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    Over 50 years ago, chromium (Cr) was proposed to be an essential trace element; however, recent studies indicate that this status should be removed as the effects of Cr supplementation appear to be pharmacological rather than nutritional.... more
    Over 50 years ago, chromium (Cr) was proposed to be an essential trace element; however, recent studies indicate that this status should be removed as the effects of Cr supplementation appear to be pharmacological rather than nutritional. The pharmacological basis for Cr's effects can explain the inability of investigators to discover a biomarker for Cr status. One potential biomarker has not been examined to date. Cr is known to be mobilized in the body in response to insulin (or insulin release in response to a glucose challenge), resulting in an increase in urinary Cr excretion. The magnitude of increase in urinary Cr loss as a function of dietary Cr intake was tested as a potential biomarker for Cr. Zucker lean rats housed in carefully controlled metal-free conditions were provided a series of purified diets containing variable Cr contents (from 16 μg/kg diet to 2,000 μg/kg) for 23 weeks. The 16 μg/kg diet contained less Cr than any diet examined to date. Urine samples were collected before and after insulin and glucose challenges (0, 2, 6, and 12 h postinjection). Urinary Cr levels were analyzed by the standard method of addition using graphite furnace atomic absorption. The rate of urinary Cr loss after a glucose or insulin challenge was found to not be dependent on the Cr content of the rats' diets. Blood iron levels of the rats were also measured to determine if the addition of Cr to the diet altered iron status. The Cr content of the diet was found to have no affect on blood iron levels. Overall, the study demonstrated that insulin-stimulated urinary Cr excretion cannot be used as a biomarker for Cr status.
    Although recent studies have shown that chromium (as the trivalent ion) is not an essential trace element, it has been demonstrated to generate beneficial effects at pharmacologically relevant doses on insulin sensitivity and cholesterol... more
    Although recent studies have shown that chromium (as the trivalent ion) is not an essential trace element, it has been demonstrated to generate beneficial effects at pharmacologically relevant doses on insulin sensitivity and cholesterol levels of rodent models of insulin insensitivity, including models of type 2 diabetes. The mode of action of Cr(III) at a molecular level is still an area of active debate; however, the movement of Cr(III) in the body, particularly in response to changes in insulin concentration, suggests that Cr(III) could act as a second messenger, amplifying insulin signaling. The evidence for the pharmacological mechanism of Cr(III)'s ability to increase insulin sensitivity by acting as a second messenger is reviewed, and proposals for testing this hypothesis are described.
    Chromium picolinate, [Cr(pic)(3)], is a popular nutritional supplement found in a variety of consumer products. Despite its popularity, safety concerns over its use have arisen. The supplement has been shown to generate clastogenic... more
    Chromium picolinate, [Cr(pic)(3)], is a popular nutritional supplement found in a variety of consumer products. Despite its popularity, safety concerns over its use have arisen. The supplement has been shown to generate clastogenic damage, mitochondrial damage, oxidative damage, and mutagenic effects in cultured cells and oxidative DNA damage and lipid peroxidation in rats. Recently [Cr(pic)(3)] has been demonstrated to generate heritable genetic change and delays in progeny development in Drosophila melanogaster. Based on the damage to chromosomes of cultured cells and of animal models, similar chromosome damage appeared to be a likely source of the mutagenic effects of the supplement in Drosophila. The current three-part study examines the effects of several chromium-containing supplements and their components on hatching and eclosion rates and success of development of first generation progeny of adult Drosophila fed food containing these compounds. It further examines the effects of the compounds on longevity of virgin male and female adults. Finally, the chromosomes in the salivary glands of Drosophila late in the third instar larval stage, which were the progeny of Drosophila whose diets were supplemented with nutritional levels of [Cr(pic)(3)], are shown to contain on average over one chromosomal aberration per two identifiable chromosomal arms. No aberrations were observed in chromosomes of progeny of untreated flies. The results suggest that human consumption of the supplement should be a matter of concern and continued investigation to provide insight into the requirements of chromium-containing supplements to give rise to genotoxic effects.
    Immediately after the successful immobilization of conalbumin onto CNBr-activated Sepharose, efforts were begun to find a less expensive support and a more benign chemistry of activation. The potential of the Sepharose-conalbumin... more
    Immediately after the successful immobilization of conalbumin onto CNBr-activated Sepharose, efforts were begun to find a less expensive support and a more benign chemistry of activation. The potential of the Sepharose-conalbumin conjugate for decontamination of several metal-containing waste-waters has been established, and a new method of chromatography has emerged, named metalloprotein affinity metal chromatography (MAMC). Efforts to immobilize conalbumin onto polystyrene/divinylbenzene co-polymers, using the well known and commercially available Merrifield, aminomethyl and plain polystyrene resins are presented here. Immobilizations of conalbumin were carried out on the Merrifield and Aminomethyl resins, but the procedures were time consuming and complicated by polymer aggregation. Because of high cost of these materials, research was directed towards the activation and functionalization of plain polystyrene/divinylbenzene co-polymers. Chlorosulfonation followed by sulfonamide formation was attempted on three commercially available polymers. Successful polysulfonamide formation was achieved with bislysine copper(II) acting as a diamine. Removal of the copper allows the unblocking of the alpha amino group of the immobilized lysine which in turn is treated with glutaraldehyde, affording an activated support for immobilization of proteins. To date, approximately 46 mg transferrin/g dry matrix have been successfully immobilized. The chemical and biological inertness of this support makes it a good candidate to scale up the procedure and continue the optimization of MAMC.
    The mutagenic and carcinogenic properties of chromium(VI) complexes have been ascribed to the formation of ternary Cr(III)-small molecule-DNA complexes. As part of these laboratories efforts to establish the structure and properties of... more
    The mutagenic and carcinogenic properties of chromium(VI) complexes have been ascribed to the formation of ternary Cr(III)-small molecule-DNA complexes. As part of these laboratories efforts to establish the structure and properties of discrete binary and ternary adducts of Cr(III) and DNA at a molecular level, the properties of Cr(III)-histidine-DNA complexes formed from Cr(III) were examined. These studies determined the composition of previously described "prereacted" chromium histidinate and reveal the reaction of "prereacted" chromium histidinate with DNA does not form ternary complexes as previously proposed. The products instead are chromium histidinate complexes weakly bound, probably in the minor groove, to DNA. These weakly bound adducts cannot be responsible for the mutagenic and carcinogenic properties ascribed to ternary Cr(III)-histidine-DNA adducts. The results of biological studies where "ternary adducts" of Cr(III), histidine, and DNA w...
    ABSTRACT
    Over fifty years ago, the element chromium (as the trivalent ion) was proposed to be an essential element for mammals with a role in maintaining proper carbohydrate and lipid metabolism. Evidence for an essential role came from dietary... more
    Over fifty years ago, the element chromium (as the trivalent ion) was proposed to be an essential element for mammals with a role in maintaining proper carbohydrate and lipid metabolism. Evidence for an essential role came from dietary studies with rodents, studies on the effects of chromium on subjects on total parenteral nutrition, and studies of the absorption and transport of chromium. Over the next several decades, chromium-containing nutritional supplements became so popular for weight loss and muscle development that sales were second only to calcium among mineral supplements. However, the failure to identify the responsible biomolecules(s) that bind chromium(III) and their mode of action, particularly a postulated species named glucose tolerance factor or GTF, resulted in the status of chromium being questioned in recent years, such that the question of its being essential needs to be formally readdressed. At the same time as chromium(III)'s popularity as a nutritional s...
    Page 1. NMR resonances at 6= 181.2 (CO), 59.4 (JCH= 195.8 Hz, CH), 67.2, and 57.3 (CPh) are assigned to the carbon atoms of the oxocyclobutenyl ring. Signals at 6= 193.2 (Jcp= 12.5 Hz, CPh) and 184.6 (JCH = 196.8 Hz ...
    The cation [Cr 3 O (O 2 CCH 2 CH 3) 6 (H 2 O) 3]+ has been shown in vitro to mimic to the oligopeptide chromodulin's ability to stimulate the tyrosine kinase activity of insulin receptor and shown in healthy and type 2 diabetic model... more
    The cation [Cr 3 O (O 2 CCH 2 CH 3) 6 (H 2 O) 3]+ has been shown in vitro to mimic to the oligopeptide chromodulin's ability to stimulate the tyrosine kinase activity of insulin receptor and shown in healthy and type 2 diabetic model rats to increase insulin sensitivity ...
    ABSTRACT
    ... Barry J. Goldstein,1* Li Zhu, Richard Hager,1 Assaf Zilbering,1 Yanjie Sun,2 and John B. Vincent2 1Department of Medicine, Jefferson Medical College, Division of Endocrinology and Metabolic Diseases, Dorrance H ... 12. Lerea KM, Tonks... more
    ... Barry J. Goldstein,1* Li Zhu, Richard Hager,1 Assaf Zilbering,1 Yanjie Sun,2 and John B. Vincent2 1Department of Medicine, Jefferson Medical College, Division of Endocrinology and Metabolic Diseases, Dorrance H ... 12. Lerea KM, Tonks NK, Krebs EG, Fischer EH, Glomset JA. ...
    Chromium(III) has generally been considered to be essential for proper carbohydrate and lipid metabolism, and, despite recent evidence to the contrary, chromium(III)-containing compounds remain one of the most popular commercial dietary... more
    Chromium(III) has generally been considered to be essential for proper carbohydrate and lipid metabolism, and, despite recent evidence to the contrary, chromium(III)-containing compounds remain one of the most popular commercial dietary supplements. Cr3, or [Cr3O(O2CCH2CH3)6(H2O)3]NO3·H2O, is a trivalent chromium compound that is a promising chromium nutritional supplement. Studies with Cr3 have indicated that it is non-toxic in developmental and short- and long-term exposure studies in rodents, but the safety of this compound to chromosomes and cells has not been explored. The current study evaluates the mutagenicity, cytotoxicity, and clastogenicity of Cr3 in bacterial and mammalian cells and compares these results with similar studies using the bestselling Cr(III) nutritional supplement, chromium picolinate (CrPic). The mutagenicity of CrPic and Cr3 was tested in Escherichia coli FX-11 and Salmonella typhimurium (TA 98 and TA 100). Cytotoxicity was measured as a decrease in plating efficiency relative to controls after treatment with Cr3 and CrPic for 24 h in CHO K1 cells. Clastogenicity was measured by counting the number of metaphases damaged and of the total number chromosomal aberrations in CHO K1 cells. Mutagenesis assays in E. coli and S. typhimurium were negative. All treatments of Cr3 produced ≥ 84% plating efficiency except 80 μg/cm2, which reduced the plating efficiency to 62%. Cr3 at any treatment level did not produce a significant increase in the number of cells with abnormal metaphases, while treatments using ≥ 40 μg/cm2 of CrPic elevated the number significantly. These data suggest that Cr3 is significantly less mutagenic in bacteria cells and less clastogenic in CHO K1 cells, while CrPic is clastogenic in CHO K1 cells.
    Recently, several studies on the effects of a compound named "chromium malate," with the proposed formula "Cr2malate3·xH2O" where x = 3.5 or 5, on the health of healthy and diabetic rats have appeared. However, the... more
    Recently, several studies on the effects of a compound named "chromium malate," with the proposed formula "Cr2malate3·xH2O" where x = 3.5 or 5, on the health of healthy and diabetic rats have appeared. However, the compound is poorly characterized, and knowing the identity of this material could be important in the interpretation of the previous and of future studies on the effects of this compound in animals. Consequently, the synthesis, characterization, and identity of this material were explored. A combination of spectroscopic, magnetic, and elemental analyses and mass spectral studies reveal that the compound is probably a polymer, not a discrete molecule, and does not have the composition previously reported. The repeating unit of the polymer possesses an antiferromagnetically coupled trinuclear Cr(III) core. The current study suggests that previous reports on chromium malate and its effects in animals must be viewed with caution.
    The possibility of the existence of a covalent enzyme-phosphoryl intermediate, E-PO3, during catalysis of phosphate ester hydrolysis by the purple acid phosphatase (PAP) from bovine spleen has been examined. Transphosphorylation... more
    The possibility of the existence of a covalent enzyme-phosphoryl intermediate, E-PO3, during catalysis of phosphate ester hydrolysis by the purple acid phosphatase (PAP) from bovine spleen has been examined. Transphosphorylation experiments show that up to 22% of the phosphoryl group from p-nitrophenyl phosphate (PNPP) can be transferred to primary alcohols. Burst experiments at high pH (9.1 or 8.1 for reduced or oxidized PAP, respectively), where hydrolysis of a phosphoenzyme intermediate is expected to be rate-limiting, show clear evidence for stoichiometric bursts of p-nitrophenolate from PNPP. The formation of base-stable, acid-sensitive adducts between PAP and the 32PO3 group of [gamma-32P]ATP has been demonstrated. The pH dependence of the kinetics parameters for reduced PAP has been determined over the range pH 3-8; a feature with a pKa of approximately 6.75 that is attributable to the enzyme-substrate complex is observed. Taken together, the present results are consistent wi...
    The nutritional biochemistry of trivalent Cr has been a poorly understood field of study; investigations of the biochemistry of the other essential transition metals have not proven as problematic. Despite over four decades of endeavour,... more
    The nutritional biochemistry of trivalent Cr has been a poorly understood field of study; investigations of the biochemistry of the other essential transition metals have not proven as problematic. Despite over four decades of endeavour, only recently has a picture of the role of Cr potentially started to be defined. The biologically-relevant form is the trivalent ion. Cr3+ appears to be required for proper carbohydrate and lipid metabolism in mammals, although fortunately Cr deficiency is difficult to achieve. Conditions that increase circulating glucose and insulin concentrations increase urinary Cr output. Cr is probably excreted in the form of the oligopeptide chromodulin. Chromodulin may be the key to understanding the role of Cr at a molecular level, as the molecule has been found to bind to activated insulin receptor, stimulating its kinase activity. A mechanism for the action of chromodulin has recently been proposed; this mechanism can serve as a potential framework for fur...
    Chromium is generally believed to be an essential trace element and to have a role in maintaining proper carbohydrate and lipid metabolism, probably by enhancing insulin signaling. Three recent events have strongly influenced biochemical... more
    Chromium is generally believed to be an essential trace element and to have a role in maintaining proper carbohydrate and lipid metabolism, probably by enhancing insulin signaling. Three recent events have strongly influenced biochemical and nutritional studies of Cr(III): (1) the Food and Nutrition Board's new daily adequate intake (AI) of Cr, (2) the Food Standards Agency's determination that Cr picolinate might have the potential to cause cancer, and (3) the National Institutes of Health's program announcement "Chromium as an adjuvant therapy for type 2 diabetes and impaired glucose tolerance." A discussion of these three events allows the current understanding of the nutritional biochemistry of Cr to be outlined.
    Chromium has been proposed to be an essential trace element useful in the treatment of diabetes, and several chromium(III) compounds have been used as nutritional supplements. However, the fate of the chromium from nutritional supplements... more
    Chromium has been proposed to be an essential trace element useful in the treatment of diabetes, and several chromium(III) compounds have been used as nutritional supplements. However, the fate of the chromium from nutritional supplements has been investigated solely by techniques, such as radio-labeling, which allow only the chromium atom to be traced, not its chemical form. This investigation examined the ability of liquid chromatography-mass spectrometry (LCMS) to follow these supplements and to elucidate the chemical composition of their degradation products in the body. Rats were utilized to examine chemical composition of a chromium supplement provided to the rats by gavage administration. Results indicate that LCMS is not a viable analytical technique for elucidating the speciation and quantification of chromium
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    The element chromium apparently has a role in maintaining proper carbohydrate and lipid metabolism in mammals. As this role probably involves potentiation of insulin signalling, chromium dietary supplementation has been postulated to... more
    The element chromium apparently has a role in maintaining proper carbohydrate and lipid metabolism in mammals. As this role probably involves potentiation of insulin signalling, chromium dietary supplementation has been postulated to potentially have effects on body composition, including reducing fat mass and increasing lean body mass. Because the supplement is absorbed better than dietary chromium, most studies have focused on the use of chromium picolinate [Cr(pic)(3)]. Cr(pic)(3) has been amazingly popular with the general public, especially with athletes who may have exercise-induced increased urinary chromium loss; however, its effectiveness in manifesting body composition changes has been an area of intense debate in the last decade. Additionally, claims have appeared that the supplement might give rise to deleterious effects. However, over a decade of human studies with Cr(pic)(3) indicate that the supplement has not demonstrated effects on the body composition of healthy individuals, even when taken in combination with an exercise training programme. Recent cell culture and in vivo rat studies have indicated that Cr(pic)(3) probably generates oxidative damage of DNA and lipids and is mutagenic, although the significance of these results on humans taking the supplement for prolonged periods of time is unknown and should be a focus for future investigations. Given that in vitro studies suggest that other forms of chromium used as nutritional supplements, such as chromium chloride, are unlikely to be susceptible to generating this type of oxidative damage, the use of these compounds, rather than Cr(pic)(3), would appear warranted. Potential neurological effects (both beneficial and deleterious) from Cr(pic)(3) supplementation require further study.
    ... Properties of [ Mn2O( 02CR)2X2( bpy)2] (X = C1-, N3-, H20) John B. Vincent,lP Hui-Lien Tsai,lb Allan G. Blackman,ln Sbeyi Wang,lP Peter DW Boyd,lf Kirsten Folting,ld John C. Huffman,ld Emil B. Lobkovsky,ld David N.... more
    ... Properties of [ Mn2O( 02CR)2X2( bpy)2] (X = C1-, N3-, H20) John B. Vincent,lP Hui-Lien Tsai,lb Allan G. Blackman,ln Sbeyi Wang,lP Peter DW Boyd,lf Kirsten Folting,ld John C. Huffman,ld Emil B. Lobkovsky,ld David N. Hendrickson,'Jb and George Christou'Jn ...
    David N. Hendrickson,*Ja George Christou,*!" Edward A. Schmitt,Ia Eduardo Libby,t John S. Bashkin," Sheyi Wang,2a Hui-Lien Tsai,la John B.... more
    David N. Hendrickson,*Ja George Christou,*!" Edward A. Schmitt,Ia Eduardo Libby,t John S. Bashkin," Sheyi Wang,2a Hui-Lien Tsai,la John B. Vincent," Peter DW Boyd,3 John C. Huffman,2b Kirsten Folting,2b Qiaoying Li,lb and William E. Streib2b Contribution from ...
    (30) Prepared from methyl butyrate by the procedure described in Corey, EJ; Kwiatkowski, GT J. Am. Chem. SOC. 1966, 88, 5653. ... (m, 16 H), 2.98 (br m, 1 H), 3.32 (br d, 1 H), 8.46 (br m, 1 H), 9.62 (br m, 1 H); I3C NMR (CDCI,) 6 60.2,... more
    (30) Prepared from methyl butyrate by the procedure described in Corey, EJ; Kwiatkowski, GT J. Am. Chem. SOC. 1966, 88, 5653. ... (m, 16 H), 2.98 (br m, 1 H), 3.32 (br d, 1 H), 8.46 (br m, 1 H), 9.62 (br m, 1 H); I3C NMR (CDCI,) 6 60.2, 58.2, 41.1, 35.0, 34.5, 29.2, 27.3,
    ... [ Mn30(02CPh)6(pyr)2(H20)]*0.5MeCN [Mn,0(02CMe>6(pyr)3](pyr) and John B. Vincent,t Hsiu-Rong Chang,s Kirsten Folting,t John C. Huffman,* George Christou,*t and David N. Hendrickson*§ ... 1980, 684. (10) Vincent, JB;... more
    ... [ Mn30(02CPh)6(pyr)2(H20)]*0.5MeCN [Mn,0(02CMe>6(pyr)3](pyr) and John B. Vincent,t Hsiu-Rong Chang,s Kirsten Folting,t John C. Huffman,* George Christou,*t and David N. Hendrickson*§ ... 1980, 684. (10) Vincent, JB; Folting, K.; Huffman, J. C.; Christou, G. Inorg. Chem. ...
    Page 1. J. Am. Chem. SOC. 1988, 110, 8531-8539 8531 iP I. J / \ Figure 2. Dc cyclic voltammetry of microperoxidase (0.5 mg/mL) in Mg(C10+)2 (0.025 M) and phosphate buffer (0.02 M) at pH 7.0, in the potential range 0 to -0.60 ...

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