Ginkgolic acid as a dual-targeting inhibitor for protein tyrosine phosphatases relevant to insulin resistance

Yoon, Sun‐Young; Lee, Ji Hee; Kwon, Se Jeong; Kang, Hyo Jin; Chung, Sang J.

doi:10.1016/j.bioorg.2018.08.011

Cited by 20 publications

(31 citation statements)

References 20 publications

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“…This in turn will also promote glucose homeostasis and reduce hyperglycemia. PTPN9 disrupts the insulin signaling pathway and thus treatment with inhibitors will result in insulin sensitization and improve glucose homeostasis [248]. Inhibition of DPP4 will increase the half-life of the incretin hormones, thereby increasing insulin secretion and allowing time to normalize blood glucose levels [249].…”

Section: Resultsmentioning

confidence: 99%

Evaluation of the Anti-Diabetic Activity of Some Common Herbs and Spices: Providing New Insights with Inverse Virtual Screening

et al. 2019

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Culinary herbs and spices are widely used as a traditional medicine in the treatment of diabetes and its complications, and there are several scientific studies in the literature supporting the use of these medicinal plants. However, there is often a lack of knowledge on the bioactive compounds of these herbs and spices and their mechanisms of action. The aim of this study was to use inverse virtual screening to provide insights into the bioactive compounds of common herbs and spices, and their potential molecular mechanisms of action in the treatment of diabetes. In this study, a library of over 2300 compounds derived from 30 common herbs and spices were screened in silico with the DIA-DB web server against 18 known diabetes drug targets. Over 900 compounds from the herbs and spices library were observed to have potential anti-diabetic activity and liquorice, hops, fennel, rosemary, and fenugreek were observed to be particularly enriched with potential anti-diabetic compounds. A large percentage of the compounds were observed to be potential polypharmacological agents regulating three or more anti-diabetic drug targets and included compounds such as achillin B from yarrow, asparasaponin I from fenugreek, bisdemethoxycurcumin from turmeric, carlinoside from lemongrass, cinnamtannin B1 from cinnamon, crocin from saffron and glabridin from liquorice. The major targets identified for the herbs and spices compounds were dipeptidyl peptidase-4 (DPP4), intestinal maltase-glucoamylase (MGAM), liver receptor homolog-1 (NR5A2), pancreatic alpha-amylase (AM2A), peroxisome proliferator-activated receptor alpha (PPARA), protein tyrosine phosphatase non-receptor type 9 (PTPN9), and retinol binding protein-4 (RBP4) with over 250 compounds observed to be potential inhibitors of these particular protein targets. Only bay leaves, liquorice and thyme were found to contain compounds that could potentially regulate all 18 protein targets followed by black pepper, cumin, dill, hops and marjoram with 17 protein targets. In most cases more than one compound within a given plant could potentially regulate a particular protein target. It was observed that through this multi-compound-multi target regulation of these specific protein targets that the major anti-diabetic effects of reduced hyperglycemia and hyperlipidemia of the herbs and spices could be explained. The results of this study, taken together with the known scientific literature, indicated that the anti-diabetic potential of common culinary herbs and spices was the result of the collective action of more than one bioactive compound regulating and restoring several dysregulated and interconnected diabetic biological processes.

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Section: Resultsmentioning

confidence: 99%

Evaluation of the Anti-Diabetic Activity of Some Common Herbs and Spices: Providing New Insights with Inverse Virtual Screening

et al. 2019

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“…However, whether inhibition of SUMOylation accounts for the manifold bioactivities exerted by GA is unclear. In fact, many different biological properties and targets are described for GA in vitro and in vivo that, on one hand, may partially explain the cytotoxic and allergic actions of GA, but also suggest beneficial pharmacological features, especially as an anti-cancer agent (Itokawa et al, 1987; Zhou et al, 2010; Baek et al, 2017a; Baek et al, 2017b; Yoon et al, 2018). In particular, DNA strand-breaking (Westendorf and Regan, 2000), activation of protein phosphatase 2C (Ahlemeyer et al, 2001), abrogation of STAT3 signaling (Baek et al, 2017b) and the PI3K/Akt/mTOR pathway (Baek et al, 2017a), transformation of mitochondria and uncoupling of oxidative phosphorylation (Hecker et al, 2002), as well as inhibition of SIRT (Ryckewaert et al, 2014) may account for cytotoxic and anti-cancer properties of GA.…”

Section: Discussionmentioning

confidence: 99%

Ginkgolic Acid is a Multi-Target Inhibitor of Key Enzymes in Pro-Inflammatory Lipid Mediator Biosynthesis

et al. 2019

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Introduction: Lipid mediators (LMs) comprise bioactive metabolites of polyunsaturated fatty acids, including pro-inflammatory prostaglandins (PGs), thromboxanes (TXs), and leukotrienes (LTs), as well as specialized pro-resolving mediators (SPMs). They are essentially biosynthesized via cyclooxygenase (COX) and lipoxygenase (LO) pathways in complex networks and regulate the progression as well as the resolution of inflammatory disorders including inflammation-triggered cancer. Ginkgolic acid (GA) is a phenolic acid contained in Ginkgo biloba L. with neuroprotective, antimicrobial, and antitumoral properties. Although LMs regulate microbial infections and tumor progression, whether GA affects LM biosynthesis is unknown and was investigated here in detail. Methods: Pharmacophore-based virtual screening was performed along with docking simulations. Activity assays were conducted for isolated human recombinant 5-LO, cytosolic phospholipase (PLA) 2 α, COX-2, and ovine COX-1. The activity of human mPGES-1 and thromboxane A 2 synthase (TXAS) was determined in crude cellular fractions. Cellular LM formation was studied using human monocytes, neutrophils, platelets, and M1- and M2-like macrophages. LMs were identified after (ultra)high-performance liquid chromatography by UV detection or ESI-tandem mass spectrometry. Results: GA was identified as virtual hit in an mPGES-1 pharmacophore-based virtual screening. Cell-free assays revealed potent suppression of mPGES-1 activity (IC 50 = 0.7 µM) that is fully reversible and essentially independent of the substrate concentration. Moreover, cell-free assays revealed COX-1 and TXAS as additional targets of GA with lower affinity (IC 50 = 8.1 and 5.2 µM). Notably, 5-LO, the key enzyme in LT biosynthesis, was potently inhibited by GA (IC 50 = 0.2 µM) in a reversible and substrate-independent manner. Docking simulations support the molecular interaction of GA with mPGES-1 and 5-LO and suggest concrete binding sites. Interestingly, interference of GA with mPGES-1, COX-1, TXAS, and 5-LO was evident also in intact cells with IC 50 values of 2.1–3.8 µM; no radical scavenging or cytotoxic properties were obvious. Analysis of LM profiles from bacteria-stimulated human M1- and M2-like macrophages confirmed the multi-target features of GA and revealed LM redirection towards the formation of 12-/15-LO products including SPM. Conclusions: We reveal GA as potent multi-target inhibitor of key enzymes in the biosynthesis of pro-inflammatory LMs that contribute to the complex pharmacological and toxicological properties of GA.

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“…Another study reported that ginkgolic acid, which is extracted from the Ginkgo bilola leaf or seed coat, can inhibit DUSP9 activity [ 87 ]. It was selected following the screening of 658 natural compounds by an enzymatic test based on a recombinant purified human DUSP9 protein.…”

Section: Dusp9 Is the Target For Therapymentioning

confidence: 99%

DUSP9, a Dual-Specificity Phosphatase with a Key Role in Cell Biology and Human Diseases

Khoubai

Grosset

2021

IJMS

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Mitogen-activated protein kinases (MAPKs) are essential for proper cell functioning as they regulate many molecular effectors. Careful regulation of MAPKs is therefore required to avoid MAPK pathway dysfunctions and pathologies. The mammalian genome encodes about 200 phosphatases, many of which dephosphorylate the MAPKs and bring them back to an inactive state. In this review, we focus on the normal and pathological functions of dual-specificity phosphatase 9 (DUSP9)/MAP kinase phosphatases-4 (MKP-4). This cytoplasmic phosphatase, which belongs to the threonine/tyrosine dual-specific phosphatase family and was first described in 1997, is known to dephosphorylate ERK1/2, p38, JNK and ASK1, and thereby to control various MAPK pathway cascades. As a consequence, DUSP9 plays a major role in human pathologies and more specifically in cardiac dysfunction, liver metabolic syndromes, diabetes, obesity and cancer including drug response and cell stemness. Here, we recapitulate the mechanism of action of DUSP9 in the cell, its levels of regulation and its roles in the most frequent human diseases, and discuss its potential as a therapeutic target.

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Ginkgolic acid as a dual-targeting inhibitor for protein tyrosine phosphatases relevant to insulin resistance

Cited by 20 publications

References 20 publications

Evaluation of the Anti-Diabetic Activity of Some Common Herbs and Spices: Providing New Insights with Inverse Virtual Screening

Evaluation of the Anti-Diabetic Activity of Some Common Herbs and Spices: Providing New Insights with Inverse Virtual Screening

Ginkgolic Acid is a Multi-Target Inhibitor of Key Enzymes in Pro-Inflammatory Lipid Mediator Biosynthesis

DUSP9, a Dual-Specificity Phosphatase with a Key Role in Cell Biology and Human Diseases

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