A Divalent Ion Is Crucial in the Structure and Dominant-Negative Function of ID Proteins, a Class of Helix-Loop-Helix Transcription Regulators.
A Divalent Ion Is Crucial in the Structure and Dominant-Negative Function of ID Proteins, a Class of Helix-Loop-Helix Transcription Regulators.
Filed under: Drug and Alcohol Rehabilitation
PLoS One. 2012; 7(10): e48591
Wong MV, Jiang S, Palasingam P, Kolatkar PR
Inhibitors of DNA binding and differentiation (ID) proteins, a dominant-negative group of helix-loop-helix (HLH) transcription regulators, are well-characterized key players in cellular fate determination during development in mammals as well as Drosophila. Although not oncogenes themselves, their upregulation by various oncogenic proteins (such as Ras, Myc) and their inhibitory effects on cell cycle proteins (such as pRb) hint at their possible roles in tumorigenesis. Furthermore, their potency as inhibitors of cellular differentiation, through their heterodimerization with subsequent inactivation of the ubiquitous E proteins, suggest possible novel roles in engineering induced pluripotent stem cells (iPSCs). We present the high-resolution 2.1Å crystal structure of ID2 (HLH domain), coupled with novel biochemical insights in the presence of a divalent ion, possibly calcium (Ca2+), in the loop of ID proteins, which appear to be crucial for the structure and activity of ID proteins. These new insights will pave the way for new rational drug designs, in addition to current synthetic peptide options, against this potent player in tumorigenesis as well as more efficient ways for stem cells reprogramming.
HubMed – drug
A Phage Display Selected 7-mer Peptide Inhibitor of the Tannerella forsythia Metalloprotease-Like Enzyme Karilysin can be Truncated to Ser-Trp-Phe-Pro.
Filed under: Drug and Alcohol Rehabilitation
PLoS One. 2012; 7(10): e48537
Skottrup PD, Sørensen G, Ksiazek M, Potempa J, Riise E
Tannerella forsythia is a gram-negative bacteria, which is strongly associated with the development of periodontal disease. Karilysin is a newly identified metalloprotease-like enzyme, that is secreted from T. forsythia. Karilysin modulates the host immune response and is therefore considered a likely drug target. In this study peptides were selected towards the catalytic domain from Karilysin (Kly18) by phage display. The peptides were linear with low micromolar binding affinities. The two best binders (peptide14 and peptide15), shared the consensus sequence XWFPXXXGGG. A peptide15 fusion with Maltose Binding protein (MBP) was produced with peptide15 fused to the N-terminus of MBP. The peptide15-MBP was expressed in E. coli and the purified fusion-protein was used to verify Kly18 specific binding. Chemically synthesised peptide15 (SWFPLRSGGG) could inhibit the enzymatic activity of both Kly18 and intact Karilysin (Kly48). Furthermore, peptide15 could slow down the autoprocessing of intact Kly48 to Kly18. The WFP motif was important for inhibition and a truncation study further demonstrated that the N-terminal serine was also essential for Kly18 inhibition. The SWFP peptide had a Ki value in the low micromolar range, which was similar to the intact peptide15. In conclusion SWFP is the first reported inhibitor of Karilysin and can be used as a valuable tool in structure-function studies of Karilysin.
HubMed – drug
Short and long term measures of anxiety exhibit opposite results.
Filed under: Drug and Alcohol Rehabilitation
PLoS One. 2012; 7(10): e48414
Fonio E, Benjamini Y, Golani I
Animal models of human diseases of the central nervous system, generalized anxiety disorder included, are essential for the study of the brain-behavior interface and obligatory for drug development; yet, these models fail to yield new insights and efficacious drugs. By increasing testing duration hundredfold and arena size tenfold, and comparing the behavior of the common animal model to that of wild mice, we raise concerns that chronic anxiety might have been measured at the wrong time, for the wrong duration, and in the wrong animal. Furthermore, the mice start the experimental session with a short period of transient adaptation to the novel environment (habituation period) and a long period reflecting the respective trait of the mice. Using common measures of anxiety reveals that mice exhibit opposite results during these periods suggesting that chronic anxiety should be measured during the post-habituation period. We recommend tools for measuring the transient period, and provide suggestions for characterizing the post habituation period.
HubMed – drug
The somatostatin analogue octreotide inhibits growth of small intestine neuroendocrine tumour cells.
Filed under: Drug and Alcohol Rehabilitation
PLoS One. 2012; 7(10): e48411
Li SC, Martijn C, Cui T, Essaghir A, Luque RM, Demoulin JB, Castaño JP, Oberg K, Giandomenico V
Octreotide is a widely used synthetic somatostatin analogue that significantly improves the management of neuroendocrine tumours (NETs). Octreotide acts through somatostatin receptors (SSTRs). However, the molecular mechanisms leading to successful disease control or symptom management, especially when SSTRs levels are low, are largely unknown. We provide novel insights into how octreotide controls NET cells. CNDT2.5 cells were treated from 1 day up to 16 months with octreotide and then were profiled using Affymetrix microarray analysis. Quantitative real-time PCR and western blot analyses were used to validate microarray profiling in silico data. WST-1 cell proliferation assay was applied to evaluate cell growth of CNDT2.5 cells in the presence or absence of 1 µM octreotide at different time points. Moreover, laser capture microdissected tumour cells and paraffin embedded tissue slides from SI-NETs at different stages of disease were used to identify transcriptional and translational expression. Microarrays analyses did not reveal relevant changes in SSTR expression levels. Unexpectedly, six novel genes were found to be upregulated by octreotide: annexin A1 (ANXA1), rho GTPase-activating protein 18 (ARHGAP18), epithelial membrane protein 1 (EMP1), growth/differentiation factor 15 (GDF15), TGF-beta type II receptor (TGFBR2) and tumour necrosis factor (ligand) superfamily member 15 (TNFSF15). Furthermore, these novel genes were expressed in tumour tissues at transcript and protein levels. We suggest that octreotide may use a potential novel framework to exert its beneficial effect as a drug and to convey its action on neuroendocrine cells. Thus, six novel genes may regulate cell growth and differentiation in normal and tumour neuroendocrine cells and have a role in a novel octreotide mechanism system.
HubMed – drug
Calcium-Activated-Calcineurin Reduces the In Vitro and In Vivo Sensitivity of Fluconazole to Candida albicans via Rta2p.
Filed under: Drug and Alcohol Rehabilitation
PLoS One. 2012; 7(10): e48369
Jia Y, Tang RJ, Wang L, Zhang X, Wang Y, Jia XM, Jiang YY
Due to the emergence of drug-resistance, first-line therapy with fluconazole (FLC) increasingly resulted in clinical failure for the treatment of candidemia. Our previous studies found that in vitro RTA2 was involved in the calcineurin-mediated resistance to FLC in C. albicans. In this study, we found that calcium-activated-calcineurin significantly reduced the in vitro sensitivity of C. albicans to FLC by blocking the impairment of FLC to the plasma membrane via Rta2p. Furthermore, we found that RTA2 itself was not involved in C. albicans virulence, but the disruption of RTA2 dramatically increased the therapeutic efficacy of FLC in a murine model of systemic candidiasis. Conversely, both re-introduction of one RTA2 allele and ectopic expression of RTA2 significantly reduced FLC efficacy in a mammalian host. Finally, we found that calcium-activated-calcineurin, through its target Rta2p, dramatically reduced the efficacy of FLC against candidemia. Given the critical roles of Rta2p in controlling the efficacy of FLC, Rta2p can be a potential drug target for antifungal therapies.
HubMed – drug
New Age Tower of Babel – www.wayoflife.org getalifemedia.com With the turn of the twenty-first century there has been a dramatic increase in the popularity and influence of New Age thought. It is also called Human Potential, New Spirituality, Self Spirituality, Self Empowerment, Alternative Spirituality, and Global Transformation. Two decades ago the New Age seemed to be more the doctrine of Hollywood movie stars (Shirley MacLaine’s “I am God”) and Star Wars enthusiasts (“may the force be with you”) and the magic-crystal pop culture of rock & roll hippies than the philosophy of the average person or something to be taken seriously in churches. As we will see, this wasn’t true then, and it definitely isn’t true today. The New Age is on the move! The New Age philosophy has permeated the self-help, personal transformation field; it has leavened education and reached deeply into business, health care, psychological counseling, drug and alcohol rehabilitation, politics, government, sports, even the military. www.wayoflife.org
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