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PubMed1989

ICRF 187 and polyhydroxyphenyl derivatives fail to protect against bleomycin induced lung injury.

The potential protective effects of ICRF 187, Didox, Amidox and VF 165 were investigated in models of bleomycin, or bleomycin and hyperoxia induced lung injury. ICRF 187, a bispiperazinedione compound, is a strong chelating agent which blocks a number of free radical mediated processes. The polyhydroxyphenyl derivatives, Didox, Amidox and VF 165, demonstrate degrees of Fe chelating activities and free radical scavenging abilities. Hamsters treated with 5.0 U/kg bleomycin followed by treatment with ICRF 187 or Didox exhibited similar mortality to the bleomycin alone treated group. In a second study, a low dose of bleomycin (1.2 U/kg) was used followed by exposure to 70% oxygen. Treatment with ICRF 187, Didox, Amidox, or VF 165 failed to protect against lung injury; with the ICRF 187 and Amidox groups exhibiting significantly increased rates of mortality over that seen in animals treated only with bleomycin and hyperoxia. No animals treated with the agents alone died. Histopathology documented that all bleomycin-treated hamsters died of severe pneumonitis. Additionally, in the agent-treated groups there was a prominent proliferation of type II pneumocytes, which demonstrated marked anaplasia, a feature not typical of early bleomycin and hyperoxia lung injury. In conclusion, ICRF 187 and the polyhydroxyphenyl derivative, Amidox, paradoxically increase bleomycin- and hyperoxia-induced lung injury. The possible mechanisms of this interaction include: (1) increased availability of Fe to bleomycin; (2) interference with the healing process; or (3) inhibition of endogenous protective effects of SOD.

2,4-Dichlorophenoxyacetic Acid↗
PubMed2005

The carboxy-terminal end of the peptide deformylase from Mycobacterium tuberculosis is indispensable for its enzymatic activity.

The peptide deformylase in bacteria is involved in removal of N-formyl group from newly synthesized proteins. The gene encoding this enzyme from Mycobacterium tuberculosis was cloned and expressed in Escherichia coli. The enzyme activity of the recombinant protein (mPDF) was insensitive to modulation by common monovalent/divalent cations. Kinetic analysis, using N-formylmethionine-alanine as the substrate, yielded K(cat)/K(m) of approximately 1220 M(-1)s(-1). Actinonin, a naturally occurring antibiotic, and 1,10-ortho-phenanthroline strongly inhibited the enzyme activity. The mPDF was very stable at 30 degrees C with a half-life of approximately 4h and exhibited resistance to oxidizing agents, like H(2)O(2). Thus, the mPDF achieved distinction in its behavior among any reported iron-containing peptide deformylases. Furthermore, amino acid sequence analysis of mPDF revealed the presence of an unusually long carboxy-terminal end (residues 182-197), which is atypical for any gram-positive bacteria. Our results, through deletion analysis, for the first time established the role of this region in mPDF enzyme activity.

Amidohydrolases↗
PubMed2006

Identification and transcriptional organization of aerobactin transport and biosynthesis cluster genes of Vibrio hollisae.

We had previously reported that Vibrio hollisae produces aerobactin in response to iron starvation. In the present study, we identified in V. hollisae ATCC33564 the aerobactin system cluster which consists of eight genes, hatCDB, iucABCD and iutA. The hatCDB genes encode proteins homologous to components of bacterial ATP binding cassette transport systems for ferric aerobactin. The iucABCD and iutA orthologs code for aerobactin biosynthesis enzymes and the ferric aerobactin receptor, respectively. In accordance with their iron-regulated expression, putative Fur box sequences were found within the respective promoter regions of hatC, iucA and iutA. The monocistronic iutA transcript was detected by northern blotting. Moreover, phenotypic comparison between the wild-type strain and its targeted gene disruptants supported the biological functions that were expected for the respective operons and genes on the basis of the homology search. The arrangement of the aerobactin gene clusters thus far found in Vibrio and enterobacterial species was compared and discussed from an evolutionary point of view.

Amino Acid Sequence↗
PubMed2006

A comparative study of metabolic engineering anti-metabolite tolerance in Escherichia coli.

A problem in strain engineering is that mutations that benefit the expression of a phenotype in one environment may impose a cost to biological fitness in a new environment. The overall objective of this study was to improve understanding of this phenomenon within the context of a classic anti-metabolite selection strategy. We have engineered Escherichia coli using three mutagenesis techniques (chemical mutagenesis, insertional mutagenesis, and plasmid-based overexpression) and assessed the relative costs and benefits to biological fitness of mutants selected for tolerance to five amino acid analogs whose target amino acids (glutamatic acid, aspartic acid, tryptophan, glycine, and serine) differ in metabolic connectivity and biosynthetic energy requirements. Our major findings include (i) the fold increase in anti-metabolite tolerance, independent of mutagenesis strategy, was much greater for aspartic acid beta-hydroxamate (AAH) compared to all other tested hydroxamates, (ii) increased tolerance to glutamic acid gamma-hydroxamate (GAH) was not achieved using any of the mutagenesis strategies, and (iii) characteristics of the anti-metabolite, rather than those of the corresponding metabolite, were more important in determining the ability to increase tolerance.

Drug Tolerance↗
PubMed2002

Actin filament formation, reorganization and migration are impaired in hepatic stellate cells under influence of trichostatin A, a histone deacetylase inhibitor.

BACKGROUND/AIMS: Previously, trichostatin A (TSA), a histone deacetylase inhibitor, has been shown to exhibit strong antifibrotic characteristics in hepatic stellate cells (HSC), which are known to play a central role in chronic liver diseases. TSA retained a more quiescent phenotype in spite of culture conditions that favor transdifferentiation into activated HSC. METHODS: To identify TSA-sensitive genes, differential mRNA display, Northern and Western blot analysis were used and genes were functionally validated by using contraction and motility assays. RESULTS: TSA prevented new actin filament formation by down-regulation of two nucleating proteins, actin related protein 2 (Arp2) and Arp3, and by up-regulation of adducin like protein 70 (ADDL70) and gelsolin, two capping proteins. RhoA, a key mediator in the development of the actin cytoskeleton, decreased following TSA exposure. Expression of proteins of Class III intermediate filaments was affected by TSA. Furthermore, F-actin and G-actin were expressed heterogeneously under influence of TSA. Functionally, TSA treatment abrogated migration of quiescent HSC, while migration was reduced in transitional HSC. The endothelin-1-induced contractility properties of HSC was not affected by TSA. CONCLUSIONS: These data indicate that TSA affects the development of the actin cytoskeleton in quiescent HSC and thereby abrogates the process of HSC transdifferentiation.

Actin Cytoskeleton↗
PubMed2006

Mixtures of SCFA, composed according to physiologically available concentrations in the gut lumen, modulate histone acetylation in human HT29 colon cancer cells.

Intake of fibre has beneficial properties on gut health. Butyrate, a product of bacterial gut fermentation, is thought to contribute to positive effects by retarding growth and enhancing apoptosis of tumour cells. One mechanism is seen in its capacity to modulate histone acetylation and thereby transcriptional activity of genes. Next to butyrate, propionate and acetate are also major products of gut fermentation and together they may exert different potencies of cellular effects than butyrate alone. Since virtually nothing is known on combination effects by SCFA mixtures, here we had the aim to assess how physiological relevant concentrations and mixtures of SCFA modulate histone acetylation in human colon cells. HT29 colon cancer cells were incubated with mixtures of butyrate, acetate and propionate and with the individual compounds as controls. Histone acetylation was determined with acid-urea gel electrophoresis and immunoblotting. Acetylated histones slowly increased over 24 h and persisted up to 72 h in butyrate-treated HT29 cells. Butyrate (5-40 mM) and propionate (20-40 mM) enhanced histone acetylation significantly after 24 h incubation, whereas acetate (2.5-80 mM) was ineffective. Mixtures of these SCFA also modulated histone acetylation, mainly due to additive effects of butyrate and propionate, but not due to acetate. In conclusion, physiological concentrations of propionate together with butyrate could have more profound biological activities than generally assumed. Together, these SCFA could possibly mediate important processes related to an altered transcriptional gene activation and thus contribute to biological effects possibly related to cancer progression or prevention.

Acetates↗
PubMed1994

Protection against a lethal dose of endotoxin by an inhibitor of tumour necrosis factor processing.

Tumour necrosis factor (tumour necrosis factor-alpha/cachectin) plays a critical role in certain physiological defensive responses but causes severe damage to the host organism when produced in excess. There are two forms of tumour necrosis factor, a type II membrane protein of relative molecular mass 26,000 (26K) and a soluble, 17K form generated from the cell-bound protein by proteolytic cleavage. The two forms of tumour necrosis factor and lymphotoxin-alpha (tumour necrosis factor-beta/lymphotoxin), a related protein, have similar but apparently not identical biological activities. A therapeutic agent which inhibited the release of tumour necrosis factor, but did not reduce the cell-associated activity or the level of lymphotoxin-alpha, might preserve the benefits of these cytokines while preventing tumour necrosis factor-induced damage. Here we describe a potent inhibitor of tumour necrosis factor processing and report that it protects mice from a lethal dose of endotoxin.

Amino Acid Sequence↗
PubMed2004

The mood stabilizer valproic acid stimulates GABA neurogenesis from rat forebrain stem cells.

Valproate, an anticonvulsant drug used to treat bipolar disorder, was studied for its ability to promote neurogenesis from embryonic rat cortical or striatal primordial stem cells. Six days of valproate exposure increased by up to fivefold the number and percentage of tubulin beta III-immunopositive neurons, increased neurite outgrowth, and decreased by fivefold the number of astrocytes without changing the number of cells. Valproate also promoted neuronal differentiation in human fetal forebrain stem cell cultures. The neurogenic effects of valproate on rat stem cells exceeded those obtained with the neurotrophins brain-derived growth factor (BDNF) or NT-3, and slightly exceeded the effects obtained with another mood stabilizer, lithium. No effect was observed with carbamazepine. Most of the newly formed neurons were GABAergic, as shown by 10-fold increases in neurons that immunostained for GABA and the GABA-synthesizing enzyme GAD65/67. Double immunostaining for bromodeoxyuridine and tubulin beta III showed that valproate increased by four- to fivefold the proliferation of neuronal progenitors derived from rat stem cells and increased cyclin D2 expression. Valproate also regulated the expression of survival genes, Bad and Bcl-2, at different times of treatment. The expression of prostaglandin E synthase, analyzed by quantitative RT-PCR, was increased by ninefold as early as 6 h into treatment by valproate. The enhancement of GABAergic neuron numbers, neurite outgrowth, and phenotypic expression via increases in the neuronal differentiation of neural stem cell may contribute to the therapeutic effects of valproate in the treatment of bipolar disorder.

Animals↗
PubMed2006

Effects of extracellular matrix-degrading proteases matrix metalloproteinases 3 and 9 on spatial learning and synaptic plasticity.

Rats learning the Morris water maze exhibit hippocampal changes in synaptic morphology and physiology that manifest as altered synaptic efficacy. Learning requires structural changes in the synapse, and multiple cell adhesion molecules appear to participate. The activity of these cell adhesion molecules is, in large part, dependent on their interaction with the extracellular matrix (ECM). Given that matrix metalloproteinases (MMPs) are responsible for transient alterations in the ECM, we predicted that MMP function is critical for hippocampal-dependent learning. In support of this, it was observed that hippocampal MMP-3 and -9 increased transiently during water maze acquisition as assessed by western blotting and mRNA analysis. The ability of the NMDA receptor channel blocker MK801 to attenuate these changes indicated that the transient MMP changes were in large part dependent upon NMDA receptor activation. Furthermore, inhibition of MMP activity with MMP-3 and -9 antisense oligonucleotides and/or MMP inhibitor FN-439 altered long-term potentiation and prevented acquisition in the Morris water maze. The learning-dependent MMP alterations were shown to modify the stability of the actin-binding protein cortactin, which plays an essential role in regulating the dendritic cytoskeleton and synaptic efficiency. Together these results indicate that changes in MMP function are critical to synaptic plasticity and hippocampal-dependent learning.

Analysis of Variance↗
PubMed1987

Iron uptake in Mycelia sterilia EP-76.

The cyclic trihydroxamic acid, N,N',N''-triacetylfusarinine C, produced by Mycelia sterilia EP-76, was shown to be a ferric ionophore for this organism. The logarithm of the association constant k for the ferric triacetylfusarinine C chelate was determined to be 31.8. Other iron-chelating agents, such as rhodotorulic acid, citric acid, and the monomeric subunit of triacetylfusarinine C, N-acetylfusarinine, delivered iron to the cells by an indirect mechanism involving iron exchange into triacetylfusarinine C. In vitro ferric ion exchange was found to be rapid with triacetylfusarinine C. Gallium uptake rates comparable to those of iron were observed with the chelating agents that transport iron into the cell. Ferrichrome, but not ferrichrome A, was also capable of delivering iron and gallium to this organism, but not by an exchange mechanism. Unlike triacetylfusarinine C, the 14C-ligand of ferrichrome was retained by the cell. A midpoint potential of -690 mV with respect to the saturated silver chloride electrode was obtained for the ferric triacetylfusarinine C complex, indicating that an unfavorable reduction potential was not the reason for the use of a hydrolytic mechanism of intracellular iron release from the ferric triacetylfusarinine C chelate.

Biological Transport, Active↗