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1997 Fluoride Abstracts. Part 1.
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Zhonghua Yu Fang Yi Xue Za Zhi 1997 Nov;31(6):330-3
[Changes of coenzyme Q content in brain tissues of rats with fluorosis]
[Article in Chinese]
Wang Y, Guan Z, Xiao K.
Department of Scientific Research, Guiyang Medical College.
Animal models with pathological damage caused by chronic fluorosis to a different extent were duplicated in Wistar rats by feeding them with 66.3 mg/L and 221 mg/L fluorine-containing water for three, five and seven months, respectively. Cholesterol, dolichol and coenzyme Q in animal brain tissues were determined by high performance liquid chromatography. Results showed that no significant difference of cholesterol and dolichol contents in brian tissues between rats with fluorosis and normal controls were detected. Coenzyme Q content of brain tissue in rats fed with fluorine-containing water decreased at early stage of fluorosis, but increased significantly at late stage. It is speculated that changes in content of coenzyme Q could correlate with changes in free radical levels induced by fluorine.
PMID: 9863064 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9772465&dopt=AbstractZhonghua Yi Xue Za Zhi 1997 Aug;77(8):592-6
[Influence of experimental fluorosis on phospholipid content and fatty acid composition in rat brain]
[Article in Chinese]
Guan Z, Wang Y, Xiao K.
Guiyang Medical College.
OBJECTIVE: To investigate the pathogenesis of brain damage by fluoride intoxication, phospholipid content, and fatty acid composition in rat brain with fluorosis were annlysed.
METHODS: Wistar rats were fed with NaF in various amounts and time periods to produce the animal model with chronic fluorosis. Phospholipid content and fatty acids composition were analysed using high performance liquid chromatography and gas chromatography, respectively.
RESULTS: All animals fed with high amount of fluoride suffered from chronic fluorosis. The total brain phospholipid content was lower in the rat treated with fluoride, which mainly influenced phosphatidylethanolamine, phosphatidylcholin, and phosphatidylserine. No modifications were detected in fatty acid and aldehyde compositions of individual phospholipid classes.
CONCLUSION: The metabolism of brain phospholipid might be interfered by fluoride accumulated in brain tissue, which is related with the degeneration of neuron. The changes of brain phospholipid could be involved in the pathogenesis of chronic fluorosis.
PMID: 9772465 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9406177&dopt=AbstractMol Cell Biochem 1997 Nov;176(1-2):317-26
Regulation of Ca2+ homeostasis by glucose metabolism in rat brain.
Nijjar M, Belgrave RL.
Department of Anatomy and Physiology, Atlantic Veterinary College, University of Prince Edward Island, Charlottetown, Canada.
In a previous communication we reported that glucose deprivation from KHRB medium resulted in a marked stimulation of Ca2+ uptake by brain tissue, suggesting a relationship between glucose and Ca2+ homeostasis in brain tissue. Experiments were carried out to investigate the significance of glucose in Ca2+ transport in brain cells. The replacement of glucose with either D-methylglucoside or 2-deoxyglucose, non-metabolizable analogues of glucose, resulted in stimulation of Ca2+ uptake just as by glucose deprivation. These data show that glucose metabolism rather than glucose transfer was necessary to stimulate Ca2+ uptake in brain tissue. Inhibition of glucose metabolism with either NaF, NaCN, or iodoacetate resulted in stimulation of Ca2+ uptake similar to that produced by glucose deprivation. These results lend further support for the concept that glucose metabolism is essential for Ca2+ homeostasis in brain. Anoxia promotes glucose metabolism through glycolytic pathway to keep up with the demand for ATP by cellular processes (the Pasteur effect). Incubation of brain slices under nitrogen gas did not alter Ca2+ uptake by brain tissue, as did glucose deprivation and the inhibitors of glucose metabolism. We conclude that glucose metabolism resulting in the synthesis of ATP is essential for Ca2+ homeostasis in brain. Verapamil and nifedipine which block voltage-gated Ca2+ channels, did not alter Ca2+ uptake stimulated by glucose deprivation, indicating that glucose deprivation-enhanced Ca2+ uptake was not mediated by Ca2+ channels. Tetrodotoxin which specifically blocks Na2+ channels, abolished Ca2+ uptake enhanced by glucose deprivation, but had no effect on Ca2+ uptake in presence of glucose (controls). These results suggest that stimulation of Ca2+ uptake by glucose deprivation may be related to Na2+ transfer via NaCa exchange in brain.
PMID: 9406177 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9062892&dopt=AbstractMol Cell Biochem 1997 Mar;168(1-2):41-9
Different mechanisms regulate phosphatidylserine synthesis in rat cerebral cortex.
Mozzi R, Andreoli V, Buratta S, Iorio A.
Istituto di Biochimica e Chimica Medica Universita di Perugia, Italy.
Transduction of extracellular signals through the membrane involves both the lipid and protein moiety. Phosphatidylserine participates to these processes as a cofactor for protein kinase C activity and thus the existence of a regulatory mechanism for its synthesis ought to be expected. In plasma membranes from rat cerebral cortex, the activity of serine base exchange enzyme, that is mainly responsible for phosphatidylserine synthesis in mammalian tissues, was reduced by the addition to the incubation mixture of AlF4- or GTP-gamma-S, known activators of G proteins, whereas ATP was almost uneffective. GTP-gamma-S inhibited the enzyme activity only at relatively high concentration (> 0.5 mM). When the synthesis of phosphatidylserine in the same cerebral area was investigated by measuring the incorporation of labelled serine into the phospholipid in the homogenate buffered at pH 7.6, ATP had an inhibitory effect as GTP-gamma-S and AlF4-. Heparin activated both serine base exchange enzyme in plasma membranes and phosphatidylserine synthesis in the homogenate. The preincubation of plasma membranes in the buffer without any other addition at 37 degrees C for 15 min reduced by 30% serine base exchange enzyme activity. The remaining activity responded to the addition of GTP-gamma-S but was insensitive to 5 mM AlF-4, a concentration that inhibited by 60% the enzyme assayed without preincubation. These results indicate the existence of different regulatory mechanisms, involving ATP and G proteins, possibly acting on different enzymes responsible for the synthesis of phosphatidylserine. Since previous studies have shown that hypoxia increases the synthesis of this phospholipid in brain slices or homogenate (Mozzi et al. Mol Cell Biochem 126: 101-107, 1993), it is possible that hypoxia may interfere with at least one of these mechanisms. This hypothesis is supported by the observation that in hypoxic homogenate 20 mM AlF-4 was not able to reduce the synthesis of phosphatidylserine as in normoxic samples. A similar difference between oxygenated and hypoxic samples, concerning their response to AlF4-, was observed when the incorporation of ethanolamine into phosphatidylethanolamine was studied. The incorporation of choline into phosphatidilcholine was, on the contrary, inhibited at a similar extent in both experimental conditions.
PMID: 9062892 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9242229&dopt=AbstractJ Toxicol Environ Health 1997 Aug 29;51(6):571-90
From Toxnet
Potentiation of organophosphorus compound-induced delayed neurotoxicity (OPIDN) in the central and peripheral nervous system of the adult hen: distribution of axonal lesions.
Randall JC, Yano BL, Richardson RJ.
Department of Environmental and Industrial Health, School of Public Health, University of Michigan, Ann Arbor 48109-2029, USA.
Clinical manifestations of mild organophosphorus compound-induced delayed neurotoxicity (OPIDN) produced by diisopropylphosphorofluoridate (DFP) in adult hens are potentiated by posttreatment with phenylmethanesulfonyl fluoride (PMSF). The purpose of this study was to assess whether potentiation of mild OPIDN produces a pattern of axonal lesions in the central and peripheral nervous system similar to that seen in severe OPIDN. Groups of 6 hens each were given the following priming/challenge doses sc at 0 and 4 h, respectively: 0.20 ml/kg corn oil/0.50 ml/kg glycerol formal (GF) (control); 0.50 mg/kg DFP/GF (low-dose DFP); 0.50 mg/kg DFP/60 mg/kg PMSF (potentiated DFP); 60 mg/kg PMSF/GF (PMSF alone); 60 mg/kg PMSF/1.5 mg/kg DFP (protected DFP); and 1.5 mg/kg DFP/GF (high-dose DFP). Two hens from each group were used to assay brain neurotoxic esterase (NTE) 24 h after the challenge dose, and the remaining hens were scored for deficits in walking, standing, and perching ability on d 18. Three hens from each group were perfusion-fixed on d 22 and neural tissues were prepared for histologic evaluation. DFP and/or PMSF caused > 88% brain NTE inhibition in all treated groups, compared to control. Protected DFP yielded no clinical deficits and a distribution and frequency of axonal lesions similar to control. PMSF alone produced a small increase in the frequency of lesions in the cervical spinal cord and peripheral nerves compared to control. Low-dose DFP caused minimal ataxia and increased frequency of axonal lesions in dorsal and lateral cervical spinal cord, ventral lumbar spinal cord, and inferior cerebellar peduncles (ICP) compared to control. Potentiated DFP and high-dose DFP produced maximal ataxia and essentially identical increases in the frequency of lesions in dorsal and ventral thoracic spinal cord, lateral lumbar spinal cord, and peripheral nerves compared to low-dose DFP. The results indicate that PMSF potentiation of mild OPIDN induced in adult hens by low-dose DFP results in an overall pattern of axonal degeneration like that produced by a threefold higher dose of DFP alone, and support the hypothesis that potentiation causes an increase in the frequency of axonal lesions in central and peripheral loci normally affected by OPIDN.
PMID: 9242229 [PubMed - indexed for MEDLINE]
- FASEB J 1997 Feb;11(3):A406
- Effects of fluoride and aluminum exposure to dams prior to and during gestation on mineral compositions of bone and selected soft tissues of female mice dams and pups.
- Koh ET, Clarke SL
- Univ. of Oklahoma Health Sci. Center, Oklahoma City, OK.
- Abstract: Sixty-four CD-1 female mice were assigned to onez of four water treatment groups: Control (distilled, deionized water) (C); Fluoride (50 ppm F as NaF) (F); Aluminum (100 ppm Al as AlCl3) (Al); and Al & F (50 ppm F & 100 ppm Al) (AlF). One-half of the animals in each group were mated. The study was terminated on the 5th days after parturition. Pregnancy and lactation (P & L) reduced tibia Al more than 50% in the C, F, and Al groups, and 34% in the AlF group. In contrast, brain Al increased 168% in the F group, and 260% to 350% in the remaining three groups. P & L decreased tibia calcium (Ca) between 10% and 20% in all four groups, whereas the kidney Ca reduction ranged from 21% to 24%. However, heart Ca increased a minimum of 11% in the F group and a maximum of 169% in the AlF group. A maximum reduction of tibia zinc by pregnancy was obtained in the AlF group, reflecting the lowest fetal zinc in the group. The study demonstrated that pregnancy and lactation may increase the need of Al, Ca, and zinc in the vital organs such as brain, heart and fetus. These extra requirements may be fulfilled at the expense of the bones and less active organs such as kidneys. The study suggests that Al may be essential during pregnancy and lactation for increased cell proliferation.
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9369984&dopt=Abstract
- No abstract available on PubMed
Ann N Y Acad Sci 1997 Oct 15;825:152-66
Toxin-induced blood vessel inclusions caused by the chronic administration of aluminum and sodium fluoride and their implications for dementia.
Isaacson RL, Varner JA, Jensen KF.
Department of Psychology, Binghamton University, New York 13902-6000, USA. isaacson@binghamton.edu
Publication Types:Review
Review, TutorialPMID: 9369984 [PubMed - indexed for MEDLINE]
Free full report available at http://www.jneurosci.org/cgi/content/full/17/16/6203J Neurosci 1997 Aug 15;17(16):6203-12
Growth factor activity of endothelin-1 in primary astrocytes mediated by adhesion-dependent and -independent pathways.
Cazaubon S, Chaverot N, Romero IA, Girault JA, Adamson P, Strosberg AD, Couraud PO.
Centre National de la Recherche Scientifique UPR 0415, Institut Cochin de Genetique Moleculaire, 75014 Paris, France.
Endothelin-1 (ET-1) has been shown to induce DNA synthesis in primary astrocytes by stimulating the extracellular signal-regulated kinase (ERK) pathway. To clarify the mechanisms responsible for the anchorage-dependent growth of astrocytes, the relationships between cell adhesion and ERK activation were investigated. Here it is reported that ET-1 promotes the formation of stress fibers and focal adhesions and the tyrosine phosphorylation of focal adhesion kinase (FAK) and paxillin, as well as Src activation and association of phosphorylated FAK with Grb2. Pretreatment of astrocytes with cytochalasin D or C3-transferase, which inhibits actin polymerization or Rho activity, respectively, prevented the activation/phosphorylation of Src, FAK, and paxillin after ET-1 stimulation; by contrast, the ERK pathway was not significantly affected. This differential activation of FAK/Src and ERK pathways was also observed with astrocytes 10 and 60 min after replating on poly-L-ornithine-precoated dishes. Collectively, these findings indicate that activation of FAK and Src is dependent on actin cytoskeleton integrity, Rho activation, and adhesion to extracellular matrix, whereas ERK activation is independent of these intracellular events and seems to correlate with activation of the newly identified protein tyrosine kinase PYK2. Induction of DNA synthesis by ET-1, however, was reduced dramatically in astrocytes pretreated with either cytochalasin D or C3-transferase. This study provides a demonstration of Rho- and adhesion-dependent activation of FAK/Src, which collaborates with adhesion-independent activation of PYK2/ERK for DNA synthesis in ET-1-stimulated astrocytes.
PMID: 9236231 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9217967&dopt=Abstract- Biosci Rep 1997 Apr;17(2):209-18
Characterisation of the role of calcium in AlF4-induced long-term potentiation in area CA1 of rat hippocampus.Breakwell NA, Publicover SJ.
School of Biological Sciences, University of Birmingham, Edgbaston, United Kingdom.
We investigated calcium influx in the long lasting potentiation induced in area CA1 of rat hippocampus by brief bath application of the G-protein activator A1F4-(NaF/AlCl3). Brief (10 min) bath application of A1F4 in standard saline (with 2 mM Ca2+) consistently induced a long lasting potentiation which was not observed if A1F4 was bath-applied in nominally calcium free saline. Increasing the potential calcium influx, either by raising extracellular calcium concentration to 3.5 mM or by addition of the voltage operated calcium channel (VOCC) agonist BayK8644, failed to increase the number of slices exhibiting potentiation or the mean level of potentiation. Bath application of AlF4 in the presence of the VOCC antagonist failed to block the potentiation and A1F4- readily induced a long lasting potentiation under voltage clamp conditions, strongly suggesting that the calcium influx required for A1F4-induced potentiation is not through NMDA receptors or VOCC channels. It is suggested that the calcium required may be provided by an ongoing recharging and emptying of IP3 sensitive intracellular Ca2+ stores.
PMID: 9217967 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9065728&dopt=AbstractBiochem Pharmacol 1997 Feb 7;53(3):255-60
Methyl arachidonyl fluorophosphonate: a potent irreversible inhibitor of anandamide amidase.
Deutsch DG, Omeir R, Arreaza G, Salehani D, Prestwich GD, Huang Z, Howlett A.
Department of Biochemistry and Cell Biology, State University of New York at Stony Brook, 11794, U.S.A. DDEUTSCH@CCMAIL.SUNYSB.EDU
Anandamide amidase (EC 3.5.1.4) is responsible for the hydrolysis of arachidonoyl ethanolamide (anandamide). Relatively selective and potent enzyme reversible inhibitors effective in the low micromolar range, such as arachidonyl trifluoromethyl ketone (Arach-CF3), have been described (Koutek et al., J Biol Chem 269: 22937-22940, 1994). In the current study, methyl arachidonyl fluorophosphonate (MAFP), an arachidonyl binding site directed phosphonylation reagent, was tested as an inhibitor of anandamide amidase and as a ligand for the CB1 cannabinoid receptor. MAFP was 800 times more potent than Arach-CF3 and phenylmethylsulfonyl fluoride (PMSF) as an amidase inhibitor in rat brain homogenates. In intact neuroblastoma cells, MAFP was also approximately 1000-fold more potent than Arach-CF3. MAFP demonstrated selectivity towards anandamide amidase for which it was approximately 3000 and 30,000-fold more potent than it was towards chymotrypsin and trypsin, respectively. MAFP displaced [3H]CP-55940 binding to the CB1 cannabinoid receptor with an IC50 of 20 nM vs 40 nM for anandamide. It bound irreversibly and prevented subsequent binding of the cannabinoid radioligand [3H]CP-55940 at that locus. These studies suggest that MAFP is a potent and specific inhibitor of anandamide amidase and, in addition, can interact with the cannabinoid receptors at the cannabinoid binding site. This is the first report of a potent and relatively selective irreversible inhibitor of arachidonoyl ethanolamide amidase.
PMID: 9065728 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9070224&dopt=Abstract
- Biochem Biophys Res Commun 1997 Feb 3;231(1):82-8
Novel inhibitors of brain, neuronal, and basophilic anandamide amidohydrolase.
De Petrocellis L, Melck D, Ueda N, Maurelli S, Kurahashi Y, Yamamoto S, Marino G, Di Marzo V.
Istituto di Cibernetica, C.N.R., Arco Felice (NA), Italy.
Mammalian brain as well as mouse neuroblastoma (N18TG2) and rat basophilic leukaemia (RBL) cells were previously shown to contain "anandamide amidohydrolase', a membrane-bound enzyme sensitive to serine and cysteine protease inhibitors and catalyzing the hydrolysis of the endogenous cannabimimetic metabolite, anandamide (arachidonoyl-ethanolamide). With the aim of developing novel inhibitors of this enzyme, we synthesized three arachidonic acid (AA) analogues, i.e. arachidonoyl-diazo-methyl-ketone (ADMK), ara-chidonoyl-chloro-methyl-ketone (ACMK) and O-acetyl-arachidonoyl-hydroxamate (AcAHA), by adding to the fatty acid moiety three functional groups previously used to synthesize irreversible inhibitors of serine and cysteine proteases. The three compounds were purified and characterized by proton nuclear magnetic resonance and electron impact mass spectrometry. Their effect was tested on anandamide amidohydrolase partially purified from N18TG2 and RBL-1 cells and porcine brain. Pre-treatment of the enzyme with each compound produced a significant inhibition, with ADMK being the most potent (IC50 = 3, 2 and 6 microM) and AcAHA the weakest (IC50 = 34, 15 and 25 microM) inhibitors. The inactivated enzyme regained its full activity when chromatographed by anion-exchange chromatography, suggesting that none of the compounds inhibited the amidohydrolase in a covalent manner. Accordingly, Lineweaver-Burk profiles showed competitive inhibition by each compound. Conversely, the irreversible inhibitor of cytosolic phospholipase As, methyl-arachidonoyl-fluoro-phosphonate (MAFP), covalently inhibited the amidohydrolase. MAFP was active at concentrations 10(3) times lower than those reported for phospholipase A2 inhibition, and is the most potent anandamide amidohydrolase inhibitor so far described (IC50 = 1-3 nM). MAFP, ADMK and ACMK, probably by inhibiting anandamide degradation, produced an apparent increase of the in vitro formation of anandamide from its biosynthetic precursor N-arachidonoyl-phosphatidyl-ethanolamine.
PMID: 9070224 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9284778&dopt=AbstractLancet 1997 Aug 23;350(9077):556-9
Comment in:
- Lancet. 1997 Oct 25;350(9086):1248-9; discussion 1249-50.
- Lancet. 1997 Oct 25;350(9086):1249; discussion 1249-50.
Epidemic of liver disease caused by hydrochlorofluorocarbons used as ozone-sparing substitutes of chlorofluorocarbons.
Hoet P, Graf ML, Bourdi M, Pohl LR, Duray PH, Chen W, Peter RM, Nelson SD, Verlinden N, Lison D.
Catholic University of Louvain, Faculty of Medicine, Brussels, Belgium.
BACKGROUND: Hydrochlorofluorocarbons (HCFCs) are used increasingly in industry as substitutes for ozone-depleting chlorofluorocarbons (CFCs). Limited studies in animals indicate potential hepatotoxicity of some of these compounds. We investigated an epidemic of liver disease in nine industrial workers who had had repeated accidental exposure to a mixture of 1,1-dichloro-2,2,2-trifluoroethane (HCFC 123) and 1-chloro-1,2,2,2-tetrafluoroethane (HCFC 124). All nine exposed workers were affected to various degrees. Both compounds are metabolised in the same way as 1-bromo-1-chloro-2,2,2-trifluoroethane (halothane) to form reactive trifluoroacetyl halide intermediates, which have been implicated in the hepatotoxicity of halothane. We aimed to test whether HCFCs 123 and 124 can result in serious liver disease.
METHODS: For one severely affected worker liver biopsy and immunohistochemical stainings for the presence of trifluoroacetyl protein adducts were done. The serum of six affected workers and five controls was tested for autoantibodies that react with human liver cytochrome-P450 2E1 (P450 2E1) and P58 protein disulphide isomerase isoform (P58).
FINDINGS: The liver biopsy sample showed hepatocellular necrosis which was prominent in perivenular zone three and extended focally from portal tracts to portal tracts and centrilobular areas (bridging necrosis). Trifluoroacetyl-adducted proteins were detected in surviving hepatocytes. Autoantibodies against P450 2E1 or P58, previously associated with halothane hepatitis, were detected in the serum of five affected workers.
INTERPRETATION: Repeated exposure of human beings to HCFCs 123 and 124 can result in serious liver injury in a large proportion of the exposed population. Although the exact mechanism of hepatotoxicity of these agents is not known, the results suggest that trifluoroacetyl-altered liver proteins are involved. In view of the potentially widespread use of these compounds, there is an urgent need to develop safer alternatives.
PMID: 9284778 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9393620&dopt=AbstractMutat Res 1997 Oct 24;393(3):283-8
Chromosomal aberrations and micronuclei in lymphocytes of workers at a phosphate fertilizer factory.
Meng Z, Zhang B.
Department of Life Sciences, Shanxi University, Taiyuan, China.
The frequencies of chromosomal aberrations (CA) and micronuclei (MN) in peripheral blood lymphocytes of 40 workers at a phosphate fertilizer factory in North China, were studied. HF and SiF4 are the main air pollutants and small amounts of dust containing fluoride, NH3 and SO2 were also present in the factory. It was shown that the chemicals caused an increase in both CA and MN. The mean frequencies per 100 metaphase of major CA type (chromosome rings, translocations, and dicentrics) of the workers and the non-exposed controls were 0.91 and 0.24 (p < 0.01), respectively. The average percentages of lymphocytes with MN of the workers and the controls were 1.55 +/- 0.71 and 0.62 +/- 0.54 (p < 0.01), respectively. Both CA frequency and MN frequency of the workers increased with length of the chemical exposure period up to 10 years.
PMID: 9393620 [PubMed - indexed for MEDLINE]
Fluoride 1997; 30(1):5-15Spin trapping technique studies on active oxygen radicals from human polymorphonuclear leukocytes during fluoride-stiumulated respiratory burst
Wang YY, Zhao BL, Li XJ, Su Z, Xi WJ
Beijing Municipal Institute of Environmental Protection, China
Summary: By means of the ESR spectrum technique it was demonstrated that fluoride (F-) stimulated human polymorphonuclear leukocytes (PMN) in a respiratory burst to generte active oxygen radicals (-O2- and -OH) and to consume oxygen (O2). The experiments using the spin trapping technique with the nitrone DMPO as the trapping agent indicated that the PMN produce the adduct DMPO-OOH under the high concentrations of F- and the adduct DMPO-OH under low concentrations of F-. Under medium concentrations of F-, DMPO-OOH was produced and then decreased in amount as a decrease occured in F- concentration. The results of tests of scavenging by superoxide dismutase (SOD) and catalase suggested that the active oxygen radicals generated in the respiratory burst originated mainly from superoxide (-O2-). By the spin probe oximetry method (CTPO and CrOX) it was shown that the O2 consumed is from the intercellular medium.
Fluoride 1997; 30(1):41-50Fluoride toxicity on rat testis and cauda epididymal tissue components and its reversal
Chinoy NJ, Shukla S, Walimbe AS, Bhattacharya S
Dr. Chinoy, Professor and Head, Zoology Department, School of Sciences, Gujarat University, Ahmedabad, India.
Summary: The toxic effects were evaluated of sodium fluoride (NaF) ingestion on the physiology of tissue components of testis and epididymis of adult, male albino rats, and the possible reversal of the effects by use of some antidotes. The results revealed that the testis and cauda epididymal proteins were altered, with disappearance of some proteins and induction of some new ones. This remained unaltered during NaF ingestion, but a significant decrease occurred in phosphatidlyethanolamine, phosphatidylserine and phosphatidylinositol. Significantly low levels of glutathione after 30 days of treatment were also obtained. On comparing the alterations in protein profile, phospholipds an glutathione in both tissues, it was evident that the protein profile was disturbed more in testis than in cauda epididymis, whereas phospholipids and gluthathione levels were affected more in cauda than in testis. The investigations into reversibility showed that ascorbic acid (vitamin C) and calcium could ameliorate fluoride toxicity.
Full free report available at http://mend.endojournals.org/cgi/content/full/11/11/1618Mol Endocrinol 1997 Oct;11(11):1618-25
Differential regulation of mitogen-activated protein/ERK kinase (MEK)1 and MEK2 and activation by a Ras-independent mechanism.
Xu S, Khoo S, Dang A, Witt S, Do V, Zhen E, Schaefer EM, Cobb MH.
University of Texas Southwestern Medical Center, Department of Pharmacology, Dallas 75235-9041, USA.
Mitogen-activated protein (MAP)/ERK kinase (MEK)1 and MEK2 are the upstream activators of the MAP kinases, ERK1 and ERK2. MEK1 and MEK2 are approximately 85% identical in sequence but have unique inserts in their C-terminal domains. MEK isoform-specific antibodies were used to examine expression and regulation of each enzyme. MEK1 and MEK2 were expressed in approximately equal amounts in several cell lines; in some, MEK1 was present in slight excess. Activation of tyrosine kinase-containing receptors, heterotrimeric G proteins, and protein kinase C enhanced the activities of both MEK isoforms in 293 and PC12 cells. AIF4-stimulated both MEK1 and MEK2 in PC12 cells expressing a dominant interfering Ras mutant that prevents nerve growth factor-dependent activation of the cascade. Carbachol also stimulated the pathway in these cells. Thus, in addition to their ability to activate Ras/Raf and the downstream ERK pathway, heterotrimeric G proteins also appear to trigger a Ras-independent mechanism to regulate this kinase cascade. In U373, Chinese hamster ovary (CHO), and INS-1 cells, MEK1 was activated by regulators of ERKs, while MEK2 was not. These data suggest that, like the MAP kinases ERK1 and ERK2, in some cell settings the two similar MEK isoforms are differentially regulated.
PMID: 9328344 [PubMed - indexed for MEDLINE]
Fluoride 1997; 30(1):43-50Toxicity of fluoride to diabetic rats
Priya CATB, Anitha K, Mohan EM, Pillai KS *, Murthy PB
* Correspondence: Department of Toxicology, Fredrick Institute of Plant Protectin and Toxicology, Tamil Nadu, India
Summary: Wistar rats were given 20 ppm fluroide in drinking water, or single administration of 115 mg/kg alloxan i.m. to induce diabetes, or single administraiton of 115 mg/kg alloxan i.m. followed by 20 ppm fluoride for 31 days. Blood sugar level increased in rats given alloxan and alloxan + fluoride. Body weight gain in rats given alloxan + fluoride decreased significantly compared to other groups. Decrease in haemoglobin and glutamic oxaloacetate transaminase (GOT) was seen only in rats given alloxan + fluoride. In this group alkaline phosphatase, the target enzyme in fluoride toxicosis, increased considerably. The toxicity of fluoride in diabetic rats was further reflected in organ weight data. This investigation shows that fluoride toxicity is greater in diabetic rats.
Fluoride 1997; 30(2):105-109Combined toxicity of fluoride and benzene hexachloride to rats
Ramesh N, Mohan EM, Priya CAYB, Stanley VA, Pillai KS, Murthy PB
Department of Toxicology, Fredrick Institute of Plant Protection and Toxicology, Padappai, Tamil Nadu, India
Summary: Sprague-Dawley rats were given various treatments of 10 ppm fluoride, 25 ppm fluroide, 25 ppm benzene hexachloride (BCH), 10 ppm fluoride + 25 ppm BHC, or 25 ppm fluoride + 25 ppm BHC for 16 weeks ad libitum. Rats showed a decrease in body weight gain, which could be attributable to BHC alone. A synergistic effect of fluoride and BHC was seen only in females given 25 ppm fluroide + 25 ppm BHC: a decease in red blood cells (RBC) and relative weight of the ovary. Females were more susceptible to the toxicity of fluroide and BHC than males
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9421230&dopt=AbstractJ Bone Miner Res 1997 Dec;12(12):1975-83
Mechanism of the mitogenic effect of fluoride on osteoblast-like cells: evidences for a G protein-dependent tyrosine phosphorylation process.
Caverzasio J, Palmer G, Suzuki A, Bonjour JP.
Department of Medicine, University Hospital of Geneva, Switzerland.
Recent results indicate that a fluoroalumino complex (AlFx) is probably the molecule responsible for the mitogenic effect of fluoride in MC3T3-E1 osteoblast-like cells. Initial analysis suggested that a tyrosine phosphorylation (tyr phos) process similar to that induced by thrombin and activation of the p42 MAP kinase (ERK 2) mediate this cellular response. In the present study, the signaling mechanism activated by AlFx was further investigated. The results indicated that AlFx dose-dependently enhanced the tyr phos of the cell adhesion proteins FAK and paxillin, as well as of the adaptor molecules p46shc, p52shc, and p66shc and their association with GRB2. Pretreatment of MC3T3-E1 cells with cytochalasin D completely prevented FAK and paxillin tyr phos without any alteration in the tyr phos of Shc proteins and activation of ERK2 induced by AlFx. This observation suggests that in confluent MC3T3-E1 cells, there is no link between the activation of FAK induced by AlFx and the stimulation of ERK2. Pretreatment of the cells with pertussis toxin inhibited Shc phosphorylation, activation of ERK2, and markedly reduced cell replication induced by AlFx. This toxin also significantly reduced the stimulation of Pi transport activity induced by AlFx in these cells. Alteration in tyr phos induced by AlFx was not associated with any detectable inhibition of tyrosine phosphatase activity in MC3T3-E1 cell homogenates, suggesting that enhanced tyr phos induced by AlFx probably resulted from activation of a tyrosine kinase. In conclusion, the results of this study suggest that the mitogenic effect of fluoride in MC3T3-E1 osteoblast-like cells is mediated by the activation of a pertussis toxin-sensitive Gi/o protein and suggest an important role for these heterotrimeric G proteins in controlling the growth and differentiation of bone-forming cells.
PMID: 9421230 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9458191&dopt=Abstract- Arch Toxicol 1997;72(1):52-8
Fluoride mediates apoptosis in osteosarcoma UMR 106 and its cytotoxicity depends on the pH.
Hirano S, Ando M.
Regional Environment Division, National Institute for Environmental Studies, Tsukuba, Ibaraki, Japan.
Although an excess intake of fluoride has been reported to cause skeletal fluorosis, very little is known about the mechanism of adverse effects of fluoride on bone. In the present study cytotoxic effects of fluoride were studied using the osteosarcoma cell line, UMR 106. The DNA ladder formation upon agarose electrophoresis and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labeling (TUNEL) staining revealed that UMR 106 underwent apoptosis following exposure to 5 mM fluoride for 8 h. On the other hand exposure to A23187, a calcium ionophore, caused necrosis while co-exposure to fluoride and A23187 inhibited fluoride-mediated apoptosis in UMR 106. The proliferation of UMR 106 cells cultured for 6 days in the presence of 0.5 mM fluoride was significantly decreased compared to the control culture. The cytotoxic effects of fluoride were modulated by both the cell density and the pH of the culture medium. The fluoride-induced viability loss in UMR 106 was enhanced in culture of high cell-density and inversely correlated with pH of the culture medium. Enhancement of fluoride cytotoxicity at acidic pH was also observed in rat alveolar macrophages and RAW 264, a macrophage cell line. The results suggest that fluoride-mediated apoptosis and culture conditions, including pH of the medium, should be taken into consideration to evaluate toxicity of fluoride in vitro.
PMID: 9458191 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9481609&dopt=AbstractJ Biolumin Chemilumin 1997 Jul-Aug;12(4):215-21
Functional integrity of human neutrophils following 24 hour incubation with hydroxyapatite and fluoride.
Dowsett SA, Hyvonen PM, Kowolik MJ.
Department of Oral Biology, Indiana Dental School, Indianapolis, USA.
We have previously shown that hydroxyapatite (HA) priming of human neutrophils to a second stimulus of formyl-methionyl-leucyl-phenylalanine (fMPL) is influenced by a bisphosphonate and fluoride. The purpose of this study was to investigate the long-term effects of low concentrations of NaF (10(-3)-10(-11) mol/LF) on HA-mediated neutrophil chemiluminescence (CL) as a measure of oxidative function. CL assays were conducted following extended time periods of incubation (30 min, 3 h, 18 h and 24 h). Results were calculated as integrals of total energy output and expressed as the difference between the experimental (NaF/HA) and control (cells alone) assays. Transmission electron microscopy (TEM) was used to estimate cellular integrity and confirm HA phagocytosis. CL inhibition was observed at all fluoride concentrations at 30 min incubation. No significant difference compared to the control was observed in the CL output at 3 or 18 h. However, at 24 h the response showed a significant increase in activity at all NaF concentrations. The TEM results confirmed the functional integrity of the neutrophils, particularly those phagocytosing HA particles up to 24 h. Based on these results we demonstrate that human peripheral blood neutrophils can be maintained in a fully functional state with respect to the respiratory burst and morphology for at least 24 h.
PMID: 9481609 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9475069&dopt=AbstractIndian J Exp Biol 1997 Aug;35(8):906-8
Gluconeogenesis and glycogenolysis in fluoride-treated rats.
Varadacharyulu NC, Rao PR.
Department of Biochemistry, Sri Krishnadevaraya University, Anantapur, India.
Intraperitonial administration of 10 mg fluoride (NaF)/kg body weight resulted in hyperglycemia in rats. Role of gluconeogenesis and glycogenolysis in this hyperglycemic response was evaluated. Results of the study indicate that the fluoride induced hyperglycemia is mainly due to increased hepatic glycogenolysis.
PMID: 9475069 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9315448&dopt=AbstractExp Gerontol 1997 Jul-Oct;32(4-5):441-50
Age-related changes in axonal transport.
Frolkis VV, Tanin SA, Gorban YN.
Institute of Gerontology, Academy of Medical Sciences of Ukraine, Ukraine.
In rats the rate of axonal transport (AT) or radiolabeled material decreased in the ventral roots of the spinal cord and the vagal and hypoglossal nerves with aging. A maximum AT deceleration in old age was observed in the vagus. The uncoupling of oxidative phosphorylation, inhibition of glycolysis and hypoxia induced a greater AT deceleration in old rats as compared to adults. Small doses of sodium fluoride accelerated AT, and this correlated with a rise in cAMP levels in ventral roots. High doses of sodium fluoride decelerated AT more markedly in old rats. It was shown that anabolic hormones (sex steroids and thyroxine) accelerated AT in both adult and old rats, whereas insulin induced a rise in AT rate in only adults. The catabolic steroid, hydrocortisone decelerated AT. In old rats castration diminished AT, while thyroidectomy had no effect. It was also shown that hydrocortisone and testosterone were transported along axons, reached fibers of the skeletal muscles, and hyperpolarized the plasma membrane. In old age the latent period was extended. Following 73 to 74 days of irradiation, AT slowed down in all the nerves studied in both adult and old rats. Following irradiation hormonal effects on AT changed, for example, the stimulatory effect of estradiol became weak, especially in old rats. Changes in AT could be an important mechanism of disordering the growth of neurons and innervated cells in old age.
PMID: 9315448 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9213223&dopt=AbstractJ Cell Biochem 1997 Aug 1;66(2):219-28
Levels of DNA strand breaks and superoxide in phorbol ester-treated human granulocytes.
Birnboim HC, Sandhu JK.
Ottawa Regional Cancer Centre, University of Ottawa, Ontario, Canada.
Phorbol ester treatment of granulocytes triggers release of superoxide (O2.-) and a concomitant burst of DNA strand breaks. The relationship between the amount of O2.- and the number of DNA breaks has not previously been explored. To quantify the relatively large amount of O2.- generated over a 40-min period by 1 x 10(6) granulocytes/mL, a discontinuous "10-min pulse" method employing cytochrome c was used; 140 nmol O2.- per 1 x 10(6) cells was detected. DNA strand breaks were quantified by fluorimetric analysis of DNA unwinding (FADU). To vary the level of O2.- released by cells, inhibitors of the respiratory burst were used. Sodium fluoride (1-10 mM) and staurosporine (2-10 nM) both inhibited O2.- production. In both cases, however, inhibition of strand breakage was considerably more pronounced than inhibition of O2.-. Zinc chloride (50-200 microM) inhibited both O2.- and DNA breaks, approximately equally. Dinophysistoxin-1 (okadaic acid) inhibited O2.- production more effectively than it inhibited DNA breaks. O2.- dismutes to H2O2, a reactive oxygen species known to cause DNA breaks. The addition of catalase to remove extracellular H2O2 had no effect on DNA breakage. Using pulse field gel electrophoresis, few double-stranded breaks were detected compared to the number detected by FADU, indicating that about 95% of breaks were single-stranded. The level of DNA breaks is not directly related to the amount of extracellular O2.- or H2O2 in PMA-stimulated granulocytes. We conclude that either an intracellular pool of these reactive oxygen species is involved in breakage or that the metabolic inhibitors are affecting a novel strand break pathway.
PMID: 9213223 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9232690&dopt=AbstractRespir Physiol 1997 May;108(2):171-9
The inhibitory effect of fluoride on carbachol-induced bovine bronchial contraction.
Zhao W, Guenard H.
Laboratoire de Physiologie, Faculte de Victor Pachon, Universite de Bordeaux 2, France.
The effect of sodium fluoride (NaF) on the responsiveness of airway smooth muscle was investigated in bovine bronchial segments. NaF (0.5-10 mM) induced a delayed concentration-dependent active pressure (AP) and reduced the lactate concentration in the solution. Pyruvate (10 mM) increased the NaF-induced contraction. There was a 50 +/- 7% decrease in carbachol (10 microM)-induced AP when bronchi were pretreated with NaF (5 mM) and a 37 +/- 9% decrease when NaF (5 mM) was added during the maintained carbachol-induced contraction. These inhibitory effects were enhanced by KCN and hypoxia. When bronchi were pre-incubated with 10 microM verapamil, a calcium channel inhibitor, the contractile effect of 5 mM NaF was reduced to 8 +/- 3% of the control. PKC activity in bronchial smooth muscle was significantly increased by NaF (5 mM). Staurosporine (30 nM) abolished the contractile effect of NaF. These results suggest that:
(1) NaF either contracts or relaxes bronchial smooth muscle depending on the experimental conditions;
(2) the relaxing effect is related to the inhibitory action of NaF on glycolysis;
(3) the contractile effect of NaF is possibly mediated by modulation of a calcium channel via a PKC-dependent pathway;
(4) carbachol-induced contraction is glycolysis pathway dependent in the absence of NaF but switches to oxidative dependent in its presence.
PMID: 9232690 [PubMed - indexed for MEDLINE
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9033286&dopt=AbstractAm J Pathol 1997 Feb;150(2):735-45
Inorganic fluoride. Divergent effects on human proximal tubular cell viability.
Zager RA, Iwata M.
Fred Hutchinson Cancer Research Center, Seattle, WA 98104, USA.
Fluoride (F) is a widely distributed nephrotoxin with exposure potentially resulting from environmental pollution and from fluorinated anesthetic use (eg, isoflurane). This study sought to characterize some of the subcellular determinants of fluoride cytotoxicity and to determine whether subtoxic F exposure affects tubular cell vulnerability to superimposed ATP depletion and nephrotoxic attack. Human proximal tubular cells (HK-2) were cultured with differing amounts of NaF (0 to 20 mmol/L, overlapping with clinically relevant intrarenal/urinary levels after fluorinated anesthetic use). After completing 24-hour exposures, cell injury was determined (vital dye uptake). Fluoride effects on cell deacylation ([3]H-C20:4 release) and PLA2 activity were also assessed. To determine whether subtoxic F exposure alters tubular cell susceptibility to superimposed injury, cells were exposed to subtoxic NaF doses for 0 to 24 hours and then challenged with simulated ischemia (ATP depletion plus Ca2+ overload) or a clinically relevant nephrotoxic insult (myoglobin exposure). NaF induced dose-dependent cytotoxicity (up to approximately 90% vital dye uptake and increased [3H]C20:4 release). Extracellular Ca2+ chelation (EGTA) and PLA2 inhibitor therapy (aristolochic acid, dibucaine, or mepacrine) each conferred significant protective effects. When subtoxic NaF doses were applied, partial cytosolic PLA2 depletion rapidly developed (approximately 85% within 3 hours, determined on cell extracts). These partially PLA2-depleted cells were markedly resistant to ATP depletion/Ca2+ ionophore injury and to myoglobin-induced attack (approximately 50% decrease in cell death).
We conclude that
1) F induces dose-dependent cytotoxicity in cultured human proximal tubular cells,
2) this occurs, in part, via Ca(2+)- and PLA2-dependent mechanism(s),
3) partial cytosolic PLA2 depletion subsequently results, and
4) subtoxic fluoride exposure can acutely increase cell resistance to further attack. Reductions in cytosolic PLA2 activity could potentially contribute to this result.
PMID: 9033286 [PubMed - indexed for MEDLINE]
Full report available at: http://ajpcell.physiology.org/cgi/content/full/273/5/C1749Am J Physiol 1997 Nov;273(5 Pt 1):C1749-55
Prostaglandin H synthase: protein synthesis-independent regulation in bovine aortic endothelial cells.
Rosenstock M, Danon A, Rimon G.
Department of Clinical Pharmacology, Corob Center for Health Sciences, Ben-Gurion University, Beer-Sheva, Israel.
The objective of the present study was to examine whether prostaglandin H synthase (PGHS) can be regulated by pathways independent of de novo synthesis of PGHS. Incubation of bovine aortic endothelial cells (BAEC) for as short as 5 min with NaF (40 mM) resulted in a 60% increase in PGHS activity. PGHS activity induced by NaF was unaffected by either 10 microM cycloheximide or 1 microM actinomycin D. Aspirin (25 microM) completely inhibited resting PGHS activity, and NaF did not induce further stimulation. NS-398 (500 nM), a specific PGHS-2 inhibitor, was ineffective. Basic fibroblast growth factor (bFGF) induced a significant increase in PGHS activity within 30 min and was insensitive to cycloheximide. The levels of PGHS-1 and PGHS-2 proteins, as measured by Western blots, were not affected by NaF or bFGF. The tyrosine kinase inhibitor genistein attenuated PGHS activity that was induced by NaF and bFGF, whereas the tyrosine phosphatase inhibitor, sodium orthovanadate, augmented these responses. The G protein activators 5'-guanylyl imidodiphosphate and guanosine 5'-O-(3-thiotriphosphate) inhibited both resting and NaF-induced PGHS activities. These results suggest-that, in BAEC, PGHS-1 activity can be regulated by tyrosine kinase and/or G proteins, independently of de novo protein synthesis.
PMID: 9374663 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9016786&dopt=AbstractBiochem Biophys Res Commun 1997 Jan 13;230(2):370-5
The nucleolar phosphoprotein P130 is a GTPase/ATPase with intrinsic property to form large complexes triggered by F- and Mg2+.
Chen HK, Yeh NH.
Institute of Microbiology and Immunology, School of Life Science, National Yang-Ming University, Taipei, Taiwan, Republic of China.
We have previously identified a human nucleolar phosphoprotein p130 whose alterations during mitosis are correlated well with the nucleolar disassembly and reassembly. Further studies found that p130 in the cell lysates or after being purified by immunoprecipitation was able to form large complexes triggered by F- and Mg2+. These sodium dodecyl sulfate-insoluble p130 molecules were readily dissociated by adding EDTA to the complexes. It is known that F- and Mg2+ act on many GTPases and ATPases through the induction of a conformational transition mimicking the nucleoside triphosphate-bound state. These initial observations led us to discover that p130 functions as a GTP/ATP binding protein with intrinsic GTPase/ATPase activities. The rate of GTP hydrolysis by purified p130 under our experimental conditions was 0.8 mol/min/mol of p130. These results imply that p130, a novel nucleolar GTPase/ATPase, may switch its conformation in a nucleotide-dependent manner.
PMID: 9016786 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9124513&dopt=AbstractAm J Physiol 1997 Mar;272(3 Pt 1):C794-803
Dual role for AlF4(-)-sensitive G proteins in the function of T84 epithelial cells: transport and barrier effects.
Ries J, Stein J, Traynor-Kaplan AE, Barrett KE.
Department of Medicine, School of Medicine, University of California, San Diego 92103, USA.
T84 monolayers were studied to determine the effect of AlF4, an activator of heterotrimeric G proteins, on Cl-secretion and intestinal barrier function. Basolateral (but not apical) addition of AlF4- increased short-circuit current (I(sc)) and decreased transepithelial resistance. Preincubation with the heavy metal chelator deferoxamine showed that both effects were dependent on Al3+. The effect on I(sc) was abolished by the intracellular Ca2+ chelator 1,2-bis(2-aminophenoxy) ethane-N,N,N',N'-tetraacetic acid or in Cl(-)-free solutions, whereas the decrease in resistance was unaffected. AlF4- also increased intracellular Ca2+, as assessed via fura 2 fluorometry. AlF4- had no effect on adenosine 3',5'-cyclic monophosphate (cAMP) or guanosine 3',5'-cyclic monophosphate (cGMP) levels in T84 cells. The effect of AlF4- on transepithelial resistance was accompanied by a decrease in cellular F-actin as well as increased transepithelial fluxes of the paracellular markers mannitol and inulin. The results indicate that AlF4(-)-sensitive G proteins regulate both epithelial secretory and barrier functions, but via different pathways. AlF4- increases Cl- secretion via a Ca2+-dependent and cAMP- and cGMP-independent mechanism in T84 cells, whereas the decrease in resistance is independent of Ca2+.
PMID: 9124513 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9409628&dopt=AbstractFood Chem Toxicol 1997 Sep;35(9):881-90
- Testing the potential of sodium fluoride to affect spermatogenesis in the rat.
Sprando RL, Collins TF, Black TN, Rorie J, Ames MJ, O'Donnell M.
Division of Toxicological Research, Center for Food Safety Applied Nutrition, Food and Drug Administration, Beltsville, MD 20708, USA.
The potential of sodium fluoride (NaF) to affect spermatogenesis and endocrine function was assessed in P and F1 generation male rats. Male and female experimental rats received sodium fluoride in their drinking water at one of four concentrations (25, 100, 175, 250 ppm). P generation male and female rats were exposed to sodium fluoride in their drinking water for 10 wk and then males were mated to females within the same treatment groups. Reproductive tissues were collected from P generation male rats after approximately 14 wk of treatment. Pregnant females (P) were exposed to sodium fluoride via their drinking water through gestation and lactation. F1 generation weanling male rats remained within the same treatment groups as their parents. F1 generation male rats were exposed to sodium fluoride in their drinking water for 14 wk, at which time reproductive tissues were collected. Dose-related effects were not observed within the P and F1 treatment groups in testis weights, prostate/seminal vesicle weights, non-reproductive organ weights, testicular spermatid counts, sperm production per gram of testis per day, sperm production per gram of testis, LH, FSH or serum testosterone concentrations. Histological changes were not observed in testicular tissues from either the P or F1 generation. We conclude that prolonged exposure to sodium fluoride in drinking water at the doses administered in this study does not adversely affect spermatogenesis or endocrine function in the P and F1 generation male rats.
PMID: 9409628 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9108480&dopt=AbstractNOTE: AG Gilman, co-author of this report, shared the 1994 Nobel Prize for the discovery of "G-proteins and the role of these proteins in signal transduction in cells."
Cell 1997 Apr 18;89(2):251-61
Structure of RGS4 bound to AlF4--activated G(i alpha1): stabilization of the transition state for GTP hydrolysis.
Tesmer JJ, Berman DM, Gilman AG, Sprang SR.
Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas 75235, USA.
RGS proteins are GTPase activators for heterotrimeric G proteins. We report here the 2.8 A resolution crystal structure of the RGS protein RGS4 complexed with G(i alpha1)-Mg2+-GDP-AlF4 . Only the core domain of RGS4 is visible in the crystal. The core domain binds to the three switch regions of G(i alpha1), but does not contribute catalytic residues that directly interact with either GDP or AlF4-. Therefore, RGS4 appears to catalyze rapid hydrolysis of GTP primarily by stabilizing the switch regions of G(i alpha1), although the conserved Asn-128 from RGS4 could also play a catalytic role by interacting with the hydrolytic water molecule or the side chain of Gln-204. The binding site for RGS4 on G(i alpha1) is also consistent with the activity of RGS proteins as antagonists of G(alpha) effectors.
PMID: 9108480 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9231714&dopt=AbstractJ Neurochem 1997 Aug;69(2):570-80
4-Hydroxynonenal, an aldehydic product of lipid peroxidation, impairs signal transduction associated with muscarinic acetylcholine and metabotropic glutamate receptors: possible action on G alpha(q/11).
Blanc EM, Kelly JF, Mark RJ, Waeg G, Mattson MP.
Sanders-Brown Center on Aging and Department of Anatomy and Neurobiology, University of Kentucky, Lexington 40536-0230, USA.
Considerable data indicate that oxidative stress and membrane lipid peroxidation contribute to neuronal degeneration in an array of age-related neurodegenerative disorders. In contrast, the impact of subtoxic levels of membrane lipid peroxidation on neuronal function is largely unknown. We now report that 4-hydroxynonenal (HNE), an aldehydic product of lipid peroxidation, disrupts coupling of muscarinic cholinergic receptors and metabotropic glutamate receptors to phospholipase C-linked GTP-binding proteins in cultured rat cerebrocortical neurons. At subtoxic concentrations, HNE markedly inhibited GTPase activity, inositol phosphate release, and elevation of intracellular calcium levels induced by carbachol (muscarinic agonist) and (RS)-3,5-dihydroxyphenyl glycine (metabotropic glutamate receptor agonist). Maximal impairment of agonist-induced responses occurred within 30 min of exposure to HNE. Other aldehydes, including malondialdehyde, had little effect on agonist-induced responses. Antioxidants that suppress lipid peroxidation did not prevent impairment of agonist-induced responses by HNE, whereas glutathione, which is known to bind and detoxify HNE, did prevent impairment of agonist-induced responses. HNE itself did not induce oxidative stress. Immunoprecipitation-western blot analysis using an antibody to HNE-protein conjugates showed that HNE can bind to G alpha(q/11). HNE also significantly suppressed inositol phosphate release induced by aluminum fluoride. Collectively, our data suggest that HNE plays a role in altering receptor-G protein coupling in neurons under conditions of oxidative stress that may occur both normally, and before cell degeneration and death in pathological settings.
PMID: 9231714 [PubMed - indexed for MEDLINE]
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