Piperine mitigates aortic vasculopathy in streptozotocin-diabetic rats via targeting TXNIP-NLRP3 signaling
Introduction
Diabetes is a metabolic disease characterized by sustained levels of hyperglycemia. Diabetes is expected to affect 592 million patients by 2035 [61]. Vascular complications are a primary cause of disabilities and high mortality rates in diabetic patients [66].
Diabetic hyperglycemia is a key contributor to vascular complications, as it enhances the upregulation of advanced glycation end products (AGEs) in the circulating blood and various tissues. AGEs interact with their receptors (RAGE) in endothelial cells, leading to the production of reactive oxygen species (ROS) and the activation of nuclear factor-κB (NF-κB), which induces a chronic inflammatory response via stimulating the expression of many cytokines and growth factors [53].
ROS also enhances the activation of nucleotide-binding oligomerization domain like receptor pyrin domain containing 3 (NLRP3) inflammasome, a novel regulator of inflammation [37]. NLRP3 activation triggers the release of the proinflammatory cytokine, interleukin-1β (IL-1 β) [22], [36].
Several studies have suggested a central role of thioredoxin interacting protein (TXNIP) in the pathogenesis of diabetic vascular complications [22], [32], [36]. TXNIP elicits excessive ROS production and induces early apoptotic signals in diabetic aortic endothelium [32] and glucose-incubated endothelial cells [29], [31], [32].
Piperine (PIP) is a major alkaloid component of black pepper. Chemically, its IUPAC name is (2E, 4E)-5-(benzo[d] [1,3] dioxol-5-yl)1-(piperidin-1-yl) penta-2,4-dien-1-one. PIP is a yellow crystalline solid with molecular formula C17H19NO3, a molecular weight of 285.33 g/mol, and a melting point of 130 °C [21], [62]. PIP has been extensively evaluated for its anti-inflammatory, antioxidant, anti-mutagenic, and hepatoprotective effects [59]. PIP showed antihyperglycemic activity and enhanced the glucose-lowering effect of metformin in diabetic mice [7], [8]. Moreover, PIP attenuated the proliferation of vascular smooth muscle cells (VSMCs) by suppressing the production of ROS [30]. PIP also ameliorated glucose tolerance and reactivity of aortic rings by reducing oxidative stress and inflammation in rats with metabolic syndrome [16]. However, the potential impacts of PIP on diabetes-associated macrovasculopathy via interfering with TXNIP-NLRP3 signaling have not yet been studied.
Therefore, this study was conducted to investigate the potential effects of PIP on STZ diabetes-associated aortopathy and explore possible mechanisms involved.
Section snippets
Chemicals and reagents
PIP and STZ were from Santa Cruz Biotechnology (Santa Cruz, CA, USA) and Sigma Aldrich Chemical Co. (St. Louis, MO, USA), respectively. All other chemicals were of the finest grade available
Animal model and grouping
Male Sprague Dawley rats, aged 6–8 weeks (250 ± 20 g), were purchased from VACSERA (Cairo, Egypt). Animals were housed under standard laboratory conditions (23 ± 2 °C; 12 h light-dark cycle; free access to standard food and water). The experimental design was accepted by the Committee of Research Ethics,
Body weight, glycemic parameters, and serum AGEs in STZ-diabetic rats
Both STZ and STZ-PIP groups showed a significant decrease in body weight relative to control rats (P < 0.0001, Fig. 1A). STZ-administered rats also showed significant elevations in fasting blood glucose (Fig. 1B), HbA1C (Fig. 1C) and serum AGE (Fig. 1D) levels by 5.7-, 1.8- and 1.3-fold, respectively, compared to those of control group. PIP treatment significantly diminished fasting blood glucose (by 27.9 %, P < 0.05), HbA1C (by 25.3 %, P < 0.001), and serum AGEs (by 19.7 %, P < 0.001) in
Discussion
In the present study, the potential impacts of PIP on type 1 diabetic vascular complications in rats were investigated. Chronic treatment with PIP successfully delayed the development of vascular complications in STZ diabetic rats via exerting antioxidant, anti-inflammatory, hypolipidemic, and hypoglycemic effects. In addition, PIP treatment restored aortic reactivity, possibly by upregulating eNOS synthase expression and attenuating endothelial apoptosis. The beneficial vascular influences of
CRediT authorship contribution statement
Manar A. Nader: Supervision, conceptualization, conceived, designed research, methodology, software, writing- reviewing, editing and approved the manuscript. Fatma M. Amin: Conducted experiments, data curation, writing- original draft preparation, software and validation. George S. G. Shehatou and Rania R. Abdelaziz: Conducted experiments, software, validation, visualization, investigation.
Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgment
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
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