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2000 Fluoride Abstracts. Part 1.
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Wei Sheng Yan Jiu 2000 Jul;29(4):216-7
[Effects of selenium and zinc on the DNA damage caused by fluoride in pallium neural cells of rats]
[Article in Chinese]
Chen J, Chen X, Yang K.
Department of Environmental Health, Tongji Medical University, Wuhan 430030, China.
To investigate the effects of fluoride on DNA damage as well as the effects of selenium and zinc against fluoride respectively or jointly in pallium neural cells of rats, single cell gel electrophoresis was used to detect the DNA damage of neural cells prepared in vitro. The results showed that the degree of DNA damage in the fluoride group and the selenium group were significantly greater than that in control group(P < 0.01). The damage in the fluoride group was even more serious. The damage in the fluoride + selenium group and fluoride + zinc group was slighter than that in the fluoride group but with no significant difference. The extent of DNA damage in the fluoride + selenium + zinc group was significantly slighter than that in the fluoride group(P < 0.05). It suggested that fluoride and selenium could induce DNA damage in pallium neural cells of rats respectively. Moreover, the joint antagonistic effect of selenium and zinc against fluoride was more obvious.
PMID: 12520922 [PubMed - in process][Note from FAN:
Definition of Pallium: - the central cortex with the subajacent white substance. SYN mantle [L. cloak] - Ref: Steadman's Concise Medical Dictionary for the Health Professions. Illustrated 4th Edition. 2001. Ed. JH Dirckx. Lippincott Williams & Wilkins.]
From TOXNETChung-Kuo Kung Kung Wei Sheng (China Public Health) 2000 Aug;16(8):697-8
[The primary study of antagonism of selenium on fluoride-induced reproductive toxicity of male rat]
[Article in Chinese]
Zhu XZ, Ying CJ, Liu SH, Yang KD, Wang QZ.
Department of Clinic Nutrition, Tongji Hospital Tongji Medical University, Wuhan, China.
English Abstract Indicator: A Abstract: The protective effect of ascorbic acid at dose level of 1.0 mg/L in drinking water against the fluoride-induced damage on reproductive system of rat was studied. 150 mg/L sodium fluoride (NaF) in drinking water of male rat can cause the significant decrease of sperm count and mobility, the increase of serum and testicular lipid peroxides (LPO) contents, and the adenosine triphosphatase (ATPase) activity depression of epididymis. All of those effects are reversible by adding adequate ascorbic acid in drinking water simultaneously. The effects of ascorbic acid against fluoride-induced damages are similar to those produced by 2.0 mg/L Na2SeO3 in the drinking water of rats. However, no significant recovery of fluoride-induced effects on GSH-Px activities in the tissues of testis and epididymis were observed in ascorbic acid and fluoride group. The mechanism of ascorbic acid on fluoride-induced damage of male reproductive system need to be further studied.
Full report available at: http://www.fluoride-journal.com/00-33-1/331-17.pdfFluoride 2000; 33(1):17-26
Effects of fluoride accumulation on some enzymes of brain and gastrocnemius muscle of mice
M Lakshmi Vani, K Pratap Reddy *
* For correspondence: Neurobiology Laboratory, Department of Zoology, Osmania University, Hyderabad - 500 007, Andhra Pradesh, India.
SUMMARY: This study reports accumulation of fluoride and altered activities of some enzymes involved in free-radical metabolism and membrane function in whole brain and gastrocnemius muscle of female mice treated with NaF (20mg/kg/body weight) for 14 days. The body weight and somatic index were decreased, whereas fluoride levels were significantly increased (p<0.01) in both brain and gastrocnemius muscle. The enzymes SOD, GST, and catalase decreased significantly (p<0.01) in contrast to XOD activity, which moderately increased. SDH, LDH, AlAT, AAT, and CPK activities and membrane-bound enzymes, viz Na + -K + , Mg ++ and Ca ++ ATPase and AChE were decreased signifi-cantly (p<0.01) in both brain and gastrocnemius muscle. The effect of fluoride on enzymes of muscle was comparatively larger, which corroborates the greater accumulation of fluoride in muscle than brain. This study therefore shows that both brain and muscle are affected by fluoride with inhibition of some enzymes associated with free-radical metabolism, energy production and transfer, membrane transport, and synaptic transmission, but with an enhanced activity of XOD.
Chinese Journal of Endemiology 2000;19(4):262-3
- As cited and abstracted in Fluoride 2001; 34(1):80
Effects of high fluoride drinking water on the cerebral functions of mice
Sun Z-R, Liu F-Z, Wu L-N, et al.
For Correspondence: Department of Environmental Health, Tianjin Medical University, Tianjin 300070, China.
Objective: To study the effects of high fluoride concentration in drinking water on the cerebral functions of mice.
Methods: Learning and memory abilities of high-fluoride exposed and control groups of mice were measured by behavior-toxicological test (Shuttle box Test), and the cholinesterase (ChE) activity in brain tissue homogenate of the mice was determined.
Results: Learning and memory abilities of high-fluoride exposed groups were significantly lower than that of the control group, while the brain ChE activities of high-fluoride exposed groups were significantly higher.
Conclusions: High fluoride concentration in drinking water can decrease the cerebral functions of mice. Fluoride is a neurotoxicant.
Chinese Journal of Endemiology 2000; 19(5):340-1.The effects of high fluoride on micronucleus rate in humans and mice
- As cited and abstracted in Fluoride 2001; 34(1):80
Li J, Zhou H-L, Yang Q, et al.
Objective: The human body and the mice were regarded as suitable subjects to study the effects of high-fluoride on micronucleus rate in mammalian animals.
Methods: In a test on the human body, the micronucleus rate of 51 adults from a high-fluoride area was compared with the micronucleus rate of 24 adults from a low-fluoride area. In a test on mice, the experimental group drank fluoride water, and the control group drank tap water. Differences were examined for significance by the chi-squared test.
Results: The micronucleus rate of adults from the high-fluoride area was higher than that of adults in the low-fluoride area, and the difference was sig-nificant (P<0.05). The micronucleus rate of mice drinking high-fluoride water was higher than that of the control group, and the difference was also signifi-cant (P<0.05).
Conclusions: High-fluoride intake increases the miconucleus rate in mammals, and can damage chromosomes. Fluoride may therefore be mutagenic.
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11134585&dopt=AbstractBrain Res 2000 Dec 22;887(1):16-22
Neonatal polyamine depletion by alpha-difluoromethylornithine: effects on adenylyl cyclase cell signaling are separable from effects on brain region growth.
Slotkin TA, Ferguson SA, Cada AM, McCook EC, Seidler FJ.
Department of Pharmacology and Cancer Biology, Box 3813, Duke University Medical Center, Durham, NC 27710, USA. t.slotkin@duke.edu
Ornithine decarboxylase (ODC) and the polyamines play an essential role in brain cell replication and differentiation. We administered alpha-difluoromethylornithine (DFMO), an irreversible inhibitor of ODC, to neonatal rats on postnatal days 5-12, during the mitotic peak of the cerebellum, a treatment regimen that leads to selective growth inhibition and dysmorphology. In adulthood, cell signaling responses mediated through the adenylyl cyclase pathway were evaluated in order to determine if synaptic dysfunction extends to regions that appear to be otherwise unaffected by DFMO. Total adenylyl cyclase catalytic activity, evaluated with the direct enzymatic stimulant, Mn(2+), was significantly elevated in male rats both in the cerebellum and in brain regions showing no growth retardation (cerebral cortex, brainstem); there were no significant effects in females. In contrast, signaling mediated through the G proteins that couple neurotransmitter receptors to adenylyl cyclase showed a deficit in the DFMO group, as evaluated with the response to fluoride; in males, there was no corresponding increase in activity as would have been expected solely from the enhancement of adenylyl cyclase, and in females, there was actually a significant decrease in the response to fluoride. Again, the deficits were not restricted to the cerebellum. Stimulation of adenylyl cyclase by isoproterenol, a beta-adrenergic receptor agonist that acts through G(s), likewise displayed deficits in both males and females, and without distinction by brain region. These results indicate that the ODC/polyamine pathway plays a role in the development of cell signaling, and hence in neurotransmission, above and beyond its role in cell replication and differentiation. Given the fact that numerous drugs and environmental contaminants have been shown to alter ODC and the polyamines in the developing brain, our findings suggest that changes in brain region growth or structure are inadequate to predict the targeting of specific neurotransmitter or signaling pathways, and that gender-selective functional defects may be present despite the absence of morphological differences.
PMID: 11134585 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10986332&dopt=AbstractBrain Res 2000 Sep 22;877(2):191-202
Ligand specific effects on aluminum incorporation and toxicity in neurons and astrocytes.
Levesque L, Mizzen CA, McLachlan DR, Fraser PE.
Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario, Canada M5S 3H2. ll5n@virginia.edu
Aluminum is present in many manufactured foods and medicines and is added to drinking water for purification purposes. It has been proposed that aluminum is a contributing factors to several neurodegenerative disorders such as Alzheimer's disease. However, this remains controversial primarily due to the unusual properties of aluminum and a lack of information on its cellular sites of action. To resolve some of these questions, we have examined aluminum uptake in both neuronal and astroglial cells as well as the role of metal speciation. The relative accumulation of four aluminum salts, aluminum maltolate, aluminum lactate, aluminum chloride and aluminum fluoride, was investigated and correlated with cell viability and intracellular distribution as determined by morin staining. Significant differences in aluminum incorporation and toxicity were observed in both neuronal and glia cells with the largest effects exhibited by the maltol species. This was accompanied by a nuclear accumulation in the neuronal cell line that was contrasted by the perinuclear, vesicular distribution in astrocytes that partially co-localized with cathepsin D, a lysosomal marker. These findings demonstrate differences in aluminum species and highlights the importance of these factors in modulating the toxic effect of aluminum.
PMID: 10986332 [PubMed - indexed for MEDLINE]
Chinese Journal of Endemiology 2000;19(2):96-8
- As cited and abstracted in Fluoride 2001; 34(1):82
Study of the mechanism of neurone apoptosis in rats from the chronic fluorosis
Lu X-H, Li G-S, Sun B
For Correspondence: Institute of Endemi c Diseases in Nornman Bethune University of Medical Sciences, Changchun 130021, China
Objective: Study the mechanism of action chronic fluorosis in neurones.
Methods: Terminal deoxyribo-nucleotide transferase-mediated dUTP-biotin nick end labeling (TUNEL) and flow cytometry (FCM) were used to observe changes of apoptosis in cerebral cells in chronic fluorosis in rats.
Results: TUNEL results show non-random expression of DAB positive stain apoptosis cells which appear only in the hippocampus CA4 region. FCM re-sults show that the percentage of DNA fragmentation increased markedly in the cerebral neurones of rats with chronic fluorosis but not in different cerebral re-gions.
Conclusions: There is a tendency for neurone apoptosis in chronic fluorosis in rats. It is most evident with changes in pathology. It is not likely that only one form of neurone damage exist in the process of chronic fluorosis. There are recessive changes and apoptosis in the process at the same time.
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11860941&dopt=AbstractZhonghua Yu Fang Yi Xue Za Zhi 2000 Nov;34(6):330-2
[Influence of free radical inducer on the level of oxidative stress in brain of rats with fluorosis]
[Article in Chinese]
Shao Q, Wang Y, Guan Z.
Department of Neurology, Guiyang Medical College, Guizhou 550004, China.
OBJECTIVE: To study changes in content of lipid peroxide and compositon of fatty acids in the brain of rats afflicated with chronic fluorosis after treatment with free radical inducer (ferric ion).
METHODS: Thirty-six Wistar rats were divided into three groups, fed with similar fodder and varied concentrations of fluoride in drinking water, and were killed five months after treatment. Lipid peroxidation was induced by ferric ions. Malondialdehyde content in brain was analysed by high-performance liquid chromatography; oxygen consumption was determined with an oxygen electrode and fatty acid composition was measured by gas chromatography in brain tissues of the rats.
RESULTS: In the brain tissues, content of malondialdehyde and oxygen consumption increased, composition of polyunsaturated fatty acids decreased and that of saturated fatty acids decreased after treatment with free radical inducer in the treated group, as compared with those in control group.
CONCLUSION: Over uptake of fluoride for a long term could cause potantial increase in the level of oxidative stress in the brain tissue.
PMID: 11860941 [PubMed - in process]
Full report available at: http://www.fluoride-journal.com/00-33-3/333-108.pdfFluoride 2000; 33(3): 108-114
The influence of fluoride ions on the viability, reduction of NBT, cytolysis, degranulation, and phagocytosis of human and rabbit neutrophils
J Bober (,a,b), E Kucharsk (c), J Zawierta (a), Z Machoy (a), D Chlubek (a), K Ciechanowski (a)
(a) Chair and Department of Biochemistry, Pomeranian Academy of Medicine, Al. Powsta • ców Wlkp. 72, 70-111 Szczecin, Poland. E-mail: biochem@pam.szczecin.pl (Head: Asst Prof Dariusz Chlubek, MD, PhD).
(b) For correspondence: Joanna Bober, MD, PhD, same address.
(c) Chair and Department of Microbiology and Immunology, Pomeranian Academy of Medicine, Al. Powsta • ców Wlkp. 72, 70-111 Szczecin, Poland.Summary: The influence of fluoride ion at concentrations of 10, 20, and 30 mmol/L on various properties of human and rabbit granulocytes was investigated. We found that fluoride ion inhibited phagocytes functions of rabbit granulocytes. It also decreased the viability of rabbit polymorphonuclear leukocytes (PMN) which was connected with increased degranulation. Fluoride ion activated mainly the oxygen-dependent bactericidal system in human neutrophils and the oxygen-independent one in rabbit neutrophils.
Full report available at: http://www.fluoride-journal.com/00-33-2/332-74.pdfFluoride 2000; 33(2): 74-78
Effect of high fluoride water on intelligence of children
Y Lu (a), ZR Sun (a), LN Wu (a), X Wang, (a), W Lu (a), SS Liu (b)
(a) Dr Yan Lu, Department of Environmental Health, Tianjin Medical University, Tianjin, China. Emai: yan_lv@hotmail.com.
(b) Tianjin Xiqing District Anti-Epidemic Station, Tianjin, China.SUMMARY: The Intelligence Quotient (IQ) was measured in 118 children, aged 10-12 years, who were life-long residents in two villages of similar population size and social, educational and economic background but differing in the level of fluoride in drinking water. The children in the high-fluoride area (drinking water fluoride 3.15 ± 0.61 mg/L [ppm]) (mean ± S.D.) had higher urinary fluoride levels (4.99 ± 2.57 mg/L) than the children in the low-fluoride area (drinking water fluoride 0.37 ± 0.04 mg/L) (urinary fluoride 1.43 ± 0.64 mg/L). The IQ of the 60 children in the high-fluoride area was significantly lower, mean 92.27 ± 20.45, than that of the 58 children in the low-fluoride area, mean 103.05 ± 13.86. More children in the high-fluoride area, 21.6%, were in the retardation (<70) or borderline (70-79) categories of IQ than children in the low fluoride area, 3.4%. An inverse relationship was also present between IQ and the urinary fluoride level. Exposure of children to high levels of fluoride may therefore carry the risk of impaired development of intelligence.
Free report available at http://www.jphysiol.org/cgi/content/full/526/1/99J Physiol 2000 Jul 1;526 Pt 1:99-108
Stimulation of Ca(2+)-independent exocytosis in rat pituitary gonadotrophs by G-protein.
Tse FW, Tse A.
Department of Pharmacology, University of Alberta, Edmonton, Alberta, Canada T6G 2H7. fred.tse@ualberta.ca
1. We employed the whole-cell recording technique in conjunction with fluorometry to measure cytosolic Ca(2+) concentration ([Ca(2+)](i)) and exocytosis (capacitance measurement) in single, identified rat gonadotrophs.
2. Direct activation of G-protein (via intracellular dialysis of non-hydrolysable analogues of GTP, but not of GDP) triggered a slow rise in capacitance even in the presence of a fast intracellular Ca(2+) chelator.
3. The broad-spectrum kinase inhibitors H7 and staurosporine did not prevent this Ca(2+)-independent exocytosis, ruling out the involvement of the cAMP and PKC pathways.
4. AlF(4)(-), a potent stimulator of heterotrimeric G-proteins, failed to stimulate any exocytosis when the intracellular Ca(2+) store was depleted, implicating the involvement of AlF(4)(-)-insensitive G-protein(s).
5. Maximal stimulation of Ca(2+)-independent exocytosis by GTP analogues did not reduce the number of readily releasable granules that were available subsequently for Ca(2+)-dependent release.
6. The last finding raises the possibility that the G-protein-stimulated Ca(2+)-independent exocytosis may regulate a pool of granules that is distinct from the Ca(2+)-dependent pool.PMID: 10878103 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11032978&dopt=Abstract
Biol Psychiatry 2000 Oct 1;48(7):665-73
Associated disturbances in calcium homeostasis and G protein-mediated cAMP signaling in bipolar I disorder.
Emamghoreishi M, Li PP, Schlichter L, Parikh SV, Cooke R, Warsh JJ.
Section of Biochemical Psychiatry, Centre for Addiction and Mental Health, Clarke Site, Toronto, Ontario, Canada.
BACKGROUND: Evidence of extensive cross-talk between calcium (Ca(2+))- and cAMP-mediated signaling systems suggests that previously reported abnormalities in Ca(2+) homeostasis in bipolar I (BP-I) patients may be linked to disturbances in the function of G proteins that mediate cAMP signaling.
METHODS: To test this hypothesis, the beta-adrenergic agonist, isoproterenol, and the G protein activator, sodium fluoride (NaF), were used to stimulate cAMP production in B lymphoblasts from healthy and BP-I subjects phenotyped on basal intracellular calcium concentration ([Ca(2+)](B)). cAMP was measured by radioimmunoassay and [Ca(2+)](B) by ratiometric fluorometry with fura-2.
RESULTS: Isoproterenol- (10 microM) stimulated cAMP formation was lower in intact B lymphoblasts from BP-I patients with high [Ca(2+)](B) (>/= 2 SD above the mean concentration of healthy subjects) compared with patients having normal B lymphoblast [Ca(2+)](B) and with healthy subjects. Although basal and NaF-stimulated cAMP production was greater in B lymphoblast membranes from male BP-I patients with high versus normal [Ca(2+)](B), there were no differences in the percent stimulation. This suggests the differences in NaF response resulted from higher basal adenylyl cyclase activity.
CONCLUSIONS: These findings suggest that trait-dependent disturbances in processes regulating beta-adrenergic receptor sensitivity and G protein-mediated cAMP signaling occur in conjunction with altered Ca(2+) homeostasis in those BP-I patients with high B lymphoblast [Ca(2+)](B).
PMID: 11032978 [PubMed - indexed for MEDLINE]
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From TOXNET
Chung-Kuo Kung Kung Wei Sheng (China Public Health) 2000 Aug;16(8):697-8
[The primary study of antagonism of selenium on fluoride-induced reproductive toxicity of male rat]
Zhu XZ, Ying CJ, Liu SH, Yang KD, Wang QZ.
Department of Clinic Nutrition, Tongji Hospital Tongji Medical University, Wuhan, China.
English Abstract Indicator: A Abstract: The protective effect of ascorbic acid at dose level of 1.0 mg/L in drinking water against the fluoride-induced damage on reproductive system of rat was studied. 150 mg/L sodium fluoride (NaF) in drinking water of male rat can cause the significant decrease of sperm count and mobility, the increase of serum and testicular lipid peroxides (LPO) contents, and the adenosine triphosphatase (ATPase) activity depression of epididymis. All of those effects are reversible by adding adequate ascorbic acid in drinking water simultaneously. The effects of ascorbic acid against fluoride-induced damages are similar to those produced by 2.0 mg/L Na2SeO3 in the drinking water of rats. However, no significant recovery of fluoride-induced effects on GSH-Px activities in the tissues of testis and epididymis were observed in ascorbic acid and fluoride group. The mechanism of ascorbic acid on fluoride-induced damage of male reproductive system need to be further studied.
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10867750&dopt=AbstractMed Hypotheses 2000 Jun;54(6):979-83
Is autism a G-alpha protein defect reversible with natural vitamin A?
Megson MN.
Pediatric and Adolescent Ability Center, Richmond, VA 23226, USA.
Autism may be a disorder linked to the disruption of the G-alpha protein, affecting retinoid receptors in the brain. A study of 60 autistic children suggests that autism may be caused by inserting a G-alpha protein defect, the pertussis toxin found in the DPT vaccine, into genetically at-risk children. This toxin separates the G-alpha protein from retinoid receptors. Those most at risk report a family history of at least one parent with a pre-existing G-alpha protein defect, including night blindness, pseudohypoparathyroidism or adenoma of the thyroid or pituitary gland. Natural vitamin A may reconnect the retinoid receptors critical for vision, sensory perception, language processing and attention. Autism spectrum disorders have increased from 1 in 10 000 in 1978 to 1 in 300 in some US communities in 1999. Recent evidence indicates that autism is a disorder of the nervous system and the immune system, affecting multiple metabolic pathways.
PMID: 10867750 [PubMed - indexed for MEDLINE]
Full editorial available at http://www.fluoride-journal.com/00-33-3/333-101.pdfFluoride 2000; 33(3):101-102
Editorial
The right control diet
Albert W Burgstahler
Excerpt:
... At present most chronic fluoride toxicity studies on rodents are conducted with standard commercial diets that contain not only substantial amounts of fluorine but also other toxic elements like aluminum and silicon. Interactions of these elements and combinations of them greatly complicate and compromise the results of long-term fluoride supplementation with such diets. On the other hand, with an optimal low-fluoride diet like Chlorycel, definitive studies can be conducted to determine how fluorides and/or other toxic substances added to it affect the lifespan of mice and rats and at what levels other adverse long-term effects in soft and hard tissues can be detected in these animals. Such a diet is clearly Òthe right controlÓ that ought to be explored.
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11233755&dopt=Abstract
Neurotoxicology 2000 Dec;21(6):1091-100Association of silicofluoride treated water with elevated blood lead.
Masters RD, Coplan MJ, Hone BT, Dykes JE.
Foundation for Neuroscience and Society, Dartmouth College, Hanover, NH 03755-3547, USA. roger.d.masters@dartmouth.edu
Previous epidemiological studies have associated silicofluoride-treated community water with enhanced child blood lead parameters. Chronic, low-level dosage of silicofluoride (SiF) has never been adequately tested for health effects in humans. We report here on a statistical study of 151,225 venous blood lead (VBL) tests taken from children ages 0-6 inclusive, living in 105 communities of populations from 15,000 to 75,000. The tests are part of a sample collected by the New York State Department of Children's Health, mostly from 1994-1998. Community fluoridation status was determined from the CDC 1992 Fluoridation Census. Covariates were assigned to each community using the 1990 U.S. Census. Blood lead measures were divided into groups based on race and age. Logistic regressions were carried out for each race/age group, as well as above and below the median of 7 covariates to test the relationship between known risk factors for lead uptake, exposure to SiF-treated water, and VBL >10 microg/dL.
RESULTS: For every age/race group, there was a consistently significant association of SiF treated community water and elevated blood lead. Logistic regressions above and below the median value of seven covariates show an effect of silicofluoride on blood lead independent of those covariates. The highest likelihood of children having VBL> 10 microg/dL occurs when they are both exposed to SiF treated water and likely to be subject to another risk factor known to be associated with high blood lead (e.g., old housing). Results are consistent with prior analyses of surveys of children's blood lead in Massachusetts and NHANES III. These data contradict the null hypothesis that there is no difference between the toxic effects of SiF and sodium fluoride, pointing to the need for chemical studies and comprehensive animal testing of water treated with commercial grade silicofluorides.
PMID: 11233755 [PubMed - indexed for MEDLINE]
Full report available at: http://www.fluoride-journal.com/00-33-2/332-79.pdfFluoride 2000; 33(2):79-84
Reproducitve toxic effects of ingestion of sodium fluoride in female rats
Ahmad S Al-Hiyasat (a), Ahmed M Elbetieha,b Homa Darmani (b)
(a) Department of Restorative Dentistry, Faculty of Dentistry, Jordan University of Science & Technology, PO Box 3030, Irbid, 22110, Jordan. Telephone: 02-7095111 (Ext. 23595). Fax: 02-7095123. Email: hiyasat@just.edu.jo.
(b) Department of Biology, Faculty of Science.SUMMARY: The objective of this study was to investigate the toxic effects of different concentrations of sodium fluoride (200, 400 and 600 ppm NaF), administered in drinking water for 30 days, on the reproductive system of adult female Sprague-Dawley rats. The rats in the two higher-dosed groups showed clinical signs of toxicity unlike those exposed to NaF at a concentration of 200 ppm. Ingestion of 200 ppm NaF had no effect on the pregnancy rate of the rats nor on the number of implantations. However, the number of viable fetuses was significantly lower than in the control group. Furthermore, the pregnant rats with resorptions and the total number of resorptions increased in the NaF-treated group. There was also a significant increase in maternal organ weights. Rats which had ingested NaF showed increases in both the absolute and relative weights of the ovaries and in the relative weights of the uterus and kidney. The maternal body weights and water consumption were significantly reduced in the treated rats. The results indicate that exposure of female rats to NaF in drinking water has adverse fetotoxic effects.
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10817665&dopt=AbstractArch Toxicol 2000 Mar;74(1):33-9
Induction and inhibition of testicular germ cell apoptosis by fluoroacetate in rats.
Shinoda K, Mitsumori K, Uneyama C, Uehara M.
Pathology Unit, Hita Laboratories, Chemicals Evaluation and Research Institute, Hita-shi, Oita, Japan. shinoda-kazutoshi@hita.cerij.or.jp
Fluoroacetate (FA), an inhibitor of aconitase, is known to lower the intracellular level of adenosine triphosphate (ATP), which recently has been suggested to be a possible determinant of the form of cell death, apoptosis or necrosis. To investigate which form of germ cell death occurs in FA-induced testicular toxicity, adult Sprague Dawley rats were given a single oral dose of FA (0.5 or 1.0 mg/kg) and euthanized at 3, 6, 12, 24, 48, and 72 h thereafter. Germ cell degeneration was histologically first found in early round spermatids at stage I and in spermatogonia at stages II-IV of seminiferous tubules 6 and 12 h, respectively, after dosing. Degenerating spermatogonia exhibited characteristic features of apoptosis as demonstrated by both electron microscopy and in situ terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL), whereas spermatids did not. At the 24 and 48 h time points, degenerating spermatids were continually present and subsequently formed multinucleated giant cells, while the number of degenerating spermatogonia and TUNEL-labeled spermatogonia was drastically and/or significantly decreased compared to those from the control group, indicating that spontaneous male germ cell apoptosis is inhibited. Coincident with these morphological changes, DNA laddering on gel electrophoresis was apparent only 12 h after dosing. The results demonstrate that FA induces either apoptosis or necrosis of male germ cells in the early stage after dosing and subsequently inhibits spontaneous apoptosis.
PMID: 10817665 [PubMed - indexed for MEDLINE]
Full report available at: http://www.fluoride-journal.com/00-33-3/333-128.pdfFluoride 2000; 33(3):128-134
Fertility effects of sodium fluoride in male mice
Ahmed Elbetieha (a), Homa Darmani, Ahmad S Al-Hiyasat (b)
(a) Department of Applied Biological Sciences, Faculty of Science, Jordan University of Science and Technology, P.O. Box 3030, Irbid 22110, Jordan. Phone: 962-2-7095111,. Ext. 23486, Fax: 962-2-7095014. E-mail: betieha@just.edu.jo;
(b) Deptartment of Restorative Dentistry, Faculty of Dentistry, Jordan University of Science and Technology.SUMMARY: Sexually mature male Swiss mice were exposed at 60 days of age to 100, 200 and 300 ppm sodium fluoride (NaF) in their drinking water for 4 weeks or 10 weeks. The effect of NaF exposure on fertility was assessed by breeding these males with untreated female mice after the exposure periods. Fertility was significantly reduced at all three concentrations by exposure for 10 weeks but not for 4 weeks. The number of implantation sites and viable fetuses was significantly reduced in females mated with males that had ingested NaF at a concentration of 200 ppm for 10 weeks. Relative weights of seminal vesicles and preputial glands were significantly increased in mice exposed to 200 and 300 ppm NaF for 4 weeks but not in mice exposed for 10 weeks. These results indicate that long-term ingestion of NaF adversely affects fertility in male mice.
Full report available at: http://www.fluoride-journal.com/00-33-4/334-154.pdfFluoride 2000; 33(4):154-158
Sister chromatid exchange frequency and chromosome aberrations in residents of fluoride endemic regions of south Gujarat
Sajayan Joseph, PK Gadhia (a)
(a) For Correspondence: Department of Biosciences, South Gujarat University Surat 395 007, Gujarat, India. E-mail: pankaj_gadhia@hotmail.com
SUMMARY: Peripheral blood lymphocytes of residents of three villages and one nearby township in South Gujarat with fluoride concentrations in the drinking water of 1.56 - 3.46 and 0.6 - 0.8 ppm, respectively, were examined for their frequency of sister chromatid exchanges (SCE) and chromosome aberrations. The rates of SCEs and chromosome aberrations in persons living in one of the endemic villages were significantly higher than in the others, and their lymphocytes were more susceptible to the clastogen Mitomycin-C.
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10959797&dopt=AbstractArch Toxicol 2000 Jul;74(4-5):226-30
Fluoride induces apoptosis by caspase-3 activation in human leukemia HL-60 cells.
Anuradha CD, Kanno S, Hirano S.
Regional Environment Division, National Institute for Environmental Studies, Tsukuba, Ibaraki, Japan.
Even though fluoride toxicity is increasingly being considered to be important, very little information is available on the mechanism of action of fluoride. In the present study, the toxicity of fluoride on human leukemia (HL-60) cells was investigated and the involvement of caspase-3 was also studied. Fluoride induced apoptosis in HL-60 cells in a dose- and time-dependent manner. Annexin staining and DNA ladder formation on agarose gel electrophoresis further revealed that HL-60 cells underwent apoptosis on exposure to 2-5 mM fluoride. Western blotting using polyclonal anti-caspase-3 antibody and mouse anti-human poly(ADP-ribose) polymerase (PARP) monoclonal antibody was performed to investigate caspase-3 and PARP activity. Fluoride led to the activation of caspase-3 which was evident by the loss of the 32 kDa precursor and appearance of the 17 kDa subunit. Furthermore, intact 116 kDa PARP was cleaved by fluoride treatment as shown by the appearance of a cleaved 89 kDa fragment. The results clearly suggest that fluoride causes cell death in HL-60 cells by causing the activation of caspase-3 which in turn cleaves PARP leading to DNA damage and ultimately cell death.
PMID: 10959797 [PubMed - indexed for MEDLINE]
J Neurophysiol 2000 Mar;83(3):1273-1282.
- As cited and abstracted in Fluoride 2000; 33(2)46
Competition between internal AlF(4)(-) and receptor-mediated stimulation of dorsal raphe neuron G-proteins coupled to calcium current inhibition
Chen Y, Penington NJ
Chen Y, Department of Physiology and Pharmacology, State University of New York, Health Science Center at Brooklyn, Brooklyn, New York 11203-2098.
Intracellular aluminum fluoride (AlF(4)(-)), placed in a patch pipette, activated a G-protein, resulting in a "tonic" inhibition of the Ca(2+) current of isolated serotonergic neurons of the rat dorsal raphe nucleus. Serotonin (5-HT) also inhibits the Ca(2+) current of these cells. After external bath application and quick removal of 5-HT to an AlF(4)(-) containing cell, there was a reversal or transient disinhibition (TD) of the inhibitory effect of AlF(4)(-) on Ca(2+) current. A short predepolarization of the membrane potential to +70 mV, a condition that is known to reverse G-protein-mediated inhibition, reversed the inhibitory effect of AlF(4)(-) on Ca(2+) current and brought the Ca(2+) current to the same level as that seen at the peak of the TD current. With AlF(4)(-) in the pipette, the TD phenomenon could be eliminated by lowering pipette MgATP, or by totally chelating pipette Al(3+). In the presence of AlF(4)(-), but with either lowered MgATP or extreme efforts to eliminate pipette Al(3+), the rate of recovery from 5-HT on wash was slowed, a condition opposite to that where a TD occurred. The putative complex of AlF(4)(-)-bound G-protein (Galpha.GDP.AlF(4)(-)) appeared to free G-betagamma-subunits, mimicking the effect on Ca(2+) channels of the G.GTP complex. The ON-rate of the inhi-bition of Ca(2+) current, after a depolarizing pulse, by betagamma-subunits released by AlF(4)(-) in the pipette was significantly slower than that of the agonist-activated G-protein. The OFF-rate of the AlF(4)(-)-mediated inhibition in response to a depolarizing pulse, a measure of the affinity of the free G-betagamma- subunit for the Ca(2+) channel, was slightly slower than that of the agonist stimulated G-protein. In summary, AlF(4)(-) modified the OFF-rate kinetics of G-protein activation by agonists, but had little effect on the kinetics of the interaction of the betagamma-subunit with Ca(2+) channels. Agonist application temporarily reversed the effects of AlF(4)(-), making it a complementary tool to GTP-gamma-S for the study of G-protein interactions.
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10793297&dopt=AbstractToxicol In Vitro 2000 Apr;14(2):185-92
Morphological transformation and effect on gap junction intercellular communication in Syrian hamster embryo cells as screening tests for carcinogens devoid of mutagenic activity.
Rivedal E, Mikalsen SO, Sanner T.
Department of Environmental and Occupational Cancer, Institute for Cancer Research, The Norwegian Radium Hospital, N-0310, Oslo, Norway. edgar.rivedal@labmed.uio.no
A large fraction of chemicals observed to cause cancer in experimental animals is devoid of mutagenic activity. It is therefore of importance to develop methods that can be used to detect and study environmental carcinogenic agents that do not interact directly with DNA. Previous studies have indicated that induction of in vitro cell transformation and inhibition of gap junction intercellular communication are endpoints that could be useful for the detection of non-genotoxic carcinogens. In the present work, 13 compounds [chlordane, Arochlor 1260, di(2-ethylhexyl)phthalate, 1,1,1-trichloro-2, 2-bis(4-chlorophenyl)ethane, limonene, sodium fluoride, ethionine, o-anisidine, benzoyl peroxide, o-vanadate, phenobarbital, 12-O-tetradecanoylphorbol 13-acetate and clofibrate] have been tested for their ability to induce morphological transformation and affect intercellular communication in Syrian hamster embryo cells. The substances were selected on the basis of being proven or suspected non-genotoxic carcinogens, and thus difficult to detect in short-term tests. The data show that nine of the 13 compounds induced morphological transformation, and seven of the 13 inhibited intercellular communication in hamster embryo cells. Taken together, 12 of the 13 substances either induced transformation or caused inhibition of communication. The data suggest that the combined use of morphological transformation and gap junction intercellular communication in Syrian hamster embryo cells may be beneficial when screening for non-genotoxic carcinogens.
PMID: 10793297 [PubMed - indexed for MEDLINE]
Full report available at: http://www.fluoride-journal.com/00-33-3/333-115.pdfFluoride 2000; 33(3):115-120
Number of fluoride ions binding to succinate dehydrogenase during mixed inhibition
Ewa Stachowska, Joanna Bober, Dariusz Chlubek (a), Zygmunt Machoy
(a) For Correspondence: Dr Dariusz Chlubek, Department of Biochemistry and Chemistry, Pomeranian Academy of Medicine, Al. Powsta • ców Wielkopolskich 72, 70 - 111 Szcze-cin, Poland. E-mail: biochem@pam.szczecin.pl
SUMMARY: We have measured the number of fluoride ions bound to one molecule of succinate dehydrogenase (SDH) of submitochondrial particles from porcine kidney cortex. Enzyme activity was studied according to the method of Dixon and the number of fluoride ions bound was established ar-ithmetically. A mixed competitive and noncompetitive inhibition of SDH by fluoride was confirmed. At high levels of succinate (~20 mM) that saturate the active site of the enzyme, the binding of one fluoride ion outside the site results in noncompetitive inhibition. At lower levels (~1 mM), the site is not saturated and inhibition is competitive, with two fluoride ions binding to each enzyme molecule.
From TOXNETChung-Kuo Kung Kung Wei Sheng (China Public Health) 2000 Sep;16(9):792-3
[The effect of fluoride-arsenic exposure on the macroelements in serum of rats' offspring]
Zhang C, Wang GQ, Liu JW, Ling B, Xiao BY
College of Public Health, Xinjiang Medical University, Urumqi, China.
English Abstract Indicator: A Abstract: In order to expose the effect of the fluoride-arsenic exposure on the macroelements in serum of rat's offspring. The contents of macroelements in serum of rats' offspring were determined with the method of two generations-one nest reproductive test. The contents of Na+, Mg++ and Ca++ in the serum were decreased when increased of exposed dose, but the changes of K+ and P+5 were not significant. After stopping the exposure for 8 weeks, the Na+, Mg++, Ca++ were increased distinctly. Fluoride-arsenic exposure can affect the levels of macroelements in serum of rats' offspring.
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11009607&dopt=Abstract
Biochemistry 2000 Oct 3;39(39):11939-47
Fluoride effects along the reaction pathway of pyrophosphatase: evidence for a second enzyme.pyrophosphate intermediate.
Baykov AA, Fabrichniy IP, Pohjanjoki P, Zyryanov AB, Lahti R.
A. N. Belozersky Institute of Physico-Chemical Biology and School of Chemistry, Moscow State University, Moscow 119899, Russia. baykov@genebee.msu.su
The fluoride ion is a potent and specific inhibitor of cytoplasmic pyrophosphatase (PPase). Fluoride action on yeast PPase during PP(i) hydrolysis involves rapid and slow phases, the latter being only slowly reversible [Smirnova, I. N., and Baykov, A. A. (1983) Biokhimiya 48, 1643-1653]. A similar behavior is observed during yeast PPase catalyzed PP(i) synthesis. The amount of enzyme.PP(i) complex formed from solution P(i) exhibits a rapid drop upon addition of fluoride, followed, at pH 7.2, by a slow increase to nearly 100% of the total enzyme. The slow reaction results in enzyme inactivation, which is not immediately reversed by dilution. These data show that fluoride binds to an enzyme.PP(i) intermediate during the slow phase and to an enzyme.P(i) intermediate during the rapid phase of the inhibition. In Escherichia coli PPase, the enzyme.PP(i) intermediate binds F(-) rapidly, explaining the lack of time dependence in the inhibition of this enzyme. The enzyme.PP(i) intermediate formed during PP(i) hydrolysis binds fluoride much faster (yeast PPase) or tighter (E. coli PPase) than the similar complex existing at equilibrium with P(i). It is concluded that PPase catalysis involves two enzyme.PP(i) intermediates, of which only one (immediately following PP(i) addition and predominating at acidic pH) can bind fluoride. Simulation experiments have indicated that interconversion of the enzyme.PP(i) intermediates is a partially rate-limiting step in the direction of hydrolysis and an exclusively rate-limiting step in the direction of synthesis.
PMID: 11009607 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11860940&dopt=AbstractZhonghua Yu Fang Yi Xue Za Zhi 2000 Nov;34(6):327-329
[Effects of fluoride on the expression of c-fos and c-jun genes and cell proliferation of rat osteoblasts]
[Article in Chinese]
Chen L, Tong A, Yu D, et Al.Department of Endocrinology, Tongji Medical University, Wuhan 430022, China.
OBJECTIVE: To investigate the effects of sodium fluoride (NaF) on the expression of c-Fos and c-Jun genes and osteoblast cell proliferation of rat osteoblasts.
METHODS: Osteoblastic cells were isolated from baby rat calvaria, and cultured in the presence of different doses of NaF (10(minus sign5) mol/L, 10(minus sign4) mol/L, and 10(minus sign3) mol/L). Cell proliferation was measured by the MTT method, and c-Fos and c-Jun expression was detected by the immunohistochemistry combined with image analysis compute system.
RESULTS: RESULTS: from the MTT assay showed that NaF increased the proliferation of rat osteoblast and induced the expression of c-Fos and c-Jun genes. The increases of c-Fos and c-Jun expression by the 3 different doses of NaF were 5.4%, 15.4% and 42.3% for the c-Fos gene and 12.1%, 14.4% and 38.6% for c-Jun gene respectively (P < 0.05 and P < 0.01).
CONCLUSION: NaF increased rat osteoblastic cell proliferation and the expression of genes involved in cell proliferation.
PMID: 11860940 [PubMed - as supplied by publisher]
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11860917&dopt=AbstractZhonghua Yu Fang Yi Xue Za Zhi 2000 May;34(3):134-135
[The effect of fluoride-arsenic exposure on the lipid peroxidation and antioxidation of the offspring of rats]
[Article in Chinese]
Zhang C, Liu J, Ling B, et Al.
School of Public Health, Xinjiang Medical University, Urumqi 830054, China.
OBJECTIVE: To provide information on the effects of the offspring of rats exposed to fluoride-arsenic.
METHODS: The levels of lipid peroxidation and the abilities of antioxidation were determined in the blood of the rats and their offsprings under two generations-one nest reproductive test.
RESULTS: The activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) in the blood decreased with the increase of exposure dose. For example, the activity of SOD, was 14.56, 13.74, 11.89 and 11.21 micromolcenter dotmin(minus sign1)center dotmg Hb(minus sign1) in different dose groups of F(2), respectively. In contrast, the concentration of lipid peroxides (LPO) increased. Eight weeks after exposure, the activities of SOD and GSH-Px increased, the activity of SOD was 13.97, 13.55, 13.47 and 12.76 micromolcenter dotmin(minus sign1)center dotmg Hb(minus sign1), respectively, and the concentration of LPO returned to normal level.
CONCLUSION: Fluoride-arsenic exposure can cause oxidative damage of the rat's offspring.
PMID: 11860917 [PubMed - as supplied by publisher]
Brain Res Dev Brain Res 2000 Apr 14;120(2):125-134
- As cited and abstracted in Fluoride 2000; 33(2):95-96
Ontogeny of G-protein expression: control by beta-adrenoceptors
Zeiders JL, Seidler FJ, Slotkin TA
Department of Pharmacology and Cancer Biology, Duke University Medical Center, Box 3813 DUMC, Durham, NC, USA.
Cardiac cell homeostasis is maintained in the face of excessive beta-adrenoceptor stimulation through the process of desensitization. Desensitization is not an inherent property of these cells but rather is acquired during development; neonates given beta-agonists actually show heterologous sensitization, involving changes in the expression and catalytic activity of adenylyl cyclase (AC) as well as an increased receptor/G-protein coupling. The current study examines the role of specific G-protein components, G(salpha) and G(ialpha), in the ontogeny of beta-adrenoceptor responses and in the transition from agonist-induced sensitization to desensitization. Between postnatal days (PN) 6 and 15 there was a significant decrease in the 52 kDa isoform of G(salpha) with no accompanying change of the 45 kDa form; over the same period, G(ialpha3) also declined substantially. In contrast, the 45 kDa isoform of G(salpha) and G(ialpha1,2) remained fairly constant over the same period and fluoride-stimulated AC activity increased. Treatment with isoproterenol on PN2-5 did not result in any significant changes in G(salpha) expression but robustly decreased G(ialpha1,2). These changes were accompanied by heterologous sensitization of AC activity at the level of AC itself, evidenced by equivalent increases in the enzymatic response to fluoride and forskolin-Mn( 2+). Isoproterenol given to older animals (PN11-14) also caused specific loss of G(i) protein, in this case targeting G(ialpha3), whereas G(salpha) again was unchanged; in contrast to the younger group, the older animals displayed heterologous desensitization of AC at the level of G-protein function (specific loss of the fluoride response). These results indicate that the normal ontogenetic increase of cardiac beta-adrenoceptor coupling to AC is not dependent on the absolute amount of G-proteins, nor on the relative balance of stimulatory (G(s)) and inhibitory (G(i)) subunits. However, the ability of receptor stimulation to downregulate G(ialpha1,2), an event which is specific to immature cardiac cells, is likely to be an important component of the resistance of the fetal/ neonatal heart to agonist-induced desensitization and hypertrophy. The maintenance of cardiac beta-adrenoceptor signaling in the face of intense stimulation is likely to play an important role in the physiologic adaptations necessary to the perinatal transition.
Biol Chem 2000 Feb;381(2):145-53
- As cited and abstracted in Fluoride 2000; 33(2):96-97
Two different mechanisms for activation of cyclic PIP synthase: by a G protein or by protein tyrosine phosphorylation
Wasner HK, Gebel M, Hucken S, Schaefer M, Kincses M
Diabetes-Forschungsinstitut, Dusseldorf, Germany
The biosynthesis of the functional, endogenous cyclic AMP antagonist, prostaglandylinositol cyclic phosphate (cyclic PIP) is performed by the plasma membrane-bound enzyme cyclic PIP synthase, which combines prostaglandin E (PGE) and activated inositol phosphate (n-IP) to cyclic PIP. The Km values of the enzyme for the substrates PGE and n-IP are in the micromolar range. The plasma membrane-bound synthase is activated by fluoride, by the stable GTP analog GMP-PNP, by protamine or biguanide, by noradrenaline, and by insulin. The activation by protamine or biguanide and fluoride (10 mM) is additive, which may indicate the presence of two different types of enzyme, comparable to phospholipase Cbeta and phospholipase Cgamma.
Plasma membrane-bound cyclic PIP synthase is inhibited by the protein tyrosine kinase inhibitor tyrphostin B46 with an IC50 of 1.7 microM. However, the solubilized and gel-filtrated enzyme is no longer inhibited by tyrphostin, indicating that the activity of cyclic PIP synthase is connected with the activity of a membrane-bound protein tyrosine kinase. Cyclic PIP synthase activity of freshly prepared plasma membranes is unstable. Upon freezing and rethawing of liver plasma membranes, this instability is increased about 2-fold. Protein tyrosine phosphatase inhibitors [vanadate, fluoride (50-100 mM)] stabilize the enzyme activity, but protease inhibitors do not, indicating that inactivation of the enzyme is connected with protein tyrosine dephosphorylation. Cyclic PIP synthase is present in all tissues tested, like brain, heart, intestine, kidney, liver, lung, skeletal muscle, spleen, and testis. Apart from liver, cyclic PIP synthase activity in most tissues is rather low, but it can be increased up to 5-fold when protein tyrosine phosphatase inhibitors like vanadate are present in the homogenization buffer. Preincubation of cyclic PIP synthase of liver plasma membranes with the tyrosine kinase src kinase causes a 2-fold increase of cyclic PIP synthase activity, though this is certainly not the physiological role played by src kinase in intact cells. The data indicate that cyclic PIP synthase can be activated by two separate mechanisms: by a G protein or by protein tyrosine phos-phorylation.
J Pharmacol Exp Ther 2000 Feb;292(2):761-8
- As cited and abstracted in Fluoride 2000; 33(2):97-98
Predominant contribution of the G protein-mediated mechanism to NaF-induced vascular contractions in diabetic rats: association with an increased level of G(qalpha) expression
Hattori Y, Matsuda N, Sato A, Watanuki S, Tomioka H, Kawasaki H, Kanno M
Department of Pharmacology, Hokkaido University School of Medicine, Sapporo, Japan. yhattori@med.hokudai.ac.jp
The purpose of this study was to determine the mechanism responsible for alterations in NaF-induced contractions of blood vessels from streptozotocin-induced diabetic rats. In the presence of AlCl3, NaF (¥7.5 mM) produced significantly greater contractions in diabetic aorta and mesenteric artery compared with age-matched controls. Pretreatment with 1 microM nifedipine eliminated the enhanced contractile responses of diabetic vessels to NaF, resulting in no difference in the magnitude of NaF-induced contractions between control and diabetic vessels. In the presence of 100 microM deferoxamine, an Al 3+ chela-tor, NaF-induced contractions of diabetic vessels were markedly attenuated, whereas only the responses to lower concentrations of NaF were reduced in control vessels. No significant difference was found in the peak amplitude of transient contractions induced by 10 microM cyclopiazonic acid between control and diabetic vessels. The addition of 10 microM okadaic acid produced attenuated contractions in diabetic vessels. These findings indicate no involvement of the inhibitory effects of NaF on endoplasmic reticular Ca 2+ -pump ATPase and protein phosphatases in the genesis of the enhanced responsive-ness of diabetic vessels to NaF. Western blot analysis showed a 2.5-fold in-crease in the expression of G(qalpha) in diabetic aortic membranes. In contrast, the G(ialpha) level was modestly decreased and the G(salpha) and G(betagamma) levels were unchanged in diabetes. The present results suggest that enhanced vascular contractions to NaF in diabetes is attributed predominantly to a G protein-mediated Ca 2+ channel acti-vation that results from markedly increased G(qalpha) expression in vascular tissues under this pathological state.
Report available at http://molpharm.aspetjournals.org/cgi/content/full/57/6/1081Mol Pharmacol 2000 Jun;57(6):1081-92
A surface-exposed region of G(salpha) in which substitutions decrease receptor-mediated activation and increase receptor affinity.
Grishina G, Berlot CH.
Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT 06520-8026, USA.
The mechanism by which receptors activate G proteins is unclear because a connection between the receptor and the nucleotide binding site has not been established. To investigate this mechanism, we evaluated the roles in receptor interaction of three potential receptor contact sites in alpha(s): the alpha2/beta4, alpha3/beta5, and alpha4/beta6 loops. Substitutions of alpha(i2) homologs for alpha(s) residues in the alpha2/beta4 loop and alanine substitutions of residues in the alpha4/beta6 loop do not affect activation by the beta(2)-adrenergic receptor. However, replacement of five alpha(s) residues in the alpha3/beta5 loop region with the homologous alpha(i2) residues decreases receptor-mediated activation of alpha(s) and increases the affinity of G(s) for this receptor. The substitutions do not alter guanine nucleotide binding or hydrolysis, or activation by aluminum fluoride, indicating that the effects on receptor interaction are not due to a destabilization of the guanine-nucleotide bound state. In a model of the receptor-G protein complex, the alpha3/beta5 loop maps near the second and third intracellular loops of the receptor. The effects of the alpha3/beta5 substitutions suggest that the wild-type residues may be receptor contact sites that are optimized to ensure the reversibility of receptor-G protein interactions. Furthermore, the alpha3/beta5 region corresponds to an exchange factor contact site in both EF-Tu and Ras, suggesting that the mechanisms by which seven-transmembrane receptors and exchange factors catalyze nucleotide exchange may share common elements.
PMID: 10825378 [PubMed - indexed for MEDLINE]
Report available at: http://www.jimmunol.org/cgi/content/full/165/5/2712J Immunol 2000 Sep 1;165(5):2712-8
Simvastatin modulates cytokine-mediated endothelial cell adhesion molecule induction: involvement of an inhibitory G protein.
Sadeghi MM, Collinge M, Pardi R, Bender JR.
Division of Cardiovascular Medicine and Boyer Center for Molecular Medicine, Yale University School of Medicine, New Haven, CT 06536, USA.
Endothelial cell adhesion molecules (CAMs) E-selectin, ICAM-1, and VCAM-1 play variably important roles in immune-mediated processes. They are induced by the proinflammatory cytokines IL-1 and TNF-alpha, and NF-kappaB is required for the regulated expression of all three genes. Regulators of this pathway could potentially be potent immune modulators. We studied the effect of a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, simvastatin, on cytokine-induced expression of CAMs in HUVEC. Unexpectedly, pretreatment with simvastatin potentiated the induction of all three endothelial CAMs by IL-1 and TNF, but not LPS or PMA, as detected by flow cytometry. Northern blot analysis demonstrated an increase in steady state IL-1-induced E-selectin mRNA levels in cells pretreated with simvastatin. This was associated with an increase in nuclear translocation of NF-kappaB, as detected by EMSA. The effect of simvastatin was reversed by mevalonate and geranylgeranyl pyrophosphate but not squalene, indicating that an inhibitory prenylated protein is involved in endothelial responses to proinflammatory cytokines. Pertussis toxin mimicked the effect of simvastatin, and the G protein activator NaF inhibited the cytokine-induced expression of endothelial CAMs, indicating that a Gialpha protein is involved. These results demonstrate that cytokine-mediated activation of the endothelium, and specifically CAM induction, can be modulated by a heterotrimeric G protein-coupled pathway. This may represent a "basal tone" of endothelial inactivation, which can either be disinhibited or amplified, depending on the stimulus.
PMID: 10946302 [PubMed - indexed for MEDLINE]
Free report available at http://www.pnas.org/cgi/content/full/97/26/14364Proc Natl Acad Sci U S A 2000 Dec 19;97(26):14364-9
Activator of G protein signaling 3 is a guanine dissociation inhibitor for Galpha i subunits.
De Vries L, Fischer T, Tronchere H, Brothers GM, Strockbine B, Siderovski DP, Farquhar MG.
Departments of Cellular and Molecular Medicine and Pathology, University of California at San Diego, La Jolla, CA 92093-0651, USA.
Activator of G protein signaling 3 (AGS3) is a newly identified protein shown to act at the level of the G protein itself. AGS3 belongs to the GoLoco family of proteins, sharing the 19-aa GoLoco motif that is a Galpha(i/o) binding motif. AGS3 interacts only with members of the Galpha(i/o) subfamily. By surface plasmon resonance, we found that AGS3 binds exclusively to the GDP-bound form of Galpha(i3). In GTPgammaS binding assays, AGS3 behaves as a guanine dissociation inhibitor (GDI), inhibiting the rate of exchange of GDP for GTP by Galpha(i3). AGS3 interacts with both Galpha(i3) and Galpha(o) subunits, but has GDI activity only on Galpha(i3), not on Galpha(o). The fourth GoLoco motif of AGS3 is a major contributor to this activity. AGS3 stabilizes Galpha(i3) in its GDP-bound form, as it inhibits the increase in tryptophan fluorescence of the Galpha(i3)-GDP subunit stimulated by AlF(4)(-). AGS3 is widely expressed as it is detected by immunoblotting in brain, testis, liver, kidney, heart, pancreas, and in PC-12 cells. Several different sizes of the protein are detected. By Northern blotting, AGS3 shows 2.3-kb and 3.5-kb mRNAs in heart and brain, respectively, suggesting tissue-specific alternative splicing. Taken together, our results demonstrate that AGS3 is a GDI. To the best of our knowledge, no other GDI has been described for heterotrimeric G proteins. Inhibition of the Galpha subunit and stimulation of heterotrimeric G protein signaling, presumably by stimulating Gbetagamma, extend the possibilities for modulating signal transduction through heterotrimeric G proteins.
PMID: 11121039 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10826650&dopt=Abstract
- Chem Biol Interact 2000 Apr 14;126(1):1-14
Spontaneous hydrolysis of 4-trifluoromethylphenol to a quinone methide and subsequent protein alkylation.
Thompson DC, Perera K, London R.
Department of Medical Pharmacology and Toxicology, Texas A&M University Health Science Center, College Station 77843-1114, USA. david.c.thompson@monsanto.com
4-Trifluoromethylphenol (4-TFMP) was cytotoxic to precision-cut rat liver slices as indicated by loss of intracellular potassium. Intracellular glutathione levels decreased and fluoride ion levels increased in a time and concentration-dependent manner. The cytotoxicity of 4-TFMP did not appear to be due to the release of fluoride, however, since equimolar concentrations of sodium fluoride or potassium fluoride were not toxic. The ortho isomer (2-TFMP), which had a threefold slower rate of fluoride release, was much less toxic to liver slices. In incubations without slices, 4-TFMP spontaneously hydrolyzed in aqueous buffer at physiological pH to form 4-hydroxybenzoic acid via a quinone methide intermediate. The quinone methide was trapped by the addition of glutathione. Analysis of the glutathione adduct indicated that all of the fluorine atoms were lost during the hydrolysis, yielding a cresol derivative with the glutathione moiety attached to a benzylic carbonyl group. The glutathione conjugate was the primary product formed at low alkylphenol/glutathione ratios; however, at higher 4-TFMP concentrations additional unidentified products were observed. 4-TFMP also inhibited the in vitro enzyme activity of purlfied glyceraldehyde-3-phosphate dehydrogenase, a sulfhydryl-dependent enzyme, in a time and concentration-dependentmanner. Loss of thiol residues closely paralleled the loss in enzyme activity. The coaddition of glutathione prevented 4-TFMP-induced loss of enzyme activity. The cytotoxicity of 4-TFMP therefore appears to be due to spontaneous quinone methide formation and subsequent alkylation of cellular macromolecules.
PMID: 10826650 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10915622&dopt=Abstract
Arch Toxicol 2000 Feb;73(12):611-7
- As cited and abstracted in Fluoride 2000; 33(2):85-86
Fluoride-induced ultrastructural changes in exocrine pancreas cells of rats: fluoride disrupts the export of zymogens from the rough endoplasmic reticulum
Matsuo S, Nakagawa H, Kiyomiya K, Kurebe
Department of Toxicology, School of Veterinary Medicine, Osaka Prefecture University, Sakai, Japan. matsuos@vet.osakafu-u.ac.jp
Influence of fluoride on exocrine pancreas cells was examined morphologically with traditional and prolonged osmium fixation techniques for electron microscopy in the enamel fluorosis model rats injected subcutaneously twice a day with 20 mg/kg body weight of sodium fluoride. Although the rough endoplasmic reticulum (rER) of exocrine pancreas cells in control rats was laminated and oriented parallel to the circumference of the nucleus, the rER of the cells in NaF-treated rats was dilated, disrupted the laminated arrangement, and changed to the globular-shape rER. Many intracisternal granules were formed in these globular-shape rER of the cells exposed to fluoride. Lots of autophagosomes were also seen in the exocrine cells with NaF treatment. The autophagosomes were limited with a double or multiple membranes, and contained cytoplasmic organelles and/or the intracisternal granules. The outer and inner leaflets of double membranes of the autophagosomes were usually separated by a distinct electron-lucent area. In prolonged osmium fixation, the area be-tween the double membranes of the autophagosome was filled with osmium reaction deposits. Many autophagosomes were encircled with the single or multiple osmiophilic layers. In some cases, the osmium positive saccules also surrounded the free surface of the globular-shape rER containing intracisternal granules. These findings indicate that fluoride disrupts the export of zymogens from the rER, resulting in formation of intracisternal granules and autophagosomes, and that the osmiophilic saccules participate in sequestration of cyto-plasmic organelles in forming autophagosomes.
Full report available at: http://www.fluoride-journal.com/00-33-1/331-17.pdfFluoride 2000; 33(1):6-16
Liver morphology and histochemistry in rats resulting from ingestion of sodium selenite and sodium fluoride
Kolodziejczyk L (a), Put A (b), Grzela P (b)
(a) Department of Biology and Medical Parasitology, Pomeranian Medical University, 70-111 Szczecin, Poland.
(b) Department of Toxicology, Pomeranian Medical University, Szczecin, Poland.SUMMARY: A morphological and histochemical assessment was made of the effect of sodium selenite and sodium fluoride on oxidative and lysosomal enzyme activity in the liver of male rats. The compounds were administered separately and together for a period of three months. Oxidative enzyme activity of a-glycerophosphate dehydrogenase (a-GlDH) and succinate dehydrogenase (SDH) increased with sodium selenite and decreased with sodium fluoride and with both compounds together. Sodium selenite in a dose of 1 0 µg/kg body weight and sodium fluoride in a dose of 20 mg/kg body weight caused an increase in the activity of acid phosphatase (AcP), while the combined dose caused a decrease in the activity of this enzyme.
http://www.fluoride-journal.com/00-33-1/331-s1.pdfFluoride 2000; 33(1):S1-S2
[XXIIIrd ISFR Conference abstracts, Szczecin, Poland, June 11-14 2000]
Lymphoid depletion of spleen due to experimental fluorosis in rats
M BŽly
National Institute of Rheumatology and Physiotherapy, and Dept of Pathology, Budapest, Hungary.
Objective: To examine qualitatively and quantitatively the histological changes in spleen of rats given sodium fluoride.
Material and Methods: Seventy-five female Wistar rats, each weighing approx. 200 g, were divided into three equal groups. Animals in groups 1 and 2 received intraperitoneally daily doses of 0.5 and 5 mg NaF, respectively, whereas group 3 (control) received physiological saline. The experiments were run for a period of 3 months.1 Afterwards, the spleen was removed for histological and histochemical examination and fixed in 1 0% formaldehyde solution. Histological sections were stained with haematoxylin and eosin, picrosirius red F3BA,2,3 and silver reagent according to Gomori. The ultrastructural changes in collagen fibres were investigated by optical polarisation methods.
Results: The lymphoid tissue mass of the spleen decreased and the relative proportion of reticulin and collagen structures increased. These changes correlated with the dose of fluoride.
Conclusions and Interpretation: The absolute and relative proportion of lymphoid tissue in spleen of rats given NaF decreased in a dose-related manner. Loss of lymphoid tissue may play an important role in the diminished reactivity of the organism and may be regarded as a consequence of fluoride toxicity.
REFERENCES
1 BŽly M. Experimental fluorosis in rats: NaF induced change in bone and bone marrow. Fluoride 1 983;1 6:1 06-11 .
2 Sweat F, Puchtler H, Rosenthal SI. Sirius red F3BA as a stain for connective tissue. Arch Path 1 964;78:69-72.
3 Constantine VS, Mowry RW. Selective staining of human dermal collagen. II. The use of Picrosirius red F3BA with polarization microscopy. J Invest Dermatol 1 968;50:4 1 9-23.
Full report available at: http://www.fluoride-journal.com/00-33-4/334-168.pdfFluoride 2000; 33(4):168-173
The influence of sodium fluoride on the clonogenicity of human hematopoietic progenitor cells: preliminary report
Boguslaw Machaliski (a), Maria Zejmo, Iwona Stecewicz, Anna Machalinska, Zygmunt Machoy, Mariusz Z Ratajczak
(a) For Correspondence: Department of General Pathology, Pomeranian Academy of Medicine, Al. Powstaców Wlkp. 72, 70-111 Szczecin, Poland. E-mail: machalin@r1.pam.szczecin.pl
SUMMARY: Since fluoride accumulates not only in bones but also in bone marrow cavities where hematopoiesis occurs, a preliminary study was under-taken of the potential toxicity of sodium fluoride (NaF) against early human myeloid (CFU-GM, Colony Forming Unit of Granulocyte-Macrophages) and erythroid (BFU-E, Burst Forming Unit of Erythrocytes) progenitors. CD34 + cells isolated from human umbilical cord blood were exposed for 30 and 120 min at 37 o C or 4 o C to increasing concentrations of NaF (0, 1, 10 and 50 mM). At 1 mM NaF, a detectable but not statistically significant stimulatory effect was observed in 7 of the 8 different sets of experiments. At 10 and 50 mM, however, NaF was significantly toxic against cord blood CFU-GM and BFU-E progenitors. Fluoride may therefore be potentially toxic toward early human hematopoietic cells.
Full report available at: http://www.fluoride-journal.com/00-33-4/334-210.pdfFluoride 2000; 33(4):210-217
Acute renal damage dose response in rats to intravenous infustion of sodium fluoride
Tomotaro Dote (a), Koichi Kono, Kan Usuda, Hiroyuki Nishiura, Teruaki Tagawa
(a) For correspondence: Department of Hygiene and Public Health, Osaka Medical Col-lege, 2-7 Daigakumachi, Takatsuki, Osaka 569, Japan. E-mail: hyg011@art.osaka-med.ac.jp
SUMMARY: Rapid acute renal injury in Wistar rats from fluoride (F) following single-dose NaF infusions of 0 mg F (control), 1 mg F (Group 1), 2 mg F (Group 2), and 3 mg F (Group 1) was assessed by examining three collections of bladder urine at 2-h intervals for six hours after the infusions. The urinary parameters investigated were: urine volume, excretion of F, creatinine, and -glutathione S-transferase (-GST), and the activity of N-acetyl- -D-glucosa-midase (NAG). Compared with the control, the urine volume increased (polyuria) in Group 1 but decreased in groups 2 and 3. F excretion increased in groups 1 and 2 but was lower in Group 3 than in Group 1. In Group 3, creatinine excretion decreased compared with the control, but the activities of -GST and NAG steadily increased in Group 3. The decreases in F and creatinine excretion in Group 3 are attributable to glomerular dysfunction, and the increases in -GST and NAG activities in Group 3 indicate acute proximal renal tube injury. The kidney toxicity of intravenous administration of NaF to laboratory rats was thus dose related, and an infusion of 3 mg F was sufficient to cause acute renal dysfunction.
Full report available at: http://www.fluoride-journal.com/00-33-4/334-182.pdfFluoride 2000; 33(4):182-186
Disturbance of protein metabolism in rats after acute poisoning with sodium fluoride
E Birkner (a), E Grucka-Mamczar (a), Z Machoy,b R Tarnawski (a), R Polaniak (a)
(a) For Correspondence: Dr Ewa Birkner, Department of Biochemistry, Silesian Academy of Medicine, 41-808 Zabrze, Jordan Str. 19, Katowice, Poland. E-mail: biochemz@infomed.slam.katowice.pl;
(b) Department of Biochemistry and Chemis-try, Pomeranian Academy of Medicine, Szczecin, Poland.SUMMARY: Six-week-old male Wistar FL strain rats were given a single intra-peritoneal injection of 35 mg of sodium fluoride/kg of body mass. After 90 min, the rats were killed to determine the concentration of fluoride, ammonia and urea in their blood serum along with the activity of glutamate dehydroge-nase (GLDH) in their liver homogenates. A statistically significant increase in the concentration of urea and fluoride in the blood serum was found, and the activity of GLDH was elevated significantly in the liver. The results indicate increased deamination of amino acids in the liver and lesions in the kidney.
Full report available at: http://www.fluoride-journal.com/01-34-1/341-34.pdfFluoride 2000; 34(1):34-42
Histopathology of fluoride-induced hepatoxicity in rabbits
A Shashi (a), SP Thapar (b)
(a) Department of Zoology, Punjabi University, Patiala - 147 002, Punjab, India. E-mail: shashi@pbi.ernet.in;
(b) Department of Anatomy, Dayanand Medical College and Hospital, Ludhiana, India.SUMMARY: The effect of chronic and acute exposure to sodium fluoride (5, 10, 20, and 50 mg/kg body weight/day) for fifteen weeks on hepatic damage in young albino rabbits was evaluated. Histopathological examination revealed increasing degrees of hepatocellular necrosis, degenerative changes, hepatic hyperplasia, extensive vacuolization in hepatocytes, and centrilobular necrosis in the liver of the exposed animals. The central vein and sinusoids of the liver were dilated and engorged with blood and were associated with small areas of haemorrhages. These effects were not observed in the control group.
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11860933&dopt=AbstractZhonghua Yu Fang Yi Xue Za Zhi 2000 Jul;34(4):215-7
[Direct effects of fluoride on activities of bone morphogenetic protein]
[Article in Chinese]
Xu S, Zheng G, Li M, et Al.
Institute of Environmental Medicine, Tongji Medical University, Wuhan 430030, China.
OBJECTIVE: To demonstrate the direct effects of fluoride on activities of bone morphogenetic protein (BMP).
METHOD: A complex sample containing BMP and sodium fluoride was implanted under the abdominal skin of young male Wistar rats. The histiological characteristcs, and activities of alkine phosphatase and acid phosphatase of the implantan were examined to study the effects of fluoride on biological activities of BMP.
RESULTS: More fibroblasts cell were transformed to osteoblats cell in animals treated by BMP with fluoride than those treated by BMP only. During bone formation induced by BMP, fluoride increased the acitivities of osteoblasts and accelerate mineralization, while inhibited the activities of osteoclast.
CONCLUSION: Fluoride can affect biological activities of BMP directly.
PMID: 11860933 [PubMed - in process]
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10741471&dopt=Abstract
Arch Toxicol 2000 Feb;73(12):611-7Fluoride-induced ultrastructural changes in exocrine pancreas cells of rats: fluoride disrupts the export of zymogens from the rough endoplasmic reticulum (rER).
Matsuo S, Nakagawa H, Kiyomiya K, Kurebe M.
Department of Toxicology, School of Veterinary Medicine, Osaka Prefecture University, Sakai, Japan. matsuos@vet.osakafu-u.ac.jp
Influence of fluoride on exocrine pancreas cells was examined morphologically with traditional and prolonged osmium fixation techniques for electron microscopy in the enamel fluorosis model rats injected subcutaneously twice a day with 20 mg/kg body weight of sodium fluoride. Although the rough endoplasmic reticulum (rER) of exocrine pancreas cells in control rats was laminated and oriented parallel to the circumference of the nucleus, the rER of the cells in NaF-treated rats was dilated, disrupted the laminated arrangement, and changed to the globular-shape rER. Many intracisternal granules were formed in these globular-shape rER of the cells exposed to fluoride. Lots of autophagosomes were also seen in the exocrine cells with NaF treatment. The autophagosomes were limited with a double or multiple membranes, and contained cytoplasmic organelles and/or the intracisternal granules. The outer and inner leaflets of double membranes of the autophagosomes were usually separated by a distinct electron-lucent area. In prolonged osmium fixation, the area between the double membranes of the autophagosome was filled with osmiun reaction deposits. Many autophagosomes were encircled with the single or multiple osmiophilic layers. In some cases, the osmium positive saccules also surrounded the free surface of the globular-shape rER containing intracisternal granules. These findings indicate that fluoride disrupts the export of zymogens from the rER, resulting in formation of intracisternal granules and autophagosomes, and that the osmiophilic saccules participate in sequestration of cytoplasmic organelles in forming autophagosomes.
PMID: 10741471 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10744203&dopt=AbstractEur J Ophthalmol 2000 Jan-Mar;10(1):32-8
Prevention of corneal keratocyte apoptosis after argon fluoride excimer laser irradiation with the free radical scavenger ubiquinone Q10.
Brancato R, Schiavone N, Siano S, Lapucci A, Papucci L, Donnini M, Formigli L, Orlandini SZ, Carella G, Carones F, Capaccioli S.
Department of Ophthalmology and Visual Sciences, San Raffaele Hospital, University of Milano, Italy. brancato.rosario@hsr.it PURPOSE:
To assess in vitro the potential of the free radical scavenger ubiquinone Q10 in preventing keratocyte apoptosis after argon fluoride (ArF) excimer laser irradiation.
METHODS: Cultured rabbit keratocytes were irradiated at very low single-pulse laser fluences. The cumulative effects generated by three total fluence doses between 12 and 45 mJ/cm2, representative of single-pulse subablative doses during photorefractive keratectomy (PRK) in humans, were evaluated. We employed the following parameters to compare pretreated (10 microM ubiquinone Q10) and untreated samples: 1) number and morphology of living cells by Trypan blue test and ultramicroscopy, respectively; 2) level of free-radical formation assessed by malonaldehyde quantitation; 3) cellular energy level evaluated by ATP assay.
RESULTS: Excimer laser irradiation kills cultured keratocytes by inducing apoptosis. The effect increases with the cumulative fluence dose. In the samples pretreated with ubiquinone Q10 there were significantly fewer cumulative apoptotic events than in the untreated ones. Quantitative analysis of malonaldehyde cellular levels suggested this protective action of ubiquinone Q10 was connected with its ability to scavenge laser-generated free radicals. ATP assay also confirmed that it raised cellular energy levels.
CONCLUSIONS: The treatment of corneal keratocytes with relatively low concentrations of ubiquinone Q10 can prevent apoptosis after ArF excimer laser irradiation. If these findings are confirmed on human keratocytes this treatment could be usefully exploited in the PRK surgical procedure. That might lead to a reduction in the occurrence of haze and curvature regression triggered by programmed cell death.PMID: 10744203 [PubMed - indexed for MEDLINE]
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