Inflammation - A Double-Edged Sword

 Inflammation is a necessary process for survival of any species during infection, injury, damage and repair but persistent inflammation is the cause of numerous diseases.  In healthy tissue there is a balance between agents that promote inflammation and those that block it. When there is an infection or injury, the pro-inflammatory agents (like tumor necrosis factor, interleukins, NF- kappaB  etc) rally to eliminate the infection or damage and return the tissue to health. When health is restored, these pro-inflammatory agents return to normal levels. In some cases however, the immune system switches from an acute mode to chronic, low-grade-inflammation that can persist for months or years.

Low grade chronic inflammation is a feature of many chronic diseases including, atherosclerosis (damage of blood vessels), arthritis, diabetes, kidney disease, high blood pressure, cancer and even obesity!

Tackling Chronic and Persistent Inflammation

One way is through the use of natural anti-inflammatory agents. Unlike the pharmaceutical agents, the natural agents have multiple benefits including: non-specificity, multiple mechanisms of action, considerably lower toxicity, synergistic action and many of these herbs have been used for hundreds of years. However, many of these natural ingredients are inherently poorly absorbed and therapeutic concentrations are difficult to achieve in tissues.

AOR is pleased to introduce a novel and a powerful formula for addressing chronic inflammation. Inflammation Relief is a multiple ingredient formula with powerful herbs that have been clinically studied. Moreover, these herbs are subjected to a unique and safe process (industry first) that forms nano-miscelle- particles that are small enough to easily penetrate the intestinal lining and enter the blood thereby considerably enhancing the absorption and bioavailability of these herbs. The proof of course is in the results.

Each soft gel of Inflammation Relief contains:

Curcumin - one of the key constituents of turmeric spice widely used in East Asian cooking and ayurveda. Curcumin is one of the most widely studied natural molecules it’s safety has been widely acknowledged. Like many natural ingredients curcumin has multiple mechanisms of action including neutralizing powerful and damaging free-radicals, preventing the activation of NF kappa B one of the most powerful inflammatory molecules.

Boswellia - Clinically studied herb for inflammation in osteoarthritis. Boswellia significantly reduced swelling, pain and improved joint mobility. Avurveda’s  answer to NSAID’s (non steroidal anti inflammatory drugs)!

Ashwaganda - Ashwaganda has numerous studies supporting its role as an anti-inflammatory especially reducing Interleukin 1 and 6 levels, key pro-inflammatory agents. Ashwaganda has synergistic activities with both curcumin and boswellia. Studies also show that ashwaganda improves the quality of life.

Oleanolic acid - Oleanolic aicd is a triterpenoid another polyphenolic molecule widely found in nature especially in herbs like rosemary, cumin and thyme. Triterpenoids are actively researched for antioxidant properties in quenching both reactive oxygen species as well as reactive nitrogen species.

Vitex Nirgundi - A lesser well known herb in the West but widely used and respected in ayurveda. Vitex’s anti-inflammatory effects have been compared to standard prescriptive NSAID’s like phenylbutazone and indomethacin. In experimental studies Vitex was shown to be as potent in reducing inflammation as both drugs.

References

Kimmatkar N, Thawani V, Hingorani L, Khiyani R. "Efficacy and tolerability of Boswellia serrata extract in treatment of osteoarthritis of knee--a randomized double blind placebo controlled trial." Phytomedicine 2003 Jan; 10(1): 3-7.

Bowellia Serrata. Monograph. Altern Med Rev. 2008 Jun;13(2):165-7.

Aggarwal BB, et al. Curcumin as "Curecumin": From kitchen to clinic. Biochemical Pharmacology Volume 75, Issue 4, 15 February 2008, Pages 787-809. 4. Satoskar RR, et al. Evaluation of anti-inflammatory property of curcumin (diferuloyl methane) in patients with postoperative inflammation. Int J Clin Pharmacol Ther Toxicol. 1986 Dec;24(12):651-4.

S.D. Deodhar, R. Sethi and R.C. Srimal, Preliminary study on antirheumatic activity of curcumin (diferuloyl methane), Indian J Med Res 71 (1980), pp. 632-634.

Aggarwal BB, et al. Withanolides potentiate apoptosis, inhibit invasion, and abolish osteoclastogenesis through suppression of nuclear factor-kappaB (NFkappaB) activation and NF-kappaB-regulated gene expression. Mol Cancer Ther. 2006 Jun;5(6):1434-45.

Kulkarni RR, et al. Treatment of osteoarthritis with a herbomineral formulation: a double-blind, placebo-controlled, cross-over study. J Ethnopharmacol. 1991 May-Jun;33(1-2):91-5.

Suh SJ, et al. Triterpenoid saponin, oleanolic acid 3-O-beta-d-glucopyranosyl(1-->3)-alpha-l-rhamnopyranosyl(1-->2)-alpha-l-arabinopyranoside (OA) from Aralia elata inhibits LPS-induced nitric oxide production by down-regulated NF-kappaB in raw 264.7 cells. Arch Biochem Biophys. 2007 Nov 15 ;467(2):227-33.

Klement JF, et al. IkappaBalpha deficiency results in a sustained NF-kappaB response and severe widespread dermatitis in mice. Mol Cell Biol. 1996 May;16(5):2341-9.

Dharmasiri MG, et al. Anti-inflammatory and analgesic activities of mature fresh leaves of Vitex negundo. J Ethnopharmacol. 2003 Aug;87(2-3):199-206.

Gupta RK, Tandon VR. Antinociceptive activity of Vitex-negundo Linn leaf extract. Indian J Physiol Pharmacol. 2005 Apr;49(2):163-70.

Vitex negundo Linn (VN) leaf extract as an adjuvant therapy to standard anti-inflammatory drugs
Vishal R. Tandon & R.K. Gupta. Indian J Med Res; 2006, 124(4): 447-50
Background & objectives: Leaves of Vitex negundo (VN) have been investigated for their anti-inflammatory activity in past, including its mechanism of action. However, nobody has evaluated its potential role as an adjuvant with standard anti-inflammatory therapy. Therefore, the present study was undertaken to investigate interaction of ethanolic leaf extract of VN Linn with standard anti-inflammatory drugs in sub-effective doses per orally (PO) to evaluate its potential role as an adjuvant therapy.
Methods: Carrageenin induced hind paw oedema and cotton pellet granuloma test in albino rats were employed to study interaction of Vitex negundo (VN) leaf extract with standard anti-inflammatory drugs in sub-effective doses per orally to evaluate its potential role as an adjuvant therapy.
Results: The sub-effective dose of VN potentiated anti-inflammatory activity of phenlbutazone and ibuprofen significantly in carrageenin induced hind paw oedema and cotton pellet granuloma models.
Interpretation & conclusion: The potentiation of anti-inflammatory activities phenlbutazone and ibuprofen by VN indicates that it may be useful as an adjuvant therapy along with standard anti-inflammatory drugs.

Curcumin, demethoxycurcumin, bisdemethoxycurcumin, tetrahydrocurcumin and turmerones differentially regulate anti-inflammatory and anti-proliferative responses through a ROS-independent mechanism
Sandur SK, Pandey MK, Sung B, Ahn KS, Murakami A, Sethi G, Limtrakul P, Badmaev V, Aggarwal BB. Carcinogenesis; 2007, 28(8):1765-1773
Curcumin, a component of turmeric (Curcuma longa), has been shown to exhibit chemopreventive activity. Whether analogs of curcumin (Cur), such as demethoxycurcumin (DMC), bisdemethoxycurcumin (BDMC), tetrahydrocurcumin (THC) and turmerones, modulate inflammatory signaling and cell proliferation signaling to same extent as curcumin was investigated. The results indicate that the relative potency for suppression of tumor necrosis factor (TNF)-induced nuclear factor-B (NF-B) activation was Cur > DMC > BDMC; thus suggesting the critical role of methoxy groups on the phenyl ring. THC, which lacks the conjugated bonds in the central seven-carbon chain, was completely inactive for suppression of the transcription factor. Turmerones also failed to inhibit TNF-induced NF-B activation. The suppression of NF-B activity correlated with inhibition of NF-B reporter activity and with down-regulation of cyclooxygenase-2, cyclin D1 and vascular endothelial growth factor, all regulated by NF-B. In contrast to NF-B activity, the suppression of proliferation of various tumor cell lines by Cur, DMC and BDMC was found to be comparable; indicating the methoxy groups play minimum role in the growth-modulatory effects of curcumin. THC and turmerones were also found to be active in suppression of cell growth but to a much lesser extent than curcumin, DMC and BDMC. Whether suppression of NF-B or cell proliferation, no relationship of any of the curcuminoid was found with reactive oxygen species (ROS) production. Overall, our results demonstrated that different analogs of curcumin present in turmeric exhibit variable anti-inflammatory and anti-proliferative activities, which do not correlate with their ability to modulate the ROS status.

Oleanolic acid induces prostacyclin release in human vascular smooth muscle cells through a cyclooxygenase-2-dependent mechanism.
Martínez-González J, Rodríguez-Rodríguez R, González-Díez M, Rodríguez C, Herrera MD, Ruiz-Gutierrez V, Badimon L. J Nutr; 2008, 138(3):443-8.
Oleanolic acid is a triterpenoid that may contribute to the cardio-protective effects of olive oil. Our goal was to assess whether oleanolic acid could modulate eicosanoid biosynthesis and to determine the mechanism involved in this effect. Human coronary smooth muscle cells (SMC) were treated with oleanolic acid, erythrodiol, or hydroxytyrosol and eicosanoid release was measured by enzyme immunoassay. Cyclooxygenase (Cox)-1 and Cox-2 protein and messenger sRNA levels were analyzed by Western blot and real-time PCR, respectively. Mitogen-activated protein kinase (MAPK) pathways were assessed using specific antibodies. Oleanolic acid induced prostaglandin I2 (PGI2) release by human coronary SMC, an effect that was prevented by celecoxib (a specific inhibitor of Cox-2). The increased PGI2 was time-and dose-dependent and was associated to the up-regulation of Cox-2. No effects were observed on thromboxane A2. Erythrodiol but not hydroxytyrosol upregulated Cox-2 expression and induced PGI2 synthesis. Oleanolic acid induced an early phosphorylation of p38 MAPK and p42/44 MAPK but not c-Jun N-terminal kinase-1 (JNK-1). SB203580 (p38MAPK inhibitor) and U0126 (MAPK kinase1/2 inhibitor) abrogated the upregulation of Cox-2 and PGI2 release induced by oleanolic acid. A peptide inhibitor of JNK-1 (L-JNKI1) did not produce any effect. The induction of Cox-2 was preceded by an early activation of cAMP regulatory element-binding protein, a key transcription factor involved in Cox-2 transcriptional upregulation. Therefore, oleanolic acid contributes to vascular homeostasis by inducing PGI2 release in a Cox-2-dependent manner. Oleanolic acid could be regarded as a bioactive molecule that may contribute to the beneficial effects of the Mediterranean diet.

Preclinical Evaluation of Targeting the Nrf2 Pathway by Triterpenoids (CDDO-Im and CDDO-Me) for Protection from LPSInduced Inflammatory Response and Reactive Oxygen Species in Human Peripheral Blood Mononuclear Cells and Neutrophils
Thimmulappa RK, Fuchs RJ, Malhotra D, Scollick C,Traore K, Bream JH, Trush MA, Liby KT, Sporn MB, Kensler TW, Biswa S. Antioxid Redox Signal; 2007, 9(11): 1963-1970
Sepsis is characterized by an inappropriate host immune-inflammatory response and sustained oxidative damage. Nrf2, a bZIP oxidant-responsive transcription factor, regulates a battery of cytoprotective genes including antioxidants and maintains cellular redox homeostasis. Mouse studies have demonstrated a critical role of Nrf2 in improving survival during sepsis. This preclinical ex vivo study using neutrophils and peripheral blood mononuclear cells (PBMCs) as a surrogate cells evaluates the efficacy of CDDO-Im and CDDO-Me [imidazole and methyl ester derivative of 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO)] to activate the Nrf2 pathway and protect from lipopolysaccharide (LPS)-induced inflammatory response in humans. CDDO-Im treatment significantly induced Nrf2-dependent antioxidative genes (HO-1, GCLC, GCLM, and NQO1) in PBMCs isolated from six normal subjects. CDDO-Im increased nuclear accumulation of Nrf2 protein. Pretreatment of PBMC by CDDO-Im significantly attenuated LPS-induced cytokine expression. Similar increases in levels of antioxidant genes and suppression of LPS-induced cytokine expression was observed after CDDO-Me pretreatment. CDDO-Im also greatly inhibited LPS, fMLP, TNF-α, and TPA-induced ROS generation in neutrophils. In conclusion, these results demonstrate that activation of the Nrf2-dependent antioxidative pathway by CDDO-Im or CDDO-Me protects against the LPS-induced inflammatory response and suggest that they can be potential therapeutic candidates for intervening sepsis syndrome.

Anti-inflammatory and analgesic activities of mature fresh leaves of Vitex negundo.
Dharmasiri MG, Jayakody JR, Galhena G, Liyanage SS, Ratnasooriya WD. J Ethnopharmacol; 2003, 87 (2-3):199-206.
This study confirmed the oral anti-inflammatory, analgesic and antihistamine properties of mature fresh leaves (MFL) of Vitex negundo L. (Verbenaceae) claimed in the Ayurveda medicine by orally treating a water extract of the leaves to rats. The early phase (2h) of carrageenan-induced rat paw oedema was significantly (P<0.01) suppressed in an inversely does-dependent (r(2)=1, P<0.01) manner by MFL. The EC(50) was 2g/kg of MFL. In the formaldehyde-induced rat paw oedema test, the 2.5 and 5g/kg leaves significantly (P<0.05) suppressed the inflammation on days 4-6 of the test. In the hot plate test, 2.5 and 5g/kg of MFL showed a significant (P<0.05) and directly dose-dependent analgesic activity at 1h of treatment while the activity was absent in the tail flick test in rats. The EC(50) for the analgesic activity was 4.1g/kg. In the formalin test, 1.25, 2.5 and 5g/kg of MFL significantly (P<0.05) suppressed the pain in both the phases of the test like aspirin. The leaves showed an inversely dose-dependent in vivo antihistamine and in vitro prostaglandin (PG) synthesis inhibition, membrane stabilising and antioxidant activities. Naloxone did not abolish the analgesic activity in the hot plate test. A 5g/kg of MFL did not impair muscle strength and co-ordination and did not induce sedation. The treatment of 5g/kg of MFL did not show signs of acute toxicity or stress. Fourteen-day oral treatment of 5g/kg of MFL significantly increased the serum activity of AST. Flowering of the tree did not abolish the analgesic and anti-inflammatory activities of the leaves. These observations revealed that the fresh leaves of Vitex negundo have anti-inflammatory and pain suppressing activities possibly mediated via PG synthesis inhibition, antihistamine, membrane stabilising and antioxidant activities. The antihistamine activity can produce the anti-itching effect claimed in Ayurveda medicine.

E Series of Prostaglandin Receptor 2-Mediated Activation of Extracellular Signal-Regulated Kinase/Activator Protein-1 Signaling Is Required for the Mitogenic Action of Prostaglandin E2 in Esophageal Squamous-Cell Carcinoma
Yu L, Wu WKK, Li ZJ, Wong HPS, Tai EKK, Li HT, Wu YC, Cho CH. Journal of Pharmacology and Experimental Therapeutics; 2008, 327:258-267.
The use of nonsteroidal anti-inflammatory drugs is associated with a lower risk for esophageal squamous cell carcinoma, in which overexpression of cyclooxygenase-2 (COX-2) is frequently reported. Prostaglandin E2 (PGE2), a COX-2-derived eicosanoid, is implicated in the promotion of cancer growth. However, the precise role of PGE2 in the disease development of esophageal squamous cell carcinoma remains elusive. In this study, we investigated the effect of PGE2 on the proliferation of cultured esophageal squamous cell carcinoma cells (HKESC-1). Results showed that HKESC-1 cells expressed all four series of prostaglandin (EP) receptors, namely, EP1 to EP4 receptors. In this regard, PGE2 and the EP2 receptor agonist (±)-15-deoxy-16S-hydroxy-17-cyclobutyl PGE1 methyl ester (butaprost) markedly increased HKESC-1 cell proliferation. Moreover, the mitogenic effect of PGE2 was significantly attenuated by RNA interference-mediated knockdown of the EP2 receptor, indicating that this receptor mediated the mitogenic effect of PGE2. In this connection, PGE2 and butaprost induced phosphorylation of extracellular signal-regulated kinases 1/2 (Erk1/2), whose down-regulation by RNA interference significantly attenuated PGE2-induced cell proliferation. In addition, PGE2 and butaprost increased c-Fos expression and activator protein 1 (AP-1) transcriptional activity, which were abolished by the mitogen-activated protein kinase/Erk kinase inhibitor 1,4-diamino-2,3-dicyano-1,4-bis(o-aminophenylmercapto)-butadiene ethanolate (U0126). AP-1-binding inhibitor curcumin also partially reversed the mitogenic effect of PGE2. Taken together, these data demonstrate for the first time that the EP2 receptor mediates the mitogenic effect of PGE2 in esophageal squamous cell carcinoma via activation of the Erk/AP-1 pathway. This study supports the growth-promoting action of PGE2 in esophageal squamous cell carcinoma and the potential application of EP2 receptor antagonists in the treatment of this disease.

Chondroprotective potential of root extracts of Withania somnifera in osteoarthritis.
Sumantran VN, Kulkarni A, Boddul S, Chinchwade T, Koppikar SJ, Harsulkar A, Patwardhan B, Chopra A, Wagh UV. J Biosci; 2007, 32(2):299-307
This is the first report describing two novel chondroprotective activities of aqueous extracts of Withania somnifera root powder.First,these extracts had a statistically significant,short-term chondroprotective effect on damaged human osteoarthritic cartilage matrix in 50% of the patients tested. Second,these extracts caused a significant and reproducible inhibition of the gelatinase activity of collagenase type 2 enzyme in vitro.

Protective effect of Withania somnifera root powder in relation to lipid peroxidation, antioxidant status, glycoproteins and bone collagen on adjuvant-induced arthritis in rats.
Rasool M, Varalakshmi P. Fundam Clin Pharmacol; 2007, 21(2):157-64
The present investigation was carried out to evaluate the protective effect of Withania somnifera Linn.Dunal (family-Solanaceae), commonly known as Ashwagandha, on adjuvant-induced arthritic rats. Results were compared with those for Indomethacin, a nonsteroidal anti-inflammatory drug. Arthritis was induced by intradermal injection of complete Freund's adjuvant (0.1 mL) into the right hind paw of Wistar albino rats. Withania somnifera root powder (1000 mg/kg/day) and Indomethacin (3 mg/kg/day) were orally administered for 8 days (from 11th to 18th day) after adjuvant injection. The anti-arthritic effect of W. somnifera root powder was assessed by measuring changes in lipid peroxidation, antioxidant status, and glycoprotein levels in plasma and spleen of arthritic animals. In addition, cartilage degradation was also assessed by estimating bone collagen, and urinary constituents in arthritic animals. Results of the present investigation showed significant increase in the level of lipid peroxides, glycoproteins, and urinary constituents with the depletion of antioxidant status and bone collagen in arthritic animals. These biochemical alterations observed were ameliorated significantly by oral administration of W. somnifera root powder (1000 mg/kg body weight) in arthritic animals. The results of this study clearly indicate that W. somnifera root powder is capable of rectifying the above biochemical changes in adjuvant arthritis.

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