Identification of Human Kinin-Forming Enzyme Inhibitors from Medicinal Herbs.

Hassan Madkhali,Zulfiqar Ali,Ikhlas A Khan,Stephen J Cutler,Zia Shariat-Madar,Hoang V Le,Amer Tarawneh

doi:10.3390/molecules26144126

Abstract

The goal of this study was to assess the pharmacological effects of black tea (Camellia sinensis var. assamica) water extract on human kinin-forming enzymes in vitro. Tea is a highly consumed beverage in the world. Factor XII (FXII, Hageman factor)-independent- and -dependent activation of prekallikrein to kallikrein leads to the liberation of bradykinin (BK) from high-molecular-weight kininogen (HK). The excessive BK production causes vascular endothelial and nonvascular smooth muscle cell permeability, leading to angioedema. The prevalence of angiotensin-converting enzyme inhibitor (ACEI)-induced angioedema appears to be through BK. Both histamine and BK are potent inflammatory mediators. However, the treatments for histamine-mediated angioedema are unsuitable for BK-mediated angioedema. We hypothesized that long-term consumption of tea would reduce bradykinin-dependent processes within the systemic and pulmonary vasculature, independent of the anti-inflammatory actions of polyphenols. A purified fraction of the black tea water extract inhibited both kallikrein and activated FXII. The black tea water extracts inhibited factor XII-induced cell migration and inhibited the production of kallikrein on the endothelial cell line. We compared the inhibitory effects of the black tea water extract and twenty-three well-known anti-inflammatory medicinal herbs, in inhibiting both kallikrein and FXII. Surprisingly, arjunglucoside II specifically inhibited the activated factor XII (FXIIa), but not the kallikrein and the activated factor XI. Taken together, the black tea water extract exerts its anti-inflammatory effects, in part, by inhibiting kallikrein and activated FXII, which are part of the plasma kallikrein–kinin system (KKS), and by decreasing BK production. The inhibition of kallikrein and activated FXII represents a unique polyphenol-independent anti-inflammatory mechanism of action for the black tea.

Highlights

FXII and kallikrein activities that function as central components of the plasma kallikrein–kinin system (KKS)
The results showed that Terminalia arjuna fruit extract inhibited the FXII-mediated S2302 hydrolysis assay, with an IC50 value of 190 ± 7.5 μg/μL (Figure 5A)
This study investigated the roles of the bioactive components in tea, in biological processes related to BK-induced angioedema, activated FXII-induced cell migration, kallikreininduced BK release from high-molecular-weight kininogen, and, in particular, the human plasma kinin-forming enzyme dynamics

Summary

Introduction

There is widespread agreement that inflammation is an important transitional state at the crossroads of multiple pathophysiological conditions, including diabetic retinopathy [1], hereditary angioedema [2,3], and Alzheimer’s disease [4], all of which share many risk factors. Bradykinin, a metabolite of the plasma kallikrein–kinin system (KKS), is frequently amplified in hereditary angioedema [5]. The deficiency or non-functionality of the C1 inhibitor results in inflammation, and cutaneous and mucosa edema [6]. Studies in in vitro and in vivo models have shown the potential of the inhibitors of KKS as anti-inflammatory and anti-edema for hereditary angioedema, via the inhibition of kallikrein or the activated

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