The tumor suppressor protein p53 is essential for neuronal death in several experimental settings and may participate human neurodegenerative disorders. Based upon recent studies characterizing chemical inhibitors of preclinical the cancer therapy field, we synthesized compound pifithrin-alpha evaluated its potential neuroprotective properties models relevant to pathogenesis stroke Pifithrin-alpha protected neurons against apoptosis induced by DNA-damaging agents, amyloid beta-peptide...

The gene encoding a novel protein designated nm23-H1, which was recently identified as identical to the A subunit of nucleotide diphosphate kinase from human erythrocytes, has been proposed play role in tumor metastasis suppression. We report that untreated neuroblastoma tumors contain cellular polypeptide (Mr = 19,000) p19, two-dimensional electrophoretic gels, occurs at significantly higher levels (P 0.0001) primary containing amplified N-myc gene. partial amino acid sequence obtained for...

Abstract Drugs currently used for patients with Parkinson's disease provide temporary relief of symptoms but do not halt or slow the underlying neurodegenerative process. Increasing evidence suggests that neurons die in by a process called apoptosis, which may be triggered mitochondrial impairment and oxidative stress. We report two novel synthetic inhibitors tumor suppressor protein p53, pifithrin‐α (PFT‐α) Z‐1‐117, are highly effective protecting midbrain dopaminergic improving behavioral...

High level expression of the nm23-H1 gene, which encodes for a nucleoside diphosphate kinase, has been found to correlate with diminished metastasis in some tumors but not others. We have previously identified protein product gene two-dimensional electrophoretic gels and designated it p19/nm23. In neuroblastoma, higher levels p19/nm23, are associated amplification N-myc oncogene, large tumor mass, metastasis, were observed advanced stage compared limited disease. Because variable different...

Cathepsin B ( CTSB ) is overexpressed in tumors of the lung, prostate, colon, breast, and stomach. However, evidence primary genomic alterations gene during tumor initiation or progression has been lacking. We have found a novel amplicon at 8p22–23 that results overexpression esophageal adenocarcinoma. Amplified Not I– Hin fI fragments were identified by two-dimensional DNA electrophoresis. Two amplified (D4 D5) cloned yielded unique sequences. Using bacterial artificial chromosome clones...

The abbreviations used are: kb, kilobase(s); PHA, phytohemagglutinin; SDS, sodium dodecyl sulfate; EBV, Epstein-Barr virus; bp, base pair(s). Characterization and Expression of the Gene for Op18phosphatase, T4 DNA ligase, proteinase K were from Bethesda Research Laboratories Boehringer Mannheim.DNA sequencing reagents U. S. Biochemical Corp.The erase-a-base nested deletion system was Promega Biotec.Random primer labeling Amersham Corp.All radioactive isotopes [a-:"P]dCTP (3000 Ci/mmol),...

Tumor suppressor protein, p53, is an intracellular protein that critical within the biochemical cascade leads to cell death via apoptosis. Recent studies identified tetrahydrobenzothiazole analogue, pifithrin-alpha (2), as a p53 inhibitor was effective in protecting neuronal cells against variety of lethal insults and reducing side effects anticancer drugs. As up-regulation has been described common feature several neurodegenerative disorders, including Alzheimer's disease, 2 novel analogues...

Highly potent human β-glucocerebrosidase inhibitors have been synthesized that appear to recognize both carbohydrate and hydrophobic binding sites. The most inhibitor, 6-nonyl isofagomine (see formula), shows an IC50 value at subnanomolar concentrations. These compounds are potential candidates for the development of small-molecule drugs treatment Gaucher disease. Supporting information this article is available on WWW under http://www.wiley-vch.de/contents/jc_2002/2005/z502662_s.pdf or from...

Thalidomide is being increasingly used in the clinical management of a wide spectrum immunologically-mediated and infectious diseases, cancers. However, mechanisms underlying its pharmacological action are still under investigation. In this regard, oral thalidomide clinically valuable treatment erythema nodosum leprosum (ENL) multiple myeloma effectively reduces tumor necrosis factor-alpha (TNF-alpha) levels angiogenesis vivo. This contrasts with relatively weak effects on TNF-alpha vitro...

Two-dimensional (2D) PAGE, using carrier ampholytes for the first-dimension separation, has provided a tool simultaneous analysis of cellular proteins. To extend utility 2D PAGE to preparative level, we have investigated use immobilized pH gradients (IPG) separation. The results obtained indicate that as much 1 mg protein can be loaded onto single IPG gel without loss resolution. Mutant polypeptides previously detected in ampholyte-based gels were equally detectable IPG-based gels. With...

We have identified a beta-thalassemia gene that carries novel nonsense mutation in Chinese patient. This mutation, G to T substitution at the first position of codon 43, changes glutamic acid coding triplet (GAG) terminator (TAG). Based on oligonucleotide hybridization studies 78 and Southeast Asian chromosomes, we estimate this accounts for small minority mutations population. Study expression cloned transient system demonstrated 65% decrease levels normally spliced mutant beta-globin mRNA....

Abstract We have recently described an 18-kilodalton polypeptide (p18) that is present in much greater abundance acute leukemic blast cells (myeloid and lymphoid) than resting or proliferating nonleukemic lymphoid chronic myeloid cells. In this report we describe the cloning of two different sized full-length cDNAs code for p18. The differ their 3'-noncoding regions as a result alternative polyadenylation. Analysis complete nucleotide sequence corresponding amino acid did not reveal...

A series of phenylcarbamate analogues geneserine (8, 10, 12, 14) were synthesized from their counterparts, the physostigmine (2-5), by oxidation. The can undergo tautomerism between N-oxide and 1,2-oxazine structures in a pH- time-dependent manner. Assessment (1)H NMR indicated that structure is adopted at neutral pH compound exists an equilibrium several epimers. Evaluation biological action to inhibit human acetylcholinesterase (AChE) butyrylcholinesterase (BChE), ex vivo, demonstrated (7,...

A chronic imbalance in DNA precursors, caused by one-carbon metabolism impairment, can result a deficiency of repair and increased damage. Although indirect evidence suggests that damage plays role neuronal apoptosis the pathogenesis neurodegenerative disorders, underlying mechanisms are poorly understood. In particular, very little is known about base excision misincorporated uracil survival. To test hypothesis associated with misincorporation critical for survival, we employed an antisense...

We have developed a database of lymphoid polypeptides detected by two-dimensional polyacrylamide gel electrophoresis to aid in studies leukemogenesis and mutation affecting protein structure. In prior studies, we observed 19-kDa phosphopolypeptide which was induced with proliferation mature T cells constitutively expressed immature thymocytes. this report describe the identification polypeptide as phosphorylated form dUTPase (EC 3.6.1.23), following cDNA cloning gene, based on partial amino...