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1.
Andrologia ; 50(1)2018 Feb.
Article in English | MEDLINE | ID: mdl-28295471

ABSTRACT

This study examined whether feeding hydroalcoholic extract of Lepidium meyenii (maca) to 8-week-old (sexually maturing) or 18-week-old (mature) male rats for more than a half year affects serum testosterone concentration and testosterone production by Leydig cells cultured with hCG, 22R-hydroxycholesterol or pregnenolone. Testosterone concentration was determined in the serum samples obtained before and 6, 12, 18 and 24 weeks after the feeding, and it was significantly increased only at the 6 weeks in the group fed with the maca extract to maturing rats when it was compared with controls. Testosterone production by Leydig cells significantly increased when cultured with hCG by feeding the maca extract to maturing rats for 27 weeks (35 weeks of age) and when cultured with 22R-hydroxycholesterol by feeding it to mature rats for 30 weeks (48 weeks of age). Overall testosterone production by cultured Leydig cells decreased to about a half from 35 to 48 weeks of age. These results suggest that feeding the maca extract for a long time to male rats may enhance the steroidogenic ability of Leydig cells to alleviate its decline with ageing, whereas it may cause only a transient increase in blood testosterone concentration in sexually maturing male rats.


Subject(s)
Aging/drug effects , Lepidium , Leydig Cells/drug effects , Plant Extracts/pharmacology , Testosterone/biosynthesis , Aging/metabolism , Animals , Chorionic Gonadotropin/pharmacology , Hydroxycholesterols/pharmacology , Leydig Cells/metabolism , Male , Pregnenolone/pharmacology , Rats , Testosterone/blood
2.
Andrologia ; 49(10)2017 Dec.
Article in English | MEDLINE | ID: mdl-28261840

ABSTRACT

Although feeding diets containing the extract powder of Lepidium meyenii (maca), a plant growing in Peru's Central Andes, increases serum testosterone concentration associated with enhanced ability of testosterone production by Leydig cells in male rats, changes in testicular steroidogenesis-related factors by the maca treatment are not known. This study examined the effects of maca on testicular gene expressions for luteinizing hormone receptor, steroidogenic acute regulatory protein and steroidogenic enzymes. Eight-week-old male rats were given the diets with or without (control) the maca extract powder (2%) for 6 weeks, and mRNA levels were determined by reverse transcription quantitative real-time PCR. The results showed that the testicular mRNA level of HSD3B1 (3ß-hydroxysteroid dehydrogenase; 3ß-HSD) increased by the treatment, whereas the levels of the other factors examined did not change. These results suggest that increased expression of 3ß-HSD gene may be involved in the enhanced steroidogenic ability by the maca treatment in rat testes.


Subject(s)
17-Hydroxysteroid Dehydrogenases/genetics , Gene Expression/drug effects , Lepidium , Plant Extracts/pharmacology , Testis/drug effects , 17-Hydroxysteroid Dehydrogenases/metabolism , Animals , Leydig Cells/drug effects , Male , Phosphoproteins/genetics , Phosphoproteins/metabolism , Rats , Receptors, LH/genetics , Receptors, LH/metabolism , Spermatogenesis/drug effects , Testis/metabolism
3.
Andrologia ; 48(3): 347-54, 2016 Apr.
Article in English | MEDLINE | ID: mdl-26174043

ABSTRACT

Although Lepidium meyenii (maca), a plant growing in Peru's central Andes, has been traditionally used for enhancing fertility and reproductive performance in domestic animals and human beings, effects of maca on reproductive organs are still unclear. This study examined whether feeding the hydroalcoholic extract powder of maca for 6 weeks affects weight of the reproductive organs, serum concentrations of testosterone and luteinising hormone (LH), number and cytoplasmic area of immunohistochemically stained Leydig cells, and steroidogenesis of cultured Leydig cells in 8-week-old male rats. Feeding the extract powder increased weight of seminal vesicles, serum testosterone level and cytoplasmic area of Leydig cells when compared with controls. Weight of prostate gland, serum LH concentration and number of Leydig cells were not affected by the maca treatment. The testosterone production by Leydig cells significantly increased when cultured with 22R-hydroxycholesterol or pregnenolone and tended to increase when cultured with hCG by feeding the extract powder. The results show that feeding the hydroalcoholic extract powder of maca for 6 weeks increases serum testosterone concentration associated with seminal vesicle stimulation in male rats, and this increase in testosterone level may be related to the enhanced ability of testosterone production by Leydig cells especially in the metabolic process following cholesterol.


Subject(s)
Lepidium , Leydig Cells/drug effects , Plant Extracts/pharmacology , Testosterone/blood , Animals , Cells, Cultured , Estradiol/blood , Leydig Cells/cytology , Leydig Cells/metabolism , Luteinizing Hormone/blood , Male , Organ Size/drug effects , Prostate/drug effects , Rats , Rats, Wistar , Testosterone/biosynthesis
4.
Phys Rev Lett ; 113(2): 021301, 2014 Jul 11.
Article in English | MEDLINE | ID: mdl-25062161

ABSTRACT

Gravitational lensing due to the large-scale distribution of matter in the cosmos distorts the primordial cosmic microwave background (CMB) and thereby induces new, small-scale B-mode polarization. This signal carries detailed information about the distribution of all the gravitating matter between the observer and CMB last scattering surface. We report the first direct evidence for polarization lensing based on purely CMB information, from using the four-point correlations of even- and odd-parity E- and B-mode polarization mapped over ∼30 square degrees of the sky measured by the POLARBEAR experiment. These data were analyzed using a blind analysis framework and checked for spurious systematic contamination using null tests and simulations. Evidence for the signal of polarization lensing and lensing B modes is found at 4.2σ (stat+sys) significance. The amplitude of matter fluctuations is measured with a precision of 27%, and is found to be consistent with the Lambda cold dark matter cosmological model. This measurement demonstrates a new technique, capable of mapping all gravitating matter in the Universe, sensitive to the sum of neutrino masses, and essential for cleaning the lensing B-mode signal in searches for primordial gravitational waves.

5.
Phys Rev Lett ; 112(13): 131302, 2014 Apr 04.
Article in English | MEDLINE | ID: mdl-24745402

ABSTRACT

We reconstruct the gravitational lensing convergence signal from cosmic microwave background (CMB) polarization data taken by the Polarbear experiment and cross-correlate it with cosmic infrared background maps from the Herschel satellite. From the cross spectra, we obtain evidence for gravitational lensing of the CMB polarization at a statistical significance of 4.0σ and indication of the presence of a lensing B-mode signal at a significance of 2.3σ. We demonstrate that our results are not biased by instrumental and astrophysical systematic errors by performing null tests, checks with simulated and real data, and analytical calculations. This measurement of polarization lensing, made via the robust cross-correlation channel, not only reinforces POLARBEAR auto-correlation measurements, but also represents one of the early steps towards establishing CMB polarization lensing as a powerful new probe of cosmology and astrophysics.

6.
Osteoporos Int ; 20(8): 1429-37, 2009 Aug.
Article in English | MEDLINE | ID: mdl-19101754

ABSTRACT

UNLABELLED: SUMMARY; A randomized placebo-controlled trial was conducted to examine the effect of daily oral 1 mg minodronate on vertebral fractures in 704 postmenopausal women with established osteoporosis for 24 months. Minodronate treatment reduced vertebral fractures by 59% without serious adverse events. Minodronate is a safe and effective bisphosphonate for osteoporosis treatment. INTRODUCTION: Minodronate increases bone mineral density (BMD) in postmenopausal osteoporotic patients. However, its efficacy in reducing osteoporotic fractures has not been tested. METHODS: To examine anti-fracture efficacy and safety of daily oral minodronate in postmenopausal women with established osteoporosis, a randomized, double-blind, placebo-controlled trial was conducted in 704 postmenopausal women (55 to 80 years) with one to five vertebral fractures and low BMD. Subjects were randomly assigned to receive daily oral 1 mg minodronate (n = 359) or placebo (n = 345) for 24 months, with daily supplements of 600 mg calcium and 200 IU vitamin D(3). RESULTS: Daily 1 mg minodronate for 24 months reduced the risk of vertebral fractures by 59% (95% CI, 36.6-73.3%). Furthermore, when fractures during the first 6 months were eliminated, the risk of vertebral fractures from 6 to 24 months was reduced by 74% in minodronate-treated group. Minodronate treatment also reduced height loss. Bone turnover markers were suppressed by about 50% after 6 months of minodronate treatment and remained suppressed thereafter. The overall safety profile including gastrointestinal safety was similar between the two groups. CONCLUSIONS: Daily oral minodronate is safe, well-tolerated, and is effective in reducing vertebral fracture risk in postmenopausal women with established osteoporosis.


Subject(s)
Bone Density Conservation Agents/therapeutic use , Diphosphonates/therapeutic use , Imidazoles/therapeutic use , Osteoporosis, Postmenopausal/drug therapy , Spinal Fractures/prevention & control , Administration, Oral , Aged , Aged, 80 and over , Biomarkers/metabolism , Body Height/drug effects , Bone Density Conservation Agents/administration & dosage , Bone Density Conservation Agents/adverse effects , Bone Remodeling/drug effects , Diphosphonates/administration & dosage , Diphosphonates/adverse effects , Double-Blind Method , Drug Administration Schedule , Female , Fractures, Bone/etiology , Fractures, Bone/prevention & control , Humans , Imidazoles/administration & dosage , Imidazoles/adverse effects , Middle Aged , Osteoporosis, Postmenopausal/complications , Osteoporosis, Postmenopausal/physiopathology , Spinal Fractures/etiology , Treatment Outcome
7.
J Clin Invest ; 82(4): 1165-72, 1988 Oct.
Article in English | MEDLINE | ID: mdl-2844851

ABSTRACT

The effects of calcitonin on lipid metabolism were investigated in three kinds of rats, one strain of rabbits, and a primary culture of rat hepatocytes. In a short-term experiment, calcitonin decreased serum cholesterol and triglycerides after injection in rats on either an ordinary or high-fat diet. In a long-term experiment, calcitonin decreased the serum cholesterol and triglycerides in uremic rats, hypothalamic obese rats, and Watanabe-heritable hyperlipidemic rabbits. In cultured hepatocytes, calcitonin reduced the incorporation of [14C]acetate into cholesterol and triglycerides in a dose-dependent way. Treatment with W7, a calmodulin inhibitor, overcame the decrease caused by calcitonin in serum lipids in rats and in the synthesis of triglycerides from acetate or palmitate in the hepatocytes, but did not alter the intracellular cAMP level or incorporation of [32P]Pi into PI in the cells. The results suggest that calcitonin lowers serum lipid levels and lipogenesis in hepatocytes in a calcium/calmodulin-dependent way.


Subject(s)
Calcitonin/administration & dosage , Calcium/physiology , Calmodulin/physiology , Lipid Metabolism , Animals , Calmodulin/antagonists & inhibitors , Cyclic AMP/metabolism , Drug Administration Schedule , Female , Injections, Subcutaneous , Intracellular Fluid/metabolism , Lipids/biosynthesis , Lipids/blood , Liver/metabolism , Male , Phosphates/metabolism , Rabbits , Rats , Rats, Inbred Strains , Sulfonamides/administration & dosage
8.
Mol Cell Biol ; 11(11): 5527-33, 1991 Nov.
Article in English | MEDLINE | ID: mdl-1656233

ABSTRACT

A murine erythroleukemia (MEL) cell line, F5-5, expressed 10,000 binding sites for erythropoietin (EPO) per cell, 10-fold more than was expressed by other murine erythroleukemia cell lines and normal erythroid progenitors. Northern (RNA) and Southern blot analyses revealed overexpression of mRNA for the EPO receptor (EPOR) and rearrangement of one of the EPOR gene alleles in F5-5 cells, respectively. Molecular cloning of F5-5-derived cDNA encoding EPOR revealed that the 5' noncoding region of the EPOR cDNA corresponds to the 3' long terminal repeat sequence of the polycythemic strain of Friend spleen focus-forming virus (F-SFFVP). The aberrant EPOR transcripts containing the 3' long terminal repeat sequence were mainly expressed in F5-5 cells. The same integration upstream of the EPOR gene was also observed in other subclones and the parent cell line. It is possible that overexpression of EPOR by viral promoter insertion will confer growth advantage to an F-SFFVP-infected erythroid progenitor cell, leading to positive clonal selection through further leukemogenic steps.


Subject(s)
Gene Expression Regulation, Viral , Mutagenesis, Insertional , Receptors, Cell Surface/genetics , Repetitive Sequences, Nucleic Acid , Spleen Focus-Forming Viruses/genetics , Amino Acid Sequence , Animals , Base Sequence , Cell Line , Cloning, Molecular , DNA, Neoplasm/genetics , Erythropoietin/metabolism , Kinetics , Leukemia, Erythroblastic, Acute , Mice , Molecular Sequence Data , Oligonucleotides , Polymerase Chain Reaction , Receptors, Cell Surface/metabolism , Receptors, Erythropoietin , Restriction Mapping
9.
Circ Res ; 87(7): E10-7, 2000 Sep 29.
Article in English | MEDLINE | ID: mdl-11009570

ABSTRACT

Vascular calcification is a common finding in atherosclerosis and a serious problem in diabetic and uremic patients. Because of the correlation of hyperphosphatemia and vascular calcification, the ability of extracellular inorganic phosphate levels to regulate human aortic smooth muscle cell (HSMC) culture mineralization in vitro was examined. HSMCs cultured in media containing normal physiological levels of inorganic phosphate (1.4 mmol/L) did not mineralize. In contrast, HSMCs cultured in media containing phosphate levels comparable to those seen in hyperphosphatemic individuals (>1.4 mmol/L) showed dose-dependent increases in mineral deposition. Mechanistic studies revealed that elevated phosphate treatment of HSMCs also enhanced the expression of the osteoblastic differentiation markers osteocalcin and Cbfa-1. The effects of elevated phosphate on HSMCs were mediated by a sodium-dependent phosphate cotransporter (NPC), as indicated by the ability of the specific NPC inhibitor phosphonoformic acid, to dose dependently inhibit phosphate-induced calcium deposition as well as osteocalcin and Cbfa-1 gene expression. With the use of polymerase chain reaction and Northern blot analyses, the NPC in HSMCs was identified as Pit-1 (Glvr-1), a member of the novel type III NPCs. These data suggest that elevated phosphate may directly stimulate HSMCs to undergo phenotypic changes that predispose to calcification and offer a novel explanation of the phenomenon of vascular calcification under hyperphosphatemic conditions. The full text of this article is available at http://www.circresaha.org.


Subject(s)
Calcification, Physiologic , Calcium/metabolism , Carrier Proteins/physiology , Muscle, Smooth, Vascular/physiology , Phosphates/physiology , Symporters , Arteries/metabolism , Cells, Cultured , Gene Expression , Humans , Receptors, Virus/metabolism , Sodium-Phosphate Cotransporter Proteins , Sodium-Phosphate Cotransporter Proteins, Type III
10.
Biochim Biophys Acta ; 1044(3): 394-8, 1990 Jun 14.
Article in English | MEDLINE | ID: mdl-2163683

ABSTRACT

Phosphatidyltransferase from Clostridium butyricum, which catalyzes transfer of the phosphatidyl moiety of phosphatidylethanolamine (PE), phosphatidylglycerol (PG) or phosphatidylserine to primary alcohols such as glycerol, serine and ethanolamine, was tested for its ability to catalyze transfer of the plasmenyl moiety from plasmalogen analogs of PE or PG to glycerol or ethanolamine, respectively. The cell membrane of C. butyricum contains high proportions of these plasmalogens. When diacyl and plasmalogen forms of PE or PG were supplied as donors in equimolar amounts to membrane particles, the diacyl forms were the preferred donors by approx. 7 and 10 to 1, respectively. When the molar ratio of PE its plasmalogen was 1:3.3, the ratio of PG formed to its plasmalogen was 1:0.66. These results show that the enzyme(s) can catalyze transfer of both the diacyl and alkenyl acyl forms of glycerophospholipids, but the diacyl forms are used preferentially.


Subject(s)
Clostridium/enzymology , Phosphatidylethanolamines/metabolism , Phosphatidylglycerols/metabolism , Phosphotransferases/metabolism , Transferases (Other Substituted Phosphate Groups) , Cell Membrane/metabolism , Kinetics , Plasmalogens/metabolism , Substrate Specificity
11.
Biochim Biophys Acta ; 793(1): 86-94, 1984 Mar 27.
Article in English | MEDLINE | ID: mdl-6422993

ABSTRACT

In order to understand the phosphatidylglycerol turnover mechanism, especially the differential turnover of diacylated and unacylated glycerol moieties of the lipid, products of phosphatidylglycerol metabolism were surveyed in vivo in Bacillus subtilis W23 and an alkalophile, Bacillus sp. strain A007. When cells of B. subtilis W23 labeled with radioactive glycerol were chased, lipoteichoic acid accumulated 90% of the radioactivity lost from the unacylated glycerol moiety of phosphatidylglycerol. Also, lipids other that phosphatidylglycerol, except diacylglycerol, and glycerol and glycerophosphate incorporated much less radioactivity. The [32P]phosphoryl group was also transferred from phosphatidylglycerol to lipoteichoic acid almost quantitatively in B. subtilis W23. A unique metabolism of phosphatidylglycerol was found in Bacillus sp. strain A007 which lacked phosphoglycolipid and lipoteichoic acid, that is, the turnover of phosphatidylglycerol of this organism was less extensive compared with that of B. subtilis W23, and both glycerol moieties of the lipid were metabolized at an identical rate. These results suggested that the major reaction involved in the turnover of phosphatidylglycerol was the transfer of glycerophosphate residue to lipoteichoic acid in a bacterium which possessed lipoteichoic acid and that several minor reactions also were involved in phosphatidylglycerol turnover.


Subject(s)
Bacillus/metabolism , Lipopolysaccharides , Phosphatidic Acids/metabolism , Phosphatidylglycerols/metabolism , Teichoic Acids/metabolism , Bacillus subtilis/metabolism , Species Specificity
12.
Biochim Biophys Acta ; 1068(1): 81-6, 1991 Sep 10.
Article in English | MEDLINE | ID: mdl-1892857

ABSTRACT

Time-resolved fluorescence depolarization measurements were carried out for human growth hormone-releasing factor analog ([Trp10]-hGRF (1-29) NH2), where the Trp10 residue was incorporated as a fluorescent probe, in the presence and the absence of 1,2-dimyristoyl-sn-glycero-3-phospho-rac- glycerol(DMPG) liposome and in aqueous 2,2,2-trifluoroethanol (TFE) solution. The fluorescence lifetimes and the rotatory correlation times of the peptide in each medium were determined. The apparent volumes of the rotatory Brownian motion unit calculated from these fluorescent parameters indicate the different mode of the fluctuation and/or the rotation of the peptide in each medium, such as: (i) In the aqueous solution, several segments of the peptide fluctuate individually. (ii) In the DMPG bilayer, both the local fluctuation of Trp residue alone and the rotation of the whole molecule exist. (iii) In the aqueous TFE solution, the monomeric peptide rotates as a rigid ellipsoid.


Subject(s)
Growth Hormone-Releasing Hormone/metabolism , Lipid Bilayers , Phospholipids/metabolism , Amino Acid Sequence , Circular Dichroism , Fluorescence Polarization , Fluorescent Dyes , Growth Hormone-Releasing Hormone/genetics , Humans , Mathematics , Molecular Sequence Data , Phosphatidylglycerols , Protein Conformation , Tryptophan
13.
Biochim Biophys Acta ; 1436(3): 426-36, 1999 Jan 04.
Article in English | MEDLINE | ID: mdl-9989273

ABSTRACT

The structures of two novel polar lipids (AGI and AI) of an aerobic hyperthermophilic archaeon, Aeropyrum pernix, were elucidated. AGI and AI were the only two major lipids and accounted for 91 mol% and 9 mol%, respectively, of total polar lipids of this organism. The core lipid of A. pernix total lipids consisted solely of 2,3-di-O-sesterterpanyl-sn-glycerol (C25,25-archaeol). The molecular weights of the free acid forms of AGI and AI were shown by FAB-mass spectrometry to be 1196 and 1034, respectively. AI was completely hydrolyzed by phosphatidylinositol-specific phospholipase C, while AGI was not hydrolyzed at all under the same condition for the hydrolysis of AI. The molar ratio of phosphate, myo-inositol, and glucose in AGI was 1.0:0.97:0.95. The positions of linkages between myo-inositol and glucose, and between myo-inositol and phosphate in AGI were determined by NMR analyses of intact AGI and glucosylinositol prepared from AGI. Finally, it was concluded that the structures of AGI and AI were 2,3-di-O-sesterterpanyl-sn-glycerol-1-phospho-1'-(2'-O-alpha-D-glu cosyl)- myo-inositol (C25,25-archaetidyl(glucosyl)inositol) and 2,3-di-O-sesterterpanyl-sn-glycerol-1-phospho-myo-inositol (C25,25-archaetidylinositol), respectively. This is the first example that a core lipid of whole polar lipids is composed of only one species C25,25-archaeol in one organism and that glucosylinositol is found in a polar lipid as a polar head group.


Subject(s)
Crenarchaeota/chemistry , Phospholipid Ethers/isolation & purification , Crenarchaeota/classification , Magnetic Resonance Spectroscopy , Molecular Structure , Phospholipid Ethers/chemistry , Spectrometry, Mass, Fast Atom Bombardment
14.
Biochim Biophys Acta ; 1390(3): 339-45, 1998 Feb 23.
Article in English | MEDLINE | ID: mdl-9487155

ABSTRACT

A new ether lipid core (designated as FU) was found in Methanothermus fervidus total lipid. Comparison with caldarchaeol showed lower mobility of FU on TLC and smaller molecular weight (m/z 1298) by 2 mass units on FAB-MS. Treatment of FU with HI followed by displacement with silver acetate afforded long chain alcohol acetate (ROAc), which was further saponified with mild alkali to its free alcohol (ROH). ROH is the long chain alcohol prepared from FU. The molecular weights of ROAc and ROH were shown by MS to be 1354 and 1186, respectively. These results suggested that the molecular formula of ROH was C80H162O4, and ROH had four hydroxyl groups, and one molecule of ROH was bound with two molecules of glycerol by four ether linkages. Because FU was not oxidized by NaIO4 and specific rotation [alpha]D of FU coincided with that of caldarchaeol, it seems that the ether linkages of FU are formed with hydroxyl groups of the sn-2 and sn-3 positions of each glycerol moiety. The structure of FU was suggested to be a modified caldarchaeol in which two hydrocarbon chains are bridged with a covalent bond. Although a few points remain to be elucidated before the final conclusion can be reached on the structure of FU due to difficulty in complete structure determination done even with every approach currently available, the most possible position of the bridge in FU hydrocarbon was proposed from the data of EI-MS of ROAc and 1H-NMR of FU. The hydrocarbon chain looks like H-shaped C80 isoprenoid.


Subject(s)
Euryarchaeota/chemistry , Lipids/isolation & purification , Ether/chemistry , Glycerol/chemistry , Glyceryl Ethers/chemistry , Lipids/chemistry , Molecular Weight , Terpenes/chemistry
15.
Diabetes ; 37(7): 857-61, 1988 Jul.
Article in English | MEDLINE | ID: mdl-2838357

ABSTRACT

The effect of sulfonylureas tolbutamide and glyburide on adenylate cyclase- and cAMP-dependent protein kinase (A-kinase) was examined in rat liver cytosol. Both tolbutamide and glyburide inhibited the A-kinase activity in a dose-dependent manner. Half-maximal inhibition was obtained at 10 mM with tolbutamide and at 0.2 mM with glyburide, indicating that glyburide was 50-fold as potent as tolbutamide. Neither tolbutamide nor glyburide affected [3H]cAMP binding to the protein kinase, but both inhibited the activity of catalytic units of the A-kinase. Lineweaver-Burk double-reciprocal plots revealed that the inhibitory effects of these drugs were noncompetitive with respect to the protein substrate histone, as well as to the phosphate-donor substrate ATP. Thus, tolbutamide and glyburide inhibited the A-kinase activity in rat liver cytosol, and it was suggested that, through the inhibition of A-kinase, the sulfonylureas would affect the carbohydrate metabolism in the liver. In fact, the relative potencies of these two drugs on A-kinase activity corresponded well with those of their reported antidiabetic effects.


Subject(s)
Cyclic AMP/pharmacology , Glyburide/pharmacology , Liver/enzymology , Protein Kinases/metabolism , Tolbutamide/pharmacology , Adenosine Triphosphate/metabolism , Adenylyl Cyclases/metabolism , Animals , Cyclic AMP/metabolism , Cytosol/enzymology , Dose-Response Relationship, Drug , Histones/metabolism , Kinetics , Male , Rats , Rats, Inbred Strains
16.
Diabetes ; 46(4): 682-7, 1997 Apr.
Article in English | MEDLINE | ID: mdl-9075811

ABSTRACT

We examined the association between the polymorphism of the apolipoprotein E (apoE) and the ACE genes and the intima-media thickness (IMT) of the carotid and femoral arteries measured using ultrasonography. The values of IMT of each artery were significantly higher in NIDDM patients (n = 356) than in control subjects (n = 235). The E4 allele or the D allele did not affect clinical characteristics, including age, fasting plasma glucose, total cholesterol, HDL cholesterol, LDL cholesterol, or blood pressure, in NIDDM or control subjects. No difference in the carotid IMT value was noted among the apoE genotypes in control or diabetic subjects. The carotid IMT was significantly higher in diabetic patients with the DD genotype (1.200 +/- 0.586 mm) than in those with the II genotypes (0.990 +/- 0.364 mm). Neither the E4 allele nor the D allele affected the femoral IMT in control or diabetic subjects. Multiple regression analysis demonstrated that the carotid IMT of NIDDM patients was associated with age, the D allele, and LDL cholesterol but not with the E4 allele, whereas that of control subjects was associated with age, sex, systolic blood pressure, LDL cholesterol, and HDL cholesterol, inversely. These results suggested that the E4 allele was not associated with the carotid or femoral IMTs, but that the D allele was statistically associated with carotid IMT in NIDDM patients but not control subjects. However, since the association was weak (2.3% explanatory power), its biological significance remains to be determined.


Subject(s)
Apolipoproteins E/genetics , Carotid Arteries/pathology , Diabetes Mellitus, Type 2/genetics , Femoral Artery/pathology , Peptidyl-Dipeptidase A/genetics , Polymorphism, Genetic/genetics , Adolescent , Adult , Aged , Aged, 80 and over , Alleles , Base Sequence , Carotid Arteries/diagnostic imaging , DNA Primers/chemistry , Diabetes Mellitus, Type 2/enzymology , Diabetes Mellitus, Type 2/epidemiology , Diabetes Mellitus, Type 2/pathology , Female , Femoral Artery/diagnostic imaging , Genotype , Humans , Japan/epidemiology , Male , Middle Aged , Risk Factors , Ultrasonography
17.
J Mol Biol ; 292(4): 909-20, 1999 Oct 01.
Article in English | MEDLINE | ID: mdl-10525414

ABSTRACT

The shape and the energetics of a functional cavity in the R2 subdomain (90-141) of the c-Myb DNA-binding domain were investigated by spectroscopy and thermodynamic analysis. We focused on the valine 103 residue located in front of the cavity. Nine mutants, in which valine 103 was substituted with alanine, 2-aminobutyric acid, norvaline, norleucine, leucine, isoleucine, allo -isoleucine, cyclohexylglycine, and cyclohexylalanine, were chemically synthesized and analyzed. These mutants provided a wide distribution of sizes which ranged from forming additional cavity space to filling and overflowing the cavity space. Temperature-scanning circular dichroism measurements and differential scanning calorimetry revealed a linear relationship between the van't Hoff enthalpy and the thermal transition temperature for the cavity-filling mutations. On the other hand, the mutants with side-chains larger than the side-chain of leucine resulted in a relatively low transition enthalpy and temperature, most likely due to the exposure of the side-chain to solvent and the increase in the entropy of the folded states. Branching at the beta-carbon atom reduced the unfolding free energy due to the steric constraint in the cavity. In particular, the mutational elongation of the side-chain from beta-carbon to the trans -to-CO direction proved to be more hindered than that from beta-carbon to the trans -to-NH. The unfolding free energy versus side-chain volume formed a bell-shaped plot with a maximum free energy for the leucine mutant. The difference in the transition free energy for cavity-filling mutants with beta-unbranched side-chains were two to four times larger than the difference in the transfer energy from organic solvent to water. Therefore, the increase in unfolding free energy would most likely be attributed to van der Waals interactions in the cavity wall, which would be a origin of stabilization by the sliding of tryptophan 95 into the cavity upon DNA binding.


Subject(s)
Amino Acid Substitution , Mutation , Proto-Oncogene Proteins c-myb/chemistry , Proto-Oncogene Proteins c-myb/metabolism , Amino Acid Sequence , Binding Sites , Calorimetry, Differential Scanning , Circular Dichroism , Hydrogen-Ion Concentration , Models, Molecular , Molecular Sequence Data , Nuclear Magnetic Resonance, Biomolecular , Protein Folding , Protein Structure, Tertiary , Proto-Oncogene Proteins c-myb/genetics , Spectrometry, Fluorescence , Temperature , Thermodynamics , Tryptophan/chemistry , Tryptophan/metabolism , Valine/chemistry , Valine/genetics , Valine/metabolism
18.
Diabetes Care ; 21(11): 1848-55, 1998 Nov.
Article in English | MEDLINE | ID: mdl-9802732

ABSTRACT

OBJECTIVE: We assessed the effects of atherosclerosis on the glomerular filtration rate (GFR) in patients with type 2 diabetes and who had micro- or normoalbuminuria. RESEARCH DESIGN AND METHODS: A total of 61 Japanese patients with type 2 diabetes were recruited from inpatients of Osaka City University Hospital. They ranged in age from 40 to 69 years (28 men and 33 women). Each subject collected a 24-h urine sample for quantitative analysis of albumin. Absence of albuminuria was defined as a urinary albumin excretion level of <30 mg/24 h (n = 36) and microalbuminuria as a level of 30-300 mg/24 h. The GFR was estimated using 99mTc diethylenetriamine pentaacetic renogram method. As indexes of atherosclerosis, we measured the intimal-medial thickness (IMT) and distensibility of the carotid artery using high-resolution B-mode ultrasonagraphy and an echo-tracking system. We measured the resistance index (RI) of the renal interlobar arteries by pulsed Doppler sonography. RESULTS: The clinical characteristics of type 2 diabetic patients with and without microalbuminuria did not differ except for duration of diabetes, which was longer in the patients with microalbuminuria. GFR also did not differ between the patients with and without microalbuminuria. GFR was significantly correlated with the patient's age (r = -0.256, P < 0.05), carotid IMT (r = -0.326, P < 0.05), carotid stiffness beta (r = -0.449, P < 0.001), and renal arterial RI (r = -0.365, P < 0.05). In multiple regression analysis, independent factors associated with GFR were carotid IMT (R2 = 0.108, P = 0.0102), carotid stiffness beta (R2 = 0.208, P = 0.0003), and renal artery RI (R2 = 0.130, P = 0.0043). CONCLUSIONS: The decline in GFR in type 2 diabetic patients in the early stages of nephropathy may be due in part to atherosclerosis.


Subject(s)
Arteriosclerosis/etiology , Diabetes Mellitus, Type 2/physiopathology , Diabetic Angiopathies/etiology , Glomerular Filtration Rate , Adult , Aged , Albuminuria/complications , Albuminuria/diagnosis , Arteriosclerosis/diagnosis , Carotid Arteries/diagnostic imaging , Diabetes Mellitus, Type 2/complications , Diabetic Angiopathies/diagnosis , Female , Humans , Japan , Kidney/blood supply , Male , Middle Aged , Radiopharmaceuticals , Technetium Tc 99m Pentetate , Ultrasonography , Vascular Resistance
19.
Diabetes Care ; 22(2): 228-32, 1999 Feb.
Article in English | MEDLINE | ID: mdl-10333938

ABSTRACT

OBJECTIVE: To determine whether impaired fasting glucose (IFG) increased the risk for hypertension in two large Japanese cohorts during the different time periods. RESEARCH DESIGN AND METHODS: We prospectively investigated two Japanese cohorts: a 1980s population, comprising 4,130 normotensive and nondiabetic men aged 35-60 years entered between 1981 and 1983, and a 1990s population, comprising 4,319 normotensive and nondiabetic men aged 35-60 years entered between 1991 and 1992. Data on lifestyle factors were obtained from questionnaires. IFG was defined as a fasting plasma glucose level > or = 110 and < 126 mg/dl. RESULTS: During the 4-year observation period, 708 cases of hypertension were confirmed in the 1980s and 848 cases were confirmed in the 1990s. In both the 1980s and 1990s populations, IFG was associated with the risk of hypertension. The frequency of IFG in men in the 1990s group was twice as high as that in the 1980s group. The multivariate-adjusted odds ratio (OR) of hypertension was 1.54 (95% CI, 1.01-2.34) for men with IFG in the 1980s population and 1.73 (1.31-2.29) in the 1990s population, compared with those without IFG in the two populations. In the 1990s population, among lean men with a BMI < or = 23 kg/m2, men with IFG had a multivariate-adjusted OR of hypertension of 2.31 (1.46-3.65) compared with those without IFG. CONCLUSIONS: This study demonstrated direct correlation between IFG and hypertension and greater incidence of this hypertension in the 1990s group than in the 1980s group.


Subject(s)
Diabetes Mellitus, Type 2/epidemiology , Glucose Intolerance/epidemiology , Health Surveys , Hypertension/epidemiology , Adult , Age Factors , Alcohol Drinking , Blood Pressure , Body Mass Index , Diabetes Mellitus, Type 2/complications , Diabetes Mellitus, Type 2/physiopathology , Diabetic Angiopathies/epidemiology , Glucose Intolerance/complications , Glucose Intolerance/physiopathology , Heart Rate , Humans , Hypertension/complications , Hypertension/physiopathology , Japan/epidemiology , Life Style , Male , Middle Aged , Risk Factors , Smoking
20.
Diabetes Care ; 22(11): 1851-7, 1999 Nov.
Article in English | MEDLINE | ID: mdl-10546019

ABSTRACT

OBJECTIVE: The aim of this study was to assess the relationship between atherotic (structural) and sclerotic (functional) changes in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: Aortic distensibility and carotid intimal-media thickness (IMT) were evaluated using carotid-femoral aortic pulse-wave velocity (a-PWV) and high-resolution B-mode ultrasonography in 271 patients with type 2 diabetes and 285 age-matched control subjects. RESULTS: a-PWV and carotid IMT were significantly higher in the patients than in the control subjects in all age-groups (P < 0.0001, respectively). The carotid IMT and a-PWV were significantly correlated with age in both the patients with type 2 diabetes and control subjects. There was a significant positive relationship between the carotid IMT and a-PWV in both the patients (r = 0.482, P < 0.0001) and control subjects (r = 0.424, P < 0.0001). The slope of the regression line for the carotid IMT to the a-PWV was significantly steeper in the diabetic patients than in the control subjects (P < 0.05). Multiple regression analysis in all subjects showed that age, diabetic state, and cigarette smoking were independently common risk factors for the increase in carotid IMT and a-PWV. In the diabetic patients, the independent risk factors associated with the carotid IMT were age, hyperlipidemia, and duration of diabetes (R2 = 0.232, P < 0.0001), while those associated with a-PWV were age and duration of diabetes (R2 = 0.334, P < 0.0001). CONCLUSIONS: The results indicated that diabetic patients showed more advanced changes in atherosis than that in sclerosis as compared with age- and sex-matched control subjects. Such atherotic changes in diabetic patients may be associated with hyperlipidemia.


Subject(s)
Aorta, Abdominal/diagnostic imaging , Carotid Arteries/diagnostic imaging , Diabetes Mellitus, Type 2/diagnostic imaging , Tunica Intima/diagnostic imaging , Tunica Media/diagnostic imaging , Adolescent , Adult , Age Distribution , Aged , Arteriosclerosis/diagnostic imaging , Case-Control Studies , Diabetes Mellitus, Type 2/physiopathology , Female , Humans , Linear Models , Male , Middle Aged , Pulsatile Flow , Regression Analysis , Risk Factors , Sclerosis/diagnostic imaging , Ultrasonography
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