A High-Fat and High-Fructose Diet Exacerbates Liver Dysfunction by Regulating Sirtuins in a Murine Model.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is rapidly emerging as the most prevalent chronic liver disease, closely linked to the escalating rates of diabesity. The Western diet's abundance of fat and fructose significantly contributes to MASLD, disrupting hepatic glucose metabolism. We previously demonstrated that a high-fat and high-fructose diet (HFHFD) led to increased body and liver weight compared to the low-fat diet (LFD) group, accompanied by glucose intolerance and liver abnormalities, indicating an intermediate state between fatty liver and liver fibrosis in the HFHFD group. Sirtuins are crucial epigenetic regulators associated with energy homeostasis and play a pivotal role in these hepatic dysregulations. Our investigation revealed that HFHFD significantly decreased Sirt1 and Sirt7 gene and protein expression levels, while other sirtuins remained unchanged. Additionally, glucose 6-phosphatase (G6Pase) gene expression was reduced in the HFHFD group, suggesting a potential pathway contributing to fibrosis progression. Chromatin immunoprecipitation analysis demonstrated a significant increase in histone H3 lysine 18 acetylation within the G6Pase promoter in HFHFD livers, potentially inhibiting G6Pase transcription. In summary, HFHFD may inhibit liver gluconeogenesis, potentially promoting liver fibrosis by regulating Sirt7 expression. This study offers an epigenetic perspective on the detrimental impact of fructose on MASLD progression.

Comparative analysis of short-chain fatty acid levels in non-alcoholic steatohepatitis rat model: Impact of high-fat high-fructose (HFHF), high fat, and Western diets.

The evidence on the role of diets in the production of short-chain fatty acids (SCFAs) was limited. The aim of this study was to assess the potential effects of high-fat high-fructose (HFHF), high-fat, and Western diets on the levels of SCFA. A research experiment employing a post-test-only control group design was carried out from January to April 2022. A total of 27 rats were randomly allocated to each study group. SCFA was measured two weeks after diet administration. Analysis of variance (ANOVA) test was used to analyze the differences among groups, and the effect estimate of each group was analyzed using post hoc Tukey. The concentrations of SCFAs post HFHF diets were recorded as follows: acetic acid at 54.60±10.58 mmol/g, propionic acid at 28.03±8.81 mmol/g, and butyric acid at 4.23±1.68 mmol/g. Following the high-fat diet, acetic acid measured 61.85±14.25 mmol/gr, propionic acid measured 25.19±5.55 mmol/gr, and butyric acid measured 6.10±2.93 mmol/gr. After the administration of Western diet, the levels of SCFA were 68.18±25.73, 29.69±12.76, and 7.48±5.51 mmol/g for acetic acid, propionic acid, and butyric acid, respectively. The level of butyric acid was significantly lower in HFHF diet group compared to the normal diet (mean difference (MD) 6.34; 95%CI: 0.61, 12.04; p=0.026). The levels of acetic acid (p=0.419) and propionic acid (p=0.316) were not statistically different among diet types (HFHF, high-fat, and Western diet). In conclusion, HFHF diet is associated with a lower level of butyric acid than the normal diet in a rat model.

Polyphenol-rich black currant and cornelian cherry juices ameliorate metabolic syndrome induced by a high-fat high-fructose diet in Wistar rats.

Diets high in fat and sugar lead to metabolic syndrome (MetS) and related chronic diseases. We investigated the effects of commercially available, cold-pressed polyphenol-rich black currant (BC) and cornelian cherry (CC) juices on the prevention of MetS in Wistar rats induced by a 10-weeks high-fat high-fructose (HFF) diet. Juice consumption, either BC or CC, with a HFF diet resulted in lower serum triglycerides compared to only the HFF consumption. Both juices also mitigated the effects of HFF on the liver, pancreas, and adipose tissue, by preserving liver and pancreas histomorphology and reducing visceral fat and adipocyte size. Furthermore, supplementation with both juices reduced glucagon and up-regulated insulin expression in the pancreas of the rats on the HFF diet, whereas the BC also showed improved glucose regulation. BC juice also reduced the expression of IL-6 and hepatic inflammation compared to the group only on HFF diet. Both juices, especially BC, could be a convenient solution for the prevention of MetS in humans.

Melatonin-mediated corrective changes in gut microbiota of experimentally chronodisrupted C57BL/6J mice.

Chronic consumption of a high-calorie diet coupled with an altered sleep-wake cycle causes disruption of circadian clock that can impact the gut microbiome leading to metabolic syndrome and associated diseases. Herein, we investigate the effects of a high fat high fructose diet (H) alone or in combination with photoperiodic shifts induced chronodisruption (CD) on gut microbiota of C57BL/6J male mice. Further, the merits of daily evening intraperitoneal administration of melatonin in restoring gut microbiota are studied herein. Experimental groups viz. H, CD and HCD mice recorded higher levels of serum pro-inflammatory cytokines (TNF-α and IL-6) and lower levels of the anti-inflammatory cytokine, IL-10. These findings correlate with a concomitant increase in the transcripts of TLR4, TNF-α, and IL-6 in small intestine of the said groups. A decrement in mRNA levels of Ocln, ZO-1 and Vdr in these groups implied towards an altered gut permeability. These results were in agreement with the observed decrement in percentage abundance of total gut microflora and Firmicutes: Bacteroidetes (F/B) ratio. Melatonin administration accounted for lower-level inflammation (serum and gut) along with an improvement in gut permeability markers. The total abundance of gut microflora and F/B ratio showed an improvement in all the melatonin-treated groups and the same is the highlight of this study. Taken together, our study is the first to report perturbations in gut microbiota resulting due to a combination of photoperiodic shifts induced CD and a high fat high calorie diet-induced lifestyle disorder. Further, melatonin-mediated rejuvenation of gut microbiome provides prima facie evidence of its role in improving gut dysbiosis that needs a detailed scrutiny.

Genistein and Sex Hormone Supplementation Modulated Hepatic PPARα, δ, and γ Subtypes and STAT1 Expressions in a NASH Rat Model with Bilateral Orchidectomy.

Nonalcoholic steatohepatitis (NASH) is a progressive form of nonalcoholic fatty liver disease (NAFLD) that is characterized by hepatic inflammation and steatosis. Currently, limited data exist regarding the risk of NASH in transgender women and the treatment options for this particular population. The use of testosterone supplementation is unfavorable for transgender women, and estrogen supplementation is linked to an increased risk of breast cancer; thus, an isoflavone derivative compound known as "genistein" could serve as a viable substitute for a hormone supplement in this context. The purpose of this study was to investigate the treatment effects and mechanisms of actions of genistein and sex hormones in orchidectomized (ORX) rats with nonalcoholic steatohepatitis induced via a high-fat high-fructose diet (HFHF) model. Male Sprague-Dawley rats (n = 42) were randomly assigned into seven groups; control, ORX + standard diet, HFHF, ORX + HFHF, ORX + HFHF diet + testosterone (50 mg/kg body weight (BW) once weekly), ORX + HFHF diet + estradiol (1.6 mg/kg BW daily), and ORX + HFHF diet + genistein (16 mg/kg BW daily). The duration of the study was 6 weeks. Some parts of liver tissue were used for histological examination by H&E staining. The determination of fat accumulation was performed using Oil Red O staining. SREBP1c and FAS gene expression were quantified using real-time PCR technique. The levels of all types of peroxisome proliferator-activated receptors (PPARs; α, δ, γ), proteins, and signal transducer and activator of transcription 1 (STAT1) signaling pathway were determined by both immunoblotting and immunohistochemistry. Rats in the ORX + HFHF group had the highest degree of hepatic steatosis, lobular inflammation, and hepatocyte ballooning, and showed higher levels of genes related to de novo lipogenesis, including SREBP1c and FAS. The expression of PPARγ and STAT1 were upregulated, while the expression of PPARα and PPARδ were downregulated in the ORX + HFHF group. Testosterone, estradiol and genistein treatments improved NASH histopathology together with the reversal of all types of PPAR protein expressions. Interestingly, genistein decreased the levels of STAT1 protein expression more than those of testosterone and estradiol treatment. Genistein and sex hormone treatment could ameliorate NASH through the upregulation of PPARα, and PPARδ, and the suppression of PPARγ and STAT1 expression.

Transcriptomic insights into the lipotoxicity of high-fat high-fructose diet in rat and mouse.

Along with the increasing prevalence of obesity worldwide, the deleterious effects of high-calorie diet are gradually recognized through more and more epidemiological studies. However, the concealed and chronic causality whitewashes its unhealthy character. Given an ingenious mechanism orchestrates the metabolic adaptation to high-fat high-fructose (HFF) diet and connive its lipotoxicity, in this study, an experimental rat/mouse model of obesity was induced and a comparative transcriptomic analysis was performed to probe the mystery. Our results demonstrated that HFF diet consumption altered the transcriptomic pattern as well as different high-calorie diet fed rat/mouse manifested distinct hepatic transcriptome. Validation with RT-qPCR and Western blotting confirmed that SREBP1-FASN involved in de novo lipogenesis partly mediated metabolic self-adaption. Moreover, hepatic ACSL1-CPT1A-CPT2 pathway involved in fatty acids ß-oxidation, played a key role in the metabolic adaption to HFF. Collectively, our findings enrich the knowledge of the chronic adaptation mechanisms and also shed light on future investigations. Meanwhile, our results also suggest that efforts to restore the fatty acids metabolic fate could be a promising avenue to fight against obesity and associated steatosis and insulin resistance challenged by HFF diet.

Unraveling the mechanisms of trans-cinnamic acid in ameliorating non-alcoholic fatty liver disease.

BACKGROUND: The prevalence of non-alcoholic fatty liver disease (NAFLD) is increasing significantly due to high amounts of fat and fructose in the diet. Phytochemicals present in herbal plants and nutrients present in food play vital roles in the management of NAFLD. One of these is trans-cinnamic acid (TCA). We are evaluate the role of TCA in NAFLD induced by a high-fat, high-fructose diet. METHODOLOGY: Rats fed a high-fat, high-fructose (HFHF) diet for ten weeks exhibited distinct signs of NAFLD. Rats were given TCA (10 mg/kg, 20 mg/kg, and 40 mg/kg) and pioglitazone (10 mg/kg) for four weeks along with a HFHF diet. At the end, body weight, food intake, liver, lipid measurements, TNF-α, antioxidants, and histopathology were evaluated. RESULTS: TCA significantly decreased serum glutamic-oxaloacetic transaminase and glutamic pyruvic transaminase in rats. Serum cholesterol, triglyceride, and low-density lipid levels were substantially decreased in TCA-treated rats compared to diseased controls. Superoxide dismutase, glutathione, and malondialdehyde were significantly decreased in rats treated with a high dose of TCA (40 mg/kg) compared to HFFD-fed rats. HFFD-fed rats exhibited fatty liver alterations, whereas rats treated with TCA exhibited significantly fewer morphologic changes associated with fatty liver disease. TCA at a high dose exhibited decreased TNF-α levels, thereby decreasing hepatic inflammation. CONCLUSION: TCA proved its role in the treatment of NAFLD by substantially reducing liver enzymes, pro-inflammatory markers (TNF-α), and lipid markers. Inclusion of TCA as a therapeutic regimen alongside diet-based treatment undoubtedly has therapeutic potential in NAFLD and related diseases.

Dry heat whole Sorghum BRS 305 flour modulate satiety and improves antioxidant response in brain of Wistar rats fed with high-fat high-fructose diet.

Sorghum BRS 305 (Sorghum bicolor L. Moench) is a cereal with high tannins and anthocyanins content and keep better the resistant starch when submitted to dry heat treatment. Our objective was to investigate the effects of BRS 305 dry heat treatment whole sorghum flour on satiety and antioxidant response in brain and adipose tissue of Wistar rats fed with a high fat high fructose diet (HFHF). Male Wistar rats were divided in two groups: control (n = 8) and HFHF (n = 16) for eight weeks. After, animals of HFHF group were divided: HFHF (n = 8) and HFHF + BRS 305 sorghum whole flour (n = 8), for 10 weeks. Sorghum consumption reduced gene expression of leptin, resistin, and endocannabinoid receptor 1 type (CB1) in adipose and brain tissues compared to HFHF group. In brain, sorghum consumption also promotes reduction in neuropeptide Y (NPY) gene expression. BRS305 sorghum consumption improved gene expression of sirtuin-1 (SIRT1) in adipose tissue, and in the brain increased heat shock protein 72 (HSP72), erythroid-derived nuclear factor 2 (NRF2), peroxisome proliferator-activated receptor alpha (PPARα), superoxide dismutase (SOD) and catalase activity compared to HFHF. In silicoanalysis showed interaction with PPARα, CB1, and leptin receptors. Advanced glycation end products (AGEs) concentrations in group HFHF + sorghum did not differ from HFHF group. Advanced glycation end products receptors (RAGEs) concentrations did not differ among experimental groups. Then, BRS 305 sorghum submitted to dry treatment was able to modulate gene expression of markers related to satiety and improve antioxidant capacity of rats fed with HFHF diet.

Protective effect of moringa seed extract on kidney damage in rats fed a high-fat and high-fructose diet.

Objective: Moringa is a common plant that contains high levels of antioxidants. In this study, we aimed to analyze the protective effect of moringa seed extract on the kidneys of a rat model maintained on a high-fat and high-fructose (HFHF) diet. Methods: An experiment with a pretest-posttest control group design was used to measure metabolic parameters and determine kidney function, while a posttest-only method was used for the control group to determine glomerular volume and superoxide dismutase (SOD) expression. Purposive sampling was used on 28 rats divided into four groups: a control (K1) group, and three groups fed a HFHF diet for 53 days (K2, K3, and K4). Subsequently, K3 and K4 were given 150 and 200 mg/kg BW per day moringa seed extract for 28 days. Data were analyzed using IBM® SPSS® Statistics version 22 software. Results: Analysis showed that the diet increased the risk of metabolic syndrome, as evidenced by weight gain, glucose, and triglycerides. The optimal dose of moringa seed extract significantly improved glomerular volume (p = 0.001). The expression of SOD in kidney tubules and glomeruli was significantly different with each group (p = 0.002 and p = 0.001) respectively. Conclusion: The administration of moringa seed extract provided a protective effect on the kidney by reducing serum creatinine levels, improving overall structure, and increasing the expression of SOD, a key antioxidant.

Raspberry ketone ameliorates nonalcoholic fatty liver disease in rats by activating the AMPK pathway.

The current study aimed to investigate the effect of orally administered raspberry ketone (RK) on ameliorating nonalcoholic fatty liver disease (NAFLD) induced in rats by high-fat high-fructose diet (HFFD) in comparison to calorie restriction (CR) regimen. Thirty male Wistar rats were divided into two experimental groups; one was fed normal chow diet (NCD, n = 6) for 15 weeks to serve as normal control group and the other group was fed HFFD (n = 24) for 7 weeks to induce NAFLD. After induction, rats in the HFFD group were randomly allocated into four groups (n = 6 rats each). One group continued on HFFD feeding for 8 weeks (NAFLD control group). The remaining 3 groups received NCD, calorie-restricted diet, or NCD along with RK (55 mg/kg/day, orally) for 8 weeks. Like CR, RK effectively attenuated NAFLD and ameliorated the changes attained by HFFD. RK upregulated the expression of the phosphorylated AMP-activated protein kinase (P-AMPK) and fatty acid oxidation factors; peroxisome proliferator-activated receptor alpha (PPAR-α) and carnitine palmitoyltransferase-1 (CPT-1) and downregulated lipogenic factors; sterol regulatory element-binding protein-1c (SREBP-1c) and fatty acid synthase (FAS) in the hepatic tissue. Also, RK improved lipid profile parameters, liver enzymes and both body and liver tissue weights. Altogether, these findings suggest that oral administration of RK, along with normal diet, ameliorated NAFLD in a way similar to CR. This approach could be an alternative to CR in the management of NAFLD, overcoming the poor compliance to long term CR regimen.

Dietary Supplementation with 20-Hydroxyecdysone Ameliorates Hepatic Steatosis and Reduces White Adipose Tissue Mass in Ovariectomized Rats Fed a High-Fat, High-Fructose Diet.

Metabolic dysfunction-associated fatty liver disease (MAFLD) is defined as hepatic steatosis in combination with overweight, diabetes, or other metabolic risk factors. MAFLD affects a significant number of the global population and imposes substantial clinical and economic burdens. With no approved pharmacotherapy, current treatment options are limited to diet and exercise. Therefore, the development of medicines for MAFLD treatment or prevention is necessary. 20-Hydroxyecdysone (20E) is a natural steroid found in edible plants and has been shown to improve metabolism and dyslipidemia. Therefore, it may be useful for MAFLD treatment. Here, we aimed to determine how dietary supplementation with 20E affects fat accumulation and lipogenesis in the liver and adipose tissue of ovariectomized rats fed a high-fat, high-fructose diet (OHFFD). We found that 20E reduced hepatic triglyceride content and visceral fat deposition. 20E increased the phosphorylation of AMP-activated protein kinase and acetyl CoA carboxylase while reducing the expression of fatty acid synthase in the liver and adipose tissue. Additionally, 20E increased hepatic expression of carnitine palmitoyltransferase-1 and reduced adipose expression of sterol regulatory element-binding protein-1. In conclusion, 20E demonstrated beneficial effects in rats with OHFFD-induced MAFLD. These findings suggest that 20E may represent a promising option for MAFLD prevention or treatment.

Comparison of Animal Models for the Study of Nonalcoholic Fatty Liver Disease.

Nonalcoholic fatty liver disease (NAFLD) is one of the most prevalent chronic liver diseases, and there is still no effective treatment for its advanced stage, nonalcoholic steatohepatitis (NASH). An ideal animal model of NAFLD/NASH is urgently needed for preclinical studies. However, the models reported previously are quite heterogeneous owing to differences in animal strains, feed formulations, and evaluation indicators, among others. In this study, we report 5 NAFLD mouse models we developed in previous studies and comprehensively compared their characteristics. The high-fat diet (HFD) model was time-consuming and characterized by early insulin resistance and slight liver steatosis at 12 weeks. However, inflammation and fibrosis were rare, even at 22 weeks. The high-fat, high-fructose, and high-cholesterol diet (FFC) exacerbates glucose and lipid metabolism disorders, showing distinct hypercholesterolemia, steatosis, and mild inflammation at 12 weeks. An FFC diet combined with streptozotocin (STZ) was a novel model that speeds up the process of lobular inflammation and fibrosis. The STAM model also used a combination of FFC and STZ but used newborn mice and showed the fastest formation of fibrosis nodules. The HFD model was appropriate for the study of early NAFLD. FFC combined with STZ accelerated the pathologic process of NASH and might be the most promising model for NASH research and drug development.

AMPK activation by AICAR reduces diet induced fatty liver in C57BL/6 mice.

Dysregulation of 5'-adenosine monophosphate-activated protein kinase (AMPK) occurs in metabolic disorders including non-alcoholic fatty liver disease (NAFLD) which makes it a molecular target for treatment. An AMPK activator, 5-aminoimidazole-4-carboxamide-1-ß-D-ribofuranoside (AICAR) alleviates NAFLD in experimental rats, however the specific mechanism remains to be explored. We aimed to study the effect of AICAR on lipid levels, oxidant-antioxidant balance, AMPK and mTOR activation and FOXO3 gene expression in liver of mice model. Fatty liver was induced in two groups of C57BL/6 mice (groups 2 and 3) by providing a high fat high fructose diet (HFFD) for 10 weeks while groups 1 and 4 animals were fed normal pellet. For the last two weeks, groups 3 and 4 were administered AICAR (150 mg/kg bw/day, i.p.) while groups 1 and 2 were administered saline. AICAR decreased fatty liver, decreased glucose and insulin in circulation, prevented the accumulation of triglycerides and collagen and ameliorated oxidative stress in HFFD fed mice. At the molecular level, AICAR upregulated FOXO3 and p-AMPK expression and reduced p-mTOR expression. AMPK activation may involve FOXO3 in protection against NAFLD. The role of AMPK, mTOR and FOXO3 crosstalk in NAFLD needs to be characterised in future.

The dual inhibitor Sacubitril-valsartan ameliorate high-fat high-fructose-induced metabolic disorders in rats superiorly compared to valsartan only.

OBJECTIVES: Sacubitril-valsartan, a recently approved treatment for heart failure, has shown some promise as a possible therapeutic option for diabetes mellitus. It is still not clear whether those beneficial effects are comparable to valsartan effects. In this work, we aimed at investigating Sacubitril-valsartan effect on metabolic changes in a model of high-fat high fructose diet-induced diabetes mellitus, in comparison to the metabolic changes induced by valsartan only. METHODS: Rats were ad libitum fed with either standard chow plus tap water for drinking (controls) or 60% beef tallow and 10% fructose drinking water (diseased) for 11 weeks. Starting in week 9, each group was subdivided into four, namely vehicle, pioglitazone, Sacubitril-valsartan and valsartan. Treatments were administered from weeks 9 to 11, while rats were maintained in their respective diet groups. KEY FINDINGS: Sacubitril-valsartan treatment significantly decreased daily food intake, body weight and epididymal white adipose weight, and normalized insulin and glycosylated haemoglobin in high-fat high fructose. Both valsartan and Sacubitril-valsartan only attenuated the elevated fasting blood glucose levels, glucose, insulin and pyruvate tolerance and increased protein kinase B phosphorylation in diseased rats. CONCLUSIONS: Sacubitril-valsartan may be an effective modulator of diabetes mellitus-associated metabolic aberration, superiorly compared to valsartan only.

Alpha-ketoglutarate partially alleviates effects of high-fat high-fructose diet in mouse muscle.

Consumption of high-calorie diets leads to excessive accumulation of storage lipids in adipose tissue. Metabolic changes occur not only in adipose tissue but in other tissues, too, such as liver, heart, muscle, and brain. This study aimed to explore the effects of high-fat high-fructose diet (HFFD) alone and in the combination with alpha-ketoglutarate (AKG), a well-known cellular metabolite, on energy metabolism in the skeletal muscle of C57BL/6J mice. Five-month-old male mice were divided into four groups - the control one fed a standard diet (10 % kcal fat), HFFD group fed a high-fat high-fructose diet (45 % kcal fat, 15 % kcal fructose), AKG group fed a standard diet with 1 % sodium AKG in drinking water, and HFFD + AKG group fed HFFD and water with 1 % sodium AKG. The dietary regimens lasted 8 weeks. Mice fed HFFD had higher levels of storage triacylglycerides, lower levels of glycogen, and total water-soluble protein, and higher activities of key glycolytic enzymes, namely hexokinase, phosphofructokinase, and pyruvate kinase, as compared with the control group. The results suggest that muscles of HFFD mice may suffer from lipotoxicity. In HFFD + AKG mice, levels of the metabolites and activities of glycolytic enzymes did not differ from the respective values in the control group, except for the activity of pyruvate kinase, which was significantly lower in HFFD + AKG group compared with the control. Thus, metabolic changes in mouse skeletal muscles, caused by HFFD, were alleviated by AKG, indicating a protective role of AKG regarding lipotoxicity.

Dietary Supplementation with D-Ribose-L-Cysteine Prevents Hepatic Stress and Pro-Inflammatory Responses in Male Wistar Rats Fed a High-Fructose High-Fat Diet.

Diets rich in fats and fructose are associated with the pathogenesis of oxidative stress-induced non-alcoholic fatty liver disease. Therefore, we investigated the effect of D-ribose-L-cysteine (DRLC) in high-fructose high-fat (HFHF) diet-fed rats. Twenty rats (n = 5), divided into four groups, were simultaneously exposed to HFHF and/or DRLC (250 mg/kg) orally during the 8 weeks of the study. Results showed that HFHF precipitated pro-inflammation and selective disruption of the oxidative stress markers. There were significant decreases in the level of antioxidants such as superoxide dismutase (SOD), glutathione peroxidase (GPX), total antioxidant capacity (TAC), hepatic SOD and GPX. Significant increases in serum levels of uric acid (UA), tumour necrosis factor-alpha (TNF-α), C-reactive protein (CRP) and hepatic Xanthine oxidase (XO) were observed in the HFHF compared to the control. In the HFHF + DRLC group, oxidative stress was mitigated due to differences in serum levels of SOD, GPX, TAC, TNF-α, liver SOD, and XO relative to control. The administration of DRLC alone caused significant reductions in malondialdehyde, UA and CRP and a significant increase in SOD compared to the control. DRLC prevents hepatic and systemic oxidative stress and pro-inflammatory events in HFHF diet-fed rats.

Curcumin nanoemulsion counteracts hepatic and cardiac complications associated with high-fat/high-fructose diet in rats.

The relationship between the incidence of cardiovascular abnormalities and non-alcoholic fatty liver disease (NAFLD) has long been postulated. Curcumin (CUR) is a potential anti-atherosclerotic agent but its poor water solubility hinders its pharmacological use. Therefore, the present study aimed to investigate the effect of formulation of CUR nanoemulsion prepared using the spontaneous emulsification technique on high fat high fructose (HFHF)-induced hepatic and cardiac complications. Fifty Wistar rats were divided into five groups. CUR nanoemulsion at doses of 5 and 10 mg/kg and conventional powdered CUR at a dose of 50 mg/kg were orally administered daily to rats for two weeks, and compared with normal control and HFHF control. Results revealed that the high dose level of CUR nanoemulsion was superior to conventional CUR in ameliorating the HFHF-induced insulin resistance status and hyperlipidemia, with beneficial impact on rats' recorded electrocardiogram (ECG), serum aspartate aminotransferase (ALT) and alanine aminotransferase (AST) levels, leptin, adiponectin, creatine phosphokinase, lactate dehydrogenase and cardiac troponin-I. In addition, hepatic and cardiac oxidative and nitrosative stresses, oxidative DNA damage and disrupted cellular energy statuses were counteracted. Results were also confirmed by histopathological examination. PRACTICAL APPLICATIONS: The use of curcumin nanoemulsion could be beneficial in combating hepatic and cardiac complications resulting from HFHF diets.

Oxidative and endoplasmic reticulum stress develop adverse metabolic effects due to the high-fat high-fructose diet consumption from birth to young adulthood.

AIMS: The early postnatal dietary intake has been considered a crucial factor affecting the offspring later life metabolic status. Consistently, this study investigated the oxidative and endoplasmic reticulum (ER) stress interventions in the induction of adverse metabolic effects due to the high-fat high-fructose diet (HFHFD) consumption from birth to young adulthood in rat offspring. MATERIALS AND METHODS: After delivery, the dams with their pups were randomly allocated into the normal diet (ND) and HFHFD groups. At weaning, the male offspring were divided into ND-None, ND-DMSO, ND-4-phenyl butyric acid (4-PBA), HFHFD-None, HFHFD-DMSO, and HFHFD-4-PBA groups and fed on their respected diets for five weeks. Then, the drug was injected for ten days. Subsequently, glucose and lipid metabolism parameters, oxidative and ER stress markers, and Wolfram syndrome1 (Wfs1) expression were assessed. KEY FINDINGS: In the HFHFD group, anthropometrical parameters, plasma high-density lipoprotein (HDL), and glucose-stimulated insulin secretion and content were decreased. Whereas, the levels of plasma leptin, low-density lipoprotein (LDL) and glucose, hypothalamic leptin, pancreatic catalase activity and glutathione (GSH), pancreatic and hypothalamic malondialdehyde (MDA), binding immunoglobulin protein (BIP) and C/EBP homologous protein (CHOP), and pancreatic WFS1 protein were increased. 4-PBA administration in the HFHFD group, decreased the hypothalamic and pancreatic MDA, BIP and CHOP levels, while, increased the Insulin mRNA and glucose-stimulated insulin secretion and content. SIGNIFICANCE: HFHFD intake from birth to young adulthood through the development of pancreatic and hypothalamic oxidative and ER stress, increased the pancreatic WFS1 protein and impaired glucose and lipid homeostasis in male rat offspring.

Hesperidin alleviates vascular dysfunction and remodelling in high-fat/high-fructose diet-fed rats by modulating oxidative stress, inflammation, AdipoR1, and eNOS expression.

Hesperidin, a flavanone glycoside, has shown antihypertensive, antioxidant, and anti-inflammatory effects. In the present study, the therapeutic effects of hesperidin on vascular function and remodelling, and possible underlying mechanisms involved in high-fat/high-fructose diet (HFFD)-fed rats were investigated. Male Sprague-Dawley rats were fed a high-fat diet plus 15% fructose in drinking water for 16 weeks. HFFD-fed rats were treated with hesperidin (30 mg/kg/day) or vehicle for the last 4 weeks. Treatment of HFFD-fed rats with hesperidin significantly attenuated metabolic alterations, vascular endothelial dysfunction and remodelling. Hesperidin markedly alleviated HFFD-induced oxidative stress and inflammation by decreasing plasma malondialdehyde level and aortic superoxide anion production, and by suppressing aortic tumor necrosis factor-α and interleukin-6 overexpression. Additionally, increased plasma levels of the adiponectin and nitric oxide metabolite, together with restoration of adiponectin receptor 1 (AdipoR1) and endothelial nitric oxide synthase (eNOS) protein expression, were also observed after treatment with hesperidin. These findings indicated that hesperidin alleviates HFFD-induced vascular dysfunction and remodelling in rats. The possible underlying mechanism may involve the reduction of oxidative stress and inflammation, and the restoration of AdipoR1and eNOS expression.

Fenofibrate Improves Cognitive Impairment Induced by High-Fat High-Fructose Diet: A Possible Role of Irisin and Heat Shock Proteins.

A high-fat, high-fructose diet (HFFD) impairs cognitive functions and increases susceptibility to neurodegenerative disorders. Irisin and heat shock protein 70 (HSP70) are well known for their role in neuroprotection. The possible neuroprotective effects of fenofibrate on HFFD-induced cognitive dysfunction and the involvement of irisin and HSP70 in these effects were investigated in this study. Rats were divided into normal control, HFFD, dimethylsulfoxide+HFFD, and fenofibrate+HFFD groups. At the end of the experiment, fenofibrate treatment restored hippocampus histological characteristics to almost normal and improved HFFD-induced cognitive deficit. It reduced body weight gain and had hypolipidemic effects by significantly lowering total cholesterol, triglycerides, and low-density lipoprotein cholesterol levels while increasing high-density lipoprotein cholesterol levels. It has antioxidant and anti-inflammatory effects as it significantly reduced the hippocampal malondialdehyde, interleukin-6, and tumor necrosis factor-alpha levels, while significantly increasing the reduced glutathione level. It prevented HFFD-induced hypoxia by significantly lowering hippocampal vascular endothelial growth factor and hypoxia-inducible factor-1 alpha levels. It significantly activated the hippocampal peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PGC-1α)/irisin/brain-derived neurotrophic factor pathway. It significantly increased hippocampal HSP70 while decreasing the HSP90 levels. It enhanced synaptic plasticity by significantly upregulating the hippocampal relative GluR1 gene expression. Furthermore, hippocampal irisin levels in the HFFD group were found to be positively correlated with cognitive function, hippocampal HSP70, and relative GluR1 gene expression levels, while negatively correlated with hippocampal HSP90 and HIF1α levels. Therefore, fenofibrate may be used as a potential medication to treat HFFD-induced neurodegenerative disorders.