Esculin reduces P2X7 and reverses mitochondrial dysfunction in the renal cortex of diabetic rats

Serralha, Robson; Rodrigues, Inri; Bertolini, A.; Lima, Deyse Y.; Nascimento, Moises; Mouro, Margaret Gori; Punaro, Giovana Rita; Visoná, Iria; Rodrigues, Adelson Marçal; Higa, Elisa M S

doi:10.1016/j.lfs.2020.117787

Cited by 12 publications

(8 citation statements)

References 56 publications

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“…Meanwhile, pretreatment with either ESC or EPO inhibited RI/R-induced oxidative stress via their antioxidant properties. Concordant with our results, the antioxidant activities of ESC were reported to improve the progression of several pathologies including renal diseases, due to its ability to scavenge ROS and inhibit neutrophil-dependent superoxide anion generation and lipid peroxidation 11 . Additionally, Liu et al 41 demonstrated that EPO pretreatment improved renal function and protected renal tissues from further damage in RI/R via its direct antioxidant activities as indicated by inducing the activity of antioxidant enzymes and inhibiting lipid peroxidation.…”

Section: Discussionsupporting

confidence: 91%

“…The animal groups were as follows; Sham (received vehicle alone), vehicle + RI/R, ESC + RI/R, EPO + RI/R, and ESC + EPO + RI/R. Rats were pretreated with ESC (50 mg/kg 11 ) or vehicle (0.5% carboxymethyl cellulose in phosphate buffer saline (PBS), Sigma Aldrich, USA) via oral gavage for 7 days and 30 min prior to RI/R. Meanwhile, EPO (Eprex®, Janssen-Cialg, Switzerland) was administered in a single dose of 1000 U/kg, IP, 30 min 20 prior to RI/R.…”

Section: Methodsmentioning

confidence: 99%

“…Esculin (ESC), a coumarin derivative, has several biological activities including vasoprotective 8 , anti-inflammatory, antioxidant 9 , and anti-apoptotic effects 10 . ESC is recently reported to exhibit nephroprotective activity against diabetic nephropathy in rats and LPS-induced AKI in mice via P2X7Rs inhibitory activities 11 , 12 . However, its protective activities against RI/R have not been previously examined.…”

Section: Introductionmentioning

confidence: 99%

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Co-treatment with Esculin and erythropoietin protects against renal ischemia–reperfusion injury via P2X7 receptor inhibition and PI3K/Akt activation

El-Maadawy

Hassan

Hafiz

et al. 2022

Sci Rep

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Renal ischemia/reperfusion (RI/R) is a critical clinical outcome with slightly reported improvement in mortality and morbidity. Effective therapies are still crucially required. Accordingly, the therapeutic effects of esculin (ESC, LCESI-MS/MS-isolated compound from Vachellia farnesiana flowers extract, with reported P2X7 receptor inhibitor activity) alone and in combination with erythropoietin (EPO) were investigated against RI/R injury and the possible underlying mechanisms were delineated. ESC and EPO were administered for 7 days and 30 min prior to RI, respectively. Twenty-four hour following reperfusion, blood and kidney samples were collected. Results revealed that pretreatment with either ESC or EPO reduced serum nephrotoxicity indices, renal oxidative stress, inflammatory, and apoptosis markers. They also ameliorated the renal histopathological injury on both endothelial and tubular epithelial levels. Notably, ESC markedly inhibited P2X7 receptors and NLRP3 inflammasome signaling (downregulated NLRP3 and Caspase-1 gene expressions), whereas EPO significantly upregulated PI3K and Akt gene expressions, also p-PI3K and p-Akt levels in renal tissues. ESC, for the first time, demonstrated effective protection against RI/R-injury and its combination with EPO exerted maximal renoprotection when compared to each monotherapy, thereby representing an effective therapeutic approach via inhibiting oxidative stress, inflammation, renal tubular and endothelial injury, apoptosis, and P2X7 receptors expression, and activating PI3K/Akt pathway.

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Section: Discussionsupporting

confidence: 91%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Co-treatment with Esculin and erythropoietin protects against renal ischemia–reperfusion injury via P2X7 receptor inhibition and PI3K/Akt activation

El-Maadawy

Hassan

Hafiz

et al. 2022

Sci Rep

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“…Serralha et al investigated DN-elicited changes in mitochondrial respiration in the kidneys of diabetic rats, and found there was a significant decrease in mitochondrial oxygen consumption and RCR in the presence of CI substrates (malate and pyruvate), whereas the respiratory rates were unchanged with succinate, the CII substrate [ 68 ]. Similarly, Christensen et al found decreases in CI-supported mitochondrial OXPHOS and total OXPHOS without changes in RCR in the diabetic rat kidney.…”

Section: Effects Of Diabetes On Mitochondrial Respiration In Animal S...mentioning

confidence: 99%

Impairment of Mitochondrial Respiration in Metabolic Diseases: An Overview

Avram

Merce

Hâncu

et al. 2022

IJMS

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Mitochondrial dysfunction has emerged as a central pathomechanism in the setting of obesity and diabetes mellitus, linking these intertwined pathologies that share insulin resistance as a common denominator. High-resolution respirometry (HRR) is a state-of-the-art research method currently used to study mitochondrial respiration and its impairment in health and disease. Tissue samples, cells or isolated mitochondria are exposed to various substrate-uncoupler-inhibitor-titration protocols, which allows the measurement and calculation of several parameters of mitochondrial respiration. In this review, we discuss the alterations of mitochondrial bioenergetics in the main dysfunctional organs that contribute to the development of the obese and diabetic phenotypes in both animal models and human subjects. Herein we review data regarding the impairment of oxidative phosphorylation as integrated mitochondrial function assessed by means of HRR. We acknowledge the critical role of this method in determining the alterations in oxidative phosphorylation occurring in the early stages of metabolic pathologies. We conclude that there is a mutual two-way relationship between mitochondrial dysfunction and insulin insensitivity that characterizes these diseases.

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“…Esculin (50 mg/kg) blocked the continuous activation of the P2X7 receptor, inhibited inflammation and oxidative stress, and ultimately reduced the production of proteinuria (an early marker of diabetic nephropathy) in STZ‐induced diabetic mice (Serralha et al, 2018; Serralha et al, 2019). In addition to directly inhibiting the activation of P2X7 receptor, esculin (50 mg/kg) improved inflammation infiltration, collagen IV deposition, oxidative stress injury and the development of kidney damage in STZ‐induced diabetic rats by restoring mitochondrial function and reducing excessive extracellular ATP level (Serralha et al, 2020). In addition, esculin (30–90 mg/kg) also reduced the level of AGEs in the serum and inhibited the accumulation of AGEs in the kidney of diabetic rats (Wang et al, 2015).…”

Section: The Pharmacological Effects Of Esculinmentioning

confidence: 99%

The pharmacological and pharmacokinetic properties of esculin: A comprehensive review

Lai

et al. 2022

Phytotherapy Research

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Cortex fraxini is a widely used traditional Chinese medicine. Esculin is one of the main active ingredients of Cortex fraxini and has attracted more and more attention from scholars. The purpose of the review is to systematically review relevant studies on the pharmacological effects and pharmacokinetic characteristics of esculin to support its further application as therapeutic agents. Pharmacological studies have shown that the anti-inflammatory and anti-oxidative stress effects of esculin are outstanding. This indicates that esculin is promising to be used to treat a variety of diseases closely related to inflammation and oxidative damage. Esculin has anti-diabetic effect, which is closely related to improving pancreas damage, promoting insulin release, and enhancing glucose homeostasis. In addition, esculin has anti-cancer, antibiosis, antivirus, neuroprotection, anti-thrombosis and treating eye diseases properties. Pharmacokinetic studies show that esculin can be quickly and evenly distributed in the body.However, the first pass effect of esculin is serious. In short, esculin is promising to treat many diseases, but further high quality studies are needed to firmly establish the clinical efficacy of esculin.

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Esculin reduces P2X7 and reverses mitochondrial dysfunction in the renal cortex of diabetic rats

Cited by 12 publications

References 56 publications

Co-treatment with Esculin and erythropoietin protects against renal ischemia–reperfusion injury via P2X7 receptor inhibition and PI3K/Akt activation

Co-treatment with Esculin and erythropoietin protects against renal ischemia–reperfusion injury via P2X7 receptor inhibition and PI3K/Akt activation

Impairment of Mitochondrial Respiration in Metabolic Diseases: An Overview

The pharmacological and pharmacokinetic properties of esculin: A comprehensive review

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