Effects of different obesogenic diets on joint integrity, inflammation and intermediate monocyte levels in a rat groove model of osteoarthritis.

Introduction: Obesogenic diets aggravate osteoarthritis (OA) by inducing low-grade systemic inflammation, and diet composition may affect OA severity. Here, we investigated the effect of diet on joint damage and inflammation in an OA rat model. Methods: Wistar-Han rats (n = 24) were fed a chow, a high-fat (HF) diet, or a high-fat/high-sucrose (HFS) for 24 weeks. OA was induced unilaterally 12 weeks after the diet onset by groove surgery, and compared to sham surgery or no surgical intervention (contralateral limb). Knee OA severity was determined by OARSI histopathology scoring system. At several timepoints monocyte populations were measured using flow cytometry, and joint macrophage response was determined via CD68 immunohistochemistry staining. Results: Groove surgery combined with HF or HFS diet resulted in higher OARSI scores, and both HF and HFS diet showed increased circulating intermediate monocytes compared to chow fed rats. Additionally, in the HFS group, minimal damage by sham surgery resulted in an increased OARSI score. HFS diet resulted in the largest metabolic dysregulation, synovial inflammation and increased CD68 staining in tibia epiphysis bone marrow. Conclusion: Obesogenic diets resulted in aggravated OA development, even with very minimal joint damage when combined with the sucrose/fat-rich diet. We hypothesize that diet-induced low-grade inflammation primes monocytes and macrophages in the blood, bone marrow, and synovium, resulting in joint damage when triggered by groove OA inducing surgery. When the metabolic dysregulation is larger, as observed here for the HFS diet, the surgical trigger required to induce joint damage may be smaller, or even redundant.

Predicting geographic and ecological distributions of triatomine species in the southern Mexican state of Puebla using ecological niche modeling.

We analyzed the geographic distribution using ecological niche modeling of three species of triatomines distributed in the Mexican state of Puebla. Punctual records were gathered for a period of 5 yr of fieldwork sampling. We used the genetic algorithm for rule-set production (GARP) to achieve the potential distribution of the ecological niche of triatomines. The models showed that Triatoma barberi and Meccus pallidipennis are sympatric and widely distributed in the central-southern part of the state, whereas T. dimidata is restricted to the northern mountains of the state with no overlapping among other species, M. bassolsae was not modeled because of the scarce number of locality records. We highlighted the warm and dry conditions in southern Puebla as important potential areas for triatomine presence. Finally, we correlated the species potential presence with the human population at risk of acquiring Chagas disease by vector-borne transmission; it is showed that M. pallidipennis presents the highest values of both ecological and poverty risk scenarios representing the main potential vector in the state.

In vitro and in vivo effects of Ranunculus peltatus subsp. baudotii methanol extract on models of eicosanoid production and contact dermatitis.

Ranunculus (Crowfoot) species are numerous and they are all reputed to be counter-irritants and are used in several topical conditions. In order to study the pharmacological mechanisms of action underlying this popular use, a methanol extract of Ranunculus peltatus was tested in vitro in various assays involving eicosanoid and human elastase release by intact cells as well as in vivo, with models of delayed-type hypersensitivity (DTH) contact dermatitis. The extract proved to be a selective inhibitor of the cyclooxygenase-1 pathway, producing the total inhibition of 12-(S)-HHTrE release at 200 microg/mL, while leaving both 5-lipoxygenase and 12-lipoxygenase activities unaffected at the same dose. The n-hexane, chloroform and ethyl acetate fractions of the crude methanol extract inhibited LTB(4) release by intact rat peritoneal neutrophils, but more polar fractions were inactive and did not increase the 5-LOX activity as seen previously for extracts of other Ranunculus species. In the in vivo models, the methanol extract reduced the dinitrofluorobenzene (DNFB)-induced oedema by 40%, but failed to inhibit the oedema brought on by oxazolone. The results agree with the age-old assertion that Water Crowfoot species can be used as a topical antiinflammatory remedy without the prominent irritant action that accompanies the application of non-aquatic Ranunculus species.

Effects of plant alkylphenols on cytokine production, tyrosine nitration and inflammatory damage in the efferent phase of contact hypersensitivity.

BACKGROUND AND PURPOSE: The phenolic compounds isoprenylhydroquinone glucoside (IHG), 3,5-dicaffeoylquinic acid (DCA), and its methyl ester (DCE) have previously been shown to inhibit both contact hypersensitivity (CHS) and peroxynitrite reactivity. The present work seeks to establish a relationship between the anti-inflammatory effect and the release of cytokines and tyrosine nitration in skin. EXPERIMENTAL APPROACH: Murine CHS was developed by means of sensitization and challenge with dinitrofluorobenzene (DNFB) or oxazolone. Ear swelling was measured 24 and 96 h after challenge. Interleukin (IL)-1beta, IL-4, and tumour necrosis factor (TNF)-alpha were measured by ELISA; and the expression of inducible nitric oxide synthase (iNOS) was detected by Western blotting. Histological samples were analysed for 3-nitrotyrosine. KEY RESULTS: In the oxazolone model, DCE reduced the 24 h swelling by 54% whereas the effect of DCA was lower (40% inhibition). All the test compounds reduced IL-1beta values 24 h after challenge with DNFB or oxazolone, DCE particularly inhibited IL-4 production (74% and 78%, respectively; P<0.01). Tyrosine nitration was also markedly reduced by DCE. In general, the test compounds limited the presence of polymorphonuclear (PMN) leukocytes in the skin. CONCLUSIONS AND IMPLICATIONS: These results suggest that the effect of 3,5-dicaffeoylquinic esters on CHS is associated with a decrease in the production of interleukins, but not with the inhibition of iNOS expression. Moreover, esterification of the carboxyl group at C-1 enhanced protection against tyrosine nitration in the skin.

Demethylnobiletin inhibits delayed-type hypersensitivity reactions, human lymphocyte proliferation and cytokine production.

BACKGROUND AND PURPOSE: Our aim was to examine the effect of demethylnobiletin on various experimental models of delayed-type hypersensitivity (DTH) reactions and to determine its influence on the mediators and enzymes involved in these reactions. EXPERIMENTAL APPROACH: DTH was induced in mice by oxazolone, dinitrofluorobenzene (DNFB) and sheep red blood cells (SRBC). The effect of demethylnobiletin on the ensuing DTH was studied, especially in relation to oedema formation, cell infiltration and tissue damage. Its activity on different mediators implicated in DTH reactions was also determined and its effect on nitric oxide synthase (NOS)-2 analysed. Finally, its influence on T lymphocyte proliferation, apoptosis and caspase 3 activity was tested. KEY RESULTS: DTH reactions were all reduced by demethylnobiletin. The experimental results suggest that the compound may act by reducing cell infiltration and by suppressing mediators such as interleukin-2 (IC50=1.63 microM), interleukin-4 (IC50=2.76 microM), tumour necrosis factor-alpha (IC50=0.66 microM), interferon-gamma (IC50=1.35 microM), and interleukin-1 beta (46% at 2.5 microM) and by concomitantly increasing the production of the anti-inflammatory cytokine, interleukin-10. In addition, while demethylnobiletin affected nitric oxide production, it did not modify NOS-2 expression. Finally, demethylnobiletin inhibited proliferation of T cells and induced their apoptosis. CONCLUSIONS AND IMPLICATIONS: Demethylnobiletin decreased DTH reactions induced by various agents. This finding, along with the fact that the compound has a low toxicity and exhibits several other interesting properties, could pave the way for other structurally related citroflavonoids to be used as pharmacological agents in complementary therapies.

Anti-inflammatory profile of dehydrocostic acid, a novel sesquiterpene acid with a pharmacophoric conjugated diene.

Sesquiterpene acids are natural products that, in contrast with the thoroughly studied sesquiterpene lactones, have received little pharmacological attention. A good source of this class of compounds is Inula viscosa (Asteraceae), a plant with documented anti-inflammatory effects. The present paper gives the results of our investigations on the biochemical mechanisms involved in the anti-inflammatory activity of one such compound, dehydrocostic acid. The most salient findings were that in vitro dehydrocostic acid inhibits leukotriene B(4) production (IC(50)=22 microM), elastase activity (IC(50)=43 microM) and bee venom phospholipase A(2) activity (IC(50)=17 microM). Furthermore, this sesquiterpenoid was effective on some models of acute edema induced by PLA(2) and 12-O-tetradecanoylphorbol 13-acetate (TPA) Comparison of these data with that known for ilicic acid firmly suggests that the presence of a semiplanar ring A is essential for an improved inhibitory activity on inflammatory mediators.

Medicinal plants and antimicrobial activity.

In the present paper, we analyze the past, present and future of medicinal plants, both as potential antimicrobial crude drugs as well as a source for natural compounds that act as new anti-infection agents. In the past few decades, the search for new anti-infection agents has occupied many research groups in the field of ethnopharmacology. When we reviewed the number of articles published on the antimicrobial activity of medicinal plants in PubMed during the period between 1966 and 1994, we found 115; however, in the following decade between 1995 and 2004, this number more than doubled to 307. In the studies themselves one finds a wide range of criteria. Many focus on determining the antimicrobial activity of plant extracts found in folk medicine, essential oils or isolated compounds such as alkaloids, flavonoids, sesquiterpene lactones, diterpenes, triterpenes or naphtoquinones, among others. Some of these compounds were isolated or obtained by bio-guided isolation after previously detecting antimicrobial activity on the part of the plant. A second block of studies focuses on the natural flora of a specific region or country; the third relevant group of papers is made up of specific studies of the activity of a plant or principle against a concrete pathological microorganism. Some general considerations must be established for the study of the antimicrobial activity of plant extracts, essential oils and the compounds isolated from them. Of utmost relevance is the definition of common parameters, such as plant material, techniques employed, growth medium and microorganisms tested.

Inhibition of nonenzymic lipid peroxidation by benzylisoquinoline alkaloids.

A group of benzylisoquinoline alkaloids, including five simple benzylisoquinolines, three phtalideisoquinolines, six aporphines, three protoberberines, and two benzophenanthridines, have been studied as inhibitors of lipid peroxidation stimulated by Fe2+/cysteine in rat liver microsomal fractions. Protopapaverine, apomorphine, laudanosoline, tetrahydroberberine, isoboldine, bulbocapnine, boldine, anonaine, glaucine, and stepholidine showed antiperoxidative effects, and structure-activity relationships were established. In simple benzylisoquinolines, the presence of phenolic hydroxyls or similar reactive groups is necessary for inhibition of peroxidation, while in aporphines and protoberberines nonhydroxylated compounds can exert antiperoxidative effects. The phtalideisoquinolines and benzophenanthridines tested were inactive.

Structure-activity relationships of polymethoxyflavones and other flavonoids as inhibitors of non-enzymic lipid peroxidation.

Polymethoxylated flavones and C-glycosyl derivatives isolated from medicinal plants besides other flavonoid compounds were studied for their influence on lipid peroxidation induced by FeSO4+ cysteine in rat liver microsomes. A number of hydroxyflavones (e.g. luteolin); C-glycosyl-flavones (e.g. orientin); methoxyflavones (e.g. gardenin D) and flavonols (e.g. datiscetin), as well as the flavanol leucocyanidol and the biflavone amentoflavone behaved as inhibitors of non-enzymic lipid peroxidation. Structure-activity relationships were established and it was observed that the structural features for active polyhydroxylated compounds were different from those of polymethoxylated flavones, antiperoxidative flavonoids possessing a high lipophilicity.

Donor cardiectomy for other transplantation centers.

Inadequate supply of donor hearts is the greatest limitation to wider utilization of heart transplantation. We performed donor cardiectomy for other transplantation centers in three cases. The donor heart functioned well in all cases, and the recipients were all discharged. Donor cardiectomy for other transplantation centers allows utilization of hearts that might otherwise be lost for transplantation.

Effect of selected triterpenoids on chronic dermal inflammation.

The activity of four natural triterpenoids on a 12-O-tetradecanoylphorbol-13-acetate multiple-dose model of skin chronic inflammation was studied. Erythrodiol and ursolic acid were significantly effective. The most important features concerning structure-activity relationship and previous data on the effect of these triterpenoids on other inflammatory conditions are discussed.

Oleanonic acid, a 3-oxotriterpene from Pistacia, inhibits leukotriene synthesis and has anti-inflammatory activity.

One of the best known bioactive triterpenoids is oleanolic acid, a widespread 3-hydroxy-17-carboxy oleanane-type compound. In order to determine whether further oxidation of carbon 3 affects anti-inflammatory activity in mice, different tests were carried out on oleanolic acid and its 3-oxo-analogue oleanonic acid, which was obtained from Pistacia terebinthus galls. The last one showed activity on the ear oedema induced by 12-deoxyphorbol-13-phenylacetate (DPP), the dermatitis induced by multiple applications of 12-O-tetradecanoyl-13-acetate (TPA) and the paw oedemas induced by bradykinin and phospholipase A2. The production of leukotriene B4 from rat peritoneal leukocytes was reduced by oleanonic acid with an IC50 of 17 microM. Negligible differences were observed in the response of both triterpenes to DPP, bradykinin, and phospholipase A2, while oleanonic acid was more active on the dermatitis by TPA and on the in vitro leukotriene formation. In conclusion, the presence of a ketone at C-3 implies an increase in the inhibitory effects on models related to 5-lipoxygenase activity and on associated in vivo inflammatory processes.

Antioxidant activity of flavonoids from Sideritis javalambrensis.

Five flavonoid glycosides, 4'-O-methylisoscutellarein 7-O-[6"'-acetylallopyranosyl(1----2)glucopyranoside], 4'-O-methylisoscutellarein 7-O-allopyranosyl(1----2)glucopyranoside, 3'-hydroxy-4'-O-methylisoscutellarein 7-O-[6"'-acetylallopyranosyl(1----2) glucopyranoside], and hypolaetin-8-glucoside have been isolated from Sideritis javalambrensis aerial parts and identified by standard methods. These glycosides have been tested for their antioxidant properties alongside other 7,8-substituted flavonoids using FeSO4/cysteine-induced microsomal lipid peroxidation. Superoxide scavenging activity was assessed in the nitroblue tetrazolium test. Among this series of flavonoids, hypolaetin-8-glucoside is the most potent inhibitor of nonenzymic lipid peroxidation. The antiperoxidative activity of these flavonoids may be related to their superoxide scavenging ability.

On the activity of trifluoperazine and palmitoylcarnitine in mice: delayed hypersensitivity models.

The effect of pre- and post-challenge treatments with trifluoperazine and palmitoylcarnitine, two protein kinase C (PKC) inhibitors characterised by their interaction with the phospholipid enzyme cofactor, on the inflammation caused by delayed hypersensitivity (DTH) to dinitrofluorobenzene (DNFB) and sheep red blood cells (SRBC) in mice is reported. The activity of dexamethasone and two immunosuppressors, azathioprine and methotrexate, is also evaluated. The effectiveness of pre-treatment with each of the test drugs diminished when the DNFB challenge dose increased, whereas trifluoperazine and azathioprine were more active when administered after the challenge at the high DNFB dose. Trifluoperazine, which is also a calmodulin-antagonist, was the more effective of the PKC inhibitors tested on DNFB-DTH (39% and 59% inhibition swelling 24 and 96 h after challenge, respectively). SRBC-DTH was sensitive only to the action of the drugs given after challenge. In this test, PKC inhibitors showed a moderate effect, in the same range as methotrexate, whereas dexamethasone suppressed the reaction. The ability of trifluoperazine in inhibiting cutaneous DTH reaction, depending on the treatment schedule and the hapten challenge dose, has been determined.

Anti-phospholipase A2 and anti-inflammatory activity of Santolina chamaecyparissus.

The activity of the Santolina chamaecyparissus methanol extract was tested against the phospholipase A2 (PLA2)-induced mouse paw edema and in vitro inhibition of PLA2 activity. After fractionation, only the dichloromethane extract was active against the PLA2 in vitro test. In addition, it reduced the edema induced by arachidonic acid, and by 12-O-tetradecanoylphorbol-13-acetate in a multidose test. After chromatography on silicagel and gel filtration on Sephadex, and using an in vitro anti-PLA2 assay-guided process, we have isolated and identified from the dichloromethane extract the flavone nepetin and four sesquiterpenes.

In vivo anti-inflammatory activity of saponins from Bupleurum rotundifolium.

Seven oleanane-type triterpene saponins were isolated from the methanolic extract of the aerial parts of Bupleurum rotundifolium. They were identified on the basis of their spectral data as 3-O-[alpha-L-rhamnopyranosyl (1-->2)-beta-D-glucopyranosyl (1-->2)-beta-D-glucopyranosyl]-28-O-[beta-D-glucopyranosyl (1-->2)-beta-D-glucopyranosyl] echinocystic acid (saponin 1), 3-O-[alpha-L-rhamnopyranosyl (1-->2)-beta-D-glucopyranosyl (1-->2)-beta-D-fucopyranosyl] 11-methoxy-primulagenin A (saponin 2), rotundioside E (saponin 3), rotundioside F (saponin 4), 3beta-sulfate, 28-O-[beta-D-glucopyranosyl (1-->6)-beta-D-glucopyranosyl (1-->2)-beta-D-glucopyranosyl (1-->2)-beta-D-glucopyranosyl] ester of primulagenin A (saponin 5), rotundioside C (saponin 6) and 3-O-[alpha-L-rhamnopyranosyl (1-->2)-beta-D-glucopyranosyl (1-->2)-beta-D-fucopyranosyl] 11-methoxy-16beta,21alpha,28-trihydroxyolean-12-ene (saponin 7). All these saponins proved to be effective against TPA-induced ear edema in mice. Their ID50 were determined to be 248, 288, 128, 99 and 297 nmol/ear for saponin 1, 2, 3, 4 and 6, respectively. Saponins 3 and 6 were also active on a TPA multiple-dose model of skin chronic inflammation.

Antioxidant activity of anti-inflammatory plant extracts.

The antioxidant properties of twenty medical herbs used in the traditional Mediterranean and Chinese medicine were studied. Extracts from Forsythia suspensa, Helichrysum italicum, Scrophularia auriculata, Inula viscosa, Coptis chinensis, Poria cocos and Scutellaria baicalensis had previously shown anti-inflammatory activity in different experimental models. Using free radical-generating systems H. italicum. I. viscosa and F. suspensa protected against enzymatic and non-enzymatic lipid peroxidation in model membranes and also showed scavenging property on the superoxide radical. All extracts were assayed at a concentration of 100 microg/ml. Most of the extracts were weak scavengers of the hydroxyl radical and C. chinensis and P. cocos exhibited the highest scavenging activity. Although S. baicalensis inhibited the lipid peroxidation in rat liver microsomes and red blood cells, the extract showed inhibitory actions on aminopyrine N-demethylase and xanthine oxidase activities as well as an pro-oxidant effect observed in the Fe3+-EDTA-H2O2 system. The results of the present work suggest that the anti-inflammatory activities of the same extracts could be explained, at least in part, by their antioxidant properties.