Publications (127) View all
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Article: In vivo stable-isotope kinetic study suggests intracellular assembly of lipoprotein(a).
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ABSTRACT: OBJECTIVE: Lipoprotein(a) [Lp(a)] consists of apolipoprotein B-100 (apoB-100) as part of an LDL-like particle and the covalently linked glycoprotein apolipoprotein(a) [apo(a)]. Detailed mechanisms of its biosynthesis, assembly, secretion and catabolism are still poorly understood. To address the Lp(a) assembly mechanism, we studied the in vivo kinetics of apo(a) and apoB-100 from Lp(a) and LDL apoB-100 in nine healthy probands using stable-isotope methodology. METHODS: The level of isotope enrichment was used to calculate the fractional synthesis rate (FSR), production rate (PR) and retention time (RT) using SAAMII software and multicompartmental modeling. RESULTS: We observed a similar mean PR for apo(a) (1.15 nmol/kg/d) and apoB-100 (1.31 nmol/kg/d) from Lp(a), which differed significantly from the PR for apoB-100 from LDL (32.6 nmol/kg/d). Accordingly, mean FSR and RT values for Lp(a)-apo(a) were similar to those of Lp(a)-apoB and different from those for LDL-apoB. CONCLUSION: Two different kinetic apoB pools within Lp(a) and LDL suggest intracellular Lp(a) assembly from apo(a) and newly synthesized LDL.Atherosclerosis 10/2012; · 3.79 Impact Factor -
Article: Lithium reduces aqauaporin-2 transcription independent of prostaglandins
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ABSTRACT: Vasopressin (AVP)-stimulated translocation and transcription of aquaporin-2 (AQP2) water channels in renal principal cells is essential for urine concentration. Twenty percent of patients treated with lithium develop nephrogenic diabetes insipidus (NDI), a disorder in which the kidney is unable to concentrate urine. In vivo and in mouse collecting duct (mpkCCD) cells, lithium treatment coincides with decreased AQP2 abundance and inactivation of glycogen synthase kinase (Gsk) 3ß. This is paralleled in vivo by an increased renal cyclooxygenase 2 (COX-2) expression and urinary prostaglandin PGE2 excretion. PGE2 reduces AVP-stimulated water reabsorption, but its precise role in lithium-induced downregulation of AQP2 is unclear. Using mpkCCD cells, we here investigated whether prostaglandins contribute to lithium-induced downregulation of AQP2. In these cells, lithium application reduced AQP2 abundance, which coincided with Gsk3 inactivation and increased COX-2 expression. Inhibition of COX by indomethacin, leading to reduced PGE2 and PGF2 levels, or dexamethasone-induced downregulation of COX-2 both increased AQP2 abundance, while PGE2 addition reduced AQP2 abundance. However, lithium did not change the prostaglandin levels, and indomethacin and dexamethasone did not prevent lithium-induced AQP2 downregulation. Further analysis revealed that lithium decreased AQP2 protein abundance, mRNA levels and transcription, while PGE2 reduced AQP2 abundance by increasing its lysosomal degradation, but not by reducing AQP2 gene transcription. In conclusion, our data reveal that in mpkCCD cells, prostaglandins decrease AQP2 protein stability by increasing its lysosomal degradation, indicating that in vivo paracrine-produced prostaglandins might have a role in lithium-induced NDI via this mechanism. However, lithium affects also AQP2 gene transcription, which is prostaglandin independent.AJP Cell Physiology 01/2012; 302:C131-C140. · 3.54 Impact Factor -
Article: Male labial gland secretions as species recognition signals in species of Bombus
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ABSTRACT: Spring queens of Bombus cryptarum from Europe, Bombus burjaeticus from the Russian Transbaikal region and Bombus moderatus from North America were collected at different localities to grow artificial colonies and obtain fresh males. Furthermore, males of Bombus florilegus, B. moderatus, Bombus magnus and Bombus occidentalis were collected in the field. Cephalic labial gland secretions of 29 specimens from these different taxa were analysed by gas chromatography/mass spectrometry (GC/MS). About 50 compounds were identified, including a mixture of straight-chain fatty acid derivatives (alkenoles, acids, acetates and esters), and the usual pattern of saturated and unsaturated hydrocarbons C21–C29. The secretions of all specimens investigated were very similar: ethyl dodecanoate was identified as the main component (90–97% peak area). Since the sum of percentage peak areas for the hydrocarbons amounted up to 3–6%, most of the remaining compounds (8 alkenoles, 6 acids, 6 acetates and 20 esters) could only be detected at very low levels (<0.1% peak area). With the exception of B. florilegus, each taxon had a sympatric bumblebee taxon that also used ethyl dodecanoate as the main component: B. magnus, sympatric with B. cryptarum in Europe, Bombus patagiatus, sympatric with B. burjaeticus in the Russian Transbaikal and B. occidentalis, sympatric with B. moderatus in North America. Male cephalic labial gland secretions of 20 specimens from these sympatric taxa were also investigated to see how far their pattern of compounds differed from that of the cryptarum complex taxa (cryptarum–burjaeticus–florilegus–moderatus). Besides some quantitative differences in ethyl dodecanoate and ethyl octadec-9-enoate, the occurrence of octadeca-9,12-dien-1-ol, octadeca-9,12,15-trien-1-ol and octadec-11-en-1-ol was an essential qualitative difference that separated the labial gland secretions of B. magnus, B. patagiatus and B. occidentalis from those of their sympatric counterparts. A principal component analysis confirmed this separation. Due to their low variability and differences in pattern of compounds compared to those of closely related sympatric bumblebees, the labial gland secretions of B. cryptarum, B. burjaeticus, B. florilegus and B. moderatus distributed across Europe, the Russian Far East and North America are very well suited to function as ‘species recognition signal’. The taxonomic consequences for the cryptarum complex taxa and their relationship to Bombus albocinctus from the Russian Far East are discussed in context ofrecent genetic investigations.Biochemical Systematics and Ecology 01/2012; 40:103-111. · 0.93 Impact Factor -
Article: A randomized comparison of pharmacokinetics of a single vaginal dose of dry misoprostol or misoprostol moistened with normal saline or with acetic acid.
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ABSTRACT: The pharmacokinetics of vaginal misoprostol as a dry tablet or as a tablet moistened with normal saline or with acetic acid were studied. For this study, 42 women requesting termination of pregnancy at gestational age of <12 weeks were recruited and received 400 µg vaginal misoprostol tablets. They were randomized into three groups: (i) dry tablets, (ii) tablets moistened with 3 ml of normal saline and (iii) tablets moistened with 3 ml of 5% acetic acid. Venous blood samples were taken at 0, 15, 30, 45, 60, 90, 120, 150, 180, 210, 240, 270, 300, 330 and 360 min after misoprostol administration. Misoprostol acid (MPA) was determined in serum samples using gas chromatography/tandem mass spectrometry. The serum peak MPA concentration (C(max)) was significantly higher and the time-to-peak concentration (T(max)) was significantly shorter in the normal saline and acetic acid groups, when compared with the dry tablet group. Both areas under the curve at 240 and 360 min (AUC(240) and AUC(360)) of the normal saline and acetic acid groups were also significantly greater than that of the dry tablet group. The coefficients of variation in C(max) and T(max) were highest in the normal saline group, while that of AUC(240) and AUC(360) were highest in the dry tablet group. The C(max) was significantly higher in subjects in the dry tablet group with vaginal pH < 5 than in those with pH 5. There were no significant differences in other pharmacokinetic parameters between subjects with vaginal pH < 5 and those with vaginal pH 5 in all three groups. Vaginal misoprostol tablets moistened with normal saline or 5% acetic acid achieved better absorption than the dry tablet. The use of vaginal misoprostol tablets moistened with normal saline or 5% acetic acid would potentially improve the clinical efficacy of misoprostol. HKClinicalTrials.com registration: HKCTR-821.Human Reproduction 09/2011; 26(11):2981-7. · 4.47 Impact Factor -
Article: Lithium reduces aquaporin-2 transcription independent of prostaglandins.
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ABSTRACT: Vasopressin (AVP)-stimulated translocation and transcription of aquaporin-2 (AQP2) water channels in renal principal cells is essential for urine concentration. Twenty percent of patients treated with lithium develop nephrogenic diabetes insipidus (NDI), a disorder in which the kidney is unable to concentrate urine. In vivo and in mouse collecting duct (mpkCCD) cells, lithium treatment coincides with decreased AQP2 abundance and inactivation of glycogen synthase kinase (Gsk) 3β. This is paralleled in vivo by an increased renal cyclooxygenase 2 (COX-2) expression and urinary prostaglandin PGE(2) excretion. PGE(2) reduces AVP-stimulated water reabsorption, but its precise role in lithium-induced downregulation of AQP2 is unclear. Using mpkCCD cells, we here investigated whether prostaglandins contribute to lithium-induced downregulation of AQP2. In these cells, lithium application reduced AQP2 abundance, which coincided with Gsk3β inactivation and increased COX-2 expression. Inhibition of COX by indomethacin, leading to reduced PGE(2) and PGF(2α) levels, or dexamethasone-induced downregulation of COX-2 both increased AQP2 abundance, while PGE(2) addition reduced AQP2 abundance. However, lithium did not change the prostaglandin levels, and indomethacin and dexamethasone did not prevent lithium-induced AQP2 downregulation. Further analysis revealed that lithium decreased AQP2 protein abundance, mRNA levels and transcription, while PGE(2) reduced AQP2 abundance by increasing its lysosomal degradation, but not by reducing AQP2 gene transcription. In conclusion, our data reveal that in mpkCCD cells, prostaglandins decrease AQP2 protein stability by increasing its lysosomal degradation, indicating that in vivo paracrine-produced prostaglandins might have a role in lithium-induced NDI via this mechanism. However, lithium affects also AQP2 gene transcription, which is prostaglandin independent.AJP Cell Physiology 08/2011; 302(1):C131-40. · 3.54 Impact Factor
