cells.

    PubMed

    Kumar, Ambrish; Fan, Daping; Dipette, Donald J; Singh, Ugra S

    2014-01-01

    Neuroblastoma is one of the most common solid tumors and accounts for ∼ 15% of all the cancer related deaths in the children. Despite the standard therapy for advanced disease including chemotherapy, surgery, and radiation, the mortality rate remains high for these patients. Hence, novel therapeutic agents are desperately needed. Here we examined the anticancer activity of a novel plant-derived compound, sparstolonin B (SsnB; 8,5'-dihydroxy-4-phenyl-5,2'-oxidoisocoumarin) using neuroblastoma cell lines of different genetics. SsnB was recently isolated from an aquatic Chinese herb, Sparganium stoloniferum, and tubers of this herb have been used in traditional Chinese medicine for the treatment of several inflammatory diseases and cancers. Our cell viability and morphological analysis indicated that SsnB at 10 µM concentration significantly inhibited the growth of both N-myc amplified (SK-N-BE(2), NGP, and IMR-32 cells) and N-myc nonamplified (SH-SY5Y and SKNF-1 cells) neuroblastoma cells. The flow cytometric analyses suggested that SsnB arrests the cell cycle progression at G2-M phase in all neuroblastoma cell lines tested. Exposure of SsnB inhibited the compact spheroid formation and reduced the tumorigenicity of SH-SY5Y cells and SK-N-BE(2) cells in in vitro 3-D cell culture assays (anchorage-independent colony formation assay and hanging drop assay). SsnB lowers the cellular level of glutathione (GSH), increases generation of reactive oxygen species and activates the cleavage of caspase-3 whereas co-incubation of a GSH precursor, N-acetylcysteine, along with SsnB attenuates the inhibitory effects of SsnB and increases the neuroblastoma cell viability. Our results for the first time demonstrate that SsnB possesses anticancer activity indicating that SsnB-induced reactive oxygen species generation promotes apoptotic cell death in neuroblastoma cells of different genetic background. Thus these data suggest that SsnB can be a promising drug candidate in

  12. PDTC, metal chelating compound, induces G1 phase cell cycle arrest in vascular smooth muscle cells through inducing p21Cip1 expression: involvement of p38 mitogen activated protein kinase.

    PubMed

    Moon, Sung-Kwon; Jung, Sun-Young; Choi, Yung-Hyun; Lee, Young-Choon; Patterson, Cam; Kim, Cheorl-Ho

    2004-02-01

    Pyrrolidine dithiocarbamate (PDTC), a metal chelating compound, is known to induce cell death in vascular smooth muscle cells (VSMC). However, the molecular mechanism for PDTC-induced VSMC death is not well understood. Addition of PDTC reduced cell growth and DNA synthesis on VSMC in low density conditions. However, in serum depleted medium, PDTC did not affect the cell viability, suggesting that certain factors in serum may mediate the cytotoxic effect of PDTC. Several metal chelators prevented the cell death induced by PDTC. In a serum-deprived condition, addition of exogenous metals, copper, iron, and zinc, restored the cytotoxic effect of PDTC. These data indicate that metals such as copper, iron, and zinc in serum may mediate the cytotoxic effect of PDTC. At low VSMC density in 10% FBS, treatment of PDTC, which induced a cell-cycle block in G1-phase, induced down-regulation of cyclins and CDKs and up-regulation of the CDK inhibitor p21 expression, whereas up-regulation of p27 or p53 by PDTC was not observed. Finally, we determined PDTC-mediated signaling pathway involved in VSMC death. Among relevant pathways, PDTC induced marked activation of p38MAPK and JNK. Expression of dominant negative p38MAPK and SB203580, a p38MAPK specific inhibitor, blocked PDTC-dependent p38MAPK, growth inhibition, and p21 expression. These data demonstrate that the p38MAPK pathway participates in p21 induction, which consequently leads to decrease of cyclin D1/cdk4 and cyclin E/cdk2 complexes and PDTC-dependent VSMC growth inhibition. In conclusion, an understanding of the molecular mechanisms of PDTC in VSMC provides a theoretical basis for clinical approaches using antioxidant therapies in atherosclerosis. PMID:14603533

  13. The ethanol extract of Scutellaria baicalensis and the active compounds induce cell cycle arrest and apoptosis including upregulation of p53 and Bax in human lung cancer cells

    SciTech Connect

    Gao Jiayu; Morgan, Winston A.; Sanchez-Medina, Alberto; Corcoran, Olivia

    2011-08-01

    Despite a lack of scientific authentication, Scutellaria baicalensis is clinically used in Chinese medicine as a traditional adjuvant to chemotherapy of lung cancer. In this study, cytotoxicity assays demonstrated that crude ethanolic extracts of S. baicalensis were selectively toxic to human lung cancer cell lines A549, SK-LU-1 and SK-MES-1 compared with normal human lung fibroblasts. The active compounds baicalin, baicalein and wogonin did not exhibit such selectivity. Following exposure to the crude extracts, cellular protein expression in the cancer cell lines was assessed using 2D gel electrophoresis coupled with MALDI-TOF-MS/Protein Fingerprinting. The altered protein expression indicated that cell growth arrest and apoptosis were potential mechanisms of cytotoxicity. These observations were supported by PI staining cell cycle analysis using flow cytometry and Annexin-V apoptotic analysis by fluorescence microscopy of cancer cells treated with the crude extract and pure active compounds. Moreover, specific immunoblotting identification showed the decreased expression of cyclin A results in the S phase arrest of A549 whereas the G{sub 0}/G{sub 1} phase arrest in SK-MES-1 cells results from the decreased expression of cyclin D1. Following treatment, increased expression in the cancer cells of key proteins related to the enhancement of apoptosis was observed for p53 and Bax. These results provide further insight into the molecular mechanisms underlying the clinical use of this herb as an adjuvant to lung cancer therapy. - Research Highlights: > Scutellaria baicalensis is a clinical adjuvant to lung cancer chemotherapy in China. > Scutellaria ethanol extracts selectively toxic to A549, SK-LU-1 and SK-MES-1. > Baicalin, baicalein and wogonin were toxic to all lung cancer cell lines. > Proteomics identified increased p53 and BAX in response to Scutellaria extracts.

  14. The Thermodynamics of the Krebs Cycle and Related Compounds

    NASA Astrophysics Data System (ADS)

    Miller, Stanley L.; Smith-Magowan, David

    1990-07-01

    A survey is made of the enthalpies of formation, third law entropies and Gibbs energies available for Krebs cycle and related compounds. These include formate, acetate, succinate, fumarate, glycine, alanine, aspartate and glutamate. The potential of the NAD+/NADH couple is recalculated based on the ethanol/acetaldehyde and isopropanol/acetone equilibria. The reported enzyme catalyzed equilibrium constants of the Krebs cycle reactions are evaluated with estimated errors. These 28 equilibria form a network of reactions that is solved by a least squares regression procedure giving Gibbs energies of formation for 21 Krebs cycle and related compounds. They appear to be accurate to ±0.4 kJṡmol-1 for some compounds but ±1 kJṡmol-1 in less favorable cases. This procedure indicates which third law ΔfG and enzyme equilibria are inaccurate, and allows very accurate ΔfG to be determined for compounds related to the Krebs cycle by measuring enzyme equilibrium constants.

  15. Preliminary evaluation of a compound cycle engine for shipboard gensets

    SciTech Connect

    Castor, J.G.; Wintucky, W.T.

    1986-06-01

    The results of a thermodynamic cycle (SFC) and weight analysis performed to establish engine configuration, size, weight and performance are reported. Baseline design configuration was a 2,000 hour MTBO Compound Cycle Engine (CCE) for a helicopter application. The CCE configuration was extrapolated out to a 10,000 MTBO for a shipboard genset application. The study showed that an advanced diesel engine design (CCE) could be substantially lighter and smaller (79% and 82% respectively) than todays contemporary genset diesel engine. Although the CCE was not optimized, it had about a 7% reduction in mission fuel consumption over today's genset diesels. The CCE is a turbocharged, power-compounded, high power density, low-compression ratio diesel engine. Major technology development areas are presented.

  16. Preliminary evaluation of a compound cycle engine for shipboard gensets

    NASA Technical Reports Server (NTRS)

    Castor, J. G.; Wintucky, W. T.

    1986-01-01

    The results of a thermodynamic cycle (SFC) and weight analysis performed to establish engine configuration, size, weight and performance are reported. Baseline design configuration was a 2,000 hour MTBO Compound Cycle Engine (CCE) for a helicopter application. The CCE configuration was extrapolated out to a 10,000 MTBO for a shipboard genset application. The study showed that an advanced diesel engine design (CCE) could be substantially lighter and smaller (79% and 82% respectively) than todays contemporary genset diesel engine. Although the CCE was not optimized, it had about a 7% reduction in mission fuel consumption over today's genset diesels. The CCE is a turbocharged, power-compounded, high power density, low-compression ratio diesel engine. Major technology development areas are presented.

  17. Microbial cycling of volatile organic sulfur compounds in anoxic environments.

    PubMed

    Lomans, B P; Pol, A; Op den Camp, H J M

    2002-01-01

    Microbial cycling of volatile organic sulfur compounds (VOSC) is investigated due to the impact these compounds are thought to have on environmental processes like global temperature control, acid precipitation and the global sulfur cycle. Moreover, in several kinds of industries like composting plants and the paper industry VOSC are released causing odor problems. Waste streams containing these compounds must be treated in order to avoid the release of these compounds to the atmosphere. This paper describes the general mechanisms for the production and degradation of methanethiol (MT) and dimethyl sulfide (DMS), two ubiquitous VOSC in anaerobic environments. Slurry incubations indicated that methylation of sulfide and MT resulting in MT and DMS, respectively, is one of the major mechanisms for VOSC in sulfide-rich anaerobic environments. An anaerobic bacterium that is responsible for the formation of MT and DMS through the anaerobic methylation of H2S and MT was isolated from a freshwater pond after enrichment with syringate as a methyl group donating compound and sole carbon source. In spite of the continuous formation of MT and DMS, steady state concentrations are generally very low. This is due to the microbial degradation of these compounds. Experiments with sulfate-rich and sulfate-amended sediment slurries demonstrated that besides methanogens, sulfate-reducing bacteria can also degrade MT and DMS, provided that sulfate is available. A methanogen was isolated that is able to grow on DMS as the sole carbon source. A large survey of sediments slurries of various origin demonstrated that both isolates are commonly occurring inhabitants of anaerobic environments.

  18. Metabolic Basis of Visual Cycle Inhibition by Retinoid and Nonretinoid Compounds in the Vertebrate Retina*

    PubMed Central

    Golczak, Marcin; Maeda, Akiko; Bereta, Grzegorz; Maeda, Tadao; Kiser, Philip D.; Hunzelmann, Silke; von Lintig, Johannes; Blaner, William S.; Palczewski, Krzysztof

    2008-01-01

    In vertebrate retinal photoreceptors, the absorption of light by rhodopsin leads to photoisomerization of 11-cis-retinal to its all-trans isomer. To sustain vision, a metabolic system evolved that recycles all-trans-retinal back to 11-cis-retinal. The importance of this visual (retinoid) cycle is underscored by the fact that mutations in genes encoding visual cycle components induce a wide spectrum of diseases characterized by abnormal levels of specific retinoid cycle intermediates. In addition, intense illumination can produce retinoid cycle by-products that are toxic to the retina. Thus, inhibition of the retinoid cycle has therapeutic potential in physiological and pathological states. Four classes of inhibitors that include retinoid and nonretinoid compounds have been identified. We investigated the modes of action of these inhibitors by using purified visual cycle components and in vivo systems. We report that retinylamine was the most potent and specific inhibitor of the retinoid cycle among the tested compounds and that it targets the retinoid isomerase, RPE65. Hydrophobic primary amines like farnesylamine also showed inhibitory potency but a short duration of action, probably due to rapid metabolism. These compounds also are reactive nucleophiles with potentially high cellular toxicity. We also evaluated the role of a specific protein-mediated mechanism on retinoid cycle inhibitor uptake by the eye. Our results show that retinylamine is transported to and taken up by the eye by retinol-binding protein-independent and retinoic acid-responsive gene product 6-independent mechanisms. Finally, we provide evidence for a crucial role of lecithin: retinol acyltransferase activity in mediating tissue specific absorption and long lasting therapeutic effects of retinoid-based visual cycle inhibitors. PMID:18195010

  19. Induced cycle structures of the hyperoctahedral group

    SciTech Connect

    Chen, W.Y.C.

    1992-06-01

    The hyperoctahedral group B{sub n} is treated as the automorphism group of the n-dimensional hypercube, denoted Q{sub n}, which is nowadays understood to be a graph on 2{sup n} vertices. It is well-known that B{sub n} can be represented by the group of signed permutations. In other words, any signed permutation induces a permutation on the vertices of Q{sub n} which preserves adjacencies. Moreover, signed permutations also a permutation group on the edge of Q{sub n}, denoted H{sub n}. We study the cycle structures of both B{sub n} and H{sub n}. The technique proposed here is to determine the induced cycle structure of a signed permutation by the number of fixed vertices or fixed edges of a signed permutation in the cyclic group generated by a signed permutation of given type. Here we directly define the type of a signed permutation by a double partition based on its signed cycle decomposition. In this way, we obtain explicit formulas for the number of induced cycles on vertices as well as edges of Q{sub n} of a signed permutation in terms of its type. By further exploring the connection between cycle indices and the structure of fixed points, we obtain the cycle indices of both B{sub n} and H{sub n}. Our formula for the cycle index of B{sub n}is much more natural and considerably simpler than that of Harrison and High. Meanwhile, the cycle structure of H{sub n} seems to have been untouched before, although it is well motivated by nonisomorphic edge colorings of Q{sub n} as well as by the recent interest in symmetries of computer networks.

  20. p53 modulates the AMPK inhibitor compound C induced apoptosis in human skin cancer cells

    SciTech Connect

    Huang, Shi-Wei; Wu, Chun-Ying; Wang, Yen-Ting; Kao, Jun-Kai; Lin, Chi-Chen; Chang, Chia-Che; Mu, Szu-Wei; Chen, Yu-Yu; Chiu, Husan-Wen; Chang, Chuan-Hsun; Liang, Shu-Mei; Chen, Yi-Ju; Huang, Jau-Ling; Shieh, Jeng-Jer

    2013-02-15

    Compound C, a well-known inhibitor of the intracellular energy sensor AMP-activated protein kinase (AMPK), has been reported to cause apoptotic cell death in myeloma, breast cancer cells and glioma cells. In this study, we have demonstrated that compound C not only induced autophagy in all tested skin cancer cell lines but also caused more apoptosis in p53 wildtype skin cancer cells than in p53-mutant skin cancer cells. Compound C can induce upregulation, phosphorylation and nuclear translocalization of the p53 protein and upregulate expression of p53 target genes in wildtype p53-expressing skin basal cell carcinoma (BCC) cells. The changes of p53 status were dependent on DNA damage which was caused by compound C induced reactive oxygen species (ROS) generation and associated with activated ataxia-telangiectasia mutated (ATM) protein. Using the wildtype p53-expressing BCC cells versus stable p53-knockdown BCC sublines, we present evidence that p53-knockdown cancer cells were much less sensitive to compound C treatment with significant G2/M cell cycle arrest and attenuated the compound C-induced apoptosis but not autophagy. The compound C induced G2/M arrest in p53-knockdown BCC cells was associated with the sustained inactive Tyr15 phosphor-Cdc2 expression. Overall, our results established that compound C-induced apoptosis in skin cancer cells was dependent on the cell's p53 status. - Highlights: ► Compound C caused more apoptosis in p53 wildtype than p53-mutant skin cancer cells. ► Compound C can upregulate p53 expression and induce p53 activation. ► Compound C induced p53 effects were dependent on ROS induced DNA damage pathway. ► p53-knockdown attenuated compound C-induced apoptosis but not autophagy. ► Compound C-induced apoptosis in skin cancer cells was dependent on p53 status.

  1. Identification of Novel Small Organic Compounds with Diverse Structures for the Induction of Epstein-Barr Virus (EBV) Lytic Cycle in EBV-Positive Epithelial Malignancies

    PubMed Central

    Choi, Chung King; Ho, Dona N.; Hui, Kwai Fung; Kao, Richard Y.; Chiang, Alan K. S.

    2015-01-01

    Phorbol esters, which are protein kinase C (PKC) activators, and histone deacetylase (HDAC) inhibitors, which cause enhanced acetylation of cellular proteins, are the main classes of chemical inducers of Epstein-Barr virus (EBV) lytic cycle in latently EBV-infected cells acting through the PKC pathway. Chemical inducers which induce EBV lytic cycle through alternative cellular pathways may aid in defining the mechanisms leading to lytic cycle reactivation and improve cells’ responsiveness towards lytic induction. We performed a phenotypic screening on a chemical library of 50,240 novel small organic compounds to identify novel class(es) of strong inducer(s) of EBV lytic cycle in gastric carcinoma (GC) and nasopharyngeal carcinoma (NPC) cells. Five hit compounds were selected after three successive rounds of increasingly stringent screening. All five compounds are structurally diverse from each other and distinct from phorbol esters or HDAC inhibitors. They neither cause hyperacetylation of histone proteins nor significant PKC activation at their working concentrations, suggesting that their biological mode of action are distinct from that of the known chemical inducers. Two of the five compounds with rapid lytic-inducing action were further studied for their mechanisms of induction of EBV lytic cycle. Unlike HDAC inhibitors, lytic induction by both compounds was not inhibited by rottlerin, a specific inhibitor of PKCδ. Interestingly, both compounds could cooperate with HDAC inhibitors to enhance EBV lytic cycle induction in EBV-positive epithelial cancer cells, paving way for the development of strategies to increase cells’ responsiveness towards lytic reactivation. One of the two compounds bears structural resemblance to iron chelators and the other strongly activates the MAPK pathways. These structurally diverse novel organic compounds may represent potential new classes of chemicals that can be used to investigate any alternative mechanism(s) leading to EBV

  2. Identification of Novel Small Organic Compounds with Diverse Structures for the Induction of Epstein-Barr Virus (EBV) Lytic Cycle in EBV-Positive Epithelial Malignancies.

    PubMed

    Choi, Chung King; Ho, Dona N; Hui, Kwai Fung; Kao, Richard Y; Chiang, Alan K S

    2015-01-01

    Phorbol esters, which are protein kinase C (PKC) activators, and histone deacetylase (HDAC) inhibitors, which cause enhanced acetylation of cellular proteins, are the main classes of chemical inducers of Epstein-Barr virus (EBV) lytic cycle in latently EBV-infected cells acting through the PKC pathway. Chemical inducers which induce EBV lytic cycle through alternative cellular pathways may aid in defining the mechanisms leading to lytic cycle reactivation and improve cells' responsiveness towards lytic induction. We performed a phenotypic screening on a chemical library of 50,240 novel small organic compounds to identify novel class(es) of strong inducer(s) of EBV lytic cycle in gastric carcinoma (GC) and nasopharyngeal carcinoma (NPC) cells. Five hit compounds were selected after three successive rounds of increasingly stringent screening. All five compounds are structurally diverse from each other and distinct from phorbol esters or HDAC inhibitors. They neither cause hyperacetylation of histone proteins nor significant PKC activation at their working concentrations, suggesting that their biological mode of action are distinct from that of the known chemical inducers. Two of the five compounds with rapid lytic-inducing action were further studied for their mechanisms of induction of EBV lytic cycle. Unlike HDAC inhibitors, lytic induction by both compounds was not inhibited by rottlerin, a specific inhibitor of PKCδ. Interestingly, both compounds could cooperate with HDAC inhibitors to enhance EBV lytic cycle induction in EBV-positive epithelial cancer cells, paving way for the development of strategies to increase cells' responsiveness towards lytic reactivation. One of the two compounds bears structural resemblance to iron chelators and the other strongly activates the MAPK pathways. These structurally diverse novel organic compounds may represent potential new classes of chemicals that can be used to investigate any alternative mechanism(s) leading to EBV

  3. Ligand modulation of a dinuclear platinum compound leads to mechanistic differences in cell cycle progression and arrest

    PubMed Central

    Menon, Vijay R.; Peterson, Erica J.; Valerie, Kristoffer; Farrell, Nicholas P.; Povirk, Lawrence F.

    2013-01-01

    Despite similar structures and DNA binding profiles, two recently synthesized dinuclear platinum compounds are shown to elicit highly divergent effects on cell cycle progression. In colorectal HCT116 cells, BBR3610 shows a classical G2/M arrest with initial accumulation in S phase, but the derivative compound BBR3610-DACH, formed by introduction of the 1,2-diaminocyclohexane (DACH) as carrier ligand, results in severe G1/S as well as G2/M phase arrest, with nearly complete S phase depletion. The origin of this unique effect was studied. Cellular interstrand crosslinking as assayed by comet analysis was similar for both compounds, confirming previous in vitro results obtained on plasmid DNA. Immunoblotting revealed a stabilization of p53 and concomitant transient increases in p21 and p27 proteins after treatment with BBR3610-DACH. Cell viability assays and cytometric analysis of p53 and p21 null cells indicated that BBR3610-DACH-induced cell cycle arrest was p21-dependent and partially p53-dependent. However, an increase in the levels of cyclin E was observed with steady state levels of CDK2 and Cdc25A, suggesting that the G1 block occurs downstream of CDK/cyclin complex formation. The G2/M block was corroborated with decreased levels of cyclin A and cyclin B1. Surprisingly, BBR3610-DACH-induced G1 block was independent of ATM and ATR. Finally, both compounds induced apoptosis, with BBR3610-DACH showing a robust PARP-1 cleavage that was not associated with caspase-3/7 cleavage. In summary, BBR3610-DACH is a DNA binding platinum agent with unique inhibitory effects on cell cycle progression that could be further developed as a chemotherapeutic agent complementary to cisplatin and oxaliplatin. PMID:24161784

  4. Parvovirus infection-induced cell death and cell cycle arrest

    PubMed Central

    Chen, Aaron Yun; Qiu, Jianming

    2011-01-01

    The cytopathic effects induced during parvovirus infection have been widely documented. Parvovirus infection-induced cell death is often directly associated with disease outcomes (e.g., anemia resulting from loss of erythroid progenitors during parvovirus B19 infection). Apoptosis is the major form of cell death induced by parvovirus infection. However, nonapoptotic cell death, namely necrosis, has also been reported during infection of the minute virus of mice, parvovirus H-1 and bovine parvovirus. Recent studies have revealed multiple mechanisms underlying the cell death during parvovirus infection. These mechanisms vary in different parvoviruses, although the large nonstructural protein (NS)1 and the small NS proteins (e.g., the 11 kDa of parvovirus B19), as well as replication of the viral genome, are responsible for causing infection-induced cell death. Cell cycle arrest is also common, and contributes to the cytopathic effects induced during parvovirus infection. While viral NS proteins have been indicated to induce cell cycle arrest, increasing evidence suggests that a cellular DNA damage response triggered by an invading single-stranded parvoviral genome is the major inducer of cell cycle arrest in parvovirus-infected cells. Apparently, in response to infection, cell death and cell cycle arrest of parvovirus-infected cells are beneficial to the viral cell lifecycle (e.g., viral DNA replication and virus egress). In this article, we will discuss recent advances in the understanding of the mechanisms underlying parvovirus infection-induced cell death and cell cycle arrest. PMID:21331319

  5. Formation of bioorganic compounds in aqueous solution induced by plasma.

    PubMed

    Harada, K; Takasaki, M; Naraoka, H; Nomoto, S

    1984-01-01

    When plasma jet of Ar-arc plasma was blown into an aqueous solution containing organic compounds, oxidation reactions were induced in the solution. The plasma-induced reaction was a powerful oxidation which could convert a methyl to a carboxyl group and cleave a carbon-carbon bond without using any oxidizing reagent. This reaction could be regarded as a model for the solar plasma-induced reaction in the primitive hydrosphere.

  6. Thermal Cycling Effects on the Thermoelectric Properties of n-Type In, Ce based Skutterudite Compounds

    SciTech Connect

    Biswas, Krishnendu; Subramanian, Mas A.; Good, Morris S.; Roberts, Kamandi C.; Hendricks, Terry J.

    2012-06-14

    N-type In-filled CoSb3 are known skutterudite compounds that have shown promising thermoelectric (TE) properties resulting in high dimensionless figure of merit values at elevated temperatures. Their use in various waste heat recovery applications will require that they survive and operate after exposure to harsh thermal cycling environments. This research focused on uncovering the thermal cycling effects on thermoelectric properties of n-type In0.2Co4Sb12 and In0.2Ce0.15Co4Sb12 skutterudite compositions as well as quantifying their temperature-dependent structural properties (elastic modulus, shear modulus, and Poisson's ratio). It was observed that the Seebeck coefficient and resistivity increased only slightly in the double-filled In,Ce skutterudite materials upon thermal cycling. In the In-filled skutterudites the Seebeck coefficient remained approximately the same on thermal cycling, while electrical resistivity increased significantly after thermal cycling. Results also show that thermal conductivity marginally decreases in the case of In-filled skutterudites, whereas the reduction is more pronounced in In, Ce-based skutterudite compounds. The possible reason for this kind of reduction can be attributed to grain pinning effects due to formation of nano inclusions. High temperature structural property measurements (i.e., Young's modulus and shear modulus) are also reported and the results show that these structural properties decrease slowly as temperature increases and the compounds are structurally stable after numerous thermal cycles.

  7. Induced natural convection thermal cycling device

    DOEpatents

    Heung, Leung Kit

    2002-08-13

    A device for separating gases, especially isotopes, by thermal cycling of a separation column using a pressure vessel mounted vertically and having baffled sources for cold and heat. Coils at the top are cooled with a fluid such as liquid nitrogen. Coils at the bottom are either electrical resistance coils or a tubular heat exchange. The sources are shrouded with an insulated "top hat" and simultaneously opened and closed at the outlets to cool or heat the separation column. Alternatively, the sources for cold and heat are mounted separately outside the vessel and an external loop is provided for each circuit.

  8. Valproic Acid Induces Antimicrobial Compound Production in Doratomyces microspores.

    PubMed

    Zutz, Christoph; Bacher, Markus; Parich, Alexandra; Kluger, Bernhard; Gacek-Matthews, Agnieszka; Schuhmacher, Rainer; Wagner, Martin; Rychli, Kathrin; Strauss, Joseph

    2016-01-01

    One of the biggest challenges in public health is the rising number of antibiotic resistant pathogens and the lack of novel antibiotics. In recent years there is a rising focus on fungi as sources of antimicrobial compounds due to their ability to produce a large variety of bioactive compounds and the observation that virtually every fungus may still contain yet unknown so called "cryptic," often silenced, compounds. These putative metabolites could include novel bioactive compounds. Considerable effort is spent on methods to induce production of these "cryptic" metabolites. One approach is the use of small molecule effectors, potentially influencing chromatin landscape in fungi. We observed that the supernatant of the fungus Doratomyces (D.) microsporus treated with valproic acid (VPA) displayed antimicrobial activity against Staphylococcus (S.) aureus and two methicillin resistant clinical S. aureus isolates. VPA treatment resulted in enhanced production of seven antimicrobial compounds: cyclo-(L-proline-L-methionine) (cPM), p-hydroxybenzaldehyde, cyclo-(phenylalanine-proline) (cFP), indole-3-carboxylic acid, phenylacetic acid (PAA) and indole-3-acetic acid. The production of the antimicrobial compound phenyllactic acid was exclusively detectable after VPA treatment. Furthermore three compounds, cPM, cFP, and PAA, were able to boost the antimicrobial activity of other antimicrobial compounds. cPM, for the first time isolated from fungi, and to a lesser extent PAA, are even able to decrease the minimal inhibitory concentration of ampicillin in MRSA strains. In conclusion we could show in this study that VPA treatment is a potent tool for induction of "cryptic" antimicrobial compound production in fungi, and that the induced compounds are not exclusively linked to the secondary metabolism. Furthermore this is the first discovery of the rare diketopiperazine cPM in fungi. Additionally we could demonstrate that cPM and PAA boost antibiotic activity against antibiotic

  9. Valproic Acid Induces Antimicrobial Compound Production in Doratomyces microspores

    PubMed Central

    Zutz, Christoph; Bacher, Markus; Parich, Alexandra; Kluger, Bernhard; Gacek-Matthews, Agnieszka; Schuhmacher, Rainer; Wagner, Martin; Rychli, Kathrin; Strauss, Joseph

    2016-01-01

    One of the biggest challenges in public health is the rising number of antibiotic resistant pathogens and the lack of novel antibiotics. In recent years there is a rising focus on fungi as sources of antimicrobial compounds due to their ability to produce a large variety of bioactive compounds and the observation that virtually every fungus may still contain yet unknown so called “cryptic,” often silenced, compounds. These putative metabolites could include novel bioactive compounds. Considerable effort is spent on methods to induce production of these “cryptic” metabolites. One approach is the use of small molecule effectors, potentially influencing chromatin landscape in fungi. We observed that the supernatant of the fungus Doratomyces (D.) microsporus treated with valproic acid (VPA) displayed antimicrobial activity against Staphylococcus (S.) aureus and two methicillin resistant clinical S. aureus isolates. VPA treatment resulted in enhanced production of seven antimicrobial compounds: cyclo-(L-proline-L-methionine) (cPM), p-hydroxybenzaldehyde, cyclo-(phenylalanine-proline) (cFP), indole-3-carboxylic acid, phenylacetic acid (PAA) and indole-3-acetic acid. The production of the antimicrobial compound phenyllactic acid was exclusively detectable after VPA treatment. Furthermore three compounds, cPM, cFP, and PAA, were able to boost the antimicrobial activity of other antimicrobial compounds. cPM, for the first time isolated from fungi, and to a lesser extent PAA, are even able to decrease the minimal inhibitory concentration of ampicillin in MRSA strains. In conclusion we could show in this study that VPA treatment is a potent tool for induction of “cryptic” antimicrobial compound production in fungi, and that the induced compounds are not exclusively linked to the secondary metabolism. Furthermore this is the first discovery of the rare diketopiperazine cPM in fungi. Additionally we could demonstrate that cPM and PAA boost antibiotic activity

  10. Nutrient cycling in bedform induced hyporheic zones

    NASA Astrophysics Data System (ADS)

    Bardini, L.; Boano, F.; Cardenas, M. B.; Revelli, R.; Ridolfi, L.

    2012-05-01

    The hyporheic zone is an ecotone connecting the stream and groundwater ecosystem that plays a significant role for stream biogeochemistry. Water exchange across the stream-sediment interface and biogeochemical reactions in the streambed concur to affect subsurface solute concentrations and eventually nutrient cycling in the fluvial corridor. In this paper we investigate the interplay of hydrological and biogeochemical processes in a duned streambed and their effect on spatial distribution of solutes. We employ a numerical model to simulate the turbulent water flow and the pressure distribution over the dunes, and then to evaluate the flow field and the biogeochemical reactions in the hyporheic sediments. Sensitivity analyses are performed to analyze the influence of hydrological and chemical properties of the system on solute reaction rates. The results demonstrate the effect of stream velocity and sediment permeability on the chemical zonation. Changing sediment permeability as well as stream velocity directly affects the nutrient supply and the residence times in the streambed, thus controlling the reaction rates under the dune. Stream-water quality is also shown to influence the reactive behavior of the sediments. In particular, the availability of dissolved organic carbon determines whether the streambed acts as a net sink or source of nitrate. This study represents a step towards a better understanding of the complex interactions between hydrodynamical and biogeochemical processes in the hyporheic zone.

  11. Polydatin inhibits growth of lung cancer cells by inducing apoptosis and causing cell cycle arrest.

    PubMed

    Zhang, Yusong; Zhuang, Zhixiang; Meng, Qinghui; Jiao, Yang; Xu, Jiaying; Fan, Saijun

    2014-01-01

    Polydatin (PD), a small natural compound from Polygonum cuspidatum, has a number of biological functions. However, the anticancer activity of PD has been poorly investigated. In the present study, thiazolyl blue tetrazolium bromide assay was used to evaluate the inhibitory effect of PD on cell growth. Cell cycle distribution and apoptosis were investigated by flow cytometry. In addition, the expression of several proteins associated with apoptosis and cell cycle were analyzed by western blot analysis. The results demonstrated that PD significantly inhibits the proliferation of A549 and NCI-H1975 lung cancer cell lines and causes dose-dependent apoptosis. Cell cycle analysis revealed that PD induces S phase cell cycle arrest. Western blot analysis showed that the expression of Bcl-2 decreased as that of Bax increased, and the expression of cyclin D1 was also suppressed. The results suggest that PD has potential therapeutic applications in the treatment of lung cancer. PMID:24348867

  12. Sister-chromatid exchanges and cell-cycle delay in Chinese hamster V79 cells treated with 9 organophosphorus compounds (8 pesticides and 1 defoliant).

    PubMed

    Chen, H H; Sirianni, S R; Huang, C C

    1982-03-01

    Significant increase of sister-chromatid exchanges (SCE) in V79 cells treated with 2 organophosphorus pesticides (OPP), fenthion and oxydemeton-methyl, was observed. The other 7 compounds (6 OPP and 1 defoliant) namely, amaze, azinphos-methyl, bolstar, DEF-defoliant, fensulfothion, monitor and nemacur caused no increase of SCE frequencies at the doses tested. All the compounds except fensulfothion and oxydemeton-methyl induced cell-cycle delay in varying degrees. Cell-cycle delay caused by an OPP was found to be dose-dependent. Based on these data as well as others reported, it would appear that OPP which induce no SCE increase and no or slight cell-cycle delay could be considered as good candidates to substitute the pesticides that have been found to be harmful to the environment. PMID:6211614

  13. Sister-chromatid exchanges and cell-cycle delay in Chinese hamster V79 cells treated with 9 organophosphorus compounds (8 pesticides and 1 defoliant).

    PubMed

    Chen, H H; Sirianni, S R; Huang, C C

    1982-03-01

    Significant increase of sister-chromatid exchanges (SCE) in V79 cells treated with 2 organophosphorus pesticides (OPP), fenthion and oxydemeton-methyl, was observed. The other 7 compounds (6 OPP and 1 defoliant) namely, amaze, azinphos-methyl, bolstar, DEF-defoliant, fensulfothion, monitor and nemacur caused no increase of SCE frequencies at the doses tested. All the compounds except fensulfothion and oxydemeton-methyl induced cell-cycle delay in varying degrees. Cell-cycle delay caused by an OPP was found to be dose-dependent. Based on these data as well as others reported, it would appear that OPP which induce no SCE increase and no or slight cell-cycle delay could be considered as good candidates to substitute the pesticides that have been found to be harmful to the environment.

  14. Salidroside induces cell-cycle arrest and apoptosis in human breast cancer cells

    SciTech Connect

    Hu, Xiaolan; Zhang, Xianqi; Qiu, Shuifeng; Yu, Daihua; Lin, Shuxin

    2010-07-16

    Research highlights: {yields} Salidroside inhibits the growth of human breast cancer cells. {yields} Salidroside induces cell-cycle arrest of human breast cancer cells. {yields} Salidroside induces apoptosis of human breast cancer cell lines. -- Abstract: Recently, salidroside (p-hydroxyphenethyl-{beta}-D-glucoside) has been identified as one of the most potent compounds isolated from plants of the Rhodiola genus used widely in traditional Chinese medicine, but pharmacokinetic data on the compound are unavailable. We were the first to report the cytotoxic effects of salidroside on cancer cell lines derived from different tissues, and we found that human breast cancer MDA-MB-231 cells (estrogen receptor negative) were sensitive to the inhibitory action of low-concentration salidroside. To further investigate the cytotoxic effects of salidroside on breast cancer cells and reveal possible ER-related differences in response to salidroside, we used MDA-MB-231 cells and MCF-7 cells (estrogen receptor-positive) as models to study possible molecular mechanisms; we evaluated the effects of salidroside on cell growth characteristics, such as proliferation, cell cycle duration, and apoptosis, and on the expression of apoptosis-related molecules. Our results demonstrated for the first time that salidroside induces cell-cycle arrest and apoptosis in human breast cancer cells and may be a promising candidate for breast cancer treatment.

  15. Emerging contaminants of public health significance as water quality indicator compounds in the urban water cycle.

    PubMed

    Pal, Amrita; He, Yiliang; Jekel, Martin; Reinhard, Martin; Gin, Karina Yew-Hoong

    2014-10-01

    The contamination of the urban water cycle (UWC) with a wide array of emerging organic compounds (EOCs) increases with urbanization and population density. To produce drinking water from the UWC requires close examination of their sources, occurrence, pathways, and health effects and the efficacy of wastewater treatment and natural attenuation processes that may occur in surface water bodies and groundwater. This paper researches in details the structure of the UWC and investigates the routes by which the water cycle is increasingly contaminated with compounds generated from various anthropogenic activities. Along with a thorough survey of chemicals representing compound classes such as hormones, antibiotics, surfactants, endocrine disruptors, human and veterinary pharmaceuticals, X-ray contrast media, pesticides and metabolites, disinfection-by-products, algal toxins and taste-and-odor compounds, this paper provides a comprehensive and holistic review of the occurrence, fate, transport and potential health impact of the emerging organic contaminants of the UWC. This study also illustrates the widespread distribution of the emerging organic contaminants in the different aortas of the ecosystem and focuses on future research needs.

  16. Platinum-zoledronate complex blocks gastric cancer cell proliferation by inducing cell cycle arrest and apoptosis.

    PubMed

    Yang, Hui; Qiu, Ling; Zhang, Li; Lv, Gaochao; Li, Ke; Yu, Huixin; Xie, Minhao; Lin, Jianguo

    2016-08-01

    A series of novel dinuclear platinum complexes based on the bisphosphonate ligands have been synthesized and characterized in our recent study. For the purpose of discovering the pharmacology and action mechanisms of this kind of compounds, the most potent compound [Pt(en)]2ZL was selected for systematic investigation. In the present study, the inhibition effect on the human gastric cancer cell lines SGC7901 and action mechanism of [Pt(en)]2ZL were investigated. The traditional 3-[4,5-dimethyl-2-thiazolyl]-2,5-diphenyl-2-tetrazolium bromide (MTT) assay and colony formation assay were carried out to study the effect of [Pt(en)]2ZL on the cell viability and proliferation capacity, respectively. The senescence-associated β-galactosidase staining and immunofluorescence staining were also performed to assess the cell senescence and microtubule polymerization. Fluorescence staining and flow cytometry (FCM) were used to monitor the cell cycle distribution and apoptosis, and Western blot analysis was applied to examine the expression of several apoptosis-related proteins. The results demonstrated that [Pt(en)]2ZL exhibited remarkable cytotoxicity and anti-proliferative effects on the SGC7901 cells in a dose- and time-dependent manner, and it also induced cell senescence and abnormal microtubule assembly. The cell apoptosis and cell cycle arrest induced by [Pt(en)]2ZL were also observed with the fluorescence staining and FCM. The expressions of cell cycle regulators (p53, p21, cyclin D1, cyclin E, and cyclin-dependent kinase (CDK)2) and apoptosis-related proteins (Bcl-2, Bax, caspase-3, poly ADP ribose polymerase (PARP), and survivin) were regulated by the treatment of [Pt(en)]2ZL, resulting in the cell cycle arrest and apoptosis. Therefore, [Pt(en)]2ZL exerted anti-tumor effect on the gastric cancer via inducing cell cycle arrest at G1/S phase and apoptosis. PMID:26891667

  17. Anaphylaxis induced by ingestion of a pollen compound.

    PubMed

    Chivato, T; Juan, F; Montoro, A; Laguna, R

    1996-01-01

    We report on the case of a 32-year-old atopic patient who showed a severe anaphylactic reaction due to the ingestion of a pollen compound prepared in an herbalist's. A few minutes after ingestion, generalized pruritus, difuse erythema, facial edema, cough, hoarseness and dysphonia appeared, and the emergency administration of subcutaneous epinephrine and intravenous methylprednisolone was necessary. Skin tests with a battery of inhalants and food allergens were performed. The patient only showed sensitization to Artemisia vulgaris, Taraxacum officinalis and Salix alba. Specific IgE levels were evaluated by FEIA-CAP giving a seric level of CAP class 3 to Artemisia vulgaris and class 2 to Taraxacum officinalis and Salix alba. Samples of the pollen compound were shown in the microscopical analysis to be 93% pollens and 6% fungi. In the qualitative study Taraxacum officinalis (15%), Artemisia vulgaris (5%) and Salix alba (15%) were the main elements identified. In summary, this case study describes a food-induced systemic reaction due to a pollen compound in an atopic patient with a history of allergic rhinitis. Pollinic patients must be informed on the risks that the consumption of these compounds might cause.

  18. Biotransformations utilizing β-oxidation cycle reactions in the synthesis of natural compounds and medicines.

    PubMed

    Swizdor, Alina; Panek, Anna; Milecka-Tronina, Natalia; Kołek, Teresa

    2012-01-01

    β-Oxidation cycle reactions, which are key stages in the metabolism of fatty acids in eucaryotic cells and in processes with a significant role in the degradation of acids used by microbes as a carbon source, have also found application in biotransformations. One of the major advantages of biotransformations based on the β-oxidation cycle is the possibility to transform a substrate in a series of reactions catalyzed by a number of enzymes. It allows the use of sterols as a substrate base in the production of natural steroid compounds and their analogues. This route also leads to biologically active compounds of therapeutic significance. Transformations of natural substrates via β-oxidation are the core part of the synthetic routes of natural flavors used as food additives. Stereoselectivity of the enzymes catalyzing the stages of dehydrogenation and addition of a water molecule to the double bond also finds application in the synthesis of chiral biologically active compounds, including medicines. Recent advances in genetic, metabolic engineering, methods for the enhancement of bioprocess productivity and the selectivity of target reactions are also described. PMID:23443116

  19. Biotransformations Utilizing β-Oxidation Cycle Reactions in the Synthesis of Natural Compounds and Medicines

    PubMed Central

    Œwizdor, Alina; Panek, Anna; Milecka-Tronina, Natalia; Kołek, Teresa

    2012-01-01

    β-Oxidation cycle reactions, which are key stages in the metabolism of fatty acids in eucaryotic cells and in processes with a significant role in the degradation of acids used by microbes as a carbon source, have also found application in biotransformations. One of the major advantages of biotransformations based on the β-oxidation cycle is the possibility to transform a substrate in a series of reactions catalyzed by a number of enzymes. It allows the use of sterols as a substrate base in the production of natural steroid compounds and their analogues. This route also leads to biologically active compounds of therapeutic significance. Transformations of natural substrates via β-oxidation are the core part of the synthetic routes of natural flavors used as food additives. Stereoselectivity of the enzymes catalyzing the stages of dehydrogenation and addition of a water molecule to the double bond also finds application in the synthesis of chiral biologically active compounds, including medicines. Recent advances in genetic, metabolic engineering, methods for the enhancement of bioprocess productivity and the selectivity of target reactions are also described. PMID:23443116

  20. Biotransformations utilizing β-oxidation cycle reactions in the synthesis of natural compounds and medicines.

    PubMed

    Swizdor, Alina; Panek, Anna; Milecka-Tronina, Natalia; Kołek, Teresa

    2012-12-05

    β-Oxidation cycle reactions, which are key stages in the metabolism of fatty acids in eucaryotic cells and in processes with a significant role in the degradation of acids used by microbes as a carbon source, have also found application in biotransformations. One of the major advantages of biotransformations based on the β-oxidation cycle is the possibility to transform a substrate in a series of reactions catalyzed by a number of enzymes. It allows the use of sterols as a substrate base in the production of natural steroid compounds and their analogues. This route also leads to biologically active compounds of therapeutic significance. Transformations of natural substrates via β-oxidation are the core part of the synthetic routes of natural flavors used as food additives. Stereoselectivity of the enzymes catalyzing the stages of dehydrogenation and addition of a water molecule to the double bond also finds application in the synthesis of chiral biologically active compounds, including medicines. Recent advances in genetic, metabolic engineering, methods for the enhancement of bioprocess productivity and the selectivity of target reactions are also described.

  1. Htsc and Related Compounds Microwave Absorption Evolution in Multiple Remagnettzation Cycles

    NASA Astrophysics Data System (ADS)

    Shirokov, M. I.

    2000-09-01

    HTSC magnetomodulated microwave absorption hysteresis signal drift during sweep cycling, comparable to the hysteresis amplitude and disappearing at Tc, is found. It is related to Neel-type pair interactions, arising between reversing inhomogenuosly at the field scan turns shielding currents of weak links contours, widely distributed across superconductor surface. Microwave response selforganization features are observed: the signal nonmonotonous saturation, oscillation with decay around new equilibrium position, irregularities points, the shifts pronounced magnetic field anisotropy in isotropic ceramics and the signal high sensitivity to the `field-plane' angle inversion in single crystals (parity violation). The magnetic energy interplay between critical and precritical contours during critical state establishment seems to be the cause. Another picture arises in related magnetic compounds: no relaxation in oxide ferrites, if isolators, and the drift logarithmic-like decay in conducting ones. Strongly sulfur-doped 1-2-3-compounds show giant signal hysteresis only in the first cycle, indicating the magnetic phase. No signal drift was detected in nonsuperconducting oxide 1-2-3-compounds. This is an intrinsic HTSC property, being essential in microwave devices.

  2. Pneumococcal Pneumolysin Induces DNA Damage and Cell Cycle Arrest

    PubMed Central

    Rai, Prashant; He, Fang; Kwang, Jimmy; Engelward, Bevin P.; Chow, Vincent T.K.

    2016-01-01

    Streptococcus pneumoniae produces pneumolysin toxin as a key virulence factor against host cells. Pneumolysin is a cholesterol-dependent cytolysin (CDC) toxin that forms lytic pores in host membranes and mediates pneumococcal disease pathogenesis by modulating inflammatory responses. Here, we show that pneumolysin, which is released during bacterial lysis, induces DNA double strand breaks (DSBs), as indicated by ataxia telangiectasia mutated (ATM)-mediated H2AX phosphorylation (γH2AX). Pneumolysin-induced γH2AX foci recruit mediator of DNA damage checkpoint 1 (MDC1) and p53 binding protein 1 (53BP1), to sites of DSBs. Importantly, results show that toxin-induced DNA damage precedes cell cycle arrest and causes apoptosis when DNA-dependent protein kinase (DNA-PK)-mediated non-homologous end joining is inhibited. Further, we observe that cells that were undergoing DNA replication harbored DSBs in greater frequency during pneumolysin treatment. This observation raises the possibility that DSBs might be arising as a result of replication fork breakdown. Additionally, neutralizing the oligomerization domain of pneumolysin with monoclonal antibody suppresses DNA damage and also cell cycle arrest, indicating that pneumolysin oligomerization is important for causing DNA damage. Taken together, this study reveals a previously unidentified ability of pneumolysin to induce cytotoxicity via DNA damage, with implications in the pathophysiology of S. pneumoniae infection. PMID:27026501

  3. Pneumococcal Pneumolysin Induces DNA Damage and Cell Cycle Arrest.

    PubMed

    Rai, Prashant; He, Fang; Kwang, Jimmy; Engelward, Bevin P; Chow, Vincent T K

    2016-01-01

    Streptococcus pneumoniae produces pneumolysin toxin as a key virulence factor against host cells. Pneumolysin is a cholesterol-dependent cytolysin (CDC) toxin that forms lytic pores in host membranes and mediates pneumococcal disease pathogenesis by modulating inflammatory responses. Here, we show that pneumolysin, which is released during bacterial lysis, induces DNA double strand breaks (DSBs), as indicated by ataxia telangiectasia mutated (ATM)-mediated H2AX phosphorylation (γH2AX). Pneumolysin-induced γH2AX foci recruit mediator of DNA damage checkpoint 1 (MDC1) and p53 binding protein 1 (53BP1), to sites of DSBs. Importantly, results show that toxin-induced DNA damage precedes cell cycle arrest and causes apoptosis when DNA-dependent protein kinase (DNA-PK)-mediated non-homologous end joining is inhibited. Further, we observe that cells that were undergoing DNA replication harbored DSBs in greater frequency during pneumolysin treatment. This observation raises the possibility that DSBs might be arising as a result of replication fork breakdown. Additionally, neutralizing the oligomerization domain of pneumolysin with monoclonal antibody suppresses DNA damage and also cell cycle arrest, indicating that pneumolysin oligomerization is important for causing DNA damage. Taken together, this study reveals a previously unidentified ability of pneumolysin to induce cytotoxicity via DNA damage, with implications in the pathophysiology of S. pneumoniae infection. PMID:27026501

  4. α-Mangostin Induces Apoptosis and Cell Cycle Arrest in Oral Squamous Cell Carcinoma Cell

    PubMed Central

    Kwak, Hyun-Ho; Park, Bong-Soo

    2016-01-01

    Mangosteen has long been used as a traditional medicine and is known to have antibacterial, antioxidant, and anticancer effects. Although the effects of α-mangostin, a natural compound extracted from the pericarp of mangosteen, have been investigated in many studies, there is limited data on the effects of the compound in human oral squamous cell carcinoma (OSCC). In this study, α-mangostin was assessed as a potential anticancer agent against human OSCC cells. α-Mangostin inhibited cell proliferation and induced cell death in OSCC cells in a dose- and time-dependent manner with little to no effect on normal human PDLF cells. α-Mangostin treatment clearly showed apoptotic evidences such as nuclear fragmentation and accumulation of annexin V and PI-positive cells on OSCC cells. α-Mangostin treatment also caused the collapse of mitochondrial membrane potential and the translocation of cytochrome c from the mitochondria into the cytosol. The expressions of the mitochondria-related proteins were activated by α-mangostin. Treatment with α-mangostin also induced G1 phase arrest and downregulated cell cycle-related proteins (CDK/cyclin). Hence, α-mangostin specifically induces cell death and inhibits proliferation in OSCC cells via the intrinsic apoptosis pathway and cell cycle arrest at the G1 phase, suggesting that α-mangostin may be an effective agent for the treatment of OSCC. PMID:27478478

  5. Pressure induced phase transitions in ceramic compounds containing tetragonal zirconia

    SciTech Connect

    Sparks, R.G.; Pfeiffer, G.; Paesler, M.A.

    1988-12-01

    Stabilized tetragonal zirconia compounds exhibit a transformation toughening process in which stress applied to the material induces a crystallographic phase transition. The phase transition is accompanied by a volume expansion in the stressed region thereby dissipating stress and increasing the fracture strength of the material. The hydrostatic component of the stress required to induce the phase transition can be investigated by the use of a high pressure technique in combination with Micro-Raman spectroscopy. The intensity of Raman lines characteristic for the crystallographic phases can be used to calculate the amount of material that has undergone the transition as a function of pressure. It was found that pressures on the order of 2-5 kBar were sufficient to produce an almost complete transition from the original tetragonal to the less dense monoclinic phase; while a further increase in pressure caused a gradual reversal of the transition back to the original tetragonal structure.

  6. Photodynamic reactions induced by compounds derived from lichens.

    PubMed

    Wennersten, G

    1979-01-01

    Contact dermatitis from lichens is now well documented but the possible influence of exposure to sunlight is less clear. Positive reactions on photopatch testing has recently been described, but whether this represented an unspecific exacerbation or a true photoallergic response was difficult to evaluate. In this study 13 different substances derived from lichens commonly found in nature were investigated with regard to their capacity to induce photo-oxidative membrane damage, as revealed by the photohemolysis technique. It was found that the earlier suggested ability to induce photosensitization could be confirmed for several of the lichen compounds investigated. It was also shown that singlet state excited oxygen may participate to some degree in some of these reactions.

  7. A novel schiff base zinc coordination compound inhibits proliferation and induces apoptosis of human osteosarcoma cells.

    PubMed

    Yan, Ming; Pang, Li; Ma, Tan-tan; Zhao, Cheng-liang; Zhang, Nan; Yu, Bing-xin; Xia, Yan

    2015-10-01

    Various kinds of schiff base metal complexes have been proven to induce apoptosis of tumor cells. However, it remains largely unknown whether schiff base zinc complexes induce apoptosis in human cancer cells. Here, we synthesized a novel schiff base zinc coordination compound (SBZCC) and investigated its effects on the growth, proliferation and apoptosis of human osteosarcoma MG-63 cells. A novel SBZCC was synthesized by chemical processes and used to treat MG-63 cells. The cell viability was determined by CCK-8 assay. The cell cycle progression, mitochondrial membrane potential and apoptotic cells were analyzed by flow cytometry. The apoptosis-related proteins levels were determined by immunoblotting. Treatment of MG-63 cells with SBZCC resulted in inhibition of cell proliferation and cell cycle arrest at G1 phase. Moreover, SBZCC significantly reduced the mitochondrial membrane potential and induced apoptosis, accompanied with increased Bax/Bcl-2 and FlasL/Fas expression as well as caspase-3/8/9 cleavage. Our results demonstrated that the synthesized novel SBZCC could inhibit the proliferation and induce apoptosis of MG-63 cells via activating both the mitochondrial and cell death receptor apoptosis pathways, suggesting that SBZCC is a promising agent for the development as anticancer drugs.

  8. Modeling and remote sensing of human induced water cycle change

    NASA Astrophysics Data System (ADS)

    Pokhrel, Yadu N.

    2016-04-01

    The global water cycle has been profoundly affected by human land-water management especially during the last century. Since the changes in water cycle can affect the functioning of a wide range of biophysical and biogeochemical processes of the Earth system, it is essential to account for human land-water management in land surface models (LSMs) which are used for water resources assessment and to simulate the land surface hydrologic processes within Earth system models (ESMs). During the last two decades, noteworthy progress has been made in modeling human impacts on the water cycle but sufficient advancements have not yet been made, especially in representing human factors in large-scale LSMs toward integrating them into ESMs. In this study, an integrated modeling framework of continental-scale water cycle, with explicit representation of climate and human induced forces (e.g., irrigation, groundwater pumping) is developed and used to reconstruct the observed water cycle changes in the past and to attribute the observed changes to climatic and human factors. The new model builds upon two different previously developed models: a global LSM called the Human Impacts and GroundWater in the MATSIRO (HiGW-MAT) and a high-resolution regional groundwater model called the LEAF-Hydro-Flood. The model is used to retro-simulate the hydrologic stores and fluxes in close dialogue with in-situ and GRACE satellite based observations at a wide range of river basin scales around the world, with a particular focus on the changes in groundwater dynamics in northwest India, Pakistan, and the High Plains and Central Valley aquifers in the US.

  9. A DNA-damage-induced cell cycle checkpoint in Arabidopsis.

    PubMed Central

    Preuss, S B; Britt, A B

    2003-01-01

    Although it is well established that plant seeds treated with high doses of gamma radiation arrest development as seedlings, the cause of this arrest is unknown. The uvh1 mutant of Arabidopsis is defective in a homolog of the human repair endonuclease XPF, and uvh1 mutants are sensitive to both the toxic effects of UV and the cytostatic effects of gamma radiation. Here we find that gamma irradiation of uvh1 plants specifically triggers a G(2)-phase cell cycle arrest. Mutants, termed suppressor of gamma (sog), that suppress this radiation-induced arrest and proceed through the cell cycle unimpeded were recovered in the uvh1 background; the resulting irradiated plants are genetically unstable. The sog mutations fall into two complementation groups. They are second-site suppressors of the uvh1 mutant's sensitivity to gamma radiation but do not affect the susceptibility of the plant to UV radiation. In addition to rendering the plants resistant to the growth inhibitory effects of gamma radiation, the sog1 mutation affects the proper development of the pollen tetrad, suggesting that SOG1 might also play a role in the regulation of cell cycle progression during meiosis. PMID:12750343

  10. Prediction of thermal cycling induced cracking in polmer matrix composites

    NASA Technical Reports Server (NTRS)

    Mcmanus, Hugh L.

    1994-01-01

    The work done in the period August 1993 through February 1994 on the 'Prediction of Thermal Cycling Induced Cracking In Polymer Matrix Composites' program is summarized. Most of the work performed in this period, as well as the previous one, is described in detail in the attached Master's thesis, 'Analysis of Thermally Induced Damage in Composite Space Structures,' by Cecelia Hyun Seon Park. Work on a small thermal cycling and aging chamber was concluded in this period. The chamber was extensively tested and calibrated. Temperatures can be controlled very precisely, and are very uniform in the test chamber. Based on results obtained in the previous period of this program, further experimental progressive cracking studies were carried out. The laminates tested were selected to clarify the differences between the behaviors of thick and thin ply layers, and to explore other variables such as stacking sequence and scaling effects. Most specimens tested were made available from existing stock at Langley Research Center. One laminate type had to be constructed from available prepreg material at Langley Research Center. Specimens from this laminate were cut and prepared at MIT. Thermal conditioning was carried out at Langley Research Center, and at the newly constructed MIT facility. Specimens were examined by edge inspection and by crack configuration studies, in which specimens were sanded down in order to examine the distribution of cracks within the specimens. A method for predicting matrix cracking due to decreasing temperatures and/or thermal cycling in all plies of an arbitrary laminate was implemented as a computer code. The code also predicts changes in properties due to the cracking. Extensive correlations between test results and code predictions were carried out. The computer code was documented and is ready for distribution.

  11. Novel synthetic protective compound, KR-22335, against cisplatin-induced auditory cell death.

    PubMed

    Shin, Yoo Seob; Song, Suk Jin; Kang, Sungun; Hwang, Hye Sook; Jung, Young-Sik; Kim, Chul-Ho

    2014-02-01

    Cisplatin [cis-diammine-dichloroplatinum (II)] is a widely used chemotherapeutic agent, and one of its most severe side effects is ototoxicity. In the course of developing a new protective agent against cisplatin-induced ototoxicity, we have been interested in a novel synthetic compound, 3-Amino-3-(4-fluoro-phenyl)-1H-quinoline-2,4-dione (KR-22335). We evaluated the effectiveness of KR-22335 as an otoprotective agent against cisplatin-induced toxicity. The otoprotective effect of KR-22335 against cisplatin was tested in vitro in cochlear organs of Corti-derived cell lines, HEI-OC1, and in vivo in a zebrafish (Danio rerio) model. Cisplatin-induced apoptosis, cell cycle arrest and an increase in intracellular reactive oxygen species (ROS) generation were demonstrated in HEI-OC1 cells. KR-22335 inhibited cisplatin-induced apoptosis and mitochondrial injury in HEI-OC1 cells. KR-22335 inhibited cisplatin-induced activation of JNK, p-38, caspase-3 and PARP in HEI-OC1 cells. Scanning and transmission electron micrographs showed that KR-22335 prevented cisplatin-induced destruction of kinocilium and stereocilia in zebrafish neuromasts. Tissue TUNEL of neuromasts in zebrafish demonstrated that KR-22335 blocked cisplatin-induced TUNEL positive hair cells in neuromasts. The results of this study suggest that KR-22335 may prevent ototoxicity caused by the administration of cisplatin through the inhibition of mitochondrial dysfunction and suppression of ROS generation. KR-22335 may be considered as a potential candidate for protective agents against cisplatin-induced ototoxicity.

  12. Comamonas testosteroni uses a chemoreceptor for tricarboxylic acid cycle intermediates to trigger chemotactic responses towards aromatic compounds.

    PubMed

    Ni, Bin; Huang, Zhou; Fan, Zheng; Jiang, Cheng-Ying; Liu, Shuang-Jiang

    2013-11-01

    Bacterial chemotaxis towards aromatic compounds has been frequently observed; however, knowledge of how bacteria sense aromatic compounds is limited. Comamonas testosteroni CNB-1 is able to grow on a range of aromatic compounds. This study investigated the chemotactic responses of CNB-1 to 10 aromatic compounds. We constructed a chemoreceptor-free, non-chemotactic mutant, CNB-1Δ20, by disruption of all 19 putative methyl-accepting chemotaxis proteins (MCPs) and the atypical chemoreceptor in strain CNB-1. Individual complementation revealed that a putative MCP (tagged MCP2201) was involved in triggering chemotaxis towards all 10 aromatic compounds. The recombinant sensory domain of MCP2201 did not bind to 3- or 4-hydroxybenzoate, protocatechuate, catechol, benzoate, vanillate and gentisate, but bound oxaloacetate, citrate, cis-aconitate, isocitrate, α-ketoglutarate, succinate, fumarate and malate. The mutant CNB-1ΔpmdF that lost the ability to metabolize 4-hydroxybenzoate and protocatechuate also lost its chemotactic response to these compounds, suggesting that taxis towards aromatic compounds is metabolism-dependent. Based on the ligand profile, we proposed that MCP2201 triggers taxis towards aromatic compounds by sensing TCA cycle intermediates. Our hypothesis was further supported by the finding that introduction of the previously characterized pseudomonad chemoreceptor (McpS) for TCA cycle intermediates into CNB-1Δ20 likewise triggered chemotaxis towards aromatic compounds.

  13. Diosgenin induces G2/M cell cycle arrest and apoptosis in human hepatocellular carcinoma cells.

    PubMed

    Li, Yongjian; Wang, Xiaorong; Cheng, Silu; Du, Juan; Deng, Zhengting; Zhang, Yani; Liu, Qun; Gao, Jingdong; Cheng, Binbin; Ling, Changquan

    2015-02-01

    Diosgenin is a major compound of Dioscoreaceae plants such as yam, which is used as a drug in Traditional Chinese Medicine, and a common vegetable worldwide. The anticancer effect of diosgenin has been reported in various tumor cells, including leukemia, gastric, colorectal, and breast cancer. However, the activity of diosgenin on hepatocellular carcinoma (HCC) and the underlying mechanism have not been completely investigated. Therefore, we investigated the efficacy and associated mechanisms of diosgenin in HCC cells. Flow cytometric analysis was performed to determine the presence of cell cycle arrest and apopotic cells. Diosgenin significantly inhibited the growth of Bel-7402, SMMC-7721 and HepG2 HCC cells in a concentration-dependent manner. Diosgenin treatment for 24 h induced G2/M cell cycle arrest and apoptosis of hepatoma cells. Diosgenin inhibited Akt phosphorylation and upregulated p21 and p27 expression, but did not alter the expression of p53, suggesting diosgenin-induced upregulation of p21 and p57 is p53-independent in HCC cells. Diosgenin induced HCC cell apoptosis by activating caspase cascades -3, -8 and -9. However, diosgenin did not affect Bcl-2 and Bax levels. In conclusion, results of the present study suggest that diosgenin may be an active anti-HCC agent obtained from natural plants and provide new insights in understanding the mechanisms of diosgenin. PMID:25434486

  14. Interannual Variations of MLS Carbon Monoxide Induced by Solar Cycle

    NASA Technical Reports Server (NTRS)

    Lee, Jae N.; Wu, Dong L.; Ruzmaikin, Alexander

    2013-01-01

    More than eight years (2004-2012) of carbon monoxide (CO) measurements from the Aura Microwave Limb Sounder (MLS) are analyzed. The mesospheric CO, largely produced by the carbon dioxide (CO2) photolysis in the lower thermosphere, is sensitive to the solar irradiance variability. The long-term variation of observed mesospheric MLS CO concentrations at high latitudes is likely driven by the solar-cycle modulated UV forcing. Despite of different CO abundances in the southern and northern hemispheric winter, the solar-cycle dependence appears to be similar. This solar signal is further carried down to the lower altitudes by the dynamical descent in the winter polar vortex. Aura MLS CO is compared with the Solar Radiation and Climate Experiment (SORCE) total solar irradiance (TSI) and also with the spectral irradiance in the far ultraviolet (FUV) region from the SORCE Solar-Stellar Irradiance Comparison Experiment (SOLSTICE). Significant positive correlation (up to 0.6) is found between CO and FUVTSI in a large part of the upper atmosphere. The distribution of this positive correlation in the mesosphere is consistent with the expectation of CO changes induced by the solar irradiance variations.

  15. Oxime-induced reactivation of carboxylesterase inhibited by organophosphorus compounds

    SciTech Connect

    Maxwell, D.M.; Lieske, C.N.; Brecht, K.M.

    1994-06-01

    A structure-activity analysis of the ability of oximes to reactivate rat plasma carboxylesterase (CaE) that was inhibited by organophosphorus (OP) compounds revealed that uncharged oximes, such as 2,3-butanedione monoxime (diacetylmonoxime) or monoisonitrosoacetone, were better reactivators than cationic oximes. Cationic oximes that are excellent reactivators of OP-inhibited acetylcholinesterase, such as pyridine-2-aldoxime or the bis-pyridine aldoximes, HI-6 and TMB. 4, produced poor reactivation of OP-inhibited CaE. The best uncharged reactivator was 2,3. butanedione monoxime, which produced complete reactivation at 0.3 mM in 2 h of CaE that was inhibited by phosphinates, alkoxy-containing phosphates, and alkoxy-containing phosphonates. Complete reactivation of CaE could be achieved even after inhibition by phosphonates with highly branched alkoxy groups, such as sarin and soman, that undergo rapid aging with acetylcholinesterase. CaE that was inhibited by phosphonates or phosphates that contained aryloxy groups were reactivated to a lesser extent. The cause of this decreased reactivation appears to be an oxime-induced aging reaction that competes with the reactivation reaction. This oxime-induced aging reaction is accelerated by electron-withdrawing substituents on the aryloxy groups of phosphonates and by the presence of multiple aryloxy groups on phosphates. Thus, reactivation and aging of OP-inhibited CaE differ from the same processes for OP- inhibited acetylcholinesterase in both their oxime specificity and inhibitor specificity and, presumably, in their underlying mechanisms.

  16. New Compounds Induce Brassinosteroid Deficient-like Phenotypes in Rice.

    PubMed

    Matsumoto, Tadashi; Yamada, Kazuhiro; Iwasaki, Ikuko; Yoshizawa, Yuko; Oh, Keimei

    2013-01-01

    Brassinosteroids (BRs) are steroidal plant hormones with potent plant growth promoting activity. Because BR-deficient mutants of rice exhibit altered plant architecture and important agronomic traits, we conducted a systemic search for specific inhibitors of BR biosynthesis to manipulate the BR levels in plant tissues. Although previous studies have been conducted with BR biosynthesis inhibitors in dicots, little is known regarding the effects of BR biosynthesis inhibition in monocot plants. In this work, we used potent inhibitors of BR biosynthesis in Arabidopsis, and we performed a hydroponic culture of rice seedlings to evaluate the effects of BR biosynthesis inhibition. Among the test compounds, we found that 1-[[2-(4-Chlorophenyl)-4-(phenoxymethyl)-1,3-dioxolan-2-yl]methyl]-1H-1,2,4-triazole (1) is a potent inhibitor that could induce phenotypes in rice seedlings that were similar to those observed in brassinosteroid deficient plants. The IC50 value for the retardation of plant growth in rice seedlings was approximately 1.27 ± 0.43 μM. The IC50 value for reducing the bending angle of the lamina joint was approximately 0.55 ± 0.15 μM. PMID:27137391

  17. Prediction of thermal cycling induced cracking in polymer matrix composites

    NASA Technical Reports Server (NTRS)

    Mcmanus, Hugh L.

    1993-01-01

    This report summarizes the work done in the period February 1993 through July 1993 on the 'Prediction of Thermal Cycling Induced Cracking In Polymer Matrix Composites' program. An oral presentation of this work was given to Langley personnel in September of 1993. This document was prepared for archival purposes. Progress studies have been performed on the effects of spatial variations in material strength. Qualitative agreement was found with observed patterns of crack distribution. These results were presented to NASA Langley personnel in November 1992. The analytical methodology developed by Prof. McManus in the summer of 1992 (under an ASEE fellowship) has been generalized. A method for predicting matrix cracking due to decreasing temperatures and/or thermal cycling in all plies of an arbitrary laminate has been implemented as a computer code. The code also predicts changes in properties due to the cracking. Experimental progressive cracking studies on a variety of laminates were carried out at Langley Research Center. Results were correlated to predictions using the new methods. Results were initially mixed. This motivated an exploration of the configuration of cracks within laminates. A crack configuration study was carried out by cutting and/or sanding specimens in order to examine the distribution of cracks within the specimens. These investigations were supplemented by dye-penetrant enhanced X-ray photographs. The behavior of thin plies was found to be different from the behavior of thicker plies (or ply groups) on which existing theories are based. Significant edge effects were also noted, which caused the traditional metric of microcracking (count of cracks on a polished edge) to be very inaccurate in some cases. With edge and configuration taken into account, rough agreement with predictions was achieved. All results to date were reviewed with NASA Langley personnel in September 1993.

  18. Pressure induced phase transition in defect chalcopyrite compounds

    NASA Astrophysics Data System (ADS)

    Meenakshi, S.

    2012-07-01

    The large band gap semiconducting compounds of the type AIIB2IIIC4VI crystallizing in the defect chalcopyrite (DCP) tetragonal structure are of great technological interest and have potential applications in non linear optical and photovoltaic devices. These compounds contain a crystallographically ordered array of vacancies (stoichiometric voids) in the cation sublattice and exhibit several interesting physical and chemical properties. The presence of the vacancies facilitates the doping of these compounds by impurities and has stimulated investigations about occurrence of order-disorder effects in the cation sublattice. In this presentation our recent experimental results on the high pressure investigations on some of the defect chalcopyrite compounds would be discussed.

  19. Rhenium(IV) compounds inducing apoptosis in cancer cells.

    PubMed

    Martínez-Lillo, José; Mastropietro, Teresa F; Lappano, Rosamaria; Madeo, Antonio; Alberto, Marta E; Russo, Nino; Maggiolini, Marcello; De Munno, Giovanni

    2011-05-14

    The anticancer properties of a series of mononuclear Re(IV) compounds of formula ReCl(4)L (where L is bpy = 2,2'-bipyridine; bpym = 2,2'-bipyrimidine; dmbpy = 4,4'-dimethyl-2,2'-bipyridine; phen = 1,10-phenanthroline) were investigated for the first time. All compounds displayed potent in vitro antiproliferative activity against selected cancer cells.

  20. A novel kind of nitrogen heterocycle compound induces apoptosis of human chronic myelogenous leukemia K562 cells.

    PubMed

    Ding, Guoyu; Liu, Feng; Yang, Ting; Jiang, Yuyang; Fu, Hua; Zhao, Yufen

    2006-06-01

    The effects of a novel kind of nitrogen heterocycle compound, which was synthesized in our laboratory previously, on human chronic myelogenous leukemia K562 cells were investigated. The morphological changes were observed by Acridine orange (AO) staining. The screened results through DNA fragmentation and the Annexin V-FITC/PI staining assay showed that compound 8 blocked cell cycles at G(1) phase which led to apoptosis. The increase of caspase-3, 8, and 9 was detected, indicating that both of death-receptor and mitochondria-pathways were activated. Compound 8 induced a biphasic alteration in mitochondrial membrane potential of K562 cells. A dramatic elevation of Ca(2+) was also observed. In addition, a transient increase of ROS was also involved in the process. This study showed that compound 8 might be a potential chemopreventive agent for chronic myelogenous leukemia. It would guide our future work to synthesize more compounds derived from compound 8, which might have better effect, and to determine the target protein. Moreover, it might also provide a background mechanism for the introduction of this new type of promising therapeutic agent.

  1. Assessment of drug-induced arrhythmic risk using limit cycle and autocorrelation analysis of human iPSC-cardiomyocyte contractility.

    PubMed

    Kirby, R Jason; Qi, Feng; Phatak, Sharangdhar; Smith, Layton H; Malany, Siobhan

    2016-08-15

    Cardiac safety assays incorporating label-free detection of human stem-cell derived cardiomyocyte contractility provide human relevance and medium throughput screening to assess compound-induced cardiotoxicity. In an effort to provide quantitative analysis of the large kinetic datasets resulting from these real-time studies, we applied bioinformatic approaches based on nonlinear dynamical system analysis, including limit cycle analysis and autocorrelation function, to systematically assess beat irregularity. The algorithms were integrated into a software program to seamlessly generate results for 96-well impedance-based data. Our approach was validated by analyzing dose- and time-dependent changes in beat patterns induced by known proarrhythmic compounds and screening a cardiotoxicity library to rank order compounds based on their proarrhythmic potential. We demonstrate a strong correlation for dose-dependent beat irregularity monitored by electrical impedance and quantified by autocorrelation analysis to traditional manual patch clamp potency values for hERG blockers. In addition, our platform identifies non-hERG blockers known to cause clinical arrhythmia. Our method provides a novel suite of medium-throughput quantitative tools for assessing compound effects on cardiac contractility and predicting compounds with potential proarrhythmia and may be applied to in vitro paradigms for pre-clinical cardiac safety evaluation. PMID:27343406

  2. Molecular markers and cell cycle inhibitors show the importance of cell cycle progression in nematode-induced galls and syncytia.

    PubMed Central

    de Almeida Engler, J; De Vleesschauwer, V; Burssens, S; Celenza, J L; Inzé, D; Van Montagu, M; Engler, G; Gheysen, G

    1999-01-01

    Root knot and cyst nematodes induce large multinucleated cells, designated giant cells and syncytia, respectively, in plant roots. We have used molecular markers to study cell cycle progression in these specialized feeding cells. In situ hybridization with two cyclin-dependent kinases and two cyclins showed that these genes were induced very early in galls and syncytia and that the feeding cells progressed through the G2 phase. By using cell cycle blockers, DNA synthesis and progression through the G2 phase, or mitosis, were shown to be essential for gall and syncytium establishment. When mitosis was blocked, further gall development was arrested. This result demonstrates that cycles of endoreduplication or other methods of DNA amplification are insufficient to drive giant cell expansion. On the other hand, syncytium development was much less affected by a mitotic block; however, syncytium expansion was inhibited. PMID:10330466

  3. Momordica cochinchinensis Spreng. seed extract suppresses breast cancer growth by inducing cell cycle arrest and apoptosis.

    PubMed

    Zheng, Lei; Zhang, Yanmin; Liu, Yanping; Yang, Xiaoyan Ou; Zhan, Yingzhuan

    2015-10-01

    The herb Momordica cochinchinensis has been used for a variety of purposes, and been shown to have anti‑cancer properties. The present study assessed the potency and the underlying mechanisms of action of the ethyl acetate extract of seeds of Momordica cochinchinensis (ESMC2) on breast cancer cells. Therefore, the effects of ESMC2 on the cell viability, cell cycle and apoptosis of MDA‑MB‑231 cells were investigated. The results showed that ESMC2 exerted a marked growth inhibitory effect on the cells. Cell cycle arrest in G2 phase following treatment with ESMC2 was associated with a marked increase in the protein levels of cyclin B1, cyclin E and cyclin-dependent kinase 1 and a decrease in cyclin D1 expression. In addition, ESMC2 dose‑dependently induced cell apoptosis, which was mediated via upregulation of the apoptosis-associated proteins p53, B-cell lymphoma 2 (Bcl‑2)‑associated X protein, Bcl-2 homologous antagonist killer and Bcl-2-associated death promoter expression, as well as downregulation of nuclear factor kappa B, Bcl‑2 and myeloid cell leukemia‑1. Furthermore, the activation of extracellular signal-regulated kinase 1/2, p38, c-Jun N-terminal kinase (JNK) and Akt phosphorylation were decreased by ESMC2 in a dose‑dependent manner, indicating that ESMC2 exerted its effects via the mitogen-activated protein kinase/JNK pathway. Furthermore, nude mouse xenotransplant models were used to evaluate the tumor growth inhibitory effects of ESMC2. The possible chemical components of ESMC2 were analyzed by gas chromatography-mass spectrometry, and 12 compounds were detected from the major peaks based on the similarity index with entries of a compound database. The results of the present study may aid in the development of novel therapies for breast cancer. PMID:26252798

  4. Momordica cochinchinensis Spreng. seed extract suppresses breast cancer growth by inducing cell cycle arrest and apoptosis.

    PubMed

    Zheng, Lei; Zhang, Yanmin; Liu, Yanping; Yang, Xiaoyan Ou; Zhan, Yingzhuan

    2015-10-01

    The herb Momordica cochinchinensis has been used for a variety of purposes, and been shown to have anti‑cancer properties. The present study assessed the potency and the underlying mechanisms of action of the ethyl acetate extract of seeds of Momordica cochinchinensis (ESMC2) on breast cancer cells. Therefore, the effects of ESMC2 on the cell viability, cell cycle and apoptosis of MDA‑MB‑231 cells were investigated. The results showed that ESMC2 exerted a marked growth inhibitory effect on the cells. Cell cycle arrest in G2 phase following treatment with ESMC2 was associated with a marked increase in the protein levels of cyclin B1, cyclin E and cyclin-dependent kinase 1 and a decrease in cyclin D1 expression. In addition, ESMC2 dose‑dependently induced cell apoptosis, which was mediated via upregulation of the apoptosis-associated proteins p53, B-cell lymphoma 2 (Bcl‑2)‑associated X protein, Bcl-2 homologous antagonist killer and Bcl-2-associated death promoter expression, as well as downregulation of nuclear factor kappa B, Bcl‑2 and myeloid cell leukemia‑1. Furthermore, the activation of extracellular signal-regulated kinase 1/2, p38, c-Jun N-terminal kinase (JNK) and Akt phosphorylation were decreased by ESMC2 in a dose‑dependent manner, indicating that ESMC2 exerted its effects via the mitogen-activated protein kinase/JNK pathway. Furthermore, nude mouse xenotransplant models were used to evaluate the tumor growth inhibitory effects of ESMC2. The possible chemical components of ESMC2 were analyzed by gas chromatography-mass spectrometry, and 12 compounds were detected from the major peaks based on the similarity index with entries of a compound database. The results of the present study may aid in the development of novel therapies for breast cancer.

  5. Signal transduction pathways leading to cell cycle arrest and apoptosis induction in cancer cells by Allium vegetable-derived organosulfur compounds: a review.

    PubMed

    Herman-Antosiewicz, Anna; Singh, Shivendra V

    2004-11-01

    Epidemiological studies continue to support the premise that dietary intake of Allium vegetables (e.g., garlic, onions and so forth) may lower the risk of various types of cancer. Anticarcinogenic effect of Allium vegetables is attributed to organosulfur compounds (OSCs) that are generated upon processing of these vegetables. Preclinical studies have provided convincing evidence to indicate that Allium vegetable-derived OSCs including diallyl sulfide, diallyl disulfide and diallyl trisulfide are highly effective in affording protection against cancer in laboratory animals induced by a variety of chemical carcinogens. Inhibition of carcinogen activation through modulation of cytochrome P450-dependent monooxygenases and/or acceleration of carcinogen detoxification via induction of phase II enzymes (glutathione transferases, quinone reductase, etc.) are believed to be responsible for protective effects of OSCs against chemically induced cancers. More recent studies have indicated that some naturally occurring OSC analogues can suppress proliferation of cancer cells in culture and inhibit growth of transplanted tumor xenografts in vivo by inducing apoptosis and/or by perturbing cell cycle progression. This review summarizes current knowledge on signal transduction pathways leading to perturbations in cell cycle progression and apoptosis induction by OSCs.

  6. High Throughput Screening Identifies a Novel Compound Protecting Cardiomyocytes from Doxorubicin-Induced Damage

    PubMed Central

    Gergely, Szabolcs; Hegedűs, Csaba; Lakatos, Petra; Kovács, Katalin; Gáspár, Renáta; Csont, Tamás; Virág, László

    2015-01-01

    Antracyclines are effective antitumor agents. One of the most commonly used antracyclines is doxorubicin, which can be successfully used to treat a diverse spectrum of tumors. Application of these drugs is limited by their cardiotoxic effect, which is determined by a lifetime cumulative dose. We set out to identify by high throughput screening cardioprotective compounds protecting cardiomyocytes from doxorubicin-induced injury. Ten thousand compounds of ChemBridge's DIVERSet compound library were screened to identify compounds that can protect H9C2 rat cardiomyocytes against doxorubicin-induced cell death. The most effective compound proved protective in doxorubicin-treated primary rat cardiomyocytes and was further characterized to demonstrate that it significantly decreased doxorubicin-induced apoptotic and necrotic cell death and inhibited doxorubicin-induced activation of JNK MAP kinase without having considerable radical scavenging effect or interfering with the antitumor effect of doxorubicin. In fact the compound identified as 3-[2-(4-ethylphenyl)-2-oxoethyl]-1,2-dimethyl-1H-3,1-benzimidazol-3-ium bromide was toxic to all tumor cell lines tested even without doxorubicine treatment. This benzimidazole compound may lead, through further optimalization, to the development of a drug candidate protecting the heart from doxorubicin-induced injury. PMID:26137186

  7. Shockwave-induced compound action potentials in the peripheral nerve.

    PubMed

    Wehner, H D; Sellier, K

    1981-01-01

    To verify a presumed interaction between shockwaves arisen by impacts of high velocity projectiles and nervous tissue an electrophysiological experiment is performed with the following results: In peripheral nerves regular compound action potentials (CAPs) are provoked by shockwaves the amplitudes of which are increased corresponding to the pressure intensity of the shockwaves. The nerve shows no electrical activity below a certain pressure threshold (0.75 bar). Saturation of the CAP amplitude occurs beyond a pressure limit of 8 bar.

  8. Radiation induced chemical changes of phenolic compounds in strawberries

    NASA Astrophysics Data System (ADS)

    Breitfellner, F.; Solar, S.; Sontag, G.

    2003-06-01

    In unirradiated strawberries four phenolic acids (gallic acid, p-coumaric acid, caffeic acid and 4-hydroxybenzoic acid), the flavonoids (+)-catechin, (-)-epicatechin and glycosides from kaempferol and quercetin were determined by reversed phase chromatography with diode array detection. Characteristic linear dose/concentration relationships were found for 4-hydroxybenzoic acid and two unidentified compounds. One of them may be usable as marker to prove an irradiation treatment.

  9. Metrological characterization of a cycle-ergometer to optimize the cycling induced by functional electrical stimulation on patients with stroke.

    PubMed

    Comolli, Lorenzo; Ferrante, Simona; Pedrocchi, Alessandra; Bocciolone, Marco; Ferrigno, Giancarlo; Molteni, Franco

    2010-05-01

    Functional electrical stimulation (FES) is a well established method in the rehabilitation of stroke patients. Indeed, a bilateral movement such as cycling induced by FES would be crucial for these patients who had an unilateral motor impairment and had to recover an equivalent use of limbs. The aim of this study was to develop a low-cost meteorologically qualified cycle-ergometer, optimized for patients with stroke. A commercial ergometer was instrumented with resistive strain gauges and was able to provide the torque produced at the right and left crank, independently. The developed system was integrated with a stimulator, obtaining a novel FES cycling device able to control in real-time the movement unbalance. A dynamic calibration of the sensors was performed and a total torque uncertainty was computed. The system was tested on a healthy subject and on a stroke patient. Results demonstrated that the proposed sensors could be successfully used during FES cycling sessions where the maximum torque produced is about 9Nm, an order of magnitude less than the torque produced during voluntary cycling. This FES cycling system will assist in future investigations on stroke rehabilitation by means of FES and in new exercise regimes designed specifically for patients with unilateral impairments.

  10. Metrological characterization of a cycle-ergometer to optimize the cycling induced by functional electrical stimulation on patients with stroke.

    PubMed

    Comolli, Lorenzo; Ferrante, Simona; Pedrocchi, Alessandra; Bocciolone, Marco; Ferrigno, Giancarlo; Molteni, Franco

    2010-05-01

    Functional electrical stimulation (FES) is a well established method in the rehabilitation of stroke patients. Indeed, a bilateral movement such as cycling induced by FES would be crucial for these patients who had an unilateral motor impairment and had to recover an equivalent use of limbs. The aim of this study was to develop a low-cost meteorologically qualified cycle-ergometer, optimized for patients with stroke. A commercial ergometer was instrumented with resistive strain gauges and was able to provide the torque produced at the right and left crank, independently. The developed system was integrated with a stimulator, obtaining a novel FES cycling device able to control in real-time the movement unbalance. A dynamic calibration of the sensors was performed and a total torque uncertainty was computed. The system was tested on a healthy subject and on a stroke patient. Results demonstrated that the proposed sensors could be successfully used during FES cycling sessions where the maximum torque produced is about 9Nm, an order of magnitude less than the torque produced during voluntary cycling. This FES cycling system will assist in future investigations on stroke rehabilitation by means of FES and in new exercise regimes designed specifically for patients with unilateral impairments. PMID:20171923

  11. Polynuclear platinum anticancer drugs are more potent than cisplatin and induce cell cycle arrest in glioma1

    PubMed Central

    Billecke, Christine; Finniss, Susan; Tahash, Laura; Miller, Cathie; Mikkelsen, Tom; Farrell, Nicholas P.; Bögler, Oliver

    2006-01-01

    We have evaluated the efficacy of the multinuclear platinum chemotherapeutics BBR3464, BBR3571, and BBR3610 against glioma cells in culture and animal models and investigated their mechanism of action at the cellular level. In a clonogenic assay, BBR3610, the most potent compound, had an IC90 dose (achieving 90% colony formation inhibition) that was 250 times lower than that of cisplatin for both LNZ308 and LN443 glioma cells. In subcutaneous xenografts of U87MG glioma cells, BBR3610 approximately doubled the time it took for a tumor to reach a predetermined size and significantly extended survival when these cells were implanted intracranially. Analysis of apoptosis and cell cycle distribution showed that BBR compounds induced G2/M arrest in the absence of cell death, while cisplatin predominantly induced apoptosis. Interestingly, the BBR compounds and cisplatin both induced extracellular signal-regulated kinase 1/2 phosphorylation, and inhibition of this pathway at the level of MEK antagonized the induction of G2/M arrest or apoptosis, respectively. Analysis of Chk1 and Chk2 status did not show any differential effects of the drugs, and it is thus unlikely to underlie the difference in response. Similarly, the drugs did not differentially modulate survivin levels, and knockdown of survivin did not convert the response to BBR3610 to apoptosis. Together, these findings support continued development of BBR3610 for clinical use against glioma and provide a framework for future investigation of mechanism of action. PMID:16723633

  12. TGEV nucleocapsid protein induces cell cycle arrest and apoptosis through activation of p53 signaling

    SciTech Connect

    Ding, Li; Huang, Yong; Du, Qian; Dong, Feng; Zhao, Xiaomin; Zhang, Wenlong; Xu, Xingang; Tong, Dewen

    2014-03-07

    Highlights: • TGEV N protein reduces cell viability by inducing cell cycle arrest and apoptosis. • TGEV N protein induces cell cycle arrest and apoptosis by regulating p53 signaling. • TGEV N protein plays important roles in TGEV-induced cell cycle arrest and apoptosis. - Abstract: Our previous studies showed that TGEV infection could induce cell cycle arrest and apoptosis via activation of p53 signaling in cultured host cells. However, it is unclear which viral gene causes these effects. In this study, we investigated the effects of TGEV nucleocapsid (N) protein on PK-15 cells. We found that TGEV N protein suppressed cell proliferation by causing cell cycle arrest at the S and G2/M phases and apoptosis. Characterization of various cellular proteins that are involved in regulating cell cycle progression demonstrated that the expression of N gene resulted in an accumulation of p53 and p21, which suppressed cyclin B1, cdc2 and cdk2 expression. Moreover, the expression of TGEV N gene promoted translocation of Bax to mitochondria, which in turn caused the release of cytochrome c, followed by activation of caspase-3, resulting in cell apoptosis in the transfected PK-15 cells following cell cycle arrest. Further studies showed that p53 inhibitor attenuated TGEV N protein induced cell cycle arrest at S and G2/M phases and apoptosis through reversing the expression changes of cdc2, cdk2 and cyclin B1 and the translocation changes of Bax and cytochrome c induced by TGEV N protein. Taken together, these results demonstrated that TGEV N protein might play an important role in TGEV infection-induced p53 activation and cell cycle arrest at the S and G2/M phases and apoptosis occurrence.

  13. Profiling the NIH Small Molecule Repository for Compounds That Generate H2O2 by Redox Cycling in Reducing Environments

    PubMed Central

    2010-01-01

    We have screened the Library of Pharmacologically Active Compounds (LOPAC) and the National Institutes of Health (NIH) Small Molecule Repository (SMR) libraries in a horseradish peroxidase–phenol red (HRP-PR) H2O2 detection assay to identify redox cycling compounds (RCCs) capable of generating H2O2 in buffers containing dithiothreitol (DTT). Two RCCs were identified in the LOPAC set, the ortho-naphthoquinone β-lapachone and the para-naphthoquinone NSC 95397. Thirty-seven (0.02%) concentration-dependent RCCs were identified from 195,826 compounds in the NIH SMR library; 3 singleton structures, 9 ortho-quinones, 2 para-quinones, 4 pyrimidotriazinediones, 15 arylsulfonamides, 2 nitrothiophene-2-carboxylates, and 2 tolyl hydrazides. Sixty percent of the ortho-quinones and 80% of the pyrimidotriazinediones in the library were confirmed as RCCs. In contrast, only 3.9% of the para-quinones were confirmed as RCCs. Fifteen of the 251 arylsulfonamides in the library were confirmed as RCCs, and since we screened 17,868 compounds with a sulfonamide functional group we conclude that the redox cycling activity of the arylsulfonamide RCCs is due to peripheral reactive enone, aromatic, or heterocyclic functions. Cross-target queries of the University of Pittsburgh Drug Discovery Institute (UPDDI) and PubChem databases revealed that the RCCs exhibited promiscuous bioactivity profiles and have populated both screening databases with significantly higher numbers of active flags than non-RCCs. RCCs were promiscuously active against protein targets known to be susceptible to oxidation, but were also active in cell growth inhibition assays, and against other targets thought to be insensitive to oxidation. Profiling compound libraries or the hits from screening campaigns in the HRP-PR H2O2 detection assay significantly reduce the timelines and resources required to identify and eliminate promiscuous nuisance RCCs from the candidates for lead optimization. PMID:20070233

  14. Supine effect of passive cycling movement induces vagal withdrawal

    PubMed Central

    Fujita, Daisuke; Kubo, Kousei; Takagi, Daisuke; Nishida, Yuusuke

    2015-01-01

    [Purpose] The purpose of this study was to examine changes in vagal tone during passive exercise while supine. [Subjects and Methods] Eleven healthy males lay supine for 5 min and then performed passive cycling for 10 min using a passive cycling machine. The lower legs moved through a range of motion defined by 90° and 180° knee joint angles at 60 rpm. Respiratory rates were maintained at 0.25 Hz to elicit respiratory sinus arrhythmia. Heart rate variability was analyzed using the time domain analysis, as the root mean squared standard differences between adjacent R-R intervals (rMSSD), and spectrum domain analysis of the high frequency (HF) component. [Results] Compared to rest, passive cycling decreased rMSSD (rest, 66.6 ± 92.6 ms; passive exercise, 53.5 ± 32.5 ms). However, no significant changes in HR or HF were observed (rest, 68.2 ± 6.9 bpm, 65.6 ± 12.0 n.u.; passive exercise, 70.2 ± 7.2 bpm, 67.9 ± 10.0 n.u.). [Conclusion] These results suggest that passive exercise decreases rMMSD through supine-stimulated mechanoreceptors with no effect on HR or HF. Therefore, rMSSD is not affected by hydrostatic pressure during passive cycling in the supine position. PMID:26696706

  15. Knowledge Based Leadership for Cycles of Culturally Induced Educational Distress.

    ERIC Educational Resources Information Center

    Powers, P. J.

    American schools have recently been exposed to a grave cycle of educational distress advanced by both internal and external constituencies for a variety of reasons, which range from political correctness to vouchers. Responses by educational administrators appeared to have found solace in the overt practice of deliberate inaction rather than…

  16. Pseudolaric Acid B Induced Cell Cycle Arrest, Autophagy and Senescence in Murine Fibrosarcoma L929 Cell

    PubMed Central

    hua Yu, Jing; yu Liu, Chun; bin Zheng, Gui; Zhang, Li Ying; hui Yan, Ming; yan Zhang, Wen; ying Meng, Xian; fang Yu, Xiao

    2013-01-01

    Objective: PAB induced various cancer cell apoptosis, cell cycle arrest and senescence. But in cell line murine fibrosarcoma L929, PAB did not induce apoptosis, but autophagy, therefore it was thought by us as a good model to research the relationship of cell cycle arrest, autophagy and senescence bypass apoptosis. Methods: Inhibitory ratio was assessed by 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) analysis. Phase contrast microscopy visualized cell morphology. Hoechst 33258 staining for nuclear change, propidium iodode (PI) staining for cell cycle, monodansylcadaverine (MDC) staining for autophagy, and rodanmine 123 staining for mitochondrial membrane potential (MMP) were measured by fluorescence microscopy or flowcytometry. Apoptosis was determined by DNA ladder test. Protein kinase C (PKC) activity was detected by PKC assay kit. SA-β-galactosidase assay was used to detect senescence. Protein expression was examined by western blot. Results: PAB inhibited L929 cell growth in time-and dose-dependent manner. At 12 h, 80 μmol/L PAB induced obvious mitotic arrest; at 24 h, PAB began to induce autophagy; at 36 h, cell-treated with PAB slip into G1 cell cycle; and 3 d PAB induced senescence. In time sequence PAB induced firstly cell cycle arrest, then autophagy, then slippage into G1 phase, lastly senescence. Senescent cells had high level of autophagy, inhibiting autophagy led to apoptosis, and no senescence. PAB activated PKC activity to induce cell cycle arrest, autophagy and senescence, inhibiting PKC activity suppressed cell cycle arrest, autophagy and senescence. Conclusion: PAB induced cell cycle arrest, autophagy and senescence in murine fibrosarcoma L929 cell through PKC. PMID:23630435

  17. ApoG2 induces cell cycle arrest of nasopharyngeal carcinoma cells by suppressing the c-Myc signaling pathway

    PubMed Central

    Hu, Zhe-Yu; Sun, Jian; Zhu, Xiao-Feng; Yang, Dajun; Zeng, Yi-Xin

    2009-01-01

    Background apogossypolone (ApoG2) is a novel derivate of gossypol. We previously have reported that ApoG2 is a promising compound that kills nasopharyngeal carcinoma (NPC) cells by inhibiting the antiapoptotic function of Bcl-2 proteins. However, some researchers demonstrate that the antiproliferative effect of gossypol on breast cancer cells is mediated by induction of cell cycle arrest. So this study was aimed to investigate the effect of ApoG2 on cell cycle proliferation in NPC cells. Results We found that ApoG2 significantly suppressed the expression of c-Myc in NPC cells and induced arrest at the DNA synthesis (S) phase in a large percentage of NPC cells. Immunoblot analysis showed that expression of c-Myc protein was significantly downregulated by ApoG2 and that the expression of c-Myc's downstream molecules cyclin D1 and cyclin E were inhibited whereas p21 was induced. To further identify the cause-effect relationship between the suppression of c-Myc signaling pathway and induction of cell cycle arrest, the expression of c-Myc was interfered by siRNA. The results of cell cycle analysis showed that the downregulation of c-Myc signaling pathway by siRNA interference could cause a significant arrest of NPC cell at S phase of the cell cycle. In CNE-2 xenografts, ApoG2 significantly downregulated the expression of c-Myc and suppressed tumor growth in vivo. Conclusion Our findings indicated that ApoG2 could potently disturb the proliferation of NPC cells by suppressing c-Myc signaling pathway. This data suggested that the inhibitory effect of ApoG2 on NPC cell cycle proliferation might contribute to its use in anticancer therapy. PMID:19698176

  18. Drought-induced Changes in Dryland Soil Biogeochemical Cycles

    NASA Astrophysics Data System (ADS)

    Belnap, J.; Darrouzet-Nardi, A.; Duniway, M.; Ferrenberg, S.; Hoover, D. L.; Reed, S.

    2015-12-01

    Approximately 41% of Earth´s terrestrial surface consists of drylands and they are an important biome on all continents. Although dryland biota would be expected to be drought adapted, they can be surprisingly vulnerable to extended dry periods with subsequent consequences for biogeochemical cycles. Biological soil crusts, constituting up to 70% of the living cover in these regions, are important in these cycles. They fix both N and C, providing a significant percentage of regional and global inputs. However, extended drought reduces both types of inputs, as biocrusts are only metabolically active when wet, yet losses continue even when soils are dry. In addition, extended droughts can result in their mortality. The amount of net soil C exchange of biocrusted soils is controversial, but in SE Utah, soil C uptake only occurred when only when soils were wet. As soils are infrequently wet, annual balances were negative during the 2 year study and with future extended droughts or increased temperatures that reduce soil moisture, these losses will become even greater. As with C, N fixation also requires biocrusts be wet and thus inputs decline with extended drought or higher temperatures that both reduce input and result in lichen and cyanobacterial mortality. And similarly, N losses continue even when soils are dry. Loss of biocrust mosses can profoundly alter N cycles. Desert plants are also affected by drought: in plots where experimental drought was imposed, plants had lower photosynthetic rates and higher leaf C:N, which will likely affect productivity and decomposition rates and thus have further impacts on soil biogeochemical cycles.

  19. Purified Brominated Indole Derivatives from Dicathais orbita Induce Apoptosis and Cell Cycle Arrest in Colorectal Cancer Cell Lines

    PubMed Central

    Esmaeelian, Babak; Benkendorff, Kirsten; Johnston, Martin R.; Abbott, Catherine A.

    2013-01-01

    Dicathais orbita is a large Australian marine gastropod known to produce bioactive compounds with anticancer properties. In this research, we used bioassay guided fractionation from the egg mass extract of D. orbita using flash column chromatography and identified fractions containing tyrindoleninone and 6-bromoisatin as the most active against colon cancer cells HT29 and Caco-2. Liquid chromatography coupled with mass spectrometry (LCMS) and 1H NMR were used to characterize the purity and chemical composition of the isolated compounds. An MTT assay was used to determine effects on cell viability. Necrosis and apoptosis induction using caspase/LDH assay and flow cytometry (PI/Annexin-V) and cell cycle analysis were also investigated. Our results show that semi-purified 6-bromoisatin had the highest anti-cancer activity by inhibiting cell viability (IC50 = ~100 µM) and increasing caspase 3/7 activity in both of the cell lines at low concentration. The fraction containing 6-bromoisatin induced 77.6% apoptosis and arrested 25.7% of the cells in G2/M phase of cell cycle in HT29 cells. Tyrindoleninone was less potent but significantly decreased the viability of HT29 cells at IC50 = 390 µM and induced apoptosis at 195 µM by increasing caspase 3/7 activity in these cells. This research will facilitate the development of these molluscan natural products as novel complementary medicines for colorectal cancer. PMID:24152558

  20. Computation Molecular Kinetics Model of HZE Induced Cell Cycle Arrest

    NASA Technical Reports Server (NTRS)

    Cucinotta, Francis A.; Ren, Lei

    2004-01-01

    Cell culture models play an important role in understanding the biological effectiveness of space radiation. High energy and charge (HZE) ions produce prolonged cell cycle arrests at the G1/S and G2/M transition points in the cell cycle. A detailed description of these phenomena is needed to integrate knowledge of the expression of DNA damage in surviving cells, including the determination of relative effectiveness factors between different types of radiation that produce differential types of DNA damage and arrest durations. We have developed a hierarchical kinetics model that tracks the distribution of cells in various cell phase compartments (early G1, late G1, S, G2, and M), however with transition rates that are controlled by rate-limiting steps in the kinetics of cyclin-cdk's interactions with their families of transcription factors and inhibitor molecules. The coupling of damaged DNA molecules to the downstream cyclin-cdk inhibitors is achieved through a description of the DNA-PK and ATM signaling pathways. For HZE irradiations we describe preliminary results, which introduce simulation of the stochastic nature of the number of direct particle traversals per cell in the modulation of cyclin-cdk and cell cycle population kinetics. Comparison of the model to data for fibroblast cells irradiated photons or HZE ions are described.

  1. UV-induced changes in cell cycle and gene expression within rabbit lens epithelial cells

    SciTech Connect

    Sidjanin, D.; Grdina, D.; Woloschak, G.E.

    1994-11-01

    Damage to lens epithelial cells is a probable initiation process in cataract formation induced by ultraviolet radiation. These experiments investigated the ability of 254 nm radiation on cell cycle progression and gene expression in rabbit lens epithelial cell line N/N1003A. No changes in expression of c-fos, c-jun, alpha- tubulin, or vimentin was observed following UV exposure. Using flow cytometry, an accumulation of cells in G1/S phase of the cell cycle 1 hr following exposure. The observed changes in gene expression, especially the decreased histone transcripts reported here may play a role in UV induced inhibition of cell cycle progression.

  2. Linalool Induces Cell Cycle Arrest and Apoptosis in Leukemia Cells and Cervical Cancer Cells through CDKIs

    PubMed Central

    Chang, Mei-Yin; Shieh, Den-En; Chen, Chung-Chi; Yeh, Ching-Sheng; Dong, Huei-Ping

    2015-01-01

    Plantaginaceae, a popular traditional Chinese medicine, has long been used for treating various diseases from common cold to cancer. Linalool is one of the biologically active compounds that can be isolated from Plantaginaceae. Most of the commonly used cytotoxic anticancer drugs have been shown to induce apoptosis in susceptible tumor cells. However, the signaling pathway for apoptosis remains undefined. In this study, the cytotoxic effect of linalool on human cancer cell lines was investigated. Water-soluble tetrazolium salts (WST-1) based colorimetric cellular cytotoxicity assay, was used to test the cytotoxic ability of linalool against U937 and HeLa cells, and flow cytometry (FCM) and genechip analysis were used to investigate the possible mechanism of apoptosis. These results demonstrated that linalool exhibited a good cytotoxic effect on U937 and HeLa cells, with the IC50 value of 2.59 and 11.02 μM, respectively, compared with 5-FU with values of 4.86 and 12.31 μM, respectively. After treating U937 cells with linalool for 6 h, we found an increased sub-G1 peak and a dose-dependent phenomenon, whereby these cells were arrested at the G0/G1 phase. Furthermore, by using genechip analysis, we observed that linalool can promote p53, p21, p27, p16, and p18 gene expression. Therefore, this study verified that linalool can arrest the cell cycle of U937 cells at the G0/G1 phase and can arrest the cell cycle of HeLa cells at the G2/M phase. Its mechanism facilitates the expression of the cyclin-dependent kinases inhibitors (CDKIs) p53, p21, p27, p16, and p18, as well as the non-expression of cyclin-dependent kinases (CDKs) activity. PMID:26703569

  3. Linalool Induces Cell Cycle Arrest and Apoptosis in Leukemia Cells and Cervical Cancer Cells through CDKIs.

    PubMed

    Chang, Mei-Yin; Shieh, Den-En; Chen, Chung-Chi; Yeh, Ching-Sheng; Dong, Huei-Ping

    2015-01-01

    Plantaginaceae, a popular traditional Chinese medicine, has long been used for treating various diseases from common cold to cancer. Linalool is one of the biologically active compounds that can be isolated from Plantaginaceae. Most of the commonly used cytotoxic anticancer drugs have been shown to induce apoptosis in susceptible tumor cells. However, the signaling pathway for apoptosis remains undefined. In this study, the cytotoxic effect of linalool on human cancer cell lines was investigated. Water-soluble tetrazolium salts (WST-1) based colorimetric cellular cytotoxicity assay, was used to test the cytotoxic ability of linalool against U937 and HeLa cells, and flow cytometry (FCM) and genechip analysis were used to investigate the possible mechanism of apoptosis. These results demonstrated that linalool exhibited a good cytotoxic effect on U937 and HeLa cells, with the IC50 value of 2.59 and 11.02 μM, respectively, compared with 5-FU with values of 4.86 and 12.31 μM, respectively. After treating U937 cells with linalool for 6 h, we found an increased sub-G1 peak and a dose-dependent phenomenon, whereby these cells were arrested at the G0/G1 phase. Furthermore, by using genechip analysis, we observed that linalool can promote p53, p21, p27, p16, and p18 gene expression. Therefore, this study verified that linalool can arrest the cell cycle of U937 cells at the G0/G1 phase and can arrest the cell cycle of HeLa cells at the G2/M phase. Its mechanism facilitates the expression of the cyclin-dependent kinases inhibitors (CDKIs) p53, p21, p27, p16, and p18, as well as the non-expression of cyclin-dependent kinases (CDKs) activity.

  4. Occurrence and distribution of psychoactive compounds and their metabolites in the urban water cycle of Berlin (Germany).

    PubMed

    Hass, Ulrike; Duennbier, Uwe; Massmann, Gudrun

    2012-11-15

    The occurrence and distribution of six psychoactive compounds (primidone, phenobarbital, oxazepam, diazepam, meprobamate, and pyrithyldione) and a metabolite of primidone (phenylethylmalonamide) were investigated in wastewater treatment plant (WWTP) effluents, surface water, groundwater of a bank filtration site, raw and final drinking water, and in groundwater affected by former sewage irrigation. Primidone and its metabolite phenylethylmalonamide were found to be ubiquitous in environmental water samples in Berlin. Maximum concentrations of 0.87 and 0.42 μg/L, respectively, were encountered in WWTP effluents. Both compounds are apparently not removed when passaging through the different compartments of the water cycle and concentrations are only reduced by dilution. Phenobarbital was present at nearly every stage of the Berlin water cycle with the exception of raw and final drinking water. The highest concentrations of phenobarbital (up to 0.96 μg/L) were measured in groundwater influenced by former sewage irrigation. Oxazepam was only present in WWTP effluents and surface waters (up to 0.18 μg/L), while diazepam was not detected in any matrix. Due to their withdrawal from the German market years ago, the pharmaceuticals meprobamate and pyrithyldione were only found in sewage farm groundwater (up to 0.50 and 0.04 μg/L, respectively) and, in case of meprobamate, also in decade old bank filtrate (0.03 μg/L). Our results indicate a high persistence of some of the investigated compounds in the aquatic system. As a consequence, these pollutants may potentially reach drinking water resources via bank filtration if present in WWTP effluents and/or surface waters in partly closed water cycles such as Berlin's.

  5. Downregulation of cell cycle-related proteins in ovarian cancer line and cell cycle arrest induced by microRNA

    PubMed Central

    Yuan, Jian-Mei; Shi, Xue-Jun; Sun, Ping; Liu, Jun-Xia; Wang, Wei; Li, Ming; Ling, Feng-Yu

    2015-01-01

    Objective: The effect of miR-449 and miR-34 on the growth, cell cycle and target gene expressions of ovarian cancer cell line SKOV3 and SKOV3-ipl was discussed. Method: Real-time quantitative reverse transcription PCR was employed to detect the expressions of miR-449a/b and miR-34b, c in SKOV3 and SKOV3-ipl cells. The two miRNAs were successfully expressed in SKOV3-ipl cells by transfection. The variations in cell growth rate and cell cycle were determined by MTS assay and flow cytometry, respectively. The expressions of cell cycle-related proteins were detected by Western Blot. Results: miR-449b and miR-34c induced the decline of the adhesiveness of SKOV3-ipl cells by 20%-30%. The number of cells arrested in G1-phase increased and the number of cells arrested in S-phase decreased significantly. The cell cycle-related proteins CDK6 and CDC254 were downregulated. miR-449b caused the expression of CDK6 and CDC25A to decrease. After the co-transfection with miR-449b and miR-34c, the relevant proteins were downregulated more significantly. The expressions of CDK6, CDC25A and cyclin A were decreased significantly. Conclusion: miR-449b and miR-34c can induce cell cycle arrest in SKOV3-ipl cells and the downregulation of CDK6, CDC25A and cyclin A. PMID:26770455

  6. Emergy Evaluations of the Global Biogeochemical Cycles of Six Biologically Active Elements and Two Compounds

    EPA Science Inventory

    Estimates of the emergy carried by the flows of biologically active elements (BAE) and compounds are needed to accurately evaluate the near and far field effects of anthropogenic wastes. The transformities and specific emergies of these elements and of their different chemical sp...

  7. Computer simulation of the heavy-duty turbo-compounded diesel cycle for studies of engine efficiency and performance

    NASA Technical Reports Server (NTRS)

    Assanis, D. N.; Ekchian, J. A.; Heywood, J. B.; Replogle, K. K.

    1984-01-01

    Reductions in heat loss at appropriate points in the diesel engine which result in substantially increased exhaust enthalpy were shown. The concepts for this increased enthalpy are the turbocharged, turbocompounded diesel engine cycle. A computer simulation of the heavy duty turbocharged turbo-compounded diesel engine system was undertaken. This allows the definition of the tradeoffs which are associated with the introduction of ceramic materials in various parts of the total engine system, and the study of system optimization. The basic assumptions and the mathematical relationships used in the simulation of the model engine are described.

  8. Valley Formation on Early Mars Caused by Carbonate-Silicate Cycle-Induced Climate Cycling

    NASA Astrophysics Data System (ADS)

    Batalha, Natasha; Kopparapu, Ravi Kumar; Haqq-Misra, Jacob; Kasting, James

    2016-10-01

    For decades, scientists have tried to explain the evidence for fluvial activity on early Mars, but a consensus has yet to emerge regarding the mechanism for producing it. One hypothesis suggests early Mars was warmed by a thick greenhouse atmosphere. Another suggests early Mars was generally cold but was warmed occasionally by impacts or by episodes of enhanced volcanism. These latter hypotheses struggle to produce the amounts of rainfall needed to form the martian valleys, but are consistent with inferred low rates of weathering compared to Earth. We suggest that both schools of thought are partly correct. Mars experienced dramatic climate cycles with extended periods of glaciation punctuated by warm periods lasting up to 10 Myr. Cycles of repeated glaciation and deglaciation occurred because stellar insolation was low, and because CO2 outgassing could not keep pace with CO2 consumption by silicate weathering followed by deposition of carbonates. In order to deglaciate early Mars , substantial outgassing of molecular hydrogen from Mars' reduced crust and mantle was also required. Our hypothesis can be tested by future Mars exploration that better establishes the time scale for valley formation.

  9. The mechanism of alcoholic beverage induced superconductivity in Fe-chalcogenide compounds

    NASA Astrophysics Data System (ADS)

    Deguchi, Keita; Demura, Satoshi; Okazaki, Hiroyuki; Denholme, Saleem; Fujioka, Masaya; Ozaki, Toshinori; Yamaguchi, Takahide; Takeya, Hiroyuki; Takano, Yoshihiko

    2013-03-01

    We have clarified the mechanism of alcoholic beverage induced superconductivity in Fe-chalcogenide compounds. Previously we reported that the bulk superconductivity in Fe-based compounds Fe(Te, Se) and Fe(Te, S) is achieved by heating in alcoholic beverages. However, the exact mechanism of how they act to enhance the superconductivity in the compounds remains unsolved. To understand the effect of alcoholic beverage treatment, we investigated the mechanism using a technology of metabolomic analysis. We found that weak acid in alcoholic beverages has the ability to deintercalate the excess Fe, which is not in favor of superconductivity. In this presentation, we will discuss the systematic mechanism to induce superconductivity in Fe-chalcogenide compounds.

  10. Anti-inflammatory and Quinone Reductase Inducing Compounds from Fermented Noni (Morinda citrifolia) Juice Exudates.

    PubMed

    Youn, Ui Joung; Park, Eun-Jung; Kondratyuk, Tamara P; Sang-Ngern, Mayuramas; Wall, Marisa M; Wei, Yanzhang; Pezzuto, John M; Chang, Leng Chee

    2016-06-24

    A new fatty acid ester disaccharide, 2-O-(β-d-glucopyranosyl)-1-O-(2E,4Z,7Z)-deca-2,4,7-trienoyl-β-d-glucopyranose (1), a new ascorbic acid derivative, 2-caffeoyl-3-ketohexulofuranosonic acid γ-lactone (2), and a new iridoid glycoside, 10-dimethoxyfermiloside (3), were isolated along with 13 known compounds (4-16) from fermented noni fruit juice (Morinda citrifolia). The structures of the new compounds, together with 4 and 5, were determined by 1D and 2D NMR experiments, as well as comparison with published values. Compounds 2 and 7 showed moderate inhibitory activities in a TNF-α-induced NF-κB assay, and compounds 4 and 6 exhibited considerable quinone reductase-1 (QR1) inducing effects.

  11. Investigation of plasma etch induced damage in compound semiconductor devices

    SciTech Connect

    Shul, R.J.; Lovejoy, M.L.; Hetherington, D.L.; Rieger, D.J.; Vawter, G.A.; Klem, J.F.; Melloch, M.R.

    1993-11-01

    We have investigated the electrical performance of mesa-isolated GaAs pn-junction diodes to determine the plasma-induced damage effects from reactive ion and reactive ion beam etching. A variety of plasma chemistries (SiCl{sub 4}, BCl{sub 3}, BCl{sub 3}/Cl{sub 2}, and Cl{sub 2}) and ion energies ranging from 100 to 400 eV were studied. We have observed that many of the RIE BCl{sub 3}/Cl{sub 2} plasmas and RIBE Cl{sub 2} plasmas yield diodes with low reverse-bias currents that are comparable to the electrical characteristics of wet-chemical-etched devices. The reverse-bias leakage currents are independent of surface morphology and sidewall profiles.

  12. Climatically induced sedimentary cycles in Pliocene deep-water carbonates

    SciTech Connect

    Gardulski, A.F. )

    1991-03-01

    Two DSDP sites (86 and 94) on the Campeche ramp in the southern Gulf of Mexico penetrated more than 100 m of Pliocene pelagic ooze. The ooze is primarily carbonate, with a much smaller volcanic ash component than occurs in some Pleistocene sediments at these sites. Cores recovered from these holes display variations in carbonate mineralogy as well as total carbonate and sand abundances that are correlated with the oxygen isotope stratigraphy. Diagenetic loss of Mg-calcite is complete by the base of the Pleistocene, but aragonite, especially high-Sr aragonite forming algal needles that were transported off the shelf to the slope, persists through upper Pliocene cores. Variations in oxygen isotope ratios in planktonic foraminifera occur throughout the Pliocene, although the amplitude of those cycles is smaller than for the Pleistocene, with its more dramatic glacial-interglacial contrasts. As in overlying Pleistocene slope sediments, cooler intervals correspond with greater abundances of aragonite in the upper Pliocene section, reflecting a shift of the shallow, productive shelf seaward across the ramp surface during times of relatively low sea level. However, the aragonite abundances in the Pliocene are reduced on average compared to the Pleistocene. This difference is due in part to diagenetic loss, but also it likely reflects the overall higher sea level that apparently characterized Pliocene oceans, trapping more algal aragonite landward. Although sea level and climatic fluctuations were indeed less extreme in the Pliocene, they were still sufficient to generate sedimentary cycles in deep-water carbonates.

  13. The menstrual cycle and susceptibility to coriolis-induced sickness.

    PubMed

    Cheung, B; Heskin, R; Hofer, K; Gagnon, M

    2001-01-01

    Survey studies on motion sickness susceptibility suggest that females tend to report greater severity in illness and higher incidence of vomiting than males. Menstruation is said to be a contributing factor. A recent study suggested that females were least susceptible to seasickness during ovulation in a "round the world" yacht race. Sixteen subjects (18-36 years old) were exposed to Coriolis cross-coupling stimulation in the laboratory. They were tested once during permenstruation (Day 1-5), ovulation (Day 12-15) and premenstruation (Day 24-28), based on a normalized 28-day cycle, in a randomised design. Physiological measurements of motion sickness included forearm and calf cutaneous blood flow. Subjective evaluation of sickness symptoms was based on Graybiel's diagnostic criteria and Golding's rating method. Our results indicated that under controlled laboratory conditions, different phases of the menstrual cycle appear to have no influence on subjective symptoms of motion sickness or on cutaneous blood flow increase in the forearm and calf. The lack of commonality between the types and levels of hormones that are released during motion sickness and those that are involved in different menstrual phases appears to support our findings.

  14. Induction of cell cycle arrest in prostate cancer cells by the dietary compound isoliquiritigenin.

    PubMed

    Lee, Yeo Myeong; Lim, Do Young; Choi, Hyun Ju; Jung, Jae In; Chung, Won-Yoon; Park, Jung Han Yoon

    2009-02-01

    Isoliquiritigenin (ISL), a flavonoid chalcone that is present in licorice, shallot, and bean sprouts, is known to have antitumorigenic activities. The present study examined whether ISL alters prostate cancer cell cycle progression. DU145 human and MatLyLu (MLL) rat prostate cancer cells were cultured with various concentrations of ISL. In both DU145 and MLL cells treated with ISL, the percentage of cells in the G1 phase increased, and the incorporation of [(3)H]thymidine decreased. ISL decreased the protein levels of cyclin D1, cyclin E, and cyclin-dependent kinase (CDK) 4, whereas cyclin A and CDK2 expressions were unaltered in cells treated with ISL. The expression of the CDK inhibitor p27(KIP1) was increased in cells treated with 20 micromol/L ISL. In addition, treatment of cells with 20 micromol/L ISL for 24 hours led to G2/M cell cycle arrest. Cell division control (CDC) 2 protein levels remained unchanged. The protein levels of phospho-CDC2 (Tyr15) and cyclin B1 were increased, and the CDC25C level was decreased by ISL dose-dependently. We demonstrate that ISL promotes cell cycle arrest in DU145 and MLL cells, thereby providing insights into the mechanisms underlying its antitumorigenic activities.

  15. Induction of cell cycle arrest in prostate cancer cells by the dietary compound isoliquiritigenin.

    PubMed

    Lee, Yeo Myeong; Lim, Do Young; Choi, Hyun Ju; Jung, Jae In; Chung, Won-Yoon; Park, Jung Han Yoon

    2009-02-01

    Isoliquiritigenin (ISL), a flavonoid chalcone that is present in licorice, shallot, and bean sprouts, is known to have antitumorigenic activities. The present study examined whether ISL alters prostate cancer cell cycle progression. DU145 human and MatLyLu (MLL) rat prostate cancer cells were cultured with various concentrations of ISL. In both DU145 and MLL cells treated with ISL, the percentage of cells in the G1 phase increased, and the incorporation of [(3)H]thymidine decreased. ISL decreased the protein levels of cyclin D1, cyclin E, and cyclin-dependent kinase (CDK) 4, whereas cyclin A and CDK2 expressions were unaltered in cells treated with ISL. The expression of the CDK inhibitor p27(KIP1) was increased in cells treated with 20 micromol/L ISL. In addition, treatment of cells with 20 micromol/L ISL for 24 hours led to G2/M cell cycle arrest. Cell division control (CDC) 2 protein levels remained unchanged. The protein levels of phospho-CDC2 (Tyr15) and cyclin B1 were increased, and the CDC25C level was decreased by ISL dose-dependently. We demonstrate that ISL promotes cell cycle arrest in DU145 and MLL cells, thereby providing insights into the mechanisms underlying its antitumorigenic activities. PMID:19298190

  16. Deuterium enrichment by selective photo-induced dissociation of an organic carbonyl compound

    DOEpatents

    Marling, John B.

    1981-01-01

    A method for producing a deuterium enriched material by photoinduced dissociation which uses as the working material a gas phase photolytically dissociable organic carbonyl compound containing at least one hydrogen atom bonded to an atom which is adjacent to a carbonyl group and consisting of molecules wherein said hydrogen atom is present as deuterium and molecules wherein said hydrogen atom is present as another isotope of hydrogen. The organic carbonyl compound is subjected to intense infrared radiation at a preselected wavelength to selectively excite and thereby induce dissociation of the deuterium containing species to yield a deuterium enriched stable molecular product. Undissociated carbonyl compound, depleted in deuterium, is preferably redeuterated for reuse.

  17. EDD induces cell cycle arrest by increasing p53 levels.

    PubMed

    Smits, Veronique A J

    2012-02-15

    Tight regulation of p53 is essential for its central role in maintaining genome stability and tumor prevention. Here, EDD/ UBR5/hHyd, hereafter called EDD, is identified as a novel regulator of p53. Downregulation of EDD results in elevated p53 protein levels both in transformed and untransformed cells. Concomitant with a rise in p53, the levels of p21, a critical p53 target, are also elevated in these conditions. Surprisingly, EDD knockdown does not affect p53 protein stability, and p53 mRNA levels do not increase significantly upon EDD depletion. Consistent with the function of p53, EDD downregulation triggers a senescent phenotype in fibroblasts at later time points. In addition, the increased p53 levels upon EDD depletion cause a G(1) arrest, as co-depletion of EDD and p53 completely rescues this effect on cell cycle progression. PMID:22374670

  18. Hispolon induces apoptosis and cell cycle arrest of human hepatocellular carcinoma Hep3B cells by modulating ERK phosphorylation.

    PubMed

    Huang, Guan-Jhong; Deng, Jeng-Shyan; Huang, Shyh-Shyun; Hu, Miao-Lin

    2011-07-13

    Hispolon is an active phenolic compound of Phellinus igniarius , a mushroom that has recently been shown to have antioxidant, anti-inflammatory, and anticancer activities. This study investigated the antiproliferative effect of hispolon on human hepatocellular carcinoma Hep3B cells by using the MTT assay, DNA fragmentation, DAPI (4,6-diamidino-2-phenylindole dihydrochloride) staining, and flow cytometric analyses. Hispolon inhibited cellular growth of Hep3B cells in a time-dependent and dose-dependent manner, through the induction of cell cycle arrest at S phase measured using flow cytometric analysis and apoptotic cell death, as demonstrated by DNA laddering. Hispolon-induced S-phase arrest was associated with a marked decrease in the protein expression of cyclins A and E and cyclin-dependent kinase (CDK) 2, with concomitant induction of p21waf1/Cip1 and p27Kip1. Exposure of Hep3B cells to hispolon resulted in apoptosis as evidenced by caspase activation, PARP cleavage, and DNA fragmentation. Hispolon treatment also activated JNK, p38 MAPK, and ERK expression. Inhibitors of ERK (PB98095), but not those of JNK (SP600125) and p38 MAPK (SB203580), suppressed hispolon-induced S-phase arrest and apoptosis in Hep3B cells. These findings establish a mechanistic link between the MAPK pathway and hispolon-induced cell cycle arrest and apoptosis in Hep3B cells. PMID:21630638

  19. Cycle training induces muscle hypertrophy and strength gain: strategies and mechanisms.

    PubMed

    Ozaki, Hayao; Loenneke, J P; Thiebaud, R S; Abe, T

    2015-03-01

    Cycle training is widely performed as a major part of any exercise program seeking to improve aerobic capacity and cardiovascular health. However, the effect of cycle training on muscle size and strength gain still requires further insight, even though it is known that professional cyclists display larger muscle size compared to controls. Therefore, the purpose of this review is to discuss the effects of cycle training on muscle size and strength of the lower extremity and the possible mechanisms for increasing muscle size with cycle training. It is plausible that cycle training requires a longer period to significantly increase muscle size compared to typical resistance training due to a much slower hypertrophy rate. Cycle training induces muscle hypertrophy similarly between young and older age groups, while strength gain seems to favor older adults, which suggests that the probability for improving in muscle quality appears to be higher in older adults compared to young adults. For young adults, higher-intensity intermittent cycling may be required to achieve strength gains. It also appears that muscle hypertrophy induced by cycle training results from the positive changes in muscle protein net balance.

  20. An analysis of a highly compounded two-stroke-cycle compression-ignition engine

    NASA Technical Reports Server (NTRS)

    Tauschek, Max J; Sather, Bernard I; Biermann, Arnold E

    1949-01-01

    Presents an analysis of a compound engine operating with manifold pressures ranging from 60 to 110 lb/sq in. absolute. The effects of engine limits (peak cylinder pressure and turbine-inlet temperature) and component efficiency are discussed. A range analysis is used to evaluate the merit of the engine. The analysis indicates that specific-fuel-consumption values of 0.32 lb/bhp-hr and specific weights of 0.8 lb/bhp are obtainable at high manifold pressures.

  1. Triptolide Abrogates Growth of Colon Cancer and Induces Cell Cycle Arrest by Inhibiting Transcriptional Activation of E2F

    PubMed Central

    Chugh, Rohit; Skube, Steven J; Majumder, Kaustav; Banerjee, Sulagna; Sangwan, Veena; Li, Lihua; Dawra, Rajinder; Subramanian, Subbaya; Saluja, Ashok; Dudeja, Vikas

    2016-01-01

    Background Despite significant progress in diagnostics and therapeutics, over fifty thousand patients die from colorectal cancer annually. Hence there is urgent need for new lines of treatment. Triptolide, a natural compound isolated from the Chinese herb Tripterygium wilfordii, is effective against multiple cancers. We have synthesized a water soluble analog of triptolide, named Minnelide, which is currently in phase I trial against pancreatic cancer. The aims of the current study were to evaluate whether triptolide/Minnelide is effective against colorectal cancer and to elucidate the mechanism by which triptolide induces cell death in colorectal cancer. Methods Efficacy of Minnelide was evaluated in subcutaneous xenograft and liver metastasis model of colorectal cancer. For mechanistic studies colon cancer cell lines HCT116 and HT29 were treated with triptolide and the effect on viability, caspase activation, annexin positivity, lactate dehydrogenase(LDH) release and cell cycle progression was evaluated. Effect of triptolide on E2F transcriptional activity, mRNA levels of E2F dependent genes, E2F1-Rb binding and proteins levels of regulator of G1-S transition was also measured. DNA binding of E2F1 was evaluated by chromatin immunoprecipitation assay. Results Triptolide decreased colon cancer cell viability in a dose- and time-dependent fashion. Minnelide markedly inhibited the growth of colon cancer in the xenograft and liver metastasis model of colon cancer and more than doubles the median survival of animals with liver metastases from colon cancer. Mechanistically we demonstrate that at low concentrations, triptolide induces apoptotic cell death but at higher concentrations it induces cell cycle arrest. Our data suggest that triptolide is able to induce G1 cell cycle arrest by inhibiting transcriptional activation of E2F1. Our data also show that triptolide downregulates E2F activity by potentially modulating events downstream of DNA binding. Conclusion

  2. Triaxial MMG investigation during FES-induced cycle movements

    NASA Astrophysics Data System (ADS)

    Gelain, M. C.; Nogueira-Neto, G. N.; Nohama, P.; Gewehr, P. M.

    2016-04-01

    Spinal cord injury is damage to the spinal cord that results in loss of functions, causes muscle, joint and bone deficits, moreover it increases the muscle tone level. FEScycling is an alternative rehabilitation process to conserve the musculoskeletal system affected by the injury in the functional state. The aim of this study is to get the legs bilaterally synchronized by FES and compare MMG signal responses. The preliminary protocol consists of five consecutive contractions. The first and the last contractions were discarded and the three intermediate contractions were analyzed. A ratio between MMG values of muscle responses during propulsion and return of pedalling phases was calculated for each cycle and each leg. The applied FES profile consisted of pulse and burst on time of 250 us and 5 ms and frequencies of 1000 Hz and 20 Hz, respectively. Results showed that greater MMG RMS values tend to occur during the propulsion phase than in the return phase. MMG Z axis of RLL and MMG X axis of LLL were the axes that presented the greatest ratios. The MMG RMS signal showed that greater values tend to occur during the propulsion phase than in the return phase of the same thigh.

  3. RhoE inhibits cell cycle progression and Ras-induced transformation.

    PubMed

    Villalonga, Priam; Guasch, Rosa M; Riento, Kirsi; Ridley, Anne J

    2004-09-01

    Rho GTPases are major regulators of cytoskeletal dynamics, but they also affect cell proliferation, transformation, and oncogenesis. RhoE, a member of the Rnd subfamily that does not detectably hydrolyze GTP, inhibits RhoA/ROCK signaling to promote actin stress fiber and focal adhesion disassembly. We have generated fibroblasts with inducible RhoE expression to investigate the role of RhoE in cell proliferation. RhoE expression induced a loss of stress fibers and cell rounding, but these effects were only transient. RhoE induction inhibited cell proliferation and serum-induced S-phase entry. Neither ROCK nor RhoA inhibition accounted for this response. Consistent with its inhibitory effect on cell cycle progression, RhoE expression was induced by cisplatin, a DNA damage-inducing agent. RhoE-expressing cells failed to accumulate cyclin D1 or p21(cip1) protein or to activate E2F-regulated genes in response to serum, although ERK, PI3-K/Akt, FAK, Rac, and cyclin D1 transcription was activated normally. The expression of proteins that bypass the retinoblastoma (pRb) family cell cycle checkpoint, including human papillomavirus E7, adenovirus E1A, and cyclin E, rescued cell cycle progression in RhoE-expressing cells. RhoE also inhibited Ras- and Raf-induced fibroblast transformation. These results indicate that RhoE inhibits cell cycle progression upstream of the pRb checkpoint.

  4. Ziyuglycoside II induces cell cycle arrest and apoptosis through activation of ROS/JNK pathway in human breast cancer cells.

    PubMed

    Zhu, Xue; Wang, Ke; Zhang, Kai; Zhu, Ling; Zhou, Fanfan

    2014-05-16

    Ziyuglycoside II, a triterpenoid saponin compound extracted from Sanguisorba officinalis L., has been reported to have a wide range of clinical applications including anti-cancer effect. In this study, the anti-proliferative effect of ziyuglycoside II in two classic human breast cancer cell lines, MCF-7 and MDA-MB-231, was extensively investigated. Our study indicated that ziyuglycoside II could effectively induce G2/M phase arrest and apoptosis in both cell lines. Cell cycle blocking was associated with the down-regulation of Cdc25C, Cdc2, cyclin A and cyclin B1 as well as the up-regulation of p21/WAF1, phospho-Cdc25C and phospho-Cdc2. Ziyuglycoside II treatment also induced reactive oxygen species (ROS) production and apoptosis by activating the extrinsic/Fas/FasL pathway as well as the intrinsic/mitochondrial pathway. More importantly, the c-Jun NH2-terminal kinase (JNK), a downstream target of ROS, was found to be a critical mediator of ziyuglycoside II-induced cell apoptosis. Further knockdown of JNK by siRNA could inhibit ziyuglycoside II-mediated apoptosis with attenuating the up-regulation of Bax and Fas/FasL as well as the down-regulation of Bcl-2. Taken together, the cell death of breast cancer cells in response to ziyuglycoside II was dependent upon cell cycle arrest and cell apoptosis via a ROS-dependent JNK activation pathway. Our findings may significantly contribute to the understanding of the anti-proliferative effect of ziyuglycoside II, in particular to breast carcinoma and provide novel insights into the potential application of such compound in breast cancer therapy. PMID:24680927

  5. Preliminary analysis of compound systems based on high temperature fuel cell, gas turbine and Organic Rankine Cycle

    NASA Astrophysics Data System (ADS)

    Sánchez, D.; Muñoz de Escalona, J. M.; Monje, B.; Chacartegui, R.; Sánchez, T.

    This article presents a novel proposal for complex hybrid systems comprising high temperature fuel cells and thermal engines. In this case, the system is composed by a molten carbonate fuel cell with cascaded hot air turbine and Organic Rankine Cycle (ORC), a layout that is based on subsequent waste heat recovery for additional power production. The work will credit that it is possible to achieve 60% efficiency even if the fuel cell operates at atmospheric pressure. The first part of the analysis focuses on selecting the working fluid of the Organic Rankine Cycle. After a thermodynamic optimisation, toluene turns out to be the most efficient fluid in terms of cycle performance. However, it is also detected that the performance of the heat recovery vapour generator is equally important, what makes R245fa be the most interesting fluid due to its balanced thermal and HRVG efficiencies that yield the highest global bottoming cycle efficiency. When this fluid is employed in the compound system, conservative operating conditions permit achieving 60% global system efficiency, therefore accomplishing the initial objective set up in the work. A simultaneous optimisation of gas turbine (pressure ratio) and ORC (live vapour pressure) is then presented, to check if the previous results are improved or if the fluid of choice must be replaced. Eventually, even if system performance improves for some fluids, it is concluded that (i) R245fa is the most efficient fluid and (ii) the operating conditions considered in the previous analysis are still valid. The work concludes with an assessment about safety-related aspects of using hydrocarbons in the system. Flammability is studied, showing that R245fa is the most interesting fluid also in this regard due to its inert behaviour, as opposed to the other fluids under consideration all of which are highly flammable.

  6. Treatment-induced cell cycle kinetics dictate tumor response to chemotherapy

    PubMed Central

    Hallett, Robin M.; Huang, Cheng; Motazedian, Ali; Auf der Mauer, Stefanie; Pond, Gregory R.; Hassell, John A.; Nordon, Robert E.; Draper, Jonathan S.

    2015-01-01

    Chemotherapy fails to provide durable cure for the majority of cancer patients. To identify mechanisms associated with chemotherapy resistance, we identified genes differentially expressed before and after chemotherapeutic treatment of breast cancer patients. Treatment response resulted in either increased or decreased cell cycle gene expression. Tumors in which cell cycle gene expression was increased by chemotherapy were likely to be chemotherapy sensitive, whereas tumors in which cell cycle gene transcripts were decreased by chemotherapy were resistant to these agents. A gene expression signature that predicted these changes proved to be a robust and novel index that predicted the response of patients with breast, ovarian, and colon tumors to chemotherapy. Investigations in tumor cell lines supported these findings, and linked treatment induced cell cycle changes with p53 signaling and G1/G0 arrest. Hence, chemotherapy resistance, which can be predicted based on dynamics in cell cycle gene expression, is associated with TP53 integrity. PMID:25749523

  7. Chemotherapy Drug Induced Discoordination of Mitochondrial Life Cycle Detected by Cardiolipin Fluctuation

    PubMed Central

    Chao, Yu-Jen; Chan, Jui-Fen; Hsu, Yuan-Hao Howard

    2016-01-01

    Chemotherapy drugs have been prescribed for the systemic treatment of cancer. We selected three chemotherapy drugs, including methotrexate, mitomycine C and vincristine to inhibit the proliferation of HT1080 human fibrosarcoma cells in S, G2 and M phases of the cell cycle respectively. These chemotherapy drugs showed significant toxicity and growth inhibition to the cancer cells measured by MTT assay. After treated with a 50% inhibitory dosage for 48 hours, these cancer cells showed significant accumulation of cardiolipin (CL), which was a reverse trend of the nutritional deficiency induced arrest at G1 phase. The quantity of each CL species was further semi-quantitated by HPLC-ion trap mass spectrometer. Methotraxate treatment caused unique increases of acyl chain length on CL, which were the opposite of the serum starvation, mitomycine C and vincristine treatments. Although mitomycine C and vincristine have different mechanisms to induce cell cycle arrest, these two drugs displayed similar effects on decreasing chain length of CL. Continuation of CL synthesis during cell cycle arrest indicated the chemotherapy drugs resulting in the discoordination of the mitochondrial life cycle from the cell cycle and thus caused the accumulation of CL. These finding reveals that the pre-remodeling nascent CL accumulates during the methotraxate induced arrest; however, the post-remodeling mature CL accumulates during the mitomycine C and vincristine induced arrest after the synthesis phase. PMID:27627658

  8. Chemotherapy Drug Induced Discoordination of Mitochondrial Life Cycle Detected by Cardiolipin Fluctuation.

    PubMed

    Chao, Yu-Jen; Chan, Jui-Fen; Hsu, Yuan-Hao Howard

    2016-01-01

    Chemotherapy drugs have been prescribed for the systemic treatment of cancer. We selected three chemotherapy drugs, including methotrexate, mitomycine C and vincristine to inhibit the proliferation of HT1080 human fibrosarcoma cells in S, G2 and M phases of the cell cycle respectively. These chemotherapy drugs showed significant toxicity and growth inhibition to the cancer cells measured by MTT assay. After treated with a 50% inhibitory dosage for 48 hours, these cancer cells showed significant accumulation of cardiolipin (CL), which was a reverse trend of the nutritional deficiency induced arrest at G1 phase. The quantity of each CL species was further semi-quantitated by HPLC-ion trap mass spectrometer. Methotraxate treatment caused unique increases of acyl chain length on CL, which were the opposite of the serum starvation, mitomycine C and vincristine treatments. Although mitomycine C and vincristine have different mechanisms to induce cell cycle arrest, these two drugs displayed similar effects on decreasing chain length of CL. Continuation of CL synthesis during cell cycle arrest indicated the chemotherapy drugs resulting in the discoordination of the mitochondrial life cycle from the cell cycle and thus caused the accumulation of CL. These finding reveals that the pre-remodeling nascent CL accumulates during the methotraxate induced arrest; however, the post-remodeling mature CL accumulates during the mitomycine C and vincristine induced arrest after the synthesis phase. PMID:27627658

  9. Cycling-Induced Changes in the Entropy Profiles of Lithium Cobalt Oxide Electrodes

    SciTech Connect

    Hudak, N. S.; Davis, L. E.; Nagasubramanian, G.

    2014-12-09

    Entropy profiles of lithium cobalt oxide (LiCoO2) electrodes were measured at various stages in the cycle life to examine performance degradation and cycling-induced changes, or lack thereof, in thermodynamics. LiCoO2 electrodes were cycled at C/2 rate in half-cells (vs. lithium anodes) up to 20 cycles or C/5 rate in full cells (vs. MCMB anodes) up to 500 cycles. The electrodes were then subjected to entropy measurements (∂E/∂T, where E is open-circuit potential and T is temperature) in half-cells at regular intervals over the approximate range 0.5 ≤ x ≤ 1 in LixCoO2. Despite significant losses in capacity upon cycling, neither cycling rate resulted in any change to the overall shape of the entropy profile relative to an uncycled electrode, indicating retention of the basic LiCoO2 structure, lithium insertion mechanism, and thermodynamics. This confirms that cycling-induced performance degradation in LiCoO2 electrodes is primarily caused by kinetic barriers that increase with cycling. In the case of electrodes cycled at C/5, there was a subtle, quantitative, and gradual change in the entropy profile in the narrow potential range of the hexagonal-to-monoclinic phase transition. The observed change is indicative of a decrease in the intralayer lithium ordering that occurs at these potentials, and it demonstrates that a cyclinginduced structural disorder accompanies the kinetic degradation mechanisms.

  10. Cycling-Induced Changes in the Entropy Profiles of Lithium Cobalt Oxide Electrodes

    DOE PAGES

    Hudak, N. S.; Davis, L. E.; Nagasubramanian, G.

    2014-12-09

    Entropy profiles of lithium cobalt oxide (LiCoO2) electrodes were measured at various stages in the cycle life to examine performance degradation and cycling-induced changes, or lack thereof, in thermodynamics. LiCoO2 electrodes were cycled at C/2 rate in half-cells (vs. lithium anodes) up to 20 cycles or C/5 rate in full cells (vs. MCMB anodes) up to 500 cycles. The electrodes were then subjected to entropy measurements (∂E/∂T, where E is open-circuit potential and T is temperature) in half-cells at regular intervals over the approximate range 0.5 ≤ x ≤ 1 in LixCoO2. Despite significant losses in capacity upon cycling, neithermore » cycling rate resulted in any change to the overall shape of the entropy profile relative to an uncycled electrode, indicating retention of the basic LiCoO2 structure, lithium insertion mechanism, and thermodynamics. This confirms that cycling-induced performance degradation in LiCoO2 electrodes is primarily caused by kinetic barriers that increase with cycling. In the case of electrodes cycled at C/5, there was a subtle, quantitative, and gradual change in the entropy profile in the narrow potential range of the hexagonal-to-monoclinic phase transition. The observed change is indicative of a decrease in the intralayer lithium ordering that occurs at these potentials, and it demonstrates that a cyclinginduced structural disorder accompanies the kinetic degradation mechanisms.« less

  11. Scorpion (Androctonus bicolor) venom exhibits cytotoxicity and induces cell cycle arrest and apoptosis in breast and colorectal cancer cell lines

    PubMed Central

    Al-Asmari, Abdulrahman K.; Riyasdeen, Anvarbatcha; Abbasmanthiri, Rajamohamed; Arshaduddin, Mohammed; Al-Harthi, Fahad Ali

    2016-01-01

    Objectives: The defective apoptosis is believed to play a major role in the survival and proliferation of neoplastic cells. Hence, the induction of apoptosis in cancer cells is one of the targets for cancer treatment. Researchers are considering scorpion venom as a potent natural source for cancer treatment because it contains many bioactive compounds. The main objective of the current study is to evaluate the anticancer property of Androctonus bicolor scorpion venom on cancer cells. Materials and Methods: Scorpions were milked by electrical stimulation of telsons and lyophilized. The breast (MDA-MB-231) and colorectal (HCT-8) cancer cells were maintained in appropriate condition. The venom cytotoxicity was assessed by 3-(4,5-di-methylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide assay, and the cellular and nuclear changes were studied with propidium iodide and 4’,6-diamidino-2-phenylindole stain, respectively. The cell cycle arrest was examined using muse cell analyzer. Results: The A. bicolor venom exerted cytotoxic effects on MDA-MB-231 and HCT-8 cells in a dose- and duration-dependent manner and induced apoptotic cell death. The treatment with this venom arrests the cancer cells in G0/G1 phase of cell cycle. Conclusions: The venom selectively induces the rate of apoptosis in MDA-MB-231 and HCT-8 cells as reflected by morphological and cell cycle studies. To the best of our knowledge, this is the first scientific evidence demonstrating the induction of apoptosis and cell cycle arrest by A. bicolor scorpion venom. PMID:27721540

  12. Tunable ultraviolet laser-induced fluorescence detection of trace plastics and dissolved organic compounds in water

    NASA Astrophysics Data System (ADS)

    Sivaprakasam, Vasanthi; Killinger, Dennis K.

    2003-11-01

    We developed a tunable (220-285-nm) UV and fixed 266-nm laser-induced fluorescence (LIF) system using a spectrometer and a cooled CCD imaging detector to measure the excitation-emission matrix spectra of various compounds in water, including quinine sulfate and plastic compound bisphenol-A. The LIF instrument was used for the fast, nonspecific determination of trace amounts of dissolved organic compounds present in natural water supplies and various brand name bottled distilled water and bottled drinking water. Plastic-related compounds that leached out of plastic utensils and containers were also detected with this instrument. The sensitivity of the system was approximately 1-2 orders of magnitude better than that for a commercial system.

  13. New potato micro-tuber-inducing cyclohexene compounds related to theobroxide from Lasiodiplodia theobromae.

    PubMed

    Takei, Ryo; Takahashi, Kosaku; Matsuura, Hideyuki; Nabeta, Kensuke

    2008-08-01

    Two new cyclohexene compounds related to theobroxide (3) were isolated from the mycelia of Lasiodiplodia theobromae OCS71. The structures of these compounds were determined to be (4S,5S)-4,5-dihydroxy-2-methyl-cyclohex-2-enone (1) and (3aS,4R,5S,7aR)-4,5-dihydroxy-7-methyl-3a,4,5,7a-tetrahydrobenzo[1,3]dioxol-2-one (2) by means of spectroscopic analyses and chemical correlation to 3. Compound 2 was shown to take up the carbonate ion to form a carbonic acid ester non-enzymatically. The compounds also showed potato micro-tuber-inducing activities at a concentration of 10(-3) M, using a culture of single-node segments of potato stems in vitro. PMID:18685216

  14. G2/M Cell Cycle Arrest and Tumor Selective Apoptosis of Acute Leukemia Cells by a Promising Benzophenone Thiosemicarbazone Compound

    PubMed Central

    Cabrera, Maia; Gomez, Natalia; Remes Lenicov, Federico; Echeverría, Emiliana; Shayo, Carina; Moglioni, Albertina; Fernández, Natalia; Davio, Carlos

    2015-01-01

    Anti-mitotic therapies have been considered a hallmark in strategies against abnormally proliferating cells. Focusing on the extensively studied family of thiosemicarbazone (TSC) compounds, we have previously identified 4,4’-dimethoxybenzophenone thiosemicarbazone (T44Bf) as a promising pharmacological compound in a panel of human leukemia cell lines (HL60, U937, KG1a and Jurkat). Present findings indicate that T44Bf-mediated antiproliferative effects are associated with a reversible chronic mitotic arrest caused by defects in chromosome alignment, followed by induced programmed cell death. Furthermore, T44Bf selectively induces apoptosis in leukemia cell lines when compared to normal peripheral blood mononuclear cells. The underlying mechanism of action involves the activation of the mitochondria signaling pathway, with loss of mitochondrial membrane potential and sustained phosphorylation of anti-apoptotic protein Bcl-xL as well as increased Bcl-2 (enhanced phosphorylated fraction) and pro-apoptotic protein Bad levels. In addition, ERK signaling pathway activation was found to be a requisite for T44Bf apoptotic activity. Our findings further describe a novel activity for a benzophenone thiosemicarbazone and propose T44Bf as a promising anti-mitotic prototype to develop chemotherapeutic agents to treat acute leukemia malignancies. PMID:26360247

  15. G2/M Cell Cycle Arrest and Tumor Selective Apoptosis of Acute Leukemia Cells by a Promising Benzophenone Thiosemicarbazone Compound.

    PubMed

    Cabrera, Maia; Gomez, Natalia; Remes Lenicov, Federico; Echeverría, Emiliana; Shayo, Carina; Moglioni, Albertina; Fernández, Natalia; Davio, Carlos

    2015-01-01

    Anti-mitotic therapies have been considered a hallmark in strategies against abnormally proliferating cells. Focusing on the extensively studied family of thiosemicarbazone (TSC) compounds, we have previously identified 4,4'-dimethoxybenzophenone thiosemicarbazone (T44Bf) as a promising pharmacological compound in a panel of human leukemia cell lines (HL60, U937, KG1a and Jurkat). Present findings indicate that T44Bf-mediated antiproliferative effects are associated with a reversible chronic mitotic arrest caused by defects in chromosome alignment, followed by induced programmed cell death. Furthermore, T44Bf selectively induces apoptosis in leukemia cell lines when compared to normal peripheral blood mononuclear cells. The underlying mechanism of action involves the activation of the mitochondria signaling pathway, with loss of mitochondrial membrane potential and sustained phosphorylation of anti-apoptotic protein Bcl-xL as well as increased Bcl-2 (enhanced phosphorylated fraction) and pro-apoptotic protein Bad levels. In addition, ERK signaling pathway activation was found to be a requisite for T44Bf apoptotic activity. Our findings further describe a novel activity for a benzophenone thiosemicarbazone and propose T44Bf as a promising anti-mitotic prototype to develop chemotherapeutic agents to treat acute leukemia malignancies. PMID:26360247

  16. Sodium butyrate reverses the inhibition of Krebs cycle enzymes induced by amphetamine in the rat brain.

    PubMed

    Valvassori, Samira S; Calixto, Karen V; Budni, Josiane; Resende, Wilson R; Varela, Roger B; de Freitas, Karolina V; Gonçalves, Cinara L; Streck, Emilio L; Quevedo, João

    2013-12-01

    There is increasing interest in the possibility that mitochondrial impairment may play an important role in bipolar disorder (BD). The Krebs cycle is the central point of oxidative metabolism, providing carbon for biosynthesis and reducing agents for generation of ATP. Recently, studies have suggested that histone deacetylase (HDAC) inhibitors may have antimanic effects. The present study aims to investigate the effects of sodium butyrate (SB), a HDAC inhibitor, on Krebs cycle enzymes activity in the brain of rats subjected to an animal model of mania induced by D-amphetamine (D-AMPH). Wistar rats were first given D-AMPH or saline (Sal) for 14 days, and then, between days 8 and 14, rats were treated with SB or Sal. The citrate synthase (CS), succinate dehydrogenase (SDH), and malate dehydrogenase (MDH) were evaluated in the prefrontal cortex, hippocampus, and striatum of rats. The D-AMPH administration inhibited Krebs cycle enzymes activity in all analyzed brain structures and SB reversed D-AMPH-induced dysfunction analyzed in all brain regions. These findings suggest that Krebs cycle enzymes' inhibition can be an important link for the mitochondrial dysfunction seen in BD and SB exerts protective effects against the D-AMPH-induced Krebs cycle enzymes' dysfunction.

  17. A novel prohibitin-binding compound induces the mitochondrial apoptotic pathway through NOXA and BIM upregulation.

    PubMed

    Moncunill-Massaguer, Cristina; Saura-Esteller, José; Pérez-Perarnau, Alba; Palmeri, Claudia Mariela; Núñez-Vázquez, Sonia; Cosialls, Ana M; González-Gironès, Diana M; Pomares, Helena; Korwitz, Anne; Preciado, Sara; Albericio, Fernando; Lavilla, Rodolfo; Pons, Gabriel; Langer, Thomas; Iglesias-Serret, Daniel; Gil, Joan

    2015-12-01

    We previously described diaryl trifluorothiazoline compound 1a (hereafter referred to as fluorizoline) as a first-in-class small molecule that induces p53-independent apoptosis in a wide range of tumor cell lines. Fluorizoline directly binds to prohibitin 1 and 2 (PHBs), two proteins involved in the regulation of several cellular processes, including apoptosis. Here we demonstrate that fluorizoline-induced apoptosis is mediated by PHBs, as cells depleted of these proteins are highly resistant to fluorizoline treatment. In addition, BAX and BAK are necessary for fluorizoline-induced cytotoxic effects, thereby proving that apoptosis occurs through the intrinsic pathway. Expression analysis revealed that fluorizoline induced the upregulation of Noxa and Bim mRNA levels, which was not observed in PHB-depleted MEFs. Finally, Noxa(-/-)/Bim(-/-) MEFs and NOXA-downregulated HeLa cells were resistant to fluorizoline-induced apoptosis. All together, these findings show that fluorizoline requires PHBs to execute the mitochondrial apoptotic pathway.

  18. Copper-binding compounds as proteasome inhibitors and apoptosis inducers in human cancer.

    PubMed

    Daniel, Kenyon G; Chen, Di; Yan, Bing; Dou, Q Ping

    2007-01-01

    The trace element copper is vital to the healthy functioning of organisms. Copper is used in a multitude of cellular activities including respiration, angiogenesis, and immune responses. Recently, copper has become a focus in medical research ranging from Alzheimer's disease to cancer. Copper modulation has been suggested to be a potential modality for therapy in these diseases. Several copper-binding compounds have been found to spontaneously complex with copper and form active proteasome inhibitors and apoptosis inducers. This review examines compounds in the quinoline and dithiocarbamate families and from the National Cancer Institute (NCI) Diversity Set that bind with copper and act as anticancer agents. In each case, it is shown that these compounds can bind with copper, inhibit the proteasome activity, and induce apoptosis in cancer cells. These activities are absent when copper is not present. Compounds alone, clioquinol and pyrrolidinedithiocarbamate as examples, are shown to have no effects in normal breast cells. Current research suggests that a possible therapeutic modality for cancer may be developed using the difference of high copper load in tumors versus low copper load in normal cells. This strategy would convert tumor cellular copper into a potent, specific proteasome inhibitor and apoptosis inducer. Thus, this approach could pave the way for the development of nontoxic anticancer therapy.

  19. Astaxanthin Inhibits Proliferation and Induces Apoptosis and Cell Cycle Arrest of Mice H22 Hepatoma Cells

    PubMed Central

    Shao, Yiye; Ni, Yanbo; Yang, Jing; Lin, Xutao; Li, Jun; Zhang, Lixia

    2016-01-01

    Background It is widely recognized that astaxanthin (ASX), a member of the carotenoid family, has strong biological activities including antioxidant, anti-inflammation, and immune-modulation activities. Previous studies have confirmed that ASX can effectively inhibit hepatoma cells in vitro. Material/Methods MTT was used to assay proliferation of mice H22 cells, and flow cytometry was used to determine apoptosis and cell cycle arrest of H22 cells in vitro and in vivo. Moreover, anti-tumor activity of ASX was observed in mice. Results ASX inhibited the proliferation of H22 cells, promoted cell necrosis, and induced cell cycle arrest in G2 phase in vitro and in vivo. Conclusions This study indicated that ASX can inhibit proliferation and induce apoptosis and cell cycle arrest in mice H22 hepatoma cells in vitro and in vivo. PMID:27333866

  20. Therapeutic tumor-specific cell cycle block induced by methionine starvation in vivo.

    PubMed

    Guo, H; Lishko, V K; Herrera, H; Groce, A; Kubota, T; Hoffman, R M

    1993-12-01

    The ability to induce a specific cell cycle block selectively in the tumor could have many uses in chemotherapy. In the present study we have achieved this goal of inducing a tumor-specific cell cycle block in vivo by depriving Yoshida sarcoma-bearing nude mice of dietary methionine. Further, we demonstrate that methionine depletion also causes the tumor to eventually regress. The antitumor effect of methionine depletion resulted in the extended survival of the tumor-bearing mice. The mice on the methionine-deprived diets maintained their body weight for the time period studied, indicating that tumor regression was not a function of body weight loss. The data reported here support future experiments utilizing methionine depletion as a target for tumor-selective cell cycle-dependent therapy.

  1. Potential for ion-induced nucleation of volatile organic compounds by radon decay in indoor environments

    SciTech Connect

    Daisey, J.M.

    1991-11-01

    There is considerable interest in the unattached'' fraction of radon progeny in indoor air because of its significance to the estimation of the risks of radon exposure. Because of its high mobility in air, the unattached fraction is more efficiently deposited in the respiratory tract. Variation in the diameter of the unattached'' fraction and in its diffusion coefficient can be due to clustering of other atmospheric species around the {sup 218}PoO{sub 2}{sup +} ion. The purpose of this study was to investigate the potential for the formation of clusters of vapor phase organic compounds, found in indoor air, around the {sup 218}PoO{sub 2}{sup +} ion and to determine which were most likely to form clusters. A secondary purpose was to provide a compilation of measurements of indoor organic compounds for future experiments and theoretical calculations by the radon research community. The classical charged liquid droplet theory (Thomson equation) was used to estimate the Gibbs free energy of ion-induced nucleation and to provide an indication of the indoor organic compounds most likely to undergo ion-induced nucleation. Forty-four volatile and semi-volatile organic compounds out of the more than 300 which have been reported in indoor air were investigated. Water vapor was included for comparison. The results indicate that there is a potential for the formation of clusters of organic compounds around the {sup 218}PoO{sub 2}{sup +} ion. The compounds with the greatest potential for cluster formation are the volatile oxidized hydrocarbons (e.g., n-butanol, phenol, hexanal, nonanal, benzaldehyde, the ketones and the acetates) and the semi-volatile organic compounds (pentachlorophenol, nicotine, chlordane, chlorpyrifos).

  2. Potential for ion-induced nucleation of volatile organic compounds by radon decay in indoor environments

    SciTech Connect

    Daisey, J.M.

    1991-11-01

    There is considerable interest in the ``unattached`` fraction of radon progeny in indoor air because of its significance to the estimation of the risks of radon exposure. Because of its high mobility in air, the unattached fraction is more efficiently deposited in the respiratory tract. Variation in the diameter of the ``unattached`` fraction and in its diffusion coefficient can be due to clustering of other atmospheric species around the {sup 218}PoO{sub 2}{sup +} ion. The purpose of this study was to investigate the potential for the formation of clusters of vapor phase organic compounds, found in indoor air, around the {sup 218}PoO{sub 2}{sup +} ion and to determine which were most likely to form clusters. A secondary purpose was to provide a compilation of measurements of indoor organic compounds for future experiments and theoretical calculations by the radon research community. The classical charged liquid droplet theory (Thomson equation) was used to estimate the Gibbs free energy of ion-induced nucleation and to provide an indication of the indoor organic compounds most likely to undergo ion-induced nucleation. Forty-four volatile and semi-volatile organic compounds out of the more than 300 which have been reported in indoor air were investigated. Water vapor was included for comparison. The results indicate that there is a potential for the formation of clusters of organic compounds around the {sup 218}PoO{sub 2}{sup +} ion. The compounds with the greatest potential for cluster formation are the volatile oxidized hydrocarbons (e.g., n-butanol, phenol, hexanal, nonanal, benzaldehyde, the ketones and the acetates) and the semi-volatile organic compounds (pentachlorophenol, nicotine, chlordane, chlorpyrifos).

  3. Using Drosophila Larval Imaginal Discs to Study Low-Dose Radiation-Induced Cell Cycle Arrest

    PubMed Central

    Yan, Shian-Jang; Li, Willis X.

    2012-01-01

    Under genotoxic stress, activation of cell cycle checkpoint responses leads to cell cycle arrest, which allows cells to repair DNA damage before continuing to cycle. Drosophila larval epithelial sacs, called imaginal discs, are an excellent in vivo model system for studying radiation-induced cell cycle arrest. Larval imaginal discs go into cell cycle arrest after being subjected to low-dose irradiation, are subject to easy genetic manipulation, are not crucial for survival of the organism, and can be dissected easily for further molecular or cellular analysis. In this chapter, we describe methods for assessing low-dose irradiation-induced cell cycle arrest. Mitotic cells are identified by immunofluorescence staining for the mitotic marker phosphorylated histone H3 (phospho-histone H3 or pH3). When wandering third-instar control larvae, without transgene expression, are exposed to 500 rads of X-ray or γ-ray irradiation, the number of pH3-positive cells in wing imaginal discs is reduced from hundreds before irradiation to approximately 30 after irradiation, with an equal distribution between the anterior and posterior compartments (Yan et al., 2011, FASEB J). Using the GAL4/UAS system, RNAi, cDNA, or microRNA sponge transgenes can be expressed in the posterior compartment of the wing disc using drivers such as engrailed (en)-Gal4, while the anterior compartment serves as an internal control. This approach makes it possible to do genome-wide genetic screening for molecules involved in radiation-induced cell cycle arrest. PMID:21870287

  4. Gravitational effects of process-induced dislocations in silicon. [during thermal cycling

    NASA Technical Reports Server (NTRS)

    Porter, W. A.; Parker, D. L.

    1974-01-01

    Matters pertaining to semiconductor device fabrication were studied in terms of the influence of gravity on the production of dislocations in silicon wafers during thermal cycling in a controlled ambient where no impurities are present and oxidation is minimal. Both n-type and p-type silicon wafers having a diameter of 1.25 in to 1.5 in, with fixed orientation and resistivity values, were used. The surface dislocation densities were measured quantitatively by the Sirtl etch technique. The results show two significant features of the plastic flow phenomenon as it is related to gravitational stress: (1) the density of dislocations generated during a given thermal cycle is directly related to the duration of the cycle; and (2) the duration of the thermal cycle required to produce a given dislocation density is inversely related to the equilibrium temperature. Analysis of the results indicates that gravitational stress is instrumental in process-induced defect generation.

  5. Exercise-induced lymphocyte apoptosis attributable to cycle ergometer exercise in endurance-trained individuals.

    PubMed

    Navalta, James Wilfred; McFarlin, Brian Keith; Lyons, Thomas Scott; Faircloth, John Clifton; Bacon, Nicholas T; Callahan, Zachary J

    2009-08-01

    Exercise as a stimulus to induce lymphocyte apoptosis remains controversial. Differences may be due to participant fitness level or the methodology of assessing cell death. Another important issue is the mode of exercise used to induce physiological changes. Treadmill exercise typically induces significant apoptosis in human lymphocytes; however, the effect of cycle exercise is less clear. The 2 main purposes of this study were to assess if cycle ergometer exercise induces similar changes in apoptosis, and to further characterize the morphological method of assessing cell death. Endurance athletes (n = 10; peak oxygen consumption = 55.1 mL.kg-1.min-1) completed a 60-min ride on a cycle ergometer at approximately 80% peak oxygen consumption. Blood samples taken before (PRE) and after (POST) exercise were used to make blood films for apoptotic analysis via the morphological technique. A significant increase was observed in the apoptotic index following cycle exercise (PRE = 7.3 +/- 2%, POST = 12.9 +/- 2%; p < 0.01). On average, it took 42 +/- 9 min to read PRE sample slides, which was significantly longer than the 27 +/- 4 min needed for POST slides (p < 0.01). To our knowledge, this study is the first to report that exercise on the cycle ergometer produces changes in lymphocyte apoptosis. The values measured during this study were about 20% lower than those we have observed following treadmill running, which may be explained by differences in active muscle mass and the resultant physiological stress between the 2 exercise modes. It is likely that cycling may result in reduced immunosuppression, compared with running at the same intensity.

  6. Dependence of pulsed focused ultrasound induced thrombolysis on duty cycle and cavitation bubble size distribution.

    PubMed

    Xu, Shanshan; Zong, Yujin; Feng, Yi; Liu, Runna; Liu, Xiaodong; Hu, Yaxin; Han, Shimin; Wan, Mingxi

    2015-01-01

    In this study, we investigated the relationship between the efficiency of pulsed, focused ultrasound (FUS)-induced thrombolysis, the duty cycle (2.3%, 9%, and 18%) and the size distribution of cavitation bubbles. The efficiency of thrombolysis was evaluated through the degree of mechanical fragmentation, namely the number, mass, and size of clot debris particles. First, we found that the total number and mass of clot debris particles were highest when a duty cycle of 9% was used and that the mean diameter of clot debris particles was smallest. Second, we found that the size distribution of cavitation bubbles was mainly centered around the linear resonance radius (2.5μm) of the emission frequency (1.2MHz) of the FUS transducer when a 9% duty cycle was used, while the majority of cavitation bubbles became smaller or larger than the linear resonance radius when a 2.3% or 18% duty cycle was used. In addition, the inertial cavitation dose from the treatment performed at 9% duty cycle was much higher than the dose obtained with the other two duty cycles. The data presented here suggest that there is an optimal duty cycle at which the thrombolysis efficiency and cavitation activity are strongest. They further indicate that using a pulsed FUS may help control the size distribution of cavitation nuclei within an active size range, which we found to be near the linear resonance radius of the emission frequency of the FUS transducer.

  7. Dux4 induces cell cycle arrest at G1 phase through upregulation of p21 expression

    SciTech Connect

    Xu, Hongliang; Wang, Zhaoxia; Jin, Suqin; Hao, Hongjun; Zheng, Lemin; Zhou, Boda; Zhang, Wei; Lv, He; Yuan, Yun

    2014-03-28

    Highlights: • Dux4 induced TE671 cell proliferation defect and G1 phase arrest. • Dux4 upregulated p21 expression without activating p53. • Silencing p21 rescued Dux4 mediated proliferation defect and cell cycle arrest. • Sp1 binding site was required for Dux4-induced p21 promoter activation. - Abstract: It has been implicated that Dux4 plays crucial roles in development of facioscapulohumeral dystrophy. But the underlying myopathic mechanisms and related down-stream events of this retrogene were far from clear. Here, we reported that overexpression of Dux4 in a cell model TE671 reduced cell proliferation rate, and increased G1 phase accumulation. We also determined the impact of Dux4 on p53/p21 signal pathway, which controls the checkpoint in cell cycle progression. Overexpression of Dux4 increased p21 mRNA and protein level, while expression of p53, phospho-p53 remained unchanged. Silencing p21 rescued Dux4 mediated proliferation defect and cell cycle arrest. Furthermore, we demonstrated that enhanced Dux4 expression increased p21 promoter activity and elevated expression of Sp1 transcription factor. Mutation of Sp1 binding site decreased dux4 induced p21 promoter activation. Chromatin immunoprecipitation (ChIP) assays confirmed the Dux4-induced binding of Sp1 to p21 promoter in vivo. These results suggest that Dux4 might induce proliferation inhibition and G1 phase arrest through upregulation of p21.

  8. Cycling induced by electrical stimulation improves muscle activation and symmetry during pedaling in hemiparetic patients.

    PubMed

    Ambrosini, Emilia; Ferrante, Simona; Ferrigno, Giancarlo; Molteni, Franco; Pedrocchi, Alessandra

    2012-05-01

    A randomized controlled trial, involving 35 post-acute hemiparetic patients, demonstrated that a four-week treatment of cycling induced by functional electrical stimulation (FES-cycling) promotes motor recovery. Analyzing additional data acquired during that study, the present work investigated whether these improvements were associated to changes in muscle strength and motor coordination. Participants were randomized to receive FES-cycling or placebo FES-cycling. Clinical outcome measures were: the Motricity Index (MI), the gait speed, the electromyography activation of the rectus femoris and biceps femoris, and the mechanical work produced by each leg during voluntary pedaling. To provide a comparison with normal values, healthy adults also carried out the pedaling test. Patients were evaluated before, after training, and at follow-up visits. A significant treatment effect in favor of FES-treated patients was found in terms of MI scores and unbalance in mechanical works, while differences in gait speed were not significant (ANCOVA). Significant improvements in the activation of the paretic muscles were highlighted in the FES group, while no significant change was found in the placebo group (Friedman test). Our findings suggested that improvements in motor functions induced by FES-cycling training were associated with a more symmetrical involvement of the two legs and an improved motor coordination. PMID:22514205

  9. Repeated freeze-thaw cycles induce embolism in drought stressed conifers (Norway spruce, stone pine).

    PubMed

    Mayr, Stefan; Gruber, Andreas; Bauer, Helmut

    2003-07-01

    Freezing and thawing lead to xylem embolism when gas bubbles caused by ice formation expand during the thaw process. However, previous experimental studies indicated that conifers are resistant to freezing-induced embolism, unless xylem pressure becomes very negative during the freezing. In this study, we show that conifers experienced freezing-induced embolism when exposed to repeated freeze-thaw cycles and simultaneously to drought. Simulating conditions at the alpine timberline (128 days with freeze-thaw events and thawing rates of up to 9.5 K h(-1) in the xylem of exposed twigs during winter), young trees of Norway spruce [Picea abies (L.) Karst.] and stone pine (Pinus cembra L.) were exposed to 50 and 100 freeze-thaw cycles. This treatment caused a significant increase in embolism rates in drought-stressed samples. Upon 100 freeze-thaw cycles, vulnerability thresholds (50% loss of conductivity) were shifted 1.8 MPa (Norway spruce) and 0.8 MPa (stone pine) towards less negative water potentials. The results demonstrate that freeze-thaw cycles are a possible reason for winter-embolism in conifers observed in several field studies. Freezing-induced embolism may contribute to the altitudinal limits of conifers.

  10. Vitexins, nature-derived lignan compounds, induce apoptosis and suppress tumor growth

    PubMed Central

    Zhou, YingJun; Liu, Yiliang Ellie; Cao, JianGuo; Zeng, GuangYao; Shen, Cui; Li, YanLan; Zhou, MeiChen; Chen, Yiding; Pu, Weiping; Potters, Louis; Shi, Eric Y.

    2009-01-01

    Purpose Lignans such as secoisolariciresinol diglucoside (SDG) in flaxseed, are metabolizes to bioactive mammalian lignans of END and ENL. Because mammalian lignans have chemical structural similarity to the natural estrogen, they are thought to behave like selective estrogen receptor modulators (SERM) and therefore have anticancer effect against hormone-related cancers. We isolated a series of lignan compounds, named as Vitexins, from the seed of Chinese herb Vitex Negundo. Experimental Design We purified several Vitexin lignan compounds. Cytotoxic and antitumor effects were analyzed in cancer cells and in tumor xenograft models. In vivo metabolism of Vitexins was determined in rat. Results Contrasts to the classical lignans, Vitexins were not metabolized to END and ENL. A mixture of Vitexins EVn-50 and purified Vitexin compound VB1 have cytotoxic effect on breast, prostate, and ovarian cancer cells and induces apoptosis with cleavage in PARP protein, up-regulation of Bax, and down-regulation of Bcl-2. This induction of apoptosis seems to be mediated by activation of caspases because inhibition of caspases activity significantly reduced induced apoptosis. We demonstrated a broad antitumor activity of EVn-50 on seven tumor xenograft models including breast, prostate, liver, and cervical cancers. Consistent with in vitro data, EVn-50 treatment induced apoptosis, down-regulated of Bcl-2, and up-regulated Bax in tumor xenografts. Conclusion Vitexin is a class of nature lignan compounds, whose action and anticancer effect is mediated by the mechanisms different from the classical lignans. Vitexin induced antitumor effect and cytotoxic activity is exerted through proapoptotic process, which is mediated by a decreased Bcl-2/Bax ratio and activation of caspases. PMID:19671865

  11. Low dose of amino-modified nanoparticles induces cell cycle arrest.

    PubMed

    Kim, Jong Ah; Åberg, Christoffer; de Cárcer, Guillermo; Malumbres, Marcos; Salvati, Anna; Dawson, Kenneth A

    2013-09-24

    The interaction of nanoscaled materials with biological systems is currently the focus of a fast-growing area of investigation. Though many nanoparticles interact with cells without acute toxic responses, amino-modified polystyrene nanoparticles are known to induce cell death. We have found that by lowering their dose, cell death remains low for several days while, interestingly, cell cycle progression is arrested. In this scenario, nanoparticle uptake, which we have recently shown to be affected by cell cycle progression, develops differently over time due to the absence of cell division. This suggests that the same nanoparticles can trigger different pathways depending on exposure conditions and the dose accumulated.

  12. The natural chlorine cycle - Formation of the carcinogenic and greenhouse gas compound chloroform in drinking water reservoirs.

    PubMed

    Forczek, Sándor T; Pavlík, Milan; Holík, Josef; Rederer, Luděk; Ferenčík, Martin

    2016-08-01

    Chlorine cycle in natural ecosystems involves formation of low and high molecular weight organic compounds of living organisms, soil organic matter and atmospherically deposited chloride. Chloroform (CHCl3) and adsorbable organohalogens (AOX) are part of the chlorine cycle. We attempted to characterize the dynamical changes in the levels of total organic carbon (TOC), AOX, chlorine and CHCl3 in a drinking water reservoir and in its tributaries, mainly at its spring, and attempt to relate the presence of AOX and CHCl3 with meteorological, chemical or biological factors. Water temperature and pH influence the formation and accumulation of CHCl3 and affect the conditions for biological processes, which are demonstrated by the correlation between CHCl3 and ΣAOX/Cl(-) ratio, and also by CHCl3/ΣAOX, CHCl3/AOXLMW, CHCl3/ΣTOC, CHCl3/TOCLMW and CHCl3/Cl(-) ratios in different microecosystems (e.g. old spruce forest, stagnant acidic water, humid and warm conditions with high biological activity). These processes start with the biotransformation of AOX from TOC, continue via degradation of AOX to smaller molecules and further chlorination, and finish with the formation of small chlorinated molecules, and their subsequent volatilization and mineralization. The determined concentrations of chloroform result from a dynamic equilibrium between its formation and degradation in the water; in the Hamry water reservoir, this results in a total amount of 0.1-0.7 kg chloroform and 5.2-15.4 t chloride. The formation of chloroform is affected by Cl(-) concentration, by concentrations and ratios of biogenic substrates (TOC and AOX), and by the ratios of the substrates and the product (feedback control by chloroform itself).

  13. The natural chlorine cycle - Formation of the carcinogenic and greenhouse gas compound chloroform in drinking water reservoirs.

    PubMed

    Forczek, Sándor T; Pavlík, Milan; Holík, Josef; Rederer, Luděk; Ferenčík, Martin

    2016-08-01

    Chlorine cycle in natural ecosystems involves formation of low and high molecular weight organic compounds of living organisms, soil organic matter and atmospherically deposited chloride. Chloroform (CHCl3) and adsorbable organohalogens (AOX) are part of the chlorine cycle. We attempted to characterize the dynamical changes in the levels of total organic carbon (TOC), AOX, chlorine and CHCl3 in a drinking water reservoir and in its tributaries, mainly at its spring, and attempt to relate the presence of AOX and CHCl3 with meteorological, chemical or biological factors. Water temperature and pH influence the formation and accumulation of CHCl3 and affect the conditions for biological processes, which are demonstrated by the correlation between CHCl3 and ΣAOX/Cl(-) ratio, and also by CHCl3/ΣAOX, CHCl3/AOXLMW, CHCl3/ΣTOC, CHCl3/TOCLMW and CHCl3/Cl(-) ratios in different microecosystems (e.g. old spruce forest, stagnant acidic water, humid and warm conditions with high biological activity). These processes start with the biotransformation of AOX from TOC, continue via degradation of AOX to smaller molecules and further chlorination, and finish with the formation of small chlorinated molecules, and their subsequent volatilization and mineralization. The determined concentrations of chloroform result from a dynamic equilibrium between its formation and degradation in the water; in the Hamry water reservoir, this results in a total amount of 0.1-0.7 kg chloroform and 5.2-15.4 t chloride. The formation of chloroform is affected by Cl(-) concentration, by concentrations and ratios of biogenic substrates (TOC and AOX), and by the ratios of the substrates and the product (feedback control by chloroform itself). PMID:27231877

  14. Positive Feedback Cycle of TNFα Promotes Staphylococcal Enterotoxin B-Induced THP-1 Cell Apoptosis

    PubMed Central

    Zhang, Xiaopeng; Shang, Weilong; Yuan, Jizhen; Hu, Zhen; Peng, Huagang; Zhu, Junmin; Hu, Qiwen; Yang, Yi; Liu, Hui; Jiang, Bei; Wang, Yinan; Li, Shu; Hu, Xiaomei; Rao, Xiancai

    2016-01-01

    Staphylococcal enterotoxin B (SEB) has been demonstrated to be of importance in Staphylococcus aureus related diseases, such as atopic dermatitis (AD). Dysregulated apoptosis in AD is remarkable, and SEB can induce apoptosis of various cell types. However, the mechanisms by which SEB induces apoptosis and influences disease processes remain unclear. In this study, the recombinant SEB-induced THP-1 monocyte apoptosis was demonstrated in the absence of preliminary cell activation in a time- and dose-dependent manner. SEB could up-regulate the expression of tumor necrosis factor alpha (TNFα) in THP-1 cells and induce apoptosis via an extrinsic pathway. TNFα could in turn increase the expression of HLA-DRa, the SEB receptor on the cell surface. As a result, a positive feedback cycle of TNFα was established. TNFα expression and SEB-induced apoptosis were decreased by knocking down the expression of either HLA-DRa or TNFR1. Therefore, the feedback cycle of TNFα is crucial for SEB functions. This work provides insights into the mechanisms of SEB-induced monocyte apoptosis and emphasizes the major role of TNFα in future related studies. PMID:27709104

  15. Raman spectrum reveals the cell cycle arrest of Triptolide-induced leukemic T-lymphocytes apoptosis

    NASA Astrophysics Data System (ADS)

    Zhang, Daosen; Feng, Yanyan; Zhang, Qinnan; Su, Xin; Lu, Xiaoxu; Liu, Shengde; Zhong, Liyun

    2015-04-01

    Triptolide (TPL), a traditional Chinese medicine extract, possesses anti-inflammatory and anti-tumor properties. Though some research results have implicated that Triptolide (TPL) can be utilized in the treatment of leukemia, it remains controversial about the mechanism of TPL-induced leukemic T-lymphocytes apoptosis. In this study, combining Raman spectroscopic data, principal component analysis (PCA) and atomic force microscopy (AFM) imaging, both the biochemical changes and morphological changes during TPL-induced cell apoptosis were presented. In contrast, the corresponding data during Daunorubicin (DNR)-induced cell apoptosis was also exhibited. The obtained results showed that Raman spectral changes during TPL-induced cell apoptosis were greatly different from DNR-induced cell apoptosis in the early stage of apoptosis but revealed the high similarity in the late stage of apoptosis. Moreover, above Raman spectral changes were respectively consistent with the morphological changes of different stages during TPL-induced apoptosis or DNR-induced apoptosis, including membrane shrinkage and blebbing, chromatin condensation and the formation of apoptotic bodies. Importantly, it was found that Raman spectral changes with TPL-induced apoptosis or DNR-induced apoptosis were respectively related with the cell cycle G1 phase arrest or G1 and S phase arrest.

  16. Bioactive compounds from liverworts: Inhibition of lipopolysaccharide-induced inducible NOS mRNA in RAW 264.7 cells by herbertenoids and cuparenoids.

    PubMed

    Harinantenaina, Liva; Quang, Dang Ngoc; Nishizawa, Takashi; Hashimoto, Toshihiro; Kohchi, Chie; Soma, Gen-Ichiro; Asakawa, Yoshinori

    2007-08-01

    The inhibition of lipopolysaccharide (LPS)-induced inducible nitric oxide synthase (iNOS) by herbertenoids and cuparenoids isolated from liverworts in RAW 264.7 macrophages was evaluated. Among compounds tested, herbertenediol, cuparenediol, 1,2-diacetoxyherbertene and 2-hydroxy-4-methoxycuparene exhibited significant activity. For 2-hydroxy-4-methoxycuparene, chosen as representative compound, the strong inhibitory activity was related to the inhibition on LPS-induced iNOS mRNA. The structure-activity relationship will be discussed.

  17. Two new isoquinoline alkaloids from Scolopendra subspinipes mutilans induce cell cycle arrest and apoptosis in human glioma cancer U87 cells.

    PubMed

    Ding, Dan; Guo, Ya-Ru; Wu, Rui-Ling; Qi, Wei-Yan; Xu, Han-Mei

    2016-04-01

    Two new isoquinoline alkaloids 1-2 and seven known compounds 3-9 were isolated from the ethanol extract of centipede Scolopendra subspinipes mutilans L. Koch. The structures were elucidated by a combination of spectroscopic analyses including 1D and 2D NMR, and HRESIMS. Compounds 1-2 exhibited good cytotoxicity with IC50 values ranging from 1.19 to 31.28μM against six human cancer cell lines and low cytotoxicity against human normal liver L-02 cell lines, suggesting that compounds 1-2 had high specific cytotoxicity on human cancer cell lines. Further analyses showed that compounds 1-2 inhibited U87 cells proliferation by arresting cell cycle progress at G0/G1 phase and inducing apoptosis through loss of mitochondrial membrane potential (MMP), activation of caspase 9/3 and down-regulation of the Bcl-2/Bax protein ratio. The results suggest that compounds 1-2 induce apoptosis in U87 cells through the mitochondria apoptosis pathway, and they deserve further research as potential anti-glioma cancer agents. PMID:26947248

  18. Photo-induced spin transition of Iron(III) compounds with pi-pi intermolecular interactions.

    PubMed

    Hayami, Shinya; Hiki, Kenji; Kawahara, Takayoshi; Maeda, Yonezo; Urakami, Daisuke; Inoue, Katsuya; Ohama, Mitsuo; Kawata, Satoshi; Sato, Osamu

    2009-01-01

    Iron(III) spin-crossover compounds [Fe(pap)(2)]ClO(4) (1), [Fe(pap)(2)]BF(4) (2), [Fe(pap)(2)]PF(6) (3), [Fe(qsal)(2)]NCS (4), and [Fe(qsal)(2)]NCSe (5) (Hpap=2-(2-pyridylmethyleneamino)phenol and Hqsal=2-[(8-quinolinylimino)methyl]phenol) were prepared and their spin-transition properties investigated by magnetic susceptibility and Mössbauer spectroscopy measurements. The iron(III) compounds exhibited spin transition with thermal hysteresis. Single crystals of the iron(III) compounds were obtained as suitable solvent adducts for X-ray analysis, and structures in high-spin (HS) and low-spin (LS) states were revealed. Light-induced excited-spin-state trapping (LIESST) effects of the iron(III) compounds were induced by light irradiation at 532 nm for 1-3 and at 800 nm for 4 and 5. The activation energy E(a) and the low-temperature tunneling rate k(HL)(T-->0) of iron(III) LIESST compound 1 were estimated to be 1079 cm(-1) and 2.4x10(-8) s(-1), respectively, by HS-->LS relaxation experiments. The Huang-Rhys factor S of 1 was also estimated to be 50, which was similar to that expected for iron(II) complexes. It is thought that the slow relaxation in iron(III) systems is achieved by the large structural distortion between HS and LS states. Introduction of strong intermolecular interactions, such as pi-pi stacking, can also play an important role in the relaxation behavior, because it can enhance the structural distortion of the LIESST complex. PMID:19191246

  19. Proliferation inhibition, cell cycle arrest and apoptosis induced in HL-60 cells by a natural diterpene ester from Daphne mucronata

    PubMed Central

    Nouri, K.; Yazdanparast, R.

    2011-01-01

    Background and the purpose of the study Gnidilatimonoein (Gn), a new diterpene ester from Daphne mucronata, possesses strong anti-metastasis and anti-tumor activities. In this study, its apoptosis and differentiation capabilities were evaluated by using the leukemia HL-60 cell line. Material and methods Cell prolifaration inhibition was estimated by MTT assay. The occurrence of apoptosis was evaluated by EtBr/AO double staining technique, cell cycle analyses and detection of apoptotic cells by Annexin V-FITC and propodium iodide (PI). Differentiation of the cells was determined by NBT reduction assay and the expression of specific cell surface markers such as CD14 and CD11b, were analyzed by flow cytometry. Results The drug decreased the growth of the cells dose- and time-dependently and the IC50 was found to be 1.3 µM. Our data suggested that Gn induced both monocytic differentiation and apoptosis among HL-60 cells. In addition, cell cycle analyses showed an increase in G1 phase population by 24 hrs, which was gradually replaced by Sub-G1 cell population (apoptotic cells) by 72 hrs. Conclusion Based on these data, the Gn-treated HL-60 cells displayed differentiation-dependent apoptosis. Thus, Gn might be a good candidate for differentiation therapy of leukemia, pending full biological evaluation of the compound among the wide array of leukemia cells. PMID:22615651

  20. Gypensapogenin H, a novel dammarane-type triterpene induces cell cycle arrest and apoptosis on prostate cancer cells.

    PubMed

    Zhang, Xiao-Shu; Zhao, Chen; Tang, Wei-zhuo; Wu, Xiao-jun; Zhao, Yu-Qing

    2015-12-01

    Gypensapogenin H (GH) is a novel dammarane-type triterpenes obtained from hydrolyzate of total saponins from Gynostemma pentaphyllum and its anti-tumor activity has been studied in previous work. In this study, we report the effects of this compound on human prostate cancer cells (DU145 and 22RV-1). It significantly inhibited proliferation, decreased survival, led to G1 cell cycle arrest and induced apoptosis in both cell lines, while having lesser effect on the growth of normal human gastric mucosa cells (GES-1), embryonic kidney cells (HEK293) and lung fibroblast cells (MRC5). Consistent with these phenotypes, we observed decreased expression of the cell cycle-related proteins cyclinD1, and CDK4, and increased expression of p21 in GH-treated cells. Besides, the anti-apoptotic Bcl-2 protein decreased in a dose-dependent manner, while Bax, cleaved caspase-3 and -9 increased upon GH treatment. Taken together, these results indicated GH exerted promising anticancer activity, and may represent a potential agent for the treatment of prostate cancer.

  1. Evidence for climate variations induced by the 11-year solar and cosmic rays cycles

    NASA Astrophysics Data System (ADS)

    Bruckman, William; Ramos, Elio

    2010-02-01

    We analyzed data from PSMSL monthly mean sea level seeking correlations between sea level fluctuations and the solar and cosmic rays 11 year cycle. The data reveals decadal variability that could be causally connected to the solar and cosmic rays cycle, since these periodic changes are correlated. It is also found that the solar (cosmic rays) cycle correlates (anti-correlates) with the mean global surface temperature anomaly. A probable explanation of the above correlations is that the solar intensity and cosmic rays variations induce oscillations in the average temperature and precipitation, with corresponding changes in the continental water and snow accumulation. Thus, for instance, a higher than average snow and water over land, and lower temperatures produce oceans thermal contraction and lower mass, implicating lower mean sea level.

  2. Vanadium-induced formation of thiadiazole and thiazoline compounds. Mononuclear and dinuclear oxovanadium(v) complexes with open-chain and cyclized thiosemicarbazone ligands.

    PubMed

    Rubcić, Mirta; Milić, Dalibor; Horvat, Gordan; Dilović, Ivica; Galić, Nives; Tomisić, Vladislav; Cindrić, Marina

    2009-11-28

    Reactions of the salicylaldehyde 4-phenylthiosemicarbazone (H(2)L) with selected vanadium(iv) and vanadium(v) precursors ([VO(acac)(2)], [VO(OAc)(2)], VOSO(4), [V(2)O(4)(acac)(2)]) were investigated under aerobic conditions in different alcohols (methanol, ethanol, propanol). In all examined cases mononuclear alkoxo vanadium(v) complexes [VOL(OR)] (1) (OR = OMe, OEt, OPr) were isolated as major products. On prolonged standing, mother liquids afforded dinuclear vanadium(v) complexes [V(2)O(3)(L(cycl))(2)(OR)(2)] (3) (OR = OMe, OEt, OPr), where L(cycl)(-) represents 1,3,4-thiadiazole ligand, formed by vanadium-induced oxidative cyclization of H(2)L. When [VO(acac)(2)] or [V(2)O(4)(acac)(2)] were used as precursors, in addition to products 1 and 3, a thiazoline derivative HL(acac)(cycl) (2) was isolated. This compound, formed by a reaction between acetylacetone and H(2)L, represented the second type of cyclic product. The products were characterized by IR and NMR spectroscopies, TG analysis, and in some cases by single-crystal X-ray diffraction. To the best of our knowledge, compounds [V(2)O(3)(L(cycl))(2)(OR)(2)] represent the first structurally characterized dinuclear vanadium(v) complexes with a thiadiazole moiety acting as a bridging ligand. Complexes 1 and 3, when dissolved in an appropriate alcohol, underwent substitution of the alkoxo ligand as confirmed by XRPD. The kinetics of reactions in methanolic solutions was qualitatively studied by UV-Vis and ESMS spectrometries. Under the experimental conditions applied, a relatively slow formation of the mononuclear complex [VOL(OMe)] and an even slower formation of the cyclic species 2 were observed, whereas the presence of dinuclear compound [V(2)O(3)(L(cycl))(2)(OMe)(2)] in the reaction mixture could not be detected.

  3. Heat-induced darkening and spectral broadening in photodarkened ytterbium-doped fiber under thermal cycling.

    PubMed

    Söderlund, Mikko J; Montiel i Ponsoda, Joan J; Koplow, Jeffrey P; Honkanen, Seppo

    2009-06-01

    We study thermal bleaching of photodarkening-induced loss in a 20-microm core diameter, large-mode-area ytterbium-doped silica fiber. Pristine and photodarkened samples are subjected to thermal cycling pulses. Recovery of the photodarkened fiber absorption coefficient initiates at approximately 350 degrees C and complete recovery is reached at approximately 625 degrees C. However, prior to recovery, the photodarkened fiber exhibits further heat-induced increase of absorption loss. This increase of loss is attributed to both a permanent increase of loss-inducing color centers and a temperature-dependent broadening of the absorption spectrum. Post-irradiation heat-induced formation of color centers suggests the presence of an intermediate energy state in the near-infrared photochemical mechanism for photodarkening. PMID:19506644

  4. Heat-induced darkening and spectral broadening in photodarkened ytterbium-doped fiber under thermal cycling.

    PubMed

    Söderlund, Mikko J; Montiel i Ponsoda, Joan J; Koplow, Jeffrey P; Honkanen, Seppo

    2009-06-01

    We study thermal bleaching of photodarkening-induced loss in a 20-microm core diameter, large-mode-area ytterbium-doped silica fiber. Pristine and photodarkened samples are subjected to thermal cycling pulses. Recovery of the photodarkened fiber absorption coefficient initiates at approximately 350 degrees C and complete recovery is reached at approximately 625 degrees C. However, prior to recovery, the photodarkened fiber exhibits further heat-induced increase of absorption loss. This increase of loss is attributed to both a permanent increase of loss-inducing color centers and a temperature-dependent broadening of the absorption spectrum. Post-irradiation heat-induced formation of color centers suggests the presence of an intermediate energy state in the near-infrared photochemical mechanism for photodarkening.

  5. Prevention of acrylonitrile-induced gastrointestinal bleeding by sulfhydryl compounds, atropine and cimetidine

    SciTech Connect

    Ghanayem, B.I.; Ahmed, A.E.

    1986-07-01

    We have recently demonstrated that acrylonitrile (VCN) causes acute gastric hemorrhage and mucosal erosions. The current studies were undertaken to investigate the effects of the sulfhydryl-containing compounds, cysteine and cysteamine, the cholinergic blocking agent atropine and the histamine H2 receptor antagonist, cimetidine on the VCN-induced gastrointestinal (GI) bleeding in rats. Our data shows that pretreatment with L-cysteine, cysteamine, atropine or cimetidine has significantly protected rats against the VCN-induced GI bleeding. A possible mechanism of the VCN-induced GI bleeding may involve the interaction of VCN with critical sulfhydryl groups that, in turn, causes alteration of acetylcholine muscarinic receptors to lead to gastric hemorrhagic lesions and bleeding.

  6. Suppression of the antiferroelectric phase during polarization cycling of an induced ferroelectric phase

    SciTech Connect

    Liu, Xiaoming; Tan, Xiaoli

    2015-08-17

    The ceramic Pb{sub 0.99}Nb{sub 0.02}[(Zr{sub 0.57}Sn{sub 0.43}){sub 0.92}Ti{sub 0.08}]{sub 0.98}O{sub 3} can exist in either an antiferroelectric or a ferroelectric phase at room temperature, depending on the thermal and electrical history. The antiferroelectric phase can be partially recovered from the induced ferroelectric phase when the applied field reverses polarity. Therefore, polarization cycling of the ferroelectric phase in the ceramic under bipolar fields at room temperature is accompanied with repeated phase transitions. In this letter, the stability of the recovered antiferroelectric phase upon electrical cycling of the ceramic is investigated. Ex-situ X-ray diffraction reveals that bipolar cycling suppresses the antiferroelectric phase; this is indirectly supported by piezoelectric coefficient d{sub 33} measurements. It is speculated that the accumulated charged point defects during polarization cycling stabilize the polar ferroelectric phase. The findings presented are important to the fundamental studies of electric fatigue and field-induced phase transitions in ferroelectrics.

  7. Listeria monocytogenes induces host DNA damage and delays the host cell cycle to promote infection

    PubMed Central

    Leitão, Elsa; Costa, Ana Catarina; Brito, Cláudia; Costa, Lionel; Pombinho, Rita; Cabanes, Didier; Sousa, Sandra

    2014-01-01

    Listeria monocytogenes (Lm) is a human intracellular pathogen widely used to uncover the mechanisms evolved by pathogens to establish infection. However, its capacity to perturb the host cell cycle was never reported. We show that Lm infection affects the host cell cycle progression, increasing its overall duration but allowing consecutive rounds of division. A complete Lm infectious cycle induces a S-phase delay accompanied by a slower rate of DNA synthesis and increased levels of host DNA strand breaks. Additionally, DNA damage/replication checkpoint responses are triggered in an Lm dose-dependent manner through the phosphorylation of DNA-PK, H2A.X, and CDC25A and independently from ATM/ATR. While host DNA damage induced exogenously favors Lm dissemination, the override of checkpoint pathways limits infection. We propose that host DNA replication disturbed by Lm infection culminates in DNA strand breaks, triggering DNA damage/replication responses, and ensuring a cell cycle delay that favors Lm propagation. PMID:24552813

  8. Suppression of the antiferroelectric phase during polarization cycling of an induced ferroelectric phase

    NASA Astrophysics Data System (ADS)

    Liu, Xiaoming; Tan, Xiaoli

    2015-08-01

    The ceramic Pb0.99Nb0.02[(Zr0.57Sn0.43)0.92Ti0.08]0.98O3 can exist in either an antiferroelectric or a ferroelectric phase at room temperature, depending on the thermal and electrical history. The antiferroelectric phase can be partially recovered from the induced ferroelectric phase when the applied field reverses polarity. Therefore, polarization cycling of the ferroelectric phase in the ceramic under bipolar fields at room temperature is accompanied with repeated phase transitions. In this letter, the stability of the recovered antiferroelectric phase upon electrical cycling of the ceramic is investigated. Ex-situ X-ray diffraction reveals that bipolar cycling suppresses the antiferroelectric phase; this is indirectly supported by piezoelectric coefficient d33 measurements. It is speculated that the accumulated charged point defects during polarization cycling stabilize the polar ferroelectric phase. The findings presented are important to the fundamental studies of electric fatigue and field-induced phase transitions in ferroelectrics.

  9. Novel antiproliferative flavonoids induce cell cycle arrest in human prostate cancer cell lines.

    PubMed

    Haddad, A Q; Venkateswaran, V; Viswanathan, L; Teahan, S J; Fleshner, N E; Klotz, L H

    2006-01-01

    Epidemiologic studies have demonstrated an inverse association between flavonoid intake and prostate cancer (PCa) risk. The East Asian diet is very high in flavonoids and, correspondingly, men in China and Japan have the lowest incidence of PCa worldwide. There are thousands of different naturally occurring and synthetic flavonoids. However, only a few have been studied in PCa. Our aim was to identify novel flavonoids with antiproliferative effect in PCa cell lines, as well as determine their effects on cell cycle. We have screened a representative subgroup of 26 flavonoids for antiproliferative effect on the human PCa (LNCaP and PC3), breast cancer (MCF-7), and normal prostate stromal cell lines (PrSC). Using a fluorescence-based cell proliferation assay (Cyquant), we have identified five flavonoids, including the novel compounds 2,2'-dihydroxychalcone and fisetin, with antiproliferative and cell cycle arresting properties in human PCa in vitro. Most of the flavonoids tested exerted antiproliferative effect at lower doses in the PCa cell lines compared to the non-PCa cells. Flow cytometry was used as a means to determine the effects on cell cycle. PC3 cells were arrested in G2/M phase by flavonoids. LNCaP cells demonstrated different cell cycle profiles. Further studies are warranted to determine the molecular mechanism of action of 2,2'-DHC and fisetin in PCa, and to establish their effectiveness in vivo.

  10. Identification of novel candidate compounds targeting TrkB to induce apoptosis in neuroblastoma.

    PubMed

    Nakamura, Yohko; Suganami, Akiko; Fukuda, Mayu; Hasan, Md Kamrul; Yokochi, Tomoki; Takatori, Atsushi; Satoh, Shunpei; Hoshino, Tyuji; Tamura, Yutaka; Nakagawara, Akira

    2014-02-01

    Neuroblastoma (NB) is one of the most frequent solid tumors in children and its prognosis is still poor. The neurotrophin receptor TrkB and its ligand brain-derived neurotrophic factor (BDNF) are expressed at high levels in high-risk NBs and are involved in defining the poor prognosis of the patients. However, the TrkB targeting therapy has never been realized in the clinic. We performed an in silico screening procedure utilizing an AutoDock/grid computing technology in order to identify novel small chemical compounds targeting the BDNF-binding domain of TrkB. For the first screening, a library of three million synthetic compounds was screened in silico and was ranked according to the Docking energy. The top-ranked 37 compounds were further functionally screened for cytotoxicity by using NB cell lines. We have finally identified seven compounds that kill NB cells with the IC50 values of 0.07-4.6 μmol/L. The terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay showed that these molecules induce apoptosis accompanied by p53 activation in NB cell lines. The candidate compounds and BDNF demonstrated an antagonistic effect on cell growth, invasion, and colony formation, possibly suggesting competition at the BDNF-binding site of TrkB. The candidate compounds had tumor-suppressive activity in xenograft and in vivo toxicity tests (oral and intravenous administrations) using mice, and did not show any abnormal signs. Using in silico Docking screening we have found new candidate TrkB inhibitors against high-risk NBs, which could lead to new anti-cancer drugs.

  11. Deciphering Complex Carbon Cycle Changes Across the K-Pg Boundary Using Compound-Specific Carbon Isotopic Analyses

    NASA Astrophysics Data System (ADS)

    Pancost, R. D.; Taylor, K. W.; Hollis, C. J.; Crouch, E. M.

    2014-12-01

    The consequences of the Cretaceous-Paleogene (K/Pg) boundary event on the Earth system have been the subject of much scrutiny. Postulated climate events include a brief (10 - 2000 yr) period of global cooling induced by sulphate aerosols (the so-called 'impact winter'), an interval of warming caused by impact-induced CO2release, as well as longer-term climatic oscillations during the subsequent 1 to 3Myr. Associated with these were putative changes in the biogeochemical cycle, manifested as carbon isotope excursions on both short- and long-term timescales. In this study we develop new biomarker-based climate and biogeochemical records for the mid-Waipara River and Branch Stream sections, NZ. At Branch Stream, a pronounced negative (ca 6 to 8 permil) carbon isotope excursion occurs at the K/Pg; the excursion is recorded by higher plant biomarkers, consistent with some terrestrial records and suggesting that the immediate aftermath of the K/Pg boundary event was characterised by the massive release of 13C-depleted reduced carbon into the ocean-atmosphere reservoir. Mixing across the K/Pg boundary at the Waipara section precludes a similar high-resolution investigation. Lower-resolution, longer-term records, however, also reveal a negative carbon istope excursion documented by both algal and higher plant biomarkers. This event appears to be distinct from that recorded at Branch Stream, being of lower magnitude and longer duration. It coincided with a transient terrestrial and marine warming and appears to have lasted at least 100 kyr and perhaps longer. We argue that this protracted negative CIE reflects a secondary and longer-term consequence of the K/Pg on the global carbon cycle. There is little evidence for an algal extinction as a range of C27 to C30 sterols continued to be deposited throughout the entire section, but changes in GDGT distributions do suggest a change in carbon export dynamics which could have impacted burial of 13C-depleted marine organic matter

  12. Surface induces different crystal structures in a room temperature switchable spin crossover compound.

    PubMed

    Gentili, Denis; Liscio, Fabiola; Demitri, Nicola; Schäfer, Bernhard; Borgatti, Francesco; Torelli, Piero; Gobaut, Benoit; Panaccione, Giancarlo; Rossi, Giorgio; Degli Esposti, Alessandra; Gazzano, Massimo; Milita, Silvia; Bergenti, Ilaria; Ruani, Giampiero; Šalitroš, Ivan; Ruben, Mario; Cavallini, Massimiliano

    2016-01-01

    We investigated the influence of surfaces in the formation of different crystal structures of a spin crossover compound, namely [Fe(L)2] (LH: (2-(pyrazol-1-yl)-6-(1H-tetrazol-5-yl)pyridine), which is a neutral compound thermally switchable around room temperature. We observed that the surface induces the formation of two different crystal structures, which exhibit opposite spin transitions, i.e. on heating them up to the transition temperature, one polymorph switches from high spin to low spin and the second polymorph switches irreversibly from low spin to high spin. We attributed this inversion to the presence of water molecules H-bonded to the complex tetrazolyl moieties in the crystals. Thin deposits were investigated by means of polarized optical microscopy, atomic force microscopy, X-ray diffraction, X-ray absorption spectroscopy and micro Raman spectroscopy; moreover the analysis of the Raman spectra and the interpretation of spin inversion were supported by DFT calculations.

  13. Single laser pulse induces spin state transition within the hysteresis loop of an Iron compound

    NASA Astrophysics Data System (ADS)

    Freysz, E.; Montant, S.; Létard, S.; Létard, J.-F.

    2004-08-01

    Within the thermal hysteresis loop of the [Fe(PM-BiA) 2(NCS) 2] compound, a single laser pulse of 14 mJ cm -2 induces a photo-conversion from the low spin (LS, S = 0) to the high spin (HS, S = 2) state of the Fe 2+ metallic center. The temporal dynamic of this phenomena indicates that the system is firstly photo-excited into the HS state and then slowly relaxes to a mixture of HS/LS state. Subsequent laser pulses do not affect the HS/LS ratio. The system can be brought back to its initial LS state by adjusting the temperature of the compound. A simple model accounts qualitatively for the observed phenomenon.

  14. Compound specific amino acid δ15N in marine sediments: A new approach for studies of the marine nitrogen cycle

    NASA Astrophysics Data System (ADS)

    Batista, Fabian C.; Ravelo, A. Christina; Crusius, John; Casso, Michael A.; McCarthy, Matthew D.

    2014-10-01

    The nitrogen (N) isotopic composition (δ15N) of bulk sedimentary N (δ15Nbulk) is a common tool for studying past biogeochemical cycling in the paleoceanographic record. Empirical evidence suggests that natural fluctuations in the δ15N of surface nutrient N are reflected in the δ15N of exported planktonic biomass and in sedimentary δ15Nbulk. However, δ15Nbulk is an analysis of total combustible sedimentary N, and therefore also includes mixtures of N sources and/or selective removal or preservation of N-containing compounds. Compound-specific nitrogen isotope analyses of individual amino acids (δ15NAA) are novel measurements with the potential to decouple δ15N changes in nutrient N from trophic effects, two main processes that can influence δ15Nbulk records. As a proof of concept study to examine how δ15NAA can be applied in marine sedimentary systems, we compare the δ15NAA signatures of surface and sinking POM sources with shallow surface sediments from the Santa Barbara Basin, a sub-oxic depositional environmental that exhibits excellent preservation of sedimentary organic matter. Our results demonstrate that δ15NAA signatures of both planktonic biomass and sinking POM are well preserved in such surface sediments. However, we also observed an unexpected inverse correlation between δ15N value of phenylalanine (δ15NPhe; the best AA proxy for N isotopic value at the base of the food web) and calculated trophic position. We used a simple N isotope mass balance model to confirm that over long time scales, δ15NPhe values should in fact be directly dependent on shifts in ecosystem trophic position. While this result may appear incongruent with current applications of δ15NAA in food webs, it is consistent with expectations that paleoarchives will integrate N dynamics over much longer timescales. We therefore propose that for paleoceanographic applications, key δ15NAA parameters are ecosystem trophic position, which determines relative partitioning of 15N

  15. Plant compounds that induce polychlorinated biphenyl biodegradation by Arthrobacter sp. strain B1B.

    PubMed Central

    Gilbert, E S; Crowley, D E

    1997-01-01

    Plant compounds that induced Arthrobacter sp. strain B1B to cometabolize polychlorinated biphenyls (PCBs) were identified by a screening assay based on the formation of a 4,4'-dichlorobiphenyl ring fission product. A chemical component of spearmint (Mentha spicata), l-carvone, induced Arthrobacter sp. strain B1B to cometabolize Aroclor 1242, resulting in significant degradation of 26 peaks in the mixture, including selected tetra- and pentachlorobiphenyls. Evidence for PCB biodegradation included peak disappearance, formation of a phenylhexdienoate ring fission product, and chlorobenzoate accumulation in the culture supernatant. Carvone was not utilized as a growth substrate and was toxic at concentrations of greater than 500 mg liter-1. Several compounds structurally related to l-carvone, including limonene, p-cymene, and isoprene, also induced cometabolism of PCBs by Arthrobacter sp. strain B1B. A structure-activity analysis showed that chemicals with an unsaturated p-menthane structural motif promoted the strongest cometabolism activity. These data suggest that certain plant-derived terpenoids may be useful for promoting enhanced rates of PCB biodegradation by soil bacteria. PMID:9143124

  16. AM251 induces apoptosis and G2/M cell cycle arrest in A375 human melanoma cells.

    PubMed

    Carpi, Sara; Fogli, Stefano; Romanini, Antonella; Pellegrino, Mario; Adinolfi, Barbara; Podestà, Adriano; Costa, Barbara; Da Pozzo, Eleonora; Martini, Claudia; Breschi, Maria Cristina; Nieri, Paola

    2015-08-01

    Human cutaneous melanoma is an aggressive and chemotherapy-resistant type of cancer. AM251 is a cannabinoid type 1 (CB1) receptor antagonist/inverse agonist with off-target antitumor activity against pancreatic and colon cancer cells. The current study aimed to characterize the in-vitro antimelanoma activity of AM251. The BRAF V600E mutant melanoma cell line, A375, was used as an in-vitro model system. Characterization tools included a cell viability assay, nuclear morphology assessment, gene expression, western blot, flow cytometry with Annexin V-FITC/7-AAD double staining, cell cycle analyses, and measurements of changes in intracellular cAMP and calcium concentrations. AM251 exerted a marked cytotoxic effect against A375 human melanoma cells with potency comparable with that observed for cisplatin without significant changes in the human dermal fibroblasts viability. AM251, at a concentration that approximates the IC50, downregulated genes encoding antiapoptotic proteins (BCL2 and survivin) and increased transcription levels of proapoptotic BAX, induced alteration of Annexin V reactivity, DNA fragmentation, chromatin condensation in the cell nuclei, and G2/M phase arrest.AM251 also induced a 40% increase in the basal cAMP levels, but it did not affect intracellular calcium concentrations. The involvement of GPR55, TRPA1, and COX-2 in the AM251 mechanism of action was excluded. The combination of AM251 with celecoxib produced a synergistic antitumor activity, although the mechanism underlying this effect remains to be elucidated. This study provides the first evidence of a proapoptotic effect and G2/M cell cycle arrest of AM251 on A375 cells. This compound may be a potential prototype for the development of promising diarylpyrazole derivatives to be evaluated in human cutaneous melanoma.

  17. Antiproliferative and cell apoptosis-inducing activities of compounds from Buddleja davidii in Mgc-803 cells

    PubMed Central

    2012-01-01

    Background Buddleja davidii is widely distributed in the southwestern region of China. We have undertaken a systematic analysis of B. davidii as a Chinese traditional medicine with anticancer activity by isolating natural products for their activity against the human gastric cancer cell line Mgc-803 and the human breast cancer cell line Bcap-37. Results Ten compounds were extracted and isolated from B. davidii, among which colchicine was identified in B. davidii for the first time. The inhibitory activities of these compounds were investigated in Mgc-803, Bcap-37 cells in vitro by MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay, and the results showed that luteolin and colchicine had potent inhibitory activities against the growth of Mgc-803 cells. Subsequent fluorescence staining and flow cytometry analysis indicated that these two compounds could induce apoptosis in Mgc-803 cells. The results also showed that the percentages of early apoptotic cells (Annexin V+/PI-, where PI is propidium iodide) and late apoptotic cells (Annexin V+/PI+) increased in a dose- and time-dependent manner. After 36 h of incubation with luteolin at 20 μM, the percentages of cells were approximately 15.4% in early apoptosis and 43.7% in late apoptosis; after 36 h of incubation with colchicine at 20 μM, the corresponding values were 7.7% and 35.2%, respectively. Conclusions Colchicine and luteolin from B. davidii have potential applications as adjuvant therapies for treating human carcinoma cells. These compounds could also induce apoptosis in tumor cells. PMID:22938042

  18. Structure-activity relationship of 9-methylstreptimidone, a compound that induces apoptosis selectively in adult T-cell leukemia cells.

    PubMed

    Takeiri, Masatoshi; Ota, Eisuke; Nishiyama, Shigeru; Kiyota, Hiromasa; Umezawa, Kazuo

    2012-01-01

    We previously reported that 9-methylstreptimidone, a piperidine compound isolated from a culture filtrate of Streptomyces, induces apoptosis selectively in adult T-cell leukemia cells. It was screened for a compound that inhibits LPS-induced NF-kappaB and NO production in mouse macrophages. However, 9-methystreptimidone is poorly obtained from the producing microorganism and difficult to synthesize. Therefore, in the present research, we studied the structure-activity relationship to look for new selective inhibitors. We found that the structure of the unsaturated hydrophobic portion of 9-methylstreptimidone was essential for the inhibition of LPS-induced NO production. Among the 9-methylstreptimidone-related compounds tested, (+/-)-4,alpha-diepi-streptovitacin A inhibited NO production in macrophage-like cells as potently as 9-methylstreptimidone and without cellular toxicity. Moreover, this compound selectively induced apoptosis in adult T-cell leukemia MT-1 cells.

  19. Middle infrared radiation induces G2/M cell cycle arrest in A549 lung cancer cells.

    PubMed

    Chang, Hsin-Yi; Shih, Meng-Her; Huang, Hsuan-Cheng; Tsai, Shang-Ru; Juan, Hsueh-Fen; Lee, Si-Chen

    2013-01-01

    There were studies investigating the effects of broadband infrared radiation (IR) on cancer cell, while the influences of middle-infrared radiation (MIR) are still unknown. In this study, a MIR emitter with emission wavelength band in the 3-5 µm region was developed to irradiate A549 lung adenocarcinoma cells. It was found that MIR exposure inhibited cell proliferation and induced morphological changes by altering the cellular distribution of cytoskeletal components. Using quantitative PCR, we found that MIR promoted the expression levels of ATM (ataxia telangiectasia mutated), ATR (ataxia-telangiectasia and Rad3-related and Rad3-related), TP53 (tumor protein p53), p21 (CDKN1A, cyclin-dependent kinase inhibitor 1A) and GADD45 (growth arrest and DNA-damage inducible), but decreased the expression levels of cyclin B coding genes, CCNB1 and CCNB2, as well as CDK1 (Cyclin-dependent kinase 1). The reduction of protein expression levels of CDC25C, cyclin B1 and the phosphorylation of CDK1 at Thr-161 altogether suggest G(2)/M arrest occurred in A549 cells by MIR. DNA repair foci formation of DNA double-strand breaks (DSB) marker γ-H2AX and sensor 53BP1 was induced by MIR treatment, it implies the MIR induced G(2)/M cell cycle arrest resulted from DSB. This study illustrates a potential role for the use of MIR in lung cancer therapy by initiating DSB and blocking cell cycle progression.

  20. A Stress-Induced Small RNA Modulates Alpha-Rhizobial Cell Cycle Progression

    PubMed Central

    Robledo, Marta; Frage, Benjamin; Wright, Patrick R.; Becker, Anke

    2015-01-01

    Mechanisms adjusting replication initiation and cell cycle progression in response to environmental conditions are crucial for microbial survival. Functional characterization of the trans-encoded small non-coding RNA (trans-sRNA) EcpR1 in the plant-symbiotic alpha-proteobacterium Sinorhizobium meliloti revealed a role of this class of riboregulators in modulation of cell cycle regulation. EcpR1 is broadly conserved in at least five families of the Rhizobiales and is predicted to form a stable structure with two defined stem-loop domains. In S. meliloti, this trans-sRNA is encoded downstream of the divK-pleD operon. ecpR1 belongs to the stringent response regulon, and its expression was induced by various stress factors and in stationary phase. Induced EcpR1 overproduction led to cell elongation and increased DNA content, while deletion of ecpR1 resulted in reduced competitiveness. Computationally predicted EcpR1 targets were enriched with cell cycle-related mRNAs. Post-transcriptional repression of the cell cycle key regulatory genes gcrA and dnaA mediated by mRNA base-pairing with the strongly conserved loop 1 of EcpR1 was experimentally confirmed by two-plasmid differential gene expression assays and compensatory changes in sRNA and mRNA. Evidence is presented for EcpR1 promoting RNase E-dependent degradation of the dnaA mRNA. We propose that EcpR1 contributes to modulation of cell cycle regulation under detrimental conditions. PMID:25923724

  1. New betulinic acid derivatives induce potent and selective antiproliferative activity through cell cycle arrest at the S phase and caspase dependent apoptosis in human cancer cells.

    PubMed

    Santos, Rita C; Salvador, Jorge A R; Cortés, Roldán; Pachón, Gisela; Marín, Silvia; Cascante, Marta

    2011-06-01

    New semisynthetic derivatives of betulinic acid (BA) RS01, RS02 and RS03 with 18-45 times improved cytotoxic activity against HepG2 cells, were tested for their ability to induce apoptosis and cell cycle arrest in HepG2, HeLa and Jurkat cells. All the compounds induced significant increase in the population at the S phase more effectively than BA. RS01, RS02 and RS03 were also found to be potent inducers of apoptosis with RS01 being markedly more potent than BA, suggesting that the introduction of the imidazolyl moiety is crucial for enhancing the induction of apoptosis and the cell cycle arrest. The mechanism of apoptosis induction has been studied in HepG2 cells and found to be mediated by activation of the postmitochondrial caspases-9 and -3 cascade and possibly by mitochondrial amplification loop involving caspase-8. These facts were corroborated by detection of mitochondrial cytochrome c release and DNA fragmentation. Because RS01, RS02 and RS03 exhibited significant improved antitumor activity with respect to BA, they may be promising new agents for the treatment of cancer. In particular, RS01 is the most promising compound with an IC(50) value 45 times lower than BA on HepG2 cells and 61 times lower than the one found for the non-tumoral Chang liver cells.

  2. Can forest trees compensate for stress-generated growth losses by induced production of volatile compounds?

    PubMed

    Holopainen, Jarmo K

    2011-12-01

    Plants produce a variety of volatile organic compounds (VOCs). Under abiotic and biotic stresses, the number and amount of produced compounds can increase. Due to their long life span and large size, trees can produce biogenic VOCs (BVOCs) in much higher amounts than many other plants. It has been suggested that at cellular and tree physiological levels, induced production of VOCs is aimed at improving plant resistance to damage by reactive oxygen species generated by multiple abiotic stresses. In the few reported cases when biosynthesis of plant volatiles is inhibited or enhanced, the observed response to stress can be attributed to plant volatiles. Reported increase, e.g., in photosynthesis has mostly ranged between 5 and 50%. A comprehensive model to explain similar induction of VOCs under multiple biotic stresses is not yet available. As a result of pathogen or herbivore attack on forest trees, the induced production of VOCs is localized to the damage site but systemic induction of emissions has also been detected. These volatiles can affect fungal pathogens and the arrival rate of herbivorous insects on damaged trees, but also act as signalling compounds to maintain the trophic cascades that may improve tree fitness by improved efficiency of herbivore natural enemies. On the forest scale, biotic induction of VOC synthesis and release leads to an amplified flow of BVOCs in atmospheric reactions, which in atmospheres rich in oxides of nitrogen (NOx) results in ozone formation, and in low NOx atmospheres results in oxidation of VOCs, removal in ozone from the troposphere and the resulting formation of biogenic secondary organic aerosol (SOA) particles. I will summarize recent advances in the understanding of stress-induced VOC emissions from trees, with special focus on Populus spp. Particular importance is given to the ecological and atmospheric feedback systems based on BVOCs and biogenic SOA formation.

  3. A novel prohibitin-binding compound induces the mitochondrial apoptotic pathway through NOXA and BIM upregulation

    PubMed Central

    Moncunill-Massaguer, Cristina; Saura-Esteller, José; Pérez-Perarnau, Alba; Palmeri, Claudia Mariela; Núñez-Vázquez, Sonia; Cosialls, Ana M.; González-Gironès, Diana M.; Pomares, Helena; Korwitz, Anne; Preciado, Sara; Albericio, Fernando; Lavilla, Rodolfo; Pons, Gabriel; Langer, Thomas; Iglesias-Serret, Daniel; Gil, Joan

    2015-01-01

    We previously described diaryl trifluorothiazoline compound 1a (hereafter referred to as fluorizoline) as a first-in-class small molecule that induces p53-independent apoptosis in a wide range of tumor cell lines. Fluorizoline directly binds to prohibitin 1 and 2 (PHBs), two proteins involved in the regulation of several cellular processes, including apoptosis. Here we demonstrate that fluorizoline-induced apoptosis is mediated by PHBs, as cells depleted of these proteins are highly resistant to fluorizoline treatment. In addition, BAX and BAK are necessary for fluorizoline-induced cytotoxic effects, thereby proving that apoptosis occurs through the intrinsic pathway. Expression analysis revealed that fluorizoline induced the upregulation of Noxa and Bim mRNA levels, which was not observed in PHB-depleted MEFs. Finally, Noxa−/−/Bim−/− MEFs and NOXA-downregulated HeLa cells were resistant to fluorizoline-induced apoptosis. All together, these findings show that fluorizoline requires PHBs to execute the mitochondrial apoptotic pathway. PMID:26497683

  4. Generalized Electron Counting in Determination of Metal-Induced Reconstruction of Compound Semiconductor Surfaces

    SciTech Connect

    Zhang, Lixin; Wang, E. G.; Xue, Qi-Kun; Zhang, S. B.; Zhang, Zhenyu

    2006-01-01

    Based on theoretical analysis, first-principles calculations, and experimental observations, we establish a generic guiding principle, embodied in generalized electron counting (GEC), that governs the surface reconstruction of compound semiconductors induced by different metal adsorbates. Within the GEC model, the adsorbates serve as an electron bath, donating or accepting the right number of electrons as the host surface chooses a specific reconstruction that obeys the classic electron-counting model. The predictive power of the GEC model is illustrated for a wide range of metal adsorbates.

  5. Springs-neaps cycles in daily total seabed light: Daylength-induced changes

    NASA Astrophysics Data System (ADS)

    Roberts, E. M.; Bowers, D. G.; Davies, A. J.

    2014-04-01

    In shallow, tidal seas, daily total seabed light is determined largely by the interaction of the solar elevation cycle, the tidal cycle in water depth, and any temporal variability in turbidity. Since tidal range, times of low water, and often turbidity vary in regular ways over the springs-neaps cycle, daily total seabed light exhibits cycles of the same periodicity. Corresponding cycles are likely to be induced in the daily total primary production of benthic algae and plants, particularly those light-limited specimens occupying the lower reaches of a sub-tidal population. Consequently, this effect is an important control on the growth patterns, depth distribution and survival of, for example, macroalgal forests and seagrass meadows. Seasonal changes in daylength exert an important additional control on these cycles, as they alter the fraction of the tidal and turbidity cycles occurring within daylight hours. Bowers et al. (1997) modelled this phenomenon numerically and predicted that for a site with low water at about midday and midnight at neaps tides, 6 am and 6 pm at springs, daily total seabed light peaks at neaps in winter, but the ‘sense' of the cycle ‘switches' so that it peaks at springs in summer - the longer daylength permits the morning and evening low water springs to contribute substantially to the daily total. Observations for such a site in North Wales (UK), presented in this paper, show that no such ‘switch' occurs, and neaps tides host the largest daily totals throughout the year. The predicted ‘switch' is not observed because turbidity increases generally at spring tides, and specifically at low water springs, both of which were not accounted for in the model. Observations at a second site in Brittany (France), diametrically opposite in terms of the times of low water at neaps and at springs, indicate a peak at springs throughout the year. Analytical tools are developed to calculate the percentage of daily total sea surface irradiance

  6. Protein PSMD8 may mediate microgravity-induced cell cycle arrest

    NASA Astrophysics Data System (ADS)

    Hang, Xiaoming; Sun, Yeqing; Xu, Dan; Wu, Di; Chen, Xiaoning

    Microgravity environment of space can induce a serial of changes in cells, such as morphology alterations, cytoskeleton disorder and cell cycle disturbance. Our previous study of simulated-microgravity on zebrafish (Danio rerio) embryos demonstrated 26s proteasome non-ATPase regulatory subunit 8 (PSMD8) might be a microgravity sensitive gene. However, functional study on PSMD8 is very limited and it has not been cloned in zebrafish till now. In this study, we tried to clone PSMD8 gene in zebrafish, quantify its protein expression level in zebrafish embryos after simulated microgravity and identify its possible function in cell cycle regulation. A rotary cell culture system (RCCS) designed by national aeronautics and apace administration (NASA) of America was used to simulate microgravity. The full-length of psmd8 gene in zebrafish was cloned. Preliminary analysis on its sequence and phylogenetic tree construction were carried out subsequently. Quantitative analysis by western blot showed that PSMD8 protein expression levels were significantly increased 1.18 and 1.22 times after 24-48hpf and 24-72hpf simulated microgravity, respectively. Moreover, a significant delay on zebrafish embryo development was found in simulated-microgravity exposed group. Inhibition of PSMD8 protein in zebrafish embryonic cell lines ZF4 could block cell cycle in G1 phase, which indicated that PSMD8 may play a role in cell cycle regulation. Interestingly, simulated-microgravity could also block ZF4 cell in G1 phase. Whether it is PSMD8 mediated cell cycle regulation result in the zebrafish embryo development delay after simulated microgravity exposure still needs further study. Key Words: PSMD8; Simulated-microgravity; Cell cycle; ZF4 cell line

  7. SPARC expression induces cell cycle arrest via STAT3 signaling pathway in medulloblastoma cells

    SciTech Connect

    Chetty, Chandramu; Dontula, Ranadheer; Gujrati, Meena; Lakka, Sajani S.

    2012-01-13

    Highlights: Black-Right-Pointing-Pointer Ectopic expression of SPARC impaired cell proliferation in medulloblastoma cells. Black-Right-Pointing-Pointer SPARC expression induces STAT3 mediated cell cycle arrest in medulloblastoma cells. Black-Right-Pointing-Pointer SPARC expression significantly inhibited pre-established tumor growth in nude-mice. -- Abstract: Dynamic cell interaction with ECM components has profound influence in cancer progression. SPARC is a component of the ECM, impairs the proliferation of different cell types and modulates tumor cell aggressive features. We previously reported that SPARC expression significantly impairs medulloblastoma tumor growth in vivo. In this study, we demonstrate that expression of SPARC inhibits medulloblastoma cell proliferation. MTT assay indicated a dose-dependent reduction in tumor cell proliferation in adenoviral mediated expression of SPARC full length cDNA (Ad-DsRed-SP) in D425 and UW228 cells. Flow cytometric analysis showed that Ad-DsRed-SP-infected cells accumulate in the G2/M phase of cell cycle. Further, immunoblot and immunoprecipitation analyses revealed that SPARC induced G2/M cell cycle arrest was mediated through inhibition of the Cyclin-B-regulated signaling pathway involving p21 and Cdc2 expression. Additionally, expression of SPARC decreased STAT3 phosphorylation at Tyr-705; constitutively active STAT3 expression reversed SPARC induced G2/M arrest. Ad-DsRed-SP significantly inhibited the pre-established orthotopic tumor growth and tumor volume in nude-mice. Immunohistochemical analysis of tumor sections from mice treated with Ad-DsRed-SP showed decreased immunoreactivity for pSTAT3 and increased immunoreactivity for p21 compared to tumor section from mice treated with mock and Ad-DsRed. Taken together our studies further reveal that STAT3 plays a key role in SPARC induced G2/M arrest in medulloblastoma cells. These new findings provide a molecular basis for the mechanistic understanding of the

  8. Effects of ply thickness on thermal cycle induced damage and thermal strain

    NASA Technical Reports Server (NTRS)

    Tompkins, Stephen S.

    1994-01-01

    An experimental study was conducted to determine the effects of ply thickness in composite laminates on thermally induced cracking and changes in the coefficient of thermal expansion, CTE. A graphite-epoxy composite material, P75/ERL 1962, in thin (1 mil) and thick (5 mils) prepregs was used to make cross-ply laminates, ((0/90)(sub n))s, with equal total thickness (n=2, n=10) and cross-ply laminates with the same total number of plies (n=2). Specimens of each laminate configuration were cycled up to 1500 times between -250 and 250 F. Thermally induced microdamage was assessed as a function of the number of cycles as was the change in CTE. The results showed that laminates fabricated with thin-plies microcracked at significantly different rates and reached significantly different equilibrium crack densities than the laminate fabricated with thick-ply and n=2. The CTE of thin-ply laminates was less affected by thermal cycling and damage than the CTE of thick-ply laminates. These differences are attributed primarily to differences in interply constraints. Observed effects of ply thickness on crack density was qualitatively predicted by a combined shear-lag stress/energy method.

  9. Solar Cycle Variability in Mean Thermospheric Composition and Temperature Induced by Atmospheric Tides

    NASA Astrophysics Data System (ADS)

    Jones, M., Jr.; Forbes, J. M.; Hagan, M. E.

    2015-12-01

    Vertically-propagating atmospheric thermal tides whose origins lie in Earth's lower atmosphere are now widely recognized as one of the dominant "meteorological" drivers of space weather. Many prior research efforts have focused on documenting and understanding the role that dissipating tides play in determining the longitudinal and seasonal variability associated with lower thermospheric winds, temperature, and constituent densities. However, considerably less attention has focused on understanding the potential solar cycle variability in the mean thermospheric state induced by the tides. In this paper we utilize the National Center for Atmospheric Research Thermosphere-Ionosphere-Electrodynamics General Circulation Model (TIE-GCM), forced with observationally-based tides at the model lower boundary from the Climatological Tidal Model of the Thermosphere (CTMT, from Oberheide et al. [2011]), to elucidate how the dissipating tides induce variations of up to 30 K in the zonal-mean thermosphere temperature between solar minimum and maximum. Numerical experiments are performed for the month of September and for solar minimum, medium, and maximum conditions in order to quantify the solar cycle variability associated with the different terms in the thermodynamic energy, major and minor neutral constituent continuity equations. Our analysis indicates that solar cycle variability in neutral temperatures results from a combination of net eddy heat transport effects and tidal modulation of net nitric oxide (NO) cooling. The chemical and dynamical pathways through which dissipating tides affect mean NO cooling differently at solar minimum and maximum are diagnosed.

  10. Simvastatin induces cell cycle arrest and inhibits proliferation of bladder cancer cells via PPARγ signalling pathway

    PubMed Central

    Wang, Gang; Cao, Rui; Wang, Yongzhi; Qian, Guofeng; Dan, Han C.; Jiang, Wei; Ju, Lingao; Wu, Min; Xiao, Yu; Wang, Xinghuan

    2016-01-01

    Simvastatin is currently one of the most common drugs for old patients with hyperlipidemia, hypercholesterolemia and atherosclerotic diseases by reducing cholesterol level and anti-lipid properties. Importantly, simvastatin has also been reported to have anti-tumor effect, but the underlying mechanism is largely unknown. We collected several human bladder samples and performed microarray. Data analysis suggested bladder cancer (BCa) was significantly associated with fatty acid/lipid metabolism via PPAR signalling pathway. We observed simvastatin did not trigger BCa cell apoptosis, but reduced cell proliferation in a dose- and time-dependent manner, accompanied by PPARγ-activation. Moreover, flow cytometry analysis indicated that simvastatin induced cell cycle arrest at G0/G1 phase, suggested by downregulation of CDK4/6 and Cyclin D1. Furthermore, simvastatin suppressed BCa cell metastasis by inhibiting EMT and affecting AKT/GSK3β. More importantly, we found that the cell cycle arrest at G0/G1 phase and the alterations of CDK4/6 and Cyclin D1 triggered by simvastatin could be recovered by PPARγ-antagonist (GW9662), whereas the treatment of PPARα-antagonist (GW6471) shown no significant effects on the BCa cells. Taken together, our study for the first time revealed that simvastatin inhibited bladder cancer cell proliferation and induced cell cycle arrest at G1/G0 phase via PPARγ signalling pathway. PMID:27779188

  11. Pressure-induced superconductivity in topological parent compound Bi2Te3

    SciTech Connect

    Zhang, J. L.; Zhang, S. J.; Weng, H. M.; Zhang, W.; Yang, L. X.; Liu, Q. Q.; Feng, S. M.; Wang, X. C.; Yu, R. C.; Cao, L. Z.; Wang, L.; Yang, W. G.; Liu, H. Z.; Zhao, W. Y.; Zhang, S. C.; Dai, X.; Fang, Z.; Jin, C. Q.

    2011-01-04

    We report a successful observation of pressure-induced superconductivity in a topological compound Bi₂Te₃ with Tc of ~3 K between 3 to 6 GPa. The combined high-pressure structure investigations with synchrotron radiation indicated that the superconductivity occurred at the ambient phase without crystal structure phase transition. The Hall effects measurements indicated the hole-type carrier in the pressure-induced superconducting Bi₂Te₃ single crystal. Consequently, the first-principles calculations based on the structural data obtained by the Rietveld refinement of X-ray diffraction patterns at high pressure showed that the electronic structure under pressure remained topologically nontrivial. The results suggested that topological superconductivity can be realized in Bi₂Te₃ due to the proximity effect between superconducting bulk states and Dirac-type surface states. We also discuss the possibility that the bulk state could be a topological superconductor.

  12. [Nervous system disorders induced by occupational exposure to arsenic and its inorganic compounds: a literature review].

    PubMed

    Sińczuk-Walczak, Halina

    2009-01-01

    This paper presents a review of the effect of arsenic (As) and its inorganic compounds on the nervous system. In humans, inhalation exposure mostly occurs in occupational conditions. In the occupational environment, the most extensive exposure to this element is observed in the copper industry. Chronic As poisoning is manifested by skin and mucous membrane lesions, impairment of the nervous system in the form of disorders of psychic functions and polyneuropathies, retrobulbar neuritis, disorders of peripheral circulation and the risk for Raynaud's syndrome. Arsenic-induced polyneuropathy is usually a very serious and chronic disease. A complete recovery is observed in only 15-20% of patients. As-induced encephalopathy is an irreversible process. PMID:20187500

  13. [Nervous system disorders induced by occupational exposure to arsenic and its inorganic compounds: a literature review].

    PubMed

    Sińczuk-Walczak, Halina

    2009-01-01

    This paper presents a review of the effect of arsenic (As) and its inorganic compounds on the nervous system. In humans, inhalation exposure mostly occurs in occupational conditions. In the occupational environment, the most extensive exposure to this element is observed in the copper industry. Chronic As poisoning is manifested by skin and mucous membrane lesions, impairment of the nervous system in the form of disorders of psychic functions and polyneuropathies, retrobulbar neuritis, disorders of peripheral circulation and the risk for Raynaud's syndrome. Arsenic-induced polyneuropathy is usually a very serious and chronic disease. A complete recovery is observed in only 15-20% of patients. As-induced encephalopathy is an irreversible process.

  14. Cinnamic acid derivatives induce cell cycle arrest in carcinoma cell lines.

    PubMed

    Sova, Matej; Žižak, Željko; Stanković, Jelena A Antic; Prijatelj, Matevž; Turk, Samo; Juranić, Zorica D; Mlinarič-Raščan, Irena; Gobec, Stanislav

    2013-08-01

    Cinnamic acid derivatives can be found in plant material, and they possess a remarkable variety of biological effects. In the present study, we have investigated the cytotoxic effects of representative cinnamic acid esters and amides. The cytotoxicity was determined by MTT test on human cervix adenocarcinoma (HeLa), myelogenous leukemia (K562), malignant melanoma (Fem-x), and estrogen-receptor-positive breast cancer (MCF-7) cells, versus peripheral blood mononuclear cells (PBMCs) without or with the addition of the plant lectin phytohemaglutinin (PHA). The compounds tested showed significant cytotoxicity (IC50s between 42 and 166 µM) and furthermore selectivity of these cytotoxic effects on the malignant cell lines versus the PBMCs was also seen, especially when electron-withdrawing groups, such as a cyano group (compound 5), were present on the aromatic rings of the alcohol or amine parts of the cinnamic acid derivatives. The additional study on cell cycle phase distribution indicated that novel cinnamic acid derivatives inhibit cell growth by induction of cell death. Thus, cinnamic acids derivatives represent important lead compounds for further development of antineoplastic agents.

  15. Photodynamically induced cell cycle and gene expression changes: precursors of apoptosis introduction?

    NASA Astrophysics Data System (ADS)

    Krammer, Barbara E.; Verwanger, Thomas; Schnitzhofer, Gerlinde

    1997-12-01

    Photodynamic tumor therapy is able to induce apoptosis with many photosensitizers. Apoptosis is based on changes in gene expression and correlated to cell cycle activities. In this study, therefore, quantitative determination of the expression of the (proto)oncoges c-myc and bcl-2 in normal and transformed fibroblasts following PDT with ALA and low dose irradiation was connected with cell cycle analysis in order to investigate, if a risk for occurrence of secondary tumors by irreversibly increased oncogene expression can be found, if phases of the cell cycle show selective sensitivity to the therapy, and if changes in one of the two or both parameters may either precede or prepare an introduction of apoptosis. The results show (1) no mutagenic risk by timely limited overexpression of c-myc and bcl-2, (2) no selective cell cycle sensitivity to the therapy; but, in contrary, sustained increase of the proliferative activity of the transformed cells by the interaction of bcl-2 and c-myc, indicating a risk of promotion of tumor regrowth in sublethally damaged areas, (3) the introduction of apoptotic processes by low dose PDT in the cytoplasm/mitochondria and less in the nucleus. Transformed cells show higher constitutive gene expression and proliferative activities than normal cells.

  16. Onset of penicillin-induced bacteriolysis in staphylococci is cell cycle dependent.

    PubMed Central

    Maidhof, H; Johannsen, L; Labischinski, H; Giesbrecht, P

    1989-01-01

    Synchronously growing staphylococci were treated with "lytic" concentrations of penicillin at different stages of their division cycle. Coulter Counter measurements and light microscopy were used to determine the onset of bacteriolysis. Independent of the stage of the division cycle at which penicillin was added, (i) the cells were always able to perform the next cell division; (ii) the following division, however, did not take place; and (iii) instead, at this time, when the onset of the subsequent cell separation was observed in control cultures, lysis of the penicillin-treated cells occurred. These results support a recent model (P. Giesbrecht, H. Labischinski, and J. Wecke, Arch. Microbiol. 141:315-324, 1985) explaining penicillin-induced bacteriolysis of staphylococci as the result of a special morphogenetic mistake during cross wall formation. Images PMID:2703473

  17. Intense two-cycle laser pulses induce time-dependent bond hardening in a polyatomic molecule.

    PubMed

    Dota, K; Garg, M; Tiwari, A K; Dharmadhikari, J A; Dharmadhikari, A K; Mathur, D

    2012-02-17

    A time-dependent bond-hardening process is discovered in a polyatomic molecule (tetramethyl silane, TMS) using few-cycle pulses of intense 800 nm light. In conventional mass spectrometry, symmetrical molecules such as TMS do not exhibit a prominent molecular ion (TMS(+)) as unimolecular dissociation into [Si(CH(3))(3)](+) proceeds very fast. Under a strong field and few-cycle conditions, this dissociation channel is defeated by time-dependent bond hardening: a field-induced potential well is created in the TMS(+) potential energy curve that effectively traps a wave packet. The time dependence of this bond-hardening process is verified using longer-duration (≥100 fs) pulses; the relatively slower falloff of optical field in such pulses allows the initially trapped wave packet to leak out, thereby rendering TMS(+) unstable once again.

  18. Penicillin Induced Persistence in Chlamydia trachomatis: High Quality Time Lapse Video Analysis of the Developmental Cycle

    PubMed Central

    Barlow, David; Wang, Yibing; Salim, Omar; Lambden, Paul R.; Clarke, Ian N.

    2009-01-01

    Background Chlamydia trachomatis is a major human pathogen with a unique obligate intracellular developmental cycle that takes place inside a modified cytoplasmic structure known as an inclusion. Following entry into a cell, the infectious elementary body (EB) differentiates into a non - infectious replicative form known as a reticulate body (RB). RBs divide by binary fission and at the end of the cycle they redifferentiate into EBs. Treatment of C.trachomatis with penicillin prevents maturation of RBs which survive and enlarge to become aberrant RBs within the inclusion in a non - infective persistent state. Persistently infected individuals may be a reservoir for chlamydial infection. The C.trachomatis genome encodes the enzymes for peptidoglycan (PG) biosynthesis but a PG sacculus has never been detected. This coupled to the action of penicillin is known as the chlamydial anomaly. We have applied video microscopy and quantitative DNA assays to the chlamydial developmental cycle to assess the effects of penicillin treatment and establish a framework for investigating penicillin induced chlamydial persistence. Principal Findings Addition of penicillin at the time of cell infection does not prevent uptake and the establishment of an inclusion. EB to RB transition occurs but bacterial cytokinesis is arrested by the second binary fission. RBs continue to enlarge but not divide in the presence of penicillin. The normal developmental cycle can be recovered by the removal of penicillin although the large, aberrant RBs do not revert to the normal smaller size but remain present to the completion of the developmental cycle. Chromosomal and plasmid DNA replication is unaffected by the addition of penicillin but the arrest of bacterial cytokinesis under these conditions results in RBs accumulating multiple copies of the genome. Conclusions We have applied video time lapse microscopy to the study of the chlamydial developmental cycle. Linked with accurate measures of genome

  19. Novel application of brain-targeting polyphenol compounds in sleep deprivation-induced cognitive dysfunction.

    PubMed

    Zhao, Wei; Wang, Jun; Bi, Weina; Ferruzzi, Mario; Yemul, Shrishailam; Freire, Daniel; Mazzola, Paolo; Ho, Lap; Dubner, Lauren; Pasinetti, Giulio Maria

    2015-10-01

    Sleep deprivation produces deficits in hippocampal synaptic plasticity and hippocampal-dependent memory storage. Recent evidence suggests that sleep deprivation disrupts memory consolidation through multiple mechanisms, including the down-regulation of the cAMP-response element-binding protein (CREB) and of mammalian target of rapamycin (mTOR) signaling. In this study, we tested the effects of a Bioactive Dietary Polyphenol Preparation (BDPP), comprised of grape seed polyphenol extract, Concord grape juice, and resveratrol, on the attenuation of sleep deprivation-induced cognitive impairment. We found that BDPP significantly improves sleep deprivation-induced contextual memory deficits, possibly through the activation of CREB and mTOR signaling pathways. We also identified brain-available polyphenol metabolites from BDPP, among which quercetin-3-O-glucuronide activates CREB signaling and malvidin-3-O-glucoside activates mTOR signaling. In combination, quercetin and malvidin-glucoside significantly attenuated sleep deprivation-induced cognitive impairment in -a mouse model of acute sleep deprivation. Our data suggests the feasibility of using select brain-targeting polyphenol compounds derived from BDPP as potential therapeutic agents in promoting resilience against sleep deprivation-induced cognitive dysfunction.

  20. Novel application of brain-targeting polyphenol compounds in sleep deprivation-induced cognitive dysfunction

    PubMed Central

    Zhao, Wei; Wang, Jun; Bi, Weina; Ferruzzi, Mario; Yemul, Shrishailam; Freire, Daniel; Mazzola, Paolo; Ho, Lap; Dubner, Lauren; Pasinetti, Giulio Maria

    2016-01-01

    Sleep deprivation produces deficits in hippocampal synaptic plasticity and hippocampal-dependent memory storage. Recent evidence suggests that sleep deprivation disrupts memory consolidation through multiple mechanisms, including the down-regulation of the cAMP-response element-binding protein (CREB) and of mammalian target of rapamycin (mTOR) signaling. In this study, we tested the effects of a Bioactive Dietary Polyphenol Preparation (BDPP), comprised of grape seed polyphenol extract, Concord grape juice, and resveratrol, on the attenuation of sleep deprivation-induced cognitive impairment. We found that BDPP significantly improves sleep deprivation-induced contextual memory deficits, possibly through the activation of CREB and mTOR signaling pathways. We also identified brain-available polyphenol metabolites from BDPP, among which quercetin-3-O-glucuronide activates CREB signaling and malvidin-3-O-glucoside activates mTOR signaling. In combination, quercetin and malvidin-glucoside significantly attenuated sleep deprivation-induced cognitive impairment in -a mouse model of acute sleep deprivation. Our data suggests the feasibility of using select brain-targeting polyphenol compounds derived from BDPP as potential therapeutic agents in promoting resilience against sleep deprivation-induced cognitive dysfunction. PMID:26235983

  1. Copper compound induces autophagy and apoptosis of glioma cells by reactive oxygen species and jnk activation

    PubMed Central

    2012-01-01

    Background Glioblastoma multiforme (GBM) is the most aggressive of the primary brain tumors, with a grim prognosis despite intensive treatment. In the past decades, progress in research has not significantly increased overall survival rate. Methods The in vitro antineoplastic effect and mechanism of action of Casiopeina III-ia (Cas III-ia), a copper compound, on rat malignant glioma C6 cells was investigated. Results Cas III-ia significantly inhibited cell proliferation, inducing autophagy and apoptosis, which correlated with the formation of autophagic vacuoles, overexpression of LC3, Beclin 1, Atg 7, Bax and Bid proteins. A decrease was detected in the mitochondrial membrane potential and in the activity of caspase 3 and 8, together with the generation of intracellular reactive oxygen species (ROS) and increased activity of c-jun NH2-terminal kinase (JNK). The presence of 3-methyladenine (as selective autophagy inhibitor) increased the antineoplastic effect of Cas III-ia, while Z-VAD-FMK only showed partial protection from the antineoplastic effect induced by Cas III-ia, and ROS antioxidants (N-acetylcysteine) decreased apoptosis, autophagy and JNK activity. Moreover, the JNK –specific inhibitor SP600125 prevented Cas III-ia-induced cell death. Conclusions Our data suggest that Cas III-ia induces cell death by autophagy and apoptosis, in part due to the activation of ROS –dependent JNK signaling. These findings support further studies of Cas III-ia as candidate for treatment of human malignant glioma. PMID:22540380

  2. Ras-mediated cell cycle arrest is altered by nuclear oncogenes to induce Schwann cell transformation.

    PubMed Central

    Ridley, A J; Paterson, H F; Noble, M; Land, H

    1988-01-01

    The cellular responses to ras and nuclear oncogenes were investigated in purified populations of rat Schwann cells. v-Ha-ras and SV40 large T cooperate to transform Schwann cells, inducing growth in soft agar and allowing proliferation in the absence of added mitogens. Expression of large T alone reduces their growth factor requirements but is insufficient to induce full transformation. In contrast, expression of v-Ha-ras leads to proliferation arrest in Schwann cells expressing a temperature-sensitive mutant of large T at the restrictive temperature. Cells arrest in either the G1 or G2/M phases of the cell cycle, and can re-enter cell division at the permissive temperature even after prolonged periods at the restrictive conditions. Oncogenic ras proteins also inhibit DNA synthesis when microinjected into Schwann cells. Adenovirus E1a and c-myc oncogenes behave similarly to SV40 large T. They cooperate with Ha-ras oncogenes to transform Schwann cells, and prevent ras-induced growth arrest. Thus nuclear oncogenes fundamentally alter the response of Schwann cells to a ras oncogene from cell cycle arrest to transformation. Images PMID:3049071

  3. Chinese medicinal herb, Acanthopanax gracilistylus, extract induces cell cycle arrest of human tumor cells in vitro.

    PubMed

    Shan, B E; Zeki, K; Sugiura, T; Yoshida, Y; Yamashita, U

    2000-04-01

    We investigated the effect of a Chinese medicinal herb, Acanthopanax gracilistylus (AG), extract (E) on the growth of human tumor cell lines in vitro. AGE markedly inhibited the proliferation of several tumor cell lines such as MT-2, Raji, HL-60, TMK-1 and HSC-2. The activity was associated with a protein of 60 kDa, which was purified by gel-filtration chromatography. Cell viability analyses indicated that the treatment with AGE inhibits cell proliferation, but does not induce cell death. The mechanism of AGE-induced inhibition of tumor cell growth involves arrest of the cell cycle at the G(0) / G(1) stage without a direct cytotoxic effect. The cell cycle arrest induced by AGE was accompanied by a decrease of phosphorylated retinoblastoma (Rb) protein. Furthermore, cyclin-dependent kinases 2 and 4 (Cdk2 and Cdk4), which are involved in the phosphorylation of Rb, were also decreased. These results suggest that AGE inhibits tumor cell growth by affecting phosphorylated Rb proteins and Cdks. PMID:10804285

  4. Prion-induced neurotoxicity: Possible role for cell cycle activity and DNA damage response

    PubMed Central

    Bujdoso, Raymond; Landgraf, Matthias; Jackson, Walker S; Thackray, Alana M

    2015-01-01

    Protein misfolding neurodegenerative diseases arise through neurotoxicity induced by aggregation of host proteins. These conditions include Alzheimer’s disease, Huntington’s disease, Parkinson’s disease, motor neuron disease, tauopathies and prion diseases. Collectively, these conditions are a challenge to society because of the increasing aged population and through the real threat to human food security by animal prion diseases. It is therefore important to understand the cellular and molecular mechanisms that underlie protein misfolding-induced neurotoxicity as this will form the basis for designing strategies to alleviate their burden. Prion diseases are an important paradigm for neurodegenerative conditions in general since several of these maladies have now been shown to display prion-like phenomena. Increasingly, cell cycle activity and the DNA damage response are recognised as cellular events that participate in the neurotoxic process of various neurodegenerative diseases, and their associated animal models, which suggests they are truly involved in the pathogenic process and are not merely epiphenomena. Here we review the role of cell cycle activity and the DNA damage response in neurodegeneration associated with protein misfolding diseases, and suggest that these events contribute towards prion-induced neurotoxicity. In doing so, we highlight PrP transgenic Drosophila as a tractable model for the genetic analysis of transmissible mammalian prion disease. PMID:26279981

  5. Flavonoid-induced conversion of catalase to its inactive form--Compound II.

    PubMed

    Krych, J; Gebicki, J L; Gebicka, L

    2014-11-01

    Flavonoids (FlaOHs), plant polyphenols, are ubiquitous components of human diet and are known as antioxidants. However, their prooxidant activity has also been reported. We have recently found that FlaOHs inhibit catalase, the heme enzyme which catalyzes the decomposition of hydrogen peroxide (H2O2) into water and molecular oxygen. The catalytic cycle proceeds with the formation of the intermediate, Compound I (Cpd I), an oxoferryl porphyrin π-cation radical, the two-electron oxidation product of a heme group. Under conditions of low H2O2 fluxes and in the presence of an appropriate substrate, Cpd I can undergo one-electron reduction to inactive Compound II (Cpd II), oxoferryl derivative without radical site. Here we show that in vitro, under low fluxes of H2O2, FlaOHs reduce Cpd I to inactive Cpd II. Measurable amounts of Cpd II can be formed even in the presence of reduced nicotinamide adenine dinucleotide phosphate (NADPH) at concentration comparable with the investigated FlaOHs. Possible mechanisms of electron transfer from FlaOH molecule to the heme are discussed.

  6. Tumor cell cycle arrest induced by shear stress: Roles of integrins and Smad

    PubMed Central

    Chang, Shun-Fu; Chang, Cheng Allen; Lee, Ding-Yu; Lee, Pei-Ling; Yeh, Yu-Ming; Yeh, Chiuan-Ren; Cheng, Cheng-Kung; Chien, Shu; Chiu, Jeng-Jiann

    2008-01-01

    Interstitial flow in and around tumor tissue affects the mechanical microenvironment to modulate tumor cell growth and metastasis. We investigated the roles of flow-induced shear stress in modulating cell cycle distribution in four tumor cell lines and the underlying mechanisms. In all four cell lines, incubation under static conditions for 24 or 48 h led to G0/G1 arrest; in contrast, shear stress (12 dynes/cm2) induced G2/M arrest. The molecular basis of the shear effect was analyzed, and the presentation on molecular mechanism is focused on human MG63 osteosarcoma cells. Shear stress induced increased expressions of cyclin B1 and p21CIP1 and decreased expressions of cyclins A, D1, and E, cyclin-dependent protein kinases (Cdk)-1, -2, -4, and -6, and p27KIP1 as well as a decrease in Cdk1 activity. Using specific antibodies and small interfering RNA, we found that the shear-induced G2/M arrest and corresponding changes in G2/M regulatory protein expression and activity were mediated by αvβ3 and β1 integrins through bone morphogenetic protein receptor type IA-specific Smad1 and Smad5. Shear stress also down-regulated runt-related transcription factor 2 (Runx2) binding activity and osteocalcin and alkaline phosphatase expressions in MG63 cells; these responses were mediated by αvβ3 and β1 integrins through Smad5. Our findings provide insights into the mechanism by which shear stress induces G2/M arrest in tumor cells and inhibits cell differentiation and demonstrate the importance of mechanical microenvironment in modulating molecular signaling, gene expression, cell cycle, and functions in tumor cells. PMID:18310319

  7. Interplay between cell cycle and autophagy induced by boswellic acid analog

    PubMed Central

    Pathania, Anup S.; Guru, Santosh K.; Kumar, Suresh; Kumar, Ashok; Ahmad, Masroor; Bhushan, Shashi; Sharma, Parduman R.; Mahajan, Priya; Shah, Bhahwal A.; Sharma, Simmi; Nargotra, Amit; Vishwakarma, Ram; Korkaya, Hasan; Malik, Fayaz

    2016-01-01

    In this study, we investigated the role of autophagy induced by boswellic acid analog BA145 on cell cycle progression in pancreatic cancer cells. BA145 induced robust autophagy in pancreatic cancer cell line PANC-1 and exhibited cell proliferation inhibition by inducing cells to undergo G2/M arrest. Inhibition of G2/M progression was associated with decreased expression of cyclin A, cyclin B, cyclin E, cdc2, cdc25c and CDK-1. Pre-treatment of cells with autophagy inhibitors or silencing the expression of key autophagy genes abrogated BA145 induced G2/M arrest and downregulation of cell cycle regulatory proteins. It was further observed that BA145 induced autophagy by targeting mTOR kinase (IC50 1 μM), leading to reduced expression of p-mTOR, p-p70S6K (T389), p-4EBP (T37/46) and p-S6 (S240/244). Notably, inhibition of mTOR signalling by BA145 was followed by attendant activation of AKT and its membrane translocation. Inhibition of Akt through pharmacological inhibitors or siRNAs enhanced BA145 mediated autophagy, G2/M arrest and reduced expression of G2/M regulators. Further studies revealed that BA145 arbitrated inhibition of mTOR led to the activation of Akt through IGFR/PI3k/Akt feedback loop. Intervention in IGFR/PI3k/Akt loop further depreciated Akt phosphorylation and its membrane translocation that culminates in augmented autophagy with concomitant G2/M arrest and cell death. PMID:27680387

  8. Synthesis of a fluorescently labeled compound for the detection of arsenic-induced apoptotic HL60 cells.

    PubMed

    Femia, A Lis; Temprana, C Facundo; Amor, M Silvia; Grasselli, Mariano; Alonso, Silvia Del V

    2012-03-01

    Arsenic compounds have shown medical usefulness since they proved to be effective in causing complete remission of acute promyelocytic leukemia. In this work we obtained a fluorescently labeled arsenic compound that can be used with current fluorescence techniques for basic and applied research, focused on arsenic-induced apoptosis studies. This compound is an arsanilic acid bearing a covalently linked FITC that was chemically synthesized and characterized by fluorescence, UV-Vis, mass and FTIR spectrometry. In addition, we assessed its apoptotic activity as well as its fluorescent labeling properties in HL60 cell line as a leukemia cell model through flow cytometry. We obtained a compound with a 1:1 FITC:arsenic ratio and a 595 m/z, confirming its structure by FTIR. This compound proved to be useful at inducing apoptosis in the leukemia cell model and labeling this apoptotic cell population, in such a way that the highest FITC fluorescence correlated with the highest arsenic amount.

  9. CDK4/6 inhibition induces epithelial cell cycle arrest and ameliorates acute kidney injury

    PubMed Central

    DiRocco, Derek P.; Bisi, John; Roberts, Patrick; Strum, Jay; Wong, Kwok-Kin; Sharpless, Norman

    2013-01-01

    Acute kidney injury (AKI) is common and urgently requires new preventative therapies. Expression of a cyclin-dependent kinase (CDK) inhibitor transgene protects against AKI, suggesting that manipulating the tubular epithelial cell cycle may be a viable therapeutic strategy. Broad spectrum small molecule CDK inhibitors are protective in some kidney injury models, but these have toxicities and epithelial proliferation is eventually required for renal repair. Here, we tested a well-tolerated, novel and specific small molecule inhibitor of CDK4 and CDK6, PD 0332991, to investigate the effects of transient cell cycle inhibition on epithelial survival in vitro and kidney injury in vivo. We report that CDK4/6 inhibition induced G0/G1 cycle arrest in cultured human renal proximal tubule cells (hRPTC) at baseline and after injury. Induction of transient G0/G1 cycle arrest through CDK4/6 inhibition protected hRPTC from DNA damage and caspase 3/7 activation following exposure to the nephrotoxins cisplatin, etoposide, and antimycin A. In vivo, mice treated with PD 0332991 before ischemia-reperfusion injury (IRI) exhibited dramatically reduced epithelial progression through S phase 24 h after IRI. Despite reduced epithelial proliferation, PD 0332991 ameliorated kidney injury as reflected by improved serum creatinine and blood urea nitrogen levels 24 h after injury. Inflammatory markers and macrophage infiltration were significantly decreased in injured kidneys 3 days following IRI. These results indicate that induction of proximal tubule cell cycle arrest with specific CDK4/6 inhibitors, or “pharmacological quiescence,” represents a novel strategy to prevent AKI. PMID:24338822

  10. The adverse effects of high fat induced obesity on female reproductive cycle and hormones

    NASA Astrophysics Data System (ADS)

    Donthireddy, Laxminarasimha Reddy

    The prevalence of obesity, an established risk and progression factor for abnormal reproductive cycle and tissue damage in female mice. It leads to earlier puberty, menarche in young females and infertility. There are extensive range of consequences of obesity which includes type-2 diabetes, cardiovascular disease and insulin resistance. Obesity is the interaction between dietary intake, genes, life style and environment. The interplay of hormones estrogen, insulin, and leptin is well known on energy homeostasis and reproduction. The aim of this study is to determine the effect of high fat induced obesity on reproductive cycles and its hormonal abnormalities on mice model. Two week, 3 month and 8 month long normal (WT) and very high fat diet (VHFD) diet course is followed. When mice are fed with very high fat diet, there is a drastic increase in weight within the first week later. There was a significant (p<0.001) increase in leptin levels in 6 month VHFD treated animals. 2 week, 3 month and 6 month time interval pap smear test results showed number of cells, length of estrous cycle and phases of the estrous cycle changes with VHFD mice(n=30) compared to normal diet mice(n=10). These results also indicate that the changes in the reproductive cycles in VHFD treated female mice could be due to the changes in hormones. Histo-pathological analyses of kidney, ovary, liver, pancreas, heart and lungs showed remarkable changes in some tissue on exposure to very high fat. Highly deposited fat packets observed surrounding the hepatocytes and nerve cells.

  11. CDK4/6 inhibition induces epithelial cell cycle arrest and ameliorates acute kidney injury.

    PubMed

    DiRocco, Derek P; Bisi, John; Roberts, Patrick; Strum, Jay; Wong, Kwok-Kin; Sharpless, Norman; Humphreys, Benjamin D

    2014-02-15

    Acute kidney injury (AKI) is common and urgently requires new preventative therapies. Expression of a cyclin-dependent kinase (CDK) inhibitor transgene protects against AKI, suggesting that manipulating the tubular epithelial cell cycle may be a viable therapeutic strategy. Broad spectrum small molecule CDK inhibitors are protective in some kidney injury models, but these have toxicities and epithelial proliferation is eventually required for renal repair. Here, we tested a well-tolerated, novel and specific small molecule inhibitor of CDK4 and CDK6, PD 0332991, to investigate the effects of transient cell cycle inhibition on epithelial survival in vitro and kidney injury in vivo. We report that CDK4/6 inhibition induced G0/G1 cycle arrest in cultured human renal proximal tubule cells (hRPTC) at baseline and after injury. Induction of transient G0/G1 cycle arrest through CDK4/6 inhibition protected hRPTC from DNA damage and caspase 3/7 activation following exposure to the nephrotoxins cisplatin, etoposide, and antimycin A. In vivo, mice treated with PD 0332991 before ischemia-reperfusion injury (IRI) exhibited dramatically reduced epithelial progression through S phase 24 h after IRI. Despite reduced epithelial proliferation, PD 0332991 ameliorated kidney injury as reflected by improved serum creatinine and blood urea nitrogen levels 24 h after injury. Inflammatory markers and macrophage infiltration were significantly decreased in injured kidneys 3 days following IRI. These results indicate that induction of proximal tubule cell cycle arrest with specific CDK4/6 inhibitors, or "pharmacological quiescence," represents a novel strategy to prevent AKI.

  12. Evaporation cycle experiments — A simulation of salt-induced peptide synthesis under possible prebiotic conditions

    NASA Astrophysics Data System (ADS)

    Saetia, Somporn; Liedl, Klaus R.; Eder, Artur H.; Rode, Bernd M.

    1993-06-01

    Evaporation cycles applied to dilute solutions of amino acids, Cu(II) and NaCl lead to peptides within 1 3 days. This simulation of possible coastal or laguna processes in a primitive earth environment gives further indications towards the relevance of the salt-induced peptide formation reaction in chemical evolution. The experiments were successfully applied to glycine, alanine, aspartic and glutamic acid. Besides isolated amino acids, also their mixtures with glycine as reaction partner were studied, leading to peptides for all of the aforementioned substances, as well as for valine and proline, which do not dimerize alone. Sequence preferences and some conservation of optical purity were observed.

  13. Compound C inhibits in vitro angiogenesis and ameliorates thrombin-induced endothelial barrier failure.

    PubMed

    Gündüz, Dursun; Klewer, Matthias; Bauer, Pascal; Tanislav, Christian; Sedding, Daniel; Rohrbach, Susanne; Schulz, Rainer; Aslam, Muhammad

    2015-12-01

    Compound C (comp. C) is a cell-permeable pyrrazolopyrimidine derivative and widely used as adenosine monophosphate-activated protein kinase (AMPK) inhibitor to characterise the role of AMPK in various physiological processes. However, its AMPK-independent effects have also been reported. In the present study we investigated the effects of moderate dose (1-10μM) comp. C on endothelial cell (EC) proliferation, in vitro angiogenesis, and endothelial barrier function. Comp. C was unable to inhibit AMPK phosphorylation (activation) induced by metformin and A-769662 in ECs even at concentration of 10μM. At lower concentration (1μM), comp. C inhibited and potentiated the inhibitory effects of metformin and A-769662 on EC proliferation, migration, tube formation, and sprouting without inducing apoptosis. However, at higher concentration (10μM), it strongly induced apoptosis as measured by enhanced caspase 3/7 activity. Moreover, comp. C antagonised thrombin-induced EC hyperpermeability accompanied by activation of Rac1 and strengthening of adherens junctions (AJs). This EC barrier protective effect was not affected by the presence of AMPK activators. The data of the present study demonstrate that long-term treatment of ECs with low concentration comp. C inhibits EC proliferation and angiogenesis without induction of apoptosis. While short-term incubation antagonises thrombin-induced EC hyperpermeability presumably via Rac1-dependent strengthening of AJs. Furthermore, higher concentration of comp. C (10μM or above) is toxic for ECs and warns that this agent should be used with caution to demonstrate the AMPK-mediated effects. PMID:26522925

  14. Vincristine induces cell cycle arrest and apoptosis in SH-SY5Y human neuroblastoma cells.

    PubMed

    Tu, Yue; Cheng, Shixiang; Zhang, Sai; Sun, Hongtao; Xu, Zhongwei

    2013-01-01

    Neuroblastoma is a common childhood tumor. Vincristine (VCR), an alkaloid extracted from Catharanthus roseus, is commonly used in combination chemotherapy. However, the mechanisms of VCR-induced neuroblastoma cell death are not clear. The aim of this study was to investigate the impact of VCR on mitosis and apoptosis of SH-SY5Y neuroblastoma cells and the underlying mechanisms. SH-SY5Y cells were treated with increasing VCR doses for different time points. Cell proliferation was detected using the MTT assay. Mitotic rate was quantified by immunofluorescence. Cell cycle and apoptosis were analyzed by flow cytometry. The mRNA and protein expression of caspase-3 and -9 (apoptotic factors), as well as cyclin B and D (cell cycle factors), was evaluated by real-time (RT)-PCR and western blot analysis, respectively. VCR inhibited SH-SY5Y cell proliferation in a time- and dose-dependent manner (P<0.05). The IC50 of VCR in SH-SY5Y cells was determined as 0.1 µM. VCR at 0.1 µM induced mitotic arrest and apoptosis, promoted the expression of caspase-3 and -9 and cyclin B, while decreasing the expression of cyclin D at 6, 12, 18 and 24 h. Except for the mRNA expression of cyclin D at 6 h, these changes were significant at both the mRNA and protein levels (P<0.05). VCR induces mitotic arrest of SH-SY5Y cells by regulating cyclin B and D. It further induces apoptosis in these cells through the activation of caspase-3 and -9. This study provides fundamental evidence for the application of VCR in neuroblastoma chemotherapy.

  15. Boletus edulis biologically active biopolymers induce cell cycle arrest in human colon adenocarcinoma cells.

    PubMed

    Lemieszek, Marta Kinga; Cardoso, Claudia; Ferreira Milheiro Nunes, Fernando Hermínio; Ramos Novo Amorim de Barros, Ana Isabel; Marques, Guilhermina; Pożarowski, Piotr; Rzeski, Wojciech

    2013-04-25

    The use of biologically active compounds isolated from edible mushrooms against cancer raises global interest. Anticancer properties are mainly attributed to biopolymers including mainly polysaccharides, polysaccharopeptides, polysaccharide proteins, glycoproteins and proteins. In spite of the fact that Boletus edulis is one of the widely occurring and most consumed edible mushrooms, antitumor biopolymers isolated from it have not been exactly defined and studied so far. The present study is an attempt to extend this knowledge on molecular mechanisms of their anticancer action. The mushroom biopolymers (polysaccharides and glycoproteins) were extracted with hot water and purified by anion-exchange chromatography. The antiproliferative activity in human colon adenocarcinoma cells (LS180) was screened by means of MTT and BrdU assays. At the same time fractions' cytotoxicity was examined on the human colon epithelial cells (CCD 841 CoTr) by means of the LDH assay. Flow cytometry and Western blotting were applied to cell cycle analysis and protein expression involved in anticancer activity of the selected biopolymer fraction. In vitro studies have shown that fractions isolated from Boletus edulis were not toxic against normal colon epithelial cells and in the same concentration range elicited a very prominent antiproliferative effect in colon cancer cells. The best results were obtained in the case of the fraction designated as BE3. The tested compound inhibited cancer cell proliferation which was accompanied by cell cycle arrest in the G0/G1-phase. Growth inhibition was associated with modulation of the p16/cyclin D1/CDK4-6/pRb pathway, an aberration of which is a critical step in the development of many human cancers including colon cancer. Our results indicate that a biopolymer BE3 from Boletus edulis possesses anticancer potential and may provide a new therapeutic/preventive option in colon cancer chemoprevention.

  16. Vapor Compression Cycle Design Program (CYCLE_D)

    National Institute of Standards and Technology Data Gateway

    SRD 49 NIST Vapor Compression Cycle Design Program (CYCLE_D) (PC database for purchase)   The CYCLE_D database package simulates the vapor compression refrigeration cycles. It is fully compatible with REFPROP 9.0 and covers the 62 single-compound refrigerants . Fluids can be used in mixtures comprising up to five components.

  17. Transition metal-induced degradation of a pharmaceutical compound in reversed-phase liquid chromatographic analysis.

    PubMed

    Wang, Qinggang; He, Brian Lingfeng; Zhang, Jin; Huang, Yande; Kleintop, Brent; Raglione, Thomas

    2015-01-01

    Drug degradation that occurs in HPLC analysis, during either sample preparation or chromatographic separation, can greatly impact method robustness and result accuracy. In this work, we report a case study of drug dimerization in HPLC analysis where proximate causes were attributed to either the LC columns or the HPLC instrument. Solution stress studies indicated that the same pseudo-dimeric degradants could also be formed rapidly when the compound was exposed to certain oxidative transition metal ions, such as Cu(II) and Fe(III). Two pseudo-dimeric degradants were isolated from transition metal stressed samples and their structures were elucidated. A degradation pathway was proposed, whereby the degradation was initiated through transition metal-induced single electron transfer oxidation. Further studies confirmed that the dimerization was induced by trace transition metals in the HPLC flow path, which could arise from either the stainless steel frits in the LC column or stainless steel tubing in the HPLC instrument. Various procedures to prevent transition metal-induced drug degradation were explored, and a general strategy to mitigate such risks is briefly discussed.

  18. Rat Liver Mitochondrial Dysfunction Induced by an Organic Arsenical Compound 4-(2-Nitrobenzaliminyl) Phenyl Arsenoxide.

    PubMed

    Jiao, Yuan-Hong; Zhang, Qian; Pan, Ling-Li; Chen, Xin-You; Lei, Ke-Lin; Zhao, Jie; Jiang, Feng-Lei; Liu, Yi

    2015-12-01

    Arsenic is successfully used in cancer chemotherapy and several cancer treatments on account of its apoptogenic effects. However, it is environmentally hazardous with potential for toxicity when distributed in the soil, water, and food, and long exposure to water contaminated with Arsenic may induce cancers. Some research studies have reported that liver is the storage site and an important target organ for Arsenic toxicity. In the present work, a new kind of organic arsenic compound, 4-(2-nitrobenzaliminyl) phenyl arsenoxide (NPA), was synthesized, and its potential involvement of mitochondria was explored. The results presented that the toxicology of NPA, at least in part, mediated mitochondrial function and may thoroughly destroy mitochondrial membrane physiological functions. NPA induced mitochondrial permeability transition pore (mtPTP) opening that induces mitochondrial biochemical abnormalities as evidenced by mitochondrial swelling, mitochondrial membrane potential breakdown, membrane fluidity alterations, and the strikingly remarkable protection of CsA. Meanwhile, both the decreased respiration rate of state 4 and the increased inner membrane H(+) permeabilization revealed that the inner membrane function regarding important energy production chain was destroyed. The toxicity of NPA is due to its interaction with mitochondrial membrane thiol protein. This conclusion is based on the protective effects of RR, DTT, and MBM(+). PMID:26087905

  19. The anthracenedione compound bostrycin induces mitochondria-mediated apoptosis in the yeast Saccharomyces cerevisiae.

    PubMed

    Xu, Chunling; Wang, Jiafeng; Gao, Ye; Lin, Huangyu; Du, Lin; Yang, Shanshan; Long, Simei; She, Zhigang; Cai, Xiaoling; Zhou, Shining; Lu, Yongjun

    2010-05-01

    Bostrycin is an anthracenedione with phytotoxic and antibacterial activity that belongs to the large family of quinones. We have isolated bostrycin from the secondary metabolites of a mangrove endophytic fungus, no. 1403, collected from the South China Sea. Using the yeast Saccharomyces cerevisiae as a model, we show that bostrycin inhibits cell proliferation by blocking the cell cycle at G1 phase and ultimately leads to cell death in a time- and dose-dependent manner. Bostrycin-induced lethal cytotoxicity is accompanied with increased levels of intracellular reactive oxygen species and hallmarks of apoptosis such as chromatin condensation, DNA fragmentation and externalization of phosphatidylserine. We further show that bostrycin decreases mitochondrial membrane electric potential and causes mitochondrial destruction during the progression of cell death. Bostrycin-induced cell death was promoted in YCA1 null yeast strain but was partially rescued in AIF1 null mutant both in fermentative and respiratory media, strongly indicating that bostrycin induces apoptosis in yeast cells through a mitochondria-mediated but caspase-independent pathway.

  20. Phyllostachys edulis Compounds Inhibit Palmitic Acid-Induced Monocyte Chemoattractant Protein 1 (MCP-1) Production

    PubMed Central

    Higa, Jason K.; Liang, Zhibin; Williams, Philip G.; Panee, Jun

    2012-01-01

    Background Phyllostachys edulis Carriere (Poaceae) is a bamboo species that is part of the traditional Chinese medicine pharmacopoeia. Compounds and extracts from this species have shown potential applications towards several diseases. One of many complications found in obesity and diabetes is the link between elevated circulatory free fatty acids (FFAs) and chronic inflammation. This study aims to present a possible application of P. edulis extract in relieving inflammation caused by FFAs. Monocyte chemoattractant protein 1 (MCP-1/CCL2) is a pro-inflammatory cytokine implicated in chronic inflammation. Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and activator protein 1 (AP-1) are transcription factors activated in response to inflammatory stimuli, and upregulate pro-inflammatory cytokines such as MCP-1. This study examines the effect of P. edulis extract on cellular production of MCP-1 and on the NF-κB and AP-1 pathways in response to treatment with palmitic acid (PA), a FFA. Methodology/Principal Findings MCP-1 protein was measured by cytometric bead assay. NF-κB and AP-1 nuclear localization was detected by colorimetric DNA-binding ELISA. Relative MCP-1 mRNA was measured by real-time quantitative PCR. Murine cells were treated with PA to induce inflammation. PA increased expression of MCP-1 mRNA and protein, and increased nuclear localization of NF-κB and AP-1. Adding bamboo extract (BEX) inhibited the effects of PA, reduced MCP-1 production, and inhibited nuclear translocation of NF-κB and AP-1 subunits. Compounds isolated from BEX inhibited MCP-1 secretion with different potencies. Conclusions/Significance PA induced MCP-1 production in murine adipose, muscle, and liver cells. BEX ameliorated PA-induced production of MCP-1 by inhibiting nuclear translocation of NF-κB and AP-1. Two O-methylated flavones were isolated from BEX with functional effects on MCP-1 production. These results may represent a possible therapeutic

  1. Conditional inactivation of PDCD2 induces p53 activation and cell cycle arrest

    PubMed Central

    Granier, Celine J.; Wang, Wei; Tsang, Tiffany; Steward, Ruth; Sabaawy, Hatem E.; Bhaumik, Mantu; Rabson, Arnold B.

    2014-01-01

    ABSTRACT PDCD2 (programmed cell death domain 2) is a highly conserved, zinc finger MYND domain-containing protein essential for normal development in the fly, zebrafish and mouse. The molecular functions and cellular activities of PDCD2 remain unclear. In order to better understand the functions of PDCD2 in mammalian development, we have examined PDCD2 activity in mouse blastocyst embryos, as well as in mouse embryonic stem cells (ESCs) and embryonic fibroblasts (MEFs). We have studied mice bearing a targeted PDCD2 locus functioning as a null allele through a splicing gene trap, or as a conditional knockout, by deletion of exon2 containing the MYND domain. Tamoxifen-induced knockout of PDCD2 in MEFs, as well as in ESCs, leads to defects in progression from the G1 to the S phase of cell cycle, associated with increased levels of p53 protein and p53 target genes. G1 prolongation in ESCs was not associated with induction of differentiation. Loss of entry into S phase of the cell cycle and marked induction of nuclear p53 were also observed in PDCD2 knockout blastocysts. These results demonstrate a unique role for PDCD2 in regulating the cell cycle and p53 activation during early embryonic development of the mouse. PMID:25150276

  2. Methamphetamine Alters the Normal Progression by Inducing Cell Cycle Arrest in Astrocytes

    PubMed Central

    Jackson, Austin R.; Shah, Ankit; Kumar, Anil

    2014-01-01

    Methamphetamine (MA) is a potent psychostimulant with a high addictive capacity, which induces many deleterious effects on the brain. Chronic MA abuse leads to cognitive dysfunction and motor impairment. MA affects many cells in the brain, but the effects on astrocytes of repeated MA exposure is not well understood. In this report, we used Gene chip array to analyze the changes in the gene expression profile of primary human astrocytes treated with MA for 3 days. Range of genes were found to be differentially regulated, with a large number of genes significantly downregulated, including NEK2, TTK, TOP2A, and CCNE2. Gene ontology and pathway analysis showed a highly significant clustering of genes involved in cell cycle progression and DNA replication. Further pathway analysis showed that the genes downregulated by multiple MA treatment were critical for G2/M phase progression and G1/S transition. Cell cycle analysis of SVG astrocytes showed a significant reduction in the percentage of cell in the G2/M phase with a concomitant increase in G1 percentage. This was consistent with the gene array and validation data, which showed that repeated MA treatment downregulated the genes associated with cell cycle regulation. This is a novel finding, which explains the effect of MA treatment on astrocytes and has clear implication in neuroinflammation among the drug abusers. PMID:25290377

  3. Actinobacillus actinomycetemcomitans toxin induces both cell cycle arrest in the G2/M phase and apoptosis.

    PubMed

    Ohguchi, M; Ishisaki, A; Okahashi, N; Koide, M; Koseki, T; Yamato, K; Noguchi, T; Nishihara, T

    1998-12-01

    We found that the culture supernatant of the periodontopathic bacterium Actinobacillus actinomycetemcomitans had a cytotoxic effect on several cell lines. In this study, we purified the toxin from the culture supernatant of A. actinomycetemcomitans Y4 by a four-step procedure: ammonium sulfate precipitation, POROS HQ/M column chromatography, polymyxin B matrix column chromatography, and Mono-Q column chromatography. The purified toxin gave two major bands of protein with molecular masses of 80 and 85 kDa upon sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The mechanism of cell death of the B-cell hybridoma cell line HS-72 was examined by observing changes in nuclear morphology, an increase in the proportion of fragmented DNA, and the typical ladder pattern of degraded chromosomal DNA, indicating the induction of apoptosis. Overexpression of human Bcl-2 suppressed apoptosis in HS-72 cells, indicating that the toxin from A. actinomycetemcomitans induces apoptosis by a Bcl-2-inhibitable mechanism. Flow cytometric analysis revealed that the toxin caused cell cycle arrest in the G2/M phase and apoptosis in HS-72 cells. In addition, aurintricarboxylic acid, a DNA endonuclease inhibitor, markedly decreased the percentage of apoptotic cells but had no effect on cell cycle arrest in the G2/M phase. Taken together, these findings suggest that the toxin from A. actinomycetemcomitans could mediate the development of periodontal diseases through cell cycle arrest in the G2/M phase and apoptosis in B lymphocytes of periodontal tissue. PMID:9826381

  4. Vapor of Volatile Oils from Litsea cubeba Seed Induces Apoptosis and Causes Cell Cycle Arrest in Lung Cancer Cells

    PubMed Central

    Seal, Soma; Chatterjee, Priyajit; Bhattacharya, Sushmita; Pal, Durba; Dasgupta, Suman; Kundu, Rakesh; Mukherjee, Sandip; Bhattacharya, Shelley; Bhuyan, Mantu; Bhattacharyya, Pranab R.; Baishya, Gakul; Barua, Nabin C.; Baruah, Pranab K.; Rao, Paruchuri G.; Bhattacharya, Samir

    2012-01-01

    Non-small cell lung carcinoma (NSCLC) is a major killer in cancer related human death. Its therapeutic intervention requires superior efficient molecule(s) as it often becomes resistant to present chemotherapy options. Here we report that vapor of volatile oil compounds obtained from Litsea cubeba seeds killed human NSCLC cells, A549, through the induction of apoptosis and cell cycle arrest. Vapor generated from the combined oils (VCO) deactivated Akt, a key player in cancer cell survival and proliferation. Interestingly VCO dephosphorylated Akt at both Ser473 and Thr308; through the suppression of mTOR and pPDK1 respectively. As a consequence of this, diminished phosphorylation of Bad occurred along with the decreased Bcl-xL expression. This subsequently enhanced Bax levels permitting the release of mitochondrial cytochrome c into the cytosol which concomitantly activated caspase 9 and caspase 3 resulting apoptotic cell death. Impairment of Akt activation by VCO also deactivated Mdm2 that effected overexpression of p53 which in turn upregulated p21 expression. This causes enhanced p21 binding to cyclin D1 that halted G1 to S phase progression. Taken together, VCO produces two prong effects on lung cancer cells, it induces apoptosis and blocked cancer cell proliferation, both occurred due to the deactivation of Akt. In addition, it has another crucial advantage: VCO could be directly delivered to lung cancer tissue through inhalation. PMID:23091605

  5. Variation of Mars' Induced Magnetospheric Boundaries over the Last Solar Cycle

    NASA Astrophysics Data System (ADS)

    Hall, B. E. S.; Sanchez-Cano, B.; Andrews, D. J.; Lester, M.; Opgenoorth, H. J.; Nichols, J. D.; Fraenz, M.

    2015-12-01

    Since Mars lacks an intrinsic global magnetic field, the solar wind interacts directly with the Martian ionosphere and upper atmosphere. This interaction gives rise to an induced magnetosphere around the planet with distinct boundaries encapsulating, and separating plasma populations of differing origin. The European Space Agency Mars Express (MEX) mission has been in operation for a full solar cycle, affording us an extensive and unique dataset to study the response of the main Martian plasma boundaries to external and internal factors. From analysis of the electron flux measured by the Analyzer of Space Plasma and Energetic Atoms Electron Spectrometer (ASPERA-3 ELS) instrument on-board MEX, we present the initial results of identification of the bow shock and induced magnetospheric boundaries along with their variation in position over the last solar cycle. Compared to other bodies in the solar system that lack an intrinsic global magnetic field, the presence of crustal magnetic fields distributed across the Southern hemisphere of Mars further complicates and differentiates the Martian plasma system. The impact of the presence of these crustal magnetic fields on the location of boundaries is also studied.

  6. Extracellular matrix metalloproteinase inducer expression in the baboon endometrium: menstrual cycle and endometriosis

    PubMed Central

    Braundmeier, A G; Fazleabas, A T; Nowak, R A

    2016-01-01

    Extracellular matrix metalloproteinase inducer (EMMPRIN; BSG) regulates tissue remodeling through matrix metalloproteinases (MMPs). In human and non-human primates, endometrial remodeling is important for menstruation and the pathogenesis of endometriosis. We hypothesized that as in humans, BSG and MMPs are expressed in the endometrium of cycling baboons, and their expression is hormonally regulated by ovarian hormones, but endometriosis disrupts this regulation. BSG expression was evaluated in the baboon endometrium by q-PCR and immunohistochemistry. In the endometrium of control cycling animals, BSG mRNA levels were highest in late secretory stage tissue. BSG protein localized to glandular epithelial cells during the proliferative phase; whereas, secretory stage tissues expressed BSG in glandular and luminal epithelia with weak stromal staining. Several MMPs were differentially expressed throughout the menstrual cycle with the highest levels found during menstruation. In ovariectomized animals, BSG endometrial mRNA levels were highest with treatment of both estrogen and progesterone than that with only estrogen. Estrogen alone resulted in BSG protein localization primarily in the endometrial glandular epithelia, while estrogen and progesterone treatment displayed BSG protein localization in both the glandular and stromal cells. Exogenous hormone treatment resulted in differential expression patterns of all MMPs compared with the control cycling animals. In the eutopic endometrium of endometriotic animals, BSG mRNA levels and protein were elevated early but decreased later in disease progression. Endometriosis elevated the expression of all MMPs except MMP7 compared with the control animals. In baboons, BSG and MMP endometrial expression is regulated by both ovarian hormones, and their expression patterns are dysregulated in endometriotic animals. PMID:20841363

  7. Toxicity of drinking water disinfection byproducts: cell cycle alterations induced by the monohaloacetonitriles.

    PubMed

    Komaki, Yukako; Mariñas, Benito J; Plewa, Michael J

    2014-10-01

    Haloacetonitriles (HANs) are a chemical class of drinking water disinfection byproducts (DBPs) that form from reactions between disinfectants and nitrogen-containing precursors, the latter more prevalent in water sources impacted by algae bloom and municipal wastewater effluent discharge. HANs, previously demonstrated to be genotoxic, were investigated for their effects on the mammalian cell cycle. Treating Chinese hamster ovary (CHO) cells with monoHANs followed by the release from the chemical treatment resulted in the accumulation of abnormally high DNA content in cells over time (hyperploid). The potency for the cell cycle alteration followed the order: iodoacetonitrile (IAN) > bromoacetonitrile (BAN) ≫ chloroacetonitrile (CAN). Exposure to 6 μM IAN, 12 μM BAN and 900 μM CAN after 26 h post-treatment incubation resulted in DNA repair; however, subsequent cell cycle alteration effects were observed. Cell proliferation of HAN-treated cells was suppressed for as long as 43 to 52 h. Enlarged cell size was observed after 52 h post-treatment incubation without the induction of cytotoxicity. The HAN-mediated cell cycle alteration was mitosis- and proliferation-dependent, which suggests that HAN treatment induced mitosis override, and that HAN-treated cells proceeded into S phase and directly into the next cell cycle. Cells with multiples genomes would result in aneuploidy (state of abnormal chromosome number and DNA content) at the next mitosis since extra centrosomes could compromise the assembly of bipolar spindles. There is accumulating evidence of a transient tetraploid state proceeding to aneuploidy in cancer progression. Biological self-defense systems to ensure genomic stability and to eliminate tetraploid cells exist in eukaryotic cells. A key tumor suppressor gene, p53, is oftentimes mutated in various types of human cancer. It is possible that HAN disruption of the normal cell cycle and the generation of aberrant cells with an abnormal number of

  8. The Involvement of Acetaldehyde in Ethanol-Induced Cell Cycle Impairment

    PubMed Central

    Scheer, Marc A.; Schneider, Katrina J.; Finnigan, Rochelle L.; Maloney, Eamon P.; Wells, Mark A.; Clemens, Dahn L.

    2016-01-01

    Background: Hepatocytes metabolize the vast majority of ingested ethanol. This metabolic activity results in hepatic toxicity and impairs the ability of hepatocytes to replicate. Previous work by our group has shown that ethanol metabolism results in a G2/M cell cycle arrest. The intent of these studies was to discern the roles of acetaldehyde and reactive oxygen, two of the major by-products of ethanol metabolism, in the G2/M cell cycle arrest. Methods: To investigate the role of ethanol metabolites in the cell cycle arrest, VA-13 and VL-17A cells were used. These are recombinant Hep G2 cells that express alcohol dehydrogenase or alcohol dehydrogenase and cytochrome P450 2E1, respectively. Cells were cultured with or without ethanol, lacking or containing the antioxidants N-acetylcysteine (NAC) or trolox, for three days. Cellular accumulation was monitored by the DNA content of the cultures. The accumulation of the cyclin-dependent kinase, Cdc2 in the inactive phosphorylated form (p-Cdc2) and the cyclin-dependent kinase inhibitor p21 were determined by immunoblot analysis. Results: Cultures maintained in the presence of ethanol demonstrated a G2/M cell cycle arrest that was associated with a reduction in DNA content and increased levels of p-Cdc2 and p21, compared with cells cultured in its absence. Inclusion of antioxidants in the ethanol containing media was unable to rescue the cells from the cell cycle arrest or these ethanol metabolism-mediated effects. Additionally, culturing the cells in the presence of acetaldehyde alone resulted in increased levels of p-Cdc2 and p21. Conclusions: Acetaldehyde produced during ethanol oxidation has a major role in the ethanol metabolism-mediated G2/M cell cycle arrest, and the concurrent accumulation of p21 and p-Cdc2. Although reactive oxygen species are thought to have a significant role in ethanol-induced hepatocellular damage, they may have a less important role in the inability of hepatocytes to replace dead or damaged

  9. Compound Poisson Processes and Clustered Damage of Radiation Induced DNA Double Strand Breaks

    NASA Astrophysics Data System (ADS)

    Gudowska-Nowak, E.; Ritter, S.; Taucher-Scholz, G.; Kraft, G.

    2000-05-01

    Recent experimental data have demonstrated that DNA damage induced by densely ionizing radiation in mammalian cells is distributed along the DNA molecule in the form of clusters. The principal constituent of DNA damage are double-strand breaks (DSB) which are formed when the breaks occur in both DNA strands and are directly opposite or separated by only a few base pairs. DSBs are believed to be most important lesions produced in chromosomes by radiation; interaction between DSBs can lead to cell killing, mutation or carcinogenesis. The paper discusses a model of clustered DSB formation viewed in terms of compound Poisson process along with the predictive essay of the formalism in application to experimental data.

  10. Galiellalactone induces cell cycle arrest and apoptosis through the ATM/ATR pathway in prostate cancer cells.

    PubMed

    García, Víctor; Lara-Chica, Maribel; Cantarero, Irene; Sterner, Olov; Calzado, Marco A; Muñoz, Eduardo

    2016-01-26

    Galiellalactone (GL) is a fungal metabolite that presents antitumor activities on prostate cancer in vitro and in vivo. In this study we show that GL induced cell cycle arrest in G2/M phase, caspase-dependent apoptosis and also affected the microtubule organization and migration ability in DU145 cells. GL did not induce double strand DNA break but activated the ATR and ATM-mediated DNA damage response (DDR) inducing CHK1, H2AX phosphorylation (fH2AX) and CDC25C downregulation. Inhibition of the ATM/ATR activation with caffeine reverted GL-induced G2/M cell cycle arrest, apoptosis and DNA damage measured by fH2AX. In contrast, UCN-01, a CHK1 inhibitor, prevented GL-induced cell cycle arrest but enhanced apoptosis in DU145 cells. Furthermore, we found that GL did not increase the levels of intracellular ROS, but the antioxidant N-acetylcysteine (NAC) completely prevented the effects of GL on fH2AX, G2/M cell cycle arrest and apoptosis. In contrast to NAC, other antioxidants such as ambroxol and EGCG did not interfere with the activity of GL on cell cycle. GL significantly suppressed DU145 xenograft growth in vivo and induced the expression of fH2AX in the tumors. These findings identify for the first time that GL activates DDR in prostate cancer.

  11. Galiellalactone induces cell cycle arrest and apoptosis through the ATM/ATR pathway in prostate cancer cells

    PubMed Central

    García, Víctor; Lara-Chica, Maribel; Cantarero, Irene; Sterner, Olov; Calzado, Marco A.; Muñoz, Eduardo

    2016-01-01

    Galiellalactone (GL) is a fungal metabolite that presents antitumor activities on prostate cancer in vitro and in vivo. In this study we show that GL induced cell cycle arrest in G2/M phase, caspase-dependent apoptosis and also affected the microtubule organization and migration ability in DU145 cells. GL did not induce double strand DNA break but activated the ATR and ATM-mediated DNA damage response (DDR) inducing CHK1, H2AX phosphorylation (fH2AX) and CDC25C downregulation. Inhibition of the ATM/ATR activation with caffeine reverted GL-induced G2/M cell cycle arrest, apoptosis and DNA damage measured by fH2AX. In contrast, UCN-01, a CHK1 inhibitor, prevented GL-induced cell cycle arrest but enhanced apoptosis in DU145 cells. Furthermore, we found that GL did not increase the levels of intracellular ROS, but the antioxidant N-acetylcysteine (NAC) completely prevented the effects of GL on fH2AX, G2/M cell cycle arrest and apoptosis. In contrast to NAC, other antioxidants such as ambroxol and EGCG did not interfere with the activity of GL on cell cycle. GL significantly suppressed DU145 xenograft growth in vivo and induced the expression of fH2AX in the tumors. These findings identify for the first time that GL activates DDR in prostate cancer. PMID:26683224

  12. Procaspase-activating compound 1 induces a caspase-3-dependent cell death in cerebellar granule neurons

    SciTech Connect

    Aziz, Gulzeb; Akselsen, Oyvind W.; Hansen, Trond V.; Paulsen, Ragnhild E.

    2010-09-15

    Procaspase-activating compound 1, PAC-1, has been introduced as a direct activator of procaspase-3 and has been suggested as a therapeutic agent against cancer. Its activation of procaspase-3 is dependent on the chelation of zinc. We have tested PAC-1 and an analogue of PAC-1 as zinc chelators in vitro as well as their ability to activate caspase-3 and induce cell death in chicken cerebellar granule neuron cultures. These neurons are non-dividing, primary cells with normal caspase-3. The results reported herein show that PAC-1 chelates zinc, activates procaspase-3, and leads to caspase-3-dependent cell death in neurons, as the specific caspase-3-inhibitor Ac-DEVD-cmk inhibited both the caspase-3 activity and cell death. Thus, chicken cerebellar granule neurons is a suitable model to study mechanisms of interference with apoptosis of PAC-1 and similar compounds. Furthermore, the present study also raises concern about potential neurotoxicity of PAC-1 if used in cancer therapy.

  13. Pressure induced structural phase transition in IB transition metal nitrides compounds

    NASA Astrophysics Data System (ADS)

    Soni, Shubhangi; Kaurav, Netram; Jain, A.; Shah, S.; Choudhary, K. K.

    2015-06-01

    Transition metal mononitrides are known as refractory compounds, and they have, relatively, high hardness, brittleness, melting point, and superconducting transition temperature, and they also have interesting optical, electronic, catalytic, and magnetic properties. Evolution of structural properties would be an important step towards realizing the potential technological scenario of this material of class. In the present study, an effective interionic interaction potential (EIOP) is developed to investigate the pressure induced phase transitions in IB transition metal nitrides TMN [TM = Cu, Ag, and Au] compounds. The long range Coulomb, van der Waals (vdW) interaction and the short-range repulsive interaction upto second-neighbor ions within the Hafemeister and Flygare approach with modified ionic charge are properly incorporated in the EIOP. The vdW coefficients are computed following the Slater-Kirkwood variational method, as both the ions are polarizable. The estimated value of the phase transition pressure (Pt) and the magnitude of the discontinuity in volume at the transition pressure are consistent as compared to the reported data.

  14. Effect of allicin and ajoene, two compounds of garlic, on inducible nitric oxide synthase.

    PubMed

    Dirsch, V M; Kiemer, A K; Wagner, H; Vollmar, A M

    1998-08-01

    Inducible nitric oxide synthase (iNOS) has recently been shown to be present in human atherosclerotic lesions and to promote the formation of deleterious peroxynitrite. Allicin and ajoene are discussed as active compounds with regard to the beneficial effects of garlic in atherosclerosis. The aim of this study was to investigate the effect of allicin and ajoene on the iNOS system in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages. Ajoene (IC50 2.5-5 microM) and allicin (IC50 15-20 microM) dose dependently reduced nitrite accumulation, a parameter for NO synthesis, in supernatants of LPS-stimulated (1 microg/ml, 20 h) macrophages. Accordingly, reduced iNOS enzyme activities were measured by conversion of L-[3H]arginine to L-[3H]citrulline in homogenates of LPS-activated cells treated with ajoene or allicin. None of these compounds, however, showed a direct effect on the catalytic-activity of iNOS. Consequently, iNOS protein and mRNA expression in ajoene (10 microM) or allicin (50 microM) treated cells were evaluated by Western blot and Northern blot analysis, respectively. Markedly reduced iNOS protein as well as mRNA levels were demonstrated. These observations indicate that allicin and ajoene inhibit the expression of iNOS in activated macrophages. The possible link of this effect to the beneficial features attributed to garlic is discussed.

  15. Pressure induced structural phase transition in IB transition metal nitrides compounds

    SciTech Connect

    Soni, Shubhangi; Kaurav, Netram Jain, A.; Shah, S.; Choudhary, K. K.

    2015-06-24

    Transition metal mononitrides are known as refractory compounds, and they have, relatively, high hardness, brittleness, melting point, and superconducting transition temperature, and they also have interesting optical, electronic, catalytic, and magnetic properties. Evolution of structural properties would be an important step towards realizing the potential technological scenario of this material of class. In the present study, an effective interionic interaction potential (EIOP) is developed to investigate the pressure induced phase transitions in IB transition metal nitrides TMN [TM = Cu, Ag, and Au] compounds. The long range Coulomb, van der Waals (vdW) interaction and the short-range repulsive interaction upto second-neighbor ions within the Hafemeister and Flygare approach with modified ionic charge are properly incorporated in the EIOP. The vdW coefficients are computed following the Slater-Kirkwood variational method, as both the ions are polarizable. The estimated value of the phase transition pressure (Pt) and the magnitude of the discontinuity in volume at the transition pressure are consistent as compared to the reported data.

  16. Effect of phenolic compounds against Aβ aggregation and Aβ-induced toxicity in transgenic C. elegans.

    PubMed

    Jagota, Seema; Rajadas, Jayakumar

    2012-01-01

    Substantial evidence suggests that the aggregation of amyloid-β (Aβ) peptide into fibrillar structures that is rich in β-sheets is implicated as the cause of Alzheimer's disease. Therefore, an attractive therapeutic strategy is to prevent or alter Aβ aggregation. Phenolic compounds are natural substances that are composed of one or more aromatic phenolic rings and present in wine, tea, fruits, vegetables and a wide variety of plants. In this work, we investigated the effects of ferulic acid, morin, quercetin and gossypol against Aβ aggregation. From the ThT and turbidity assays, it is observed that in addition to the fibril aggregate, another type of aggregate is formed in the presence of morin, quercetin, and gossypol. On the other hand, ferulic acid did not prevent fibril formation, but it did appear to reduce the average length of fibrils compared to Aβ alone. To study the protective effects of phenolic compounds on Aβ-induced toxicity, we utilized the nematode Caenorhabditis elegans (C. elegans) as an in vivo model organism, human Aβ is expressed intracellularly in the body wall muscle. We found that exposure of Caenorhabditis elegans to ferulic acid give more protection against Aβ toxicity than morin, quercetin and gossypol. PMID:21858698

  17. Nickel compounds induce histone ubiquitination by inhibiting histone deubiquitinating enzyme activity

    SciTech Connect

    Ke Qingdong; Ellen, Thomas P.; Costa, Max

    2008-04-15

    Nickel (Ni) compounds are known carcinogens but underlying mechanisms are not clear. Epigenetic changes are likely to play an important role in nickel ion carcinogenesis. Previous studies have shown epigenetic effects of nickel ions, including the loss of histone acetylation and a pronounced increase in dimethylated H3K9 in nickel-exposed cells. In this study, we demonstrated that both water-soluble and insoluble nickel compounds induce histone ubiquitination (uH2A and uH2B) in a variety of cell lines. Investigations of the mechanism by which nickel increases histone ubiquitination in cells reveal that nickel does not affect cellular levels of the substrates of this modification, i.e., ubiquitin, histones, and other non-histone ubiquitinated proteins. In vitro ubiquitination and deubiquitination assays have been developed to further investigate possible effects of nickel on enzymes responsible for histone ubiquitination. Results from the in vitro assays demonstrate that the presence of nickel did not affect the levels of ubiquitinated histones in the ubiquitinating assay. Instead, the addition of nickel significantly prevents loss of uH2A and uH2B in the deubiquitinating assay, suggesting that nickel-induced histone ubiquitination is the result of inhibition of (a) putative deubiquitinating enzyme(s). Additional supporting evidence comes from the comparison of the response to nickel ions with a known deubiquitinating enzyme inhibitor, iodoacetamide (IAA). This study is the first to demonstrate such effects of nickel ions on histone ubiquitination. It also sheds light on the possible mechanisms involved in altering the steady state of this modification. The study provides further evidence that supports the notion that nickel ions alter epigenetic homeostasis in cells, which may lead to altered programs of gene expression and carcinogenesis.

  18. Unprecedented inhibition of tubulin polymerization directed by gold nanoparticles inducing cell cycle arrest and apoptosis

    NASA Astrophysics Data System (ADS)

    Choudhury, Diptiman; Xavier, Paulrajpillai Lourdu; Chaudhari, Kamalesh; John, Robin; Dasgupta, Anjan Kumar; Pradeep, Thalappil; Chakrabarti, Gopal

    2013-05-01

    The effect of gold nanoparticles (AuNPs) on the polymerization of tubulin has not been examined till now. We report that interaction of weakly protected AuNPs with microtubules (MTs) could cause inhibition of polymerization and aggregation in the cell free system. We estimate that single citrate capped AuNPs could cause aggregation of ~105 tubulin heterodimers. Investigation of the nature of inhibition of polymerization and aggregation by Raman and Fourier transform-infrared (FTIR) spectroscopies indicated partial conformational changes of tubulin and microtubules, thus revealing that AuNP-induced conformational change is the driving force behind the observed phenomenon. Cell culture experiments were carried out to check whether this can happen inside a cell. Dark field microscopy (DFM) combined with hyperspectral imaging (HSI) along with flow cytometric (FC) and confocal laser scanning microscopic (CLSM) analyses suggested that AuNPs entered the cell, caused aggregation of the MTs of A549 cells, leading to cell cycle arrest at the G0/G1 phase and concomitant apoptosis. Further, Western blot analysis indicated the upregulation of mitochondrial apoptosis proteins such as Bax and p53, down regulation of Bcl-2 and cleavage of poly(ADP-ribose) polymerase (PARP) confirming mitochondrial apoptosis. Western blot run after cold-depolymerization revealed an increase in the aggregated insoluble intracellular tubulin while the control and actin did not aggregate, suggesting microtubule damage induced cell cycle arrest and apoptosis. The observed polymerization inhibition and cytotoxic effects were dependent on the size and concentration of the AuNPs used and also on the incubation time. As microtubules are important cellular structures and target for anti-cancer drugs, this first observation of nanoparticles-induced protein's conformational change-based aggregation of the tubulin-MT system is of high importance, and would be useful in the understanding of cancer therapeutics

  19. Cell Cycle-Dependent Mechanisms Underlie Vincristine-Induced Death of Primary Acute Lymphoblastic Leukemia Cells.

    PubMed

    Kothari, Anisha; Hittelman, Walter N; Chambers, Timothy C

    2016-06-15

    Microtubule-targeting agents (MTA), such as the taxanes and vinca alkaloids, are used to treat a variety of cancers due to their ability to perturb microtubule dynamics. In cell culture, MTAs exert their anticancer effects primarily by causing mitotic arrest and cell death. However, accumulating indirect evidence suggests that MTAs may exert their cytotoxicity in human tumors by interfering with interphase microtubules. In this study, we sought to develop and characterize an experimental system in which to test the hypothesis that MTAs induce cell death during interphase. Primary adult acute lymphoblastic leukemia (ALL) cells treated with vincristine only weakly exhibited colocalization between mitotic and apoptotic markers and major characteristics of mitotic death, such as an increase in cells with 4N DNA content before the appearance of cells with <2N DNA content, suggesting a mixed response. Therefore, we separated ALL cells into distinct phases of the cell cycle by centrifugal elutriation, labeled cells with 5-ethynyl-2'-deoxyuridine (EdU), and then treated each population with vincristine. Cells isolated during G1 underwent cell death without evidence of EdU uptake, indicating that the cytotoxic effects of vincristine took place during G1 Conversely, cells isolated during S or G2-M phases underwent death following mitotic arrest. Thus, vincristine induces distinct death programs in primary ALL cells depending on cell-cycle phase, and cells in G1 are particularly susceptible to perturbation of interphase microtubules. Primary ALL cells may therefore provide a powerful model system in which to study the multimodal mechanisms underlying MTA-induced cell death. Cancer Res; 76(12); 3553-61. ©2016 AACR. PMID:27197148

  20. Arecoline induced cell cycle arrest, apoptosis, and cytotoxicity to human endothelial cells.

    PubMed

    Tseng, Shuei-Kuen; Chang, Mei-Chi; Su, Cheng-Yao; Chi, Lin-Yang; Chang, Jenny Zwei-Ching; Tseng, Wan-Yu; Yeung, Sin-Yuet; Hsu, Ming-Lun; Jeng, Jiiang-Huei

    2012-08-01

    Betel quid (BQ) chewing is a common oral habit in South Asia and Taiwan. BQ consumption may increase the risk of oral squamous cell carcinoma (OSCC), oral submucous fibrosis (OSF), and periodontitis as well as systemic diseases (atherosclerosis, hypertension, etc.). However, little is known about the toxic effect of BQ components on endothelial cells that play important roles for angiogenesis, carcinogenesis, tissue fibrosis, and cardiovascular diseases. EAhy 926 (EAHY) endothelial cells were exposed to arecoline, a major BQ alkaloid, for various time periods. Cytotoxicity was estimated by 3-(4, 5- dimethylthiazol-2-yl)-2, 5-diphenyl tetrazolium bromide assay. The cell cycle distribution of EAHY cells residing in sub-G0/G1, G0/G1, S-, and G2/M phases was analyzed by propidium iodide staining of cellular DNA content and flow cytometry. Some EAHY cells retracted, became round-shaped in appearance, and even detached from the culture plate after exposure to higher concentrations of arecoline (> 0.4 mM). At concentrations of 0.4 and 0.8 mM, arecoline induced significant cytotoxicity to EAHY cells. At similar concentrations, arecoline induced G2/M cell cycle arrest and increased sub-G0/G1 population, a hallmark of apoptosis. Interestingly, prolonged exposure to arecoline (0.1 mM) for 12 and 21 days significantly suppressed the proliferation of EAHY cells, whereas EAHY cells showed adaptation and survived when exposed to 0.05 mM arecoline. These results suggest that BQ components may contribute to the pathogenesis of OSF and BQ chewing-related cardiovascular diseases via toxicity to oral or systemic endothelial cells, leading to impairment of vascular function. During BQ chewing, endothelial damage may be induced by areca nut components and associate with the pathogenesis of OSF, periodontitis, and cardiovascular diseases.

  1. Cell Cycle-Dependent Mechanisms Underlie Vincristine-Induced Death of Primary Acute Lymphoblastic Leukemia Cells.

    PubMed

    Kothari, Anisha; Hittelman, Walter N; Chambers, Timothy C

    2016-06-15

    Microtubule-targeting agents (MTA), such as the taxanes and vinca alkaloids, are used to treat a variety of cancers due to their ability to perturb microtubule dynamics. In cell culture, MTAs exert their anticancer effects primarily by causing mitotic arrest and cell death. However, accumulating indirect evidence suggests that MTAs may exert their cytotoxicity in human tumors by interfering with interphase microtubules. In this study, we sought to develop and characterize an experimental system in which to test the hypothesis that MTAs induce cell death during interphase. Primary adult acute lymphoblastic leukemia (ALL) cells treated with vincristine only weakly exhibited colocalization between mitotic and apoptotic markers and major characteristics of mitotic death, such as an increase in cells with 4N DNA content before the appearance of cells with <2N DNA content, suggesting a mixed response. Therefore, we separated ALL cells into distinct phases of the cell cycle by centrifugal elutriation, labeled cells with 5-ethynyl-2'-deoxyuridine (EdU), and then treated each population with vincristine. Cells isolated during G1 underwent cell death without evidence of EdU uptake, indicating that the cytotoxic effects of vincristine took place during G1 Conversely, cells isolated during S or G2-M phases underwent death following mitotic arrest. Thus, vincristine induces distinct death programs in primary ALL cells depending on cell-cycle phase, and cells in G1 are particularly susceptible to perturbation of interphase microtubules. Primary ALL cells may therefore provide a powerful model system in which to study the multimodal mechanisms underlying MTA-induced cell death. Cancer Res; 76(12); 3553-61. ©2016 AACR.

  2. Enzyme entrapped nanoporous scaffolds formed through flow induced gelation in microfluidic filter device for sensitive biosensing of organophosphorus compounds

    SciTech Connect

    Lu, Donglai; Shao, Guocheng; Du, Dan; Wang, Jun; Wang, Limin; Wang, Wanjun; Lin, Yuehe

    2011-02-01

    A novel and versatile processing method was developed for the formation of gel scaffolds with in-situ AChE-AuNPs immobilization for biosensing of organophosphorus compounds. The biosensor designed by our new approach shows high sensitivity, selectivity and reactivation efficiency. This flow induced immobilziation technique opens up new pathways for designing simple, fast, biocompatible, and cost-effective process for enhanced sensor performance and on-site testing of a variety of toxic organophosphorus compounds.

  3. Mutations induced by 1-nitrosopyrene and related compounds during DNA replication in human cells and induction of homologous recombination by these compounds.

    PubMed

    Maher, V M; Bhattacharyya, N P; Mah, M C; Boldt, J; Yang, J L; McCormick, J J

    1993-03-01

    The transformation of normal human cells into cancer cells is a multistep process. Evidence suggests that a minimum of five independent steps (changes) are required for the development of certain kinds of human cancer, as well as for malignant transformation of human cells in culture. Mutations are one of the mechanisms involved in bringing about such changes. A single DNA base substitution mutation can activate an oncogene or inactivate a tumor suppressor gene. Because the action of tumor suppressor genes is to prevent cells from becoming malignant, the activity of both copies of such genes must be eliminated before suppression is lifted. Homologous mitotic recombination between a mutant tumor suppressor gene allele and its non-mutant allele is one mechanism for accomplishing this. The present study was designed to investigate the mechanisms by which certain carcinogenic compounds found in diesel exhaust particles and structurally-related N-substituted aryl carcinogens induce such base substitution mutations and homologous recombination events in mammalian cells in culture, including human cells. The system we employed to determine rapidly the kinds of mutations induced by these compounds, as well as the location of the point mutations in the target gene, involved a circular DNA molecule (plasmid) carrying a small target gene, supF. The target gene was exposed in vitro to radiolabeled compounds and then was allowed to replicate in human cells where the mutations were formed. The sites of mutation induction were compared with the sites of stable binding of the carcinogens to the DNA (adducts). The system used to determine whether these agents could induce homologous recombination consisted of a thymidine kinase-deficient mouse L cell line with a recombination substrate stably integrated into the genome. To determine whether or not excision repair was involved in the mechanism by which carcinogens induced recombination, the recombination substrate was introduced

  4. Respiratory syncytial virus matrix protein induces lung epithelial cell cycle arrest through a p53 dependent pathway.

    PubMed

    Bian, Tao; Gibbs, John D; Örvell, Claes; Imani, Farhad

    2012-01-01

    Respiratory syncytial virus (RSV) is the major cause of viral respiratory infections in children. Our previous study showed that the RSV infection induced lung epithelial cell cycle arrest, which enhanced virus replication. To address the mechanism of RSV-induced cell cycle arrest, we examined the contribution of RSV-matrix (RSV-M) protein. In this report, we show that in both the A549 cell line and primary human bronchial epithelial (PHBE) cells, transfection with RSV-M protein caused the cells to proliferate at a slower rate than in control cells. The cell cycle analysis showed that RSV-M protein induced G1 phase arrest in A549 cells, and G1 and G2/M phase arrest in PHBE cells. Interestingly, RSV-M expression induced p53 and p21 accumulation and decreased phosphorylation of retinoblastoma protein (Rb). Further, induction of cell cycle arrest by RSV-M was not observed in a p53-deficient epithelial cell line (H1299). However, cell cycle arrest was restored after transfection of p53 cDNA into H1299 cells. Taken together, these results indicate that RSV-M protein regulates lung epithelial cell cycle through a p53-dependent pathway, which enhances RSV replication.

  5. Respiratory Syncytial Virus Matrix Protein Induces Lung Epithelial Cell Cycle Arrest through a p53 Dependent Pathway

    PubMed Central

    Bian, Tao; Gibbs, John D.; Örvell, Claes; Imani, Farhad

    2012-01-01

    Respiratory syncytial virus (RSV) is the major cause of viral respiratory infections in children. Our previous study showed that the RSV infection induced lung epithelial cell cycle arrest, which enhanced virus replication. To address the mechanism of RSV-induced cell cycle arrest, we examined the contribution of RSV-matrix (RSV-M) protein. In this report, we show that in both the A549 cell line and primary human bronchial epithelial (PHBE) cells, transfection with RSV-M protein caused the cells to proliferate at a slower rate than in control cells. The cell cycle analysis showed that RSV-M protein induced G1 phase arrest in A549 cells, and G1 and G2/M phase arrest in PHBE cells. Interestingly, RSV-M expression induced p53 and p21 accumulation and decreased phosphorylation of retinoblastoma protein (Rb). Further, induction of cell cycle arrest by RSV-M was not observed in a p53-deficient epithelial cell line (H1299). However, cell cycle arrest was restored after transfection of p53 cDNA into H1299 cells. Taken together, these results indicate that RSV-M protein regulates lung epithelial cell cycle through a p53-dependent pathway, which enhances RSV replication. PMID:22662266

  6. Simulations of airglow variations induced by the CO2 increase and solar cycle variation from 1980 to 1991

    NASA Astrophysics Data System (ADS)

    Huang, Tai-Yin

    2016-09-01

    Airglow intensity and Volume Emission Rate (VER) variations induced by the increase of CO2 gas concentration and F10.7 variation (used as a proxy for the 11-year solar cycle variation) were investigated for the period from 1980 to 1991, encompassing a full solar cycle. Two airglow models are used to simulate the induced variations of O(1S) greenline, O2(0,1) atmospheric band , and OH(8,3) airglow for this study. The results show that both the airglow intensities and peak VERs correlate positively with the F10.7 solar cycle variation and display a small linear trend due to the increase of CO2 gas concentration. The solar-cycle induced airglow intensity variations show that O(1S) greenline has the largest variation (~26%) followed by the O2(0,1) atmospheric band (~23%) and then OH(8,3) airglow (~8%) over the 11 year timespan. The magnitudes of the induced airglow intensity variations by the increase of CO2 gas concentration are about an order of magnitude smaller than those by the F10.7 solar cycle variation. In general, the F10.7 solar cycle variation and CO2 increase do not seem to systematically alter the VER peak altitude of the airglow emissions, though the OH(8,3) VER peak altitude moves up slightly during the years when the F10.7 value falls under 100 SFU.

  7. Inducible nucleotide excision repair (NER) of UV-induced cyclobutane pyrimidine dimers in the cell cycle of the budding yeast Saccharomyces cerevisiae: evidence that inducible NER is confined to the G1 phase of the mitotic cell cycle.

    PubMed

    Scott, A D; Waters, R

    1997-03-18

    We previously reported on an inducible component of nucleotide excision repair in Saccharomyces cerevisiae that is controlled by the RAD16 gene. Here we describe a study of this event at the MAT alpha and HML alpha mating-type loci and on the transcribed (TS) and nontranscribed (NTS) strands of the RAD16 gene. Events were examined at various stages of the mitotic cycle in cells synchronised by centrifugal elutriation. Repair of cyclobutane pyrimidine dimers (CPDs) following a single UV dose does not vary significantly in different stages of the mitotic cell cycle. CPDs are removed more rapidly from the transcriptionally active MAT alpha locus than from the silent HML alpha locus, and the TS of RAD16 is repaired faster than the NTS in all stages of the cycle following a single UV irradiation. Enhanced excision of CPDs at MAT alpha and HML alpha can be induced only in the G1 and early S stages of the cell cycle. Here prior irradiation of cells with 25 J/m2 enhances the removal of CPDs following a second UV dose of 70 J/m2. The level of enhancement of repair does not differ significantly between MAT alpha and HML alpha in G1. Enhanced removal of CPDs is absent when cells receive the inducing dose in late S or G2/M. Repair of CPDs in both strands of RAD16 is similarly enhanced only if cells receive the initial irradiation in G1 and early S. The level of enhanced removal of CPDs is not significantly different in the TS and NTS of RAD16 either in asynchronous cells or in cells preirradiated in G1 and early S. It has been shown by others that UV-induced expression of RAD16 remains at high levels if cells are held in G1 by treatment with alpha factor. Therefore the increase in RAD16 transcript levels in G1 may be responsible for the ability to enhance NER solely in this stage of the cell cycle.

  8. Compound 331 selectively induces glioma cell death by upregulating miR-494 and downregulating CDC20.

    PubMed

    Zhang, Lei; Niu, Tianhui; Huang, Yafei; Zhu, Haichuan; Zhong, Wu; Lin, Jian; Zhang, Yan

    2015-01-01

    Malignant gliomas are the most common malignant tumors in the central nervous system (CNS). Up to date, the prognosis of glioma is still very poor, effective therapy with less side-effect is very necessary. Herein, we identify a compound named as "331" selectively induced cell death in glioma cells but not in astrocytes. Compound 331 upregulated miR-494 and downregulated CDC20 in glioma cells but not in astrocytes. These results suggest that compound 331 could be a potential drug selectively targeting glioma cells through upregulating miR-494 and downregulating CDC20. PMID:26153143

  9. Compound 331 selectively induces glioma cell death by upregulating miR-494 and downregulating CDC20

    PubMed Central

    Zhang, Lei; Niu, Tianhui; Huang, Yafei; Zhu, Haichuan; Zhong, Wu; Lin, Jian; Zhang, Yan

    2015-01-01

    Malignant gliomas are the most common malignant tumors in the central nervous system (CNS). Up to date, the prognosis of glioma is still very poor, effective therapy with less side-effect is very necessary. Herein, we identify a compound named as “331” selectively induced cell death in glioma cells but not in astrocytes. Compound 331 upregulated miR-494 and downregulated CDC20 in glioma cells but not in astrocytes. These results suggest that compound 331 could be a potential drug selectively targeting glioma cells through upregulating miR-494 and downregulating CDC20. PMID:26153143

  10. Metallomics insights into the programmed cell death induced by metal-based anticancer compounds.

    PubMed

    Tan, Cai-Ping; Lu, Yi-Ying; Ji, Liang-Nian; Mao, Zong-Wan

    2014-05-01

    Since the discovery of cisplatin more than 40 years ago, enormous research efforts have been dedicated to developing metal-based anticancer agents and to elucidating the mechanisms involved in the action of these compounds. Abnormal metabolism and the evasion of apoptosis are important hallmarks of malignant transformation, and the induction of apoptotic cell death has been considered to be a main pathway by which cytotoxic metal complexes combat cancer. However, many cancers have cellular defects involving the apoptotic machinery, which results in an acquired resistance to apoptotic cell death and therefore reduced chemotherapeutic effectiveness. Over the past decade, it has been revealed that a growing number of cell death pathways induced by metal complexes are not dependent on apoptosis. Metal complexes specifically triggering these alternative cell death pathways have been identified and explored as novel cancer treatment options. In this review, we discuss recent examples of metallomics studies on the different types of cell death induced by metal-based anticancer drugs, especially on the three major forms of programmed cell death (PCD) in mammalian cells: apoptosis, autophagy and regulated necrosis, also called necroptosis.

  11. Bond randomness induced magnon decoherence in a spin-(1)/(2) ladder compound

    NASA Astrophysics Data System (ADS)

    Náfrádi, B.; Keller, T.; Manaka, H.; Stuhr, U.; Zheludev, A.; Keimer, B.

    2013-01-01

    We have used a combination of neutron resonant spin-echo and triple-axis spectroscopies to determine the energy and linewidth of the magnon resonance in IPA-Cu(Cl0.95Br0.05)3, a model spin-1/2 ladder antiferromagnet where Br substitution induces bond randomness. We find that the bond defects induce a blue shift, δΔ, and broadening, δΓ, of the magnon gap excitation compared to the pure compound. At temperatures exceeding the energy scale of the interladder exchange interactions, δΔ and δΓ are temperature independent within the experimental error, in agreement with Matthiessen's rule according to which magnon-defect scattering yields a temperature independent contribution to the magnon mean free path. Upon cooling, δΔ and δΓ become temperature dependent and saturate at values lower than those observed at higher temperature, consistent with the crossover from one-dimensional to two-dimensional spin correlations with decreasing temperature previously observed in pure IPA-CuCl3. These results indicate limitations in the applicability of Matthiessen's rule for magnon scattering in low-dimensional magnets.

  12. Anti-amyloid compounds protect from silica nanoparticle-induced neurotoxicity in the nematode C. elegans

    PubMed Central

    Scharf, Andrea; Gührs, Karl-Heinz; von Mikecz, Anna

    2016-01-01

    Abstract Identifying nanomaterial-bio-interactions are imperative due to the broad introduction of nanoparticle (NP) applications and their distribution. Here, we demonstrate that silica NPs effect widespread protein aggregation in the soil nematode Caenorhabditis elegans ranging from induction of amyloid in nucleoli of intestinal cells to facilitation of protein aggregation in body wall muscles and axons of neural cells. Proteomic screening revealed that exposure of adult C. elegans with silica NPs promotes segregation of proteins belonging to the gene ontology (GO) group of “protein folding, proteolysis and stress response” to an SDS-resistant aggregome network. Candidate proteins in this group include chaperones, heat shock proteins and subunits of the 26S proteasome which are all decisively involved in protein homeostasis. The pathway of protein homeostasis was validated as a major target of silica NPs by behavioral phenotyping, as inhibitors of amyloid formation rescued NP-induced defects of locomotory patterns and egg laying. The analysis of a reporter worm for serotonergic neural cells revealed that silica NP-induced protein aggregation likewise occurs in axons of HSN neurons, where presynaptic accumulation of serotonin, e.g. disturbed axonal transport reduces the capacity for neurotransmission and egg laying. The results suggest that in C. elegans silica NPs promote a cascade of events including disturbance of protein homeostasis, widespread protein aggregation and inhibition of serotonergic neurotransmission which can be interrupted by compounds preventing amyloid fibrillation. PMID:26444998

  13. Quinuclidine compounds differently act as agonists of Kenyon cell nicotinic acetylcholine receptors and induced distinct effect on insect ganglionic depolarizations.

    PubMed

    Mathé-Allainmat, Monique; Swale, Daniel; Leray, Xavier; Benzidane, Yassine; Lebreton, Jacques; Bloomquist, Jeffrey R; Thany, Steeve H

    2013-12-01

    We have recently demonstrated that a new quinuclidine benzamide compound named LMA10203 acted as an agonist of insect nicotinic acetylcholine receptors. Its specific pharmacological profile on cockroach dorsal unpaired median neurons (DUM) helped to identify alpha-bungarotoxin-insensitive nAChR2 receptors. In the present study, we tested its effect on cockroach Kenyon cells. We found that it induced an inward current demonstrating that it bounds to nicotinic acetylcholine receptors expressed on Kenyon cells. Interestingly, LMA10203-induced currents were completely blocked by the nicotinic antagonist α-bungarotoxin. We suggested that LMA10203 effect occurred through the activation of α-bungarotoxin-sensitive receptors and did not involve α-bungarotoxin-insensitive nAChR2, previously identified in DUM neurons. In addition, we have synthesized two new compounds, LMA10210 and LMA10211, and compared their effects on Kenyon cells. These compounds were members of the 3-quinuclidinyl benzamide or benzoate families. Interestingly, 1 mM LMA10210 was not able to induce an inward current on Kenyon cells compared to LMA10211. Similarly, we did not find any significant effect of LMA10210 on cockroach ganglionic depolarization, whereas these three compounds were able to induce an effect on the central nervous system of the third instar M. domestica larvae. Our data suggested that these three compounds could bind to distinct cockroach nicotinic acetylcholine receptors. PMID:23884575

  14. A novel class I histone deacetylase inhibitor, I-7ab, induces apoptosis and arrests cell cycle progression in human colorectal cancer cells.

    PubMed

    Yang, Liyan; Liang, Qiannan; Shen, Ke; Ma, Li; An, Na; Deng, Weiping; Fei, Zhewei; Liu, Jianwen

    2015-04-01

    Epigenetic mutations are closely associated with human diseases, especially cancers. Among them, dysregulations of histone deacetylases (HDACs) are commonly observed in human cancers. Recent years, HDAC inhibitors have been identified as promising anticancer agents; several HDAC inhibitors have been applied in clinical practice. In this study, we synthesized a novel N-hydroxyacrylamide-derived HDAC inhibitor, I-7ab, and examined its antitumor activity. Our investigations demonstrated that I-7ab exerted cytotoxicity toward and inhibited the growth of human cancer cell lines at micromolar concentrations. Among tested cells, HCT116 was the most sensitive one to the treatment of I-7ab. However, I-7ab displayed far less cytotoxicity in human normal cells. In HCT116 cells, I-7ab inhibited the expression of class I HDACs, especially that of HDAC3, and suppressed EGFR signaling pathway. With respect to the cytotoxic effect of I-7ab, it induced apoptosis via increasing the Bax/Bcl-2 ratio and suppressing the translocation of NF-κB. Other than inducing apoptosis, I-7ab inhibited the expression of cyclin B1 and thereby arrests cell cycle progression at G2/M phase. Further analyses revealed potential role of p53 and p21 in I-7ab-induced apoptosis and cell cycle arrest. According to our findings, I-7ab may serve as a lead compound for potential antitumor drugs.

  15. Organophosphorus compound-induced delayed neurotoxicity in white leghorn hens assessed by Fluoro-Jade.

    PubMed

    Carlson, Kent; Ehrich, Marion

    2004-01-01

    Certain organophosphorus (OP) compounds can induce a delayed neuropathy, termed OPIDN, that involves central and peripheral nervous system axons, terminals, and perikarya. Historically, OPIDN has been characterized by staining neural sections with silver or hematoxylin and eosin (H and E). This study utilized a novel staining method, Fluoro-Jade, for evaluating the distribution and extent of OPIDN in the central nervous system of hens. Results were then compared to synoptically sectioned and stained H and E preparations. White Leghorn hens were injected with phenyl saligenin phosphate (PSP, 2.5 mg/kg, intramuscular [im]), triphenyl phosphite (TPPi, 500 mg/kg, subcutaneous [sc]), or dimethyl sulfoxide vehicle (DMSO, 0.5 ml/kg, im or sc) and evaluated clinically for signs of neurological dysfunction associated with OPIDN. Hens were sacrificed 7, 14, and 21 days post dosing. Brains and spinal cords were removed immediately following sacrifice, fixed in formalin, and embedded in paraffin. Microtome-cut sections (7 micro m) were then stained with Fluoro-Jade (0.001%, w/v) or H&E. Staining with Fluoro-Jade revealed time-dependent degeneration of nerve fibers and terminals (with PSP and TPPi), or cell bodies (with TPPi) in lamina VII, spinocerebellar, and medial pontine-spinal tracts of the lumbar spinal cord, in white matter and mossy fibers of foliae I-V and IX of the cerebellum, and in medullary, pontine, and midbrain nuclei and paleostriatal fibers surrounding the optic tract. TPPi-induced degeneration was more extensive than that induced by PSP and affected additional cerebellar folia, medullary, pontine, midbrain, and forebrain nuclei and fiber tracts. H&E-stained sections revealed fewer sites of neurodegeneration when compared to Fluoro-Jade. These results demonstrate that Fluoro-Jade is a sensitive method for staining neural tissue affected by OPIDN.

  16. A Dunnione Compound MB12662 Improves Cisplatin-Induced Tissue Injury and Emesis

    PubMed Central

    Park, Dongsun; Jo, In Geun; Jang, Ja Young; Kwak, Tae Hwan; Yoo, Sang Ku; Jeon, Jeong Hee; Choi, Ehn-Kyoung; Joo, Seong Soo; Kim, Okjin; Kim, Yun-Bae

    2015-01-01

    The present study was aimed to investigate the effects of MB12662, a synthetic dunnione compound, on cisplatin-induced vomiting reflexes and intestinal, renal, immune system, and hematopoietic toxicities in ferrets and mice, respectively. Male ICR mice were orally administered MB12662 (5, 10, 25 or 50 mg/kg) for 10 days, during which intraperitoneally challenged with cisplatin (3.5 mg/kg) from day 4 to 7, and sacrificed on day 10 for the pathological examination. Male ferrets were orally administered MB12662 (25, 50 or 100 mg/kg) for 7 days, subcutaneously challenged with cisplatin (5 mg/kg), and monitored for vomiting reflexes and survival of the animals. Four-day injection of cisplatin (3.5 mg/kg) to mice caused body weight loss and degeneration and atrophy of intestinal villi, reducing villi/crypt ratio to a half level of control animals. Cisplatin also induced renal and hepatic toxicities, and depletion of splenocytes and bone marrow progenitor cells. The systemic toxicities including decreased villi/crypt ratio, immune system atrophy, splenocyte depletion, and decreased cellularity in bone marrow were improved by MB12662. Cisplatin (5 mg/kg) induced retching and emetic responses of ferrets, which were remarkably attenuated by MB12662 in a dose-dependent manner. All the ferrets pretreated with MB12662 survived the challenge of cisplatin, in comparison with 40% mortality in vehicle-treated animals, and blood parameters of nephrotoxicity and hepatotoxicity were markedly recovered. It is expected that MB12662 could be a candidate for the body protection against burden, including emesis, of chemotherapeutic agents. PMID:26336585

  17. 3-Monoglucuronyl glycyrrhretinic acid is a possible marker compound related to licorice-induced pseudoaldosteronism.

    PubMed

    Makino, Toshiaki

    2014-01-01

    One of the most common adverse effects of traditional Japanese kampo and traditional Chinese medicine is pseudoaldosteronism caused by licorice. In this review, the authors describe the mechanisms of licorice-induced pseudoaldosteronism by the pharmacokinetics of chemical constituents and its metabolites containing licorice. Glycyrrhizin (GL), the main constituent of licorice, is absorbed as glycyrrhetinic acid (GA), which is a metabolite of GL produced by enterobacteria before its release into the circulation. Circulating GA is metabolized in the liver to become 3-monoglucuronyl-glycyrrhetinic acid (3MGA), which is excreted into the bile via multidrug resistance protein 2 (Mrp2). If Mrp2 function is damaged for some reason, 3MGA is secreted from the liver into the circulation, and excreted into the urine via organic anion transporters expressed at the basolateral side of tubular epithelial cells. Circulating GA cannot be excreted into the urine since GA binds highly to serum albumin and thus does not pass through glomerular filtration and is not a substrate of transporters expressed on tubular epithelial cells. Licorice-induced pseudoaldosteronism develops due to the inhibition of type 2 11β-hydrosteroid dehydrogenase (11β-HSD2) which results in the accumulation of cortisol in tubular epithelial cells that activate mineral corticoid receptors to stimulate the excretion of potassium that results in hypokalemia. GA, unlike 3MGA, cannot pass through tubular epithelial cells and cannot inhibit the enzyme in the cells. Therefore, 3MGA may be a genuine causative agent for licorice-induced pseudoaldosteronism. When licorice is used, 3MGA in plasma or urine could function as a marker compound to prevent the adverse effects.

  18. Curcumin loaded PLGA-poloxamer blend nanoparticles induce cell cycle arrest in mesothelioma cells.

    PubMed

    Mayol, Laura; Serri, Carla; Menale, Ciro; Crispi, Stefania; Piccolo, Maria Teresa; Mita, Luigi; Giarra, Simona; Forte, Maurizio; Saija, Antonina; Biondi, Marco; Mita, Damiano Gustavo

    2015-06-01

    The pharmacological potential of curcumin (CURC) is severely restricted because of its low water solubility/absorption, short half-life and poor bioavailability. To overcome these issues, CURC-loaded nanoparticles (NPs) were produced by a double emulsion technique. In particular, NPs were made up of an amphiphilic blend of poloxamers and PLGA to confer stealth properties to the NPs to take advantage of the enhanced permeability and retention (EPR) effect. Different surface properties of NPs made up of bare PLGA and PLGA/poloxamer blend were confirmed by the different interactions of these NPs with serum proteins and also by their ability to be internalized by mesothelioma cell line. The uptake of PLGA/poloxamer NPs induces a persistent block in G0/G1 phase of the cell cycle up to 72 h, thus overcoming the drug tolerance phenomenon, normally evidenced with free CURC.

  19. Cryogenic hydrogen-induced air-liquefaction technologies for combined-cycle propulsion applications

    NASA Technical Reports Server (NTRS)

    Escher, William J. D.

    1992-01-01

    Given here is a technical assessment of the realization of cryogenic hydrogen induced air liquefaction technologies in a prospective onboard aerospace vehicle process setting. The technical findings related to the status of air liquefaction technologies are reviewed. Compact lightweight cryogenic heat exchangers, heat exchanger atmospheric constituent fouling alleviation measures, para/ortho-hydrogen shift-conversion catalysts, cryogenic air compressors and liquid air pumps, hydrogen recycling using slush hydrogen as a heat sink, liquid hydrogen/liquid air rocket-type combustion devices, and technically related engine concepts are discussed. Much of the LACE work is related to aerospaceplane propulsion concepts that were developed in the 1960's. Emphasis is placed on the Liquid Air Cycle Engine (LACE).

  20. Static mechanical strain induces capillary endothelial cell cycle re-entry and sprouting

    NASA Astrophysics Data System (ADS)

    Zeiger, A. S.; Liu, F. D.; Durham, J. T.; Jagielska, A.; Mahmoodian, R.; Van Vliet, K. J.; Herman, I. M.

    2016-08-01

    Vascular endothelial cells are known to respond to a range of biochemical and time-varying mechanical cues that can promote blood vessel sprouting termed angiogenesis. It is less understood how these cells respond to sustained (i.e., static) mechanical cues such as the deformation generated by other contractile vascular cells, cues which can change with age and disease state. Here we demonstrate that static tensile strain of 10%, consistent with that exerted by contractile microvascular pericytes, can directly and rapidly induce cell cycle re-entry in growth-arrested microvascular endothelial cell monolayers. S-phase entry in response to this strain correlates with absence of nuclear p27, a cyclin-dependent kinase inhibitor. Furthermore, this modest strain promotes sprouting of endothelial cells, suggesting a novel mechanical ‘angiogenic switch’. These findings suggest that static tensile strain can directly stimulate pathological angiogenesis, implying that pericyte absence or death is not necessarily required of endothelial cell re-activation.

  1. Curcumin loaded PLGA-poloxamer blend nanoparticles induce cell cycle arrest in mesothelioma cells.

    PubMed

    Mayol, Laura; Serri, Carla; Menale, Ciro; Crispi, Stefania; Piccolo, Maria Teresa; Mita, Luigi; Giarra, Simona; Forte, Maurizio; Saija, Antonina; Biondi, Marco; Mita, Damiano Gustavo

    2015-06-01

    The pharmacological potential of curcumin (CURC) is severely restricted because of its low water solubility/absorption, short half-life and poor bioavailability. To overcome these issues, CURC-loaded nanoparticles (NPs) were produced by a double emulsion technique. In particular, NPs were made up of an amphiphilic blend of poloxamers and PLGA to confer stealth properties to the NPs to take advantage of the enhanced permeability and retention (EPR) effect. Different surface properties of NPs made up of bare PLGA and PLGA/poloxamer blend were confirmed by the different interactions of these NPs with serum proteins and also by their ability to be internalized by mesothelioma cell line. The uptake of PLGA/poloxamer NPs induces a persistent block in G0/G1 phase of the cell cycle up to 72 h, thus overcoming the drug tolerance phenomenon, normally evidenced with free CURC. PMID:25794477

  2. Anti-hepatoma cells function of luteolin through inducing apoptosis and cell cycle arrest.

    PubMed

    Ding, Shixiong; Hu, Airong; Hu, Yaoren; Ma, Jianbo; Weng, Pengjian; Dai, Jinhua

    2014-04-01

    The aim of this study is to explore the apoptotic induction and cell cycle arrest function of luteolin on the liver cancer cells and the related mechanism. The liver cancer cell line SMMC-7721, BEL-7402, and normal liver cells HL-7702 were treated with different concentrations of luteolin. Cell proliferation ability was tested. Morphological changes of the apoptotic cells were observed under inverted fluorescence microscope after Hoechst33342 staining. We investigated the effect of luteolin on cell cycling and apoptosis with flow cytometry. The mitochondrial membrane potential changes were analyzed after JC-1 staining. Caspases-3 and Bcl-2 family proteins expression were analyzed by real-time PCR. Cell proliferation of SMMC-7721 and BEL-7402 were inhibited by luteolin, and the inhibition was dose-time-dependent. Luteolin could arrest the cells at G1/S stage, reduce mitochondrial membrane potential, and induce higher apoptosis rate and the typical apoptotic morphological changes of the liver carcinoma cells. Q-RT-PCR results also showed that luteolin increased Bax and caspase-3 expression significantly and upregulated Bcl-2 expression in a dose-dependent manner in liver carcinoma cells. However, the normal liver cells HL-7702 was almost not affected by luteolin treatment. Luteolin can inhibit SMMC-7721 and BEL-7402 cell proliferation in a time- and dose-dependent manner. And the mechanism maybe through arresting cell cycle at phase G1/S, enhancing Bax level, reducing anti-apoptotic protein Bcl-2 level, resulting in activating caspase-3 enzyme and decrease of mitochondrial membrane potential, and finally leading to cell apoptosis.

  3. Tetrandrine induces G1/S cell cycle arrest through the ROS/Akt pathway in EOMA cells and inhibits angiogenesis in vivo.

    PubMed

    Xiao, Wenkai; Jiang, Yajie; Men, Qiuxu; Yuan, Ling; Huang, Zebo; Liu, Ting; Li, Wenhua; Liu, Xin

    2015-01-01

    Tetrandrine, a bisbenzylisoquinoline alkaloid, is known to inhibit tumor cell proliferation and induce apoptosis in cancer models in vitro and in vivo. In the present study, tetrandrine significantly inhibited the proliferation of mouse endothelial cells (EOMA cell) and induced G1/S arrest in EOMA cells, in which the expressions of cyclin D and cyclin E and CDKs were downregulated. Tetrandrine treatment also caused intracellular accumulation of reactive oxygen species (ROS). Pretreatment with NAC, which is a ROS inhibitor, blocked G1/S cell arrest and cyclin regulation induced by tetrandrine, implying that ROS generation plays an important role in tetrandrine-induced cell cycle arrest. Furthermore, a decreased phospho-Akt protein level after tetrandrine treatment was reversible with the removal of the intracellular ROS by NAC. Notably, overexpression of Akt decreased tetrandrine-induced G1/S arrest. Finally, we verified the antiangiogenic effects of tetrandrine in vivo in a liver cancer xenograft model in nude mice. In conclusion, tetrandrine inhibits EOMA cell growth through the ROS/Akt pathway, and it could be a promising compound for cancer therapy as an inhibitor of tumor vascular growth. PMID:25355542

  4. Synthesis, characterization, cytotoxicity, a poptosis and cell cycle arrest of dibenzoxanthenes derivatives

    NASA Astrophysics Data System (ADS)

    Wang, Xiu-Zhen; Yao, Jun-Hua; Jiang, Guang-Bin; Wang, Ji; Huang, Hong-Liang; Liu, Yun-Jun

    2014-12-01

    Two new dibenzoxanthenes compounds 1 and 2 have been synthesized and characterized by analytical and spectral methods. The crystal structure of compound 2 informs that the five rings of compound are almost planar. The DNA binding properties of two compounds were studied by absorption titration, viscosity measurement and luminescence. These results indicate that two compounds interact with calf thymus DNA through intercalative mode. Agarose gel electrophoresis experiment shows that PBR 322 DNA can be induced to cleave by two compounds under photoactivated condition. Compound 1 exhibits higher cytotoxicity than compound 2 toward MG-63, BEL-7402 and A549 cells. The apoptosis and cellular uptake of MG-63 cells were studied by fluorescence microscopy. Two compounds can also enhance the level of reactive oxygen species (ROS) and decrease the mitochondrial membrane potential. Compound 1 induces cell cycle arrest in G2/M phase and compound 2 induces cell cycle arrest in G0/G1 phase in MG-63.

  5. Biostimulation induces syntrophic interactions that impact C, S and N cycling in a sediment microbial community

    PubMed Central

    Handley, Kim M; VerBerkmoes, Nathan C; Steefel, Carl I; Williams, Kenneth H; Sharon, Itai; Miller, Christopher S; Frischkorn, Kyle R; Chourey, Karuna; Thomas, Brian C; Shah, Manesh B; Long, Philip E; Hettich, Robert L; Banfield, Jillian F

    2013-01-01

    Stimulation of subsurface microorganisms to induce reductive immobilization of metals is a promising approach for bioremediation, yet the overall microbial community response is typically poorly understood. Here we used proteogenomics to test the hypothesis that excess input of acetate activates complex community functioning and syntrophic interactions among autotrophs and heterotrophs. A flow-through sediment column was incubated in a groundwater well of an acetate-amended aquifer and recovered during microbial sulfate reduction. De novo reconstruction of community sequences yielded near-complete genomes of Desulfobacter (Deltaproteobacteria), Sulfurovum- and Sulfurimonas-like Epsilonproteobacteria and Bacteroidetes. Partial genomes were obtained for Clostridiales (Firmicutes) and Desulfuromonadales-like Deltaproteobacteria. The majority of proteins identified by mass spectrometry corresponded to Desulfobacter-like species, and demonstrate the role of this organism in sulfate reduction (Dsr and APS), nitrogen fixation and acetate oxidation to CO2 during amendment. Results indicate less abundant Desulfuromonadales, and possibly Bacteroidetes, also actively contributed to CO2 production via the tricarboxylic acid (TCA) cycle. Proteomic data indicate that sulfide was partially re-oxidized by Epsilonproteobacteria through nitrate-dependent sulfide oxidation (using Nap, Nir, Nos, SQR and Sox), with CO2 fixed using the reverse TCA cycle. We infer that high acetate concentrations, aimed at stimulating anaerobic heterotrophy, led to the co-enrichment of, and carbon fixation in Epsilonproteobacteria. Results give an insight into ecosystem behavior following addition of simple organic carbon to the subsurface, and demonstrate a range of biological processes and community interactions were stimulated. PMID:23190730

  6. Dihydroartemisinin (DHA) induces ferroptosis and causes cell cycle arrest in head and neck carcinoma cells.

    PubMed

    Lin, Renyu; Zhang, Ziheng; Chen, Lingfeng; Zhou, Yunfang; Zou, Peng; Feng, Chen; Wang, Li; Liang, Guang

    2016-10-10

    Head and neck cancer is the sixth most common cancer worldwide. Dihydroartemisinin (DHA), a semi-synthetic derivative of artemisinin, exhibits a wide range of biological roles including a highly efficient and specific anti-tumor activity. Here, we aimed to examine the effect of DHA on head and neck carcinoma cells and elucidate the potential mechanisms. We used five head and neck carcinoma cell lines and two non-tumorigenic normal epithelial cell lines to achieve our goals. Cells were exposed to DHA and subjected to cellular activity assays including viability, cell cycle analysis, cell death, and angiogenic phenotype. Our results show that DHA causes cell cycle arrest which is mediated through Forkhead box protein M1 (FOXM1). We also demonstrate that DHA induces ferroptosis and apoptosis in head and neck carcinoma cells. Lastly, our results show that DHA alters the angiogenic phenotype of cancer cells by reducing the expression of angiogenic factors and the ability of cancer cells to support endothelial cell tubule formation. Our study suggests that DHA specifically causes head and neck cancer cell death through contribution from both ferroptosis and apoptosis. DHA may represent an effective strategy in head and neck cancer treatment.

  7. Radiation-induced cardiomyopathy as a function of radiation beam gating to the cardiac cycle

    NASA Astrophysics Data System (ADS)

    Gladstone, David J.; Flanagan, Michael F.; Southworth, Jean B.; Hadley, Vaughn; Thibualt, Melissa Wei; Hug, Eugen B.; Hoopes, P. Jack

    2004-04-01

    Portions of the heart are often unavoidably included in the primary treatment volume during thoracic radiotherapy, and radiation-induced heart disease has been observed as a treatment-related complication. Such complications have been observed in humans following radiation therapy for Hodgkin's disease and treatment of the left breast for carcinoma. Recent attempts have been made to prevent re-stenosis following angioplasty procedures using external beam irradiation. These attempts were not successful, however, due to the large volume of heart included in the treatment field and subsequent cardiac morbidity. We suggest a mechanism for sparing the heart from radiation damage by synchronizing the radiation beam with the cardiac cycle and delivering radiation only when the heart is in a relatively hypoxic state. We present data from a rat model testing this hypothesis and show that radiation damage to the heart can be altered by synchronizing the radiation beam with the cardiac cycle. This technique may be useful in reducing radiation damage to the heart secondary to treatment for diseases such as Hodgkin's disease and breast cancer.

  8. Quantitative stratigraphic models of rifts based on orbitally induced lake cycles

    SciTech Connect

    Olsen, P.E.; Schlische, R.W.

    1988-02-01

    Orbitally induced lacustrine cycles in the rift sequences of the Newark Supergroup provide a direct measure of sedimentation rates (S) averaged at the 20 thousand year level. For the Triassic, the basins followed a pattern exemplified by the Newark basin: early fluvial fill, followed by lacustrine deposition where S slowly and exponentially decreased. Once lacustrine deposition began, lakes fluctuated with orbital cycles; however, maximum lake depth (MLD) began shallow, rapidly deepened, then slowly and exponentially shallowed toward the Triassic-Jurassic boundary. These observations suggest a model based on the filling of a trough, the simplest of which is a graben where the volumetric sedimentation rate (V) is constant and extension is uniform. First, S equals subsidence until hydrographic closure. Afterward, S = BV/L(B/sup 2/D/sup 2/ + (2BVt(A-D))/L)/sup minus/1/2 (t = time after closure and A, D, B, and L are the final widths, depth, and length of the graben). The observed changes in MLD conform to the predictions of this filing model. Half-graben are more complex, but similar patterns result. Major deviations reflect tectonic events. One dramatic deviation occurred at the Triassic-Jurassic boundary, where S and MLD greatly increased. This coincided with massive tholeitic magmatism, probably reflecting increased extension rates and a marked basin asymmetry. This model explains why Newark hydrocarbon targets are in strata of either the early Late Triassic or Early Jurassic, because those intervals were deposited by the deepest lakes.

  9. Quantitative stratigraphic models of rifts based on orbitally induced lake cycles

    SciTech Connect

    Olsen, P.E.; Schlische, R.W.

    1988-01-01

    Orbitally induced lacustrine cycles in the rift sequences of the Newark Supergroup provide a direct measure of sedimentation rates (S) averaged at the 20 thousand year level. For the Triassic, the basins followed a pattern exemplified by the Newark basin: early fluvial fill, followed by lacustrine deposition where S slowly and exponentially decreased. Once lacustrine deposition began, lakes fluctuated with orbital cycles; however, maximum lake depth (MLD) began shallow, rapidly deepened, then slowly and exponentially shallowed toward the Triassic-Jurassic boundary. These observations suggest a model based on the filling of a trough, the simplest of which is a graben where the volumetric sedimentation rate (V) is constant and extension in uniform. The observed changes in MLD conform to the predictions of this filling model. Half-graben are more complex, but similar patterns result. Major deviations reflect tectonic events. One dramatic deviation occurred at the Triassic-Jurassic boundary, where subsidence and MLD greatly increased. This coincided with massive tholeiitic magmatism, probably reflecting increased extension rates and a marked basin asymmetry. This model explains why Newark hydrocarbon targets are in strata of either the early Late Triassic or Early Jurassic, because those intervals were deposited by the deepest lakes.

  10. Biostimulation induces syntrophic interactions that impact C, S and N cycling in a sediment microbial community.

    PubMed

    Handley, Kim M; VerBerkmoes, Nathan C; Steefel, Carl I; Williams, Kenneth H; Sharon, Itai; Miller, Christopher S; Frischkorn, Kyle R; Chourey, Karuna; Thomas, Brian C; Shah, Manesh B; Long, Philip E; Hettich, Robert L; Banfield, Jillian F

    2013-04-01

    Stimulation of subsurface microorganisms to induce reductive immobilization of metals is a promising approach for bioremediation, yet the overall microbial community response is typically poorly understood. Here we used proteogenomics to test the hypothesis that excess input of acetate activates complex community functioning and syntrophic interactions among autotrophs and heterotrophs. A flow-through sediment column was incubated in a groundwater well of an acetate-amended aquifer and recovered during microbial sulfate reduction. De novo reconstruction of community sequences yielded near-complete genomes of Desulfobacter (Deltaproteobacteria), Sulfurovum- and Sulfurimonas-like Epsilonproteobacteria and Bacteroidetes. Partial genomes were obtained for Clostridiales (Firmicutes) and Desulfuromonadales-like Deltaproteobacteria. The majority of proteins identified by mass spectrometry corresponded to Desulfobacter-like species, and demonstrate the role of this organism in sulfate reduction (Dsr and APS), nitrogen fixation and acetate oxidation to CO2 during amendment. Results indicate less abundant Desulfuromonadales, and possibly Bacteroidetes, also actively contributed to CO2 production via the tricarboxylic acid (TCA) cycle. Proteomic data indicate that sulfide was partially re-oxidized by Epsilonproteobacteria through nitrate-dependent sulfide oxidation (using Nap, Nir, Nos, SQR and Sox), with CO2 fixed using the reverse TCA cycle. We infer that high acetate concentrations, aimed at stimulating anaerobic heterotrophy, led to the co-enrichment of, and carbon fixation in Epsilonproteobacteria. Results give an insight into ecosystem behavior following addition of simple organic carbon to the subsurface, and demonstrate a range of biological processes and community interactions were stimulated.

  11. Noise-induced dispersion and breakup of clusters in cell cycle dynamics

    PubMed Central

    Gong, Xue; Moses, Gregory; Neiman, Alexander B.; Young, Todd

    2014-01-01

    We study the effects of random perturbations on collective dynamics of a large ensemble of interacting cells in a model of the cell division cycle. We consider a parameter region for which the unperturbed model possesses asymptotically stable two-cluster periodic solutions. Two biologically motivated forms of random perturbations are considered: bounded variations in growth rate and asymmetric division. We compare the effects of these two dispersive mechanisms with additive Gaussian white noise perturbations. We observe three distinct phases of the response to noise in the model. First, for weak noise there is a linear relationship between the applied noise strength and the dispersion of the clusters. Second, for moderate noise strengths the clusters begin to mix, i.e. individual cells move between clusters, yet the population distribution clearly continues to maintain a two-cluster structure. Third, for strong noise the clusters are destroyed and the population is characterized by a uniform distribution. The second and third phases are separated by an order - disorder phase transition that has the characteristics of a Hopf bifurcation. Furthermore, we show that for the cell cycle model studied, the effects of bounded random perturbations are virtually indistinguishable from those induced by additive Gaussian noise, after appropriate scaling of the variance of noise strength. We then use the model to predict the strength of coupling among the cells from experimental data. In particular, we show that coupling must be rather strong to account for the observed clustering of cells given experimentally estimated noise variance. PMID:24694583

  12. DNA Damage-Induced Cell Cycle Regulation and Function of Novel Chk2 Phosphoresidues▿ †

    PubMed Central

    Buscemi, Giacomo; Carlessi, Luigi; Zannini, Laura; Lisanti, Sofia; Fontanella, Enrico; Canevari, Silvana; Delia, Domenico

    2006-01-01

    Chk2 kinase is activated by DNA damage to regulate cell cycle arrest, DNA repair, and apoptosis. Phosphorylation of Chk2 in vivo by ataxia telangiectasia-mutated (ATM) on threonine 68 (T68) initiates a phosphorylation cascade that promotes the full activity of Chk2. We identified three serine residues (S19, S33, and S35) on Chk2 that became phosphorylated in vivo rapidly and exclusively in response to ionizing radiation (IR)-induced DNA double-strand breaks in an ATM- and Nbs1-dependent but ataxia telangiectasia- and Rad3-related-independent manner. Phosphorylation of these residues, restricted to the G1 phase of the cell cycle, was induced by a higher dose of IR (>1 Gy) than that required for phosphorylation of T68 (0.25 Gy) and declined by 45 to 90 min, concomitant with a rise in Chk2 autophosphorylation. Compared to the wild-type form, Chk2 with alanine substitutions at S19, S33, and S35 (Chk2S3A) showed impaired dimerization, defective auto- and trans-phosphorylation activities, and reduced ability to promote degradation of Hdmx, a phosphorylation target of Chk2 and regulator of p53 activity. Besides, Chk2S3A failed to inhibit cell growth and, in response to IR, to arrest G1/S progression. These findings underscore the critical roles of S19, S33, and S35 and argue that these phosphoresidues may serve to fine-tune the ATM-dependent response of Chk2 to increasing amounts of DNA damage. PMID:16940182

  13. Comparative efficacy of systemic acquired resistance-inducing compounds against rust infection in sunflower plants.

    PubMed

    Amzalek, Esther; Cohen, Yigal

    2007-02-01

    ABSTRACT Four inducers of systemic acquired resistance (SAR) were examined for their efficacy in controlling rust infection caused by Puccinia helianthi in sunflower plants. Of the four compounds, DL-3-amino-n-butanoic acid (DL-beta-aminobutyric acid [BABA]) was the most effective and sodium salicylate (NaSA) was the least effective in protecting against rust. In leaf disk assays, full protection was obtained with BABA at 25 mug/ml, benzodiathiazol-S-methyl ester (BTH) at 100 mug/ml, 2,6-di-chloroisonicotinic acid (INA) at 100 mug/ml, and NaSA at >200 mug/ml. L-2-amino-n-butanoic acid (AABA) was partially effective, whereas N-methyl-BABA and 4-aminobutnoic acid (GABA) were ineffective. The R-enantiomer of BABA, but not the S-enantiomer, was more effective than the racemic mixture. In intact plants, BABA applied as a foliar spray or a root dip, before or after (up to 48 h) inoculation, provided significant protection for 8 days. BTH, INA, and NaSA were less protective and more phytotoxic compared with BABA. BABA did not affect urediospore germination, germ tube growth, appressorial formation, or initial ingress of P. helianthi, but strongly suppressed mycelial colonization in the mesophyll and, consequently, pustule and urediospore formation. No accumulation of defense compounds (phenolics, lignin, or callose) was detected in BABA-treated inoculated or noninoculated plants. This is the first report on the activity of BABA against an obligate Basidomycete pathogen in planta.

  14. Deoxyelephantopin from Elephantopus scaber L. induces cell-cycle arrest and apoptosis in the human nasopharyngeal cancer CNE cells

    SciTech Connect

    Su, Miaoxian; Chung, Hau Yin; Li, Yaolan

    2011-07-29

    Highlights: {yields} Deoxyelephantopin (ESD) inhibited cell proliferation in the human nasopharyngeal cancer CNE cells. {yields} ESD induced cell cycle arrest in S and G2/M phases via modulation of cell cycle regulatory proteins. {yields} ESD triggered apoptosis by dysfunction of mitochondria and induction of both intrinsic and extrinsic apoptotic signaling pathways. {yields} ESD also triggered Akt, ERK, and JNK signaling pathways. -- Abstract: Deoxyelephantopin (ESD), a naturally occurring sesquiterpene lactone present in the Chinese medicinal herb, Elephantopus scaber L. exerted anticancer effects on various cultured cancer cells. However, the cellular mechanisms by which it controls the development of the cancer cells are unavailable, particularly the human nasopharyngeal cancer CNE cells. In this study, we found that ESD inhibited the CNE cell proliferation. Cell cycle arrest in S and G2/M phases was also found. Western blotting analysis showed that modulation of cell cycle regulatory proteins was responsible for the ESD-induced cell cycle arrest. Besides, ESD also triggered apoptosis in CNE cells. Dysfunction in mitochondria was found to be associated with the ESD-induced apoptosis as evidenced by the loss of mitochondrial membrane potential ({Delta}{Psi}m), the translocation of cytochrome c, and the regulation of Bcl-2 family proteins. Despite the Western blotting analysis showed that both intrinsic and extrinsic apoptotic pathways (cleavage of caspases-3, -7, -8, -9, and -10) were triggered in the ESD-induced apoptosis, additional analysis also showed that the induction of apoptosis could be achieved by the caspase-independent manner. Besides, Akt, ERK and JNK pathways were found to involve in ESD-induced cell death. Overall, our findings provided the first evidence that ESD induced cell cycle arrest, and apoptosis in CNE cells. ESD could be a potential chemotherapeutic agent in the treatment of nasopharyngeal cancer (NPC).

  15. The Hydroclimate of East Africa: Seasonal cycle, Decadal Variability, and Human-induced Climate Change

    NASA Astrophysics Data System (ADS)

    Yang, Wenchang

    land areas and a bimodal annual cycle with the major rainy season during MAM (often called the ``long rains'' by local people) and the second during OND (the "short rains"). To explore these distinctive features, we use the ERA-Interim Re-Analysis data to analyze the associated annual cycles of atmospheric convective stability, circulation and moisture budget. The atmosphere over East Africa is found to be convectively stable, in general, year-round but with an annual cycle dominated by the surface moist static energy (MSE), which is in phase with the precipitation annual cycle. Throughout the year, the atmospheric circulation is dominated by a pattern of convergence near the surface, divergence in the lower troposphere and convergence again at upper levels. Consistently, the convergence of the vertically integrated moisture flux is mostly negative across the year, but becomes weakly positive in the two rainy seasons. It is suggested the semi-arid/arid climate in East Africa and its bimodal rainfall annual cycle can be explained by the ventilation mechanism, in which the atmospheric convective stability over East Africa is controlled by the import of low MSE air from the relatively cool Indian Ocean off the coast and the cold winter hemisphere. During the rainy seasons, however, the off-coast SST increases (and is warmest during the long rains season) and the northerly or southerly weakens, and consequently the air imported into East Africa becomes less stable. The MSE framework is then applied to study the coupling-induced bias of the East African rainfall annual cycle often found in CMIP3/5 coupled models that overestimates the OND rainfall and underestimates the MAM rainfall, by comparing the historical (coupled) and the AMIP runs (SST-forced) for each model. It is found that a warm north and cold south SST bias over the Indian Ocean induced in coupled models is responsible for the dry MAM rainfall bias over East Africa while the ocean dynamics induced warm west and

  16. 5-(2-Carboxyethenyl) isatin derivative induces G{sub 2}/M cell cycle arrest and apoptosis in human leukemia K562 cells

    SciTech Connect

    Zhou, Yao; Zhao, Hong-Ye; Han, Kai-Lin; Yang, Yao; Song, Bin-Bin; Guo, Qian-Nan; Fan, Zhen-Chuan; Zhang, Yong-Min; Teng, Yu-Ou; Yu, Peng

    2014-08-08

    Highlights: • 5-(2-Carboxyethenyl) isatin derivative (HKL 2H) inhibited K562’s proliferation. • HKL 2H caused the morphology change of G{sub 2}/M phase arrest and typical apoptosis. • HKL 2H induced G2/M cell cycle phase arrest in K562 cells. • HKL 2H induced apoptosis in K562 cells through the mitochondrial pathway. - Abstract: Our previous study successfully identified that the novel isatin derivative (E)-methyl 3-(1-(4-methoxybenzyl)-2,3-dioxoindolin-5-yl) acrylate (HKL 2H) acts as an anticancer agent at an inhibitory concentration (IC{sub 50}) level of 3 nM. In this study, the molecular mechanism how HKL 2H induces cytotoxic activity in the human chronic myelogenous leukemia K562 cells was investigated. Flow cytometric analysis showed that the cells were arrested in the G{sub 2}/M phase and accumulated subsequently in the sub-G{sub 1} phase in the presence of HKL 2H. HKL 2H treatment down-regulated the expressions of CDK1 and cyclin B but up-regulated the level of phosphorylated CDK1. Annexin-V staining and the classic DNA ladder studies showed that HKL 2H induced the apoptosis of K562 cells. Our study further showed that HKL 2H treatment caused the dissipation of mitochondrial membrane potential, activated caspase-3 and lowered the Bcl-2/Bax ratio in K562 cells, suggesting that the HKL 2H-causing programmed cell death of K562 cells was caused via the mitochondrial apoptotic pathway. Taken together, our data demonstrated that HKL 2H, a 5-(2-carboxyethenyl) isatin derivative, notably induces G{sub 2}/M cell cycle arrest and mitochondrial-mediated apoptosis in K562 cells, indicating that this compound could be a promising anticancer candidate for further investigation.

  17. DNA replication stress induces deregulation of the cell cycle events in root meristems of Allium cepa

    PubMed Central

    Żabka, Aneta; Polit, Justyna Teresa; Maszewski, Janusz

    2012-01-01

    Background and Aims Prolonged treatment of Allium cepa root meristems with changing concentrations of hydroxyurea (HU) results in either premature chromosome condensation or cell nuclei with an uncommon form of biphasic chromatin organization. The aim of the current study was to assess conditions that compromise cell cycle checkpoints and convert DNA replication stress into an abnormal course of mitosis. Methods Interphase-mitotic (IM) cells showing gradual changes of chromatin condensation were obtained following continuous 72 h treatment of seedlings with 0·75 mm HU (without renewal of the medium). HU-treated root meristems were analysed using histochemical stainings (DNA-DAPI/Feulgen; starch-iodide and DAB staining for H2O2 production), Western blotting [cyclin B-like (CBL) proteins] and immunochemistry (BrdU incorporation, detection of γ-H2AX and H3S10 phosphorylation). Key Results Continuous treatment of onion seedlings with a low concentration of HU results in shorter root meristems, enhanced production of H2O2, γ-phosphorylation of H2AX histones and accumulation of CBL proteins. HU-induced replication stress gives rise to axially elongated cells with half interphase/half mitotic structures (IM-cells) having both decondensed and condensed domains of chromatin. Long-term HU treatment results in cell nuclei resuming S phase with gradients of BrdU labelling. This suggests a polarized distribution of factors needed to re-initiate stalled replication forks. Furthermore, prolonged HU treatment extends both the relative time span and the spatial scale of H3S10 phosphorylation known in plants. Conclusions The minimum cell length and a threshold level of accumulated CBL proteins are both determining factors by which the nucleus attains commitment to induce an asynchronous course of chromosome condensation. Replication stress-induced alterations in an orderly route of the cell cycle events probably reflect a considerable reprogramming of metabolic functions of

  18. Methylsulfonylmethane (MSM), an organosulfur compound, is effective against obesity-induced metabolic disorders in mice.

    PubMed

    Sousa-Lima, Inês; Park, Shin-Young; Chung, Michelle; Jung, Hyun Ju; Kang, Min-Cheol; Gaspar, Joana M; Seo, Ji A; Macedo, M Paula; Park, Kyong Soo; Mantzoros, Christos; Lee, Seung-Hoon; Kim, Young-Bum

    2016-10-01

    Methylsulfonylmethane (MSM), an organosulfur compound, has been used as a dietary supplement that can improve various metabolic diseases. However, the effect of MSM on obesity-linked metabolic disorders remains unclear. The goal of the current study is to determine whether MSM has beneficial effects on glucose and lipid homeostasis in obesity-associated pathophysiologic states. High-fat diet-induced obese (DIO) and genetically obese diabetic db/db mice treated with MSM (1%-5% v/v, by drinking water) were studied. Metabolic parameters involved in glucose and lipid metabolism were determined. Treatment of DIO mice with MSM leads to a significant decrease in blood glucose levels. DIO mice treated with MSM are hypersensitive to insulin, as evidenced by decreased serum insulin and an increase in the area above the curve during an ITT. Concurrently, MSM reduces hepatic triglyceride and cholesterol contents in DIO mice. These effects are accompanied by reductions in gene expression of key molecules involved in lipogenesis and inflammation. FACS analysis reveals that MSM markedly increases the frequency of B cells and decreases the frequency of myeloid cells in peripheral blood and in bone marrow. Moreover, overnutrition-induced changes of femur microarchitecture are restored by MSM. In db/db mice, a marked impairment in glucose and lipid metabolic profiles is notably ameliorated when MSM is supplemented. These data suggest that MSM has beneficial effects on multiple metabolic dysfunctions, including hyperglycemia, hyperinsulinemia, insulin resistance, and inflammation. Thus, MSM could be the therapeutic option for the treatment of obesity-related metabolic disorders such as type 2 diabetes and fatty liver diseases. PMID:27621186

  19. Triazene compounds induce apoptosis in O6-alkylguanine-DNA alkyltransferase deficient leukemia cell lines.

    PubMed

    Tentori, L; Graziani, G; Gilberti, S; Lacal, P M; Bonmassar, E; D'Atri, S

    1995-11-01

    Previous studies demonstrated that triazene compounds (TZC) possess antitumor, antimetastatic and immunosuppressive activity, and induce novel antigenic properties in neoplastic cells. Moreover, TZC showed marked antitumor activity in patients with acute myelogenous leukemias (AML). In most cases leukemic blasts with low levels of the repair enzyme O6-alkyl-guanine-DNA alkyltransferase (OGAT) were highly susceptible to TZC. Therefore the cytotoxic effects of TZC against human leukemic cells and the influence of OGAT modulation were investigated. Five leukemia cell lines were treated with the in vitro active derivative of dacarbazine: 5-(3-methyl-1-triazeno) imidazole-4-carboxamide (MTIC), or with temozolomide (TZM), which is readily cleaved to form the linear triazene MTIC in aqueous solution. The results showed that treatment with TZC at concentrations ranging between 62.5 and 250 microM significantly inhibited cell growth of U-937 and K-562 leukemia cell lines, both with undetectable OGAT activity. Growth inhibition was accompanied by DNA fragmentation and reduction of cell volume characteristic of cell undergoing apoptosis. In contrast, Daudi, HL-60 and Jurkat leukemia cell lines, characterized by high levels of the repair enzyme, were resistant to concentrations of TZC up to 500 microM. Treatment of resistant lines with O6-benzylguanine (BG, a specific inhibitor of OGAT) rendered HL-60 and Daudi but not Jurkat cells sensitive to cytotoxic effects and apoptosis mediated by MTIC. The results presented suggest that: (1) apoptosis is involved in cytotoxic activity of TZC; (2) OGAT could have a role in preventing programmed cell death induced by TZC; and (3) treatment with BG could potentiate cytotoxic and apoptotic effects of TZC on leukemic cell lines when high level of OGAT activity is the main factor involved in resistance to TZC.

  20. Mutagenicity of nitro derivatives induced by exposure of aromatic compounds to nitrogen dioxide.

    PubMed

    Tokiwa, H; Nakagawa, R; Morita, K; Ohnishi, Y

    1981-08-01

    Mutagenic nitro derivatives were readily induced when 6 kinds of chemicals were exposed to 10 ppm of nitrogen dioxide (NO2). Single nitro derivatives were formed from pyrene, phenanthrene, fluorene or chrysene. Carbazole and fluoranthene each produced 2 derivatives substituted with nitro groups at different positions. The formation of nitro derivatives was enhanced by exposure of pyrene to NO2 containing nitric acid (HNO3, less than 100-fold enhancement) or sulphur dioxide (SO2, less than 15-fold enhancement). After 24 h of exposure the yields of the nitro derivative were 0.02% with 1 ppm of NO2 in air and 2.85% with NO2 (1 ppm) containing traces of HNO3. The nitro derivatives from all but phenanthrene and carbazole were chemically identified by means of gas chromatography (GC) and mass spectrometry (MS), and the mutagenicity of the 4 kinds of authentic nitro derivatives was tested by using Salmonella strains TA98 and TA1538 with or without the S9 fraction from rat liver treated with Aroclor 1254. The nitro derivative induced from pyrene was determined to be 1-nitropyrene; that of chrysene was 6-nitrochrysene; that of fluorene was 2-nitrofluorene; and those of fluoranthene were 3-nitrofluoranthene, and 8-nitrofluoranthene. Tested with strain TA98 in the absence of the S9 fraction, the first 4 of these derivatives yielded, respectively, 3050, 269, 433 and 13 400 revertants per nmole. Thus, each nitro derivative formed was potentially a direct-acting frameshift-type mutagen. Each compound exposed to NO2 showed a decreased mutagenic activity when tested in the presence of S9 mix. A possible explanation comes from experiments in which 1-nitropyrene was incubated with the S9 mix at 37 degree C for 10 min, and 1-aminopyrene was formed. The mutagenic activity of 1-aminopyrene was appreciable, but only about one-tenth of that of 1-nitropyrene in the Ames test. PMID:7022189

  1. Plumbagin induces cell death through a copper-redox cycle mechanism in human cancer cells.

    PubMed

    Nazeem, S; Azmi, Asfar S; Hanif, Sarmad; Ahmad, Aamir; Mohammad, Ramzi M; Hadi, S M; Kumar, K Sateesh

    2009-09-01

    Plumbagin, a naphthoquinone derived from the medicinal plant Plumbago zeylanica has been shown to exert anticancer and anti-proliferative activities in cells in culture as well as animal tumor models. In our previous paper, we have reported the cytotoxic action of plumbagin in plasmid pBR322 DNA as well as human peripheral blood lymphocytes through a redox mechanism involving copper. Copper has been shown to be capable of mediating the action of several plant-derived compounds through production of reactive oxygen species (ROS). The objective of the present study was to determine whether plumbagin induces apoptosis in human cancer cells through the same mechanism which we proposed earlier. Using 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt assay, 3-(4,5-B-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay for cell growth inhibition, histone/DNA ELISA, homogeneous caspase-3/7 assay for apoptosis as well as alkaline comet assay for DNA single-strand breaks detection in this report, we confirm that plumbagin causes effective cell growth inhibition, induces apoptosis and generates single-strand breaks in cancer cells. Incubation of cancer cells with scavengers of ROS and neocuproine inhibited the cytotoxic action of plumbagin proving that generation of ROS and Cu(I) are the critical mediators in plumbagin-induced cell growth inhibition. This study is the first to investigate the copper-mediated anticancer mechanism of plumbagin in human cancer cells and these properties of plumbagin could be further explored for the development of anticancer agents with higher therapeutic indices, especially for skin cancer.

  2. The natural compound benzoxazolin-2(3H)-one selectively retards cell cycle in lettuce root meristems.

    PubMed

    Sánchez-Moreiras, Adela M; de la Peña, Teodoro Coba; Reigosa, Manuel J

    2008-08-01

    Benzoxazolin-2(3H)-one (BOA) is a natural plant product that is phytotoxic to target plant species, inhibiting germination and growth and causing oxidative damage. We investigated its effects on the root meristems of seedlings of lettuce (Lactuca sativa) by means of light and transmission electron microscopy, flow cytometry, and conventional determination of mitotic index. Flow cytometry analyses and mitotic index showed a retard of cell cycle in BOA-treated meristems with selective activity at G2/M checkpoint.

  3. Strain induced superconductivity in the parent compound BaFe2As2.

    PubMed

    Engelmann, J; Grinenko, V; Chekhonin, P; Skrotzki, W; Efremov, D V; Oswald, S; Iida, K; Hühne, R; Hänisch, J; Hoffmann, M; Kurth, F; Schultz, L; Holzapfel, B

    2013-01-01

    The discovery of superconductivity with a transition temperature, Tc, up to 65 K in single-layer FeSe (bulk Tc=8 K) films grown on SrTiO3 substrates has attracted special attention to Fe-based thin films. The high Tc is a consequence of the combined effect of electron transfer from the oxygen-vacant substrate to the FeSe thin film and lattice tensile strain. Here we demonstrate the realization of superconductivity in the parent compound BaFe2As2 (no bulk Tc) just by tensile lattice strain without charge doping. We investigate the interplay between strain and superconductivity in epitaxial BaFe2As2 thin films on Fe-buffered MgAl2O4 single crystalline substrates. The strong interfacial bonding between Fe and the FeAs sublattice increases the Fe-Fe distance due to the lattice misfit, which leads to a suppression of the antiferromagnetic spin density wave and induces superconductivity with bulk Tc≈10 K. These results highlight the role of structural changes in controlling the phase diagram of Fe-based superconductors.

  4. Spiral magnetic order and pressure-induced superconductivity in transition metal compounds

    PubMed Central

    Wang, Yishu; Feng, Yejun; Cheng, J.-G.; Wu, W.; Luo, J. L.; Rosenbaum, T. F.

    2016-01-01

    Magnetic and superconducting ground states can compete, cooperate and coexist. MnP provides a compelling and potentially generalizable example of a material where superconductivity and magnetism may be intertwined. Using a synchrotron-based non-resonant X-ray magnetic diffraction technique, we reveal a spiral spin order in MnP and trace its pressure evolution towards superconducting order via measurements in a diamond anvil cell. Judging from the magnetostriction, ordered moments vanish at the quantum phase transition as pressure increases the electron kinetic energy. Spins remain local in the disordered phase, and the promotion of superconductivity is likely to emerge from an enhanced coupling to residual spiral spin fluctuations and their concomitant suppression of phonon-mediated superconductivity. As the pitch of the spiral order varies across the 3d transition metal compounds in the MnP family, the magnetic ground state switches between antiferromagnet and ferromagnet, providing an additional tuning parameter in probing spin-fluctuation-induced superconductivity. PMID:27708255

  5. Proteomics Study on Nonallergic Hypersensitivity Induced by Compound 4880 and Ovalbumin.

    PubMed

    Xu, Yubin; Guo, Na; Dou, Deqiang; Ran, Xiaoku; Ma, Xiande; Kuang, Haixue

    2016-01-01

    Nonallergic hypersensitivity reaction (NHR) accounts for more than 77% of all immune-mediated immediate hypersensitivity reactions and has become a serious threat to public health. Here, proteomics was used to study the NHR mechanism of two typical substances, the compound 4880 and ovalbumin. Twelve different proteins were suggested as potential biomarkers for examining the NHR mechanism, and our results revealed that the mechanism mainly encompassed 2 processes, i.e., generation and effect processes. The generation process could be classified as direct stimulation, complement (classical and alternative), coagulation, kallikrein-kinin, and integrated pathways. Thus glutathione peroxidase 1, terminal complement complex (complement factor 4d and Bb), coagulation 13, kininogen-1, and IgE could be used as candidate biomarkers for the indication of the corresponding pathways respectively, the proteins were further confirmed by ELISA. And the effect process was mainly composed of histamine as well as proteins such as DCD and MYLPF, which could be used as important indices for the symptoms of NHR. Our study differs from previous studies in that C4880 was found to not only be involved in the direct stimulation pathway, but also in the activated complement and kallikrein-kinin pathways through the coagulation pathway. We also report for the first time that ovalbumin-induced NHR could be a combination of the coagulation, classical complement, and integrated pathways.

  6. Rapid composition analysis of compound semiconductor thin film solar cell by laser induced breakdown spectroscopy

    NASA Astrophysics Data System (ADS)

    Lee, S. H.; Kim, C. K.; In, J. H.; Jeong, S. H.

    2014-03-01

    The characteristics of laser-induced breakdown spectroscopy (LIBS) such as short measurement time and no sample preparation provide clear advantages over other analytical techniques for rapid elemental analysis at manufacturing sites where the composition of products need to be determined in real-time for process monitoring or quality control. Thin film solar cells based on CuIn1-xGaxSe2 (CIGS), polycrystalline compound semiconductor material, have unique advantages of high efficiency (>20%), long-term stability, and low manufacturing cost over other types of solar cell. The electrical and optical properties of the thin CIGS films are closely related to the concentration ratios among its major constituent elements Cu, In, Ga and Se such as Ga/(Ga + In) and Cu/(Ga + In), and thus an accurate measurement of the composition of CIGS thin films has been an issue among CIGS solar cell researchers, requiring a fast and reliable technique for composition analysis. This paper presents the results of nanosecond (ns) and femtosecond (fs) laser based LIBS analysis of thin CIGS films. The critical issues for LIBS analysis of CIGS thin films such are discussed in comparison with ns- and fs-LIBS measurement results. The calibration of LIBS signal intensity ratios with respect to reference concentration data is carried out and the results of optimal line selection for LIBS analysis, depth profiling capability, and reproducibility are discussed.

  7. Structural and functional alterations of catalase induced by acriflavine, a compound causing apoptosis and necrosis.

    PubMed

    Attar, Farnoosh; Khavari-Nejad, Sarah; Keyhani, Jacqueline; Keyhani, Ezzatollah

    2009-08-01

    Acriflavine is an antiseptic agent causing both apoptosis and necrosis in yeast. In this work, its effect on the structure and function of catalase, a vital enzyme actively involved in protection against oxidative stress, was investigated. In vitro kinetic studies showed that acriflavine inhibited the enzymatic activity in a competitive manner. The residual activity detectable after preincubation of catalase (1.5 nmol/L) with various concentrations of acriflavine went from 50% to 20% of the control value as the acriflavine concentration increased from 30 to 90 micromol/L. Correlatively with the decrease in activity, alterations in the enzyme's conformation were observed as indicated by fluorescence spectroscopy, circular dichroism spectroscopy, and electronic absorption spectroscopy. The enzyme's intrinsic fluorescence obtained upon excitation at either 297 nm (tryptophan residues) or 280 nm (tyrosine and tryptophan residues) decreased as a function of acriflavine concentration. Circular dichroism studies showed alterations of the protein structure by acriflavine with up to 13% decrease in alpha helix, 16% increase in beta-sheet content, 17% increase in random coil, and 4% increase in beta turns. Spectrophotometric studies showed a blueshift and modifications in the chromicity of catalase at 405 nm, corresponding to an absorbance band due to the enzyme's prosthetic group. Thus, acriflavine induced in vitro a profound change in the structure of catalase so that the enzyme could no longer function. Our results showed that acriflavine, a compound producing apoptosis and necrosis, can have a direct effect on vital functions in cells by disabling key enzymes.

  8. Proton-induced damage on 2-aminooxazole, a potential prebiotic compound.

    PubMed

    Bacchus-Montabonel, Marie-Christine

    2015-01-29

    Among the complex organic molecules detected in space, in the interstellar medium, on meteorites or comets, special interest is devoted to the potentially exobiologic-relevant species. In the hypothesis, widely discussed, of a possible exogen origin of life, the transport of such compounds and their survival is indeed a fundamental question. Recently, suggestion has been made that 2-aminooxazole could be a possible precursor of RNA nucleotides on early earth and its stability to UV radiation or to collisions may be determinant. We have thus undertaken a detailed theoretical study of the charge transfer collision dynamics induced by the impact of 2-aminooxazole with protons, which could be an important process in particular in proton-rich environments. The theoretical treatment has been developed through ab initio quantum chemistry molecular calculations followed by semiclassical collision dynamics. The results are compared to previous investigations on DNA and RNA building blocks in order to extract some qualitative trends in the damage of prebiotic species under spatial radiation. PMID:25574775

  9. Spiral magnetic order and pressure-induced superconductivity in transition metal compounds

    NASA Astrophysics Data System (ADS)

    Wang, Yishu; Feng, Yejun; Cheng, J.-G.; Wu, W.; Luo, J. L.; Rosenbaum, T. F.

    2016-10-01

    Magnetic and superconducting ground states can compete, cooperate and coexist. MnP provides a compelling and potentially generalizable example of a material where superconductivity and magnetism may be intertwined. Using a synchrotron-based non-resonant X-ray magnetic diffraction technique, we reveal a spiral spin order in MnP and trace its pressure evolution towards superconducting order via measurements in a diamond anvil cell. Judging from the magnetostriction, ordered moments vanish at the quantum phase transition as pressure increases the electron kinetic energy. Spins remain local in the disordered phase, and the promotion of superconductivity is likely to emerge from an enhanced coupling to residual spiral spin fluctuations and their concomitant suppression of phonon-mediated superconductivity. As the pitch of the spiral order varies across the 3d transition metal compounds in the MnP family, the magnetic ground state switches between antiferromagnet and ferromagnet, providing an additional tuning parameter in probing spin-fluctuation-induced superconductivity.

  10. Proteomics Study on Nonallergic Hypersensitivity Induced by Compound 4880 and Ovalbumin

    PubMed Central

    Xu, Yubin; Guo, Na; Dou, Deqiang; Ran, Xiaoku; Ma, Xiande; Kuang, Haixue

    2016-01-01

    Nonallergic hypersensitivity reaction (NHR) accounts for more than 77% of all immune-mediated immediate hypersensitivity reactions and has become a serious threat to public health. Here, proteomics was used to study the NHR mechanism of two typical substances, the compound 4880 and ovalbumin. Twelve different proteins were suggested as potential biomarkers for examining the NHR mechanism, and our results revealed that the mechanism mainly encompassed 2 processes, i.e., generation and effect processes. The generation process could be classified as direct stimulation, complement (classical and alternative), coagulation, kallikrein-kinin, and integrated pathways. Thus glutathione peroxidase 1, terminal complement complex (complement factor 4d and Bb), coagulation 13, kininogen-1, and IgE could be used as candidate biomarkers for the indication of the corresponding pathways respectively, the proteins were further confirmed by ELISA. And the effect process was mainly composed of histamine as well as proteins such as DCD and MYLPF, which could be used as important indices for the symptoms of NHR. Our study differs from previous studies in that C4880 was found to not only be involved in the direct stimulation pathway, but also in the activated complement and kallikrein-kinin pathways through the coagulation pathway. We also report for the first time that ovalbumin-induced NHR could be a combination of the coagulation, classical complement, and integrated pathways. PMID:26829397

  11. Gene expression for peroxisome-associated enzymes in hepatocellular carcinomas induced by ciprofibrate, a hypolipidemic compound

    SciTech Connect

    Rao, M.S.; Nemali, M.R.; Reddy, J.K.

    1986-03-05

    Administration of hypolipidemic compounds leads to marked proliferation of peroxisomes and peroxisome-associated enzymes (PAE) in the livers of rodents and non-rodent species. The increase peroxisome-associated enzymes such as fatty acid ..beta..-oxidation system and catalase is shown to be due to an increase in the levels of mRNA. In this experiment they have examined hepatocellular carcinomas (HCC), induced in male F-344 rats by ciprofibrate (0.025%, w/w for 60 weeks), for gene expression of PAE. Total RNA was purified from HCC as well as from control and ciprofibrate (0.025% for 2 weeks) fed rat livers. Northern blot analysis was performed using (32/sub p/)cDNA probes for albumin, fatty acetyl-CoA oxidase, enoyl-CoA hydratase 3-hydroxyacyl-CoA dehydrogenase bifunctional enzyme and catalase. mRNA levels in HCC for albumin, fatty acid ..beta..-oxidation enzymes and catalase were comparable with those levels observed in the livers of rats given ciprofibrate for 2 weeks. In control livers the mRNAs for ..beta..-oxidation enzymes were low. Albumin mRNA levels in all the 3 groups were comparable. Additional studies are necessary to determine whether the increased level of mRNAs for the ..beta..-oxidation enzymes in HCC is due to the effect of ciprofibrate or to the gene amplification.

  12. Novel piperazine core compound induces death in human liver cancer cells: possible pharmacological properties

    PubMed Central

    Samie, Nima; Muniandy, Sekaran; Kanthimathi, M. S.; Haerian, Batoul Sadat; Raja Azudin, Raja Elina

    2016-01-01

    The current study evaluates the cytotoxic mechanism of a novel piperazine derivate designated as PCC against human liver cancer cells. In this context, human liver cancer cell lines, SNU-475 and 243, human monocyte/macrophage cell line, CRL-9855, and human B lymphocyte cell line, CCL-156, were used to determine the IC50 of PCC using the standard MTT assay. PCC displayed a strong suppressive effect on SNU-475 and SNU-423 cells with an IC50 value of 6.98 ± 0.11 μg/ml and 7.76 ± 0.45 μg/ml respectively, after 24 h of treatment. Significant dipping in the mitochondrial membrane potential and elevation in the released of cytochrome c from the mitochondria indicated the induction of the intrinsic apoptosis pathway by PCC. Activation of this pathway was further evidenced by significant activation of caspase 3/7 and 9. PCC was also shown to activate the extrinsic pathways of apoptosis via activation of caspase-8 which is linked to the suppression of NF-ƙB translocation to the nucleus. Cell cycle arrest in the G1 phase was confirmed by flow cytometry and up-regulation of glutathione reductase expression was quantified by qPCR. This study suggests that PCC is a simultaneous inducer of intrinsic and extrinsic pathways of apoptosis in liver cancer cell lines. PMID:27072064

  13. Crude Garlic Extract Inhibits Cell Proliferation and Induces Cell Cycle Arrest and Apoptosis of Cancer Cells In Vitro.

    PubMed

    Bagul, Mukta; Kakumanu, Srikanth; Wilson, Thomas A

    2015-07-01

    Garlic and its lipid-based extracts have played an important medicinal role in humans for centuries that includes antimicrobial, hypoglycemic, and lipid-lowering properties. The present study was to investigate the effects of crude garlic extract (CGE) on the proliferation of human breast, prostate, hepatic, and colon cancer cell lines and mouse macrophageal cells, not previously studied. The human cancer cell lines, such as hepatic (Hep-G2), colon (Caco-2), prostate (PC-3), and breast (MCF-7), were propagated at 37°C; air/CO2 (95:5 v/v) using the ATCC-formulated RPMI-1640 Medium and 10% fetal bovine serum (FBS), while the mouse macrophage cell line (TIB-71) was propagated at 37°C; air/CO2 (95:5 v/v) using the ATCC-formulated DMEM and 10% FBS. All cells were plated at a density of ∼5000 cells/well. After overnight incubation, the cells were treated with 0.125, 0.25, 0.5, or 1 μg/mL of CGE an additional 72 h. Inhibition of cell proliferation of 80-90% was observed for Hep-G2, MCF-7, TIB-71, and PC-3 cells, but only 40-55% for the Caco-2 cells when treated with 0.25, 0.5, or 1 μg/mL. In a coculture study of Caco-2 and TIB-71 cells, inhibition of cell proliferation of 90% was observed for Caco-2 cells compared to the 40-55% when cultured separately. CGE also induced cell cycle arrest and had a fourfold increase in caspase activity (apoptosis) in PC-3 cells when treated at a dose of 0.5 or 1 μg/mL. This investigation of CGE clearly highlights the fact that the lipid bioactive compounds in CGE have the potential as promising anticancer agents.

  14. Resveratrol induces cell cycle arrest in human gastric cancer MGC803 cells via the PTEN-regulated PI3K/Akt signaling pathway.

    PubMed

    Jing, Xiaoping; Cheng, Weiwei; Wang, Shiying; Li, Pin; He, Li

    2016-01-01

    Resveratrol is a polyphenolic compound that is extracted from Polygonum cuspidatum and is used in traditional Chinese medicine. Previous data have shown that resveratrol inhibits the growth of human gastric cancer. MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide] and trypan blue assays showed that resveratrol significantly decreased the survival rate of MGC803 cells in a concentration- and time-dependent manner. Our flow cytometric analysis showed that resveratrol treatment arrested the cells at the G0/G1 phase of the cell cycle. Furthermore, western blotting demonstrated that resveratrol decreased the protein expression of phospho-glycogen synthase kinase 3β (p-GSK3β), cyclin D1, phospho-phosphatase and tensin homologue (p-PTEN), phospho-phosphatidylinositol 3'-OH kinase (p-PI3K), and phospho-protein kinase B (p-PKB/Akt). We also found that resveratrol inhibited the progression of the cell cycle in MGC803 cells by repressing p-PI3K and p-Akt expression. Meanwhile, resveratrol did not decrease the phosphorylation level of Akt when the PTEN gene expression was knocked down by an siRNA in the MGC803 cells. Taken together, these results suggest that resveratrol induced cell cycle arrest in human gastric cancer MGC803 cells by regulating the PTEN/PI3K/Akt signaling pathway.

  15. Resveratrol induces cell cycle arrest in human gastric cancer MGC803 cells via the PTEN-regulated PI3K/Akt signaling pathway.

    PubMed

    Jing, Xiaoping; Cheng, Weiwei; Wang, Shiying; Li, Pin; He, Li

    2016-01-01

    Resveratrol is a polyphenolic compound that is extracted from Polygonum cuspidatum and is used in traditional Chinese medicine. Previous data have shown that resveratrol inhibits the growth of human gastric cancer. MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide] and trypan blue assays showed that resveratrol significantly decreased the survival rate of MGC803 cells in a concentration- and time-dependent manner. Our flow cytometric analysis showed that resveratrol treatment arrested the cells at the G0/G1 phase of the cell cycle. Furthermore, western blotting demonstrated that resveratrol decreased the protein expression of phospho-glycogen synthase kinase 3β (p-GSK3β), cyclin D1, phospho-phosphatase and tensin homologue (p-PTEN), phospho-phosphatidylinositol 3'-OH kinase (p-PI3K), and phospho-protein kinase B (p-PKB/Akt). We also found that resveratrol inhibited the progression of the cell cycle in MGC803 cells by repressing p-PI3K and p-Akt expression. Meanwhile, resveratrol did not decrease the phosphorylation level of Akt when the PTEN gene expression was knocked down by an siRNA in the MGC803 cells. Taken together, these results suggest that resveratrol induced cell cycle arrest in human gastric cancer MGC803 cells by regulating the PTEN/PI3K/Akt signaling pathway. PMID:26530632

  16. The cranberry flavonoids PAC DP-9 and quercetin aglycone induce cytotoxicity and cell cycle arrest and increase cisplatin sensitivity in ovarian cancer cells.

    PubMed

    Wang, Yifei; Han, Alex; Chen, Eva; Singh, Rakesh K; Chichester, Clinton O; Moore, Richard G; Singh, Ajay P; Vorsa, Nicholi

    2015-05-01

    Cranberry flavonoids (flavonols and flavan-3-ols), in addition to their antioxidant properties, have been shown to possess potential in vitro activity against several cancers. However, the difficulty of isolating cranberry compounds has largely limited anticancer research to crude fractions without well-defined compound composition. In this study, individual cranberry flavonoids were isolated to the highest purity achieved so far using gravity and high performance column chromatography and LC-MS characterization. MTS assay indicated differential cell viability reduction of SKOV-3 and OVCAR-8 ovarian cancer cells treated with individual cranberry flavonoids. Treatment with quercetin aglycone and PAC DP-9, which exhibited the strongest activity, induced apoptosis, led to caspase-3 activation and PARP deactivation, and increased sensitivity to cisplatin. Furthermore, immunofluorescence microscopy and western blot study revealed reduced expression and activation of epidermal growth factor receptor (EGFR) in PAC DP-9 treated SKOV-3 cells. In addition, quercetin aglycone and PAC DP-9 deactivated MAPK-ERK pathway, induced downregulation of cyclin D1, DNA-PK, phospho-histone H3 and upregulation of p21, and arrested cell cycle progression. Overall, this study demonstrates promising in vitro cytotoxic and anti-proliferative properties of two newly characterized cranberry flavonoids, quercetin aglycone and PAC DP-9, against ovarian cancer cells. PMID:25776829

  17. The Ethanolic Extract of Taiwanofungus camphoratus (Antrodia camphorata) Induces Cell Cycle Arrest and Enhances Cytotoxicity of Cisplatin and Doxorubicin on Human Hepatocellular Carcinoma Cells

    PubMed Central

    Lin, Liang-Tzung; Tai, Chen-Jei; Su, Ching-Hua; Chang, Fang-Mo; Choong, Chen-Yen; Wang, Chien-Kai; Tai, Cheng-Jeng

    2015-01-01

    Taiwanofungus camphoratus (synonym Antrodia camphorata) is a widely used medicinal fungus in the folk medicine of Taiwan with several pharmacological features such as anti-inflammatory, liver protection, antihypertensive, and antioxidative activities. The ethanolic extract of T. camphoratus (TCEE) which contains abundant bioactive compounds including triterpenoids and polysaccharides also has antitumor effects in various human cancer cell lines. The aims of this study are to clarify the antitumor effects of TCEE on human hepatocellular carcinoma cells and also evaluate the combination drug effects with conventional chemotherapy agents, cisplatin and doxorubicin. In the present study, the TCEE treatment induced cell cycle arrest and suppressed cell growth on both Hep3B and HepJ5 cells. Expression of cell cycle inhibitors, P21 and P27, and activation of apoptosis executer enzyme, caspase-3, were also induced by TCEE. In combination with the chemotherapy agents, TCEE treatment further enhanced the tumor suppression efficiency of cisplatin and doxorubicin. These results together suggested that TCEE is a potential ingredient for developing an integrated chemotherapy for human liver cancer. PMID:26557666

  18. Unprecedented inhibition of tubulin polymerization directed by gold nanoparticles inducing cell cycle arrest and apoptosis

    NASA Astrophysics Data System (ADS)

    Choudhury, Diptiman; Xavier, Paulrajpillai Lourdu; Chaudhari, Kamalesh; John, Robin; Dasgupta, Anjan Kumar; Pradeep, Thalappil; Chakrabarti, Gopal

    2013-05-01

    The effect of gold nanoparticles (AuNPs) on the polymerization of tubulin has not been examined till now. We report that interaction of weakly protected AuNPs with microtubules (MTs) could cause inhibition of polymerization and aggregation in the cell free system. We estimate that single citrate capped AuNPs could cause aggregation of ~105 tubulin heterodimers. Investigation of the nature of inhibition of polymerization and aggregation by Raman and Fourier transform-infrared (FTIR) spectroscopies indicated partial conformational changes of tubulin and microtubules, thus revealing that AuNP-induced conformational change is the driving force behind the observed phenomenon. Cell culture experiments were carried out to check whether this can happen inside a cell. Dark field microscopy (DFM) combined with hyperspectral imaging (HSI) along with flow cytometric (FC) and confocal laser scanning microscopic (CLSM) analyses suggested that AuNPs entered the cell, caused aggregation of the MTs of A549 cells, leading to cell cycle arrest at the G0/G1 phase and concomitant apoptosis. Further, Western blot analysis indicated the upregulation of mitochondrial apoptosis proteins such as Bax and p53, down regulation of Bcl-2 and cleavage of poly(ADP-ribose) polymerase (PARP) confirming mitochondrial apoptosis. Western blot run after cold-depolymerization revealed an increase in the aggregated insoluble intracellular tubulin while the control and actin did not aggregate, suggesting microtubule damage induced cell cycle arrest and apoptosis. The observed polymerization inhibition and cytotoxic effects were dependent on the size and concentration of the AuNPs used and also on the incubation time. As microtubules are important cellular structures and target for anti-cancer drugs, this first observation of nanoparticles-induced protein's conformational change-based aggregation of the tubulin-MT system is of high importance, and would be useful in the understanding of cancer therapeutics

  19. Neuroprotective Properties of Compounds Extracted from Dianthus superbus L. against Glutamate-induced Cell Death in HT22 Cells

    PubMed Central

    Yun, Bo-Ra; Yang, Hye Jin; Weon, Jin Bae; Lee, Jiwoo; Eom, Min Rye; Ma, Choong Je

    2016-01-01

    Background: Dianthus superbus L. has been used in Chinese herbal medicine as a diuretic and anti-inflammatory agent. Objective: In this study, we isolated ten bioactive compounds from D. superbus and evaluated their neuroprotective activity against glutamate-induced cell death in the hippocampal neuronal HT22 cells. Materials and Methods: New compound, (E)-methyl-4-hydroxy-4-(8a-methyl-3-oxodecahydronaphthalen-4a-yl) (1) and, nine known compounds, diosmetin-7-O (2’’,6’’-di-O-α-L-rhamnopyranosyl)-β-D-glucopyranoside (2), 4-hydroxy-3-methoxy-pentyl ester benzenepropanoic acid (3), vanillic acid (4), 4-hydroxy-benzeneacetic acid (5), 4-methoxybenzeneacetic acid (6), (E)-4-methoxycinnamic acid (7), 3-methoxy-4-hydroxyphenylethanol (8), hydroferulic acid (9), and methyl hydroferulate (10), were isolated by bioactivity-guided separation. Structures of the isolated compounds were identified on the basis of 1H nuclear magnetic resonance (NMR), 13C NMR, and two-dimensional NMR spectra, while their neuroprotective properties were evaluated by performing the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Results: D. superbus extract had a neuroprotective effect and isolated 10 compounds. Among the compounds, compounds 5 and 6 effectively protected HT22 cells against glutamate toxicity. Conclusion: In conclusion, the extract of D. superbus and compounds isolated from it exhibited neuroprotective properties, suggesting therapeutic potential for applications in neurotoxic diseases. SUMMARY D. superbus extract significantly protected on glutamate-induced cell death in HT22 cellsNew compound, (E)-methyl-4-hydroxy-4-(8a-methyl-3-oxodecahydronaphthalen-4a-yl) (1) and, nine known compounds, diosmetin-7-O(2’’,6’’-di-O-α-L-rhamnopyranosyl)-β-D-glucopyranoside (2), 4-hydroxy-3-methoxy-pentyl ester benzenepropanoic acid (3), vanillic acid (4), 4-hydroxy-benzeneacetic acid (5), 4-methoxybenzeneacetic acid (6), (E)-4-methoxycinnamic acid (7), 3

  20. Linking global-change induced shifts in soil nitrogen cycling with the abundance of key microorganisms

    NASA Astrophysics Data System (ADS)

    Carey, C.; Eviner, V.; Beman, M.; Hart, S. C.

    2013-12-01

    understanding of the regulatory role of the soil microbial community in terrestrial N cycling and also help to improve our understanding of the controls on global change-induced shifts in ecosystem functioning.

  1. Knockdown of the Cell Cycle Inhibitor p21 Enhances Cartilage Formation by Induced Pluripotent Stem Cells

    PubMed Central

    Diekman, Brian O.; Thakore, Pratiksha I.; O'Connor, Shannon K.; Willard, Vincent P.; Brunger, Jonathan M.; Christoforou, Nicolas; Leong, Kam W.

    2015-01-01

    The limited regenerative capacity of articular cartilage contributes to progressive joint dysfunction associated with cartilage injury or osteoarthritis. Cartilage tissue engineering seeks to provide a biological substitute for repairing damaged or diseased cartilage, but requires a cell source with the capacity for extensive expansion without loss of chondrogenic potential. In this study, we hypothesized that decreased expression of the cell cycle inhibitor p21 would enhance the proliferative and chondrogenic potential of differentiated induced pluripotent stem cells (iPSCs). Murine iPSCs were directed to differentiate toward the chondrogenic lineage with an established protocol and then engineered to express a short hairpin RNA (shRNA) to reduce the expression of p21. Cells expressing the p21 shRNA demonstrated higher proliferative potential during monolayer expansion and increased synthesis of glycosaminoglycans (GAGs) in pellet cultures. Furthermore, these cells could be expanded ∼150-fold over three additional passages without a reduction in the subsequent production of GAGs, while control cells showed reduced potential for GAG synthesis with three additional passages. In pellets from extensively passaged cells, knockdown of p21 attenuated the sharp decrease in cell number that occurred in control cells, and immunohistochemical analysis showed that p21 knockdown limited the production of type I and type X collagen while maintaining synthesis of cartilage-specific type II collagen. These findings suggest that manipulating the cell cycle can augment the monolayer expansion and preserve the chondrogenic capacity of differentiated iPSCs, providing a strategy for enhancing iPSC-based cartilage tissue engineering. PMID:25517798

  2. Knockdown of the cell cycle inhibitor p21 enhances cartilage formation by induced pluripotent stem cells.

    PubMed

    Diekman, Brian O; Thakore, Pratiksha I; O'Connor, Shannon K; Willard, Vincent P; Brunger, Jonathan M; Christoforou, Nicolas; Leong, Kam W; Gersbach, Charles A; Guilak, Farshid

    2015-04-01

    The limited regenerative capacity of articular cartilage contributes to progressive joint dysfunction associated with cartilage injury or osteoarthritis. Cartilage tissue engineering seeks to provide a biological substitute for repairing damaged or diseased cartilage, but requires a cell source with the capacity for extensive expansion without loss of chondrogenic potential. In this study, we hypothesized that decreased expression of the cell cycle inhibitor p21 would enhance the proliferative and chondrogenic potential of differentiated induced pluripotent stem cells (iPSCs). Murine iPSCs were directed to differentiate toward the chondrogenic lineage with an established protocol and then engineered to express a short hairpin RNA (shRNA) to reduce the expression of p21. Cells expressing the p21 shRNA demonstrated higher proliferative potential during monolayer expansion and increased synthesis of glycosaminoglycans (GAGs) in pellet cultures. Furthermore, these cells could be expanded ∼150-fold over three additional passages without a reduction in the subsequent production of GAGs, while control cells showed reduced potential for GAG synthesis with three additional passages. In pellets from extensively passaged cells, knockdown of p21 attenuated the sharp decrease in cell number that occurred in control cells, and immunohistochemical analysis showed that p21 knockdown limited the production of type I and type X collagen while maintaining synthesis of cartilage-specific type II collagen. These findings suggest that manipulating the cell cycle can augment the monolayer expansion and preserve the chondrogenic capacity of differentiated iPSCs, providing a strategy for enhancing iPSC-based cartilage tissue engineering.

  3. Biostimulation induces syntrophic interactions that impact C, S and N cycling in a sediment microbial community

    SciTech Connect

    Handley, KM; Verberkmoes, Nathan C; Steefel, Carl I; Sharon, I; Williams, Ken; Miller, CS; Frischkorn, Kyle C; Chourey, Karuna; Thomas, Brian; Shah, Manesh B; Long, Phil; Hettich, Robert {Bob} L; Banfield, Jillian F.

    2013-01-01

    Stimulation of subsurface microorganisms to induce reductive immobilization of metals is a promising approach for bioremediation, yet the overall microbial community response is typically poorly understood. Here we used community proteogenomics to test the hypothesis that excess input of acetate activates syntrophic interactions among autotrophs and heterotrophs. A flow-through sediment column was incubated in a groundwater well of an acetate-amended aquifer. Genomic sequences from the community recovered during microbial sulfate reduction were used to econstruct, de novo, near-complete genomes for Desulfobacter (Deltaproteobacteria) and relatives of Sulfurovum and Sulfurimonas (Epsilonproteobacteria), and Bacteroidetes. Partial genomes were obtained for Clostridiales (Firmicutes) and Desulfuromonadales-like Deltaproteobacteria. The majority of proteins identified by mass spectrometry corresponded to Desulfobacter-like species, and demonstrate the role of this organism in sulfate reduction (Dsr and APS), nitrogen-fixation (Nif) and acetate oxidation to CO2 during amendment. Results suggest less abundant Desulfuromonadales and Bacteroidetes also actively contributed to CO2 production via the TCA cycle. Proteomic data indicate that sulfide was partially re-oxidized by Epsilonproteobacteria through nitrate-dependent sulfide oxidation (using Nap, Nir, Nos, SQR and Sox), with CO2 fixed using the reverse TCA cycle. Modeling shows that this reaction was thermodynamically possible, and kinetically favorable relative to acetate-dependent denitrification. We conclude that high-levels of carbon amendment aimed to stimulate anaerobic heterotrophy led to carbon fixation in co-dependent chemoautotrophs. These results have implications for understanding complex ecosystem behavior, and show that high levels of organic carbon supplementation can expand the range of microbial functionalities accessible for ecosystem manipulation.

  4. 2-(3,5-Dihydroxyphenyl)-6-hydroxybenzothiazole arrests cell growth and cell cycle and induces apoptosis in breast cancer cell lines.

    PubMed

    Rajabi, Mehdi

    2012-03-01

    2-Arylbenzothiazoles are an important class of bicyclic privileged substructures present in various natural or synthetic compounds that have been shown to possess anticancer, antifungal, antibacterial, anti-inflammatory, and antiallergic activities. This study examined the antiproliferative properties of 2-(3,5-dihydroxyphenyl)-6-hydroxybenzothiazole (DH) and its molecular mechanism of action in human breast cancer MDA-MB-231 cells. DH inhibits the growth of MDA-MB-231 cells with an IC(50) value of 25 μM in a dose/time-dependent manner as measured by the microculture tetrazolium method. Cell cycle analysis by flow cytometry showed that DH-induced growth arrest could be associated to apoptosis in MDA-MB-231 cells. PMID:21838530

  5. The natural organosulfur compound dipropyltetrasulfide prevents HOCl-induced systemic sclerosis in the mouse

    PubMed Central

    2013-01-01

    Introduction The aim of this study was to test the naturally occurring organosulfur compound dipropyltetrasulfide (DPTTS), found in plants, which has antibiotic and anticancer properties, as a treatment for HOCl-induced systemic sclerosis in the mouse. Methods The prooxidative, antiproliferative, and cytotoxic effects of DPTTS were evaluated ex vivo on fibroblasts from normal and HOCl mice. In vivo, the antifibrotic and immunomodulating properties of DPTTS were evaluated in the skin and lungs of HOCl mice. Results H2O2 production was higher in fibroblasts derived from HOCl mice than in normal fibroblasts (P < 0.05). DPTTS did not increase H2O2 production in normal fibroblasts, but DPTTS dose-dependently increased H2O2 production in HOCl fibroblasts (P < 0.001 with 40 μM DPTTS). Because H2O2 reached a lethal threshold in cells from HOCl mice, the antiproliferative, cytotoxic, and proapoptotic effects of DPTTS were significantly higher in HOCl fibroblasts than for normal fibroblasts. In vivo, DPTTS decreased dermal thickness (P < 0.001), collagen content in skin (P < 0.01) and lungs (P < 0.05), αSMA (P < 0.01) and pSMAD2/3 (P < 0.01) expression in skin, formation of advanced oxidation protein products and anti-DNA topoisomerase-1 antibodies in serum (P < 0.05) versus untreated HOCl mice. Moreover, in HOCl mice, DPTTS reduced splenic B-cell counts (P < 0.01), the proliferative rates of B-splenocytes stimulated by lipopolysaccharide (P < 0.05), and T-splenocytes stimulated by anti-CD3/CD28 mAb (P < 0.001). Ex vivo, it also reduced the production of IL-4 and IL-13 by activated T cells (P < 0.05 in both cases). Conclusions The natural organosulfur compound DPTTS prevents skin and lung fibrosis in the mouse through the selective killing of diseased fibroblasts and its immunomodulating properties. DPTTS may be a potential treatment for systemic sclerosis. PMID:24286210

  6. Novel Platinum(II) compounds modulate insulin-degrading enzyme activity and induce cell death in neuroblastoma cells.

    PubMed

    Tundo, Grazia R; Sbardella, Diego; De Pascali, Sandra A; Ciaccio, Chiara; Coletta, Massimo; Fanizzi, Francesco P; Marini, Stefano

    2015-01-01

    The properties of three novel Platinum(II) compounds toward the insulin-degrading enzyme (IDE) enzymatic activity have been investigated under physiological conditions. The rationale of this study resides on previous observations that these compounds, specifically designed and synthesized by some of us, induce apoptosis in various cancer cell lines, whereas IDE has been proposed as a putative oncogene involved in neuroblastoma onset and progression. Two of these compounds, namely [PtCl(O,O'-acac)(DMSO)] and [Pt(O,O'-acac)(γ-acac)(DMS)], display a modulatory behavior, wherefore activation or inhibition of IDE activity occurs over different concentration ranges (suggesting the existence of two binding sites on the enzyme). On the other hand, [Pt(O,O'-acac)(γ-acac)(DMSO)] shows a typical competitive inhibitory pattern, characterized by a meaningful affinity constant (K i  = 0.95 ± 0.21 μM). Although all three compounds induce cell death in neuroblastoma SHSY5Y cells at concentrations exceeding 2 μM, the two modulators facilitate cells' proliferation at concentrations ≤ 1.5 μM, whereas the competitive inhibitor [Pt(O,O'-acac)(γ-acac)(DMSO)] only shows a pro-apoptotic activity at all investigated concentrations. These features render the [Pt(O,O'-acac)(γ-acac)(DMSO)] a promising "lead compound" for the synthesis of IDE-specific inhibitors (not characterized yet) with therapeutic potentiality.

  7. Desorption of low-volatility compounds induced by dynamic friction between microdroplets and an ultrasonically vibrating blade.

    PubMed

    Usmanov, D T; Hiraoka, K; Wada, H; Morita, S; Nonami, H

    2016-02-21

    Friction plays an important role in desorption and/or ionization of nonvolatile compounds in mass spectrometry, e.g., sonic spray, easy ambient sonic-spray ionization, solvent-assisted inlet ionization, desorption electrospray, etc. In our previous work, desorption of low molecular weight compounds induced by solid/solid dynamic friction was studied. The objective of this work was to investigate desorption of low-volatility compounds induced by liquid/solid friction. Water/methanol (1/1) microdroplets with ∼30 μm in diameter were generated by using a piezoelectric microdroplet generator. They were injected to analytes deposited on the flat surface of a blade vibrating ultrasonically with the frequency of 40 kHz. Neutral molecules desorbed from the blade were ionized by a helium dielectric barrier discharge (DBD), generating strong signals for samples including drugs, explosives, and insecticides. These signals were not detected when either the blade vibrator or the piezoelectric microdroplet generator was off. In contrast, for ionic compounds such as 1-butyl-3-methylimidazolium bis(trifluoro-methylsulfonyl)imide, p-chlorobenzyl pyridinium chloride, and rhodamine B, strong ion signals were obtained when the vibrator and droplet generator were on, but DBD was off. Sub-nanogram limits of detection were attained for low-volatility compounds. PMID:26779570

  8. Redox cycling compounds generate H2O2 in HTS buffers containing strong reducing reagents – real hits or promiscuous artifacts?

    PubMed Central

    Johnston, Paul A.

    2010-01-01

    Redox cycling compounds (RCCs) generate µM concentrations of hydrogen peroxide (H2O2) in the presence of strong reducing agents, common buffer components used to maintain the catalytic activity and/or folding of target proteins for high throughput screening (HTS) assays. H2O2 generated by RCCs can indirectly inhibit the catalytic activity of proteins by oxidizing accessible cysteine, tryptophan, methionine, histidine or selenocysteine residues, and indeed several important classes of protein targets are susceptible to H2O2-mediated inactivation; protein tyrosine phosphatases, cysteine proteases, and metalloenzymes. The main sources of H2O2 in cells are the Nox enzyme/SOD systems, peroxisome metabolism, and the autoxidation of reactive chemicals by enzyme mediated redox cycling at both the microsomal and mitochondrial sites of electron transport. Given the role of H2O2 as a second messenger involved in the regulation of many signaling pathways it is hardly surprising that compounds which can generate intracellular H2O2 by enzyme mediated redox cycling would have pleiotropic effects. RCCs can therefore have serious negative consequences for the probe and/or lead generation process: primary HTS assay hit rates may be inflated by RCC false positives; critical resources will be diverted to develop and implement follow up assays to distinguish RCCs from real hits; and screening databases will become annotated with the promiscuous activity of RCCs. In an attempt to mitigate the serious impact of RCCs on probe and lead generation, two groups have independently developed assays to indentify RCCs. PMID:21075044

  9. Redox cycling compounds generate H2O2 in HTS buffers containing strong reducing reagents--real hits or promiscuous artifacts?

    PubMed

    Johnston, Paul A

    2011-02-01

    Redox cycling compounds (RCCs) generate μM concentrations of hydrogen peroxide (H(2)O(2)) in the presence of strong reducing agents, common buffer components used to maintain the catalytic activity and/or folding of target proteins for high throughput screening (HTS) assays. H(2)O(2) generated by RCCs can indirectly inhibit the catalytic activity of proteins by oxidizing accessible cysteine, tryptophan, methionine, histidine, or selenocysteine residues, and indeed several important classes of protein targets are susceptible to H(2)O(2)-mediated inactivation; protein tyrosine phosphatases, cysteine proteases, and metalloenzymes. The main sources of H(2)O(2) in cells are the Nox enzyme/SOD systems, peroxisome metabolism, and the autoxidation of reactive chemicals by enzyme mediated redox cycling at both the microsomal and mitochondrial sites of electron transport. Given the role of H(2)O(2) as a second messenger involved in the regulation of many signaling pathways it is hardly surprising that compounds that can generate intracellular H(2)O(2) by enzyme mediated redox cycling would have pleiotropic effects. RCCs can therefore have serious negative consequences for the probe and/or lead generation process: primary HTS assay hit rates may be inflated by RCC false positives; crucial resources will be diverted to develop and implement follow up assays to distinguish RCCs from real hits; and screening databases will become annotated with the promiscuous activity of RCCs. In an attempt to mitigate the serious impact of RCCs on probe and lead generation, two groups have independently developed assays to indentify RCCs.

  10. DIBROMOACETIC ACID-INDUCED ELEVATIONS IN CIRCULATING ESTRADIOL: EFFECTS IN BOTH CYCLING AND OVARIECTOMIZED/STEROID-PRIMED FEMALE RATS

    EPA Science Inventory

    RTD-03-031
    Goldman, JM and Murr, AS. Dibromoacetic Acid-induced Elevations in Circulating Estradiol: Effects in Both Cycling and Ovariectomized/Steroid-primed Female Rats. Reproductive Toxicology (in press).

    Abstract

    Oral exposures to high concentrations of th...

  11. DIBROMOACETIC ACID-INDUCED ELEVATIONS OF ESTRADIOL IN THE CYCLING AND OVARIECTOMOZED/ESTRADIOL-IMPLANTED FEMALE RAT

    EPA Science Inventory

    Goldman, JM and Murr, AS. Dibromoacetic Acid-induced Elevations of Estradiol in Both Cycling and Ovariectomized / Estradiol-implanted Female Rats

    ABSTRACT
    Haloacetic acids are one of the principal classes of disinfection by-products generated by the chlorination of mun...

  12. X-ray Inducible Luminescence and Singlet Oxygen Sensitization by an Octahedral Molybdenum Cluster Compound: A New Class of Nanoscintillators.

    PubMed

    Kirakci, Kaplan; Kubát, Pavel; Fejfarová, Karla; Martinčík, Jiří; Nikl, Martin; Lang, Kamil

    2016-01-19

    Newly synthesized octahedral molybdenum cluster compound (n-Bu4N)2[Mo6I8(OOC-1-adamantane)6] revealed uncharted features applicable for the development of X-ray inducible luminescent materials and sensitizers of singlet oxygen, O2((1)Δg). The compound exhibits a red-NIR luminescence in the solid state and in solution (e.g., quantum yield of 0.76 in tetrahydrofuran) upon excitation by UV-vis light. The luminescence originating from the excited triplet states is quenched by molecular oxygen to produce O2((1)Δg) with a high quantum yield. Irradiation of the compound by X-rays generated a radioluminescence with the same emission spectrum as that obtained by UV-vis excitation. It proves the formation of the same excited triplet states regardless of the excitation source. By virtue of the described behavior, the compound is suggested as an efficient sensitizer of O2((1)Δg) upon X-ray excitation. The luminescence and radioluminescence properties were maintained upon embedding the compound in polystyrene films. In addition, polystyrene induced an enhancement of the radioluminescence intensity via energy transfer from the scintillating polymeric matrix. Sulfonated polystyrene nanofibers were used for the preparation of nanoparticles which form stable dispersions in water, while keeping intact the luminescence properties of the embedded compound over a long time period. Due to their small size and high oxygen diffusivity, these nanoparticles are suitable carriers of sensitizers of O2((1)Δg). The presented results define a new class of nanoscintillators with promising properties for X-ray inducible photodynamic therapy.

  13. Quadruple sulfur isotope constraints on the origin and cycling of volatile organic sulfur compounds in a stratified sulfidic lake

    NASA Astrophysics Data System (ADS)

    Oduro, Harry; Kamyshny, Alexey; Zerkle, Aubrey L.; Li, Yue; Farquhar, James

    2013-11-01

    We have quantified the major forms of volatile organic sulfur compounds (VOSCs) distributed in the water column of stratified freshwater Fayetteville Green Lake (FGL), to evaluate the biogeochemical pathways involved in their production. The lake's anoxic deep waters contain high concentrations of sulfate (12-16 mmol L-1) and sulfide (0.12 μmol L-1 to 1.5 mmol L-1) with relatively low VOSC concentrations, ranging from 0.1 nmol L-1 to 2.8 μmol L-1. Sulfur isotope measurements of combined volatile organic sulfur compounds demonstrate that VOSC species are formed primarily from reduced sulfur (H2S/HS-) and zero-valent sulfur (ZVS), with little input from sulfate. Thedata support a role of a combination of biological and abiotic processes in formation of carbon-sulfur bonds between reactive sulfur species and methyl groups of lignin components. These processes are responsible for very fast turnover of VOSC species, maintaining their low levels in FGL. No dimethylsulfoniopropionate (DMSP) was detected by Electrospray Ionization Mass Spectrometry (ESI-MS) in the lake water column or in planktonic extracts. These observations indicate a pathway distinct from oceanic and coastal marine environments, where dimethylsulfide (DMS) and other VOSC species are principally produced via the breakdown of DMSP by plankton species.

  14. Production of organic compounds in plasmas - A comparison among electric sparks, laser-induced plasmas, and UV light

    NASA Astrophysics Data System (ADS)

    Scattergood, T. W.; McKay, C. P.; Borucki, W. J.; Giver, L. P.; van Ghyseghem, H.; Parris, J. E.; Miller, S. L.

    1989-10-01

    In order to ascertain the features of organic compound-production in planetary atmospheres under the effects of plasmas and shocks, various mixtures of N2, CH4, and H2 modeling the atmosphere of Titan were subjected to discrete sparks, laser-induced plasmas, and UV radiation. The experimental results obtained suggest that UV photolysis from the plasma is an important organic compound synthesis process, as confirmed by the photolysis of gas samples that were exposed to the light but not to the shock waves emitted by the sparks. The thermodynamic equilibrium theory is therefore incomplete in the absence of photolysis.

  15. Production of organic compounds in plasmas - A comparison among electric sparks, laser-induced plasmas, and UV light

    NASA Technical Reports Server (NTRS)

    Scattergood, Thomas W.; Mckay, Christopher P.; Borucki, William J.; Giver, Lawrence P.; Van Ghyseghem, Hilde

    1989-01-01

    In order to ascertain the features of organic compound-production in planetary atmospheres under the effects of plasmas and shocks, various mixtures of N2, CH4, and H2 modeling the atmosphere of Titan were subjected to discrete sparks, laser-induced plasmas, and UV radiation. The experimental results obtained suggest that UV photolysis from the plasma is an important organic compound synthesis process, as confirmed by the photolysis of gas samples that were exposed to the light but not to the shock waves emitted by the sparks. The thermodynamic equilibrium theory is therefore incomplete in the absence of photolysis.

  16. Acting Role of Background Gas in the Emission Response of Laser-Induced Plasmas of Energetic Nitro Compounds.

    PubMed

    Delgado, Tomás; Vadillo, José M; Laserna, J Javier

    2016-08-01

    This study focuses on the analysis of the optical emission response obtained by laser-induced breakdown spectroscopy from energetic nitro compounds in condensed phase sampled in atmospheres of variable composition. The influence of different background gases was evaluated from the characteristic emissions of the excited species coexisting in the plasma plume and conclusions concerning the main pathways involved in the generation of such emission species were extracted. Different reactive (O2, N2, H2) and inert (Ar, He) gases were tested to establish the comparative emission features of organic compounds. PMID:27449368

  17. Protective effect of bioactive compounds from Lonicera japonica Thunb. against H2O2-induced cytotoxicity using neonatal rat cardiomyocytes

    PubMed Central

    Wang, Chen; Wang, Gang; Liu, Hong; Hou, Yun-long

    2016-01-01

    Objective(s): Pharmacological studies showed that the extracts of Jin Yin Hua and its active constituents have lipid lowering, antipyretic, hepatoprotective, cytoprotective, antimicrobial, antibiotic, antioxidative, antiviral, and anti-inflammatory effects. The purpose of the present study was to investigate the protective effects of caffeoylquinic acids (CQAs) from Jin Yin Hua against hydrogen peroxide (H2O2)-induced and hypoxia-induced cytotoxicity using neonatal rat cardiomyocytes. Materials and Methods: Seven CQAs (C1 to C7) isolated and identified from Jin Yin Hua were used to examine the effects of H2O2-induced and hypoxia-induced cytotoxicity. We studied C4 and C6 as preventative bioactive compounds of the reactive oxygen species (ROS) production, apoptotic pathway, and apoptosis-related gene expression. Results: C4 and C6 were screened as bioactive compounds to exert a cytoprotective effect against oxidative injury. Pretreatment with C4 and C6, dose-dependently attenuated hypoxia-induced ROS production and reduced the ratio of GSSG/GStotal. Western blot data revealed that the inhibitory effect of C4 on H2O2-induced up and down-regulation of Bcl-2, Bax, caspase-3, and cleaved caspase-3. Apoptosis was evaluated by detection of DNA fragmentation using TUNEL assay, and quantified with Annexin V/PI staining. Conclusion: In vitro experiments revealed that both C4 and C6 protect cardiomyocytes from necrosis and apoptosis during H2O2-induced injury, via inhibiting the generation of ROS and activation of caspase-3 apoptotic pathway. These results demonstrated that CQAs might be a class of compounds which possess potent myocardial protective activity against the ischemic heart diseases related to oxidative stress. PMID:27096070

  18. Macroalgal Morphogenesis Induced by Waterborne Compounds and Bacteria in Coastal Seawater.

    PubMed

    Grueneberg, Jan; Engelen, Aschwin H; Costa, Rodrigo; Wichard, Thomas

    2016-01-01

    Axenic gametes of the marine green macroalga Ulva mutabilis Føyn (Ria Formosa, locus typicus) exhibit abnormal development into slow-growing callus-like colonies with aberrant cell walls. Under laboratory conditions, it was previously demonstrated that all defects in growth and thallus development can be completely abolished when axenic gametes are inoculated with a combination of two specific bacterial strains originally identified as Roseobacter sp. strain MS2 and Cytophaga sp. strain MS6. These bacteria release diffusible morphogenetic compounds (= morphogens), which act similar to cytokinin and auxin. To investigate the ecological relevance of the waterborne bacterial morphogens, seawater samples were collected in the Ria Formosa lagoon (Algarve, Southern Portugal) at 20 sampling sites and tidal pools to assess their morphogenetic effects on the axenic gametes of U. mutabilis. Specifically the survey revealed that sterile-filtered seawater samples can completely recover growth and morphogenesis of U. mutabilis under axenic conditions. Morphogenetic activities of free-living and epiphytic bacteria isolated from the locally very abundant Ulva species (i.e., U. rigida) were screened using a multiwell-based testing system. The most represented genera isolated from U. rigida were Alteromonas, Pseudoalteromonas and Sulfitobacter followed by Psychrobacter and Polaribacter. Several naturally occurring bacterial species could emulate MS2 activity (= induction of cell divisions) regardless of taxonomic affiliation, whereas the MS6 activity (= induction of cell differentiation and cell wall formation) was species-specific and is probably a feature of difficult-to-culture bacteria. Interestingly, isolated bacteroidetes such as Algoriphagus sp. and Polaribacter sp. could individually trigger complete Ulva morphogenesis and thus provide a novel mode of action for bacterial-induced algal development. This study also highlights that the accumulation of algal growth factors in

  19. Macroalgal Morphogenesis Induced by Waterborne Compounds and Bacteria in Coastal Seawater

    PubMed Central

    Grueneberg, Jan; Engelen, Aschwin H.; Costa, Rodrigo; Wichard, Thomas

    2016-01-01

    Axenic gametes of the marine green macroalga Ulva mutabilis Føyn (Ria Formosa, locus typicus) exhibit abnormal development into slow-growing callus-like colonies with aberrant cell walls. Under laboratory conditions, it was previously demonstrated that all defects in growth and thallus development can be completely abolished when axenic gametes are inoculated with a combination of two specific bacterial strains originally identified as Roseobacter sp. strain MS2 and Cytophaga sp. strain MS6. These bacteria release diffusible morphogenetic compounds (= morphogens), which act similar to cytokinin and auxin. To investigate the ecological relevance of the waterborne bacterial morphogens, seawater samples were collected in the Ria Formosa lagoon (Algarve, Southern Portugal) at 20 sampling sites and tidal pools to assess their morphogenetic effects on the axenic gametes of U. mutabilis. Specifically the survey revealed that sterile-filtered seawater samples can completely recover growth and morphogenesis of U. mutabilis under axenic conditions. Morphogenetic activities of free-living and epiphytic bacteria isolated from the locally very abundant Ulva species (i.e., U. rigida) were screened using a multiwell-based testing system. The most represented genera isolated from U. rigida were Alteromonas, Pseudoalteromonas and Sulfitobacter followed by Psychrobacter and Polaribacter. Several naturally occurring bacterial species could emulate MS2 activity (= induction of cell divisions) regardless of taxonomic affiliation, whereas the MS6 activity (= induction of cell differentiation and cell wall formation) was species-specific and is probably a feature of difficult-to-culture bacteria. Interestingly, isolated bacteroidetes such as Algoriphagus sp. and Polaribacter sp. could individually trigger complete Ulva morphogenesis and thus provide a novel mode of action for bacterial-induced algal development. This study also highlights that the accumulation of algal growth factors in

  20. Fangchinoline induces G1 arrest in breast cancer cells through cell-cycle regulation.

    PubMed

    Xing, Zhibo; Zhang, Youxue; Zhang, Xianyu; Yang, Yanmei; Ma, Yuyan; Pang, Da

    2013-12-01

    Fangchinoline, an alkaloid derived from the dry roots of Stephaniae tetrandrine S. Moore (Menispermaceae), has been shown to possess cytotoxic, anti-inflammatory, and antioxidant properties. In this study, we used Fangchinoline to inhibit breast cancer cell proliferation and to investigate its underlying molecular mechanisms. Human breast cancer cell lines, MCF-7 and MDA-MB-231, were both used in this study. We found that Fangchinoline significantly decreased cell proliferation in a dose-dependent manner and induced G1-phase arrest in both cell lines. In addition, upon analysis of expression of cell cycle-related proteins, we found that Fangchinoline reduced expression of cyclin D1, cyclin D3, and cyclin E, and increased expression of the cyclin-dependent kinase (CDK) inhibitors, p21/WAF1, and p27/KIP1. Moreover, Fangchinoline also inhibited the kinase activities of CDK2, CDK4, and CDK6. These results suggest that Fangchinoline can inhibit human breast cancer cell proliferation and thus may have potential applications in cancer therapy. PMID:23401195

  1. Oncogenic Herpesvirus Utilizes Stress-Induced Cell Cycle Checkpoints for Efficient Lytic Replication.

    PubMed

    Balistreri, Giuseppe; Viiliäinen, Johanna; Turunen, Mikko; Diaz, Raquel; Lyly, Lauri; Pekkonen, Pirita; Rantala, Juha; Ojala, Krista; Sarek, Grzegorz; Teesalu, Mari; Denisova, Oxana; Peltonen, Karita; Julkunen, Ilkka; Varjosalo, Markku; Kainov, Denis; Kallioniemi, Olli; Laiho, Marikki; Taipale, Jussi; Hautaniemi, Sampsa; Ojala, Päivi M

    2016-02-01

    Kaposi's sarcoma herpesvirus (KSHV) causes Kaposi's sarcoma and certain lymphoproliferative malignancies. Latent infection is established in the majority of tumor cells, whereas lytic replication is reactivated in a small fraction of cells, which is important for both virus spread and disease progression. A siRNA screen for novel regulators of KSHV reactivation identified the E3 ubiquitin ligase MDM2 as a negative regulator of viral reactivation. Depletion of MDM2, a repressor of p53, favored efficient activation of the viral lytic transcription program and viral reactivation. During lytic replication cells activated a p53 response, accumulated DNA damage and arrested at G2-phase. Depletion of p21, a p53 target gene, restored cell cycle progression and thereby impaired the virus reactivation cascade delaying the onset of virus replication induced cytopathic effect. Herpesviruses are known to reactivate in response to different kinds of stress, and our study now highlights the molecular events in the stressed host cell that KSHV has evolved to utilize to ensure efficient viral lytic replication.

  2. The effects of rehydration on cycling performance after exercise-induced dehydration.

    PubMed

    Singh, R; Brouns, F; Kovacs, E

    2002-06-01

    The effects of 7.6% carbohydrate-electrolyte solution (CES) and placebos (P) on rehydration (R) after exercise-induced dehydration and on a subsequent time-trial (TT) of cycling performance were studied. Thirteen male subjects exercised in a thermally-controlled environment (28 degrees C, 63% RH) until 3% of their body weight was lost. After exercise, the subjects moved to a neutral environment (22 degrees C) and rested for 30 minutes prior to a 2-hour R period. During R, subjects were fed CES or P to a maximum volume of 120% of previous body mass loss at 0, 30, and 60 minutes, in bolus-doses of 50%, 40% and 30% respectively. After R, subjects performed a 1-hour TT with no further fluid intake. % R with CES was significantly higher than with P (70 +/- 3% vs 60 +/- 5%; p < 0.01). During the TT, blood glucose dropped in the CES group but not in the P group. It was found that, despite a more effective R with CES, the performance results did not differ between groups (65.1 +/- 2.2 minutes and 65.2 +/- 2.3 minutes for CES and P respectively). It is suggested that an insulin-mediated rebound effect on CHO metabolism during TT, in which no further CHO was supplied, nullified the benefits of rehydration.

  3. The role of shock induced trailing-edge separation in limit cycle oscillations

    NASA Technical Reports Server (NTRS)

    Cunningham, Atlee M., Jr.

    1989-01-01

    The potential role of shock induced trailing edge separation (SITES) in limit cycle oscillations (LCO) was established. It was shown that the flip-flop characteristics of transition to and from SITES as well as its hysteresis could couple with wing modes with torsional motion and low damping. This connection led to the formulation of a very simple nonlinear math model using the linear equations of motion with a nonlinear step forcing function with hysteresis. A finite difference solution with time was developed and calculations were made for the F-111 TACT were used to determine the step forcing function due to SITES transition. Since no data were available for the hysteresis, a parameter study was conducted allowing the hysteresis effect to vary. Very small hysteresis effects, which were within expected bounds, were required to obtain reasonable response levels that essentially agreed with flight test results. Also in agreement with wind tunnel tests, LCO calculations for the 1/6 scale F-111 model showed that the model should have not experienced LCO.

  4. Oncogenic Herpesvirus Utilizes Stress-Induced Cell Cycle Checkpoints for Efficient Lytic Replication.

    PubMed

    Balistreri, Giuseppe; Viiliäinen, Johanna; Turunen, Mikko; Diaz, Raquel; Lyly, Lauri; Pekkonen, Pirita; Rantala, Juha; Ojala, Krista; Sarek, Grzegorz; Teesalu, Mari; Denisova, Oxana; Peltonen, Karita; Julkunen, Ilkka; Varjosalo, Markku; Kainov, Denis; Kallioniemi, Olli; Laiho, Marikki; Taipale, Jussi; Hautaniemi, Sampsa; Ojala, Päivi M

    2016-02-01

    Kaposi's sarcoma herpesvirus (KSHV) causes Kaposi's sarcoma and certain lymphoproliferative malignancies. Latent infection is established in the majority of tumor cells, whereas lytic replication is reactivated in a small fraction of cells, which is important for both virus spread and disease progression. A siRNA screen for novel regulators of KSHV reactivation identified the E3 ubiquitin ligase MDM2 as a negative regulator of viral reactivation. Depletion of MDM2, a repressor of p53, favored efficient activation of the viral lytic transcription program and viral reactivation. During lytic replication cells activated a p53 response, accumulated DNA damage and arrested at G2-phase. Depletion of p21, a p53 target gene, restored cell cycle progression and thereby impaired the virus reactivation cascade delaying the onset of virus replication induced cytopathic effect. Herpesviruses are known to reactivate in response to different kinds of stress, and our study now highlights the molecular events in the stressed host cell that KSHV has evolved to utilize to ensure efficient viral lytic replication. PMID:26891221

  5. Dietary excess vanadium induces lesions and changes of cell cycle of spleen in broilers.

    PubMed

    Cui, Wei; Cui, Hengmin; Peng, Xi; Fang, Jing; Zuo, Zhicai; Liu, Xiaodong; Wu, Bangyuan

    2011-11-01

    The purpose of this 42-day study was to investigate the effects of dietary excess vanadium on spleen growth and lesions by determining morphological changes and cell cycle of spleen. Four hundred twenty 1-day-old avian broilers were divided into six groups and fed on a corn-soybean basal diet as control diet or the same diet amended to contain 5, 15, 30, 45, 60 ppm of vanadium supplied as ammonium metavanadate. When compared with that of control group, the relative weight of spleen was significantly raised in 5- and 15-ppm groups, but depressed in 45- and 60-ppm groups. The gross lesions of spleen showed obvious atrophy with decreased volume and pale color in 45- and 60-ppm groups. Histopathologically, lymphocytes in splenic corpuscle and periarterial lymphatic sheath were variously decreased in number in 30-, 45-, and 60-ppm groups. The percentage of static phase (G0/G1) was significantly decreased, and the percentage of synthesis period (S) phase and the proliferating index (PI) were significantly increased in 5- and 15-ppm groups. The percentage of G0/G1 phase was significantly increased, and the percentage of mitotic phase (G2+M), S phase, and PI significantly decreased in 45- and 60-ppm groups. These results suggested that dietary excess vanadium (45 and 60 ppm) could inhibit growth of spleen and induce lesions in spleen in chicken.

  6. Oncogenic Herpesvirus Utilizes Stress-Induced Cell Cycle Checkpoints for Efficient Lytic Replication

    PubMed Central

    Turunen, Mikko; Diaz, Raquel; Lyly, Lauri; Pekkonen, Pirita; Rantala, Juha; Ojala, Krista; Sarek, Grzegorz; Teesalu, Mari; Denisova, Oxana; Peltonen, Karita; Julkunen, Ilkka; Varjosalo, Markku; Kainov, Denis; Kallioniemi, Olli; Laiho, Marikki; Taipale, Jussi; Hautaniemi, Sampsa; Ojala, Päivi M.

    2016-01-01

    Kaposi’s sarcoma herpesvirus (KSHV) causes Kaposi’s sarcoma and certain lymphoproliferative malignancies. Latent infection is established in the majority of tumor cells, whereas lytic replication is reactivated in a small fraction of cells, which is important for both virus spread and disease progression. A siRNA screen for novel regulators of KSHV reactivation identified the E3 ubiquitin ligase MDM2 as a negative regulator of viral reactivation. Depletion of MDM2, a repressor of p53, favored efficient activation of the viral lytic transcription program and viral reactivation. During lytic replication cells activated a p53 response, accumulated DNA damage and arrested at G2-phase. Depletion of p21, a p53 target gene, restored cell cycle progression and thereby impaired the virus reactivation cascade delaying the onset of virus replication induced cytopathic effect. Herpesviruses are known to reactivate in response to different kinds of stress, and our study now highlights the molecular events in the stressed host cell that KSHV has evolved to utilize to ensure efficient viral lytic replication. PMID:26891221

  7. Cypermethrin Induces Macrophages Death through Cell Cycle Arrest and Oxidative Stress-Mediated JNK/ERK Signaling Regulated Apoptosis.

    PubMed

    Huang, Fang; Liu, Qiaoyun; Xie, Shujun; Xu, Jian; Huang, Bo; Wu, Yihua; Xia, Dajing

    2016-06-17

    Cypermethrin is one of the most highly effective synthetic pyrethroid insecticides. The toxicity of cypermethrin to the reproductive and nervous systems has been well studied. However, little is known about the toxic effect of cypermethrin on immune cells such as macrophages. Here, we investigated the cytotoxicity of cypermethrin on macrophages and the underlying molecular mechanisms. We found that cypermethrin reduced cell viability and induced apoptosis in RAW 264.7 cells. Cypermethrin also increased reactive oxygen species (ROS) production and DNA damage in a dose-dependent manner. Moreover, cypermethrin-induced G1 cell cycle arrest was associated with an enhanced expression of p21, wild-type p53, and down-regulation of cyclin D1, cyclin E and CDK4. In addition, cypermethrin treatment activated MAPK signal pathways by inducing c-Jun N-terminal kinase (JNK) and extracellular regulated protein kinases 1/2 ERK1/2 phosphorylation, and increased the cleaved poly ADP-ribose polymerase (PARP). Further, pretreatment with antioxidant N-acetylcysteine (NAC) effectively abrogated cypermethrin-induced cell cytotoxicity, G1 cell cycle arrest, DNA damage, PARP activity, and JNK and ERK1/2 activation. The specific JNK inhibitor (SP600125) and ERK1/2 inhibitor (PD98059) effectively reversed the phosphorylation level of JNK and ERK1/2, and attenuated the apoptosis. Taken together, these data suggested that cypermethrin caused immune cell death via inducing cell cycle arrest and apoptosis regulated by ROS-mediated JNK/ERK pathway.

  8. Cypermethrin Induces Macrophages Death through Cell Cycle Arrest and Oxidative Stress-Mediated JNK/ERK Signaling Regulated Apoptosis

    PubMed Central

    Huang, Fang; Liu, Qiaoyun; Xie, Shujun; Xu, Jian; Huang, Bo; Wu, Yihua; Xia, Dajing

    2016-01-01

    Cypermethrin is one of the most highly effective synthetic pyrethroid insecticides. The toxicity of cypermethrin to the reproductive and nervous systems has been well studied. However, little is known about the toxic effect of cypermethrin on immune cells such as macrophages. Here, we investigated the cytotoxicity of cypermethrin on macrophages and the underlying molecular mechanisms. We found that cypermethrin reduced cell viability and induced apoptosis in RAW 264.7 cells. Cypermethrin also increased reactive oxygen species (ROS) production and DNA damage in a dose-dependent manner. Moreover, cypermethrin-induced G1 cell cycle arrest was associated with an enhanced expression of p21, wild-type p53, and down-regulation of cyclin D1, cyclin E and CDK4. In addition, cypermethrin treatment activated MAPK signal pathways by inducing c-Jun N-terminal kinase (JNK) and extracellular regulated protein kinases 1/2 ERK1/2 phosphorylation, and increased the cleaved poly ADP-ribose polymerase (PARP). Further, pretreatment with antioxidant N-acetylcysteine (NAC) effectively abrogated cypermethrin-induced cell cytotoxicity, G1 cell cycle arrest, DNA damage, PARP activity, and JNK and ERK1/2 activation. The specific JNK inhibitor (SP600125) and ERK1/2 inhibitor (PD98059) effectively reversed the phosphorylation level of JNK and ERK1/2, and attenuated the apoptosis. Taken together, these data suggested that cypermethrin caused immune cell death via inducing cell cycle arrest and apoptosis regulated by ROS-mediated JNK/ERK pathway. PMID:27322250

  9. The Management of Drug-induced Manipulation of the Estrous Cycle in Normal Cows and Heifers

    PubMed Central

    Wenkoff, Martin S.

    1987-01-01

    Part I Prostaglandin-induced Synchronization of Estrus in Beef Cattle Prostaglandin-induced regression of the mature cyclic corpus luteum in cows and heifers triggers a sequence of physiological events that results in a return to estrus in two to five days. There are several breeding management programs based on this premise. These programs range from attempts to synchronize estrus in entire herds with two injections of prostaglandin eleven days apart and breeding artificially, to simply shortening diestrus in responsive cattle with a single injection and bullbreeding. In this paper, several programs are discussed. No single program will be successful in all situations. Programs must be modified to fit each herd and its management. The factors that most commonly lead to program failure include inadequate nutrition, short postpartum interval, and mismanagement of heifers and first-calf heifers. Part II The Synchronization of Estrus in Embryo Transfer Recipients Using Various Synchronization Compounds Approximately 1800 recipient cows were synchronized for embryo transplants in three separate trials. The response rates, distribution of estrus, cull rates, and pregnancy rates of the synchronization products were compared. The pregnancy rates in prostaglandin-induced estrus in embryo transfer recipients were found to be no different from those in recipients that were used after natural noninduced estrus. The specific prostaglandin analog fenprostalene was tested for efficacy using various combinations of route of administration and antibiotic addition. There were no adverse reactions and neither the addition of oxytetracycline nor the route of administration had any effect on estrus rate, distribution, or pregnancy rates, which were not different from those achieved with the control prostaglandin analog cloprostenol. Part III Timed Breeding in Prostaglandin-synchronized Dairy Heifers Five groups of 20 to 40 Holstein heifers were treated with two doses of cloprostenol

  10. A molecular understanding of D-homoestrone-induced G2/M cell cycle arrest in HeLa human cervical carcinoma cells.

    PubMed

    Minorics, Renáta; Bózsity, Noémi; Molnár, Judit; Wölfling, János; Mernyák, Erzsébet; Schneider, Gyula; Ocsovszki, Imre; Zupkó, István

    2015-10-01

    2-Methoxyestradiol (ME), one of the most widely investigated A-ring-modified metabolites of estrone, exerts significant anticancer activity on numerous cancer cell lines. Its pharmacological actions, including cell cycle arrest, microtubule disruption and pro-apoptotic activity, have already been described in detail. The currently tested D-ring-modified analogue of estrone, D-homoestrone, selectively inhibits cervical cancer cell proliferation and induces a G2/M phase cell cycle blockade, resulting in the development of apoptosis. The question arose of whether the difference in the chemical structures of these analogues can influence the mechanism of anticancer action. The aim of the present study was therefore to elucidate the molecular contributors of intracellular processes induced by D-homoestrone in HeLa cells. Apoptosis triggered by D-homoestrone develops through activation of the intrinsic pathway, as demonstrated by determination of the activities of caspase-8 and -9. It was revealed that D-homoestrone-treated HeLa cells are not able to enter mitosis because the cyclin-dependent kinase 1-cyclin B complex loses its activity, resulting in the decreased inactivation of stathmin and a concomitant disturbance of microtubule formation. However, unlike 2-ME, D-homoestrone does not exert a direct effect on tubulin polymerization. These results led to the conclusion that the D-homoestrone-triggered intracellular processes resulting in a cell cycle arrest and apoptosis in HeLa cells differ from those in the case of 2-ME. This may be regarded as an alternative mechanism of action among steroidal anticancer compounds.

  11. Genome-scale metabolic modeling to provide insight into the production of storage compounds during feast-famine cycles of activated sludge.

    PubMed

    Tajparast, Mohammad; Frigon, Dominic

    2013-01-01

    Studying storage metabolism during feast-famine cycles of activated sludge treatment systems provides profound insight in terms of both operational issues (e.g., foaming and bulking) and process optimization for the production of value added by-products (e.g., bioplastics). We examined the storage metabolism (including poly-β-hydroxybutyrate [PHB], glycogen, and triacylglycerols [TAGs]) during feast-famine cycles using two genome-scale metabolic models: Rhodococcus jostii RHA1 (iMT1174) and Escherichia coli K-12 (iAF1260) for growth on glucose, acetate, and succinate. The goal was to develop the proper objective function (OF) for the prediction of the main storage compound produced in activated sludge for given feast-famine cycle conditions. For the flux balance analysis, combinations of three OFs were tested. For all of them, the main OF was to maximize growth rates. Two additional sub-OFs were used: (1) minimization of biochemical fluxes, and (2) minimization of metabolic adjustments (MoMA) between the feast and famine periods. All (sub-)OFs predicted identical substrate-storage associations for the feast-famine growth of the above-mentioned metabolic models on a given substrate when glucose and acetate were set as sole carbon sources (i.e., glucose-glycogen and acetate-PHB), in agreement with experimental observations. However, in the case of succinate as substrate, the predictions depended on the network structure of the metabolic models such that the E. coli model predicted glycogen accumulation and the R. jostii model predicted PHB accumulation. While the accumulation of both PHB and glycogen was observed experimentally, PHB showed higher dynamics during an activated sludge feast-famine growth cycle with succinate as substrate. These results suggest that new modeling insights between metabolic predictions and population ecology will be necessary to properly predict metabolisms likely to emerge within the niches of activated sludge communities. Nonetheless

  12. RCC1-dependent activation of Ran accelerates cell cycle and DNA repair, inhibiting DNA damage–induced cell senescence

    PubMed Central

    Cekan, Pavol; Hasegawa, Keisuke; Pan, Yu; Tubman, Emily; Odde, David; Chen, Jin-Qiu; Herrmann, Michelle A.; Kumar, Sheetal; Kalab, Petr

    2016-01-01

    The coordination of cell cycle progression with the repair of DNA damage supports the genomic integrity of dividing cells. The function of many factors involved in DNA damage response (DDR) and the cell cycle depends on their Ran GTPase–regulated nuclear–cytoplasmic transport (NCT). The loading of Ran with GTP, which is mediated by RCC1, the guanine nucleotide exchange factor for Ran, is critical for NCT activity. However, the role of RCC1 or Ran⋅GTP in promoting cell proliferation or DDR is not clear. We show that RCC1 overexpression in normal cells increased cellular Ran⋅GTP levels and accelerated the cell cycle and DNA damage repair. As a result, normal cells overexpressing RCC1 evaded DNA damage–induced cell cycle arrest and senescence, mimicking colorectal carcinoma cells with high endogenous RCC1 levels. The RCC1-induced inhibition of senescence required Ran and exportin 1 and involved the activation of importin β–dependent nuclear import of 53BP1, a large NCT cargo. Our results indicate that changes in the activity of the Ran⋅GTP–regulated NCT modulate the rate of the cell cycle and the efficiency of DNA repair. Through the essential role of RCC1 in regulation of cellular Ran⋅GTP levels and NCT, RCC1 expression enables the proliferation of cells that sustain DNA damage. PMID:26864624

  13. Comparison of the pedalling performance induced by magnetic and electrical stimulation cycle ergometry in able-bodied subjects.

    PubMed

    Szecsi, J; Straube, A; Fornusek, C

    2014-04-01

    The purpose of the study was to compare the mechanical power and work generated by able-bodied subjects during functional magnetic stimulation (FMS) vs. functional electrical stimulation (FES) induced ergometer training conditions. Both stimulation methods were applied at a 30 Hz frequency to the quadriceps muscles of 22 healthy able-bodied subjects to induce cycling for 4× four minutes or until exhaustion. FMS was performed via large surface, cooled coils, while FES was applied with a typical stimulation setup used for cycling. Significantly more (p<10(-3)) muscular power was generated by FMS (23.8 ± 9.1W [mean ± SD]) than by FES (11.3 ± 11.3 W). Additionally, significantly more (p<10(-6)) work was produced by FMS than by FES (4.413 ± 2.209 kJ vs. 0.974 ± 1.269 kJ). The increase in the work was paralleled by a significant prolongation of time to cycling failure (181.8 ± 33.4s vs. 87.0 ± 54.0 s, respectively, p<10(-5)). Compared to FES, FMS can produce more intense and longer cycling exercise in able-bodied subjects. The differing dynamic behaviour of FMS and FES in the presented measurement setup might be related to stimulation induced pain and fatigue mechanisms of the neuromuscular system.

  14. Comparison of the pedalling performance induced by magnetic and electrical stimulation cycle ergometry in able-bodied subjects.

    PubMed

    Szecsi, J; Straube, A; Fornusek, C

    2014-04-01

    The purpose of the study was to compare the mechanical power and work generated by able-bodied subjects during functional magnetic stimulation (FMS) vs. functional electrical stimulation (FES) induced ergometer training conditions. Both stimulation methods were applied at a 30 Hz frequency to the quadriceps muscles of 22 healthy able-bodied subjects to induce cycling for 4× four minutes or until exhaustion. FMS was performed via large surface, cooled coils, while FES was applied with a typical stimulation setup used for cycling. Significantly more (p<10(-3)) muscular power was generated by FMS (23.8 ± 9.1W [mean ± SD]) than by FES (11.3 ± 11.3 W). Additionally, significantly more (p<10(-6)) work was produced by FMS than by FES (4.413 ± 2.209 kJ vs. 0.974 ± 1.269 kJ). The increase in the work was paralleled by a significant prolongation of time to cycling failure (181.8 ± 33.4s vs. 87.0 ± 54.0 s, respectively, p<10(-5)). Compared to FES, FMS can produce more intense and longer cycling exercise in able-bodied subjects. The differing dynamic behaviour of FMS and FES in the presented measurement setup might be related to stimulation induced pain and fatigue mechanisms of the neuromuscular system. PMID:24209389

  15. Epitaxial strain induced ferroelectricity in rocksalt binary compound: Hybrid functional Ab initio calculation and soft mode group theory analysis

    NASA Astrophysics Data System (ADS)

    Kim, Bog G.

    2011-05-01

    We have studied the detailed mechanism of epitaxial strain induced ferroelectricity in rocksalt binary compound by ab initio calculation and soft mode group theory analysis. By applying compressive strain, cubic binary rocksalt (F m3m) transforms into tetragonal (I 4/mmm) structure. With increasing compressive strain, tetragonal structure becomes unstable against spontaneous transformation to lower symmetry tetragonal structure (I 4/mm), evident both from ab initio calculation and from soft mode group theory analysis. For the tensile strain, phase transition sequence can be cubic binary rocksalt to tetragonal (I 4/mmm) and to orthorhombic structure (I m2m). From ab initio calculation and space group analysis, we propose that the epitaxial strain induced ferroelectricity of rocksalt binary compound is the generic property.

  16. The Promoter of Rv0560c Is Induced by Salicylate and Structurally-Related Compounds in Mycobacterium tuberculosis

    PubMed Central

    Schuessler, Dorothée L.; Parish, Tanya

    2012-01-01

    Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), is a major global health threat. During infection, bacteria are believed to encounter adverse conditions such as iron depletion. Mycobacteria synthesize iron-sequestering mycobactins, which are essential for survival in the host, via the intermediate salicylate. Salicylate is a ubiquitous compound which is known to induce a mild antibiotic resistance phenotype. In M. tuberculosis salicylate highly induces the expression of Rv0560c, a putative methyltransferase. We identified and characterized the promoter and regulatory elements of Rv0560c. PRv0560c activity was highly inducible by salicylate in a dose-dependent manner. The induction kinetics of PRv0560c were slow, taking several days to reach maximal activity, which was sustained over several weeks. Promoter activity could also be induced by compounds structurally related to salicylate, such as aspirin or para-aminosalicylic acid, but not by benzoate, indicating that induction is specific to a structural motif. The −10 and −35 promoter elements were identified and residues involved in regulation of promoter activity were identified in close proximity to an inverted repeat spanning the −35 promoter element. We conclude that Rv0560c expression is controlled by a yet unknown repressor via a highly-inducible promoter. PMID:22485172

  17. Jungermannenone A and B induce ROS- and cell cycle-dependent apoptosis in prostate cancer cells in vitro

    PubMed Central

    Guo, Yan-xia; Lin, Zhao-min; Wang, Mei-juan; Dong, Yi-wen; Niu, Huan-min; Young, Charles YF; Lou, Hong-xiang; Yuan, Hui-qing

    2016-01-01

    Aim: Jungermannenone A and B (JA, JB) are new ent-kaurane diterpenoids isolated from Chinese liverwort Jungermannia fauriana, which show anti-proliferation activities in cancer cells. In this study we investigated the mechanisms underlying the anticancer action of JA and JB in PC3 human prostate cancer cells in vitro. Methods: A panel of 9 human cancer cell lines was tested. Cell proliferation was assessed with a real-time cell analyzer and MTT assay. Cell apoptosis, cell cycle distribution and ROS levels were measured using cytometry. Mitochondrial damage was examined by transmission electron microscopy. DNA damage was detected with comet assay. Apoptotic, DNA damage- and cell cycle-related proteins were analyzed using Western blotting. The expression of DNA repair genes was measured with qRT-PCR. Results: Both JA and JB exerted potent anti-proliferative action against the 9 cancer cell lines, and PC3 cells were more sensitive with IC50 values of 1.34±0.09 and 4.93±0.20 μmol/L, respectively. JA (1.5 μmol/L) and JB (5 μmol/L) induced PC3 cell apoptosis, which was attenuated by the caspase inhibitor Z-VAD. Furthermore, both JA and JB caused mitochondrial damage and ROS accumulation in PC3 cells, whereas vitamin C blocked the ROS accumulation and attenuated the cytotoxicity of JA and JB. Moreover, both JA and JB induced DNA damage, accompanied by downregulated DNA repair proteins Ku70/Ku80 and RDA51. JA induced marked cell cycle arrest at the G0/G1 phase, which was related to c-Myc suppression, whereas JB enforced the cell cycle blockade in the G2/M phase, which associated with activation of the JNK signaling. Conclusion: Both JA and JB induce prostate cancer apoptosis via ROS accumulation and induction of cell cycle arrest. PMID:27133304

  18. Potential for ion-induced nucleation of volatile organic compounds by radon decay in indoor environments

    SciTech Connect

    Daisey, J.M. ); Hopke, P.K. )

    1993-07-01

    The theoretical potential for the formation of clusters of vapor-phase organic compounds found in indoor air around the [sup 218]PoO[sub x][sup +] ion was investigated as well as which compounds were most likely to form clusters. A compilation of measurements of indoor organic compounds has been made for future experiments and theoretical calculations by the radon research community. Forty-four volatile and semivolatile organic compounds out of the more than 300 that have been reported in indoor air were investigated. Water vapor was included for comparison. The results indicate that there is a potential for the formation of clusters of organic compounds around the [sup 218]PoO[sub x][sup +] ion. The compounds with the greatest potential for cluster formation are the volatile oxidized hydrocarbons (e.g., n-butanol, phenol, hexanal, nonanal, benzaldehyde, the ketones, and the acetates) and the semivolatile organic compounds (pentachlorophenol, nicotine, chlordane, chlorpyrifos). Although the estimated diameters are consistent with the measured diameters for the unattached fraction, the state of experimental and theoretical knowledge in this area is not sufficiently developed to judge the quantitative validity of these predictions. 48 refs., 1 fig., 5 tabs.

  19. Inhibition of pokeweed mitogen-induced B cell differentiation by compounds containing primary amine or hydrazine groups.

    PubMed Central

    de Boccardo, G; Drayer, D; Rubin, A L; Novogrodsky, A; Reidenberg, M M; Stenzel, K H

    1985-01-01

    The present study examined the effect of two drugs, which contain either an aromatic amine or hydrazine moiety and are known to induce lupus like syndromes in man (procainamide and hydralazine) and an aliphatic amine (dansylcadaverine), on pokeweed mitogen (PWM)-induced B cell production of immunoglobulin G (IgG). These compounds all inhibited IgG production and generation of IgG plaque forming cells, whereas derivatives of them, without free amine groups, had little or no effect. The compounds inhibited differentiation of B cells to plasma cells, rather than production and secretion of IgG. Mitogen free culture supernatants of peripheral blood mononuclear cells (PBM) activated by the oxidizing mitogen, neuraminidase and galactose oxidase (NAGO), prevented the inhibition of B cell maturation. Moreover, incubation of NAGO treated PBM with hydralazine prevented the production of soluble factors capable of promoting B cell maturation in the presence of hydralazine. We conclude from these studies that procainamide, hydralazine and dansylcadaverine inhibit PWM-induced B cell maturation to plasma cells by an indirect mechanism, via inhibition of production of lymphokines by helper cells. The primary amine or hydrazine group appears to be required for the inhibitory effect, since analogues of the inhibitory compounds, without primary amine groups, are non-inhibitory. PMID:3882287

  20. New pathway for the formation of metallic cubic phase Ge-Sb-Te compounds induced by an electric current.

    PubMed

    Park, Yong-Jin; Cho, Ju-Young; Jeong, Min-Woo; Na, Sekwon; Joo, Young-Chang

    2016-02-23

    The novel discovery of a current-induced transition from insulator to metal in the crystalline phase of Ge2Sb2Te5 and GeSb4Te7 have been studied by means of a model using line-patterned samples. The resistivity of cubic phase Ge-Sb-Te compound was reduced by an electrical current (~1 MA/cm(2)), and the final resistivity was determined based on the stress current density, regardless of the initial resistivity and temperature, which indicates that the conductivity of Ge-Sb-Te compound can be modulated by an electrical current. The minimum resistivity of Ge-Sb-Te materials can be achieved at high kinetic rates by applying an electrical current, and the material properties change from insulating to metallic behavior without a phase transition. The current-induced metal transition is more effective in GeSb4Te7 than Ge2Sb2Te5, which depends on the intrinsic vacancy of materials. Electromigration, which is the migration of atoms induced by a momentum transfer from charge carriers, can easily promote the rearrangement of vacancies in the cubic phase of Ge-Sb-Te compound. This behavior differs significantly from thermal annealing, which accompanies a phase transition to the hexagonal phase. This result suggests a new pathway for modulating the electrical conductivity and material properties of chalcogenide materials by applying an electrical current.

  1. New pathway for the formation of metallic cubic phase Ge-Sb-Te compounds induced by an electric current

    PubMed Central

    Park, Yong-Jin; Cho, Ju-Young; Jeong, Min-Woo; Na, Sekwon; Joo, Young-Chang

    2016-01-01

    The novel discovery of a current-induced transition from insulator to metal in the crystalline phase of Ge2Sb2Te5 and GeSb4Te7 have been studied by means of a model using line-patterned samples. The resistivity of cubic phase Ge-Sb-Te compound was reduced by an electrical current (~1 MA/cm2), and the final resistivity was determined based on the stress current density, regardless of the initial resistivity and temperature, which indicates that the conductivity of Ge-Sb-Te compound can be modulated by an electrical current. The minimum resistivity of Ge-Sb-Te materials can be achieved at high kinetic rates by applying an electrical current, and the material properties change from insulating to metallic behavior without a phase transition. The current-induced metal transition is more effective in GeSb4Te7 than Ge2Sb2Te5, which depends on the intrinsic vacancy of materials. Electromigration, which is the migration of atoms induced by a momentum transfer from charge carriers, can easily promote the rearrangement of vacancies in the cubic phase of Ge-Sb-Te compound. This behavior differs significantly from thermal annealing, which accompanies a phase transition to the hexagonal phase. This result suggests a new pathway for modulating the electrical conductivity and material properties of chalcogenide materials by applying an electrical current. PMID:26902593

  2. Impact of metal-induced degradation on the determination of pharmaceutical compound purity and a strategy for mitigation.

    PubMed

    Dotterer, Sally K; Forbes, Robert A; Hammill, Cynthia L

    2011-04-01

    Case studies are presented demonstrating how exposure to traces of transition metals such as copper and/or iron during sample preparation or analysis can impact the accuracy of purity analysis of pharmaceuticals. Some compounds, such as phenols and indoles, react with metals in the presence of oxygen to produce metal-induced oxidative decomposition products. Compounds susceptible to metal-induced decomposition can degrade following preparation for purity analysis leading to falsely high impurity results. Our work has shown even metals at levels below 0.1 ppm can negatively impact susceptible compounds. Falsely low results are also possible when the impurities themselves react with metals and degrade prior to analysis. Traces of metals in the HPLC mobile phase can lead to chromatographic artifacts, affecting the reproducibility of purity results. To understand and mitigate the impact of metal induced decomposition, a proactive strategy is presented. The pharmaceutical would first be tested for reactivity with specific transition metals in the sample solvent/diluents and in the HPLC mobile phase. If found to be reactive, alternative sample diluents and/or mobile phases with less reactive solvents or addition of a metal chelator would be explored. If unsuccessful, glassware cleaning or sample solution refrigeration could be investigated. By employing this strategy during method development, robust purity methods would be delivered to the quality control laboratories, preventing future problems from potential sporadic contamination of glassware with metals. PMID:21163601

  3. New pathway for the formation of metallic cubic phase Ge-Sb-Te compounds induced by an electric current.

    PubMed

    Park, Yong-Jin; Cho, Ju-Young; Jeong, Min-Woo; Na, Sekwon; Joo, Young-Chang

    2016-01-01

    The novel discovery of a current-induced transition from insulator to metal in the crystalline phase of Ge2Sb2Te5 and GeSb4Te7 have been studied by means of a model using line-patterned samples. The resistivity of cubic phase Ge-Sb-Te compound was reduced by an electrical current (~1 MA/cm(2)), and the final resistivity was determined based on the stress current density, regardless of the initial resistivity and temperature, which indicates that the conductivity of Ge-Sb-Te compound can be modulated by an electrical current. The minimum resistivity of Ge-Sb-Te materials can be achieved at high kinetic rates by applying an electrical current, and the material properties change from insulating to metallic behavior without a phase transition. The current-induced metal transition is more effective in GeSb4Te7 than Ge2Sb2Te5, which depends on the intrinsic vacancy of materials. Electromigration, which is the migration of atoms induced by a momentum transfer from charge carriers, can easily promote the rearrangement of vacancies in the cubic phase of Ge-Sb-Te compound. This behavior differs significantly from thermal annealing, which accompanies a phase transition to the hexagonal phase. This result suggests a new pathway for modulating the electrical conductivity and material properties of chalcogenide materials by applying an electrical current. PMID:26902593

  4. Phyllanthus spp. Induces Selective Growth Inhibition of PC-3 and MeWo Human Cancer Cells through Modulation of Cell Cycle and Induction of Apoptosis

    PubMed Central

    Tang, Yin-Quan; Jaganath, Indu Bala; Sekaran, Shamala Devi

    2010-01-01

    Background Phyllanthus is a traditional medicinal plant that has been used in the treatment of many diseases including hepatitis and diabetes. The main aim of the present work was to investigate the potential cytotoxic effects of aqueous and methanolic extracts of four Phyllanthus species (P.amarus, P.niruri, P.urinaria and P.watsonii) against skin melanoma and prostate cancer cells. Methodology/Principal Findings Phyllanthus plant appears to possess cytotoxic properties with half-maximal inhibitory concentration (IC50) values of 150–300 µg/ml for aqueous extract and 50–150 µg/ml for methanolic extract that were determined using the MTS reduction assay. In comparison, the plant extracts did not show any significant cytotoxicity on normal human skin (CCD-1127Sk) and prostate (RWPE-1) cells. The extracts appeared to act by causing the formation of a clear “ladder” fragmentation of apoptotic DNA on agarose gel, displayed TUNEL-positive cells with an elevation of caspase-3 and -7 activities. The Lactate Dehydrogenase (LDH) level was lower than 15% in Phyllanthus treated-cancer cells. These indicate that Phyllanthus extracts have the ability to induce apoptosis with minimal necrotic effects. Furthermore, cell cycle analysis revealed that Phyllanthus induced a Go/G1-phase arrest on PC-3 cells and a S-phase arrest on MeWo cells and these were accompanied by accumulation of cells in the Sub-G1 (apoptosis) phase. The cytotoxic properties may be due to the presence of polyphenol compounds such as ellagitannins, gallotannins, flavonoids and phenolic acids found both in the water and methanol extract of the plants. Conclusions/Significance Phyllanthus plant exerts its growth inhibition effect in a selective manner towards cancer cells through the modulation of cell cycle and induction of apoptosis via caspases activation in melanoma and prostate cancer cells. Hence, Phyllanthus may be sourced for the development of a potent apoptosis-inducing anticancer agent. PMID

  5. Dynamic response of UV-absorbing compounds, quantum yield and the xanthophyll cycle to diel changes in UV-B and photosynthetic radiations in an aquatic liverwort.

    PubMed

    Fabón, Gabriel; Monforte, Laura; Tomás-Las-Heras, Rafael; Núñez-Olivera, Encarnación; Martínez-Abaigar, Javier

    2012-01-01

    We studied the diel responses of the liverwort Jungermannia exsertifolia subsp. cordifolia to radiation changes under laboratory conditions. The samples were exposed to three radiation regimes: P (only PAR), PA (PAR+UV-A), and PAB (PAR+UV-A+UV-B). The day was divided in four periods: darkness, a first low-PAR period, the high-PAR plus UV period, and a second low-PAR period. After 15 days of culture, we measured photosynthetic pigments, chlorophyll fluorescence and UV-absorbing compounds in the four periods of the day on two consecutive days. With respect to UV-absorbing compounds, we analyzed their global amount (as the bulk UV absorbance of methanolic extracts) and the concentration of seven hydroxycinnamic acid derivatives, both in the soluble (mainly vacuolar) and insoluble (cell wall-bound) fractions of the plant extracts. PAB samples increased the bulk UV absorbance of the soluble and insoluble fractions, and the concentrations of p-coumaroylmalic acid in the soluble fraction and p-coumaric acid in the cell wall. Most of these variables showed significant diel changes and responded within a few hours to radiation changes (more strongly to UV-B), increasing at the end of the period of high-PAR plus UV. F(v)/F(m), Φ(PSII), NPQ and the components of the xanthophyll cycle showed significant and quick diel changes in response to high PAR, UV-A and UV-B radiation, indicating dynamic photoinhibition and protection of PSII from excess radiation through the xanthophyll cycle. Thus, the liverwort showed a dynamic protection and acclimation capacity to the irradiance level and spectral characteristics of the radiation received.

  6. Compound-specific 15N stable isotope probing of N assimilation by the soil microbial biomass: a new methodological paradigm in soil N cycling

    NASA Astrophysics Data System (ADS)

    Charteris, A. F.; Knowles, T. D. J.; Michaelides, K.; Evershed, R. P.

    2015-10-01

    A compound-specific nitrogen-15 stable isotope probing (15N-SIP) technique is described which allows investigation of the fate of inorganic- or organic-N amendments to soils. The technique uses gas chromatography-combustion-isotope ratio mass spectrometry (GC-C-IRMS) to determine the δ15N values of individual amino acids (AAs; determined as N-acetyl, O-isopropyl derivatives) as proxies of biomass protein production. The δ15N values are used together with AA concentrations to quantify N assimilation of 15N-labelled substrates by the soil microbial biomass. The utility of the approach is demonstrated through incubation experiments using inorganic 15N-labelled substrates ammonium (15NH4+) and nitrate (15NO3-) and an organic 15N-labelled substrate, glutamic acid (15N-Glu). Assimilation of all the applied substrates was undetectable based on bulk soil properties, i.e. % total N (% TN), bulk soil N isotope composition and AA concentrations, all of which remained relatively constant throughout the incubation experiments. In contrast, compound-specific AA δ15N values were highly sensitive to N assimilation, providing qualitative and quantitative insights into the cycling and fate of the applied 15N-labelled substrates. The utility of this 15N-AA-SIP technique is considered in relation to other currently available methods for investigating the microbially-mediated assimilation of nitrogenous substrates into the soil organic N pool. This approach will be generally applicable to the study of N cycling in any soil, or indeed, in any complex ecosystem.

  7. Cell cycle-dependent DNA damage signaling induced by ICRF-193 involves ATM, ATR, CHK2, and BRCA1

    SciTech Connect

    Park, Iha; Avraham, Hava Karsenty . E-mail: havraham@bidmc.harvard.edu

    2006-07-01

    Topoisomerase II is essential for cell proliferation and survival and has been a target of various anticancer drugs. ICRF-193 has long been used as a catalytic inhibitor to study the function of topoisomerase II. Here, we show that ICRF-193 treatment induces DNA damage signaling. Treatment with ICRF-193 induced G2 arrest and DNA damage signaling involving {gamma}-H2AX foci formation and CHK2 phosphorylation. DNA damage by ICRF-193 was further demonstrated by formation of the nuclear foci of 53BP1, NBS1, BRCA1, MDC1, and FANCD2 and increased comet tail moment. The DNA damage signaling induced by ICRF-193 was mediated by ATM and ATR and was restricted to cells in specific cell cycle stages such as S, G2, and mitosis including late and early G1 phases. Downstream signaling of ATM and ATR involved the phosphorylation of CHK2 and BRCA1. Altogether, our results demonstrate that ICRF-193 induces DNA damage signaling in a cell cycle-dependent manner and suggest that topoisomerase II might be essential for the progression of the cell cycle at several stages including DNA decondensation.

  8. Growth inhibition and apoptosis in cancer cells induced by polyphenolic compounds of Acacia hydaspica: Involvement of multiple signal transduction pathways

    PubMed Central

    Afsar, Tayyaba; Trembley, Janeen H.; Salomon, Christine E.; Razak, Suhail; Khan, Muhammad Rashid; Ahmed, Khalil

    2016-01-01

    Acacia hydaspica R. Parker is known for its medicinal uses in multiple ailments. In this study, we performed bioassay-guided fractionation of cytotoxic compounds from A. hydaspica and investigated their effects on growth and signaling activity in prostate and breast cancer cell lines. Four active polyphenolic compounds were identified as 7-O-galloyl catechin (GC), catechin (C), methyl gallate (MG), and catechin-3-O-gallate (CG). The four compounds inhibited prostate cancer PC-3 cell growth in a dose-dependent manner, whereas CG and MG inhibited breast cancer MDA-MB-231 cell growth. All tested compounds inhibited cell survival and colony growth in both cell lines, and there was evidence of chromatin condensation, cell shrinkage and apoptotic bodies. Further, acridine orange, ethidium bromide, propidium iodide and DAPI staining demonstrated that cell death occurred partly via apoptosis in both PC-3 and MDA-MB-231 cells. In PC-3 cells treatment repressed the expression of anti-apoptotic molecules Bcl-2, Bcl-xL and survivin, coupled with down-regulation of signaling pathways AKT, NFκB, ERK1/2 and JAK/STAT. In MDA-MB-231 cells, treatment induced reduction of CK2α, Bcl-xL, survivin and xIAP protein expression along with suppression of NFκB, JAK/STAT and PI3K pathways. Our findings suggest that certain polyphenolic compounds derived from A. hydaspica may be promising chemopreventive/therapeutic candidates against cancer. PMID:26975752

  9. Growth inhibition and apoptosis in cancer cells induced by polyphenolic compounds of Acacia hydaspica: Involvement of multiple signal transduction pathways.

    PubMed

    Afsar, Tayyaba; Trembley, Janeen H; Salomon, Christine E; Razak, Suhail; Khan, Muhammad Rashid; Ahmed, Khalil

    2016-01-01

    Acacia hydaspica R. Parker is known for its medicinal uses in multiple ailments. In this study, we performed bioassay-guided fractionation of cytotoxic compounds from A. hydaspica and investigated their effects on growth and signaling activity in prostate and breast cancer cell lines. Four active polyphenolic compounds were identified as 7-O-galloyl catechin (GC), catechin (C), methyl gallate (MG), and catechin-3-O-gallate (CG). The four compounds inhibited prostate cancer PC-3 cell growth in a dose-dependent manner, whereas CG and MG inhibited breast cancer MDA-MB-231 cell growth. All tested compounds inhibited cell survival and colony growth in both cell lines, and there was evidence of chromatin condensation, cell shrinkage and apoptotic bodies. Further, acridine orange, ethidium bromide, propidium iodide and DAPI staining demonstrated that cell death occurred partly via apoptosis in both PC-3 and MDA-MB-231 cells. In PC-3 cells treatment repressed the expression of anti-apoptotic molecules Bcl-2, Bcl-xL and survivin, coupled with down-regulation of signaling pathways AKT, NFκB, ERK1/2 and JAK/STAT. In MDA-MB-231 cells, treatment induced reduction of CK2α, Bcl-xL, survivin and xIAP protein expression along with suppression of NFκB, JAK/STAT and PI3K pathways. Our findings suggest that certain polyphenolic compounds derived from A. hydaspica may be promising chemopreventive/therapeutic candidates against cancer. PMID:26975752

  10. Arctic sea-ice melting: Effects on hydroclimatic variability and on UV-induced carbon cycling

    NASA Astrophysics Data System (ADS)

    Sulzberger, Barbara

    2016-04-01

    change on biogeochemical cycling: interactions and feedbacks, Photochemical & Photobiological Sciences, 14(1), 127-148. Francis, J. A., S. J. Vavrus (2012), Evidence linking Arctic amplification to extreme weather in mid-latitudes, Geophysical Research Letters, 39, doi: 10.1029/2012GL051000. Haaland, S., D. Hongve, H. Laudon, G. Riise, R. D. Vogt (2010), Quantifying the drivers of the increasing colored organic matter in boreal surface waters, Environmental Science & Technology, 44(8), 2975-2980. IPCC Climate Change 2013 - The Physical Science Bases (2013). Schubert, S., H. Wang, M. Suarez (2011), Warm season subseasonal variability and climate extremes in the Northern Hemisphere: The role of stationary Rossby waves, Journal of Climate, 24(18), 4773-4792. Screen, J. A. (2013), Influence of Arctic sea ice on European summer precipitation, Environmental Research Letters, 8(4), doi: 10.1088/1748-9326/8/4/044015. Sulzberger, B., E. Durisch-Kaiser (2009), Chemical characterization of dissolved organic matter (DOM): A prerequisite for understanding UV-induced changes of DOM absorption properties and bioavailability, Aquatic Sciences, 71(2), 104-126.

  11. Novel therapeutic compound tuftsin-phosphorylcholine attenuates collagen-induced arthritis.

    PubMed

    Bashi, T; Shovman, O; Fridkin, M; Volkov, A; Barshack, I; Blank, M; Shoenfeld, Y

    2016-04-01

    Treatment with helminthes and helminthes ova improved the clinical symptoms of several autoimmune diseases in patients and in animal models. Phosphorylcholine (PC) proved to be the immunomodulatory molecule. We aimed to decipher the tolerogenic potential of tuftsin-PC (TPC), a novel helminth-based compound in collagen-induced arthritis (CIA) a mouse model of rheumatoid arthritis (RA). CIA DBA/1 mice were treated with TPC subcutaneously (5 µg/0.1 ml) or orally (250 µg/0.1 ml), starting prior to disease induction. The control groups were treated with PBS. Collagen antibodies were tested by enzyme-linked immunosorbent assay (ELISA), cytokine protein levels by ELISA kits and regulatory T (Treg ) and regulatory B (Breg ) cell phenotypes by fluorescence-activated cell sorter (FACS). TPC-treated mice had a significantly lower arthritis score of 1.5 in comparison with control mice 11.8 (P < 0.0001) in both subcutaneous and orally treated groups at day 31. Moreover, histology analysis demonstrated highly inflamed joints in control mice, whereas TPC-treated mice maintained normal joint structure. Furthermore, TPC decreased the titres of circulating collagen II antibodies in mice sera (P < 0.0001), enhanced expression of IL-10 (P < 0.0001) and inhibited production of tumour necrosis factor (TNF)-α, interleukin (IL)-17 and IL-1β (P < 0.0001). TPC significantly expanded the CD4(+) CD25(+) forkhead box protein 3 (FoxP3(+) ) Treg cells and CD19(+) IL-10(+) CD5(high) CD1d(high) T cell immunoglobulin mucin-1 (TIM-1(+) ) Breg cell phenotypes (P < 0.0001) in treated mice. Our data indicate that treatment with TPC attenuates CIA in mice demonstrated by low arthritic score and normal joints histology. TPC treatment reduced proinflammatory cytokines and increased anti-inflammatory cytokine expression, as well as expansion of Treg and Breg cells. Our results may lead to a new approach for a natural therapy for early rheumatoid arthritis onset. PMID:26618631

  12. Dynamic evaluation of a regional air quality model: Assessing the emissions-induced weekly ozone cycle

    NASA Astrophysics Data System (ADS)

    Pierce, Thomas; Hogrefe, Christian; Trivikrama Rao, S.; Porter, P. Steven; Ku, Jia-Yeong

    2010-09-01

    Air quality models are used to predict changes in pollutant concentrations resulting from envisioned emission control policies. Recognizing the need to assess the credibility of air quality models in a policy-relevant context, we perform a dynamic evaluation of the Community Multiscale Air Quality (CMAQ) modeling system for the "weekend ozone effect" to determine if observed changes in ozone due to weekday-to-weekend (WDWE) reductions in precursor emissions can be accurately simulated. The weekend ozone effect offers a unique opportunity for dynamic evaluation, as it is a widely documented phenomenon that has persisted since the 1970s. In many urban areas of the Unites States, higher ozone has been observed on weekends than weekdays, despite dramatically reduced emissions of ozone precursors (nitrogen oxides [NO x] and volatile organic compounds [VOCs]) on weekends. More recent measurements, however, suggest shifts in the spatial extent or reductions in WDWE ozone differences. Using 18 years (1988-2005) of observed and modeled ozone and temperature data across the northeastern United States, we re-examine the long-term trends in the weekend effect and confounding factors that may be complicating the interpretation of this trend and explore whether CMAQ can replicate the temporal features of the observed weekend effect. The amplitudes of the weekly ozone cycle have decreased during the 18-year period in our study domain, but the year-to-year variability in weekend minus weekday (WEWD) ozone amplitudes is quite large. Inter-annual variability in meteorology appears to influence WEWD differences in ozone, as well as WEWD differences in VOC and NO x emissions. Because of the large inter-annual variability, modeling strategies using a single episode lasting a few days or a few episodes in a given year may not capture the WEWD signal that exists over longer time periods. The CMAQ model showed skill in predicting the absolute values of ozone concentrations during the

  13. Serum estradiol but not gonadotropin levels decrease acutely after insulin-induced hypoglycemia in cycling women.

    PubMed

    Bing-You, R G; Spratt, D I

    1992-10-01

    Although corticotropin-releasing hormone (CRH) acutely suppresses gonadotropin-releasing hormone (GnRH) secretion in animal models, its effect on the hypothalamic-pituitary-gonadal axis in humans is not well defined. To further evaluate the acute effects of adrenal axis activation on the hypothalamic-pituitary-gonadal axis in humans, we employed a model of insulin-induced hypoglycemia to stimulate endogenous CRH secretion in eight cycling women. Serum samples were obtained immediately before and 15, 30, 45, 60, 75, 90, and 120 min following iv insulin (0.15 U/kg) or saline injection. To ensure that the degree of hypothalamic-pituitary-adrenal activation in our subjects was similar to that observed in severely ill patients with hypogonadotropism, serum cortisol (F) levels were also measured in a group of acutely ill patients selected to have hypogonadotropism. All women experienced symptomatic hypoglycemia after insulin injection. Differences between serum F levels in hypoglycemic vs. control sessions were evident at 30 min (P < 0.01) and maximum at 120 min (P < 0.0001) after insulin injection. Serum estradiol levels were significantly lower following hypoglycemia than during control sessions (P < 0.001). In contrast, serum LH and FSH levels were not significantly different between control and hypoglycemic sessions. Peak serum F levels in these hypoglycemic women were similar to F levels in critically ill patients with hypogonadotropism. These results demonstrate that stress and/or hypoglycemia can acutely decrease circulating estradiol levels. In addition, these data suggest that endogenous CRH does not play a major role in acute suppression of GnRH (over 2 h) in humans. Further studies are required to identify longer term effects of CRH on GnRH secretion which may be present in hypothalamic amenorrhea or hypogonadotropic hypogonadism of critical illness.

  14. Cytokinin delays dark-induced senescence in rice by maintaining the chlorophyll cycle and photosynthetic complexes.

    PubMed

    Talla, Sai Krishna; Panigrahy, Madhusmita; Kappara, Saivishnupriya; Nirosha, P; Neelamraju, Sarla; Ramanan, Rajeshwari

    2016-03-01

    The phytohormone cytokinin (CK) is known to delay senescence in plants. We studied the effect of a CK analog, 6-benzyl adenine (BA), on rice leaves to understand the possible mechanism by which CK delays senescence in a drought- and heat-tolerant rice cultivar Nagina22 (N22) using dark-induced senescence (DIS) as a surrogate for natural senescence of leaves. Leaves of N22-H-dgl162, a stay-green mutant of N22, and BA-treated N22 showed retention of chlorophyll (Chl) pigments, maintenance of the Chl a/b ratio, and delay in reduction of both photochemical efficiency and rate of oxygen evolution during DIS. HPLC analysis showed accumulation of 7-hydroxymethyl chlorophyll (HmChl) during DIS, and the kinetics of its accumulation correlated with progression of senescence. Transcriptome analysis revealed that several plastid-localized genes, specifically those associated with photosystem II (PSII), showed higher transcript levels in BA-treated N22 and the stay-green mutant leaves compared with naturally senescing N22 leaves. Real-time PCR analyses showed that genes coding for enzymes associated with Chl a/b interconversion and proteins associated with light-harvesting complexes maintained higher transcript levels up to 72h of DIS following BA treatment. The pigment-protein complexes analyzed by green gel remained intact in both N22-H-dgl162 and BA-treated N22 leaves even after 96h of DIS. Thus, CK delays senescence by accumulation of HmChl and up-regulating genes in the Chl cycle, thereby maintaining the Chl a/b ratio. Also, CK treatment retains higher transcript levels of PSII-related genes, resulting in the stability of photosynthetic pigment complexes and functional stay-greenness in rice. PMID:26826216

  15. Hypoxia Inducible Factor 1 Alpha Is Expressed in Germ Cells throughout the Murine Life Cycle

    PubMed Central

    Gardner, Lauren H.; Mathews, Juanita; Yamazaki, Yuki; Allsopp, Richard C.

    2016-01-01

    Pluripotent stem cells of the early embryo, and germ line cells, are essential to ensure uncompromised development to adulthood as well as species propagation, respectively. Recently, the transcription factor hypoxia inducible factor 1 alpha (Hif1α) has been shown to have important roles in embryonic stem cells; in particular, regulation of conversion to glycolytic metabolism and, as we have shown, maintenance of functional levels of telomerase. In the present study, we sought to assess whether Hif1α was also expressed in the primitive cells of the murine embryo. We observed expression of Hif1α in pre-implantation embryos, specifically the 2-cell stage, morula, and blastocyst. Robust Hif1α expression was also observed in male and female primordial germ cells. We subsequently assessed whether Hif1α was expressed in adult male and female germ cells. In the testis, Hif1α was robustly expressed in spermatogonial cells, in both juvenile (6-week old) and adult (3-month old) males. In the ovaries, Hif1α was expressed in mature oocytes from adult females, as assessed both in situ and in individual oocytes flushed from super-ovulated females. Analysis of Hif1α transcript levels indicates a mechanism of regulation during early development that involves stockpiling of Hif1α protein in mature oocytes, presumably to provide protection from hypoxic stress until the gene is re-activated at the blastocyst stage. Together, these observations show that Hif1α is expressed throughout the life-cycle, including both the male and female germ line, and point to an important role for Hif1α in early progenitor cells. PMID:27148974

  16. Prognostic Value of Chemotherapy-Induced Neutropenia at the First Cycle in Invasive Breast Cancer

    PubMed Central

    Ma, Rui-Min; Chen, Chuan-Zhi; Zhang, Wei; You, Jie; Huang, Du-Ping; Guo, Gui-Long

    2016-01-01

    Abstract Chemotherapy-induced neutropenia (CIN) was the most apparent side effects of bone marrow suppression with adjuvant chemotherapy. Recently, several studies revealed that CIN may predict better outcomes. However, the researches upon breast cancer were still indefinite. We reviewed the female patients with pathologically diagnosed invasive breast cancer at the First Affiliated Hospital of Wenzhou Medical University, between Jan 2008 and Dec 2010. The lowest neutrophil counts in the second week after the first cycle of chemotherapy were collected. Clinicopathological characteristics and survival rates were compared and analyzed between the CIN group and non-CIN group. The median follow-up time was 62 months. The differences of over-all survival and local recurrence-free survival between the 2 groups were nonsense (P = 0.938, P = 0.695, respectively). But the disease-free survival and distant metastasis-free survival of the CIN group were statically significantly better (HR = 0.391, P = 0.009, and HR = 0.315, P = 0.005, respectively). The bone metastasis-free survival may be responsible for the differences (HR = 0.469, P = 0.005). Subgroup analyses showed the CIN may predict lower bone metastases rates with ER positive status, premenopause or younger age (≤ 40) (P = 0.002, P = 0.004, and P = 0.0001, respectively). Cox analysis showed younger ages, N staging, and the presence of CIN were associated with bone metastasis-free survival independently adjusting to peritumoral vascular invasion (P < 0.05). CIN may predict a decreased recurrence risk of breast cancer, especially bone metastases. PMID:27043697

  17. Cytokinin delays dark-induced senescence in rice by maintaining the chlorophyll cycle and photosynthetic complexes

    PubMed Central

    Talla, Sai Krishna; Panigrahy, Madhusmita; Kappara, Saivishnupriya; Nirosha, P; Neelamraju, Sarla; Ramanan, Rajeshwari

    2016-01-01

    The phytohormone cytokinin (CK) is known to delay senescence in plants. We studied the effect of a CK analog, 6-benzyl adenine (BA), on rice leaves to understand the possible mechanism by which CK delays senescence in a drought- and heat-tolerant rice cultivar Nagina22 (N22) using dark-induced senescence (DIS) as a surrogate for natural senescence of leaves. Leaves of N22-H-dgl162, a stay-green mutant of N22, and BA-treated N22 showed retention of chlorophyll (Chl) pigments, maintenance of the Chl a/b ratio, and delay in reduction of both photochemical efficiency and rate of oxygen evolution during DIS. HPLC analysis showed accumulation of 7-hydroxymethyl chlorophyll (HmChl) during DIS, and the kinetics of its accumulation correlated with progression of senescence. Transcriptome analysis revealed that several plastid-localized genes, specifically those associated with photosystem II (PSII), showed higher transcript levels in BA-treated N22 and the stay-green mutant leaves compared with naturally senescing N22 leaves. Real-time PCR analyses showed that genes coding for enzymes associated with Chl a/b interconversion and proteins associated with light-harvesting complexes maintained higher transcript levels up to 72h of DIS following BA treatment. The pigment–protein complexes analyzed by green gel remained intact in both N22-H-dgl162 and BA-treated N22 leaves even after 96h of DIS. Thus, CK delays senescence by accumulation of HmChl and up-regulating genes in the Chl cycle, thereby maintaining the Chl a/b ratio. Also, CK treatment retains higher transcript levels of PSII-related genes, resulting in the stability of photosynthetic pigment complexes and functional stay-greenness in rice. PMID:26826216

  18. Factors of force potentiation induced by stretch-shortening cycle in plantarflexors.

    PubMed

    Fukutani, Atsuki; Kurihara, Toshiyuki; Isaka, Tadao

    2015-01-01

    Muscle force is potentiated by countermovement; this phenomenon is called stretch-shortening cycle (SSC) effect. In this study, we examined the factors strongly related to SSC effect in vivo, focusing on tendon elongation, preactivation, and residual force enhancement. Twelve healthy men participated in this study. Ankle joint angle was passively moved by a dynamometer, with a range of motion from 15° dorsiflexion (DF) to 15° plantarflexion (PF). Muscle contraction was evoked by electrical stimulation, with stimulation timing adjusted to elicit three types of contraction: (1) concentric contraction without preliminary contraction (CON), (2) concentric contraction after preliminary eccentric contraction (ECC), and (3) concentric contraction after preliminary isometric contraction (ISO). Joint torque was recorded at DF5°, PF0°, and PF5°, respectively. SSC effect was calculated as the ratio of joint torque obtained in ECC or ISO with respect to that obtained in CON at the aforementioned three joint angles. SSC effect was prominent in the first half of movement in both ECC (DF5°, 329.3 ± 101.2%; PF0°, 159.2 ± 29.4%; PF5°, 125.5 ± 20.8%) and ISO (DF5°, 276.4 ± 87.0%; PF0°, 134.5 ± 24.5%; PF5°, 106.8 ± 18.0%) conditions. SSC effect was significantly larger in ECC than in ISO at all joint angles (P < 0.001). Even without preliminary eccentric contraction (i.e., ISO condition), SSC effect was clearly large, indicating that a significant part of SSC effect is derived from preactivation. However, the active lengthening-induced force potentiation mechanism (residual force enhancement) also contributes to SSC effect.

  19. Phospholipid hydroperoxide glutathione peroxidase induces a delay in G1 of the cell cycle.

    PubMed

    Wang, Hong P; Schafer, Freya Q; Goswami, Prabhat C; Oberley, Larry W; Buettner, Garry R

    2003-06-01

    Phospholipid hydroperoxide glutathione peroxidase (PhGPx) is an antioxidant enzyme that reduces cellular phospholipid hydroperoxides (PLOOHs) to alcohols. Cellular peroxide tone has been implicated in cell growth and differentiation. By reducing the PLOOH level in the cell membrane, PhGPx regulates the peroxide tone and thereby might be involved in cell growth. We hypothesized that overexpression of PhGPx in human breast cancer cells would decrease their growth rate. We stably transfected MCF-7 cells (Wt) with L-PhGPx and measured cell doubling time, plating efficiency, and cell cycle phase transit times. P-4 cells (8-fold increase in PhGPx activity) showed a 2-fold increase in doubling time; doubling time increased directly with PhGPx activity (r = 0.95). The higher the PhGPx activity, the lower the plating efficiency (r = -0.86). The profile of other antioxidant enzymes was unchanged. Overexpression of PhGPx lowered the steady-state level of PLOOH (by > 60%). Results from bromodeoxyuridine pulse-chase experiments and flow cytometry indicate that PhGPx induced a delay in MCF-7 proliferation that was primarily due to a slower progression from G1 to S. These results support the hypothesis that PhGPx plays a regulatory role in the progression of MCF-7 cells from G1 to S possibly by regulating the steady-state levels of PLOOH. These data suggest that PhGPx can lower the peroxide tone, which might change the cellular redox environment resulting in a delay in G1 transit. Thus, PhGPx could be an important factor in cell growth. PMID:12868489

  20. Vitamin A deficiency increases protein catabolism and induces urea cycle enzymes in rats.

    PubMed

    Esteban-Pretel, Guillermo; Marín, M Pilar; Cabezuelo, Francisco; Moreno, Verónica; Renau-Piqueras, Jaime; Timoneda, Joaquín; Barber, Teresa

    2010-04-01

    Chronic vitamin A deficiency induces a substantial delay in the rates of weight and height gain in both humans and experimental animals. This effect has been associated with an impaired nutrient metabolism and loss of body protein. Therefore, we analyzed the effect of vitamin A deficiency on endogenous proteolysis and nitrogen metabolism and its reversibility with all-trans retinoic acid (RA). Male weanling rats, housed in pairs, were pair-fed a vitamin A-deficient (VAD) or control diet until they were 60 d old. A group of deficient rats were further treated with daily intraperitoneal injections of all-trans RA for 10 d. Final body and tissue (i.e. liver and heart) weights were significantly lower and tissue:body weight ratios were similar in VAD rats and in controls. Conversely, the epididymal white fat:body weight ratio and the plasma concentrations of alanine aminotransferase and adiponectin were significantly higher in VAD rats, which also had hepatic macrovesicular lipid accumulations. Plasma and gastrocnemius muscle 3-methylhistidine, urine nitrogen, and plasma and urine urea concentrations were all significantly higher in the VAD group. The expression of the genes encoding urea cycle enzymes and their activities increased in VAD livers. These changes were partially reverted by all-trans RA. We propose that fuel partitioning in vitamin A deficiency may shift from fatty acids to protein catabolism as an energy source. Our results emphasize the importance of vitamin A on the energy balance control system and they provide an explanation for the role of vitamin A in protein turnover, development, and growth.

  1. Compound 49b Prevents Diabetes-Induced Apoptosis through Increased IGFBP-3 Levels

    PubMed Central

    Zhang, Qiuhua; Guy, Kimberly; Pagadala, Jayaprakash; Jiang, Youde; Walker, Robert J; Liu, Luhong; Soderland, Carl; Kern, Timothy S; Ferry, Robert; He, Hui; Yates, C. Ryan; Miller, Duane D; Steinle, Jena J

    2012-01-01

    Purpose. To determine whether Compound 49b, a novel PKA-activating drug, can prevent diabetic-like changes in the rat retina through increased insulin-like growth factor binding protein-3 (IGFBP-3) levels. Methods. For the cell culture studies, we used both human retinal endothelial cells (REC) and retinal Müller cells in either 5 mM (normal) or 25 mM (high) glucose. Cells were treated with 50 nM Compound 49b alone of following treatment with protein kinase A (PKA) siRNA or IGFBP-3 siRNA. Western blotting and ELISA analyses were done to verify PKA and IGFBP-3 knockdown, as well as to measure apoptotic markers. For animal studies, we used streptozotocin-treated rats after 2 and 8 months of diabetes. Some rats were treated topically with 1 mM Compound 49b. Analyses were done for retinal thickness, cell numbers in the ganglion cell layer, pericyte ghosts, and numbers of degenerate capillaries, as well as electroretinogram and heart morphology. Results. Compound 49b requires active PKA and IGFBP-3 to prevent apoptosis of REC. Compound 49b significantly reduced the numbers of degenerate capillaries and pericyte ghosts, while preventing the decreased retinal thickness and loss of cells in the ganglion cell layer. Compound 49b maintained a normal electroretinogram, with no changes in blood pressure, intraocular pressure, or heart morphological changes. Conclusions. Topical Compound 49b is able to prevent diabetic-like changes in the rat retina, without producing systemic changes. Compound 49b is able to prevent REC apoptosis through increasing IGFBP-3 levels, which are reduced in response to hyperglycemia. PMID:22467575

  2. An Ingenol Derived from Euphorbia kansui Induces Hepatocyte Cytotoxicity by Triggering G0/G1 Cell Cycle Arrest and Regulating the Mitochondrial Apoptosis Pathway in Vitro.

    PubMed

    Yan, Xiaojing; Zhang, Li; Cao, Yudan; Yao, Weifeng; Tang, Yuping; Ding, Anwei

    2016-01-01

    Natural product lingenol, a purified diterpenoid compound derived from the root of Euphorbia kansui, exerts serious hepatotoxicity; however, the molecular mechanisms remain to be defined. In the present study, cell counting Kit-8 (CCK-8), inverted phase contrast microscope and flow cytometry were used to demonstrate that lingenol significantly inhibited L-O2 cells proliferation, and induced cell cycle arrest and apoptosis. Moreover, the results investigated that lingenol markedly disrupted mitochondrial functions by high content screening (HCS). In addition, the up-regulation of cytochrome c, AIF and Apaf-1 and activation of caspases were found in L-O2 cells detected by Western blotting and ELISA assay, which was required for lingenol activation of cytochrome c-mediated caspase cascades and AIF-mediated DNA damage. Mechanistic investigations revealed that lingenol significantly down-regulated the Bcl-2/Bax ratio and enhanced the reactive oxygen species (ROS) in L-O2 cells. These data collectively indicated that lingenol modulation of ROS and Bcl-2/Bax ratio led to cell cycle arrest and mitochondrial-mediated apoptosis in L-O2 cells in vitro. All of these results will be helpful to reveal the hepatotoxicity mechanism of Euphorbia kansui and to effectively guide safer and better clinical application of this herb. PMID:27338329

  3. Pravastatin induces cell cycle arrest and decreased production of VEGF and bFGF in multiple myeloma cell line.

    PubMed

    Trojan, P J J; Bohatch-Junior, M S; Otuki, M F; Souza-Fonseca-Guimarães, F; Svidnicki, P V; Nogaroto, V; Fernandes, D; Krum, E A; Favero, G M

    2016-02-01

    Multiple myeloma (MM) is a B cell bone marrow neoplasia characterized by inflammation with an intense secretion of growth factors that promote tumor growth, cell survival, migration and invasion. The aim of this study was to evaluate the effects of pravastatin, a drug used to reduce cholesterol, in a MM cell line.Cell cycle and viability were determinate by Trypan Blue and Propidium Iodide. IL6, VEGF, bFGF and TGFβ were quantified by ELISA and qRT-PCR including here de HMG CoA reductase. It was observed reduction of cell viability, increase of cells in G0/G1 phase of the cell cycle and reducing the factors VEGF and bFGF without influence on 3-Methyl-Glutaryl Coenzyme A reductase expression.The results demonstrated that pravastatin induces cell cycle arrest in G0/G1 and decreased production of growth factors in Multiple Myeloma cell line. PMID:26909624

  4. Plumbagin induces cell cycle arrest and autophagy and suppresses epithelial to mesenchymal transition involving PI3K/Akt/mTOR-mediated pathway in human pancreatic cancer cells

    PubMed Central

    Wang, Feng; Wang, Qi; Zhou, Zhi-Wei; Yu, Song-Ning; Pan, Shu-Ting; He, Zhi-Xu; Zhang, Xueji; Wang, Dong; Yang, Yin-Xue; Yang, Tianxing; Sun, Tao; Li, Min; Qiu, Jia-Xuan; Zhou, Shu-Feng

    2015-01-01

    Plumbagin (PLB), an active naphthoquinone compound, has shown potent anticancer effects in preclinical studies; however, the effect and underlying mechanism of PLB for the treatment of pancreatic cancer is unclear. This study aimed to examine the pancreatic cancer cell killing effect of PLB and investigate the underlying mechanism in human pancreatic cancer PANC-1 and BxPC-3 cells. The results showed that PLB exhibited potent inducing effects on cell cycle arrest in PANC-1 and BxPC-3 cells via the modulation of cell cycle regulators including CDK1/CDC2, cyclin B1, cyclin D1, p21 Waf1/Cip1, p27 Kip1, and p53. PLB treatment concentration- and time-dependently increased the percentage of autophagic cells and significantly increased the expression level of phosphatase and tensin homolog, beclin 1, and the ratio of LC3-II over LC3-I in both PANC-1 and BxPC-3 cells. PLB induced inhibition of phosphatidylinositol 3-kinase (PI3K)/protein kinase B/mammalian target of rapamycin and p38 mitogen-activated protein kinase (p38 MAPK) pathways and activation of 5′-AMP-dependent kinase as indicated by their altered phosphorylation, contributing to the proautophagic activities of PLB in both cell lines. Furthermore, SB202190, a selective inhibitor of p38 MAPK, and wortmannin, a potent, irreversible, and selective PI3K inhibitor, remarkably enhanced PLB-induced autophagy in PANC-1 and BxPC-3 cells, indicating the roles of PI3K and p38 MAPK mediated signaling pathways in PLB-induced autophagic cell death in both cell lines. In addition, PLB significantly inhibited epithelial to mesenchymal transition phenotype in both cell lines with an increase in the expression level of E-cadherin and a decrease in N-cadherin. Moreover, PLB treatment significantly suppressed the expression of Sirt1 in both cell lines. These findings show that PLB promotes cell cycle arrest and autophagy but inhibits epithelial to mesenchymal transition phenotype in pancreatic cancer cells with the involvement of

  5. Natural compound oblongifolin C inhibits autophagic flux, and induces apoptosis and mitochondrial dysfunction in human cholangiocarcinoma QBC939 cells

    PubMed Central

    Zhang, Aiqing; He, Wei; Shi, Huimin; Huang, Xiaodan; Ji, Guozhong

    2016-01-01

    The compounds, which are obtained from natural plants or microbes may offer potential as one of the strategies for the management of cholangiocarcinoma. Oblongifolin C (OC), a natural small molecule compound extracted and purified from Garcinia yunnanensis Hu, can activate the mitochondrial apoptotic pathway in human cervical cancer cells. However, the direct effects of OC on cholangiocarcinoma cells are not well defined. The effect of OC on cell apoptosis and its underlying mechanisms were investigated in cultured QBC939 cells by the methyl thiazol tetrazolium assay, mitochondrial membrane potential, ATP content and western blot analysis. The present study reported that the in vitro treatment of human cholangiocarcinoma QBC939 cells with different concentrations (5, 10, 20 and 40 μM) of OC decreased cell viability and induced apoptosis in a dose-dependent manner. The results of the present study also showed that OC-induced QBC939 cell apoptosis was mediated through the inhibition of autophagy and mitochondrial dysfunction (MtD). Additionally, inhibiting autophagy increased OC-induced apoptosis and MtD, whereas exposure to the autophagy inducer, rapmycin, attenuated these changes. Together, the results of the present study are the first, to the best of our knowledge, to identify OC as a chemotherapeutic agent against human cholangiocarcinoma QBC939 cells in vitro via the regulation of autophagy and MtD. PMID:27499017

  6. Inactivation of HDAC1 or HDAC2 induces gamma globin expression without altering cell cycle or proliferation.

    PubMed

    Esrick, Erica B; McConkey, Marie; Lin, Katherine; Frisbee, Alyse; Ebert, Benjamin L

    2015-07-01

    Other than hydroxyurea, no pharmacologic agents are clinically available for fetal hemoglobin (HbF) induction in sickle cell disease (SCD). An optimal candidate would induce HbF without causing cell cycle inhibition and would act independently of hydroxyurea in order to yield additional HbF induction when combined. We explored whether inhibition of histone deacetylase (HDAC) 1 or HDAC2 could achieve these goals. In human erythroid progenitor cells, shRNA knockdown of the HDAC1 or HDAC2 genes induced gamma globin, without altering cellular proliferation in vitro, and without altering cell cycle phase. Treatment with hydroxyurea in combination with HDAC2 knockdown yielded a further increase in gamma globin expression. Additionally, when CD34+ cells were treated with both hydroxyurea and MS-275 (an inhibitor of HDAC 1, 2, and 3), an additive induction of relative gamma globin expression was achieved. Our findings support further clinical investigation of HDAC inhibitors in combination with hydroxyurea in SCD patients.

  7. Restraint stress-induced central monoaminergic & oxidative changes in rats & their prevention by novel Ocimum sanctum compounds

    PubMed Central

    Ahmad, Ausaf; Rasheed, Naila; Chand, Kailash; Maurya, Rakesh; Banu, Naheed; Palit, Gautam

    2012-01-01

    Background & objectives: Ocimum sanctum (OS) is known to possess various therapeutic properties. We have earlier isolated and characterized three OS compounds; Ocimarin, Ocimumoside A and Ocimumoside B. However, their role in modulating stress-induced central changes is unexplored. Thus, the present study was aimed to investigate the effect of these OS compounds on restraint stress (RS)-induced changes in the monoaminergic and antioxidant systems in the frontal cortex, striatum and hippocampus of rats. Methods: RS was produced by immobilizing (restraining) the Sprague Dawley rats for a period of 2.5 h inside cylindrical steel tubes. The monoamine levels and the in vivo antioxidant status in brain regions were evaluated by HPLC-EC and spectrophotometric assays, respectively. Results: RS significantly increased the dopamine levels in the frontal cortex and decreased in the striatum and hippocampus, and accompanied with selective increase of dopamine metabolites compared to the NS control group. The serotonin and its metabolite levels were significantly increased, while noradrenaline levels were decreased by RS in the three brain regions studied. The activities of superoxide dismutase and glutathione peroxidase in the frontal cortex and striatum were significantly increased by RS with decreased glutathione levels and increased lipid peroxidation. Pre-treatment with Ocimumoside A and B (40 mg/kg po) for a period of 3 days prevented the RS-induced changes with an efficacy similar to that of standard anti-stress (Panax quinquefolium; 100 mg/kg po) and antioxidant (Melatonin; 20 mg/kg ip) drugs, while, Ocimarin failed to modulate these changes. OS compounds per se had no effect on these parameters. Interpretation & conclusions: The present findings showed the anti-stress potential of Ocimumoside A and B in relation to their simultaneous modulatory effects on the central monoaminergic and antioxidant systems implicating their therapeutic importance in stress

  8. The nonstructural protein NP1 of human bocavirus 1 induces cell cycle arrest and apoptosis in Hela cells

    SciTech Connect

    Sun, Bin; Cai, Yingyue; Li, Yongshu; Li, Jingjing; Liu, Kaiyu; Li, Yi; Yang, Yongbo

    2013-05-25

    Human bocavirus type 1 (HBoV1) is a newly identified pathogen associated with human respiratory tract illnesses. Previous studies demonstrated that proteins of HBoV1 failed to cause cell death, which is considered as a possible common feature of bocaviruses. However, our work showed that the NP1 of HBoV1 induced apoptotic cell death in Hela cells in the absence of viral genome replication and expression of other viral proteins. Mitochondria apoptotic pathway was involved in the NP1-induced apoptosis that was confirmed by apoptotic characteristics including morphological changes, DNA fragmentation and caspase activation. We also demonstrated that the cell cycle of NP1-transfected Hela cells was transiently arrested at G2/M phase followed by rapid appearance of apoptosis and that the N terminal domain of NP1 was critical to its nuclear localization and function in apoptosis induction in Hela cells. These findings might provide alternative information for further study of mechanism of HBoV1 pathogenesis. - Highlights: ► NP1 protein of HBoV1 induced apoptosis in Hela cells was first reported. ► NP1 induced-apoptosis followed the cell cycle arrest at G2/M phase. ► The NP1 induced-apoptosis was mediated by mitochondrion apoptotic pathway. ► N terminal of NP1 was critical for apoptosis induction and nuclear localization.

  9. H4 Histamine Receptors Mediate Cell Cycle Arrest in Growth Factor-Induced Murine and Human Hematopoietic Progenitor Cells

    PubMed Central

    Petit-Bertron, Anne-France; Machavoine, François; Defresne, Marie Paule; Gillard, Michel; Chatelain, Pierre; Mistry, Prakash

    2009-01-01

    The most recently characterized H4 histamine receptor (H4R) is expressed preferentially in the bone marrow, raising the question of its role during hematopoiesis. Here we show that both murine and human progenitor cell populations express this receptor subtype on transcriptional and protein levels and respond to its agonists by reduced growth factor-induced cell cycle progression that leads to decreased myeloid, erythroid and lymphoid colony formation. H4R activation prevents the induction of cell cycle genes through a cAMP/PKA-dependent pathway that is not associated with apoptosis. It is mediated specifically through H4R signaling since gene silencing or treatment with selective antagonists restores normal cell cycle progression. The arrest of growth factor-induced G1/S transition protects murine and human progenitor cells from the toxicity of the cell cycle-dependent anticancer drug Ara-C in vitro and reduces aplasia in a murine model of chemotherapy. This first evidence for functional H4R expression in hematopoietic progenitors opens new therapeutic perspectives for alleviating hematotoxic side effects of antineoplastic drugs. PMID:19662098

  10. The effect of intense interval cycle-training on unloading-induced dysfunction and atrophy in the human calf muscle.

    PubMed

    Hotta, Norio; Ishida, Koji; Sato, Kohei; Koike, Teruhiko; Katayama, Keisho; Akima, Hiroshi

    2011-01-01

    We investigated whether intense interval training on a cycle ergometer would prevent loss of muscle strength and atrophy in the human calf during unilateral lower limb suspension (ULLS). The present study involved 11 healthy men. We defined unloading leg and contralateral leg as ULLS-leg and CONT-leg, respectively. The subjects were divided into 2 groups: one with single-leg cycling training (Tr-UL, n=6); the other as a control (UL, n=5). The Tr-UL group performed an intense 25-min interval cycling training up to 80% of peak oxygen uptake on alternate days during 20-d ULLS. It was found that: 1) in maximal voluntary contraction (MVC) and the cross-sectional area of the planter flexor, there was a significant time- (pre-ULLS and post-ULLS) by-leg (ULLS-leg and CONT-leg) interaction; 2) in voluntary activation during MVC evaluated by the twitch interpolation technique, no significant time-by-leg interaction was detected but the trend of change from before to after ULLS tended to be different between ULLS-leg and CONT-leg; and 3) regarding ULLS-leg, the change in any parameters was not significantly different between the Tr-UL and UL groups. These results suggest that unloading induces dysfunction and atrophy in the human calf and that high-intensity interval training on a cycle ergometer cannot significantly prevent unloading-induced deconditioning in the human calf.

  11. Rapid response of the steatosis-sensing hepatokine LECT2 during diet-induced weight cycling in mice.

    PubMed

    Chikamoto, Keita; Misu, Hirofumi; Takayama, Hiroaki; Kikuchi, Akihiro; Ishii, Kiyo-Aki; Lan, Fei; Takata, Noboru; Tajima-Shirasaki, Natsumi; Takeshita, Yumie; Tsugane, Hirohiko; Kaneko, Shuichi; Matsugo, Seiichi; Takamura, Toshinari

    2016-09-23

    Dieting often leads to body weight cycling involving repeated weight loss and regain. However, little information is available regarding rapid-response serum markers of overnutrition that predict body weight alterations during weight cycling. Here, we report the rapid response of serum leukocyte cell-derived chemotaxin 2 (LECT2), a hepatokine that induces insulin resistance in skeletal muscle, during diet-induced weight cycling in mice. A switch from a high-fat diet (HFD) to a regular diet (RD) in obese mice gradually decreased body weight but rapidly decreased serum LECT2 levels within 10 days. In contrast, a switch from a RD to a HFD rapidly elevated serum LECT2 levels. Serum LECT2 levels showed a positive correlation with liver triglyceride contents but not with adipose tissue weight. This study demonstrates the rapid response of LECT2 preceding body weight alterations during weight cycling in mice and suggests that measurement of serum LECT2 may be clinically useful in the management of obesity. PMID:27562717

  12. Organic compounds characteristics associated with heat-induced increases of water repellency in Australian eucalypt forest soils

    NASA Astrophysics Data System (ADS)

    Atanassova, Irena; Doerr, Stefan H.

    2010-05-01

    Ground surface heating during wildfires often leads to increased water repellency in soils. The effect of elevated soil temperature on water repellency has been investigated in many laboratory-based studies and temperature thresholds for increases in, and destruction of, water repellency have been established. However, little is known about the changes in organic compounds patterns and their chemical structure that associated with these changes. Here we report on the characterisation of the chemical changes of organic compounds associated with heat-induced increases in water repellency in Eucalypt soils of different repellency levels. Fires are very common in eucalypt forest environments and soils under eucalypt species exhibit one of the most severe repellency levels, providing an ideal study case. Three SE Australian eucalypt forest soils from different locations (two sands and one sandy loam) were heated in the laboratory for 10 min at 300° C. Laboratory heating resulted in extreme repellency in the three soils studied. Heated and unheated control samples were then extracted by accelerated solvent extraction (ASE) with iso-propanol/ammonia mixture (IPA/NH3 95:5). Extraction led to the elimination of any water repellency present both in the original (heated) and the control samples. Organic compounds in the IPA/NH3 solvent were measured in extracts of increasing polarity in order to solubilise the residue. Before heating, the total solvent extracts from the soils with sandy texture were dominated by n-alkanols, terpenoids, C16 acid, C29 alkane, β-sitosterol and polar compounds such as glycerol, monosaccharides and glycosides. Fatty acids with chain length over C20 were detected in the sandy soils, while the soil of heavier texture (sandy loam) lacked longer than C20 fatty acids and had lower concentrations of alkanols (exceeding C26 chain lenght) and alkanes (C29, C31). Alkane patterns were characterized by the predominance of C21 - C31 homologues with a

  13. Recently Confirmed Apoptosis-Inducing Lead Compounds Isolated from Marine Sponge of Potential Relevance in Cancer Treatment

    PubMed Central

    Essack, Magbubah; Bajic, Vladimir B.; Archer, John A.C.

    2011-01-01

    Despite intense efforts to develop non-cytotoxic anticancer treatments, effective agents are still not available. Therefore, novel apoptosis-inducing drug leads that may be developed into effective targeted cancer therapies are of interest to the cancer research community. Targeted cancer therapies affect specific aberrant apoptotic pathways that characterize different cancer types and, for this reason, it is a more desirable type of therapy than chemotherapy or radiotherapy, as it is less harmful to normal cells. In this regard, marine sponge derived metabolites that induce apoptosis continue to be a promising source of new drug leads for cancer treatments. A PubMed query from 01/01/2005 to 31/01/2011 combined with hand-curation of the retrieved articles allowed for the identification of 39 recently confirmed apoptosis-inducing anticancer lead compounds isolated from the marine sponge that are selectively discussed in this review. PMID:22131960

  14. Photoperiod and aggression induce changes in ventral gland compounds exclusively in male Siberian hamsters.

    PubMed

    Rendon, Nikki M; Soini, Helena A; Scotti, Melissa-Ann L; Weigel, Ellen R; Novotny, Milos V; Demas, Gregory E

    2016-05-01

    Chemical communication is a critical component of social behavior as it facilitates social encounters, allows for evaluation of the social partner, defines territories and resources, and advertises information such as sex and physiological state of an animal. Odors provide a key source of information about the social environment to rodents; however, studies identifying chemical compounds have thus far focused primarily on few species, particularly the house mouse. Moreover, considerably less attention has been focused on how environmental factors, reproductive phenotype, and behavioral context alter these compounds outside of reproduction. We examined the effects of photoperiod, sex, and social context on chemical communication in the seasonally breeding Siberian hamster. We sampled ventral gland secretions in both male and female hamsters before and after an aggressive encounter and identified changes in a range of volatile compounds. Next, we investigated how photoperiod, reproductive phenotype, and aggression altered ventral gland volatile compound composition across the sexes. Males exhibited a more diverse chemical composition, more sex-specific volatiles, and showed higher levels of excretion compared to females. Individual volatiles were also differentially excreted across photoperiod and reproductive phenotype, as well as differentially altered in response to an aggressive encounter. Female volatile compound composition, in contrast, did not differ across photoperiods or in response to aggression. Collectively, these data contribute to a greater understanding of context-dependent changes in chemical communication in a seasonally breeding rodent.

  15. Photoperiod and aggression induce changes in ventral gland compounds exclusively in male Siberian hamsters.

    PubMed

    Rendon, Nikki M; Soini, Helena A; Scotti, Melissa-Ann L; Weigel, Ellen R; Novotny, Milos V; Demas, Gregory E

    2016-05-01

    Chemical communication is a critical component of social behavior as it facilitates social encounters, allows for evaluation of the social partner, defines territories and resources, and advertises information such as sex and physiological state of an animal. Odors provide a key source of information about the social environment to rodents; however, studies identifying chemical compounds have thus far focused primarily on few species, particularly the house mouse. Moreover, considerably less attention has been focused on how environmental factors, reproductive phenotype, and behavioral context alter these compounds outside of reproduction. We examined the effects of photoperiod, sex, and social context on chemical communication in the seasonally breeding Siberian hamster. We sampled ventral gland secretions in both male and female hamsters before and after an aggressive encounter and identified changes in a range of volatile compounds. Next, we investigated how photoperiod, reproductive phenotype, and aggression altered ventral gland volatile compound composition across the sexes. Males exhibited a more diverse chemical composition, more sex-specific volatiles, and showed higher levels of excretion compared to females. Individual volatiles were also differentially excreted across photoperiod and reproductive phenotype, as well as differentially altered in response to an aggressive encounter. Female volatile compound composition, in contrast, did not differ across photoperiods or in response to aggression. Collectively, these data contribute to a greater understanding of context-dependent changes in chemical communication in a seasonally breeding rodent. PMID:26944610

  16. Platelet-activating factor induces cell cycle arrest and disrupts the DNA damage response in mast cells

    PubMed Central

    Puebla-Osorio, N; Damiani, E; Bover, L; Ullrich, S E

    2015-01-01

    Platelet-activating factor (PAF) is a potent phospholipid modulator of inflammation that has diverse physiological and pathological functions. Previously, we demonstrated that PAF has an essential role in ultraviolet (UV)-induced immunosuppression and reduces the repair of damaged DNA, suggesting that UV-induced PAF is contributing to skin cancer initiation by inducing immune suppression and also affecting a proper DNA damage response. The exact role of PAF in modulating cell proliferation, differentiation or transformation is unclear. Here, we investigated the mechanism(s) by which PAF affects the cell cycle and impairs early DNA damage response. PAF arrests proliferation in transformed and nontransformed human mast cells by reducing the expression of cyclin-B1 and promoting the expression of p21. PAF-treated cells show a dose-dependent cell cycle arrest mainly at G2–M, and a decrease in the DNA damage response elements MCPH1/BRIT-1 and ataxia telangiectasia and rad related (ATR). In addition, PAF disrupts the localization of p-ataxia telangiectasia mutated (p-ATM), and phosphorylated-ataxia telangiectasia and rad related (p-ATR) at the site of DNA damage. Whereas the potent effect on cell cycle arrest may imply a tumor suppressor activity for PAF, the impairment of proper DNA damage response might implicate PAF as a tumor promoter. The outcome of these diverse effects may be dependent on specific cues in the microenvironment. PMID:25950475

  17. Luteolin induces cell cycle arrest and apoptosis through extrinsic and intrinsic signaling pathways in MCF-7 breast cancer cells.

    PubMed

    Park, Su-Ho; Ham, Sunyoung; Kwon, Tae Ho; Kim, Man Sub; Lee, Dong Hun; Kang, Jeoung-Woo; Oh, Sei-Ryang; Yoon, Do-Young

    2014-01-01

    Luteolin is a common flavonoid that exists in medicinal herbs, fruits, and vegetables. Luteolin has biochemical functions including anti-allergy, anti-inflammation, and anti-cancer functions. However, its efficacy and precise mode of action against breast cancer are still under study. To elucidate whether luteolin exhibits an anticancer effect in breast cancer, MCF-7 breast cancer cells were incubated with luteolin, and apoptosis was assessed by observing nuclear morphological changes and by performing cell viability assay, cell cycle analysis, annexin V-FITC/PI double staining, western blotting, RT-PCR, and mitochondrial membrane potential measurements. Luteolin inhibited growth through perturbation of cell cycle progression at the sub-G1 and G1 phases in MCF-7 cells. Furthermore, luteolin enhanced the expression of death receptors, such as DR5, and activated caspase cascades. It enhanced the activities of caspase-8/-9/-3 in a dose-dependent manner, followed by inactivation of PARP. Activation of caspase-8 and caspase-9 induced caspase-3 activity, respectively, in apoptosis of extrinsic and intrinsic pathways. Luteolin also induced mitochondrial membrane potential collapse and cytochrome c release, and increased Bax expression by inhibiting expression of Bcl-2. Taken together, these results suggest that luteolin provokes cell cycle arrest and induces apoptosis by activating the extrinsic and intrinsic pathways. PMID:25272060

  18. Honokiol, a chemopreventive agent against skin cancer, induces cell cycle arrest and apoptosis in human epidermoid A431 cells.

    PubMed

    Chilampalli, Chandeshwari; Guillermo, Ruth; Kaushik, Radhey S; Young, Alan; Chandrasekher, Gudiseva; Fahmy, Hesham; Dwivedi, Chandradhar

    2011-11-01

    Honokiol is a plant lignan isolated from bark and seed cones of Magnolia officinalis. Recent studies from our laboratory indicated that honokiol pretreatment decreased ultraviolet B-induced skin cancer development in SKH-1 mice. The aim of the present investigation was to study the effects of honokiol on human epidermoid squamous carcinoma A431 cells and to elucidate possible mechanisms involved in preventing skin cancer. A431 cells were pretreated with different concentrations of honokiol for a specific time period and investigated for effects on apoptosis and cell cycle analysis. Treatment with honokiol significantly decreased cell viability and cell proliferation in a concentration- and time-dependent manner. Honokiol pretreatment at 50 μmol/L concentration induced G0/G1 cell cycle arrest significantly (P < 0.05) and decreased the percentage of cells in the S and G2/M phase. Honokiol down-regulated the expression of cyclin D1, cyclin D2, Cdk2, Cdk4 and Cdk6 proteins and up-regulated the expression of Cdk's inhibitor proteins p21 and p27. Pretreatment of A431 cells with honokiol leads to induction of apoptosis and DNA fragmentation. These findings indicate that honokiol provides its effects in squamous carcinoma cells by inducing cell cycle arrest at G0/G1 phase and apoptosis.

  19. Honokiol, a chemopreventive agent against skin cancer, induces cell cycle arrest and apoptosis in human epidermoid A431 cells.

    PubMed

    Chilampalli, Chandeshwari; Guillermo, Ruth; Kaushik, Radhey S; Young, Alan; Chandrasekher, Gudiseva; Fahmy, Hesham; Dwivedi, Chandradhar

    2011-11-01

    Honokiol is a plant lignan isolated from bark and seed cones of Magnolia officinalis. Recent studies from our laboratory indicated that honokiol pretreatment decreased ultraviolet B-induced skin cancer development in SKH-1 mice. The aim of the present investigation was to study the effects of honokiol on human epidermoid squamous carcinoma A431 cells and to elucidate possible mechanisms involved in preventing skin cancer. A431 cells were pretreated with different concentrations of honokiol for a specific time period and investigated for effects on apoptosis and cell cycle analysis. Treatment with honokiol significantly decreased cell viability and cell proliferation in a concentration- and time-dependent manner. Honokiol pretreatment at 50 μmol/L concentration induced G0/G1 cell cycle arrest significantly (P < 0.05) and decreased the percentage of cells in the S and G2/M phase. Honokiol down-regulated the expression of cyclin D1, cyclin D2, Cdk2, Cdk4 and Cdk6 proteins and up-regulated the expression of Cdk's inhibitor proteins p21 and p27. Pretreatment of A431 cells with honokiol leads to induction of apoptosis and DNA fragmentation. These findings indicate that honokiol provides its effects in squamous carcinoma cells by inducing cell cycle arrest at G0/G1 phase and apoptosis. PMID:21908486

  20. Protective effects of the compounds isolated from the seed of Psoralea corylifolia on oxidative stress-induced retinal damage

    SciTech Connect

    Kim, Kyung-A; Shim, Sang Hee; Ahn, Hong Ryul; Jung, Sang Hoon

    2013-06-01

    The mechanism underlying glaucoma remains controversial, but apoptosis caused by increased levels of reactive oxygen species (ROS) is thought to play a role in its pathogenesis. We investigated the effects of compounds isolated from Psoralea corylifolia on oxidative stress-induced cell death in vitro and in vivo. Transformed retinal ganglion cells (RGC-5) were treated with L-buthione-(S,R)-sulfoximine (BSO) and glutamate in the presence or with pre-treatment with compound 6, bakuchiol isolated from P. corylifolia. We observed reduced cell death in cells pre-treated with bakuchiol. Moreover, bakuchiol inhibited the oxidative stress-induced decrease of mitochondrial membrane potential (MMP, ΔΨm). Furthermore, while intracellular Ca{sup 2+} was high in RGC-5 cells after exposure to oxidative stress, bakuchiol reduced these levels. In an in vivo study, in which rat retinal damage was induced by intravitreal injection of N-methyl-D-aspartate (NMDA), bakuchiol markedly reduced translocation of AIF and release of cytochrome c, and inhibited up-regulation of cleaved caspase-3, cleaved caspase-9, and cleaved PARP. The survival rate of retinal ganglion cells (RGCs) 7 days after optic nerve crush (ONC) in mice was significantly decreased; however, bakuchiol attenuated the loss of RGCs. Moreover, bakuchiol attenuated ONC-induced up-regulation of apoptotic proteins, including cleaved PARP, cleaved caspase-3, and cleaved caspase-9. Bakuchiol also significantly inhibited translocation of mitochondrial AIF into the nuclear fraction and release of mitochondrial cytochrome c into the cytosol. These results demonstrate that bakuchiol isolated from P. corylifolia has protective effects against oxidative stress-induced retinal damage, and may be considered as an agent for treating or preventing retinal degeneration. - Highlights: • Psoralea corylifolia have neuroprotective effects in vitro and in vivo. • Bakuchiol attenuated the increase of apoptotic proteins induced by oxidative

  1. Nanowired drug delivery of antioxidant compound H-290/51 enhances neuroprotection in hyperthermia-induced neurotoxicity.

    PubMed

    Muresanu, Dafin F; Sharma, Aruna; Tian, Z Ryan; Smith, Mark A; Sharma, Hari Shanker

    2012-02-01

    Nanoparticles from the environment or through industrial sources can induce profound alterations in human health, often leading to brain dysfunction. However, it is still unclear whether nanoparticle intoxication could also alter the physiological or pathological responses of additional brain injury, stress response or disease processes. Military personals engaged in combat or peacekeeping operations are often exposed to nanoparticles from various environmental sources, e.g., Ag, Cu, Si, C, Al. In addition, these military personals are often exposed to high environmental heat, or gun and missle explosion injury leading to head or spinal trauma. Thus it is likely that additional CNS injury or stress-induced pathophysiological processes are influenced by nanoparticle intoxication. In this situation, when a combination of nanoparticles and central nervous system (CNS) injury or stress exist together, drug therapy needed to correct these anomalies may not work as effectively as in normal situation. Previous studies from our laboratory show that nanoparticle-intoxicated animals when subjected to hyperthermia resulted in exacerbation of brain pathology. In these animals, antioxidant compounds, e.g., H-290/51 that inhibits free radical formation and induces marked neuroprotection in normal rats after heat stress, failed to protect brain damage when a combination of nanoparticles and heat exposure was used. However, nanowired H-290/51 resulted in better neuroprotection in nanoparticles intoxicated animals after heat stress. Interestingly, high doses of the normal compound induced some neuroprotection in these nanoparticle-treated, heat-stressed rats. These observations suggest that a combination of nanoparticles and heat stress is dangerous and in such situations modification of drug dosage is needed to achieve comparable neuroprotection. In this review possible mechanisms of nanoparticle-induced exacerbation of heat induced neurotoxicity and brain protection achieved by

  2. Inducing myoblast re-entry into the cell cycle: a potential mechanism for laser-enhanced skeletal muscle regeneration

    NASA Astrophysics Data System (ADS)

    Liu, T.; Fang, Y.; Zhang, C. P.; Chen, P.; Wang, C. Z.; Kang, H. X.; Shen, B. J.; Liang, J.; Fu, X. B.

    2014-09-01

    This study investigated the effect of low-level laser irradiation (LLLI) on the cell cycle and proliferative activity of cultured myoblasts, and sought to elucidate the possible cellular mechanism by which LLLI promotes the regeneration of skeletal muscle in vivo. Primary myoblasts isolated from rat hindlegs were irradiated with helium-neon laser light at different energy densities. Distributions of cell-cycle subpopulations and the expression of cell-cycle regulatory proteins in myoblasts were assessed using flow cytometric analysis and western blot assay. It was found that laser irradiation stimulated cell-cycle entry; induced the expression of cyclin A and cyclin D; and increased cell proliferation index and bromodeoxyuridine incorporation as compared to the unirradiated control cells, indicating LLLI augmented the number of proliferative myoblasts in the S phase and G2/M phase of the cell cycle. These results suggest that LLLI at certain fluxes and wavelengths could activate quiescent myoblasts, leading to cell division and facilitating new myofiber formation. This could contribute to the improvement of skeletal muscle regeneration following trauma and myopathic diseases.

  3. K562 cells display different vulnerability to H₂O₂ induced oxidative stress in differing cell cycle phases.

    PubMed

    Akcakaya, Handan; Dal, Fulya; Tok, Sabiha; Cinar, Suzan-Adin; Nurten, Rustem

    2015-02-01

    Oxidative stress can be defined as the increase of oxidizing agents like reactive oxygen and nitrogen species, or the imbalance between the antioxidative defense mechanism and oxidants. Cell cycle checkpoint response can be defined as the arrest of the cell cycle functioning after damaging chemical exposure. This temporary arrest may be a period of time given to the cells to repair the DNA damage before entering the cycle again and completing mitosis. In order to determine the effects of oxidative stress on several cell cycle phases, human erytroleukemia cell line (K562) was synchronized with mimosine and genistein, and cell cycle analysis carried out. Synchronized cells were exposed to oxidative stress with hydrogen peroxide (H2O2) at several concentrations and different times. Changes on mitochondria membrane potential (ΔΨm) of K562 cells were analyzed in G1, S, and G2 /M using Rhodamine 123 (Rho 123). To determine apoptosis and necrosis, stressed cells were stained with Annexin V (AnnV) and propidium iodide (PI) for flow cytometry. Changes were observed in the ΔΨm of synchronized and asynchronized cells that were exposed to oxidative stress. Synchronized cells in S phase proved resistant to the effects of oxidative stress and synchronized cells at G2 /M phase were sensitive to the effects of H2O2 -induced oxidative stress at 500 μM and above.

  4. Ethanol extract of Innotus obliquus (Chaga mushroom) induces G1 cell cycle arrest in HT-29 human colon cancer cells

    PubMed Central

    Lee, Hyun Sook; Kim, Eun Ji

    2015-01-01

    BACKGROUND/OBJECTIVES Inonotus obliquus (I. obliquus, Chaga mushroom) has long been used as a folk medicine to treat cancer. In the present study, we examined whether or not ethanol extract of I. obliquus (EEIO) inhibits cell cycle progression in HT-29 human colon cancer cells, in addition to its mechanism of action. MATERIALS/METHODS To examine the effects of Inonotus obliquus on the cell cycle progression and the molecular mechanism in colon cancer cells, HT-29 human colon cancer cells were cultured in the presence of 2.5 - 10 µg/mL of EEIO, and analyzed the cell cycle arrest by flow cytometry and the cell cycle controlling protein expression by Western blotting. RESULTS Treatment cells with 2.5 - 10 µg/mL of EEIO reduced viable HT-29 cell numbers and DNA synthesis, increased the percentage of cells in G1 phase, decreased protein expression of CDK2, CDK4, and cyclin D1, increased expression of p21, p27, and p53, and inhibited phosphorylation of Rb and E2F1 expression. Among I. obliquus fractions, fraction 2 (fractionated by dichloromethane from EEIO) showed the same effect as EEIO treatment on cell proliferation and cell cycle-related protein levels. CONCLUSIONS These results demonstrate that fraction 2 is the major fraction that induces G1 arrest and inhibits cell proliferation, suggesting I. obliquus could be used as a natural anti-cancer ingredient in the food and/or pharmaceutical industry. PMID:25861415

  5. Acute photo-induced toxicity and toxicokinetics of single compounds and mixtures of polycyclic aromatic hydrocarbons in zebrafish.

    PubMed

    Willis, Alison M; Oris, James T

    2014-09-01

    The present study examined photo-induced toxicity and toxicokinetics for acute exposure to selected polycyclic aromatic hydrocarbons (PAHs) in zebrafish. Photo-enhanced toxicity from co-exposure to ultraviolet (UV) radiation and PAHs enhanced the toxicity and exhibited toxic effects at PAH concentrations orders of magnitude below effects observed in the absence of UV. Because environmental exposure to PAHs is usually in the form of complex mixtures, the present study examined the photo-induced toxicity of both single compounds and mixtures of PAHs. In a sensitive larval life stage of zebrafish, acute photo-induced median lethal concentrations (LC50s) were derived for 4 PAHs (anthracene, pyrene, carbazole, and phenanthrene) to examine the hypothesis that phototoxic (anthracene and pyrene) and nonphototoxic (carbazole and phenanthrene) pathways of mixtures could be predicted from single exposures. Anthracene and pyrene were phototoxic as predicted; however, carbazole exhibited moderate photo-induced toxicity and phenanthrene exhibited weak photo-induced toxicity. The toxicity of each chemical alone was used to compare the toxicity of mixtures in binary, tertiary, and quaternary combinations of these PAHs, and a predictive model for environmental mixtures was generated. The results indicated that the acute toxicity of PAH mixtures was additive in phototoxic scenarios, regardless of the magnitude of photo-enhancement. Based on PAH concentrations found in water and circumstances of high UV dose to aquatic systems, there exists potential risk of photo-induced toxicity to aquatic organisms.

  6. Radiation-induced crystalline-to-amorphous transition in intermetallic compounds of the Cu-Ti alloy system

    SciTech Connect

    Lam, N.Q.; Okamoto, P.R.; Devanathan, R. ); Sabochick, M.J. . Computer Applications Div.)

    1992-02-01

    Recent progress in molecular-dynamics studies of radiation-induced crystalline-to-amorphous transition in the ordered intermetallic compounds of the Cu-Ti system is discussed. The effect of irradiation was simulated by the generation of Frenkel pairs,which resulted in both the formation of stable point defects and chemical disorder upon defect recombination. The thermodynamic, structural and mechanical responses of the compounds during irradiation were determined by monitoring changes in the system potential energy, volume expansion, pair correlation function, diffraction patterns, and elastic constants. It was found that the intermetallics Cu{sub 4}Ti{sub 3}, CuTi, and CuTi{sub 2} could be rendered amorphous by the creation of Frenkel pairs, but Cu{sub 4}Ti could not, consistent with experimental observations during electron irradiation. However, the simulations showed that Cu{sub 4}Ti did become amorphous when clusters of Frenkel pairs were introduced, indicating that this compound may be susceptible to amorphization by heavy-ion bombardment. A generalization of the Lindemann criterion was used to develop a thermodynamic description of solid-state amorphization as a disorder- induced melting process.

  7. Salvinorin A analogues PR-37 and PR-38 attenuate compound 48/80-induced itch responses in mice

    PubMed Central

    Salaga, M; Polepally, P R; Zielinska, M; Marynowski, M; Fabisiak, A; Murawska, N; Sobczak, K; Sacharczuk, M; Do Rego, J C; Roth, B L; Zjawiony, J K; Fichna, J

    2015-01-01

    Background and Purpose The opioid system plays a crucial role in several physiological processes in the CNS and in the periphery. It has also been shown that selective opioid receptor agonists exert potent inhibitory action on pruritus and pain. In this study we examined whether two analogues of Salvinorin A, PR-37 and PR-38, exhibit antipruritic properties in mice. Experimental Approach To examine the antiscratch effect of PR-37 and PR-38 we used a mouse model of compound 48/80-induced pruritus. In order to elucidate the mechanism of action of tested compounds, specific antagonists of opioid and cannabinoid receptors were used. The effect of PR-37 on the CNS was assessed by measuring motor parameters and exploratory behaviours in mice. Key Results PR-37 and PR-38, jnjected s.c., significantly reduced the number of compound 48/80-induced scratching behaviours in mice in a dose- and time-dependent manner. PR-38 was also active when orally administered. The antiscratch activity of PR-37 was blocked by the selective κ opioid receptor antagonist, nor-binaltorphimine, and that of PR-38 by the selective μ opioid receptor antagonist, β-funaltrexamine. Conclusion and Implications In conclusion, a novel framework for the development of new antipruritic drugs derived from salvinorin A has been validated. PMID:26040667

  8. Impact of brine-induced stratification on the glacial carbon cycle

    NASA Astrophysics Data System (ADS)

    Bouttes, N.; Paillard, D.; Roche, D. M.

    2010-04-01

    During the cold period of the Last Glacial Maximum (LGM, about 21 000 years ago) atmospheric CO2 was around 190 ppm (Monnin et al., 2001), much lower than the pre-industrial concentration of 280 ppm. The causes of this substantial drop remain partially unresolved, despite intense research. Understanding the origin of reduced atmospheric CO2 during glacial times is crucial to comprehend the evolution of the different carbon reservoirs within the Earth system (atmosphere, terrestrial biosphere and ocean). In this context, the ocean is believed to play a major role as it can store large amounts of carbon (Sigman and Boyle, 2000), especially in the abyss, which is a carbon reservoir that is thought to have expanded during glacial times. To create this larger reservoir, one possible mechanism is to produce very dense glacial waters, thereby stratifying the deep ocean and reducing the carbon exchange between the deep and surface ocean (Paillard and Parrenin, 2004). The existence of such very dense waters has been inferred in the LGM deep Atlantic from sediment pore water salinity (Adkins et al., 2002). Based on these observations, we study the impact of a brine mechanism on the glacial carbon cycle. This mechanism relies on the formation and rapid sinking of brines, very salty water released during sea ice formation, which brings salty dense water down to the bottom of the ocean. It provides two major features: a direct link from the surface to the deep ocean along with an efficient way of setting a strong stratification. We show with the CLIMBER-2 coupled carbon-climate model (Petoukhov et al., 2000) that such a brine mechanism can account for a significant decrease in atmospheric CO2 and contribute to the glacial-interglacial change. This mechanism can be amplified by low vertical diffusion resulting from the brine-induced stratification. The results obtained substantially improve the modeled glacial distribution of oceanic δ13C as well as the deep ocean salinity in

  9. microRNA-449a functions as a tumor suppressor in neuroblastoma through inducing cell differentiation and cell cycle arrest

    PubMed Central

    Zhao, Zhenze; Ma, Xiuye; Sung, Derek; Li, Monica; Kosti, Adam; Lin, Gregory; Chen, Yidong; Pertsemlidis, Alexander; Hsiao, Tzu-Hung; Du, Liqin

    2015-01-01

    microRNA-449a (miR-449a) has been identified to function as a tumor suppressor in several types of cancers. However, the role of miR-449a in neuroblastoma has not been intensively investigated. We recently found that the overexpression of miR-449a significantly induces neuroblastoma cell differentiation, suggesting its potential tumor suppressor function in neuroblastoma. In this study, we further investigated the mechanisms underlying the tumor suppressive function of miR-449a in neuroblastoma. We observed that miR-449a inhibits neuroblastoma cell survival and growth through 2 mechanisms—inducing cell differentiation and cell cycle arrest. Our comprehensive investigations on the dissection of the target genes of miR-449a revealed that 3 novel targets- MFAP4, PKP4 and TSEN15 -play important roles in mediating its differentiation-inducing function. In addition, we further found that its function in inducing cell cycle arrest involves down-regulating its direct targets CDK6 and LEF1. To determine the clinical significance of the miR-449a-mediated tumor suppressive mechanism, we examined the correlation between the expression of these 5 target genes in neuroblastoma tumor specimens and the survival of neuroblastoma patients. Remarkably, we noted that high tumor expression levels of all the 3 miR-449a target genes involved in regulating cell differentiation, but not the target genes involved in regulating cell cycle, are significantly correlated with poor survival of neuroblastoma patients. These results suggest the critical role of the differentiation-inducing function of miR-449a in determining neuroblastoma progression. Overall, our study provides the first comprehensive characterization of the tumor-suppressive function of miR-449a in neuroblastoma, and reveals the potential clinical significance of the miR-449a-mediated tumor suppressive pathway in neuroblastoma prognosis. PMID:25760387

  10. UV-B-induced DNA damage mediates expression changes of cell cycle regulatory genes in Arabidopsis root tips.

    PubMed

    Jiang, Lei; Wang, Yan; Björn, Lars Olof; Li, Shaoshan

    2011-04-01

    Even though a number of studies have shown that UV-B radiation inhibits plant growth and regulates the cell cycle progress, little is known about the molecular and cellular mechanisms. Here, we developed a synchronous root-tip cell system to investigate expression changes of cell cycle marker genes and DNA damage under UV-B radiation. Expression analysis of cell cycle marker genes revealed that G1-to-S transition in root-tip cells was accomplished within 6 h. In the in vivo synchronous root-tip cells, high level of UV-B radiation (0.45 W m(-2)) induced expression changes of the cell cycle regulatory genes. Genes involved in G1-to-S transition, Histone H4 and E2Fa, were down-regulated by UV-B radiation during 2-6 h; whereas transcripts for KRP2, a negative regulator of G1-to-S transition, were up-regulated by UV-B at 2 h. The peak time for transcript level of CYCD3;1, a positive factor in G1-to-S transition, was delayed by UV-B radiation. Interestingly, a medium level of UV-B radiation (0.25 W m(-2)) did not change the expression of these genes in root tip cells from wild type. However, cell cycle regulatory genes were greatly affected in uvh1 mutant, which exhibited higher content of cyclobutane pyrimidine dimers (CPDs). Ascorbic acid treatment did not change the expression pattern of cell cycle regulatory genes that were affected by high-level UV-B. Our results implied that UV-B-induced DNA damage results in the delay of G1-to-S transition of plant cell cycle. UV-B-induced G1-to-S arrest may be a protective mechanism that prevents cells with damaged DNA from dividing and may explain the plant growth inhibition under increased solar UV-B radiation.

  11. Overexpression of GSTA2 protects against cell cycle arrest and apoptosis induced by the DNA inter-strand crosslinking nitrogen mustard, mechlorethamine.

    PubMed

    Xie, Jingping; Shults, Keith; Flye, Leanne; Jiang, Fen; Head, David R; Briggs, Robert C

    2005-05-15

    The effectiveness of bifunctional alkylating nitrogen mustard compounds in chemotherapy is related to their ability to form DNA inter-strand crosslinks. Patients exposed to DNA inter-strand crosslinking (ICL) agents subsequently experience an elevated incidence of myelodysplastic syndromes (MDS) and MDS related acute myeloid leukemia. Fanconi's anemia (FA) patients are deficient in the repair of crosslink DNA damage and they experience a high incidence of MDS. These observations indicate that hematopoietic cells are specific target for the transforming effects of DNA crosslinking damage. Changes in transcript levels were characterized in human hematopoietic cells occurring in response to the nitrogen mustard, mechlorethamine (HN2), but not in response to monofunctional analogs. Only modest changes in a few gene transcripts were detected in HL60 cells exposed to levels of HN2 tittered to maximal dose that caused growth suppression with minimal cell death and allowed eventual resumption of normal cell growth. Under conditions of transient growth suppression, a subset of glutathione-S-transferase (GST) isoenzyme genes was consistently upregulated three to fourfold by HN2, but not by monofunctional analogs. Subsequent efforts to confirm the changes detected by microarray analyses revealed an unexpected dependence on treatment conditions. The GST alpha class A2 subfamily member transcripts were upregulated 24 h after a 1 h exposure to HN2 that caused an extensive, but transient block in late S/G2 cell cycle phase, but were minimally altered with continuous exposure. The 1-h exposure to HN2 caused a transient late S/G2 cell cycle arrest in both the HL-60 cell line and the Colo 320HSR human colon cancer cell line. Overexpression of GSTA2 by transient transfection protected Colo 320HSR cells against both cycle arrest and apoptosis following exposure to HN2. Overexpression of GSTA2 in Colo 320HSR cells induced after exposure to HN2 did not alter cycle arrest or apoptosis

  12. Cell cycle arrest induced by MPPa-PDT in MDA-MB-231 cells

    NASA Astrophysics Data System (ADS)

    Liang, Liming; Bi, Wenxiang; Tian, Yuanyuan

    2016-05-01

    Photodynamic therapy (PDT) is a medical treatment using a photosensitizing agent and light source to treat cancers. Pyropheophorbidea methyl ester (MPPa), a derivative of chlorophyll, is a novel potent photosensitizer. To learn more about this photosensitizer, we examined the cell cycle arrest in MDA-MB-231. Cell cycle and apoptosis were measured by flow cytometer. Checkpoints of the cell cycle were measured by western blot. In this study, we found that the expression of Cyclin D1 was obviously decreased, while the expression of Chk2 and P21 was increased after PDT treatment. This study showed that MPPa-PDT affected the checkpoints of the cell cycle and led the cells to apoptosis.

  13. Thrombospondin-1 signaling through CD47 inhibits cell cycle progression and induces senescence in endothelial cells

    PubMed Central

    Gao, Qi; Chen, Kexin; Gao, Lu; Zheng, Yang; Yang, Yong-Guang

    2016-01-01

    CD47 signaling in endothelial cells has been shown to suppress angiogenesis, but little is known about the link between CD47 and endothelial senescence. Herein, we demonstrate that the thrombospondin-1 (TSP1)-CD47 signaling pathway is a major mechanism for driving endothelial cell senescence. CD47 deficiency in endothelial cells significantly improved their angiogenic function and attenuated their replicative senescence. Lack of CD47 also suppresses activation of cell cycle inhibitors and upregulates the expression of cell cycle promoters, leading to increased cell cycle progression. Furthermore, TSP1 significantly accelerates replicative senescence and associated cell cycle arrest in a CD47-dependent manner. These findings demonstrate that TSP1-CD47 signaling is an important mechanism driving endothelial cell senescence. Thus, TSP1 and CD47 provide attractive molecular targets for treatment of aging-associated cardiovascular dysfunction and diseases involving endothelial dysregulation. PMID:27607583

  14. The Oxygen Rich Postnatal Environment Induces Cardiomyocyte Cell Cycle Arrest Through DNA Damage Response

    PubMed Central

    Puente, Bao N.; Kimura, Wataru; Muralidhar, Shalini A.; Moon, Jesung; Amatruda, James F.; Phelps, Kate L.; Grinsfelder, David; Rothermel, Beverly A.; Chen, Rui; Garcia, Joseph A.; Santos, Celio X.; Thet, SuWannee; Mori, Eiichiro; Kinter, Michael T.; Rindler, Paul M.; Zacchigna, Serena; Mukherjee, Shibani; Chen, David J.; Mahmoud, Ahmed I.; Giacca, Mauro; Rabinovitch, Peter S.; Aroumougame, Asaithamby; Shah, Ajay M.; Szweda, Luke I.; Sadek, Hesham A.

    2014-01-01

    Summary The mammalian heart has a remarkable regenerative capacity for a short period of time after birth, after which the majority of cardiomyocytes permanently exit cell cycle. We sought to determine the primary post-natal event that results in cardiomyocyte cell-cycle arrest. We hypothesized that transition to the oxygen rich postnatal environment is the upstream signal that results in cell cycle arrest of cardiomyocytes. Here we show that reactive oxygen species (ROS), oxidative DNA damage, and DNA damage response (DDR) markers significantly increase in the heart during the first postnatal week. Intriguingly, postnatal hypoxemia, ROS scavenging, or inhibition of DDR all prolong the postnatal proliferative window of cardiomyocytes, while hyperoxemia and ROS generators shorten it. These findings uncover a previously unrecognized protective mechanism that mediates cardiomyocyte cell cycle arrest in exchange for utilization of oxygen dependent aerobic metabolism. Reduction of mitochondrial-dependent oxidative stress should be important component of cardiomyocyte proliferation-based therapeutic approaches. PMID:24766806

  15. Synthesis of α, β-unsaturated carbonyl based compounds as acetylcholinesterase and butyrylcholinesterase inhibitors: characterization, molecular modeling, QSAR studies and effect against amyloid β-induced cytotoxicity.

    PubMed

    Bukhari, Syed Nasir Abbas; Jantan, Ibrahim; Masand, Vijay H; Mahajan, Devidas T; Sher, Muhammad; Naeem-ul-Hassan, M; Amjad, Muhammad Wahab

    2014-08-18

    A series of novel carbonyl compounds was synthesized by a simple, eco-friendly and efficient method. These compounds were screened for anti-oxidant activity, in vitro cytotoxicity and for inhibitory activity for acetylcholinesterase and butyrylcholinesterase. The effect of these compounds against amyloid β-induced cytotoxicity was also investigated. Among them, compound 14 exhibited strong free radical scavenging activity (18.39 μM) while six compounds (1, 3, 4, 13, 14, and 19) were found to be the most protective against Aβ-induced neuronal cell death in PC12 cells. Compounds 4 and 14, containing N-methyl-4-piperidone linker, showed high acetylcholinesterase inhibitory activity as compared to reference drug donepezil. Molecular docking and QSAR (Quantitative Structure-Activity Relationship) studies were also carried out to determine the structural features that are responsible for the acetylcholinesterase and butyrylcholinesterase inhibitory activity.

  16. Kinetic model of C/H/N/O emissions in laser-induced breakdown spectroscopy of organic compounds

    SciTech Connect

    Dagdigian, Paul J.; Khachatrian, Ani; Babushok, Valeri I.

    2010-05-01

    A kinetic model to predict the relative intensities of the atomic C/H/N/O emission lines in laser-induced breakdown spectroscopy (LIBS) has been developed for organic compounds. The model includes a comprehensive set of chemical processes involving both neutral and ionic chemistry and physical excitation and de-excitation of atomic levels affecting the neutral, ionic, and excited-state species concentrations. The relative excited-state atom concentrations predicted by this modeling are compared with those derived from the observed LIBS intensities for 355 nm ns laser irradiation of residues of two organic compounds on aluminum substrate. The model reasonably predicts the relative excited-state concentrations, as well as their time profiles. Comparison of measured and computed concentrations has also allowed an estimation of the degree of air entrainment.

  17. Ionic Strength-Induced Formation of Smectite Quasicrystals Enhances Nitroaromatic Compound Sorption

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The influence of ionic strength on nitroaromatic compound sorption from water by K+- and Ca2+-saturated smectite (SWy-2) was examined. The results indicated that sorption of 1,3-dinitrobenzene by K-SWy-2 increased up to 2.2 times as KCl ionic strength increased from 0.01 to 0.30 M. In contrast, sorp...

  18. Pressure-induced bonding and compound formation in xenon-hydrogen solids

    SciTech Connect

    Somayazulu, Maddury; Dera, Przemyslaw; Goncharov, Alexander F; Gramsch, Stephen A; Liermann, Peter; Yang, Wenge; Liu, Zhenxian; Mao, Ho-kwang; Hemley, Russell J

    2010-11-03

    Closed electron shell systems, such as hydrogen, nitrogen or group 18 elements, can form weakly bound stoichiometric compounds at high pressures. An understanding of the stability of these van der Waals compounds is lacking, as is information on the nature of their interatomic interactions. We describe the formation of a stable compound in the Xe-H{sub 2} binary system, revealed by a suite of X-ray diffraction and optical spectroscopy measurements. At 4.8 GPa, a unique hydrogen-rich structure forms that can be viewed as a tripled solid hydrogen lattice modulated by layers of xenon, consisting of xenon dimers. Varying the applied pressure tunes the Xe-Xe distances in the solid over a broad range from that of an expanded xenon lattice to the distances observed in metallic xenon at megabar pressures. Infrared and Raman spectra indicate a weakening of the intramolecular covalent bond as well as persistence of semiconducting behaviour in the compound to at least 255 GPa.

  19. Four terpene synthases produce major compounds of the gypsy moth feeding-induced volatile blend of Populus trichocarpa.

    PubMed

    Danner, Holger; Boeckler, G Andreas; Irmisch, Sandra; Yuan, Joshua S; Chen, Feng; Gershenzon, Jonathan; Unsicker, Sybille B; Köllner, Tobias G

    2011-06-01

    After herbivore damage, many plants increase their emission of volatile compounds, with terpenes usually comprising the major group of induced volatiles. Populus trichocarpa is the first woody species with a fully sequenced genome, enabling rapid molecular approaches towards characterization of volatile terpene biosynthesis in this and other poplar species. We identified and characterized four terpene synthases (PtTPS1-4) from P. trichocarpa which form major terpene compounds of the volatile blend induced by gypsy moth (Lymantria dispar) feeding. The enzymes were heterologously expressed and assayed with potential prenyl diphosphate substrates. PtTPS1 and PtTPS2 accepted only farnesyl diphosphate and produced (-)-germacrene D and (E,E)-α-farnesene as their major products, respectively. In contrast, PtTPS3 and PtTPS4 showed both mono- and sesquiterpene synthase activity. They produce the acyclic terpene alcohols linalool and nerolidol but exhibited opposite stereospecificity. qRT-PCR analysis revealed that the expression of the respective terpene synthase genes was induced after feeding of gypsy moth caterpillars. The TPS enzyme products may play important roles in indirect defense of poplar to herbivores and in mediating intra- and inter-plant signaling.

  20. Amino-functionalized nanoparticles as inhibitors of mTOR and inducers of cell cycle arrest in leukemia cells.

    PubMed

    Loos, Cornelia; Syrovets, Tatiana; Musyanovych, Anna; Mailänder, Volker; Landfester, Katharina; Simmet, Thomas

    2014-02-01

    Activation of the mammalian target of rapamycin (mTOR) has been implicated in anticancer drug resistance, type 2 diabetes, and aging. Here, we show that surface functionalization of polystyrene nanoparticles with amino groups (PS-NH2), but not with carboxyl groups (PS-COOH), induces G2 cell-cycle arrest and inhibition of proliferation in three leukemia cell lines. Besides, PS-NH2 inhibit angiogenesis and proliferation of leukemia cells xenografted onto the chick chorioallantoic membrane. At the molecular level, PS-NH2 inhibit, whereas PS-COOH activate mTOR signaling in leukemia cells. Consistently, PS-NH2 block activation of the mTOR downstream targets, Akt and p70 ribosomal S6 kinase 1, and induce overexpression of the cell-cycle regulator p21(Cip1/Waf1) and degradation of cyclin B1. After addition, both types of particles rapidly induce autophagy in leukemia cells. Yet, only in PS-NH2-treated cells, acidic vesicular organelles show elevated pH and impaired processing of procathepsin B. Moreover, solely in PS-NH2-treated cells, autophagy is followed by permeabilization of acidic vesicular organelles and induction of apoptosis. By contrast, primary macrophages, which do not exhibit activated mTOR signaling, proved relatively resistant to PS-NH2-induced toxicity. These data indicate that functionalized nanoparticles can be used to control activation of mTOR signaling pathways, and to influence proliferation and viability of malignant cells.

  1. Amino-functionalized nanoparticles as inhibitors of mTOR and inducers of cell cycle arrest in leukemia cells.

    PubMed

    Loos, Cornelia; Syrovets, Tatiana; Musyanovych, Anna; Mailänder, Volker; Landfester, Katharina; Simmet, Thomas

    2014-02-01

    Activation of the mammalian target of rapamycin (mTOR) has been implicated in anticancer drug resistance, type 2 diabetes, and aging. Here, we show that surface functionalization of polystyrene nanoparticles with amino groups (PS-NH2), but not with carboxyl groups (PS-COOH), induces G2 cell-cycle arrest and inhibition of proliferation in three leukemia cell lines. Besides, PS-NH2 inhibit angiogenesis and proliferation of leukemia cells xenografted onto the chick chorioallantoic membrane. At the molecular level, PS-NH2 inhibit, whereas PS-COOH activate mTOR signaling in leukemia cells. Consistently, PS-NH2 block activation of the mTOR downstream targets, Akt and p70 ribosomal S6 kinase 1, and induce overexpression of the cell-cycle regulator p21(Cip1/Waf1) and degradation of cyclin B1. After addition, both types of particles rapidly induce autophagy in leukemia cells. Yet, only in PS-NH2-treated cells, acidic vesicular organelles show elevated pH and impaired processing of procathepsin B. Moreover, solely in PS-NH2-treated cells, autophagy is followed by permeabilization of acidic vesicular organelles and induction of apoptosis. By contrast, primary macrophages, which do not exhibit activated mTOR signaling, proved relatively resistant to PS-NH2-induced toxicity. These data indicate that functionalized nanoparticles can be used to control activation of mTOR signaling pathways, and to influence proliferation and viability of malignant cells. PMID:24331713

  2. E. adenophorum induces Cell Cycle Arrest and Apoptosis of Splenocytes through the Mitochondrial Pathway and Caspase Activation in Saanen Goats

    PubMed Central

    He, Yajun; Mo, Quan; Hu, Yanchun; Chen, Weihong; Luo, Biao; Wu, Lei; Qiao, Yan; Xu, Ruiguang; Zhou, Yancheng; Zuo, Zhicai; Deng, Junliang; He, Wei; Wei, Yahui

    2015-01-01

    The precise cytotoxicity of E. Adenophorum in relation to the cell cycle and apoptosis of splenocytes in Saanen goats remains unclear. In the present study, 16 Saanen goats were randomly divided into four groups, which were fed on 0%, 40%, 60% and 80% E. adenophorum diets. The results of TUNEL, DAPI and AO/EB staining, flow cytometry analysis and DNA fragmentation assays showed that E. adenophorum induced typical apoptotic features in splenocytes, suppressed splenocyte viability, and caused cell cycle arrest in a dose-dependent manner. However, westernblot, ELISA, qRT-PCR and caspase activity analyses showed that E. adenophoruminhibited Bcl-2 expression, promoted Bax translocation to the mitochondria, triggered the release of Cytc from the mitochondria into the cytosol, and activated caspase-9 and -3 and the subsequent cleavage of PARP. Moreover, in E. adenophorum-induced apoptosis, the protein levels of Fas, Bid, FasL and caspase-8 showed no significant changes. E. adenophorum treatment induced the collapse of ΔΨm. Moreover, these data suggested that E. adenophorum induces splenocyte apoptosis via the activation of the mitochondrial apoptosis pathway in splenocytes. These findings provide new insights into the mechanisms underlying the effects of E. adenophorum cytotoxicity on splenocytes. PMID:26527166

  3. E. adenophorum Induces Cell Cycle and Apoptosis of Renal Cells through Mitochondrial Pathway and Caspase Activation in Saanen Goat

    PubMed Central

    Hu, Yanchun; Luo, Biao; Wu, Lei; Qiao, Yan; Mo, Quan; Xu, Ruiguang; Zhou, Yancheng; Ren, Zhihua; Zuo, Zhicai; Deng, Junliang; Peng, Guangneng; He, Wei; Wei, Yahui

    2015-01-01

    The cytotoxicity effects of E. adenophorum on cell cycle and apoptosis of renal cells in Saanen goat was evaluated by TUNEL, DAPI, AO/EB staining, DNA fragmentation assay, Caspase activity, Western-blot, qRT-PCR and flow cytometry analysis. 16 saanen goats randomly divided into four groups were fed on 0%, 40%, 60% and 80% E. adenophorum diets. The Results showed that E. adenophorum induced typical apoptotic features of renal cells. E. adenophorum significantly suppressed renal cells viability, caused cell cycle activity arrest and induced typical apoptotic features in a dose-dependent manner. However, the protein levels of Fas/FasL, Bid and caspase-8 did not appear significant changes in the process of E. adenophorum-induced apoptosis. Moreover, E. adenophorum administration slightly decreased Bcl-2 expression, promoted Bax translocation to mitochondria, triggered the release of Cyt c from mitochondria into cytosol and activated caspase-9, -3, and cleaved PARP. The mitochondrial p53 translocation was significantly activated, accompanied by a significant increase in the loss of ΔΨm, Cyt c release and caspase-9 activation. Above all, these data suggest that E. adenophorum induces renal cells apoptosis via the activation of mitochondria-mediated apoptosis pathway in renal cells. These findings may provide new insights to understand the mechanisms involved in E. adenophorum-caused cytotoxicity of renal cells. PMID:26382060

  4. Integrated operation of the photorespiratory cycle and cytosolic metabolism in the modulation of primary nitrogen assimilation and export of organic N-transport compounds from leaves: a hypothesis.

    PubMed

    Misra, Jitendra B

    2014-02-15

    Photorespiration is generally considered to be an essentially dissipative process, although it performs some protective and essential functions. A theoretical appraisal indicates that the loss of freshly assimilated CO2 due to photorespiration in well-watered plants may not be as high as generally believed. Even under moderately adverse conditions, these losses may not exceed 10%. The photorespiratory metabolism of the source leaves of well-watered and well-nourished crop plants ought to be different from that of other leaves because the fluxes of the export of both carbohydrates and organic N-transport compounds in source leaves is quite high. With a heuristic approach that involved the dovetailing of certain metabolic steps with the photorespiratory cycle (PR-cycle), a novel network is proposed to operate in the source-leaves of well-watered and well-nourished plants. This network allows for the diversion of metabolites from their cyclic-routes in sizeable quantities. With the removal of considerable quantities of glycine and serine from the cyclic route, the number of RuBP oxygenation events would be several times those of the formation of hydroxypyruvate. Thus, to an extreme extent, photorespiratory metabolism would become open-ended and involve much less futile recycling of glycine and serine. Conversion of glyoxylate to glycine has been proposed to be a crucial step in the determination of the relative rates of the futile (cyclic) and anabolic (open-ended) routes. Thus, in the source leaves of well-watered and well-nourished plants, the importance of the cyclic route is limited to the salvaging of photorespiratory intermediates for the regeneration of RuBP. The proposed network is resilient enough to coordinate the rates of the assimilation of carbon and nitrogen in accordance with the moisture and N-fertility statuses of the soil.

  5. Newly synthesized bis-benzimidazole compound 8 induces apoptosis, autophagy and reactive oxygen species generation in HeLa cells.

    PubMed

    Chu, Naying; Yao, Guodong; Liu, Yuan; Cheng, Maosheng; Ikejima, Takashi

    2016-09-01

    Compound 8 (C8) is a newly synthesized bis-benzimidazole derivative and exerts significant anti-tumor activity in vitro. Previous studies demonstrated that C8 induced apoptosis and autophagy in human promyelocytic leukemia HL60 cells. However, cytotoxicity study on human peripheral blood mononuclear cells (hPBMC) showed that C8 exhibited less toxicity in normal cells. In this study, the molecular mechanism of C8 on human cervical carcinoma HeLa cells was investigated. The results showed that C8 inhibited the growth of HeLa cells and triggered both apoptotic and autophagic cell death. Subsequent experiment also indicated that reactive oxygen species (ROS) generation was induced in C8-treated HeLa cells. Since ROS scavenger decreased the ratio of apoptotic and autophagic cells, ROS generation contributed to C8-induced apoptosis and autophagy. Furthermore, inhibitors of apoptosis and autophagy also reduced ROS generation, respectively. Autophagy inhibition increased cell growth compared to C8-treated group and attenuated apoptotic cell death, indicating that C8-induced autophagy promoted apoptosis for cell death. However, the percentage of autophagic cells was enhanced when limiting apoptosis process. Taken together, C8 induced ROS-mediated apoptosis and autophagy in HeLa cells, autophagy promoted apoptosis but the former was antagonized by the latter. The data also gave us a new perspective on the anti-tumor effect of C8. PMID:27497983

  6. Newly synthesized bis-benzimidazole compound 8 induces apoptosis, autophagy and reactive oxygen species generation in HeLa cells.

    PubMed

    Chu, Naying; Yao, Guodong; Liu, Yuan; Cheng, Maosheng; Ikejima, Takashi

    2016-09-01

    Compound 8 (C8) is a newly synthesized bis-benzimidazole derivative and exerts significant anti-tumor activity in vitro. Previous studies demonstrated that C8 induced apoptosis and autophagy in human promyelocytic leukemia HL60 cells. However, cytotoxicity study on human peripheral blood mononuclear cells (hPBMC) showed that C8 exhibited less toxicity in normal cells. In this study, the molecular mechanism of C8 on human cervical carcinoma HeLa cells was investigated. The results showed that C8 inhibited the growth of HeLa cells and triggered both apoptotic and autophagic cell death. Subsequent experiment also indicated that reactive oxygen species (ROS) generation was induced in C8-treated HeLa cells. Since ROS scavenger decreased the ratio of apoptotic and autophagic cells, ROS generation contributed to C8-induced apoptosis and autophagy. Furthermore, inhibitors of apoptosis and autophagy also reduced ROS generation, respectively. Autophagy inhibition increased cell growth compared to C8-treated group and attenuated apoptotic cell death, indicating that C8-induced autophagy promoted apoptosis for cell death. However, the percentage of autophagic cells was enhanced when limiting apoptosis process. Taken together, C8 induced ROS-mediated apoptosis and autophagy in HeLa cells, autophagy promoted apoptosis but the former was antagonized by the latter. The data also gave us a new perspective on the anti-tumor effect of C8.

  7. Effect of Locomotor Respiratory Coupling Induced by Cortical Oxygenated Hemoglobin Levels During Cycle Ergometer Exercise of Light Intensity.

    PubMed

    Oyanagi, Keiichi; Tsubaki, Atsuhiro; Yasufuku, Yuichi; Takai, Haruna; Kera, Takeshi; Tamaki, Akira; Iwata, Kentaro; Onishi, Hideaki

    2016-01-01

    This study aimed to clarify the effects of locomotor-respiratory coupling (LRC) induced by light load cycle ergometer exercise on oxygenated hemoglobin (O2Hb) in the dorsolateral prefrontal cortex (DLPFC), supplementary motor area (SMA), and sensorimotor cortex (SMC). The participants were 15 young healthy adults (9 men and 6 women, mean age: 23.1 ± 1.8 (SEM) years). We conducted a task in both LRC-inducing and LRC-non-inducing conditions for all participants. O2Hb was measured using near-infrared spectroscopy. The LRC frequency ratio during induction was 2:1; pedaling rate, 50 rpm; and intensity of load, 30 % peak volume of oxygen uptake. The test protocol included a 3-min rest prior to exercise, steady loading motion for 10 min, and 10-min rest post exercise (a total of 23 min). In the measurement of O2Hb, we focused on the DLPFC, SMA, and SMC. The LRC frequency was significantly higher in the LRC-inducing condition (p < 0.05). O2Hb during exercise was significantly lower in the DLPFC and SMA, under the LRC-inducing condition (p < 0.05). The study revealed that even light load could induce LRC and that O2Hb in the DLPFC and SMA decreases during exercise via LRC induction.

  8. Glucose restriction induces transient G2 cell cycle arrest extending cellular chronological lifespan.

    PubMed

    Masuda, Fumie; Ishii, Mahiro; Mori, Ayaka; Uehara, Lisa; Yanagida, Mitsuhiro; Takeda, Kojiro; Saitoh, Shigeaki

    2016-01-01

    While glucose is the fundamental source of energy in most eukaryotes, it is not always abundantly available in natural environments, including within the human body. Eukaryotic cells are therefore thought to possess adaptive mechanisms to survive glucose-limited conditions, which remain unclear. Here, we report a novel mechanism regulating cell cycle progression in response to abrupt changes in extracellular glucose concentration. Upon reduction of glucose in the medium, wild-type fission yeast cells undergo transient arrest specifically at G2 phase. This cell cycle arrest is dependent on the Wee1 tyrosine kinase inhibiting the key cell cycle regulator, CDK1/Cdc2. Mutant cells lacking Wee1 are not arrested at G2 upon glucose limitation and lose viability faster than the wild-type cells under glucose-depleted quiescent conditions, suggesting that this cell cycle arrest is required for extension of chronological lifespan. Our findings indicate the presence of a novel cell cycle checkpoint monitoring glucose availability, which may be a good molecular target for cancer therapy. PMID:26804466

  9. Induced thermo-mechanical stress in CPV receivers with cycled high intensity light

    NASA Astrophysics Data System (ADS)

    Pérez, Valentín; Antón, Ignacio; Herrero, Rebeca; Nogueira, Eduardo; Núñez, Rubén; del Cañizo, Carlos; Sala, Gabriel

    2014-09-01

    CPV receivers are made of materials with very different lineal expansion coefficients. Strong variations in DNI due to the passage of clouds can cause sudden temperature changes that creates mechanical stress. For common solder and metal filled polymers the plastic limit could be reached causing substantial fatigue. The best forecast of receiver reliability is therefore achieved by applying an intermittent light source with nominal irradiance level and a number of cycles equal to the expected cloud passages for a given site. The UPM has developed specialized equipment, dubbed the LYSS (Light cYcling Stressing Source), for carrying out such experiments. The small thermal capacity of receivers allows simulating more than 25000 cycles per week. The number of deep transients expected for Madrid in 30 years operation, based on available data, is about 45000. We are currently using the system to cycle a "Ge/Ag Epoxy/aluminum" receiver, which shows no degradation after 20000 cycles. The equipment can cast up to 200 and 70 W/cm2 on 0.1 and 1 cm2 cells, respectively.

  10. Laser-induced fluorescence detection strategies for sodium atoms and compounds in high-pressure combustors

    NASA Technical Reports Server (NTRS)

    Weiland, Karen J. R.; Wise, Michael L.; Smith, Gregory P.

    1993-01-01

    A variety of laser-induced fluorescence schemes were examined experimentally in atmospheric pressure flames to determine their use for sodium atom and salt detection in high-pressure, optically thick environments. Collisional energy transfer plays a large role in fluorescence detection. Optimum sensitivity, at the parts in 10 exp 9 level for a single laser pulse, was obtained with the excitation of the 4p-3s transition at 330 nm and the detection of the 3d-3p fluorescence at 818 nm. Fluorescence loss processes, such as ionization and amplified spontaneous emission, were examined. A new laser-induced atomization/laser-induced fluorescence detection technique was demonstrated for NaOH and NaCl. A 248-nm excimer laser photodissociates the salt molecules present in the seeded flames prior to atom detection by laser-induced fluorescence.

  11. Hinokitiol Induces DNA Damage and Autophagy followed by Cell Cycle Arrest and Senescence in Gefitinib-Resistant Lung Adenocarcinoma Cells

    PubMed Central

    Li, Lan-Hui; Wu, Ping; Lee, Jen-Yi; Li, Pei-Rong; Hsieh, Wan-Yu; Ho, Chao-Chi; Ho, Chen-Lung; Chen, Wan-Jiun; Wang, Chien-Chun; Yen, Muh-Yong; Yang, Shun-Min; Chen, Huei-Wen

    2014-01-01

    Despite good initial responses, drug resistance and disease recurrence remain major issues for lung adenocarcinoma patients with epidermal growth factor receptor (EGFR) mutations taking EGFR-tyrosine kinase inhibitors (TKI). To discover new strategies to overcome this issue, we investigated 40 essential oils from plants indigenous to Taiwan as alternative treatments for a wide range of illnesses. Here, we found that hinokitiol, a natural monoterpenoid from the heartwood of Calocedrus formosana, exhibited potent anticancer effects. In this study, we demonstrated that hinokitiol inhibited the proliferation and colony formation ability of lung adenocarcinoma cells as well as the EGFR-TKI-resistant lines PC9-IR and H1975. Transcriptomic analysis and pathway prediction algorithms indicated that the main implicated pathways included DNA damage, autophagy, and cell cycle. Further investigations confirmed that in lung cancer cells, hinokitiol inhibited cell proliferation by inducing the p53-independent DNA damage response, autophagy (not apoptosis), S-phase cell cycle arrest, and senescence. Furthermore, hinokitiol inhibited the growth of xenograft tumors in association with DNA damage and autophagy but exhibited fewer effects on lung stromal fibroblasts. In summary, we demonstrated novel mechanisms by which hinokitiol, an essential oil extract, acted as a promising anticancer agent to overcome EGFR-TKI resistance in lung cancer cells via inducing DNA damage, autophagy, cell cycle arrest, and senescence in vitro and in vivo. PMID:25105411

  12. Boron neutron capture therapy induces cell cycle arrest and cell apoptosis of glioma stem/progenitor cells in vitro

    PubMed Central

    2013-01-01

    Background Glioma stem cells in the quiescent state are resistant to clinical radiation therapy. An almost inevitable glioma recurrence is due to the persistence of these cells. The high linear energy transfer associated with boron neutron capture therapy (BNCT) could kill quiescent and proliferative cells. Methods The present study aimed to evaluate the effects of BNCT on glioma stem/progenitor cells in vitro. The damage induced by BNCT was assessed using cell cycle progression, apoptotic cell ratio and apoptosis-associated proteins expression. Results The surviving fraction and cell viability of glioma stem/progenitor cells were decreased compared with differentiated glioma cells using the same boronophenylalanine pretreatment and the same dose of neutron flux. BNCT induced cell cycle arrest in the G2/M phase and cell apoptosis via the mitochondrial pathway, with changes in the expression of associated proteins. Conclusions Glioma stem/progenitor cells, which are resistant to current clinical radiotherapy, could be effectively killed by BNCT in vitro via cell cycle arrest and apoptosis using a prolonged neutron irradiation, although radiosensitivity of glioma stem/progenitor cells was decreased compared with differentiated glioma cells when using the same dose of thermal neutron exposure and boronophenylalanine pretreatment. Thus, BNCT could offer an appreciable therapeutic advantage to prevent tumor recurrence, and may become a promising treatment in recurrent glioma. PMID:23915425

  13. Expression of RB C pocket fragments in HSF induces delayed cell cycle progression and sensitizes to apoptosis upon cellular stresses.

    PubMed

    Chung, Junah; Cho, Jae-We; Baek, Won-Ki; Suh, Seong-Il; Kwon, Taeg Kyu; Park, Jong-Wook; Suh, Min-Ho

    2002-08-01

    The retinoblastoma protein (RB) plays an important role in growth suppression through the formation of multiple protein complexes with its target proteins using A/B and C pockets. Even though the A/B and C pockets co-operate for growth suppression, the function of RB in growth arrest is inhibited by the coexpression of RB C fragments with full length RB in the absence of p53, which implies that C pocket fragments are likely to act as a dominant-negative inhibitor of RB function. In contrast, the loss of the RB functions in the presence of p53 triggers a cell cycle arrest or apoptosis by p53-dependent pathways. Thus, it still remains to be elucidated whether the expression of RB C pocket fragments in the presence of p53 induces delayed cell cycle progression and sensitizes cells to apoptosis through p53-dependent pathways. Our results show that the expression of RB C pocket fragments not only induces delayed cell cycle progression, which is mediated by the down-regulation of cyclin A, cyclin E, and E2F-1, but also sensitizes cells to apoptosis through p53-dependent pathways. PMID:12153616

  14. Magnetic Precursor of the Pressure-Induced Superconductivity in Fe-Ladder Compounds

    NASA Astrophysics Data System (ADS)

    Chi, Songxue; Uwatoko, Yoshiya; Cao, Huibo; Hirata, Yasuyuki; Hashizume, Kazuki; Aoyama, Takuya; Ohgushi, Kenya

    2016-07-01

    The pressure effects on the antiferromagentic orders in iron-based ladder compounds CsFe2Se3 and BaFe2S3 have been studied using neutron diffraction. With identical crystal structure and similar magnetic structures, the two compounds exhibit highly contrasting magnetic behaviors under moderate external pressures. In CsFe2Se3 the ladders are brought much closer to each other by pressure, but the stripe-type magnetic order shows no observable change. In contrast, the stripe order in BaFe2S3 undergoes a quantum phase transition where an abrupt increase of Néel temperature by more than 50% occurs at about 1 GPa, accompanied by a jump in the ordered moment. With its spin structure unchanged, BaFe2S3 enters an enhanced magnetic phase that bears the characteristics of an orbital selective Mott phase, which is the true neighbor of superconductivity emerging at higher pressures.

  15. The antitumor natural compound falcarindiol promotes cancer cell death by inducing endoplasmic reticulum stress

    PubMed Central

    Jin, H R; Zhao, J; Zhang, Z; Liao, Y; Wang, C-Z; Huang, W-H; Li, S-P; He, T-C; Yuan, C-S; Du, W

    2012-01-01

    Falcarindiol (FAD) is a natural polyyne with various beneficial biological activities. We show here that FAD preferentially kills colon cancer cells but not normal colon epithelial cells. Furthermore, FAD inhibits tumor growth in a xenograft tumor model and exhibits strong synergistic killing of cancer cells with 5-fluorouracil, an approved cancer chemotherapeutic drug. We demonstrate that FAD-induced cell death is mediated by induction of endoplasmic reticulum (ER) stress and activation of the unfolded protein response (UPR). Decreasing the level of ER stress, either by overexpressing the ER chaperone protein glucose-regulated protein 78 (GRP78) or by knockout of components of the UPR pathway, reduces FAD-induced apoptosis. In contrast, increasing the level of ER stress by knocking down GRP78 potentiates FAD-induced apoptosis. Finally, FAD-induced ER stress and apoptosis is correlated with the accumulation of ubiquitinated proteins, suggesting that FAD functions at least in part by interfering with proteasome function, leading to the accumulation of unfolded protein and induction of ER stress. Consistent with this, inhibition of protein synthesis by cycloheximide significantly decreases the accumulation of ubiquitinated proteins and blocks FAD-induced ER stress and cell death. Taken together, our study shows that FAD is a potential new anticancer agent that exerts its activity through inducing ER stress and apoptosis. PMID:22914324

  16. Gallium compound GaQ(3) -induced Ca(2+) signalling triggers p53-dependent and -independent apoptosis in cancer cells.

    PubMed

    Gogna, Rajan; Madan, Esha; Keppler, Bernhard; Pati, Uttam

    2012-05-01

    BACKGROUND AND PURPOSE A novel anti-neoplastic gallium complex GaQ(3) (KP46), earlier developed by us, is currently in phase I clinical trial. GaQ(3) induced S-phase arrest and apoptosis via caspase/PARP cleavage in a variety of cancers. However, the underlying mechanism of apoptosis is unknown. Here, we have explored the mechanism(s) of GaQ(3) -induced apoptosis in cancer cells, focusing on p53 and intracellular Ca(2+) signalling. EXPERIMENTAL APPROACH GaQ(3) -induced cytotoxicity and apoptosis were determined in cancer cell lines, with different p53 status (p53(+/+) , p53(-/-) and p53 mutant). Time course analysis of intracellular Ca(2+) calcium release, p53 promoter activation, p53-nuclear/cytoplasmic movements and reactive oxygen species (ROS) were conducted. Ca(2+) -dependent formation of the p53-p300 transcriptional complex was analysed by co-immunoprecipitation and chromatin immunoprecipitation. Ca(2+) signalling, p53, p300 and ROS were serially knocked down to study Ca(2+) -p53-ROS ineractions in GaQ(3) -induced apoptosis. KEY RESULTS GaQ(3) triggered intracellular Ca(2+) release stabilizing p53-p300 complex and recruited p53 to p53 promoter, leading to p53 mRNA and protein synthesis. p53 induced higher intracellular Ca(2+) release and ROS followed by activation of p53 downstream genes including those for the micro RNA mir34a. In p53(-/-) and p53 mutant cells, GaQ(3) -induced Ca(2+) -signalling generated ROS. ROS further increased membrane translocation of FAS and FAS-mediated extrinsic apoptosis. CONCLUSIONS AND IMPLICATIONS This study disclosed a novel mechanism of Ca(2+) -signalling-mediated p53 activation and ROS up-regulation. Understanding the mechanism of GaQ(3) -induced apoptosis will help establish this gallium-based organic compound as a potent anti-cancer drug.

  17. Effects of various chemical compounds on spontaneous and hydrogen peroxide-induced reversion in strain TA104 of Salmonella typhimurium.

    PubMed

    Han, J S

    1992-04-01

    In experiments designed to determine which active oxygen species contribute to hydrogen peroxide (HP)-induced reversion in strain TA104 of Salmonella typhimurium, 1,10-phenanthroline (an iron chelator, which prevents the formation of hydroxyl radicals from HP and DNA-bound iron by the Fenton reaction), sodium azide (a singlet oxygen scavenger), and potassium iodide (an hydroxyl radical scavenger) inhibited HP-induced reversion. These results indicate that hydroxyl radicals generated from HP by the Fenton reaction, and perhaps singlet oxygen, contribute to HP-induced reversion in TA104. However, reduced glutathione (reduces Fe3+ to Fe2+ and/or HP to water), diethyldithiocarbamic acid (an inhibitor of superoxide dismutase), diethyl maleate (a glutathione scavenger), and 3-amino-1,2,4-triazole (an inhibitor of catalase) did not inhibit HP-induced reversion in TA104. Thus, superoxide radical anions and HP itself do not appear to be the cause of HP-induced reversion in this strain. In experiments on the effect of 5 common dietary compounds (beta-carotene, retinoic acid, and vitamins A, C and E), chlorophyllin (CHL), and ergothioneine, the frequency of revertants in TA104 increased above the spontaneous frequency in the presence of beta-carotene or vitamin C (about 2-fold) or vitamin A (about 3-fold). The 5 dietary antimutagens and CHL did not inhibit HP-induced reversion in TA104. However, L-ergothioneine inhibited HP-induced reversion in this strain. Therefore, it is likely that L-ergothioneine is a scavenger of hydroxyl radicals or an inhibitor of their formation, and perhaps of singlet oxygen, at the concentrations tested in TA104.

  18. Atomic disorder induced by mechanical milling in the intermetallic compound CoAl

    NASA Astrophysics Data System (ADS)

    Di, L. M.; Bakker, H.; de Boer, F. R.

    1992-10-01

    The stoichiometric intermetallic compound CoAl with the CsCl-structure was subjected to ball milling. Structural changes during ball milling were studied by measurements of the magnetization and the lattice parameter. The behaviour of Coal upon milling turns out to be quite similar to that of CoGa. The increase of the magnetization and the decrease of the lattice parameter with the milling time show that, similar to CoGa, triple-defect disorder is generated by ball milling. By comparing the measured magnetization to the magnetization of Co xAl 100- x compounds with excess Co, the concentration of defects is derived for milled samples. In order to interpret our results, the existing experimental data of lattice parameters, X-ray densities calculated from the lattice parameters and macroscopic densities for Co xAl 100- x compounds were analyzed according to Edelin's equations. The defect volumes for vacancies and anti-site atoms obtained by fitting these experimental data have reasonable values. By means of the defect concentrations obtained from our magnetization measurements and the defect volumes by fitting the experimental data, the change of the lattice parameter was calculated by means of Edelin's equation. The agreement between the calculated lattice parameter and the measured lattice parameter is quite satisfactory.

  19. Identification of Novel Compounds Inhibiting Chikungunya Virus-Induced Cell Death by High Throughput Screening of a Kinase Inhibitor Library

    PubMed Central

    Gomes, Rafael G. B.; da Silva, Camila T.; Taniguchi, Juliana B.; No, Joo Hwan; Lombardot, Benoit; Schwartz, Olivier; Hansen, Michael A. E.; Freitas-Junior, Lucio H.

    2013-01-01

    Chikungunya virus (CHIKV) is a mosquito-borne arthrogenic alphavirus that causes acute febrile illness in humans accompanied by joint pains and in many cases, persistent arthralgia lasting weeks to years. The re-emergence of CHIKV has resulted in numerous outbreaks in the eastern hemisphere, and threatens to expand in the foreseeable future. Unfortunately, no effective treatment is currently available. The present study reports the use of resazurin in a cell-based high-throughput assay, and an image-based high-content assay to identify and characterize inhibitors of CHIKV-infection in vitro. CHIKV is a highly cytopathic virus that rapidly kills infected cells. Thus, cell viability of HuH-7 cells infected with CHIKV in the presence of compounds was determined by measuring metabolic reduction of resazurin to identify inhibitors of CHIKV-associated cell death. A kinase inhibitor library of 4,000 compounds was screened against CHIKV infection of HuH-7 cells using the resazurin reduction assay, and the cell toxicity was also measured in non-infected cells. Seventy-two compounds showing ≥50% inhibition property against CHIKV at 10 µM were selected as primary hits. Four compounds having a benzofuran core scaffold (CND0335, CND0364, CND0366 and CND0415), one pyrrolopyridine (CND0545) and one thiazol-carboxamide (CND3514) inhibited CHIKV-associated cell death in a dose-dependent manner, with EC50 values between 2.2 µM and 7.1 µM. Based on image analysis, these 6 hit compounds did not inhibit CHIKV replication in the host cell. However, CHIKV-infected cells manifested less prominent apoptotic blebs typical of CHIKV cytopathic effect compared with the control infection. Moreover, treatment with these compounds reduced viral titers in the medium of CHIKV-infected cells by up to 100-fold. In conclusion, this cell-based high-throughput screening assay using resazurin, combined with the image-based high content assay approach identified compounds against CHIKV having a novel

  20. Lithium increases proliferation of hippocampal neural stem/progenitor cells and rescues irradiation-induced cell cycle arrest in vitro.

    PubMed

    Zanni, Giulia; Di Martino, Elena; Omelyanenko, Anna; Andäng, Michael; Delle, Ulla; Elmroth, Kecke; Blomgren, Klas

    2015-11-10

    Radiotherapy in children causes debilitating cognitive decline, partly linked to impaired neurogenesis. Irradiation targets primarily cancer cells but also endogenous neural stem/progenitor cells (NSPCs) leading to cell death or cell cycle arrest. Here we evaluated the effects of lithium on proliferation, cell cycle and DNA damage after irradiation of young NSPCs in vitro.NSPCs were treated with 1 or 3 mM LiCl and we investigated proliferation capacity (neurosphere volume and bromodeoxyuridine (BrdU) incorporation). Using flow cytometry, we analysed apoptosis (annexin V), cell cycle (propidium iodide) and DNA damage (γH2AX) after irradiation (3.5 Gy) of lithium-treated NSPCs.Lithium increased BrdU incorporation and, dose-dependently, the number of cells in replicative phase as well as neurosphere growth. Irradiation induced cell cycle arrest in G1 and G2/M phases. Treatment with 3 mM LiCl was sufficient to increase NSPCs in S phase, boost neurosphere growth and reduce DNA damage. Lithium did not affect the levels of apoptosis, suggesting that it does not rescue NSPCs committed to apoptosis due to accumulated DNA damage.Lithium is a very promising candidate for protection of the juvenile brain from radiotherapy and for its potential to thereby improve the quality of life for those children who survive their cancer.

  1. Some effects of thermal-cycle-induced deformation in rocket thrust chambers

    NASA Technical Reports Server (NTRS)

    Hannum, N. P.; Price, R. G., Jr.

    1981-01-01

    The deformation process observed in the hot gas side wall of rocket combustion chambers was investigaged for three different liner materials. Five thrust chambers were cycled to failure by using hydrogen and oxygen as propellants at a chamber pressure of 4.14 MN/cu m. The deformation was observed nondestructively at midlife points and destructively after failure occurred. The cyclic life results are presented with an accompanying discussion about the problems of life prediction associated with the types of failures encountered in the present work. Data indicating the deformation of the thrust chamber liner as cycles are accumulated are presented for each of the test thrust chambers. From these deformation data and observation of the failure sites it is evident that modeling the failure process as classic low cycle thermal fatigue is inadequate as a life prediction method.

  2. MYC-repressed long noncoding RNAs antagonize MYC-induced cell proliferation and cell cycle progression

    PubMed Central

    Jeon, Young-Jun; Fadda, Paolo; Alder, Hansjuerg; Croce, Carlo M.

    2015-01-01

    The transcription factor MYC is a proto-oncogene regulating cell proliferation, cell cycle, apoptosis and metabolism. The recent identification of MYC-regulated long noncoding RNAs (lncRNAs) expands our knowledge of the role of lncRNAs in MYC functions. Here, we identify MYC-repressed lncRNAs named MYCLo-4, -5 and -6 by comparing 3 categories of lncRNAs (downregulated in highly MYC-expressing colorectal cancer, up-regulated by MYC knockdown in HCT116, upregulated by MYC knockdown in RKO). The MYC-repressed MYCLos are implicated in MYC-modulated cell proliferation through cell cycle regulation. By screening cell cycle-related genes regulated by MYC and the MYC-repressed MYCLos, we identified the MYC-repressed gene GADD45A as a target gene of the MYC-repressed MYCLos such as MYCLo-4 and MYCLo-6. PMID:26003165

  3. Pain‑relieving effect of a compound isolated from white peony root oral liquid on acute radiation‑induced esophagitis.

    PubMed

    Wang, Zhiyu; Shen, Li; Li, Xing; Shu, Xin; Shan, Baoen; Zhang, Li; Gong, Yanjun; Dong, Zhiming

    2013-06-01

    Acute radiation‑induced esophagitis (ARIE) is a common complication of radiotherapy. The aim of this study was to clarify the molecular mechanism of pain relief by the compound of white peony root oral liquid (cWPROL) in ARIE. An animal model of ARIE was established and either cWPROL or a mixture of lidocaine, dexamethasone and gentamycin (mLDG) was administered. We indirectly observed rat symptoms of pain by recording the weight of food and the volume of water consumed by the rats, along with changes in body weight. Additionally, the expression levels of substance P (SP) in the esophageal tissues were detected by immunohistochemistry. It was demonstrated that cWPROL was able to release the pain of ARIE by decreasing the expression of SP; this may be one of the molecular mechanisms via which cWPROL induces pain relief.

  4. Compound-specific nitrogen isotope analysis of amino acids: a possible new tool for reconstruction of paleo-nitrogen sources and cycling

    NASA Astrophysics Data System (ADS)

    Batista, F. C.; Ravelo, A. C.; McCarthy, M. D.

    2010-12-01

    Compound specific nitrogen isotopes of amino acids (δ 15N-AA) are a unique new geochemical tool, increasingly used in modern ecological and food web studies. For the first time, δ15N-AA allows elucidation of the molecular-level basis of whole sedimentary δ15N values and diagenetic alteration of the primary signal. Thus, this technique has implications for paleoceanographic studies of nitrogen cycling, in particular, understanding whole sediment δ15N reconstructions. Here we analyze δ15N-AA on a suite of samples (plankton tows, sediment traps and multicores) collected in the Santa Barbara Basin to investigate preservation and alteration of individual δ15N-AA signals from primary production, through export of primary production from the surface ocean, and finally during early sedimentary diagenesis. We use this sample suite to compare specific aspects of δ15N-AA with bulk δ15N-AA values to explore the potential of these new measurements to: (1) understand the molecular basis of the bulk δ15N-AA record, and (2) monitor specific AA expected to have unaltered δ15N-AA signatures representative of exported primary production.

  5. Population pharmacokinetic modeling and dosing simulations of nitrogen-scavenging compounds: disposition of glycerol phenylbutyrate and sodium phenylbutyrate in adult and pediatric patients with urea cycle disorders.

    PubMed

    Monteleone, Jon P R; Mokhtarani, M; Diaz, G A; Rhead, W; Lichter-Konecki, U; Berry, S A; Lemons, C; Dickinson, K; Coakley, D; Lee, B; Scharschmidt, B F

    2013-07-01

    Sodium phenylbutyrate and glycerol phenylbutyrate mediate waste nitrogen excretion in the form of urinary phenylacetylglutamine (PAGN) in patients with urea cycle disorders (UCDs); rare genetic disorders characterized by impaired urea synthesis and hyperammonemia. Sodium phenylbutyrate is approved for UCD treatment; the development of glycerol phenylbutyrate afforded the opportunity to characterize the pharmacokinetics (PK) of both compounds. A population PK model was developed using data from four Phase II/III trials that collectively enrolled patients ages 2 months to 72 years. Dose simulations were performed with particular attention to phenylacetic acid (PAA), which has been associated with adverse events in non-UCD populations. The final model described metabolite levels in plasma and urine for both drugs and was characterized by (a) partial presystemic metabolism of phenylbutyric acid (PBA) to PAA and/or PAGN, (b) slower PBA absorption and greater presystemic conversion with glycerol phenylbutyrate, (c) similar systemic disposition with saturable conversion of PAA to PAGN for both drugs, and (d) body surface area (BSA) as a significant covariate accounting for age-related PK differences. Dose simulations demonstrated similar PAA exposure following mole-equivalent PBA dosing of both drugs and greater PAA exposure in younger patients based on BSA.

  6. A sex-inducing pheromone triggers cell cycle arrest and mate attraction in the diatom Seminavis robusta

    PubMed Central

    Moeys, Sara; Frenkel, Johannes; Lembke, Christine; Gillard, Jeroen T. F.; Devos, Valerie; Van den Berge, Koen; Bouillon, Barbara; Huysman, Marie J. J.; De Decker, Sam; Scharf, Julia; Bones, Atle; Brembu, Tore; Winge, Per; Sabbe, Koen; Vuylsteke, Marnik; Clement, Lieven; De Veylder, Lieven; Pohnert, Georg; Vyverman, Wim

    2016-01-01

    Although sexual reproduction is believed to play a major role in the high diversification rates and species richness of diatoms, a mechanistic understanding of diatom life cycle control is virtually lacking. Diatom sexual signalling is controlled by a complex, yet largely unknown, pheromone system. Here, a sex-inducing pheromone (SIP+) of the benthic pennate diatom Seminavis robusta was identified by comparative metabolomics, subsequently purified, and physicochemically characterized. Transcriptome analysis revealed that SIP+ triggers the switch from mitosis-to-meiosis in the opposing mating type, coupled with the transcriptional induction of proline biosynthesis genes, and the release of the proline-derived attraction pheromone. The induction of cell cycle arrest by a pheromone, chemically distinct from the one used to attract the opposite mating type, highlights the existence of a sophisticated mechanism to increase chances of mate finding, while keeping the metabolic losses associated with the release of an attraction pheromone to a minimum. PMID:26786712

  7. Inhibition of root growth by narciclasine is caused by DNA damage-induced cell cycle arrest in lettuce seedlings.

    PubMed

    Hu, Yanfeng; Li, Jiaolong; Yang, Lijing; Nan, Wenbin; Cao, Xiaoping; Bi, Yurong

    2014-09-01

    Narciclasine (NCS) is an Amaryllidaceae alkaloid isolated from Narcissus tazetta bulbs. Its phytotoxic effects on plant growth were examined in lettuce (Lactuca sativa L.) seedlings. Results showed that high concentrations (0.5-5 μM) of NCS restricted the growth of lettuce roots in a dose-dependent manner. In NCS-treated lettuce seedlings, the following changes were detected: reduction of mitotic cells and cell elongation in the mature region, inhibition of proliferation of meristematic cells, and cell cycle. Moreover, comet assay and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay indicated that higher levels NCS (0.5-5 μM) induced DNA damage in root cells of lettuce. The decrease in meristematic cells and increase in DNA damage signals in lettuce roots in responses to NCS are in a dose-dependent manner. NCS-induced reactive oxygen species accumulation may explain an increase in DNA damage in lettuce roots. Thus, the restraint of root growth is due to cell cycle arrest which is caused by NCS-induced DNA damage. In addition, it was also found that NCS (0.5-5 μM) inhibited the root hair development of lettuce seedlings. Further investigations on the underlying mechanism revealed that both auxin and ethylene signaling pathways are involved in the response of root hairs to NCS. PMID:24482192

  8. Light-mediated DNA Repair Prevents UVB-induced Cell Cycle Arrest in Embryos of the Crustacean Macrobrachium olfersi.

    PubMed

    Zeni, Eliane Cristina; Ammar, Dib; Leal, Mayana Lacerda; da Silva, Heloisa Schramm; Allodi, Silvana; Müller, Yara Maria Rauh; Nazari, Evelise Maria

    2015-01-01

    High levels of ultraviolet-B (UVB) radiation can negatively affect aquatic animals. Macrobrachium olfersi is a prawn that lives in clear freshwaters and during the breeding season, females carry eggs in an external brood pouch. Therefore, we hypothesize that eggs are also exposed to environmental UVB radiation. The aim of this study was to investigate whether UVB radiation induces DNA damage and compromises cell cycle in embryos of M. olfersi. In laboratory, UVB irradiance (310 mW. cm(-2) ) that embryos receive in the natural environment was simulated. After irradiation, embryos were kept under different light conditions in order to recognize the presence of cell repair. UVB radiation induces DNA damage, specifically thymine dimers. After 48 h of UVB exposure, a significant decrease in the level of these dimers was observed in embryos kept under visible light while it remained constant in the dark. Moreover, under visible light and darkness, a decrease in proliferation was observed after 48 h of irradiation. An increase in PCNA expression and decrease in p53 expression were observed after, respectively, 1 and 48 h of exposure. Our results showed that UVB radiation disturbs the cell cycle and induces DNA damage in M. olfersi embryos. However, under visible light these embryos showed successful DNA repair.

  9. Alisertib Induces Cell Cycle Arrest, Apoptosis, Autophagy and Suppresses EMT in HT29 and Caco-2 Cells

    PubMed Central

    Ren, Bao-Jun; Zhou, Zhi-Wei; Zhu, Da-Jian; Ju, Yong-Le; Wu, Jin-Hao; Ouyang, Man-Zhao; Chen, Xiao-Wu; Zhou, Shu-Feng

    2015-01-01

    Colorectal cancer (CRC) is one of the most common malignancies worldwide with substantial mortality and morbidity. Alisertib (ALS) is a selective Aurora kinase A (AURKA) inhibitor with unclear effect and molecular interactome on CRC. This study aimed to evaluate the molecular interactome and anticancer effect of ALS and explore the underlying mechanisms in HT29 and Caco-2 cells. ALS markedly arrested cells in G2/M phase in both cell lines, accompanied by remarkable alterations in the expression level of key cell cycle regulators. ALS induced apoptosis in HT29 and Caco-2 cells through mitochondrial and death receptor pathways. ALS also induced autophagy in HT29 and Caco-2 cells, with the suppression of phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR), but activation of 5′ AMP-activated protein kinase (AMPK) signaling pathways. There was a differential modulating effect of ALS on p38 MAPK signaling pathway in both cell lines. Moreover, induction or inhibition of autophagy modulated basal and ALS-induced apoptosis in both cell lines. ALS potently suppressed epithelial to mesenchymal transition (EMT) in HT29 and Caco-2 cells. Collectively, it suggests that induction of cell cycle arrest, promotion of apoptosis and autophagy, and suppression of EMT involving mitochondrial, death receptor, PI3K/Akt/mTOR, p38 MAPK, and AMPK signaling pathways contribute to the cancer cell killing effect of ALS on CRC cells. PMID:26729093

  10. Inhibition of root growth by narciclasine is caused by DNA damage-induced cell cycle arrest in lettuce seedlings.

    PubMed

    Hu, Yanfeng; Li, Jiaolong; Yang, Lijing; Nan, Wenbin; Cao, Xiaoping; Bi, Yurong

    2014-09-01

    Narciclasine (NCS) is an Amaryllidaceae alkaloid isolated from Narcissus tazetta bulbs. Its phytotoxic effects on plant growth were examined in lettuce (Lactuca sativa L.) seedlings. Results showed that high concentrations (0.5-5 μM) of NCS restricted the growth of lettuce roots in a dose-dependent manner. In NCS-treated lettuce seedlings, the following changes were detected: reduction of mitotic cells and cell elongation in the mature region, inhibition of proliferation of meristematic cells, and cell cycle. Moreover, comet assay and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay indicated that higher levels NCS (0.5-5 μM) induced DNA damage in root cells of lettuce. The decrease in meristematic cells and increase in DNA damage signals in lettuce roots in responses to NCS are in a dose-dependent manner. NCS-induced reactive oxygen species accumulation may explain an increase in DNA damage in lettuce roots. Thus, the restraint of root growth is due to cell cycle arrest which is caused by NCS-induced DNA damage. In addition, it was also found that NCS (0.5-5 μM) inhibited the root hair development of lettuce seedlings. Further investigations on the underlying mechanism revealed that both auxin and ethylene signaling pathways are involved in the response of root hairs to NCS.

  11. Bioactive compounds of Eriocaulon sieboldianum blocking proliferation and inducing apoptosis of HepG2 cells might be involved in Aurora kinase inhibition.

    PubMed

    Fan, Yanhua; Lu, Hongyuan; Ma, Hongda; Feng, Fan; Hu, Xiaolong; Zhang, Qiao; Wang, Jian; Xu, Yongnan; Zhao, Qingchun

    2015-12-01

    Eriocaulon sieboldianum (Sieb. & Zucc. ex Steud.) is an edible and medicinal plant used in traditional Chinese medicine. Often in combination with other herbs, it is processed into healthcare beverages for expelling wind-heat, protecting eyes, and reducing blood lipids. Besides, its water decoction together with other herbs has been utilized to treat cancer in China. However, the active ingredients and the precise cellular mechanisms of E. sieboldianum remain to be elucidated. The Aurora kinase family plays critical roles in the regulation of cell division and has attracted great attention to the identification of small-molecule Aurora kinase inhibitors for potential treatment of cancer. A molecular docking study was employed for docking of the most bioactive compounds. Hispidulin (HPDL) and quercetin-3-O-(6''-O-galloyl)-β-D-galactopyranoside (QGGP) were singled out as potent inhibitors of Aurora kinase. Their inhibitory activity towards Aurora kinase was further confirmed by the obvious decrease in autophosphorylation of Aurora-A (Thr288) and Aurora-B (Thr232). Moreover, the induction of cell cycle arrest in HepG2 cells and the suppressed phosphorylation of histone H3 were also consistent with the inhibition of Aurora kinase. The data indicate that the E. sieboldianum extract and its two active compounds, HPDL and QGGP, could effectively induce apoptosis via p53, MAPKs and the mitochondrial apoptotic pathways. These findings could improve the understanding and enhance the development of drugs based on E. sieboldianum and raise its application value in anticancer therapy or prevention. In addition, our results indicated that Aurora kinase might be a novel target of HPDL and QGGP. PMID:26369427

  12. Bioactive compounds of Eriocaulon sieboldianum blocking proliferation and inducing apoptosis of HepG2 cells might be involved in Aurora kinase inhibition.

    PubMed

    Fan, Yanhua; Lu, Hongyuan; Ma, Hongda; Feng, Fan; Hu, Xiaolong; Zhang, Qiao; Wang, Jian; Xu, Yongnan; Zhao, Qingchun

    2015-12-01

    Eriocaulon sieboldianum (Sieb. & Zucc. ex Steud.) is an edible and medicinal plant used in traditional Chinese medicine. Often in combination with other herbs, it is processed into healthcare beverages for expelling wind-heat, protecting eyes, and reducing blood lipids. Besides, its water decoction together with other herbs has been utilized to treat cancer in China. However, the active ingredients and the precise cellular mechanisms of E. sieboldianum remain to be elucidated. The Aurora kinase family plays critical roles in the regulation of cell division and has attracted great attention to the identification of small-molecule Aurora kinase inhibitors for potential treatment of cancer. A molecular docking study was employed for docking of the most bioactive compounds. Hispidulin (HPDL) and quercetin-3-O-(6''-O-galloyl)-β-D-galactopyranoside (QGGP) were singled out as potent inhibitors of Aurora kinase. Their inhibitory activity towards Aurora kinase was further confirmed by the obvious decrease in autophosphorylation of Aurora-A (Thr288) and Aurora-B (Thr232). Moreover, the induction of cell cycle arrest in HepG2 cells and the suppressed phosphorylation of histone H3 were also consistent with the inhibition of Aurora kinase. The data indicate that the E. sieboldianum extract and its two active compounds, HPDL and QGGP, could effectively induce apoptosis via p53, MAPKs and the mitochondrial apoptotic pathways. These findings could improve the understanding and enhance the development of drugs based on E. sieboldianum and raise its application value in anticancer therapy or prevention. In addition, our results indicated that Aurora kinase might be a novel target of HPDL and QGGP.

  13. Impurity induced antiferromagnetic order in Haldane gap compound SrNi2-xMgxV2O8

    NASA Astrophysics Data System (ADS)

    Pahari, B.; Ghoshray, K.; Ghoshray, A.; Samanta, T.; Das, I.

    2007-05-01

    The effect of nonmagnetic Mg doping in SrNi2V2O8, a Haldane gap system with a disordered ground state, was investigated using DC magnetic susceptibility and heat capacity measurements in polycrystalline samples of SrNi2-xMgxV2O8 with x=0.03, 0.05, 0.07, 0.1 and 0.14. The results clearly reveal that the substitution of Ni(S=1) ion by Mg(S=0) ion induces a magnetic phase transition with the ordering temperatures lying in the range 3.4-4.3 K, for the samples with lowest and highest value of x. The intrachain exchange constant (J/kB) and the Haldane gap (Δ) for all the compounds were estimated to be ∼98±2 and 25 K, respectively, which are close to that of the undoped compound. The magnetization data further suggest that the compounds exhibit metamagnetic behavior below TN, supporting a picture of antiferromagnet with significant magnetic anisotropy and competing intrachain and interchain interactions.

  14. Cytotoxicity of atropine to human corneal epithelial cells by inducing cell cycle arrest and mitochondrion-dependent apoptosis.

    PubMed

    Tian, Cheng-Lei; Wen, Qian; Fan, Ting-Jun

    2015-10-01

    Atropine is an anticholinergic drug for mydriasis in eye clinic, and its abuse might be cytotoxic to the cornea and result in blurred vision. However, the cytotoxicity of atropine to the cornea and its cellular and molecular mechanisms remain unknown. In this study, we investigated the cytotoxicity of atropine to corneal epithelium and its underlying mechanisms using an in vitro model of non-transfected human corneal epithelial (HCEP) cells. Our results showed that atropine, above the concentration of 0.3125 g/l (1/32 of its therapeutic dosage in eye clinic), had a dose- and time-dependent toxicity to HCEP cells by inducing morphological abnormality, cytopathic effect, viability decline, and proliferation retardation. Moreover, the proliferation-retarding effect of atropine on the cells was achieved by inducing G1/S phase arrest and downregulation of E-cadherin and β-catenin. Besides, atropine also had an apoptosis-inducing effect on the cells by inducing phosphatidylserine externalization, plasma membrane permeability elevation, DNA fragmentation and apoptotic body formation. Furthermore, atropine could also induce activations of caspase-2, -3 and -9, disruption of mitochondrial transmembrane potential, downregulation of Bcl-2 and Bcl-xL, upregulation of Bax and Bad, and upregulation of cytoplasmic cytochrome c and apoptosis-inducing factor, implying a death receptor-mediated mitochondrion-dependent pathway is most probably involved in the apoptosis of HCEP cells induced by atropine. Taken together, our results suggest that atropine has remarkable cytotoxicity to HCEP cells by inducing cell cycle arrest and death receptor-mediated mitochondrion-dependent apoptosis.

  15. Somatostatin receptor-1 induces cell cycle arrest and inhibits tumor growth in pancreatic cancer.

    PubMed

    Li, Min; Wang, Xiaochi; Li, Wei; Li, Fei; Yang, Hui; Wang, Hao; Brunicardi, F Charles; Chen, Changyi; Yao, Qizhi; Fisher, William E

    2008-11-01

    Functional somatostatin receptors (SSTR) are lost in human pancreatic cancer. Transfection of SSTR-1 inhibited pancreatic cancer cell proliferation in vitro. We hypothesize that stable transfection of SSTR-1 may inhibit pancreatic cancer growth in vivo possibly through cell cycle arrest. In this study, we examined the expression of SSTR-1 mRNA in human pancreatic cancer tissue specimens, and investigated the effect of SSTR-1 overexpression on cell proliferation, cell cycle, and tumor growth in a subcutaneous nude mouse model. We found that SSTR-1 mRNA was downregulated in the majority of pancreatic cancer tissue specimens. Transfection of SSTR-1 caused cell cycle arrest at the G(0)/G(1) growth phase, with a corresponding decline of cells in the S (mitotic) phase. The overexpression of SSTR-1 significantly inhibited subcutaneous tumor size by 71% and 43% (n = 5, P < 0.05, Student's t-test), and inhibited tumor weight by 69% and 47% (n = 5, P < 0.05, Student's t-test), in Panc-SSTR-1 and MIA-SSTR-1 groups, respectively, indicating the potent inhibitory effect of SSTR-1 on pancreatic cancer growth. Our data demonstrate that overexpression of SSTR-1 significantly inhibits pancreatic cancer growth possibly through cell cycle arrest. This study suggests that gene therapy with SSTR-1 may be a potential adjuvant treatment for pancreatic cancer.

  16. Somatostatin Receptor-1 Induces Cell Cycle Arrest and Inhibits Tumor Growth in Pancreatic Cancer

    PubMed Central

    Li, Min; Wang, Xiaochi; Li, Wei; Li, Fei; Yang, Hui; Wang, Hao; Brunicardi, F. Charles; Chen, Changyi; Yao, Qizhi; Fisher, William E.

    2010-01-01

    Functional somatostatin receptors (SSTRs) are lost in human pancreatic cancer. Transfection of SSTR-1 inhibited pancreatic cancer cell proliferation in vitro. We hypothesize that stable transfection of SSTR-1 may inhibit pancreatic cancer growth in vivo possibly through cell cycle arrest. In this study, we examined the expression of SSTR-1 mRNA in human pancreatic cancer tissue specimens, and investigated the effect of SSTR-1 overexpression on cell proliferation, cell cycle, and tumor growth in in a subcutaneous nude mouse model. We found that SSTR-1 mRNA was downregulated in the majority of pancreatic cancer tissue specimens. Transfection of SSTR-1 caused cell cycle arrest at the G0/G1 growth phase, with a corresponding decline of cells in the S (mitotic) phase. The overexpression of SSTR-1 significantly inhibited subcutaneous tumor size by 71% and 43% (n=5, p<0.05, t-test), and inhibited tumor weight by 69% and 47%, (n=5, p<0.05, t-test), in Panc-SSTR-1 and MIA-SSTR-1 groups, respectively, indicating the potent inhibitory effect of SSTR-1 on pancreatic cancer growth. Our data demonstrate that overexpression of SSTR-1 significantly inhibits pancreatic cancer growth possibly through cell cycle arrest. This study suggests that gene therapy with SSTR-1 may be a potential adjuvant treatment for pancreatic cancer. PMID:18823376

  17. Time-Course of Changes in Choroidal Thickness after Complete Mydriasis Induced by Compound Tropicamide in Children

    PubMed Central

    Zeng, Junwen; Jin, Wei; Long, Wen; Lan, Weizhong; Yang, Xiao

    2016-01-01

    Purpose The aim of this study was to investigate the time-course of changes in choroidal thickness (ChT) following complete mydriasis induced by compound tropicamide. Methods ChT was measured by OCT with the enhanced-depth imaging technique (Spectralis HRA+OCT, Heidelberg Engineering, Germany) at nine locations of the fundus: subfoveal ChT (SFChT) and ChT at 1 mm and 3 mm from the fovea in four quadrants. Mydriasis was induced with compound tropicamide (0.5% tropicamide plus 0.5% phenylephrine hydrochloride, three doses at 5-minute intervals). Measurements were conducted prior to the instillation and at 0, 30, and 60 min following complete mydriasis. Results at different time-points were compared using repeated-measures ANOVA to investigate the time-course of the changes. Results Thirty-nine subjects (mean age 11.9±2 years; 16 males and 23 females) were enrolled in the study. Compound tropicamide resulted in a statistically significant decrease in SFChT at 0, 30, and 60 min after complete mydriasis, as compared to baseline (−5±4 μm, −12±4 μm, and −13±4 μm, respectively; all P<0.0001). No significant changes were detected in the parafoveal choroid except at 1 mm temporal (T1mm) and nasal (N1mm) to the fovea at 30 and 60 min (T1mm: −6±4 μm and −7±5 μm at 30 and 60 min; N1mm: −6±4 μm and −7±5 μm at 30 and 60 min, respectively; all P<0.0001). Repeated-measures ANOVA showed a significant interaction between the time after complete mydriasis and the effect of the mydriasis agent. Conclusions Complete mydriasis induced by compound tropicamide led to choroidal thinning, and the magnitude varied over time. PMID:27622495

  18. No exercise-induced increase in serum BDNF after cycling near a major traffic road.

    PubMed

    Bos, I; Jacobs, L; Nawrot, T S; de Geus, B; Torfs, R; Int Panis, L; Degraeuwe, B; Meeusen, R

    2011-08-15

    Commuting by bike has a clear health enhancing effect. Moreover, regular exercise is known to improve brain plasticity, which results in enhanced cognition and memory performance. Animal research has clearly shown that exercise upregulates brain-derived neurotrophic factor (BDNF - a neurotrophine) enhancing brain plasticity. Studies in humans found an increase in serum BDNF concentration in response to an acute exercise bout. Recently, more evidence is emerging suggesting that exposure to air pollution (such as particulate matter (PM)) is higher in commuter cyclists compared to car drivers. Furthermore, exposure to PM is linked to negative neurological effects, such as neuroinflammation and cognitive decline. We carried-out a cross-over experiment to examine the acute effect of exercise on serum BDNF, and the potential effect-modification by exposure to traffic-related air pollution. Thirty eight physically fit, non-asthmatic volunteers (mean age: 43, 26% women) performed two cycling trials, one near a major traffic road (Antwerp Ring, R1, up to 260,000 vehicles per day) and one in an air-filtered room. The air-filtered room was created by reducing fine particles as well as ultrafine particles (UFP). PM10, PM2.5 and UFP were measured. The duration (∼20min) and intensity of cycling were kept the same for each volunteer for both cycling trials. Serum BDNF concentrations were measured before and 30min after each cycling trial. Average concentrations of PM10 and PM2.5 were 64.9μg/m(3) and 24.6μg/m(3) in cycling near a major ring way, in contrast to 7.7μg/m(3) and 2.0μg/m(3) in the air-filtered room. Average concentrations of UFP were 28,180 particles/cm(3) along the road in contrast to 496 particles/cm(3) in the air-filtered room. As expected, exercise significantly increased serum BDNF concentration after cycling in the air-filtered room (+14.4%; p=0.02). In contrast, serum BDNF concentrations did not increase after cycling near the major traffic route (+0.5%; p

  19. Poplar root exudates contain compounds that induce the expression of MiSSP7 in Laccaria bicolor.

    PubMed

    Plett, Jonathan M; Martin, Francis

    2012-01-01

    Communication between organisms is crucial for their survival, especially for sessile organisms such as plants that depend upon interactions with mutualistic organisms to maximize their nutrient acquisition. This communication can take the form of the exchange of volatile compounds, metabolites or effectors - small protein signals secreted from the colonizing cell that change the biology of the host cell.  We recently characterized the first mutualistic effector protein from an ectomycorrhizal fungus, a small secreted protein named MiSSP7 encoded by Laccaria bicolor.  Ectomycorrhizal fungi are soil-borne mutualistic organisms whose hyphae wrap around host roots and grow into the root apoplastic space where the fungus exchanges nutrients such as nitrogen and phosphorus in return for plant derived sugars.  The MiSSP7 protein is induced by root exudates and is highly expressed throughout the root colonization process.  Its presence was responsible for alterations to the plant transcriptomic profile, a mechanism by which MiSSP7 may aid in the formation of the symbiotic interface. Here we further discuss the implications of these findings and, further, we demonstrate that the production of MiSSP7 is induced by two flavonoids, rutin and quercitrin, a class of compounds normally found within the exudates of plant roots.  We also consider the interesting similarities between the mechanisms of effector induction and action between pathogenic and mutualistic fungi.  

  20. [Nervous system disorders induced by occupational exposure to aluminium compounds: a literature review].

    PubMed

    Sińczuk-Walczak, H

    2001-01-01

    This is a review of the literature on the effect of aluminum (Al) and its compounds on the nervous system. The role of aluminum in etiology of some degenerative diseases of the nervous system, e.g. Alzheimer disease, amyotrophic lateral sclerosis or dementia, is presented. The special attention was turned to the effects of aluminum on the nervous system functions in persons occupationally exposed to metal-containing dusts and fumes, manifested mostly by neurobehavioral disorders and changes in the brain bioelectric functions and less frequently pronounced by clinical neurological symptoms.

  1. Intercalation-induced phases in layer compounds of the A /SUP III/ B /SUP VI/ -type

    SciTech Connect

    Kovalyuk, Z.D.; Pyrlya, M.N.; Seredyuk, A.I.; Tovstyuk, K.D.

    1986-03-01

    The authors investigate the kinetics of combined electrochemical intercalation and the physicochemical properties of the introduced phases. InSe and GaSe single crystals were used in the experiments; the crystals were grown by the Bridgman method. The authors determined the concentration dependences of the electrode potentials and electrical conductivity of the compounds InSe and GaSe intercalated with lithium and lead. The results of the measurements are presented. Lithium and lead enter into the matrix of the crystals in a nonconducting state.

  2. Large drought-induced variations in oak leaf volatile organic compound emissions during PINOT NOIR 2012

    SciTech Connect

    Geron, Chris; Gu, Lianhong; Daly, Ryan; Harley, Peter; Rasmussen, Rei; Seco, Roger; Guenther, Alex; Karl, Thomas

    2015-12-17

    Here, leaf-level isoprene and monoterpene emissions were collected and analyzed from five of the most abundant oak (Quercus) species in Central Missouri's Ozarks Region in 2012 during PINOT NOIR (Particle Investigations at a Northern Ozarks Tower – NOx, Oxidants, Isoprene Research). June measurements, prior to the onset of severe drought, showed isoprene emission rates and leaf temperature responses similar to those previously reported in the literature and used in Biogenic Volatile Organic Compound (BVOC) emission models. During the peak of the drought in August, isoprene emission rates were substantially reduced, and response to temperature was dramatically altered, especially for the species in the red oak subgenus (Erythrobalanus).

  3. Geomagnetically Induced Currents, a space weather hazard. Case study - Europe under intense geomagnetic storms of the solar cycle 23

    NASA Astrophysics Data System (ADS)

    Dobrica, V.; Demetrescu, Cr.; Stefan, C.; Greculeasa, R.

    2016-05-01

    The interaction of the solar wind and heliospheric magnetic field with the magnetosphere and ionosphere results in variations of the geomagnetic field that induce hazardous electric currents in grounded technological systems (electric power and hydrocarbon transportation networks), the so-called geomagnetically induced currents (GICs). In order to evaluate the hazard induced on the European continent, we present a study of the surface electric field induced by 16 intense (Dst < -150 nT) geomagnetic storms, based on the analysis of the geomagnetic records from the European network of observatories, study that tend to solve the geophysical part of the problem. The evolution during storm development and the sources of the disturbance field are explored in case of the largest geomagnetic storm in the cycle 23 (Dst = -422 nT, November 20-21, 2003), and the geographical distribution of the maximum induced surface geoelectric field over Europe by the 16 storms considered in the study is presented. As source proxies, the Dst geomagnetic index, showing the disturbed field produced by the magnetospheric ring current at the geomagnetic equator, the AL geomagnetic index, showing the disturbed field produced by the ionospheric electrojet at auroral latitude, and the PC geomagnetic index, showing the disturbed field produced by the polar cap current, were examined.

  4. Benzo[a]pyrene-induced cell cycle progression occurs via ERK-induced Chk1 pathway activation in human lung cancer cells.

    PubMed

    Wang, Bing-Yen; Wu, Sung-Yu; Tang, Sheau-Chung; Lai, Chien-Hung; Ou, Chu-Chyn; Wu, Ming-Fang; Hsiao, Yi-Min; Ko, Jiunn-Liang

    2015-03-01

    Benzo[a]pyrene (B[a]P) is a potent lung carcinogen derived from tobacco smoking and environmental contamination. This study aimed to investigate the signal transduction pathway responsible for B[a]P-induced non-small cell lung cancer (NSCLC) development. We exposed the human NSCLC cell lines Calu-1, CL3, H1299, CH27, H23, and H1355 to B[a]P and assessed cell cycle progression using flow cytometry. Expression of cell cycle mediators was measured using Western blot analyses and electrophoretic mobility shift assays (EMSAs). B[a]P exposure dramatically induced S-phase accumulation in H1355 cells. Phospho-p53 (Ser15 and Ser20), phospho-ERK, phospho-p38, and Bax were significantly increased in H1355 cells whereas phospho-Rb was decreased in these cells. In addition, B[a]P induced phosphorylation of checkpoint kinase-1 (Chk1) but not Chk2. EMSA experiments revealed a slower migrating band after c-Myc bound the E-box in response to B[a]P treatment, which was abolished upon the addition of the ERK inhibitor PD98059 in H1355 cells. Phospho-ERK inhibition and dominant negative mutant Chk1 expression reversed B[a]P-induced S phase accumulation and downregulated phospho-Chk1 and phospho-ERK expression. Taken together, these results suggest that activation of ERK and its downstream mediator Chk1 may contribute to B[a]P-induced S phase accumulation in H1355 cells. The results could help in the development of lung cancer treatments that target the Chk1 pathway through ERK.

  5. An Evaluation of Sensor Performance for Harmful Compounds by Using Photo-Induced Electron Transfer from Photosynthetic Membranes to Electrodes

    PubMed Central

    Kasuno, Megumi; Kimura, Hiroki; Yasutomo, Hisataka; Torimura, Masaki; Murakami, Daisuke; Tsukatani, Yusuke; Hanada, Satoshi; Matsushita, Takayuki; Tao, Hiroaki

    2016-01-01

    Rapid, simple, and low-cost screening procedures are necessary for the detection of harmful compounds in the effluent that flows out of point sources such as industrial outfall. The present study investigated the effects on a novel sensor of harmful compounds such as KCN, phenol, and herbicides such as 3-(3,4-dichlorophenyl)-1,1-dimethylurea (DCMU), 2-chloro-4-ethylamino-6-isopropylamino-1,3,5-triazine (atrazine), and 2-N-tert-butyl-4-N-ethyl-6-methylsulfanyl-1,3,5-triazine-2,4-diamine (terbutryn). The sensor employed an electrode system that incorporated the photocurrent of intra-cytoplasmic membranes (so-called chromatophores) prepared from photosynthetic bacteria and linked using carbon paste electrodes. The amperometric curve (photocurrent-time curve) of photo-induced electron transfer from chromatophores of the purple photosynthetic bacterium Rhodobacter sphaeroides to the electrode via an exogenous electron acceptor was composed of two characteristic phases: an abrupt increase in current immediately after illumination (I0), and constant current over time (Ic). Compared with other redox compounds, 2,5-dichloro-1,4-benzoquinone (DCBQ) was the most useful exogenous electron acceptor in this system. Photo-reduction of DCBQ exhibited Michaelis-Menten-like kinetics, and reduction rates were dependent on the amount of DCBQ and the photon flux intensity. The Ic decreased in the presence of KCN at concentrations over 0.05 μM (=μmol·dm−3). The I0 decreased following the addition of phenol at concentrations over 20 μM. The Ic was affected by terbutryn at concentrations over 10 μM. In contrast, DCMU and atrazine had no effect on either I0 or Ic. The utility of this electrode system for the detection of harmful compounds is discussed. PMID:27023553

  6. An Evaluation of Sensor Performance for Harmful Compounds by Using Photo-Induced Electron Transfer from Photosynthetic Membranes to Electrodes.

    PubMed

    Kasuno, Megumi; Kimura, Hiroki; Yasutomo, Hisataka; Torimura, Masaki; Murakami, Daisuke; Tsukatani, Yusuke; Hanada, Satoshi; Matsushita, Takayuki; Tao, Hiroaki

    2016-01-01

    Rapid, simple, and low-cost screening procedures are necessary for the detection of harmful compounds in the effluent that flows out of point sources such as industrial outfall. The present study investigated the effects on a novel sensor of harmful compounds such as KCN, phenol, and herbicides such as 3-(3,4-dichlorophenyl)-1,1-dimethylurea (DCMU), 2-chloro-4-ethylamino-6-isopropylamino-1,3,5-triazine (atrazine), and 2-N-tert-butyl-4-N-ethyl-6-methylsulfanyl-1,3,5-triazine-2,4-diamine (terbutryn). The sensor employed an electrode system that incorporated the photocurrent of intra-cytoplasmic membranes (so-called chromatophores) prepared from photosynthetic bacteria and linked using carbon paste electrodes. The amperometric curve (photocurrent-time curve) of photo-induced electron transfer from chromatophores of the purple photosynthetic bacterium Rhodobacter sphaeroides to the electrode via an exogenous electron acceptor was composed of two characteristic phases: an abrupt increase in current immediately after illumination (I₀), and constant current over time (Ic). Compared with other redox compounds, 2,5-dichloro-1,4-benzoquinone (DCBQ) was the most useful exogenous electron acceptor in this system. Photo-reduction of DCBQ exhibited Michaelis-Menten-like kinetics, and reduction rates were dependent on the amount of DCBQ and the photon flux intensity. The Ic decreased in the presence of KCN at concentrations over 0.05 μM (=μmol·dm(-3)). The I₀ decreased following the addition of phenol at concentrations over 20 μM. The Ic was affected by terbutryn at concentrations over 10 μM. In contrast, DCMU and atrazine had no effect on either I₀ or Ic. The utility of this electrode system for the detection of harmful compounds is discussed. PMID:27023553

  7. Design of a symmetry controller for cycling induced by electrical stimulation: preliminary results on post-acute stroke patients.

    PubMed

    Ambrosini, Emilia; Ferrante, Simona; Schauer, Thomas; Ferrigno, Giancarlo; Molteni, Franco; Pedrocchi, Alessandra

    2010-08-01

    This study deals with the design of a controller for cycling induced by functional electrical stimulation. The controller will be exploitable in the rehabilitation of hemiparetic patients who need to recover motor symmetry. It uses the pulse width as the control variable in the stimulation of the two legs in order to nullify the unbalance between the torques produced at the two crank arms. It was validated by means of isokinetic trials performed both by healthy subjects and stroke patients. The results showed that the controller was able to reach, and then maintain, a symmetrical pedaling. In the future, the controller will be validated on a larger number of stroke patients.

  8. Design of a symmetry controller for cycling induced by electrical stimulation: preliminary results on post-acute stroke patients.

    PubMed

    Ambrosini, Emilia; Ferrante, Simona; Schauer, Thomas; Ferrigno, Giancarlo; Molteni, Franco; Pedrocchi, Alessandra

    2010-08-01

    This study deals with the design of a controller for cycling induced by functional electrical stimulation. The controller will be exploitable in the rehabilitation of hemiparetic patients who need to recover motor symmetry. It uses the pulse width as the control variable in the stimulation of the two legs in order to nullify the unbalance between the torques produced at the two crank arms. It was validated by means of isokinetic trials performed both by healthy subjects and stroke patients. The results showed that the controller was able to reach, and then maintain, a symmetrical pedaling. In the future, the controller will be validated on a larger number of stroke patients. PMID:20528850

  9. Electrophilic iodine(I) compounds induced semipinacol rearrangement via C-X bond cleavage.

    PubMed

    Tsuji, Nobuya; Kobayashi, Yusuke; Takemoto, Yoshiji

    2014-11-18

    Neutral electrophilic iodine(I) species proved to be efficient reagents for C-X bond cleavage of various cyclic and acyclic α-silyloxyhalides, and the induced desilylative semipinacol rearrangement provided the corresponding ketones in good yields. The reaction is operationally simple, and proceeds under mild conditions with good functional group compatibility. Mechanistic investigations, including computational studies, were also performed.

  10. Bioassay-Guided Isolation of Neuroprotective Compounds from Uncaria rhynchophylla against Beta-Amyloid-Induced Neurotoxicity

    PubMed Central

    Xian, Yan-Fang; Lin, Zhi-Xiu; Mao, Qing-Qiu; Hu, Zhen; Zhao, Ming; Che, Chun-Tao; Ip, Siu-Po

    2012-01-01

    Uncaria rhynchophylla is a component herb of many Chinese herbal formulae for the treatment of neurodegenerative diseases. Previous study in our laboratory has demonstrated that an ethanol extract of Uncaria rhynchophylla ameliorated cognitive deficits in a mouse model of Alzheimer's disease induced by D-galactose. However, the active ingredients of Uncaria rhynchophylla responsible for the anti-Alzheimer's disease activity have not been identified. This study aims to identify the active ingredients of Uncaria rhynchophylla by a bioassay-guided fractionation approach and explore the acting mechanism of these active ingredients by using a well-established cellular model of Alzheimer's disease, beta-amyloid- (Aβ-) induced neurotoxicity in PC12 cells. The results showed that six alkaloids, namely, corynoxine, corynoxine B, corynoxeine, isorhynchophylline, isocorynoxeine, and rhynchophylline were isolated from the extract of Uncaria rhynchophylla. Among them, rhynchophylline and isorhynchophylline significantly decreased Aβ-induced cell death, intracellular calcium overloading, and tau protein hyperphosphorylation in PC12 cells. These results suggest that rhynchophylline and isorhynchophylline are the major active ingredients responsible for the protective action of Uncaria rhynchophylla against Aβ-induced neuronal toxicity, and their neuroprotective effect may be mediated, at least in part, by inhibiting intracellular calcium overloading and tau protein hyperphosphorylation. PMID:22778778

  11. Magnetic Precursor of the Pressure-Induced Superconductivity in Fe-Ladder Compounds

    DOE PAGES

    Chi, Songxue; Uwatoko, Yoshiya; Cao, Huibo; Hirata, Yasuyuki; Hashizume, Kazuki; Aoyama, Takuya; Ohgushi, Kenya

    2016-07-21

    We studied the pressure effects on the antiferromagentic orders in iron-based ladder compounds CsFemore » $_2$Se$_3$ and BaFe$_2$S$_3$ using single crytal neutron diffraction technique. With identical crystal structure and similar magnetic structures, the two compounds exhibit highly contrasting magnetic behaviors under moderate external pressures. In CsFe$_2$Se$_3$ the ladders are brought much closer to each other by pressure, but the stripe-type of magnetic order shows no observable change. Furthermore, the stripe order in BaFe$_2$S$_3$, undergoes a quantum phase transition where an abrupt increase of $$N\\acute{e}el$$ temperature by more than 50$$\\%$$ occurs at about 1 GPa, accompanied by a jump in ordered moment. Finally, with its spin structure unchanged, BaFe$_2$S$_3$ enters an enhanced magnetic phase that bears the characteristics of an orbital selective Mott phase, which is the true herald for superconductivity emerging at higher pressures.« less

  12. Magnetic Precursor of the Pressure-Induced Superconductivity in Fe-Ladder Compounds.

    PubMed

    Chi, Songxue; Uwatoko, Yoshiya; Cao, Huibo; Hirata, Yasuyuki; Hashizume, Kazuki; Aoyama, Takuya; Ohgushi, Kenya

    2016-07-22

    The pressure effects on the antiferromagentic orders in iron-based ladder compounds CsFe_{2}Se_{3} and BaFe_{2}S_{3} have been studied using neutron diffraction. With identical crystal structure and similar magnetic structures, the two compounds exhibit highly contrasting magnetic behaviors under moderate external pressures. In CsFe_{2}Se_{3} the ladders are brought much closer to each other by pressure, but the stripe-type magnetic order shows no observable change. In contrast, the stripe order in BaFe_{2}S_{3} undergoes a quantum phase transition where an abrupt increase of Néel temperature by more than 50% occurs at about 1 GPa, accompanied by a jump in the ordered moment. With its spin structure unchanged, BaFe_{2}S_{3} enters an enhanced magnetic phase that bears the characteristics of an orbital selective Mott phase, which is the true neighbor of superconductivity emerging at higher pressures. PMID:27494496

  13. Vascular relaxation induced by Eucommiae Ulmoides Oliv. and its compounds Oroxylin A and wogonin: implications on their cytoprotection action

    PubMed Central

    Akinyi, Mary; Gao, Xiu Mei; Li, Yu Hong; Wang, Bing Yao; Liu, Er Wei; Chai, Li Juan; JawoBah, Abdulai; Fan, Guan Wei

    2014-01-01

    The vascular relaxation action of Eucommiae Ulmoides Oliv. also known as Duzhong has been seen on arteries of the heart such as the aorta and the coronary artery which are elastic in nature. Duzhong is historically an active ingredient commonly used in hypertensive herbal prescriptions in China. This work investigated the vasodilating effect of Duzhong and its compounds (wogonin 10 μM and oroxylin-A) in the isolated intact rat heart, perfused retrograde according the method of Langendorff and the cytoprotective effect in EA.hy926 cell lines Coronary perfusion pressure was monitored with a pressure transducer connected to a side-arm of the aortic perfusion cannula. Duzhong induced vasorelaxation in a dose dependent manner, on precontracting the vessels with endothelin-1, Duzhong 10 mg/ml, wogonin 10 μM and oroxylin-A 10 μM could significantly lower the perfusion pressure in reference to positive control SNP, Duzhong induced vasodilation was not inhibited by L-NAME (nitric oxide inhibitor), but was significantly inhibited by Tetraethyl ammonium (TEA, a K+ channel blocker and almost abolished by potassium chloride. The underlying mechanism was carried out in EA.hy926 cell lines. When these cells were treated with H2O2, there was higher expression of NOX-4, TNF-α and COX-2 mRNA. However, wogonin treatment attenuated the mRNA of NOX-4, TNF-α and COX-2. Wogonin also upregulated the mRNA expression of CAT, SOD-1 and GSR in oxidative stress induced by H2O2 EA.hy926 cells. Duzhong and compounds can exert an in vitro relaxation effect of the coronary artery and improve the heart function in Langendorff apparatus. This action appears to be endothelium dependent but not NO mediated. Cell culture findings indicated that wogonin can exert vascular and cellular protection by scavenging Reactive Oxygen Species. PMID:25419347

  14. Training effects induced by cycling of magnetic field in ferromagnetic rich phase-separated nanocomposite manganites

    NASA Astrophysics Data System (ADS)

    Das, Kalipada; Das, I.

    2015-12-01

    We have carried out an experimental investigation of magneto-transport and magnetic properties of charge-ordered Pr0.67Ca0.33MnO3 (PCMO) and ferromagnetic La0.67Sr0.33MnO3 (LSMO) nanoparticles along with a nanocomposite consisting of those two types of nanoparticles. From the magneto-transport measurements, clear irreversibility is observed in the field dependence of resistance due to magnetic field cycling in the case of PCMO nanoparticles. The value of resistance increases during such a field cycling. However such an irreversibility is absent in the case of LSMO nanoparticles as well as nanocomposites. On the other hand, the magnetic measurements indicate the gradual growth of antiferromagnetic phases in all samples leading to a decrease in magnetization. These inconsistencies between magneto-transport and magnetic behaviors are attributed to the magnetic training effects.

  15. mTORC1 Induces Purine Synthesis Through Control of the Mitochondrial Tetrahydrofolate Cycle

    PubMed Central

    Ricoult, Stéphane J.H.; Asara, John M.; Manning, Brendan D.

    2016-01-01

    In response to growth signals, mTOR complex 1 (mTORC1) stimulates anabolic processes underlying cell growth. We found that mTORC1 increases metabolic flux through the de novo purine synthesis pathway in various mouse and human cells, thereby influencing the nucleotide pool available for nucleic acid synthesis. mTORC1 had transcriptional effects on multiple enzymes contributing to purine synthesis, with expression of the mitochondrial tetrahydrofolate (mTHF) cycle enzyme methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) being closely associated with mTORC1 signaling in both normal and cancer cells. MTHFD2 expression and purine synthesis were stimulated by ATF4, which was activated by mTORC1 independent of its canonical induction downstream of eIF2α phosphorylation. Thus, mTORC1 stimulates the mTHF cycle, which contributes one-carbon units to enhance production of purine nucleotides in response to growth signals. PMID:26912861

  16. Finite Element Modeling of Thermal Cycling Induced Microcracking in Carbon/Epoxy Triaxial Braided Composites

    NASA Technical Reports Server (NTRS)

    Zhang, Chao; Binienda, Wieslaw K.; Morscher, Gregory; Martin, Richard E.

    2012-01-01

    The microcrack distribution and mass change in PR520/T700s and 3502/T700s carbon/epoxy braided composites exposed to thermal cycling was evaluated experimentally. Acoustic emission was utilized to record the crack initiation and propagation under cyclic thermal loading between -55 C and 120 C. Transverse microcrack morphology was investigated using X-ray Computed Tomography. Different performance of two kinds of composites was discovered and analyzed. Based on the observations of microcrack formation, a meso-mechanical finite element model was developed to obtain the resultant mechanical properties. The simulation results exhibited a decrease in strength and stiffness with increasing crack density. Strength and stiffness reduction versus crack densities in different orientations were compared. The changes of global mechanical behavior in both axial and transverse loading conditions were studied. Keywords: Thermal cycles; Microcrack; Finite Element Model; Braided Composite

  17. Regulation of oncogene-induced cell cycle exit and senescence by chromatin modifiers

    PubMed Central

    David, Gregory

    2012-01-01

    Oncogene activation leads to dramatic changes in numerous biological pathways controlling cellular division, and results in the initiation of a transcriptional program that promotes transformation. Conversely, it also triggers an irreversible cell cycle exit called cellular senescence, which allows the organism to counteract the potentially detrimental uncontrolled proliferation of damaged cells. Therefore, a tight transcriptional control is required at the onset of oncogenic signal, coordinating both positive and negative regulation of gene expression. Not surprisingly, numerous chromatin modifiers contribute to the cellular response to oncogenic stress. While these chromatin modifiers were initially thought of as mere mediators of the cellular response to oncogenic stress, recent studies have uncovered a direct and specific regulation of chromatin modifiers by oncogenic signals. We review here the diverse functions of chromatin modifiers in the cellular response to oncogenic stress, and discuss the implications of these findings on the regulation of cell cycle progression and proliferation by activated oncogenes. PMID:22825329

  18. Radiation-induced cell cycle delay measured in two mouse tumors in vivo using bromodeoxyuridine

    SciTech Connect

    Wilson, G.D.; Martindale, C.A.; Soranson, J.A.; Bourhis, J.; Carl, U.M.; McNally, N.J. )

    1994-02-01

    The magnitude of the delay of cells in the phases of the cell cycle after irradiation may be related to the radioresponsiveness of tumor cell populations. In this study we have quantified division delay in two mouse tumors in vivo after single and fractionated doses of X rays and single doses of neutrons. The incorporation of bromodeoxyuridine and flow cytometry provided a sensitive and quantitative method to detect cell cycle perturbations after radiation treatment. The more rapidly growing SAF tumor showed less G[sub 2]-phase delay per gray than a more slowly proliferating tumor, the Rh (0.9 vs 1.8 h). In addition, the SAF tumor failed to show any G[sub 1]/S-phase delay while the Rh tumor experienced a longer G[sub 1]-phase delay while the Rh tumor experienced a longer G[sub 1]-phase delay than that measured for G[sub 2] phase (3.1 vs 1.8 h). There was a trend in both tumors for lower doses to be more effective in producing cell cycle delays. Neutrons caused longer G[sub 2]-phase delays on a unit dose basis, 2.5 and 5.4 h for the SAF and Rh tumors, respectively. The RBE for neutrons for division delay was found to be 2.9 and 2.8 for the SAF and Rh tumors, while the RBE for growth delay was 3.4 and 3.5. Fractionation of the X-ray dose caused a reduction in division delay at higher total doses (10 or 12 Gy) but was without effect at the lower dose studied (6 Gy). These studies show the feasibility of measuring cell cycle delays in vivo, and future developments are suggested for a possible predictive test in patients receiving radiotherapy. 17 refs., 6 figs., 2 tabs.

  19. Jade-1S phosphorylation induced by CK1α contributes to cell cycle progression.

    PubMed

    Borgal, Lori; Rinschen, Markus M; Dafinger, Claudia; Liebrecht, Valérie I; Abken, Hinrich; Benzing, Thomas; Schermer, Bernhard

    2016-01-01

    The PHD zinc finger protein Jade-1S is a component of the HBO1 histone acetyltransferase complex and binds chromatin in a cell cycle-dependent manner. Jade-1S also acts as an E3 ubiquitin ligase for the canonical Wnt effector protein β-catenin and is influenced by CK1α-mediated phosphorylation. To further elucidate the functional impact of this phosphorylation, we used a stable, low-level expression system to express either wild-type or mutant Jade-1S lacking the N-terminal CK1α phosphorylation motif. Interactome analyses revealed that the Jade-1S mutant unable to be phosphorylated by CK1α has an increased binding affinity to proteins involved in chromatin remodelling, histone deacetylation, transcriptional repression, and ribosome biogenesis. Interestingly, cells expressing the mutant displayed an elongated cell shape and a delay in cell cycle progression. Finally, phosphoproteomic analyses allowed identification of a Jade-1S site phosphorylated in the presence of CK1α but closely resembling a PLK1 phosphorylation motif. Our data suggest that Jade-1S phosphorylation at an N-terminal CK1α motif creates a PLK1 phospho-binding domain. We propose CK1α phosphorylation of Jade 1S to serve as a molecular switch, turning off chromatin remodelling functions of Jade-1S and allowing timely cell cycle progression. As Jade-1S protein expression in the kidney is altered upon renal injury, this could contribute to understanding mechanisms underlying epithelial injury repair.

  20. Disorder-induced structural transitions in topological insulating Ge-Sb-Te compounds

    SciTech Connect

    Kim, Jeongwoo; Jhi, Seung-Hoon

    2015-05-21

    The mechanism for the fast switching between amorphous, metastable, and crystalline structures in chalcogenide phase-change materials has been a long-standing puzzle. Based on first-principles calculations, we study the atomic and electronic properties of metastable Ge{sub 2}Sb{sub 2}Te{sub 5} and investigate the atomic disorder to understand the transition between crystalline hexagonal and cubic structures. In addition, we study the topological insulating property embedded in these compounds and its evolution upon structural changes and atomic disorder. We also discuss the role of the surface-like states arising from the topological insulating property in the metal-insulator transition observed in the hexagonal structure.

  1. Strain induced topological phase transitions in monolayer honeycomb structures of group-V binary compounds

    PubMed Central

    Nie, Yaozhuang; Rahman, Mavlanjan; Wang, Daowei; Wang, Can; Guo, Guanghua

    2015-01-01

    We present first-principles calculations of electronic structures of a class of two-dimensional (2D) honeycomb structures of group-V binary compounds. Our results show these new 2D materials are stable semiconductors with direct or indirect band gaps. The band gap can be tuned by applying lattice strain. During their stretchable regime, they all exhibit metal-indirect gap semiconductor-direct gap semiconductor-topological insulator (TI) transitions with increasing strain from negative (compressive) to positive (tensile) values. The topological phase transition results from the band inversion at the Γ point which is due to the evolution of bonding and anti-bonding states under lattice strain. PMID:26656257

  2. SMN-inducing compounds for the treatment of spinal muscular atrophy

    PubMed Central

    Lorson, Monique A; Lorson, Christian L

    2013-01-01

    Spinal muscular atrophy (SMA) is a leading genetic cause of infant mortality. A neurodegenerative disease, it is caused by loss of SMN1, although low, but essential, levels of SMN protein are produced by the nearly identical gene SMN2. While no effective treatment or therapy currently exists, a new wave of therapeutics has rapidly progressed from cell-based and preclinical animal models to the point where clinical trials have initiated for SMA-specific compounds. There are several reasons why SMA has moved relatively rapidly towards novel therapeutics, including: SMA is monogenic; the molecular understanding of SMN gene regulation has been building for nearly 20 years; and all SMA patients retain one or more copies of SMN2 that produces low levels of full-length, fully functional SMN protein. This review primarily focuses upon the biology behind the disease and examines SMN1- and SMN2-targeted therapeutics. PMID:23157239

  3. Large drought-induced variations in oak leaf volatile organic compound emissions during PINOT NOIR 2012

    DOE PAGES

    Geron, Chris; Gu, Lianhong; Daly, Ryan; Harley, Peter; Rasmussen, Rei; Seco, Roger; Guenther, Alex; Karl, Thomas

    2015-12-17

    Here, leaf-level isoprene and monoterpene emissions were collected and analyzed from five of the most abundant oak (Quercus) species in Central Missouri's Ozarks Region in 2012 during PINOT NOIR (Particle Investigations at a Northern Ozarks Tower – NOx, Oxidants, Isoprene Research). June measurements, prior to the onset of severe drought, showed isoprene emission rates and leaf temperature responses similar to those previously reported in the literature and used in Biogenic Volatile Organic Compound (BVOC) emission models. During the peak of the drought in August, isoprene emission rates were substantially reduced, and response to temperature was dramatically altered, especially for themore » species in the red oak subgenus (Erythrobalanus).« less

  4. Active hexose correlated compound modulates LPS-induced hypotension and gut injury in rats.

    PubMed

    Doursout, Marie-Francoise; Liang, Yangyan; Sundaresan, Alamelu; Wakame, Koji; Fujii, Hajime; Takanari, Jun; Devakottai, Sundar; Kulkarni, Anil

    2016-10-01

    We hypothesized that AHCC; (Amino UP Chemical Co., Ltd., Sapporo, Japan), a mushroom mycelium extract obtained from liquid culture of Lentinula edodes, restores immune function in LPS-induced inflammation in the gut, especially when the nitric oxide signaling pathway is impaired. This is the first inter-disciplinary proposal to identify molecular mechanisms involved in LPS-induced immune dysfunction in the gut in conscious animals treated or non-treated with AHCC, a promoter of immune support. Specifically, we have tested the effects of AHCC on LPS-induced deleterious effects on blood pressure and gut injury in conscious rats. The time course of biological markers of innate/acquired immune responses, and inflammation/oxidative stress is fully described in the present manuscript. Rats were randomly assigned into 3 groups (N=6 per group). Group 1 received 10% of AHCC in drinking water for 5days; Group 2 received lipopolysaccharide (LPS; Escherichia coli 0111:B4 purchased from Sigma) only at 20mg/kg IV; Group 3 received combined treatments (AHCC + LPS). LPS was administered at 20mg/kg IV, 5days following AHCC treatment. We have demonstrated that AHCC decreased the LPS-deleterious effects of blood pressure and also decreased inflammatory markers e.g., cytokines, nitric oxide and edema formation. Finally, AHCC diminished lymphocyte infiltration, restoring gut architecture. Because AHCC was administered prior to LPS, our results indicate the potential impact of AHCC's prophylactic effects on LPS inflammation. Consequently, additional experiments are warrant to assess its therapeutic effects in sepsis-induced inflammation. PMID:27500458

  5. Pressure induced magneto-structural phase transitions in layered RMn2X2 compounds (invited)

    NASA Astrophysics Data System (ADS)

    Kennedy, Shane; Wang, Jianli; Campbell, Stewart; Hofmann, Michael; Dou, Shixue

    2014-05-01

    We have studied a range of pseudo-ternaries derived from the parent compound PrMn2Ge2, substituting for each constituent element with a smaller one to contract the lattice. This enables us to observe the magneto-elastic transitions that occur as the Mn-Mn nearest neighbour distance is reduced and to assess the role of Pr on the magnetism. Here, we report on the PrMn2Ge2-xSix, Pr1-xYxMn2Ge2, and PrMn2-xFexGe2 systems. The pressure produced by chemical substitution in these pseudo-ternaries is inherently non-uniform, with local pressure variations dependent on the local atomic distribution. We find that concentrated chemical substitution on the R or X site (e.g., in Pr0.5Y0.5Mn2Ge2 and PrMn2Ge0.8Si1.2) can produce a separation into two distinct magnetic phases, canted ferromagnetic and canted antiferromagnetic, with a commensurate phase gap in the crystalline lattice. This phase gap is a consequence of the combination of phase separation and spontaneous magnetostriction, which is positive on transition to the canted ferromagnetic phase and negative on transition to the canted antiferromagnetic phase. Our results show that co-existence of canted ferromagnetic and antiferromagnetic phases depends on chemical pressure from the rare earth and metalloid sites, on local lattice strain distributions and on applied magnetic field. We demonstrate that the effects of chemical pressure bear close resemblance to those of mechanical pressure on the parent compound.

  6. Chemotaxis of Rhizobium meliloti towards Nodulation Gene-Inducing Compounds from Alfalfa Roots

    PubMed Central

    Dharmatilake, Amitha J.; Bauer, Wolfgang D.

    1992-01-01

    Luteolin, a flavone present in seed exudates of alfalfa, induces nodulation genes (nod) in Rhizobium meliloti and also serves as a biochemically specific chemoattractant for the bacterium. The present work shows that R. meliloti RCR2011 is capable of very similar chemotactic responses towards 4′,7-dihydroxyflavone, 4′,7-Dihydroxyflavanone, and 4,4′-dihydroxy-2-methoxychalcone, the three principal nod gene inducers secreted by alfalfa roots. Chemotactic responses to the root-secreted nod inducers in capillary assays were usually two- to four-fold above background and, for the flavone and flavonone, occurred at concentrations lower than those required for half-maximal induction of the nodABC genes. Complementation experiments indicated that the lack of chemotactic responsiveness to luteolin seen in nodD1 and nodA mutants of R. meliloti was not due to mutations in the nod genes, as previously thought. Thus, while nod gene induction and flavonoid chemotaxis have the same biochemical specificity, these two functions appear to have independent receptors or transduction pathways. The wild-type strain was found to suffer selective, spontaneous loss of chemotaxis towards flavonoids during laboratory subculture. PMID:16348685

  7. Detection of Sugars via Chirality Induced in Europium(III) Compounds.

    PubMed

    Wu, Tao; Průša, Jiří; Kessler, Jiří; Dračínský, Martin; Valenta, Jan; Bouř, Petr

    2016-09-01

    Detection and resolution of simple monosaccharides are difficult tasks because their structure is quite similar. The present study shows that circularly polarized luminescence (CPL) induced in europium complexes provides very specific spectral patterns for fructose, mannose, glucose, and galactose. Differences were also observed between bare Eu(3+) ion and its complexes, when interacting with these sugars. The CPL spectra were measured on a Raman optical activity (ROA) spectrometer, which ensured high fluorescence intensity owing to the strong 532 nm laser excitation. The induced fluorescence was recorded in the same spectrum as the vibrational Raman bands. On the basis of the ligand field theory, most fluorescence spectral peaks could be assigned to f-shell europium transitions. Additional information on the interaction of the lanthanide with the sugar component was provided by measurement of time-dependent fluorescence, as formation of different complexes led to variations in fluorescence decay times. In nuclear magnetic resonance (NMR), the paramagnetic metal ion interacting with the sugars caused specific changes in (13)C chemical shifts. The spectroscopic data and molecular dynamics modeling showed that the interaction between the monosaccharides and Eu ion is rather weak due to the competition of the OH sugar groups with water molecules. However, multiple binding modes are possible, which contributes to the complexity and specificity of the spectra. The induced chirality and fluorescence spectra thus appear to be convenient means for monosaccharide detection and identification. PMID:27525502

  8. A genetically-based latitudinal cline in the emission of herbivore-induced plant volatile organic compounds.

    PubMed

    Wason, Elizabeth L; Agrawal, Anurag A; Hunter, Mark D

    2013-08-01

    The existence of predictable latitudinal variation in plant defense against herbivores remains controversial. A prevailing view holds that higher levels of plant defense evolve at low latitudes compared to high latitudes as an adaptive plant response to higher herbivore pressure on low-latitude plants. To date, this prediction has not been examined with respect to volatile organic compounds (VOCs) that many plants emit, often thus attracting the natural enemies of herbivores. Here, we compared genetically-based constitutive and herbivore-induced aboveground vegetative VOC emissions from plants originating across a gradient of more than 10° of latitude (>1,500 km). We collected headspace VOCs from Asclepias syriaca (common milkweed) originating from 20 populations across its natural range and grown in a common garden near the range center. Feeding by specialist Danaus plexippus (monarch) larvae induced VOCs, and field environmental conditions (temperature, light, and humidity) also influenced emissions. Monarch damage increased plant VOC concentrations and altered VOC blends. We found that genetically-based induced VOC emissions varied with the latitude of plant population origin, although the pattern followed the reverse of that predicted-induced VOC concentration increased with increasing latitude. This pattern appeared to be driven by a greater induction of sesquiterpenoids at higher latitudes. In contrast, constitutive VOC emission did not vary systematically with latitude, and the induction of green leafy volatiles declined with latitude. Our results do not support the prevailing view that plant defense is greater at lower than at higher latitudes. That the pattern holds only for herbivore-induced VOC emission, and not constitutive emission, suggests that latitudinal variation in VOCs is not a simple adaptive response to climatic factors.

  9. A genetically-based latitudinal cline in the emission of herbivore-induced plant volatile organic compounds.

    PubMed

    Wason, Elizabeth L; Agrawal, Anurag A; Hunter, Mark D

    2013-08-01

    The existence of predictable latitudinal variation in plant defense against herbivores remains controversial. A prevailing view holds that higher levels of plant defense evolve at low latitudes compared to high latitudes as an adaptive plant response to higher herbivore pressure on low-latitude plants. To date, this prediction has not been examined with respect to volatile organic compounds (VOCs) that many plants emit, often thus attracting the natural enemies of herbivores. Here, we compared genetically-based constitutive and herbivore-induced aboveground vegetative VOC emissions from plants originating across a gradient of more than 10° of latitude (>1,500 km). We collected headspace VOCs from Asclepias syriaca (common milkweed) originating from 20 populations across its natural range and grown in a common garden near the range center. Feeding by specialist Danaus plexippus (monarch) larvae induced VOCs, and field environmental conditions (temperature, light, and humidity) also influenced emissions. Monarch damage increased plant VOC concentrations and altered VOC blends. We found that genetically-based induced VOC emissions varied with the latitude of plant population origin, although the pattern followed the reverse of that predicted-induced VOC concentration increased with increasing latitude. This pattern appeared to be driven by a greater induction of sesquiterpenoids at higher latitudes. In contrast, constitutive VOC emission did not vary systematically with latitude, and the induction of green leafy volatiles declined with latitude. Our results do not support the prevailing view that plant defense is greater at lower than at higher latitudes. That the pattern holds only for herbivore-induced VOC emission, and not constitutive emission, suggests that latitudinal variation in VOCs is not a simple adaptive response to climatic factors. PMID:23888386

  10. Extracts of centipede Scolopendra subspinipes mutilans induce cell cycle arrest and apoptosis in A375 human melanoma cells.

    PubMed

    Ma, Weina; Liu, Rui; Qi, Junpeng; Zhang, Yanmin

    2014-07-01

    Extracts from the centipede Scolopendra genus, have been used in traditional medicine for the treatment of various diseases and have been found to exhibit anticancer activity in tumor cells. To investigate the potential and associated antitumor mechanism of alcohol extracts of the centipede Scolopendra subspinipes mutilans (AECS), cell viability, cell cycle and cell apoptosis were studied and the results revealed that AECS inhibits A375 cell proliferation in a dose- and time-dependent manner. In addition, AECS was found to arrest the cell cycle of A375 cells at the S phase, which was accompanied by a marked increase in the protein levels of cyclin E and a decrease in the protein levels of cyclin D1. In a cell culture system, AECS markedly induced the apoptosis of A375 cells, which was closely associated with the effects on the Bcl-2 family, whereby decreased Bcl-2 and increased Bak, Bax and Bad expression levels were observed. The underlying mechanism of AECS inhibiting A375 cell proliferation was associated with the induction of cell cycle arrest and apoptosis, indicating that AECS may present as a potential therapeutic agent for administration in human melanoma cancer intervention.

  11. Extracts of centipede Scolopendra subspinipes mutilans induce cell cycle arrest and apoptosis in A375 human melanoma cells.

    PubMed

    Ma, Weina; Liu, Rui; Qi, Junpeng; Zhang, Yanmin

    2014-07-01

    Extracts from the centipede Scolopendra genus, have been used in traditional medicine for the treatment of various diseases and have been found to exhibit anticancer activity in tumor cells. To investigate the potential and associated antitumor mechanism of alcohol extracts of the centipede Scolopendra subspinipes mutilans (AECS), cell viability, cell cycle and cell apoptosis were studied and the results revealed that AECS inhibits A375 cell proliferation in a dose- and time-dependent manner. In addition, AECS was found to arrest the cell cycle of A375 cells at the S phase, which was accompanied by a marked increase in the protein levels of cyclin E and a decrease in the protein levels of cyclin D1. In a cell culture system, AECS markedly induced the apoptosis of A375 cells, which was closely associated with the effects on the Bcl-2 family, whereby decreased Bcl-2 and increased Bak, Bax and Bad expression levels were observed. The underlying mechanism of AECS inhibiting A375 cell proliferation was associated with the induction of cell cycle arrest and apoptosis, indicating that AECS may present as a potential therapeutic agent for administration in human melanoma cancer intervention. PMID:24959287

  12. PLK1 blockade enhances therapeutic effects of radiation by inducing cell cycle arrest at the mitotic phase.

    PubMed

    Inoue, Minoru; Yoshimura, Michio; Kobayashi, Minoru; Morinibu, Akiyo; Itasaka, Satoshi; Hiraoka, Masahiro; Harada, Hiroshi

    2015-10-27

    The cytotoxicity of ionizing radiation depends on the cell cycle phase; therefore, its pharmacological manipulation, especially the induction of cell cycle arrest at the radiosensitive mitotic-phase (M-phase), has been attempted for effective radiation therapy. Polo-like kinase 1 (PLK1) is a serine/threonine kinase that functions in mitotic progression, and is now recognized as a potential target for radiosensitization. We herein investigated whether PLK1 blockade enhanced the cytotoxic effects of radiation by modulating cell cycle phases of cancer cells using the novel small molecule inhibitor of PLK1, TAK-960. The TAK-960 treatment exhibited radiosensitizing effects in vitro, especially when it increased the proportion of M-phase cells. TAK-960 did not sensitize cancer cells to radiation when an insufficient amount of time was provided to induce mitotic arrest. The overexpression of a PLK1 mutant, PLK1-R136G&T210D, which was confirmed to cancel the TAK-960-mediated increase in the proportion of mitotic cells, abrogated the radiosensitizing effects of TAK-960. A tumor growth delay assay also demonstrated that the radiosensitizing effects of TAK-960 depended on an increase in the proportion of M-phase cells. These results provide a rational basis for targeting PLK1 for radiosensitization when considering the therapeutic time window for M-phase arrest as the best timing for radiation treatments.

  13. Involvement of miR-15a in G0/G1 Phase Cell Cycle Arrest Induced by Porcine Circovirus Type 2 Replication.

    PubMed

    Quan, Rong; Wei, Li; Zhu, Shanshan; Wang, Jing; Cao, Yongchang; Xue, Chunyi; Yan, Xu; Liu, Jue

    2016-01-01

    Many viruses exploit the host cell division cycle to favour their own growth. Here we demonstrated that porcine circovirus type 2 (PCV2), which is a major causative agent of an emerging and important swine disease complex, PCV2-associated diseases, caused G0/G1 cell cycle arrest through degradation of cyclin D1 and E followed by reduction of retinoblastoma phosphorylation in synchronized PCV2-infected cells dependent upon virus replication. This induction of G0/G1 cell cycle arrest promoted PCV2 replication as evidenced by increased viral protein expression and progeny virus production in the synchronized PCV2-infected cells. To delineate a mechanism of miRNAs in regulating PCV2-induced G0/G1 cell cycle arrest, we determined expression levels of some relevant miRNAs and found that only miR-15a but not miR-16, miR-21, and miR-34a was significantly changed in the PCV2-infected cells. We further demonstrated that upregulation of miR-15a promoted PCV2-induced G0/G1 cell cycle arrest via mediating cyclins D1 and E degradation, in which involves PCV2 growth. These results reveal that G0/G1 cell cycle arrest induced by PCV2 may provide favourable conditions for viral protein expression and progeny production and that miR-15a is implicated in PCV2-induced cell cycle control, thereby contributing to efficient viral replication. PMID:27302568

  14. Involvement of miR-15a in G0/G1 Phase Cell Cycle Arrest Induced by Porcine Circovirus Type 2 Replication

    PubMed Central

    Quan, Rong; Wei, Li; Zhu, Shanshan; Wang, Jing; Cao, Yongchang; Xue, Chunyi; Yan, Xu; Liu, Jue

    2016-01-01

    Many viruses exploit the host cell division cycle to favour their own growth. Here we demonstrated that porcine circovirus type 2 (PCV2), which is a major causative agent of an emerging and important swine disease complex, PCV2-associated diseases, caused G0/G1 cell cycle arrest through degradation of cyclin D1 and E followed by reduction of retinoblastoma phosphorylation in synchronized PCV2-infected cells dependent upon virus replication. This induction of G0/G1 cell cycle arrest promoted PCV2 replication as evidenced by increased viral protein expression and progeny virus production in the synchronized PCV2-infected cells. To delineate a mechanism of miRNAs in regulating PCV2-induced G0/G1 cell cycle arrest, we determined expression levels of some relevant miRNAs and found that only miR-15a but not miR-16, miR-21, and miR-34a was significantly changed in the PCV2-infected cells. We further demonstrated that upregulation of miR-15a promoted PCV2-induced G0/G1 cell cycle arrest via mediating cyclins D1 and E degradation, in which involves PCV2 growth. These results reveal that G0/G1 cell cycle arrest induced by PCV2 may provide favourable conditions for viral protein expression and progeny production and that miR-15a is implicated in PCV2-induced cell cycle control, thereby contributing to efficient viral replication. PMID:27302568

  15. Xerophilusin B induces cell cycle arrest and apoptosis in esophageal squamous cell carcinoma cells and does not cause toxicity in nude mice.

    PubMed

    Yao, Ran; Chen, Zhaoli; Zhou, Chengcheng; Luo, Mei; Shi, Xuejiao; Li, Jiagen; Gao, Yibo; Zhou, Fang; Pu, Jianxin; Sun, Handong; He, Jie

    2015-01-23

    Esophageal cancer is the eighth most common cancer in the world and ranks as the sixth leading cause of cancer-related mortality. Esophageal cancer has a poor prognosis partially due to its low sensitivity to chemotherapy agents, and the development of new therapeutic agents is urgently needed. Here, the antitumor activity of a natural ent-kaurane diterpenoid, xerophilusin B (1), which was isolated from Isodon xerophilus, a perennial herb frequently used in Chinese folk medicine for tumor treatment, was investigated. Compound 1 exhibited antiproliferative effects against esophageal squamous cell carcinoma (ESCC) cell lines in a time- and dose-dependent manner with lower toxicity against normal human and murine cell lines. In vivo studies demonstrated that 1 inhibited tumor growth of a human esophageal tumor xenograft in BALB/c nude mice without significant secondary adverse effects, indicating its safety in treating ESCC. Furthermore, 1 induced G2/M cell cycle arrest and promoted apoptosis through mitochondrial cytochrome c-dependent activation of the caspase-9 and caspase-3 cascade pathway in ESCC cell lines. In conclusion, the observations herein reported showed that 1 is a potential chemotherapeutic agent for ESCC and merits further preclinical and clinical investigation for cancer drug development. PMID:25555195

  16. Compound-specific isotope analysis of nitrogen in sedimentary porphyrins: A novel and powerful approach for reconstructing the nitrogen cycle of the past ocean

    NASA Astrophysics Data System (ADS)

    Kashiyama, Y.; Ogawa, N. O.; Chikaraishi, Y.; Grosjean, E.; Summons, R.; Maslen, E.; Grice, K.; Godfrey, L.; Quan, T. M.; Falkowski, P. G.; Kitazato, H.; Ohkouchi, N.

    2008-12-01

    Nitrogen isotopic composition of organic matter produced by primary photosynthetic organisms is crucial information on the state of their nitrogen metabolisms and thus can be a key to understand nitrogen cycle of the past ocean. Unlike the isotopic signal of bulk sedimentary samples, sedimentary porphyrins, the diagenetic products of chlorophylls, directly reflect isotopic compositions of photoautotrophs. We have developed methods for compound-specific nitrogen isotopic analyses of (1) sedimentary porphyrins that were isolated from extractable organic matter and (2) maleimides, chemical degradation products of porphyrins, that were oxidatively extracted from residual organic matter after organic extraction. The former includes (1) isolation and purification of various species of sedimentary porphyrins using high-performance liquid chromatography and (2) determination of nitrogen isotopic compositions of isolated porphyrins on a high- sensitivity elemental analyzer-isotope ratio mass spectrometer (IRMS) system that allows determination of isotopic composition on nanomole-scale nitrogen. The latter method analyzes isotopic composition of maleimides on gas chromatography-combustion-IRMS. Applying these methods, we determine nitrogen isotopic composition of sedimentary porphyrins from various geological samples from the Archean to the Miocene. In the black shales deposited during the Cretaceous Oceanic Anoxic Events, the nitrogen isotopic composition of porphyrins generally ranged from -7 to -4‰, which suggests that the average δ15N value for the entire photoautotrophic community at these times ranged -3 to +1‰ considering the empirical isotopic relationships that the tetrapyrrole nuclei of chlorophylls are depleted in 15N by ~5‰ relative to cell. This finding suggests that nitrogen utilized in the primary production was supplied mainly through N2-fixation by diazotrophic cyanobacteria in these oceans.

  17. Resveratrol Induces Cell Cycle Arrest and Apoptosis in Malignant NK Cells via JAK2/STAT3 Pathway Inhibition

    PubMed Central

    Quoc Trung, Ly; Espinoza, J. Luis; Takami, Akiyoshi; Nakao, Shinji

    2013-01-01

    Natural killer (NK) cell malignancies, particularly aggressive NK cell leukaemias and lymphomas, have poor prognoses. Although recent regimens with L-asparaginase substantially improved outcomes, novel therapeutic approaches are still needed to enhance clinical response. Resveratrol, a naturally occurring polyphenol, has been extensively studied for its anti-inflammatory, cardioprotective and anti-cancer activities. In this study, we investigated the potential anti-tumour activities of resveratrol against the NK cell lines KHYG-1, NKL, NK-92 and NK-YS. Resveratrol induced robust G0/G1 cell cycle arrest, significantly suppressed cell proliferation and induced apoptosis in a dose- and time-dependent manner for all four cell lines. In addition, resveratrol suppressed constitutively active STAT3 in all the cell lines and inhibited JAK2 phosphorylation but had no effect on other upstream mediators of STAT3 activation, such as PTEN, TYK2, and JAK1. Resveratrol also induced downregulation of the anti-apoptotic proteins MCL1 and survivin, two downstream effectors of the STAT3 pathway. Finally, resveratrol induced synergistic effect on the apoptotic and antiproliferative activities of L-asparaginase against KHYG-1, NKL and NK-92 cells. These results suggest that resveratrol may have therapeutic potential against NK cell malignancies. Furthermore, our finding that resveratrol is a bonafide JAK2 inhibitor extends its potential benefits to other diseases with dysregulated JAK2 signaling. PMID:23372833

  18. HIV-1 Vpr-Induced Apoptosis Is Cell Cycle Dependent and Requires Bax but Not ANT

    PubMed Central

    Andersen, Joshua L; DeHart, Jason L; Zimmerman, Erik S; Ardon, Orly; Kim, Baek; Jacquot, Guillaume; Benichou, Serge; Planelles, Vicente

    2006-01-01

    The HIV-1 accessory protein viral protein R (Vpr) causes G2 arrest and apoptosis in infected cells. We previously identified the DNA damage–signaling protein ATR as the cellular factor that mediates Vpr-induced G2 arrest and apoptosis. Here, we examine the mechanism of induction of apoptosis by Vpr and how it relates to induction of G2 arrest. We find that entry into G2 is a requirement for Vpr to induce apoptosis. We investigated the role of the mitochondrial permeability transition pore by knockdown of its essential component, the adenine nucleotide translocator. We found that Vpr-induced apoptosis was unaffected by knockdown of ANT. Instead, apoptosis is triggered through a different mitochondrial pore protein, Bax. In support of the idea that checkpoint activation and apoptosis induction are functionally linked, we show that Bax activation by Vpr was ablated when ATR or GADD45α was knocked down. Certain mutants of Vpr, such as R77Q and I74A, identified in long-term nonprogressors, have been proposed to inefficiently induce apoptosis while activating the G2 checkpoint in a normal manner. We tested the in vitro phenotypes of these mutants and found that their abilities to induce apoptosis and G2 arrest are indistinguishable from those of HIV-1NL4–3 vpr, providing additional support to the idea that G2 arrest and apoptosis induction are mechanistically linked. PMID:17140287

  19. Life cycle assessment of vehicle lightweighting: a physics-based model of mass-induced fuel consumption.

    PubMed

    Kim, Hyung Chul; Wallington, Timothy J

    2013-12-17

    Lightweighting is a key strategy used to improve vehicle fuel economy. Replacing conventional materials (e.g., steel) with lighter alternatives (e.g., aluminum, magnesium, and composites) decreases energy consumption and greenhouse gas (GHG) emissions during vehicle use, but often increases energy consumption and GHG emissions during materials and vehicle production. Assessing the life-cycle benefits of mass reduction requires a quantitative description of the mass-induced fuel consumption during vehicle use. A new physics-based method for estimating mass-induced fuel consumption (MIF) is proposed. We illustrate the utility of this method by using publicly available data to calculate MIF values in the range of 0.2-0.5 L/(100 km 100 kg) based on 106 records of fuel economy tests by the U.S. Environmental Protection Agency for 2013 model year vehicles. Lightweighting is shown to have the most benefit when applied to vehicles with high fuel consumption and high power. Use of the physics-based model presented here would place future life cycle assessment studies of vehicle lightweighting on a firmer scientific foundation.

  20. Asparanin A induces G(2)/M cell cycle arrest and apoptosis in human hepatocellular carcinoma HepG2 cells.

    PubMed

    Liu, Wei; Huang, Xue-Feng; Qi, Qi; Dai, Qin-Sheng; Yang, Li; Nie, Fei-Fei; Lu, Na; Gong, Dan-Dan; Kong, Ling-Yi; Guo, Qing-Long

    2009-04-17

    We recently established that asparanin A, a steroidal saponin extracted from Asparagus officinalis L., is an active cytotoxic component. The molecular mechanisms by which asparanin A exerts its cytotoxic activity are currently unknown. In this study, we show that asparanin A induces G(2)/M phase arrest and apoptosis in human hepatocellular carcinoma HepG2 cells. Following treatment of HepG2 cells with asparanin A, cell cycle-related proteins such as cyclin A, Cdk1 and Cdk4 were down-regulated, while p21(WAF1/Cip1) and p-Cdk1 (Thr14/Tyr15) were up-regulated. Additionally, we observed poly (ADP-ribose) polymerase (PARP) cleavage and activation of caspase-3, caspase-8 and caspase-9. The expression ratio of Bax/Bcl-2 was increased in the treated cells, where Bax was also up-regulated. We also found that the expression of p53, a modulator of p21(WAF1/Cip1) and Bax, was not affected in asparanin A-treated cells. Collectively, our findings demonstrate that asparanin A induces cell cycle arrest and triggers apoptosis via a p53-independent manner in HepG2 cells. These data indicate that asparanin A shows promise as a preventive and/or therapeutic agent against human hepatoma. PMID:19254688

  1. SKLB70326, a novel small-molecule inhibitor of cell-cycle progression, induces G{sub 0}/G{sub 1} phase arrest and apoptosis in human hepatic carcinoma cells

    SciTech Connect

    Han, Yuanyuan; He, Haiyun; Peng, Feng; Liu, Jiyan; Dai, Xiaoyun; Lin, Hongjun; Xu, Youzhi; Zhou, Tian; Mao, Yongqiu; Xie, Gang; Yang, Shengyong; Yu, Luoting; Yang, Li; Zhao, Yinglan

    2012-05-18

    Highlights: Black-Right-Pointing-Pointer SKLB70326 is a novel compound and has activity of anti-HCC. Black-Right-Pointing-Pointer SKLB70326 induces cell cycle arrest and apoptosis in HepG2 cells. Black-Right-Pointing-Pointer SKLB70326 induces G{sub 0}/G{sub 1} phase arrest via inhibiting the activity of CDK2, CDK4 and CDK6. Black-Right-Pointing-Pointer SKLB70326 induces apoptosis through the intrinsic pathway. -- Abstract: We previously reported the potential of a novel small molecule 3-amino-6-(3-methoxyphenyl)thieno[2.3-b]pyridine-2-carboxamide (SKLB70326) as an anticancer agent. In the present study, we investigated the anticancer effects and possible mechanisms of SKLB70326 in vitro. We found that SKLB70326 treatment significantly inhibited human hepatic carcinoma cell proliferation in vitro, and the HepG2 cell line was the most sensitive to its treatment. The inhibition of cell proliferation correlated with G{sub 0}/G{sub 1} phase arrest, which was followed by apoptotic cell death. The SKLB70326-mediated cell-cycle arrest was associated with the downregulation of cyclin-dependent kinase (CDK) 2, CDK4 and CDK6 but not cyclin D1 or cyclin E. The phosphorylation of the retinoblastoma protein (Rb) was also observed. SKLB70326 treatment induced apoptotic cell death via the activation of PARP, caspase-3, caspase-9 and Bax as well as the downregulation of Bcl-2. The expression levels of p53 and p21 were also induced by SKLB70326 treatment. Moreover, SKLB70326 treatment was well tolerated. In conclusion, SKLB70326, a novel cell-cycle inhibitor, notably inhibits HepG2 cell proliferation through the induction of G{sub 0}/G{sub 1} phase arrest and subsequent apoptosis. Its potential as a candidate anticancer agent warrants further investigation.

  2. Transfer of cryopreserved - thawed embryos in hCG induced natural or clomiphene citrate cycles yields similar live birth rates in normo-ovulatory women

    PubMed Central

    Fatemi, Human M.; Blockeel, Christophe; Stoop, Dominic; Albuarki, H.; Verheyen, Greta; Devroey, Paul

    2010-01-01

    Introduction The purpose of this retrospective analysis is to compare the efficiency of hCG-induced natural and Clomiphene citrate (CC) cycles in normovulatory patients undergoing frozen embryo transfer (FET). Materials and methods It was retrospectively conducted in the Dutchspeaking Free University of Brussels and covered the period from April 2003 to August 2006. In particular, 428 day-three FET cycles belonging to the two comparative groups were recruited. Of these FET cycles, 261 were hCG-induced natural and 167 clomiphene citrate-induced cycles. Results No statistically significant difference was observed in live birth rate between CC and natural group (22.2% versus 22.6%), respectively (P = 0.708). Except for the number of embryos transferred (1.72 ± 0.46 for CC group versus 1.63 ± 0.48 for natural group, P = 0.045), no other parameters seem to influence the outcome. Discussion To our knowledge, this is the first attempt to investigate which of the above mentioned regimens is optimal for normo-ovulatory women in FET cycles. A similar delivery outcome was observed for hCG–induced natural and CC-induced cycles used for endometrial preparation in FET. PMID:20703796

  3. Protective Effect of Total Phenolic Compounds from Inula helenium on Hydrogen Peroxide-induced Oxidative Stress in SH-SY5Y Cells

    PubMed Central

    Wang, J.; Zhao, Y. M.; Zhang, B.; Guo, C. Y.

    2015-01-01

    Inula helenium has been reported to contain a large amount of phenolic compounds, which have shown promise in scavenging free radicals and prevention of neurodegenerative diseases. This study is to investigate the neuroprotective effects of total phenolic compounds from I. helenium on hydrogen peroxide-induced oxidative damage in human SH-SY5Y cells. Antioxidant capacity of total phenolic compounds was determined by radical scavenging activity, the level of intracellular reactive oxygen species and superoxide dismutase activity. The cytotoxicity of total phenolic compounds was determined using a cell counting kit-8 assay. The effect of total phenolic compounds on cell apoptosis due to hydrogen peroxide-induced oxidative damage was detected by Hoechst 33258 and Annexin-V/PI staining using fluorescence microscope and flow cytometry, respectively. Mitochondrial function was evaluated using the mitochondrial membrane potential and mitochondrial ATP synthesis by JC-1 dye and high performance liquid chromatography, respectively. It was shown that hydrogen peroxide significantly induced the loss of cell viability, increment of apoptosis, formation of reactive oxygen species, reduction of superoxide dismutase activity, decrease in mitochondrial membrane potential and a decrease in adenosine triphosphate production. On the other hand, total phenolic compounds dose-dependently reversed these effects. This study suggests that total phenolic compounds exert neuroprotective effects against hydrogen peroxide-induced oxidative damage via blocking reactive oxygen species production and improving mitochondrial function. The potential of total phenolic compounds and its neuroprotective mechanisms in attenuating hydrogen peroxide-induced oxidative stress-related cytotoxicity is worth further exploration. PMID:26009648