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Anecdotal reports of 3 cases illustrating a spectrum of resistant common warts treated with cryotherapy followed by topical imiquimod and salicylic acid.

Imiquimod is an immunomodulator with indirect antiproliferative and antiviral properties known to be effective against anogenital warts. However, its use for common warts has not been validated in prospective, controlled trials. We present 3 anecdotal case reports illustrating one treatment approach for a spectrum of resistant, common warts with combination therapy consisting of cryosurgery followed by administration of imiquimod and salicylic acid. The efficacy of this combined destructive and immunomodulatory therapy proved to be 50% to 100% effective after 6 to 9 weeks.

Adjuvants, Immunologic↗

Beta-1,3 glucan sulfate, but not beta-1,3 glucan, induces the salicylic acid signaling pathway in tobacco and Arabidopsis.

Sulfate substituents naturally occurring in biomolecules, such as oligosaccharides and polysaccharides, can play a critical role in major physiological functions in plants and animals. We show that laminarin, a beta-1,3 glucan with elicitor activity in tobacco (Nicotiana tabacum), becomes, after chemical sulfation, an inducer of the salicylic acid (SA) signaling pathway in tobacco and Arabidopsis thaliana. In tobacco cell suspensions, the oxidative burst induced by the laminarin sulfate PS3 was Ca2+ dependent but partially kinase independent, whereas laminarin triggered a strickly kinase-dependent oxidative burst. Cells treated with PS3 or laminarin remained fully responsive to a second application of laminarin or PS3, respectively, suggesting two distinct perception systems. In tobacco leaves, PS3, but not laminarin, caused electrolyte leakage and triggered scopoletin and SA accumulation. Expression of different families of Pathogenesis-Related (PR) proteins was analyzed in wild-type and mutant tobacco as well as in Arabidopsis. Laminarin induced expression of ethylene-dependent PR proteins, whereas PS3 triggered expression of ethylene- and SA-dependent PR proteins. In Arabidopsis, PS3-induced PR1 expression was also NPR1 (for nonexpressor of PR genes1) dependent. Structure-activity analysis revealed that (1) a minimum chain length is essential for biological activity of unsulfated as well as sulfated laminarin, (2) the sulfate residues are essential and cannot be replaced by other anionic groups, and (3) moderately sulfated beta-1,3 glucans are active. In tobacco, PS3 and curdlan sulfate induced immunity against Tobacco mosaic virus infection, whereas laminarin induced only a weak resistance. The results open new routes to work out new molecules suitable for crop protection.

Arabidopsis↗

Quantitation of the hydroxyl radical adducts of salicylic acid by micellar electrokinetic capillary chromatography: oxidizing species formed by a Fenton reaction.

There has been controversy concerning the products formed by a Fenton reaction. We determined the hydroxyl radical (.OH) generated in a Fenton reaction system with no iron chelator using micellar electrokinetic capillary chromatography (MECC). The hydroxyl radical generated in this Fenton system attacked salicylic acid to produce major products of 2,3- and 2,5-dihydroxybenzoic acid (DHB), 2,3-DHB being prominent. Hydroxyl radical scavengers, such as mannitol, ethanol, thiourea and a ferric chelator, Desferal, significantly diminished the peaks for DHBs, showing production of .OH. We compared the MECC method with the electron paramagnetic resonance (EPR) spin trapping technique. The quantity of DHBs obtained by MECC increased dose-dependently up to 1 microM Fe2+ at a fixed concentration of H2O2, whereas that of the spin adduct by EPR showed a bell-shaped curve. This quantitation of .OH adducts by MECC supports the proposal that the oxidizing species formed by a Fenton reaction with no chelator is .OH. The EPR spin trapping method appears to be erroneous, particularly when iron is present at a higher concentration than hydrogen peroxide. The application of this method to the paraquat effect in vitro is demonstrated, and the possibility for analysis of .OH in vivo is also discussed.

Chromatography↗

Salicylic acid permeation: a comparative study with different vehicles and membranes.

Considering the skin's function, different dermal pharmaceutical forms can be developed according to the type of therapeutic activity, active principle and excipients involved in the formulation, such as "transdermal preparations". In the present study, the permeation parameters of the non-steroidal anti-inflammatory drug, salicylic acid (SA) through synthetic membrane, polyvinyliden difluoride, and a biological membrane, egg shell membrane, with different vehicles, propylene glycol, isopropyl alcohol and carbopol gel, were determined. The reported physicochemical parameters of SA from CG were significantly higher than those obtained using PG and IP. This is attributed to the lipophilic nature of the vehicle that facilitates the release and penetration of the active principle, thus acting sinergically. The permeation profiles of SA allow us to state that permeation kinetics is of first order, so that the flux values obtained are in direct proportion to the specific rates of drug release.

2-Propanol↗

Solubility prediction of salicylic acid in water-ethanol-propylene glycol mixtures using the Jouyban-Acree model.

To show the applicability of a solution model, i.e. the Jouyban-Acree model, for predicting the solubility of a solute in ternary solvent systems based on model constants computed using solubility data of the solute in binary solvent systems, the solubility of salicylic acid in water-ethanol, water-propylene glycol, ethanol-propylene glycol mixtures was determined. A minimum number of three data points from each binary system was used to calculate the binary interaction parameters of the model. Then the solubility in other binary solvent compositions and also in a number of ternary solvents was predicted, and the mean percentage deviation (MPD) was calculated as an accuracy criterion. The overall MPD (+/-SD) was 7.3 (+/-7.3)% and those of a similar predictive model was 15.7 (+/-11.5)%. The mean difference between the proposed and a previous model was statistically significant (paired t-test, p < 0.004).

Algorithms↗

Ethylene-dependent salicylic acid regulates an expanded cell death response to a plant pathogen.

The molecular events associated with susceptible plant responses to disease-causing organisms are not well understood. We have previously shown that ethylene-insensitive tomato plants infected with Xanthomonas campestris pv. vesicatoria have greatly reduced disease symptoms relative to wild-type cultivars. Here we show that salicylic acid (SA) is also an important component of the susceptible disease response. SA accumulates in infected wild-type tissues and is correlated with necrosis but does not accumulate in ethylene-insensitive plants. Exogenous feeding of SA to ethylene-deficient plants restores necrosis, indicating that reduced disease symptoms are associated with failure to accumulate SA. These results indicate a mechanism for co-ordination of phytohormone signals that together constitute a susceptible response to pathogens.

Cell Death↗

Protection by aspirin of indomethacin-induced small intestinal damage in rats: mediation by salicylic acid.

Most of non-steroidal anti-inflammatory drugs (NSAIDs) except aspirin (ASA) produce intestinal damage in rats. In the present study, we re-examined the intestinal toxic effect of ASA in rats, in comparison with various NSAIDs, and investigated why ASA does not cause damage in the small intestine, in relation to its metabolite salicylic acid (SA). Various NSAIDs (indomethacin; 10 mg/kg; flurbiprofen; 20 mg/kg; naproxen; 40 mg/kg; dicrofenac; 40 mg/kg; ASA; 20-200 mg/kg) were administered s.c., and the small intestinal mucosa was examined macroscopically 24 h later. All NSAIDs tested, except ASA, caused hemorrhagic lesions in the small intestine, with a decrease of mucosal PGE(2) contents. ASA did not provoke any damage, despite inhibiting (prostaglandin) PG production, and prevented the occurrence of intestinal lesions induced by indomethacin, in a dose-related manner. This protective action of ASA was mimicked by the equimolar doses of SA (17.8-178 mg/kg). Indomethacin caused intestinal hypermotility, in preceding to the occurrence of lesion, and this event was followed by increases of enterobacterial translocation in the mucosa. Both ASA and SA prevented both the intestinal hypermotility and the bacterial translocation seen after indomethacin treatment. In addition, the protective effect of SA was not significantly influenced by either the adenosine deaminase or the adenosine receptor antagonists. Following administration of ASA, the blood SA levels reached a peak within 30 min and remained elevated for more than 7 h. These results suggest that SA has a cytoprotective action against indomethacin-induced small intestinal lesions, and this action may be associated with inhibition of the intestinal hypermotility and the bacterial translocation, but not mediated by endogenous adenosine. Failure of ASA to induce intestinal damage may be explained, at least partly, by a protective action of SA, the metabolite of ASA.

Adenosine Deaminase↗

Mi-1-Mediated aphid resistance involves salicylic acid and mitogen-activated protein kinase signaling cascades.

The tomato Mi-1 gene confers resistance to root-knot nematodes (Meloidogyne spp.), potato aphids (Macrosiphum eluphorbiae), and whiteflies (Bemisia tabaci and B. tabaci biotype B). Resistance to potato aphid is developmentally regulated and is not associated with induction of a hypersensitive response. The NahG transgene that eliminates endogenous salicylic acid (SA) was used to test the role of the SA signaling pathway in the resistance mediated by Mi-1 to potato aphids. Aphids survived longer on NahG tomato plants than on wild type. However, aphid reproduction was not affected on NahG tomato. Aphid resistance in Mi-1 NahG plants was completely abolished and the phenotype was successfully rescued by application of BTH (benzo(1,2,3)-thiaiazole-7-carbothioic acid S-methyl ester), indicating that the SA signaling pathway is an important component of Mi-1-mediated aphid resistance. Using virus-induced gene silencing, one or more mitogen-activated protein kinase (MAPK) cascades required for Mi-1-mediated aphid resistance were identified. Silencing plants for MAPK kinase (LeMKK2) and MAPKs (LeMPK2 and LeMPK1, or LeMPK3) resulted in attenuation of Mi-1-mediated aphid resistance. These results further demonstrate that resistance gene-mediated signaling events against piercing-sucking insects are similar to those against other plant pathogens.

Animals↗

Controlled levels of salicylic acid are required for optimal photosynthesis and redox homeostasis.

Sudden exposure of plants to high light (HL) leads to metabolic and physiological disruption of the photosynthetic cells. Changes in ROS content, adjustment of photosynthetic processes and the antioxidant pools and, ultimately, gene induction are essential components for a successful acclimation to the new light conditions. The influence of salicylic acid (SA) on plant growth, short-term acclimation to HL, and on the redox homeostasis of Arabidopsis thaliana leaves was assessed here. The dwarf phenotype displayed by mutants with high SA content (cpr1-1, cpr5-1, cpr6-1, and dnd1-1) was less pronounced when these plants were grown in HL, suggesting that the inhibitory effect of SA on growth was partly overcome at higher light intensities. Moreover, higher SA content affected energy conversion processes in low light, but did not impair short-term acclimation to HL. On the other hand, mutants with low foliar SA content (NahG and sid2-2) were impaired in acclimation to transient exposure to HL and thus predisposed to oxidative stress. Low and high SA levels were strictly correlated to a lower and higher foliar H(2)O(2) content, respectively. Furthermore high SA was also associated with higher GSH contents, suggesting a tight correlation between SA, H(2)O(2) and GSH contents in plants. These observations implied an essential role of SA in the acclimation processes and in regulating the redox homeostasis of the cell. Implications for the role of SA in pathogen defence signalling are also discussed.

Acclimatization↗

Structure of a rice beta-glucanase gene regulated by ethylene, cytokinin, wounding, salicylic acid and fungal elicitors.

A rice beta-glucanase gene was sequenced and its expression analyzed at the level of mRNA accumulation. This gene (Gns1) is expressed at relatively low levels in germinating seeds, shoots, leaves, panicles and callus, but it is expressed at higher levels in roots. Expression in the roots appears to be constitutive. Shoots express Gns1 at much higher levels when treated with ethylene, cytokinin, salicylic acid, and fungal elicitors derived from the pathogen Sclerotium oryzae or from the non-pathogen Saccharomyces cereviseae. Shoots also express Gns1 at higher levels in response to wounding. Expression in the shoots is not significantly affected by auxin, gibberellic acid or abscisic acid. The beta-glucanase shows 82% amino acid similarity to the barley 1,3;1,4-beta-D-glucanases, and from hybridization studies it is the beta-glucanase gene in the rice genome closest to the barley 1,3;1,4-beta-glucanase EI gene. The mature peptide has a calculated molecular mass of 32 kDa. The gene has a large 3145 bp intron in the codon for the 25th amino acid of the signal peptide. The gene exhibits a very strong codon bias of 99% G + C in the third position of the codon in the mature peptide coding region, but only 61% G + C in the signal peptide region.

Amino Acid Sequence↗

Correlation of serum aspirin esterase activity and half-life of salicylic acid.

An inverse correlation was found between the serum aspirin esterase activity in human subjects and the biological half-life of salicylic acid in serum and a direct relationship between the values of the elimination rate constant and the activity of this enzyme. The rate of acetylsalicylic acid breakdown may be one of the factors which influences the biological half-life of salicylates in the organism and may participate also in determining the individual response to the administered drug.

Adult↗

Copper--ligand interactions and the physiological free radical processes. Part 3. Influence of histidine, salicylic acid and anthranilic acid on copper-driven Fenton chemistry in vitro.

With a view to the possible use of copper(II)-*OH inactivating ligand (OIL) complexes as regulators of inflammation, the reactivity of the copper(II)-ascorbate system with hydrogen peroxide has been investigated in the presence of three key substances: histidine (the main copper(II) low molecular mass ligand in extracellular fluid), salicylic acid (the well-known nonsteroidal antiinflammatory drug, previously shown to be potentiated by copper(II) in animal models of inflammation), and anthranilic acid (an inactive substance by itself, known to be activated by copper(II) in the same models) at physiological pH (7.4) and inflammatory pH (5.5). Such substances may affect the amount of TBARS detected in solution following copper-mediated Fenton-like reactions through three distinct mechanisms: (i) by decreasing the Cu(II)/Cu(I) redox potential, i.e. at the expense of *OH radical production, (ii) by scavenging *OH radicals in the body of the solution, and/or (iii) by acting as a true OIL, i.e. at the expense of *OH detection. Redox potential measurements of initial solutions have been performed in parallel to TBARS determinations to help discriminate between different ligand influences. Computer-aided speciation has been used to understand the role of copper(II) distribution on the ligand effects characterised. Contrary to previous interpretations, histidine has been found to mainly affect *OH production by lowering the redox potential of the Cu(II)/Cu(I) couple. Salicylate, which has no effect on *OH production, has been confirmed to mainly scavenge *OH radicals in the body of the solution. Anthranilate, which both increases *OH production and decreases *OH detection, behaves as a potential OIL. These results tend to confirm our previous hypothesis that copper potentiation of antiinflammatory substances is indirect, i.e. independent of any interaction between metal and drug, whereas copper activation of substances that are inactive by themselves results from specific metal-substance interactions taking place at inflammatory sites.

Copper↗

Induction of nopaline synthase promoter activity by H2O2 has no direct correlation with salicylic acid.

Transgenic tobacco (Nicotiana tabacum L.) plants carrying a fusion between the nopaline synthase (nos) promoter and chloramphenicol acetyltransferase (CAT) reporter gene (caf) were tested for their response to treatment with H2O2. The nos promoter-driven CAT activity increased significantly by addition of H2O2, reaching the maximum level at 15 mM. Kinetic analysis for CAT activity showed that induction by H2O2 was similar to that of methyl jasmonate (MJ), but was much slower than induction by salicylic acid (SA). Time-course experiments for mRNA level also revealed that the response to H2O2 treatment was similar to that of MJ. The nos promoter displayed a rapid and transient induction of mRNA with SA treatment, with the maximum levels occurring at 3 h, whereas the levels induced by H2O2 or MJ treatment increased continuously during the 11-h experimental period. The antioxidants N-acetyl-L-cysteine and catechol did not alter the SA effect. The responses of the nos promoter to H2O2, MJ, and wounding were significantly reduced by deletions of the CAAT box region and the sequence between -112 and -101. However, these deletions did not significantly alter the SA response. This suggests that H2O2 may have a different mechanism from that of SA for inducing nos promotor activity.

Acetylcysteine↗

Arabidopsis thaliana PAD4 encodes a lipase-like gene that is important for salicylic acid signaling.

The Arabidopsis PAD4 gene previously was found to be required for expression of multiple defense responses including camalexin synthesis and PR-1 gene expression in response to infection by the bacterial pathogen Pseudomonas syringae pv. maculicola. This report describes the isolation of PAD4. The predicted PAD4 protein sequence displays similarity to triacyl glycerol lipases and other esterases. The PAD4 transcript was found to accumulate after P. syringae infection or treatment with salicylic acid (SA). PAD4 transcript levels were very low in infected pad4 mutants. Treatment with SA induced expression of PAD4 mRNA in pad4-1, pad4-3, and pad4-4 plants but not in pad4-2 plants. Induction of PAD4 expression by P. syringae was independent of the regulatory factor NPR1 but induction by SA was NPR1-dependent. Taken together with the previous observation that pad4 mutants have a defect in accumulation of SA upon pathogen infection, these results suggest that PAD4 participates in a positive regulatory loop that increases SA levels, thereby activating SA-dependent defense responses.

Amino Acid Sequence↗

[Possible involvement of hydrogen peroxide and salicylic acid in the legume-rhizobium symbiosis].

H2O2 content was studied in the roots and epicotyls of pea (Pisum sativum L.) with normal (cultivar Marat) and disturbed (non-nodulating mutant K14 and hypernodulating mutant Nod3) regulation of root nodulation after inoculation with active industrial strain of Rhizobium leguminosarum by. viceae 250a/CIAM 1026. Pea biotypes differed by H2O2 content in the roots and epicotyls. Exogenous salicylic acid (SA) (0.2 mM) affected H2O2 and SA contents in the roots in an inoculation-dependent manner. The involvement of hydrogen peroxide and SA as signaling molecules as well as of antibacterial agents in the pea-rhizobium interaction at the initial stages of symbiosis is proposed.

Hydrogen Peroxide↗

Salicylic acid and ethylene pathways are differentially activated in melon cotyledons by active or heat-denatured cellulase from Trichoderma longibrachiatum.

Infiltration of cellulase (EC 3.2.1.4) from Trichoderma longibrachiatum into melon (Cucumis melo) cotyledons induced several key defense mechanisms and hypersensitive reaction-like symptoms. An oxidative burst was observed 3 hours after treatment and was followed by activation of ethylene and salicylic acid (SA) signaling pathways leading to marked induction of peroxidase and chitinase activities. The treatment of cotyledons by heat-denatured cellulase also led to some induction of peroxidase and chitinase activities, but the oxidative burst and SA production were not observed. Co-infiltration of aminoethoxyvinil-glycine (an ethylene inhibitor) with the active cellulase did not affect the high increase of peroxidase and chitinase activities. In contrast, co-infiltration of aminoethoxyvinil-glycine with the denatured enzyme blocked peroxidase and chitinase activities. Our data suggest that the SA pathway (induced by the cellulase activity) and ethylene pathway (induced by heat-denatured and active protein) together coordinate the activation of defense mechanisms. We found a partial interaction between both signaling pathways since SA caused an inhibition of the ethylene production and a decrease in peroxidase activity when co-infiltrated with denatured cellulase. Treatments with active or denatured cellulase caused a reduction in powdery mildew (Sphaerotheca fuliginea) disease.

Adaptation, Physiological↗

The effect of acetyl salicylic acid and dipyridamole on thromboembolic complications in splenectomized patients with myelofibrosis.

The effect of combined treatment with acetyl salicylic acid and dipyridamole on thrombic phenomena was studied in splenectomized patients with an aggressive form of myelofibrosis. 3 of these patients had thrombotic episodes, shortened platelet survival and an abnormal platelet aggregation pattern. The treatment with antiplatelet drugs resulted in a decreased platelet utilization as evidenced by clinical improvement and an increasing platelet concentration.

Aged↗

Salicylic acid regulates flowering time and links defence responses and reproductive development.

Flowering relies on signaling networks that integrate endogenous and external cues. Normally, plants flower at a particular season, reflecting day length and/or temperature cues. However, plants can surpass this seasonal regulation and show precocious flowering under stress environmental conditions. Here, we show that UV-C light stress activates the transition to flowering in Arabidopsis thaliana through salicylic acid (SA). Moreover, SA also regulates flowering time in non-stressed plants, as SA-deficient plants are late flowering. The regulation of flowering time by SA seems to involve the photoperiod and autonomous pathways, but it does not require the function of the flowering time genes CONSTANS (CO), FCA, or FLOWERING LOCUS C (FLC).

Arabidopsis↗