A novel role for small molecule glycomimetics in the protection against lipid-induced endothelial dysfunction: Involvement of Akt/eNOS and Nrf2/ARE signaling

Mahmoud, Ayman M.; Wilkinson, Fiona; Jones, Alan M.; Wilkinson, James A.; Romero, Miguel; Duarte, Juan; Alexander, M. Yvonne

doi:10.1016/j.bbagen.2016.08.013

Cited by 64 publications

(50 citation statements)

References 56 publications

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“…An explanation for this declined expression of Nrf2 could be the chronic and surplus production of ROS. This notion is supported by our recent findings where we demonstrated downregulation of the Nrf2/ARE/HO-1 pathway in different conditions with excessive production of ROS [34, 48, 72–74]. Furthermore, the anti-inflammatory effect of C. molmol resin extract could be attributed, at least in part, to the activation of Nrf2.…”

Section: Discussionsupporting

confidence: 78%

Commiphora molmol Modulates Glutamate‐Nitric Oxide‐cGMP and Nrf2/ARE/HO‐1 Pathways and Attenuates Oxidative Stress and Hematological Alterations in Hyperammonemic Rats

Mahmoud

Alqahtani

Othman

et al. 2017

Oxidative Medicine and Cellular Longevity

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Hyperammonemia is a serious complication of liver disease and may lead to encephalopathy and death. This study investigated the effects of Commiphora molmol resin on oxidative stress, inflammation, and hematological alterations in ammonium chloride- (NH4Cl-) induced hyperammonemic rats, with an emphasis on the glutamate-NO-cGMP and Nrf2/ARE/HO-1 signaling pathways. Rats received NH4Cl and C. molmol for 8 weeks. NH4Cl-induced rats showed significant increase in blood ammonia, liver function markers, and tumor necrosis factor-alpha (TNF-α). Concurrent supplementation of C. molmol significantly decreased circulating ammonia, liver function markers, and TNF-α in hyperammonemic rats. C. molmol suppressed lipid peroxidation and nitric oxide and enhanced the antioxidant defenses in the liver, kidney, and cerebrum of hyperammonemic rats. C. molmol significantly upregulated Nrf2 and HO-1 and decreased glutamine and nitric oxide synthase, soluble guanylate cyclase, and Na+/K+-ATPase expression in the cerebrum of NH4Cl-induced hyperammonemic rats. Hyperammonemia was also associated with hematological and coagulation system alterations. These alterations were reversed by C. molmol. Our findings demonstrated that C. molmol attenuates ammonia-induced liver injury, oxidative stress, inflammation, and hematological alterations. This study points to the modulatory effect of C. molmol on glutamate-NO-cGMP and Nrf2/ARE/HO-1 pathways in hyperammonemia. Therefore, C. molmol might be a promising protective agent against hyperammonemia.

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Section: Discussionsupporting

confidence: 78%

Commiphora molmol Modulates Glutamate‐Nitric Oxide‐cGMP and Nrf2/ARE/HO‐1 Pathways and Attenuates Oxidative Stress and Hematological Alterations in Hyperammonemic Rats

Mahmoud

Alqahtani

Othman

et al. 2017

Oxidative Medicine and Cellular Longevity

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“…Thus, it could also be exploited to counteract the anti-angiogenic effect of aging on ECFCs. Parallel work conducted on an endothelial model of lipid-induced oxidative stress showed that the glycomimetic C3 was able to recruit the Nrf2/ARE and Akt/eNOS signaling pathways, thereby exerting a cytoprotective effect and rescuing NO release [ 175 ]. Similarly, pre-treatment of diabetic ECFCs with adiponectin rescued in vitro migration and neovessel formation in a mouse model of hindlimb ischemia under both normo- and hyperglycemic conditions [ 176 ].…”

Section: Manipulation Of Pro-angiogenic Signaling Pathways To Imprmentioning

confidence: 99%

Therapeutic Potential of Endothelial Colony-Forming Cells in Ischemic Disease: Strategies to Improve their Regenerative Efficacy

Faris

Negri

Perna

et al. 2020

IJMS

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Cardiovascular disease (CVD) comprises a range of major clinical cardiac and circulatory diseases, which produce immense health and economic burdens worldwide. Currently, vascular regenerative surgery represents the most employed therapeutic option to treat ischemic disorders, even though not all the patients are amenable to surgical revascularization. Therefore, more efficient therapeutic approaches are urgently required to promote neovascularization. Therapeutic angiogenesis represents an emerging strategy that aims at reconstructing the damaged vascular network by stimulating local angiogenesis and/or promoting de novo blood vessel formation according to a process known as vasculogenesis. In turn, circulating endothelial colony-forming cells (ECFCs) represent truly endothelial precursors, which display high clonogenic potential and have the documented ability to originate de novo blood vessels in vivo. Therefore, ECFCs are regarded as the most promising cellular candidate to promote therapeutic angiogenesis in patients suffering from CVD. The current briefly summarizes the available information about the origin and characterization of ECFCs and then widely illustrates the preclinical studies that assessed their regenerative efficacy in a variety of ischemic disorders, including acute myocardial infarction, peripheral artery disease, ischemic brain disease, and retinopathy. Then, we describe the most common pharmacological, genetic, and epigenetic strategies employed to enhance the vasoreparative potential of autologous ECFCs by manipulating crucial pro-angiogenic signaling pathways, e.g., extracellular-signal regulated kinase/Akt, phosphoinositide 3-kinase, and Ca2+ signaling. We conclude by discussing the possibility of targeting circulating ECFCs to rescue their dysfunctional phenotype and promote neovascularization in the presence of CVD.

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“…We then applied the methodology to the original medicinal chemistry challenge, the sodium salt of glycomimetic C3 (10). 8 High conversion and an isolated yield of 76% on a 500 mg scale was achieved. The methodology was applied to the Fmocprotected amino acid, serine, resulting in excellent yields (95% under normal conditions) and 90% at a non-denaturing temperature (11) both using 4.0 eq.…”

mentioning

confidence: 94%

“…1 Sulfate groups on glycosaminoglycans (GAGs) such as heparin, heparan sulfate and chondroitin sulfate, facilitate molecular interactions and protein ligand binding at the cellular surface, 2 an area of interest in drug discovery. 3 Heparin (an anticoagulant), 4 avibactam s (a b-lactamase inhibitor), 5 sotradecol (a treatment for varicose veins), 6 the sulfate metabolite of paracetamol (an analgesic), 7 and the glycomimetic C3 (used to study atherosclerosis), 8 contain organosulfate motifs (Fig. 1).…”

mentioning

confidence: 99%

Sulfation made simple: a strategy for synthesising sulfated molecules

2019

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A novel role for small molecule glycomimetics in the protection against lipid-induced endothelial dysfunction: Involvement of Akt/eNOS and Nrf2/ARE signaling

Abstract: Background: Glycomimetics are a diverse array of saccharide-inspired compounds, designed to mimic the

Cited by 64 publications

References 56 publications

Commiphora molmol Modulates Glutamate‐Nitric Oxide‐cGMP and Nrf2/ARE/HO‐1 Pathways and Attenuates Oxidative Stress and Hematological Alterations in Hyperammonemic Rats

Commiphora molmol Modulates Glutamate‐Nitric Oxide‐cGMP and Nrf2/ARE/HO‐1 Pathways and Attenuates Oxidative Stress and Hematological Alterations in Hyperammonemic Rats

Therapeutic Potential of Endothelial Colony-Forming Cells in Ischemic Disease: Strategies to Improve their Regenerative Efficacy

Sulfation made simple: a strategy for synthesising sulfated molecules

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