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Potential Therapeutic Drugs (potential + therapeutic_drug)
Selected AbstractsEffects of rapamycin on accumulation of , -, , - and , -globin mRNAs in erythroid precursor cells from , -thalassaemia patientsEUROPEAN JOURNAL OF HAEMATOLOGY, Issue 5 2006Eitan Fibach Abstract:, We studied the effects of rapamycin on cultures of erythroid progenitors derived from the peripheral blood of 10 , -thalassaemia patients differing widely with respect to their potential to produce foetal haemoglobin (HbF). For this, we employed the two-phase liquid culture procedure for growing erythroid progenitors, high performance liquid chromatography for analysis of HbF production and reverse transcription polymerase chain reaction for quantification of the accumulation of globin mRNAs. The results demonstrated that rapamycin induced an increase of HbF in cultures from all the , -thalassaemia patients studied and an increase of their overall Hb content/cell. The inducing effect of rapamycin was restricted to , -globin mRNA accumulation, being only minor for , -globin and none for , -globin mRNAs. The ability of rapamycin to preferentially increase , -globin mRNA content and production of HbF in erythroid precursor cells from , -thalassaemia patients is of great importance as this agent (also known as sirolimus or rapamune) is already in clinical use as an anti-rejection agent following kidney transplantation. These data suggest that rapamycin warrants further evaluation as a potential therapeutic drug in , -thalassaemia and sickle cell anaemia. [source] Gold (III) porphyrin complexes induce apoptosis and cell cycle arrest and inhibit tumor growth in colon cancerCANCER, Issue 19 2009Shuiping Tu MD Abstract BACKGROUND: Gold (III) compounds have exhibited favorable antitumor properties both in vitro and in vivo. In a previous study, the authors reported that the novel gold (III) complex 1a (gold 1a) exhibited strong cytotoxicity in some tumor cell lines. In the current study, the effect of gold 1a was investigated on colon cancer cells. METHODS: The cytotoxicity of gold 1a was determined by using the 3-(4,5-dimethyl-2-thihazyl)-2,5-diphenyl-2H-tetrazolium bromide method. Flow cytometry was used to detect apoptosis and cell cycle. The expression of protein was evaluated by Western blot assay. Tumor growth in vivo was evaluated in nude mice. RESULTS: Gold 1a exhibited marked cytotoxic effects in vitro to human colon cancer, and the concentration of drug required to inhibit cell growth by 50% compared with control (IC50) values ranged from 0.2 ,M to 3.4 ,M, which represented 8.7-fold to 20.8-fold greater potency than that of cisplatin. Gold 1a significantly induced apoptosis and cell cycle arrest and cleaved caspase 3, caspase 7, and poly(ADP-ribose) polymerase; released cytochrome C, and up-regulated p53, p21, p27, and Bax. In vivo, intraperitoneal injection of gold 1a at doses of 1.5 mg/kg and 3.0 mg/kg significantly inhibited tumor cell proliferation, induced apoptosis, and suppressed colon cancer tumor growth. An acute toxicology study indicated that gold 1a at effective antitumor concentrations did not cause any toxic side effects in mice. CONCLUSIONS: The current results suggested that gold 1a may be a new potential therapeutic drug for colon cancer. Cancer 2009. © 2009 American Cancer Society. [source] The emerging role of adipocytokines as inflammatory mediators in inflammatory bowel diseaseINFLAMMATORY BOWEL DISEASES, Issue 9 2005Konstantinos Karmiris MD Abstract Anorexia, malnutrition, altered body composition and development of mesenteric obesity are well known features of inflammatory bowel disease (IBD). Recent data suggest that dysregulation of protein secretion by white adipose tissue is involved in these manifestations of patients with IBD. Adipocytes are recently recognized as endocrine cells that secrete a variety of bioactive substances known as adipocytokines. There is evidence that adipocytokines are involved in inflammatory and metabolic pathways in human beings. Overexpression of adipocytokines such as leptin, adiponectin and resistin in mesenteric adipose tissue of operated patients with Crohn's disease has recently been reported, suggesting that mesenteric adipocytes in IBD may act as immunoregulating cells. Therefore, it could be suggested that adipocytokines play an important role in the disease pathogenesis. Moreover, modulators of mesenteric adipose function have been suggested as potential therapeutic drugs in IBD. In this review, the importance of white adipose tissue function and adipocytokines, is discussed with respect to IBD. [source] Mutations of key hydrophobic surface residues of 11,-hydroxysteroid dehydrogenase type 1 increase solubility and monodispersity in a bacterial expression systemPROTEIN SCIENCE, Issue 7 2009Alexander J. Lawson Abstract 11,-Hydroxysteroid dehydrogenase type 1 (11,-HSD1) is a key enzyme in the conversion of cortisone to the functional glucocorticoid hormone cortisol. This activation has been implicated in several human disorders, notably the metabolic syndrome where 11,-HSD1 has been identified as a novel target for potential therapeutic drugs. Recent crystal structures have revealed the presence of a pronounced hydrophobic surface patch lying on two helices at the C-terminus. The physiological significance of this region has been attributed to facilitating substrate access by allowing interactions with the endoplasmic reticulum membrane. Here, we report that single mutations that alter the hydrophobicity of this patch (I275E, L266E, F278E, and L279E in the human enzyme and I275E, Y266E, F278E, and L279E in the guinea pig enzyme) result in greatly increased yields of soluble protein on expression in E. coli. Kinetic analyses of both reductase and dehydrogenase reactions indicate that the F278E mutant has unaltered Km values for steroids and an unaltered or increased kcat. Analytical ultracentrifugation shows that this mutation also decreases aggregation of both the human and guinea pig enzymes, resulting in greater monodispersity. One of the mutants (guinea pig F278E) has proven easy to crystallize and has been shown to have a virtually identical structure to that previously reported for the wild-type enzyme. The human F278E enzyme is shown to be a suitable background for analyzing the effects of naturally occurring mutations (R137C, K187N) on enzyme activity and stability. Hence, the F278E mutants should be useful for many future biochemical and biophysical studies of the enzyme. [source] Multivalent Drug Design and Inhibition of Cholera Toxin by Specific and Transient Protein,Ligand InteractionsCHEMICAL BIOLOGY & DRUG DESIGN, Issue 5 2008Jiyun Liu Multivalent inhibitors of the cholera toxin B pentamer are potential therapeutic drugs for treating cholera and serve as models for demonstrating multivalent ligand effects through a structure-based approach. A crucial yet often overlooked aspect of multivalent drug design is the length, rigidity and chemical composition of the linker used to connect multiple binding moieties. To specifically study the role of chemical linkers in multivalent ligand design, we have synthesized a series of compounds with one and two binding motifs connected by several different linkers. These compounds have affinity for and potency against the cholera toxin B pentamer despite the fact that none can simultaneously bind two toxin receptor sites. Results from saturation transfer difference NMR reveal transient, non-specific interactions between the cholera toxin and linker groups contribute significantly to overall binding affinity of monovalent compounds. However, the same random protein,ligand interactions do not appear to affect binding of bivalent molecules. Moreover, the binding affinities and potencies of these ,non-spanning' bivalent ligands appear to be wholly independent of linker length. Our detailed analysis identifies multiple effects that account for the improved inhibitory potencies of bivalent ligands and suggest approaches to further improve the activity of this class of compounds. [source] | ||||||||||