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PubMed1979

Suppression of natural antitumour defence mechanisms by phorbol esters.

Chemical carcinogenesis in certain tissues occurs in at least two stages: initiation, producing irreversible tissue alterations, and promotion (by agents, themselves non-carcinogenic), enhancing the outgrowth of transformed cells. Among the various tumour-promoting compounds isolated from croton oil, phorbol-12-myristate-13-acetate (PMA), is the most potent. Cell culture studies have shown that the phorbol diesters and structurally related substances induce a variety of dramatic changes in diverse eukaryotic cells. Spreading, differentiation, metabolism, DNA synthesis, expression of cell surface glycopeptides, deoxyglucose transport, as well as polyamine, plasminogen activator and ornithine decarboxylase activity are altered. These findings indicate that tumour promoters potentiate expression of the transformed phenotype in cells already malignantly transformed and also induce reversible manifestations of the transformed phenotype in normal cells. It is not known whether these agents additionally influence host effector systems involved in antitumour resistance. The present study is concerned with the effects of PMA on spontaneous in vitro cytotoxicity by macrophages and/or natural killer (NK) cells, and on the resistance to rat fibrosarcoma in vivo considered to depend on these normal effectors, in particular on mononuclear phagocytes.

Animals↗
PubMed1980

Chemical inducers of differentiation in Friend leukaemia cells inhibit lymphocyte mitogenesis.

Several phorbol esters, the potent tumour-promoting agents isolated from croton oil, induce proliferation of human lymphocytes and enhance the mitogenic effect of lectins on bovine lymphocytes. While studying the mitogenic properties of one of these agents, phorbol myristate acetate (PMA), we found that dimethyl sulphoxide (DMSO), frequently used as a solvent for PMA, markedly inhibits PMA-induced mitogenesis at DMSO concentrations that have little effect on phytohaemagglutinin (PHA)-induced responses. DMSO, as well as a variety of other organic compounds, induce erythroid differentiation in Friend leukaemia (FL) cells. Phorbol esters, on the other hand, are potent inhibitors of both spontaneous and induced cellular differentiation. We therefore investigated the relationship between the potency of compounds to induce erythroid differentiation in FL cells and their potency to inhibit lymphocyte proliferation induced by PMA and other mitogens. We report here that many of the compounds that induce erythroid differentiation in FL cells are similar to DMSO in selectively suppressing PMA-induced lymphocyte mitogenesis.

Animals↗
PubMed1980

Phorbol ester-induced differentiation of chronic lymphocytic leukaemia cells.

The croton oil-derived tumour-promoting agent 12-O-tetra-decanoyl-phorbol-13-acetate (TPA) exerts pleiotropic effects on the differentiation and proliferation of both normal and malignant animal and human cells in vitro. TPA is mitogenic in nanomolar concentration to chickens embryo fibroblasts and human T lymphocytes and inhibits the terminal differentiation of various committed embryonic cells and mouse Friend erythroleukaemia or myeloid leukaemia cells. TPA induces a terminal cell differentiation in some murine and human myeloid leukaemia and histiocytic lymphoma cells. We report here the effect of TPA on chronic lymphocytic leukaemia (CLL) biopsy cells in vitro. In four out of five CLL patients studied, TPA induced the appearance of 90-100% of lymphoblastoid and plasmacytoid cells after 4 days of culture. Under the influence of TPA, 86-97% of the cells expressed with time increasing amounts of intracytoplasmic immunoglobulin (C-Ig) of the same phenotype as that detected on the surface (S-Ig) of fresh, non-induced CLL cells. A parallel decrease in both monoclonal S-Ig density and DNA synthesis of the CLL cells was observed. Electron microscopic studies showed a muturation towards plasma cells. We therefore conclude that TPA is capable of inducing differentiation of CLL cells in vitro.

Cell Differentiation↗
PubMed1979

The carcinogenicity of 15,16-dihydro-11-methyl-cyclopenta[a]phenanthren-17-one.

Direct comparison of skin-tumour induction by 15,16-dihydro-11-methylcyclopenta[a]phenanthren-17-one (I) and by benzo[a]pyrene on mouse skin, both by repeated application or by initiation with a single dose followed by promotion with croton oil, demonstrated that these two carcinogens have similar potency. After repeated application of (I) the mean latent period for skin-tumour induction was linearly related to the logarithm of the dose over a 10-fold dose range. Under these conditions, application of the aryl-hydrocarbon-hydroxylase inhibitor 7,8-benzoflavone together with (I) inhibited tumour induction by about 40%. By contrast, in the 2-stage experiment, little effect on tumour incidence or latent period was observed when this inhibitor was applied with the single initiating dose of (I). Co-administration of the epoxide-hydratase inhibitor 1,1,1-trichloropropene oxide caused enhancement by shortening the latent period. After s.c. injection of (I) into mice, a similar number of tumours was induced on skin remote from the site of injection by promotion with corton oil begun either one week or 6 months after initiation. Gastric instillation of (I) into female rats induced mammary adenocarcinomas.

Animals↗
PubMed1997

Reversal of tolerance to the antitransit effects of morphine during acute intestinal inflammation in mice.

1. The aim of investigation was to establish and compare the reversibility of tolerance to the antitransit effects of morphine by three different procedures: (a) acute inflammation of the gut, (b) lorglumide a cholecystokininA (CCKA) receptor antagonist, or (c) MK-801, an N-methyl-D-aspartate (NMDA) receptor ion channel blocker. The type of interaction between morphine and lorglumide or MK-801 on the inhibition of gastrointestinal transit (GIT) in naive animals was also evaluated. 2. Male Swiss CD-1 mice were implanted with 75 mg of morphine base or placebo pellets. Gastrointestinal transit was assessed with a charcoal meal and results expressed as % inhibition of GIT. Inflammation was induced by the intragastric (p.o.) administration of croton oil (CO), while controls received castor oil (CA) or saline (SS). Morphine was administered by subcutaneous (s.c.) or intracerebroventricular (i.c.v.) injection, to naive and tolerant animals treated with CO, CA or SS. Dose-response curves for s.c. morphine were also performed in naive and tolerant mice receiving 5.2 or 7.4 nmol (s.c.) lorglumide or MK-801, respectively. 3. The ED50 values for inhibition of GIT by s.c. morphine were: 45.9 +/- 2.7 and 250.1 +/- 3.1 nmol in naive and tolerant animals, respectively, demonstrating a five fold decrease in the potency of morphine. In naive animals, inflammation (CO) decreased the ED50 of morphine three times (14.4 +/- 2.2 nmol). However, no tolerance to s.c. morphine (ED50 16.4 +/- 2.6 nmol) was manifested during intestinal inflammation. After i.c.v. administration, a similar degree of tolerance to morphine was observed (4.8 fold decrease in potency). Intestinal inflammation had no effect on the ED50 values of i.c.v. morphine in naive and tolerant animals, showing that reversal of tolerance is related to local mechanism/s. Mean values for intestinal pH were 6.9 +/- 0.04 and 6.2 +/- 0.04 in SS and CO treated mice, respectively. In addition, morphine was 74 times more potent by the i.c.v. than by the s.c. route (naive-SS). 4. Morphine and lorglumide interacted synergistically in naive animals; in addition, the administration of lorglumide reversed tolerance to s.c. morphine. No interaction (additivity) was observed in naive animals when morphine and MK-801 were administered in combination. However, the drug completely reversed tolerance to the antitransit effects of morphine. 5. The present investigation shows that acute inflammation of the gut reverses tolerance to the antitransit effects of s.c. morphine by a peripheral mechanism. Qualitatively similar results were obtained after the administration of lorglumide or MK-801. Our results suggest that a local decrease in pH could play an important role during inflammation, while antagonism of endogenous compensatory systems would explain the reversal of tolerance induced by lorglumide or MK-801.

Acute Disease↗
PubMed2006

Effect of Boswellia serrata on intestinal motility in rodents: inhibition of diarrhoea without constipation.

Clinical studies suggest that the Ayurvedic plant Boswellia serrata may be effective in reducing diarrhoea in patients with inflammatory bowel disease. In the present study, we evaluated the effect of a Boswellia serrata gum resin extract (BSE) on intestinal motility and diarrhoea in rodents. BSE depressed electrically-, acetylcholine-, and barium chloride-induced contractions in the isolated guinea-pig ileum, being more potent in inhibiting the contractions induced by acetylcholine and barium chloride. The inhibitory effect of BSE on acetylcholine-induced contractions was reduced by the L-type Ca(2+) channel blockers verapamil and nifedipine, but not by the sarcoplasmic reticulum Ca(2+)-ATPase inhibitor cyclopiazonic acid, by the phosphodiesterase type IV inhibitor rolipram or by the lipoxygenase inhibitor zileuton. 3-acetyl-11-keto-beta-boswellic acid, one of the main active ingredients of B. serrata, inhibited acetylcholine-induced contractions. BSE inhibited upper gastrointestinal transit in croton oil-treated mice as well as castor oil-induced diarrhoea. However, BSE did not affect intestinal motility in control mice, both in the small and in the large intestine. It is concluded that BSE directly inhibits intestinal motility with a mechanism involving L-type Ca(2+) channels. BSE prevents diarrhoea and normalizes intestinal motility in pathophysiological states without slowing the rate of transit in control animals. These results could explain, at least in part, the clinical efficacy of this Ayurvedic remedy in reducing diarrhoea in patients with inflammatory bowel disease.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed2006

Itraconazole suppresses an elicitation phase of a contact hypersensitivity reaction.

Contact dermatitis is caused by epicutaneous exposure to environmentally and/or industrially derived allergens. As the exposure is unavoidable in many instances, therapeutic suppression of allergic inflammation appears to be of clinical relevance. It was recently reported that itraconazole (ITZ), an anti-fungal agent, may be of therapeutic importance in allergic skin diseases. Therefore, we were interested in the effect of ITZ on contact hypersensitivity (CHS). Mice (C3H/HeN or Balb/c) were administered with ITZ orally before sensitization or challenged with haptens (dinitrofluorobenzene or oxazolone). Consequently, the administration of ITZ before challenge, but not before sensitization, significantly suppressed the reaction. Intriguingly, ITZ failed to suppress the irritant dermatitis induced by croton oil or benzalkonium chloride, suggesting that it may affect molecule(s) rather selectively involved in the elicitation of CHS. To further analyze mechanisms involved, splenic T cells obtained from sensitized or naive mice were stimulated with plate-bound anti-CD3 in the presence or absence of ITZ and release of cytokines was tested by ELISA. T cells from hapten-immunized mice produced a significant amount of IFN-gamma, which was markedly suppressed by ITZ. Our study demonstrates that ITZ selectively suppresses the elicitation phase of CHS possibly via downmodulation of IFN-gamma.

Administration, Oral↗
PubMed2000

Ascorbic acid reduction of active chlorine prior to determining Ames mutagenicity of chlorinated natural organic matter (NOM).

Many potable water disinfection byproducts (DBPs) that result from the reaction of natural organic matter (NOM) with oxidizing chlorine are known or suspected to be carcinogenic and mutagenic. The Ames assay is routinely used to assess an overall level of mutagenicity for all compounds in samples from potable water supplies or laboratory studies of DBP formation. Reduction of oxidizing disinfectants is required since these compounds can kill the bacteria or react with the agar, producing chlorinated byproducts. When mutagens are collected by passing potable water through adsorbing resins, active chlorine compounds react with the resin, producing undesirable mutagenic artifacts. The bioanalytical and chemoanalytical needs of drinking water DBP studies required a suitable reductant. Many of the candidate compounds failed to meet those needs, including 2,4-hexadienoic (sorbic) acid, 2,4-pentanedione (acetylacetone), 2-butenoic (crotonic) acid, 2-butenedioic (maleic and fumaric) acids and buten-2-ol (crotyl alcohol). Candidates were rejected if they (1) reacted too slowly with active chlorine, (2) formed mutagenic byproducts, or (3) interfered in the quantitation of known chlorination DBPs. L-Ascorbic acid reacts rapidly and stoichiometrically with active chlorine and has limited interactions with halogenated DBPs. In this work, we found no interference from L-ascorbic acid or its oxidation product (dehydroascorbic acid) in mutagenicity assays of chlorinated NOM using Salmonella typhimurium TA100, with or without metabolic activation (S9). This was demonstrated for both aqueous solutions of chlorinated NOM and concentrates derived from the involatile, ether-extractable chlorinated byproducts of those solutions.

Ascorbic Acid↗
PubMed2003

Asymmetric synthesis of anti-(2S,3S)- and syn-(2R,3S)-diaminobutanoic acid.

Conjugate addition of homochiral lithium N-benzyl-N-alpha-methylbenzylamide to tert-butyl (E)-cinnamate or tert-butyl (E)-crotonate and in situ amination with trisyl azide results in the exclusive formation of the corresponding 2-diazo-3-amino esters in > 95% de. Amination of the lithium (E)-enolates of tert-butyl (3S,alphaR)-3-N-benzyl-N-alpha-methylbenzylamino-3-phenylpropanoate or tert-butyl (3S,alphaS)-3-N-benzyl-N-alpha-methylbenzylaminobutanoate with trisyl azide gives the (2R,3R,alphaR)- and (2S,3S,alphaS )-anti-2-azido-3-amino esters in good yields and in 85% de and > 95% de respectively. Alternatively, tert-butyl anti-(2S,3S,alphaS)-2-hydroxy-3-N-benzyl-N-alpha-methylbenzylaminobutanoate may be converted selectively to tert-butyl anti-(2S,3S,alphaS)-2-azido-3-N-benzyl-N-alpha-methylbenzylaminobutanoate by aziridinium ion formation and regioselective opening with azide. Deprotection of tert-butyl (2S,3S,alphaS)-2-azido-3-aminobutanoate via Staudinger reduction, hydrogenolysis and ester hydrolysis furnishes anti-(2S,3S)-diaminobutanoic acid in 98%, de and 98% ee. The asymmetric synthesis of the diastereomeric syn-(2R,3S)-diaminobutanoic acid (98% de and 98% ee) was accomplished via functional group manipulation of tert-butyl anti-(2S,3S,alphaS)-2-hydroxy-3-N-benzyl-N-alpha-methylbenzylaminobutanoate in a protocol involving azide inversion of tert-butyl (2S,3S)-2-mesyloxy-3-N-Boc-butanoate and subsequent deprotection.

Journal Article↗
PubMed2005

Measurements of biogenic hydrocarbons and carbonyl compounds emitted by trees from temperate warm Atlantic rainforest, Brazil.

This study is part of a three-year project on biogenic volatile organic compound (VOC) emissions from trees of the temperate warm Atlantic rainforest found in the metropolitan area of Sao Paulo City (MASP). No study of VOC emission rates from plant species has been carried out in the temperate warm Atlantic rainforest of Brazil prior to this work. Eleven species were selected (Alchornea sidifolia, Cupania oblongifolia, Cecropia pachystachia, Syagrus romanzoffiana, Casearia sylvestris, Machaerium villosum, Trema micrantha, Croton floribundus, Myrcia rostrata, Solanum erianthum and Ficus insipida) and some of them were studied in urban, sub-urban and forest areas inside the MASP in order to evaluate biogenic VOC composition at sites characterized by different emission sources. Biogenic VOC emissions were determined by placing branches of plants in a dynamic enclosure system, an all-Teflon cuvette, and by sampling the compounds in the air leaving the cuvette. Pre-concentration using adsorbents to retain the VOC, followed by GC-MS after thermal desorption of the sample, was employed to determine the amount of biogenic hydrocarbons. The collection of carbonyl compounds on a 2,4-dinitrophenylhydrazine coated silica followed by HPLC-UV was used to analyze low molecular weight carbonyl compounds. Emission rates of isoprene, alpha-pinene, camphene and limonene ranged from 0.01 to 2.16 microg C h(-1) g(-1) and emission rates of aldehydes (C(2)-C(6)), acrolein, methacrolein and 2-butanone ranged from 1.5 x 10(-2) to 2.3 micro g C h(-1) g (-1). Ambient and leaf temperatures, relative humidity, light intensity, O(3) and NO(x) levels in the local atmosphere were monitored during experiments. It was possible to identify different biogenic VOCs emitted from typical plants of temperate warm Atlantic rainforest. The emission rates were reported as a function of the type of site investigated and were only provided for compounds for which quantification was feasible. Other biogenic compounds were only identified.

Brazil↗
PubMed1970

Fatty acid metabolism in the perfused rat liver.

1. The formation of acetoacetate, beta-hydroxybutyrate and glucose was measured in the isolated perfused rat liver after addition of fatty acids. 2. The rates of ketone-body formation from ten fatty acids were approximately equal and independent of chain length (90-132mumol/h per g), with the exception of pentanoate, which reacted at one-third of this rate. The [beta-hydroxybutyrate]/[acetoacetate] ratio in the perfusion medium was increased by long-chain fatty acids. 3. Glucose was formed from all odd-numbered fatty acids tested. 4. The rate of ketone-body formation in the livers of rats kept on a high-fat diet was up to 50% higher than in the livers of rats starved for 48h. In the livers of fat-fed rats almost all the O(2) consumed was accounted for by the formation of ketone bodies. 5. The ketone-body concentration in the blood of fat-fed rats rose to 4-5mm and the [beta-hydroxybutyrate]/[acetoacetate] ratio rose to 11.5. 6. When the activity of the microsomal mixed-function oxidase system, which can bring about omega-oxidation of fatty acids, was induced by treatment of the rat with phenobarbitone, there was no change in the ketone-body production from fatty acids, nor was there a production of glucose from even-numbered fatty acids. The latter would be expected if omega-oxidation occurred. Thus omega-oxidation did not play a significant role in the metabolism of fatty acids. 7. Arachidonate was almost quantitatively converted into ketone bodies and yielded no glucose, demonstrating that gluconeogenesis from poly-unsaturated fatty acids with an even number of carbon atoms does not occur. 8. The rates of ketogenesis from unsaturated fatty acids (sorbate, undecylenate, crotonate, vinylacetate) were similar to those from the corresponding saturated fatty acids. 9. Addition of oleate together with shorter-chain fatty acids gave only a slightly higher rate of ketone-body formation than oleate alone. 10. Glucose, lactate, fructose, glycerol and other known antiketogenic substances strongly inhibited endogenous ketogenesis but had no effects on the rate of ketone-body formation in the presence of 2mm-oleate. Thus the concentrations of free fatty acids and of other oxidizable substances in the liver are key factors determining the rate of ketogenesis.

Acetoacetates↗
PubMed1976

Effect of pent-4-enoic acid, propionic acid and other short-chain fatty acids on citrulline synthesis in rat liver mitochondria.

19 The effect of pent-4-enoic acid, propionic acid and several other short-chain fatty acids on citrulline synthesis in rat liver mitochondria was studied. 2.Pent-4-enoate at 1 mM inhibited mitochondrial citulline synthesis by about 80-90%. It is concluded that pent-4-enoate inhibits citrulline synthesis by interfering with some aspect of mitochondrial energy metabolism. This results in impairment of mitochondrial ornithine uptake or depletion of mitochondrial ATP, which, in turn, impairs carbamoyl phosphate synthesis or both. Evidence in support of this conclusion includes: pent-4-enoate has no effect on citrulline synthesis supported by succinate or exogenous ATP; pent-4-enoate lowers the medium plus mitochondrial ATP concentration; finally, when glutamate is the oxidizable substrate, pent-4-enoate decreases the carbamoyl phosphate concentration in mitochondria incubated without ornithine to minimize citrulline synthesis and impairs the mitochondrial uptake of ornithine, but it has neither effect when succinate is the oxidizable substrate. 4. Propionate, butyrate and crotonate also inhibit mitochondrial citrulline synthesis, but much less than pent-4-enoate. 5. Acetate, pentanoate, pent-2-enoate, hexanoate, octanoate, isovalerate, tiglylate and alpha-methylbutyrate have little or no effect on mitochondrial citrulline synthesis.

Adenosine Triphosphate↗
PubMed2001

Stress response, tachykinin, and cutaneous inflammation.

In the last decade, several new aspects of glucocorticoid (GC)-actions on immune cells have been recognized. This recognition has been largely obtained through clinical observations of stress-induced exacerbations of certain dermatologic diseases. To clarify whether GC modulates cutaneous inflammatory reactions besides its known anti-inflammatory effect, first we examined the effect of long-term application of topical GC on several kinds of inflammatory responses induced in the murine model and demonstrated that these regimens significantly augmented the classical contact sensitivity reaction, the croton oil-induced irritant reaction, and the IgE-mediated biphasic cutaneous reaction. In addition, large dose topical steroid and its withdrawal enhanced scratching behavior in hapten-challenged mice. This augmented scratching behavior correlated with the induction of preprotachykinin mRNA expression in the challenged skin. In an in vitro experiment, a low-dose, stress-induced level of glucocorticoid significantly upregulated hapten-induced proinflammatory cytokine (IL1alpha) production by murine keratinocyte cell line Pam 212 and induced substance P peptide production from cultured human keratinocytes. Our results suggest that unsuitable use of GC in addition to stress-induced GC may modulate immune function in the skin through aberrant production of tachykinin, such as substance P or other epidermal cell derived cytokines.

Animals↗
PubMed1999

The irritancy of anthralin is inhibited by repeat applications of a subirritant concentration.

Anthralin is a safe, effective treatment for psoriasis, but its efficacy is hampered by the side-effects of irritation and staining of the uninvolved skin. To avoid burning, it is customary to start at low concentrations and increase every 48-72 h until the therapeutically effective concentration is reached, which takes time and appears to prolong treatment. We felt that if the minimal erythema concentration (MEC) of anthralin could be determined initially in an individual, this ought to be near or at the final achievable therapeutic concentration. Hence, by analogy with ultraviolet therapy, treatment could start just below this concentration and thus avoid delay. A series of concentrations of anthralin in Lassar's paste was applied to the back for 3 h, and erythemal responses assessed at 24 and 48 h. MECs (0.015-0.03%) were far below those usually reached during normal therapy. To test the possibility that the skin was adapting to anthralin, we pretreated areas of skin with a subirritant concentration of anthralin (0.007%) for 3 h on 2 consecutive days prior to application of the full dose series. On the pretreated areas, the MEC increased fourfold from 0. 015% to 0.06% (P < 0.01); the concentration of anthralin required to produce the mid-point on the dose-response curve increased from 0. 06% to 0.25% (P = 0.01), demonstrating a clear adaptive response. One pretreatment produced a 52% reduction in erythema compared with control challenge, and maximal 61% inhibition was seen after three applications. Pretreatment with a subirritant concentration of a control irritant, croton oil, had no effect on the response to anthralin and vice versa. Pretreatment of skin with danthron, the non-irritant oxidation product of anthralin, had no effect, suggesting that the attenuation effect is specific to native anthralin. To see whether the attenuation might be due to modulation of xenobiotic metabolizing enzymes, skin was pretreated with inducers and inhibitors of the cytochrome P450 and NADPH-dependent quinone reductase (NDQR) enzyme systems. However, no effect was seen. In conclusion, we have shown that the irritant response to anthralin is attenuated by repeated applications of a subirritant concentration of anthralin; this is not a non-specific response to all irritants, but a specific property of native anthralin, and the enzymes P450 and NDQR are apparently not responsible for this effect.

Adaptation, Physiological↗
PubMed2002

Confocal laser scanning microscopic observation of glycocalyx production by Staphylococcus aureus in mouse skin: does S. aureus generally produce a biofilm on damaged skin?

BACKGROUND: Bacteria that adhere to damaged tissues encase themselves in a hydrated matrix of polysaccharides, forming a slimy layer known as a biofilm. This is the first report of detection of glycocalyx production by Staphylococcus aureus using confocal laser scanning microscopy (CLSM) on damaged skin tissues. OBJECTIVES: To analyse glycocalyx production by S. aureus cells on damaged skin tissues and the influence of polymorphonuclear leucocytes (PMNs) and various antimicrobial agents on its production using CLSM in cyclophosphamide (Cy)-treated (neutropenic) or non-Cy-treated (normal) mice. METHODS: S. aureus cells were inoculated on damaged skin tissues in neutropenic or normal mice with or without topical application of antimicrobial agents. S. aureus cells were stained with safranine, and positive staining with fluorescein isothiocyanate-conjugated concanavalin A was considered to indicate the presence of glycocalyx. RESULTS: All S. aureus cells tested on damaged skin tissues formed microcolonies encircled by glycocalyx. The colony counts of S. aureus cells on croton oil dermatitis in normal mice treated with 2% fusidic acid ointment were about 100 times lower than those in neutropenic mice (control). CONCLUSIONS: As S. aureus cells can generally produce a biofilm on damaged skin tissues, antimicrobial agents may not eradicate S. aureus cells without the help of PMNs. S. aureus glycocalyx may play a crucial role in colonization and adherence to damaged skin tissues.

Animals↗
PubMed1999

Evaluation of skin viscoelasticity and anisotropy by measurement of speed of shear wave propagation with viscoelasticity skin analyzer.

Skin viscoelasticity was evaluated by a fast, noninvasive assay based on the measurement of the speed of elastic shear wave propagation in the skin by a new portable and user-friendly viscoelasticity skin analyzer. The range of speed of elastic shear wave propagation measured by viscoelasticity skin analyzer allows the evaluation of the stiffness of a wide spectrum of artificial materials as well as the viscoelasticity of skin of laboratory animals and human subjects. The directional nature of the measurement enables to monitor the anisotropy of the materials tested. The speed of elastic shear wave propagation was shown to have a positive correlation with the stiffness of the material tested. In symmetric contralateral areas of intact skin in rabbit ears, similar viscoelasticity and anisotropy were observed. Twenty-four hours after the induction of local edema by croton oil, skin stiffness and anisotropy were significantly increased. In healthy human subjects of both sexes significant variations in skin stiffness and anisotropy were observed in three different skin areas along the forearms, but the speed of elastic shear wave propagation was similar in the symmetric contralateral areas. Age (17-65 y) seemed to have a limited effect on the viscoelasticity of the forearm skin. Hydrating creams decreased the stiffness of the forearm skin for only approximately 3 h. The stiffness and anisotropy of the skin of the breasts in female volunteers (20-86 y) increased with age, but the speed of elastic shear wave propagation was similar in symmetric contralateral areas in the same individuals. Based on these results, we propose the application of the viscoelasticity skin analyzer in experimental and clinical practice for quantitative evaluation of skin condition.

Administration, Topical↗
PubMed2003

Sex differences in opioid-induced enhancement of contact hypersensitivity.

Previous research has demonstrated that, in male rats, the magnitude of contact hypersensitivity (CHS) can be enhanced by morphine treatment. The present experiments test the hypothesis that the mu-opioids morphine, etorphine, and buprenorphine would produce significant sex differences in the magnitude of 2,4-dinitrofluorobenzene-induced CHS. During tests conducted over a 192-h period, morphine, etorphine, and buprenorphine administered before elicitation of CHS on the external surface of the ear (pinna) potentiated the CHS response, and the magnitude of this enhancement was significantly greater in females than males. By contrast, morphine had no effect on croton oil-induced irritant contact dermatitis, indicating that morphine's effects on CHS do not generalize to immunologically nonspecific forms of contact dermatitis. Activation of brain mu-opioid receptors is responsible for the effects of morphine on CHS, because intracerebroventricular treatment with the mu-opioid receptor antagonist beta-funaltrexamine blocked morphine potentiation of CHS in females and males. The sex differences in morphine potentiation of CHS appear to be a result of the gonadal hormonal milieu, because castration enhanced the CHS response following vehicle and morphine treatment, whereas ovariectomy significantly attenuated the enhancement of CHS by morphine. Because ovariectomy had no effect on the CHS response following vehicle treatment, the presence of female gonadal hormones may underlie the sex differences in morphine potentiation of CHS in gonadally intact animals. Overall, these results support an increased sensitivity to the modulatory effects of opioids on the CHS response in females that depends on the interaction between gonadal hormones and the central mu-opioid system.

Animals↗
PubMed1999

Anti-inflammatory activities of hypocretenolides from Leontodon hispidus.

Hypocretenolides, a small group of sesquiterpene lactones with an unusual ring structure, are constituents of a small number of species from the Lactuceae tribe (Asteraceae). Three biogenetically closely related 14-hypocretenolides from Leontodon hispidus L. were investigated for a putative anti-inflammatory activity. 14-Hydroxyhypocretenolide-beta-D-glucoside-4'-14"-hydroxyhypocr etenoate significantly exhibited in vivo anti-inflammatory activity in the croton oil-induced mouse ear edema. To obtain first information regarding the molecular targets which might be affected by this constituent, two in vitro bioassays were performed: (i) DNA binding activity of the transcription factor NF-kappa B was evaluated by electrophoretic mobility shift assay (EMSA) using TNF-alpha-activated Jurkat T cells and (ii) nitrite accumulation in cell culture supernatants of LPS-activated RAW 264.7 macrophages was determined as a parameter for inducible nitric oxide synthase (iNOS)-dependent nitric oxide release. In order to gain information about structure-activity relationships, additionally the aglycone 14-hydroxyhypocretenolide and its D-glycoside were investigated in these in vitro systems. 14-Hydroxyhypocretenolide-beta-D-glucoside-4'-14"-hydroxyhypocr etenoate as well as its aglycone exhibited activity in both test systems, whereas the D-glucoside was not or only weakly active.

Animals↗