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Biomedical subjects

M E Baker

Publications and source records attributed to M E Baker.

At least 73 records · Page 4Linked to original sources
PubMed1995

Endocrine activity of plant-derived compounds: an evolutionary perspective.

Although plants have long been known to have important pharmacological effects in humans, the mechanism by which plant-derived compounds act in humans is still being elucidated. Two important pathways for the biological actions of plant-derived compounds involved binding either to hormone receptors or to enzymes that metabolize hormones. What are the origins of this interaction between plant-derived compounds and animals? And what insights can we gain from investigating this question? Some answers come from recent sequence analyses, revealing that 17 beta-hydroxysteroid dehydrogenase, which regulates estrogen and androgen levels in humans, and 15-hydroxyprostaglandin dehydrogenase, which regulates prostaglandin E2 and F2 alpha levels in humans, have a common ancestor with proteins in rhizobia that are important in forming nitrogen-fixing nodules in legume roots, and 3 beta-hydroxysteroid dehydrogenase, which regulates progestin and androgen levels in humans, has a common ancestor with enzymes important in the synthesis of anthocyanins. This evolutionary kinship, when combined with the structural similarities between flavonoids, licorice-derived compounds, and steroid hormones, provides another perspective on the hormone-like activity of flavonoids and other plant-derived compounds in humans: some of the hormone-like activity of plant-derived compounds is due to binding to steroid and prostaglandin dehydrogenases.

Alcohol Oxidoreductases↗
PubMed1995

The current role of percutaneous biopsy in the evaluation of renal masses.

Percutaneous biopsy of intraabdominal masses is a safe and accurate means of obtaining a tissue diagnosis without surgical exploration. It is often sufficient to determine treatment plans and in many instances, obviates the need for surgery. Percutaneous biopsy of renal masses has traditionally had a limited role in the United States. However, with a recent increase in the detection of small renal masses because of the widespread use of abdominal computed tomography (CT), there is an increasing role for percutaneous biopsy in the management of renal masses. Percutaneous biopsy of renal masses is indicated to differentiate between a primary renal cell carcinoma and metastatic disease in patients with a known extrarenal primary. Percutaneous biopsy is also indicated to establish a diagnosis of renal lymphoma and abscess. Complications of percutaneous biopsy include bleeding, pneumothorax, and tumor seeding along the needle tract; fortunately, these complications are uncommon. We will review the indications, techniques, complications, sensitivity, and accuracy of CT and ultrasound-guided biopsy of renal masses. Urologists and radiologists should both be familiar with the indications and contraindications of percutaneous biopsy to insure the appropriate management of renal masses.

Biopsy, Needle↗
PubMed1994

Adding a positive charge at residue 46 of Drosophila alcohol dehydrogenase increases cofactor specificity for NADP+.

We previously reported that the D39N mutant of Drosophila alcohol dehydrogenase (ADH), in which Asp-39 is replaced with asparagine, has a 60-fold increase in affinity for NADP+ and a 1.5-fold increase in kcat compared to wild-type ADH [Chen et al. (1991) Eur. J. Biochem. 202, 263-267] and proposed that this part of ADH is close to the 2'-phosphate on the ribose moiety of NADP+. Here we report the effect of replacing Ala-46 with an argine residue, and A46R mutant, on binding of NADP+ to ADH and its catalytic efficiency with the NADP+ cofactor, and a modeling of the three-dimensional structure of the NAD(+)-binding region of ADH. The A46R mutant has a 2.5-fold lower Km(app)NADP+ and a 3-fold higher kcat with NADP+ compared to wild-type ADH; binding of NAD+ to the mutant was unchanged and kcat with NAD+ was lowered by about 30%. For the A46R mutant, the ratio of kcat/Km of NAD+ to NADP+ is 85, over ten-fold lower than that for wild-type ADH. Our model of the 3D structure of the NAD(+)-binding region of ADH shows that Ala-46 is over 10 A from the ribose moiety of NAD+, which would suggest that there is little interaction between this residue and NAD+ and explain why its mutation to arginine has little effect on NAD+ binding. However, the positive charge at residue 46 can neutralize some of the coulombic repulsion between Asp-39 and the 2'-phosphate on the ribose moiety of NADP+, which would increase its affinity for the A46R mutant. We also constructed a double mutant, D39N/A46R mutant, which we find has a 30-fold lower Km(app)NADP+ and 8-fold higher kcat with NADP+ as a cofactor compared to wild-type ADH; binding of NAD+ to this double mutant was lowered by 5-fold and kcat was increased by 1.5-fold. As a result, kcat/Km for the double mutant was the same for NAD+ and NADP+. The principle effect of the two mutations in ADH is to alter its affinity for the nucleotide cofactor; kcat decreases slightly in A46R with NAD+ and remains unchanged or increases in the other mutants.

Alanine↗
PubMed1994

Licorice and enzymes other than 11 beta-hydroxysteroid dehydrogenase: an evolutionary perspective.

Licorice has long been known to promote the healing of ulcers. In the 1950s, studies with licorice-derived compounds revealed that the anti-ulcer effects of licorice are due to inhibition of 15-hydroxyprostaglandin dehydrogenase and delta 13-prostaglandin reductase. 15-Hydroxyprostaglandin dehydrogenase converts prostaglandins E2 and F2 alpha to 15-ketoprostaglandins, which are inactive. delta 13-Prostaglandin reductase metabolizes the inactive delta 13-prostaglandin to 13,14-dihydro,15-ketoprostaglandin, which is further metabolized and excreted in urine. Thus, licorice-derived compounds have the effect of raising the local concentration of prostaglandins that promote mucous secretion and cell proliferation in the stomach, leading to healing of ulcers. 11 beta-Hydroxysteroid dehydrogenase, which also is inhibited by licorice-derived compounds, shares a common ancestor with 15-hydroxyprostaglandin dehydrogenase. Both enzymes are homologous to Streptomyces hydrogenans 3 alpha,20 beta-hydroxysteroid dehydrogenase, which also is inhibited by licorice. Thus, licorice inhibits enzymes that diverged at least 2 billion years ago from a common ancestor. Other oxidoreductases in bacteria, plants, and animals that are inhibited by licorice-derived compounds are likely to be discovered in the future.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed1994

Sequence analysis of steroid- and prostaglandin-metabolizing enzymes: application to understanding catalysis.

Amino acid sequence comparisons have revealed that mammalian 11 beta-hydroxysteroid and 17 beta-hydroxysteroid dehydrogenases and bacterial 3 alpha, 20 beta- and 3 beta-hydroxysteroid dehydrogenases are homologs; that is, these enzymes are descended from a common ancestor. These steroid dehydrogenases are also homologous to human 15-hydroxyprostaglandin dehydrogenase and to proteins found in Rhizobia, bacteria that form nitrogen-fixing nodules in the roots of legumes. We constructed a multiple sequence alignment of these proteins, which, when combined with the recently determined tertiary structure of Streptomyces hydrogenans 3 alpha, 20 beta-hydroxysteroid dehydrogenase and a homologous enzyme, rat dihydropteridine reductase, identifies segments and residues that are likely to be structurally important in the functioning of these enzymes especially regarding specificity for NADPH and NADH.

Amino Acid Sequence↗
PubMed1994

Development of an optical formaldehyde sensor based on the use of immobilized pararosaniline.

The colorimetric indicator pararosaniline has been immobilized onto the cation-exchange resins Amberlite IRC-50, Dowex 50W-X8 and cellulose phosphate by electrostatic bonding. The reflectance of each reagent phase was measured using a bifurcated fibre-optic system and a flow cell. Pararosaniline immobilized on cellulose phosphate was found to respond to formaldehyde without requiring the addition of sulfite to develop the purple chromogen. This immobilized system demonstrated a linear response to 50-2500 micrograms of formaldehyde and had a correlation coefficient of 0.9979. Acetaldehyde and butyraldehyde did not produce any interference. However, exposure to the unsaturated aldehydes, acrolein and crotonaldehyde, gave rise to responses that were much greater than that observed with formaldehyde.

Colorimetry↗
PubMed1994

Hepatic adenoma: MR characteristics and correlation with pathologic findings.

OBJECTIVE: The purpose of this study was to describe the MR appearance of hepatic adenomas and correlate the MR imaging features with pathologic findings. MATERIALS AND METHODS: MR examinations were performed in 14 patients with 66 hepatic adenomas. The diagnosis of hepatic adenoma was proved pathologically in nine patients (22 lesions). In five other patients (44 lesions), who had type I glycogen storage disease and were known to be at risk for hepatic adenomas, the diagnosis was established by repeated sonographic examinations that showed stability, reduction, or resolution of hepatic tumors. T1- and T2-weighted spin-echo MR images obtained at 1.5 T were retrospectively reviewed for the signal intensity of the lesions relative to liver, the signal pattern, the presence of a capsule, and the presence of hemorrhage. Histopathologic specimens (22 lesions) were reviewed for fat content (graded 0-3), the presence of a capsule, and the presence of hemorrhage. RESULTS: On T1-weighted images, 51 (77%) of 66 lesions were hyperintense, 11 (17%) were hypointense, and four (6%) were isointense with respect to liver. On T2-weighted images, 49 (74%) of 66 lesions were hyperintense, 12 (18%) were isointense, and five (8%) were hypointense. Sixty-one (92%) of 66 lesions were heterogeneous. Eleven (17%) of 66 lesions were hemorrhagic. Of the 22 lesions reviewed histopathologically, 17 were hyperintense on T1-weighted images; 15 of these had a fat content of grade 2 or 3 and two had hemorrhage. All 15 lesions that had a fat content of grade 2 or 3 were hyperintense on T1-weighted images. CONCLUSION: Hepatic adenomas have a variable MR appearance but most often are hyperintense with respect to liver on T1- and T2-weighted images. The high signal intensity often relates to the increased fat content of these lesions.

Adenoma, Liver Cell↗
PubMed1994

CT of the liver in patients with metastatic breast carcinoma treated by chemotherapy: findings simulating cirrhosis.

OBJECTIVE: Although the hepatotoxic effects of systemic chemotherapy are well known, CT findings in the liver after systemic chemotherapy have received little attention in the literature. In some patients with breast carcinoma metastatic to the liver who have received chemotherapy, a morphologic pattern develops similar to that associated with cirrhosis. This pattern is characterized by a lobular hepatic contour, segmental volume loss, and enlargement of the caudate lobe. The purpose of this study was to describe the CT appearance of this pseudocirrhosis and to correlate it with pathologic findings. MATERIALS AND METHODS: We reviewed 65 CT examinations of 22 patients with stage IV breast carcinoma with hepatic metastases, who were receiving systemic chemotherapy and for whom abdominal CT scans showed pseudocirrhosis. Nineteen of 22 patients had follow-up CT scans at intervals ranging from 1 to 15 months. Criteria for the diagnosis of pseudocirrhosis included a lobular hepatic contour, segmental volume loss, and enlargement of the caudate lobe. CT findings were correlated with pathologic findings in seven patients. RESULTS: In all patients, CT scans showed retraction of the capsular surface of the liver (15 diffuse, seven focal) with a lobular margin, a finding also seen in advanced cirrhosis. The retraction occurred at the site of subjacent metastases. Findings evolved over 1-3 months. Six of seven patients had pathologic findings suggestive of nodular regenerative hyperplasia. No patients had pathologic evidence of cirrhosis. CONCLUSION: In patients undergoing systemic chemotherapy for breast cancer metastatic to the liver, a pattern may develop that mimics the CT appearance of hepatic cirrhosis. Pathologic findings suggest nodular regenerative hyperplasia as a possible cause.

Adult↗
PubMed1993

Site-specific mutagenesis of Drosophila alcohol dehydrogenase: evidence for involvement of tyrosine-152 and lysine-156 in catalysis.

Amino acid sequence comparisons reveal that tyrosine-152 and lysine-156 of Drosophila alcohol dehydrogenase (ADH) are conserved in homologous dehydrogenases, suggesting that these residues are important in catalysis. To test this hypothesis, we used site-directed mutagenesis to substitute tyrosine-152 with phenylalanine, histidine, or glutamic acid or to substitute lysine-156 with isoleucine. All of these mutants are catalytically inactive. Two mutants were active: A cysteine mutation of tyrosine-152 has 0.25% of wild-type ADH activity, while an arginine substitution of lysine-156 retains 2.2% of wild-type ADH activity. Kinetic analysis shows that the cysteine mutant increases Km(ethanol) 56-fold and Km(propan-2-ol) 100-fold, while Km(NAD) values are essentially unaltered. The arginine mutant also shows the significant enlargement of Km(ethanol), but not of Km(NAD). Furthermore, the cysteine mutant and arginine mutant have different substrate specificity and behave differently on competitive inhibition than wild-type ADH. These results suggest that both tyrosine-152 and lysine-156 have essential roles in catalysis by Drosophila ADH.

1-Propanol↗
PubMed1993

Chicken sterol carrier protein 2/sterol carrier protein x: cDNA cloning reveals evolutionary conservation of structure and regulated expression.

The chicken is a useful model for studies of lipid biochemistry because of the profound changes in lipid metabolism during development and the marked effects of estrogen on its lipids. Here we report the cloning of a cDNA encoding chicken sterol carrier protein 2 (SCP2)/sterol carrier protein x (SCPx), proteins that are believed to play key roles in intracellular lipid movement and metabolism. The 2.4-kb clone, isolated from a liver cDNA library by homology screening with a rat SCP2 cDNA, encodes a 58-kDa polypeptide, SCPx, which encompasses the sequence for SCP2 at its C-terminus. Comparison of the deduced amino acid sequence of the chicken protein with those of mammals revealed conservation of structure from an evolutionary standpoint. Like the other vertebrate SCPx proteins, the chicken protein contains a conserved Arg-Gly-Asp sequence and a cysteine residue in the N-terminus that aligns with the active site cysteine of Escherichia coli 3-ketoacyl-CoA thiolase, a protein that was previously shown to be homologous to vertebrate SCPx. Northern blot analysis of poly(A)+ RNA from different chicken tissues revealed two mRNA species, one of 2.5 kb, encoding SCPx, and one of 1.4 kb, presumably encoding SCP2. High levels of the 2.5 and 1.4-kb mRNAs were found in liver, intestine, and ovarian granulosa cells, consistent with a role for these proteins in lipid metabolism. There was no change in the 2.5-kb mRNA in chicken liver with development (Day 20 embryo to 4 weeks posthatch), but there was a 10-fold increase in the 1.4-kb mRNA by 1 week posthatch. Treatment of roosters with a single injection of estradiol (25 mg/kg) caused a twofold increase in the 2.5-kb mRNA in liver at 6 h after estradiol administration, reaching a maximum fourfold increase at 48 h, while the 1.4-kb mRNA increased twofold at 48 h. The two SCP2/SCPx mRNAs were most abundant in granulosa cells from small follicles. A reduction in SCP2/SCPx gene expression was observed with follicular maturation, correlating with falling estrogen production. In summary, we have documented (i) marked conservation of SCP2/SCPx structure across species and (ii) developmental and hormonal regulation of the mRNAs which encode proteins thought to be involved in lipid metabolism.

Amino Acid Sequence↗
PubMed1993

Inhibition of 3,5,3'-triiodothyronine binding to its receptor in rat liver by protease inhibitors and substrates.

Various protease inhibitors (e.g. phenylmethanesulfonyl fluoride (PMSF), tosyl-phenylalanine chloromethyl ketone (TosPheCH2Cl)) and substrates (e.g., tosyl-arginine methyl ester (TosArgOMe), tryptophan methyl ester (TrpOMe)) inhibit the binding of adrenal and sex steroids to their cognate receptors (Hubbard and Kalimi (1985) Mol. Cell. Biochem. 66, 101-109). Here we extend this finding to the receptor for 3,5,3'-triiodothyronine (T3) in rat liver nuclei. We find that PMSF, TosPheCH2Cl and other protease inhibitors as well as TosArgOMe, TrpOMe, tyrosine methyl ester (TyrOMe) and tyrosine ethyl ester (TyrOEt) inhibit binding of 125I-T3 to its receptor in rat liver nuclei. Inhibition by protease substrates appears to be at or close to the hormone binding domain. By analogy with the known mechanism of binding of protease inhibitors and substrates to enzymes, we suggest that the T3 receptor contains a nucleophilic site at or close to the hormone binding domain.

Animals↗
PubMed1993

Aldosterone stimulated differentiation of mouse 3T3-L1 cells into adipocytes.

We find that 1-10 nM aldosterone can induce differentiation of 3T3-L1 cells into adipose cells as evaluated by microscopic accumulation of fat droplets and quantitative measurement of triglycerides and of glycerol-3-phosphate dehydrogenase, an enzyme specific for adipocyte differentiation. Moreover, the aldosterone antagonist ZK91587 inhibits aldosterone-but not glucocorticoid-mediated differentiation of 3T3-L1 cells. Steroid binding assays with 3T3-L1 cells indicate the presence of specific binding sites for aldosterone. We conclude that there is an aldosterone receptor-mediated pathway for terminal differentiation of 3T3-L1 cells into adipose cells. Receptors for aldosterone have also been found in a variety of cells that do not function to regulate sodium and potassium transport. The aldosterone receptor may have a role in regulation expression of genes involved in differentiation of these cells.

3T3 Cells↗