ABSTRACT
The expansion of DNA repeat sequences is associated with many genetic diseases in humans. Simple bulge DNA structures have been implicated as intermediates in DNA slippage within the DNA repeat regions. To probe the possible role of bulged structures in DNA slippage, we designed and synthesized a pair of simple chiral spirocyclic compounds [Xi Z, Ouyang D & Mu HT (2006) Bioorg Med Chem Lett 16, 1180-1184], DDI-1A and DDI-1B, which mimic the molecular architecture of the enediyne antitumor antibiotic neocarzinostatin chromophore. Both compounds strongly stimulated slippage in various DNA repeats in vitro. Enhanced slippage synthesis was found to be synchronous for primer and template. CD spectra and UV thermal stability studies supported the idea that DDI-1A and DDI-1B exhibited selective binding to the DNA bulge and induced a significant conformational change in bulge DNA. The proposed mechanism for the observed in vitro expansion of long DNA is discussed.
Subject(s)
DNA-Directed DNA Polymerase/metabolism , DNA/chemistry , Glucosamine/pharmacology , Spiro Compounds/pharmacology , Trinucleotide Repeat Expansion/drug effects , DNA/biosynthesis , DNA/drug effects , DNA Replication , Glucosamine/chemistry , Kinetics , Nucleic Acid Conformation , Spiro Compounds/chemistry , Templates, GeneticABSTRACT
OBJECTIVE: To assess the clinical significance of electrophysiological tests of bulbocavernosus reflex (BCR), ischiocavernosus reflex (ICR) and pudenda somatosensory evoked potential (PSEP) for patients with erectile dysfunction (ED). METHODS: Electrophysiological tests of BCR, ICR and PSEP were performed for 232 ED patients with IIEF-5 scores of 2-20 (10.39 +/- 5.52), another 21 normal volunteer controls underwent the same tests, and the results were compared. RESULTS: Abnormal results, such as prolonged and advanced latencies, were found in 94 (40.5%) of the patients, which suggested neurotic ED with different degrees of cauda equine nerve injuries. CONCLUSION: Electrophysiological tests of BCR, ICR and PSEP can objectively reveal the functional state of the cauda equine nerve and offer an important support to the diagnosis of nerve-mediated ED.
Subject(s)
Erectile Dysfunction/physiopathology , Muscle, Smooth/physiopathology , Penis/physiopathology , Reflex/physiology , Adult , Aged , Case-Control Studies , Electrophysiology , Evoked Potentials, Somatosensory , Humans , Male , Middle Aged , Penis/innervationABSTRACT
Synthesis of chiral spirocyclic helical compounds containing leucine that mimic the molecular architecture of the potent DNA bulge binder obtained from the natural product metabolite NCSi-gb has been accomplished. The interaction between the compounds and DNA was studied by circular dichroism (CD) method. The results suggested that the two synthetic diastereoisomers specifically targeted the bulge site of DNA and induced conformational change of bulged DNA greatly.
Subject(s)
DNA/chemistry , DNA/metabolism , Leucine/chemistry , Molecular Mimicry , Nucleic Acid Conformation , Zinostatin/chemistry , Zinostatin/metabolism , Base Sequence , Biological Products/chemistry , Biological Products/metabolism , Circular Dichroism , Cyclization , DNA/chemical synthesis , Leucine/analysis , Nucleic Acid Conformation/drug effects , Nucleic Acid Denaturation , Stereoisomerism , Temperature , TitrimetryABSTRACT
The designed simpler chiral spirocyclic helical compounds that mimic the molecular architecture of the DNA bulge binder NCSi-gb have been prepared. It has been found that the synthesized spirocyclic compounds have strong stimulation effect on DNA slippage synthesis. Their stimulation activities on DNA strand slippage suggest that they may bind to or induce the formation of a non Watson-Crick structure during in vitro replication of DNA triplet repeats.
Subject(s)
DNA Replication/drug effects , DNA/biosynthesis , DNA/genetics , Trinucleotide Repeats/genetics , Amination , Carbohydrates/chemistry , Cyclization , DNA/chemistry , DNA-Directed DNA Polymerase/metabolism , Molecular Structure , Nucleic Acid Conformation , Stereoisomerism , Stimulation, ChemicalABSTRACT
OBJECTIVE: To investigate the association between polymorphism of CYP17 gene and serum hormone concentrations in aged men. METHODS: Eighty-three healthy men at the average age of 66.7 were divided into a < 66.7 group (n = 36) and a > 66.7 group (n = 47), and the polymorphism of CYP17 gene in the 5' promoter region was investigated by PCR using DNA from the men's peripheral blood lymphocytes. A new recognition site was created for the restriction enzyme MspA1 I by transition (T --> C) in the risk allele (A2). Three genotypes A1/A1, A1/A2, A2/A2 were established, serum sex-hormone levels measured, and mean hormone concentration evaluated in each genotype and age group. RESULTS: No evidence was found that the testosterone (T) level, estrogen (E2) level and T/E2 ratio were associated with the genotype of CYP17 gene. There was no significant difference in T and E2 levels between the two groups, but there was a significant increase in the T/E2 ratio (P < 0.05). CONCLUSION: A2 allele does not increase sex hormone levels in aged men, but the T/E, ratio was higher in the > 66.7 group than in the < 66.7 group. This may be closely associated with the mechanism of benign prostate hyperplasia and prostate cancer in aged men.
