Current Molecular Pharmacology - Volume 6, Issue 3, 2013

Transient receptor potential (TRP) channels are important candidates mediating Ca2+ influx in excitable and nonexcitable cells such as normal and neoplastic hematopoietic tissues. They are non selective cation channels implicated in Ca2+ signaling in hematologic tumor cells. Here, we review the growing experimental evidence indicating that TRP channels should be included among the genes whose expression is altered in hematologic malignancies such as leukemias (AML, ALL, CML and CLL), B- and T-lymphomas and multiple myelomas (MM). These effects depend on the widespread roles played by the TRP channels in the modulation of the proliferation, differentiation and apoptosis of the hematopoietic cells. The analysis of the expression of the different TRP channels belonging to the TRPMs, TRPVs, TRPCs, TRPPs channel families expressed in different hematological malignacies, evidenced a widespread expression of TRPV2 channel in the myeloid and lymphoid leukemias, and a very peculiar expression of this channel in different types of B cell lymphomas and multiple myeloma, that is parallel to the restricted expression of TRPV2 in normal immune cells with respect to its presence in other human tissues. In vivo studies in children AML and ALL patients also evidenced the presence of a genetic polymorphism of the TRPM5 gene, that reduced the risk to develop leukemia in the children. Finally, the coexpression of TRPV5 and TRPV6 channels in lymphocytes, and their involvement in the radioresistance of K562 erythroleukemia cells to ionizing radiation exposure is of more interest. Thus in conclusion, the TRP channels represent promising targets for hematologic cancer therapy, and their exploitation may open to novel pharmaceutical and clinical approaches.

In humans, glucocorticoid excess may cause neuropsychiatric symptoms, including psychosis and cognitive impairment, and glucocorticoid signaling hyperactivation may sensitize to substance of abuse. The aim of this work was to evaluate whether exposure to glucocorticoid excess triggers molecular changes in dopaminergic and opioidergic systems within relevant forebrain areas. We acutely exposed Sprague-Dawley rats to dexamethasone, a glucocorticoid analog, or vehicle and evaluated the mRNA expression of dopamine D1 and D2 receptors and enkephalin within the cortex, the striatum, and the midbrain. Dexamethasone reduced mRNA expression of D1 receptor and enkephalin in the cortex. In the striatum, dexamethasone reduced the expression of D1 receptor mRNA, but not that of D2 receptor and enkephalin. No significant changes in D2 receptor mRNA expression were observed in the midbrain. Basal distribution of D1 and D2 receptor mRNA showed a clear-cut striatal/cortical gradient, while this distribution was less obvious for enkephalin mRNA. Dexamethasone increased the cortico-striatal separation in terms of D1 and D2 receptor mRNA expression. These molecular changes may represent adaptive mechanisms to dexamethasone-induced potentiation of dopaminergic and opioidergic transmission, mostly in cortical areas.

The aim of the study was to determine the allele and genotype frequencies of rs1532624 SNP of the cholesteryl ester transfer protein gene (CETP) among 116 Jordanian patients taking statins, and to study the impact of the genotypes on response to statin therapy. The study was approved by the Institutional review Board (IRB) of The Jordan University Hospital. An informed consent was signed by every participant. A single fragment encoding a 307 bp sequence of the CETP gene, including the SNP of interest at position 14645 in intron 7, was amplified using a polymerase chain reaction (PCR) technique directly from whole blood. The PCR product was then subjected to DNA sequencing. The frequencies of the genotypes of the homozygous minor allele (AA), the homozygous major allele (CC), and the heterozygous allele (CA) were 0.121, 0.405, and 0.474, respectively. The minor allele (A) frequency was 0.358. The frequencies did not deviate from Hardy-Weinberg equilibrium. The lipid profile before the start of statin therapy was similar for all genotypes regarding total cholesterol (TC), low density lipoprotein cholesterol (LDL-C), and triglycerides, while high density lipoprotein cholesterol (HDL-C) was significantly higher in the AA genotype. The AA genotype was also associated with significantly lower CETP activity than the other genotypes. The response to statin therapy was less in the AA genotype than the other genotypes for TC and LDL-C. In conclusion, the homozygous minor allele subjects have higher base line HDL-C, and lower CETP activity than the other genotypes (CA and CC). They also have less reduction in TC and LDL-C after statin therapy.

Bisphenol A (BPA), the highest volume chemical produced in the whole world is widely used in the production of polycarbonate plastics and epoxy resins. Polycarbonate plastics are used especially in the manufacture of consumer products. The exposure of BPA to humans occurs through food contamination from polycarbonate bottles and food and beverage cans. Dust is also a contributor to the total daily exposure of BPA. Thus, BPA has a high potential for human consumption. The U.S. Food and Drug Administration (FDA) recently announced concern about the safety of BPA and the need for more research data. This article reviews toxicity of BPA in general and kidney in particular using clinical and experimental literature. BPA is toxic to aquatic organisms, animals and humans. BPA is cytotoxic and mutagenic and exerts various adverse effects on immune, endocrine, reproductive, developmental and nervous systems in animals and human and exhibits toxicity by all routes of exposure. Metabolism of BPA is much more rapid in humans than in rodents. BPA increases estrogen metabolism in the kidney and upregulates cytochrome p-450 aromatase activity by means of steroidogenesis. BPA acts as biomarker for renal disease and exhibits nephrotoxicity. BPA toxicity with reference to human exposure level and also carcinogenicity are lacking. While focusing on kidney, this review suggests that further research is required to evaluate the molecular mechanism of BPA induced nephrotoxicity. Protective role of antioxidants against BPA induced toxicity / nephrotoxicity is discussed in this literature.

Transcription factors (TFs) orchestrate multiple cellular processes through tight regulation via post-translational modifications (PTMs). Thus, decoding the combinations of PTMs should provide critical layer of information that can be integrated into highly specific cellular outputs to reveal a network of genes and their target-specific regulation. Protein modifications play a decisive role in various drug responses and eventually in prognosis for many life-threatening diseases, and recent studies demonstrate that TF-based drug designing must consider structural and functional changes due to PTMs, yet we are just beginning to grasp this enormity and the impact on normal development and disease pathophysiology.

The cannabinoid receptor CB2 is highly expressed in immune cells suggesting an important role in numerous diseases such as inflammation, cancer, osteoporosis and liver diseases relating to modulation of the immune system. As a consequence, activation of receptor CB2 is a promising therapeutic strategy for the treatment of a large range of diseases. Indeed, selective CB2 agonists display beneficial anti-inflammatory, anti-cancer and antifibrogenic properties and positive effects on liver disease and osteoporosis. This article reviews the CB2 involvement in the immune system and the promising therapeutical potential of selective CB2 agonists in the treatment of several immune-related diseases.

Hypoxia has been reported to regulate both stem cell maintenance and differentiation. Wnt signaling is also a key regulator in stem cells. The recent discovery of functional cross-regulation between the Wnt pathway and HIF- 1α/HIF-2α signaling further highlights the complexity of the role of hypoxia in the regulation of stem cells. In this report we reveal that human CML cell lines treated under hypoxic conditions increase the percentage of leukemia stem/initiating-like cells, as judged by surface marker expression, colony forming ability and quiescence. We demonstrate that differential usage of the Kat3 coactivators, CREBBP/Creb Binding Protein (CBP) and EP300 (p300) by catenin, with increased CBP/catenin signaling at the expense of p300/catenin signaling, is mechanistically correlated with the increase in the leukemia stem/initiating-like population. A specific small molecule inhibitor of CBP/catenin dependent transcription, ICG-001, can reverse these effects further demonstrating the critical involvement of CBP/catenin signaling in enhancing and maintaining the leukemia stem/initiating-like cell population under hypoxic conditions.