Targeted treatment for osteoarthritis: drugs and delivery system.

The management of osteoarthritis (OA) is a clinical challenge due to the particular avascular, dense, and occluded tissue structure. Despite numerous clinical reports and animal studies, the pathogenesis and progression of OA are still not fully understood. On the basis of traditional drugs, a large number of new drugs have been continuously developed. Intra-articular (IA) administration for OA hastens the development of targeted drug delivery systems (DDS). OA drugs modification and the synthesis of bioadaptive carriers contribute to a qualitative leap in the efficacy of IA treatment. Nanoparticles (NPs) are demonstrated credible improvement of drug penetration and retention in OA. Targeted nanomaterial delivery systems show the prominent biocompatibility and drug loading-release ability. This article reviews different drugs and nanomaterial delivery systems for IA treatment of OA, in an attempt to resolve the inconsonance between in vitro and in vivo release, and explore more interactions between drugs and nanocarriers, so as to open up new horizons for the treatment of OA.

Ribes nigrum Leaf Extract Preferentially Inhibits IFN-γ-Mediated Inflammation in HaCaT Keratinocytes.

Ribes nigrum L. (blackcurrant) leaf extracts, due to high levels of flavonols and anthocyanins, have been shown to exhibit beneficial effects in inflammatory diseases. However, whereas their traditional use has been investigated and validated in several models of inflammation and oxidative stress, the possible impact on skin disorders is still largely unknown. The purpose of this work was to elucidate the effects of R. nigrum leaf extract (RNLE) on keratinocyte-derived inflammatory mediators, elicited by a Th1 or Th2 cytokine milieu. HaCaT cells were challenged with TNF-α, either alone or in combination with the costimulatory cytokines IFN-γ or IL-4, and the release of proinflammatory cytokines and mediators (IL-8, IL-6, s-ICAM-1, and TSLP) was evaluated. The results showed that RNLE preferentially interferes with IFN-γ signaling, demonstrating only negligible activity on TNF-α or IL-4. This effect was attributed to flavonols, which might also account for the ability of RNLE to impair TNF-α/IL-4-induced TSLP release in a cAMP-independent manner. These results suggest that RNLE could have an antiallergic effect mediated in keratinocytes via mechanisms beyond histamine involvement. In conclusion, the discovery of RNLE preferential activity against IFN-γ-mediated inflammation suggests potential selectivity against Th1 type response and the possible use in Th1 inflammatory diseases.

Polyphenols from Lonicera caerulea L. Berry Inhibit LPS-Induced Inflammation through Dual Modulation of Inflammatory and Antioxidant Mediators.

Lonicera caerulea L. berry polyphenols (LCBP) are considered as major components for bioactivity. This study aimed to clarify the molecular mechanisms by monitoring inflammatory and antioxidant mediator actions in lipopolysaccharide (LPS)-induced mouse paw edema and macrophage cell model. LCBP significantly attenuated LPS-induced paw edema (3.0 ± 0.1 to 2.8 ± 0.1 mm, P < 0.05) and reduced (P < 0.05) serum levels of monocyte chemotactic protein-1 (MCP-1, 100.9 ± 2.3 to 58.3 ± 14.5 ng/mL), interleukin (IL)-10 (1596.1 ± 424.3 to 709.7 ± 65.7 pg/mL), macrophage inflammatory protein (MIP)-1α (1761.9 ± 208.3 to 1369.1 ± 56.4 pg/mL), IL-6 (1262.8 ± 71.7 to 499.0 ± 67.1 pg/mL), IL-4 (93.3 ± 25.7 to 50.7 ± 12.5 pg/mL), IL-12(p-70) (580.4 ± 132.0 to 315.2 ± 35.1 pg/mL), and tumor necrosis factor-α (TNF-α, 2045.5 ± 264.9 to 1270.7 ± 158.6 pg/mL). Cell signaling analysis revealed that LCBP inhibited transforming growth factor ß activated kinase-1 (TAK1)-mediated mitogen-activated protein kinase (MAPK) and nuclear factor-κB (NF-κB) pathways, and enhanced the expression of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and manganese-dependent superoxide dismutase (MnSOD) in earlier response. Moreover, cyanidin 3-glucoside (C3G) and (-)-epicatechin (EC), two major components of LCBP, directly bound to TAK1. These data demonstrated that LCBP might inhibit LPS-induced inflammation by modulating both inflammatory and antioxidant mediators.

Cholecalciferol (vitamin D 3) improves cognitive dysfunction and reduces inflammation in a rat fatty liver model of metabolic syndrome.

AIM: The aim of this study was to examine the effects of cholecalciferol on systemic inflammation and memory in the setting of fatty liver disease in rats. MATERIALS AND METHODS: To induce the development of fatty liver disease, the rats were fed a 35% fructose solution over 8 weeks. Group I (n=6) was designated as the control group and fed with standard rat chow. Group II (n=6) was provided with, standard rat chow, and 0.3 µg/kg/day of oral cholecalciferol over a duration of 2 weeks. In addition to standard rat chow, group III (n=6) and group IV (n=6) were given 4 mL of the 35% fructose solution per day via oral gavage for 8 weeks. However, group IV was also given 0.3 µg/kg/day of oral cholecalciferol over 2 weeks. After the treatment period, passive avoidance tasks were performed by all groups. The liver and brain were harvested for subsequent biochemical and histopathologic analyses. KEY FINDINGS: The development of fatty liver extends the memory latency period of passively avoiding tasks after 1 trial. Moreover, there were increases in brain TNF-α and plasma MDA levels according to two-way analysis of variance. Cholecalciferol supplementation decreased the latency period of passively avoiding tasks in rats with hepatosteatosis, and also significantly reduced brain TNF-α and plasma MDA levels. SIGNIFICANCE: Fatty liver may contribute to the development of systemic inflammation, which affects cognition and causes deficits in memory; however, the anti-inflammatory and antioxidant properties of vitamin D may improve the cognitive function of rats with hepatosteatosis.

Inflammatory milieu as an early marker of kidney injury in offspring rats from diabetic mothers.

The present study investigated the early presence of inflammatory response in renal tissue of young offspring from diabetic mothers. The effect of L-arginine (L-arg) supplementation was also investigated. The offspring was divided into four groups: group CO (controls); group DO (diabetic offspring); group CA (CO receiving 2% L-arg solution) and group DA (DO receiving the 2% L-arg solution). Glycemia, arterial pressure and renal function were evaluated; gene and protein expression of pro-inflammatory cytokines were also measured. Blood pressure levels were significantly increased in 2 and 6 month-old DO rats, whereas L-arg administration caused a significant decrease in the DA group, at both ages. DO rats showed a significantly blunted glycemic response to exogenous insulin. In 2 month-old DO animals, renal protein expression of pro-inflammatory molecules was significantly increased. At six months of age, we also observed an increase in gene expression of pro-inflammatory molecules, whereas L-arg supplementation prevented this increase at both ages. Our data suggest that activation of inflammatory pathways is present early in the kidney of DO rats, and that L-arg can attenuate the expression of these markers of tissue inflammation. Our results also reinforce the concept that intrauterine environmental factors are a fundamental determinant in the development of metabolic and vascular diseases later in life.

Neuroinflammation and endoplasmic reticulum stress are coregulated by crocin to prevent demyelination and neurodegeneration.

Endoplasmic reticulum (ER) stress is a homeostatic mechanism, which is used by cells to adapt to intercellular and intracellular changes. Moreover, ER stress is closely linked to inflammatory pathways. We hypothesized that ER stress is an integral component of neuroinflammation and contributes to the development of neurological diseases. In autopsied brain specimens from multiple sclerosis (MS) and non-MS patients, XBP-1 spliced variant (XBP-1/s) was increased in MS brains (p < 0.05) and was correlated with the expression of the human endogenous retrovirus-W envelope transcript, which encodes the glycoprotein, Syncytin-1 (p < 0.05). In primary human fetal astrocytes transfected with a Syncytin-1-expressing plasmid, XBP-1/s, BiP, and NOS2 were induced, which was suppressed by crocin treatment (p < 0.05). Crocin also protected oligodendrocytes exposed to cytotoxic supernatants derived from Syncytin-1-expressing astrocytes (p < 0.05) and NO-mediated oligodendrocytotoxicity (p < 0.05). During experimental autoimmune encephalomyelitis (EAE), the transcript levels of the ER stress genes XBP-1/s, BiP, PERK, and CHOP were increased in diseased spinal cords compared with healthy littermates (p < 0.05), although CHOP expression was not involved in the EAE disease phenotype. Daily treatment with crocin starting on day 7 post-EAE induction suppressed ER stress and inflammatory gene expression in spinal cords (p < 0.05), which was accompanied by preserved myelination and axonal density, together with reduced T cell infiltration and macrophage activation. EAE-associated neurobehavioral deficits were also ameliorated by crocin treatment (p < 0.05). These findings underscored the convergent roles of pathogenic ER stress and immune pathways in neuroinflammatory disease and point to potential therapeutic applications for crocin.

Supplemental and highly elevated tocopherol doses differentially regulate allergic inflammation: reversibility of α-tocopherol and γ-tocopherol's effects.

We have reported that supplemental doses of the α- and γ-tocopherol isoforms of vitamin E decrease and increase, respectively, allergic lung inflammation. We have now assessed whether these effects of tocopherols are reversible. For these studies, mice were treated with Ag and supplemental tocopherols in a first phase of treatment followed by a 4-wk clearance phase, and then the mice received a second phase of Ag and tocopherol treatments. The proinflammatory effects of supplemental levels of γ-tocopherol in phase 1 were only partially reversed by supplemental α-tocopherol in phase 2, but were completely reversed by raising α-tocopherol levels 10-fold in phase 2. When γ-tocopherol levels were increased 10-fold (highly elevated tocopherol) so that the lung tissue γ-tocopherol levels were equal to the lung tissue levels of supplemental α-tocopherol, γ-tocopherol reduced leukocyte numbers in the lung lavage fluid. In contrast to the lung lavage fluid, highly elevated levels of γ-tocopherol increased inflammation in the lung tissue. These regulatory effects of highly elevated tocopherols on tissue inflammation and lung lavage fluid were reversible in a second phase of Ag challenge without tocopherols. In summary, the proinflammatory effects of supplemental γ-tocopherol on lung inflammation were partially reversed by supplemental levels of α-tocopherol but were completely reversed by highly elevated levels of α-tocopherol. Also, highly elevated levels of γ-tocopherol were inhibitory and reversible in lung lavage but, importantly, were proinflammatory in lung tissue sections. These results have implications for future studies with tocopherols and provide a new context in which to review vitamin E studies in the literature.

Long-term prednisolone treatments increase bioactive vitamin B6 synthesis in vivo.

The etiology of vitamin B(6) depletion in inflammation remains unknown. Hepatic vitamin B(6) decreased in adrenalectomized rats, and such reductions were restored by an acute muscle injection of a very high dose of glucocorticoids. We tested the hypothesis that long-term prednisolone treatment for treating inflammation restores vitamin B(6) status by induction of tissue B6 metabolic enzymes. Two independent in vivo models were used. Lewis rats and C57BL/6J mice received prednisolone regimens that reflected clinical prednisolone uses in treating human inflammation. We found: 1) prednisolone increased circulating B6 vitamer pyridoxal 5'-phosphate (PLP; bioactive B6 vitamer), pyridoxal (PL), and 4-pyridoxic acid without altering vitamin B(6) excretion; 2) prednisolone simultaneously induced the hepatic PLP-synthesizing enzyme pyridoxine kinase (PDXK) and pyridoxamine-5'-phosphate oxidase (PMPO) and suppressed PLP catabolic enzyme pyridoxal-5'-phosphate phosphatase (PDXP); and 3) elevations in circulating PL were caused by its release from the liver, not by PLP dephosphorylation (PDXP was suppressed and alkaline phosphatase was unaltered). We conclude that long-term prednisolone treatments promoted hepatic bioactive vitamin B(6) synthesis by inducing the synthesizing enzymes PDXK and PMPO and simultaneously suppressing the catabolic enzyme PDXP. Prednisolone increased circulating B6 vitamer without altering urinary B6 excretion. As the major form of vitamin B(6) across cell membrane, elevated circulating PL may facilitate the cellular uptake and utilization of B6. The elevated plasma PLP may increase vitamin B(6) supply to tissues with a higher B6 demand during inflammation. Results from two independent in vivo models suggested a potential advantage of clinical prednisolone use in treating inflammation with respect to vitamin B(6) status.

Areca-nut extract modulates antigen-specific immunity and augments inflammation in ovalbumin-sensitized mice.

Areca-nut chewing has been linked to oral cancer and many other diseases, in which immune deterioration and tissue inflammation are plausibly involved. Recent studies reported that areca-nut extract (ANE) affected the functionality of lymphocytes and neutrophils in vitro. In the present study, we investigated the immunomodulatory effect of ANE in vivo. Ovalbumin (OVA)-sensitized mice were daily administered with ANE (5-50 mg/kg) for 10 doses by intraperitoneal injection from days 1 to 5 and from 8 to 12. The mice were systemically sensitized with OVA on day 3, and their footpads were challenged with OVA to induce delayed-type hypersensitivity (DTH) reactions on day 13. The serum level of OVA-specific IgM and IgG(1) was significantly attenuated by 5 and 25 mg/kg of ANE, whereas OVA-specific IgG(2a) was markedly enhanced by 50 mg/kg of ANE. The production of interferon (IFN)-γ by splenocytes reexposed to OVA in culture was markedly augmented by ANE (25 and 50 mg/kg). In addition, ANE (25 and 50 mg/kg) demonstrated an enhancing effect on DTH reactions, including the tissue swelling, the infiltration of CD3(+) and F4/80(+) cells, and the expression of IFN-γ and tumor necrosis factor (TNF)-α in the footpads challenged with OVA. The phagocytic activity and TNF-α production by the splenic CD11b(+) cells were also enhanced in ANE-treated groups. Taken together, these results demonstrated that ANE modulated antigen-specific immune responses and promoted inflammatory reactions in vivo, which may contribute to immune deregulation associated with areca-related diseases.

Natural anti-inflammatory products and leukotriene inhibitors as complementary therapy for bronchial asthma.

OBJECTIVE: To assess the efficacy of a combination of Boswellia serrata, licorice root (Glycyrrhiza glabra) and Tumeric root (Curcuma longa) as natural leukotriene inhibitor, antiinflammatory and antioxidant products respectively in controlling bronchial asthma. SUBJECTS AND METHODS: The study comprised 63 patients with bronchial asthma that are further subdivided into two groups .Group 1 receiving oral capsule (combined herb) in a soft-gelatin capsule 3 times daily for 4weeks and group 2 receiving placebo. Plasma leukotriene C(4) (LTC(4))(,) nitric oxide (NO) and malondialdehyde (MDA) levels were measured and pulmonary function was also assessed in all patients enrolled in the study. RESULTS: There was a statistically significant decrease in the plasma levels of LTC(4), (MDA), and NO in target therapy group when compared with placebo group. CONCLUSION: The used extract contained Boswellia serrata, Curcuma longa and Glycyrrhiza has a pronounced effect in the management of bronchial asthma.

Docosahexaenoic acid-enriched fish oil attenuates kidney disease and prolongs median and maximal life span of autoimmune lupus-prone mice.

The therapeutic efficacy of individual components of fish oils (FOs) in various human inflammatory diseases still remains unresolved, possibly due to low levels of n-3 fatty acids docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) or lower ratio of DHA to EPA. Because FO enriched with DHA (FO-DHA) or EPA (FO-EPA) has become available recently, we investigated their efficacy on survival and inflammatory kidney disease in a well-established animal model of human systemic lupus erythematosus. Results show for the first time that FO-DHA dramatically extends both the median (658 d) and maximal (848 d) life span of (NZB x NZW)F1 (B x W) mice. In contrast, FO-EPA fed mice had a median and maximal life span of approximately 384 and 500 d, respectively. Investigations into possible survival mechanisms revealed that FO-DHA (versus FO-EPA) lowers serum anti-dsDNA Abs, IgG deposition in kidneys, and proteinuria. Further, FO-DHA lowered LPS-mediated increases in serum IL-18 levels and caspase-1-dependent cleavage of pro-IL-18 to mature IL-18 in kidneys. Moreover, FO-DHA suppressed LPS-mediated PI3K, Akt, and NF-kappaB activations in kidney. These data indicate that DHA, but not EPA, is the most potent n-3 fatty acid that suppresses glomerulonephritis and extends life span of systemic lupus erythematosus-prone short-lived B x W mice, possibly via inhibition of IL-18 induction and IL-18-dependent signaling.

Different activities of Schinus areira L.: anti-inflammatory or pro-inflammatory effect.

The anti-inflammatory drugs possess many serious side effects at doses commonly prescribed. It is really important to discover novel regulators of inflammation from natural sources with minimal adverse effects. Schinus areira L. is a plant native from South America and is used in folk medicine as an anti-inflammatory herb. For this study, the activity of aqueous extracts on inflammation and the effect on superoxide anion production in mice macrophages were assayed. Aqueous extracts were prepared by soaking herbs in cold water (cold extract), boiling water (infusion), and simmering water (decoction). Cold extract possess an anti-inflammatory activity. Decoction and infusion showed pro-inflammatory activity. Cold extract increased the production of superoxide anion. It has been proposed to use diverse methods to obtain extracts of S. areira L. with different effects. Cold extract, decoction, and infusion could be utilized as extracts or as pharmacological preparations for topical application.

Central interleukin-10 attenuates lipopolysaccharide-induced changes in food intake, energy expenditure and hypothalamic Fos expression.

Lipopolysaccharide (LPS) is often used to mimic acute infection and induces hypophagia, the selective partitioning of fat for energy, and fever. Interleukin-10 (IL-10) is an anti-inflammatory cytokine expressed in the brain which attenuates LPS-induced hypophagia; however the potential sites of interaction within the brain have not been investigated. Hypothalamic orexin (ORX) and melanin-concentrating hormone (MCH) regulate energy expenditure and food intake although the regulation of these neuropeptides through the interactions between central IL-10 and the inflammatory consequences of peripheral LPS have not been investigated. The present study in the rat investigated during the dark phase of the light-dark cycle the ability of central IL-10 (250 ng, i.c.v.) to attenuate the changes in food intake, energy substrate partitioning, and central Fos expression within the hypothalamus to peripheral LPS (100 microg/kg, i.p.); Fos expression changes specifically within ORX and MCH neurons were also investigated. Central IL-10 attenuated the peripheral LPS-induced hypophagia, reduction in motor activity, fever and reduction in respiratory exchange ratio. Central IL-10 also attenuated peripheral LPS-induced increases in Fos expression within ORX neurons and decreases in Fos expression within unidentified cells of the caudal arcuate nucleus. In contrast, both IL-10 and LPS injection independently decreased Fos expression within MCH neurons. The present study provides further insight into the interactions within the brain between the anti-inflammatory cytokine IL-10, the inflammatory consequences of LPS, and neuropeptides known to regulate energy expenditure and food intake.

Inhibitory effects of Cynodon dactylon L. on inflammation and oxidative stress in adjuvant treated rats.

Cynodon dactylon is one of the 10 auspicious herbs that constitute the group Dasapushpam in Ayurveda. Traditionally Cynodon dactylon L. is used against many chronic inflammatory diseases in India. The present study was carried out to evaluate the protective effect of Cynodon dactylon against rats with adjuvant- induced arthritis. Arthritis was induced by intradermal injection of complete Freund's adjuvant into the right hind paw produce inflammation of the joint. A significant increase in the levels of inflammatory mediators, myeloperoxidase, nitrite, C-reactive protein, ceruloplasmin was observed. This was associated with oxidative stress with a marked reduction in the activity of catalase, superoxide dismutase, glutathione peroxidase and the levels of glutathione, vitamins C and E and an increase in the lipid peroxidation as indicated by the higher levels of thiobarbituric acid reactive substances. Cynodon dactylon (20mg/kg/b.wt) was orally administered to arthritic rats after adjuvant injection produced a significant attenuation in the inflammatory response, oxidative stress and ameliorated the arthritic changes to near normal conditions. Hence, the results of this study clearly indicate that Cynodon dactylon extract has a promising protective role against arthritis.

Cardioprotective roles of aged garlic extract, grape seed proanthocyanidin, and hazelnut on doxorubicin-induced cardiotoxicity.

Doxorubicin (DXR) is a chemotherapeutic agent used effectively in the treatment of several childhood malignancies. During treatment, cardiotoxicity caused by cell damage due to the free oxygen radicals that are generated is a major limiting factor. This study was undertaken to determine whether DXR-induced cardiotoxicity could be prevented by natural foods with antioxidant properties such as aged garlic extract (AGEX), grape seed proanthocyanidin (PA), and hazelnut. Wistar albino male rats were assigned randomly to 9 groups each consisting of 15 rats. AGEX, PA, and hazelnut groups received these antioxidants in addition to their standard rat diet. They were also treated with cumulative intraperitoneal (i.p.) injections according to 2 different regimens: either a high-dose of 15 mg/kg DXR (3.75 mg/kg per week for 4 weeks) or a low-dose of 7.5 mg/kg DXR (1.875 mg/kg per week for 4 weeks). The control group received i.p. 0.9% saline. AGEX, PA, or hazelnut supplements were given orally to the groups for a 6-week period starting 1 week before the DXR treatment and ending 1 week after the treatment. One week after the last DXR injection, heart tissue samples were analyzed to determine malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), and xanthine oxidase (XO) levels, and serum samples were taken for creatine kinase (CK). There were no significant changes in MDA levels among the control, DXR-treated groups, or supplemented groups that received additional natural antioxidant foods. SOD enzyme levels were decreased in rats treated with DXR. PA prevented the decrease at low doses of DXR. DXR treatment decreased CAT enzyme levels, but additional PA and hazelnut consumption increased these levels at low cumulative doses. XO enzyme levels were decreased in AGEX and hazelnut groups, but PA prevented the decrease. CK levels were elevated after DXR administration, indicating myocardial injury, but PA significantly reversed this. Although there were no differences histopathologically between AGEX, PA, and hazelnut groups, the protective effects of AGEX and PA were evident in electron microscopy. In conclusion, the positive effects of natural antioxidant foods on the prevention of DXR-induced cardiac injury could not be clearly shown on the basis of antioxidant enzymes. However, the electron microscopic changes clearly demonstrated the protective effects of AGEX and PA. The supplementation of these antioxidant foods over longer periods may show more definitive results. Human studies with different doses are needed to evaluate the effects of these foods on the human heart.

Rapid appearance of resolvin precursors in inflammatory exudates: novel mechanisms in resolution.

Resolution of inflammation is essential. Although supplementation of omega-3 fatty acids is widely used, their availability at sites of inflammation is not known. To this end, a multidisciplinary approach was taken to determine the relationship of circulating omega-3 to inflammatory exudates and the generation of resolution signals. In this study, we monitored resolvin precursors in evolving exudates, which initially paralleled increases in edema and infiltrating neutrophils. We also prepared novel microfluidic chambers to capture neutrophils from a drop of blood within minutes that permitted single-cell monitoring. In these, docosahexaenoic acid-derived resolvin D1 rapidly stopped neutrophil migration, whereas precursor docosahexaenoic acid did not. In second organ injury via ischemia-reperfusion, resolvin metabolically stable analogues were potent organ protectors reducing neutrophils. Together, these results indicate that circulating omega-3 fatty acids rapidly appear in inflammatory sites that require conversion to resolvins that control excessive neutrophil infiltration, protect organs, and foster resolution.

Lack of analgesia by oral standardized cannabis extract on acute inflammatory pain and hyperalgesia in volunteers.

BACKGROUND: Cannabinoid-induced analgesia was shown in animal studies of acute inflammatory and neuropathic pain. In humans, controlled clinical trials with Delta-tetrahydrocannabinol or other cannabinoids demonstrated analgesic efficacy in chronic pain syndromes, whereas the data in acute pain were less conclusive. Therefore, the aim of this study was to investigate the effects of oral cannabis extract in two different human models of acute inflammatory pain and hyperalgesia. METHODS: The authors conducted a double-blind, crossover study in 18 healthy female volunteers. Capsules containing Delta-tetrahydrocannabinol-standardized cannabis extract or active placebo were orally administered. A circular sunburn spot was induced at one upper leg. Heat and electrical pain thresholds were determined at the erythema, the area of secondary hyperalgesia, and the contralateral leg. Intradermal capsaicin-evoked pain and areas of flare and secondary hyperalgesia were measured. Primary outcome parameters were heat pain thresholds in the sunburn erythema and the capsaicin-evoked area of secondary hyperalgesia. Secondary measures were electrical pain thresholds, sunburn-induced secondary hyperalgesia, and capsaicin-induced pain. RESULTS: Cannabis extract did not affect heat pain thresholds in the sunburn model. Electrical thresholds (250 Hz) were significantly lower compared with baseline and placebo. In the capsaicin model, the area of secondary hyperalgesia, flare, and spontaneous pain were not altered. CONCLUSION: To conclude, no analgesic or antihyperalgesic activity of cannabis extract was found in the experiments. Moreover, the results even point to the development of a hyperalgesic state under cannabinoids. Together with previous data, the current results suggest that cannabinoids are not effective analgesics for the treatment of acute nociceptive pain in humans.

Hyaluronan fragments act as an endogenous danger signal by engaging TLR2.

Upon tissue injury, high m.w. hyaluronan (HA), a ubiquitously distributed extracellular matrix component, is broken down into lower m.w. (LMW) fragments, which in turn activate an innate immune response. In doing so, LMW HA acts as an endogenous danger signal alerting the immune system of a breach in tissue integrity. In this report, we demonstrate that LMW HA activates the innate immune response via TLR-2 in a MyD88-, IL-1R-associated kinase-, TNFR-associated factor-6-, protein kinase Czeta-, and NF-kappaB-dependent pathway. Furthermore, we show that intact high m.w. HA can inhibit TLR-2 signaling. Finally, we demonstrate that LMW HA can act as an adjuvant promoting Ag-specific T cell responses in vivo in wild-type but not TLR-2(null) mice.

Antiinflammatory efficacy of extracts of latex of Calotropis procera against different mediators of inflammation.

The latex of the plant Calotropis procera has been reported to exhibit potent antiinflammatory activity against carrageenin and formalin that are known to release various mediators. In the present study, we have evaluated the efficacy of extracts prepared from the latex of C procera against inflammation induced by histamine, serotonin, compound 48/80, bradykinin (BK), and prostaglandin E2 (PGE2) in the rat paw oedema model. The paw oedema was induced by the subplantar injection of various inflammagens and oedema volume was recorded using a plethysmometer. The aqueous and methanol extracts of the dried latex (DL) and standard antiinflammatory drugs were administered orally 1 hour before inducing inflammation. The inhibitory effect of the extracts was also evaluated against cellular influx induced by carrageenin. The antiinflammatory effect of aqueous and methanolic extracts of DL was more pronounced than phenylbutazone (PBZ) against carrageenin while it was comparable to chlorpheniramine and PBZ against histamine and PGE2, respectively. Both extracts produced about 80%, 40%, and 30% inhibition of inflammation induced by BK, compound 48/80, and serotonin. The histological analysis revealed that the extracts were more potent than PBZ in inhibiting cellular infiltration and subcutaneous oedema induced by carrageenin. The extracts of DL exert their antiinflammatory effects mainly by inhibiting histamine and BK and partly by inhibiting PGE2.

Anti-inflammatory plant flavonoids and cellular action mechanisms.

Plant flavonoids show anti-inflammatory activity in vitro and in vivo. Although not fully understood, several action mechanisms are proposed to explain in vivo anti-inflammatory action. One of the important mechanisms is an inhibition of eicosanoid generating enzymes including phospholipase A2, cyclooxygenases, and lipoxygenases, thereby reducing the concentrations of prostanoids and leukotrienes. Recent studies have also shown that certain flavonoids, especially flavone derivatives, express their anti-inflammatory activity at least in part by modulation of proinflammatory gene expression such as cyclooxygenase-2, inducible nitric oxide synthase, and several pivotal cytokines. Due to these unique action mechanisms and significant in vivo activity, flavonoids are considered to be reasonable candidates for new anti-inflammatory drugs. To clearly establish the therapeutic value in inflammatory disorders, in vivo anti-inflammatory activity, and action mechanism of varieties of flavonoids need to be further elucidated. This review summarizes the effect of flavonoids on eicosanoid and nitric oxide generating enzymes and the effect on expression of proinflammatory genes. In vivo anti-inflammatory activity is also discussed. As natural modulators of proinflammatory gene expression, certain flavonoids have a potential for new anti-inflammatory agents.