Jaganmay Sarkar

Protective role of epigallocatechin-3-gallate in health and disease: A perspective

Tea is the most popular beverages all over the world. Polyphenols are found ubiquitously in tea leaves and their regular consumption has been associated with a reduced risk of a number of chronic diseases including cancer, cardiovascular and neurodegenerative diseases. Epigallocatechin-3-gallate (EGCG) is the most abundant polyphenol in tea leaves and received great attention due to their protective role in the prevention of the diseases. Rather than eliciting direct antioxidant effects, the mechanisms by which tea polyphenol express these beneficial properties appear to involve their interaction with cellular signaling pathways and related machinery that mediate cell function under both normal and pathological conditions. The central focus of this review is to provide an overview of the role that the major tea polyphenol, EGCG plays in preventing cancer, cardiovascular and neurodegenerative diseases. This review present epidemiological data, human intervention study findings, as well as animal and in vitro studies in support of these actions and delineates the molecular mechanism associated with the action of EGCG in ameliorating of such diseases.

Inhibition of MMP-9 by green tea catechins and prediction of their interaction by molecular docking analysis

Green tea polyphenolic catechins have been shown to prevent various types of diseases such as pulmonary hypertension (PAH), cancer and cardiac and neurological disorders. Matrix metalloproteinases (MMPs) play an important role in the development of PAH. The present study demonstrated that among the four green tea catechins (EGCG, ECG, EC and EGC), EGCG and ECG inhibit pro-/active MMP-9 activities in pulmonary artery smooth muscle cell culture supernatant. Based on the above, we investigated the interactions of pro-/active MMP-9 with the green tea catechins by computational methods. In silico molecular docking analysis revealed a strong interaction between pro-/active MMP-9 and EGCG/ECG, and galloyl group appears to be responsible for this enhanced interaction. The molecular docking studies corroborate our experimental observation that EGCG and ECG are mainly active in preventing both the proMMP-9 and MMP-9 activities.

Role of Spm-Cer-S1P signalling pathway in MMP-2 mediated U46619-induced proliferation of pulmonary artery smooth muscle cells: protective role of epigallocatechin-3-gallate.

During remodelling of pulmonary artery, marked proliferation of pulmonary artery smooth muscle cells (PASMCs) occurs, which contributes to pulmonary hypertension. Thromboxane A2 (TxA2) has been shown to produce pulmonary hypertension. The present study investigates the inhibitory effect of epigallocatechin‐3‐gallate (EGCG) on the TxA2 mimetic, U46619‐induced proliferation of PASMCs. U46619 at a concentration of 10 nM induces maximum proliferation of bovine PASMCs. Both pharmacological and genetic inhibitors of p38MAPK, NF‐κB and MMP‐2 significantly inhibit U46619‐induced cell proliferation. EGCG markedly abrogate U46619‐induced p38MAPK phosphorylation, NF‐κB activation, proMMP‐2 expression and activation, and also the cell proliferation. U46619 causes an increase in the activation of sphingomyelinase (SMase) and sphingosine kinase (SPHK) and also increase sphingosine 1 phosphate (S1P) level. U46619 also induces phosphorylation of ERK1/2, which phosphorylates SPHK leading to an increase in S1P level. Both pharmacological and genetic inhibitors of SMase and SPHK markedly inhibit U46619‐induced cell proliferation. Additionally, pharmacological and genetic inhibitors of MMP‐2 markedly abrogate U46619‐induced SMase activity and S1P level. EGCG markedly inhibit U46619‐induced SMase activity, ERK1/2 and SPHK phosphorylation and S1P level in the cells. Overall, Sphingomyeline–Ceramide–Sphingosine‐1‐phosphate (Spm–Cer–S1P) signalling axis plays an important role in MMP‐2 mediated U46619‐induced proliferation of PASMCs. Importantly, EGCG inhibits U46619 induced increase in MMP‐2 activation by modulating p38MAPK–NFκB pathway and subsequently prevents the cell proliferation. Copyright

Inhibition of pro-/active MMP-2 by green tea catechins and prediction of their interaction by molecular docking studies

Matrix metalloproteinases (MMPs) play a crucial role in developing different types of lung diseases, e.g., pulmonary arterial hypertension (PAH). Green tea polyphenolic catechins such as EGCG and ECG have been shown to ameliorate various types of diseases including PAH. Our present study revealed that among the four green tea catechins (EGCG, ECG, EC, and EGC), EGCG and ECG inhibit pro-/active MMP-2 activities in pulmonary artery smooth muscle cell (PASMC) culture supernatant. Based on the above, we investigated the interactions of pro-/active MMP-2 with the green tea catechins by computational methods. In silico analysis revealed a strong interaction of pro-/active MMP-2 with EGCG/ECG, and galloyl group has been observed to be responsible for this interaction. The in silico analysis corroborated our experimental observation that EGCG and ECG are active in preventing both the proMMP-2 and MMP-2 activities. Importantly, these two catechins appeared to be better inhibitors for proMMP-2 in comparison to MMP-2 as revealed by gelatin zymogram and also by molecular docking studies. In many type of cells, activation of proMMP-2 occurs via an increase in the level of MT1-MMP (MMP-14). We, therefore, determined the interactions of MT1-MMP with the green tea catechins by molecular docking analysis. The study revealed a strong interaction of MT1-MMP with EGCG/ECG, and galloyl group has been observed to be responsible for the interaction.

Cross-talk between NADPH oxidase-PKCα-p(38)MAPK and NF-κB-MT1MMP in activating proMMP-2 by ET-1 in pulmonary artery smooth muscle cells.

Treatment of bovine pulmonary artery smooth muscle cells with endothelin-1 (ET-1) caused an increase in the expression and activation of proMMP-2 in the cells. The present study was undertaken to determine the underlying mechanisms involved in this scenario. We demonstrated that (i) pretreatment with NADPH oxidase inhibitor, apocynin; PKC-α inhibitor, Go6976; p38MAPK inhibitor SB203580 and NF-κB inhibitor, Bay11-7082 inhibited the expression and activation of proMMP-2 induced by ET-1; (ii) ET-1 treatment to the cells stimulated NADPH oxidase and PKCα activity, p38MAPK phosphorylation as well as NF-κB activation by translocation of NF-κBp65 subunit from cytosol to the nucleus, and subsequently by increasing its DNA-binding activity; (iii) ET-1 increases MT1-MMP expression, which was inhibited upon pretreatment with apocynin, Go6976, SB293580, and Bay 11-7082; (iv) ET-1 treatment to the cells downregulated TIMP-2 level. Although apocynin and Go6976 pretreatment reversed ET-1 effect on TIMP-2 level, yet pretreatment of the cells with SB203580 and Bay 11-7082 did not show any discernible change in TIMP-2 level by ET-1. Overall, our results suggest that ET-1-induced activation of proMMP-2 is mediated via cross-talk between NADPH oxidase-PKCα-p38MAPK and NFκB-MT1MMP signaling pathways along with a marked decrease in TIMP-2 expression in the cells.

Phospholemman: A Brief Overview

Na+/K+-ATPase (NKA) plays the key role in maintaining Na+ and K+ gradients in cells, which is essential for regulation of cell volume and membrane potential. PLM (aka FXYD1) interacts with NKA and Na+/Ca2+ exchanger (NCX) and modulates their activities in tissue specific and physiological state specific manner. Protein kinase A (PKA) and protein kinase C (PKC) targets different pools of PLM associated with NKA and NCX, thereby regulating their activities. Additionally, some signal transducers such as phosphatases, phosphodiesterases and nitric oxide play important roles in modulating functions of PLM, especially under phosphorylated conditions, toward the activities of NKA and NCX. Understanding the above phenomenon is of significance in developing novel therapeutics for recovery of patients suffering from a variety of pathophysiological conditions, especially cardiovascular and neural diseases.

Role of catechins on ET-1 induced stimulation of PLD and NADPH oxidase activities in pulmonary smooth muscle cells: Determination of the probable mechanism by molecular docking studies

The treatment of human pulmonary artery smooth muscle cells with ET-1 stimulates the activity of PLD and NADPH oxidase, but this stimulation is inhibited by pretreatment with bosentan (ET-1 receptor antagonist), FIPI (PLD inhibitor), apocynin (NADPH oxidase inhibitor), and EGCG and ECG (catechins having a galloyl group), but not EGC and EC (catechins devoid of a galloyl group). Herein, using molecular docking analyses based on our biochemical studies, we determined the probable mechanism by which the catechins containing a galloyl group inhibit the stimulation of PLD activity induced by ET-1. The ET-1-induced stimulation of PLD activity was inhibited by SecinH3 (inhibitor of cytohesin). Arf6 and cytohesin-1 are associated in the cell membrane, which is not inhibited by the catechins during ET-1 treatment of the cells. However, EGCG and ECG inhibited the binding of GTPγS with Arf6, even in the presence of cytohesin-1. The molecular docking analyses revealed that the catechins containing a galloyl group (EGCG and ECG) with cytohesin-1-Arf6GDP, but not the catechins without a galloyl group (EGC and EC), prevent GDP-GTP exchange in Arf6, which seems to be an important mechanism for inhibiting the activation of PLD induced by ET-1, and subsequently increases the activity of NADPH oxidase.

Role of Proteases in Lung Disease: A Brief Overview

Proteases play an important role in health and disease of the lung. In the normal lungs, proteases maintain their homeostatic functions that regulate processes like its regeneration and repair. Dysregulation of proteases–antiproteases balance is crucial in the manifestation of different types of lung diseases. Chronic inflammatory lung pathologies are associated with a marked increase in protease activities. Thus, in addition to protease activities, inhibition of anti-proteolytic control mechanisms are also important for effective microbial infection and inflammation in the lung. Herein, we briefly summarize the role of different proteases and to some extent antiproteases in regulating a variety of lung diseases.

Pathophysiological Aspects of Lipoprotein-Associated Phospholipase A 2 : A Brief Overview

Macrophages are known to produce significant amount of lipoprotein-associated phospholipase A2 (Lp-PLA2). In human plasma Lp-PLA2 circulates in association with low- and high-density lipoproteins (LDL and HDL), where LDL-associated Lp-PLA2 was found to be associated with atherosclerosis lesions. Studies have also suggested that LDL and the modified forms of LDL such as oxidized LDL (oxLDL) and glycated LDL (gLDL), and also apolipoprotein E (apoE) isoforms, are also found to be associated with Lp-PLA2 for initiation and progression of vascular lesions. Additionally, Chlamydia pneumoniae infection can increase Lp-PLA2 activity in the macrophages of atherosclerotic plaque. In adolescents, Lp-PLA2 changes occur with obesity and it shows important association with markers of cardiovascular disorder. Lp-PLA2 levels can be lowered by two main pharmacologic interventions—indirectly, by lowering LDL, or directly, by lowering Lp-PLA2 activity. Notably, darapladib (a product of GlaxoSmithKline) is now considered as an important therapeutic agent to inhibit Lp-PLA2 activity. However, some studies are still in progress to determine its pharmacokinetics and to prove it as a safe drug.

Exercise and Matrix Metalloproteases in Health and Disease: A Brief Overview

Systematic exercise plays a great deal with health for people to improve and/or prevent many diseases such as hypertension, coronary heart disease and diabetes. However, strenuous exercise markedly increases expression and activation of matrix metalloproteases and thereby causes changes in the regulation of skeletal muscle and tendon functions, immune response, aging and angiogenic processes. This review provides information on some cellular and molecular responses that underlie the prophylactic effects of exercise in some pathophysiological conditions including age related diseases involving matrix metalloproteases.