Monomethylarsonous acid inhibited endogenous cholesterol biosynthesis in human skin fibroblasts

Human exposure to arsenic in drinking water is a widespread public health concern, and such exposure is known to be associated with many human diseases. The detailed molecular mechanisms about how arsenic species contribute to the adverse human health effects, however, remain incompletely understood. Monomethylarsonous acid [MMA(III)] is a highly toxic and stable metabolite of inorganic arsenic. To exploit the mechanisms through which MMA(III) exerts its cytotoxic effect, we adopted a quantitative proteomic approach, by coupling stable isotope labeling by amino acids in cell culture (SILAC) with LC-MS/MS analysis, to examine the variation in the entire proteome of GM00637 human skin fibroblasts following acute MMA(III) exposure. Among the ~ 6500 unique proteins quantified, ~ 300 displayed significant changes in expression after exposure with 2 μM MMA(III) for 24 h. Subsequent analysis revealed the perturbation of de novo cholesterol biosynthesis, selenoprotein synthesis and Nrf2 pathways evoked by MMA(III) exposure. Particularly, MMA(III) treatment resulted in considerable down-regulation of several enzymes involved in cholesterol biosynthesis. In addition, real-time PCR analysis showed reduced mRNA levels of select genes in this pathway. Furthermore, MMA(III) exposure contributed to a distinct decline in cellular cholesterol content and significant growth inhibition of multiple cell lines, both of which could be restored by supplementation of cholesterol to the culture media. Collectively, the present study demonstrated that the cytotoxicity of MMA(III) may arise, at least in part, from the down-regulation of cholesterol biosynthesis enzymes and the resultant decrease of cellular cholesterol content.     

The role of aquaporin-1 in idiopathic and drug-induced intracranial hypertension

Idiopathic intracranial hypertension is a common disorder affecting mainly healthy, young, overweight women. The pathogenesis of this condition is unknown, but it has been shown to follow treatment with several compounds including corticosteroids and vitamin A derivatives. This paper will offer a novel hypothesis and insight on the pathogenesis of drug induced intracranial hypertension following a review and analysis of the literature. Both corticosteroids and vitamin A derivatives have been shown to upregulate the expression of aquaporin 1, a water channel protein. Aquaporin 1 is widely distributed in the human brain and is associated with water secretion into the subarachnoid space. Aquaporin 1 was also shown to participate in the regulation of weight. Agents used for treating idiopathic intracranial hypertension reduce aquaporin 1 expression. Based on these observations, we propose that aquaporin 1 has a pathogenetic role in drug induced idiopathic intracranial hypertension. Over expression of this gene causes increased intracranial pressure, and downregulation reduces pressure and alleviates the symptomatology and complications of idiopathic intracranial hypertension.     

Developmental and genetic aspects of congenital diaphragmatic hernia

Congenital diaphragmatic hernia (CDH) is a frequent occurring cause of neonatal respiratory distress and occurs 1 in every 3,000 liveborns. Ventilatory support and pharmaceutical treatment of the co-occurring lung hypoplasia and pulmonary hypertension are insufficient in, respectively, 20% of isolated cases and 60% of complex ones leading to early perinatal death. The exact cause of CDH remains to be identified in the majority of human CDH patients and prognostic factors predicting treatment refraction are largely unknown. Their identification is hampered by the multifactorial and heterogenic nature of this congenital anomaly. However, application of high-resolution molecular cytogenetic techniques to patients' DNA now enables detection of chromosomal aberrations in 30% of the patients. Furthermore, recent insights in rodent embryogenesis pointed to a specific disruption of the early mesenchymal structures in the primordial diaphragm of CDH-induced offspring. Together, these data allowed for the introduction of new hypotheses on CDH pathogenesis, although many issues remain to be resolved. In this review, we have combined these new insights and remaining questions on diaphragm pathogenesis with a concise overview of the clinical, embryological, and genetic data available.     

Synthesis of [11C]Bexarotene by Cu-Mediated [11C]Carbon Dioxide Fixation and Preliminary PET Imaging

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The liver as a target organ of retinoids

Retinoids have several biological functions including cell growth, differentiation and apoptosis. In liver, retinoids are known to be associated with regeneration, fibrosis and carcinogenesis. The facts that retinoid droplets in stellate cells are lost with progression of liver disease and that effectiveness of an acyclic retinoid on second primary liver cancer suggest the importance of liver as a target organ of retinoids. Our recent work has indicated that retinoids have antioxidant effects in association with regulation of fatty acid metabolism. In this review article, we discussed the important function of retinoids in liver, mainly from molecular aspects.     

Comedolytic effect of topically applied active vitamin D3 analogue on pseudocomedones in the rhino mouse

BACKGROUND: Retinoids and active vitamin D(3) analogues regulate the proliferation and differentiation of keratinocytes and are effective in the treatment of psoriasis. Retinoids are known to be effective against acne vulgaris through comedolysis. However, the comedolytic effect of active vitamin D(3) analogues has not been reported. OBJECTIVES: To investigate whether maxacalcitol, one of the active vitamin D(3) analogues, has a comedolytic effect by using spontaneously comedogenic rhino mice. METHODS: Rhino mice were treated topically with tretinoin and maxacalcitol once daily for 2 and 4 weeks, respectively. The dermal side of the epidermal sheet was observed to determine the size of the utricle. Haematoxylin and eosin-stained vertical sections were used to measure utricle diameter and density and to evaluate histological changes. RESULTS: Maxacalcitol (25 microg g(-1)) and tretinoin (0.1%) significantly decreased the size and the diameter of the utricle after 1 week of treatment. However, maxacalcitol did not affect the density while tretinoin did have an effect. Histopathologically, maxacalcitol and tretinoin markedly induced epidermal hyperplasia accompanied by a minor accumulation of inflammatory cells in the dermis, with and without hypercornification, respectively. CONCLUSIONS: These results indicate that maxacalcitol has a prominent effect on comedolysis and that its mechanism of action may be different from that of retinoids.