Erythropoietin induction in Hep3B cells is not affected by inhibition of heme biosynthesis

AbstractErythropoietin (Epo) is one of the physiologically important genes whose transcription is up-regulated by hypoxia. Our laboratory previously proposed that the sensor of this event is a heme protein which turns over rapidly. We have investigated the effects of four inhibitors of heme synthesis (4,6-dioxoheptanoic acid (DHA), isoniazid (INH), N-methyl protoporphyrin IX (MPP), and deferoxamine mesylate (DSF)) on hypoxia-, cobalt-, and DSF-induced erythropoietin (Epo) mRNA expression, heme biosynthesis, and cell viability in Hep3B cells. DHA (0.1–1.0 mM) inhibited heme biosynthesis more than 85%, but did not suppress Epo mRNA expression. Epo mRNA expression was inhibited only at higher concentrations of DHA (2, 4 mM) which also inhibited cell viability. No suppression of Epo mRNA expression by INH was observed at doses known to inhibit heme biosynthesis. MPP did not suppress Epo mRNA expression although it showed an inhibitory effect on heme biosynthesis without any decreased cell viability. 130 μM DSF, a dose which inhibited heme biosynthesis without cell toxicity, suppressed hypoxia-induced Epo mRNA expression, but enhanced cobalt-induced Epo mRNA expression. These results show that although the oxygen sensor is probably a heme protein it does not turn over rapidly. Therefore, cobalt is unlikely to act by substituting for heme iron

Bach1 gene ablation reduces steatohepatitis in mouse MCD diet model

Bach1 is a transcriptional repressor of heme oxygenase-1 (HO-1, a.k.a. HSP-32), which is an inducible enzyme and has anti-oxidation/anti-inflammatory properties shown in various models of organ injuries. Since oxidative stress plays a pivotal role in the pathogenesis of nonalcoholic steatohepatitis (NASH), HO-1 induction would be expected to prevent the development of NASH. In this study, we investigated the influence of Bach1 ablation in mice on the progression of NASH in methionine-choline deficient (MCD) diet model. Bach1 ablation resulted in significant induction of HO-1 mRNA and its activity in the liver. When fed MCD diet, Bach1−/− mice exhibited negligible hepatic steatosis compared to pronounced steatohepatitis in wild type mice with 6-fold increase in hepatic triglyceride content. Whereas feeding of MCD diet decreased mRNA expressions of peroxisome proliferator-activated receptor (PPAR) α and microsomal triglyceride transfer protein (MTP) in wild type mice, there were no change in Bach1−/− mice. In addition, hepatic concentration of malondialdehyde (MDA), a biomarker for oxidative stress as well as plasma alanine aminotransferase (ALT) was significantly lower in Bach1−/− mice. These findings suggest that Bach1 ablation exerts hepatoprotective effect against steatohepatitis presumably via HO-1 induction and may be a potential therapeutic target

Lexicographic Expected Utility with a Subjective State Space

This paper provides a model that allows for a criterion of admissibility basedon a subjective state space. For this purpose, we build a non-Archimedeanmodel of preference with subjective states, generalizing Blume, Brandenburger,and Dekel [2], who present a non-Archimedean model with exogenous states;and Dekel, Lipman, and Rustichini [4], who present an Archimedean modelwith an endogenous state space. We interpret the representation as modelingan agent who has several "hypotheses" about her state space, and who viewssome as "infinitely less relevant" than others

Bilateral Carotid and Vertebral Rete Mirabile Presenting with a Prominent Anterior Spinal Artery Mimicking a Spinal Dural AV Fistula at MRI

Bilateral carotid and vertebral rete mirabile (CVRM) is a very rare condition. We report a new case of CVRM initially detected by magnetic resonance imaging (MRI) of the cervical spine. MRI demonstrated tortuous vascular signal voids limited to the anterior cerebrospinal fluid space mimicking spinal dural arteriovenous fistula. A diagnosis of CVRM was confirmed on the basis of angiographic findings of rete formation associated with bilateral aplasia of the cavernous internal carotid and vertebral arteries without abnormal arteriovenous connection