UMLS:C0011570 - FACTA Search

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Query: UMLS:C0011570 (depression)
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The thymoma cell line EL4.IL-2 (EL-4) was used as a T-cell model to assess the immunotoxic effects of several mycotoxins produced by the Aspergillus-Penicillium and the Fusarium groups. EL-4 cells were stimulated with phorbol 12-myristate 12-acetate (PMA) in the presence of mycotoxins at various concentrations for 5 d and culture supernatants were analyzed for interleukins (IL) IL-2 and IL-5 by enzyme-linked immunosorbent assay (ELISA). The cytokine effects were further related to proliferation and cell viability using the MTT [3-(4,5-dimethylthiazol-2-yl) 2,5-diphenyltetrazolium bromide] assay with absorbance at 570 nm (A570) as the endpoint indicator. IL-2 and IL-5 levels were dramatically increased by cyclopiazonic acid at 50-1000 ng/ml, whereas IL-2 was significantly decreased at 10 microgram/ml. Proliferation was slightly increased at 100-1000 ng/ml cyclopiazonic acid but markedly depressed at 5 and 10 microgram/ml. When EL-4 cells were exposed to 5 and 10 microgram/ml of ochratoxin A, IL-2 production was markedly increased while IL-5 production was significantly decreased. The A570 was significantly decreased by ochratoxin A at 10 microgram/ml. IL-2 and Il-5 production was almost totally suppressed by patulin at concentrations > or = 500 ng/ml and by T-2 toxin at > or = 5 ng/ml. These effects occurred concurrently with marked depression of A570 in the MTT assay. Although A570 was unaffected by either zearalenone or alpha-zearalenol exposure, both IL-2 and IL-5 levels were significantly elevated by these toxins at 5 or 10 microgram/ml. IL-2 and IL-5 production were not affected in EL-4 cells cultured with either the Aspergillus-Penicillium toxins aflatoxin B1 and secalonic acid or the Fusarium toxins wortmannin, fumonisin B1, or fusaric acid at concentrations up to 10 microgram/ml. In total, the EL-4 culture studies indicated that cyclopiazonic acid, ochratoxin A, zearalenone, and alpha-zearalenol could stimulate cytokine production whereas patulin and T-2 toxin were inhibitory. Cytokine dysregulation was not always related directly to perturbations in proliferation. The results suggest that the EL-4 thymoma cell line could be a simple and effective in vitro model for evaluating immunotoxicity of various classes of environmental chemicals.
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PMID:Effects of mycotoxins on cytokine production and proliferation in EL-4 thymoma cells. 869 8

1. This report examines alterations in presynaptic and postsynaptic processes mediated by gamma-aminobutyric acid-B (GABAB) receptors within hippocampal region CA1 in a model of chronic temporal lobe epilepsy (TLE). Intracellular recordings were obtained in pyramidal cells from combined hippocampal/parahippocampal control slices and slices obtained > or = 1 mo after a period of self-sustaining limbic status epilepticus (SSLSE) induced by continuous hippocampal stimulation. 2. Monosynaptic inhibitory postsynaptic potentials (IPSPs) were evoked by placement of the stimulating electrode in stratum pyramidale within 500 microns of the recording electrode in the presence of the ionotropic glutamate receptor antagonists 6-cyano-7-nitroquinoxaline-2,3-dione and D(-)-2-amino-5-phosphonovaleric acid. Control IPSPs exhibited early (GABAA-receptor-mediated) and late (GABAB-receptor-mediated) components. In contrast, post-SSLSE IPSPs displayed only a GABAA-receptor-mediated IPSP. Post-SSLSE IPSPs were completely eliminated by antagonists of the GABAA receptor (bicuculline methiodide and picrotoxin). In control tissue, GABAB receptor antagonists P-(3-aminopropyl)-P-diethoxymethyl-phosphinic acid (CGP 55845A), 3-N[1-(S)-(3,4-dichlorophenyl) ethyl]amino-2-(S)- hydroxypropyl-P-benzyl-phosphinic acid (CGP 35348), and 2-hydroxysaclofen eliminated the late component of the biphasic IPSP but had no discernible effect on IPSPs evoked in post-SSLSE CA1 pyramidal cells. 3. A paired pulse paradigm was employed to investigate the integrity of presynaptic GABAB-receptor-mediated inhibition of GABA release. To isolate pure GABAA-receptor-mediated responses, and thus facilitate comparison with post-SSLSE tissue, control neurons were penetrated with intracellular electrodes containing Cs2SO4/lidocaine, N-ethyl bromide (QX-314), and IPSPs were evoked employing the monosynaptic IPSP protocol. In controls, paired pulses [interpulse intervals (IPIs) of 70-1,500 ms] resulted in a diminution of the second early, GABAA-receptor-mediated chloride IPSP (IPSPA) relative to the first; maximum paired pulse depression (PPD) occurred at an IPI of 100 ms. GABAB receptor antagonists reduced PPD without affecting the amplitude of IPSPAs; the GABAB receptor agonist baclofen reduced the amplitude of both the first and second IPSPA and largely alleviated PPD. In contrast, no PPD was evident at any IPI in post-SSLSE neurons. Neither antagonists nor agonists of GABAB-receptor-mediated processes had an effect on either the degree of PPD or the amplitude of IPSPs. 4. To better approximate the pattern of CA1 pyramidal cell activation occurring during epileptiform activity. IPSPAs were evoked by trains of stimuli. In controls, mean monosynaptic IPSPA amplitude decreased by approximately 60% during a 3-Hz, 5-s train, with more than half the decline coming between the first and second IPSPs. In post-SSLSE, no significant IPSPA depression resulted from delivery of stimulus trains. Baclofen reduced the amplitude of control IPSPAs evoked during stimulus trains; both agonist and antagonists significantly lessened the degree of IPSP depression. These same agents altered neither IPSP amplitude nor the degree of use-dependent IPSP depression produced in post-SSLSE tissue during stimulus trains. 5. We conclude that a dysfunction of both presynaptic and postsynaptic GABAB-receptor-mediated processes occurs in hippocampal area CA1 in the post-SSLSE model of TLE. GABAB receptor agonists and antagonists had no effect on post-SSLSE CA1 pyramidal cell synaptic responses, whereas antagonists of the GABAA receptor completely eliminated IPSPs. Repetitive activation produced no use-dependent synaptic depression. The implications of these findings for the epileptogenic potential of post-SSLSE CA1 and the "dormant basket cell" hypothesis are discussed.
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PMID:Profound disturbances of pre- and postsynaptic GABAB-receptor-mediated processes in region CA1 in a chronic model of temporal lobe epilepsy. 887 Dec 36

Low-frequency stimulation is associated with long-term depression (LTD) of synaptic efficacy in various brain structures. Like long-term potentiation (LTP), homosynaptic LTD in area CA1 of the hippocampus appears to require NMDA receptor activation, changes in postsynaptic calcium concentration and phospholipase A2 (PLA2) activation. Arachidonic acid (AA) is released after the activation of calcium-dependent phospholipases and free AA is rapidly metabolized to a family of bioactive products (the eicosanoids) which are thought to be both intracellular and extracellular messengers. In the present study, we investigated the involvement of the cyclooxygenase and lipoxygenase pathways of AA metabolism in the formation of homosynaptic LTD in the rat hippocampus. Stimulation at 1 Hz for 15 min was used to produce homosynaptic depression in area CA1 of hippocampal slices. LTD induction was partially blocked by bromophenacyl bromide (50-100 microM), a selective PLA2 inhibitor, and by the a nonselective lipoxygenase inhibitor nordihydroguaiaretic acid (NDGA; 100 microM). In contrast, the specific cyclooxygenase blocker indomethacin (100 microM) did not significantly reduce hippocampal LTD. Since NDGA interferes with LTD formation, we examined whether specific inhibitors of 5- and 12-lipoxygenases were capable of blocking LTD expression. The 12-lipoxygenase inhibitor baicalein at a concentration of 50 microM reduced LTP formation when given in the bath, an effect that was less pronounced with the 5-lipoxygenase inhibitor AA-861. These data suggest that the activation of endogenous PLA2 and the formation of 12-lipoxygenase metabolites of AA may be important factors controlling the expression of hippocampal LTD.
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PMID:Involvement of the 12-lipoxygenase pathway of arachidonic acid metabolism in homosynaptic long-term depression of the rat hippocampus. 888 86

Effect of diisopropylphosphorofluoridate (DFP), an irreversible cholinesterase (ChE) inhibitor, on compound action potential (CAP) of sciatic nerve in vitro was examined. Further, the role of cholinesterase reactivator (1 acetyl-4-hydroxy imino methyl pyridinium bromide; SPK-3) in reversing DFP-induced changes was also evaluated. Diisopropylphosphorofluoridate produced a dose-dependent depression of the CAP. A concentration as low as 0.01 microM DFP produced a 5% depression (P < 0.05) and the maximal depression (30% of control) was observed with 1 microM. The SPK-3 (up to 10 microM) had no effect on the CAP; SPK-3 (10 microM) antagonized the DFP-induced depression of the CAP partially but not after 1 microM DFP. However, the inhibitory concentration of DFP to produce 50% of the maximal depression (IC50) was 0.38 +/- 0.025 microM in the presence of SPK-3 (10 microM; n = 4), against 0.15 +/- 0.05 microM for DFP alone (n = 7). These IC50 values were significantly different (P < 0.05, Student's t-test). The DFP decreased nerve ChE activity by 41% in the absence of SPK-3 and by 31% in the presence of SPK-3. Although SPK-3 could not completely reactivate the inhibited enzyme, it seems reasonable to conclude that the DFP-induced depression of the action potential of sciatic nerve was mediated by inhibiting the ChE activity.
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PMID:Diisopropylphosphorofluoridate-induced depression of compound action potential of frog sciatic nerve in vitro is mediated through the inhibition of cholinesterase activity. 895 95

We have hypothesized that a major role of the apical H(+)-pump in mitochondria-rich (MR) cells of amphibian skin is to energize active uptake of Cl- via an apical Cl-/HCO3(-)-exchanger. The activity of the H+ pump was studied by monitoring mucosal [H+]-profiles with a pH-sensitive microelectrode. With gluconate as mucosal anion, pH adjacent to the cornified cell layer was 0.98 +/- 0.07 (mean +/- SEM) pH-units below that of the lightly buffered bulk solution (pH = 7.40). The average distance at which the pH-gradient is dissipated was 382 +/- 18 microns, corresponding to an estimated "unstirred layer" thickness of 329 +/- 29 microns. Mucosal acidification was dependent on serosal pCO2, and abolished after depression of cellular energy metabolism, confirming that mucosal acidification results from active transport of H+. The [H+] was practically similar adjacent to all cells and independent of whether the microelectrode tip was positioned near an MR-cell or a principal cell. To evaluate [H+]-profiles created by a multitude of MR-cells, a mathematical model is proposed which assumes that the H+ distribution is governed by steady diffusion from a number of point sources defining a set of particular solutions to Laplace's equation. Model calculations predicted that with a physiological density of MR cells, the [H+] profile would be governed by so many sources that their individual contributions could not be experimentally resolved. The flux equation was integrated to provide a general mathematical expression for an external standing [H+]-gradient in the unstirred layer. This case was treated as free diffusion of protons and proton-loaded buffer molecules carrying away the protons extruded by the pump into the unstirred layer; the expression derived was used for estimating stationary proton-fluxes. The external [H+]-gradient depended on the mucosal anion such as to indicate that base (HCO3-) is excreted in exchange not only for Cl-, but also for Br- and I-, indicating that the active fluxes of these anions can be attributed to mitochondria-rich cells.
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PMID:Proton pump activity of mitochondria-rich cells. The interpretation of external proton-concentration gradients. 899 67

2-Bromopropane (2BP, isopropyl bromide), a substitute for freon, has recently been suspected to be the causative chemical for the outbreak of some reproductive dysfunctions such as amenorrhea and oligospermia in workers who has been exposed to this solvent in an electronic factory. Bacterial mutation assays, chromosome aberration analysis in vitro, and micronucleus tests in vivo, were carried out to clarify the mutagenicity of 2BP. 2BP induced mutagenicity in Salmonella typhimurium TA100 with metabolic activation in a dose-dependant manner. 2BP induced mutagenicity in TA1535 as well, with or without metabolic activation. These observations indicated that 2BP induced the base-pair substitution type mutations in Salmonella strains. The chromosome aberration analysis showed negative results in Chinese hamster lung cells treated with different concentrations, ranging from 0.077 to 2.46 mg/ml for 6 h with metabolic activation and for 24 h without metabolic activation. The micronucleus frequencies were recorded by examining polychromatic erythrocytes in the bone marrows of rats which were intraperitoneally injected with 2BP for 28 days. There was no significant increase in the micronucleus frequencies at any of the different doses of 2BP (125 mg/ kg b.w./day, 250 mg/kg b.w./day, and 500 mg/kg b.w./day). However, in comparison to controls, there was a significant decrease in the percentage of polychromatic erythrocytes in the total number of erythrocytes. This suggests that there may be bone marrow depression in hematopoiesis at these dose levels of 2BP. Despite the dose levels which showed hematopoietic inhibition in the bone marrow, no micronucleus formation was induced.
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PMID:Mutagenicity of 2-bromopropane. 900 6

Nitric oxide (NO), a diffusible and unstable gas, has been implicated in inter- and intra-cellular communication in the nervous system. NO also plays a role in neural development, plasticity and alterations of synaptic function such as long-term potentiation and long-term depression (Gally et al.: Proc NY Acad Sci, 87: 354-355, 1990; Zhuo et al.: Science 260:1946-1950, 1993; Schuman and Madison.: Science 254:1503-1506, 1991; Bruhwyler et al.: Neurosci Biobehav Rev 17:373-384, 1993) some of which likely involve growth and remodelling of neurites. Some actions of NO are mediated directly by protein modification (e.g., nitrosylation) and others by activation of soluble guanylyl cyclase (soluble GC), which increases intracellular levels of guanosine 3',5'-cyclic monophosphate (cGMP). NO is synthesized by the enzyme nitric oxide synthase (NOS), which is induced by treatment of CNS neurons (Holtzman et al.: Neurobiol Disease 1:51-60, 1994) or pheochromocytoma PC12 cells (Hirsch et al.: Curr Biol 3:749-754, 1993) with NGF. NO has been proposed to mediate some of the effects of NGF on PC12 cells by inhibiting cell division (Peunova and Enikolopov: Nature 374:68-73, 1995). In addition, NO can substitute for NGF by delaying the death of trophic factor-deprived PC12 cells through a mechanism that does not involve a cytostatic action (Farinelli et al.: J Neurosci 16:2325-2334, 1996). We investigated whether NO stimulated neurite outgrowth from hippocampal neurons and PC12 cells. Primary cultures of E17 mouse hippocampal neurons co-cultured with neopallial astrocytes were exposed to the NO donors sodium nitrite (100 microM) or sodium nitroprusside (100 nM). After 48 hr, NO donor-treated cultures contained a greater proportion of cells bearing neurites and neurites that were much longer than those found in control cultures. In cultures of PC12 cells, NO donors also enhanced the neuritogenic effects of NGF. The proportion of PC12 cells with neurites 48 hr after exposure to NO donors sodium nitrite (100 microM-10mM) or sodium nitroprusside (100 nM-1 micro M) plus 2.5S nerve growth factor (NGF) was approximately twice the proportion of cells with neurites in sister cultures grown in NGF alone. Neither of the NO donors elicited neurites from the PC12 cells in the absence of NGF. The effects of the NO donors were likely mediated by release of NO since their effects were antagonized by addition of hemoglobin, which avidly binds NO, to the culture medium. The enhancement by NO of NGF-mediated neurite outgrowth in PC12 cells appeared to occur through a cGMP-dependent mechanism. The NO donors stimulated a prompt increase in intracellular cGMP in PC12 cells. Moreover their action was mimicked by addition of the membrane-permeant cGMP analogs 8-Bromo-cGMP (8-Br-cGMP) and para (chlorophenylthio)-cGMP (pCPT-cGMP) to the culture medium and by atrial natriuretic factor which stimulates particulate guanylyl cyclase. The neuritogenic activity of the NO donors was inhibited by LY83583 and methylene blue, inhibitors of guanylyl cyclase. These data imply that NO may act alone or with other growth factors to regulate synapse formation and maintenance by stimulating neurite outgrowth.
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PMID:Nitric oxide donors enhance neurotrophin-induced neurite outgrowth through a cGMP-dependent mechanism. 905 36

The cellular mechanisms that underlie transient synaptic potentiation were studied in visual cortical slices of adult guinea pigs (> or = age 5 wk postnatal). Postsynaptic potentials (PSPs) elicited by stimulation of the white matter/layer VI border were recorded with conventional intracellular techniques from layer II/III neurons. Transient potentiation (average duration 23 +/- 3 min, mean +/- SE) was evoked by 60 low-frequency (0.1 Hz) pairings of weak afferent stimulation with coincident intracellular depolarizing pulses (80 ms) of the postsynaptic cell. Fifty-one percent (47 of 92) of the pairing protocols led to significant enhancement (+26 +/- 3%) of the PSP peak amplitude. Blockade of action potential output from the recorded neuron during pairing with Lidocaine, N-ethyl bromide quaternary salt in the recording micropipette did not reduce the likelihood of potentiation (7 of 14 protocols = 50%). Thus transient synaptic potentiation does not require action potential output from the paired cell or recurrent synaptic activation in the local cortical circuit. Rather, the modification occurs at synaptic sites that directly impinge onto the activated neuron. Intracellular postsynaptic blockade of inhibitory PSPs only onto the paired cell with the chloride channel blocker 4,4'-dinitro-stilbene-2,2'-disulfonic acid and the potassium channel blocker cesium in he micropipette also did not reduce the likelihood of induction of potentiation (6 of 9 protocols = 67%). These results suggest that the potentiation is due to a true upregulation of excitatory synaptic transmission and that it does not require a reduction of inhibitory components of the compound PSP for induction. Chelation of postsynaptic intracellular calcium with 1,2-bis-2-aminophenoxy ethane-N,N,N',N'-tetraacetic acid (BAPTA) in all cases effectively blocked the induction of potentiation (no change in the PSP, 9 of 13 protocols; induction of synaptic depression, 4 of 13 protocols), suggesting that a rise in the intracellular postsynaptic calcium level is critical for the pairing-induced synaptic potentiation to occur. Bath application of the N-methyl-D-aspartate (NMDA) receptor antagonist 2-amino-5-phosphonovaleric acid (APV) reversibly blocked potentiation of the PSP peak amplitude in most cells (14 of 16) that were capable of significant potentiation of control solution. Blockade of nitric oxide production with bath application of the competitive inhibitor of nitric oxide synthase, L-nitro-arginine (LNA), did not significantly affect the likelihood of synaptic potentiation (11 of 20 cells). It did, however, block subsequent enhancement for several cells (2 of 4) that had previously had their inputs potentiated. Moreover, LNA increased the overall average magnitude of synaptic potentiation (with an additional +28%) when induction was successful. These results suggest that endogenous cortical nitric oxide production can both positively and negatively modulate this NMDA receptor-mediated type of synaptic plasticity.
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PMID:Transient synaptic potentiation in the visual cortex. I. Cellular mechanisms. 908 95

In our previous study, pairing-induced transient synaptic potentiation in supragranular layers of the visual cortex was described in mature guinea pigs. In the present study, the development of this type of synaptic plasticity and the underlying cellular mechanisms that mediate it were evaluated in animals from postnatal day (PND) 5 to 180. Potentiation is more reliably evoked in younger animals (likelihood: 75%, PND 5-30; 51%, PND > or = 34), and the magnitude of the effect is greater (+40 +/- 3%, mean +/- SE, PND 5-30; +26 +/- 3%, PND > or = 34). Similar to data obtained from the mature animals, visual cortical transient synaptic potentiation in the immature cortex occurs at excitatory synaptic sites directly activated by the stimulation, and activation by local recurrent cortical circuits is not necessary for the induction of this potentiation. This is demonstrated by 1) experiments in which action potential output from the paired neuron was blocked by Lidocaine, N-ethyl bromide quaternary salt applied into the neuron (5 of 5), and 2) experiments in which the contribution to the compound postsynaptic potential by inhibitory synapses was eliminated by selective, intracellular blockade by gamma-aminobutyric acid-mediated inhibitory postsynaptic potentials only onto the recorded neuron (7 of 11). Thus these perturbations do not reduce the likelihood or magnitude of this synaptic potentiation. In contrast to the N-methyl-D-aspartate (NMDA) receptor dependence for induction of this synaptic potentiation in the cortex of mature animals, in the young animals' cortices (PND 11-27) potentiation is readily induced during blockade of NMDA receptors (72%, 13 of 18, did not different from control: 75%, 40 of 53). Thus the NMDA receptor becomes functionally linked to a synaptic potentiation cascade during development, replacing another 2-amino-5-phosphonovaleric acid (APV)-insensitive potentiation process in the neonatal cortex. Postsynaptic intracellular calcium has a critical role in the induction of this form of synaptic potentiation in all ages studied. Synaptic potentiation was prevented (8 of 11 cases) or was replaced by synaptic depression (3 of 11 cells) in experiments in which postsynaptic calcium levels were reduced by intracellular application of 1,2-bis-2-aminophenoxy ethane-N,N,N',N'-tetraacetic acid (BAPTA) in the cortex of young (PND 7-14) animals, or in which the extracellular calcium concentrations was lowered. Inhibition of postsynaptic calcium-induced calcium release blocked synaptic potentiation (4 of 4 cells). Prolonged superfusion (3 h) of the nitric oxide synthase inhibitor L-nitro-arginine (LNA) did not significantly affect the likelihood (in LNA, 81%; 13 of 16 cells), or the magnitude (+38 +/- 7% increase in LNA vs. +40 +/- 3% in control cases) of potentiation, in contrast to its effects in the mature cortex.
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PMID:Transient synaptic potentiation in the visual cortex. II. Developmental regulation. 908 96

To study the cytophysiological effects of ethanol systematically, L929 cells, a fibroblastic cell line derived from mouse connective tissue, were exposed to various concentrations of ethanol (12.5, 50, 100 and 200 mM) for short (3 and 6 h) and longer (24 or 26 h) durations. Ethanol-induced cellular responses were analysed by a combination of the following assays: number of cells, amounts of DNA and protein, MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) assay and cell cycle. Ethanol dose-dependently suppressed these cellular functions, except that 12.5 mM exposures for both 6 and 26 h increased the amount of protein in spite of almost no change in other cellular functions, compared to the control. The most marked dose-dependency was observed in a reduction of formazan product in an MTT assay after both 6 and 26 h exposures to ethanol, being independent of the number of cells and probably reflecting dose-dependent depression of mitochondrial respiration. A G2 + M block in the cell cycle, an inhibition of cell division, was induced after short-term exposures (3 and 6 h) to 100 and 200 mM ethanol, but the block was released before 24 h had passed. Alternatively, prolonged exposures (24 h) to 50-200 mM ethanol induced a G0/G1 block, resulting in a decrease in the amount of DNA below the control value. Moreover, the percentage of the S phase was decreased gradually and dose-dependently throughout the 24 h exposure. Thus, high concentrations of ethanol (50, 100 and 200 mM) perturbed the cell cycle progression by causing both a transient G2 + M block (an inhibition of mitosis) and a continuous G0/G1 block, though the latter was masked by the G2 + M block during short-term exposure. The cells seem finally to acquire some tolerance to ethanol so as to pass through mitosis, but much less tolerance to pass through the checkpoint from the G1 to the S phase, which results in a decline in proliferation.
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PMID:Ethanol induces transient arrest of cell division (G2 + M block) followed by G0/G1 block: dose effects of short- and longer-term ethanol exposure on cell cycle and cell functions. 910 8

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