A previous study from our laboratory showed that troxerutin (TX) provides cardioprotection by mitigating lipid abnormalities in a high-fat high-fructose diet (HFFD)-fed mice model of metabolic syndrome (MS). The present study aims to investigate the reversal effect of TX on the fibrogenic changes in the myocardium of HFFD-fed mice. Adult male Mus musculus mice were grouped into four and fed either control diet or HFFD for 60 days. Each group was divided into two, and the mice were either treated or untreated with TX (150 mg/kg bw, p.o) from the 16th day. HFFD-fed mice showed marked changes in the electrocardiographic data. Increased levels of myocardial superoxide, p22phox subunit of NADPH oxidase, transforming growth factor (TGF), smooth muscle actin (α-SMA), and matrix metalloproteinases (MMPs)-9 and -2, and decreased levels of tissue inhibitors of MMPs-1 and -2 were observed. Furthermore, degradation products of troponin I and myosin light chain-1 were observed in the myocardium by immunoblotting. Rise in collagen was observed by hydroxyproline assay, while fibrotic changes were noticed by histology and Western blotting. Hypertrophy of cardiomyocytes and myocardial calcium accumulation were also observed in HFFD-fed mice. TX treatment exerted cardioprotective and anti-fibrotic effects in HFFD-fed mice by improving cardiac contractile function, reducing superoxide production and by favorably modifying the fibrosis markers. These findings suggest that TX could be cardioprotective through its antioxidant and antifibrogenic actions. This new finding could pave way for translation studies to human MS.

Fructose-rich diet is known to cause metabolic dysregulation, oxidative stress, and inflammation. We aimed to compare the effects of two dietary proteins of animal and plant origins on fructose-induced oxidative stress and inflammatory changes in liver. Wistar rats were fed either starch or fructose (60%) diet with casein or soy protein (20%) as the protein source for 8 weeks. Glucose and insulin, glycated hemoglobin and fructosamine, AOPP, and FRAP were determined in circulation. Intracellular ROS, oxidatively modified proteins (4-HNE and 3-NT adducts), adiponectin, TNF-α, IL-6 and PAI-1 mRNA expression, phosphorylation and activation of JNK and IKKβ, and NF-κB binding activity were assayed in liver. In comparison with starch fed group, fructose + casein group registered significant decline in antioxidant potential and increase in plasma glucose, insulin, and glycated proteins. Increased ROS production, 4-HNE and 3-NT modified proteins, JNK and IKKβ activation, and NF-κB binding activity were observed in them along with increased gene expression of PAI-1, IL-6, and TNF-α and decreased adiponectin expression. Substitution of soy protein for casein reduced oxidative modification and inflammatory changes in fructose-fed rats. These data suggest that soy protein but not casein can avert the adverse effects elicited by chronic consumption of fructose.

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Endoplasmic reticulum (ER), a dynamic organelle, plays an essential role in organizing the signaling pathways involved in cellular adaptation, resilience, and survival. Impairment in the functions of ER occurs in a variety of nutritive disorders including obesity and type 2 diabetes. Here, we hypothesize that (scopoletin) SPL, a coumarin, has the potential to alleviate ER stress induced in vitro and in vivo models by lipotoxicity. To test this hypothesis, the ability of SPL to restore the levels of proteins of ER stress was analyzed. Rat insulinoma 5f (RIN5f) cells and Sprague Dawley rats were the models used for this study. Groups of control and high-fat, high-fructose diet (HFFD)-fed rats were treated with either SPL or 4-phenylbutyric acid. Status of ER stress was enumerated by quantitative RT-PCR, Western blot, electron microscopic, and immunohistochemical studies. Proximal proteins of ER stress inositol requiring enzyme 1 (IRE1), protein kinase like endoplasmic reticulum kinase (PERK), and activating transcription factor 6 (ATF6) were reduced in the β-cells by SPL. The subsequent signaling proteins X-box binding protein 1, eukaryotic initiation factor2α, activating transcription factor 4, and C/EBP homologous protein were also suppressed in their expression levels when treated with SPL. IRE1, PERK signaling leads to c-Jun-N-terminal kinases phosphorylation, a kinase that interrupts insulin signaling, which was also reverted upon scopoletin treatment. Finally, we confirm that SPL has the ability to suppress the stress proteins and limit pancreatic ER stress which might help in delaying the progression of insulin resistance.

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