Bixin ameliorates high fat diet-induced cardiac injury in mice through inflammation and oxidative stress suppression
Introduction
Diabetic cardiomyopathy is known as one of the most common complications for diabetes and also as a main reason for the mortality to diabetic patients at accumulated risk for cardiovascular diseases development [1], [2]. Additionally, obesity is known as a global disease, which is related to cardiovascular diseases, including cardiomyocyte hypertrophy and cardiac fibrosis [3], [4]. Obesity has been well reported as an important reason, leading to diabetes and metabolic syndrome in animals, which is closely associated with cardiovascular diseases progression [5], [6]. Obesity promotes cardiovascular disease via many mechanisms including ectopic lipid deposition, hyperglycemia, and the development of a procoagulant state [7], [8], [9]. Though, a lot of evidences indicated the possible molecular mechanisms and therapeutic strategies, the specific pathophysiology of obesity-associated cardiac injury is still complex, regarding to apoptosis, fibrosis, inflammation and oxidative stress, and novel treatments are still needed to be investigated [10], [11]. Thus, here in our study, we attempted to establish obesity animal model via high fat diet feeding for a consecutive long time according to previous studies to induce cardiac injury [12]. Bixin, isolated from the seeds of Bixa orellana, is a carotenoid. The carotenoid bixin (BX) may reduce inflammatory response and oxidative damage [13]. Previous studies have indicated that bixin consumption could be an adjuvant to prevent atherosclerosis by reducing oxidative damage, inflammatory response and dyslipidemia [14], [15]. Thus, our study is aimed to explore if bixin could be also used as an effective therapeutic strategy for improving cardiac injury and to reveal the underlying molecular mechanism.
Previous studies have indicated that long time exposure to high fat diet feeding could lead to fibrosis development in liver and also in heart [16], [17]. Fibrosis, including the cardiac, is a disease with a lot of abnormal collagen accumulation in the muscle fibers through activating α-SMA, collagen type I and collagen type III [18], [19]. Additionally, fibrosis progression has a close relationship with inflammation response [20]. Further, the toll-like receptor 4 (TLR4) is one of the pattern recognition receptors, playing an important role in the inflammatory response induction and activating the down-streaming signaling, including nuclear factor kappa B (NF-κB) [21]. Activation of TLR4 leads to the expression of NF-κB dependent pro-inflammatory cytokines, such as interleukin 1β (IL-1β), interleukin 18 (IL-18) and tumor necrosis factor-α (TNF-α) [22], [23]. It is reported that high-fat diet results in hyperlipidemia, and up-regulates the concentration of lipopolysaccharide (LPS) in serum, which is a stimulator for TLR4 activation [24]. Thus, blocking excessive TLR4 expression is an available therapeutic strategy for cardiac injury treatment in order to inhibit inflammation induced by high fat diet, which might be a possible molecular mechanism indicating the effects of bixin on treating cardiac injury.
Oxidative stress has been well investigated in various diseases, leading to cells damage via diverse mechanisms [25], [26]. Oxidative stress could be induced by many external stresses, including irradiation, ultraviolet light, and ischemia/reperfusion [27]. As previously reported, high fat diet is also a typical stress, leading to reactive oxygen species (ROS) accumulation through disrupting the balance of oxidants and anti-oxidants [28]. For instance, during the process of oxidative stress, anti-oxidant SOD, as well as ROS scavenger of nuclear factor-E2-related factor 2 (Nrf2) and HO-1, is expressed lowly [29], [30]. A large number of natural compounds, used in traditional medicine due to their anti-oxidant and anti-inflammatory properties, have been exhibited to induce Nrf2 expression, protecting against various types of stresses [31], [32]. Furthermore, oxidative stress has been reported in cardiac injury development under various situations, including high fat diet-induced obesity in animals [33], [34]. Therefore, we supposed that bixin might perform its role in ameliorating high fat diet-induced cardiac injury through ROS suppression in mice.
In our study, we investigated the role of bixin in cardiac injury induced by high fat diet in mice. We clearly indicated that bixin administration protect high fat diet-induced mice against cardiac fibrosis, inflammation and ROS generation through TLR4/NF-κB signaling pathway regulation and Nrf2-mediated ROS production in vivo and in vitro.
Section snippets
Animal models
Totally 80 male, 6–8 weeks, C57BL/6 mice weighed 20–25 g were purchased from the Experimental Animal Center of Shandong (Shandong, China). All animal experiments were performed to minimize animal suffering according to the Guide for the Care and Use of Laboratory Animals which was issued by the National Institutes of Health in 1996 (http://www.most.gov.cn). Before the experiments, all mice were housed in a specific pathogen-free, temperature and humidity-controlled environment (25 ± 2 °C, 50 ± 5%
Bixin restrained systemic metabolism disorder in high fat diet-induced mice
High fat diet-induced mice were treated with various concentrations of bixin in order to calculate the possibly protective effects on systemic metabolism disorder. As shown in Fig. 1B and C, the OGTT and ITT results indicated that insulin resistance was significantly observed in the experimental mice only treated with high fat diet. However, the insulin resistance in the groups treated with bixin was suppressed shown in a dose-dependent manner, which was comparable to the HFD group. And the
Discussion
Our study illustrated that bixin protected mice against cardiac injury induced by high fat diet in mouse model and in cardiac muscle cells. The protective role of bixin in suppressing cardiac injury is linked to reduction of collagen accumulation, inactivity of TLR4/NF-κB signaling pathway and down-regulation of ROS generation. ROS generation suppressed by bixin was related to Nrf2 expression, which was a major regulator for ROS production [29], [30], [31], [32]. The findings in our study
Competing financial interests
The authors declare no competing financial interests.
References (60)
- et al.
Obesity and its association to phenotype and clinical course in hypertrophic cardiomyopathy
J. Am. Coll. Cardiol.
(2013) - et al.
Overview of epidemiology and contribution of obesity to cardiovascular disease
Prog. Cardiovasc. Dis.
(2014) - et al.
Obesity, metabolic dysfunction, and cardiac fibrosis: pathophysiological pathways, molecular mechanisms, and therapeutic opportunities
Transl. Res.
(2014) - et al.
Systemic administration of the apocarotenoid bixin protects skin against solar UV-induced damage through activation of NRF2
Free Radic. Biol. Med.
(2015) - et al.
Attenuation of endoplasmic reticulum stress using the chemical chaperone 4-phenylbutyric acid prevents cardiac fibrosis induced by isoproterenol
Exp. Mol. Pathol.
(2012) - et al.
Dexmedetomidine inhibits inflammatory reaction in lung tissues of septic rats by suppressing TLR4/NF-κB pathway
Mediators Inflamm.
(2013) - et al.
Role of oxidative stress in the pathogenesis of nonalcoholic steatohepatitis
Free Radic. Biol. Med.
(2012) - et al.
Brain oxidative stress: detection and mapping of anti-oxidant marker ‘Glutathione’ in different brain regions of healthy male/female, MCI and Alzheimer patients using non-invasive magnetic resonance spectroscopy
Biochem. Biophys. Res. Commun.
(2012) - et al.
Berberine activates Nrf2 nuclear translocation and protects against oxidative damage via a phosphatidylinositol 3-kinase/Akt-dependent mechanism in NSC34 motor neuron-like cells
Eur. J. Pharm. Sci.
(2012) - et al.
Nuclear heme oxygenase-1 (HO-1) modulates subcellular distribution and activation of Nrf2: impacting metabolic and anti-oxidant defenses
J. Biol. Chem.
(2014)
The protection by octreotide against experimental ischemic stroke: up-regulated transcription factor Nrf2, HO-1 and down-regulated NF-κB expression
Brain Res.
Effect of obesity reduction on preservation of heart function and attenuation of left ventricular remodeling, oxidative stress and inflammation in obese mice
J. Transl. Med.
Nanoceria restrains PM2.5-induced metabolic disorder and hypothalamus inflammation by inhibition of astrocytes activation related NF-κB pathway in Nrf2 deficient mice
Free Radic. Biol. Med.
Interplay of oxidative: nitrosative/nitrative stress, inflammation, cell death and autophagy in diabetic cardiomyopathy
Biochim. Biophys. Acta (BBA)-Mol. Basis Dis.
Cardiovascular remodelling in coronary artery disease and heart failure
Lancet
Diabetic cardiomyopathy: bench to bedside
Heart Fail. Clin.
Inhibition of high-mobility group box 1 improves myocardial fibrosis and dysfunction in diabetic cardiomyopathy
Int. J. Cardiol.
Astragalus polysaccharide inhibits isoprenaline-induced cardiac hypertrophy via suppressing Ca2+-mediated calcineurin/NFATc3 and CaMKII signaling cascades
Environ. Toxicol. Pharmacol.
ROS production and NF-κB activation triggered by RAC1 facilitate WNT-driven intestinal stem cell proliferation and colorectal cancer initiation
Cell Stem Cell
Fisetin inhibits osteoclastogenesis through prevention of RANKL-induced ROS production by Nrf2-mediated up-regulation of phase II antioxidant enzymes
J. Pharmacol. Sci.
Reactive oxygen species (ROS) homeostasis and redox regulation in cellular signaling
Cell. Signal.
Reactive oxygen species in cancer: a dance with the devil
Cancer Cell
Diabetic cardiomyopathy: understanding the molecular and cellular basis to progress in diagnosis and treatment
Heart Fail. Rev.
Metabolic stress-induced activation of FoxO1 triggers diabetic cardiomyopathy in mice
J. Clin. Invest.
Obesity cardiomyopathy and systolic function: obesity is not independently associated with dilated cardiomyopathy
Heart Fail. Rev.
The relationship between high-fat dairy consumption and obesity: cardiovascular, and metabolic disease
Eur. J. Nutr.
Overweight and obesity: a review of their relationship to metabolic syndrome, cardiovascular disease, and cancer in South America
Nutr. Rev.
Hyperglycemia-induced oxidative stress and its role in diabetes mellitus related cardiovascular diseases
Curr. Pharm. Des.
Assessment of epicardial fat volume and myocardial triglyceride content in severely obese subjects: relationship to metabolic profile, cardiac function and visceral fat
Int. J. Obes.
Predictors and prevention of diabetic cardiomyopathy
Diabetes Metab. Syndr. Obes.
Cited by (45)
The apocarotenoid production in microbial biofactories: An overview
2023, Journal of BiotechnologyBixin-loaded colloidal nanodelivery systems, techniques and applications
2023, Food ChemistryEpidemiological role of plant pigment bixin in adipaging: In vivo pilot study
2022, Clinical Epidemiology and Global HealthCitation Excerpt :Also, increasing bixin supplementation showed significant reduction in fat mass in B+, B++, B+++ groups (p < 0.01) vs. the NC group. Our results are in concurrence with data published earlier on the role of bixin in improving cardiac injury in rats,28 anti-hyperlipidaemic effects in rabbits,29 and improvement in metabolic health of C57BL/6 mice30 owing to its antioxidant properties and inhibitory mechanism on enzymes involved in fat and carbohydrate digestion.31 However, statistically significant impact of bixin on increase in lean mass was observed only at high bixin dosage, such as in B++ (p < 0.05) and B+++ (p < 0.01) groups and not at lower dose of bixin in B+ group.
Treating leishmaniasis in Amazonia, part 2: Multi-target evaluation of widely used plants to understand medicinal practices
2022, Journal of EthnopharmacologyCitation Excerpt :In terms of immunomodulatory or anti-inflammatory properties, few studies appear available concerning B. orellana crude plant extracts, and concern leaves (Lima Viana et al., 2018; Yong et al., 2018). Bixin however, the major natural carotenoid extracted from B. orellana seeds, is highlighted for its anti-inflammatory properties, notably in various in vivo models (Pacheco et al., 2019; Somacal et al., 2015; Xu and Kong, 2017). Many other carotenoids were also isolated from the seeds and could also account for the observed biological effect (Vilar et al., 2014).
Olfactory and gustatory disorders caused by COVID-19: How to regain the pleasure of eating?
2022, Trends in Food Science and Technology