Comments to the editor concerning the paper entitled "Preclinical renal cancer chemopreventive efficacy of geraniol by modulation of multiple molecular pathways" Shiekh Tanveer Ahmad et al

Shiekh Tanveer Ahmad et al. (2011) reported in their recent manuscript very interesting results that we would like to compare with our recent findings on the similar topic. The authors reported that “treatment of GOH in rats, having chronic exposure of Fe-NTA (feric nitrilotriacetate) resulted in marked decline” of the “markers of inflammation, proliferation and apoptosis. The present data together with reports available in literature, suggest GOH to be a promising candidate for chemoprevention of renal carcinogenesis” (Ahmad et al., 2011). In our previous studies we have analyzed the anti-inflammatory properties of the geraniol (GOH) although in others models of disease. Our research team is studying since 2008 (Marcuzzi et al., 2008) the mevalonate kinase deficiency (MKD), due to mutations in the MVK gene coding for the enzyme mevalonate kinase (MK), that causes a shortage of isoprenoids, such as the geraniol, intermediate compounds of pathway, and the cholesterol, its final product. MKD is a rare autosomal recessive inborn disorder of cholesterol biosynthesis, characterized by recurrent inflammatory episodes variably associated with lymphadenopathy, abdominal involvement, arhtralgia, rash, and, in most severe cases, by psychomotor delay (Haas and Hoffmann, 2007). Since MKD is still an orphan drug disease, our interest is the discovery of potential candidates for an ethiologic therapy. In our experience isoprenoids compounds such as GOH are able to limit the inflammatory response in MKD. In our hypothesis the introduction of exogenous isoprenoids could counteract the shortage of isoprenoid intermediates characteristic of MKD. The results of Shiekh Tanveer Ahmad et al. (2011) open an interesting scenario. As mentioned by the authors (Cardozo et al., 2011; Carnesecchi et al., 2004; Kim et al., 2011; Ong et al., 2006; Wiseman et al., 2007; Yu et al., 1995) the GOH is studied for its adjuvants anticancer properties on various types of cancers. In our experience we have tested with success, some anticancer drugs with GOH in our model of MKD (Marcuzzi et al., 2011), such as Tipifarnib®, and we speculate about a potential synergized between these drugs. In summary, we agree with the study by Ahmad et al. (2011) and underline the pivotal role of geraniol to rescue the phenotype inflammation

Evolutionary hypothesis of the Mevalonate Kinase Deficiency

Mevalonate Kinase Deficiency (MKD) is an autosomal-recessively inherited disorder of cholesterol biosynthesis with higher prevalence in the Netherlands and other North European countries. MKD is due to mutations in the second enzyme of mevalonate pathway (mevalonate kinase, MK/MVK) which results in reduced enzymatic activity and in the consequent shortage of downstream compounds. In most severe cases the deregulation of mevalonate pathway is associated with a decrease in serum cholesterol. More than 100 pathological mutations have been described in the MVK gene so far, and a founder effect has been hypothesized as responsible for the diffusion of the most frequent disease-associated mutations. In the acute phase of disease, patients affected with MKD present low cholesterol levels comparable to their basal physiologic conditions, already characterized by lower cholesterol levels when compared to healthy individuals. Low cholesterol levels are widely known to correlate with the reduction of cardiovascular events. We hypothesize a selective advantage for heterozygote carriers of the most frequent MVK mutations in those countries where the diet is characterized by high consumption of saturated animal fats rich in cholesterol. This could explain the maintenance in North European population of the main mutations leading to MKD and the distribution world-wide of these mutations that followed the migrations of North European populations

Database tools in genetic diseases research.

The knowledge of the human genome is in continuous progression: a large number of databases have been developed to make meaningful connections among worldwide scientific discoveries. This paper reviews bioinformatics resources and database tools specialized in disseminating information regarding genetic disorders. The databases described are useful for managing sample sequences, gene expression and post-transcriptional regulation. In relation to data sets available from genome-wide association studies, we describe databases that could be the starting point for developing studies in the field of complex diseases, particularly those in which the causal genes are difficult to identify

Analysis of the beta-globin gene in DNA of suspected thalassemic great apes

DNA was recovered from teeth of 2 great ape skeletons, Pan troglodytes (Ptr) and Pongo pygmaeus (Ppy), belonging to a 19th-century zoological collection. The skeletons presented morphological alterations possibly associated with \u3b2-thalassemia: Ptr had deformation of the calvaria and oro-maxillo-facial bones with porotic hyperostosis and extended osteoporotic lesions of the skeleton, while Ppy showed a general marked widening of the calvarial diploe but moderate osteoporotic signs on the post-cranial skeleton. We screened Ptr and Ppy for mutations in the \u3b2-globin gene (exons 1, 2, and 3) because we suspected thalassemia. Ptr \u3b2-globin sequences showed the highest degree of similarity with the human ones (99.8%), while those of Ppy were slightly different (98.2%). The results were consistent with the phylogenetic relationships between their \u3b2-globin gene sequences. We did not find any mutation in the \u3b2-globin gene of Ptr and Ppy; therefore, we conclude that, in spite of skeletal alterations, the 2 subjects analyzed were not affected by \u3b2-thalassemia

Letter: inflammatory bowel disease, complementary and alternative medicine, and genetics

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Lovastatin-induced apoptosis is modulated by geranylgeraniol in a neuroblastoma cell line.

Mevalonic aciduria (MA), the most severe form of mevalonate kinase deficiency (MKD), is still an orphan drug disease and the pathogenetic mechanisms underlying neuronal dysfunction is still poorly understood. In our study we have investigated the apoptotic mechanism mediated by the exposure of the cultured neuroblastoma cell line, SH-SY5Y, to lovastatin in absence or in presence of the isoprenoid, geranylgeraniol, with the aim of unraveling the pathogenesis of MA. Lovastatin, blocks the mevalonate pathway inhibiting the 3-hydroxy-3-methylglutaryl-CoA reductase (HMG-CR), an enzyme of the mevalonate pathway upstream the mevalonate kinase enzyme, reproducing biochemical features similar to those found in MKD. We demonstrate that apoptosis in neuronal lovastatin treated-cells is induced by the mitochondrial pathway, with caspase-9 as the initiator and caspase-3 as the effector caspase. The presence of geranylgeraniol modulates both the caspase-9 and caspase-3 activity in a dose-dependent way, confirming that this isoprenoid enters the mevalonate pathway, is metabolized and finally is able to by-pass the statin biochemical block reconstituting the mevalonate pathway. According to our findings, it should not be the time course adopted that modulates the apoptotic response but rather the isoprenoid itself. Being aware that our results have been obtained using a biochemical model of MKD, and not cells from patients with the disease, we believe our findings increase the knowledge of MA pathogenesis, and may possibly contribute to the development of novel therapeutic strategies