Fatty acid synthase (FASN) is crucial to de novo long-chain fatty acid synthesis, needed to meet cancer cells’ increased demands for membrane, energy, and protein production. We investigated FASN overexpression as a therapeutic and chemosensitization target in ovarian cancer tissue, cell lines, and primary cell cultures. FASN expression at mRNA and protein levels was determined by quantitative real-time polymerase chain reaction and immunoblotting and immunohistochemistry, respectively. FASN inhibition’s impact on cell viability, apoptosis, and fatty acid metabolism was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium-bromide assay, cell death detection enzyme-linked immunosorbent assay, immunoblotting, and 18 F-fluoromethylcholine uptake measurement, respectively. Relative to that in healthy fallopian tube tissue, tumor tissues had 1.8-fold average FASN protein overexpression; cell lines and primary cultures had 11-fold–100-fold mRNA and protein overexpression. In most samples, the FASN inhibitor cerulenin markedly decreased FASN expression and cell viability and induced apoptosis. Unlike concomitant administration, sequential cerulenin/cisplatin treatment reduced cisplatin’s half maximal inhibitory concentration profoundly (up to 54%) in a cisplatin-resistant cell line, suggesting platinum (re)sensitization. Cisplatin-resistant cells displayed lower 18 F-fluoro-methylcholine uptake than did cisplatin-sensitive cells, suggesting that metabolic imaging might help guide therapy. FASN inhibition induced apoptosis in chemosensitive and platinum-resistant ovarian cancer cells and may reverse cisplatin resistance.

Several recently published studies have suggested that decreasing VEGF levels result in placental oxidative stress in preeclampsia, although the question as to how decreased VEGF concentrations increase oxidative stress still remains unanswered. Here, we show that VEGF activated Nrf2, the main regulating factor of the intracellular redox balance, in the cytotrophic cell line BeWo. In turn, this activated the production of antioxidative enzymes thioredoxin, thioredoxin reductase, and heme oxygenase-1, which showed a decrease in their expression in the placentas of preeclamptic women. Nevertheless, this activation occurred without oxidative stress stimulus. As a consequence, the activation of Nrf2 protected BeWo cells against H(2)O(2)/Fe(2+)-induced oxidative damage. We further show that VEGF up-regulated the expression of itself. A positive feedback loop was described in which VEGF activated Nrf2 in an ERK1/2-dependent manner; the up-regulation of HO-1 expression by Nrf2 augmented the production of carbon monoxide, which in turn up-regulated VEGF expression. In conclusion, VEGF induces the Nrf2 pathway to protect against oxidative stress and, via a positive feedback loop, to elevate VEGF expression. Therefore, decreased VEGF bioavailability during preeclampsia may result in higher vulnerability to placental oxidative cell damage and a further reduction of VEGF bioavailability, a vicious circle that may end up in preeclampsia.

Small for gestational age neonates (SGA) could be subdivided into two groups according to the underlying causes leading to low birth weight. Intrauterine growth restriction (IUGR) is a pathologic condition with diminished growth velocity and fetal compromised well-being, while non-growth restricted SGA neonates are constitutionally (genetically determined) small. Antenatal sonographic measurements are used to differentiate these two subgroups. Maternal metabolic changes contribute to the pathogenesis of IUGR. A disturbed lipid metabolism and cholesterol supply might affect the fetus, with consequences for fetal programming of cardiovascular diseases. We evaluated fetal serum lipids and hypothesized a more atherogenic lipoprotein profile in IUGR fetuses. Umbilical cord serum lipids and oxidative modified, low-density lipoprotein (oxLDL) concentrations were measured by colorimetric enzymatic measurements, or by ELISA. Values of IUGR (n=36) and constitutionally small for gestational age neonates (SGA, n=22) were compared with those of healthy, adequate for gestational age, born neonates (CN, n=97). SAS-statistic software was used and two-way ANOVA was adjusted for gestational age at delivery. Fetal high-density lipoprotein cholesterol (HDL-C) and total cholesterol (TC) concentrations were found to be lower in the IUGR compared to the CN and SGA groups (HDL-C: P<0.001, TC: P<0.01). Atherogenic indices, including the oxLDL/LDL-C ratio, were increased in the IUGR compared to the CN group (oxLDL/LDL-C ratio: P<0.001). Our results support the hypothesis of a disturbed cholesterol supply in IUGR fetuses. Born SGA has been shown to be a risk factor for developing cardiovascular disease later in life. Since HDL-C has anti-inflammatory properties, a reduced HDL-C during fetal development, and an increase in atherogenic indices, might provide a link to this observation in IUGR fetuses.

Objective: Lipids and steroid hormones are closely linked. While cholesterol is the substrate for (placental) steroid hormone synthesis, steroid hormones regulate hepatic lipid production. The aim of this study was to quantify circulating steroid hormones and lipid metabolites, and to characterize their interactions in normal and pathological pregnancies with a focus on hepatic and placental pathologies. Methods: A total of 216 serum samples were analyzed. Group A consisted of 32 patients with uncomplicated pregnancies who were analyzed at three different time-points in pregnancy (from the first through the third trimester) and once post partum. Group B consisted of 36 patients (24th to 42nd week of gestation) with pregnancy pathologies (IUGR n = 10, preeclampsia n = 13, HELLP n = 6, intrahepatic cholestasis n = 7) and 31 controls with uncomplicated pregnancies. Steroid profiles including estradiol, progesterone, and dehydroepiandrosterone were measured by GC-MS and compared with lipid concentrations. Results: In Group A, cholesterol and triglycerides correlated positively with estradiol (cholesterol ρ = 0.50, triglycerides ρ = 0.57) and progesterone (ρ = 0.49, ρ = 0.53) and negatively with dehydroepiandrosterone (ρ = − 0.47, ρ = − 0.38). Smoking during pregnancy affected estradiol concentrations, leading to lower levels in the third trimester compared to non-smoking patients (p < 0.05). In Group B, cholesterol levels were found to be lower in IUGR pregnancies and in patients with HELLP syndrome compared to controls (p < 0.05). Steroid hormone concentrations of estradiol (p < 0.05) and progesterone (p < 0.01) were lower in pregnancies with IUGR. Discussion: Lipid and steroid levels were affected most in IUGR pregnancies, while only minor changes in concentrations were observed for other pregnancy-related disorders. Each of the analyzed entities displayed specific changes. However, since the changes were most obvious in pregnancies complicated by IUGR and only minor changes were observed in pregnancies where patients had impaired liver function, our data suggests that placental rather than maternal hepatic function strongly determines lipid and steroid levels in pregnancy. Zielsetzung: Lipide und Steroidhormone stehen in wechselseitiger Beziehung zueinander. Cholesterin ist Ausgangssubstanz für die (plazentare) Steroidhormonsynthese. Die Lipidproduktion in der Leber wird von Steroidhormonen reguliert. Ziel der Studie war es, die Konzentration von Steroidhormonen und Lipiden im Blut im Verlauf der Schwangerschaft und bei Schwangerschaftspathologien mit Beteiligung von Leber oder Plazenta zu quantifizieren. Methoden: 216 Serumproben wurden analysiert. Gruppe A bestand aus 32 Patientinnen mit unkomplizierter Schwangerschaft, denen zu drei Zeitpunkten im Schwangerschaftsverlauf sowie einmal postpartal Blut abgenommen wurde. Gruppe B bestand aus 36 Patientinnen (24.–42. SSW) mit Schwangerschaftspathologien (intrauterine Wachstumsrestriktion [IUGR] n = 10, Präeklampsie n = 13, HELLP-Syndrom n = 6, intrahepatische Cholestase n = 7) sowie 31 Frauen mit unkomplizierter Schwangerschaft. Ein Steroidprofil einschließlich Estradiol, Progesteron und Dehydroepiandrosteron wurde mit der Gaschromatografie-Massenspektrometrie (GC-MS) erstellt und mit Lipidkonzentrationen verglichen. Ergebnisse: In der Gruppe A korrelierten Cholesterin- und Triglyzeridwerte positiv mit Estradiol (Cholesterin ρ = 0,50, Triglyzeride ρ = 0,57) und Progesteron (ρ = 0,49, ρ = 0,53) und negativ mit Dehydroepiandrosteron (ρ = − 0,47, ρ = − 0,38). Rauchen während der Schwangerschaft führte zu niedrigeren Estradiolkonzentrationen im 3. Trimenon im Vergleich zu Nichtrauchern (p < 0,05). In der Gruppe B wies die IUGR-Gruppe deutlichste Veränderungen auf. Hier zeigten sich verglichen mit der Kontrollgruppe insbesondere Werte für Cholesterin, Estradiol (p < 0,05) und Progesteron (p < 0,01) erniedrigt. Diskussion: Jede der analysierten pathologischen Entitäten wies ein spezifisches Lipid- und Steroidhormon-Profil auf. Die deutlichsten Abweichungen von unkomplizierten Schwangerschaften zeigten Frauen mit IUGR. Schwangerschaften mit pathologischem Leberfunktionstest zeichneten sich durch eher geringe Veränderungen aus. Dies deutet darauf hin, dass Lipid- und Steroidspiegel während der Schwangerschaft stärker von der plazentaren als von der hepatischen Funktion bestimmt werden.

Objective. To evaluate the oxidative state of lipoproteins in pregnancies complicated by intrauterine growth restriction (IUGR) in comparison to preeclampsia (PE) and healthy pregnant control subjects (CN). Methods. Maternal serum of 20 PE, 29 IUGR, and 29 gestational age-matched CN were analyzed. Total cholesterol (TC), low-density lipoprotein (LDL)-bound cholesterol (LDL-C), and oxidized LDL (oxLDL) concentration were measured once between 25 and 34 weeks of gestation. Statistical estimates were performed by Student's t-test. Results. Serum concentrations of LDL-C and TC were significantly reduced in IUGR [LDL-C: CN – mean = 146 mg/dL, SD = ± 40.1; IUGR – mean = 102 mg/dL, SD = ± 27.3 (p < 0.0001); PE – mean = 130 mg/dL, SD = 38.8 mg/dL; TC: CN – mean = 259/dL, SD = ± 46.8; IUGR – mean = 218 mg/dL, SD = ± 35.0 (p < 0.001); PE – mean = 244 mg/dL, SD = 48.2]. There was no significant difference in oxLDL/LDL-C ratio within the three groups (CN: mean = 0.76, SD = 0.24; IUGR: mean = 0.74, SD = 0.12; PE: mean = 0.77, SD = 0.22). Conclusion. Our results show a lower maternal LDL-C and TC concentration in IUGR pregnancies. These data contribute to the hypothesis of a decreased cholesterol supply to the fetus in IUGR. However, we could not confirm the hypothesis of an altered oxidative state in neither IUGR nor PE.