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1.
J Cell Biochem ; 124(2): 294-307, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36585945

RESUMO

The arachidonic acid (AA) metabolic pathway, plays a vital role in the production of eicosanoids by the action of pro-inflammatory secretory phospholipase A2 (PLA2 ). Release of eicosanoids is known to be involved in many inflammatory diseases. Identification of the inhibitory molecules of this AA pathway enzyme along with the regulation of intracellular signaling cascades may be a finer choice to develop as a powerful anti-inflammatory drug. In this regard, we have screened few cell-permeable antioxidant molecules Tempo, Mito-TEMPO, N,N'-Bis(salicylideneamino)ethane-manganese(II) (EUK)-134, and EUK-8 against pro-inflammatory sPLA2 s. Among these, we found EUK-8 is a potent inhibitor with its IC50 value ranges 0.7-2.0 µM for sPLA2 s isolated from different sources. Furthermore, docking studies confirm the strong binding of EUK-8 towards sPLA2 . In vivo effect of EUK-8 was studied in HSF-sPLA2 -induced edema in mouse paw model. In addition to neutralizing the edema, EUK-8 significantly reduces the phosphorylation level of inflammatory proteins such as p38 member of MAPK pathway, Akt, and p65 along with the suppression of pro-inflammatory cytokine (interleukin-6) and chemokine (CXCL1) in edematous tissue. This shows that EUK-8 not only inhibits the sPLA2 activity, it also plays an important role in the regulation of sPLA2 -induced cell signaling cascades. Apart from the sPLA2 inhibition, we also examine the regulatory actions of EUK-8 with other downstream enzymes of AA pathway such as 5-LOX assay in human polymorphonuclear leukocytes (PMNs) and COX-2 expression in carrageenan-λ induced paw edema. Here EUK-8 significantly inhibits 5-LOX enzyme activity and downregulates COX-2 expression. These data indicate that EUK-8 found to be a promising multitargeted inhibitory molecule toward inflammatory pathway. In conclusion, mitochondrial targeted antioxidant EUK-8 is not only the powerful antioxidant, also a potent anti-inflammatory molecule and may be a choice of molecule for pharmacological applications.


Assuntos
Fosfolipases A2 Secretórias , Camundongos , Humanos , Animais , Fosfolipases A2 Secretórias/efeitos adversos , Fosfolipases A2 Secretórias/metabolismo , Antioxidantes/uso terapêutico , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ciclo-Oxigenase 2/metabolismo , Regulação para Baixo , Anti-Inflamatórios/uso terapêutico , Edema/induzido quimicamente
2.
J Cell Biochem ; 120(8): 12843-12858, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30861186

RESUMO

Hemostasis is a tightly regulated process which maintains a fluid state of blood within the vasculature and provides thrombotic response upon tissue injury. Various scientific studies have implicated the role of plant latex proteases in hemostasis using in vitro experiments. However, in vivo models substantiate their role in hemostasis. Therefore, in the present study, the effect of plant latex thrombin-like proteases (PTLPs) on hemostasis was investigated systematically using mice tail bleeding as a preclinical model. In this direction, latex protease fractions (LPFs), which showed potent thrombin-like activity, were selected as they act directly on fibrinogen to form clot and quickly stop bleeding. Thrombin-like activity was exhibited mainly by cysteine proteases. Calotropis gigantea, Carica papaya, Jatropha curcas, Oxystelma esculentum, Tabernaemontana divaricata, and Vallaris solanacea LPFs and papain from C. papaya latex significantly reduced bleeding on a topical application in normal and aspirin administered mice. In addition, PTLPs accelerated the clotting of factor VIII deficient plasma, while, papain brought back the clotting time to normal levels acting like a bypassing agent. Further, papain failed to show activity in the presence of specific cysteine protease inhibitor iodoacetic acid; confirming protease role in all the activities exhibited. At the tested dose, PTLPs except C. gigantea did not show toxicity. Further, structural and sequence comparison between PTLPs and human thrombin revealed structural and sequence dissimilarity indicating their unique nature. The findings of the present study may open up a new avenue for considering PTLPs including papain in the treatment of bleeding wounds.


Assuntos
Aspirina/efeitos adversos , Cisteína Endopeptidases/administração & dosagem , Fator VIII/metabolismo , Hemorragia/tratamento farmacológico , Látex/química , Animais , Asclepias/química , Calotropis/química , Carica , Cisteína Endopeptidases/farmacologia , Modelos Animais de Doenças , Hemorragia/induzido quimicamente , Hemorragia/metabolismo , Homeostase , Humanos , Jatropha/química , Camundongos , Papaína/administração & dosagem , Papaína/farmacologia , Proteínas de Plantas/administração & dosagem , Proteínas de Plantas/farmacologia , Tabernaemontana/química
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