Interview with Anna Meenan, MD. Interview by Ina May Gaskin.
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Delivery, Obstetric↗
Biomedical subjects
A Meenan
Publications and source records attributed to A Meenan.
Inhibition of cholesterol synthesis and cell growth by 24(R,S),25-iminolanosterol and triparanol in cultured rat hepatoma cells.
24(R,S),25-Iminolanosterol (IL) and triparanol added to cultures of rat hepatoma cells, H4-II-C3 (H4), interrupt the conversion of lanosterol to cholesterol and, depending on their concentrations, cause the accumulation in the cells of intermediates in the lanosterol to cholesterol conversion. At 45 microM, both substances cause the accumulation of 5 alpha-cholesta-8(9),24-dien-3 beta-ol (zymosterol), and at the low concentration of 4.5 microM, they cause the accumulation of cholesta-5.24-dien-3 beta-ol (desmosterol). The effect of intermediate concentrations of 9 or 22.5 microM of either substance is to cause the accumulation in the cells of three sterols: cholesta-5,7,24-trien-3 beta-ol, zymosterol, and desmosterol. The synthesis of these intermediary sterols, not found normally in H4 cells, is particularly pronounced in cultures kept in lipid-depleted media that contain the inhibitors and proceeds by the use of endogenous substrates at the expense of cholesterol. The synthesis of cholesterol from [14C]acetate or [2-14C]mevalonate is completely blocked by either inhibitor even at 4.5 microM. IL or triparanol inhibits the growth of H4 cells. Cells seeded into either full growth or lipid-depleted medium containing 22.5 microM IL will not grow unless the media are supplemented with low density lipoproteins (60 micrograms/ml). Supplementation of the media with 4.6 mM mevalonate does not counteract the inhibitory effect of IL on cell growth.
Animals↗
Congenital hypothyroidism.
This paper presents a case report of congenital hypothyroidism that illustrates some of the issues in screening for this disorder. Congenital hypothyroidism has several causes, the most common of which is thyroid dysgenesis. Most affected infants have no historical clues or physical findings to suggest diagnosis. Neonatal screening combining thyroxine and thyrotropin screening have resulted in increased detection, although false-negatives do occur, and the physician must carefully observe all newborns for the findings of congenital hypothyroidism. Early treatment improves the prognosis considerably. This paper reviews the pathophysiology, diagnosis, and treatment of congenital hypothyroidism.
Congenital Hypothyroidism↗
Effects of 2,3-iminosqualene on cultured cells.
2,3-Iminosqualene (ISq) is a powerful inhibitor of squalene oxide:lanosterol cyclase (EC 5.4.99.7). When added to lipid-depleted culture media (LDM) of rat hepatoma (H-4-II-E-C3) or Chinese hamster ovary (CHO) cells at a concentration of 10 micrograms ml-1, it causes the cells to float off the substratum in a few days. Lipoproteins in the culture medium completely counteract this effect. Cells in lipoprotein-containing media (FGM) grow normally in the presence of ISq. Irrespective of the culture medium, ISq at 10 micrograms ml-1 causes an almost complete and apparently irreversible inactivation of the squalene oxide cyclase in CHO and H4 cells and the accumulation in the cells of squalene, of squalene 2,3-oxide (mostly), and of squalene 2,3-22,23-dioxide when [14C]acetate or [14C]mevalonate is fed to the cells. Chronic treatment of H4 cells with ISq failed to elicit induction of the cyclase, but increased the conversion of mevalonate into squalene and squalene dioxide, and depressed the conversion of squalene oxide to the dioxide. Cells loaded with squalene and the squalene oxides from mevalonate in the presence of ISq get rid of these substances by rapidly secreting them into the media and by some unidentified metabolic processes.
Animals↗
Regulation of 3-hydroxy-3-methylglutaryl coenzyme A reductase: search for the enzyme's repressor derived from mevalonate.
Three inhibitors of squalene 2,3-oxide-lanosterol cyclase (AMO 1618, 4,4,10 beta-trimethyl-trans-decal-3 beta-ol (TMD) and 2,3-iminosqualene (ISq] were used to study effects on 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, and on sterol and polyprenyl synthesis from [14C]acetate and [14C]mevalonate in cultured rat hepatoma (H4) cells. After a 4 h exposure of cultures to AMO 1618 or TMD, followed by removal of the inhibitors, the utilization of [14C]acetate for synthesis of digitonin-precipitable sterols increased about twofold, an increase parallelled by the rise in HMG-CoA reductase. Mevalonate at 2.3 mM counteracted the effects of these inhibitors on the reductase. When (R)-[2-14C]mevalonate at 2.3 mM was included with the two inhibitors in the culture media, the cells were still able to synthesize cholesterol although in lesser amounts than the controls. In the presence of TMD the H4 cells also accumulated [14C]squalene 2,3-oxide and [14C]squalene 2,3-22,23-dioxide. ISq added to cells kept in full-growth medium (10 micrograms ml-1) caused an almost complete and irreversible inactivation of the squalene oxide-lanosterol cyclase but did not inhibit polyprenyl synthesis, as the amount of [14C]mevalonate converted into squalene, squalene 2,3-oxide, squalene 2,3-22,23-dioxide plus a little cholesterol was equal to the amount converted by control cells into cholesterol plus squalene. After a 24 h exposure of cells kept in full-growth medium to ISq (10 micrograms ml-1), the levels of HMG-CoA reductase rose about twofold. ISq completely abolished the suppressive effect of 2.3 mM (R)-mevalonate on the reductase. Chromatin isolated from cell nuclei contains cholesterol, which is renewed biosynthetically. It is argued that the suppressor of HMG-CoA reductase, derived from mevalonate, is a sterol and not a non-steroidal product of mevalonate metabolism.
Acyl Coenzyme A↗
Role of mevalonate in regulation of cholesterol synthesis and 3-hydroxy-3-methylglutaryl coenzyme A reductase in cultured cells and their cytoplasts.
H4-II-E-C3 hepatoma cells in culture respond to lipid-depleted media and to mevinolin with increased sterol synthesis from [14C]acetate and rise of 3-hydroxy-3-methylglutaryl coenzyme A reductase levels. Mevalonate at 4 mM concentration represses sterol synthesis and the reductase, and completely abolishes the effects of mevinolin. Mevalonate has little or no effect on sterol synthesis or reductase in enucleated hepatoma cells (cytoplasts) or on reductase in cytoplasts of cultured Chinese hamster ovary (CHO) cells. The sterol-synthesizing system of hepatoma cell cytoplasts and the reductase in the cytoplasts of CHO cells were completely stable for at least 4 hr. While reductase levels and sterol synthesis from acetate followed parallel courses, the effects on sterol synthesis--both increases and decreases--exceeded those on reductase. In vitro translation of hepatoma cell poly(A)+RNAs under various culture conditions gave an immunoprecipitable polypeptide with a mass of 97,000 daltons. The poly(A)+RNA from cells exposed for 24 hr to lipid-depleted media plus mevinolin (1 microgram/ml) contained 2.8 to 3.6 times more reductase-specific mRNA than that of cells kept in full-growth medium, or cells exposed to lipid-depleted media plus mevinolin plus mevalonate. Northern blot hybridization of H4 cell poly(A)+RNAs with [32P]cDNA to the reductase of CHO cells gave two 32P-labeled bands of 4.6 and 4.2 K-bases of relative intensities 1.0, 0.61-1.1, 2.56, and 1.79 from cells kept, respectively, in full-growth medium, lipid-depleted medium plus mevinolin plus mevalonate, lipid-depleted medium plus mevinolin, and lipid-depleted medium. These values approximate the reductase levels of these cells. We conclude that mevalonate suppresses cholesterol biosynthesis in part by being a source of a product that decreases the level of reductase-specific mRNA.
Animals↗
The distribution of acidic mucopolysaccharides in corneal stroma.
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Animals↗
Concerning the role of 24,25-dihydrolanosterol and lanostanol in sterol biosynthesis by cultured cells.
Rat hepatoma cells (H4-II-E-C3) efficiently converted a dietary supplement of [2-3H]24,25-dihydrolanosterol (1) to [3H]cholesterol while [2-3H]lanostanol (4,4,14 alpha-trimethylcholestanol (2) was recovered from the cells without apparent transformation, although it was esterified and induced an accumulation of lanosterol. A comparison of the chromatographic (TLC, GLC and HPLC), spectral (MS and 1H-NMR) and physical properties of 1 and 2 is given for the first time. The inability to detect 2 in nature coupled with our findings that 1 but not 2 is metabolized to cholesterol by H4 cells is interpreted to imply that the biosynthetic inclusion of the delta 8(9)-bond during the cyclization process of squalene-oxide to a tetracyclic product is an evolutionary adaptation selected for because the olefinic linkage is structually important in the subsequent conversion of lanosterol and its stereoisomers, e.g., cycloartenol, to delta 5-sterols.
Animals↗
Glyburide versus glipizide in the treatment of patients with non-insulin-dependent diabetes mellitus.
Thirty-four adults with non-insulin-dependent diabetes mellitus were randomly assigned to receive either oral glyburide or oral glipizide in a multicenter comparative trial. Fasting blood glucose and hemoglobin A1c (HbA1c) were assessed at the beginning of the titration phase, the beginning of maintenance therapy, and the end of maintenance therapy. Maintenance therapy lasted approximately 3 months. The initial mean total dose of glyburide (5.4 mg) was significantly lower than that of glipizide (10.6 mg) (P = 0.04) and remained significantly lower at the beginning of maintenance therapy (7.8 mg versus 15.3 mg; P < 0.01) and at the end of the trial (10 mg versus 16.8 mg; P = 0.05). Although significant differences were not detected for fasting blood glucose or HbA1c, patients received higher total doses of glipizide compared with glyburide at the middle and final evaluations to maintain the fasting blood glucose between 3.9 and 10 mmol/L and HbA1c at < 9%. No serious adverse reactions were observed in any patient. These results indicate that doses of glipizide required to maintain blood glucose between 3.9 and 10 mmol/L and HbA1c at < 9% increased over time. Seventy-five percent of patients receiving glyburide were controlled with once-daily dosing compared with 29.4% of those treated with glipizide. Both glyburide and glipizide provide safe and effective treatment for patients with non-insulin-dependent diabetes mellitus, but more patients will benefit from once-daily therapy with glyburide.
Diabetes Mellitus, Type 2↗