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In thalassemia, deficient globin-chain production during erythropoiesis results in anemia. Thalassemia may be further complicated by iron overload (frequently exacerbated by blood transfusion), which induces numerous endocrine diseases, hepatic cirrhosis, cardiac failure and even death. Accumulation of iron in the absence of blood transfusions may result from inappropriate suppression of the iron-regulating peptide hepcidin by an erythropoietic mechanism. To test this hypothesis, we examined erythroblast transcriptome profiles from 15 healthy, nonthalassemic donors. Growth differentiation factor 15 (GDF15), a member of the transforming growth factor-[beta] superfamily, showed increased expression and secretion during erythroblast maturation. Healthy volunteers had mean GDF15 serum concentrations of 450 [plus or minus] 50 pg/ml. In comparison, individuals with [beta]-thalassemia syndromes had elevated GDF15 serum levels (mean 66,000 [plus or minus] 9,600 pg/ml; range 4,800-248,000 pg/ml; P [less than] 0.05) that were positively correlated with the levels of soluble transferrin receptor, erythropoietin and ferritin. Serum from thalassemia patients suppressed hepcidin mRNA expression in primary human hepatocytes, and depletion of GDF15 reversed hepcidin suppression. These results suggest that GDF15 overexpression arising from an expanded erythroid compartment contributes to iron overload in thalassemia syndromes by inhibiting hepcidin expression., Author(s): Toshihiko Tanno [1]; Natarajan V Bhanu [1]; Patricia A Oneal [1]; Sung-Ho Goh [1]; Pamela Staker [1]; Y Terry Lee [1]; John W Moroney [2]; Christopher H Reed [2]; [...]

Garlic is appealing as an anti-carcinogenic agent due to its ability to induce apoptosis in vitro and inhibit the formation and growth of tumors in animals in vivo. Diallyl disulfide (DADS) is a constituent of garlic that suppresses neoplastic cell growth and induces apoptosis. We examined the effects of DADS on various cancer cell lines to better understand its effect on apoptosis and apoptosis-related genes. The nonsteroidal anti-inflammatory drug (NSAID)-activated gene (NAG-1) has proapoptotic and antitumorigenic activities and is upregulated by anticancer agents such as NSAIDs. In this study, human colorectal HCT-116 (wild-type p53), HCT-15 (p53 mutant) and human prostate PC-3 (p53 mutant) cells were exposed to DADS. DADS inhibited cell proliferation in all cell lines albeit to a lesser extent in HCT-15 and PC-3 cells at 11.5 and 23/[micro]mol/L. In HCT-116 cells, DADS induced p53 and NAG-1 in a dose-dependent manner and the induction of p53 preceded that of NAG-1. In HCT-116 cells, NAG-1 protein expression was increased 2.4-fold [+ or -] 0.6 at 4.6/[micro]mol/L and 6.1-fold [+ or -] 1.7 at 23/[micro]mol/L DADS, whereas p53 was induced 1.5-fold [+ or -] 0.1 and 2.3-fold [+ or -] 0.4. DADS did not induce NAG-1 or p53 in p53 mutant cell lines; however, NAG-1 expression was induced by sulindac sulfide. HCT-116 cells treated with 4.6 and 23 [micro]mol/L DADS resulted in a 1.9- and 2.9-fold increase in apoptosis, respectively. In contrast, 23/[micro]mol/L DADS induced apoptosis only 1.8-fold in HCT-15 cells and not at all in PC-3 cells. Thus, DADS-induced apoptosis and NAG-1 protein expression appear to occur via p53. J. Nutr. 132: 773-778, 2002. KEY WORDS: * apoptosis * colorectal cancer * diallyl disulfide (DADS)* NAG-1 * p53

Retinoids are essential for mucous differentiation of the airway epithelium. Rat tracheal epithelial cells cutured in a medium rich in retinoic acid (RA) displayed mucous differentiation while cells cultured in the absence of RA displayed squamous differentiation. Prostaglandin (PG) and phospholipase A2 (PLA2) were produced at high levels by the mucous phenotype and at low levels by the squamous phenotype. In contrast, cells cultured in medium without RA showed no changes in PG and PLA2 expression. These data suggest that retinoid-induced differentiation regulates PG and PLA2 expression in airway epithelium.

Tyrosyl radicals were characterized and their role in hydroperoxide-dependent regulation of prostaglandin endoperoxide (PGH) synthase were determined. A tyrosyl radical is formed during incubation of PGH synthase 1 with arachidonate or peroxide. No strong evidence for the role of this radical in cyclooxygenase catalysis was found. However, it is proposed that the radical is associated with suicide inactivation of the peroxidase activity of PGH synthase 1.

Many volatile organic chemicals (VOCs) have not been tested for sensory pulmonary irritation. Development of an in vitro non-animal sensory irritation assay that is suitable for a large number of chemicals is needed to replace the mouse assay. An adverse outcome pathway (AOP) is designed to provide a clear description of the biochemical and cellular processes leading to toxicological effects or an adverse outcome. The AOP for chemical sensory pulmonary irritation was developed according to the Organization for Economic Co-operation and Development guidance including the Bradford Hill criteria for weight of evidence to determine the confidence in the AOP. The proposed AOP is based on an in-depth review of the relevant scientific literature to identify the molecular initiating event (MIE) for respiratory irritation. The activation of TRPA1 receptor (transient receptor potential cation channel, subfamily A, member 1) is the MIE leading to sensory irritation. A direct measure of TRPA1 activation in vitro should identify chemical sensory irritants and provide an estimate of potency. Fibroblasts expressing TRPA1 are used to determine TRPA1 activation and irritant potency. We report a linear relationship between the in vivo RD50 and the in vitro pEC50 values (R = 0.81) to support this hypothesis. We propose that this in vitro assay, after additional analysis and validation, could serve as a suitable candidate to replace the mouse sensory irritation assay. [ABSTRACT FROM AUTHOR]