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Sample records for cycle inducing compounds

  1. 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.

  2. 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.

  3. Arctigenin, a natural lignan compound, induces G0/G1 cell cycle arrest and apoptosis in human glioma cells

    PubMed Central

    Maimaitili, Aisha; Shu, Zunhua; Cheng, Xiaojiang; Kaheerman, Kadeer; Sikandeer, Alifu; Li, Weimin

    2017-01-01

    The aim of the current study was to investigate the anticancer potential of arctigenin, a natural lignan compound, in malignant gliomas. The U87MG and T98G human glioma cell lines were treated with various concentrations of arctigenin for 48 h and the effects of arctigenin on the aggressive phenotypes of glioma cells were assessed. The results demonstrated that arctigenin dose-dependently inhibited the growth of U87MG and T98G cells, as determined using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and bromodeoxyuridine incorporation assays. Arctigenin exposure also induced a 60–75% reduction in colony formation compared with vehicle-treated control cells. However, arctigenin was not observed to affect the invasiveness of glioma cells. Arctigenin significantly increased the proportion of cells in the G0/G1 phase and reduced the number of cells in the S phase, as compared with the control group (P<0.05). Western blot analysis demonstrated that arctigenin increased the expression levels of p21, retinoblastoma and p53 proteins, and significantly decreased the expression levels of cyclin D1 and cyclin-dependent kinase 4 proteins. Additionally, arctigenin was able to induce apoptosis in glioma cells, coupled with increased expression levels of cleaved caspase-3 and the pro-apoptotic BCL2-associated X protein. Furthermore, arctigenin-induced apoptosis was significantly suppressed by the pretreatment of cells with Z-DEVD-FMK, a caspase-3 inhibitor. In conclusion, the results suggest that arctigenin is able to inhibit cell proliferation and may induce apoptosis and cell cycle arrest at the G0/G1 phase in glioma cells. These results warrant further investigation of the anticancer effects of arctigenin in animal models of gliomas. PMID:28356992

  4. Arctigenin, a natural lignan compound, induces G0/G1 cell cycle arrest and apoptosis in human glioma cells.

    PubMed

    Maimaitili, Aisha; Shu, Zunhua; Cheng, Xiaojiang; Kaheerman, Kadeer; Sikandeer, Alifu; Li, Weimin

    2017-02-01

    The aim of the current study was to investigate the anticancer potential of arctigenin, a natural lignan compound, in malignant gliomas. The U87MG and T98G human glioma cell lines were treated with various concentrations of arctigenin for 48 h and the effects of arctigenin on the aggressive phenotypes of glioma cells were assessed. The results demonstrated that arctigenin dose-dependently inhibited the growth of U87MG and T98G cells, as determined using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and bromodeoxyuridine incorporation assays. Arctigenin exposure also induced a 60-75% reduction in colony formation compared with vehicle-treated control cells. However, arctigenin was not observed to affect the invasiveness of glioma cells. Arctigenin significantly increased the proportion of cells in the G0/G1 phase and reduced the number of cells in the S phase, as compared with the control group (P<0.05). Western blot analysis demonstrated that arctigenin increased the expression levels of p21, retinoblastoma and p53 proteins, and significantly decreased the expression levels of cyclin D1 and cyclin-dependent kinase 4 proteins. Additionally, arctigenin was able to induce apoptosis in glioma cells, coupled with increased expression levels of cleaved caspase-3 and the pro-apoptotic BCL2-associated X protein. Furthermore, arctigenin-induced apoptosis was significantly suppressed by the pretreatment of cells with Z-DEVD-FMK, a caspase-3 inhibitor. In conclusion, the results suggest that arctigenin is able to inhibit cell proliferation and may induce apoptosis and cell cycle arrest at the G0/G1 phase in glioma cells. These results warrant further investigation of the anticancer effects of arctigenin in animal models of gliomas.

  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. 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.

  8. 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.

  9. 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.

  10. Phenolic Compounds Isolated from Caesalpinia coriaria Induce S and G2/M Phase Cell Cycle Arrest Differentially and Trigger Cell Death by Interfering with Microtubule Dynamics in Cancer Cell Lines.

    PubMed

    Sánchez-Carranza, Jessica Nayelli; Alvarez, Laura; Marquina-Bahena, Silvia; Salas-Vidal, Enrique; Cuevas, Verónica; Jiménez, Elizabeth W; Veloz G, Rafael A; Carraz, Maelle; González-Maya, Leticia

    2017-04-22

    Caesalpinia coriaria (C. coriaria), also named cascalote, has been known traditionally in México for having cicatrizing and inflammatory properties. Phytochemical reports on Caesalpinia species have identified a high content of phenolic compounds and shown antineoplastic effects against cancer cells. The aim of this study was to isolate and identify the active compounds of a water:acetone:ethanol (WAE) extract of C. coriaria pods and characterize their cytotoxic effect and cell death induction in different cancer cell lines. The compounds isolated and identified by chromatography and spectroscopic analysis were stigmasterol, ethyl gallate and gallic acid. Cytotoxic assays on cancer cells showed different ranges of activities. A differential effect on cell cycle progression was observed by flow cytometry. In particular, ethyl gallate and tannic acid induced G2/M phase cell cycle arrest and showed interesting effect on microtubule stabilization in Hep3B cells observed by immunofluorescence. The induction of apoptosis was characterized by morphological characteristic changes, and was supported by increases in the ratio of Bax/Bcl-2 expression and activation of caspase 3/7. This work constitutes the first phytochemical and cytotoxic study of C. coriaria and showed the action of its phenolic constituents on cell cycle, cell death and microtubules organization.

  11. 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.

  12. Novel synthetic organosulfur compounds induce apoptosis of human leukemic cells.

    PubMed

    Wong, W W; Macdonald, S; Langler, R F; Penn, L Z

    2000-01-01

    It has been well documented that natural organosulfur compounds (OSCs) derived from plants such as garlic, onions and mahogany trees possess antiproliferative properties; however, the essential chemical features of the active OSC compounds remain unclear. To investigate the association between OSC structure and growth inhibitory activity, we synthesized novel relatives of dysoxysulfone, a natural OSC derived from the Fijian medicinal plant, Dysoxylum richii. In this study, we have examined the antiproliferative effects of these novel OSCs on a model human leukemic cell system and show that the compounds segregate into three groups. Group I, consisting of compounds A, B, G and J, did not affect either cell proliferation or the cell cycle profile of the leukemic cell lines. Group II, consisting of compounds F and H, induced the cells to undergo apoptosis from the G2/M phase of the cell cycle. Group III, consisting of compounds C, D, E and I, decreased cell proliferation and induced apoptosis throughout the cell cycle. The apoptotic agonists of Group II and III shared a common disulfide moiety, essential for leukemic cell cytotoxicity. Interestingly, Group II compounds did not affect cell viability of normal human diploid cells, suggesting the regions flanking the disulfide group contributes to the specificity of cell killing. Thus, we provide evidence that structure-activity analysis of natural products can identify novel compounds for the development of new therapeutics that can trigger apoptosis in a tumor-specific manner.

  13. 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.

  14. 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.

  15. 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.

  16. Influence of sulfur compounds on the terrestrial carbon cycle

    NASA Astrophysics Data System (ADS)

    Eliseev, A. V.

    2015-11-01

    Using the climate model developed at the A.M. Obukhov Institute of Atmospheric Physics, Russian Academy of Sciences (IAP RAS CM), numerical experiments have been conducted in line with the Coupled Model Intercomparison Project Phase 5 (CMIP5), but scaling the anthropogenic emissions of sulfur compounds into the troposphere by ±25%. Two types of impacts of sulfur compounds on climate and the global carbon cycle are considered: climate impact (CI, associated with the influence of tropospheric sulfates on climate and, as a consequence, on the carbon cycle characteristics) and ecological impact (EI, associated with the influence of SO2 on the rate of photosynthesis of terrestrial plants). The climate impact was found to be generally more important than the ecological one. However, in a number of regions, the EI is comparable to CI, including in the southeast parts of North America and, especially, of Asia. The contribution of EI to the change in global characteristics of terrestrial ecosystems in the 20th century is likewise considerable. The CI is generally more sensitive to the uncertainty in anthropogenic emissions of sulfur compounds into the troposphere than the EI.

  17. 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.

  18. Radiation-induced amorphization of intermetallic compounds

    NASA Astrophysics Data System (ADS)

    Lam, N. Q.; Sabochick, M. J.; Okamoto, P. R.

    1994-06-01

    In the present paper, important results of our recent computer simulation of radiation-induced amorphization in the ordered compounds CuTi and Cu4Ti3 are summarized. The energetic, structural, thermodynamic and mechanical responses of these intermetallics during chemical disordering, point-defect production and heating were simulated, using molecular dynamics and embedded-atom potentials. From the atomistic details obtained, the critical role of radiation-induced structural disorder in driving the crystalline-to-amorphous phase transformation is discussed.

  19. 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.

  20. Novel Glycopyrrolidine Compounds Inhibit Human Cancer Cell Proliferation and Induce Apoptotic Mode of Cell Death.

    PubMed

    Bhoopalan, Hemadev; Tentu, Shilpa; R, Prasana; S, Purushothaman; Venu, Akkanapally; Raghunathan, Ragavachary; Pakala, Suresh Babu; Rayala, Suresh Kumar; Venkatraman, Ganesh

    2017-04-21

    Spirocyclic compounds, present in a number of bioactive natural alkaloids, are cyclic systems containing one carbon atom common to two rings. A highly regioselective glycopyrrolidine compound library was synthesized using 1,3-dipolar cycloaddition method, and its efficacy was tested on cell lines representing most commonly occurring cancers and the molecular mechanism of cell death deciphered. Results showed that among the 16 compounds screened, RPRR210 showed the most potent anticancer activity and induced cell cycle arrest, inhibited migration, caused cell death by inducing apoptosis through the intrinsic pathway, and were nontoxic to normal cells.

  1. Natural Compounds as Modulators of Cell Cycle Arrest: Application for Anticancer Chemotherapies.

    PubMed

    Bailon-Moscoso, Natalia; Cevallos-Solorzano, Gabriela; Romero-Benavides, Juan Carlos; Orellana, Maria Isabel Ramirez

    2017-04-01

    Natural compounds from various plants, microorganisms and marine species play an important role in the discovery novel components that can be successfully used in numerous biomedical applications, including anticancer therapeutics. Since uncontrolled and rapid cell division is a hallmark of cancer, unraveling the molecular mechanisms underlying mitosis is key to understanding how various natural compounds might function as inhibitors of cell cycle progression. A number of natural compounds that inhibit the cell cycle arrest have proven effective for killing cancer cells in vitro, in vivo and in clinical settings. Significant advances that have been recently made in the understanding of molecular mechanisms underlying the cell cycle regulation using the chemotherapeutic agents is of great importance for improving the efficacy of targeted therapeutics and overcoming resistance to anticancer drugs, especially of natural origin, which inhibit the activities of cyclins and cyclin-dependent kinases, as well as other proteins and enzymes involved in proper regulation of cell cycle leading to controlled cell proliferation.

  2. The effect of freeze/thaw cycles on the stability of compounds in DMSO.

    PubMed

    Kozikowski, Barbara A; Burt, Thomas M; Tirey, Debra A; Williams, Lisa E; Kuzmak, Barbara R; Stanton, David T; Morand, Kenneth L; Nelson, Sandra L

    2003-04-01

    A diverse set of 320 compounds from the Procter & Gamble Pharmaceuticals organic compound repository was prepared as 20-mM DMSO solutions and stored at 4 degrees C under argon in pressurized canisters to simulate a low-humidity environment. The plates were subjected to 25 freeze/thaw cycles while being exposed to ambient atmospheric conditions after each thaw to simulate the time and manner by which compound plates are exposed to the atmosphere during typical liquid-handling and high-throughput screening processes. High-performance liquid chromatography-mass spectrometry with evaporative light-scattering detection was used to quantitate the amount of compound remaining after every 5th freeze/thaw cycle. Control plates were stored either at room temperature under argon or at 4 degrees C under argon without freeze/thaw cycling and were evaluated at the midpoint and the endpoint of the study. The study was conducted over a short time period (i.e., 7 weeks) to minimize the effect of compound degradation over time due to the exposure of the compounds to DMSO. The results from this study will be used to determine the maximum number of freeze/thaw cycles that can be achieved while maintaining acceptable compound integrity.

  3. Role of natural phenolic compounds in cancer chemoprevention via regulation of the cell cycle.

    PubMed

    Jafari, Samineh; Saeidnia, Soodabeh; Abdollahi, Mohammad

    2014-01-01

    Natural phenolic compounds have been considered as one of the interesting secondary metabolites for their chemopreventive and chemotherapeutic effects in cancer for a long time. These are a large and diverse family of phytochemicals classified into several subgroups such as simple phenols, lignans, phenylpropanoids, flavonoids, coumarins, etc. The antioxidant potential of phenolic compounds is almost bolded in the treatment and prevention of cancer. Due to the concerns on the diverse effects of antioxidants in cancer, differentiation and clarification of their anti-neoplastic mechanisms are necessary. An important mechanism for phenolic compounds is related to their direct effect on the cell cycle progression, which has not been discussed in detail so far. This study aims to criticize the evidence on regulatory mechanisms of phenolic compounds in the cell cycle. Recent studies indicate that phenolic compounds from several subgroups significantly inhibit the proliferation of different cancer cells. The structural diversity of these compounds influences various components involved in cell cycle regulation. Forming active metabolites and sensitizing cancerous cells to chemotherapeutic medicines are additional values of these compounds. In the recent years, many studies on neoplastic cell cultures have been carried out to investigate the mechanisms of action of these compounds but dissimilarity of in vitro systems in comparison with human body in terms of metabolism and bioavailability is a major concern. Therefore, further studies are still needed.

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

    PubMed

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

    2013-12-15

    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.

  5. 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

  6. Chiral organic compounds in induced cholesteric mesophases

    NASA Astrophysics Data System (ADS)

    Kutulya, Lidiya A.

    1998-09-01

    The results of original investigations being in touch with regularities of the chiral components molecular structure effect on the properties of induced cholesteric mesophases were generalized. It was shown that presence of an elongate (pi) -electron fragment in the chiral dopants molecules is general requirement of high helical twisting power ((beta) ). (beta) values and the character of temperature dependences of induced helical pitch are significantly effected by molecular shape of chiral dopants. Variation of the extent of (pi) -electron fragment anisometry, and also incorporation and variation of terminal alkyl or alkoxyl groups at chiral dopants molecules are useful approach to a regulation of temperature dependences of induced cholesteric helix pitch. Influence on thermal stability of mesophases of different types of chiral dopants was analyzed.

  7. Elimination of quiescent slow-cycling cells via reducing quiescence depth by natural compounds purified from Ganoderma lucidum.

    PubMed

    Dai, Jian; Miller, Matthew A; Everetts, Nicholas J; Wang, Xia; Li, Peng; Li, Ye; Xu, Jian-Hua; Yao, Guang

    2017-02-21

    The medical mushroom Ganoderma lucidum has long been used in traditional Chinese medicine and shown effective in the treatment of many diseases including cancer. Here we studied the cytotoxic effects of two natural compounds purified from Ganoderma lucidum, ergosterol peroxide and ganodermanondiol. We found that these two compounds exhibited cytotoxicity not only against fast proliferating cells, but on quiescent, slow-cycling cells. Using a fibroblast cell-quiescence model, we found that the cytotoxicity on quiescent cells was due to induced apoptosis, and was associated with a shallower quiescent state in compound-treated cells, resultant from the increased basal activity of an Rb-E2F bistable switch that controls quiescence exit. Accordingly, we showed that quiescent breast cancer cells (MCF7), compared to its non-transformed counterpart (MCF10A), were preferentially killed by ergosterol peroxide and ganodermanondiol treatment presumably due to their already less stable quiescent state. The cytotoxic effect of natural Ganoderma lucidum compounds against quiescent cells, preferentially on quiescent cancer cells vs. non-cancer cells, may help future antitumor development against the slow-cycling cancer cell subpopulations including cancer stem and progenitor cells.

  8. Mechanisms of sulindac-induced apoptosis and cell cycle arrest.

    PubMed

    Jung, Barbara; Barbier, Valerie; Brickner, Howard; Welsh, John; Fotedar, Arun; McClelland, Michael

    2005-02-28

    The mechanism underlying the chemopreventive effects of the non-steroidal anti-inflammatory drug sulindac remains unclear. Its active metabolite, sulindac sulfide, induces cell cycle arrest as well as apoptosis in mammalian cell lines. We now show that in murine thymocytes, sulindac sulfide-induced cell death is p53, bax, Fas, and FasL independent. In contrast, bcl2 transgenic thymocytes are resistant to sulindac sulfide-induced apoptosis. In addition, we demonstrate that sulindac sulfide-induced cell cycle arrest in mouse embryonic fibroblasts (MEFs) is partly mediated by the retinoblastoma tumor suppressor protein (Rb) and the cyclin kinase inhibitor p21waf1/cip1. Furthermore, MEFs deficient in p21 or Rb are more susceptible to sulindac sulfide-induced cell death. These results suggest that sulindac may selectively target premalignant cells with cell cycle checkpoint deficits.

  9. Mechanical Motion Induced by Spatially Distributed Limit-Cycle Oscillators

    NASA Astrophysics Data System (ADS)

    Sakaguchi, Hidetsugu; Mukae, Yuuki

    2017-03-01

    Spatially distributed limited-cycle oscillators are seen in various physical and biological systems. In internal organs, mechanical motions are induced by the stimuli of spatially distributed limit-cycle oscillators. We study several mechanical motions by limit-cycle oscillators using simple model equations. One problem is deformation waves of radius oscillation induced by desynchronized limit-cycle oscillators, which is motivated by peristaltic motion of the small intestine. A resonance-like phenomenon is found in the deformation waves, and particles can be transported by the deformation waves. Another is the beating motion of the heart. The expansion and contraction motion is realized by a spatially synchronized limit-cycle oscillation; however, the strong beating disappears by spiral chaos, which is closely related to serious arrhythmia in the heart.

  10. Induced natural convection thermal cycling device

    DOEpatents

    Heung, Leung Kit [Aiken, SC

    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.

  11. [Treatment of anovulatory cycle induced sterility].

    PubMed

    Botella Llusia, J

    1983-03-01

    Of all the clinical aspects of human sterility, the anovulatory cycle is undoubtedly 1 that has produced the widest range of therapuetic successes. While in other fields progress has been very slow (male sterility or tubal obstruction), ovarian pharmacoendocrinology has shown several advances over recent years. This progress is due partly to new chemicals such as urinary menopausal gonadotropins, LH-RH, and their analogues Clomiphene and Bromocriptine. Contributing further to these good results is a greater knowledge of the etiology of anovulation and a more accurate selection of cases for treatment.

  12. Prediction of thermal cycling induced matrix cracking

    NASA Technical Reports Server (NTRS)

    Mcmanus, Hugh L.

    1992-01-01

    Thermal fatigue has been observed to cause matrix cracking in laminated composite materials. A method is presented to predict transverse matrix cracks in composite laminates subjected to cyclic thermal load. Shear lag stress approximations and a simple energy-based fracture criteria are used to predict crack densities as a function of temperature. Prediction of crack densities as a function of thermal cycling is accomplished by assuming that fatigue degrades the material's inherent resistance to cracking. The method is implemented as a computer program. A simple experiment provides data on progressive cracking of a laminate with decreasing temperature. Existing data on thermal fatigue is also used. Correlations of the analytical predictions to the data are very good. A parametric study using the analytical method is presented which provides insight into material behavior under cyclical thermal loads.

  13. Natural Compounds as Modulators of Cell Cycle Arrest: Application for Anticancer Chemotherapies

    PubMed Central

    Bailon-Moscoso, Natalia; Cevallos-Solorzano, Gabriela; Romero-Benavides, Juan Carlos; Orellana, Maria Isabel Ramirez

    2017-01-01

    Natural compounds from various plants, microorganisms and marine species play an important role in the discovery novel components that can be successfully used in numerous biomedical applications, including anticancer therapeutics. Since uncontrolled and rapid cell division is a hallmark of cancer, unraveling the molecular mechanisms underlying mitosis is key to understanding how various natural compounds might function as inhibitors of cell cycle progression. A number of natural compounds that inhibit the cell cycle arrest have proven effective for killing cancer cells in vitro, in vivo and in clinical settings. Significant advances that have been recently made in the understanding of molecular mechanisms underlying the cell cycle regulation using the chemotherapeutic agents is of great importance for improving the efficacy of targeted therapeutics and overcoming resistance to anticancer drugs, especially of natural origin, which inhibit the activities of cyclins and cyclin-dependent kinases, as well as other proteins and enzymes involved in proper regulation of cell cycle leading to controlled cell proliferation. PMID:28367072

  14. 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

  15. 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.

  16. Lipoxygenase inhibitors induce arrest of tumor cells in S-phase of the cell cycle.

    PubMed

    Hofmanová, J; Soucek, K; Pacherník, J; Kovaríková, M; Hoferová, Z; Minksová, K; Netíková, J; Kozubík, A

    2002-01-01

    Inhibitors of the lipoxygenase pathway of arachidonic acid metabolism represent a potential anti-tumor drugs. These compounds have been found to inhibit the growth and induce the apoptosis of various tumor cells both in vitro and in vivo. In this study, the effects of the lipoxygenase inhibitors esculetin and nordihydroguaiaretic acid (NDGA) on the progression of the cell cycle were investigated in eight mammalian cell lines of different origin. Flow cytometric analyses of cell cycle distribution after staining of DNA with propidium iodide or 7-aminoactinomycin D and DNA synthesis using incorporation of 5-bromo-2'-deoxy-uridine showed that both esculetin and NDGA suppress cell growth by interrupting the progression of cells through S-phase that results in their accumulation in this phase of the cell cycle. The possible mechanisms of these effects and the significance of the findings for the improvement of anticancer therapy targeted on cell cycle is discussed.

  17. 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.

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

    PubMed Central

    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

  19. Ibuprofen and apigenin induce apoptosis and cell cycle arrest in activated microglia.

    PubMed

    Elsisi, Nahed S; Darling-Reed, Selina; Lee, Eunsook Y; Oriaku, Ebenezer T; Soliman, Karam F

    2005-02-28

    In case of injury or disease, microglia are recruited to the site of the pathology and become activated as evidenced by morphological changes and expression of pro-inflammatory cytokines. Evidence suggests that microglia proliferate by cell division to create gliosis at the site of pathological conditions such as the amyloid plaques in Alzheimer's disease and the substantia nigra of Parkinson's disease patients. The hyperactivation of microglia contributes to neurotoxicity. In the present study we tested the hypothesis that anti-inflammatory compounds modulate the progression of cell cycle and induce apoptosis of the activated cells. We investigated the effects of ibuprofen (non-steroidal anti-inflammatory drug) and apigenin (a flavonoid with anti-inflammatory and anti-proliferative properties) on the cell cycle of the murine microglial cell line BV-2. The findings indicate that apigenin-induced cell cycle arrest preferentially in the G2/M phase and ibuprofen caused S phase arrest. The binding of annexin V-FITC to the membranes of cells which indicates the apoptotic process were examined, whereas the DNA was stained with propidium iodide. Both apigenin and ibuprofen induced apoptosis significantly in early and late stages. The induction of apoptosis by ibuprofen and apigenin was confirmed using TUNEL assay, revealing that 25 microM apigenin and 250 microM ibuprofen significantly increased apoptosis in BV-2 cells. The results from the present study suggest that anti-inflammatory compounds might inhibit microglial proliferation by modulating the cell cycle progression and apoptosis.

  20. Magnetic field aberration induced by cycle stress

    NASA Astrophysics Data System (ADS)

    En, Yang; luming, Li; Xing, Chen

    2007-05-01

    Magneto-mechanical effect has been causing people's growing interest because of its relevance to several technology problems. One of them is the variation of surface magnetic field induced by stress concentration under the geomagnetic field. It can be used as an innovative, simple and convenient potential NDE method, called as magnetic memory method. However, whether and how this can be used as a quantitative measurement method, is still a virginal research field where nobody sets foot in. In this paper, circle tensile stress within the elastic region was applied to ferromagnetic sample under geomagnetic field. Experiment results on the relation between surface magnetic field and elastic stress were presented, and a simple model was derived. Simulation of the model was reconciled with the experimental results. This can be of great importance for it provides a brighter future for the promising Magnetic Memory NDE method—the potential possibility of quantitative measurement.

  1. Dynamics of radiation-induced amorphization in intermetallic compounds

    SciTech Connect

    Lam, N.Q.; Okamoto, P.R. ); Devanathan, R. Northwestern Univ., Evanston, IL . Dept. of Materials Science and Engineering); Meshii, M. . Dept. of Materials Science and Engineering)

    1992-06-01

    Recent progress in molecular-dynamics simulations of radiation-induced crystalline-to-amorphous transition in intermetallic compounds and the relationship between amorphization and melting are discussed. By focusing on the mean-square static displacement, which provides a generic measure of energy stored in the lattice in the forms of chemical and topological disorder, a unified description of solid-state amorphization as a disorder-induced, isothermal melting process can be developed within the framework of a generalized Lindemann criterion.

  2. [Application of small molecule compounds inducing differentiation of stem cells].

    PubMed

    Li, Xia; Shan, Lei; Li, Wen-lin; Zhang, Shou-de; Zhang, Wei-dong

    2011-02-01

    With the development of stem cells and regenerative medicine (treatment of various diseases using stem cells) research, the induction of differentiation of human stem cell technology has also made significant progress. The development of chemical biology offers a variety of small biological molecules for stem cell biology. This review focuses on how small molecule compounds (natural and synthetic) induce differentiation of stem cells.

  3. Developmental cycle and pharmaceutically relevant compounds of Salinispora actinobacteria isolated from Great Barrier Reef marine sponges.

    PubMed

    Ng, Yi Kai; Hewavitharana, Amitha K; Webb, Richard; Shaw, P Nicholas; Fuerst, John A

    2013-04-01

    The developmental cycle of the obligate marine antibiotic producer actinobacterium Salinispora arenicola isolated from a Great Barrier Reef marine sponge was investigated in relation to mycelium and spore ultrastructure, synthesis of rifamycin antibiotic compounds, and expression of genes correlated with spore formation and with rifamycin precursor synthesis. The developmental cycle of S. arenicola M413 on solid agar medium was characterized by substrate mycelium growth, change of colony color, and spore formation; spore formation occurred quite early in colony growth but development of black colonies occurred only at late stages, correlated with a change in spore maturity in relation to cell wall layers. Rifamycins were detected throughout the growth cycle, but changed in relative quantity at particular phases in the cycle, with a marked increase after 32 days. Expression of the spore division gene ssgA and the rifK gene for 3-amino-5-hydroxybenzoate synthase responsible for rifamycin precursor synthesis was seen even at early stages of the growth cycle. ssgA expression significantly increased between days 26 and 31, but rifK expression effectively remained constant throughout the growth cycle, consistent with the early synthesis of rifamycin. Factors other than precursor synthesis may be responsible for an observed late increase in rifamycin production. A useful approach for measuring and exploring the regulation of antibiotic synthesis and gene expression in the marine natural product producer S. arenicola has been established.

  4. 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.

  5. Xanthones from the Leaves of Garcinia cowa Induce Cell Cycle Arrest, Apoptosis, and Autophagy in Cancer Cells.

    PubMed

    Xia, Zhengxiang; Zhang, Hong; Xu, Danqing; Lao, Yuanzhi; Fu, Wenwei; Tan, Hongsheng; Cao, Peng; Yang, Ling; Xu, Hongxi

    2015-06-19

    Two new xanthones, cowaxanthones G (1) and H (2), and 23 known analogues were isolated from an acetone extract of the leaves of Garcinia cowa. The isolated compounds were evaluated for cytotoxicity against three cancer cell lines and immortalized HL7702 normal liver cells, whereby compounds 1, 5, 8, and 15-17 exhibited significant cytotoxicity. Cell cycle analysis using flow cytometry showed that 5 induced cell cycle arrest at the S phase in a dose-dependent manner, 1 and 16 at the G2/M phase, and 17 at the G1 phase, while 16 and 17 induced apoptosis. Moreover, autophagy analysis by GFP-LC3 puncta formation and western blotting suggested that 17 induced autophagy. Taken together, our results suggest that these xanthones possess anticancer activities targeting cell cycle, apoptosis, and autophagy signaling pathways.

  6. 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.

  7. 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

  8. Elevated Choline-Containing Compound Levels in Rapid Cycling Bipolar Disorder.

    PubMed

    Cao, Bo; Stanley, Jeffrey A; Passos, Ives Cavalcante; Mwangi, Benson; Selvaraj, Sudhakar; Zunta-Soares, Giovana B; Soares, Jair C

    2017-03-29

    Previous studies have found increased levels of choline-containing compounds (ie, glycerophosphocholine plus phosphocholine (GPC+PC)) in bipolar disorder using in vivo proton magnetic resonance spectroscopy ((1)H MRS), especially in bipolar I disorder (BD-I). Increased levels of GPC+PC suggest alterations in the membrane phospholipids metabolism in bipolar disorder. Rapid cycling (RC) bipolar disorder is considered as a severe course of bipolar disorder, but it is unclear whether rapid cycling bipolar disorder is linked to highly altered membrane phospholipid metabolism. The purpose of this study was to investigate whether the regional extent of elevated GPC+PC were greater in BD-I patients with rapid cycling compared to BD-I patients without rapid cycling and healthy controls. Using a multi-voxel (1)H MRS approach at 3 Tesla with high spatial resolution and absolute quantification, GPC+PC levels from the anterior cingulate cortex (ACC), caudate and putamen of 16 RC BD-I, 34 non-RC BD-I and 44 healthy controls were assessed. We found significantly elevated GPC+PC levels in ACC, putamen and caudate of RC BD-I patients compared to healthy controls (P<0.005) and in ACC compared to non-RC BD-I patients (P<0.05). These results suggest greater alteration of membrane phospholipid metabolisms in rapid cycling BD-I compared to non-rapid-cycling BD-I.Neuropsychopharmacology advance online publication, 29 March 2017; doi:10.1038/npp.2017.39.

  9. Potential of the compound specific isotope analysis of individual amino acid for studying past nitrogen cycle

    NASA Astrophysics Data System (ADS)

    Choi, Bohyung; Shin, Kyung-Hoon

    2016-04-01

    The nitrogen isotope ratio of bulk sediment has been widely used for studying nitrogen cycle in the marine environment. However, since organic nitrogen in sediment is regarded as a mixture of organic matter, it is challenging to identify its exact sources. Recently, compound specific nitrogen isotope analysis of amino acid (CSIA AAs) has been introduced as a potential tool for complement of bulk nitrogen isotope since amino acid more directly reflects information on primary producer and trophic position. However, studies on CSIA of amino acid in sediments are scarce due to the complexities of the analytical method and relatively high analytica costl. In this study, we established a method of the CSIA AAs which is more suitable for the analysis of sediments and accessed if the CSIA AAs can be used for the study of past nitrogen cycle.

  10. Compound K suppresses ultraviolet radiation-induced apoptosis by inducing DNA repair in human keratinocytes.

    PubMed

    Cai, Bao-Xiang; Luo, Dan; Lin, Xiang-Fei; Gao, Jie

    2008-11-01

    Ultraviolet (UV)-induced DNA damage is a crucial molecular trigger for sunburn cell formation and skin cancer. Nucleotide excision repair (NER) is the main mechanism in repairing UVB-induced DNA damage of mammalian cells. The purpose of this study is to investigate the functional role of ginsenoside compound K on HaCaT cells (a keratinocyte-derived permanent cell line) irradiated by UV. Hoechst 33258 staining were performed in analyzing UV-induced apoptosis on keratinocytes which were treated with compound K. ImmunoDotBlot assay was used in detecting cyclobutane pyrimidine dimers, the main DNA damage. Western blot analysis was applied for analyzing XPC and ERCC1, two of the NER proteins. Compound K inhibited UV-induced apoptosis of keratinocytes and caused a notable reduction in UV-specific DNA lesions which was due to induction of DNA repair. In agreement with this, compound K induced the expression of particular components of the NER complex, such as XPC and ERCC1. Our results demonstrate that compound K can protect cells from apoptosis induced by UV radiation by inducing DNA repair.

  11. 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

  12. 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.

  13. Alantolactone Induces Apoptosis and Cell Cycle Arrest on Lung Squamous Cancer SK-MES-1 Cells.

    PubMed

    Zhao, Peng; Pan, Zhenxiang; Luo, Yungang; Zhang, Leilei; Li, Xin; Zhang, Guangxin; Zhang, Yifan; Cui, Ranji; Sun, Mei; Zhang, Xingyi

    2015-05-01

    Alantolactone, a sesquiterpene lactone compound, has variety of pharmacological properties, including anti-inflammatory and antineoplastic effects. In our study, alantolactone inhibited cancer cell proliferation. To explore the mechanisms underlying its antitumor action, we further examined apoptotic cells and cell cycle distribution using flow cytometry analysis. Alantolactone triggered apoptosis and induced cell cycle G1/G0 phase arrest. Furthermore, the expressions of caspases-8, -9, -3, PARP, and Bax were significantly upregulated, while antiapoptotic factor Bcl-2 expression was inhibited. In addition, the expressions of cyclin-dependent kinase 4 (CDK4), CDK6, cyclin D3, and cyclin D1 were downregulated by alantolactone. Therefore, our findings indicated that alantolactone has an antiproliferative role on lung squamous cancer cells, and it may be a promising chemotherapeutic agent for squamous lung cancer SK-MES-1 cells. © 2015 Wiley Periodicals, Inc.

  14. Naphthoquinones from Onosma paniculata induce cell-cycle arrest and apoptosis in melanoma Cells.

    PubMed

    Kretschmer, Nadine; Rinner, Beate; Deutsch, Alexander J A; Lohberger, Birgit; Knausz, Heike; Kunert, Olaf; Blunder, Martina; Boechzelt, Herbert; Schaider, Helmut; Bauer, Rudolf

    2012-05-25

    Activity-guided fractionation of a petroleum ether-soluble extract of the roots of Onosma paniculata, which has been shown to affect the cell cycle and to induce apoptosis in melanoma cells, led to the isolation of several shikonin derivatives, namely, β-hydroxyisovalerylshikonin (1), acetylshikonin (2), dimethylacrylshikonin (3), and a mixture of α-methylbutyrylshikonin and isovalerylshikonin (4+5). All compounds exhibited strong cytotoxicity against eight cancer cell lines and MRC-5 lung fibroblasts, with 3 found to possess the most potent cytotoxicity toward four melanoma cell lines (SBcl2, WM35, WM9, and WM164). Furthermore, 3 and the mixture of 4+5 were found to interfere with cell-cycle progression in these cell lines and led to an increasing number of cells in the subG1 region as well as to caspase-3/7 activation, indicating apoptotic cell death.

  15. Identification of benzazole compounds that induce HIV-1 transcription

    PubMed Central

    Michaels, Daniel; Chen, Guangming; Schiralli Lester, Gillian M.; Nodder, Sarah; Weetall, Marla; Karp, Gary M.; Gu, Zhengxian; Colacino, Joseph M.; Henderson, Andrew J.

    2017-01-01

    Despite advances in antiretroviral therapy, HIV-1 infection remains incurable in patients and continues to present a significant public health burden worldwide. While a number of factors contribute to persistent HIV-1 infection in patients, the presence of a stable, long-lived reservoir of latent provirus represents a significant hurdle in realizing an effective cure. One potential strategy to eliminate HIV-1 reservoirs in patients is reactivation of latent provirus with latency reversing agents in combination with antiretroviral therapy, a strategy termed “shock and kill”. This strategy has shown limited clinical effectiveness thus far, potentially due to limitations of the few therapeutics currently available. We have identified a novel class of benzazole compounds effective at inducing HIV-1 expression in several cellular models. These compounds do not act via histone deacetylase inhibition or T cell activation, and show specificity in activating HIV-1 in vitro. Initial exploration of structure-activity relationships and pharmaceutical properties indicates that these compounds represent a potential scaffold for development of more potent HIV-1 latency reversing agents. PMID:28658263

  16. 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.

  17. Microscale Transformations of Some Lead Compounds. A Cycle for Lead Minimizing the Production of Wastes

    NASA Astrophysics Data System (ADS)

    Arnáiz, Francisco J.; Pedrosa, María R.

    1999-12-01

    Lead and its more common salts have for a long time been used to perform a number of experiments. In recent years, owing to the importance of minimizing the production of hazardous chemicals, there is a tendency to replace experiments involving toxic compounds by others that, while illustrating the same principles, make use of products more environmentally friendly. Although in many instances this replacement can be made without significant loss of educational value, we consider it necessary to acquaint students with techniques used in the processing of hazardous chemicals. This set of basic experiments emphasizes that toxic products can be conveniently studied by using a combination of microscale techniques and simple schemes to recycle wastes. Here we propose a basic cycle for lead involving the consecutive transformation of lead(II) acetate to lead(II) formate, lead powder, and lead(II) oxide, with special emphasis on minimizing the production of wastes.

  18. Compound ICA-105574 prevents arrhythmias induced by cardiac delayed repolarization.

    PubMed

    Meng, Jing; Shi, Chenxia; Li, Lin; Du, Yumin; Xu, Yanfang

    2013-10-15

    Impaired ventricular repolarization can lead to long QT syndrome (LQT), a proarrhythmic disease with high risk of developing lethal ventricular tachyarrhythmias. The compound ICA-105574 is a recently developed hERG activator and it enhances IKr current with very high potency by removing the channel inactivation. The present study was designed to investigate antiarrhythmic properties of ICA-105574. For comparison, the effects of another compound NS1643 was in-parallel assessed, which also acts primarily to attenuate channel inactivation with moderate potency. We found that both ICA-105574 and NS1643 concentration-dependently shortened action potential duration (APD) in ventricular myocytes, and QT/QTc intervals in isolated guinea-pig hearts. ICA-105574, but not NS1643, completely prevented ventricular arrhythmias in intact guinea-pig hearts caused by IKr and IKs inhibitors, although both ICA-105574 and NS1643 could reverse the drug-induced prolongation of APD in ventricular myocytes. Reversing prolongation of QT/QTc intervals and antagonizing the increases in transmural dispersion of repolarization and instability of the QT interval induced by IKr and IKs inhibitors contributed to antiarrhythmic effect of ICA-105574. Meanwhile, ICA-105574 at higher concentrations showed a potential proarrhythmic risk in normal hearts. Our results suggest that ICA-105574 has more efficient antiarrhythmic activity than NS1643. However, its potential proarrhythmic risk implies that benefits and risks should be seriously taken into consideration for further developing this type of hERG activators.

  19. A Flavone Constituent from Myoporum bontioides Induces M-Phase Cell Cycle Arrest of MCF-7 Breast Cancer Cells.

    PubMed

    Weng, Jing-Ru; Bai, Li-Yuan; Lin, Wei-Yu; Chiu, Chang-Fang; Chen, Yu-Chang; Chao, Shi-Wei; Feng, Chia-Hsien

    2017-03-15

    Myoporum bontioides is a traditional medicinal plant in Asia with various biological activities, including anti-inflammatory and anti-bacterial characteristics. To identify the bioactive constituents from M. bontioides, a newly-identified flavone, 3,4'-dimethoxy-3',5,7-trihydroxyflavone (compound 1), along with eight known compounds, were investigated in human MCF-7 breast cancer, SCC4 oral cancer, and THP-1 monocytic leukemia cells. Among these compounds, compound 1 exhibited the strongest antiproliferative activity with half-maximal inhibitory concentration (IC50) values ranging from 3.3 μM (MCF-7) to 8.6 μM (SCC4). Flow cytometric analysis indicated that compound 1 induced G2/M cell cycle arrest in MCF-7 cells. Mechanistic evidence suggests that the G2/M arrest could be attributable to compound 1's modulatory effects on the phosphorylation and expression of numerous key signaling effectors, including cell division cycle 2 (CDC2), CDC25C, and p53. Notably, compound 1 downregulated the expression of histone deacetylase 2 (HDAC2) and HDAC4, leading to increased histone H3 acetylation and p21 upregulation. Together, these findings suggest the translational potential of compound 1 as a breast cancer treatment.

  20. 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.

  1. 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.

  2. Sonoporation-Induced Apoptosis and Cell Cycle Arrest: Initial Findings

    NASA Astrophysics Data System (ADS)

    Zhong, Wenjing; Sit, Wai Hung; Wan, Jennifer M. F.; Yu, Alfred C. H.

    2011-09-01

    Sonoporation is known to be able to temporarily permeabilize cells, but during this process it may have traumatic impact on cell viability. In this work, we found that sonoporation may induce apoptosis and G2/M-phase cell cycle arrest in some cells hours after ultrasonic exposure in vitro. Methods: Suspensions of HL-60 leukemia cells were prepared (106 cells/ml), and a 1% v/v microbubble solution was added to induce sonoporation during ultrasound exposure. They were then placed 7 cm away from a 2.54 cm-diameter, 1 MHz unfocused ultrasound probe, and these samples were insonated for 1 min with ultrasound pulses (10% duty cycle, 1 kHz pulse repetition frequency). In this study, two levels of peak negative ultrasound pressure were used: 0.3 MPa and 0.5 MPa. After exposure, the cell suspensions were further incubated. They were harvested after 4 h, 8 h, 12 h and 24 h to analyze the cell-cycle distribution (sub-G1, G0/G1, S, G2/M) at these time points using propidium iodide staining and flow cytometry. Results: Some sonoporation-treated cells had undergone apoptosis by 4h, and the largest number of apoptotic cells (sub-G1 phase) was observed after 12h (0.3 MPa group: 25.0%; 0.5 MPa group: 27.2%). Also, after experiencing sonoporation, some viable cells were stopped in the G2/M phase without undergoing cytokinesis, and the maximum G2/M population rise was seen after 12h (0.3 MPa group: +12.2%; 0.5 MPa group: +14.7%). This was accompanied by decreases in the populations of G0/G1-phase and S-phase.

  3. Atomistic Simulation of Radiation-Induced Amorphization of Intermetallic Compounds.

    NASA Astrophysics Data System (ADS)

    Devanathan, Ramaswami

    Electron irradiation-induced amorphization of the intermetallic compounds NiZr, NiZr_2, FeTi and CuTi was examined using molecular dynamics simulations. Embedded-atom potentials, fitted to the properties of the pure metals and compounds, were used to model the interactions between the atoms. Electron irradiation was simulated by two different processes: randomly chosen atoms of different species were exchanged to create chemical disorder, and Frenkel pairs were introduced into the simulation cell at random. The resulting configurations corresponding to various damage doses were relaxed and the thermodynamic, structural, and mechanical properties were evaluated as functions of dose. The evolution of the system structure during the simulation was monitored using a new approach that combines molecular dynamics with the multislice method. Electron diffraction patterns were calculated from simulated configurations in an effort to maintain consistency with experiments, and improve the sensitivity to structural changes. The results of the simulation indicate that the mechanism of amorphization can vary from compound to compound. Chemical disorder was sufficient to cause amorphization in NiZr and NiZr_2, while Frenkel pairs were required in addition to chemical disorder in CuTi, and FeTi. During the process of amorphization, the energy and volume increased with dose and saturated at the corresponding levels of a quenched liquid. The variation of the volume with dose was remarkably similar to that of the energy. The pair-correlation functions, diffraction patterns, and projection of atom positions indicated the occurence of amorphization. In addition, the elastic constants C_{44 } and C^' became equal. Prior to the attainment of elastic isotropy, the average shear elastic constant decreased by about 50% of its value in the perfect crystal. In an effort to understand the elastic softening prior to amorphization and explore similarities between melting and amorphization, the

  4. 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.

  5. Crambescidin-816 acts as a fungicidal with more potency than crambescidin-800 and -830, inducing cell cycle arrest, increased cell size and apoptosis in Saccharomyces cerevisiae.

    PubMed

    Rubiolo, Juan A; Ternon, Eva; López-Alonso, Henar; Thomas, Olivier P; Vega, Félix V; Vieytes, Mercedes R; Botana, Luis M

    2013-11-08

    In this paper, we show the effect of crambescidin-816, -800, and -830 on Saccharomyces cerevisiae viability. We determined that, of the three molecules tested, crambescidin-816 was the most potent. Based on this result, we continued by determining the effect of crambescidin-816 on the cell cycle of this yeast. The compound induced cell cycle arrest in G2/M followed by an increase in cell DNA content and size. When the type of cell death was analyzed, we observed that crambescidin-816 induced apoptosis. The antifungal effect indicates that crambescidins, and mostly crambescidin-816, could serve as a lead compound to fight fungal infections.

  6. 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. Copyright © 2013 John Wiley & Sons, Ltd.

  7. Cytotoxicity of the compounds isolated from Pulsatilla chinensis saponins and apoptosis induced by 23-hydroxybetulinic acid.

    PubMed

    Liu, Ming; Zhao, Xingzeng; Xiao, Lin; Liu, Ge; Liu, Haizhou; Wang, Xiangyun; Feng, Xu; Lin, Xiukun

    2015-01-01

    The rizoma of Pulsatilla chinensis (Bunge) Regel has been used as a traditional Chinese medicinal herb for thousands of years. Total saponins from P. chinensis can induce the apoptosis of solid cancer cells; however, their activity on chronic myeloid leukemia and the mechanisms remains unknown. To study the activity of total saponins and the main active fractions from P. chinensis saponins on chronic myeloid leukemia, and to illustrate the mechanisms underlying the anticancer activities. The cytotoxic activity were assayed by MTT; cell cycle arrest and apoptosis were tested by flow cytometry system; changes in the mitochondrial membrane potential were determined using JC-1; and the apoptosis signaling pathway was determined by western blotting. We demonstrated that total P. chinensis saponin displayed cytotoxic activity against K562 cell line. In addition, we identified 23-hydroxybetulinic acid (HBA), pulchinenoside A (PA), and anemoside B4 (AB4) from the total saponins, with the most cytotoxic compound HBA. Glycosylation at C3 and C28 of HBA significantly reduces its cytotoxicity. HBA could promote cell cycle arrest at S phase and induce apoptosis via intrinsic pathway. HBA disrupts mitochondrial membrane potential significantly (p < 0.01) and selectively downregulates the levels of Bcl-2, survivin and upregulates Bax, cytochrome C, cleaved caspase-9 and -3. Total saponins from P. chinensis may be effective natural products against human chronic myelogenous leukemia; HBA is one of the bioactive components responsible for its anticancer activity, and could be further investigated as an alternative therapeutic drug for leukemia.

  8. [Ascorbate-glutathione cycle enzymes activity in Zea mays leaves under salinity and treatment by adaptogenic compounds].

    PubMed

    Konturs'ka, O O; Palladina, T O

    2012-01-01

    The effect of different salinity levels and synthetic compounds treatments on ascorbate-glutathione cycle enzymes activity in maize leaves has been investigated. One-day seedlings exposition with 0.05 M NaCl increased ascorbate peroxidase activity, whereas 10-day exposition did not affect it. However the exposition with 0.1 M NaCl, which is extreme for maize, decreased ascorbate peroxidase activity in leaves during 10 days. On the other hand glutathione reductase activity in leaves increased under both salt concentrations. Seeds treatments with Methyure and Ivine increased ascorbate peroxidase activity in the leaves of seedlings under 0.1 M NaCl, but did not affect glutathione reductase activity as compared to the salt control. The results obtained have shown differences of ascorbate-glutathione cycle enzymes responses to salt exposition of seedlings and the effects of adaptogenic compounds on the ascorbate-glutathione cycle via ascorbate peroxidase activation.

  9. 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.

  10. Non Equilibrium Transformations of Molecular Compounds Induced Mechanically

    SciTech Connect

    Descamps, M.; Willart, J. F.; Dudognon, E.

    2006-05-05

    Results clarifying the effects of mechanical milling on molecular solids are shortly reviewed. Special attention has been paid to the temperature of milling with regard to the glass transition temperature of the compounds. It is shown that decreasing the grinding temperature has for incidence to increase the amorphization tendency whereas milling above Tg produces a crystal-to-crystal transformation between polymorphic varieties. These observations contradict the usual proposition that grinding transforms the physical state only by a heating effect which induces a local melting. Equilibrium thermodynamics does not seem to be appropriate for describing the process. The driven alloys concept offers a more rational framework to interpret the effect of the milling temperature. Other results are presented which demonstrate the possibility for grinding to realize low temperature solid state alloying which offers new promising ways to stabilize amorphous molecular solids. In a second part the effect of dehydration of a molecular hydrate is described. It is shown that the rate of the dehydration process is a driving force for this other type of mechanical non equilibrium transformation.

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

    PubMed

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

    2013-08-13

    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.

  12. Ion beam induced luminescence of doped yttrium compounds

    NASA Astrophysics Data System (ADS)

    Rossi, P.; Brice, D. K.; Seager, C. H.; McDaniel, F. D.; Vizkelethy, G.; Doyle, B. L.

    2004-06-01

    Rare earth doped yttrium oxide (yttria) and silicate, Y 2O 3:Eu and Y 2SiO 5:Tb, are the most promising phosphors for advanced devices such as flat panel field-emission-displays. However, their light yield for electron excitation has proven to be lower than that predicted by early models. New experimental data are needed to improve the theoretical understanding of the cathodoluminescence (CL) that will, in turn, lead to materials that are significantly brighter. Beside the existing CL and photo luminescence (PL) measurements, one can provide new information by studying ion-induced luminescence (IL). Ions penetrate substantially deeper than electrons and their light yield should therefore not depend on surface effects. Moreover, the energy density released by ions can be much higher than that of electrons and photons, which results in possible saturation effects, further testing the adequacy of models. We exposed the above yttrium compounds to three ion beams, H (3 MeV), C (20 MeV), Cu (50 MeV), which have substantially different electronic stopping powers. H was selected to provide an excitation close to CL, but without surface effects. The C and Cu allowed an evaluation of saturation effects because of their higher stopping powers. The IL experiments involved measuring the transient light intensity signal radiating from thin phosphor layers following their exposure to ˜200 ns ion beam pulses. We present the transient yield curves for the two materials and discuss a general model for this behavior.

  13. 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.

  14. Apoptosis and cell cycle disturbances induced by coumarin and 7-hydroxycoumarin on human lung carcinoma cell lines.

    PubMed

    Lopez-Gonzalez, Jose Sullivan; Prado-Garcia, Heriberto; Aguilar-Cazares, Dolores; Molina-Guarneros, Juan A; Morales-Fuentes, Jorge; Mandoki, Juan Jose

    2004-03-01

    Coumarin and 7-hydroxycoumarin have anti-tumour actions in vitro and in vivo. There are no previous reports on the cytostatic and apoptotic actions of coumarin and 7-hydroxycoumarin in non-small cell lung carcinoma (NSCLC) cell lines. Here we report on: (1) the inhibition of cell proliferation, (2) the phase in which cell cycle arrest occurs, and (3) the induction of apoptosis. Inhibition of cell proliferation was determined by 3H-thymidine incorporation. The effects on cell cycle phases were determined at 100 microg/ml of coumarin or 7-hydroxycoumarin using propidium iodide and flow cytometry. Higher concentrations were used to study apoptosis, detected by: (1) morphological cell changes, (2) subG1 peak detection and (3) Annexin-V assay. Peripheral blood mononuclear cells (PBMC) stimulated with phytohemagglutinin were used as controls. The actions of these compounds depended on drug concentrations and on histological cell type. Coumarin and 7-hydroxycoumarin inhibited cell growth by inducing cell cycle arrest in the G1 phase in all the lung carcinoma cell lines. Apoptosis required large concentrations of the coumarin compounds and was observed in adenocarcinomas. Apoptosis was not associated with intra-nucleosomal DNA fragmentation. Apoptosis was not observed in squamous lung carcinoma cell lines, but an increase in G1 cell cycle arrest was detected. In PBMC, only large concentrations of the coumarin compounds elicited a cystostatic action. Coumarins in combination with other anti-neoplastic drugs might increase the effectiveness of NSCLC treatments.

  15. Drug-induced cell cycle modulation leading to cell-cycle arrest, nuclear mis-segregation, or endoreplication

    PubMed Central

    2011-01-01

    Background Cancer cell responses to chemotherapeutic agents vary, and this may reflect different defects in DNA repair, cell-cycle checkpoints, and apoptosis control. Cytometry analysis only quantifies dye-incorporation to examine DNA content and does not reflect the biological complexity of the cell cycle in drug discovery screens. Results Using population and time-lapse imaging analyses of cultured immortalized cells expressing a new version of the fluorescent cell-cycle indicator, Fucci (Fluorescent Ubiquitination-based Cell Cycle Indicator), we found great diversity in the cell-cycle alterations induced by two anticancer drugs. When treated with etoposide, an inhibitor of DNA topoisomerase II, HeLa and NMuMG cells halted at the G2/M checkpoint. HeLa cells remained there, but NMuMG cells then overrode the checkpoint and underwent nuclear mis-segregation or avoided the checkpoint and entered the endoreplication cycle in a drug concentration dependent manner. In contrast, an inhibitor of Cdk4 led to G1 arrest or endoreplication in NMuMG cells depending upon the initial cell-cycle phase of drug exposure. Conclusions Drug-induced cell cycle modulation varied not only between different cell types or following treatment with different drugs, but also between cells treated with different concentrations of the same drug or following drug addition during different phases of the cell cycle. By combining cytometry analysis with the Fucci probe, we have developed a novel assay that fully integrates the complexity of cell cycle regulation into drug discovery screens. This assay system will represent a powerful drug-discovery tool for the development of the next generation of anti-cancer therapies. PMID:21226962

  16. Tachyzoite-induced life cycle of Toxoplasma gondii in cats.

    PubMed

    Dubey, J P

    2002-08-01

    The tachyzoite-induced cycle of Toxoplasma gondii was studied in 46 cats. Tachyzoites of the M-7741 or Me-49 strain of T. gondii were administered orally to cats by pouring into the mouth or by stomach tube, or by intraintestinal inoculation. Ten weaned cats that had been inoculated with tachyzoites directly in the intestine were killed 1, 3, 6, 9, 12, 15, 18, or 25 days later, and their tissues were studied histologically and bioassayed in mice. Toxoplasma gondii was demonstrable in the blood of 8 cats and in other tissues of all these 10. Four out of five 1- to 8-day-old cats fed tachyzoites by stomach tube became infected with T. gondii, and 1 became ill because of toxoplasmosis. All 19 weaned cats fed tachyzoites (poured into the mouth) became infected, and 6 died of acute toxoplasmosis 9-15 days after being fed T. gondii. Six out of 12 weaned cats fed tachyzoites by stomach tube became infected but were asymptomatic. Overall, 12 out of 26 cats observed for 19 days or more shed oocysts with a prepatent period (pp) of 19 days or more, with the sole exception of 1 cat that shed oocysts with a pp of 5 days. Enteroepithelial stages of T. gondii were not found in any cat before oocysts were shed. Cats shed up to 360 million oocysts in a day, and oocysts were shed for 4-6 days.

  17. Evidence of solar induced cycles of high seismic activity

    NASA Astrophysics Data System (ADS)

    Duma, G.

    2010-12-01

    In the past century, several observational results and corresponding publications indicate a systematic seismic performance with respect to the time of day and seasons as well. Such effects could be caused only by solar or lunar influence. In addition, a possible relation with the solar cycles was discussed in some papers, too. Intensive studies on these topics have also been performed at the Central Institute for Meteorology and Geodynamics (ZAMG), Vienna, Austria. They strongly confirm the above mentioned effects. In order to verify a solar influence on earthquake activity correlations were performed between the three-hour magnetic index Kp and the energy release of earthquakes in the long term. Kp characterizes the magnetic field disturbances which are mainly caused by the solar particle radiation, the solar wind. Kp is determined on a routine basis from magnetic records of 13 observatories worldwide and is continuously published by ISGI, France. Three regions of continental size were investigated, using the USGS (PDE) earthquake catalogue data, from 1974 on: N-America, S-America and Eurasia. The statistic analyses reveal that from 1974 to 2009 the index Kp varies in cycles with periods between 9 and 12 years, somewhat different to the sunspot number cycles (no. 21, 22, 23) of 11 years. As to the seismic energy release, the sqrt (energy E) of an event is taken as measure, which relates to the ‘strain release’ due to the earthquake (Benioff). For Kp the monthly averages were computed, for the strain release the monthly sums of sqrt(E), hereinafter referred to as STR. From the statistic estimates of the relation Kp-STR for all the three regions N-America, S-America and Eurasia it becomes evident, that the correlation is highly significant: earthquake activity, quantified by the monthly STR, follows the Kp cycles with high coincidence. A quantitative analysis reveals that on an annual basis, the sum of released energy by earthquakes changes by a factor up to

  18. Benzylidenetetralones, cyclic chalcone analogues, induce cell cycle arrest and apoptosis in HCT116 colorectal cancer cells.

    PubMed

    Drutovic, David; Chripkova, Martina; Pilatova, Martina; Kruzliak, Peter; Perjesi, Pal; Sarissky, Marek; Lupi, Monica; Damia, Giovanna; Broggini, Massimo; Mojzis, Jan

    2014-10-01

    Colorectal cancer is the third most common cancer in the world, with 1.2 million new cancer cases annually. Chalcones are secondary metabolite precursors of flavonoids that exhibit diverse biological activities, including antioxidant and antitumor activities. The aim of this study was to investigate the antiproliferative effect of new synthetic chalcone derivatives on HCT116 cells. (E)-2-(2',4'-dimethoxybenzylidene)-1-tetralone (Q705) was found to be the most active (IC50 = 3.44 ± 0.25 μM). Based on these results, this compound was chosen for further analysis of its biochemical and molecular mechanisms. Our results showed that Q705 inhibited the growth and clonogenicity of HCT116 cells. The results of a flow cytometric analyses suggested that this compound caused a significant cell cycle arrest in G2/M phase and increased the proportion of cells in the subG0/G1 phase, marker of apoptosis. Q705-induced apoptosis was confirmed by TdT-mediated dUTP nick end labelling (TUNEL) assay. Treatment of HCT116 cells with this chalcone significantly increased the caspase-3,-7 activity and resulted in cleavage of poly-ADP-ribose polymerase (PARP). Changes in the nuclear morphology such as chromatin condensation were also observed. These effects were associated with a decreased expression of bcl-xL and increased overall ratio of bax/bcl-xL mRNA levels. Immunofluorescence and qRT-PCR analysis revealed that Q705 induced H2AX histone modifications characteristic of DNA damage, disruption of microtubule organization and downregulation of tubulins. In summary, these results suggest that the cyclic chalcone analogue Q705 has potential as a new compound for colorectal cancer therapy.

  19. T Cell Receptor-induced Activation and Apoptosis In Cycling Human T Cells Occur throughout the Cell Cycle

    PubMed Central

    Karas, Michael; Zaks, Tal Z.; JL, Liu; LeRoith, Derek

    1999-01-01

    Previous studies have found conflicting associations between susceptibility to activation-induced cell death and the cell cycle in T cells. However, most of the studies used potentially toxic pharmacological agents for cell cycle synchronization. A panel of human melanoma tumor-reactive T cell lines, a CD8+ HER-2/neu-reactive T cell clone, and the leukemic T cell line Jurkat were separated by centrifugal elutriation. Fractions enriched for the G0–G1, S, and G2–M phases of the cell cycle were assayed for T cell receptor-mediated activation as measured by intracellular Ca2+ flux, cytolytic recognition of tumor targets, and induction of Fas ligand mRNA. Susceptibility to apoptosis induced by recombinant Fas ligand and activation-induced cell death were also studied. None of the parameters studied was specific to a certain phase of the cell cycle, leading us to conclude that in nontransformed human T cells, both activation and apoptosis through T cell receptor activation can occur in all phases of the cell cycle. PMID:10588669

  20. High-Throughput Chemical Screening Identifies Compounds that Inhibit Different Stages of the Phytophthora agathidicida and Phytophthora cinnamomi Life Cycles

    PubMed Central

    Lawrence, Scott A.; Armstrong, Charlotte B.; Patrick, Wayne M.; Gerth, Monica L.

    2017-01-01

    Oomycetes in the genus Phytophthora are among the most damaging plant pathogens worldwide. Two important species are Phytophthora cinnamomi, which causes root rot in thousands of native and agricultural plants, and Phytophthora agathidicida, which causes kauri dieback disease in New Zealand. As is the case for other Phytophthora species, management options for these two pathogens are limited. Here, we have screened over 100 compounds for their anti-oomycete activity, as a potential first step toward identifying new control strategies. Our screening identified eight compounds that showed activity against both Phytophthora species. These included five antibiotics, two copper compounds and a quaternary ammonium cation. These compounds were tested for their inhibitory action against three stages of the Phytophthora life cycle: mycelial growth, zoospore germination, and zoospore motility. The inhibitory effects of the compounds were broadly similar between the two Phytophthora species, but their effectiveness varied widely among life cycle stages. Mycelial growth was most successfully inhibited by the antibiotics chlortetracycline and paromomycin, and the quaternary ammonium salt benzethonium chloride. Copper chloride and copper sulfate were most effective at inhibiting zoospore germination and motility, whereas the five antibiotics showed relatively poor zoospore inhibition. Benzethonium chloride was identified as a promising antimicrobial, as it is effective across all three life cycle stages. While further testing is required to determine their efficacy and potential phytotoxicity in planta, we have provided new data on those agents that are, and those that are not, effective against P. agathidicida and P. cinnamomi. Additionally, we present here the first published protocol for producing zoospores from P. agathidicida, which will aid in the further study of this emerging pathogen. PMID:28769905

  1. High-Throughput Chemical Screening Identifies Compounds that Inhibit Different Stages of the Phytophthora agathidicida and Phytophthora cinnamomi Life Cycles.

    PubMed

    Lawrence, Scott A; Armstrong, Charlotte B; Patrick, Wayne M; Gerth, Monica L

    2017-01-01

    Oomycetes in the genus Phytophthora are among the most damaging plant pathogens worldwide. Two important species are Phytophthora cinnamomi, which causes root rot in thousands of native and agricultural plants, and Phytophthora agathidicida, which causes kauri dieback disease in New Zealand. As is the case for other Phytophthora species, management options for these two pathogens are limited. Here, we have screened over 100 compounds for their anti-oomycete activity, as a potential first step toward identifying new control strategies. Our screening identified eight compounds that showed activity against both Phytophthora species. These included five antibiotics, two copper compounds and a quaternary ammonium cation. These compounds were tested for their inhibitory action against three stages of the Phytophthora life cycle: mycelial growth, zoospore germination, and zoospore motility. The inhibitory effects of the compounds were broadly similar between the two Phytophthora species, but their effectiveness varied widely among life cycle stages. Mycelial growth was most successfully inhibited by the antibiotics chlortetracycline and paromomycin, and the quaternary ammonium salt benzethonium chloride. Copper chloride and copper sulfate were most effective at inhibiting zoospore germination and motility, whereas the five antibiotics showed relatively poor zoospore inhibition. Benzethonium chloride was identified as a promising antimicrobial, as it is effective across all three life cycle stages. While further testing is required to determine their efficacy and potential phytotoxicity in planta, we have provided new data on those agents that are, and those that are not, effective against P. agathidicida and P. cinnamomi. Additionally, we present here the first published protocol for producing zoospores from P. agathidicida, which will aid in the further study of this emerging pathogen.

  2. Reconstructing 40ky of N cycling from stable isotopes of plant compounds in a Siberian permafrost soil

    NASA Astrophysics Data System (ADS)

    Enders, S. K.; Houlton, B. Z.; Ohkouchi, N.; Wagner, D.; Ogawa, N. O.; Chikaraishi, Y.; Suga, H.

    2015-12-01

    Terrestrial nitrogen (N) cycling has an important dual role in regulating global climate, as N is both a limiting plant nutrient and a constituent of a potent greenhouse gas. Reconstructing past terrestrial N cycling is a valuable complement to experimental manipulation of complex climate-carbon-N interactions, but has been challenged by shortcomings of available proxies. We here examine 40ky of terrestrial N cycling on the landscape of northeast Siberia as recorded in N-isotopes of chlorophyll degradation products preserved in a permafrost soil core. This dataset gives insight into the response of the N cycle to concurrent changes in climate, plant community, and atmospheric pCO2 that accompany a cycle of glaciation. This study is the first application to temporal reconstruction of this compound-specific, soil-based proxy for an integrated foliar N isotope signal. We infer ~10 per mil swings in foliar N-isotope values at this site, pointing to the sensitivity of denitrification at high latitudes to changes in environmental conditions. We further observe the effect of increases in N-fixing species on stimulating N cycling as recorded by our proxy. We do not see an effect of progressive N limitation due to pre-anthropogenic increases in pCO2 accompanying deglaciation.

  3. Effect of Thermal Cycle on the Formation of Intermetallic Compounds in Laser Welding of Aluminum-Steel Overlap Joints

    NASA Astrophysics Data System (ADS)

    Fan, J.; Thomy, C.; Vollertsen, F.

    The intermetallic compound (IMC) (or intermetallic phase layer) has a significant influence on the mechanical properties ofjoints between dissimilar metals obtained by thermal processes such as laser welding. Its formation is basically affected by thermal cycles in the joining or contact zone, where the IMC is formed. Within this study, the influence of the thermal cycle on the formation of the IMC during laser welding of an aluminum-steel (Al99.5-DC01) overlap joint was investigated. The temperature was measured directly by a thermocouple, and the weld seam was analyzed by scanning electron microscope (SEM). The influence of peak temperature, cooling time and the integral of the thermal cycle on the thickness of the IMC was identified and discussed. It was identified that cooling time has the biggest influence on the thickness of the IMC.

  4. Ginsenoside compound K induces apoptosis in nasopharyngeal carcinoma cells via activation of apoptosis-inducing factor

    PubMed Central

    2014-01-01

    Background Nasopharyngeal carcinoma (NPC) has a high incidence rate in Southern China. Although there are conventional therapies, the side effects and toxicities are not always tolerable for patients. Recently, the tumoricidal effect of ginsenosides on different cancer cells has been studied. This study aims to investigate the anti-cancer effect of ginsenosides on NPC cells and their underlying mechanism. Methods The cytotoxicity of ginsenosides on NPC cell line HK-1 was measured by MTT assay. Apoptosis was detected by propidium iodide staining followed by flow cytometry. A xenograft tumor model was established by injecting nude mice with HK-1 cells. The activation of caspases and apoptosis-inducing factor (AIF) were evaluated by Western blot analysis. Nuclear translocation of AIF was also studied by immunofluorescence staining. Mitochondrial membrane potential was measured by JC-1 dye using flow cytometry. Results Four ginsenosides, 20 (S)-Rh2, compound K (CK), panaxadiol (PD) and protopanaxadiol (PPD), induced apoptotic cell death in HK-1 cells in a concentration-dependent manner. CK inhibited HK-1 xenograft tumor growth most extensively and depleted mitochondrial membrane potential depolarization and induced translocation of AIF from cytoplasm to nucleus in HK-1 cells. In addition, depletion of AIF by siRNA abolished CK-induced HK-1 cell death. Conclusion Ginsenoside CK-induced apoptosis of HK-1 cells was mediated by the mitochondrial pathway and could significantly inhibit tumor growth in vivo. PMID:24690317

  5. Novel tetrahydroacridine and cyclopentaquinoline derivatives with fluorobenzoic acid moiety induce cell cycle arrest and apoptosis in lung cancer cells by activation of DNA damage signaling.

    PubMed

    Szymański, Paweł; Olszewska, Paulina; Mikiciuk-Olasik, Elżbieta; Różalski, Antoni; Maszewska, Agnieszka; Markiewicz, Łukasz; Cuchra, Magda; Majsterek, Ireneusz

    2017-03-01

    Lung cancer is still the leading cause of cancer-related death worldwide, indicating a necessity to develop more effective therapy. Acridine derivatives are potential anticancer agents due to their ability to intercalate DNA as well as inhibit enzymes involved in replication and transcription. Recently, we have evaluated anticancer activity of 32 novel acridine-based compounds. We found that the most effective were tetrahydroacridine and cyclopentaquinoline derivatives with fluorobenzoic acid containing eight and nine carbon atoms in the aliphatic chain. The aim of this study was to determine the molecular mechanisms of compounds-induced cell cycle arrest and apoptosis in human lung adenocarcinoma cells. All compounds activated Ataxia telangiectasia mutated kinase and phosphorylated histone H2A.X at Ser139 indicating DNA damage. Treatment of cells with the compounds increased phosphorylation and accumulation of p53 that regulate cell cycle as well as apoptosis. All compounds induced G0/1 cell cycle arrest by phosphorylation of cyclin-dependent kinase 2 at Tyr15 resulting in attenuation of the kinase activity. In addition, cyclopentaquinoline derivatives induced expression of cyclin-dependent kinase 2 inhibitor, p21; however, tetrahydroacridine derivatives had no significant effect on p21. Moreover, all compounds decreased the mitochondrial membrane potential accompanied by increased expression of Bax and down-regulation of Bcl-2, suggesting activation of the mitochondrial pathway. All compounds also significantly attenuated the migration rates of lung cancer cells. Collectively, our findings suggest a central role of activation of DNA damage signaling in response to new acridine derivatives treatment to induce cell cycle arrest and apoptosis in cancer cells and provide support for their further development as potential drug candidates.

  6. 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

    2004-11-02

    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.

  7. 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. © The Royal Society of Chemistry 2011

  8. Acanthamoeba induces cell-cycle arrest in host cells.

    PubMed

    Sissons, James; Alsam, Selwa; Jayasekera, Samantha; Kim, Kwang Sik; Stins, Monique; Khan, Naveed Ahmed

    2004-08-01

    Acanthamoeba can cause fatal granulomatous amoebic encephalitis (GAE) and eye keratitis. However, the pathogenesis and pathophysiology of these emerging diseases remain unclear. In this study, the effects of Acanthamoeba on the host cell cycle using human brain microvascular endothelial cells (HBMEC) and human corneal epithelial cells (HCEC) were determined. Two isolates of Acanthamoeba belonging to the T1 genotype (GAE isolate) and T4 genotype (keratitis isolate) were used, which showed severe cytotoxicity on HBMEC and HCEC, respectively. No tissue specificity was observed in their ability to exhibit binding to the host cells. To determine the effects of Acanthamoeba on the host cell cycle, a cell-cycle-specific gene array was used. This screened for 96 genes specific for host cell-cycle regulation. It was observed that Acanthamoeba inhibited expression of genes encoding cyclins F and G1 and cyclin-dependent kinase 6, which are proteins important for cell-cycle progression. Moreover, upregulation was observed of the expression of genes such as GADD45A and p130 Rb, associated with cell-cycle arrest, indicating cell-cycle inhibition. Next, the effect of Acanthamoeba on retinoblastoma protein (pRb) phosphorylation was determined. pRb is a potent inhibitor of G1-to-S cell-cycle progression; however, its function is inhibited upon phosphorylation, allowing progression into S phase. Western blotting revealed that Acanthamoeba abolished pRb phosphorylation leading to cell-cycle arrest at the G1-to-S transition. Taken together, these studies demonstrated for the first time that Acanthamoeba inhibits the host cell cycle at the transcriptional level, as well as by modulating pRb phosphorylation using host cell-signalling mechanisms. A complete understanding of Acanthamoeba-host cell interactions may help in developing novel strategies to treat Acanthamoeba infections.

  9. 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.

  10. Two host-inducible genes of Rhizobium fredii and characterization of the inducing compound.

    PubMed Central

    Sadowsky, M J; Olson, E R; Foster, V E; Kosslak, R M; Verma, D P

    1988-01-01

    Random transcription fusions with Mu d1(Kan lac) generated three mutants in Rhizobium fredii (strain USDA 201) which showed induction of beta-galactosidase when grown in root exudate of the host plants Glycine max, Phaseolus vulgaris, and Vigna ungliculata. Two genes were isolated from a library of total plasmid DNA of one of the mutants, 3F1. These genes, present in tandem on a 4.2-kilobase HindIII fragment, appear in one copy each on the symbiotic plasmid and do not hybridize to the Rhizobium meliloti common nodulation region. They comprise two separate transcriptional units coding for about 450 and 950 nucleotides, both of which are transcribed in the same direction. The two open reading frames are separated by 586 base pairs, and the 5H regions of the two genes show a common sequence. No similarity was found with the promoter areas of Rhizobium trifolii, R. meliloti, or Bradyrhizobium japonicum nif genes and with any known nodulation genes. Regions homologous to both sequences were detected in EcoRI digests of genomic DNAs from B. japonicum USDA 110, USDA 122, and 61A76, but not in genomic DNA from R. trifolii, Rhizobium leguminosarum, or Rhizobium phaseoli. Mass spectrometry and nuclear magnetic resonance analysis indicated that the inducing compound has properties of 4',7-dihydroxyisoflavone, daidzein. These results suggest that, in addition to common nodulation genes, several other genes appear to be specifically induced by compounds in the root exudate of the host plants. Images PMID:2447061

  11. Role of DNA methylation in cell cycle arrest induced by Cr (VI) in two cell lines.

    PubMed

    Lou, Jianlin; Wang, Yu; Yao, Chunji; Jin, Lingzhi; Wang, Xiuzhi; Xiao, Yun; Wu, Nanxiang; Song, Peng; Song, Yang; Tan, Yufeng; Gao, Ming; Liu, Kecheng; Zhang, Xing

    2013-01-01

    Hexavalent chromium [Cr(IV)], a well-known industrial waste product and an environmental pollutant, is recognized as a human carcinogen. But its mechanisms of carcinogenicity remain unclear, and recent studies suggest that DNA methylation may play an important role in the carcinogenesis of Cr(IV). The aim of our study was to investigate the effects of Cr(IV) on cell cycle progress, global DNA methylation, and DNA methylation of p16 gene. A human B lymphoblastoid cell line and a human lung cell line A549 were exposed to 5-15 µM potassium dichromate or 1.25-5 µg/cm² lead chromate for 2-24 hours. Cell cycle was arrested at G₁ phase by both compounds in 24 hours exposure group, but global hypomethylation occurred earlier than cell cycle arrest, and the hypomethylation status maintained for more than 20 hours. The mRNA expression of p16 was significantly up-regulated by Cr(IV), especially by potassium dichromate, and the mRNA expression of cyclin-dependent kinases (CDK4 and CDK6) was significantly down-regulated. But protein expression analysis showed very little change of p16 gene. Both qualitative and quantitative results showed that DNA methylation status of p16 remained unchanged. Collectively, our data suggested that global hypomethylation was possibly responsible for Cr(IV)-induced G₁ phase arrest, but DNA methylation might not be related to up-regulation of p16 gene by Cr(IV).

  12. Role of DNA Methylation in Cell Cycle Arrest Induced by Cr (VI) in Two Cell Lines

    PubMed Central

    Lou, Jianlin; Wang, Yu; Yao, Chunji; Jin, Lingzhi; Wang, Xiuzhi; Xiao, Yun; Wu, Nanxiang; Song, Peng; Song, Yang; Tan, Yufeng; Gao, Ming; Liu, Kecheng; Zhang, Xing

    2013-01-01

    Hexavalent chromium [Cr(IV)], a well-known industrial waste product and an environmental pollutant, is recognized as a human carcinogen. But its mechanisms of carcinogenicity remain unclear, and recent studies suggest that DNA methylation may play an important role in the carcinogenesis of Cr(IV). The aim of our study was to investigate the effects of Cr(IV) on cell cycle progress, global DNA methylation, and DNA methylation of p16 gene. A human B lymphoblastoid cell line and a human lung cell line A549 were exposed to 5–15 µM potassium dichromate or 1.25–5 µg/cm2 lead chromate for 2–24 hours. Cell cycle was arrested at G1 phase by both compounds in 24 hours exposure group, but global hypomethylation occurred earlier than cell cycle arrest, and the hypomethylation status maintained for more than 20 hours. The mRNA expression of p16 was significantly up-regulated by Cr(IV), especially by potassium dichromate, and the mRNA expression of cyclin-dependent kinases (CDK4 and CDK6) was significantly down-regulated. But protein expression analysis showed very little change of p16 gene. Both qualitative and quantitative results showed that DNA methylation status of p16 remained unchanged. Collectively, our data suggested that global hypomethylation was possibly responsible for Cr(IV) - induced G1 phase arrest,but DNA methylation might not be related to up-regulation of p16 gene by Cr(IV). PMID:23940686

  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. Adenosine induces G2/M cell-cycle arrest by inhibiting cell mitosis progression.

    PubMed

    Jia, Kun-Zhi; Tang, Bo; Yu, Lu; Cheng, Wei; Zhang, Rong; Zhang, Jian-Fa; Hua, Zi-Chun

    2009-12-16

    Cellular adenosine accumulates under stress conditions. Few papers on adenosine are concerned with its function in the cell cycle. The cell cycle is the essential mechanism by which all living things reproduce and the target machinery when cells encounter stresses, so it is necessary to examine the relationship between adenosine and the cell cycle. In the present study, adenosine was found to induce G-2/M cell-cycle arrest. Furthermore, adenosine was found to modulate the expression of some important proteins in the cell cycle, such as cyclin B and p21, and to inhibit the transition of metaphase to anaphase in mitosis.

  15. Sesquiterpene lactones from Ambrosia spp. are active against a murine lymphoma cell line by inducing apoptosis and cell cycle arrest.

    PubMed

    Martino, Renzo; Beer, María Florencia; Elso, Orlando; Donadel, Osvaldo; Sülsen, Valeria; Anesini, Claudia

    2015-10-01

    Sesquiterpene lactones (STLs) are natural terpenoid compounds. They have been recognized as antitumor agents. The purpose of this investigation was to explore the antiproliferative effects of psilostachyin, psilostachyin C, peruvin and cumanin on the murine lymphoma cell line BW5147. Cells were treated with the STLs at different concentrations. Tritiated thymidine uptake was employed to determine cell proliferation. MTT assay was used to analyze cell viability. Flow cytometry assay with annexin V-FITC and propidium iodide was employed to evaluate cell death. Reactive oxygen species (ROS), mitochondrial membrane potential and cell cycle analysis were also evaluated by flow cytometry. Antioxidant enzymes activities were determined spectrophotometrically by kinetic assays. Results showed that these STLs inhibited cell proliferation in a concentration-dependent manner by exerting cytotoxicity through apoptosis. Psilostachyin C was the most active and the less toxic compound. This STL induced apoptosis with an impairment in mitochondrial membrane potential. Psilostachyin C was able to induce ROS generation, related to a modulation of the antioxidant enzymes activity. In addition, it induced cell cycle arrest in S phase. In conclusion, psilostachyin C was found to be active against lymphoma cells exerting both cytostatic and cytotoxic effects. These findings may provide a novel approach for lymphoma treatment. Copyright © 2015 Elsevier Ltd. All rights reserved.

  16. Physicochemical Nature of Perfluoroalkyl Compounds Induced by Fluorine.

    PubMed

    Hasegawa, Takeshi

    2017-05-09

    Perfluoroalkyl (Rf ) compounds have unique characters represented by a significantly high hydrophobic property, which often makes us consider that Rf groups should be interacted with each other via the 'hydrophobic interaction' as found for a normal hydrocarbon. Due to a similar intuitive and simplistic speculation, the Rf -specific material properties have long been enveloped in darkness for comprehensive understanding, which should lucidly be discussed within a framework of physical chemistry. Here, we show studies on the stratified dipole arrays (SDA) theory, which readily explains the Rf -specific material characters in a comprehensive manner based on only a few fundamental physical parameters of fluorine. The SDA theory encompasses some conventional theories that account for only a part of material properties. In addition, we show that the concept of vibrational spectroscopy of Rf compounds should also be revised, since the mass of fluorine is larger than that of carbon, which is opposite to the hydrocarbon case. In this manner, chemistry of Rf compounds needs another fully revised concept, which cannot be replaced by an extended concept of normal hydrocarbon compounds. © 2017 The Chemical Society of Japan & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  17. S-52, a novel nootropic compound, protects against β-amyloid induced neuronal injury by attenuating mitochondrial dysfunction.

    PubMed

    Gao, Xin; Zheng, Chun Yan; Qin, Guo Wei; Tang, Xi Can; Zhang, Hai Yan

    2012-10-01

    Accumulating evidence suggests that β-amyloid (Aβ)-induced oxidative DNA damage and mitochondrial dysfunction may initiate and contribute to the progression of Alzheimer's disease (AD). This study evaluated the neuroprotective effects of S-52, a novel nootropic compound, on Aβ-induced mitochondrial failure. In an established paradigm of moderate cellular injury induced by Aβ, S-52 was observed to attenuate the toxicity of Aβ to energy metabolism, mitochondrial membrane structure, and key enzymes in the electron transport chain and tricarboxylic acid cycle. In addition, S-52 also effectively inhibited reactive oxygen species accumulation dose dependently not only in Aβ-harmed cells but also in unharmed, normal cells. The role of S-52 as a scavenger of free radicals is involved in the antioxidative effect of this compound. The beneficial effects on mitochondria and oxidative stress extend the neuroprotective effects of S-52. The present study provides crucial information for better understanding the beneficial profiles of this compound and discovering novel potential drug candidates for AD therapy.

  18. Calotropin from Asclepias curasavica induces cell cycle arrest and apoptosis in cisplatin-resistant lung cancer cells.

    PubMed

    Mo, En-Pan; Zhang, Rong-Rong; Xu, Jun; Zhang, Huan; Wang, Xiao-Xiong; Tan, Qiu-Tong; Liu, Fang-Lan; Jiang, Ren-Wang; Cai, Shao-Hui

    2016-09-16

    Calotropin (M11), an active compound isolated from Asclepias curasavica L., was found to exert strong inhibitory and pro-apoptotic activity specifically against cisplatin-induced resistant non-small cell lung cancer (NSCLC) cells (A549/CDDP). Molecular mechanism study revealed that M11 induced cell cycle arrest at the G2/M phase through down-regulating cyclins, CDK1, CDK2 and up-regulating p53 and p21. Furthermore, M11 accelerated apoptosis through the mitochondrial apoptotic pathway which was accompanied by increase Bax/Bcl-2 ratio, decrease in mitochondrial membrane potential, increase in reactive oxygen species production, activations of caspases 3 and 9 as well as cleavage of poly ADP-ribose polymerase (PARP). The activation and phosphorylation of JNK was also found to be involved in M11-induced apoptosis, and SP610025 (specific JNK inhibitor) partially prevented apoptosis induced by M11. In contrast, all of the effects that M11 induce cell cycle arrest and apoptosis in A549/CDDP cells were not significant in A549 cells. Drugs with higher sensitivity against resistant tumor cells than the parent cells are rather rare. Results of this study supported the potential application of M11 on the non-small lung cancer (NSCLC) with cisplatin resistance.

  19. 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.

  20. Synthetic phosphoethanolamine induces cell cycle arrest and apoptosis in human breast cancer MCF-7 cells through the mitochondrial pathway.

    PubMed

    Ferreira, Adilson Kleber; Meneguelo, Renato; Pereira, Alexandre; Filho, Otaviano Mendonça R; Chierice, Gilberto Orivaldo; Maria, Durvanei Augusto

    2013-07-01

    Phosphoethanolamine (Pho-s) is a compound involved in phospholipid turnover, acting as a substrate for many phospholipids of the cell membranes. In a recent study, we showed that Pho-s has antitumor effect in the several tumor cells. In this study we evaluated the antitumor activity of synthetic Pho-s on MCF-7 breast cancer cells. Here we demonstrate that Pho-s is cytotoxic to MCF-7 cells in a dose-dependent manner, while it is cytotoxic to MCF10 only at higher concentrations. In addition, Pho-s induces a disruption in mitochondrial membrane potential (Δψm). Furthermore, Pho-s induces mitochondria aggregates in the cytoplasm and DNA fragmentation of MCF-7 cells visualized by confocal microscopy. In agreement with the reduction on Δψm, we showed that Pho-s induces apoptosis followed by an increase in cytochrome c expression and capase-3-like activity in MCF-7 cells. Our results demonstrate that Pho-s induces a cell cycle arrest in the G1 phase through an inhibition of cyclin D1 and stimulates p53. An additional highlight of this study is the finding that Pho-s inhibits Bcl-2, inducing apoptosis through the mitochondrial pathway. Taken together, these results show that Pho-s is a promising compound in the fight against cancer. Copyright © 2013 Elsevier Masson SAS. All rights reserved.

  1. 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...

  2. 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...

  3. 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.

  4. 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.

  5. Potencies of estrogenic compounds in in vitro screening assays and in life cycle tests with zebrafish in vivo.

    PubMed

    Segner, H; Navas, J M; Schäfers, C; Wenzel, A

    2003-03-01

    The objective of this study was to compare the estrogenic potency of environmental estrogens at two testing tiers: at the initial level of in vitro screening assays, and at the level of definitive fish reproduction tests in vivo. The in vitro tests included a recombinant yeast estrogen receptor (ER) assay, a competitive radioreceptor assay using the hepatic ER of carp (Cyprinus carpio), and assays on vitellogenin induction in cultured hepatocytes of rainbow trout (Oncorhynchus mykiss) and carp. In vivo, full life cycle tests with zebrafish (Danio rerio) were performed, using fertilization success as estrogen-sensitive reproductive endpoint. The test compounds included the natural estrogen 17beta-estradiol (E2) (only applied in the in vitro assays); the synthetic estrogen ethynylestradiol (EE2); and two xenoestrogens, 4-tert-octylphenol (OP) and bisphenol A (BPA). Among the in vitro assays, differences were observed in the relative ranking of the test substances, and in the absolute sensitivity (EC50 values), although the interassay differences of EC50 values were within one order of magnitude. The in vivo activity of the test compounds was not accurately predicted by the in vitro assays, with respect to neither sensitivity nor ranking. The in vitro assays tended to overestimate the relative potency of the xenoestrogens; i.e. the ratio between the activity of the reference compound, EE2, and that of the test compound. The best prediction of the in vivo fish test results was obtained from the recombinant yeast assay.

  6. Temperature Cycles Induce Early Maturation in Channel Catfish

    USDA-ARS?s Scientific Manuscript database

    A major impediment in improvement of channel catfish by selective breeding is that a high percent of fish do not spawn until the third year. The conditions that lead to sexual maturation in fish have not been established. Size, nutritional state and number of seasonal cycles have all been suggeste...

  7. 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.

  8. Distinct patterns of cleavage and translocation of cell cycle control proteins in CD95-induced and p53-induced apoptosis.

    PubMed Central

    Park, Weon Seo; Jung, Kyeong Cheon; Chung, Doo Hyun; Nam, Woo-Dong; Choi, Won Jin; Bae, Youngmee

    2003-01-01

    Apoptotic cell death induced by p53 occurs at a late G1 cell cycle checkpoint termed the restriction (R) point, and it has been proposed that p53-induced apoptosis causes upregulation of CD95. However, as cells with defective in CD95 signaling pathway are still sensitive to p53-induced apoptosis, CD95 cannot be the sole factor resulting in apoptosis. In addition, unlike p53-induced apoptosis, the relationship between CD95-mediated apoptosis and the cell cycle is not clearly understood. It would therefore be worth investigating whether CD95-mediated cell death is pertinent with p53-induced apoptosis in view of cell cycle related molecules. In this report, biochemical analysis showed that etoposide-induced apoptosis caused the induction and the nuclear translocation of effector molecules involved in G1 cell cycle checkpoint. However, there was no such translocation in the case of CD95-mediated death. Thus, although both types of apoptosis involved caspase activation, the cell cycle related proteins responded differently. This argues against the idea that p53-induced apoptosis occurs through the induction of CD95/CD95L expression. PMID:12923319

  9. Quinones and aromatic chemical compounds in particulate matter induce mitochondrial dysfunction: implications for ultrafine particle toxicity.

    PubMed

    Xia, Tian; Korge, Paavo; Weiss, James N; Li, Ning; Venkatesen, M Indira; Sioutas, Constantinos; Nel, Andre

    2004-10-01

    Particulate pollutants cause adverse health effects through the generation of oxidative stress. A key question is whether these effects are mediated by the particles or their chemical compounds. In this article we show that aliphatic, aromatic, and polar organic compounds, fractionated from diesel exhaust particles (DEPs), exert differential toxic effects in RAW 264.7 cells. Cellular analyses showed that the quinone-enriched polar fraction was more potent than the polycyclic aromatic hydrocarbon (PAH)-enriched aromatic fraction in O2 .- generation, decrease of membrane potential (Delta-Psi m), loss of mitochondrial membrane mass, and induction of apoptosis. A major effect of the polar fraction was to promote cyclosporin A (CsA)-sensitive permeability transition pore (PTP) opening in isolated liver mitochondria. This opening effect is dependent on a direct effect on the PTP at low doses as well as on an effect on Delta-Psi m at high doses in calcium (Ca2+)-loaded mitochondria. The direct PTP effect was mimicked by redox-cycling DEP quinones. Although the aliphatic fraction failed to perturb mitochondrial function, the aromatic fraction increased the Ca2+ retention capacity at low doses and induced mitochondrial swelling and a decrease in Delta-Psi m at high doses. This swelling effect was mostly CsA insensitive and could be reproduced by a mixture of PAHs present in DEPs. These chemical effects on isolated mitochondria could be reproduced by intact DEPs as well as ambient ultrafine particles (UFPs). In contrast, commercial polystyrene nanoparticles failed to exert mitochondrial effects. These results suggest that DEP and UFP effects on the PTP and Delta-Psi m are mediated by adsorbed chemicals rather than the particles themselves.

  10. Quinones and Aromatic Chemical Compounds in Particulate Matter Induce Mitochondrial Dysfunction: Implications for Ultrafine Particle Toxicity

    PubMed Central

    Xia, Tian; Korge, Paavo; Weiss, James N.; Li, Ning; Venkatesen, M. Indira; Sioutas, Constantinos; Nel, Andre

    2004-01-01

    Particulate pollutants cause adverse health effects through the generation of oxidative stress. A key question is whether these effects are mediated by the particles or their chemical compounds. In this article we show that aliphatic, aromatic, and polar organic compounds, fractionated from diesel exhaust particles (DEPs), exert differential toxic effects in RAW 264.7 cells. Cellular analyses showed that the quinone-enriched polar fraction was more potent than the polycyclic aromatic hydrocarbon (PAH)–enriched aromatic fraction in O2•− generation, decrease of membrane potential (ΔΨm), loss of mitochondrial membrane mass, and induction of apoptosis. A major effect of the polar fraction was to promote cyclosporin A (CsA)–sensitive permeability transition pore (PTP) opening in isolated liver mitochondria. This opening effect is dependent on a direct effect on the PTP at low doses as well as on an effect on ΔΨm at high doses in calcium (Ca2+)-loaded mitochondria. The direct PTP effect was mimicked by redox-cycling DEP quinones. Although the aliphatic fraction failed to perturb mitochondrial function, the aromatic fraction increased the Ca2+ retention capacity at low doses and induced mitochondrial swelling and a decrease in ΔΨm at high doses. This swelling effect was mostly CsA insensitive and could be reproduced by a mixture of PAHs present in DEPs. These chemical effects on isolated mitochondria could be reproduced by intact DEPs as well as ambient ultrafine particles (UFPs). In contrast, commercial polystyrene nanoparticles failed to exert mitochondrial effects. These results suggest that DEP and UFP effects on the PTP and ΔΨm are mediated by adsorbed chemicals rather than the particles themselves. PMID:15471724

  11. Pseudolaric acid B induced cell cycle arrest, autophagy and senescence in murine fibrosarcoma l929 cell.

    PubMed

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

    2013-01-01

    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. 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. 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. PAB induced cell cycle arrest, autophagy and senescence in murine fibrosarcoma L929 cell through PKC.

  12. Contribution of sea ice in the Southern Ocean to the cycling of volatile halogenated organic compounds

    NASA Astrophysics Data System (ADS)

    Granfors, Anna; Karlsson, Anders; Mattsson, Erik; Smith, Walker O.; Abrahamsson, Katarina

    2013-08-01

    The contribution of sea ice to the flux of biogenic volatile halogenated organic compounds to the atmosphere in the Southern Ocean is currently not known. To approach this question, we measured halocarbons in sea ice, sea ice brine, and surface water of the Amundsen and Ross Seas. Concentrations in sea ice of these compounds, normalized to seawater salinity, ranged from 0.2 to 810 pmol L-1. Salinity-normalized chlorophyll a concentrations in the ice ranged from 3.5 to 190 µg L-1. Our results suggest biological production of halocarbons in sea ice, with maxima of halogenated organics and chlorophyll a commonly found in the interior of the ice cores. Iodinated VHOCs were found to be more enriched in sea ice than brominated ones. Furthermore, depth distributions indicated a transport of halocarbons from sea ice to air and underlying water.

  13. 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.

  14. Compound

    NASA Astrophysics Data System (ADS)

    Suzumura, Akitoshi; Watanabe, Masaki; Nagasako, Naoyuki; Asahi, Ryoji

    2014-06-01

    Recently, Cu-based chalcogenides such as Cu3SbSe4, Cu2Se, and Cu2SnSe3 have attracted much attention because of their high thermoelectric performance and their common feature of very low thermal conductivity. However, for practical use, materials without toxic elements such as selenium are preferable. In this paper, we report Se-free Cu3SbS4 thermoelectric material and improvement of its figure of merit ( ZT) by chemical substitutions. Substitutions of 3 at.% Ag for Cu and 2 at.% Ge for Sb lead to significant reductions in the thermal conductivity by 37% and 22%, respectively. These substitutions do not sacrifice the power factor, thus resulting in enhancement of the ZT value. The sensitivity of the thermal conductivity to chemical substitutions in these compounds is discussed in terms of the calculated phonon dispersion and previously proposed models for Cu-based chalcogenides. To improve the power factor, we optimize the hole carrier concentration by substitution of Ge for Sb, achieving a power factor of 16 μW/cm K2 at 573 K, which is better than the best reported for Se-based Cu3SbSe4 compounds.

  15. 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.

  16. 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.

  17. 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.

  18. RAD001 (everolimus) induces dose-dependent changes to cell cycle regulation and modifies the cell cycle response to vincristine.

    PubMed

    Saunders, P O; Weiss, J; Welschinger, R; Baraz, R; Bradstock, K F; Bendall, L J

    2013-10-01

    More than 50% of adults and ~20% of children with pre-B acute lymphoblastic leukemia (ALL) relapse following treatment. Dismal outcomes for patients with relapsed or refractory disease mandate novel approaches to therapy. We have previously shown that the combination of the mTOR inhibitor RAD001 (everolimus) and the chemotherapeutic agent vincristine increases the survival of non-obese diabetic/severe combined immuno-deficient (NOD/SCID) mice bearing human ALL xenografts. We have also shown that 16 μM RAD001 synergized with agents that cause DNA damage or microtubule disruption in pre-B ALL cells in vitro. Here, we demonstrate that RAD001 has dose-dependent effects on the cell cycle in ALL cells, with 1.5 μM RAD001 inhibiting pRb, Ki67 and PCNA expression and increasing G0/1 cell cycle arrest, whereas 16 μM RAD001 increases pRb, cyclin D1, Ki67 and PCNA, with no evidence of an accumulation of cells in G0/1. Transition from G2 into mitosis was promoted by 16 μM RAD001 with reduced phosphorylation of cdc2 in cells with 4 N DNA content. However, 16 μM RAD001 preferentially induced cell death in cells undergoing mitosis. When combined with vincristine, 16 μM RAD001 reduced the vincristine-induced accumulation of cells in mitosis, probably as a result of increased death in this population. Although 16 μM RAD001 weakly activated Chk1 and Chk2, it suppressed strong vincristine-induced activation of these cell cycle checkpoint regulators. We conclude that RAD001 enhances chemosensitivity at least in part through suppression of cell cycle checkpoint regulation in response to vincristine and increased progression from G2 into mitosis.

  19. Recovery of the Cell Cycle Inhibition in CCl(4)-Induced Cirrhosis by the Adenosine Derivative IFC-305.

    PubMed

    Chagoya de Sánchez, Victoria; Martínez-Pérez, Lidia; Hernández-Muñoz, Rolando; Velasco-Loyden, Gabriela

    2012-01-01

    Introduction. Cirrhosis is a chronic degenerative illness characterized by changes in normal liver architecture, failure of hepatic function, and impairment of proliferative activity. The aim of this study is to know how IFC-305 compound induces proliferation of the liver during reversion of cirrhosis. Methods. Once cirrhosis has been installed by CCl(4) treatment for 10 weeks in male Wistar rats, they were divided into four groups: two received saline and two received the compound; all were euthanized at 5 and 10 weeks of treatment. Liver homogenate, mitochondria, and nucleus were used to measure cyclins, CDKs, and cell cycle regulatory proteins PCNA, pRb, p53, E2F, p21, p27, HGF, liver ATP, and mitochondrial function. Results. Diminution and small changes were observed in the studied proteins in the cirrhotic animals without treatment. The IFC-305-treated rats showed a clear increase in most of the proteins studied mainly in PCNA and CDK6, and a marked increased in ATP and mitochondrial function. Discussion/Conclusion. IFC-305 induces a recovery of the cell cycle inhibition promoting recovery of DNA damage through the action of PCNA and p53. The increase in energy and preservation of mitochondrial function contribute to recovering the proliferative function.

  20. Recovery of the Cell Cycle Inhibition in CCl4-Induced Cirrhosis by the Adenosine Derivative IFC-305

    PubMed Central

    Chagoya de Sánchez, Victoria; Martínez-Pérez, Lidia; Hernández-Muñoz, Rolando; Velasco-Loyden, Gabriela

    2012-01-01

    Introduction. Cirrhosis is a chronic degenerative illness characterized by changes in normal liver architecture, failure of hepatic function, and impairment of proliferative activity. The aim of this study is to know how IFC-305 compound induces proliferation of the liver during reversion of cirrhosis. Methods. Once cirrhosis has been installed by CCl4 treatment for 10 weeks in male Wistar rats, they were divided into four groups: two received saline and two received the compound; all were euthanized at 5 and 10 weeks of treatment. Liver homogenate, mitochondria, and nucleus were used to measure cyclins, CDKs, and cell cycle regulatory proteins PCNA, pRb, p53, E2F, p21, p27, HGF, liver ATP, and mitochondrial function. Results. Diminution and small changes were observed in the studied proteins in the cirrhotic animals without treatment. The IFC-305-treated rats showed a clear increase in most of the proteins studied mainly in PCNA and CDK6, and a marked increased in ATP and mitochondrial function. Discussion/Conclusion. IFC-305 induces a recovery of the cell cycle inhibition promoting recovery of DNA damage through the action of PCNA and p53. The increase in energy and preservation of mitochondrial function contribute to recovering the proliferative function. PMID:23056951

  1. 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

    2015-11-26

    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.

  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. 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.

  4. A Pyrazolo[3,4-d]pyrimidine compound inhibits Fyn phosphorylation and induces apoptosis in natural killer cell leukemia

    PubMed Central

    Laurenzana, Ilaria; Caivano, Antonella; Trino, Stefania; De Luca, Luciana; Rocca, Francesco La; Simeon, Vittorio; Tintori, Cristina; D'Alessio, Francesca; Teramo, Antonella; Zambello, Renato; Traficante, Antonio; Maietti, Maddalena; Semenzato, Gianpietro; Schenone, Silvia; Botta, Maurizio

    2016-01-01

    Natural killer (NK) cell neoplasms are characterized by clonal proliferation of cytotoxic NK cells. Since there is no standard treatment to date, new therapeutic options are needed, especially for NK aggressive tumors. Fyn tyrosine kinase has a key role in different biological processes, such as cell growth and differentiation, being also involved in the pathogenesis of hematologic malignancies. Our previous studies led us to identify 4c pyrazolo[3,4-d]pyrimidine compound capable of inhibiting Fyn activation and inducing apoptosis in different cancer cell lines. Here we investigated the presence of Fyn and the effect of its inhibitor in NK malignant cells. Firstly, we showed Fyn over-expression in NK leukemic cells compared to peripheral blood mononuclear cells from healthy donors. Subsequently, we demonstrated that 4c treatment reduced cell viability, induced caspase 3-mediate apoptosis and cell cycle arrest in NK cells. Moreover, by inhibiting Fyn phosphorylation, 4c compound reduced Akt and P70 S6 kinase activation and changed the expression of genes involved in cell death and survival in NK cells. Our study demonstrated that Fyn is involved in the pathogenesis of NK leukemia and that it could represent a potential target for this neoplasm. Moreover, we proved that Fyn inhibitor pyrazolo[3,4-d]pyrimidine compound, could be a started point to develop new therapeutic agents. PMID:27566560

  5. 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.

  6. 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.

  7. Hydroxyl radical-induced formation of highly oxidized organic compounds.

    PubMed

    Berndt, Torsten; Richters, Stefanie; Jokinen, Tuija; Hyttinen, Noora; Kurtén, Theo; Otkjær, Rasmus V; Kjaergaard, Henrik G; Stratmann, Frank; Herrmann, Hartmut; Sipilä, Mikko; Kulmala, Markku; Ehn, Mikael

    2016-12-02

    Explaining the formation of secondary organic aerosol is an intriguing question in atmospheric sciences because of its importance for Earth's radiation budget and the associated effects on health and ecosystems. A breakthrough was recently achieved in the understanding of secondary organic aerosol formation from ozone reactions of biogenic emissions by the rapid formation of highly oxidized multifunctional organic compounds via autoxidation. However, the important daytime hydroxyl radical reactions have been considered to be less important in this process. Here we report measurements on the reaction of hydroxyl radicals with α- and β-pinene applying improved mass spectrometric methods. Our laboratory results prove that the formation of highly oxidized products from hydroxyl radical reactions proceeds with considerably higher yields than previously reported. Field measurements support these findings. Our results allow for a better description of the diurnal behaviour of the highly oxidized product formation and subsequent secondary organic aerosol formation in the atmosphere.

  8. Hydroxyl radical-induced formation of highly oxidized organic compounds

    PubMed Central

    Berndt, Torsten; Richters, Stefanie; Jokinen, Tuija; Hyttinen, Noora; Kurtén, Theo; Otkjær, Rasmus V.; Kjaergaard, Henrik G.; Stratmann, Frank; Herrmann, Hartmut; Sipilä, Mikko; Kulmala, Markku; Ehn, Mikael

    2016-01-01

    Explaining the formation of secondary organic aerosol is an intriguing question in atmospheric sciences because of its importance for Earth's radiation budget and the associated effects on health and ecosystems. A breakthrough was recently achieved in the understanding of secondary organic aerosol formation from ozone reactions of biogenic emissions by the rapid formation of highly oxidized multifunctional organic compounds via autoxidation. However, the important daytime hydroxyl radical reactions have been considered to be less important in this process. Here we report measurements on the reaction of hydroxyl radicals with α- and β-pinene applying improved mass spectrometric methods. Our laboratory results prove that the formation of highly oxidized products from hydroxyl radical reactions proceeds with considerably higher yields than previously reported. Field measurements support these findings. Our results allow for a better description of the diurnal behaviour of the highly oxidized product formation and subsequent secondary organic aerosol formation in the atmosphere. PMID:27910849

  9. Hydroxyl radical-induced formation of highly oxidized organic compounds

    NASA Astrophysics Data System (ADS)

    Berndt, Torsten; Richters, Stefanie; Jokinen, Tuija; Hyttinen, Noora; Kurtén, Theo; Otkjær, Rasmus V.; Kjaergaard, Henrik G.; Stratmann, Frank; Herrmann, Hartmut; Sipilä, Mikko; Kulmala, Markku; Ehn, Mikael

    2016-12-01

    Explaining the formation of secondary organic aerosol is an intriguing question in atmospheric sciences because of its importance for Earth's radiation budget and the associated effects on health and ecosystems. A breakthrough was recently achieved in the understanding of secondary organic aerosol formation from ozone reactions of biogenic emissions by the rapid formation of highly oxidized multifunctional organic compounds via autoxidation. However, the important daytime hydroxyl radical reactions have been considered to be less important in this process. Here we report measurements on the reaction of hydroxyl radicals with α- and β-pinene applying improved mass spectrometric methods. Our laboratory results prove that the formation of highly oxidized products from hydroxyl radical reactions proceeds with considerably higher yields than previously reported. Field measurements support these findings. Our results allow for a better description of the diurnal behaviour of the highly oxidized product formation and subsequent secondary organic aerosol formation in the atmosphere.

  10. Bracken-fern extracts induce cell cycle arrest and apoptosis in certain cancer cell lines.

    PubMed

    Roudsari, Motahhareh Tourchi; Bahrami, Ahmad Reza; Dehghani, Hesam

    2012-01-01

    Bracken fern [Pteridium aquilinem (L.) kuhn (Dennstaedtiaceae)] is one of the most common species on the planet. It has been consumed by humans and animals for centuries. Use by some human groups is because they believe bracken fern is good for health as plant medicine. However, it is also one of the few known plants that can cause tumors in farm animals. Many interested groups have focused their attention on bracken fern because of these interesting features. In order to evaluate the biological effects of exposure to this plant in cellular level, human cancer cell lines were treated with the fern dichloromethane extracts and the genotoxic and cytotoxic effects were studied. Anti-proliferative/cytotoxic effects were evaluated by cell count, MTT assay and flow cytometry methods with three different cancer cell lines, TCC, NTERA2, and MCF-7, and two normal cells, HDF1 and HFF3. Pro-apoptotic effects of the extracts were determined by DAPI staining and comet assay, on TCC cancer cells compared to the normal control cell lines. Cellular morphology was examined by light microscopy. Our present study showed that the extract caused DNA damage and apoptosis at high concentrations (200 μg/mL) and also it may induce cell cycle arrest (G2/M phase) at mild concentrations (50 and 30 μg/mL) depending on the cell type and tumor origin. These results indicate that bracken fern extract is a potent source of anticancer compounds that could be utilized pharmaceutically.

  11. Bromine isotope analysis - a tool for investigating biogeochemical cycle of bromine-containing organic and inorganic compounds in the environment

    NASA Astrophysics Data System (ADS)

    Gelman, F.; Bernstein, A.; Levin, E.; Ronen, Z.; Halicz, L.

    2012-04-01

    Bromine naturally occurs mainly in the form of bromide and is usually considered as a conservative tracer in the groundwater system. However, nowadays many synthetically produced organobromine compounds are introduced into the environment by humans. Due to a possible toxic effect of these compounds, investigation of their fate in the nature is of the utmost importance. In this sense, examination of isotopic composition of inorganic and organic bromine may serve as a powerful tool for understanding Br geochemical cycle. Due to a relatively small mass difference between the isotopes 81Br and 79Br, bromine isotope fractionation originating from biotic and abiotic processes is expected to be in the range of several permille. Therefore, a highly precise technique for the bromine isotope ratio analysis is required. This work presents a new methodology for the precise determination of bromine isotope ratio in inorganic bromides and individual organic compounds by MC-ICPMS. Attained external precision (2σ) up to 0.1‰ allowed employment of the developed technique for determination of the bromine isotope composition in organic and inorganic bromides and Br KIE in biogeochemical processes.

  12. The Integrins Involved in Soybean Agglutinin-Induced Cell Cycle Alterations in IPEC-J2

    PubMed Central

    Pan, Li; Zhao, Yuan; Yuan, Zhijie; Farouk, Mohammed Hamdy; Zhang, Shiyao; Bao, Nan; Qin, Guixin

    2017-01-01

    Soybean agglutinin (SBA) is an anti-nutritional factor of soybean, affecting cell proliferation and inducing cytotoxicity. Integrins are transmembrane receptors, mediating a variety of cell biological processes. This research aims to study the effects of SBA on cell proliferation and cell cycle progression of the intestinal epithelial cell line from piglets (IPEC-J2), to identify the integrin subunits especially expressed in IPEC-J2s, and to analyze the functions of these integrins on IPEC-J2 cell cycle progression and SBA-induced IPEC-J2 cell cycle alteration. The results showed that SBA lowered cell proliferation rate as the cell cycle progression from G0/G1 to S phase (P < 0.05) was inhibited. Moreover, SBA lowered mRNA expression of cell cycle-related gene CDK4, Cyclin E and Cyclin D1 (P < 0.05). We successfully identified integrins α2, α3, α6, β1, and β4 in IPEC-J2s. These five subunits were crucial to maintain normal cell proliferation and cell cycle progression in IPEC-J2s. Restrain of either these five subunits by their inhibitors, lowered cell proliferation rate, and arrested the cells at G0/G1 phase of cell cycle (P < 0.05). Further analysis indicated that integrin α2, α6, and β1 were involved in the blocking of G0/G1 phase induced by SBA. In conclusion, these results suggested that SBA lowered the IPEC-J2 cell proliferation rate through the perturbation of cell cycle progression. Furthermore, integrins were important for IPEC-J2 cell cycle progression, and they were involved in the process of SBA-induced cell cycle progression alteration, which provide a basis for further revealing SBA anti-proliferation and anti-nutritional mechanism. PMID:28222496

  13. 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.

  14. 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.

  15. Cell cycle dependence of boron uptake from two boron compounds used for clinical neutron capture therapy.

    PubMed

    Yoshida, F; Matsumura, A; Shibata, Y; Yamamoto, T; Nakauchi, H; Okumura, M; Nose, T

    2002-12-10

    In neutron capture therapy, it is important that the boron is selectively uptaken by tumor cells. In the present study, we used flow cytometry to sort the cells in the G0/G1 phase and those in the G2/M phase, and the boron concentration in each fraction was measured with inductively coupled plasma atomic emission spectroscopy. The results revealed that sodium borocaptate and boronophenylalanine (BPA), were associated with higher rates of boron uptake in the G2/M than in the G0/G1 phase. However, the difference was more prominent in the case of BPA. The G2/M:G0/G1 ratio decreased as a function of exposure time in BPA containing culture medium, thereby indicating the cell cycle dependency of BPA uptake. Such heterogeneity of boron uptake by tumor cells should be considered for microdosimetry.

  16. Radioactive-induced tumors by phosphorus-32 as colloidal compound

    SciTech Connect

    Ubios, A.M.; Silberman, F.S.; Cabrini, R.L.

    1983-05-01

    Chromic colloidal phosphate labeled with 32P, which has been proposed for the treatment of several articular diseases, was injected intra-articularly in the knee joint of adult Wistar rats. After a 270 days minimum latent period, tumors began to appear in the injected zone, to a 70% frequency. Ten lung metastases were detected. In five cases, squamous cell carcinomas were induced in the injected area. The relevance of a sound evaluation of the risk involved in treatments with radioactive isotopes, is discussed.

  17. Annual cycle of volatile organic compound exchange between a boreal pine forest and the atmosphere

    NASA Astrophysics Data System (ADS)

    Rantala, P.; Aalto, J.; Taipale, R.; Ruuskanen, T. M.; Rinne, J.

    2015-10-01

    Long-term flux measurements of volatile organic compounds (VOC) over boreal forests are rare, although the forests are known to emit considerable amounts of VOCs into the atmosphere. Thus, we measured fluxes of several VOCs and oxygenated VOCs over a Scots-pine-dominated boreal forest semi-continuously between May 2010 and December 2013. The VOC profiles were obtained with a proton transfer reaction mass spectrometry, and the fluxes were calculated using vertical concentration profiles and the surface layer profile method connected to the Monin-Obukhov similarity theory. In total fluxes that differed significantly from zero on a monthly basis were observed for 13 out of 27 measured masses. Monoterpenes had the highest net emission in all seasons and statistically significant positive fluxes were detected from March until October. Other important compounds emitted were methanol, ethanol+formic acid, acetone and isoprene+methylbutenol. Oxygenated VOCs showed also deposition fluxes that were statistically different from zero. Isoprene+methylbutenol and monoterpene fluxes followed well the traditional isoprene algorithm and the hybrid algorithm, respectively. Emission potentials of monoterpenes were largest in late spring and autumn which was possibly driven by growth processes and decaying of soil litter, respectively. Conversely, largest emission potentials of isoprene+methylbutenol were found in July. Thus, we concluded that most of the emissions of m/z 69 at the site consisted of isoprene that originated from broadleaved trees. Methanol had deposition fluxes especially before sunrise. This can be connected to water films on surfaces. Based on this assumption, we were able to build an empirical algorithm for bi-directional methanol exchange that described both emission term and deposition term. Methanol emissions were highest in May and June and deposition level increased towards autumn, probably as a result of increasing relative humidity levels leading to

  18. Annual cycle of volatile organic compound exchange between a boreal pine forest and the atmosphere

    NASA Astrophysics Data System (ADS)

    Rantala, P.; Aalto, J.; Taipale, R.; Ruuskanen, T. M.; Rinne, J.

    2015-06-01

    Long-term flux measurements of volatile organic compounds (VOC) over boreal forests are rare, although the forests are known to emit considerable amounts of VOCs into the atmosphere. Thus, we measured fluxes of several VOCs and oxygenated VOCs over a Scots pine dominated boreal forest semi-continuously between May 2010 and December 2013. The VOC profiles were obtained with a proton-transfer-reaction mass-spectrometry, and the fluxes were calculated using vertical concentration profiles and the surface layer profile method connected to the Monin-Obukhov similarity theory. In total fluxes that differed significantly from zero on a monthly basis were observed for 14 out 27 measured masses. Monoterpenes had the highest net emission in all seasons and statistically significant positive fluxes were detected from March until November. Other important compounds emitted were methanol, ethanol/formic acid, acetone and isoprene/MBO. Oxygenated VOCs showed also deposition fluxes that were statistically different from zero. Isoprene/methylbutenol and monoterpene fluxes followed well the traditional isoprene algorithm and the hybrid algorithm, respectively. Emission potentials of monoterpenes were largest in late spring and fall which was possibly driven by growth processes and decaying of soil litter, respectively. Conversely, largest emission potentials of isoprene/methylbutenol were found in July. Thus, we concluded that most of the emissions of m/z 69 at the site consisted of isoprene that originated from broadleaved trees. Methanol had deposition fluxes especially before sunrise. This can be connected to water films on surfaces. Based on this assumption, we were able to build an empirical algorithm for bi-directional methanol exchange that described both emission term and deposition term. Methanol emissions were highest in May and June and deposition level increased towards fall, probably as a result of increasing relative humidity levels leading to predominance of

  19. Seasonal cycles of biogenic volatile organic compound fluxes and concentrations in a California citrus orchard

    NASA Astrophysics Data System (ADS)

    Fares, S.; Park, J.-H.; Gentner, D. R.; Weber, R.; Ormeño, E.; Karlik, J.; Goldstein, A. H.

    2012-07-01

    Orange trees are widely cultivated in Mediterranean climatic regions where they are an important agricultural crop. Citrus have been characterized as emitters of volatile organic compounds (VOC) in chamber studies under controlled environmental conditions, but an extensive characterization at field scale has never been performed using modern measurement methods, and is particularly needed considering the complex interactions between the orchards and the polluted atmosphere in which Citrus is often cultivated. For one year, in a Valencia orange orchard in Exeter, California, we measured fluxes using PTRMS (Proton Transfer Reaction Mass Spectrometer) and eddy covariance for the most abundant VOC typically emitted from citrus vegetation: methanol, acetone, and isoprenoids. Concentration gradients of additional oxygenated and aromatic compounds from the ground level to above the canopy were also measured. In order to characterize concentrations of speciated biogenic VOC (BVOC) in leaves, we analyzed leaf content by GC-MS (Gas Chromatography-Mass Spectrometery) regularly throughout the year. We also characterize in more detail concentrations of speciated BVOC in the air above the orchard by in-situ GC-MS during a few weeks in spring flowering and summer periods. Here we report concentrations and fluxes of the main VOC species emitted by the orchard, discuss how fluxes measured in the field relate to previous studies made with plant enclosures, and describe how VOC content in leaves and emissions change during the year in response to phenological and environmental parameters. The orchard was a source of monoterpenes and oxygenated VOC. The highest emissions were observed during the springtime flowering period, with mid-day fluxes above 2 nmol m-2 s-1 for methanol and up to 1 nmol m-2 s-1 for acetone and monoterpenes. During hot summer days emissions were not as high as we expected considering the known dependence of biogenic emissions on temperature. We provide evidence

  20. Seasonal cycles of biogenic volatile organic compound fluxes and concentrations in a California citrus orchard

    NASA Astrophysics Data System (ADS)

    Fares, S.; Park, J.-H.; Gentner, D. R.; Weber, R.; Ormeño, E.; Karlik, J.; Goldstein, A. H.

    2012-10-01

    Orange trees are widely cultivated in Mediterranean climatic regions where they are an important agricultural crop. Citrus have been characterized as emitters of volatile organic compounds (VOC) in chamber studies under controlled environmental conditions, but an extensive characterization at field scale has never been performed using modern measurement methods, and is particularly needed considering the complex interactions between the orchards and the polluted atmosphere in which Citrus is often cultivated. For one year, in a Valencia orange orchard in Exeter, California, we measured fluxes using PTRMS (Proton Transfer Reaction Mass Spectrometer) and eddy covariance for the most abundant VOC typically emitted from citrus vegetation: methanol, acetone, and isoprenoids. Concentration gradients of additional oxygenated and aromatic compounds from the ground level to above the canopy were also measured. In order to characterize concentrations of speciated biogenic VOC (BVOC) in leaves, we analyzed leaf content by GC-MS (Gas Chromatography - Mass Spectrometery) regularly throughout the year. We also characterized in more detail concentrations of speciated BVOC in the air above the orchard by in-situ GC-MS during a few weeks in spring flowering and summer periods. Here we report concentrations and fluxes of the main VOC species emitted by the orchard, discuss how fluxes measured in the field relate to previous studies made with plant enclosures, and describe how VOC content in leaves and emissions change during the year in response to phenological and environmental parameters. The orchard was a source of monoterpenes and oxygenated VOC. The highest emissions were observed during the springtime flowering period, with mid-day fluxes above 2 nmol m-2 s-1 for methanol and up to 1 nmol m-2 s-1 for acetone and monoterpenes. During hot summer days emissions were not as high as we expected considering the known dependence of biogenic emissions on temperature. We provide

  1. Competition between the compound and the pre-compound emission processes in α-induced reactions at near astrophysical energy to well above it

    NASA Astrophysics Data System (ADS)

    Sharma, Manoj Kumar; Sharma, Vijay Raj; Yadav, Abhiskek; Singh, Pushpendra P.; Singh, B. P.; Prasad, R.

    2016-04-01

    The study of pre-compound emission in α-induced reactions, particularly at the low incident energies, is of considerable interest as the pre-compound emission is more likely to occur at higher energies. With a view to study the competition between the compound and the pre-compound emission processes in α-induced reactions at different energies and with different targets, a systematics for neutron emission channels in targets 51V, 55Mn, 93Nb, 121, 123Sb and 141Pr at energy ranging from astrophysical interest to well above it, has been developed. The off-line γ-ray-spectrometry based activation technique has been adopted to measure the excitation functions. The experimental excitation functions have been analysed within the framework of the compound nucleus mechanism based on the Weisskopf-Ewing model and the pre-compound emission calculations based on the geometry dependent hybrid model. The analysis of the data shows that experimental excitation functions could be reproduced only when the pre-compound emission, simulated theoretically, is taken into account. The strength of pre-compound emission process for each system has been obtained by deducing the pre-compound fraction. Analysis of data indicates that in α-induced reactions, the pre-compound emission process plays an important role, particularly at the low incident energies, where the pure compound nucleus process is likely to dominate.

  2. Solar Cycle Dependence of Umbral Magneto-Induced Line Broadening

    NASA Astrophysics Data System (ADS)

    Schad, T. A.; Penn, M. J.

    2008-05-01

    Studies of the solar cycle dependence of peak umbral magnetic field strength have focused upon measurements of continuum intensity and the Zeeman splitting of infrared spectral lines. Here we extend the discussion into a measurement of effective line width using eleven years of spectromagnetograms from the Kitt Peak Vacuum Telescope (KPVT). The KPVT observed the 868.8 nm Fe I absorption line in opposing states of circular polarization between 1992 and 2003, deriving full-disk images of line-of-sight (LOS) velocity, LOS magnetic flux, continuum intensity, equivalent line width, and central line depth. We determine an effective spectral line width through a relation of the measured equivalent line widths and central line depths. Developing a basic model of the Stokes line profiles using the Seares formalism, we illustrate that a change in the effective line width within the umbra as determined using the KPVT data is consistent with the change in the Zeeman splitting. We discuss the effect of observed distance from disk center, stray light, and the unknown inclination angle of the magnetic field. Within individual sunspots observed near disk center, the determined effective line width decreases with distance from the umbral core consistent with the studied magnetic field gradient. Measurements of different sunspots show a clear dependence on umbral size consistent with previous studies of the umbral magnetic field. Using this effective line width as a diagnostic for magnetic field, we examine the dependence of maximum magnetic field strength on the phase of the solar cycle. We present a comprehensive statistical analysis using a sample size of over 3500 umbral measurements.

  3. Root-induced cycling of lead in salt marsh sediments.

    PubMed

    Sundby, Bjørn; Caetano, Miguel; Vale, Carlos; Gobeil, Charles; George, Luther W; Nuzzio, Donald B

    2005-04-01

    A gold-mercury amalgam microelectrode was used in situ to measure Pb(II) by anodic stripping voltammetry and O2, Fe(II), Mn(II), and HS- by square-wave voltammetry in sediment pore water in a Haliomione portulacoides stand in a Tagus estuary salt marsh. The measurements were made in spring, summer, and fall, and were supplemented with analysis of Pb in solid phases and stable isotope analysis of Pb. In spring, the pore water was anoxic, Fe(II) reached concentrations as high as 1700 micromol/L, and Pb(II) was undetectable (<0.1 micromol/L). However, in summer, the pore water was oxic, Fe(II) was undetectable, and Pb(II) was present throughout the 20 cm deep root zone in concentrations reaching 6 micromol/L. In fall, low levels of O2 and Pb(II) were detected in the upper half of the root zone, and low concentrations of Fe(II) were detected in the lower half. The annual cycle of Pb is controlled by the growth and decay of roots. Roots deliver oxygen, which oxidizes lead-bearing solid phases and releases Pb(II) to the sediment pore water. Iron oxides, which form in the rhizosphere when Fe(II) is oxidized, are apparently not efficient sorbents for Pb(II) under the organic-rich conditions in this sediment. This allows Pb(II) to remain soluble and available for uptake by the roots. In fall and winter,when roots decay and the oxygen flux to the sediment stops, Pb is released from the decaying roots and returned to and precipitated in the anoxic sediment, likely as a sulfide. On an annual basis more than 20% of the total mass of Pb in the root zone cycles between root tissue and inorganic sediment phases. Depending on location, anthropogenic Pb constitutes 30-90% of total Pb in Tagus Estuary salt marshes.

  4. Cell cycle-arrested tumor cells exhibit increased sensitivity towards TRAIL-induced apoptosis

    PubMed Central

    Ehrhardt, H; Wachter, F; Grunert, M; Jeremias, I

    2013-01-01

    Resting tumor cells represent a huge challenge during anticancer therapy due to their increased treatment resistance. TNF-related apoptosis-inducing ligand (TRAIL) is a putative future anticancer drug, currently in phases I and II clinical studies. We recently showed that TRAIL is able to target leukemia stem cell surrogates. Here, we tested the ability of TRAIL to target cell cycle-arrested tumor cells. Cell cycle arrest was induced in tumor cell lines and xenografted tumor cells in G0, G1 or G2 using cytotoxic drugs, phase-specific inhibitors or RNA interference against cyclinB and E. Biochemical or molecular arrest at any point of the cell cycle increased TRAIL-induced apoptosis. Accordingly, when cell cycle arrest was disabled by addition of caffeine, the antitumor activity of TRAIL was reduced. Most important for clinical translation, tumor cells from three children with B precursor or T cell acute lymphoblastic leukemia showed increased TRAIL-induced apoptosis upon knockdown of either cyclinB or cyclinE, arresting the cell cycle in G2 or G1, respectively. Taken together and in contrast to most conventional cytotoxic drugs, TRAIL exerts enhanced antitumor activity against cell cycle-arrested tumor cells. Therefore, TRAIL might represent an interesting drug to treat static-tumor disease, for example, during minimal residual disease. PMID:23744361

  5. 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.

  6. 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.

  7. 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.

  8. Impact of estrogenic compounds on DNA integrity in human spermatozoa: evidence for cross-linking and redox cycling activities.

    PubMed

    Bennetts, L E; De Iuliis, G N; Nixon, B; Kime, M; Zelski, K; McVicar, C M; Lewis, S E; Aitken, R J

    2008-05-10

    A great deal of circumstantial evidence has linked DNA damage in human spermatozoa with adverse reproductive outcomes including reduced fertility and high rates of miscarriage. Although oxidative stress is thought to make a significant contribution to DNA damage in the male germ line, the factors responsible for creating this stress have not been elucidated. One group of compounds that are thought to be active in this context are the estrogens, either generated as a result of the endogenous metabolism of androgens within the male reproductive tract or gaining access to the latter as a consequence of environmental exposure. In this study, a wide variety of estrogenic compounds were assessed for their direct effects on human spermatozoa in vitro. DNA integrity was assessed using the Comet and TUNEL assays, lesion frequencies were quantified by QPCR using targets within the mitochondrial and nuclear (beta-globin) genomes, DNA adducts were characterized by mass spectrometry and redox activity was monitored using dihydroethidium (DHE) as the probe. Of the estrogenic and estrogen analogue compounds evaluated, catechol estrogens, quercetin, diethylstilbestrol and pyrocatechol stimulated intense redox activity while genistein was only active at the highest doses tested. Other estrogens and estrogen analogues, such as 17beta-estradiol, nonylphenol, bisphenol A and 2,3-dihydroxynaphthalene were inactive. Estrogen-induced redox activity was associated with a dramatic loss of motility and, in the case of 2-hydroxyestradiol, the induction of significant DNA fragmentation. Mass spectrometry also indicated that catechol estrogens were capable of forming dimers that can cross-link the densely packed DNA strands in sperm chromatin, impairing nuclear decondensation. These results highlight the potential importance of estrogenic compounds in creating oxidative stress and DNA damage in the male germ line and suggest that further exploration of these compounds in the aetiology of male

  9. 6-Nitro-2-(3-hydroxypropyl)-1H-benz[de]isoquinoline-1,3-dione, a potent antitumor agent, induces cell cycle arrest and apoptosis

    PubMed Central

    2010-01-01

    Background Anticancer activities of several substituted naphthalimides (1H-benz[de]isoquinoline-1,3-diones) are well documented. Some of them have undergone Phase I-II clinical trials. Presently a series of ten N-(hydroxyalkyl) naphthalimides (compounds 1a-j) were evaluated as antitumor agents. Methods Compounds 1a-j were initially screened in MOLT-4, HL-60 and U-937 human tumor cell lines and results were compared with established clinical drugs. Cytotoxicities of compounds 1d and 1i were further evaluated in a battery of human tumor cell lines and in normal human peripheral blood mononuclear cells. Cell cycle analysis of compound 1i treated MOLT-4 cells was studied by flow cytometry. Its apoptosis inducing effect was carried out in MOLT-4 and HL-60 cells by flow cytometry using annexin V-FITC/PI double staining method. The activities of caspase-3 and caspase-6 in MOLT-4 cells following incubation with compound 1i were measured at different time intervals. Morphology of the MOLT-4 cells after treatment with 1i was examined under light microscope and transmission electron microscope. 3H-Thymidine and 3H-uridine incorporation in S-180 cells in vitro following treatment with 8 μM concentration of compounds 1d and 1i were studied. Results 6-Nitro-2-(3-hydroxypropyl)-1H-benz[de]isoquinoline-1,3-dione (compound 1i), has exhibited maximum activity as it induced significant cytotoxicity in 8 out of 13 cell lines employed. Interestingly it did not show any cytotoxicity against human PBMC (IC50 value 273 μM). Cell cycle analysis of compound 1i treated MOLT-4 cells demonstrated rise in sub-G1 fraction and concomitant accumulation of cells in S and G2/M phases, indicating up-regulation of apoptosis along with mitotic arrest and/or delay in exit of daughter cells from mitotic cycle respectively. Its apoptosis inducing effect was confirmed in flow cytometric study in MOLT-4 and the action was mediated by activation of both caspase 3 and 6. Light and transmission electron

  10. 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.

  11. Not all boronic acids with a five-membered cycle induce tremor, neuronal damage and decreased dopamine.

    PubMed

    Pérez-Rodríguez, Maribel; García-Mendoza, Esperanza; Farfán-García, Eunice D; Das, Bhaskar C; Ciprés-Flores, Fabiola J; Trujillo-Ferrara, José G; Tamay-Cach, Feliciano; Soriano-Ursúa, Marvin A

    2017-06-06

    Several striatal toxins can be used to induce motor disruption. One example is MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), whose toxicity is accepted as a murine model of parkinsonism. Recently, 3-Thienylboronic acid (3TB) was found to produce motor disruption and biased neuronal damage to basal ganglia in mice. The aim of this study was to examine the toxic effects of four boronic acids with a close structural relationship to 3TB (all having a five-membered cycle), as well as boric acid and 3TB. These boron-containing compounds were compared to MPTP regarding brain access, morphological disruption of the CNS, and behavioral manifestations of such disruption. Data was collected through acute toxicity evaluations, motor behavior tests, necropsies, determination of neuronal survival by immunohistochemistry, Raman spectroscopic analysis of brain tissue, and HPLC measurement of dopamine in substantia nigra and striatum tissue. Each compound showed a distinct profile for motor disruption. For example, motor activity was not disrupted by boric acid, but was decreased by two boronic acids (caused by a sedative effect). 3TB, 2-Thienyl and 2-furanyl boronic acid gave rise to shaking behavior. The various manifestations generated by these compounds can be linked, in part, to different levels of dopamine (measured by HPLC) and degrees of neuronal damage in the basal ganglia and cerebellum. Clearly, motor disruption is not induced by all boronic acids with a five-membered cycle as substituent. Possible explanations are given for the diverse chemico-morphological changes and degrees of disruption of the motor system, considering the role of boron and the structure-toxicity relationship. Copyright © 2017 Elsevier B.V. All rights reserved.

  12. Modulation of collision-induced changes in canine heart repolarization by cycle length.

    PubMed

    Spitzer, K W; Steinhaus, B M; Hirai, M; Haws, C W; Burgess, M J

    1991-01-01

    The possibility that cycle length modulates the electronic effect of activation sequence on repolarization was investigated in experiments using isolated canine cardiac Purkinje strands, in situ canine ventricular myocardium, and computer simulations. Action potential durations and refractory periods during one-way propagation were compared to those obtained during action potential collision. In both the computer simulations and the Purkinje strand experiments, collision decreased action potential duration more at long cycle lengths than at short cycle lengths. Comparably, collision of activation fronts in ventricular myocardium was associated with greater reductions in refractory period during pacing at long cycle lengths than at short cycle lengths. Theoretic considerations indicate that the magnitude of electrotonic effects of activation sequence on repolarization are directly related to action potential height and the square root of membrane resistance during repolarization and are inversely related to conduction velocity. In computer simulations and Purkinje strand experiments, changes in conduction velocity and action potential height elicited by decreasing cycle length could not fully account for the cycle length dependence of collision-induced changes in repolarization. Time-varying membrane resistance of a single cell was calculated in the simulations by briefly hyperpolarizing the membrane and determining the change in total ionic current. Membrane resistance during repolarization was less at short cycle lengths than at long cycle lengths. The results suggest the cycle length dependence of collision-induced changes in repolarization results largely from the effect of cycle length on membrane resistance during action potential repolarization, with changes in action potential height and conduction velocity playing a lesser role.

  13. Ultrafast laser induced local magnetization dynamics in Heusler compounds

    NASA Astrophysics Data System (ADS)

    Elliott, P.; Müller, T.; Dewhurst, J. K.; Sharma, S.; Gross, E. K. U.

    2016-12-01

    The overarching goal of the field of femtomagnetism is to control, via laser light, the magnetic structure of matter on a femtosecond time scale. The temporal limits to the light-magnetism interaction are governed by the fact that the electron spin interacts indirectly with light, with current studies showing a laser induced global loss in the magnetic moment on a time scale of the order of a few 100 s of femtoseconds. In this work, by means of ab-initio calculations, we show that more complex magnetic materials - we use the example of the Heusler and half-Heusler alloys - allow for purely optical excitations to cause a significant change in the local moments on the order of 5 fs. This, being purely optical in nature, represents the ultimate mechanism for the short time scale manipulation of spins. Furthermore, we demonstrate that qualitative behaviour of this rich magnetic response to laser light can be deduced from the ground-state spectrum, thus providing a route to tailoring the response of some complex magnetic materials, like the Heuslers, to laser light by the well established methods for material design from ground-state calculations.

  14. Ultrafast laser induced local magnetization dynamics in Heusler compounds

    PubMed Central

    Elliott, P.; Müller, T.; Dewhurst, J. K.; Sharma, S.; Gross, E. K. U.

    2016-01-01

    The overarching goal of the field of femtomagnetism is to control, via laser light, the magnetic structure of matter on a femtosecond time scale. The temporal limits to the light-magnetism interaction are governed by the fact that the electron spin interacts indirectly with light, with current studies showing a laser induced global loss in the magnetic moment on a time scale of the order of a few 100 s of femtoseconds. In this work, by means of ab-initio calculations, we show that more complex magnetic materials - we use the example of the Heusler and half-Heusler alloys - allow for purely optical excitations to cause a significant change in the local moments on the order of 5 fs. This, being purely optical in nature, represents the ultimate mechanism for the short time scale manipulation of spins. Furthermore, we demonstrate that qualitative behaviour of this rich magnetic response to laser light can be deduced from the ground-state spectrum, thus providing a route to tailoring the response of some complex magnetic materials, like the Heuslers, to laser light by the well established methods for material design from ground-state calculations. PMID:27966585

  15. Calculation of radiation damage induced by neutrons in compound materials

    NASA Astrophysics Data System (ADS)

    Lunéville, L.; Simeone, D.; Jouanne, C.

    2006-07-01

    Many years have been devoted to study the behaviour of solids submitted to impinging particles like ions or neutrons. The nuclear evaluations describe more and more accurately the various neutron-atom interactions. Anisotropic neutron-atom cross-sections are now available for many elements. Moreover, clear mathematical formalism now allows to calculate the number of displacements per atom in polyatomic targets in a realistic way using the binary collision approximation (BCA) framework. Even if these calculations do not take into account relaxation processes at the end of the displacement spike, they can be used to compare damages induced by different facilities like pressurized water reactors (PWR), fast breeder reactors (FBR), high temperature reactors (HTR) and fusion facilities like the European Spallation Source (ESS) and the International Fusion Material Irradiation Facility (IFMIF) on a defined material. In this paper, a formalism is presented to describe the neutron-atom cross-section and primary recoil spectra taking into account the anisotropy of nuclear reactions extracted from nuclear evaluations. Such a formalism permitted to compute displacement per atom production rate, primary and weighted recoil spectra within the BCA. The multigroup approximation has been used to calculate displacement per atom production rate and recoil spectra for a define nuclear reactor. All these informations are useful to compare recoil spectra and displacement per atom production rate produced by particle accelerator and nuclear reactor.

  16. Ultrafast laser induced local magnetization dynamics in Heusler compounds.

    PubMed

    Elliott, P; Müller, T; Dewhurst, J K; Sharma, S; Gross, E K U

    2016-12-14

    The overarching goal of the field of femtomagnetism is to control, via laser light, the magnetic structure of matter on a femtosecond time scale. The temporal limits to the light-magnetism interaction are governed by the fact that the electron spin interacts indirectly with light, with current studies showing a laser induced global loss in the magnetic moment on a time scale of the order of a few 100 s of femtoseconds. In this work, by means of ab-initio calculations, we show that more complex magnetic materials - we use the example of the Heusler and half-Heusler alloys - allow for purely optical excitations to cause a significant change in the local moments on the order of 5 fs. This, being purely optical in nature, represents the ultimate mechanism for the short time scale manipulation of spins. Furthermore, we demonstrate that qualitative behaviour of this rich magnetic response to laser light can be deduced from the ground-state spectrum, thus providing a route to tailoring the response of some complex magnetic materials, like the Heuslers, to laser light by the well established methods for material design from ground-state calculations.

  17. 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.

  18. Phenolic compounds from Pueraria lobata protect PC12 cells against Aβ-induced toxicity.

    PubMed

    Choi, Yun-hyeok; Hong, Seong Su; Shin, Yu Su; Hwang, Bang Yeon; Park, So-Young; Lee, Dongho

    2010-10-01

    Bioassay-guided fractionation of the EtOAc-soluble extract of Pueraria lobata based on the inhibition of Aβ-induced toxicity in PC12 cells resulted in the isolation of four known active compounds, genistein (8), biochanin A (9), sissotrin (10), and puerol B (11). Of these, genistein (8) and biochanin A (9) exhibited potent neuroprotective effects with ED(50) values of 33.7 and 27.8 μM, respectively. In addition, a new coumestan, 2-(α,α-dimethylallyl)coumestrol (1) was isolated and characterized, but proved to be inactive, as were additional seven known compounds. The structure of new compound 1 was determined using spectroscopic techniques.

  19. 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.

  20. Study of irradiation-induced amorphization in intermetallic compounds

    SciTech Connect

    Koike, J.

    1989-01-01

    Irradiation-induced amorphization was studied in situ in the high voltage electron microscope interfaced to a tandem accelerator. Variation of elastic properties during irradiation was studied with Brillouin scattering spectroscopy, and its relation to amorphization were explored. Four important topics were investigated. (1) The temperature dependence of the critical dose for amorphization and its correlation with chemical disordering were studied in CuTi and Zr{sub 3}Al with 1-MeV electron irradiation from 10 to 295 K. Similar temperature dependence was observed in CuTi between the critical dose for amorphization and the chemical disordering rate. Chemical disordering is a major driving force for amorphization. The critical dose for amorphization of Zr{sub 3}Al was twenty times larger than that of CuTi and attributed to the differences in point defect mobility and ordering energy. (2) Projectile mass dependence of amorphization behavior was studied in CuTi irradiated with Ne{sup +},Kr{sup +},Xe{sup +}ions. The dose dependence of the amorphous volume fraction indicated that with increasing mass from Ne{sup +} to Kr{sup +} amorphization kinetics changes from the cascade overlap to the direct-impact amorphization. In relation to the kinetics variation, the critical temperature increased with increasing projectile mass and explained in terms of the thermal stability of the primary damage. (3) Effects of simultaneous and sequential irradiation with Kr+ and electrons were studied in CuTi and Zr{sub 3}Al. Both additive and retardation effects were observed depending on temperature and the electron-to-Kri dose rate ratio and explained as the interaction between point defects and cascade damages. (4) Study of elastic properties during Kr{sup +} irradiation revealed that in FeTi, a large dilation and shear modulus softening accompanied with chemical disordering preceded amorphization, but not observed in NiAl.

  1. AMBIENT PARTICULATE MATTER INDUCES ALVEOLAR EPITHELIAL CELL CYCLE ARREST: ROLE OF G1 CYCLINS

    PubMed Central

    Zhang, Jingmei; Ghio, Andrew J.; Gao, Mingxing; Wei, Ke; Rosen, Glenn D.; Upadhyay, Daya

    2007-01-01

    We hypothesized that the ambient air pollution particles (PM) induce cell cycle arrest in alveolar epithelial cells (AEC). Exposure of PM (25μg/cm2) to AEC induced cells cycle arrest in G1 phase, inhibited DNA synthesis, blocked cell proliferation and caused decrease in cyclin E, A, D1 and Cyclin E- cyclin-dependent kinase(CDK)-2 kinase activity after 4h. PM induced upregulation of CDK inhibitor, p21 protein and p21 activity in AEC. SiRNAp21 blocked PM–induced downregulation of cyclins and AEC G1 arrest. Accordingly, we provide the evidence that PM induces AEC G1 arrest by altered regulation of G1 cyclins and CDKs. PMID:17977533

  2. Ambient particulate matter induces alveolar epithelial cell cycle arrest: role of G1 cyclins.

    PubMed

    Zhang, Jingmei; Ghio, Andrew J; Gao, Mingxing; Wei, Ke; Rosen, Glenn D; Upadhyay, Daya

    2007-11-13

    We hypothesized that the ambient air pollution particles (particulate matter; PM) induce cell cycle arrest in alveolar epithelial cells (AEC). Exposure of PM (25microg/cm(2)) to AEC induced cells cycle arrest in G1 phase, inhibited DNA synthesis, blocked cell proliferation and caused decrease in cyclin E, A, D1 and Cyclin E- cyclin-dependent kinase (CDK)-2 kinase activity after 4h. PM induced upregulation of CDK inhibitor, p21 protein and p21 activity in AEC. SiRNAp21 blocked PM-induced downregulation of cyclins and AEC G1 arrest. Accordingly, we provide the evidence that PM induces AEC G1 arrest by altered regulation of G1 cyclins and CDKs.

  3. 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

  4. Nuclear Collisions Induced by Single-Cycle Laser Pulses:

    NASA Astrophysics Data System (ADS)

    Zhi, Miaochan; Sokolov, Alexei

    2004-10-01

    Fusion occurs when light nuclei of hydrogen (H), deuterium (D), or tritium (T), join together to produce helium, neutrons, and energy. If harnessed on earth, fusion has the potential to provide a clean and virtually unlimited source of energy. The two present techniques for controlled fusion all rely on hot plasma. Thermal motion of the nuclei results in random nuclear collisions, which can be energetic enough to produce fusion when the temperature is high. We propose a ``new method'' which doesn't require preparation and confinement of hot and dense plasma, but works in a molecular gas. It uses the fact that nuclei in a molecule are pre-aligned in front of each other and can be driven into each other by the very strong and ultra-short laser pulse since the nuclei of different masses will acquire different velocities when driven by the same electric field. The nuclei may collide with high kinetic energy needed to overcome the Coulomb Barrier. These collisions may lead to fusion. Realization of this technique will require ultrashort (few-femtosecond, single-cycle) laser pulses with field intensities approaching 10^23W/cm^2. We have performed a classical simulation of nuclear motion under the action of the Coulomb repulsion and a strong laser field. We have also done a simple statistical ensemble calculation. From our results, we can see that collision will occur on a sub-attosecond time scale. On that timescale the nuclei will experience large acceleration and emit zeptosecond bursts of light.

  5. The novel compound OSI-461 induces apoptosis and growth arrest in human acute myeloid leukemia cells.

    PubMed

    Singh, Raminder; Fröbel, Julia; Cadeddu, Ron-Patrick; Bruns, Ingmar; Schroeder, Thomas; Brünnert, Daniela; Wilk, Christian Matthias; Zerbini, Luiz Fernando; Haas, Rainer; Czibere, Akos

    2012-02-01

    Acute myeloid leukemia (AML) is a heterogeneous hematological malignancy. Treatment of patients suffering from high-risk AML as defined by clinical parameters, cytogenetics, and/or molecular analyses is often unsuccessful. OSI-461 is a pro-apoptotic compound that has been proposed as a novel therapeutic option for patients suffering from solid tumors like prostate or colorectal carcinoma. But little is known about its anti-proliferative potential in AML. Hence, we treated bone marrow derived CD34(+) selected blast cells from 20 AML patients and the five AML cell lines KG-1a, THP-1, HL-60, U-937, and MV4-11 with the physiologically achievable concentration of 1 μM OSI-461 or equal amounts of DMSO as a control. Following incubation with OSI-461, we found a consistent induction of apoptosis and an accumulation of cells in the G2/M phase of the cell cycle. In addition, we demonstrate that the OSI-461 mediated anti-proliferative effects observed in AML are associated with the induction of the pro-apoptotic cytokine mda-7/IL-24 and activation of the growth arrest and DNA-damage inducible genes (GADD) 45α and 45γ. Furthermore, OSI-461 treated leukemia cells did not regain their proliferative potential for up to 8 days after cessation of treatment following the initial 48 h treatment period with 1 μM OSI-461. This indicates sufficient targeting of the leukemia-initiating cells in our in vitro experiments through OSI-461. The AML samples tested in this study included samples from patients who were resistant to conventional chemotherapy and/or had FLT3-ITD mutations demonstrating the high potential of OSI-461 in human AML.

  6. 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

  7. 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.

  8. 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

  9. 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

  10. 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

  11. Can pharmacologic hyperprolactinemia and breast-suction induce lactation in women with normal menstrual cycles?

    PubMed

    Polatti, F; Brambilla, A; Mandelli, B; Forgione, A

    1984-01-01

    Six women--age range 21/24--with regular ovulatory cycles, voluntarily underwent with L-Sulpiride (100 mg/die) from the 5th to the 19th day of the cycle. On the 13th, 14th and 15th day of therapy breast suction by syringe breast-pump was performed on each woman every 6 hours and for 4' from either breast. Milk secretion was poor and showed no noticeable increase in the three days of breast suction. L-Sulpiride-induced hyperprolactinemia combined with nipple stimulation-induced increased PRL secretion failed to stimulate milk secretion at a level comparable with physiologic lactation in puerperium.

  12. Fuling Granule, a Traditional Chinese Medicine Compound, Suppresses Cell Proliferation and TGFβ-Induced EMT in Ovarian Cancer.

    PubMed

    Tao, Fangfang; Ruan, Shanming; Liu, Wenhong; Wang, Libin; Xiong, Yang; Shen, Minhe

    2016-01-01

    The compound fuling granule (CFG) is a traditional Chinese drug which has been used to treat ovarian cancer in China for over twenty years. Nevertheless, the underlying molecular mechanism of its anti-cancer effect remains unclear. In this study, microarray data analysis was performed to search differentially expressed genes in CFG-treated ovarian cancer cells. Several cell cycle and epithelial-mesenchymal transition (EMT) related genes were identified. The microarray analyses also revealed that CFG potentially regulates EMT in ovarian cancer. We also found that, functionally, CFG significantly suppresses ovarian cancer cell proliferation by cell cycle arrest, apoptosis and senescence and the AKT/GSK-3β pathway is possibly involved. Additionally, the invasion and migration ability of ovarian cancer induced by TGFβ is significantly suppressed by CFG. In conclusion, our results demonstrated that CFG suppresses ovarian cancer cell proliferation as well as TGFβ1-induced EMT in vitro. Finally, we discovered that CFG suppresses tumor growth and distant metastasis in vivo. Overall, these findings provide helpful clues to design novel clinical treatments against cancer.

  13. Fuling Granule, a Traditional Chinese Medicine Compound, Suppresses Cell Proliferation and TGFβ-Induced EMT in Ovarian Cancer

    PubMed Central

    Ruan, Shanming; Liu, Wenhong; Wang, Libin; Xiong, Yang; Shen, Minhe

    2016-01-01

    The compound fuling granule (CFG) is a traditional Chinese drug which has been used to treat ovarian cancer in China for over twenty years. Nevertheless, the underlying molecular mechanism of its anti-cancer effect remains unclear. In this study, microarray data analysis was performed to search differentially expressed genes in CFG-treated ovarian cancer cells. Several cell cycle and epithelial-mesenchymal transition (EMT) related genes were identified. The microarray analyses also revealed that CFG potentially regulates EMT in ovarian cancer. We also found that, functionally, CFG significantly suppresses ovarian cancer cell proliferation by cell cycle arrest, apoptosis and senescence and the AKT/GSK-3β pathway is possibly involved. Additionally, the invasion and migration ability of ovarian cancer induced by TGFβ is significantly suppressed by CFG. In conclusion, our results demonstrated that CFG suppresses ovarian cancer cell proliferation as well as TGFβ1-induced EMT in vitro. Finally, we discovered that CFG suppresses tumor growth and distant metastasis in vivo. Overall, these findings provide helpful clues to design novel clinical treatments against cancer. PMID:28036353

  14. The seleno-organic compound ebselen impairs mitochondrial physiology and induces cell death in AR42J cells.

    PubMed

    Santofimia-Castaño, Patricia; Garcia-Sanchez, Lourdes; Ruy, Deborah Clea; Fernandez-Bermejo, Miguel; Salido, Gines M; Gonzalez, Antonio

    2014-09-17

    Ebselen is a seleno-organic compound that causes cell death in several cancer cell types. The mechanisms underlying its deleterious effects have not been fully elucidated. In this study, the effects of ebselen (1 μM-40 μM) on AR42J tumor cells have been examined. Cell viability was studied using AlamarBlue(®) test. Cell cycle phase determination was carried out by flow cytometry. Changes in intracellular free Ca(2+) concentration were followed by fluorimetry analysis of fura-2-loaded cells. Distribution of mitochondria, mitochondrial Ca(2+) concentration and mitochondrial membrane potential were monitored by confocal microscopy of cells loaded with Mitotracker Green™ FM, rhod-2 or TMRM respectively. Caspase-3 activity was calculated following the luorogenic substrate ACDEVD-AMC signal with a spectrofluorimeter. Results show that cell viability decreased in the presence of ebselen. An increase in the number of cells in the S-phase of the cell cycle was observed. Ebselen induced a concentration-dependent mobilization of Ca(2+) from agonist- and thapsigargin-sensitive Ca(2+) pools. Ebselen induced also a transient increase in mitochondrial Ca(2+) concentration, a progressive decrease of the mitochondrial membrane potential and a disruption of the mitochondrial network. Finally, a concentration-dependent increase in caspase-3 activity was detected. We conclude that ebselen exerts deleterious actions on the cells that involve the impairment of mitochondrial physiology and the activation of caspase-3-mediated apoptotic pathway. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  15. AP4 is required for mitogen- and c-MYC-induced cell cycle progression

    PubMed Central

    Jackstadt, Rene; Hermeking, Heiko

    2014-01-01

    AP4 represents a c-MYC-inducible bHLH-LZ transcription factor, which displays elevated expression in many types of tumors. We found that serum-starved AP4-deficient mouse embryo fibroblasts (MEFs) were unable to resume proliferation and showed a delayed S-phase entry after restimulation. Furthermore, they accumulated as tetraploid cells due to a cytokinesis defect. In addition, AP4 was required for c-MYC-induced cell cycle re-entry. AP4-deficient MEFs displayed decreased expression of CDK2 (cyclin-dependent kinase 2), which we characterized as a conserved and direct AP4 target. Activation of an AP4 estrogen receptor fusion protein (AP4-ER) enhanced proliferation of human diploid fibroblasts in a CDK2-dependent manner. However, in contrast to c-MYC-ER, AP4-ER activation was not sufficient to induce cell cycle re-entry or apoptosis in serum-starved MEFs. AP4-deficiency was accompanied by increased spontaneous and c-MYC-induced DNA damage in MEFs. Furthermore, c-MYC-induced apoptosis was decreased in AP4-deficient MEFs, suggesting that induction of apoptosis by c-MYC is linked to its ability to activate AP4 and thereby cell cycle progression. Taken together, these results indicate that AP4 is a central mediator and coordinator of cell cycle progression in response to mitogenic signals and c-MYC activation. Therefore, inhibition of AP4 function may represent a therapeutic approach to block tumor cell proliferation. PMID:25261373

  16. Kefir induces cell-cycle arrest and apoptosis in HTLV-1-negative malignant T-lymphocytes

    PubMed Central

    Maalouf, Katia; Baydoun, Elias; Rizk, Sandra

    2011-01-01

    Background: Adult lymphoblastic leukemia (ALL) is a malignancy that occurs in white blood cells. The overall cure rate in children is 85%, whereas it is only 40% in adults. Kefir is an important probiotic that contains many bioactive ingredients, which give it unique health benefits. It has been shown to control several cellular types of cancer. Purpose: The present study investigates the effect of a cell-free fraction of kefir on CEM and Jurkat cells, which are human T-lymphotropic virus type I (HTLV-1)-negative malignant T-lymphocytes. Methods: Cells were incubated with different kefir concentrations. The cytotoxicity of the compound was evaluated by determining the percentage viability of cells. The effect of all the noncytotoxic concentrations of kefir on the proliferation of CEM and Jurkat cells was then assessed. The levels of transforming growth factor-alpha (TGF-α), transforming growth factor- beta1 (TGF-β1), matrix metalloproteinase-2 (MMP-2), and MMP-9 mRNA upon kefir treatment were then analyzed using reverse transcriptase polymerase chain reaction (RT-PCR). Finally, the growth inhibitory effects of kefir on cell-cycle progression/apoptosis were assessed by Cell Death Detection (ELISA) and flow cytometry. Results: The maximum cytotoxicity recorded after 48-hours treatment with 80 μg/μL kefir was only 42% and 39% in CEM and Jurkat cells, respectively. The percent reduction in proliferation was very significant, and was dose-, and time-dependent. In both cell lines, kefir exhibited its antiproliferative effect by downregulating TGF-α and upregulating TGF-β1 mRNA expression. Upon kefir treatment, a marked increase in cell-cycle distribution was noted in the preG1 phase of CEM and Jurkat cells, indicating the proapoptotic effect of kefir, which was further confirmed by Cell Death Detection ELISA. However, kefir did not affect the mRNA expression of metalloproteinases needed for the invasion of leukemic cell lines. Conclusion: In conclusion, kefir is

  17. Kefir induces cell-cycle arrest and apoptosis in HTLV-1-negative malignant T-lymphocytes.

    PubMed

    Maalouf, Katia; Baydoun, Elias; Rizk, Sandra

    2011-02-14

    Adult lymphoblastic leukemia (ALL) is a malignancy that occurs in white blood cells. The overall cure rate in children is 85%, whereas it is only 40% in adults. Kefir is an important probiotic that contains many bioactive ingredients, which give it unique health benefits. It has been shown to control several cellular types of cancer. The present study investigates the effect of a cell-free fraction of kefir on CEM and Jurkat cells, which are human T-lymphotropic virus type I (HTLV-1)-negative malignant T-lymphocytes. Cells were incubated with different kefir concentrations. The cytotoxicity of the compound was evaluated by determining the percentage viability of cells. The effect of all the noncytotoxic concentrations of kefir on the proliferation of CEM and Jurkat cells was then assessed. The levels of transforming growth factor-alpha (TGF-α), transforming growth factor- beta1 (TGF-β1), matrix metalloproteinase-2 (MMP-2), and MMP-9 mRNA upon kefir treatment were then analyzed using reverse transcriptase polymerase chain reaction (RT-PCR). Finally, the growth inhibitory effects of kefir on cell-cycle progression/apoptosis were assessed by Cell Death Detection (ELISA) and flow cytometry. The maximum cytotoxicity recorded after 48-hours treatment with 80 μg/μL kefir was only 42% and 39% in CEM and Jurkat cells, respectively. The percent reduction in proliferation was very significant, and was dose-, and time-dependent. In both cell lines, kefir exhibited its antiproliferative effect by downregulating TGF-α and upregulating TGF-β1 mRNA expression. Upon kefir treatment, a marked increase in cell-cycle distribution was noted in the preG(1) phase of CEM and Jurkat cells, indicating the proapoptotic effect of kefir, which was further confirmed by Cell Death Detection ELISA. However, kefir did not affect the mRNA expression of metalloproteinases needed for the invasion of leukemic cell lines. In conclusion, kefir is effective in inhibiting proliferation and inducing

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

    PubMed

    Sivaprakasam, Vasanthi; Killinger, Dennis K

    2003-11-20

    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.

  19. 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.

  20. Xanthohumol induces apoptosis and S phase cell cycle arrest in A549 non-small cell lung cancer cells

    PubMed Central

    Yong, Wai Kuan; Ho, Yen Fong; Malek, Sri Nurestri Abd

    2015-01-01

    Background: Xanthohumol, a major prenylated chalcone found in female hop plant, Humulus lupulus, was reported to have various chemopreventive and anti-cancer properties. However, its apoptotic effect on human alveolar adenocarcinoma cell line (A549) of non-small cell lung cancer (NSCLC) was unknown. Objective: This study aimed to investigate the effects of xanthohumol on apoptosis in A549 human NSCLC cells. Materials and Methods: A549 cell proliferation was determined by sulforhodamine B assay. Morphological changes of the cells were studied via phase contrast and fluorescent microscopy. Induction of apoptosis was assessed by Annexin-V fluorescein isothiocyanate/propidium iodide (Annexin V-FITC/PI) staining, DNA fragmentation (TUNEL) assay mitochondrial membrane potential assay, cell cycle analysis, and caspase activity studies. Results: Xanthohumol was found to decrease cell proliferation in A549 cells but had relatively low cytotoxicity on normal human lung fibroblast cell line (MRC-5). Typical cellular and nuclear apoptotic features were also observed in A549 cells treated with xanthohumol. Onset of apoptosis in A549 cells was further confirmed by externalization of phosphatidylserine, changes in mitochondrial membrane potential, and DNA fragmentation in the cells after treatment. Xanthohumol induced accumulation of cells in sub G1 and S phase based on cell cycle analysis and also increased the activities of caspase-3, -8, and -9. Conclusion: This work suggests that xanthohumol as an apoptosis inducer, may be a potent therapeutic compound for NSCLC. PMID:26664015

  1. Receptor-selective retinoids inhibit the growth of normal and malignant breast cells by inducing G1 cell cycle blockade.

    PubMed

    Wu, Kendall; DuPré, Elizabeth; Kim, Heetae; Tin-U, Caesar K; Bissonnette, Reid P; Lamph, William W; Brown, Powel H

    2006-03-01

    Despite advances in treatment, breast cancer continues to be the second leading cause of cancer mortality in women. Statistics suggest that while focus on treatment should continue, chemopreventive approaches should also be pursued. Previous studies have demonstrated that naturally occurring retinoids such as 9-cis retinoic acid (9cRA) can prevent breast cancer in animal models. However, these studies have also shown that these compounds are too toxic for general use. Work from our laboratory showed that an RXR-selective retinoid LGD1069 prevented tumor development in animal models of cancer with reduced toxicity as compared to an RAR-selective retinoid TTNPB. In the present study, we investigated the mechanisms by which receptor-selective retinoids inhibit the growth of normal and malignant breast cells. Our results demonstrate that the synthetic retinoids tested are as effective as 9cRA in suppressing the growth of normal human mammary epithelial cells (HMECs) and estrogen receptor-positive (ER-positive) breast cancer cells. Although the receptor-selective retinoids induce minimal amounts of apoptosis in T47D breast cancer cells, the predominant factor that leads to growth arrest is G1 cell cycle blockade. Our data indicate that this blockade results from the downregulation of Cyclin D1 and Cyclin D3, which in turn causes Rb hypophosphorylation. Non-toxic retinoids that are potent inducers of cell cycle arrest may be particularly useful for the prevention of breast cancer.

  2. Jatamanvaltrate P induces cell cycle arrest, apoptosis and autophagy in human breast cancer cells in vitro and in vivo.

    PubMed

    Yang, Bo; Zhu, Rui; Tian, Shasha; Wang, Yiqi; Lou, Siyue; Zhao, Huajun

    2017-03-10

    Jatamanvaltrate P is a novel iridoid ester isolated from Valeriana jatamansi Jones, a traditional medicine used to treat nervous disorders. In this study, we found that Jatamanvaltrate P possessed notable antitumor properties and therefore evaluated its anticancer effects against human breast cancer cells in vitro and in vivo. Jatamanvaltrate P inhibited the growth and proliferation of MCF-7 and triple-negative breast cancer (TNBC) cell lines (MDA-MB-231, MDA-MB-453 and MDA-MB-468) in a concentration-dependent manner, while displayed relatively low cytotoxicity to human breast epithelial cells (MCF-10A). Treatment with Jatamanvaltrate P induced G2/M-phase arrest in TNBC and G0/G1-phase arrest in MCF-7 cells. Further study of the molecular mechanisms of this cytotoxic compound demonstrated that Jatamanvaltrate P enhanced cleavage of PARP and caspases, while decreased the expression levels of cell cycle-related Cyclin B1, Cyclin D1 and Cdc-2. It also activated autophagy, as indicated by the triggered autophagosome formation and increased LC3-II levels. Autophagy inhibition by 3-MA co-treatment undermined Jatamanvaltrate P-induced cell death. Finally, Jatamanvaltrate P exhibited a potential antitumor effect in MDA-MB-231 xenografts without apparent toxicity. These results suggest that Jatamanvaltrate P is a potential therapeutic agent for breast cancer, providing a basis for development of the compound as a novel chemotherapeutic agent.

  3. 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.

  4. Ecdysone signaling induces two phases of cell cycle exit in Drosophila cells

    PubMed Central

    Guo, Yongfeng; Flegel, Kerry; Kumar, Jayashree; McKay, Daniel J.

    2016-01-01

    ABSTRACT During development, cell proliferation and differentiation must be tightly coordinated to ensure proper tissue morphogenesis. Because steroid hormones are central regulators of developmental timing, understanding the links between steroid hormone signaling and cell proliferation is crucial to understanding the molecular basis of morphogenesis. Here we examined the mechanism by which the steroid hormone ecdysone regulates the cell cycle in Drosophila. We find that a cell cycle arrest induced by ecdysone in Drosophila cell culture is analogous to a G2 cell cycle arrest observed in the early pupa wing. We show that in the wing, ecdysone signaling at the larva-to-puparium transition induces Broad which in turn represses the cdc25c phosphatase String. The repression of String generates a temporary G2 arrest that synchronizes the cell cycle in the wing epithelium during early pupa wing elongation and flattening. As ecdysone levels decline after the larva-to-puparium pulse during early metamorphosis, Broad expression plummets, allowing String to become re-activated, which promotes rapid G2/M progression and a subsequent synchronized final cell cycle in the wing. In this manner, pulses of ecdysone can both synchronize the final cell cycle and promote the coordinated acquisition of terminal differentiation characteristics in the wing. PMID:27737823

  5. Self-induced redox cycling coupled luminescence on nanopore recessed disk-multiscale bipolar electrodes

    DOE PAGES

    Ma, Chaoxiong; Zaino III, Lawrence P.; Bohn, Paul W.

    2015-03-25

    Self-induced redox cycling at nanopore ring-disk electrodes is coupled, through a bipolar electrode, to a remote fluorigenic reporter reaction. We present a new configuration for coupling fluorescence microscopy and voltammetry using self-induced redox cycling for ultrasensitive electrochemical measurements. An array of nanopores, each supporting a recessed disk electrode separated by 100 nm in depth from a planar multiscale bipolar top electrode, was fabricated using multilayer deposition, nanosphere lithography, and reactive-ion etching. Self-induced redox cycling was induced on the disk electrode producing ~30× current amplification, which was independently confirmed by measuring induced electrogenerated chemiluminescence from Ru(bpy)32/3+/tri-n-propylamine on the floating bipolar electrode.more » In this design, redox cycling occurs between the recessed disk and the top planar portion of a macroscopic thin film bipolar electrode in each nanopore. Electron transfer also occurs on a remote (mm-distance) portion of the planar bipolar electrode to maintain electroneutrality. This couples the electrochemical reactions of the target redox pair in the nanopore array with a reporter, such as a potential-switchable fluorescent indicator, in the cell at the distal end of the bipolar electrode. Oxidation or reduction of reversible analytes on the disk electrodes were accompanied by reduction or oxidation, respectively, on the nanopore portion of the bipolar electrode and then monitored by the accompanying oxidation of dihydroresorufin or reduction of resorufin at the remote end of the bipolar electrode, respectively. In both cases, changes in fluorescence intensity were triggered by the reaction of the target couple on the disk electrode, while recovery was largely governed by diffusion of the fluorescent indicator. Reduction of 1 nM of Ru(NH3)63+ on the nanoelectrode array was detected by monitoring the fluorescence intensity of resorufin, demonstrating high

  6. Self-induced redox cycling coupled luminescence on nanopore recessed disk-multiscale bipolar electrodes

    SciTech Connect

    Ma, Chaoxiong; Zaino III, Lawrence P.; Bohn, Paul W.

    2015-03-25

    Self-induced redox cycling at nanopore ring-disk electrodes is coupled, through a bipolar electrode, to a remote fluorigenic reporter reaction. We present a new configuration for coupling fluorescence microscopy and voltammetry using self-induced redox cycling for ultrasensitive electrochemical measurements. An array of nanopores, each supporting a recessed disk electrode separated by 100 nm in depth from a planar multiscale bipolar top electrode, was fabricated using multilayer deposition, nanosphere lithography, and reactive-ion etching. Self-induced redox cycling was induced on the disk electrode producing ~30× current amplification, which was independently confirmed by measuring induced electrogenerated chemiluminescence from Ru(bpy)32/3+/tri-n-propylamine on the floating bipolar electrode. In this design, redox cycling occurs between the recessed disk and the top planar portion of a macroscopic thin film bipolar electrode in each nanopore. Electron transfer also occurs on a remote (mm-distance) portion of the planar bipolar electrode to maintain electroneutrality. This couples the electrochemical reactions of the target redox pair in the nanopore array with a reporter, such as a potential-switchable fluorescent indicator, in the cell at the distal end of the bipolar electrode. Oxidation or reduction of reversible analytes on the disk electrodes were accompanied by reduction or oxidation, respectively, on the nanopore portion of the bipolar electrode and then monitored by the accompanying oxidation of dihydroresorufin or reduction of resorufin at the remote end of the bipolar electrode, respectively. In both cases, changes in fluorescence intensity were triggered by the reaction of the target couple on the disk electrode, while recovery was largely governed by diffusion of the fluorescent indicator. Reduction of 1 nM of Ru(NH3)63+ on the nanoelectrode array was detected by monitoring the fluorescence

  7. Identification of Biologically Relevant Compounds in Aboveground and Belowground Induced Volatile Blends

    PubMed Central

    Qiu, Bao-Li; Hordijk, Cornelis A.; Vet, Louise E. M.; Jansen, Jeroen J.

    2010-01-01

    Plants under attack by aboveground herbivores emit complex blends of volatile organic compounds (VOCs). Specific compounds in these blends are used by parasitic wasps to find their hosts. Belowground induction causes shifts in the composition of aboveground induced VOC blends, which affect the preference of parasitic wasps. To identify which of the many volatiles in the complex VOC blends may explain parasitoid preference poses a challenge to ecologists. Here, we present a case study in which we use a novel bioinformatics approach to identify biologically relevant differences between VOC blends of feral cabbage (Brassica oleracea L.). The plants were induced aboveground or belowground with jasmonic acid (JA) and shoot feeding caterpillars (Pieris brassicae or P. rapae). We used Partial Least Squares—Discriminant Analysis (PLSDA) to integrate and visualize the relation between plant-emitted VOCs and the preference of female Cotesia glomerata. Overall, female wasps preferred JA-induced plants over controls, but they strongly preferred aboveground JA-induced plants over belowground JA-induced plants. PLSDA revealed that the emission of several monoterpenes was enhanced similarly in all JA-treated plants, whereas homoterpenes and sesquiterpenes increased exclusively in aboveground JA-induced plants. Wasps may use the ratio between these two classes of terpenes to discriminate between aboveground and belowground induced plants. Additionally, it shows that aboveground applied JA induces different VOC biosynthetic pathways than JA applied to the root. Our bioinformatic approach, thus, successfully identified which VOCs matched the preferences of the wasps in the various choice tests. Additionally, the analysis generated novel hypotheses about the role of JA as a signaling compound in aboveground and belowground induced responses in plants. PMID:20737198

  8. 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

  9. Valproic acid induces apoptosis and cell cycle arrest in poorly differentiated thyroid cancer cells.

    PubMed

    Catalano, Maria G; Fortunati, Nicoletta; Pugliese, Mariateresa; Costantino, Lucia; Poli, Roberta; Bosco, Ornella; Boccuzzi, Giuseppe

    2005-03-01

    Poorly differentiated thyroid carcinoma is an aggressive human cancer that is resistant to conventional therapy. Histone deacetylase inhibitors are a promising class of drugs, acting as antiproliferative agents by promoting differentiation, as well as inducing apoptosis and cell cycle arrest. Valproic acid (VPA), a class I selective histone deacetylase inhibitor widely used as an anticonvulsant, promotes differentiation in poorly differentiated thyroid cancer cells by inducing Na(+)/I(-) symporter and increasing iodine uptake. Here, we show that it is also highly effective at suppressing growth in poorly differentiated thyroid cancer cell lines (N-PA and BHT-101). Apoptosis induction and cell cycle arrest are the underlying mechanisms of VPA's effect on cell growth. It induces apoptosis by activating the intrinsic pathway; caspases 3 and 9 are activated but not caspase 8. Cell cycle is selectively arrested in G(1) and is associated with the increased expression of p21 and the reduced expression of cyclin A. Both apoptosis and cell cycle arrest are induced by treatment with 1 mm VPA, a dose that promotes cell redifferentiation and that is slightly above the serum concentration reached in patients treated for epilepsy. These multifaceted properties make VPA of clinical interest as a new approach to treating poorly differentiated thyroid cancer.

  10. 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).

  11. Competition-induced starvation drives large-scale population cycles in Antarctic krill.

    PubMed

    Ryabov, Alexey B; de Roos, André M; Meyer, Bettina; Kawaguchi, So; Blasius, Bernd

    2017-07-01

    Antarctic krill (Euphausia superba) - one of the most abundant animal species on Earth - exhibits a 5-6 year population cycle, with oscillations in biomass exceeding one order of magnitude. Previous studies have postulated that the krill cycle is induced by periodic climatological factors, but these postulated drivers neither show consistent agreement, nor are they supported by quantitative models. Here, using data analysis complemented with modeling of krill ontogeny and population dynamics, we identify intraspecific competition for food as the main driver of the krill cycle, while external climatological factors possibly modulate its phase and synchronization over large scales. Our model indicates that the cycle amplitude increases with reduction of krill loss rates. Thus, a decline of apex predators is likely to increase the oscillation amplitude, potentially destabilizing the marine food web with drastic consequences for the entire Antarctic ecosystem.

  12. 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.

  13. 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.

  14. The Phenomenology of Ion Implantation-Induced Blistering and Thin-Layer Splitting in Compound Semiconductors

    NASA Astrophysics Data System (ADS)

    Singh, R.; Christiansen, S. H.; Moutanabbir, O.; Gösele, U.

    2010-10-01

    Hydrogen and/or helium implantation-induced surface blistering and layer splitting in compound semiconductors such as InP, GaAs, GaN, AlN, and ZnO are discussed. The blistering phenomenon depends on many parameters such as the semiconductor material, ion fluence, ion energy, and implantation temperature. The optimum values of these parameters for compound semiconductors are presented. The blistering and splitting processes in silicon have been studied in detail, motivated by the fabrication of the widely used silicon-on-insulator wafers. Hence, a comparison of the blistering process in Si and compound semiconductors is also presented. This comparative study is technologically relevant since ion implantation-induced layer splitting combined with direct wafer bonding in principle allows the transfer of any type of semiconductor layer onto any foreign substrate of choice—the technique is known as the ion-cut or Smart-Cut™ method. For the aforementioned compound semiconductors, investigations regarding layer transfer using the ion-cut method are still in their infancy. We report feasibility studies of layer transfer by the ion-cut method for some of the most important and widely used compound semiconductors. The importance of characteristic values for successful wafer bonding such as wafer bow and surface flatness as well as roughness are discussed, and difficulties in achieving some of these values are pointed out.

  15. Compound Cycle Engine Program.

    DTIC Science & Technology

    1986-01-01

    the combustor replaced by a power producing diesel core. The turbomachinery maps were essentially lifted from existing turbine engines, with the study...additive samples for evaluation. Figure 11 shows a schematic of the Hohman wear rig and preliminary test results. The Stauffer STL plus 10 percent TAP ...Cruise Missile, and APU Propulsion Systems." AIAA Paper 86-1545, June 1986. 6. Larkin, T., Staton, D., and Mongia , H., "Rotorcraft Propulsion for Year 2000

  16. 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).

  17. 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).

  18. 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.

  19. Molecular docking of the anticancer bioactive compound proceraside with macromolecules involved in the cell cycle and DNA replication.

    PubMed

    Gurung, A B; Ali, M A; Bhattacharjee, A; AbulFarah, M; Al-Hemaid, F; Abou-Tarboush, F M; Al-Anazi, K M; Al-Anazi, F S M; Lee, J

    2016-05-09

    The bioactive compounds proceraside A, frugoside and calotropin, which were extracted from the root bark of Calotropis procera (Aiton) W.T. Aiton (family Asclepiadaceae), were recently reported to inhibit the growth of inhibition against various human cancer cell lines in vitro. However, their modes of action have not been clearly defined. Therefore, we attempted an in silico approach to gain insights into their binding modes against the following selected molecular targets: CDK-2, CDK-6, topoisomerase I, BCL-2, VEGFR-2, telomere: G-quadruplex, and topoisomerase II. These targets were selected based on their key roles in cancer progression via the regulation of the cell cycle and DNA replication. Molecular-docking analyses revealed that proceraside A was the best docked ligand against all the targets, with the exception of telomere-G: quadruplex. Furthermore, it displayed the lowest binding energies and inhibition constants, and critical hydrogen bonds and hydrophobic interactions with the targets were also revealed. The present study may aid in the identification of possible targets for proceraside A, and might provide a plausible explanation for its proven anti-tumor activities. Moreover, the result of this study may further guide structure-activity relationship studies used to generate more potent target-specific inhibitors.

  20. Redox Cycling and Increased Oxygen Utilization Contribute to Diquat-induced Oxidative Stress and Cytotoxicity in Chinese Hamster Ovary Cells Overexpressing NADPH-cytochrome P450 Reductase

    PubMed Central

    Fussell, Karma C.; Udasin, Ronald G.; Gray, Joshua P.; Mishin, Vladimir; Smith, Peter J.S.; Heck, Diane E.; Laskin, Jeffrey D.

    2011-01-01

    Diquat and paraquat are non-specific defoliants that induce toxicity in many organs including the lung, liver, kidney and brain. This toxicity is thought to be due to the generation of reactive oxygen species (ROS). An important pathway leading to ROS production by these compounds is redox cycling. In the present studies, diquat and paraquat redox cycling was characterized using human recombinant NADPH-cytochrome P450 reductase, rat liver microsomes, and Chinese Hamster Ovary (CHO) cells constructed to overexpress cytochrome P450 reductase (CHO-OR) and wild type control cells (CHO-WT). In redox cycling assays with recombinant cytochrome P450 reductase and microsomes, diquat was 10-40 times more effective in generating ROS when compared to paraquat (KM = 1.0 and 44.2 μM, respectively for H2O2 generation by diquat and paraquat using recombinant enzyme, and 15.1 and 178.5 μM, respectively for microsomes). In contrast, at saturating concentrations, these compounds showed similar redox cycling activity (Vmax ≈ 6.0 nmoles H2O2/min/mg protein) for recombinant enzyme and microsomes. Diquat and paraquat also redox cycle in CHO cells. Significantly more activity was evident in CHO-OR cells than CHO-WT cells. Diquat redox cycling in CHO cells was associated with marked increases in protein carbonyl formation, a marker of protein oxidation, as well as cellular oxygen consumption, measured using oxygen microsensors; greater activity was detected in CHO-OR cells than CHO-WT cells. These data demonstrate that ROS formation during diquat redox cycling can generate oxidative stress. Enhanced oxygen utilization during redox cycling may reduce intracellular oxygen available for metabolic reactions and contribute to toxicity. PMID:21215309

  1. Redox cycling and increased oxygen utilization contribute to diquat-induced oxidative stress and cytotoxicity in Chinese hamster ovary cells overexpressing NADPH-cytochrome P450 reductase.

    PubMed

    Fussell, Karma C; Udasin, Ronald G; Gray, Joshua P; Mishin, Vladimir; Smith, Peter J S; Heck, Diane E; Laskin, Jeffrey D

    2011-04-01

    Diquat and paraquat are nonspecific defoliants that induce toxicity in many organs including the lung, liver, kidney, and brain. This toxicity is thought to be due to the generation of reactive oxygen species (ROS). An important pathway leading to ROS production by these compounds is redox cycling. In this study, diquat and paraquat redox cycling was characterized using human recombinant NADPH-cytochrome P450 reductase, rat liver microsomes, and Chinese hamster ovary (CHO) cells constructed to overexpress cytochrome P450 reductase (CHO-OR) and wild-type control cells (CHO-WT). In redox cycling assays with recombinant cytochrome P450 reductase and microsomes, diquat was 10-40 times more effective at generating ROS compared to paraquat (K(M)=1.0 and 44.2μM, respectively, for H(2)O(2) generation by diquat and paraquat using recombinant enzyme, and 15.1 and 178.5μM, respectively for microsomes). In contrast, at saturating concentrations, these compounds showed similar redox cycling activity (V(max)≈6.0nmol H(2)O(2)/min/mg protein) for recombinant enzyme and microsomes. Diquat and paraquat also redox cycle in CHO cells. Significantly more activity was evident in CHO-OR cells than in CHO-WT cells. Diquat redox cycling in CHO cells was associated with marked increases in protein carbonyl formation, a marker of protein oxidation, as well as cellular oxygen consumption, measured using oxygen microsensors; greater activity was detected in CHO-OR cells than in CHO-WT cells. These data demonstrate that ROS formation during diquat redox cycling can generate oxidative stress. Enhanced oxygen utilization during redox cycling may reduce intracellular oxygen available for metabolic reactions and contribute to toxicity. Copyright © 2010 Elsevier Inc. All rights reserved.

  2. Estrous Cycle Induces Peripheral Sensitization in Trigeminal Ganglion Neurons: An Animal Model of Menstrual Migraine.

    PubMed

    Saleeon, Wachirapong; Jansri, Ukkrit; Srikiatkhachorn, Anan; Bongsebandhu-phubhakdi, Saknan

    2016-02-01

    Many women experience menstrual migraines that develop into recurrent migraine attacks during menstruation. In the human menstrual cycle, the estrogen level fluctuates according to changes in the follicular and luteal phases. The rat estrous cycle is used as an animal model to study the effects of estrogen fluctuation. To investigate whether the estrous cycle is involved in migraine development by comparing the neuronal excitability of trigeminal ganglion (TG) neurons in each stage of the estrous cycle. Female rats were divided into four experimental groups based on examinations of the cytologies of vaginal smears, and serum analyses of estrogen levels following each stage of the estrous cycle. The rats in each stage of the estrous cycle were anesthetized and their trigeminal ganglia were removed The collections of trigeminal ganglia were cultured for two to three hours, after which whole-cell patch clamp experiments were recorded to estimate the electrophysiological properties of the TG neurons. There were many vaginal epithelial cells and high estrogen levels in the proestrus and estrus stages of the estrous cycle. Electrophysiological studies revealed that the TG neurons in the proestrus and estrus stages exhibited significantly lower thresholds of stimulation, and significant increase in total spikes compared to the TG neurons that were collected in the diestrus stage. Our results revealed that high estrogen levels in the proestrus and estrus stages altered the thresholds, rheobases, and total spikes of the TG neurons. High estrogen levels in the estrous cycle induced an increase in neuronal excitability and the peripheral sensitization of TG neurons. These findings may provide an explanation for the correlation of estrogen fluctuations during the menstrual cycle with the pathogenesis of menstrual migraines.

  3. Are phenolic compounds released from the Mediterranean shrub Cistus albidus responsible for changes in N cycling in siliceous and calcareous soils?

    Treesearch

    Eva Castells; Josep Peñuelas; David W. Valentine

    2004-01-01

    We studied the effects of Cistus albidus leaf leachates on nitrogen-cycling processes in two siliceous soils (granite and schist) and one calcareous soil. We compared those effects with gross N-transformation rates in soils sampled underneath Cistus. Our results show that although phenolic compounds leached from green foliage...

  4. The mysterious human epidermal cell cycle, or an oncogene-induced differentiation checkpoint

    PubMed Central

    Gandarillas, Alberto

    2012-01-01

    Fifteen years ago, we reported that proto-oncogene MYC promoted differentiation of human epidermal stem cells, a finding that was surprising to the MYC and the skin research communities. MYC was one of the first human oncogenes identified, and it had been strongly associated with proliferation. However, it was later shown that MYC could induce apoptosis under low survival conditions. Currently, the notion that MYC promotes epidermal differentiation is widely accepted, but the cell cycle mechanisms that elicit this function remain unresolved. We have recently reported that keratinocytes respond to cell cycle deregulation and DNA damage by triggering terminal differentiation. This mechanism might constitute a homeostatic protection face to cell cycle insults. Here, I discuss recent and not-so-recent evidence suggesting the existence of a largely unexplored oncogene-induced differentiation response (OID) analogous to oncogene-induced apoptosis (OIA) or senescence (OIS). In addition, I propose a model for the role of the cell cycle in skin homeostasis maintenance and for the dual role of MYC in differentiation. PMID:23114621

  5. Recent climate-induced variations in terrestrial carbon cycle over tropics: A model simulation

    NASA Astrophysics Data System (ADS)

    Ichii, K.; Nemani, R. R.; Hashimoto, H.

    2003-12-01

    Tropical forests accounts for about 20 percent of the world terrestrial carbon and one-third of global terrestrial NPP. Atmospheric inversion studies show that additional factors such as CO2 fertilization and climate changes, should work as a carbon sink despite of CO2 emission due to deforestation in tropical regions. However, responses of tropical ecosystems to environmental changes and current carbon sink mechanisms are still unknown. The goal of this study is (1) to characterize the climate influences on tropical carbon cycle such as GPP, NPP and NEP, and (2) to analyze recent interannual variations in terrestrial carbon cycle over tropics. We investigated the relationship between climate factors (temperature, precipitation, radiation, and VPD) and several carbon cycle components, and analyzed recent carbon cycle variations over tropics using Biome BGC with NCEP reanalysis climate data from 1982 to 1999. In tropical ecosystems, interannual variations in GPP are mainly explained by radiation variations, and temperature and precipitation variation are secondary important. NPP and NEP interannual variations are primarily determined by temperature variation, and radiation came as a secondary important factors. Precipitation, which was considered as an important climate factor that control interannual variations in carbon cycle in tropics, has little effects on interannual variation in tropical carbon cycle possibly because of abundant rainfall. Then, recent interannual variations in terrestrial carbon cycle over tropics were analyzed from 1982-1999. Tropics show gradual increases in GPP, NPP, and NEP at a rate of several percent per recent 18 years with large drop in 1998. Both climate change and CO2 fertilization have impact on recent enhancement of terrestrial carbon uptake. Of all climate factors, radiation-induced enhancement shows important role in enhancing CO2 uptake over Amazon. On the other hand, variations in precipitation and vapor pressure did not make

  6. Cephalochromin induces G0/G1 cell cycle arrest and apoptosis in A549 human non-small-cell lung cancer cells by inflicting mitochondrial disruption.

    PubMed

    Hsiao, Che-Jen; Hsiao, George; Chen, Wei-Lin; Wang, Shih-Wei; Chiang, Chun-Ping; Liu, Li-Ya; Guh, Jih-Hwa; Lee, Tzong-Huei; Chung, Chi-Li

    2014-04-25

    The fungus-derived compound cephalochromin, isolated from the fermented broth of Cosmospora vilior YMJ89051501, shows growth-inhibitory and apoptotic activity against human lung cancer A549 cells in a concentration-dependent manner with an IC50 value of 2.8 μM at 48 h. Cephalochromin induced cell cycle arrest at the G0/G1 phase through down-regulation of cyclin D1, cyclin E, Cdk 2, and Cdk 4 expressions. Cephalochromin markedly increased the hypodiploid sub-G1 phase (apoptosis) of the cell cycle at 48 h as measured by flow cytometric analysis. Reactive oxygen species generation and loss of the mitochondrial membrane potential (MMP) were also markedly induced by cephalochromin. Moreover, the immunoblotting assays showed that cephalochromin reduced survivin and Bcl-xL expression and induced the activation of caspase-8, -9, and -3 and the cleavage of poly(ADP-ribose) polymerase, indicating the involvement of a caspase signaling cascade. The caspase inhibitor Z-VAD-fmk significantly suppressed cephalochromin-induced apoptosis. Cephalochromin also triggered LC3 II, autophagic marker, expression. Taken together, this is the first report that cephalochromin induced an antiproliferative effect on human lung cancer cells through mitochondrial disruption and down-regulation of survivin, leading to cell cycle arrest at the G0/G1 phase, loss of MMP, and subsequently apoptotic cell death.

  7. Hispolon from Phellinus linteus induces G0/G1 cell cycle arrest and apoptosis in NB4 human leukaemia cells.

    PubMed

    Chen, Yi-Chuan; Chang, Heng-Yuan; Deng, Jeng-Shyan; Chen, Jian-Jung; Huang, Shyh-Shyun; Lin, I-Hsin; Kuo, Wan-Lin; Chao, Wei; Huang, Guan-Jhong

    2013-01-01

    Hispolon (a phenolic compound isolated from Phellinus linteus) has been shown to possess strong antioxidant, anti-inflammatory, anticancer, and antidiabetic properties. In this study, we investigated the antiproliferative effect of hispolon on human hepatocellular carcinoma NB4 cells using the MTT assay, DNA fragmentation, DAPI (4, 6-diamidino-2-phenylindole dihydrochloride) staining, and flow cytometric analysis. Hispolon inhibited the cellular growth of NB4 cells in a dose-dependent manner through the induction of cell cycle arrest at G0/G1 phase measured using flow cytometric analysis and apoptotic cell death, as demonstrated by DNA laddering. Exposure of NB4 cells to hispolon-induced apoptosis-related protein expressions, such as the cleavage form of caspase 3, caspase 8, caspase 9, poly (ADP ribose) polymerase, and the proapoptotic Bax protein. Western blot analysis showed that the protein levels of extrinsic apoptotic proteins (Fas and FasL), intrinsic related proteins (cytochrome c), and the ratio of Bax/Bcl-2 were increased in NB4 cells after hispolon treatment. Hispolon-induced G0/G1-phase arrest was associated with a marked decrease in the protein expression of p53, cyclins D1, and cyclins E, and cyclin-dependent kinases (CDKs) 2, and 4, with concomitant induction of p21waf1/Cip1 and p27Kip1. We conclude that hispolon induces both of extrinsic and intrinsic apoptotic pathways in NB4 human leukemia cells in vitro.

  8. Metabolic demand and muscle damage induced by eccentric cycling of knee extensor and flexor muscles.

    PubMed

    Peñailillo, Luis; Guzmán, Nicolás; Cangas, José; Reyes, Alvaro; Zbinden-Foncea, Hermann

    2017-03-01

    The aim of this study was to examine the metabolic demand and extent of muscle damage of eccentric cycling targeting knee flexor (FLEX) and knee extensor (EXT) muscles. Eight sedentary men (23.3 ± 0.7 y) underwent two eccentric cycling sessions (EXT and FLEX) of 30 min each, at 60% of the maximum power output. Oxygen consumption (VO2), heart rate (HR) and rated perceived exertion (RPE) were measured during cycling. Countermovement and squat jumps (CMJ and SJ), muscle flexibility, muscle soreness and pain pressure threshold (PPT) of knee extensor and flexor muscles were measured before, immediately after and 1-4 days after cycling. FLEX showed greater VO2 (+23%), HR (+14%) and RPE (+18%) than EXT. CMJ and SJ performance decreased similarly after cycling. Muscle soreness increased more after EXT than FLEX and PPT decreased in knee extensor muscles after EXT and decreased in knee flexor muscles after FLEX. Greater loss of muscle flexibility in knee flexor muscles after FLEX was observed. Eccentric cycling of knee flexor muscles is metabolically more demanding than that of knee extensors, however muscle damage induced is similar. Knee flexors experienced greater loss of muscle flexibility possibly due to increased muscle stiffness following eccentric contractions.

  9. A Pyrazolo[3,4-d]pyrimidine Compound Reduces Cell Viability and Induces Apoptosis in Different Hematological Malignancies

    PubMed Central

    Laurenzana, Ilaria; Caivano, Antonella; La Rocca, Francesco; Trino, Stefania; De Luca, Luciana; D’Alessio, Francesca; Schenone, Silvia; Falco, Geppino; Botta, Maurizio; Del Vecchio, Luigi; Musto, Pellegrino

    2016-01-01

    Molecular targeted therapies are based upon drugs acting on tumors by interfering with specific targets involved in growth and spread of cancer. Many targeted therapies were approved by Food and Drug Administration as standard treatment, others were introduced into preclinical or clinical studies on hematological malignancies (HMs). The development of drug-resistance in some HMs and the lack of effective treatments in other ones emphasized the need for searching new molecular targets and therapeutic agents. The aim of this study was to evaluate the effects of 4c pyrazolo[3,4-d]pyrimidine compound, a Src inhibitor, on lymphoid and myeloid neoplasms. Here, we demonstrated its ability to reduce cell viability, induce apoptosis and cell cycle arrest in lymphoid cell lines such as Jurkat, SKMM1, Derl-2/7, and myeloid cell lines, such as Jurl-MK1. Moreover, we reported a high expression of a Src kinase, Fyn, in these cell lines compared to healthy subjects. This study was a starting point to investigate 4c pyrazolo[3,4-d]pyrimidine compound as a drug for HMs and Src kinases as its potential molecular targets. PMID:27872592

  10. A global response induced in Escherichia coli by redox-cycling agents overlaps with that induced by peroxide stress.

    PubMed Central

    Greenberg, J T; Demple, B

    1989-01-01

    Escherichia coli treated with nontoxic levels of the superoxide-generating redox-cycling agents menadione and paraquat showed dramatic changes in protein composition as monitored by two-dimensional gel analysis. The distribution of proteins synthesized after treatment with these agents overlapped significantly with that seen after hydrogen peroxide treatment, and it included all the proteins in the oxyR regulon. The redox-cycling agents also elicited the synthesis of at least 33 other proteins that were not seen with hydrogen peroxide, including three heat shock proteins, the Mn-containing superoxide dismutase, the DNA repair protein endonuclease IV, and glucose-6-phosphate dehydrogenase. At least some of these redox-inducible proteins appear to be part of a specific response to intracellular superoxide. E. coli is thus equipped with a network of inducible responses against oxidative damage, controlled in multiple regulatory pathways. Images PMID:2472381

  11. A global response induced in Escherichia coli by redox-cycling agents overlaps with that induced by peroxide stress.

    PubMed

    Greenberg, J T; Demple, B

    1989-07-01

    Escherichia coli treated with nontoxic levels of the superoxide-generating redox-cycling agents menadione and paraquat showed dramatic changes in protein composition as monitored by two-dimensional gel analysis. The distribution of proteins synthesized after treatment with these agents overlapped significantly with that seen after hydrogen peroxide treatment, and it included all the proteins in the oxyR regulon. The redox-cycling agents also elicited the synthesis of at least 33 other proteins that were not seen with hydrogen peroxide, including three heat shock proteins, the Mn-containing superoxide dismutase, the DNA repair protein endonuclease IV, and glucose-6-phosphate dehydrogenase. At least some of these redox-inducible proteins appear to be part of a specific response to intracellular superoxide. E. coli is thus equipped with a network of inducible responses against oxidative damage, controlled in multiple regulatory pathways.

  12. Phenolic compounds isolated from Dioscorea zingiberensis protect against pancreatic acinar cells necrosis induced by sodium taurocholate.

    PubMed

    Du, Dan; Jin, Tao; Zhang, Rui; Hu, Liqiang; Xing, Zhihua; Shi, Na; Shen, Yan; Gong, Meng

    2017-03-15

    One new bibenzyl (1) and one new phenanthrene (2), together with two known bibenzyls (3-4) and four known diarylheptanoids (5-8) were isolated from the rhizomes of Dioscorea zingiberensis. The structures of 1-2 were elucidated by spectroscopic methods including 1D and 2D NMR. Phenols 1-8 were evaluated for their anti-pancreatitic activities on sodium taurocholate (NaT)-induced pancreatic acinars necrosis. Notably, 0.5mM of compound 6 exhibited comparable inhibitory effect with 5mM of caffeine. Furthermore, compound 6 prevented the ATP depletion and excessive ROS production which could be also involved in mitochondria-mediated injuries in acute pancreatitis. As a result, compound 6 has been demonstrated to be a potential candidate for mediating mitochondrial dysfunction to prevent pancreatic necrosis. This study is also the first report on the isolation of bibenzyls and diarylheptanoids from this plant. Copyright © 2017 Elsevier Ltd. All rights reserved.

  13. Volatile compounds induced by herbivory act as aggregation kairomones for the Japanese beetle (Popillia japonica Newman).

    PubMed

    Loughrin, J H; Potter, D A; Hamilton-Kemp, T R

    1995-10-01

    The Japanese beetle is a polyphagous insect that typically aggregates on preferred host plants in the field. We studied the response of Japanese beetles to artificial damage, fresh feeding damage, and overnight feeding damage to test the hypothesis that beetles are attracted to feeding-induced volatiles. Crabapple leaves that had been damaged overnight by Japanese beetles or fall webworms attracted significantly more Japanese beetles than did undamaged leaves. Artificially damaged leaves or leaves freshly damaged by Japanese beetles, however, were not significantly more attractive than undamaged leaves. Leaves that had been damaged overnight by Japanese beetles or fall webworms produced a complex mixture of aliphatic compounds, phenylpropanoid-derived compounds, and terpenoids. In comparison, artificially damaged leaves or leaves with fresh Japanese beetle feeding damage generated a less complex blend of volatiles, mainly consisting of green-leaf odors. Feeding-induced odors may facilitate host location and/or mate finding by the Japanese beetle.

  14. Pressure-induced anomalous valence crossover in cubic YbCu5-based compounds.

    PubMed

    Yamaoka, Hitoshi; Tsujii, Naohito; Suzuki, Michi-To; Yamamoto, Yoshiya; Jarrige, Ignace; Sato, Hitoshi; Lin, Jung-Fu; Mito, Takeshi; Mizuki, Jun'ichiro; Sakurai, Hiroya; Sakai, Osamu; Hiraoka, Nozomu; Ishii, Hirofumi; Tsuei, Ku-Ding; Giovannini, Mauro; Bauer, Ernst

    2017-07-19

    A pressure-induced anomalous valence crossover without structural phase transition is observed in archetypal cubic YbCu5 based heavy Fermion systems. The Yb valence is found to decrease with increasing pressure, indicating a pressure-induced crossover from a localized 4f (13) state to the valence fluctuation regime, which is not expected for Yb systems with conventional c-f hybridization. This result further highlights the remarkable singularity of the valence behavior in compressed YbCu5-based compounds. The intermetallics Yb2Pd2Sn, which shows two quantum critical points (QCP) under pressure and has been proposed as a potential candidate for a reentrant Yb(2+) state at high pressure, was also studied for comparison. In this compound, the Yb valence monotonically increases with pressure, disproving a scenario of a reentrant non-magnetic Yb(2+) state at the second QCP.

  15. 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

  16. Resveratrol may reduce oxidative stress induced by platinum compounds in human plasma, blood platelets and lymphocytes.

    PubMed

    Olas, Beata; Wachowicz, Barbara; Majsterek, Ireneusz; Blasiak, Janusz

    2005-07-01

    Resveratrol (trans-3,4',5-trihydroxystilbene), a polyphenolic compound found in grapes and wine, has been shown to have anti-inflammatory, anti-oxidant, anti-tumor and anti-platelet activities. Using different methods, we show that resveratrol reduces oxidative stress induced by cisplatin (cis-diamminedichloroplatinum II) and selenium-cisplatin conjugate ([NH(3)](2)Pt(SeO(3)), Se-Pt) in human blood platelets, lymphocytes and plasma. Resveratrol decreased the production of 8-epi-prostaglandin F(2) (a biomarker of lipid peroxidation) in control blood platelets and platelets treated with platinum compounds (10 microg/ml), and markedly reduced activities of different anti-oxidative enzymes (glutathione peroxidase, superoxide dismutase and catalase) in these cells. A combined action of resveratrol and Se-Pt evoked a significant decrease of DNA damage (measured by comet assay) in lymphocytes compared with cells treated with Se-Pt only. Resveratrol also caused a distinct reduction of total anti-oxidant level in plasma after incubation with platinum compounds. Therefore, anti-oxidative activity of resveratrol may diminish oxidative stress and damage to cellular biomolecules (lipids, proteins and DNA) induced by platinum compounds.

  17. Isolation of furocoumarins from bergamot fruits as HL-60 differentiation-inducing compounds.

    PubMed

    Kawaii, S; Tomono, Y; Katase, E; Ogawa, K; Yano, M

    1999-10-01

    The HL-60 differentiation-inducing compounds in bergamot fruits were isolated with column chromatography and identified as bergamottin, bergapten, and citropten by (1)H and (13)C NMR. Their HL-60 differentiation-inducing activity was measured by examining nitro blue tetrazolium (NBT) reducing, nonspecific acid esterase (NSE), specific esterase (SE), and phagocytic activities, and bergamottin showed the strongest activity among the coumarins isolated from bergamot fruits. The structure-activity relationship obtained from HL-60 differentiation assay suggests that hydrophobicity of furocoumarins is correlated with their activity.

  18. 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

  19. SIRT1 activating compounds reduce oxidative stress mediated neuronal loss in viral induced CNS demyelinating disease.

    PubMed

    Khan, Reas S; Dine, Kimberly; Das Sarma, Jayasri; Shindler, Kenneth S

    2014-01-02

    Multiple sclerosis (MS) is characterized by central nervous system inflammation and demyelination, and increasing evidence demonstrates significant neuronal damage also occurs and is associated with permanent functional impairment. Current MS therapies have limited ability to prevent neuronal damage, suggesting additional neuroprotective therapies are needed. Compounds that activate the NAD+-dependent SIRT1 deacetylase prevent neuronal loss in an autoimmune-mediated MS model, but the mechanism of this effect is unknown, and it is unclear whether SIRT1 activating compounds exert similar effects in demyelinating disease induced by other etiologies. We measured neuronal loss in C57BL/6 mice inoculated with a neurotropic strain of mouse hepatitis virus, MHV-A59, that induces an MS-like disease. Oral treatment with the SIRT1 activating compound SRTAW04 significantly increased SIRT1 activity within optic nerves and prevented neuronal loss during optic neuritis, an inflammatory demyelinating optic nerve lesion that occurs in MS and its animal models. MHV-A59 induced neuronal loss was associated with reactive oxygen species (ROS) accumulation, and SRTAW04 treatment significantly reduced ROS levels while promoting increased expression of enzymes involved in mitochondrial function and reduction of ROS. SRTAW04 exerted similar protective effects in EAE spinal cords, with decreased demyelination. Results demonstrate that SIRT1 activating compounds prevent neuronal loss in viral-induced demyelinating disease similar to their effects in autoimmune-mediated disease. One mechanism of this neuroprotective effect involves increasing mitochondrial biogenesis with reduction of oxidative stress. SIRT1 activators represent a potential neuroprotective therapy for MS. Understanding common mechanisms of these effects in distinct disease models will help identify targets for more specific therapies.

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

    PubMed

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

    2009-08-15

    Lignans such as secoisolariciresinol diglucoside 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 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. 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. Contrasts to the classic lignans, Vitexins were not metabolized to END and ENL. A mixture of Vitexins EVn-50 and purified Vitexin compound 6-hydroxy-4-(4-hydroxy-3-methoxyphenyl)-3-hydroxymethyl-7-methoxy-3, 4-dihydro-2-naphthaldehyde have cytotoxic effect on breast, prostate, and ovarian cancer cells and induces apoptosis with cleavage in poly ADP ribose polymerase 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 showed 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. Vitexin is a class of nature lignan compounds, whose action and anticancer effect is mediated by the mechanisms different from the classic 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.

  1. Compound K induces apoptosis via CAMK-IV/AMPK pathways in HT-29 colon cancer cells.

    PubMed

    Kim, Do Yeon; Park, Min Woo; Yuan, Hai Dan; Lee, Hyo Jung; Kim, Sung Hoon; Chung, Sung Hyun

    2009-11-25

    Although compound K (CK), an intestinal metabolite of ginseng protopanaxadiol saponins, has been known to induce apoptosis in various cancer cells, association of AMP-activated protein kinase (AMPK) with apoptosis in HT-29 colon cancer cells remains unclear. We hypothesized that CK may exert an anticancer activity through modulating the AMPK pathway in HT-29 cells. CK-induced apoptosis was associated with the disruption of the mitochondrial membrane potential, release of apoptogenic factors (cytochrome c and apoptosis-inducing factor) from mitochondria, and cleavage of caspase-9, caspase-3, caspase-8, Bid, and PARP proteins. This apoptotic effect of CK on colon cancer cells was found to be initiated by AMPK activation, and AMPK was activated through phosphorylation by Ca2+/calmodulin-activated protein kinase-IV (CAMK-IV). Treatment of HT-29 cells with compound C (AMPK inhibitor) or siRNA for AMPK completely abolished the CK-induced apoptosis. STO-609, CAMKs inhibitor, also attenuated CK-induced AMPK activation and apoptosis. In conclusion, the present study demonstrates that CK-mediated cell death of HT-29 colon cancer cells is regulated by CAMK-IV/AMPK pathways, and these findings provide a molecular basis for the anticancer effect of CK.

  2. 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

  3. 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.

  4. Instant detection and identification of concealed explosive-related compounds: Induced Stokes Raman versus infrared.

    PubMed

    Elbasuney, Sherif; El-Sherif, Ashraf F

    2017-01-01

    The instant detection of explosives and explosive-related compounds has become an urgent priority in recent years for homeland security and counter-terrorism applications. Modern techniques should offer enhancement in selectivity, sensitivity, and standoff distances. Miniaturisation, portability, and field-ruggedisation are crucial requirements. This study reports on instant and standoff identification of concealed explosive-related compounds using customized Raman technique. Stokes Raman spectra of common explosive-related compounds were generated and spectrally resolved to create characteristic finger print spectra. The scattered Raman emissions over the band 400:2000cm(-1) were compared to infrared absorption using FTIR. It has been demonstrated that the two vibrational spectroscopic techniques were opposite and completing each other. Molecular vibrations with strong absorption in infrared (those involve strong change in dipole moments) induced weak signals in Raman and vice versa. The tailored Raman offered instant detection, high sensitivity, and standoff detection capabilities. Raman demonstrated characteristic fingerprint spectra with stable baseline and sharp intense peaks. Complete correlations of absorption/scattered signals to certain molecular vibrations were conducted to generate an entire spectroscopic profile of explosive-related compounds. This manuscript shades the light on Raman as one of the prevailing technologies for instantaneous detection of explosive-related compounds. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  5. Lipoic acid suppresses compound 48/80-induced anaphylaxis-like reaction

    PubMed Central

    Choi, Yun Ho; Chai, Ok Hee; Han, Eui-Hyeog; Choi, Su-Young; Kim, Hyoung Tae

    2010-01-01

    Alpha-lipoic acid (LA), a naturally occurring dithiol compound, is an essential cofactor in metabolic reactions involved in energy utilization. LA improves glycemic control, reduces diabetic polyneuropathies, atherosclerosis, and allergic inflammation. The effects of LA on mast cell-mediated anaphylactic reactions, however, are unknown. LA dose-dependently inhibited systemic and passive cutaneous anaphylaxis-like reactions in mice induced by compound 48/80, a condensation product of N-methyl-p-methoxyphenethylamine and formaldehyde. Pretreatment with LA, prior to induction of the systemic anaphylaxis-like reaction with compound 48/80, reduced plasma histamine levels in a dose-dependent manner. In our in vitro study, LA decreased histamine release from rat peritoneal mast cells (RPMCs) triggered by compound 48/80. Moreover, an increase in calcium uptake activated by compound 48/80 was inhibited by LA. LA also significantly elevated intracellular cyclic adenosine-3',5' monophosphate (cAMP) levels in RPMCs. This inhibition of mediator release from RPMCs may be due to inhibition of calcium uptake and augmentation of intracellular cAMP levels. Based on these results, we suggest that LA may be a potential remedy for allergy-related diseases. PMID:21267406

  6. Spontaneous nitric oxide in hepatocyte monolayers and inhibition of compound-induced apoptosis.

    PubMed

    Dilworth, C; Bigot-Lasserre, D; Bars, R

    2001-12-01

    Primary cultures of hepatocytes are a widely used in vitro model for biochemical research. Following isolation, hepatocytes produce large amounts of nitric oxide (NO), which is known to have both pro- and anti-apoptotic effects in hepatocytes in vivo and in vitro. Previous work has not determined the effect of these increased levels of NO on the response of hepatocytes to apoptotic stimuli. Here we report that levels of nitrites are elevated in hepatocyte monolayers from 24 h onwards. Addition of the inducible nitric oxide synthase (iNOS) inhibitor, Nomega-nitro-L-arginine methyl ester (L-NAME), to the medium inhibited this increase in nitrites. These results indicate that the increase in nitrite is most likely due to the formation of NO. Elevated nitrite levels had no effect either on basal levels of apoptosis or on ATP and GSH. Apoptosis was induced by transforming growth factor beta-1 (TGFbeta-1) or glycochenodeoxycholate (GCDC). Both compounds caused moderate hepatocyte apoptosis; however, addition of L-NAME prior to exposure significantly increased the level of apoptosis observed with the two compounds. Both TGFbeta-1 and GCDC had no effect on hepatocyte ATP or GSH levels; however, as a consequence of secondary necrosis, TGFbeta-1 exposure significantly increased levels of lactate dehydrogenase (LDH) leakage. These findings indicate that the increased levels of NO associated with the culture of hepatocytes have an inhibitory effect on compound-induced apoptosis in the cells.

  7. A power-cycling-induced failure mechanism in IGBT multichip modules

    SciTech Connect

    Malberti, P.; Ciappa, M.; Cattomio, R.

    1995-12-31

    Catastrophic burn-out occurring during power-cycling of Insulated Gate Bipolar Transistors (IGBT) multichip modules have been observed to arise as a secondary failure mechanism caused by the lifting of the emitter aluminum bonding wires. In effect, the successive lift-off of the aluminum wires results in a current crowding through few IGBT cells with consequent triggering of the internal parasitic thyristor-structure. Basing on failure analysis data, this paper presents a simple qualitative model for the time dependent lift-off of aluminum bondwires in IGBT modules occurring during either field operation, or accelerated tests. This power-cycling induced failure mechanism is described in terms of the reconstruction of the aluminum interconnection as consequence of plastic deformation. Some practical conclusions are finally drawn for power cycle testing and for optimal thermal design.

  8. Cell cycle phase perturbations and apoptosis in tumour cells induced by aplidine

    PubMed Central

    Erba, E; Bassano, L; Di Liberti, G; Muradore, I; Chiorino, G; Ubezio, P; Vignati, S; Codegoni, A; Desiderio, M A; Faircloth, G; Jimeno, J; D'Incalci, M

    2002-01-01

    Aplidine, dehydrodidemnin B, is a marine depsipeptide isolated from the Mediterranean tunicate Aplidium albicans currently in phase II clinical trial. In human Molt-4 leukaemia cells Aplidine was found to be cytotoxic at nanomolar concentrations and to induce both a G1 arrest and a G2 blockade. The drug-induced cell cycle perturbations and subsequent cell death do not appear to be related to macromolecular synthesis (protein, RNA, DNA) since the effects occur at concentrations (e.g. 10 nM) in which macromolecule synthesis was not markedly affected. Ten nM Aplidine for 1 h inhibited ornithine decarboxylase activity, with a subsequently strong decrease in putrescine levels. This finding has questionable relevance since addition of putrescine did not significantly reduce the cell cycle perturbations or the cytotoxicity of Aplidine. The cell cycle perturbations caused by Aplidine were also not due to an effect on the cyclin-dependent kinases. Although the mechanism of action of Aplidine is still unclear, the cell cycle phase perturbations and the rapid induction of apoptosis in Molt-4 cells appear to be due to a mechanism different from that of known anticancer drugs. British Journal of Cancer (2002) 86, 1510–1517. DOI: 10.1038/sj/bjc/6600265 www.bjcancer.com © 2002 Cancer Research UK PMID:11986788

  9. Cell cycle phase perturbations and apoptosis in tumour cells induced by aplidine.

    PubMed

    Erba, E; Bassano, L; Di Liberti, G; Muradore, I; Chiorino, G; Ubezio, P; Vignati, S; Codegoni, A; Desiderio, M A; Faircloth, G; Jimeno, J; D'Incalci, M

    2002-05-06

    Aplidine, dehydrodidemnin B, is a marine depsipeptide isolated from the Mediterranean tunicate Aplidium albicans currently in phase II clinical trial. In human Molt-4 leukaemia cells Aplidine was found to be cytotoxic at nanomolar concentrations and to induce both a G(1) arrest and a G(2) blockade. The drug-induced cell cycle perturbations and subsequent cell death do not appear to be related to macromolecular synthesis (protein, RNA, DNA) since the effects occur at concentrations (e.g. 10 nM) in which macromolecule synthesis was not markedly affected. Ten nM Aplidine for 1 h inhibited ornithine decarboxylase activity, with a subsequently strong decrease in putrescine levels. This finding has questionable relevance since addition of putrescine did not significantly reduce the cell cycle perturbations or the cytotoxicity of Aplidine. The cell cycle perturbations caused by Aplidine were also not due to an effect on the cyclin-dependent kinases. Although the mechanism of action of Aplidine is still unclear, the cell cycle phase perturbations and the rapid induction of apoptosis in Molt-4 cells appear to be due to a mechanism different from that of known anticancer drugs. Copyright 2002 Cancer Research UK

  10. Dihydromyricetin induces cell cycle arrest and apoptosis in melanoma SK-MEL-28 cells.

    PubMed

    Zeng, Guofang; Liu, Jie; Chen, Hege; Liu, Bin; Zhang, Qingyu; Li, Mingyi; Zhu, Runzhi

    2014-06-01

    Dihydromyricetin (DHM) exhibits multiple pharmacological activities; however, the role of DHM in anti-melanoma activities and the underlying molecular mechanisms are unclear. The aim of the present study was to evaluate the effects of DHM on cell proliferation, cell cycle distribution and apoptosis in the human melanoma SK-MEL-28 cell line, and to explore the related mechanisms. The effect of DHM on cell proliferation was investigated by MTT assay, and cell cycle distribution was determined by flow cytometry. TUNEL assay was used to evaluate DHM-mediated apoptosis, and western blotting was applied to examine expression levels of p53, p21, Cdc25A, Cdc2, P-Cdc2, Bax, IKK-α, NF-κB p65, p38 and P-p38 proteins. The results revealed that DHM suppressed cell proliferation of SK-MEL-28 cells in a concentration- and time-dependent manner, and caused cell cycle arrest at the G1/S phase. DHM increased the production of p53 and p21 proteins and downregulated the production of Cdc25A, Cdc2 and P-Cdc2 proteins, which induced cell cycle arrest. Additionally, DHM significantly induced the apoptosis of SK-MEL-28 cells, and enhanced the expression levels of Bax proteins and decreased the protein levels of IKK-α, NF-κB (p65) and P-p38. The results suggest that DHM may be a novel and effective candidate agent to inhibit the growth of melanoma.

  11. Low molecular weight apple polysaccharides induced cell cycle arrest in colorectal tumor.

    PubMed

    Li, Yuhua; Mei, Lin; Niu, Yinbo; Sun, Yang; Huang, Haitao; Li, Qian; Kong, Xianghe; Liu, Li; Li, Zhiquan; Mei, Qibing

    2012-04-01

    Dietary components play an important role in cancer prevention. Many ingredients from apples have been proven to have antitumor potency. We thus made low molecular weight apple polysaccharides (LMWAP) and evaluated the effects of it on colorectal cancer (CRC). The effects of LMWAP on human colon carcinoma cells (HT-29) were evaluated using a microarray. Then, cell-cycle distribution was measured by flow cytometric analysis. A colitis-associated colorectal cancer mouse model was used to assess the effect of LMWAP on in vivo CRC prevention. Treatment of HT-29 cells with LMWAP resulted in 333 genes expression over cutoff values (≥2-fold). Further analysis demonstrated that pathways of cell cycle were mainly influenced. At the concentrations from 0.001 to 0.1 mg/mL, LMWAP induced a G(0)/G(1) phase block in HT-29 cells in a dose-dependent way. In vivo studies revealed that administration of LMWAP could protect ICR mice against CRC effectively. The results of Western blot suggested LMWAP induced cell-cycle arrest in a p53 independent manner. These data indicate that LMWAP could inhibit the development of CRC through affecting cell cycle, and it has potential for clinical prevention for colon cancer.

  12. 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

  13. 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.

  14. 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

    2009-06-08

    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.

  15. Model for Estimating Life-Cycle Costs Associated with Noise-Induced Hearing Loss

    DTIC Science & Technology

    2007-01-10

    decisions. Currently, the cash outlays by the government for noise-induced hearing loss ( NIHL ) caused to service personnel by loud systems and spaces are...un-accounted for in estimates of life-cycle costs. A companion report demonstrated that a NIHL prediction algorithm from the American National...compensation costs of the predicted NIHL in this population. A numerical example of the algorithm operation was included. Using cost values applicable to

  16. A novel DNA intercalator, butylamino-pyrimido[4',5':4,5]selenolo(2,3-b)quinoline, induces cell cycle arrest and apoptosis in leukemic cells.

    PubMed

    Shahabuddin, M S; Nambiar, Mridula; Choudhary, Bibha; Advirao, Gopal M; Raghavan, Sathees C

    2010-02-01

    DNA intercalators are one of the most commonly used chemotherapeutic agents. Novel intercalating compounds of pyrimido[4',5':4,5]selenolo(2,3-b)quinoline series having a butylamino or piperazino group at fourth position (BPSQ and PPSQ, respectively) are studied. Our results showed that BPSQ induced cytotoxicity whereas PPSQ was cytostatic. The cytotoxicity induced by BPSQ was concentration- and time-dependent. Cell cycle analysis and tritiated thymidine assay revealed that BPSQ affects the cell cycle progression by arresting at S phase. The absence of p-histone H3 and reduction in the levels of PCNA in the cells treated with BPSQ further confirmed the cell cycle arrest. Further, annexin V staining, DNA fragmentation, nuclear condensation and changes in the expression levels of BCL2/BAD confirmed the activation of apoptosis. Activation of caspase 8 and lack of cleavage of caspase 9, caspase 3 and PARP suggest the possibility of BPSQ triggering extrinsic pathway for induction of apoptosis, which is discussed. Hence, we have identified a novel compound which would have clinical relevance in cancer chemotherapeutics.

  17. Thioredoxin 1 modulates apoptosis induced by bioactive compounds in prostate cancer cells.

    PubMed

    Rodriguez-Garcia, Aida; Hevia, David; Mayo, Juan C; Gonzalez-Menendez, Pedro; Coppo, Lucia; Lu, Jun; Holmgren, Arne; Sainz, Rosa M

    2017-08-01

    Accumulating evidence suggests that natural bioactive compounds, alone or in combination with traditional chemotherapeutic agents, could be used as potential therapies to fight cancer. In this study, we employed four natural bioactive compounds (curcumin, resveratrol, melatonin, and silibinin) and studied their role in redox control and ability to promote apoptosis in androgen sensitive and insensitive prostate cancer cells. Here is shown that curcumin and resveratrol promote ROS production and induce apoptosis in LNCaP and PC-3. An increase in reactive species is a trigger event in curcumin-induced apoptosis and a consequence of resveratrol effects on other pathways within these cells. Moreover, here we demonstrated that these four compounds affect differently one of the main intracellular redox regulator, the thioredoxin system. Exposure to curcumin and resveratrol promoted TRX1 oxidation and altered its subcellular location. Furthermore, resveratrol diminished TRX1 levels in PC-3 cells and increased the expression of its inhibitor TXNIP. Conversly, melatonin and silibinin only worked as cytostatic agents, reducing ROS levels and showing preventive effects against TRX oxidation. All together, this work explores the effect of compounds currently tested as chemo-preventive agents in prostate cancer therapy, on the TRX1 redox state and function. Our work shows the importance that the TRX system might have within the differences found in their mechanisms of action. These bioactive compounds trigger different responses and affect ROS production and redox systems in prostate cancer cells, suggesting the key role that redox-related pathways might play in processes like differentiation or survival in prostate cancer. Copyright © 2017. Published by Elsevier B.V.

  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.

  19. Modulation of 17{beta}-estradiol-induced responses in fish by cytochrome P4501A1 inducing compounds

    SciTech Connect

    Anderson, M.J.; Hinton, D.E.

    1995-12-31

    Some compounds which induce cytochrome P4501A1 (CYP1A1) are antiestrogenic in mammalian bioassay, and this effect is linked to aryl hydrocarbon (Ah) receptor. Liver of fish synthesizes estrogen-inducible egg yolk precursor protein vitellogenin (Vg) which is critical for oocyte maturation and ovarian development. To determine if Ah receptor-linked endocrine modulation could occur in fish liver, primary cultures of juvenile rainbow trout (Oncorhynchus mykiss) liver cells were co-administered 17{beta}-estradiol and CYP1A1 inducing compounds. Vitellogenin and albumin, estimated by ELISA measurement of concentration in the media 48 hrs after treatment, formed the basis for the test. Cellular CYP1A1 protein content and catalytic activity was estimated by ELISA and ethoxyresorufin-O-deethylase (EROD) activity assays respectively. Equivalent viability (mitochondrial dehydrogenase activity) and secretary functional capacity (albumin synthesis) were estimated and correlated with other results. In descending order, 2,3,4,7,8 pentachlorodibenzofuran (10{sup {minus}12} to 10{sup {minus}8} M) > 2,3,7,8 tetrachlorodibenzo-p-dioxin {approx_equal} 2,3,7,8 tetrachlorodibenzofuran (10{sup {minus}11} to 10{sup {minus}8} M) > {beta}-naphthoflavone (10{sup {minus}7} to 10{sup {minus}6} M) inhibited Vg synthesis in 17{beta}-estradiol treated liver cells. Potency of inhibition directly related to strength as an inducer of CYP1A1 protein. At 10-8 M, PCB congeners 77, 126, and 156 did not inhibit Vg synthesis and induced no or only moderate CYP1A1 protein. At 10-8 M, PCB congener 114, a weak CYP1A1 inducer, potentiated Vg synthesis relative to cells treated with 17{beta}-estradiol alone. This study increases their understanding of the consequences of hepatic CYP1A1 induction, forewarns of reproductive impairment of sexually maturing fishes exposed to CYP1A1 inducing compounds and argues for further, more detailed in vivo investigation.

  20. 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.

  1. Marine Benthic Diatoms Contain Compounds Able to Induce Leukemia Cell Death and Modulate Blood Platelet Activity

    PubMed Central

    Prestegard, Siv Kristin; Oftedal, Linn; Coyne, Rosie Theresa; Nygaard, Gyrid; Skjærven, Kaja Helvik; Knutsen, Gjert; Døskeland, Stein Ove; Herfindal, Lars

    2009-01-01

    In spite of the high abundance and species diversity of diatoms, only a few bioactive compounds from them have been described. The present study reveals a high number of mammalian cell death inducing substances in biofilm-associated diatoms sampled from the intertidal zone. Extracts from the genera Melosira, Amphora, Phaeodactylum and Nitzschia were all found to induce leukemia cell death, with either classical apoptotic or autophagic features. Several extracts also contained inhibitors of thrombin-induced blood platelet activation. Some of this activity was caused by a high content of adenosine in the diatoms, ranging from 0.07 to 0.31 μg/mg dry weight. However, most of the bioactivity was adenosine deaminase-resistant. An adenosine deaminase-resistant active fraction from one of the extracts was partially purified and shown to induce apoptosis with a distinct phenotype. The results show that benthic diatoms typically found in the intertidal zone may represent a richer source of interesting bioactive compounds than hitherto recognized. PMID:20098602

  2. Pfaffosidic Fraction from Hebanthe paniculata Induces Cell Cycle Arrest and Caspase-3-Induced Apoptosis in HepG2 Cells

    PubMed Central

    da Silva, Tereza Cristina; Cogliati, Bruno; Latorre, Andréia Oliveira; Akisue, Gokithi; Nagamine, Márcia Kazumi; Haraguchi, Mitsue; Hansen, Daiane; Sanches, Daniel Soares; Dagli, Maria Lúcia Zaidan

    2015-01-01

    Hebanthe paniculata roots (formerly Pfaffia paniculata and popularly known as Brazilian ginseng) show antineoplastic, chemopreventive, and antiproliferative properties. Functional properties of these roots and their extracts are usually attributed to the pfaffosidic fraction, which is composed mainly by pfaffosides A–F. However, the therapeutic potential of this fraction in cancer cells is not yet entirely understood. This study aimed to analyze the antitumoral effects of the purified pfaffosidic fraction or saponinic fraction on the human hepatocellular carcinoma HepG2 cell line. Cellular viability, proliferation, and apoptosis were evaluated, respectively, by MTT assay, BrdU incorporation, activated caspase-3 immunocytochemistry, and DNA fragmentation assay. Cell cycle was analyzed by flow cytometry and the cell cycle-related proteins were analyzed by quantitative PCR and Western blot. The cells exposed to pfaffosidic fraction had reduced viability and cellular growth, induced G2/M at 48 h or S at 72 h arrest, and increased sub-G1 cell population via cyclin E downregulation, p27KIP1 overexpression, and caspase-3-induced apoptosis, without affecting the DNA integrity. Antitumoral effects of pfaffosidic fraction from H. paniculata in HepG2 cells originated by multimechanisms of action might be associated with cell cycle arrest in the S phase, by CDK2 and cyclin E downregulation and p27KIP1 overexpression, besides induction of apoptosis through caspase-3 activation. PMID:26075002

  3. 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.

  4. Compound mechanism hypothesis on +Gz induced brain injury and dysfunction of learning and memory

    NASA Astrophysics Data System (ADS)

    Sun, Xi-Qing; Li, Jin-Sheng; Cao, Xin-Sheng; Wu, Xing-Yu

    2005-08-01

    We systematically studied the effect of high- sustained +Gz on the brain and its mechanism in past ten years by animal centrifuge experiments. On the basis of the facts we observed and the more recent advances in acceleration physiology, we put forward a compound mechanism hypothesis to offer a possible explanation for +Gz-induced brain injury and dysfunction of learning and memory. It states that, ischemia during high G exposure might be the main factor accounting for +Gz-induced brain injury and dysfunction of learning and memory, including transient depression of brain energy metabolism, disturbance of ion homeostasis, increased blood-brain barrier permeability, increased brain nitric oxide synthase expression, and the protective effect of heat shock protein 70. In addition, the large rapid change of intracranial pressure and increased stress during +Gz exposure, and the hemorrheologic change after +Gz exposure might be one of the important factors accounting for +Gz-induced brain injury and dysfunction of learning and memory.

  5. A novel curcumin derivative which inhibits P-glycoprotein, arrests cell cycle and induces apoptosis in multidrug resistance cells.

    PubMed

    Lopes-Rodrigues, Vanessa; Oliveira, Ana; Correia-da-Silva, Marta; Pinto, Madalena; Lima, Raquel T; Sousa, Emília; Vasconcelos, M Helena

    2017-01-15

    Cancer multidrug resistance (MDR) is a major limitation to the success of cancer treatment and is highly associated with the overexpression of drug efflux pumps such as P-glycoprotein (P-gp). In order to achieve more effective chemotherapeutic treatments, it is important to develop P-gp inhibitors to block/decrease its activity. Curcumin (1) is a secondary metabolite isolated from the turmeric of Curcuma longa L.. Diverse biological activities have been identified for this compound, particularly, MDR modulation in various cancer cell models. However, curcumin (1) has low chemical stability, which severely limits its application. In order to improve stability and P-gp inhibitory effect, two potential more stable curcumin derivatives were synthesized as building blocks, followed by several curcumin derivatives. These compounds were then analyzed in terms of antitumor and anti-P-gp activity, in two MDR and sensitive tumor lines (from chronic myeloid leukemia and non-small cell lung cancer). We identified from a series of curcumin derivatives a novel curcumin derivative (1,7-bis(3-methoxy-4-(prop-2-yn-1-yloxy)phenyl)hepta-1,6-diene-3,5-dione, 10) with more potent antitumor and anti-P-gp activity than curcumin (1). This compound (10) was shown to promote cell cycle arrest (at the G2/M phase) and induce apoptosis in the MDR chronic myeloid leukemia cell line. Therefore it is a really interesting P-gp inhibitor due to its ability to inhibit both P-gp function and expression.

  6. 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.

  7. Chemiluminescence response induced by mesenteric ischaemia/reperfusion: effect of antioxidative compounds ex vivo

    PubMed Central

    Nosál'ová, Viera; Sotníková, Ružena; Drábiková, Katarína; Fialová, Silvia; Košťálová, Daniela; Banášová, Silvia; Navarová, Jana

    2010-01-01

    Ischaemia and reperfusion (I/R) play an important role in human pathophysiology as they occur in many clinical conditions and are associated with high morbidity and mortality. Interruption of blood supply rapidly damages metabolically active tissues. Restoration of blood flow after a period of ischaemia may further worsen cell injury due to an increased formation of free radicals. The aim of our work was to assess macroscopically the extent of intestinal pathological changes caused by mesenteric I/R, and to study free radical production by luminol enhanced chemiluminescence (CL) of ileal samples. In further experiments, the antioxidative activity of the drugs tested was evaluated spectrophotometrically by the use of the DPPH radical. We studied the potential protective ex vivo effect of the plant origin compound arbutin as well as of the pyridoindole stobadine and its derivative SMe1EC2. I/R induced pronounced haemorrhagic intestinal injury accompanied by increase of myeloperoxidase (MPO) and N-acetyl-β-D-glucosaminidase (NAGA) activity. Compared to sham operated (control) rats, there was only a slight increase of CL response after I/R, probably in association with neutrophil increase, indicated by enhanced MPO activity. All compounds significantly reduced the peak values of CL responses of the ileal samples ex vivo, thus reducing the I/R induced increase of free radical production. The antioxidants studied showed a similar inhibitory effect on the CL response influenced by mesenteric I/R. If proved in vivo, these compounds would represent potentially useful therapeutic antioxidants. PMID:21217883

  8. 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

  9. Small compound inhibitors of basal glucose transport inhibit cell proliferation and induce apoptosis in cancer cells via glucose-deprivation-like mechanisms.

    PubMed

    Liu, Yi; Zhang, Weihe; Cao, Yanyan; Liu, Yan; Bergmeier, Stephen; Chen, Xiaozhuo

    2010-12-08

    Cancer cells depend heavily on glucose as both energy and biosynthesis sources and are found to upregulate glucose transport and switch their main energy supply pathway from oxidative phosphorylation to glycolysis. These molecular and metabolic changes also provide targets for cancer treatment. Here we report that novel small molecules inhibited basal glucose transport and cell proliferation, and induced apoptosis in lung and breast cancer cells without affecting much their normal cell counterparts. Cancer cells survived the compound treatment lost their capability to proliferate. Mechanistic study indicates that the cancer cell inhibition by the test compounds has a component of apoptosis and the induced apoptosis was p53-independent and caspase 3-dependent, similar to those resulted from glucose deprivation. Compound treatment also led to cell cycle arrest in G1/S phase. The inhibition of cancer cell growth was partially relieved when additional glucose was supplied to cells, suggesting that the inhibition was due to, at least in part, the inhibition of basal glucose transport. When used in combination, the test compounds demonstrated synergistic effects with anticancer drugs cisplatin or paclitaxel in inhibition of cancer cell growth. All these results suggest that these glucose transport inhibitors mimic glucose deprivation and work through inhibiting basal glucose transport. These inhibitors have the potential to complement and replace traditional glucose deprivation, which cannot be used in animals, as new tools to study the effects of glucose transport and metabolism on cancer and normal cells.

  10. Altered cytotoxicity of ROS-inducing compounds by sodium pyruvate in cell culture medium depends on the location of ROS generation.

    PubMed

    Kelts, Jessica L; Cali, James J; Duellman, Sarah J; Shultz, John

    2015-01-01

    Induction of oxidative stress by drugs and other xenobiotics is an important mechanism of cytotoxicity. However, in vitro studies on the relationship between oxidative stress and cytotoxicity in cultured cells is frequently complicated by the fact that cell culture medium components affect reactive oxygen species (ROS) exposures in ways that vary with the mode of ROS production. The objectives of this study were to first determine the mode of ROS induction by certain model compounds when they are applied to cultured cells, and then to determine how ROS induction and cytotoxicity were affected by the ROS-quenching medium component pyruvate. Three compounds, eseroline, benserazide, and pyrogallol induced H2O2 in cell culture media independent of cells. However, another compound, menadione, induced H2O2 in a manner largely dependent on the MDA-MB-231 breast cancer cells used in this study, which is consistent with its known mechanism of inducing ROS through intracellular redox cycling. 1 mM pyruvate, as well as catalase, reduced the H2O2 in culture wells with each ROS inducer tested but it only reduced the cytotoxicity of cell-independent inducers. It reduced the cytotoxicity of benserazide and pyrogallol >10-fold and of eseroline about 2.5-fold, but had no effect on menadione cytotoxicity. From this data, it was concluded that depending on the mechanism of ROS induction, whether intra- or extracellular, a ROS-quenching medium component such as pyruvate will differentially affect the net ROS-induction and cytotoxicity of a test compound.

  11. Topography induced spatial variations in diurnal cycles of assimilation and latent heat of Mediterranean forest

    NASA Astrophysics Data System (ADS)

    van der Tol, C.; Dolman, A. J.; Waterloo, M. J.; Raspor, K.

    2007-02-01

    The aim of this study is to explain topography induced spatial variations in the diurnal cycles of assimilation and latent heat of Mediterranean forest. Spatial variations of the fluxes are caused by variations in weather conditions and in vegetation characteristics. Weather conditions reflect short-term effects of climate, whereas vegetation characteristics, through adaptation and acclimation, long-term effects of climate. In this study measurements of plant physiology and weather conditions are used to explain observed differences in the fluxes. A model is used to study which part of the differences in the fluxes is caused by weather conditions and which part by vegetation characteristics. Data were collected at four experimental sub-Mediterranean deciduous forest plots in a heterogeneous terrain with contrasting aspect, soil water availability, humidity and temperature. We used a sun-shade model to scale fluxes from leaf to canopy, and calculated the canopy energy balance. Parameter values were derived from measurements of light interception, leaf chamber photosynthesis, leaf nitrogen content and 13C isotope discrimination in leaf material. Leaf nitrogen content is a measure of photosynthetic capacity, and 13C isotope discrimination of water use efficiency. For validation, sap-flux based measurements of transpiration were used. The model predicted diurnal cycles of transpiration and stomatal conductance, both their magnitudes and differences in afternoon stomatal closure between slopes of different aspect within the confidence interval of the validation data. Weather conditions mainly responsible for the shape of the diurnal cycles, and vegetation parameters for the magnitude of the fluxes. Although the data do not allow for a quantification of the two effects, the differences in vegetation parameters and weather among the plots and the sensitivity of the fluxes to them suggest that the diurnal cycles were more strongly affected by spatial variations in

  12. 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.

  13. Middle Infrared Radiation Induces G2/M Cell Cycle Arrest in A549 Lung Cancer Cells

    PubMed Central

    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 G2/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 G2/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. PMID:23335992

  14. 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. Copyright © 2011 Elsevier Masson SAS. All rights reserved.

  15. 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

  16. 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.

  17. The natural compounds piperovatine and piperlonguminine induce autophagic cell death on Trypanosoma cruzi.

    PubMed

    Veiga-Santos, Phercyles; Desoti, Vânia Cristina; Miranda, Nathielle; Ueda-Nakamura, Tânia; Dias-Filho, Benedito Prado; Silva, Sueli Oliveira; Cortez, Diogenes Aparício Garcia; de Mello, João Carlos Palazzo; Nakamura, Celso Vataru

    2013-03-01

    The currently available treatments for Chagas disease show limited therapeutic potential and are associated with serious side effects. Our group has been attempting to find alternative drugs isolated from natural products as a potential source of pharmacological agents against Trypanosoma cruzi. Here, we demonstrate the antitrypanosomal activity of the amides piperovatine and piperlonguminine isolated from Piper ovatum against epimastigotes and intracellular amastigotes. We also investigated the mechanisms of action of these compounds on extracellular amastigote and epimastigote forms of T. cruzi. These amides showed low toxicity to LLCMK(2) mammalian cells. By using transmission and scanning electron microscopy, we observed that the compounds caused severe alterations in T. cruzi. These alterations were mainly located in plasma membrane and mitochondria. Furthermore, the study of treated parasites labeled with Rh123, PI and MDC corroborate with our TEM data. These mitochondrial dysfunctions induced by the amides might trigger biochemical alterations that lead to cell death. Altogether, our data evidence a possible autophagic process.

  18. Compound K, a metabolite of ginseng saponin, inhibits colorectal cancer cell growth and induces apoptosis through inhibition of histone deacetylase activity.

    PubMed

    Kang, Kyoung Ah; Piao, Mei Jing; Kim, Ki Cheon; Zheng, Jian; Yao, Cheng Wen; Cha, Ji Won; Kim, Hye Sun; Kim, Dong Hyun; Bae, Suk Chul; Hyun, Jin Won

    2013-12-01

    In this study, we investigated the molecular mechanisms underlying the anti-proliferative effects of Compound K, with specific reference to histone modification. Exposure of HT-29 human colon cancer cells to Compound K resulted in time-dependent inhibition of histone deacetylase (HDAC) activity, mRNA and protein expression. Compound K treatment induced unmethylation of the RUNX3 promoter region such as TSA treatment and an accumulation of acetylated histones H3 and H4 within the total cellular chromatin, resulting in an enhanced ability of these histones to bind to the promoter sequences of the tumor suppressor gene Runt-related transcription factor 3 (RUNX3). Treatment of cells with Compound K increased the mRNA and protein expression of RUNX3, as well as p21, a downstream target of RUNX3. These alterations were consistent with cell cycle arrest at the G0/G1 phases and induction of apoptosis. Our results provide new insights into the mechanisms of Compound K action in human colorectal cancer cells and suggest that HDAC inhibition presents a novel approach to prevent or treat colorectal cancer.

  19. 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

  20. Protective effect of an aminothiazole compound against γ-radiation induced oxidative damage.

    PubMed

    De, Strayo; Devasagayam, Thomas P A

    2011-11-01

    Ionizing radiation causes its biological effects mainly through oxidative damage induced by reactive oxygen species. During radiotherapy of cancer, one of the undesirable side-effects is toxicity to normal cells. Compounds with antioxidant activities are being tried as 'prophylactic radioprotectants' to overcome this problem. We evaluated the protective effect of an aminothiazole compound, in the form of dendrodoine analogue (DA) originally derived from a marine tunicate, against γ-radiation-induced damage to lipid, protein, and DNA besides its cytotoxicity. Oxidative damage was examined by different biochemcial assays. Our studies reveal that DA gave significant protection, in fairly low concentrations, against damage induced by γ-radiation to rat liver mitochondria, plasmid pBR322 DNA, and mouse splenic lymphocytes in vitro. It also protected against oxidative damage in whole-body irradiated mice exposed to therapeutic dose of radiation (2 Gy) in vivo. Spleen, a major target organ for radiation damage, of the irradiated mice showed significant protection when treated with DA, as examined by histopathology. In conclusion, due to the possible protective effects against normal cells/tissues both in vitro and in vivo, DA shows potential to be a radioprotector for possible use during radiotherapy.

  1. Allergy-Inducing Chromium Compounds Trigger Potent Innate Immune Stimulation Via ROS-Dependent Inflammasome Activation.

    PubMed

    Adam, Christian; Wohlfarth, Jonas; Haußmann, Maike; Sennefelder, Helga; Rodin, Annette; Maler, Mareike; Martin, Stefan F; Goebeler, Matthias; Schmidt, Marc

    2017-02-01

    Chromium allergy is a common occupational skin disease mediated by chromium (VI)-specific T cells that induce delayed-type hypersensitivity in sensitized individuals. Additionally, chromium (VI) can act as an irritant. Both responses critically require innate immune activation, but if and how chromium (VI) elicits this signal is currently unclear. Using human monocytes, primary human keratinocytes, and murine dendritic cells we show that chromium (VI) compounds fail to trigger direct proinflammatory activation but potently induce processing and secretion of IL-1β. IL-1β release required priming by phorbol-ester or toll-like receptor stimulation and was prevented by inhibition of K(+) efflux, NLRP3 depletion or caspase-1 inhibition, identifying chromium (VI) as a hapten activator of the NLRP3 inflammasome. Inflammasome activation was initiated by mitochondrial reactive oxygen species production triggered by chromium (VI), as indicated by sensitivity to treatment with the ROS scavenger N-acetyl cysteine and a coinciding failure of K(+) efflux, caspase-1, or NLRP3 inhibition to prevent mitochondrial reactive oxygen species accumulation. IL-1β release further correlated with cytotoxicity that was secondary to reactive oxygen species, K(+) efflux, and NLRP3 activation. Trivalent chromium was unable to induce mitochondrial reactive oxygen species production, inflammasome activation, and cytotoxicity, suggesting that oxidation state-specific differences in mitochondrial reactivity may determine inflammasome activation and allergic/irritant capacity of different chromium compounds.

  2. Novel hydrogen sulfide-releasing compound, S-propargyl-cysteine, prevents STZ-induced diabetic nephropathy

    SciTech Connect

    Qian, Xin; Li, Xinghui; Ma, Fenfen; Luo, Shanshan; Ge, Ruowen; Zhu, Yizhun

    2016-05-13

    In this work, we demonstrated for the first time that S-propargyl-cysteine (SPRC, also named as ZYZ-802), a novel hydrogen sulfide (H{sub 2}S)-releasing compound, had renoprotective effects on streptozotocin (STZ)-induced diabetic kidney injury. SPRC treatment significantly reduced the level of creatinine, kidney to body weight ratio and in particular, markedly decreased 24-h urine microalbuminuria excretion. SPRC suppressed the mRNA expression of fibronectin and type IV collagen. In vitro, SPRC inhibited mesangial cells over-proliferation and hypertrophy induced by high glucose. Additionally, SPRC attenuated inflammation in diabetic kidneys. SPRC also reduced transforming growth factor β1 (TGF-β1) signaling and expression of phosphorylated Smad3 (p-Smad3) pathway. Moreover, SPRC inhibited phosphorylation of ERK, p38 protein. Taken together, SPRC was demonstrated to be a potential therapeutic candidate to suppress diabetic nephropathy. - Highlights: • We synthesized a novel hydrogen sulfide-releasing compound, S-propargyl-cysteine (SPRC). • SPRC was preliminarily demonstrated to prevent STZ-induced diabetic nephropathy (DN). • SPRC may exert potential therapeutic candidate to suppress DN.

  3. 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

  4. Novel Pactamycin Analogs Induce p53 Dependent Cell-Cycle Arrest at S-Phase in Human Head and Neck Squamous Cell Carcinoma (HNSCC) Cells

    PubMed Central

    Guha, Gunjan; Liang, Xiaobo; Kulesz-Martin, Molly F.; Mahmud, Taifo; Indra, Arup Kumar; Ganguli-Indra, Gitali

    2015-01-01

    Pactamycin, although putatively touted as a potent antitumor agent, has never been used as an anticancer drug due to its high cytotoxicity. In this study, we characterized the effects of two novel biosynthetically engineered analogs of pactamycin, de-6MSA-7-demethyl-7-deoxypactamycin (TM-025) and 7-demethyl-7-deoxypactamycin (TM-026), in head and neck squamous cell carcinoma (HNSCC) cell lines SCC25 and SCC104. Both TM-025 and TM-026 exert growth inhibitory effects on HNSCC cells by inhibiting cell proliferation. Interestingly, unlike their parent compound pactamycin, the analogs do not inhibit synthesis of nascent protein in a cell-based assay. Furthermore, they do not induce apoptosis or autophagy in a dose- or a time-dependent manner, but induce mild senescence in the tested cell lines. Cell cycle analysis demonstrated that both analogs significantly induce cell cycle arrest of the HNSCC cells at S-phase resulting in reduced accumulation of G2/M-phase cells. The pactamycin analogs induce expression of cell cycle regulatory proteins including master regulator p53, its downstream target p21Cip1/WAF1, p27kip21, p19, cyclin E, total and phospho Cdc2 (Tyr15) and Cdc25C. Besides, the analogs mildly reduce cyclin D1 expression without affecting expression of cyclin B, Cdk2 and Cdk4. Specific inhibition of p53 by pifithrin-α reduces the percentage of cells accumulated in S-phase, suggesting contribution of p53 to S-phase increase. Altogether, our results demonstrate that Pactamycin analogs TM-025 and TM-026 induce senescence and inhibit proliferation of HNSCC cells via accumulation in S-phase through possible contribution of p53. The two PCT analogs can be widely used as research tools for cell cycle inhibition studies in proliferating cancer cells with specific mechanisms of action. PMID:25938491

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

    NASA Astrophysics Data System (ADS)

    Tompkins, Stephen S.

    1994-07-01

    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.

  6. 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

  7. Honokiol induces cell cycle arrest and apoptosis in human gastric carcinoma MGC-803 cell line.

    PubMed

    Yan, Bin; Peng, Zhi-Yong

    2015-01-01

    Gastric carcinoma is a malignant tumor that responds poorly to both chemotherapy and radiation therapy. In our study, we investigated the anti-cancer effect of honokiol, an active component isolated and purified from the Magnolia officinalis, in human gastric carcinoma MGC-803 cell line. The cell viability was detected by the CCK8 assay. The cell apoptosis and cell cycle arrest were assessed by flow cytometer. The protein expression of cell cycle regulators and tumor suppressors were analyzed by western blotting. Treatment of human gastric carcinoma cells with honokiol induced cell death in a dose-and time-dependent manner by using CCK8 assay. Consistent with the CCK8 assay, the flow cytometry results showed that the proportion of apoptosis cells had gained when the cells were exposed to honokiol. Moreover, Cyclin B1, CDC2 and cdc25C were downregulated, and the expression of p-CDC2 and p-cdc25c was significantly upregulated upon honokiol treatment. P53 and p21 were significantly upregulated by honokiol treatment. Treatment of MGC-803 cells with honokiol significantly increased the pro-apoptotic Bax level and decreased the anti-apoptotic Bcl-2 level. These results confirmed that honokiol could induce apoptosis and cell cycle arrest, the underlying molecular mechanisms, at least partially, through activation p53 signaling and downregulation CDC2/cdc25C expression.

  8. 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.

  9. [Cell cycle arrest at M phase induced by vinblastine in MOLT-4 cells].

    PubMed

    Zhong, Yi-Sheng; Pan, Chang-Chuan; Jin, Chang-Nan; Li, Jian-Jun; Xiong, Gong-Peng; Zhang, Jian-Xi; Gong, Jian-Ping

    2009-04-01

    This study was purposed to investigate the biological effect of vinblastine (VLS), usually known as inductor of mitotic arrest, on MOLT-4 of ALL cells and to evaluate its significance. The cell arrest in M phase and/or cell apoptosis were induced by treatment of MOLT-4 cells with 0.05 microg/ml VLS for 0 - 12 hours; the DNA histogram was detected by flow cytometry; the morphological changes of cells were observed by confocal microscopy; the cell cycle distribution, cell apoptosis and morphological changes of cells before and after arrest were analyzed by using arrest increasing rate (AIR), arrest efficiency (AE), apoptosis rate (AR) and morphologic parameters respectively. The results indicated that the cell arrest did not accompanied by significant increase of apoptosis rate; the DNA histogram of cell arrest showed dynamic change of cell cycle in time-dependent manner; the arrest efficiency could be quantified. The cell arrest at M phase was accompanied by cell stack in S phase, the cell proliferation rate dropped after cell arrest occurred. The cells arrested at M phase possessed of characteristic morphologic features in cell mitosis. It is concluded that the vinblastine can solely induce arrest of MOLT-4 cells at M phase. This study provides experimental basis for further investigating the relation of cell cycle arrest to apoptosis, mechanism of checkpoint and development of new anticancer drugs.

  10. 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.

  11. Tangeretin induces cell cycle arrest and apoptosis through upregulation of PTEN expression in glioma cells.

    PubMed

    Ma, Li-Li; Wang, Da-Wei; Yu, Xu-Dong; Zhou, Yan-Ling

    2016-07-01

    Tangeretin (TANG), present in peel of citrus fruits, has been shown to various medicinal properties such as chemopreventive and neuroprotective. However, the chemopreventive effect of TANG on glioblastoma cells has not been examined. The present study was designed to explore the anticancer potential of TANG in glioblastoma cells and to investigate the related mechanism. Human glioblastoma U-87MG and LN-18 cells were treated with 45μM concentration of TANG and cell growth was measured by MTT assay. The cell cycle distribution and cell death were measured by flow cytometry. The expression of cell cycle and apoptosis related genes were analyzed by quantitative RT-PCR and western blot. The cells treated with TANG were significantly increased cell growth suppression and cell death effects than vehicle treated cells. Further, TANG treatment increases G2/M arrest and apoptosis by modulating PTEN and cell-cycle regulated genes such as cyclin-D and cdc-2 mRNA and protein expressions. Moreover, the ability of TANG to decrease cell growth and to induce cell death was compromised when PTEN was knockdown by siRNA. Taken together, the chemopreventive effect of TANG is associated with regulation of cell-cycle and apoptosis in glioblastoma, thereby attenuating glioblastoma cell growth. Hence, the present findings suggest that TANG may be a therapeutic agent for glioblastoma treatment. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  12. [Cycle arrest of prostate carcinoma DU-145 cells induced by pseudolaric acid B].

    PubMed

    Mai, Xia; Xu, Zhong-Wei; Chen, Xiao-Yi; Cao, Bo; Xu, Rui-Cheng

    2012-11-01

    To study the effect of pseudolaric acid B (PLAB) on cell proliferation and cycle of human prostate carcinoma DU-145 cells. method: Its inhibitory effect on the cell growth was measured by MTT method. Characteristics of cell death were determined by Hoechest 33342 staining. The cell cycle was detected by flow cytometry. The expressions of cyclin B1, cyclin D1 and CDK1 were detected by Real time-PCR and Western blot, respectively. PLAB notably inhibited DU-145 cell growth in a dose- and time dependent manner (P < 0.05). Its IC50 values of PLAB for DU-145 cells for 24, 48 and 72 h were 4.53, 2.39 and 2.08 micromol x L(-1), respectively. Having been treated with 5 micromol x L(-1) PLAB for 24 h, the cells showed such apoptosis characteristics as nuclei chromatin condensation and apoptotic body. With the increase in PLAB concentration, the proportion of G2/M phase cells strikingly increased in a dose- and time dependent manner (P < 0.05), meanwhile cyclin B1 and CDK1 showed over-expressions (P < 0.05), and the cyclin D1 showed under-expression (P < 0.05). PLAB can inhibit the growth of DU-145 cells and induce the cell cycle G2/M arrest, accompanied with the over-expression of cyclin B1 and CDK1, which may be related with its regulation cycle-associated protein degradation.

  13. 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.

  14. 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.

  15. Virtual screening of chemical compounds active against breast cancer cell lines based on cell cycle modelling, prediction of cytotoxicity and interaction with targets.

    PubMed

    Konova, V; Lagunin, A; Pogodin, P; Kolotova, E; Shtil, A; Poroikov, V

    2015-01-01

    Bio- and chemoinformatics methods are widely used for the detection of mechanisms of cancer, to search for potential drug targets and their ligands. Regulatory network analysis based on signalling pathways, and cell cycle regulation provides better understanding of diseases with multiple mechanisms of pathogenesis. We developed an approach for in silico prediction of the cytotoxic effect of chemical compounds in non-transformed and breast cancer cell lines. This approach combines the prediction of the interaction between chemical compounds and human proteins, cytotoxicity and regulatory network modelling taking into account gene expression. Application of our approach to virtual screening of libraries of commercially available compounds allowed selection of dozens of promising hits. These molecules are predicted to interact with the identified targets and exhibit cytotoxicity against breast cancer cell lines but not non-tumour human cell lines. Experimental testing of 49 selected compounds against MDA-MB-231 and MCF7 breast cancer cell lines confirmed the activity of eight compounds with IC50 values ranged from 0.8 to 50 μM. Thus, the developed approach may be applied for virtual screening for cytotoxic compounds against tumour cell lines.

  16. 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.

  17. Laser-induced forward transfer of a bis-pyrene compound for OTFTs

    NASA Astrophysics Data System (ADS)

    Constantinescu, Catalin; Diallo, Abdou Karim; D'Aleo, Anthony; Fages, Frédéric; Videlot-Ackermann, Christine; Delaporte, Philippe; Alloncle, Anne-Patricia

    2015-05-01

    We present results on a newly synthesized bis-pyrene compound that, besides the typical fluorescence, also exhibits semiconducting properties. Thin films have been grown by vacuum thermal evaporation on oxidized silicon and on transparent quartz substrates. Micrometric-sized pixels have subsequently been printed by laser-induced forward transfer (LIFT), in air and at low pressure (90 mbar), by using a Nd:YAG laser source (355 nm, 50 ps pulse duration) to produce functional organic thin film transistors (o-TFTs). Top-contact (TC) configurations are emphasized, and the influence of the pressure and laser fluence during the LIFT procedure is discussed.

  18. Effect of dietary phenolic compounds on apoptosis of human cultured endothelial cells induced by oxidized LDL

    PubMed Central

    Vieira, Otilia; Escargueil-Blanc, Isabelle; Meilhac, Olivier; Basile, Jean-Pierre; Laranjinha, Joao; Almeida, Leonor; Salvayre, Robert; Nègre-Salvayre, Anne

    1998-01-01

    Oxidized low density lipoproteins (LDL) are toxic to cultured endothelial cells. Mildly oxidized LDL, characterized by relatively low levels of TBARS and only minor modifications of apoB, were obtained by using 2 experimental model systems of oxidation, namely oxidation by u.v. radiation or ferrylmyoglobin (a two electron oxidation product from the reaction of metmyoglobin with H2O2). Toxic concentrations of mildly oxidized LDL induce apoptosis (programmed cell death) of cultured endothelial cells, as shown by typical morphological features, by the in situ TUNEL procedure and by DNA fragmentation revealed on gel electrophoresis. This apoptosis is calcium-dependent and subsequent to the intense and sustained cytosolic [Ca2+]i peak elicited by oxidized LDL. Five naturally occurring phenolic compounds present in food and beverages were able to prevent, in a concentration-dependent manner, the apoptosis of endothelial cells induced by oxidized LDL. Among the compounds tested, caffeic acid was the most effective. Under the conditions used, the protective effect of caffeic acid (IC50 8.3±2.1 μmol  l−1) in the prevention of apoptosis induced by oxidized LDL was significantly higher than that of the other compounds tested (IC50s were 12.4±3.2, 14.1±4.1, 20.4±4.4 and 72.6±9.2 μmol  l−1 for ferulic, protocatechuic, ellagic and p-coumaric acids, respectively). The anti-apoptotic effect of caffeic acid results from the addition of two effects, (i) the antioxidant effect which prevents LDL oxidation and subsequent toxicity (‘indirect' protective effect); (ii) a ‘direct' cytoprotective effect, acting at the cellular level. Effective concentrations of caffeic acid acted at the cellular level by blocking the intense and sustained cytosolic [Ca2+]i rise elicited by oxidized LDL. In conclusion, phenolic acids (caffeic and ferulic acids being the most potent of the compounds tested under the conditions used) exhibit a potent cytoprotective effect of

  19. Is Moderate Intensity Cycling Sufficient to Induce Cardiorespiratory and Biomechanical Modifications of Subsequent Running?

    PubMed

    Walsh, Joel A; Dawber, James P; Lepers, Romuald; Brown, Marc; Stapley, Paul J

    2017-04-01

    Walsh, JA, Dawber, JP, Lepers, R, Brown, M, and Stapley, PJ. Is moderate intensity cycling sufficient to induce cardiorespiratory and biomechanical modifications of subsequent running? J Strength Cond Res 31(4): 1078-1086, 2017-This study sought to determine whether prior moderate intensity cycling is sufficient to influence the cardiorespiratory and biomechanical responses during subsequent running. Cardiorespiratory and biomechanical variables measured after moderate intensity cycling were compared with control running at the same intensity. Eight highly trained, competitive triathletes completed 2 separate exercise tests; (a) a 10-minute control run (no prior cycling) and, (b) a 30-minute transition run (TR) (preceded by 20-minute of variable cadence cycling, i.e., run versus cycle-run). Respiratory, breathing frequency (fb), heart rate (HR), cost of running (Cr), rate constant, stride length, and stride frequency variables were recorded, normalized, and quantified at the mean response time (MRT), third minute, 10th minute (steady state), and overall for the control run (CR) and TR. Cost of running increased (p ≤ 0.05) at all respective times during the TR. The V[Combining Dot Above]E/V[Combining Dot Above]CO2 and respiratory exchange ratio (RER) were significantly (p < 0.01) elevated at the MRT and 10th minute of the TR. Furthermore, overall mean increases were recorded for Cr, V[Combining Dot Above]E, V[Combining Dot Above]E/V[Combining Dot Above]CO2, RER, fb (p < 0.01), and HR (p ≤ 0.05) during the TR. Rate constant values for oxygen uptake were significantly different between CR and TR (0.48 ± 0.04 vs. 0.89 ± 0.15; p < 0.01). Stride length decreased across all recorded points during the TR (p ≤ 0.05) and stride frequency increased at the MRT and 3 minutes (p < 0.01). The findings suggest that at moderate intensity, prior cycling influences the cardiorespiratory response during subsequent running. Furthermore, prior cycling seems to have a sustained

  20. Validation of the neuroinflammation cycle as a drug discovery target using integrative chemical biology and lead compound development with an Alzheimer's disease-related mouse model.

    PubMed

    Hu, Wenhui; Ralay Ranaivo, Hantamalala; Craft, Jeffrey M; Van Eldik, Linda J; Watterson, D Martin

    2005-04-01

    The neuroinflammation cycle has been proposed as a potential therapeutic target in the development of new approaches to altering Alzheimer's disease (AD) progression. However, the efficacy and toxicological profile of compounds that focus only on classical NSAID targets have been disappointing to date. Therefore, we recently initiated an unbiased, integrative chemical biology approach that used a hierarchal set of cell-based screens, followed by efficacy analysis in a new AD-relevant animal model that more closely resembles human pathology endpoints in terms of neuroinflammation and neuronal loss. The prior investigations provided a proof of concept that targeting the neuroinflammation cycle may be a viable drug discovery approach for AD. However, recent informatics analyses of the high attrition rate in drug development have identified the need for starting drug development with lead compounds that are well below cut off values in computed molecular properties in order to facilitate late stage medicinal chemistry refinement to improve in vivo functions. We describe here how we are leveraging our novel, unbiased, integrative chemical biology approach for the rapid discovery of potential lead compounds for AD drug discovery. Specifically, we show that orally bioavailable compounds with the desired physical properties and in vivo functions can be identified in focused synthetic libraries composed of chemical diversifications of the inactive but privileged pyridazine molecular fragment.

  1. Permanence induced by life-cycle resonances: the periodical cicada problem.

    PubMed

    Kon, Ryusuke

    2012-01-01

    Periodical cicadas are known for their unusually long life cycle for insects and their prime periodicity of either 13 or 17 years. One of the explanations for the prime periodicity is that the prime periods are selected to prevent cicadas from resonating with predators with submultiple periods. This paper considers this hypothesis by investigating a population model for periodical predator and prey. The study shows that if the periods of the two periodical species are not coprime, then the predator cannot resist the invasion of the prey. On the other hand, if the periods are coprime, then the predator can resist the invasion of the prey. It is also shown that if the periods are not coprime, then the life-cycle resonance can induce a permanent system, in which no cohorts are missing in both populations. On the other hand, if the periods are coprime, then the system cannot be permanent.

  2. Experimental investigation of flow induced limit cycle oscillations in a tensioned ribbon

    NASA Astrophysics Data System (ADS)

    Chatterjee, Punnag; Mazzoleni, Nicholas; Bryant, Matthew

    2017-04-01

    Researchers have performed theoretical investigations of flow induced limit cycle oscillations (LCOs) of tensioned ribbons. Furthermore, attempts have been made to tap into the energy harvesting capability of such ribbons, owing to its structural simplicity, low weight and ease of fabrication. However, in order to tune the ribbon to perform optimally at a given location, a robust, reliable model of the ribbon is essential to predict the limit cycle behavior. The model needs validation across a broad spectrum of its operating envelope based on experimentally obtained results. This paper seeks to provide experimental data for a sample tensioned ribbon in cross flow to serve as basis for validation of an aeroelastic model. This paper experimentally characterizes a PTFE (polytetrafluoroethylene) ribbon of aspect ratio 18 across a range of applied axial preload tension and wind speeds.

  3. Morphological evaluation of Day 8 embryos developed during induced aluteal cycles in the mare.

    PubMed

    Leisinger, C A; Medina, V; Markle, M L; Paccamonti, D L; Pinto, C R F

    2017-09-25

    A novel in vivo model utilizing serial administrations of PGF2α to induce aluteal cycles in the mare was used to evaluate the effects of progesterone-deprivation on the morphology of in vivo preimplantation embryos. We hypothesized that equine embryos produced during induced aluteal cycles (AL) would be developmentally affected, characterized by earlier embryo stage at collection, smaller embryo diameter, and lower quality grade, compared with those collected on the same day post-ovulation from control cycles during diestrus (high progesterone; > 4 ng/mL). Seven cyclic mares with a median age of 6.5 years (range 3-16) were utilized in a crossover design. Mares in estrus were artificially inseminated to a fertile stallion and randomly assigned to control or AL groups. Mares received either saline solution (control mares) or PGF2α (AL mares), twice daily on days 0, 1, and 2 and once daily on days 3 and 4. Serial blood samples were collected daily during estrus and until the day of embryo collection 8 days after ovulation. Mares were monitored until they returned to estrus, and artificially inseminated. Mares were switched to the opposite treatment group only after a successful embryo collection occurred during the previous cycle. Only cycles that produced embryos were used for analyses. No significant rise in progesterone was observed in the AL group with mean concentrations of plasma progesterone remaining <1.0 ng/mL from ovulation until embryo collection on Day 8. This is in sharp contrast to the control (luteal) cycle where a post-ovulatory rise in plasma progesterone was observed. The mean daily concentrations of plasma progesterone were significantly higher in control vs. AL group beginning at Day 3 and remained so until Day 8. The mean (±SEM) embryo diameter of AL embryos was 171 ± 5 μm compared to 756 ± 99 μm for control embryos. The majority of the Day 8 AL embryos were classified as morulas (3/9) or early blastocysts (5/9) with only 2

  4. Interhemispheric coupling induced by the Holton-Tan effect and its sensitivity to the solar cycle

    NASA Astrophysics Data System (ADS)

    Matthias, Vivien; Becker, Erich

    2016-04-01

    The modulation of the northern winter polar vortex due to the Holton-Tan (HT) effect results in changes of the gravity wave (GW) drag in the mesosphere/ lower thermosphere (MLT). According to the interhemispheric coupling mechanism, one expects an associated modulation of the entire residual circulation from the summer to the winter pole, including a corresponding variability of the southern summer mesopause temperature. In a preceding study we studied this possible vertical and global extension of the HT effect on the basis of the CMAM30 (Canadian Middle Atmosphere Model) data. We found that a clear effect shows up only when sorting the data according to the phases of the 11-year solar cycle. In particular, the strongest interhemispheric coupling induced by the HT effect in January is visible during solar maximum, while the effect is much weaker during solar minimum and even reversed during the transition phases. In the present study we analyze sensitivity experiments with a new version of the KMCM (Kühlungsborn Mechanistic general Circulation Model; T42,L115) that includes self-generated QBO. Different phases of the solar cycle are mimicked by absorption of solar insolation by ozone around the stratopause. The model runs reproduce the behavior as detected from the CMAM30 data, confirming that the primary cause for the solar-cycle-induced variations of the HT effect are due to the solar heating around the stratopause. In order to explain the simulated sensitivity of the MLT to the solar cycle, we will analyze the differences among the model runs with respect to the dynamics of Rossby waves and GWs and their wave-wave and wave-mean flow interactions. For example, the stratospheric planetary wave drag is weaker during solar transition than during both solar minimum and maximum.

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

    PubMed

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

    2015-08-12

    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.

  6. [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.

  7. Pressure-induced superconductivity in topological parent compound Bi2Te3

    PubMed Central

    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.

    2011-01-01

    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. PMID:21173267

  8. High-dose irradiation induces cell cycle arrest, apoptosis, and developmental defects during Drosophila oogenesis.

    PubMed

    Shim, Hee Jin; Lee, Eun-Mi; Nguyen, Long Duy; Shim, Jaekyung; Song, Young-Han

    2014-01-01

    Ionizing radiation (IR) treatment induces a DNA damage response, including cell cycle arrest, DNA repair, and apoptosis in metazoan somatic cells. Because little has been reported in germline cells, we performed a temporal analysis of the DNA damage response utilizing Drosophila oogenesis as a model system. Oogenesis in the adult Drosophila female begins with the generation of 16-cell cyst by four mitotic divisions of a cystoblast derived from the germline stem cells. We found that high-dose irradiation induced S and G2 arrests in these mitotically dividing germline cells in a grp/Chk1- and mnk/Chk2-dependent manner. However, the upstream kinase mei-41, Drosophila ATR ortholog, was required for the S-phase checkpoint but not for the G2 arrest. As in somatic cells, mnk/Chk2 and dp53 were required for the major cell death observed in early oogenesis when oocyte selection and meiotic recombination occurs. Similar to the unscheduled DNA double-strand breaks (DSBs) generated from defective repair during meiotic recombination, IR-induced DSBs produced developmental defects affecting the spherical morphology of meiotic chromosomes and dorsal-ventral patterning. Moreover, various morphological abnormalities in the ovary were detected after irradiation. Most of the IR-induced defects observed in oogenesis were reversible and were restored between 24 and 96 h after irradiation. These defects in oogenesis severely reduced daily egg production and the hatch rate of the embryos of irradiated female. In summary, irradiated germline cells induced DSBs, cell cycle arrest, apoptosis, and developmental defects resulting in reduction of egg production and defective embryogenesis.

  9. 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

  10. 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

  11. Berberine induces cell cycle arrest and apoptosis in human gastric carcinoma SNU-5 cell line

    PubMed Central

    Lin, Jing-Pin; Yang, Jai-Sing; Lee, Jau-Hong; Hsieh, Wen-Tsong; Chung, Jing-Gung

    2006-01-01

    AIM: To investigate the relationship between the inhibited growth (cytotoxic activity) of berberine and apoptotic pathway with its molecular mechanism of action. METHODS: The in vitro cytotoxic techniques were complemented by cell cycle analysis and determination of sub-G1 for apoptosis in human gastric carcinoma SNU-5 cells. Percentage of viable cells, cell cycle, and sub-G1 group (apoptosis) were examined and determined by the flow cytometric methods. The associated proteins for cell cycle arrest and apoptosis were examined by Western blotting. RESULTS: For SNU-5 cell line, the IC (50) was found to be 48 μmol/L of berberine. In SNU-5 cells treated with 25-200 μmol/L berberine, G2/M cell cycle arrest was observed which was associated with a marked increment of the expression of p53, Wee1 and CDk1 proteins and decreased cyclin B. A concentration-dependent decrease of cells in G0/G1 phase and an increase in G2/M phase were detected. In addition, apoptosis detected as sub-G0 cell population in cell cycle measurement was proved in 25-200 μmol/L berberine-treated cells by monitoring the apoptotic pathway. Apoptosis was identified by sub-G0 cell population, and upregulation of Bax, downregulation of Bcl-2, release of Ca2+, decreased the mitochondrial membrane potential and then led to the release of mitochondrial cytochrome C into the cytoplasm and caused the activation of caspase-3, and finally led to the occurrence of apoptosis. CONCLUSION: Berberine induces p53 expression and leads to the decrease of the mitochondrial membrane potential, Cytochrome C release and activation of caspase-3 for the induction of apoptosis. PMID:16440412

  12. 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

  13. 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.

  14. Cytoprotective Effects of Organosulfur Compounds against Methimazole Induced Toxicity in Isolated Rat Hepatocytes

    PubMed Central

    Heidari, Reza; Babaei, Hossein; Eghbal, Mohammad Ali

    2013-01-01

    Purpose: Methimazole is a drug widely used in hyperthyroidism. However, life threatening hepatotoxicity has been associated with its clinical use. No protective agent has been found to be effective against methimazole induced hepatotoxicity yet. Hence, the capacity of organosulfur compounds to protect rat hepatocytes against cytotoxic effects of methimazole and its proposed toxic metabolite, N-methylthiourea was evaluated. Methods: Hepatocytes were prepared by the method of collagenase enzyme perfusion via portal vein. Cells were treated with different concentrations of methimazole, N methylthiourea, and organosulfur chemicals. Cell death, protein carbonylation, reactive oxygen species formation, lipid peroxidation, and mitochondrial depolarization were assessed as toxicity markers and the role of organosulfurs administration on them was investigated. Results: Methimazole caused a decrease in cellular glutathione content, mitochondrial membrane potential (ΔΨm) collapse, and protein carbonylation. In addition, an increase in reactive oxygen species (ROS) formation and lipid peroxidation was observed. Treating hepatocytes with N methylthiourea caused a reduction in hepatocytes glutathione reservoirs and an elevation in carbonylated proteins, but no significant ROS formation, lipid peroxidation, or mitochondrial depolarization was observed. N-acetyl cysteine, allylmercaptan, and diallyldisulfide attenuated cell death and prevented ROS formation and lipid peroxidation caused by methimazole. Furthermore, organosulfur compounds diminished methimazole induced mitochondrial damage and reduced the carbonylated proteins. In addition, these chemicals showed protective effects against cell death and protein carbonylation induced by methimazole metabolite. Conclusion: Organosulfur chemicals extend their protective effects against methimazole-induced toxicity by attenuating oxidative stress caused by this drug and preventing the adverse effects of methimazole and/or its

  15. Polydatin, a natural precursor of resveratrol, induces cell cycle arrest and differentiation of human colorectal Caco-2 cell

    PubMed Central

    2013-01-01

    Background Human colon adenocarcinoma cells are resistant to chemotherapeutic agents, such as anthracyclines, that induce death by increasing the reactive oxygen species. A number of studies have been focused on chemo-preventive use of resveratrol as antioxidant against cardiovascular diseases, aging and cancer. While resveratrol cytotoxic action was due to its pro-oxidant properties. In this study, we investigate whether the Resveratrol (trans-3,5,49-trihydroxystilbene) and its natural precursor Polydatin (resveratrol-3-O-b-mono- D-glucoside, the glycoside form of resveratrol) combination, might have a cooperative antitumor effect on either growing or differentiated human adenocarcinoma colon cancer cells. Methods The polydatin and resveratrol pharmacological interaction was evaluated in vitro on growing and differentiated Caco-2 cell lines by median drug effect analysis calculating a combination index with CalcuSyn software. We have selected a synergistic combination and we have evaluated its effect on the biological and molecular mechanisms of cell death. Results Simultaneous exposure to polydatin and resveratrol produced synergistic antiproliferative effects compared with single compound treatment. We demonstrated that polydatin alone or in combination with resveratrol at 3:1 molar ratio synergistically modulated oxidative stress, cell cycle, differentiation and apoptosis. Worthy of note treatment with polydatin induced a nuclear localization and decreased expression of heat shock protein 27, and vimentin redistributed within the cell. Conclusions From morphological, and biochemical outcome we obtained evidences that polydatin induced a transition from a proliferative morphology to cell-specific differentiated structures and caused human CaCo-2 cell death by induction of apoptosis. Our data suggest the potential use of polydatin in combination chemotherapy for human colon cancer. PMID:24138806

  16. 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.

  17. The Sophora Flavescens flavonoid compound trifolirhizin inhibits acetylcholine induced airway smooth muscle contraction

    PubMed Central

    Zeng, Jia; Zhan, Jixun; Brown, LaVerne; Sampson, Hugh; Goldfarb, Joseph; Emala, Charles; Li, Xiu-Min

    2014-01-01

    Asthma is a serious health problem worldwide, particularly in industrialized countries. Despite a better understanding of the pathophysiology of asthma, there are still considerable gaps in knowledge as well as a need for new classes of drugs. ASHMI™ (Anti-asthma Herbal Medicine Intervention) is an aqueous extract of Ganoderma lucidum (Fr.) P. Karst (Ling Zhi), Sophora flavescens Aiton (Ku Shen) and Glycyrrhiza uralensis Fisch. ex DC (Gan Cao). It prevents allergic asthma airway hyper-reactivity in mice and inhibits acetylcholine (ACh) induced airway smooth muscle (ASM) contraction in tracheal rings from allergic asthmatic mice. The purpose of this research was to identify individual herb(s) and their active compound(s) that inhibit ASM contraction. It was found that Sophora flavescens (S. flavescens), but not Ganoderma lucidum (G. lucidum) or Glycyrrhiza uralensis (G. uralensis) aqueous extracts, inhibited ASM contraction in tracheal rings from asthmatic mice. Bioassay-guided isolation and identification of flavonoid fractions/compound(s) via methylene chloride extraction, preparative HPLC fractionation, and LC-MS and NMR spectroscopic analyses showed that trifolirhizin is an active constituent that inhibits acetylcholine mediated ASM contraction or directly relaxes pre-contracted ASM independent of β2-adrenoceptors. PMID:23993294

  18. The Sophora flavescens flavonoid compound trifolirhizin inhibits acetylcholine induced airway smooth muscle contraction.

    PubMed

    Yang, Nan; Liang, Banghao; Srivastava, Kamal; Zeng, Jia; Zhan, Jixun; Brown, LaVerne; Sampson, Hugh; Goldfarb, Joseph; Emala, Charles; Li, Xiu-Min

    2013-11-01

    Asthma is a serious health problem worldwide, particularly in industrialized countries. Despite a better understanding of the pathophysiology of asthma, there are still considerable gaps in knowledge as well as a need for classes of drugs. ASHMI™ (Anti-asthma Herbal Medicine Intervention) is an aqueous extract of Ganoderma lucidum (Fr.) P. Karst (Ling Zhi), Sophora flavescens Aiton (Ku Shen) and Glycyrrhiza uralensis Fisch. ex DC (Gan Cao). It prevents allergic asthma airway hyper-reactivity in mice and inhibits acetylcholine (ACh) induced airway smooth muscle (ASM) contraction in tracheal rings from allergic asthmatic mice. The purpose of this research was to identify individual herb(s) and their active compound(s) that inhibit ASM contraction. It was found that S. flavescens, but not G. lucidum or G. uralensis aqueous extracts, inhibited ASM contraction in tracheal rings from asthmatic mice. Bioassay-guided isolation and identification of flavonoid fractions/compound(s) via methylene chloride extraction, preparative HPLC fractionation, and LC-MS and NMR spectroscopic analyses showed that trifolirhizin is an active constituent that inhibits acetylcholine mediated ASM contraction or directly relaxes pre-contracted ASM independent of β2-adrenoceptors. Copyright © 2013 Elsevier Ltd. All rights reserved.

  19. Ambient ionization and direct identification of volatile organic compounds with microwave-induced plasma mass spectrometry.

    PubMed

    Li, Dandan; Tian, Yong-Hui; Zhao, Zhongjun; Li, Wenwen; Duan, Yixiang

    2015-02-01

    An innovative method of volatile organic compounds analysis by using microwave-induced plasma ionization (MIPI) source in combination with an ambient ion trap mass spectrometer is presented here. Using MIPI for direct sample vapor, analysis was achieved without any sample preparation or subsequent heating. The relative abundance of the target compounds can be obtained almost instantly within a few seconds. The ionization processes of different volatile compounds was optimized, and the limits of detection were identified in the range of 0.15-4.5 pptv or 0.73-8.80 pg ml(-1). The relative standard deviation (RSD) is in the range of 4-14%, while correlation coefficients of the working curves (R(2)) are better than 0.98. The new method possesses advantages of ease operation, time-saving, high sensitivity and inexpensive setup. In addition, the ionization processes of short n-alkane chains were investigated with the MIPI technique, and a unique [M + 13](+) was detected, which has not been reported in detail by any other related ionization techniques. An ionization mechanism was proposed on the basis of the experimental results obtained in this work and available information in literatures, in which the n-alkanes in the plasma environment possibly generate protonated cyclopentadiene [M - 5](+) or alkyl-substituted analogues as well as hydrous ions [M + 13](+) and [M + 13 + 18](+), as shown in Scheme 1 in the main text.

  20. Purified Lesser weever fish venom (Trachinus vipera) induces eryptosis, apoptosis and cell cycle arrest

    PubMed Central

    Fezai, Myriam; Slaymi, Chaker; Ben-Attia, Mossadok; Lang, Florian; Jemaà, Mohamed

    2016-01-01

    Accidents caused by the sting of Trachinus vipera (known as Lesser weever fish) are relatively common in shallow waters of the Mediterranean. Symptoms after the sting vary from severe pain to edema or even tissue necrosis in some cases. Here we show that purified Lesser weever fish venom induces eryptosis, the suicidal erythrocyte death, and apoptosis of human colon carcinoma cells. The venom leads to erythrocyte shrinkage, phosphatidylserine translocation and increased intracellular Ca2+, events typical for eryptosis. According to mitochondrial staining cancer cells dyed after the activation of the intrinsic apoptotic pathway. Trachinus vipera venom further causes cell cycle arrest. PMID:27995979

  1. 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.

  2. Evaporation cycle experiments--a simulation of salt-induced peptide synthesis under possible prebiotic conditions.

    PubMed

    Saetia, S; Liedl, K R; Eder, A H; Rode, B 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.

  3. Induced root-secreted phenolic compounds as a belowground plant defense

    PubMed Central

    Burlat, Vincent; Schurr, Ulrich; Röse, Ursula SR

    2010-01-01

    Rhizosphere is the complex place of numerous interactions between plant roots, microbes and soil fauna. Whereas plant interactions with aboveground organisms are largely described, unravelling plant belowground interactions remains challenging. Plant root chemical communication can lead to positive interactions with nodulating bacteria, mycorriza or biocontrol agents or to negative interactions with pathogens or root herbivores. A recent study1 suggested that root exudates contribute to plant pathogen resistance via secretion of antimicrobial compounds. These findings point to the importance of plant root exudates as belowground signalling molecules, particularly in defense responses. In our report,2 we showed that under Fusarium attack the barley root system launched secretion of phenolic compounds with antimicrobial activity. The secretion of de novo biosynthesized t-cinnamic acid induced within 2 days illustrates the dynamic of plant defense mechanisms at the root level. We discuss the costs and benefits of induced defense responses in the rhizosphere. We suggest that plant defense through root exudation may be cultivar dependent and higher in wild or less domesticated varieties. PMID:20699651

  4. Large reversible magnetocaloric effect induced by metamagnetic transition in antiferromagnetic HoNiGa compound

    NASA Astrophysics Data System (ADS)

    Wang, Yi-Xu; Zhang, Hu; Wu, Mei-Ling; Tao, Kun; Li, Ya-Wei; Yan, Tim; Long, Ke-Wen; Long, Teng; Pang, Zheng; Long, Yi

    2016-12-01

    The magnetic properties and magnetocaloric effects (MCE) of HoNiGa compound are investigated systematically. The HoNiGa exhibits a weak antiferromagnetic (AFM) ground state below the Ńeel temperature TN of 10 K, and the AFM ordering could be converted into ferromagnetic (FM) ordering by external magnetic field. Moreover, the field-induced FM phase exhibits a high saturation magnetic moment and a large change of magnetization around the transition temperature, which then result in a large MCE. A large -ΔSM of 22.0 J/kg K and a high RC value of 279 J/kg without magnetic hysteresis are obtained for a magnetic field change of 5 T, which are comparable to or even larger than those of some other magnetic refrigerant materials in the same temperature range. Besides, the μ0H2/3 dependence of well follows the linear fitting according to the mean-field approximation, suggesting the nature of second-order FM-PM magnetic transition under high magnetic fields. The large reversible MCE induced by metamagnetic transition suggests that HoNiGa compound could be a promising material for magnetic refrigeration in low temperature range. Project supported by the National Natural Science Foundation of China (Grant Nos. 51671022 and 51427806), the Beijing Natural Science Foundation, China (Grant No. 2162022), and the Fundamental Research Funds for the Central Universities, China (Grant No. FRF-TP-15-002A3).

  5. 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

  6. 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.

  7. 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

  8. Effect of histamine antagonists on myocardial carcinine metabolism during compound 48/80-induced shock.

    PubMed

    Fitzpatrick, J C; Fisher, H; Flancbaum, L

    1990-10-01

    Carcinine (beta-alanylhistamine) is an imidazole dipeptide that exists in mammalian hearts, increases cardiac contractility, and is metabolically linked to carnosine (beta-alanylhistidine), a non-mast cell histidine and histamine precursor during stress. We have previously shown that tissue carnosine levels are regulated by H1 and H2 receptors. This study evaluated the effects of H1, H2, and mast cell degranulation blockers on metabolism of carcinine and related imidazoles during shock induced by compound 48/80, a mast cell degranulator. Fifty 125-g male Sprague-Dawley rats were divided into nine ip treatment groups: saline, 48/80, lodoxamide (LOD, mast cell degranulation inhibitor), diphenhydramine (DPH, H1 antagonist), cimetidine (CIM, H2 antagonist), LOD + 48/80, CIM + 48/80, DPH + 48/80, or DPH + CIM + 48/80. Heart tissue was analyzed at 30 min by HPLC. 48/80 caused decreases in myocardial carnosine (P less than 0.01) and histidine (P less than 0.0001) levels and concomitant increases in carcinine (P less than 0.01), histamine (P less than 0.01), and 3-methylhistamine (P less than 0.05) compared to those of controls. These changes were inhibited by LOD or DPH. Treatment with CIM significantly increased myocardial carcinine levels compared to 48/80 alone (P less than 0.001) without an additional effect on the other compounds. These data indicate that carcinine is involved in the cardiac response to stress via the carnosine-histidine-histamine pathway. Compound 48/80-induced shock increases histamine metabolism via this pathway resulting in mobilization of myocardial carnosine and histidine to carcinine and histamine; this effect is increased by H2 receptor blockade.

  9. 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.

  10. 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.

  11. Compound Danshen injection improves endotoxin-induced microcirculatory disturbance in rat mesentery

    PubMed Central

    Han, Jing-Yan; Horie, Yoshinori; Miura, Soichiro; Akiba, Yasutada; Guo, Jun; Li, Dan; Fan, Jing-Yu; Liu, Yu-Ying; Hu, Bai-He; An, Li-Hua; Chang, Xin; Xu, Man; Guo, De-An; Sun, Kai; Yang, Ji-Ying; Fang, Shu-Ping; Xian, Ming-Ji; Kizaki, Masahiro; Nagata, Hiroshi; Hibi, Toshifumi

    2007-01-01

    AIM: To investigate the effect of compound Danshen injection on lipopolysaccharide (LPS)-induced rat mesenteric microcirculatory dysfunctions and the underlying possible mechanism by an inverted intravital microscope and high-speed video camera system. METHODS: LPS was continuously infused through the jugular artery of male Wistar rats at the dose of 2 mg/kg per hour. Changes in mesenteric microcirculation, such as diameters of arterioles and venules, velocity of RBCs in venules, leukocyte rolling, adhesion and emigration, free radicals released from post-capillary venules, FITC-albumin leakage and mast cell degranulation, were observed through an inverted intravital microscope assisted with CCD camera and SIT camera. Meanwhile, the expression of adhesion molecules CD11b/CD18 and the production of free radical in neutrophils, and the expression of intercellular adhesion molecule 1 (ICAM-1) in human umbilical vein endothelial cells (HUVECs) were quantified by flow cytometry (FACS) in vitro. RESULTS: The continuous infusion with LPS resulted in a number of responses in microcirculation, including a significant increase in the positive region of venule stained with Monastral blue B, rolling and adhesion of leukocytes, production of oxygen radical in venular wall, albumin efflux and enhanced mast cell degranulation in vivo, all of which, except for the leukocyte rolling, were attenuated by the treatment with compound Danshen injection. Experiments performed in vitro further revealed that the expression of CD11b/CD18 and the production of oxygen free radical in neutrophils, and the expression of ICAM-1 in HUVECs were increased by exposure to LPS, and they were attenuated by compound Danshen injection. CONCLUSION: These results suggest that compound Danshen injection is an efficient drug with multi-targeting potential for improving the microcirculatory disturbance. PMID:17659708

  12. Attenuation of 2-methoxyethanol-induced testicular toxicity in the rat by simple physiological compounds.

    PubMed

    Mebus, C A; Welsch, F; Working, P K

    1989-06-01

    2-Methoxyethanol (2-ME) is an industrial solvent which is toxic to both male and female reproductive systems of laboratory animals. Earlier data have demonstrated that the developmental toxicity of 2-ME can be attenuated by simple physiological compounds such as serine, acetate, sarcosine, glycine, and D-glucose. The present experiments were designed to evaluate the same compounds for their ability to ameliorate the testicular toxicity that occurs in rats after 2-ME exposure. The extent of testicular damage was assessed by quantitating daily sperm production (DSP) on Day 24 following a single dose of 2-ME (6.6 mmol/kg, 500 mg/kg). Serine completely eliminated 2-ME-induced decreases in DSP, while glucose was without effect. Acetate, sarcosine, and glycine were of similar efficacy resulting in DSP that was significantly greater than that observed in rats which received 2-ME alone. Histopathological studies revealed that 2-ME treatment resulted in stage-specific degeneration of late stage pachytene spermatocytes 24 hr after treatment. No apparent degenerative changes occurred after concurrent treatment with serine. Similarly, serine also prevented the decreased number of spermatids in the lumina of the seminiferous tubules on Day 24 after 2-ME exposure alone. All of the compounds utilized in this study are linked to oxidation pathways involving tetrahydrofolic acid as a catalyst for one-carbon moiety transfer into purine and pyrimidine bases which are necessary precursors for DNA and RNA synthesis. The ability of these compounds to attenuate the testicular toxicity of 2-ME may result from their ability to donate one-carbon units which can be used in purine base biosynthesis. Reduced availability of bases would be expected to affect late stage pachytene spermatocytes which are known to be undergoing rapid RNA synthesis.

  13. Few-cycle pulse laser-induced damage of thin films in air and vacuum ambience

    NASA Astrophysics Data System (ADS)

    Kafka, Kyle R. P.; Talisa, Noah; Tempea, Gabriel; Austin, Drake R.; Neacsu, Catalin; Chowdhury, Enam A.

    2016-12-01

    Laser-induced damage mechanisms were investigated for an ultra-broadband chirped mirror, as part of a systematic study of few-cycle pulse laser-induced damage threshold (LIDT) of widely-used ultra-broadband optics, in vacuum and in air, for single and multi-pulse regimes (S-on-1). Microscopic analysis of damage morphology suggests that three different damage mechanisms occur across the fluence range 0.15-0.4J/cm2, while no ablation was yet observed. The three regimes resulted in shallow swelling (< 10 nm tall), tall blistering ( 150 nm tall), and annular blistering (damage suppressed at highest intensity, forming a ring shape). Descriptions of the potential mechanisms are discussed.

  14. Propionibacterium acnes inhibits FOXM1 and induces cell cycle alterations in human primary prostate cells.

    PubMed

    Sayanjali, Behnam; Christensen, Gitte J M; Al-Zeer, Munir A; Mollenkopf, Hans-Joachim; Meyer, Thomas F; Brüggemann, Holger

    2016-11-01

    Propionibacterium acnes has been detected in diseased human prostate tissue, and cell culture experiments suggest that the bacterium can establish a low-grade inflammation. Here, we investigated its impact on human primary prostate epithelial cells. Microarray analysis confirmed the inflammation-inducing capability of P. acnes but also showed deregulation of genes involved in the cell cycle. qPCR experiments showed that viable P. acnes downregulates a master regulator of cell cycle progression, FOXM1. Flow cytometry experiments revealed that P. acnes increases the number of cells in S-phase. We tested the hypothesis that a P. acnes-produced berninamycin-like thiopeptide is responsible for this effect, since it is related to the FOXM1 inhibitor siomycin. The thiopeptide biosynthesis gene cluster was strongly expressed; it is present in subtype IB of P. acnes, but absent from type IA, which is most abundant on human skin. A knock-out mutant lacking the gene encoding the berninamycin-like peptide precursor was unable to downregulate FOXM1 and to halt the cell cycle. Our study reveals a novel host cell-interacting activity of P. acnes.

  15. 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

  16. The phytohormone auxin induces G1 cell-cycle arrest of human tumor cells.

    PubMed

    Ester, Katja; Curković-Perica, Mirna; Kralj, Marijeta

    2009-10-01

    The plant hormone auxin is the key regulator of plant growth and development. Auxin regulates transcription of plant genes by targeting degradation of transcriptional repressor proteins Aux/IAA. While there are many reports describing its potential to modulate human cell functions, the majority are based on auxin action following enzymatic activation. A study focused on auxin alone and its antiproliferative potential, with emphasis on modulation of the cell cycle, has not been performed. Therefore, we analyzed tumor growth inhibitory effects and the cell-cycle perturbations of natural (IAA, IBA) and synthetic (NAA, 2,4-D) auxins. All derivatives showed cytostatic effects on selected human tumor cell lines. The cell-cycle analysis revealed that IAA and 2,4-D induce strong G1 arrest, along with a drastic decrease in the percentage of S-phase cells in MCF-7 cell line. This phenomenon demonstrates that auxins may have novel, unexploited antitumor potential and should be further investigated. Georg Thieme Verlag KG Stuttgart-New York.

  17. Methamphetamine alters the normal progression by inducing cell cycle arrest in astrocytes.

    PubMed

    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.

  18. Tyrphostin AG-related compounds attenuate H2O2-induced TRPM2-dependent and -independent cellular responses.

    PubMed

    Yamamoto, Shinichiro; Toda, Takahiro; Yonezawa, Ryo; Negoro, Takaharu; Shimizu, Shunichi

    2017-05-01

    TRPM2 is a Ca(2+)-permeable channel that is activated by H2O2. TRPM2-mediated Ca(2+) signaling has been implicated in the aggravation of inflammatory diseases. Therefore, the development of TRPM2 inhibitors to prevent the aggravation of these diseases is expected. We recently reported that some Tyrphostin AG-related compounds inhibited the H2O2-induced activation of TRPM2 by scavenging the intracellular hydroxyl radical. In the present study, we examined the effects of AG-related compounds on H2O2-induced cellular responses in human monocytic U937 cells, which functionally express TRPM2. The effects of AG-related compounds on H2O2-induced changes in intracellular Ca(2+) concentrations, extracellular signal-regulated kinase (ERK) activation, and CXCL8 secretion were assessed using U937 cells. Ca(2+) influxes via TRPM2 in response to H2O2 were blocked by AG-related compounds. AG-related compounds also inhibited the H2O2-induced activation of ERK, and subsequent secretion of CXCL8 mediated by TRPM2-dependent and -independent mechanisms. Our results show that AG-related compounds inhibit H2O2-induced CXCL8 secretion following ERK activation, which is mediated by TRPM2-dependent and -independent mechanisms in U937 cells. We previously reported that AG-related compounds blocked H2O2-induced TRPM2 activation by scavenging the hydroxyl radical. The inhibitory effects of AG-related compounds on TRPM2-independent responses may be due to scavenging of the hydroxyl radical. Copyright © 2017 The Authors. Production and hosting by Elsevier B.V. All rights reserved.

  19. 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

  20. Vapor of volatile oils from Litsea cubeba seed induces apoptosis and causes cell cycle arrest in lung cancer cells.

    PubMed

    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 Ser(473) and Thr(308); 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.

  1. UV radiation-induced accumulation of photoprotective compounds in the green alga Tetraspora sp. CU2551.

    PubMed

    Rastogi, Rajesh P; Incharoensakdi, Aran

    2013-09-01

    The effect of UV radiation on the accumulation of novel mycosporine-like amino acids (MAAs) along with their photoprotective function was investigated in the green alga Tetraspora sp. CU2551. No UV-absorbing compound was detected in this organism growing under normal light condition while two MAAs with absorption maxima at 324 nm and 322 nm were found to be accumulated after UV irradiation. The effects of UV exposure time with different cut-off filter foils namely 295 (PAR + UV-A + UV-B), 320 (PAR + UV-A) and 395 nm (PAR only) were studied on induction of the synthesis of these MAAs. Concentration of MAAs was found to increase with increase in exposure time under UV radiation. Furthermore, the antioxidant and photoprotective action of these MAAs was also investigated. The role of MAAs in diminishing the UV-induced production of ROS in vivo was also demonstrated using the oxidant-sensing probe 2',7'-dichlorodihydrofluorescein diacetate (DCFH-DA) and results obtained supported the results of DPPH free radical scavenging assay. The MAAs also exhibited efficient photoprotective ability on Escherichia coli cells against UV-B stress. Thus, the MAAs in Tetraspora sp. CU2551 may act as efficient antioxidants as well as UV-sunscreen. This is the first report for the UV-induced synthesis and co-accumulation of these MAAs and their photoprotective actions in Tetraspora sp. which is a member of the class Chlorophyceae. Moreover, UV-induced accumulation as well as photoprotective function of these compounds may facilitate this chlorophyte to perform important ecological functions in harsh environmental conditions with high UV-B fluxes in their brightly lit habitats.

  2. Compound 48/80-induced serotonin release from brain mast cells

    SciTech Connect

    Lambracht-Hall, M.; Marathias, K.P.; Theoharides, T.C.

    1986-03-01

    Mast cells secrete a variety of potent mediators and are mostly known to participate in allergic reactions. Here the authors report that perfused brain mast cells can take up and release serotonin (5-HT) in response to compound 48/80. Thalamic or hypothalamic slices were loaded with /sup 3/H-5-HT (5 x 10/sup -7/M, for 12 min at 37/sup 0/C), washed and placed in individual 2 ml-perfusion wells. A Krebs-Ringer bicarbonate buffer with 1 x 10/sup -6/M imipramine (KRB + IMI) saturated with 5% CO/sub 2//95% O/sub 2/ at 37/sup 0/C and pH 7.4, was used throughout at a perfusion rate of 1 ml/min. After a 60 min wash in KRB + IMI, with or without Ca/sup +2/ + 0.1 M EDTA, the slices were perfused for 45 min with 100 ..mu..g/ml compound 48/80 with or without Ca/sup +2/. The tissue was washed for 30 min as before and then perfused with high K/sup +/ KRB (40mM KCl) for 45 min to induce neuronal depolarization. Finally, calcium was restored to Ca/sup +2/-depleted tissues and all samples were again perfused for 45 min with high K/sup +/ KRB. The first 5-HT peak due to 48/80-induced mast cell release was independent of extracellular Ca/sup +2/, while the second 5-HT peak due to high K/sup +/ was not. These studies indicate that the 48/80-induced 5-HT release was not of neuronal origin and that brain mast cells can utilize intracellular Ca/sup +2/, much like their peritoneal counterparts. The authors are now studying brain mast cells secretion in response to neuropeptides.

  3. Toxic but Drank: Gustatory Aversive Compounds Induce Post-ingestional Malaise in Harnessed Honeybees

    PubMed Central

    Ayestaran, Ainara

    2010-01-01

    Background Deterrent substances produced by plants are relevant due to their potential toxicity. The fact that most of these substances have an unpalatable taste for humans and other mammals contrasts with the fact that honeybees do not reject them in the range of concentrations in which these compounds are present in flower nectars. Here we asked whether honeybees detect and ingest deterrent substances and whether these substances are really toxic to them. Results We show that pairing aversive substances with an odor retards learning of this odor when it is subsequently paired with sucrose. Harnessed honeybees in the laboratory ingest without reluctance a considerable volume (20 µl) of various aversive substances, even if some of them induce significant post-ingestional mortality. These substances do not seem, therefore, to be unpalatable to harnessed bees but induce a malaise-like state that in some cases results in death. Consistently with this finding, bees learning that one odor is associated with sugar, and experiencing in a subsequent phase that the sugar was paired with 20 µl of an aversive substance (devaluation phase), respond less than control bees to the odor and the sugar. Such stimulus devaluation can be accounted for by the malaise-like state induced by the aversive substances. Conclusion Our results indicate that substances that taste bitter to humans as well as concentrated saline solutions base their aversive effect on the physiological consequences that their ingestion generates in harnessed bees rather than on an unpalatable taste. This conclusion is only valid for harnessed bees in the laboratory as freely-moving bees might react differently to aversive compounds could actively reject aversive substances. Our results open a new possibility to study conditioned taste aversion based on post-ingestional malaise and thus broaden the spectrum of aversive learning protocols available in honeybees. PMID:21060877

  4. Fractographic finger printing of proton-irradiation-induced disordering and amorphization of intermetallic compounds

    SciTech Connect

    Cheng, J.; Yuan, M.; Wagner, C. N. J.; Ardell, A. J.

    1989-05-01

    The intermetallic compounds NiTi, NiTi/sub 2/, CuZr, CuTi/sub 2/, and Zr/sub 3/Al were irradiated by 2 MeV protons at various temperatures between --175 /degree/C and --44 /degree/C to a fluence of 1.9/times/10/sup 22/ H/sup +//m/sup 2/. Transmission electron microscopy, electron diffraction, and x-ray diffraction were used to evaluate the extents of disordering and amorphization induced by irradiation in the samples. Both phenomena progressed to varying extents in the five compounds, depending on the irradiation temperature and dose. It was observed that the C-A transition began before the degree of long-range order was reduced significantly, and that the amorphous phase nucleated homogeneously throughout the crystalline matrix. A major finding of the current investigation is that the technique of scanning electron fractography provides a useful correlation between the features of the fractured surfaces and the microstructural alterations induced by the proton irradiations. When amorphization is complete the fracture surfaces are either featureless (e.g., NiTi/sub 2/) or contain branching features resembling river patterns. In some cases (especially in CuZr) these are similar to the markings seen on the surface of fractured amorphous ribbons produced by melt-spinning. In general, however, there is not a particularly good correlation between the features on the fracture surfaces of the irradiated and melt-spun ribbons. When the microstructure consists of amorphous regions embedded in a partially disordered crystalline matrix, there is consierable evidence for irradiation-induced ductility. In such cases, exemplified by the results on NiTi and Zr/sub 3/Al, the fracture surfaces contain dimples, characteristic of ductile fracture, suggesting that disordering promotes ductility.

  5. Icarisid II inhibits the proliferation of human osteosarcoma cells by inducing apoptosis and cell cycle arrest.

    PubMed

    Tang, Yuanyuan; Xie, Mao; Jiang, Neng; Huang, Feifei; Zhang, Xiao; Li, Ruishan; Lu, Jingjing; Liao, Shijie; Liu, Yun

    2017-06-01

    Icarisid II, one of the main active components of Herba Epimedii extracts, shows potent antitumor activity in various cancer cell lines, including osteosarcoma cells. However, the anticancer mechanism of icarisid II against osteosarcoma U2OS needs further exploration. This study aims to investigate further antitumor effects of icarisid II on human osteosarcoma cells and elucidate the underlying mechanism. We cultivated human osteosarcoma USO2 cells in vitro using different concentrations of icarisid II (0-30 µM). Cell viability was detected at 24, 48, and 72 h using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide analysis. Cell cycle was tested by flow cytometry after treatment with icarisid II for 48 h. Annexin V-allophycocyanin and 7-aminoactinomycin D staining were conducted to detect cell apoptosis. Quantitative real-time polymerase chain reaction and Western blot assay were performed to measure the levels of genes and proteins related to cell cycle and apoptosis. Results showed that icarisid II significantly inhibited the proliferation and induced apoptosis of human osteosarcoma U2OS cells. The half maximal inhibitory concentration values were 14.44, 11.02, and 7.37 µM at 24, 48, and 72 h, respectively. Cell cycle was arrested in the G2/M phase in vitro. In addition, icarisid II upregulated the expression levels of P21 and CyclinB1 whereas downregulated the expression levels of CyclinD1, CDC2, and P-Cdc25C, which were related to cell cycle arrest in U2OS cells. The cell apoptotic rate increased in a dose-dependent manner after treatment with icarisid II for 48 h. Icarisid II induced apoptosis by upregulating Bax, downregulating Bcl-2, and activating apoptosis-related proteins, including cleaved caspase-3, caspase-7, caspase-9, and poly (ADP-ribose) polymerase. These data indicate that icarisid II exhibits an antiproliferation effect on human osteosarcoma cells and induces apoptosis by activating the caspase family in a time- and dose

  6. 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.

  7. Estrogen Leads to Reversible Hair Cycle Retardation through Inducing Premature Catagen and Maintaining Telogen

    PubMed Central

    Lei, Xiao-hua; Deng, Zhi-li; Guo, Wei-xiang; Qiu, Zhi-fang; Liu, Shuang; Wang, Xin-yue; Zhang, He; Duan, En-kui

    2012-01-01

    Estrogen dysregulation causes hair disorder. Clinical observations have demonstrated that estrogen raises the telogen/anagen ratio and inhibits hair shaft elongation of female scalp hair follicles. In spite of these clinical insights, the properties of estrogen on hair follicles are poorly dissected. In the present study, we show that estrogen induced apoptosis of precortex cells and caused premature catagen by up-regulation of TGF β2. Immediately after the premature catagen, the expression of anagen chalone BMP4 increased. The up-regulation of BMP4 may further function to prevent anagen transition and maintain telogen. Interestingly, the hair follicle stem cell niche was not destructed during these drastic structural changes caused by estrogen. Additionally, dermal papilla cells, the estrogen target cells in hair follicles, kept their signature gene expressions as well as their hair inductive potential after estrogen treatment. Retention of the characteristics of both hair follicle stem cells and dermal papilla cells determined the reversibility of the hair cycle suppression. These results indicated that estrogen causes reversible hair cycle retardation by inducing premature catagen and maintaining telogen. PMID:22792225

  8. Canthin-6-one induces cell death, cell cycle arrest and differentiation in human myeloid leukemia cells.

    PubMed

    Vieira Torquato, Heron F; Ribeiro-Filho, Antonio C; Buri, Marcus V; Araújo Júnior, Roberto T; Pimenta, Renata; de Oliveira, José Salvador R; Filho, Valdir C; Macho, Antonio; Paredes-Gamero, Edgar J; de Oliveira Martins, Domingos T

    2017-04-01

    Canthin-6-one is a natural product isolated from various plant genera and from fungi with potential antitumor activity. In the present study, we evaluate the antitumor effects of canthin-6-one in human myeloid leukemia lineages. Kasumi-1 lineage was used as a model for acute myeloid leukemia. Cells were treated with canthin-6-one and cell death, cell cycle and differentiation were evaluated in both total cells (Lin(+)) and leukemia stem cell population (CD34(+)CD38(-)Lin(-/low)). Among the human lineages tested, Kasumi-1 was the most sensitive to canthin-6-one. Canthin-6-one induced cell death with apoptotic (caspase activation, decrease of mitochondrial potential) and necrotic (lysosomal permeabilization, double labeling of annexin V/propidium iodide) characteristics. Moreover, canthin-6-one induced cell cycle arrest at G0/G1 (7μM) and G2 (45μM) evidenced by DNA content, BrdU incorporation and cyclin B1/histone 3 quantification. Canthin-6-one also promoted differentiation of Kasumi-1, evidenced by an increase in the expression of myeloid markers (CD11b and CD15) and the transcription factor PU.1. Furthermore, a reduction of the leukemic stem cell population and clonogenic capability of stem cells were observed. These results show that canthin-6-one can affect Kasumi-1 cells by promoting cell death, cell cycle arrest and cell differentiation depending on concentration used. Canthin-6-one presents an interesting cytotoxic activity against leukemic cells and represents a promising scaffold for the development of molecules for anti-leukemic applications, especially by its anti-leukemic stem cell activity. Copyright © 2017 Elsevier B.V. All rights reserved.

  9. A Topical Mitochondria-Targeted Redox-Cycling Nitroxide Mitigates Oxidative Stress-Induced Skin Damage.

    PubMed

    Brand, Rhonda M; Epperly, Michael W; Stottlemyer, J Mark; Skoda, Erin M; Gao, Xiang; Li, Song; Huq, Saiful; Wipf, Peter; Kagan, Valerian E; Greenberger, Joel S; Falo, Louis D

    2017-03-01

    Skin is the largest human organ, and it provides a first line of defense that includes physical, chemical, and immune mechanisms to combat environmental stress. Radiation is a prevalent environmental stressor. Radiation-induced skin damage ranges from photoaging and cutaneous carcinogenesis caused by UV exposure, to treatment-limiting radiation dermatitis associated with radiotherapy, to cutaneous radiation syndrome, a frequently fatal consequence of exposures from nuclear accidents. The major mechanism of skin injury common to these exposures is radiation-induced oxidative stress. Efforts to prevent or mitigate radiation damage have included development of antioxidants capable of reducing reactive oxygen species. Mitochondria are particularly susceptible to oxidative stress, and mitochondrial-dependent apoptosis plays a major role in radiation-induced tissue damage. We reasoned that targeting a redox cycling nitroxide to mitochondria could prevent reactive oxygen species accumulation, limiting downstream oxidative damage and preserving mitochondrial function. Here we show that in both mouse and human skin, topical application of a mitochondrially targeted antioxidant prevents and mitigates radiation-induced skin damage characterized by clinical dermatitis, loss of barrier function, inflammation, and fibrosis. Further, damage mitigation is associated with reduced apoptosis, preservation of the skin's antioxidant capacity, and reduction of irreversible DNA and protein oxidation associated with oxidative stress. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

  10. Notch signaling in response to excitotoxicity induces neurodegeneration via erroneous cell cycle reentry.

    PubMed

    Marathe, S; Liu, S; Brai, E; Kaczarowski, M; Alberi, L

    2015-11-01

    Neurological disorders such as Alzheimer's disease, stroke and epilepsy are currently marred by the lack of effective treatments to prevent neuronal death. Erroneous cell cycle reentry (CCR) is hypothesized to have a causative role in neurodegeneration. We show that forcing S-phase reentry in cultured hippocampal neurons is sufficient to induce neurodegeneration. We found that kainic-acid treatment in vivo induces erroneous CCR and neuronal death through a Notch-dependent mechanism. Ablating Notch signaling in neurons provides neuroprotection against kainic acid-induced neuronal death. We further show that kainic-acid treatment activates Notch signaling, which increases the bioavailability of CyclinD1 through Akt/GSK3β pathway, leading to aberrant CCR via activation of CyclinD1-Rb-E2F1 axis. In addition, pharmacological blockade of this pathway at critical steps is sufficient to confer resistance to kainic acid-induced neurotoxicity in mice. Taken together, our results demonstrate that excitotoxicity leads to neuronal death in a Notch-dependent manner through erroneous CCR.

  11. Notch signaling in response to excitotoxicity induces neurodegeneration via erroneous cell cycle reentry

    PubMed Central

    Marathe, S; Liu, S; Brai, E; Kaczarowski, M; Alberi, L

    2015-01-01

    Neurological disorders such as Alzheimer's disease, stroke and epilepsy are currently marred by the lack of effective treatments to prevent neuronal death. Erroneous cell cycle reentry (CCR) is hypothesized to have a causative role in neurodegeneration. We show that forcing S-phase reentry in cultured hippocampal neurons is sufficient to induce neurodegeneration. We found that kainic-acid treatment in vivo induces erroneous CCR and neuronal death through a Notch-dependent mechanism. Ablating Notch signaling in neurons provides neuroprotection against kainic acid-induced neuronal death. We further show that kainic-acid treatment activates Notch signaling, which increases the bioavailability of CyclinD1 through Akt/GSK3β pathway, leading to aberrant CCR via activation of CyclinD1-Rb-E2F1 axis. In addition, pharmacological blockade of this pathway at critical steps is sufficient to confer resistance to kainic acid-induced neurotoxicity in mice. Taken together, our results demonstrate that excitotoxicity leads to neuronal death in a Notch-dependent manner through erroneous CCR. PMID:25822340

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

    PubMed

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

    2016-03-31

    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. 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. 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. 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 cells.

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

    PubMed

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

    2014-10-07

    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

  14. 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.

  15. 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

  16. Auranofin, as an anti-rheumatic gold compound, suppresses LPS-induced homodimerization of TLR4.

    PubMed

    Youn, Hyung S; Lee, Joo Y; Saitoh, Shin I; Miyake, Kensuke; Hwang, Daniel H

    2006-12-01

    Toll-like receptors (TLRs), which are activated by invading microorganisms or endogenous molecules, evoke immune and inflammatory responses. TLR activation is closely linked to the development of many chronic inflammatory diseases including rheumatoid arthritis. Auranofin, an Au(I) compound, is a well-known and long-used anti-rheumatic drug. However, the mechanism as to how auranofin relieves the symptom of rheumatoid arthritis has not been fully clarified. Our results demonstrated that auranofin suppressed TLR4-mediated activation of transcription factors, NF-kappaB and IRF3, and expression of COX-2, a pro-inflammatory enzyme. This suppression was well correlated with the inhibitory effect of auranofin on the homodimerization of TLR4 induced by an agonist. Furthermore, auranofin inhibited NF-kappaB activation induced by MyD88-dependent downstream signaling components of TLR4, MyD88, IKKbeta, and p65. IRF3 activation induced by MyD88-independent signaling components, TRIF and TBK1, was also downregulated by auranofin. Our results first demonstrate that auranofin suppresses the multiple steps in TLR4 signaling, especially the homodimerization of TLR4. The results suggest that the suppression of TLR4 activity by auranofin may be the molecular mechanism through which auranofin exerts anti-rheumatic activity.

  17. Inhibition of sodium current by taurine magnesium coordination compound prevents cesium chloride-induced arrhythmias.

    PubMed

    Yin, Yongqiang; Wen, Ke; Wu, Yanna; Kang, Yi; Lou, Jianshi

    2012-05-01

    The mechanism(s) by which taurine magnesium coordination compound (TMCC) inhibits experimental arrhythmias remains poorly understood. The purpose of this study was to observe the effects of TMCC against cesium chloride-induced arrhythmia in the rabbit heart and find whether the antiarrhythmic activity is related to inhibition of sodium current. Early afterdepolarization was induced by 1.5 mM cesium chloride (1 ml kg(-1)) through intravenous injection. The monophasic action potentials (MAP) and electrocardiograms were simultaneously recorded. The effect of TMCC on functional refractory periods (FRPs) in the left atrium was also observed in vitro. Arrhythmias onset was significantly retarded by TMCC. The number of ventricular premature contractions and incidence of monophasic ventricular tachycardia and polyphasic ventricular tachycardia in 10 min were decreased by TMCC. These effects can be abolished by veratridine (10 μg kg(-1)). MAP duration at 90% repolarization was significantly prolonged by TMCC, which can be prolonged even longer by veratridine (10 μg kg(-1)). In vitro experiments showed that FRPs was prolonged by TMCC which can be cancelled by veratridine (10 μg kg(-1)). TMCC prevents cesium chloride-induced arrhythmias, and inhibition of sodium current, in part, contributes to the antiarrhythmic effect of TMCC.

  18. 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.

  19. Natural compound Alternol induces oxidative stress-dependent apoptotic cell death preferentially in prostate cancer cells.

    PubMed

    Tang, Yuzhe; Chen, Ruibao; Huang, Yan; Li, Guodong; Huang, Yiling; Chen, Jiepeng; Duan, Lili; Zhu, Bao-Ting; Thrasher, J Brantley; Zhang, Xu; Li, Benyi

    2014-06-01

    Prostate cancers at the late stage of castration resistance are not responding well to most of current therapies available in clinic, reflecting a desperate need of novel treatment for this life-threatening disease. In this study, we evaluated the anticancer effect of a recently isolated natural compound, Alternol, in multiple prostate cancer cell lines with the properties of advanced prostate cancers in comparison to prostate-derived nonmalignant cells. As assessed by trypan blue exclusion assay, significant cell death was observed in all prostate cancer cell lines except DU145 but not in nonmalignant (RWPE-1 and BPH1) cells. Further analyses revealed that Alternol-induced cell death was an apoptotic response in a dose- and time-dependent manner, as evidenced by the appearance of apoptosis hallmarks such as caspase-3 processing and PARP cleavage. Interestingly, Alternol-induced cell death was completely abolished by reactive oxygen species scavengers N-acetylcysteine and dihydrolipoic acid. We also demonstrated that the proapoptotic Bax protein was activated after Alternol treatment and was critical for Alternol-induced apoptosis. Animal xenograft experiments in nude mice showed that Alternol treatment largely suppressed tumor growth of PC-3 xenografts but not Bax-null DU-145 xenografts in vivo. These data suggest that Alternol might serve as a novel anticancer agent for patients with late-stage prostate cancer. ©2014 American Association for Cancer Research.

  20. 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.

  1. GnRH-agonist induced depressive and anxiety symptoms during in vitro fertilization-embryo transfer cycles.

    PubMed

    Bloch, Miki; Azem, Foad; Aharonov, Inbar; Ben Avi, Irit; Yagil, Yaron; Schreiber, Shaul; Amit, Ami; Weizman, Abraham

    2011-01-01

    To determine whether the use of a GnRH agonist inducing a hypogonadic state during IVF-ET cycles induces negative mood symptoms, we conducted a prospective randomized study in 108 women comparing two different controlled ovarian stimulation protocols. A significant phase effect was observed for depression and anxiety symptoms during IVF-ET cycles reflecting an increase in symptoms between the hypogonadal phase and the peak in gonadotropin stimulation; however, the hypogonadal phase induced by the GnRH agonist was not associated with a significant increase in any of the studied mood parameters.

  2. Centchroman induces redox-dependent apoptosis and cell-cycle arrest in human endometrial cancer cells.

    PubMed

    Shyam, Hari; Singh, Neetu; Kaushik, Shweta; Sharma, Ramesh; Balapure, Anil K

    2017-04-01

    Centchroman (CC) or Ormeloxifene has been shown to induce apoptosis and cell cycle arrest in various types of cancer cells. This has, however, not been addressed for endometrial cancer cells where its (CC) mechanism of action remains unclear. This study focuses on the basis of antineoplasticity of CC by blocking the targets involved in the cell cycle, survival and apoptosis in endometrial cancer cells. Ishikawa Human Endometrial Cancer Cells were cultured under estrogen deprived medium, exposed to CC and analyzed for proliferation and apoptosis. Additionally, we also analyzed oxidative stress induced by CC. Cell viability studies confirmed the IC50 of CC in Ishikawa cells to be 20 µM after 48 h treatment. CC arrests the cells in G0/G1 phase through cyclin D1 and cyclin E mediated pathways. Phosphatidylserine externalization, nuclear morphology changes, DNA fragmentation, PARP cleavage, and alteration of Bcl-2 family protein expression clearly suggest ongoing apoptosis in the CC treated cells. Activation of caspase 3 & 9, up-regulation of AIF and inhibition of apoptosis by z-VAD-fmk clearly explains the participation of the intrinsic pathway of programmed cell death. Further, the increase of ROS, loss of MMP, inhibition of antioxidant (MnSOD, Cu/Zn-SOD and GST) and inhibition of apoptosis with L-NAC suggests CC induced oxidative stress leading to apoptosis via mitochondria mediated pathway. Therefore, CC could be a potential therapeutic agent for the treatment of Endometrial Cancer adjunct to its utility as a contraceptive and an anti-breast cancer agent.

  3. 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.

  4. Metabolical shifts towards alternative BTEX biodegradation intermediates induced by perfluorinated compounds in firefighting foams.

    PubMed

    Montagnolli, Renato Nallin; Lopes, Paulo Renato Matos; Cruz, Jaqueline Matos; Claro, Marina Turini; Quiterio, Gabriela Mercuri; Bidoia, Ederio Dino

    2017-04-01

    The type and concentration of perfluorinated compounds (PFCs) can induce different types of enzymes and promote alternate patterns of BTEX transformation. However, it is not known how the presence of active fluorocarbon-degrading microbial populations affects the transformation of BTEX. In addition to chemical analysis at the molecular level, our research approached the aqueous film forming fire-fighting foams (AFFF) and BTEX co-contamination at a large-scale with respirometers to quantify the total microbial metabolism of soil via CO2 output levels. The intended outcome of this research was to obtain and characterize shifts in BTEX degradation at a set realistic environmental condition while measuring byproducts and CO2 production. Both methodologies complimentarily provided an in-depth knowledge of the environmental behavior of fire-fighting foams. The biodegradation was monitored using headspace sampling and two types of gas chromatography: thermal conductivity detector and flame ionization detector. Headspace samples were periodically withdrawn for BTEX biodegradation and CO2 production analysis. Our research suggests the discovery of an altered metabolic pathway in aromatic hydrocarbons biodegradation that is directly affected by fluorinated substances. The fluorinated compounds affected the BTEX biodegradation kinetics, as PFCs may contribute to a shift in styrene and catechol concentrations in co-contamination scenarios. A faster production of styrene and catechol was detected. Catechol is also rapidly consumed, thus undergoing further metabolic stages earlier under the presence of PFCs. The release of AFFF compounds not only changes byproducts output but also drastically disturbs the soil microbiota according to the highly variable CO2 yields. Therefore, we observed a high sensitivity of microbial consortia due to PFCs in the AFFF formulation, therefore shifting their BTEX degradation routes in terms of intermediate products concentration. Copyright © 2016

  5. Irradiation-induced disordering and amorphization of Al3Ti-based intermetallic compounds

    NASA Astrophysics Data System (ADS)

    Park, Jeong-Yong; Kim, Il-Hyun; Motta, Arthur T.; Ulmer, Christopher J.; Kirk, Marquis A.; Ryan, Edward A.; Baldo, Peter M.

    2015-12-01

    An in situ ion-irradiation study, simultaneously examined using transmission electron microscopy, was performed to investigate irradiation-induced disordering and amorphization of Al3Ti-based intermetallic compounds. Thin foil samples of two crystalline structures: D022-structured Al3Ti and L12-structured (Al,Cr)3Ti were irradiated using 1.0 MeV Kr ions at a temperature range from 40 K to 573 K to doses up to 4.06 × 1015 ions/cm2. The results showed that both the compounds underwent an order-disorder transformation under irradiation, where both Al3Ti and (Al,Cr)3Ti ordered structures were fully transformed to the disordered face-centered cubic (FCC) structure except at the highest irradiation temperature of 573 K. A slightly higher irradiation dose was required for order-disorder transformation in case of Al3Ti as compared to (Al,Cr)3Ti at a given temperature. However, their amorphization resistances were different: while the disordered FCC (Al,Cr)3Ti amorphized at the irradiation dose of 6.25 × 1014 ions/cm2 (0.92 dpa) at 40 K and 100 K, the Al3Ti compound with the same disordered FCC structure maintained crystallinity up to 4.06 × 1015 ions/cm2 (5.62 dpa) at 40 K. The critical temperature for amorphization of (Al,Cr)3Ti under Kr ion irradiation is likely between 100 K and room temperature and the critical temperature for disordering between room temperature and 573 K.

  6. Involvement of Mcl1 in diallyl disulfide-induced G2/M cell cycle arrest in HL-60 cells.

    PubMed

    Yi, Lan; Ji, Xiao-Xia; Tan, Hui; Feng, Mei-Yan; Tang, Yi; Wen, Ling; Su, Qi

    2012-06-01

    Diallyl disulfide (DADS) has shown potential as a therapeutic agent in various cancers. Previously, we found that myeloid cell leukemia sequence 1 (Mcl1) was downregulated in DADS-induced cell cycle arrest in HL-60 human leukemia cells. Here, we investigated the role of this protein in DADS-induced G2/M cell cycle arrest in HL-60 cells. We demonstrated that DADS treatment significantly increased the proportion of G2/M phase HL-60 cells (P<0.05) and caused a time-dependent significant downregulation of Mcl1 and the cell cycle-related proteins PCNA and CDK1 (P<0.05). Small interfering RNA-mediated knockdown of Mcl1 expression in HL-60 cells arrested the cell cycle in G2/M phase. By co-immunoprecipitation, we demonstrated that Mcl1 associated with PCNA and CDK1 in G2/M cell cycle arrest in DADS-treated HL-60 cells. DADS decreased the interaction of Mcl1 with PCNA and CDK1, leading to G2/M cell cycle arrest in HL-60 cells. Mcl1 plays an important role in DADS-induced G2/M cell cycle arrest in HL-60 human leukemia cells.

  7. A Novel Gallium Compound Synergistically Enhances Bortezomib-induced Apoptosis in Mantle Cell Lymphoma Cells

    PubMed Central

    Chitambar, Christopher R.; Purpi, David P.

    2010-01-01

    Combination chemotherapy forms the backbone of cancer treatment. There is a need for new drug combinations for the treatment of mantle cell lymphoma (MCL). Herein, we show that gallium maltolate, a novel gallium compound, synergizes with bortezomib, a proteasome inhibitor, to induce cell death in MCL Granta cells. Cells exposed to either agent displayed caspase-3 activation, a loss of mitochondrial membrane potential, and a decrease in chymotrypsin-like activity. These effects were increased with both agents in combination. Our results show for the first time that the proteasome may be a target for gallium maltolate and suggest that the therapeutic potential of combination bortezomib and gallium maltolate warrants further investigation. PMID:20334913

  8. Two new compounds from Semen celosiae and their protective effects against CCl₄-induced hepatotoxicity.

    PubMed

    Xue, Qian; Sun, Zhen-Liang; Guo, Mei-Li; Wang, Ying; Zhang, Ge; Wang, Xiao-Kang

    2011-04-01

    Two new oleanolic acid saponins, namely celosin A (1) and celosin B (2), together with six known compounds, stigmasterol, β-sitosterol, β-daucosterol, hexacosoic acid, palmitic acid and stearic acid, were isolated from the ethanolic extract of Semen celosiae. The structures of celosin A (1) and celosin B (2) were determined by spectral analysis (including 1D- and 2D-NMR). The hepatoprotective activity of 1 and 2 with oral doses 1.0, 2.0 and 4.0 mg kg⁻¹ were investigated by carbon tetrachloride CCl₄-induced hepatotoxicity in mice. The results indicate that they have significant hepatoprotective effects, and that these hepatoprotective effects may be due to the antioxidant capability.

  9. 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.

  10. 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.

  11. 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.

  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. 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.

  14. Purified vitexin compound 1 induces apoptosis through activation of FOXO3a in hepatocellular carcinoma.

    PubMed

    Wang, Jian-Gang; Zheng, Xing-Xing; Zeng, Guang-Yao; Zhou, Ying-Jun; Yuan, Hong

    2014-01-01

    We previously reported that purified vitexin compound 1 (VB1, a neolignan from the seed of Chinese herb Vitex negundo) exhibited antitumor activity in cancer cell lines and xenograft models. In the present study, we examined the molecular mechanisms by which activation of the FOXO3a transcription factor mediated VB1-induced apoptosis in hepatocellular carcinoma (HCC) cells. The effects of VB1 on the proliferation of HCC cell lines HepG2, Hep3B, Huh-7 and human embryo liver L-02 cells were investigated using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Apoptotic death in HepG2 cells was examined using an enzyme-linked immunosorbent assay (ELISA) detection kit, flow cytometry after propidium iodide (PI) staining, and by DNA agarose gel electrophoresis. Caspase activity was measured using ELISA. The AKT/FOXO3a and ERK/FOXO3a pathways were analyzed using western blotting. VB1 inhibited human HCC cell proliferation in a concentration-dependent manner and increased the percentage of sub-G1 population HepG2 cells. Histone/DNA fragmentation and active caspase-3, -8 and -9 levels increased in a concentration-dependent manner and a DNA ladder was formed. The phosphorylation of AKT and ERK1/2 were inhibited and FOXO3a transcription factor was activated, resulting in apoptotic death. Knockdown of AKT1 by small interfering RNA (siRNA) and the MEK1/2 inhibitor, PD98059, enhanced VB1-induced apoptosis and FOXO3a transcriptional activity. Suppression of FOXO3a expression by siRNA inhibited VB1-induced apoptosis. VB1 induced expression of Bim, TRAIL, DR4 and DR5. Activation of the FOXO3a transcription factor appears to mediate pro-apoptotic effects of VB1 by inhibiting the AKT and ERK pathways.

  15. Morphine-induced Straub tail reaction in mice treated with serotonergic compounds.

    PubMed

    Belozertseva, Irina V; Dravolina, Olga A; Tur, Margarita A; Semina, Marina G; Zvartau, Edwin E; Bespalov, Anton Yu

    2016-11-15

    Constitutively active 5-HT2 receptors have been suggested to contribute to motoneuronal excitability, muscle spasms and spasticity. Accordingly, 5-HT2C receptor inverse agonists have been demonstrated in pilot experiments to reduce spasticity in animal model of spasticity and patients with spinal cord injuries. Thus, 5-HT2C receptor inverse agonists may represent a novel class of anti-spasticity agents justifying a search for compounds with robust 5-HT2C receptor inverse agonist activity either among the existing medications or via a dedicated drug discovery program. Morphine-induced Straub tail response in mice is regarded as a model of transient spasticity that may be suitable for supporting such drug discovery efforts. Subcutaneous injection of morphine (10-60mg/kg) induced a dose-dependent Straub tail reaction in male Swiss mice with maximum response obtained 15-30min after the morphine administration. When given prior to morphine, 5-HT2B/2C receptor inverse agonists cyproheptadine (1-10mg/kg, i.p.) and SB206553 (0.3-3mg/kg, i.p.) diminished Straub tail reaction dose-dependently without affecting spontaneous locomotor activity. In contrast, 5-HT2B/2C receptor antagonist methysergide (1-5.6mg/kg, i.p.) and 5-HT2C receptor antagonist SB242084 (1-5.6mg/kg, i.p.) as well as 5-HT2A receptor inverse agonist pimavanserin (1-10mg/kg, i.p.) had no appreciable effects on Straub tail response. Taken together, the findings indicate that constitutive activity of 5-HT2B/2C receptor may be involved in the mechanisms of morphine-induced spasticity. Thus, morphine-induced Straub tail response may be evaluated further as a candidate higher throughput test to identify 5-HT2C receptor inverse agonists with anti-spasticity effects in vivo.

  16. Characterization and quenching of friction-induced limit cycles of electro-hydraulic servovalve control systems with transport delay.

    PubMed

    Wang, Yuan-Jay

    2010-10-01

    This paper develops a systematic and straightforward methodology to characterize and quench the friction-induced limit cycle conditions in electro-hydraulic servovalve control systems with transport delay in the transmission line. The nonlinear friction characteristic is linearized by using its corresponding describing function. The delay time in the transmission line, which could accelerate the generation of limit cycles is particularly considered. The stability equation method together with parameter plane method provides a useful tool for the establishment of necessary conditions to sustain a limit cycle directly in the constructed controller coefficient plane. Also, the stable region, the unstable region, and the limit cycle region are identified in the parameter plane. The parameter plane characterizes a clear relationship between limit cycle amplitude, frequency, transport delay, and the controller coefficients to be designed. The stability of the predicted limit cycle is checked by plotting stability curves. The stability of the system is examined when the viscous gain changes with respect to the temperature of the working fluid. A feasible stable region is characterized in the parameter plane to allow a flexible choice of controller gains. The robust prevention of limit cycle is achieved by selecting controller gains from the asymptotic stability region. The predicted results are verified by simulations. It is seen that the friction-induced limit cycles can be effectively predicted, removed, and quenched via the design of the compensator even in the case of viscous gain and delay time variations unconditionally.

  17. Ultraviolet radiation-induced injury, chemokines, and leukocyte recruitment: An amplification cycle triggering cutaneous lupus erythematosus.

    PubMed

    Meller, Stephan; Winterberg, Franziska; Gilliet, Michel; Müller, Anja; Lauceviciute, Ingrida; Rieker, Juliane; Neumann, Norbert J; Kubitza, Robert; Gombert, Michael; Bünemann, Erich; Wiesner, Ulrike; Franken-Kunkel, Petra; Kanzler, Holger; Dieu-Nosjean, Marie-Caroline; Amara, Ali; Ruzicka, Thomas; Lehmann, Percy; Zlotnik, Albert; Homey, Bernhard

    2005-05-01

    To investigate the activation and recruitment pathways of relevant leukocyte subsets during the initiation and amplification of cutaneous lupus erythematosus (LE). Quantitative real-time polymerase chain reaction was used to perform a comprehensive analysis of all known chemokines and their receptors in cutaneous LE lesions, and the cellular origin of these chemokines and receptors was determined using immunohistochemistry. Furthermore, cytokine- and ultraviolet (UV) light-mediated activation pathways of relevant chemokines were investigated in vitro and in vivo. In the present study, we identified the CXCR3 ligands CXCL9 (interferon-gamma [IFNgamma]-induced monokine), CXCL10 (IFNgamma-inducible protein 10), and CXCL11 (IFN-inducible T cell alpha chemoattractant) as being the most abundantly expressed chemokine family members in cutaneous LE. Expression of these ligands corresponded with the presence of a marked inflammatory infiltrate consisting of mainly CXCR3-expressing cells, including skin-homing lymphocytes and blood dendritic cell antigen 2-positive plasmacytoid dendritic cells (PDCs). Within cutaneous LE lesions, PDCs accumulated within the dermis and were activated to produce type I IFN, as detected by the expression of the IFNalpha-inducible genes IRF7 and MxA. IFNalpha, in turn, was a potent and rapid inducer of CXCR3 ligands in cellular constituents of the skin. Furthermore, we demonstrated that the inflammatory CXCR3 ligands cooperate with the homeostatic chemokine CXCL12 (stromal cell-derived factor 1) during the recruitment of pathogenically relevant leukocyte subsets. Moreover, we showed that UVB irradiation induces the release of CCL27 (cutaneous T cell-attracting chemokine) from epidermal compartments into dermal compartments and up-regulates the expression of a distinct set of chemokines in keratinocytes. Taken together, our data suggest an amplification cycle in which UV light-induced injury induces apoptosis, necrosis, and chemokine production

  18. 2'-Nitroflavone induces cell cycle arrest and apoptosis in HeLa human cervical carcinoma cells.

    PubMed

    Cárdenas, Mariano G; Blank, Viviana C; Marder, Mariel; Roguin, Leonor P

    2008-09-08

    The mechanism of antitumor action of a synthetic nitroflavone derivative, 2'-nitroflavone, was evaluated in vitro in HeLa human cervix adenocarcinoma cells. We showed that the nitroflavone derivative slowed down the cell cycle at the S phase and increase the population of cells at the G2/M phase after 24h of incubation. The treatment with 2'-nitroflavone also induced an apoptotic response, characterized by an increase of the sub-G1 fraction of cells, by cells with chromatin condensation and membrane blebbing, by a typical ladder of DNA fragmentation and by detection of apoptotic cells stained with Annexin V. The observed apoptosis was regulated by caspase-8 and -9, both contributing to the activation of the effector caspase-3. In addition, inhibitors of caspase-8 or -9 partially protected HeLa cells from 2'-nitroflavone-induced cell death. We also found that 2'-nitroflavone did not affect the total amount of Bax and Bcl-2 proteins, although a translocation of Bax from cytosol to mitochondria was evident after 6h of exposure. Furthermore, 2'-nitroflavone decreased the expression of the anti-apoptotic Bcl-XL protein, induced the release of cytochrome C to cytosol and increased the levels of Fas and Fas-L. Our results indicated that both death receptor and mitochondria-dependent pathways are involved in the apoptotic cell death triggered by 2'-nitroflavone and suggest that this derivative could be a potentially useful agent for the treatment of certain malignancies.

  19. 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.

  20. 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.

  1. Cytotoxicity of the redox cycling compound diquat in isolated hepatocytes: involvement of hydrogen peroxide and transition metals.

    PubMed

    Sandy, M S; Moldeus, P; Ross, D; Smith, M T

    1987-11-15

    Diquat is a hepatotoxin whose toxicity in vivo and in vitro is mediated by redox cycling and greatly enhanced by pretreatment with 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), an inhibitor of glutathione reductase. The mechanism by which redox cycling mediates diquat cytotoxicity is unclear, however. Here, we have attempted to examine the roles of three potential products of redox cycling, namely superoxide anion radical (O2-.), hydrogen peroxide (H2O2), and hydroxyl radical (.OH), in the toxicity of diquat to BCNU-treated isolated hepatocytes. Addition of high concentrations of catalase, but not superoxide dismutase, to the incubations provided some protection against the toxic effect of diquat, but much better protection was observed when catalase was added in combination with the iron chelator desferrioxamine. Addition of desferrioxamine alone also provided considerable protection, whereas the addition of copper ions enhanced diquat cytotoxicity. Taken together, these results indicate that both H2O2 and the transition metals iron and copper could play major roles in the cytotoxicity of diquat. The role of O2-. remains less clear, however, but studies with diethylenetriaminepentaacetic acid indicate that O2-. is unlikely to significantly contribute to the reduction of Fe3+ to Fe2+. The hydroxyl radical or a related species seems the most likely ultimate toxic product of the H2O2/Fe2+ interaction, but hydroxyl radical scavengers afforded only minimal protection.

  2. The Pressure-Induced Structural Response of A2Hf2O7 (A=Y, Sm, Eu, Gd, Dy, Yb) Compounds from 0.1-50 GPa

    NASA Astrophysics Data System (ADS)

    Turner, K. M.; Rittman, D.; Heymach, R.; Turner, M.; Tracy, C.; Mao, W. L.; Ewing, R. C.

    2016-12-01

    A2B2O7 (A, B= cations) compounds have structures that make their properties conducive to many applications; for example they are a proposed waste-form for actinides generated in the nuclear fuel cycle. This interest in part is due to their structural responses to extreme environments of high P, T, or under intense irradiation. Depending on their cationic radius ratio, ra/rb, A2B2O7 compounds either crystallize as pyrochlore (ra/rb=1.46-1.7) or "defect fluorite" (ra/rb>1.46). The structure types are similar: they are derivatives of ideal fluorite with two cations and 1/8 missing anions. In pyrochlore, the cations and anion vacancy are ordered. In "defect fluorite"-structured oxides, the cations and anion vacancies are random. A2B2O7 compounds rarely amorphize in extreme environments. Rather, they disorder and undergo phase transitions; this resistance to amorphization contributes to the durability of this potential actinide waste-form. Under high-pressure, A2B2O7 compounds are known to disorder or form a cottunite-like phase. Their radius ratio affects their response to extreme environments; "defect fluorite" type compounds tend to disorder, and pyrochlore type compounds tend to form the cottunite-like phase. We have examined six A2Hf2O7 compounds (A=Y, Sm, Eu, Gd, Dy, Yb) in situ to 50 GPa. By keeping the B-site constant (Hf), we examined the effect of a changing radius ratio on the pressure-induced structural response of hafnates. We used symmetric DACs, ruby fluorescence, stainless steel gaskets, and methanol: ethanol (4:1 by volume) pressure medium. We characterized these materials with in situ Raman spectroscopy at Stanford University, and synchrotron X-Ray Diffraction (XRD) at APS 16 BM-D and ALS 12.2.2. The compounds were pyrochlore structured (Sm, Eu, Gd) and "defect-fluorite" structured (Y, Dy, Yb) hafnates . These compounds undergo a slow phase transition to a high-pressure cotunnite-like phase between 18-30 GPa. They undergo disordering of their cation

  3. The effects of exercise-induced muscle damage on cycling time-trial performance.

    PubMed

    Burt, Dean G; Twist, Craig

    2011-08-01

    Previous research has advocated that plyometric training improves endurance performance. However, a consequence of such a training is the immediate and prolonged appearance of exercise-induced muscle damage (EIMD). This study examined whether a single bout of plyometric exercise, designed to elicit muscle damage, affected cycling endurance performance. Seventeen participants were randomly assigned to either a muscle damage (n = 7 men, 1 woman) or nonmuscle damage (n = 8 men, 1 woman) group. Before and at 48 hours, participants were measured for perceived muscle soreness, peak isokinetic strength, and physiological, metabolic, and perceptual responses during 5-minute submaximal cycling at ventilatory threshold (VT) and a 15-minute time trial. Perceived muscle soreness and isokinetic strength (p < 0.05) were significantly altered in the muscle damage group after EIMD. No changes in heart rate or blood lactate were evident during submaximal exercise (p > 0.05). However, VO2, V(E), and rating of perceived exertion (RPE) values were increased at VT in the muscle damage group at 48 hours after EIMD (p < 0.05). During the time trial, mean power output, distance covered, and VO2 were lower in the muscle damage group at 48 hours after EIMD (p < 0.05). However, there was no change in RPE (p > 0.05), suggesting effort perception was unchanged during time-trial performance after EIMD. In conclusion, individuals using concurrent plyometric and endurance training programs to improve endurance performance should be aware of the acute impact of muscle-damaging exercise on subsequent cycling performance.

  4. Synthesis of new heterocyclic compounds based on pyrazolopyridine scaffold and evaluation of their neuroprotective potential in MPP(+)-induced neurodegeneration.

    PubMed

    Jouha, Jabrane; Loubidi, Mohammed; Bouali, Jamila; Hamri, Salha; Hafid, Abderrafia; Suzenet, Franck; Guillaumet, Gérald; Dagcı, Taner; Khouili, Mostafa; Aydın, Fadime; Saso, Luciano; Armagan, Güliz

    2017-03-31

    Neurodegenerative disorders including Alzheimer's disease, Parkinson's disease, and Huntington's disease affect millions of people in the world. Thus several new approaches to treat brain disorders are under development. The aim of the present study is to synthesize potential neuroprotective heterocyclic compounds based on pyrazolopyridine derivatives and then to evaluate their effects in MPP(+)-induced neurodegeneration in human neuroblastoma cell line (SH-SY5Y cells). The effects of the compounds on cell viability were measured by MTT assay and the changes in apoptosis-related proteins including bax, Bcl-2, Bcl-xl and caspase-3 were investigated by western blot technique. Based on the cell viability results obtained by MTT assay, the percentage of neuroprotection-induced by compounds against MPP(+)-induced neurotoxicity in SH-SY5Y cells was between 20% and 30% at 5 μM concentrations of all synthesized compounds. Moreover, the downregulation in pro-apoptotic proteins including bax and caspase-3 were found following the novel synthesized compounds treatments and these effects were observed in a dose-dependent manner. Our results provide an evidence that these heterocyclic compounds based on pyrazolopyridine derivatives may have a role on dopaminergic neuroprotection via antiapoptotic pathways.

  5. Organopalladium compound 7b targets mitochondrial thiols and induces caspase-dependent apoptosis in human myeloid leukemia cells.

    PubMed

    Moraes, V W R; Caires, A C F; Paredes-Gamero, E J; Rodrigues, T

    2013-06-06

    The advances in the treatment of chronic myeloid leukemia (CML) during the last years were also accompanied by the development of evading strategies by tumor cells, resulting in chemotherapy resistance in some patients. Patented organopalladium compounds derived from the reaction of N,N-dimethyl-1-phenethylamine (dmpa) with [1,2-ethanebis(diphenylphosphine)] (dppe) exhibited a potent antitumor activity in vivo and in vitro in melanoma cells. We showed here that the cyclopalladated derivative [Pd2(R(+))C(2), N-dmpa)2(μ-dppe)Cl2], named compound 7b, was highly effective to promote cell death in the K562 human leukemia cells and its mechanisms of action were investigated. It was shown that compound 7b was able to promote exclusively apoptotic cell death in K562 cells associated to cytochrome c release and caspase 3 activation. This cytotoxic effect was not observed in normal peripheral mononuclear blood cells. The compound 7b-induced intrinsic apoptotic pathway was triggered by the protein thiol oxidation that resulted in the dissipation of the mitochondrial transmembrane potential. The preventive effect of the dithiothreitol on the compound 7b-induced cell death and all downstream events associated to apoptosis confirmed that death signal was elicited by the thiol oxidation. These findings contribute to the elucidation of the palladacycle 7b-induced cell death mechanism and present this compound as a promising drug in the CML antitumor chemotherapy.

  6. Organopalladium compound 7b targets mitochondrial thiols and induces caspase-dependent apoptosis in human myeloid leukemia cells

    PubMed Central

    Moraes, V W R; Caires, A C F; Paredes-Gamero, E J; Rodrigues, T

    2013-01-01

    The advances in the treatment of chronic myeloid leukemia (CML) during the last years were also accompanied by the development of evading strategies by tumor cells, resulting in chemotherapy resistance in some patients. Patented organopalladium compounds derived from the reaction of N,N-dimethyl-1-phenethylamine (dmpa) with [1,2-ethanebis(diphenylphosphine)] (dppe) exhibited a potent antitumor activity in vivo and in vitro in melanoma cells. We showed here that the cyclopalladated derivative [Pd2(R(+))C2, N-dmpa)2(μ-dppe)Cl2], named compound 7b, was highly effective to promote cell death in the K562 human leukemia cells and its mechanisms of action were investigated. It was shown that compound 7b was able to promote exclusively apoptotic cell death in K562 cells associated to cytochrome c release and caspase 3 activation. This cytotoxic effect was not observed in normal peripheral mononuclear blood cells. The compound 7b-induced intrinsic apoptotic pathway was triggered by the protein thiol oxidation that resulted in the dissipation of the mitochondrial transmembrane potential. The preventive effect of the dithiothreitol on the compound 7b-induced cell death and all downstream events associated to apoptosis confirmed that death signal was elicited by the thiol oxidation. These findings contribute to the elucidation of the palladacycle 7b-induced cell death mechanism and present this compound as a promising drug in the CML antitumor chemotherapy. PMID:23744358

  7. Long-Term Plasticity in Reflex Excitability Induced by Five Weeks of Arm and Leg Cycling Training after Stroke.

    PubMed

    Klarner, Taryn; Barss, Trevor S; Sun, Yao; Kaupp, Chelsea; Loadman, Pamela M; Zehr, E Paul

    2016-11-03

    Neural connections remain partially viable after stroke, and access to these residual connections provides a substrate for training-induced plasticity. The objective of this project was to test if reflex excitability could be modified with arm and leg (A & L) cycling training. Nineteen individuals with chronic stroke (more than six months postlesion) performed 30 min of A & L cycling training three times a week for five weeks. Changes in reflex excitability were inferred from modulation of cutaneous and stretch reflexes. A multiple baseline (three pretests) within-subject control design was used. Plasticity in reflex excitability was determined as an increase in the conditioning effect of arm cycling on soleus stretch reflex amplitude on the more affected side, by the index of modulation, and by the modulation ratio between sides for cutaneous reflexes. In general, A & L cycling training induces plasticity and modifies reflex excitability after stroke.

  8. Long-Term Plasticity in Reflex Excitability Induced by Five Weeks of Arm and Leg Cycling Training after Stroke

    PubMed Central

    Klarner, Taryn; Barss, Trevor S.; Sun, Yao; Kaupp, Chelsea; Loadman, Pamela M.; Zehr, E. Paul

    2016-01-01

    Neural connections remain partially viable after stroke, and access to these residual connections provides a substrate for training-induced plasticity. The objective of this project was to test if reflex excitability could be modified with arm and leg (A & L) cycling training. Nineteen individuals with chronic stroke (more than six months postlesion) performed 30 min of A & L cycling training three times a week for five weeks. Changes in reflex excitability were inferred from modulation of cutaneous and stretch reflexes. A multiple baseline (three pretests) within-subject control design was used. Plasticity in reflex excitability was determined as an increase in the conditioning effect of arm cycling on soleus stretch reflex amplitude on the more affected side, by the index of modulation, and by the modulation ratio between sides for cutaneous reflexes. In general, A & L cycling training induces plasticity and modifies reflex excitability after stroke. PMID:27827888

  9. 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).

  10. 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.

  11. Magnetization changes in 2% Mn pipeline steel induced by uniaxial tensile stress cycles of increasing amplitude

    SciTech Connect

    Guo, X.; Atherton, D.L.

    1995-09-01

    The application of cyclic stress to a ferromagnetic normally gives irreversible magnetization shifts towards the anhysteretic magnetization. Here experimental measurements are presented that show the irreversible magnetization changes induced by cyclic uniaxial isofield stress applied after magnetization at particular points on minor hysteresis loops. Selecting the (M,H) point and magnetization history, then applying stress cycles of increasing amplitude enables irreversible changes, initially away from and later toward the anhysteretic curve, to be obtained. Examples of a second inversion (i.e., irreversible shifts initially toward, then away and subsequently, toward the anhysteretic magnetization) with increasing amplitude cyclic uniaxial stress are also given. Preisach diagrams are used to interpret these results qualitatively in terms of local, more extensive and global anhysteretic states.

  12. Parthenolide induces apoptosis and cell cycle arrest of human 5637 bladder cancer cells in vitro.

    PubMed

    Cheng, Guang; Xie, Liping

    2011-08-09

    Parthenolide, the principal component of sesquiterpene lactones present in medical plants such as feverfew (Tanacetum parthenium), has been reported to have anti-tumor activity. In this study, we evaluated the therapeutic potential of parthenolide against bladder cancer and its mechanism of action. Treatment of bladder cancer cells with parthenolide resulted in a significant decrease in cell viability. Parthenolide induced apoptosis through the modulation of Bcl-2 family proteins and poly (ADP-ribose) polymerase degradation. Treatment with parthenolide led to G1 phase cell cycle arrest in 5637 cells by modulation of cyclin D1 and phosphorylated cyclin-dependent kinase 2. Parthenolide also inhibited the invasive ability of bladder cancer cells. These findings suggest that parthenolide could be a novel therapeutic agent for treatment of bladder cancer.

  13. 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.

  14. Hyperacetylation in prostate cancer induces cell cycle aberrations, chromatin reorganization and altered gene expression profiles

    PubMed Central

    Watson, Jenny A; McKenna, Declan J; Maxwell, Perry; Diamond, James; Arthur, Ken; McKelvey-Martin, Valerie J; Hamilton, Peter W

    2010-01-01

    Abstract Histone acetylation is a fundamental mechanism in the regulation of local chromatin conformation and gene expression. Research has focused on the impact of altered epigenetic environments on the expression of specific genes and their pathways. However, changes in histone acetylation also have a global impact on the cell. In this study we used digital texture analysis to assess global chromatin patterns following treatment with trichostatin A (TSA) and have observed significant alterations in the condensation and distribution of higher-order chromatin, which were associated with altered gene expression profiles in both immortalised normal PNT1A prostate cell line and androgen-dependent prostate cancer cell line LNCaP. Furthermore, the extent of TSA-induced disruption was both cell cycle and cell line dependent. This was illustrated by the identification of sub-populations of prostate cancer cells expressing high levels of H3K9 acetylation in the G2/M phase of the cell cycle that were absent in normal cell populations. In addition, the analysis of enriched populations of G1 cells showed a global decondensation of chromatin exclusively in normal cells. PMID:19583812

  15. 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.

  16. Irradiation-induced protein inactivation reveals Golgi enzyme cycling to cell periphery

    PubMed Central

    Jarvela, Timothy; Linstedt, Adam D.

    2012-01-01

    Acute inhibition is a powerful technique to test proteins for direct roles and order their activities in a pathway, but as a general gene-based strategy, it is mostly unavailable in mammalian systems. As a consequence, the precise roles of proteins in membrane trafficking have been difficult to assess in vivo. Here we used a strategy based on a genetically encoded fluorescent protein that generates highly localized and damaging reactive oxygen species to rapidly inactivate exit from the endoplasmic reticulum (ER) during live-cell imaging and address the long-standing question of whether the integrity of the Golgi complex depends on constant input from the ER. Light-induced blockade of ER exit immediately perturbed Golgi membranes, and surprisingly, revealed that cis-Golgi-resident proteins continuously cycle to peripheral ER-Golgi intermediate compartment (ERGIC) membranes and depend on ER exit for their return to the Golgi. These experiments demonstrate that ER exit and extensive cycling of cis-Golgi components to the cell periphery sustain the mammalian Golgi complex. PMID:22421362

  17. 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.

  18. 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.

  19. Protective effect of captopril, olmesartan, melatonin and compound 21 on doxorubicin-induced nephrotoxicity in rats.

    PubMed

    Hrenák, J; Arendášová, K; Rajkovičová, R; Aziriová, S; Repová, K; Krajčírovičová, K; Celec, P; Kamodyová, N; Bárta, A; Adamcová, M; Paulis, L; Simko, F

    2013-01-01

    Chronic kidney disease (CKD) represents a serious public health problem with increasing prevalence and novel approaches to renal protection are continuously under investigation. The aim of this study was to compare the effect of melatonin and angiotensin II type 2 receptor agonist compound 21 (C21) to angiotensin converting enzyme inhibitor captopril and angiotensin II type 1 receptor blocker olmesartan on animal model of doxorubicin nephrotoxicity. Six groups of 3-month-old male Wistar rats (12 per group) were treated for four weeks. The first group served as a control. The remaining groups were injected with a single dose of doxorubicin (5 mg/kg i.v.) at the same day as administration of either vehicle or captopril (100 mg/kg/day) or olmesartan (10 mg/kg/day) or melatonin (10 mg/kg/day) or C21 (0.3 mg/kg/day) was initiated. After four week treatment, the blood pressure and the level of oxidative stress were enhanced along with reduced glomerular density and increased glomerular size. Captopril, olmesartan and melatonin prevented the doxorubicin-induced increase in systolic blood pressure. All four substances significantly diminished the level of oxidative burden and prevented the reduction of glomerular density and modestly prevented the increase of glomerular size. We conclude that captopril, olmesartan, melatonin and C21 exerted a similar level of renoprotective effects in doxorubicin-induced nephrotoxicity.

  20. Olive oil phenolic compounds inhibit homocysteine-induced endothelial cell adhesion regardless of their different antioxidant activity.

    PubMed

    Manna, Caterina; Napoli, Daniela; Cacciapuoti, Giovanna; Porcelli, Marina; Zappia, Vincenzo

    2009-05-13

    In this study, we examine the effect of extra virgin olive oil phenolic compounds on homocysteine-induced endothelial dysfunction and whether the protective effects are related to their different scavenging activities. Structurally related compounds have been assayed for their ability to reduce homocysteine-induced monocyte adhesion as well as the cell surface expression of intercellular adhesion molecule-1 (ICAM-1) in EA.hy.926 cells. As well-known, among the selected phenolic compounds, hydroxytyrosol, homovanillyl alcohol, and the hydroxycinnamic acid derivatives caffeic and ferulic acid display high scavenging activities, while tyrosol and p-coumaric acid are poorly active. All of the tested compounds, approaching potential in vivo concentrations, significantly reduce homocysteine-induced cell adhesion and ICAM-1 expression. Interestingly, we report the first evidence that monophenols tyrosol and p-coumaric acid are selectively protective only in homocysteine-activated cells, while they are ineffective in reducing ICAM-1 expression induced by TNFalpha. Finally, we report the synergistic effect of o-diphenolic and monophenolic compounds.

  1. 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.

  2. Gamma radiation induced cell cycle perturbations and DNA damage in Catla Catla as measured by flow cytometry.

    PubMed

    Anbumani, S; Mohankumar, Mary N

    2015-03-01

    Gamma radiation induced cell cycle perturbations and DNA damage in Catla catla were analyzed in erythrocytes at different time points using flow cytometry (FCM). Protracted exposure to radiation induced damage between days 12 and 45. Disturbances in cell cycle machinery, i.e., proportional increase and decrease in Gap0 or quiescent/Gap1 (G0/G1), Synthesis (S) and Gap2/Mitotic (G2/M) phases were observed at both acute and protracted treatments. Both acute and protracted exposures induced apoptosis with a notable significance between days 3 and 6 at protracted and on day 45 at acute doses. Fish exposed protractedly avail some DNA repair mechanisms than acutely exposed. This is the first study to analyze radiation induced DNA damage under laboratory conditions and suggests that flow cytometry can also be an alternate tool to screen genotoxicity induced by ionizing radiation in fish. Copyright © 2014 Elsevier Inc. All rights reserved.

  3. Evodiamine Prevents Glioma Growth, Induces Glioblastoma Cell Apoptosis and Cell Cycle Arrest through JNK Activation.

    PubMed

    Wu, Wen-Shin; Chien, Chih-Chiang; Liu, Kao-Hui; Chen, Yen-Chou; Chiu, Wen-Ta

    2017-01-01

    Evodiamine (EVO) is an active medicinal compound derived from the traditional herbal medicine Evodia rutaecarpa. It has been reported that evodiamine has several beneficial biological properties, including anticancer and anti-inflammatory activities. However, the in vitro and in vivo anticancer activities of EVO against the growth of glioblastoma cells remain undefined. EVO induced significant decreases in the viability of U87 and C6 glioma cells, but not of primary astrocytes, according with the occurrence of apoptotic characteristics including DNA ladders, caspase-3 and poly(ADP ribose) polymerase (PARP) protein cleavage, and hypodiploid cells. The disruption of the mitochondrial membrane potential (MMP) was detected, and it was found that the peptidyl caspase-9 inhibitor, Z-LEHD-FMK, significantly prevented glioma cells from EVO-induced apoptosis. Increased c-Jun N-terminal kinase (JNK) protein phosphorylation by EVO was observed, and the addition of JNK inhibitors, SP600125 and JNKI inhibited the EVO-induced apoptosis was inhibited. Additionally, EVO treatment induced G2/M arrest with increased polymerized tubulin protein expression in U87 and C6 cells. Elevated expressions of the cyclin B1, p53, and phosphorylated (p)-p53 proteins were detected in EVO-treated glioma cells, and these were inhibited by JNK inhibitors. An in vivo study showed that EVO significantly reduced the growth of gliomas elicited by the subcutaneous injection of U87 cells with increases in cyclin B1, p53, and p-p53 protein expressions in tumors. An analysis of eight EVO-related chemicals showed that alkyl groups at position 14 in EVO are important for its anti-glioma effects which involve both apoptosis and G2/M arrest. Evidence is provided that supports EVO induction of apoptosis and G2/M arrest via the activation of JNK-mediated gene expression and disruption of MMP in glioblastoma cells. EVO was shown to penetrate the blood-brain barrier; EVO is therefore predicted to be a promising

  4. Tumor cycling hypoxia induces chemoresistance in glioblastoma multiforme by upregulating the expression and function of ABCB1

    PubMed Central

    Chou, Chii-Wen; Wang, Chi-Chung; Wu, Chung-Pu; Lin, Yu-Jung; Lee, Yu-Chun; Cheng, Ya-Wen; Hsieh, Chia-Hung

    2012-01-01

    Tumor cycling hypoxia is now a well-recognized phenomenon in animal and human solid tumors. However, how tumor cycling hypoxia impacts chemotherapy is unclear. In the present study, we explored the impact and the mechanism of cycling hypoxia on tumor microenvironment-mediated chemoresistance. Hoechst 33342 staining and hypoxia-inducible factor–1 (HIF-1) activation labeling together with immunofluorescence imaging and fluorescence-activated cell sorting were used to isolate hypoxic tumor subpopulations from human glioblastoma xenografts. ABCB1 expression, P-glycoprotein function, and chemosensitivity in tumor cells derived from human glioblastoma xenografts or in vitro cycling hypoxic stress-treated glioblastoma cells were determined using Western blot analysis, drug accumulation and efflux assays, and MTT assay, respectively. ABCB1 expression and P-glycoprotein function were upregulated under cycling hypoxia in glioblastoma cells concomitant with decreased responses to doxorubicin and BCNU. However, ABCB1 knockdown inhibited these effects. Moreover, immunofluorescence imaging and flow cytometric analysis for ABCB1, HIF-1 activation, and Hoechst 3342 in glioblastoma revealed highly localized ABCB1 expression predominantly in potentially cycling hypoxic areas with HIF-1 activation and blood perfusion in the solid tumor microenvironment. The cycling hypoxic tumor cells derived from glioblastoma xenografts exhibited higher ABCB1 expression, P-glycoprotein function, and chemoresistance, compared with chronic hypoxic and normoxic cells. Tumor-bearing mice that received YC-1, an HIF-1α inhibitor, exhibited suppressed tumor microenvironment-induced ABCB1 induction and enhanced survival rate in BCNU chemotherapy. Cycling hypoxia plays a vital role in tumor microenvironment-mediated chemoresistance through the HIF-1–dependent induction of ABCB1. HIF-1 blockade before and concurrent with chemotherapy could suppress cycling hypoxia-induced chemoresistance. PMID:22946104

  5. The effect of topically applied salicylic compounds on serotonin-induced scratching behaviour in hairless rats.

    PubMed

    Thomsen, J S; Simonsen, L; Benfeldt, E; Jensen, S B; Serup, J

    2002-08-01

    There is a strong need for antipruritic substances for treating itch in clinical dermatology. In one recent human study, topically applied acetylsalicylic acid has been described to rapidly decrease histamine-induced itch. We have established a model for periferally elicited pruritus by injecting serotonin into the rostral back area (neck) in rats. Using this model, we aimed to investigate the antipruritic potential of four different salicylic compounds, which all possess different skin penetration characteristics. Eighteen rats were studied for 6 weeks. Prior to serotonin injections (2 mg/ml, 50 micro l), 10 micro l of test substances was applied to a circular area 18 mm in diameter. The four substances were salicylic acid, butyl salicylate, diethylamine salicylate and salicylamide, all solubilized in dimethyl isosorbide to a concentration of 5% w/w. Diethylamine salicylate and salicylamide were previously shown to be slowly absorbed through rat skin in contrast to salicylic acid and butyl salicylate. After serotonin injections, scratching was monitored by video recording for 1.5 h. Compared with the vehicle, a lower number of scratch sequences were seen when diethylamine salicylate (P < 0.001) and salicylamide (P = 0.005) had been applied. The numbers of scratch sequences were lower with diethylamine salicylate and salicylamide than with the vehicle throughout the 1.5-h study period. We conclude that topical application of diethylamine salicylate and salicylamide could suppress serotonin-induced scratching in rats. The antipruritic effect seems to be related to the slow drug release of the two substances. The results may be clinically relevant as serotonin induces itch in humans.

  6. 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.

  7. Enhancement of fracture healing in the rat, modulated by compounds that stimulate inducible nitric oxide synthase

    PubMed Central

    Rajfer, R. A.; Kilic, A.; Neviaser, A. S.; Schulte, L. M.; Hlaing, S. M.; Landeros, J.; Ferrini, M. G.; Ebramzadeh, E.

    2017-01-01

    Objectives We investigated the effects on fracture healing of two up-regulators of inducible nitric oxide synthase (iNOS) in a rat model of an open femoral osteotomy: tadalafil, a phosphodiesterase inhibitor, and the recently reported nutraceutical, COMB-4 (consisting of L-citrulline, Paullinia cupana, ginger and muira puama), given orally for either 14 or 42 days. Materials and Methods Unilateral femoral osteotomies were created in 58 male rats and fixed with an intramedullary compression nail. Rats were treated daily either with vehicle, tadalafil or COMB-4. Biomechanical testing of the healed fracture was performed on day 42. The volume, mineral content and bone density of the callus were measured by quantitative CT on days 14 and 42. Expression of iNOS was measured by immunohistochemistry. Results When compared with the control group, the COMB-4 group exhibited 46% higher maximum strength (t-test, p = 0.029) and 92% higher stiffness (t-test, p = 0.023), but no significant changes were observed in the tadalafil group. At days 14 and 42, there was no significant difference between the three groups with respect to callus volume, mineral content and bone density. Expression of iNOS at day 14 was significantly higher in the COMB-4 group which, as expected, had returned to baseline levels at day 42. Conclusion This study demonstrates an enhancement in fracture healing by an oral natural product known to augment iNOS expression. Cite this article: R. A. Rajfer, A. Kilic, A. S. Neviaser, L. M. Schulte, S. M. Hlaing, J. Landeros, M. G. Ferrini, E. Ebramzadeh, S-H. Park. Enhancement of fracture healing in the rat, modulated by compounds that stimulate inducible nitric oxide synthase: Acceleration of fracture healing via inducible nitric oxide synthase. Bone Joint Res 2017:6:–97. DOI: 10.1302/2046-3758.62.BJR-2016-0164.R2. PMID:28188129

  8. An Aqueous Extract of Tuberaria lignosa Inhibits Cell Growth, Alters the Cell Cycle Profile, and Induces Apoptosis of NCI-H460 Tumor Cells.

    PubMed

    Pereira, Joana M; Lopes-Rodrigues, Vanessa; Xavier, Cristina P R; Lima, M João; Lima, Raquel T; Ferreira, Isabel C F R; Vasconcelos, M Helena

    2016-05-06

    Tuberaria lignosa (Sweet) Samp. is found in European regions, and has antioxidant properties due to its composition in ascorbic acid and phenolic compounds. Given its traditional use and antioxidant properties, the tumor cell growth inhibitory potential of aqueous extracts from T. lignosa (prepared by infusion and decoction) was investigated in three human tumor cell lines: MCF-7 (breast adenocarcinoma), NCI-H460 (non-small cell lung cancer), and HCT-15 (human colorectal adenocarcinoma). Both extracts inhibited the growth of these cell lines; the most potent one being the T. lignosa extract obtained by infusion in the NCI-H460 cells (GI50 of approximately 50 μg/mL). Further assays were carried out with this extract in NCI-H460 cells. At 100 μg/mL or 150 μg/mL it caused an increase in the percentage of cells in the G0/G1 phase and a decrease of cells in S phase of the cell cycle. Additionally, these concentrations caused an increase in the percentage of apoptotic cells. In agreement, a decrease in total poly (ADP-ribose) polymerase (PARP) and pro-caspase 3 levels was found. In conclusion, the T. lignosa extract obtained by infusion was more potent in NCI-H460 cells, altering the cell cycle progression and inducing apoptosis. This work highlights the importance of T. lignosa as a source of bioactive compounds with tumor cell growth inhibitory potential.

  9. Induction of cell cycle arrest and apoptosis in HT-29 human colon cancer cells by the dietary compound luteolin.

    PubMed

    Lim, Do Y; Jeong, Yoonhwa; Tyner, Angela L; Park, Jung H Y

    2007-01-01

    Luteolin is 3',4',5,7-tetrahydroxyflavone found in celery, green pepper, and perilla leaf that inhibits tumorigenesis in animal models. We examined luteolin-mediated regulation of cell cycle progression and apoptosis in the HT-29 human colon cancer cell line. Luteolin decreased DNA synthesis and viable HT-29 cell numbers in a concentration-dependent manner. It inhibited cyclin-dependent kinase (CDK)4 and CDK2 activity, resulting in G1 arrest with a concomitant decrease of phosphorylation of retinoblastoma protein. Activities of CDK4 and CDK2 decreased within 2 h after luteolin treatment, with a 38% decrease in CDK2 activity (P < 0.05) observed in cells treated with 40 micromol/l luteolin. Luteolin inhibited CDK2 activity in a cell-free system, suggesting that it directly inhibits CDK2. Cyclin D1 levels decreased after luteolin treatment, although no changes in expression of cyclin A, cyclin E, CDK4, or CDK2 were detected. Luteolin also promoted G2/M arrest at 24 h posttreatment by downregulating cyclin B1 expression and inhibiting cell division cycle (CDC)2 activity. Luteolin promoted apoptosis with increased activation of caspases 3, 7, and 9 and enhanced poly(ADP-ribose) polymerase cleavage and decreased expression of p21(CIP1/WAF1), survivin, Mcl-1, Bcl-x(L), and Mdm-2. Decreased expression of these key antiapoptotic proteins could contribute to the increase in p53-independent apoptosis that was observed in HT-29 cells. We demonstrate that luteolin promotes both cell cycle arrest and apoptosis in the HT-29 colon cancer cell line, providing insight about the mechanisms underlying its antitumorigenic activities.

  10. 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

  11. 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).

  12. Parkin induces G2/M cell cycle arrest in TNF-α-treated HeLa cells.

    PubMed

    Lee, Min Ho; Cho, Yoonjung; Jung, Byung Chul; Kim, Sung Hoon; Kang, Yeo Wool; Pan, Cheol-Ho; Rhee, Ki-Jong; Kim, Yoon Suk

    2015-08-14

    Parkin is a known tumor suppressor. However, the mechanism by which parkin acts as a tumor suppressor remains to be fully elucidated. Previously, we reported that parkin expression induces caspase-dependent apoptotic cell death in TNF-α-treated HeLa cells. However, at that time, we did not consider the involvement of parkin in cell cycle control. In the current study, we investigated whether parkin is involved in cell cycle regulation and suppression of cancer cell growth. In our cell cycle analyses, parkin expression induced G2/M cell cycle arrest in TNF-α-treated HeLa cells. To elucidate the mechanism(s) by which parkin induces this G2/M arrest, we analyzed cell cycle regulatory molecules involved in the G2/M transition. Parkin expression induced CDC2 phosphorylation which is known to inhibit CDC2 activity and cause G2/M arrest. Cyclin B1, which is degraded during the mitotic transition, accumulated in response to parkin expression, thereby indicating parkin-induced G2/M arrest. Next, we established that Myt1, which is known to phosphorylate and inhibit CDC2, increased following parkin expression. In addition, we found that parkin also induces increased Myt1 expression, G2/M arrest, and reduced cell viability in TNF-α-treated HCT15 cells. Furthermore, knockdown of parkin expression by parkin-specific siRNA decreased Myt1 expression and phosphorylation of CDC2 and resulted in recovered cell viability. These results suggest that parkin acts as a crucial molecule causing cell cycle arrest in G2/M, thereby suppressing tumor cell growth.

  13. 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.

  14. 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

  15. Dietary Compound Kaempferol Inhibits Airway Thickening Induced by Allergic Reaction in a Bovine Serum Albumin-Induced Model of Asthma.

    PubMed

    Shin, Daekeun; Park, Sin-Hye; Choi, Yean-Jung; Kim, Yun-Ho; Antika, Lucia Dwi; Habibah, Nurina Umy; Kang, Min-Kyung; Kang, Young-Hee

    2015-12-16

    Asthma is characterized by aberrant airways including epithelial thickening, goblet cell hyperplasia, and smooth muscle hypertrophy within the airway wall. The current study examined whether kaempferol inhibited mast cell degranulation and prostaglandin (PG) release leading to the development of aberrant airways, using an in vitro model of dinitrophenylated bovine serum albumin (DNP-BSA)-sensitized rat basophilic leukemia (RBL-2H3) mast cells and an in vivo model of BSA-challenged asthmatic mice. Nontoxic kaempferol at 10-20 μM suppressed β-hexosaminidase release and cyclooxygenase 2 (COX2)-mediated production of prostaglandin D2 (PGD2) and prostaglandin F2α (PGF2α) in sensitized mast cells. Oral administration of ≤20 mg/kg kaempferol blocked bovine serum albumin (BSA) inhalation-induced epithelial cell excrescence and smooth muscle hypertrophy by attenuating the induction of COX2 and the formation of PGD2 and PGF2α, together with reducing the anti-α-smooth muscle actin (α-SMA) expression in mouse airways. Kaempferol deterred the antigen-induced mast cell activation of cytosolic phospholipase A2 (cPLA2) responsive to protein kinase Cμ (PKCμ) and extracellular signal-regulated kinase (ERK). Furthermore, the antigen-challenged activation of Syk-phospholipase Cγ (PLCγ) pathway was dampened in kaempferol-supplemented mast cells. These results demonstrated that kaempferol inhibited airway wall thickening through disturbing Syk-PLCγ signaling and PKCμ-ERK-cPLA2-COX2 signaling in antigen-exposed mast cells. Thus, kaempferol may be a potent anti-allergic compound targeting allergic asthma typical of airway hyperplasia and hypertrophy.

  16. The ginsenoside metabolite compound K, a novel agonist of glucocorticoid receptor, induces tolerance to endotoxin-induced lethal shock.

    PubMed

    Yang, Chul-Su; Ko, Sung-Ryong; Cho, Byung-Goo; Shin, Dong-Min; Yuk, Jae-Min; Li, Shengjin; Kim, Jin-Man; Evans, Ronald M; Jung, Jun-Sub; Song, Dong-Keun; Jo, Eun-Kyeong

    2008-01-01

    Compound K (C-K), a protopanaxadiol ginsenoside metabolite, was previously shown to have immunomodulatory effects. Here, we describe a novel therapeutic role for C-K in the treatment of lethal sepsis through the modulation of Toll-like receptor (TLR) 4-associated signalling via glucocorticoid receptor (GR) binding. In mononuclear phagocytes, C-K significantly repressed the activation of TLR4/lipopolysaccharide (LPS)-induced NF-kappaB and mitogen-activated protein kinases (MAPKs), as well as the secretion of pro-inflammatory cytokines. However C-K did not affect the TLR3-mediated expression of interferon-beta or the nuclear translocation of IRF-3. C-K competed with the synthetic glucocorticoid dexamethasone for binding to GR and activated glucocorticoid responsive element (GRE)-containing reporter plasmids in a dose-dependent manner. In addition, the blockade of GR with either the GR antagonist RU486 or a siRNA against GR substantially reversed the anti-inflammatory effects of C-K. Furthermore, TLR4-dependent repression of inflammatory response genes by C-K was mediated through the disruption of p65/interferon regulatory factor complexes. Importantly, pre- or post-treatment with C-K significantly rescued mice from Gram-negative bacterial LPS-induced lethal shock by lowering their systemic inflammatory cytokine levels and by reversing the lethal sequelae of sepsis. Collectively, these results demonstrate that C-K, as a functional ligand of GR, regulates distinct TLR4-mediated inflammatory responses, and suggest a novel therapy for Gram-negative septic shock.

  17. Role of p21 in SP600125-induced cell cycle arrest, endoreduplication, and apoptosis.

    PubMed

    Moon, Dong-Oh; Choi, Yung Hyun; Kim, Gi-Young

    2011-10-01

    The anti-cancer effect of the c-Jun N-terminal kinase (JNK) inhibitor SP600125 has been well evaluated in human cancer cells. However the role of p21 in SP600125-mediated G(2)/M distribution is not fully understood. Our results showed that the transcriptional activation of p21 by SP600125 is mediated through the proximal regions of multiple Sp1 sites in the p21 promoter following ERK-dependent phosphorylation of Sp1. In this process, p21 induces endoreduplication through the inhibition of cyclin E/Cdk2 activity at 24 h but does not directly regulate cyclin B1/Cdc2 activity. Furthermore, SP600125 induces the phosphorylation of p21 at Thr 145 through the PI3K/Akt pathway. Akt-mediated phosphorylation of p21 and protection of apoptosis are completely abolished by inhibitors of PI3K and Akt. In summary using time points, we identified the dual functions of p21 as an inhibitor of cell-cycle progression at 24 h and as an anti-apoptotic factor at 48 h. © Springer Basel AG 2011

  18. Few-cycle pulse laser induced damage threshold determination of ultra-broadband optics.

    PubMed

    Kafka, Kyle R P; Talisa, Noah; Tempea, Gabriel; Austin, Drake R; Neacsu, Catalin; Chowdhury, Enam A

    2016-12-12

    A systematic study of few-cycle pulse laser induced damage threshold (LIDT) determination was performed for commercially-available ultra-broadband optics, (i.e. chirped mirrors, silver mirrors, beamsplitters, etc.) in vacuum and in air, for single and multi-pulse regime (S-on-1). Multi-pulse damage morphology at fluences below the single-pulse LIDT was studied in order to investigate the mechanisms leading to the onset of damage. Stark morphological contrast was observed between multi-pulse damage sites formed in air versus those in vacuum. One effect of vacuum testing compared to air included suppression of laser-induced periodic surface structures (LIPSS) formation, possibly influenced by a reduced presence of damage debris. Another effect of vacuum was occasional lowering of LIDT, which appears to be due to the stress-strain performance of the coating design during laser irradiation and under the external stress of vacuum ambience. A fused silica substrate is also examined, and a non-LIPSS nanostructuring is observed on the surface. Possible mechanisms are discussed.

  19. Grape Seed Extract Induces Cell Cycle Arrest and Apoptosis in Human Colon Carcinoma Cells

    PubMed Central

    Kaur, Manjinder; Mandair, Reinuka; Agarwal, Rajesh; Agarwal, Chapla

    2008-01-01

    One approach to control colorectal cancer (CRC) is its preventive intervention by dietary agents or those consumed as supplements. However, since most of these products are often consumed by patients as an alternative and complementary medicine (CAM) practice, a scientific base such as efficacy, mechanism and standardized preparation, needs to be developed. Grape seed extract (GSE) is one such supplement widely consumed by humans for its several health benefits. We reported recently that GSE inhibits CRC cell HT29 growth in culture and nude mice xenograft. Since GSE is available commercially through different vendors, here we assessed whether GSE from two different manufacturers produces comparable biological effects in a panel of human CRC cell lines. Our results show that irrespective of source, GSE strongly inhibits LoVo, HT29 and SW480 cell growth, with a G1 arrest in LoVo and HT29 cells, but an S and/or G2/M arrest in SW480 cell cycle progression. GSE also induced Cip/p21 levels in all three cell lines. Furthermore, an induction of apoptosis was observed in all three cell lines by GSE. Taken together, our findings suggest that GSE could be an effective CAM agent against CRC possibly due to its strong growth inhibitory and apoptosis inducing effects. PMID:19003575

  20. Grape seed extract induces cell cycle arrest and apoptosis in human colon carcinoma cells.

    PubMed

    Kaur, Manjinder; Mandair, Reinuka; Agarwal, Rajesh; Agarwal, Chapla

    2008-01-01

    One approach to control colorectal cancer (CRC) is its preventive intervention by dietary agents or those consumed as supplements. However, because most of these products are often consumed by patients as an complementary and alternative medicine practice, a scientific base such as efficacy, mechanism, and standardized preparation needs to be developed. Grape seed extract (GSE) is one such supplement widely consumed by humans for its several health benefits. We reported recently that GSE inhibits CRC cell HT29 growth in culture and nude mice xenograft. Because GSE is available commercially through different vendors, here we assessed whether GSE from 2 different manufacturers produces comparable biological effects in a panel of human CRC cell lines. Our results show that irrespective of source, GSE strongly inhibits LoVo, HT29, and SW480 cell growth, with a G1 arrest in LoVo and HT29 cells but an S and/or G2/M arrest in SW480 cell cycle progression. GSE also induced Cip/p21 levels in all 3 cell lines. Furthermore, an induction of apoptosis was observed in all 3 cell lines by GSE. Taken together, our findings suggest that GSE could be an effective CAM agent against CRC possibly due to its strong growth inhibitory and apoptosis-inducing effects.

  1. Antibacterial active compounds from Hypericum ascyron L. induce bacterial cell death through apoptosis pathway.

    PubMed

    Li, Xiu-Mei; Luo, Xue-Gang; Si, Chuan-Ling; Wang, Nan; Zhou, Hao; He, Jun-Fang; Zhang, Tong-Cun

    2015-01-01

    Hypericum ascyron L. has been used as a traditional medicine for the treatment of wounds, swelling, headache, nausea and abscesses in China for thousands of years. However, modern pharmacological studies are still necessary to provide a scientific basis to substantiate their traditional use. In this study, the mechanism underlying the antimicrobial effect of the antibacterial activity compounds from H. ascyron L. was investigated. Bioguided fractionation of the extract from H. ascyron L. afforded antibacterial activity fraction 8. The results of cup plate analysis and MTT assay showed that the MIC and MBC of fraction 8 is 5 mg/mL. Furthermore, using Annexin V-FITC/PI, TUNEL labeling and DNA gel electrophoresis, we found that cell death with apoptosis features similar to those in eucaryon could be induced in bacteria strains after exposure to the antibacterial activity compounds from H. ascyron L. at moderate concentration. In addition, we further found fraction 8 could disrupt the cell membrane potential indicate that fraction 8 exerts pro-apoptotic effects through a membrane-mediated apoptosis pathway. Finally, quercetin and kaempferol 3-O-β-(2″-acetyl)-galactopyranoside, were identified from fraction 8 by means of Mass spectrometry and Nuclear magnetic resonance. To our best knowledge, this study is the first to show that Kaempferol 3-O-β-(2″-acetyl)-galactopyranoside coupled with quercetin had significant antibacterial activity via apoptosis pathway, and it is also the first report that Kaempferol 3-O-β-(2″-acetyl)-galactopyranoside was found in clusiacea. Our data might provide a rational base for the use of H. ascyron L. in clinical, and throw light on the development of novel antibacterial drugs. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

  2. 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.

  3. 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.

  4. Esculetin, a natural coumarin compound, evokes Ca(2+) movement and activation of Ca(2+)-associated mitochondrial apoptotic pathways that involved cell cycle arrest in ZR-75-1 human breast cancer cells.

    PubMed

    Chang, Hong-Tai; Chou, Chiang-Ting; Lin, You-Sheng; Shieh, Pochuen; Kuo, Daih-Huang; Jan, Chung-Ren; Liang, Wei-Zhe

    2016-04-01

    Esculetin (6,7-dihydroxycoumarin), a derivative of coumarin compound, is found in traditional medicinal herbs. It has been shown that esculetin triggers diverse cellular signal transduction pathways leading to regulation of physiology in different models. However, whether esculetin affects Ca(2+) homeostasis in breast cancer cells has not been explored. This study examined the underlying mechanism of cytotoxicity induced by esculetin and established the relationship between Ca(2+) signaling and cytotoxicity in human breast cancer cells. The results showed that esculetin induced concentration-dependent rises in the intracellular Ca(2+) concentration ([Ca(2+)]i) in ZR-75-1 (but not in MCF-7 and MDA-MB-231) human breast cancer cells. In ZR-75-1 cells, this Ca(2+) signal response was reduced by removing extracellular Ca(2+) and was inhibited by the store-operated Ca(2+) channel blocker 2-aminoethoxydiphenyl borate (2-APB). In Ca(2+)-free medium, pre-treatment with the endoplasmic reticulum Ca(2+) pump inhibitor thapsigargin (TG) abolished esculetin-induced [Ca(2+)]i rises. Conversely, incubation with esculetin abolished TG-induced [Ca(2+)]i rises. Esculetin induced cytotoxicity that involved apoptosis, as supported by the reduction of mitochondrial membrane potential and the release of cytochrome c and the proteolytic activation of caspase-9/caspase-3, which were partially reversed by pre-chelating cytosolic Ca(2+) with 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid-acetoxymethyl ester (BAPTA-AM). Moreover, esculetin increased the percentage of cells in G2/M phase and regulated the expressions of p53, p21, CDK1, and cyclin B1. Together, in ZR-75-1 cells, esculetin induced [Ca(2+)]i rises by releasing Ca(2+) from the ER and causing Ca(2+) influx through 2-APB-sensitive store-operated Ca(2+) entry. Furthermore, esculetin activated Ca(2+)-associated mitochondrial apoptotic pathways that involved G2/M cell cycle arrest. Graphical abstract The summary of esculetin

  5. 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

  6. A monastrol-derived compound, LaSOM 63, inhibits ecto-5'nucleotidase/CD73 activity and induces apoptotic cell death of glioma cell lines.

    PubMed

    Figueiró, Fabrício; Mendes, Franciane Brackmann; Corbelini, Patricia Frasson; Janarelli, Fernanda; Jandrey, Elisa Helena Farias; Russowsky, Dennis; Eifler-Lima, Vera Lucia; Battastini, Ana Maria Oliveira

    2014-04-01

    Glioblastoma multiforme is the most malignant type of glioma. Ecto-5'-nucleotidase (ecto-5'NT), a glioma-overexpressed enzyme can induce a protective effect on tumor cells. Monastrol, a kinesin spindle protein-specific inhibitor, is reported to be an interesting prototype for cancer therapy. We describe the effect of LaSOM 63, a monastrol derivative, on ecto-5'NT activity and on glioma cell survival. Glioma cells were treated with LaSOM 63 and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), trypan blue assay (viability), flow cytometry (cell cycle/cell death) and malachite green method for ecto-5'NT activity were carried out. Treatment with LaSOM 63 reduces glioma cell viability and cell growth. In contrast to monastrol, LaSOM 63 did not cause glioma cell-cycle arrest, but inhibited ecto-5'NT enzyme activity. Furthermore, this compound induces apoptotic death of C6 and U138 glioma cells. LaSOM 63 may be useful for in vivo experiments on the treatment of GBM.

  7. EQCM Measurements: Redox-Induced Changes in Solvent and Ion Content in Anchored Redox Monolayers of Organosulfur Compounds and Their Electrocatalysis on Gold Electrodes

    DTIC Science & Technology

    1990-08-01

    EQCM Mwasurements: Redox-Induced Changes in Solvent and M0 Content in Anchored Redox Monolayers of Organosulfur CD Compounds and their Electrocatalysis ...REDOX-INDUCED CHANGES IN SOLVENT AND ION CONTENT IN ANCHORED REDOX MONOLAYERS OF ORGANOSULFUR COMPOUNDS AND THEIR ELECTROCATALYSIS ON GOLD...Measurements: Redox-Induced Changes in Solvent and Ion Content in Anchored Redox Monolayers of Organosulfur Compounds and their Electrocatalysis on

  8. 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.

  9. Mechanism of T-oligo-induced cell cycle arrest in Mia-PaCa pancreatic cancer cells.

    PubMed

    Rankin, Andrew M; Sarkar, Sibaji; Faller, Douglas V

    2012-06-01

    DNA oligonucleotides with sequence homology to human telomeric DNA (T-oligo) induce cell cycle arrest, followed by apoptosis, senescence, or autophagy in a human cancer cell type-specific manner. T-oligo has potential as a new therapeutic strategy in oncology because of its ability to target certain types of tumor cells while sparing normal ones. In the present study, we demonstrate the T-oligo-induced S-phase cell cycle arrest in four pancreatic cancer cell lines. To further contribute to the mechanistic understanding of T-oligo, we also identify cyclin dependent kinase 2 (cdk2) as a functional mediator in the T-oligo-induced cell cycle arrest of pancreatic cancer cells. Ectopic expression of a constitutively active cdk2 mutant abrogates T-oligo-induced cell cycle arrest in these tumor cells while knockdown of cdk2 expression alone recapitulates the T-oligo effect. Finally, we demonstrate the dispensability of T-oligo-induced ATM/ATR-mediated DNA damage response-signaling pathways, which have long been considered functional in the T-oligo signaling mechanism.

  10. Disrupted light-dark cycle abolishes circadian expression of peripheral clock genes without inducing behavioral arrhythmicity in mice.

    PubMed

    Oishi, Katsutaka; Higo-Yamamoto, Sayaka; Yamamoto, Saori; Yasumoto, Yuki

    2015-03-06

    The environmental light-dark (LD) cycle entrains the central circadian clock located in the suprachiasmatic nucleus (SCN) of mammals. The present study examined the effects of disrupted LD cycles on peripheral clocks in mice housed under a normal 12 h light-12 h dark cycle (LD 12:12) or an ultradian LD 3:3 cycle. Drinking behavior seemed to be free-running with a long period (26.03 h) under ultradian LD 3:3 cycles, in addition to light-induced direct suppression (masking effect). Core body temperature completely lost robust circadian rhythm and acquired a 6-h rhythm with a low amplitude under LD 3:3. Robust circadian expression of Per1, Per2, Clock and Bmal1 mRNAs was similarly flattened to intermediate levels in the liver, heart and white adipose tissue under LD 3:3. Robust circadian expression of Rev-erbα mRNA was completely damped in these tissues. Circadian expression of Dbp, a clock-controlled gene, was also disrupted in these tissues from mice housed under LD 3:3. The aberrant LD cycle seemed to induce the loss of circadian gene expression at the level of transcription, because rhythmic pre-mRNA expression of these genes was also abolished under LD 3:3. In addition to the direct effect of the aberrant LD cycle, abolished systemic time cues such as those of plasma corticosterone and body temperature might be involved in the disrupted expression of these circadian genes under LD 3:3. Our findings suggest that disrupted environmental LD cycles abolish the normal oscillation of peripheral clocks and induce internal desynchrony in mammals.

  11. Cell Cycle Regulators Guide Mitochondrial Activity in Radiation-Induced Adaptive Response

    PubMed Central

    Alexandrou, Aris T.

    2014-01-01

    Abstract Significance: There are accruing concerns on potential genotoxic agents present in the environment including low-dose ionizing radiation (LDIR) that naturally exists on earth's surface and atmosphere and is frequently used in medical diagnosis and nuclear industry. Although its long-term health risk is being evaluated and remains controversial, LDIR is shown to induce temporary but significant adaptive responses in mammalian cells and animals. The mechanisms guiding the mitochondrial function in LDIR-induced adaptive response represent a unique communication between DNA damage and cellular metabolism. Elucidation of the LDIR-regulated mitochondrial activity may reveal new mechanisms adjusting cellular function to cope with hazardous environmental stress. Recent Advances: Key cell cycle regulators, including Cyclin D1/CDK4 and Cyclin B1/cyclin-dependent kinase 1 (CDK1) complexes, are actively involved in the regulation of mitochondrial functions via phosphorylation of their mitochondrial targets. Accumulating new evidence supports a concept that the Cyclin B1/CDK1 complex acts as a mediator in the cross talk between radiation-induced DNA damage and mitochondrial functions to coordinate cellular responses to low-level genotoxic stresses. Critical Issues: The LDIR-mediated mitochondrial activity via Cyclin B1/CDK1 regulation is an irreplaceable network that is able to harmonize vital cellular functions with adjusted mitochondrial metabolism to enhance cellular homeostasis. Future Directions: Further investigation of the coordinative mechanism that regulates mitochondrial activities in sublethal stress conditions, including LDIR, will reveal new insights of how cells cope with genotoxic injury and will be vital for future targeted therapeutic interventions that reduce environmental injury and cancer risk. Antioxid. Redox Signal. 20, 1463–1480. PMID:24180340

  12. Cell cycle regulators guide mitochondrial activity in radiation-induced adaptive response.

    PubMed

    Alexandrou, Aris T; Li, Jian Jian

    2014-03-20

    There are accruing concerns on potential genotoxic agents present in the environment including low-dose ionizing radiation (LDIR) that naturally exists on earth's surface and atmosphere and is frequently used in medical diagnosis and nuclear industry. Although its long-term health risk is being evaluated and remains controversial, LDIR is shown to induce temporary but significant adaptive responses in mammalian cells and animals. The mechanisms guiding the mitochondrial function in LDIR-induced adaptive response represent a unique communication between DNA damage and cellular metabolism. Elucidation of the LDIR-regulated mitochondrial activity may reveal new mechanisms adjusting cellular function to cope with hazardous environmental stress. Key cell cycle regulators, including Cyclin D1/CDK4 and Cyclin B1/cyclin-dependent kinase 1 (CDK1) complexes, are actively involved in the regulation of mitochondrial functions via phosphorylation of their mitochondrial targets. Accumulating new evidence supports a concept that the Cyclin B1/CDK1 complex acts as a mediator in the cross talk between radiation-induced DNA damage and mitochondrial functions to coordinate cellular responses to low-level genotoxic stresses. The LDIR-mediated mitochondrial activity via Cyclin B1/CDK1 regulation is an irreplaceable network that is able to harmonize vital cellular functions with adjusted mitochondrial metabolism to enhance cellular homeostasis. Further investigation of the coordinative mechanism that regulates mitochondrial activities in sublethal stress conditions, including LDIR, will reveal new insights of how cells cope with genotoxic injury and will be vital for future targeted therapeutic interventions that reduce environmental injury and cancer risk.

  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. Purified vitexin compound 1 suppresses tumor growth and induces cell apoptosis in a mouse model of human choriocarcinoma.

    PubMed

    Tan, Zhihui; Zhang, Yi; Deng, Jun; Zeng, Guangyao; Zhang, Yu

    2012-03-01

    In our previous study, we had isolated a series of lignan compounds, termed vitexins, from the seed of Chinese herb Vitex negundo and found broad antitumor activities of these compounds in many cancer xenograft models and cell lines. This study was aimed to determine the antitumor effect of purified vitexin compound 1 (VB1) on choriocarcinoma in vitro and in vivo. The severe combined immunodeficiency mouse model of choriocarcinoma was established to investigate the in vivo effect of VB1. Its effect on proliferation and apoptosis in JEG-3 cell line was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, colony formation assay and flow cytometry, respectively. The expression of caspase-3, Bcl-2, and some molecules involved in the mammalian target of rapamycin (mTOR) signaling was detected by Western blot. Vitexin compound 1 significantly inhibited the growth of choriocarcinoma in severe combined immunodeficient mice and reduced the serum β-human chorionic gonadotropin level. Vitexin compound 1 inhibited cell proliferation, induced apoptosis, and inhibited the mTOR signaling in JEG-3 cell line. Vitexin compound 1 could inhibit choriocarcinoma via inducing cell apoptosis and suppressing the mTOR pathway.

  15. Development of Novel Bifunctional Compounds that Induce Apoptosis in Prostate Cancer Cells

    DTIC Science & Technology

    2007-03-01

    as well as clues to the reasons why the 11β compound is able to trigger apoptosis while other aniline mustard compounds such as chlorambucil do not. REFERENCES None included. APPENDICIES None included.

  16. Functional inhibition of aquaporin-3 with a gold-based compound induces blockage of cell proliferation.

    PubMed

    Serna, Ana; Galán-Cobo, Ana; Rodrigues, Claudia; Sánchez-Gomar, Ismael; Toledo-Aral, Juan José; Moura, Teresa F; Casini, Angela; Soveral, Graça; Echevarría, Miriam

    2014-11-01

    AQP3 has been correlated with higher transport of glycerol, increment of ATP content, and larger proliferation capacity. Recently, we described the gold(III) complex Auphen as a very selective and potent inhibitor of AQP3's glycerol permeability (Pgly ). Here we evaluated Auphen effect on the proliferation of various mammalian cell lines differing in AQP3 expression level: no expression (PC12), moderate (NIH/3T3) or high (A431) endogenous expression, cells stably expressing AQP3 (PC12-AQP3), and human HEK293T cells transiently transfected (HEK-AQP3) for AQP3 expression. Proliferation was evaluated in the absence or presence of Auphen (5 μM) by counting number of viable cells and analyzing 5-bromo-2'-deoxyuridine (BrdU) incorporation. Auphen reduced ≈50% the proliferation in A431 and PC12-AQP3, ≈15% in HEK-AQP3 and had no effect in PC12-wt and NIH/3T3. Strong arrest in the S-G2/M phases of the cell cycle, supported by analysis of cyclins (A, B1, D1, E) levels, was observed in AQP3-expressing cells treated with Auphen. Flow-cytometry of propidium iodide incorporation and measurements of mitochondrial dehydrogenases activity confirmed absence of cytotoxic effect of the drug. Functional studies evidenced ≈50% inhibition of A431 Pgly by Auphen, showing that the compound's antiproliferative effect correlates with its ability to inhibit AQP3 Pgly . Role of Cys-40 on AQP3 permeability blockage by Auphen was confirmed by analyzing the mutated protein (AQP3-Ser-40). Accordingly, cells transfected with mutated AQP3 gained resistance to the antiproliferative effect of Auphen. These results highlight an Auphen inhibitory effect on proliferation of cells expressing AQP3 and suggest a targeted therapeutic effect on carcinomas with large AQP3 expression.

  17. Chikusetsusaponin IVa methyl ester induces G1 cell cycle arrest, triggers apoptosis and inhibits migration and invasion in ovarian cancer cells.

    PubMed

    Chen, Xin; Wu, Qiu-Shuang; Meng, Fan-Cheng; Tang, Zheng-Hai; Chen, Xiuping; Lin, Li-Gen; Chen, Ping; Qiang, Wen-An; Wang, Yi-Tao; Zhang, Qing-Wen; Lu, Jin-Jian

    2016-12-01

    Panacis Japonici Rhizoma (PJR) is one of the most famous Chinese medical herbs that is known for exhibiting potential anti-cancer effects. This study aims to isolate and investigate the anti-cancer potential of saponins from PJR in ovarian cancer cells. The compounds were separated by comprehensive chromatographic methods. By comparison of the 1H- and 13C NMR data, as well as the HR-ESI-MS data, with the corresponding references, the structures of compounds were determined. MTT assay was performed to evaluate cell viability, along with flow cytometry for cell cycle analysis. JC-1 staining, Annexin V-PI double staining as well as Hoechst 33; 342 staining were used for detecting cell apoptosis. Western blot analysis was conducted to determine the relative protein level. Transwell assays were performed to investigate the effect of the saponin on cell migration and invasion and zymography experiments were used to detect the enzymatic activities. Eleven saponins were isolated from PJR and their anti-proliferative effects were evaluated in human ovarian cancer cells. Chikusetsusaponin IVa methyl ester (1) exhibited the highest anti-proliferative potential among these isolates with the IC50 values at less than 10 µM in both ovarian cancer A2780 and HEY cell lines. Compound 1 induced G1 cell cycle arrest accompanied with an S phase decrease, and down-regulated the expression of cyclin D1, CDK2, and CDK6. Further study showed that compound 1 effectively decreased the cell mitochondrial membrane potential, increased the annexin V positive cells and nuclear chromatin condensation, as well as enhanced the expression of cleaved PARP, Bax and cleaved-caspase 3 while decreasing that of Bcl-2. Moreover, compound 1 suppressed the migration and invasion of HEY and A2780 cells, down-regulated the expression of Cdc42, Rac, RohA, MMP2 and MMP9, and decreased the enzymatic activities of MMP2 and MMP9. These results provide a comprehensive evaluation of compound 1 as a potential agent

  18. Compound C induces protective autophagy in cancer cells through AMPK inhibition-independent blockade of Akt/mTOR pathway.

    PubMed

    Vucicevic, Ljubica; Misirkic, Maja; Janjetovic, Kristina; Vilimanovich, Urosh; Sudar, Emina; Isenovic, Esma; Prica, Marko; Harhaji-Trajkovic, Ljubica; Kravic-Stevovic, Tamara; Bumbasirevic, Vladimir; Trajkovic, Vladimir

    2011-01-01

    In the present study, we report that compound C, an inhibitor of a key intracellular energy sensor AMP-activated protein kinase (AMPK), can induce autophagy in cancer cells. The induction of autophagy in U251 human glioma cell line was demonstrated by acridine orange staining of intracellular acidic vesicles, Beclin 1 induction, p62 decrease and conversion of LC3-I to autophagosome-associated LC3-II in the presence of proteolysis inhibitors. The presence of autophagosome-like vesicles was confirmed by transmission electron microscopy. Compound C-mediated inhibition of AMPK and raptor in U251 cells was associated with paradoxical decrease in phosphorylation of AMPK/raptor-repressed mTOR, a major negative regulator of autophagy, and its downstream target p70S6K. The phosphorylation of an mTOR activator Akt and the PI3K-activating kinase Src was also impaired in compound C-treated cells. The siRNA-mediated AMPK silencing did not reduce the activity of the Akt/mTOR/p70S6K pathway and AMPK activators metformin and AIC AR failed to block compound C-induced autophagy. Autophagy inhibitors bafilomycin and chloroquine significantly increased the cytotoxicity of compound C towards U251 cells, as confirmed by increase in lactate dehydrogenase release, DNA fragmentation and caspase-3 activation. Similar effects of compound C were also observed in C6 rat glioma, L929 mouse fibrosarcoma and B16 mouse melanoma cell lines. Since compound C has previously been reported to suppress AMPK-dependent autophagy in different cell types, our findings suggest that the effects of compound C on autophagy might be dose-, cell type- and/or context-dependent. By demonstrating the ability of compound C to induce autophagic response in cancer cells via AMPK inhibition-independent downregulation of Akt/mTOR pathway, our results warrant caution when using compound C to inhibit AMPK-dependent cellular responses, but also support further exploration of compound C and related molecules as potential

  19. Elicitation of induced resistance against Pectobacterium carotovorum and Pseudomonas syringae by specific individual compounds derived from native Korean plant species.

    PubMed

    Song, Geun Cheol; Ryu, Shi Yong; Kim, Young Sup; Lee, Ji Young; Choi, Jung Sup; Ryu, Choong-Min

    2013-10-16

    Plants have developed general and specific defense mechanisms for protection against various enemies. Among the general defenses, induced resistance has distinct characteristics, such as broad-spectrum resistance and long-lasting effectiveness. This study evaluated over 500 specific chemical compounds derived from native Korean plant species to determine whether they triggered induced resistance against Pectobacterium carotovorum supsp. carotovorum (Pcc) in tobacco (Nicotiana tabacum) and Pseudomonas syringae pv. tomato (Pst) in Arabidopsis thaliana. To select target compound(s) with direct and indirect (volatile) effects, a new Petri-dish-based in vitro disease assay system with four compartments was developed. The screening assay showed that capsaicin, fisetin hydrate, jaceosidin, and farnesiferol A reduced the disease severity significantly in tobacco. Of these four compounds, capsaicin and jaceosidin induced resistance against Pcc and Pst, which depended on both salicylic acid (SA) and jasmonic acid (JA) signaling, using Arabidopsis transgenic and mutant lines, including npr1 and NahG for SA signaling and jar1 for JA signaling. The upregulation of the PR2 and PDF1.2 genes after Pst challenge with capsaicin pre-treatment indicated that SA and JA signaling were primed. These results demonstrate that capsaicin and jaceosidin can be effective triggers of strong induced resistance against both necrotrophic and biotrophic plant pathogens.

  20. Compound 19e, a Novel Glucokinase Activator, Protects against Cytokine-Induced Beta-Cell Apoptosis in INS-1 Cells

    PubMed Central

    Oh, Yoon Sin; Seo, Eunhui; Park, Kaapjoo; Jun, Hee-Sook

    2017-01-01

    Previously, compound 19e, a novel heteroaryl-containing benzamide derivative, was identified as a potent glucokinase activator (GKA) and showed a glucose-lowering effect in diabetic mice. In this study, the anti-apoptotic actions of 19e were evaluated in INS-1 pancreatic beta-cells co-treated with TNF-α and IL-1β to induce cell death. Compound 19e protected INS-1 cells from cytokine-induced cell death, and the effect was similar to treatment with another GKA or exendin-4. Compound 19e reduced annexin-V stained cells and the expression of cleaved caspase-3 and poly (ADP-ribose) polymerase protein, as well as upregulated the expression of B-cell lymphoma-2 protein. Compound 19e inhibited apoptotic signaling via induction of the ATP content, and the effect was correlated with the downregulation of nuclear factor-κB p65 and inducible nitric oxide synthase. Further, 19e increased NAD-dependent protein deacetylase sirtuin-1 (SIRT1) deacetylase activity, and the anti-apoptotic effect of 19e was attenuated by SIRT1 inhibitor or SIRT1 siRNA treatment. Our results demonstrate that the novel GKA, 19e, prevents cytokine-induced beta-cell apoptosis via SIRT1 activation and has potential as a therapeutic drug for the preservation of pancreatic beta-cells. PMID:28405188

  1. Gadolinium-based Compounds Induce NLRP3-dependent IL-1β Production and Peritoneal Inflammation

    PubMed Central

    Schmidt-Lauber, Christian; Bossaller, Lukas; Abujudeh, Hani H.; Vladimer, Gregory I.; Christ, Anette; Fitzgerald, Katherine A.; Latz, Eicke; Gravallese, Ellen M.; Marshak-Rothstein, Ann; Kay, Jonathan

    2015-01-01

    Objective Nephrogenic systemic fibrosis (NSF) is a progressive fibrosing disorder that may develop in patients with chronic kidney disease (CKD) after administration of gadolinium-based contrast agents (GBCAs). In the setting of impaired renal clearance of GBCAs, gadolinium (Gd) deposits in various tissues and fibrosis subsequently develops. However, the precise mechanism by which fibrosis occurs in NSF is incompletely understood. Because other profibrotic agents, such silica or asbestos, activate the NOD-like receptor protein 3 (NLRP3) inflammasome and initiate IL-1β release with the subsequent development of fibrosis, we evaluated the effects of GBCAs on inflammasome activation. Methods Bone marrow derived macrophages (BMDM) from C57BL/6, Nlrp3−/− and Asc−/− mice were incubated with three Gd-containing compounds and IL-1β activation and secretion was detected by ELISA and Western blot analysis. Inflammasome activation and regulation was investigated in IL-4- and IFNγ-polarized macrophages by ELISA, qRT-PCR and NanoString nCounter analysis. Furthermore, C57BL/6 and Nlrp3−/− mice were injected i.p. with GBCA and recruitment of inflammatory cells to the peritoneum was analyzed by FACS. Results Both free Gd and GBCAs activate the NLRP3 inflammasome and induce IL-1β secretion in vitro. Gd-DTPA also induces the recruitment of neutrophils and inflammatory monocytes to the peritoneum in vivo. Gd activated IL-4-polarized macrophages more effectively than IFNγ-polarized macrophages, which preferentially expressed genes known to downregulate inflammasome activity. Conclusion These data suggest that Gd released from GBCAs triggers a NLRP3 inflammasome-dependent inflammatory response that leads to fibrosis in an appropriate clinical setting. The preferential activation of IL-4-differentiated macrophages is consistent with the predominantly fibrotic presentation of NSF. PMID:24914072

  2. 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.

  3. 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.

  4. Silymarin induces cell cycle arrest and apoptosis in ovarian cancer cells.

    PubMed

    Fan, Li; Ma, Yalin; Liu, Ying; Zheng, Dongping; Huang, Guangrong

    2014-11-15

    The polyphenolic flavonoid silymarin that is the milk thistle extract has been found to possess an anti-cancer effect against various human epithelial cancers. In this study, to explore the regulative effect of silymarin on human ovarian cancer line A2780s and PA-1 cells, 3-[4, 5-dimethylthiazol-2-yl]-2, 5-diphenyltetrazolium bromide assay and flow cytometry were respectively used to determine the inhibitory effect of silymarin on the both cell lines, and to measure their cell cycle progression. Apoptosis induction and mitochondrial membrane potential damage were separately detected by terminal deoxynucleotidyl transferase-mediated 2'-deoxyuridine 5'-triphosphate nick end labeling assay and 5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazolylcarbocyanine iodide staining. Additionally, western blotting was applied to determine cytochrome C release and expression levels of p53, p21, p27, p16, CDK2, Bax, Bcl-2, procaspase-9, procaspase-3, cleaved caspase-9 and caspase-3 proteins. The activity of caspase-9 and caspase-3 was measured using Caspase-Glo-9 and Caspase-Glo-3 assay. The results indicated that silymarin effectively suppressed cell growth in a dose- and time-dependent manner, and arrested cell cycle progression at G1/S phase in A2780s and PA-1 cells via up-regulation of p53, p21, and p27 protein expression, and down-regulation of CDK2 protein expression. Additionally, silymarin treatment for 24h at 50 and 100µg/ml resulted in a reduction of mitochondrial membrane potential and cytochrome C release, and significantly induced apoptosis in A2780s and PA-1 cells by increasing Bax and decreasing Bcl-2 protein expression, and activation of caspase-9 and caspase-3. Therefore, silymarin is a possible potential candidate for the prevention and treatment of ovarian cancer. Copyright © 2014 Elsevier B.V. All rights reserved.

  5. miR-22 promotes apoptosis of osteosarcoma cells via inducing cell cycle arrest.

    PubMed

    Gai, Pengzhou; Sun, Hongliang; Wang, Guangda; Xu, Qiang; Qi, Xiaojun; Zhang, Zuofu; Jiang, Lei

    2017-04-01

    To study the effects of miR-22 on the proliferation and the apoptosis of osteosarcoma MG-63 cell line and to explore the potential molecular mechanism that miR-22 regulates this biological process. Quantitive real-time polymerase chain reaction (RT-qPCR) was performed to explore the miRNA level of miR-22. The MG-63 cell line was infected with miR-22 mimics for establishment of miR-22 overexpression. Non-infected cells were in blank group and cells infected with empty vector were served as negative control (NC group). MTT assay was conducted to measure cell viability. The cell cycle and apoptosis were explored using flow cytometry and the apoptosis-related markers were detected by western blotting. RT-qPCR results revealed that the miR-22 miRNA level in the MG-63 cells was significantly lower than that in osteoblasts (P<0.05). MTT assay showed that the MG-63 cells infected with miR-22 mimics exhibited markedly decreased proliferation ability compared with blank and empty vector (NC) groups. Next, we found that overexpression of miR-22 remarkably increased the apoptosis of the MG-63 cells, evidenced from the flow cytometry results and elevated Bax and reduced Bcl-2. Furthermore, results revealed that percentage of the cells at G0/G1 phase in miR-22 mimic group (66.75±3.67%) was significantly higher than blank (52.9±2.58%) and NC (50.5±2.45%) groups. miR-22 attenuated the proliferation and induced the apoptosis of the MG-63 cells via promoting G0/G1 cell cycle arrest. Thus, miR-22 may have the potential to be a novel therapeutic in treatment of osteosarcoma.

  6. Mitochondrial uncoupling protein 2 induces cell cycle arrest and necrotic cell death.

    PubMed

    Palanisamy, Arun P; Cheng, Gang; Sutter, Alton G; Evans, Zachary P; Polito, Carmen C; Jin, Lan; Liu, John; Schmidt, Michael G; Chavin, Kenneth D

    2014-03-01

    Uncoupling protein 2 (UCP2) is a mitochondrial membrane protein that regulates energy metabolism and reactive oxygen species (ROS) production. We generated mouse carboxy- and amino-terminal green fluorescent protein (GFP)-tagged UCP2 constructs to investigate the effect of UCP2 expression on cell proliferation and viability. UCP2-transfected Hepa 1-6 cells did not show reduced cellular adenosine triphosphate (ATP) but showed increased levels of glutathione. Flow cytometry analysis indicated that transfected cells were less proliferative than nontransfected controls, with most cells blocked at the G1 phase. The effect of UCP2 on cell cycle arrest could not be reversed by providing exogenous ATP or oxidant supply, and was not affected by the chemical uncoupler carbonyl cyanide-p-trifluoromethoxyphenylhydrazone (FCCP). However, this effect of UCP2 was augmented by treatment with genistein, a tyrosine kinase inhibitor, which by itself did not affect cell proliferation on control hepatocytes. Western blotting analysis revealed decreased expression levels of CDK6 but not CDK2 and D-type cyclins. Examination of cell viability in UCP2-transfected cells with Trypan Blue and Annexin-V staining revealed that UCP2 transfection led to significantly increased cell death. However, characteristics of apoptosis were absent in UCP2-transfected Hepa 1-6 cells, including lack of oligonucleosomal fragmentation (laddering) of chromosomal DNA, release of cytochrome c from mitochondria, and cleavage of caspase-3. In conclusion, our results indicate that UCP2 induces cell cycle arrest at G1 phase and causes nonapoptotic cell death, suggesting that UCP2 may act as a powerful influence on hepatic regeneration and cell death in the steatotic liver.

  7. 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

    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.

  8. 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

  9. 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

  10. Bioactive compounds isolated from apple, tea, and ginger protect against dicarbonyl induced stress in cultured human retinal epithelial cells.

    PubMed

    Sampath, Chethan; Zhu, Yingdong; Sang, Shengmin; Ahmedna, Mohamed

    2016-02-15

    Methylglyoxal (MGO) is known to be a major precursor of advanced glycation end products (AGEs) which are linked to diabetes and its related complications. Naturally occurring bioactive compounds could play an important role in countering AGEs thereby minimizing the risk associated with their formation. In this study, eight specific bioactive compounds isolated from apple, tea and ginger were evaluated for their AGEs scavenging activity using Human Retinal Pigment Epithelial (H-RPE) cells treated with MGO. Among the eight specific compounds evaluated, (-)-epigallocatechin 3-gallate (EGCG) from tea, phloretin in apple, and [6]-shogaol and [6]-gingerol from ginger were found to be most effective in preventing MGO-induced cytotoxicity in the epithelial cells. Investigation of possible underlying mechanisms suggests that that these compounds could act by modulating key regulative detoxifying enzymes via modifying nuclear factor-erythroid 2-related factor 2 (Nrf2) function. MGO-induced cytotoxicity led to increased levels of AGEs causing increase in Nε-(Carboxymethyl) lysine (CML) and glutathione (GSH) levels and over expression of receptor for advanced glycation end products (RAGE). Data also showed that translocation of Nrf2 from cytosol to nucleus was inhibited, which decreased the expression of detoxifying enzyme like heme oxygenase-1 (HO-1). The most potent bioactive compounds scavenged dicarbonyl compounds, inhibited AGEs formation and significantly reduced carbonyl stress by Nrf2 related pathway and restoration of HO-1 expression. These findings demonstrated the protective effect of bioactive compounds derived from food sources against MGO-induced carbonyl stress through activation of the Nrf2 related defense pathway, which is of significant importance for therapeutic interventions in complementary treatment/management of diabetes-related complications. Copyright © 2016. Published by Elsevier GmbH.

  11. 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

  12. 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.

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

    PubMed Central

    WANG, YIFEI; HAN, ALEX; CHEN, EVA; SINGH, RAKESH K.; CHICHESTER, CLINTON O.; MOORE, RICHARD G.; SINGH, AJAY P.; VORSA, NICHOLI

    2015-01-01

    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, phosphohistone 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

  14. Oxidation of carbon sources via the tricarboxylic acid cycle during calcium-induced conidiation of Penicillium notatum.

    PubMed

    Pitt, D; Mosley, M J

    1986-01-01

    The TCA cycle was examined during Ca2+-induced conidiation in Penicillium notatum over the 12-h period after addition of Ca2+ to vegetative cultures. Conidiation was independent of Ca2+ when certain intermediates and derivatives of the TCA cycle served as sole carbon sources. Arsenite and malonate augmented the effect of Ca2+ on conidiation but did not substitute for it. Mitochondria from vegetative cells had low rates of oxidation of TCA cycle intermediates and, with the exception of pyruvate, aconitate and glutamate, these were poorly linked to phosphorylation processes. Calcium ions affected mitochondrial function causing reduced oxidation of oxoglutarate, elimination of pyruvate oxidation and a decline in respiratory control of these substrates with increased oxidation of NADH and NADPH. Radiorespirometric studies and enzyme searches revealed a complete but weakly oxidative TCA cycle in vegetative cells. In Ca2+-induced cells oxoglutarate dehydrogenase activity was deleted within 6.5 h of Ca2+ addition and this was accompanied by establishment of an 'incomplete Krebs cycle'. Calcium-induced conidiation was associated with increased capacity for acetate and glutamate metabolism involving an activated glyoxylate shunt which may be related to enhanced biosynthetic demand. The metabolic basis of the Ca2+ effect on conidiation is discussed in connection with previous findings.

  15. Paeonol, a Major Compound of Moutan Cortex, Attenuates Cisplatin-Induced Nephrotoxicity in Mice

    PubMed Central

    Lee, Hyojung; Lee, Gihyun; Kim, Hyunseong; Bae, Hyunsu

    2013-01-01

    Cisplatin is an effective chemotherapeutic agent that is used for the treatment of a variety of cancers; however, its nephrotoxicity limits the use of this drug. In the present study, we examined whether paeonol, a major compound of Moutan Cortex, has protective effects on cisplatin-induced acute renal failure in mice. To accomplish this, Balb/c mice (6 to 8 wk of age, weighing 20 to 25 g) were administered, Moutan Cortex (300 mg/kg) or paeonol (20 mg/kg) once a day. At day 4, mice received cisplatin (30, 20, or 10 mg/kg) intraperitoneally. The paeonol-treated group showed marked attenuation of serum creatine and blood urea nitrogen levels as well as reduced levels of proinflammatory cytokines and nitric oxide when compared to the control group. In addition, the paeonol-treated group showed prolonged survival and marked attenuation of renal tissue injury. Taken together, these results demonstrated that paeonol can prevent the renal toxic effects of cisplatin. PMID:24171038

  16. 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.

  17. 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.

  18. Reduction in hypericin-induced phototoxicity by Hypericum perforatum extracts and pure compounds

    PubMed Central

    Schmitt, Laura A.; Liu, Yi; Murphy, Patricia A.; Petrich, Jacob W.; Dixon, Philip M.; Birt, Diane F.

    2006-01-01

    Clinical evidence suggests that administration of Hypericum perforatum (Hp) extracts containing the photo-activated hypericin compounds may cause fewer skin photosensitization reactions than administration of pure hypericin. This study was conducted to determine whether the phototoxicity of hypericin in HaCaT keratinocytes could be attenuated by H. perforatum extracts and constituents. Two extracts, when supplemented with 20 μM hypericin: (1) an ethanol re-extraction of residue following a chloroform extraction (denoted ethanol(-chloroform)) (3.35 μM hypericin and 124.0 μM total flavonoids); and (2) a chloroform extract (hypericin and flavonoids not detected), showed 25% and 50% (p < 0.0001) less phototoxicity than 20 μM hypericin alone. Two H. perforatum constituents, when supplemented with 20 μM hypericin: (1) 10 μM chlorogenic acid; and (2) 0.25 μM pyropheophorbide, exhibited 24% (p < 0.05) and 40% (p < 0.05) less phototoxicity than 20 μM hypericin alone. The peroxidation of arachidonic acid was assessed as a measure of oxidative damage by photo-activated hypericin, but this parameter of lipid peroxidation was not influenced by the extracts or constituents. However α-tocopherol, a known antioxidant also did not influence the amount of lipid peroxidation induced in this system. These observations indicate that hypericin combined with H. perforatum extracts or constituents may exert less phototoxicity than pure hypericin, but possibly not through a reduction in arachidonic acid peroxidation. PMID:16859921

  19. 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.

  20. 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.

  1. 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

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

    PubMed

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

    2016-10-06

    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.

  3. The natural compound forskolin synergizes with dexamethasone to induce cell death in myeloma cells via BIM.

    PubMed

    Follin-Arbelet, Virginie; Misund, Kristine; Naderi, Elin Hallan; Ugland, Hege; Sundan, Anders; Blomhoff, Heidi Kiil

    2015-08-26

    We have previously demonstrated that activation of the cyclic adenosine monophosphate (cAMP) pathway kills multiple myeloma (MM) cells both in vitro and in vivo. In the present study we have investigated the potential of enhancing the killing of MM cell lines and primary MM cells by combining the cAMP-elevating compound forskolin with the commonly used MM therapeutic drugs melphalan, cyclophosphamide, doxorubicin, bortezomib and dexamethasone. We observed that forskolin potentiated the killing induced by all the tested agents as compared to treatment with the single agents alone. In particular, forskolin had a synergistic effect on the dexamethasone-responsive cell lines H929 and OM-2. By knocking down the proapoptotic BCL-2 family member BIM, we proved this protein to be involved in the synergistic induction of apoptosis by dexamethasone and forskolin. The ability of forskolin to maintain the killing of MM cells even at lower concentrations of the conventional agents suggests that forskolin may be used to diminish treatment-associated side effects. Our findings support a potential role of forskolin in combination with current conventional agents in the treatment of MM.

  4. Adrenocorticotropin-induced hypertension in rats: role of ouabain-like compound.

    PubMed

    Yamada, K; Goto, A; Omata, M

    1997-04-01

    We examined the role of ouabain-like compound (OLC) in hypertension associated with corticotropin (ACTH) excess in rats. Physiological saline solution (1 mL/kg) or synthetic ACTH-Z (0.5 mg/kg) was injected intramuscularly for 15 days to 14 control and 13 male Wistar rats. Significant increases in blood pressure and plasma sodium/potassium ratio, and decreases in plasma potassium concentration and urinary sodium/potassium ratio were observed in ACTH-treated rats. The plasma OLC level was higher in ACTH-treated group (control; 76 +/- 13, ACTH; 202 +/- 48 pmol/L, P < .05). Plasma OLC level correlated with systolic blood pressure (SPB; r = 0.53, P < .01). Urinary OLC excretion was also higher in ACTH-treated group (control; 0.95 +/- 0.01, ACTH; 3.32 +/- 0.67 pmol/day, P < .01). A significant relation was also found between urinary OLC excretion and SBP (r = 0.66, P < .01). Plasma potassium concentration negatively correlated with SBP (r = -0.48, P < .01) and urinary sodium/potassium ratio also correlated inversely with urinary OLC excretion (r = -0.55, P < .01). Measurement of OLC levels after the fractionation of urine by reverse-phase high performance liquid chromatography showed that the major OLC peak in urine from both groups coincided with that of authentic ouabain. These results suggest the contribution of OLC to ACTH-induced hypertension in rats.

  5. Laser- and UV-LED-induced fluorescence detection of dissolved organic compounds in water

    NASA Astrophysics Data System (ADS)

    Sharikova, Anna V.; Killinger, Dennis K.

    2010-04-01

    We have developed a laser-induced fluorescence (LIF) system to detect and continuously observe in real time the levels of colored dissolved organic matter (CDOM) or Dissolved Organic Compounds (DOCs) in water from various sources, such as tap water and reverse osmosis processed water. At the same time, we have studied deep-UV light emitting diodes (LEDs) as alternative light sources for our system, which would make the apparatus cheaper and more compact. Our portable LIF system had two interchangeable microchip Nd:YAG lasers, operating at 266 nm and 355 nm, as UV sources, and fluorescence was measured over the range of 260-680 nm. The fluorescence was collected at 90º to the laser beam. We have also studied deep-UV LEDs emitting between 265 nm and 355 nm as alternative sources of fluorescence excitation. The average laser power was approximately 30 times that of the LED. Fluorescence spectra from sea water, tap water, and reverse osmosis water for both excitation sources were also measured, and similar spectra were observed. Differences in the signal intensity due to the difference in the laser and LED excitation intensity were consistent with theory.

  6. Studies on the role of neurotoxic esterase in organophosphorous compound-induced delayed neurotoxicity

    SciTech Connect

    Carrington, C.D.

    1984-01-01

    Neurotoxic esterase (NTE) is a protein with esterase activity that is proposed to be the site at which organophosphorus compound (OP) induced delayed neurotoxicity (OPIDIN) is initiated. The role of NTE in OPIDIN in unknown. The studies described in this dissertation were designed to further elucidate potential mechanisms underlying the involvement of NTE in OPIDN. The prophylactic effect of phenylmethylsulfonyl fluoride (PMSF) was found to be correlated with the time course of inhibition of NTE by PMSF and two neurotoxic OPs, and is therefore most likely to be due to the prevention of the binding of the OP to the initiation site. A membrane bound protein labelled with /sup 3/H-diisopropyl phosphorofluoridate (DiFP) with an apparent molecular weight of 160 K was the major binding site with a specificity similar to that of NTE. Recovery of NTE activity following in vivo inhibition by DiFP was found to be slower in hen brain when compared to chicks or rats. Differences in recovery in peripheral nerve were not found to be correlated with differences in susceptibility between species or between young and adult animals. The anterograde transport rate for NTE was estimated to be about 300 mm/day. Since exchange between mobile and stationary transport pools appeared to be rapid, it is concluded that the proximodistal delay in NTE recovery is due to a dilution of newly synthesized NTE by inhibited NTE as it is transported down the nerve.

  7. Spiral Magnetic Order and Pressure-Induced Superconductivity in Transition Metal Compounds

    SciTech Connect

    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.

  8. Large Drought-induced Variations in Oak Leaf Volatile Organic Compound Emissions during PINOT NOIR 2012

    EPA Pesticide Factsheets

    Leaf level oak isoprene emissions and co2/H2O exchange in the Ozarks, USABAGeron.csv is the speciated biomass displayed in Figure 1.Biomass Dry Weights.xlsx is used to convert leaf area to dry leaf biomass and is used in Figure 2.Daly Ozarks leaf ISOP.txt and MOFLUX_Isoprene Summary_refined Tcurve da