Polyphenolics isolated from virgin coconut oil inhibits adjuvant induced arthritis in rats through antioxidant and anti-inflammatory action.

We evaluated the protective efficacy of the polyphenolic fraction from virgin coconut oil (PV) against adjuvant induced arthritic rats. Arthritis was induced by intradermal injection of complete Freund's adjuvant. The activities of inflammatory, antioxidant enzymes and lipid peroxidation were estimated. PV showed high percentage of edema inhibition at a dose of 80mg/kg on 21st day of adjuvant arthritis and is non toxic. The expression of inflammatory genes such as COX-2, iNOS, TNF-α and IL-6 and the concentration of thiobarbituric acid reactive substance were decreased by treatment with PV. Antioxidant enzymes were increased and on treatment with PV. The increased level of total WBC count and C-reactive protein in the arthritic animals was reduced in PV treated rats. Synovial cytology showed that inflammatory cells and reactive mesothelial cells were suppressed by PV. Histopathology of paw tissue showed less edema formation and cellular infiltration on supplementation with PV. Thus the results demonstrated the potential beneficiary effect of PV on adjuvant induced arthritis in rats and the mechanism behind this action is due to its antioxidant and anti-inflammatory effects.

Regulation of inflammation in cancer by eicosanoids.

Inflammation in the tumor microenvironment is now recognized as one of the hallmarks of cancer. Endogenously produced lipid autacoids, locally acting small molecule lipid mediators, play a central role in inflammation and tissue homeostasis, and have recently been implicated in cancer. A well-studied group of autacoid mediators that are the products of arachidonic acid metabolism include: the prostaglandins, leukotrienes, lipoxins and cytochrome P450 (CYP) derived bioactive products. These lipid mediators are collectively referred to as eicosanoids and are generated by distinct enzymatic systems initiated by cyclooxygenases (COX 1 and 2), lipoxygenases (5-LOX, 12-LOX, 15-LOXa, 15-LOXb), and cytochrome P450s, respectively. These pathways are the target of approved drugs for the treatment of inflammation, pain, asthma, allergies, and cardiovascular disorders. Beyond their potent anti-inflammatory and anti-cancer effects, non-steroidal anti-inflammatory drugs (NSAIDs) and COX-2 specific inhibitors have been evaluated in both preclinical tumor models and clinical trials. Eicosanoid biosynthesis and actions can also be directly influenced by nutrients in the diet, as evidenced by the emerging role of omega-3 fatty acids in cancer prevention and treatment. Most research dedicated to using eicosanoids to inhibit tumor-associated inflammation has focused on the COX and LOX pathways. Novel experimental approaches that demonstrate the anti-tumor effects of inhibiting cancer-associated inflammation currently include: eicosanoid receptor antagonism, overexpression of eicosanoid metabolizing enzymes, and the use of endogenous anti-inflammatory lipid mediators. Here we review the actions of eicosanoids on inflammation in the context of tumorigenesis. Eicosanoids may represent a missing link between inflammation and cancer and thus could serve as therapeutic target(s) for inhibiting tumor growth.

Cyclooxygenase inhibition during allergic sensitization increases STAT6-independent primary and memory Th2 responses.

Immune sensitization and memory generation are required for the development of allergic inflammation. Our previous studies demonstrate that the cyclooxygenase (COX) metabolic pathway is actively involved in allergic responses and COX inhibition increases allergic airway inflammation in a STAT6-independent fashion. To test the hypothesis that COX inhibition augments allergic inflammation by enhancing immune sensitization and memory, we sensitized STAT6 knockout mice with an i.p. injection of OVA with aluminum hydroxide as an adjuvant and treated the mice with the COX inhibitor indomethacin or vehicle for analyses of the primary and memory immune responses. We found that COX inhibition during immune sensitization, but not the allergic challenge phase, was necessary and sufficient to increase allergic inflammation. COX inhibition during sensitization increased the numbers of mature dendritic cells and activated CD4 T cells in the spleen and augmented OVA-specific IL-5 and IL-13 responses of the splenic CD4 T cells at day 5 after sensitization. COX inhibition during sensitization also augmented allergic Th2 response to OVA challenge 90 days after the sensitization. Therefore, COX inhibition during allergic sensitization augments allergic responses by enhancing Th2 cell activation and memory generation and the proallergic effect is STAT6-independent. These findings provide a mechanistic explanation for the increased allergic inflammation previously shown in the mice treated with COX inhibitors and in COX-deficient mice and suggest that use of COX-inhibiting drugs during initial allergen exposure may increase the risk of developing allergic responses.

Nimesulide, a COX-2 inhibitor, does not reduce lesion size or number in a nude mouse model of endometriosis.

BACKGROUND: Women with endometriosis have elevated levels of cyclooxygenase-2 (COX-2) in peritoneal macrophages and endometriotic tissue. Inhibition of COX-2 has been shown to reduce inflammation, angiogenesis and cellular proliferation. It may also downregulate aromatase activity in ectopic endometrial lesions. Ectopic endometrial establishment and growth are therefore likely to be suppressed in the presence of COX-2 inhibitors. We hypothesized that COX-2 inhibition would reduce the size and number of ectopic human endometrial lesions in a nude mouse model of endometriosis. METHODS: The selective COX-2 inhibitor, nimesulide, was administered to estrogen-supplemented nude mice implanted with human endometrial tissue. Ten days after implantation, the number and size of ectopic endometrial lesions were evaluated and compared with lesions from a control group. Immunohistochemical assessment of vascular development and macrophage and myofibroblast infiltration in control and treated lesions was performed. RESULTS: There was no difference in the number or size of ectopic endometrial lesions in control and nimesulide-treated nude mice. Nimesulide did not induce a visually identifiable difference in blood vessel development or macrophage or myofibroblast infiltration in nude mouse explants. CONCLUSION: The hypothesized biological properties of COX-2 inhibition did not influence lesion number or size in the nude mouse model of endometriosis.

An aqueous extract of Platycodi radix inhibits LPS-induced NF-kappaB nuclear translocation in human cultured airway epithelial cells.

We investigated the effects of aqueous extract from Platycodi radix (AEPR), a traditional drug used to treat acute lung inflammatory disease, on lipopolysaccharide (LPS)-induced inflammation in A549 human cultured airway epithelial cells. Nuclear factor-kappaB (NF-kappaB) and its inhibitory regulator, inhibitory kappaB (I-kappaB), play crucial roles in LPS-induced inflammatory response. We show that LPS-induced nuclear translocation of NF-kappaBp65 is inhibited by AEPR. LPS-induced expression of I-kappaBalpha, which is expressed by LPS-induced activation of NF-kappaB, is inhibited by AEPR as well. Besides LPS-induced expression of a group of genes, such as tumor necrosis factor-alpha (TNF-alpha), inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), are repressed by AEPR. We also found that expression of heat shock protein 70 (Hsp70), which has an anti-inflammatory activity, is increased by AEPR plus LPS. These results suggest that AEPR may act as a therapeutic agent for inflammatory disease through regulating the activity of NF-kappaB and expression of inflammatory genes.

Ginsenoside Rh1 possesses antiallergic and anti-inflammatory activities.

BACKGROUND: Ginseng (the root of Panax ginseng C.A. Meyer, Araliaceae) has been reported to possess various biological activities, including anti-inflammatory and antitumor actions. In this study, we investigated the antiallergic activity of ginsenosides isolated from ginseng. METHOD: We isolated ginsenosides by silica gel column chromatography and examined their in vitro and in vivo antiallergic effect on rat peritoneal mast cells and on IgE-induced passive cutaneous anaphylaxis (PCA) in mice. The in vitro anti-inflammatory activity of ginsenoside Rh1 (Rh1) in RAW264.7 cells was investigated. RESULTS: Rh1 potently inhibited histamine release from rat peritoneal mast cells and the IgE-mediated PCA reaction in mice. The inhibitory activity of Rh1 (87% inhibition at 25 mg/kg) on the PCA reaction was found to be more potent than that of disodium cromoglycate (31% inhibition at 25 mg/kg); Rh1 was also found to have a membrane-stabilizing action as revealed by differential scanning calorimetry. It also inhibited inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) protein expression in RAW 264.7 cells, and the activation of the transcription factor, NF-kappaB, in nuclear fractions. CONCLUSION: The antiallergic action of Rh1 may originate from its cell membrane-stabilizing and anti-inflammatory activities, and can improve the inflammation caused by allergies.

The IL-1 family and inflammatory diseases.

IL-1 and its related family member IL-18 are primarily proinflammatory cytokines by their ability to stimulate the expression of genes associated with inflammation and autoimmune diseases. For IL-1 (IL-1alpha and IL-1beta), the most salient and relevant properties are the initiation of cyclooxygenase type 2 (COX-2), type 2 phospholipase A and inducible nitric oxide synthase (iNOS). This accounts for the large amount of prostaglandin-E2 (PGE2), platelet activating factor and nitric oxide (NO) produced by cells exposed to IL-1 or in animals or humans injected with IL-1. Another important member of the proinflammatory IL-1 family is IL-18. IL-18 is also an important player in autoimmune disease because of its ability to induce IFNgamma, particularly in combination with IL-12 or IL-15. Both IL-1 and IL-18 increase the expression of adhesion molecules such as intercellular adhesion molecule-1 (ICAM-1) on mesenchymal cells and vascular-cell adhesion molecule-1 (VCAM-1) on endothelial cells. This latter property promotes the infiltration of inflammatory and immunocompetent cells into the extravascular space. IL-1 and IL-18 are also an angiogenic factors by increasing the expression of vascular endothelial growth factor; IL-1 and IL-18 thus play a role in pannus formation and blood vessel supply. The strongest case for the importance of IL-1 in disease processes come from the administration of the IL-1 receptor antagonist, also a member of the IL-1 family and IL-18 binding protein (IL-18BP), a constitutively expressed and secreted protein that binds and neutralizes IL-18. Data from the human genome project have revealed other members of the IL-1 family. However, these appear to be antagonists rather than agonists. IL-1 also acts as an adjuvant during antibody production and stimulates bone marrow stem cells for differentiation in the myeloid series. IL-1 is distinct from tumor necrosis factor (TNF); IL-1 and TNFalpha share several biological properties but the salient difference is that TNF receptor signaling induces programmed cell death whereas IL-1 receptor signaling does not. In fact, IL-1 is a hematopoietic growth factor and IL-1 was administered to humans to reduce the nadir of white blood cells and platelets in patients during bone-marrow transplantation. This property, of IL-1 is not observed in the responses to TNFalpha. Furthermore, in animal models of destructive rheumatoid arthritis, IL-1 is necessary but TNFalpha is not.

Leukotriene and prostanoid pathway enzymes in bronchial biopsies of seasonal allergic asthmatics.

Cysteinyl-leukotrienes and prostaglandin D2 generated by the 5-lipoxygenase (5-LO) and cyclooxygenase (COX) pathways, respectively, cause bronchoconstriction, leukocyte recruitment, and bronchial hyperresponsiveness in asthma. We characterized the cellular expression of 5-LO and COX enzymes using immunohistochemistry on bronchial biopsies from 12 allergic asthmatic patients before and during seasonal exposure to birch pollen. Bronchial responsiveness (p = 0.004) and symptoms (p < 0.005) increased and peak expiratory flow (PEF; p < or = 0.02) decreased in the pollen season. In-season biopsies had 2-fold more cells immunostaining for 5-LO (p = 0.02), 5-LO-activating protein (FLAP; p = 0.04), and leukotriene (LT)A4 hydrolase (p = 0.05), and 4-fold more for the terminal enzyme for cysteinyl-leukotriene synthesis, LTC4 synthase (p = 0.02). Immunostaining for COX-1, COX-2, and PGD2 synthase was unchanged. Increased staining for LTC4 synthase was due to increased eosinophils (p = 0.035) and an increased proportion of eosinophils expressing the enzyme (p = 0.047). Macrophages also increased (p = 0.019), but mast cells and T-lymphocyte subsets were unchanged. Inverse correlations between PEF and 5-LO(+) cell counts link increased expression of 5-LO pathway enzymes in eosinophils and macrophages within the bronchial mucosa to deterioration of lung function during seasonal allergen exposure.

Feedback control of the arachidonate cascade in rheumatoid synoviocytes by 15-deoxy-Delta(12,14)-prostaglandin J2.

Rheumatoid arthritis (RA) is a chronic polyarticular joint disease associated with massive synovial proliferation, inflammation, and angiogenesis. PPAR-gamma ligands, both 15-deoxy-Delta(12,14)-prostaglandin J2 (15d- PGJ2) and troglitazone (TRO), can inhibit the growth of RA synoviocytes in vitro, and suppress the chronic inflammation of adjuvant-induced arthritis in rats, but the potency of 15d-PGJ2 is higher than TRO. Prostaglandin (PG) E2 plays important roles in joint erosion and synovial inflammation. In the present study, 15d-PGJ2, but not TRO and other prostanoids, suppressed interleukin (IL)-1beta-induced PGE2 synthesis in rheumatoid synovial fibroblasts (RSFs) through the inhibition of cyclooxygenase (COX-2) and cytosolic phospholipase A2 (cPLA2) expression. Furthermore, the inhibition was not affected by pretreatment with anti-PPAR-gamma antibody. It means that this anti-inflammatory effect of 15d-PGJ2 for PG synthesis may be independent of PPAR-gamma and 15d-PGJ2 is a key regulator of negative feedback of the arachidonate cascade on the COX pathway. These findings provide new insight into the feedback mechanism of the arachidonate cascade.

Control of salivary secretion by nitric oxide and its role in neuroimmunomodulation.

In many in vivo systems exposure to endotoxins (LPS) leads to the co-induction of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), which is important to the regulation of the function of different systems during infection. In submandibular glands (SMG) neural (n)NOS is localized in neural terminals and in striated, granular convoluted and excretory ducts, endothelial (e)NOS in vascular endothelium and ducts, and iNOS in macrophages and in tubules and ducts. In normal adult male rats, injection of an inhibitor of NOS decreased the stimulated salivary secretion and a donor of NO potentiated it, indicating that NO exerts a stimulatory role. A single high dose of LPS (5 mg/kg, i.p.) induced an increase in NOS activity measured by the 14C-citrulline method, increased PGE content almost 100% as measured by RIA, and blocked stimulated salivary secretion. The administration of a specific iNOS inhibitor, aminoguanidine (AG), with LPS not only decreased NOS activity but significantly decreased PGE content, indicating that NO triggered the activation of COX-2. LPS increased conversion of labeled arachidonate to prostaglandins (PGs) showing that COX was induced. Since a PGE1 analogue blocked stimulated salivation, the LPS-induced inhibition of salivation is probably due to release of PGs. Therefore, the use of inhibitors of iNOS and COX-2 could be very useful to increase salivation during infection since saliva has antimicrobial actions.