Papain Ameliorates the MPAs Formation-Mediated Activation of Monocytes by Inhibiting Cox-2 Expression via Regulating the MAPKs and PI3K/Akt Signal Pathway

Abstract

Monocytes activation and subsequent inflammatory response mediated by monocyte-platelet aggregates (MPAs) formation play the key roles in the early pathogenesis of atherosclerosis (AS). Exploration of novel drugs to ameliorate MPAs formation-mediated monocytes activation would be helpful for the treatment of AS patients. Papain has definite pharmacological effects including antiplatelet, thrombolysis, and anti-inflammation. However, its effect on MPAs formation and the following monocytes activation remains vague. This study aimed to illustrate the underlying mechanisms of papain on MPAs formation-initiated monocytes activation in vitro. In this study, Papain, Cox-2 inhibitor (NS-398), and NF-κB agonist (TNF-α) were used as the treating agents, respectively. MPAs formation and activated monocytes were measured by flow cytometry (FCM). Cox-2 mRNA, MCP-1, and proteins of Cox-2 and NF-κB signal pathway were detected by qRT-PCR, ELISA, and western blotting, respectively. As we observed, papain exhibited the powerful inhibitory effects on thrombin-mediated MPAs formation and monocytes activation in a concentration-dependent manner as what Cox-2 inhibitor demonstrated. However, the inhibitory tendency was significantly reversed by TNF-α. We also discovered that both Cox-2 mRNA and protein expression as well as the release of MCP-1 of monocyte was inhibited by either papain or NS-398, but TNF-α stimulated Cox-2 expression and release of MCP-1. The results of western blotting assay indicated that thrombin-mediated proteins expression of MAPKs and PI3K/Akt signal pathway was inhibited by papain and NS-398. However, TNF-α notably abated the inhibitory effects of papain on the process of MPAs-initiated monocytes activation. Our findings suggest that papain can inhibit the MPAs formation-mediated activation of monocytes by inhibiting the MAPKs and PI3K/Akt signal pathway.

Beneficial Role of Carica papaya Extracts and Phytochemicals on Oxidative Stress and Related Diseases: A Mini Review

“…Papain is the most widely exploited proteolytic enzyme from the Carica papaya L. and it has been used to help with meat tenderization and digestion. It is worth to note that papain exhibited great potential as a medication [ 4 ], as it is suggested to exhibit drug-like properties for atherosclerosis and associated conditions, which involve monocyte-platelet aggregate (MPA)-regulated inflammation [ 6 ]. Relevant and significant studies have been conducted to evaluate the benefits of the Carica papaya extracts and chemical constituents.…”

Poly (γ‐glutamic acid)/chitooligo‐saccharide/papain hydrogel prevents hypertrophic scar during skin wound healing

“…In addition, Peng Wang et al discovered the Notch1/Jagged1 signaling pathway and achieved the purpose of scar treatment by inhibiting this pathway 11 . Combined with the functions of papain, the prevention from HS formation during wound healing might be ascribed to that papain influenced many types of cells participating in tissue regeneration, for example, inhibited the angiogenic effect of HUVECs via interfering with AKT, MEK1/2, and SAPK/JNK phosphorylation 20 ; degraded tight junction proteins (ZO‐1, claudin‐4, occludin) in human Keratinocytes 21 ; inhibited the MPAs formation‐mediated activation of monocytes via inhibiting the MAPKs and PI3K/Akt signal pathway 21 …”

“…Besides, papain could degrade tight junction proteins (ZO‐1, claudin‐4, occludin) in human Keratinocytes 20 . Papain was also reported to inhibit the MPAs formation‐mediated activation of monocytes via inhibiting the MAPKs and PI3K/Akt signal pathway 21 . even allograft islets‐induced T cells activation could be inhibited by10 mg/ml papain pre‐treatment 22 .…”

The Role of Monocytes Cellular and Molecular Mechanisms in the Development of Systemic Immune Inflammation. Part 1

“…В настоящее время одним из современных представлений, лежащих в основе развития иммунного воспаления, является активация и направленная миграция моноцитов, которая регулируется также продуктами деградации фибрина и коллагена. В дальнейшем развивается воспаление, вызванное взаимодействием тромбоцитов и моноцитов с формированием моноцит-тромбоцитарных агрегатов (МТА) [50,51]. Известно, что неповрежденный и здоровый эндотелий регулирует и тормозит активацию тромбоцитов [51], тогда как нарушение целостности эндотелия может играть прямую роль в активации тромбоцитов [52,53].…”