Effect of etodolac on prostaglandin E2 biosynthesis, active oxygen generation and bradykinin formation

Inoue, Kichiro; Motonaga, Asahiko; Dainaka, Junichi; Nishimura, Tomoo; Hashii, Haruko; Yamate, K.; Ueda, Fusao; Kimura, Kiyoshi

doi:10.1016/0952-3278(94)90065-5

Cited by 27 publications

(17 citation statements)

References 24 publications

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“…A wide range of therapeutic benefits are claimed for bromelain, introduced as a therapeutic compound since 1957. Bromelain's principle activities include: the reversible inhibition of platelet aggregation (Morita et al, 1979), fibrinolytic activity (Maurer et al, 2000), anti-inflammatory action (Inoue et al, 1994), the modulation of cytokines and immunity (Desser et al, 1994;Munzig et al, 1995), skin debridement of burns (Rosenberg et al, 2004), anti-tumour activity (Batkin et al, 1988), enhanced absorption of other drugs (Tinozzi and Venegoni, 1978), mucolytic properties (Hunter et al, 1957), a digestion aid (Knill-Jones et al, 1970), enhanced wound healing (Tassman et al, 1965) and cardiovascular and circulatory improvement (Taussig and Nieper, 1979). In addition to the cysteine protease, bromelain preparations also contains other biologically active compounds such as peroxidase, acid phosphatase, several protease inhibitors and organically bound calcium.…”

Section: Use Of Cysteine Proteases In Pharmacy and Medicinementioning

confidence: 99%

Cysteine Proteases

Grzonka¹,

Kasprzykowski²,

Wiczk³

2007

Industrial Enzymes

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Section: Use Of Cysteine Proteases In Pharmacy and Medicinementioning

confidence: 99%

Cysteine Proteases

Grzonka¹,

Kasprzykowski²,

Wiczk³

2007

Industrial Enzymes

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“…These include the experimental allergic encephalomyelitis (EAE) model of the human autoimmune disease multiple sclerosis (3), carrageenan-induced pleurisy in the rat (4)(5)(6), immunologically mediated arteriosclerosis in rat aortic allografts (7), rheumatologic diseases in mice and humans (8)(9)(10)(11)(12)(13), and allergic asthma (14) and rhinitis (15). Some studies demonstrated that bromelain had efficacy similar to standard anti-inflammatory drugs such as dexamethasone (5,6) or non-steroidal anti-inflammatory agents (NSAIDs) (8,10,11,16). Our previous studies showed that oral administration of 5 mg bromelain/day markedly decreased the development and severity of inflammatory bowel disease in IL-10 −/− mice (17).…”

Section: Introductionmentioning

confidence: 99%

Bromelain treatment decreases neutrophil migration to sites of inflammation

Fitzhugh

Shan

Dewhirst

et al. 2008

Clinical Immunology

116

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Bromelain, a mixture of proteases derived from pineapple stem, has been reported to have therapeutic benefits in a variety of inflammatory diseases, including murine inflammatory bowel disease. The purpose of this work was to understand potential mechanisms for this anti-inflammatory activity. Exposure to bromelain in vitro has been shown to remove a number of cell surface molecules that are vital to leukocyte trafficking, including CD128a/CXCR1 and CD128b/CXCR2 that serve as receptors for the neutrophil chemoattractant IL-8 and its murine homologues. We hypothesized that specific proteolytic removal of CD128 molecules by bromelain would inhibit neutrophil migration to IL-8 and thus decrease acute responses to inflammatory stimuli. Using an in vitro chemotaxis assay, we demonstrated a 40% reduction in migration of bromelain-vs. sham-treated human neutrophils in response to rhIL-8. Migration to the bacterial peptide analog fMLP was unaffected, indicating that bromelain does not induce a global defect in leukocyte migration. In vivo bromelain treatment generated a 50 -85% reduction in neutrophil migration in 3 different murine models of leukocyte migration into the inflamed peritoneal cavity. Intravital microscopy demonstrated that although in vivo bromelain treatment transiently decreased leukocyte rolling, its primary long-term effect was abrogation of firm adhesion of leukocytes to blood vessels at the site of inflammation. These changes in adhesion were correlated with rapid re-expression of the bromelain-sensitive CD62L/L-selectin molecules that mediate rolling following in vivo bromelain treatment and minimal re-expression of CD128 over the time period studied. Taken together, these studies demonstrate that bromelain can effectively decrease neutrophil migration to sites of acute inflammation and support the specific removal of the CD128 chemokine receptor as a potential mechanism of action.

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“…The level of proof, method of enzyme administration and dose and quality of the studies vary, but beneficial effects were observed in a number of different models, including experimental allergic encephalomyelitis (EAE) model of the human autoimmune disease multiple sclerosis, carrageenan-induced pleurisy in the rat, immunologically mediated arteriosclerosis in rat aortic allografts, rheumatologic diseases in mice and humans, and allergic asthma (reviewed in [9] and [10]). Some studies demonstrated that bromelain had an efficacy similar to standard anti-inflammatory drugs such as dexamethasone [11,12] or non-steroidal anti-inflammatory agents (NSAIDs) [13-16]. However, the exact mode of action is unclear.…”

Section: Introductionmentioning

confidence: 99%

Plant proteolytic enzyme papain abrogates angiogenic activation of human umbilical vein endothelial cells (HUVEC) in vitro

Mohr¹,

Desser²

2013

BMC Complement Altern Med

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BackgroundVascular endothelial growth factor (VEGF) is a key regulator of physiologic and pathogenic angiogenesis in diseases such as cancer and diabetic retinopathy. It is known that cysteine proteases from plants, like bromelain and papain are capable to suppress inflammatory activation. Recent studies have demonstrated that they may interfere with angiogenesis related pathways as well. The aim of this study was to investigate the anti-angiogenic effects of papain on human umbilical vein endothelial cells (HUVEC) in vitro.MethodsCell viability after prolonged treatment with papain was investigated by life cell staining and lactate dehydrogenase release assay. Angiogenic activation was assessed by ELISA against phosphorylated proteins AKT, MEK1/2, ERK1/2, SAPK/JNK and p38-MAPK. Growth inhibition was determined by means of an MTT-assay and cell migration by means of a scratch assay. Capability to form a capillary network was investigated using a tube formation assay.ResultsPapain did not induce proteolysis or cell detachment of HUVEC in a concentration range between 0 and 25 μg/mL. Four hours treatment with 10 μg/mL papain resulted in a reduced susceptibility of endothelial cells to activation by VEGF as determined by phosphorylation levels of Akt, MEK1/2, SAPK/JNK. Papain exerted a distinct inhibitory effect on cell growth, cell migration and tube formation with inhibition of tube formation detectable at concentrations as low as 1 μg/mL. Bromelain and ficin displayed similar effects with regard to cell growth and tube formation.ConclusionPapain showed a strong anti-angiogenic effect in VEGF activated HUVEC. This effect may be due to interference with AKT, MEK1/2 and SAPK/JNK phosphorylation. Two other plant derived cysteine proteases displayed similar inhibition of HUVEC cell growth and tube formation. These findings indicate that plant proteolytic enzymes may have potential as preventive and therapeutic agents against angiogenesis related human diseases.

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Effect of etodolac on prostaglandin E2 biosynthesis, active oxygen generation and bradykinin formation

Cited by 27 publications

References 24 publications

Cysteine Proteases

Cysteine Proteases

Bromelain treatment decreases neutrophil migration to sites of inflammation

Plant proteolytic enzyme papain abrogates angiogenic activation of human umbilical vein endothelial cells (HUVEC) in vitro

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