The Experts below are selected from a list of 132 Experts worldwide ranked by ideXlab platform

Robert Alan Gadski - One of the best experts on this subject based on the ideXlab platform.

  • synthesis and in vitro biological activity of 4α 2 propenyl 5α cholest 24 en 3α ol a 24 25 dehydro analog of the Hypocholesterolemic Agent 4α 2 propenyl 5α cholestan 3α ol
    Steroids, 1999
    Co-Authors: Ho-shen Lin, Don B Mcclure, Ashraff A. Rampersaud, Michael Enrico Richett, Lisa Selsam Beavers, Richard Waltz Harper, Anthony J Gardner, Patrick I Eacho, Patricia S Foxworthy, Robert Alan Gadski
    Abstract:

    4Alpha-(2-propenyl)-5alpha-cholestan-3alpha-ol (LY295427) was previously identified from a Chinese hamster ovary (CHO) cell-based low density lipoprotein receptor/luciferase (LDLR/Luc) assay to be a potent transcriptional activator of the LDL receptor promoter in the presence of 25-hydroxycholesterol. To investigate the effect of the 24,25-unsaturation in the D-ring side chain (desmosterol D-ring side chain) on antagonizing the repressing effect of 25-hydroxycholesterol, 4alpha-(2-propenyl)-5alpha-cholest-24-en-3alpha-ol (17), a 24,25-dehydro analog of LY295427, was thus synthesized from lithocholic acid via the formation of 3alpha-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-4alpha- (2-propenyl)-5alpha-cholan-24-al (15). Test results showed that 17 had an EC30 value of 2.6 microM, comparable to 2.9 microM of LY295427, in the CHO cell-based LDLR/Luc assay in the presence of 25-hydroxycholesterol. Apparently, the built-in 24,25-unsaturation in the D-ring side chain of 17 had added little effect to antagonizing the repressing effect of 25-hydroxycholesterol. In the [1-14C-acetate]cholesterol biosynthesis inhibition assay, 17 at 10 microg/ml (23 microM) has been shown to inhibit the cholesterol biosynthesis in CHO cells by 38% relative to the vehicle control; whereas LY295427 showed no inhibition in the same assay in our previous studies. In contrast to LY295427, the built-in 24,25-unsaturation in the D-ring side chain of 17 has conferred an inhibitory effect on cholesterol biosynthesis in CHO cells. In summary, the observed LDL receptor promoter activity of 17 is related to its ability to prevent 25-hydroxycholesterol from exerting the repressing effect via an undetermined mechanism and, in part, to inhibit the cholesterol biosynthesis.

  • Synthesis of 4α-(2-propenyl)-5,6-secocholestan-3α-ol, a Novel B-ring Seco Analog of the Hypocholesterolemic Agent 4α-(2-propenyl)-5α-cholestan-3α-ol
    Steroids, 1998
    Co-Authors: Ho-shen Lin, Don B Mcclure, Ashraff A. Rampersaud, Michael Enrico Richett, Lisa Selsam Beavers, Robert Alan Gadski
    Abstract:

    Abstract 4α-(2-Propenyl)-5α-cholestan-3α-ol (LY295427) was previously identified from a CHO cell-based assay to be a potent LDL receptor up-regulator and had demonstrated to be an effective Agent in lowering plasma cholesterol levels in hypercholesterolemic hamsters. In order to investigate the effect of flexibility of the 3α-hydroxy-bearing A-ring on the activity, 4α-(2-propenyl)-5,6-secocholestan-3α-ol ( 11 ), a B-ring seco analog of LY295427, is thus synthesized from cholest-4-en-3-one. Test results indicate that 11 is not active in the CHO cell-based LDL receptor/luciferase assay at concentrations up to 20 μg/mL. The result underlines the importance of maintaining the A-B-C-D ring rigidity of the 3α-sterols in terms of binding to the putative oxysterol receptor.

  • ly295427 a novel Hypocholesterolemic Agent enhances 3h 25 hydroxycholesterol binding to liver cytosolic proteins
    Journal of Lipid Research, 1996
    Co-Authors: N Bowling, W F Matter, Robert Alan Gadski, Don B Mcclure, T Schreyer, P A Dawson, Chris J Vlahos
    Abstract:

    LY295427, (3 alpha,4 alpha,5 alpha)-4-(2-propenylcholestan-3-ol), acts through an unknown mechanism to derepress the transcription of the low density lipoprotein (LDL) receptor in the presence of 25-hydroxycholesterol (25-OH chol). Preincubation with LY295427 in Chinese hamster ovary (CHO) cells increased uptake of 25-OH chol in a time-dependent manner, suggesting that the drug interfered with the negative feedback mechanism of 25-OH chol on LDL receptor expression. To explore the mechanism by which LY295427 inhibited the suppressive actions of 25-OH chol, the radioactive ligand [3H]25-OH chol and specific antibodies to the oxysterol binding protein (OSBP) were used to identify possible drug:protein interactions. After separation by anion exchange chromatography, protein fractions from hamster liver cytosol were found to selectively bind [3H]25-OH chol with high affinity. In fractions in which 25-OH chol binding was evident, and in other distinct fractions that lacked specific binding, addition of LY295427 increased [3H]25-OH chol binding 2- to 5-fold. LY306039, the 3 beta-isomer of LY295427, failed to derepress the LDL receptor in CHO cells, and it had no effect on [3H]25-OH chol binding. Analysis of Western blots using polyclonal antibodies to OSBP showed that specific [3H]25-OH chol binding in the absence of LY295427 was present only in fractions containing OSBP. However, enhanced [3H]25-OH chol binding in the presence of LY295427 was evident in distinct fractions after immunodepletion of both the 90-100 kDa form of OSBP and a 170 kDa protein; and specific binding of a radioiodinated analog of LY295427 was detected in select fractions lacking [3H]25-OH chol binding in the absence of LY295427. Moreover, LY295427 did not displace or enhance [3H]25-OH chol binding to OSBP purified to near homogeneity. These data suggest that LY295427, while not dependent on the presence of oxysterol binding protein, binds to cytosolic protein(s) that interact with 25-hydroxycholesterol and other oxystcrols, thus preventing the repression of the LDL receptor.

M A Siimes - One of the best experts on this subject based on the ideXlab platform.

  • sitostanol ester margarine in dietary treatment of children with familial hypercholesterolemia
    Journal of Lipid Research, 1995
    Co-Authors: Helena Gylling, M A Siimes
    Abstract:

    In familial hypercholesterolemia (FH) the lowering of serum cholesterol levels should be started in childhood in order to prevent coronary artery disease later in life. How- ever, treatment of children is problematic. We studied the effects of sitostanol (3 g/day) ester dissolved in rapeseed oil margarine as a Hypocholesterolemic Agent in one homozy- gous and 14 heterozygous children with FH maintained on a low cholesterol diet for 6 weeks, using a double-blind cross- over design. Absorption and synthesis of cholesterol were evaluated by measuring serum plant sterol and cholesterol precursor proportions to cholesterol by gas-liquid chroma- tography. The compliance was good, and the children could not distinguish by taste the two margarines without and with sitostanol ester. Sitostanol margarine significantly reduced serum total, intermediate density (IDL), and low density lipo- protein (LDL) cholesterol by 11, 26, and 15%, respectively, and increased HDL/LDL cholesterol ratio by 27%. The pro- portions of serum A8cholestenol, lathosterol, and des- mosterol were significantly increased by 36, 19, and 18%, and those of serum cholestanol, campesterol, and sitosterol were significantly decreased by 9, 42 and 29%, respectively, sug- gesting that cholesterol absorption was decreased and synthe- sis was compensatorily increased. High basal precursor sterol proportions predicted a high decrease in LDL cholesterol levels. I In conclusion, partial replacement of normal die- tary fat consumption by sitostanol ester margarine appears to be an effective and safe Hypocholesterolemic treatment in children with FH.-Gylling, H., M. A. Shes, and T. A. Miettinen. Sitostanol ester margarine in dietary treatment of children with familial hypercholesterolemia. J. Lipid Res. 1995.36: 1807-1812.

  • sitostanol ester margarine in dietary treatment of children with familial hypercholesterolemia
    Journal of Lipid Research, 1995
    Co-Authors: Helena Gylling, M A Siimes
    Abstract:

    In familial hypercholesterolemia (FH) the lowering of serum cholesterol levels should be started in childhood in order to prevent coronary artery disease later in life. However, treatment of children is problematic. We studied the effects of sitostanol (3 g/day) ester dissolved in rapeseed oil margarine as a Hypocholesterolemic Agent in one homozygous and 14 heterozygous children with FH maintained on a low cholesterol diet for 6 weeks, using a double-blind crossover design. Absorption and synthesis of cholesterol were evaluated by measuring serum plant sterol and cholesterol precursor proportions to cholesterol by gas-liquid chromatography. The compliance was good, and the children could not distinguish by taste the two margarines without and with sitostanol ester. Sitostanol margarine significantly reduced serum total, intermediate density (IDL), and low density lipoprotein (LDL) cholesterol by 11, 26, and 15%, respectively, and increased HDL/LDL cholesterol ratio by 27%. The proportions of serum delta 8-cholestenol, lathosterol, and desmosterol were significantly increased by 36, 19, and 18%, and those of serum cholestanol, campesterol, and sitosterol were significantly decreased by 9, 42 and 29%, respectively, suggesting that cholesterol absorption was decreased and synthesis was compensatorily increased. High basal precursor sterol proportions predicted a high decrease in LDL cholesterol levels. In conclusion, partial replacement of normal dietary fat consumption by sitostanol ester margarine appears to be an effective and safe Hypocholesterolemic treatment in children with FH.

Helena Gylling - One of the best experts on this subject based on the ideXlab platform.

  • sitostanol ester margarine in dietary treatment of children with familial hypercholesterolemia
    Journal of Lipid Research, 1995
    Co-Authors: Helena Gylling, M A Siimes
    Abstract:

    In familial hypercholesterolemia (FH) the lowering of serum cholesterol levels should be started in childhood in order to prevent coronary artery disease later in life. How- ever, treatment of children is problematic. We studied the effects of sitostanol (3 g/day) ester dissolved in rapeseed oil margarine as a Hypocholesterolemic Agent in one homozy- gous and 14 heterozygous children with FH maintained on a low cholesterol diet for 6 weeks, using a double-blind cross- over design. Absorption and synthesis of cholesterol were evaluated by measuring serum plant sterol and cholesterol precursor proportions to cholesterol by gas-liquid chroma- tography. The compliance was good, and the children could not distinguish by taste the two margarines without and with sitostanol ester. Sitostanol margarine significantly reduced serum total, intermediate density (IDL), and low density lipo- protein (LDL) cholesterol by 11, 26, and 15%, respectively, and increased HDL/LDL cholesterol ratio by 27%. The pro- portions of serum A8cholestenol, lathosterol, and des- mosterol were significantly increased by 36, 19, and 18%, and those of serum cholestanol, campesterol, and sitosterol were significantly decreased by 9, 42 and 29%, respectively, sug- gesting that cholesterol absorption was decreased and synthe- sis was compensatorily increased. High basal precursor sterol proportions predicted a high decrease in LDL cholesterol levels. I In conclusion, partial replacement of normal die- tary fat consumption by sitostanol ester margarine appears to be an effective and safe Hypocholesterolemic treatment in children with FH.-Gylling, H., M. A. Shes, and T. A. Miettinen. Sitostanol ester margarine in dietary treatment of children with familial hypercholesterolemia. J. Lipid Res. 1995.36: 1807-1812.

  • sitostanol ester margarine in dietary treatment of children with familial hypercholesterolemia
    Journal of Lipid Research, 1995
    Co-Authors: Helena Gylling, M A Siimes
    Abstract:

    In familial hypercholesterolemia (FH) the lowering of serum cholesterol levels should be started in childhood in order to prevent coronary artery disease later in life. However, treatment of children is problematic. We studied the effects of sitostanol (3 g/day) ester dissolved in rapeseed oil margarine as a Hypocholesterolemic Agent in one homozygous and 14 heterozygous children with FH maintained on a low cholesterol diet for 6 weeks, using a double-blind crossover design. Absorption and synthesis of cholesterol were evaluated by measuring serum plant sterol and cholesterol precursor proportions to cholesterol by gas-liquid chromatography. The compliance was good, and the children could not distinguish by taste the two margarines without and with sitostanol ester. Sitostanol margarine significantly reduced serum total, intermediate density (IDL), and low density lipoprotein (LDL) cholesterol by 11, 26, and 15%, respectively, and increased HDL/LDL cholesterol ratio by 27%. The proportions of serum delta 8-cholestenol, lathosterol, and desmosterol were significantly increased by 36, 19, and 18%, and those of serum cholestanol, campesterol, and sitosterol were significantly decreased by 9, 42 and 29%, respectively, suggesting that cholesterol absorption was decreased and synthesis was compensatorily increased. High basal precursor sterol proportions predicted a high decrease in LDL cholesterol levels. In conclusion, partial replacement of normal dietary fat consumption by sitostanol ester margarine appears to be an effective and safe Hypocholesterolemic treatment in children with FH.

Ho-shen Lin - One of the best experts on this subject based on the ideXlab platform.

  • synthesis and in vitro biological activity of 4α 2 propenyl 5α cholest 24 en 3α ol a 24 25 dehydro analog of the Hypocholesterolemic Agent 4α 2 propenyl 5α cholestan 3α ol
    Steroids, 1999
    Co-Authors: Ho-shen Lin, Don B Mcclure, Ashraff A. Rampersaud, Michael Enrico Richett, Lisa Selsam Beavers, Richard Waltz Harper, Anthony J Gardner, Patrick I Eacho, Patricia S Foxworthy, Robert Alan Gadski
    Abstract:

    4Alpha-(2-propenyl)-5alpha-cholestan-3alpha-ol (LY295427) was previously identified from a Chinese hamster ovary (CHO) cell-based low density lipoprotein receptor/luciferase (LDLR/Luc) assay to be a potent transcriptional activator of the LDL receptor promoter in the presence of 25-hydroxycholesterol. To investigate the effect of the 24,25-unsaturation in the D-ring side chain (desmosterol D-ring side chain) on antagonizing the repressing effect of 25-hydroxycholesterol, 4alpha-(2-propenyl)-5alpha-cholest-24-en-3alpha-ol (17), a 24,25-dehydro analog of LY295427, was thus synthesized from lithocholic acid via the formation of 3alpha-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-4alpha- (2-propenyl)-5alpha-cholan-24-al (15). Test results showed that 17 had an EC30 value of 2.6 microM, comparable to 2.9 microM of LY295427, in the CHO cell-based LDLR/Luc assay in the presence of 25-hydroxycholesterol. Apparently, the built-in 24,25-unsaturation in the D-ring side chain of 17 had added little effect to antagonizing the repressing effect of 25-hydroxycholesterol. In the [1-14C-acetate]cholesterol biosynthesis inhibition assay, 17 at 10 microg/ml (23 microM) has been shown to inhibit the cholesterol biosynthesis in CHO cells by 38% relative to the vehicle control; whereas LY295427 showed no inhibition in the same assay in our previous studies. In contrast to LY295427, the built-in 24,25-unsaturation in the D-ring side chain of 17 has conferred an inhibitory effect on cholesterol biosynthesis in CHO cells. In summary, the observed LDL receptor promoter activity of 17 is related to its ability to prevent 25-hydroxycholesterol from exerting the repressing effect via an undetermined mechanism and, in part, to inhibit the cholesterol biosynthesis.

  • Synthesis of 4α-(2-propenyl)-5,6-secocholestan-3α-ol, a Novel B-ring Seco Analog of the Hypocholesterolemic Agent 4α-(2-propenyl)-5α-cholestan-3α-ol
    Steroids, 1998
    Co-Authors: Ho-shen Lin, Don B Mcclure, Ashraff A. Rampersaud, Michael Enrico Richett, Lisa Selsam Beavers, Robert Alan Gadski
    Abstract:

    Abstract 4α-(2-Propenyl)-5α-cholestan-3α-ol (LY295427) was previously identified from a CHO cell-based assay to be a potent LDL receptor up-regulator and had demonstrated to be an effective Agent in lowering plasma cholesterol levels in hypercholesterolemic hamsters. In order to investigate the effect of flexibility of the 3α-hydroxy-bearing A-ring on the activity, 4α-(2-propenyl)-5,6-secocholestan-3α-ol ( 11 ), a B-ring seco analog of LY295427, is thus synthesized from cholest-4-en-3-one. Test results indicate that 11 is not active in the CHO cell-based LDL receptor/luciferase assay at concentrations up to 20 μg/mL. The result underlines the importance of maintaining the A-B-C-D ring rigidity of the 3α-sterols in terms of binding to the putative oxysterol receptor.

Don B Mcclure - One of the best experts on this subject based on the ideXlab platform.

  • synthesis and in vitro biological activity of 4α 2 propenyl 5α cholest 24 en 3α ol a 24 25 dehydro analog of the Hypocholesterolemic Agent 4α 2 propenyl 5α cholestan 3α ol
    Steroids, 1999
    Co-Authors: Ho-shen Lin, Don B Mcclure, Ashraff A. Rampersaud, Michael Enrico Richett, Lisa Selsam Beavers, Richard Waltz Harper, Anthony J Gardner, Patrick I Eacho, Patricia S Foxworthy, Robert Alan Gadski
    Abstract:

    4Alpha-(2-propenyl)-5alpha-cholestan-3alpha-ol (LY295427) was previously identified from a Chinese hamster ovary (CHO) cell-based low density lipoprotein receptor/luciferase (LDLR/Luc) assay to be a potent transcriptional activator of the LDL receptor promoter in the presence of 25-hydroxycholesterol. To investigate the effect of the 24,25-unsaturation in the D-ring side chain (desmosterol D-ring side chain) on antagonizing the repressing effect of 25-hydroxycholesterol, 4alpha-(2-propenyl)-5alpha-cholest-24-en-3alpha-ol (17), a 24,25-dehydro analog of LY295427, was thus synthesized from lithocholic acid via the formation of 3alpha-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-4alpha- (2-propenyl)-5alpha-cholan-24-al (15). Test results showed that 17 had an EC30 value of 2.6 microM, comparable to 2.9 microM of LY295427, in the CHO cell-based LDLR/Luc assay in the presence of 25-hydroxycholesterol. Apparently, the built-in 24,25-unsaturation in the D-ring side chain of 17 had added little effect to antagonizing the repressing effect of 25-hydroxycholesterol. In the [1-14C-acetate]cholesterol biosynthesis inhibition assay, 17 at 10 microg/ml (23 microM) has been shown to inhibit the cholesterol biosynthesis in CHO cells by 38% relative to the vehicle control; whereas LY295427 showed no inhibition in the same assay in our previous studies. In contrast to LY295427, the built-in 24,25-unsaturation in the D-ring side chain of 17 has conferred an inhibitory effect on cholesterol biosynthesis in CHO cells. In summary, the observed LDL receptor promoter activity of 17 is related to its ability to prevent 25-hydroxycholesterol from exerting the repressing effect via an undetermined mechanism and, in part, to inhibit the cholesterol biosynthesis.

  • Synthesis of 4α-(2-propenyl)-5,6-secocholestan-3α-ol, a Novel B-ring Seco Analog of the Hypocholesterolemic Agent 4α-(2-propenyl)-5α-cholestan-3α-ol
    Steroids, 1998
    Co-Authors: Ho-shen Lin, Don B Mcclure, Ashraff A. Rampersaud, Michael Enrico Richett, Lisa Selsam Beavers, Robert Alan Gadski
    Abstract:

    Abstract 4α-(2-Propenyl)-5α-cholestan-3α-ol (LY295427) was previously identified from a CHO cell-based assay to be a potent LDL receptor up-regulator and had demonstrated to be an effective Agent in lowering plasma cholesterol levels in hypercholesterolemic hamsters. In order to investigate the effect of flexibility of the 3α-hydroxy-bearing A-ring on the activity, 4α-(2-propenyl)-5,6-secocholestan-3α-ol ( 11 ), a B-ring seco analog of LY295427, is thus synthesized from cholest-4-en-3-one. Test results indicate that 11 is not active in the CHO cell-based LDL receptor/luciferase assay at concentrations up to 20 μg/mL. The result underlines the importance of maintaining the A-B-C-D ring rigidity of the 3α-sterols in terms of binding to the putative oxysterol receptor.

  • ly295427 a novel Hypocholesterolemic Agent enhances 3h 25 hydroxycholesterol binding to liver cytosolic proteins
    Journal of Lipid Research, 1996
    Co-Authors: N Bowling, W F Matter, Robert Alan Gadski, Don B Mcclure, T Schreyer, P A Dawson, Chris J Vlahos
    Abstract:

    LY295427, (3 alpha,4 alpha,5 alpha)-4-(2-propenylcholestan-3-ol), acts through an unknown mechanism to derepress the transcription of the low density lipoprotein (LDL) receptor in the presence of 25-hydroxycholesterol (25-OH chol). Preincubation with LY295427 in Chinese hamster ovary (CHO) cells increased uptake of 25-OH chol in a time-dependent manner, suggesting that the drug interfered with the negative feedback mechanism of 25-OH chol on LDL receptor expression. To explore the mechanism by which LY295427 inhibited the suppressive actions of 25-OH chol, the radioactive ligand [3H]25-OH chol and specific antibodies to the oxysterol binding protein (OSBP) were used to identify possible drug:protein interactions. After separation by anion exchange chromatography, protein fractions from hamster liver cytosol were found to selectively bind [3H]25-OH chol with high affinity. In fractions in which 25-OH chol binding was evident, and in other distinct fractions that lacked specific binding, addition of LY295427 increased [3H]25-OH chol binding 2- to 5-fold. LY306039, the 3 beta-isomer of LY295427, failed to derepress the LDL receptor in CHO cells, and it had no effect on [3H]25-OH chol binding. Analysis of Western blots using polyclonal antibodies to OSBP showed that specific [3H]25-OH chol binding in the absence of LY295427 was present only in fractions containing OSBP. However, enhanced [3H]25-OH chol binding in the presence of LY295427 was evident in distinct fractions after immunodepletion of both the 90-100 kDa form of OSBP and a 170 kDa protein; and specific binding of a radioiodinated analog of LY295427 was detected in select fractions lacking [3H]25-OH chol binding in the absence of LY295427. Moreover, LY295427 did not displace or enhance [3H]25-OH chol binding to OSBP purified to near homogeneity. These data suggest that LY295427, while not dependent on the presence of oxysterol binding protein, binds to cytosolic protein(s) that interact with 25-hydroxycholesterol and other oxystcrols, thus preventing the repression of the LDL receptor.