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PubMed1994

Pattern of cytokine gene expression in brains of mice protected by picolinic acid against lethal intracerebral infection with Candida albicans.

Recently, we demonstrated that intracerebral (i.c.) administration of picolinic acid (PLA) confers protection against a lethal local challenge with the opportunistic pathogen Candida albicans. By histopathological studies, we show here that mice receiving PLA treatment survive challenge and no evidence of fungal invasion is found within the brain compartment. In contrast, PLA-untreated mice succumb to infection within 7-10 days and show massive brain colonization with extensive granulomatous reaction. By PCR analysis, we show that, unlike naive brains, PLA-treated brains show transient activation of TNF alpha, IL-1 beta and IL-6 genes. C. albicans infection results in high levels of all cytokine transcripts, the phenomenon being long-lasting in PLA-untreated brains, while gradually declining in PLA-treated brains. The only exception is IL-1 beta, whose levels remain high at the latest time-points tested, also in PLA-treated brains. Finally, IL-1 alpha, constitutively detectable in naive brains, is slightly enhanced by C. albicans challenge, regardless of prior treatment. These findings, together with the knowledge that PLA is a potent co-stimulus for macrophages, suggest the involvement of cytokine circuits, likely of macrophage origin, in anti-Candida resistance established by PLA at the cerebral level.

Animals↗
PubMed1993

Protective effect of picolinic acid on mice intracerebrally infected with lethal doses of Candida albicans.

We have studied the effects of picolinic acid (PLA), a product of tryptophan degradation, on mouse susceptibility to intracerebral infection with Candida albicans. We show that intraperitoneal administration of PLA significantly enhances the median survival time of mice inoculated with the lethal challenge. Furthermore, intracerebral administration of this agent induces a protective state against the local lethal infection, the phenomenon depending upon the administration schedule and doses of PLA employed. According to survival data, yeast growth in the brain as well as yeast colonization of the kidneys are drastically reduced in PLA-treated mice compared with those for untreated controls. Northern (RNA) blot analysis of brain tissues demonstrates that mRNA levels specific for tumor necrosis factor and interleukin 1 are augmented and induced, respectively, after inoculation of PLA. These results indicate that PLA has a protective effect likely involving elicitation of a cytokine response in vivo against fungal infections.

Animals↗
PubMed1987

Antiproliferative activity of picolinic acid due to macrophage activation.

Activation and subsequent enhancement of cytotoxicity of mouse peritoneal macrophages (M phi) by picolinic acid (PLA) in vivo have been reported previously by the authors' group. The optimum dose was found to be 100 mg/kg. PLA-stimulated M phi lysed different tumor targets in vitro, MBL-2 lymphoma cells and Madison 109 lung carcinoma cells, with equal efficiency. Treatment with PLA was performed daily for 5 consecutive days with a dose of 100 mg/kg intraperitoneally in C57/BL mice, which previously had been inoculated with MBL-2 tumor cells. Treatment was initiated on the first day after tumor inoculation. Oral treatment with PLA (200 mg/kg) dissolved in the drinking water was also performed for 7 days. In addition, some groups received PLA treatment 1 or 2 days before tumor implantation but not afterwards, to elucidate the in vivo efficacy of M phi activation. Intraperitoneal therapy with PLA after tumor inoculation resulted in a highly significant increase in lifespan (46%); intraperitoneal pretreatment caused a significant increase (15%); orally administered PLA was without effect. Thus intraperitoneal treatment with PLA was found to have protective and therapeutic effects against the MBL-2 ascites tumor in vivo. These effects are most likely caused by macrophage activation.

Animals↗
PubMed2002

Antagonistic effect of picolinic acid and interferon-gamma on macrophage inflammatory protein-1alpha/beta production.

The L-tryptophan catabolite, picolinic acid (PA), is an activator of macrophage effector functions and an inducer of macrophage inflammatory protein-1alpha (MIP-1alpha) and -1beta (MIPs). We have investigated the regulation of PA-induced MIPs production in mouse macrophages. We demonstrated a dose- and time-dependent downregulation of MIPs mRNA by the Th1 cytokine, IFN-gamma, that was associated with inhibition of intracellular chemokine production and secretion. This effect was IFN-gamma-specific because MIPs induction was unaffected by the Th2 cytokines, IL-10 and IL-4, or the proinflammatory stimulus, LPS. Moreover, MIPs downregulation by IFN-gamma was dependent on both mRNA destabilization and gene transcription inhibition. These results demonstrate that MIP-1alpha/beta production by macrophages is a tightly regulated process resulting from the interaction between inhibitory stimuli derived from the immune system and stimulatory signals of non-immunologic origin. The antagonistic effect of PA and IFN-gamma on MIPs production may be important for the regulation of the inflammatory responses in vivo.

Animals↗
PubMed1994

Picolinic acid protects against quinolinic acid-induced depletion of NADPH diaphorase containing neurons in the rat striatum.

Previous studies in our laboratory have demonstrated that focal injections of picolinic acid (PIC) protect the cholinergic neurons of the nucleus basalis magnocellularis (nbm) against quinolinic acid (QUIN)-induced neurotoxicity. The present study was designed to examine the effects of chronic infusions of QUIN and PIC on nicotinamide adenine dinucleotide (NADPH) diaphorase containing neurons of the rat striatum. Using osmotic minipumps, QUIN (6 nmol/h) and PIC (18 nmol/h) were infused alone or in combination to examine the neurotoxic effects of QUIN and the potential anti-neurotoxic action of PIC. Exposure to QUIN for 7 days severely depleted NADPH diaphorase-positive neurons. When co-infused with this neurotoxic dose of QUIN, PIC attenuated the depletion of NADPH diaphorase neurons induced by QUIN. The infusion of PIC alone did not affect the number of these neurons. These results indicate that PIC itself is not neurotoxic and effectively prevents chronic QUIN-induced neurotoxicity in the rat striatum. Since PIC and QUIN are derived from the same metabolic pathway, a balance between endogenous compounds that produce neurotoxicity and those antagonizing these effects may be important in normal neuronal function.

Amino Acid Oxidoreductases↗
PubMed1988

Influence of dietary picolinic acid on mineral metabolism in the rat.

Male rats were fed isonitrogenous, isocaloric diets containing different amounts of dietary zinc and picolinic acid (PA) (25, 60, 120 ppm Zn, 0, 20, 40, 60 mmol PA/kg diet) and balance collections of urine and faeces made over a 4-day period. Rats fed 25 ppm Zn were in negative Zn and Cu balance during the experiment. Faecal Zn, but not urinary Zn excretion was elevated with increasing dietary Zn supply. Urinary Zn, Cu and Mg excretion increased with increasing intakes of dietary PA, regardless of Zn intake. Tissue Zn levels were unaffected by dietary Zn or PA. It is concluded that dietary PA forms soluble complexes with metal ions which are rapidly absorbed but are then re-excreted in urine and may not be available for metabolism or incorporation into tissues.

Animals↗
PubMed2003

Macrophage activating properties of the tryptophan catabolite picolinic acid.

Recent studies have suggested a role for aminoacid catabolites as important regulators of macrophage (Mphi) activities. We reported previously that picolinic acid (PA), a tryptophan catabolite produced under inflammatory conditions and a costimulus with IFNgamma of Mphi effector functions, is a selective inducer of the Mphi inflammatory protein-1alpha (MIP-1alpha) and -1beta (MIPs), two CC-chemokines involved in the elicitation of the inflammatory reactions and in the development of the Th1 responses. In this study, we have investigated the effects of IFNgamma on PA-induced MIPs expression and secretion by mouse Mphi as well as the regulation of MIP-1alpha/beta receptor, CCR5, by both stimuli alone or in combination. We demonstrated that IFNgamma inhibited MIPs mRNA stimulation by PA in a dose-and time-dependent fashion, despite its ability to induce other CC- or CXC chemokines. MIPs mRNA down-regulation was associated with decreased intracellular chemokine expression and secretion and was dependent on both mRNA destabilization and gene transcription inhibition. Moreover, IFNgamma inhibitory effects were stimulus-specific because MIPs induction by PA was either unaffected or increased by the anti-inflammatory cytokines, IL-10 and IL-4, or the pro-inflammatory stimulus, LPS, respectively. In contrast, we found that IFNgamma increased CCR5 basal expression, whereas PA down-regulated both constitutive and IFNgamma-induced CCR5 mRNA and protein levels. These results demonstrate that IFNgamma and PA have reciprocal effects on the production of MIPs chemokines and the expression of their receptor. The concerted action of IFNgamma and PA on MIP-1alpha/beta chemokine/receptor system is likely to be of pathophysiological significance and to represent an important regulatory mechanism for leukocyte recruitment and distribution into damaged tissues during inflammatory responses.

Animals↗
PubMed2000

The tryptophan catabolite picolinic acid selectively induces the chemokines macrophage inflammatory protein-1 alpha and -1 beta in macrophages.

We previously found that the tryptophan catabolite picolinic acid (PA) is a costimulus for the activation of macrophage effector functions. In this study, we have investigated the ability of PA to modulate the expression of chemokines in macrophages. We demonstrate that PA is a potent activator of the inflammatory chemokines MIP (macrophage inflammatory protein)-1 alpha and MIP-1 beta (MIPs) mRNA expression in mouse macrophages in a dose- and time-dependent fashion and through a de novo protein synthesis-dependent process. The induction by PA occurred within 3 h of treatment and reached a peak in 12 h. The stimulatory effects of PA were selective for MIPs because other chemokines, including monocyte chemoattractant protein-1, RANTES, IFN-gamma-inducible protein-10, MIP-2, and macrophage-derived chemokine, were not induced under the same experimental conditions and were not an epiphenomenon of macrophage activation because IFN-gamma did not affect MIPs expression. Induction of both MIP-1 alpha and MIP-1 beta by PA was associated with transcriptional activation and mRNA stabilization, suggesting a dual molecular mechanism of control. Iron chelation could be involved in MIPs induction by PA because iron sulfate inhibited the process and the iron-chelating agent, desferrioxamine, induced MIPs expression. We propose the existence of a new pathway leading to inflammation initiated by tryptophan catabolism that can communicate with the immune system through the production of PA, followed by secretion of chemokines by macrophages. These results establish the importance of PA as an activator of macrophage proinflammatory functions, providing the first evidence that this molecule can be biologically active without the need for a costimulatory agent.

Adjuvants, Immunologic↗
PubMed2005

Antimicrobial activity of picolinic acid against extracellular and intracellular Mycobacterium avium complex and its combined activity with clarithromycin, rifampicin and fluoroquinolones.

OBJECTIVES: A natural metal ion chelator, picolinic acid (PA), is known to potentiate macrophage antimycobacterial activity. Here, we studied the antimicrobial activity of PA against extracellular and intramacrophage Mycobacterium avium complex (MAC) organisms. METHODS: MAC organisms, MAC-infected macrophages or MAC-infected type II pneumocytes were cultured in the presence or absence of PA with or without antimycobacterial drugs, and residual bacterial cfu of extracellular or intracellular MAC were counted on 7H11 agar plates. RESULTS: First, PA exhibited antimicrobial activity against extracellular and intramacrophage MAC. The effect of PA was mimicked by other metal ion-chelating agents, such as ethylenediamine tetraacetic acid and O,O'-bis (2-aminophenyl) ethyleneglycol-N,N,N',N'-tetraacetic acid. Second, PA potentiated antimicrobial effects of a two-drug combination of clarithromycin/rifampicin and some fluoroquinolones (levofloxacin, sitafloxacin and gatifloxacin) against extracellular and intramacrophage MAC. Similar combined effects of PA with clarithromycin/rifampicin were also seen in the case of MAC residing within type II alveolar epithelial cells. CONCLUSIONS: PA exerted an appreciable anti-MAC activity, when used singly or in combination with some antimycobacterial drugs (clarithromycin/rifampicin and fluoroquinolones), suggesting the usefulness of PA as an adjunct for clinical antimicrobial chemotherapy of MAC infections.

Animals↗
PubMed2004

Alpha-picolinic acid, a fungal toxin and mammal apoptosis-inducing agent, elicits hypersensitive-like response and enhances disease resistance in rice.

Alpha-picolinic acid (PA), a metabolite of tryptophan and an inducer of apoptosis in the animal cell, has been reported to be a toxin produced by some of plant fungal pathogens and used in screening for disease resistant mutants. Here, we report that PA is an efficient apoptosis agent triggering cell death of hypersensitive-like response in planta. Confirmed by Fluorescence Activated Cell Sorter (FACS), rice suspension cells and leaves exhibited programmed cell death induced by PA. The PA-induced cell death was associated with the accumulation of reactive oxygen species that could be blocked by diphenylene iodonium chloride, indicating that the generation of reactive oxygen species was NADPH-oxidase dependent. We also demonstrated the induction of rice defense-related genes and subsequent resistant enhancement by PA against the rice blast fungus Magnaporthe grisea. Hence, it was concluded that the PA-stimulated defense response likely involves the onset of the hypersensitive response in rice, which also provides a simple eliciting tool for studying apoptosis in the plant cell.

Apoptosis↗
PubMed2005

An Os(II)--bisbipyridine--4-picolinic acid complex mediates the biocatalytic growth of au nanoparticles: optical detection of glucose and acetylcholine esterase inhibition.

The complex Os(II)-bisbipyridine-4-picolinic acid, [Os(bpy)(2)PyCO(2)H](2+) (1), mediates the biocatalyzed growth of Au nanoparticles, Au NPs, and enables the spectroscopic assay of biocatalyzed transformations and enzyme inhibition by following the Au NP plasmon absorbance. In one system, [Os(bpy)(2)PyCO(2)H](2+) mediates the biocatalyzed oxidation of glucose and the growth of Au NPs in the presence of glucose oxidase, GOx, AuCl(4) (-), citrate and Au NP seeds. The mechanism of the Au NPs growth involves the oxidation of the [Os(bpy)(2)PyCO(2)H](2+) complex by AuCl(4) (-) to form [Os(bpy)(2)PyCO(2)H](3+) and Au(I). The [Os(bpy)(2)PyCO(2)H](3+) complex mediates the GOx biocatalyzed oxidation of glucose and the regeneration of the mediator 1. Citrate reduces Au(I) and enlarges the Au seeds by the catalytic deposition of gold on the Au NP seeds. In the second system, the enzyme acetylcholine esterase, AChE, is assayed by the catalytic growth of the Au NPs. The hydrolysis of acetylcholine (2) by AChE to choline is followed by the [Os(bpy)(2)PyCO(2)H](3+) mediated oxidation of choline to betaine and the concomitant growth of the Au NPs. The mediated growth of the Au NPs is inhibited by 1,5-bis(4-allyldimethylammonium-phenyl)pentane-3-one dibromide (3). A competitive inhibition process was demonstrated (K(M)=0.13 mM, K(I)=2.6 microM) by following the growth of the Au NPs.

2,2'-Dipyridyl↗
PubMed1982

Antitumor activity of picolinic acid in CBA/J mice.

The growth of a solid tumor induced by im implantation of Ehrlich ascites tumor cells in inbred CBA/J mice was retarded by treatment with an iron chelator, picolinic acid (PLA). Survival of the mice was also significantly increased after PLA treatment. However, the iron chelator deferoxamine had no such effects; tumor growth was slightly enhanced, and survival was decreased.

Animals↗
PubMed2004

Conversion from arenes having a benzene ring to those having a picolinic acid by simple growing cell reactions using Escherichia coli that expressed the six bacterial genes involved in biphenyl catabolism.

The comprehensive bioconversion of aromatic compounds with a benzene ring to a picolinic acid was achieved with a recombinant Escherichia coli strain that expressed the six genes involved in biphenyl catabolism, these being the bphA1(2072)A2A3A4 genes encoding the evolved biphenyl dioxygenase, the bphB gene encoding dihydrodiol dehydrogenase, and the bphC gene encoding catechol 2,3-dioxygenase.

Benzene Derivatives↗
PubMed2002

Blood glucose lowering and toxicological effects of zinc (II) complexes with maltol, threonine, and picolinic acid.

The blood glucose lowering effects in KK-Ay mice with type 2 diabetes mellitus (DM) receiving daily an intraperitoneal (i.p.) administration of Zn(II) complexes with maltol, L-threonine, and picolinic acid for 14 days were estimated under the same conditions, and dose-dependent blood glucose lowering effects in the dose range of 0.2-3.0 mg Zn/kg body weight were found. Among them, the bis(maltolato)Zn(II) complex exhibited the highest blood sugar lowering effect at the dose of 3.0 mg Zn/kg. The improvement of DM was confirmed with oral glucose tolerance tests as well as blood HbA1c levels after the administration of the three Zn(II) complexes at the dose of 3.0 mg Zn/kg. For the purpose of the clinical trial of the complexes in the future, we examined the toxic effects of these three Zn(II) complexes in regard of the LD50 values and hepatic cytochrome P450 levels. The LD50 values of the three Zn(II) complexes exhibited high values compared with that of ZnCl2. No changes of both CYP1A1 and CYP2E1 levels in the liver of KK-Ay mice treated with the three Zn(II) complexes were observed. The obtained results will be important when the complexes are tried for clinical use.

Animals↗
PubMed2004

Picolinic acids as inhibitors of dopamine beta-monooxygenase: QSAR and putative binding site.

Dopamine beta-monooxygenase (DBM, EC 1.14.17.1) catalyzes the oxidation of dopamine into (R)-noradrenaline. DBM inhibitors may act as antihypertensive drugs. A series of 22 picolinic acids substituted in 4- and 5-position was previously synthesized and tested for inhibition of DBM from bovine adrenal medulla. The QSAR of these compounds were investigated by Hansch analysis and comparative molecular field analysis (CoMFA). The correlation of pI(50) values with electronic (nucleophilic substituent constant sigma(p) (-), oxygen net charges and highest occupied molecular orbital energy calculated by AMPAC-AM1), hydrophobic (pi values of R(4)) and steric descriptors (molar refraction and Sterimol parameters of R(5)) indicated that a more negatively charged carboxylate moiety, more lipophilic R(4) groups as well as wider bulk and higher molar refraction of 5-substituents increase DBM inhibition. The CoMFA approach generally reproduced these QSAR in terms of steric and electrostatic field variables, the latter restricted to the carboxylate area. To predict a putative binding site, dopamine and fusaric acid were docked into a partial homology model of DBM derived from a crystal structure of peptidylglycine alpha-hydroxylating monooxygenase (EC 1.14.17.3). The inhibitor is suggested to interact by its carboxylate group with the copper site CuB and the protonated amino group of dopamine according to the uncompetitive type of inhibition. R(4) points to a tyrosine side chain. R(5) protrudes into the fringe of the catalytic crevice. It may "freeze" to the solvated surface of polar amino acids and additionally contact an isoleucine residue. Taken together, the model explains the QSAR results by corresponding types of interaction.

Adrenal Medulla↗
PubMed1983

Increased membrane-associated nucleoside diphosphate kinase activity as a possible basis for enhanced guanine nucleotide-dependent adenylate cyclase activity induced by picolinic acid treatment of simian virus 40-transformed normal rat kidney cells.

A biochemical analysis of an increase in guanine nucleotide-dependent adenylate cyclase activity induced by treatment of cultured SV40-transformed normal rat kidney cells with picolinic acid is described. In purified membranes from drug-treated cells with an ATP regenerating system in assay, GTP- and GTP plus hormone-stimulated adenylate cyclase activities were increased, whereas basal and NaF-stimulated cyclase activities, and steady state rate with guanosine 5'-(beta, gamma-imino)triphosphate were essentially unaltered by drug treatment. In assay systems devoid of ATP regenerating system, the drug-induced increase in cyclase activity was seen with GDP as well as with GTP, it being larger with GDP than with GTP in terms of activity ratio, whereas such an increase was not observed with their analogs, guanosine 5'-O-(2-thiodiphosphate) or guanosine 5'-(beta, gamma-imino)triphosphate. Guanosine 5'-(beta, gamma-imino)triphosphate-stimulated from drug-treated membranes became less sensitive to the inhibition by GDP as shown by a rightward shift in inhibition curve, but this shift could not be reproduced with guanosine 5'-O-(2-thiodiphosphate). From these results, it was concluded that altered guanine nucleotide metabolism in membranes was involved. Neither the amount of guanine nucleotide-binding protein nor its related functions including GTPase activity were changed by drug treatment. However, we observed in the drug-treated cell membranes, an increase in activity of nucleoside diphosphate kinase, an additional factor which has been proposed to play a role in regulating adenylate cyclase by replenishing GTP near the guanine nucleotide binding site (Kimura, N., and Shimada, N. (1983) J. Biol. Chem. 258, 2278-2283). The altered features of adenylate cyclase with the natural guanine nucleotides induced by drug treatment were explained as a result of this enhanced nucleoside diphosphate kinase activity associated with the membranes.

Adenylyl Cyclases↗