Protocatechuic Acid, a Phenolic from Sansevieria roxburghiana Leaves, Suppresses Diabetic Cardiomyopathy via Stimulating Glucose Metabolism, Ameliorating Oxidative Stress, and Inhibiting Inflammation

Abstract

Persistent hyperglycemia, impairment of redox status and establishment of inflammatory pathophysiology integrally play important role in the pathogenesis of diabetic cardiomyopathy (DC). Present study examined the therapeutic potential of protocatechuic acid isolated from the Sansevieria roxburghiana rhizomes against DC employing rodent model of type 2 diabetes (T2D). T2D was induced by high fat diet + a low-single dose of streptozotocin (35 mg/kg, i.p.). T2D rats exhibited significantly (p < 0.01) high fasting blood glucose level. Alteration in serum lipid profile (p < 0.01) and increased levels of lactate dehydrogenase (p < 0.01) and creatine kinase (p < 0.01) in the sera of T2D rats revealed the occurrence of hyperlipidemia and diabetic pathophysiology. A significantly (p < 0.01) high levels of serum C-reactive protein and pro-inflammatory mediators revealed the establishment of inflammatory occurrence in T2D rats. Besides, significantly high levels of troponins in the sera revealed the establishment of cardiac dysfunctions in T2D rats. However, protocatechuic acid (50 and 100 mg/kg, p.o.) treatment could significantly reverse the changes in serum biochemical parameters related to cardiac dysfunctions. Molecular mechanism studies demonstrated impairment of signaling cascade, IRS1/PI3K/Akt/AMPK/p 38/GLUT4, in glucose metabolism in the skeletal muscle of T2D rats. Significant (p < 0.01) activation of polyol pathway, enhanced production of AGEs, oxidative stress and up-regulation of inflammatory signaling cascades (PKC/NF-κB/PARP) were observed in the myocardial tissue of T2D rats. However, protocatechuic acid (50 and 100 mg/kg, p.o.) treatment could significantly (p < 0.05–0.01) stimulate glucose metabolism in skeletal muscle, regulated glycemic and lipid status, reduced the secretion of pro-inflammatory cytokines, and restored the myocardial physiology in T2D rats near to normalcy. Histological assessments were also in agreement with the above findings. In silico molecular docking study again supported the interactions of protocatechuic acid with different signaling molecules, PI3K, IRS, Akt, AMPK PKC, NF-κB and PARP, involved in glucose utilization and inflammatory pathophysiology. In silico ADME study predicted that protocatechuic acid would support the drug-likeness character. Combining all, results would suggest a possibility of protocatechuic acid to be a new therapeutic agent for DC in future.

Effect of Rosmarinic Acid and Sinapic Acid on Oxidative Stress Parameters in the Cardiac Tissue and Serum of Type 2 Diabetic Female Rats

“…Therefore, it can be concluded, that the model reflecting the changes observed in the type 2 diabetes in humans in the most adequate manner is a model in which a high-fat diet is combined with a single injection of a low dose of streptozotocin [52,53]. It should be noted that the majority of studies describing the effect of tested substances on parameters affected by both the type 1 and type 2 diabetes is based on the experiments conducted on male laboratory animals [17,[19][20][21][22][23][24][25][32][33][34][35]37,38,50,51,[54][55][56][57][58][59][60][61][62]. Following the suggestion of The National Institutes of Health (NIH) to use female animals in the laboratory studies [63] and reports about sex-dependent metabolic differences [64,65], our experiment was conducted on female rats.…”

“…HFD: high-fat diet; STZ: streptozotocin; RA: rosmarinic acid; SA: sinapic acid; C: control rats; DM2: HFD + STZ-induced type 2 diabetic rats; RA10 and RA50: HFD + STZ-induced diabetic rats treated with rosmarinic acid at a dose of 10 mg/kg and 50 mg/kg, respectively; SA5 and SA25: HFD + STZ-induced diabetic rats treated with sinapic acid at a dose of 5 mg/kg and 25 mg/kg, respectively, for 28 days. 24 h after the administration of the last dose of phenolic acids and overnight fasting, rats were euthanized by injection of ketamine and xylazine mixture and cardiac exsanguination. In order to separate the serum required for biochemical assays, the blood obtained from the heart was centrifuged.…”

Protocatechuic acid attenuates angiotensin II‐induced cardiac fibrosis in cardiac fibroblasts through inhibiting the NOX4/ROS/p38 signaling pathway

“…In addition, PCA treatment could significantly reverse the changes in serum biochemical parameters related to cardiac dysfunctions in T2D rats (Bhattacharjee et al, ). The T2D rats exhibits significantly high levels of intercellular ROS in the myocardial tissue, whereas PCA treatment could significantly alleviate ROS production (Bhattacharjee et al, ). Petronio et al (Petronio et al, ) proved that PCA has the capacity as a scavenger of nonradical oxidant species, which could be particularly relevant for NOX4.…”

“…Besides, PCA significantly decreases plasma HbA1c and cardiac MDA levels, increases BCL2 expression, and improves cardiac mitochondrial function (Petronio, Zeraik, Fonseca, & Ximenes, 2013). In addition, PCA treatment could significantly reverse the changes in serum biochemical parameters related to cardiac dysfunctions in T2D rats (Bhattacharjee et al, 2017). The T2D rats exhibits significantly high levels of intercellular ROS in the myocardial tissue, whereas PCA treatment could significantly alleviate ROS production (Bhattacharjee et al, 2017).…”

“…PCA has been shown to exert anti-inflammatory, anti-hyperglycemic, antiapoptotic, antitumor, and antimicrobial activities (Semaming, Pannengpetch, Chattipakorn, & Chattipakorn, 2015). In addition, PCA was found to suppress diabetic cardiomyopathy via stimulating glucose metabolism, ameliorating oxidative stress, and inhibiting inflammation (Bhattacharjee et al, 2017). PCA also exhibits cardioprotective effects in ischemia-reperfusion injury of isolated rat hearts (Drevensek, Lunder, Benkovic, Strukelj, & Kreft, 2016).…”