High-fat High-fructose Diet Research Articles

Neuroprotective Roles of Lauric Acid and Resveratrol: Shared Benefits in Neuroinflammation and Anxiety, Distinct Effects on Memory Enhancement

ABSTRACTNeuroinflammation can be triggered by a high‐fat/high‐fructose diet (HFFD), and CD36 may be an underlying mechanism. Lauric acid (LA), the major fatty acid in coconut oil, and resveratrol, the plant‐based polyphenolic compound, may exert anti‐inflammatory effects. Therefore, this study investigated the possible effects of LA and resveratrol on diet‐induced neuroinflammation and CD36. Healthy male C57BL/6 mice (8 weeks of age, n = 31) were fed a control diet (10%kcal fat) or diets containing high fat (60%kcal fat) and fructose (5% w/v fructose drinking water) for 6 weeks, ad libitum. Supplemented to the HFFD, mice daily received resveratrol (7.5 mg/kg) (HFFD‐RSV) or LA (750 mg/kg) (HFFD‐LA). At the end of the study, HFFD resulted in anxiety‐like behavior, reduced locomotor activity, neuroinflammation (increased brain GFAP, IL‐6, MCP‐1, IFN‐γ, TNF‐α), and systemic inflammation (increased plasma GFAP, IFN‐γ, TNF‐α, IL‐12p70, reduced plasma IL‐10). HFFD‐RSV and HFFD‐LA alleviated HFFD‐induced anxiety‐like behavior, neuroinflammation, and systemic inflammation. HFFD‐LA improved memory. Brain and plasma CD36 levels were increased by HFFD and reduced by HFFD‐RSV or HFFD‐LA. Dietary resveratrol and LA intake may alleviate HFFD‐induced neuroinflammation, systemic inflammation, and anxiety‐like behavior and improve memory, as CD36 may be an underlying mechanism.

Unveiling Lipidomic Alterations in Metabolic Syndrome: A Study of Plasma, Liver, and Adipose Tissues in a Dietary-Induced Rat Model

Metabolic syndrome (MetS) is a complex condition characterized by fat accumulation, dyslipidemia, impaired glucose control and hypertension. In this study, rats were fed a high-fat high-fructose (HFF) diet in order to develop MetS. After ten weeks, the dietary-induced MetS was confirmed by higher body fat percentage, lower HDL-cholesterol and increased blood pressure in the HFF-fed rats compared to the normal-fed control animals. However, the effect of MetS development on the lipidomic signature of the dietary-challenged rats remains to be investigated. To reveal the contribution of specific lipids to the development of MetS, the lipid profiling of rat tissues particularly susceptible to MetS was performed using untargeted UHPLC-QTOF-MS/MS lipidomic analysis. A total of 37 lipid species (mainly phospholipids, triglycerides, sphingolipids, cholesterol esters, and diglycerides) in plasma, 43 lipid species in liver, and 11 lipid species in adipose tissue were identified as dysregulated between the control and MetS groups. Changes in the lipid signature of selected tissues additionally revealed systemic changes in the dietary-induced rat model of MetS.

7005 Characterization of Clinical Candidate Miricorilant in Preclinical Models for NASH

Abstract Disclosure: T.J. Moll: None. E.M. Viho: None. M. Gentenaar: None. H. Hunt: Employee; Self; Corcept Therapeutics. O.C. Meijer: Grant Recipient; Self; Corcept Therapeutics. J. Kroon: Research Investigator; Self; Corcept Therapeutics. Background and aim: Miricorilant (CORT118335) is a selective glucocorticoid receptor (GR) modulator that is under clinical development for the treatment of non-alcohol steatohepatitis (NASH). It was previously shown that miricorilant treatment effectively lowers hepatic lipid content in mouse models of NASH. The aim of this study is to further characterize the effects of miricorilant in the mouse liver and in human liver tissue. Methods: In mouse liver tissue, we investigated the agonistic and antagonistic properties of miricorilant on GR activity. Eight-week-old male C57BL/6J mice were fed with a control diet or miricorilant-supplemented diet (resulting in an estimated dose of 60 mg/kg/day) for 6 days and 1.5 mg/kg corticosterone was injected to monitor the effects of miricorilant on GR-responsive gene expression. We next accessed the time-dependency of the lipid-lowering effects of miricorilant in the mouse liver. Mice were fed with a high-fat, high-fructose diet (HFHFD) for 3 weeks before treatment with 60 mg/kg/day miricorilant for one, three or six days by oral gavage, and triglyceride content in the liver was measured at endpoint. In human liver tissue, we investigated the effects of miricorilant on precision-cut liver slices (PCLS) obtained from two independent donors with pre-existing steatosis. PCLS were cultured for a total of 168 hours in the presence of 100 nM hydrocortisone, and with or without an exogenous lipid challenge. PCLS were treated with 200-600 nM miricorilant for 96 hours before triglyceride content was measured. RNA-sequencing was performed on PCLS after 24 hours of 200-400 nM miricorilant exposure. Results: In the mouse liver, miricorilant exhibited a unique combination of agonistic and antagonistic properties on GR-responsive gene expression. Miricorilant effectively lowered HFHFD-induced lipid accumulation in the mouse liver as soon as three days after treatment. In human PCLS, miricorilant treatment lowered triglyceride content in both donors. RNA-sequencing revealed respectively 40 and 128 differentially expressed genes after 200 and 400 nM miricorilant treatment. Pathway analysis revealed very-low-density lipoprotein (VLDL) particle remodeling as a significant enriched pathway, providing a possible explanation for the lowered triglyceride content upon miricorilant treatment. Conclusion: Miricorilant rapidly and effectively lowers hepatic lipid content in the mouse liver and in human PCLS, possibly via modulation of VLDL remodeling. Presentation: 6/2/2024

CHIP ameliorates nonalcoholic fatty liver disease via promoting K63- and K27-linked STX17 ubiquitination to facilitate autophagosome-lysosome fusion

The fusion of autophagosomes and lysosomes is essential for the prevention of nonalcoholic fatty liver disease (NAFLD). Here, we generate a hepatocyte-specific CHIP knockout (H-KO) mouse model that develops NAFLD more rapidly in response to a high-fat diet (HFD) or high-fat, high-fructose diet (HFHFD). The accumulation of P62 and LC3 in the livers of H-KO mice and CHIP-depleted cells indicates the inhibition of autophagosome-lysosome fusion. AAV8-mediated overexpression of CHIP in the murine liver slows the progression of NAFLD induced by HFD or HFHFD feeding. Mechanistically, CHIP induced K63- and K27-linked polyubiquitination at the lysine 198 residue of STX17, resulting in increased STX17-SNAP29-VAMP8 complex formation. The STX17 K198R mutant was not ubiquitinated by CHIP; it interfered with its interaction with VAMP8, rendering STX17 incapable of inhibiting steatosis development in mice. These results indicate that a signaling regulatory mechanism involving CHIP-mediated non-degradative ubiquitination of STX17 is necessary for autophagosome-lysosome fusion.

Lygodium microphyllum Inhibits de Novo Lipogenesis Activity in the Hepatocytes of High-Fat High-Fructose-Induced Rats by Increasing the Levels of SIRT1 and AMPK.

The prevalence of non-alcoholic fatty liver disease (NAFLD) is currently of great concern due to its risk of developing T2DM and cardiovascular disease. The development of NAFLD may be initiated by de novo lipogenesis in the hepatocytes. Sirtuin1 (SIRT1) and adenosine monophosphate-activated protein kinase (AMPK), are responsible for the lipogenesis mechanism. Interestingly, plant sterols, such as beta-sitosterol and stigmasterol, have the potential to lower the LDL-cholesterol in dyslipidemic patients. Beta-sitosterol was present in the ethanol extract of Lygodium microphyllum herbs at a concentration of 283.55µg/g extract. This sterol interacted with the active allosteric-binding site of SIRT1 and AMPK similarly to the proteins' activators. To investigate the anti-lipogenesis activity of the ethanol extract of L. microphyllum (ELM) in the liver tissue of rats through the SIRT1 and AMPK levels. Forty male Wistar rats were used in this study: (1) normal control group; (2) high-fat high-fructose diet (HFHFD) rats; (3) HFHFD rats treated with metformin; (4) HFHFD rats treated with resveratrol; (5) HFHFD rats treated with beta-sitosterol; (6-8) HFHFD rats treated with ELM doses of 200, 400, and 600 mg/kg BW. Rats in the normal control group were fed regular chow, while other groups of rats were given HFHFD for 35 days. All drugs were given orally on D15 till D35. On D35, the rats were sacrificed, and the liver organs were examined for the liver index, morphology, NAFLD activity score (NAS), and levels of SIRT1 and AMPK. ELM improves the morphology, the liver index, the steatosis condition, and the NAS of HFHFD-induced NAFLD rats. ELM increases the levels of SIRT1 and AMPK in the liver tissue of HFHFD-induced NAFLD rats. ELM may have the potential to inhibit de novo lipogenesis by increasing the levels of SIRT1 and AMPK.

Metformin and intermittent fasting mitigate high fat-fructose diet-induced liver and skeletal muscle injury through upregulation of mitophagy genes in rats

BackgroundHigh fat-fructose diet is a proinflammatory diet that increases risk of hepatocytes and myocytes steatosis and fibrosis. Finding anti-inflammatory strategies to fight these harmful effects is paid attention to nowadays. This study compared the effects of two widely anti-inflammatory interventions—metformin and intermittent fasting on myocytes and hepatocyte injury induced by proinflammatory diet and tracking possible underlying mechanisms. In this work, rats fed high fat-fructose diet were subdivided into untreated group, treated by metformin, and/or intermittent fasting.ResultsMetformin (300 mg/kg/day) and intermittent fasting (3 days/week) specially their combination for 4 weeks showed significant improvement in insulin resistance, lipid profile, antioxidants (p < 0.05), as well as enhanced hepatocytes and myocytes repair and reduced collagen deposition through upregulation of mitophagy-related genes: PINK1, PARKIN, LAMP2, and PPAR-α (p < 0.05).ConclusionsIntermittent fasting has beneficial metabolic and molecular therapeutic effects against proinflammatory diet-induced injury. Their results are like those of metformin sparing its adverse effects. Their combination showed additional effects against diet-induced myocytes and hepatocyte injury by upregulation of mitophagy-related genes without the need of increasing the dose of metformin.Graphic abstract

Physiological responses and microbiota shifts after spermidine administration as a postbiotic on rodents fed a high-fat high-fructose diet.

The consumption of a high-fat high-fructose diet partly resemble the western dietary patterns, which is closely associated with excessive body adiposity and metabolic disorders, such as obesity and type 2 diabetes. Moreover, this unhealthy regime produces unfavourable changes on the faecal microbiota, potentially interfering with microorganisms postbiotic function, such as spermidine, a natural polyamine that has been involved in the control of weight gain. The study aimed to analyse the repercussions of spermidine supplementation on somatic measurements, metabolic markers, and the faecal microbiota profile of rats fed a diet rich in fat and fructose. Indeed, Wistar males with oral administration of spermidine (20mg/kg/day) for 6 weeks were evaluated for food and energy intake, biochemical markers, and faecal microbiota signatures. The daily use of spermidine decreased weight gain ( P < 0.01), reduced feed efficiency ( P < 0.01), and attenuated visceral fat deposition ( P < 0.01), although no effect on energy intake, hepatic weight, triglyceride and glucose index and atherogenic indexes. Similarly, the consumption of spermidine partially restored the presence of microbial species, notably Akkermansia muciniphila. Elevated concentrations of this species were linked to a decrease in triglycerides ( P = 0.04), indicating that the supplementation of spermidine might contribute to managing energy fuel homeostasis in association with an obesogenic diet.

Comparative effects of viable Lactobacillus rhamnosus GG and its heat-inactivated paraprobiotic in the prevention of high-fat high-fructose diet-induced non-alcoholic fatty liver disease in rats.

Nonalcoholic fatty liver disease (NAFLD) is one of the most prevalent chronic liver alterations worldwide, being gut microbiota dysbiosis one of the contributing factors to its development. The aim of this research is to compare the potential effects of a viable probiotic (Lactobacillus rhamnosus GG) with those exerted by its heat-inactivated paraprobiotic counterpart in a dietary rodent model of NAFLD. The probiotic administration effectively prevented the hepatic lipid accumulation induced by a high-fat high-fructose diet feeding, as demonstrated by chemical (lower TG content) and histological (lower steatosis grade and lobular inflammation) analyses. This effect was mainly mediated by the downregulation of lipid uptake (FATP2 protein expression) and upregulating liver TG release to bloodstream (MTTP activity) in rats receiving the probiotic. By contrast, the effect of the paraprobiotic preventing diet-induced liver lipid accumulation was milder, and mainly derived from the downregulation of hepatic de novo lipogenesis (SREBP-1c protein expression and FAS activity) and TG assembly (DGAT2 and AQP9 protein expression). The obtained results demonstrate that under these experimental conditions, the effects induced by the administration of viable L. rhamnosus GG preventing liver lipid accumulation in rats fed a diet rich in saturated fat and fructose differ from those induced by its heat-inactivated paraprobiotic counterpart.

The Effect of Sacha Inchi Tempe on Blood Glucose, HOMA-IR, and TNF-ɑ in Rats with Metabolic Syndrome

This research aimed to evaluate the impact of sacha inchi tempe (Plukenetia volubilis L.) on Fasting Blood Glucose (FBG), Homeostatic Model Assessment for Insulin Resistance (HOMA-IR), and Tumor Necrosis Factor Alpha (TNF-ɑ) levels. In addition, metabolic syndrome was induced in 36 male Wistar rats aged 2 months at 150–200 g weight by giving a High-Fat High-Fructose diet (HFFD) for 2 weeks. The extract was administered through oral gavage in dose-dependent manner and rats were allocated into 6 groups, namely: 1). Normal control or K0; 2). Negative control or K-; 3). Positive control or K+ with 0.18 mg/200 g BB of simvastatin; 4). Intervention with 0.9 g sacha inchi tempe or P1; 5). Intervention with 1.8 g sacha inchi tempe or P2, and; 6). Intervention with 3.6 g sacha inchi tempe or P3. Meanwhile, normal chow rats were used and served as the control group. After 2 and 5 weeks of induction and intervention, blood was drawn to determine FBG. Blood insulin was examined after 5 week of intervention. Rats were euthanized at the end of the intervention for hepatic TNF-α analysis before calculating HOMA-IR. The result showed that there was a significant difference (p&lt;0.05) in FBG, HOMA-IR and hepatic TNF-α levels after sacha inchi tempe treatment. Rats receiving the highest dose of sacha inchi tempe had the most significant reduction (p&lt;0.05) in FBG, HOMA-IR and hepatic TNF-α, when compared to simvastatin group. Therefore, sacha inchi tempe could attenuate glycemic and inflammation profiles in metabolic syndrome.

Ferroptosis is a targetable detrimental factor in metabolic dysfunction-associated steatotic liver disease

There is an unmet clinical need for pharmacologic treatment for metabolic dysfunction-associated steatotic liver disease (MASLD). Hepatocyte cell death is a hallmark of this highly prevalent chronic liver disease, but the dominant type of cell death remains uncertain. Here we report that ferroptosis, an iron-catalyzed mode of regulated cell death, contributes to MASLD. Unsupervised clustering in a cohort of biopsy-proven MASLD patients revealed a subgroup with hepatic ferroptosis signature and lower glutathione peroxidase 4 (GPX4) levels. Likewise, a subgroup with reduced ferroptosis defenses was discerned in public transcriptomics datasets. Four weeks of choline-deficient L-amino acid-defined high-fat diet (CDAHFD) induced MASLD with ferroptosis in mice. Gpx4 overexpression did not affect steatohepatitis, instead CDAHFD protected from morbidity due to hepatocyte-specific Gpx4 knockout. The ferroptosis inhibitor UAMC-3203 attenuated steatosis and alanine aminotransferase in CDAHFD and a second model, i.e., the high-fat high-fructose diet (HFHFD). The effect of monounsaturated and saturated fatty acids supplementation on ferroptosis susceptibility was assessed in human HepG2 cells. Fat-laden HepG2 showed a drop in ferroptosis defenses, increased phosphatidylglycerol with two polyunsaturated fatty acid (PUFA) lipid tails, and sustained ferroptosis sensitivity. In conclusion, this study identified hepatic ferroptosis as a detrimental factor in MASLD patients. Unexpectedly, non-PUFA supplementation to hepatocytes altered lipid bilayer composition to maintain ferroptosis sensitivity. Based on findings in in vivo models, ferroptosis inhibition represents a promising therapeutic target in MASLD.

Aronia melanocarpa fruit juice prevents hepatic impairment in rats subjected to metabolic syndrome

AbstractThis study evaluated the effects of Aronia melanocarpa fruit juice (AMFJ) on the liver in a model of high-fat, high-fructose (HFHF) diet-induced metabolic syndrome (MS). Fifty rats were allocated to five groups – Control, MS, MS+AMFJ2.5, MS+AMFJ5, and MS+AMFJ10. The control group was fed a standard diet, while the other groups were provided a HFHF diet. During MS induction, daily oral treatment was performed. Control and MS groups received 10.0 mL kg−1 distilled water, while the other three groups received AMFJ at doses of 2.5, 5.0, and 10.0 mL kg−1, respectively. After 10 weeks, liver samples were collected and inspected histologically as well as immunohistochemically to determine the expression of Bax, Bcl-2, and MAC387. Bax/Bcl-2 ratio was calculated. In MS rats, steatotic, inflammatory and degenerative alterations of the liver were detected, Bax and MAC387 were markedly elevated, while Bcl-2 was non-significantly reduced. The Bax/Bcl-2 ratio significantly increased. The histopathological alterations were prevented by the AMFJ treatment. Compared to MS group, Bax and MAC387 values were significantly lower and Bcl-2 value was higher resulting in significantly lower (P &lt; 0.001) Bax/Bcl-2 ratio in all AMFJ-treated groups. AMFJ, administered during MS induction in rats, prevented the occurrence of inflammatory, steatotic, degenerative, and pro-apoptotic changes in the liver.

Single high-dose intravenous injection of Wharton’s jelly-derived mesenchymal stem cell exerts protective effects in a rat model of metabolic syndrome

BackgroundMetabolic syndrome (MetS) is a significant epidemiological problem worldwide. It is a pre-morbid, chronic and low-grade inflammatory disorder that precedes many chronic diseases. Wharton’s jelly-derived mesenchymal stem cells (WJ-MSCs) could be used to treat MetS because they express high regenerative capacity, strong immunomodulatory properties and allogeneic biocompatibility. This study aims to investigate WJ-MSCs as a therapy against MetS in a rat model.MethodsTwenty-four animals were fed with high-fat high-fructose (HFHF) diet ad libitum. After 16 weeks, the animals were randomised into treatment groups (n = 8/group) and received a single intravenous administration of vehicle, that is, 3 × 106 cells/kg or 10 × 106 cells/kg of WJ-MSCs. A healthy animal group (n = 6) fed with a normal diet received the same vehicle as the control (CTRL). All animals were periodically assessed (every 4 weeks) for physical measurements, serum biochemistry, glucose tolerance test, cardiovascular function test and whole-body composition. Post-euthanasia, organs were weighed and processed for histopathology. Serum was collected for C-reactive protein and inflammatory cytokine assay.ResultsThe results between HFHF-treated groups and healthy or HFHF-CTRL did not achieve statistical significance (α = 0.05). The effects of WJ-MSCs were masked by the manifestation of different disease subclusters and continuous supplementation of HFHF diet. Based on secondary analysis, WJ-MSCs had major implications in improving cardiopulmonary morbidities. The lungs, liver and heart show significantly better histopathology in the WJ-MSC-treated groups than in the untreated CTRL group. The cells produced a dose-dependent effect (high dose lasted until week 8) in preventing further metabolic decay in MetS animals.ConclusionsThe establishment of safety and therapeutic proof-of-concept encourages further studies by improving the current therapeutic model.

Behavioral Effects of Chronic Japanese Quince Fruit Juice Administration to Rats with Diet-Induced Metabolic Syndrome

Abstract Introduction Metabolic syndrome (MS) is often associated with anxiety and depression. Chaenomeles japonica (Thunb.) Lindl, also known as Chaenomeles maulei or Japanese quince, is a medicinal plant with a long history of use forits health-promoting properties. Aim The aim of this study was to investigate the effects of Japanese quince fruit juice (JQFJ) administration on locomotor activity, anxiety and depressive behavior in rats with diet-induced MS. Materials and methods Forty adult male Wistar rats were divided into 4 groups: MS, MS+JQFJ2.5, MS+JQFJ5 and MS+JQFJ10. All groups received a high-fat high-fructose diet for the induction of MS. MS animals were daily orally treated with distilled water and the other groups with JQFJ at doses of 2.5 ml/kg, 5 ml/kg and 10 ml/kg, respectively. During the 10th week of the experiment, behavioral tests were carried out. Results In the open Held test, no effect of JQFJ treatment on locomotor activity was observed. In the elevated plus maze test, a dose-dependent increase in the time spent in the open arms (OA) of the apparatus and in the ratio time spent in OA vs. total time spent in any of the arms was interpreted as an anxiolytic effect. The immobility time in the forced swim test did not differ significantly among the groups, which demonstrated a lack of anti-depressant action. Conclusions Chronic Japanese quince fruit juice administration produced a dose-dependent anxiolytic-like effect in rats with diet-induced MS, probably due to its high content of polyphenols.

Preventive and Therapeutic Efficacy of Roselle Beverage Residue in Late-Stage Type 2 Diabetic Rats

The residue from roselle beverage production is rich in polyphenols and dietary fiber. We investigated its potential as a preventive and therapeutic agent for type 2 diabetes mellitus (T2DM). Male Wistar rats were fed a high-fat high-fructose diet (HFFD) for 17 weeks, reaching insulin resistance by week 9, and induced to T2DM with streptozotocin (STZ) at week 13. Roselle beverage residue (RBR) was administered ad libitum mixed at 6% with the HFFD. Rats received HFFD+RBR as a preventive strategy starting at week 1 (healthy) and week 9 (insulin resistant), whereas the treatment strategy in T2DM rats started at week 14 alone or in combination with metformin (200 mg/kg/day), with a control metformin-treated group. All RBR-supplemented groups showed reduced serum glucose levels (1.4-fold to 1.8-fold) compared with the HFFD+STZ control group. Preventive RBR administration enhanced pancreatic function, leading to improved insulin sensitivity (6.5-fold to 7.9-fold). Gene expression analysis identified slight alterations in hepatic and skeletal muscle glucose metabolism. Additionally, RBR supplementation demonstrated a preventive role in mitigating hyperuricemia (2.1-fold to 2.2-fold), with no effect on glomerular hyperfiltration. While the exact mechanisms underlying RBR effects remain to be fully elucidated, our findings highlight its promising potential as a dietary supplement for preventing and treating T2DM.

High-Fat-High-Fructose Diet Elicits Brown Adipocyte Dysfunction through miRNA-103 Induced miRNA Biogenesis Pathway

Background: Obesity is a critical public health concern with its prevalence growing at an alarming rate worldwide. The Western diet that typically includes high-fat or high-fructose components is one of the leading contributing factors of obesity. Recent findings demonstrate the essential role of BAT in regulating whole-body metabolism. However, the explicit mechanism through which BAT maintains homeostasis is still unknown. Methods: Six-week-old C57BL/6 male mice were fed either a low-fat diet (LFD) or a high-fat high-fructose diet (HFHFD) for 4, 12, and 20 weeks. Results: We observed a significant increase in BAT weight under HFHFD along with BAT whitening in a time-dependent manner. This was also accompanied by a significant decrease in UCP1 and PGC1α protein, as well as a significant increase in the Bax/Bcl-2 ratio as early as 12 weeks, indicating increased apoptosis under HFHFD. Interestingly, miRNA-103 expression that holds a seed sequence within the miRNA biogenesis machinery, Dicer, was significantly upregulated after 12 and 20 weeks of HFHFD. Dicer and another biogenesis regulator, TRBP2, exhibited significant upregulation at 4 weeks of HFHFD. Conversely, those gene expressions were significantly downregulated at 12 and 20 weeks of HFHFD, followed by a significant decrease in the protein level at 12 weeks. To confirm the mechanistic connection, miRNA-103 knockdown in vitro significantly upregulated Dicer and the TRBP2 gene. However, only Dicer exhibited a significant increase at the translational level. Conclusion: Overall, we conclude that HFHFD may elicit BAT dysfunction by inhibiting Dicer via miRNA-103.

Modulatory effects of rutin and vitamin A on hyperglycemia induced glycation, oxidative stress and inflammation in high-fat-fructose diet animal model.

In the current study we investigated the impact of combination of rutin and vitamin A on glycated products, the glyoxalase system, oxidative markers, and inflammation in animals fed a high-fat high-fructose (HFFD) diet. Thirty rats were randomly divided into six groups (n = 5). The treatments, metformin (120 mg/kg), rutin (100 mg/kg), vitamin A (43 IU/kg), and a combination of rutin (100 mg/kg) and vitamin A (43 IU/kg) were given to relevant groups of rats along with high-fructose high-fat diet for 42 days. HbA1c, D-lactate, Glyoxylase-1, Hexokinase 2, malondialdehyde (MDA), glutathione peroxidase (GPx), catalase (CAT), nuclear transcription factor-B (NF-κB), interleukin-6 (IL-6), interleukin-8 (IL-8) and histological examinations were performed after 42 days. The docking simulations were conducted using Auto Dock package. The combined effects of rutin and vitamin A in treated rats significantly (p < 0.001) reduced HbA1c, hexokinase 2, and D-lactate levels while preventing cellular damage. The combination dramatically (p < 0.001) decreased MDA, CAT, and GPx in treated rats and decreased the expression of inflammatory cytokines such as IL-6 andIL-8, as well as the transcription factor NF-κB. The molecular docking investigations revealed that rutin had a strong affinity for several important biomolecules, including as NF-κB, Catalase, MDA, IL-6, hexokinase 2, and GPx. The results propose beneficial impact of rutin and vitamin A as a convincing treatment strategy to treat AGE-related disorders, such as diabetes, autism, alzheimer's, atherosclerosis.

Berberine ameliorates nonalcoholic fatty liver disease-induced bone loss by inhibiting ferroptosis

BackgroundNonalcoholic fatty liver disease (NAFLD) may contribute to osteoporosis. Berberine is a traditional Chinese medicine and was recently shown to be beneficial in NAFLD. However, little is known about its impact on bone loss induced by NAFLD. AimWe aimed to explore the role of berberine in bone loss and determine its underlying mechanisms in NAFLD. MethodsC57BL/6 mice were fed a high-fat high-fructose high-glucose diet (HFFGD) for 16 weeks to establish a NAFLD mouse model. The mice were administered berberine (300 mg/kg/d) by gavage, and fatty liver levels and bone loss indicators were tested. ResultsBerberine significantly improved HFFGD-induced weight gain, hepatic lipid accumulation and increases in serum liver enzymes, thereby alleviating NAFLD. Berberine increased trabecular number (Tb. N), trabecular thickness (Tb. Th), bone volume to tissue volume ratio (BV/TV), and decreased trabecular separation (Tb. Sp) and restored bone loss in NAFLD. Mechanistically, berberine significantly inhibited ferroptosis and 4-hydroxynonenal (4-HNE), prostaglandin-endoperoxide synthase 2 (PTGS2), and transferrin (TF) levels and increased ferritin heavy chain (FTH) levels in the femurs of HFFGD-fed mice. Moreover, berberine also activated the solute carrier family 7 member 11 (SLC7A11)/glutathione (GSH)/glutathione peroxidase 4 (GPX4) signaling pathway. ConclusionBerberine significantly ameliorates bone loss induced by NAFLD by activating the SLC7A11/GSH/GPX4 signaling pathway and inhibiting ferroptosis. Therefore, berberine may serve as a therapeutic agent for NAFLD-induced bone loss.

Hepatocyte-Specific Fads1 Overexpression Attenuates Western Diet-Induced Metabolic Phenotypes in a Rat Model.

Fatty acid desaturase 1 (FADS1) is a rate-limiting enzyme in long-chain polyunsaturated fatty acid (LCPUFA) synthesis. Reduced activity of FADS1 was observed in metabolic dysfunction-associated steatotic liver disease (MASLD). The aim of this study was to determine whether adeno-associated virus serotype 8 (AAV8) mediated hepatocyte-specific overexpression of Fads1 (AAV8-Fads1) attenuates western diet-induced metabolic phenotypes in a rat model. Male weanling Sprague-Dawley rats were fed with a chow diet, or low-fat high-fructose (LFHFr) or high-fat high-fructose diet (HFHFr) ad libitum for 8 weeks. Metabolic phenotypes were evaluated at the endpoint. AAV8-Fads1 injection restored hepatic FADS1 protein levels in both LFHFr and HFHFr-fed rats. While AAV8-Fads1 injection led to improved glucose tolerance and insulin signaling in LFHFr-fed rats, it significantly reduced plasma triglyceride (by ~50%) and hepatic cholesterol levels (by ~25%) in HFHFr-fed rats. Hepatic lipidomics analysis showed that FADS1 activity was rescued by AAV8-FADS1 in HFHFr-fed rats, as shown by the restored arachidonic acid (AA)/dihomo-γ-linolenic acid (DGLA) ratio, and that was associated with reduced monounsaturated fatty acid (MUFA). Our data suggest that the beneficial role of AAV8-Fads1 is likely mediated by the inhibition of fatty acid re-esterification. FADS1 is a promising therapeutic target for MASLD in a diet-dependent manner.

Comparative Neuroprotective Effects of Moringa oleifera Seed Oil and Aqueous Extract on Cognitive Functions on a High-Fat, High-Fructose Diet Mice: Focus on Senescence Markers.

Several studies have demonstrated that Moringa oleifera (MO) has different pharmacological properties, including neuroprotective effects. However, the role of MO in preventing brain impairment in high-fat, high-fructose diet (HFFD) remains unknown. This study aimed to investigate the neuroprotective effects of MO leaves aqueous extract (MOE) and moringa seed oil (MOO) against brain impairment in mice with HFFD. Twenty-eight male mice were randomly divided into four groups: normal diet, HFFD, HFFD + MOE 500 mg/kgBW, and HFFD + MOO 2 mL/kgBW. Cognitive function was assessed using the Y-maze and novel object recognition (NOR) tests. The p16, p21, and BDNF expressions were analyzed using the RT-PCR method. Senescence-associated beta-galactosidase (SA-β-gal) staining in the brain was also performed. The results showed that administration of MOE or MOO could increase the percentage of alternation and recognition of new objects, prevent the increase of p16 and p21 expression, and ameliorate SA-β-Gal activity in the brain. MOO, but not MOE, increased BDNF expression in senescence brains isolated from HFFD mice. The findings indicate that MOO and MOE possess neuroprotective properties, with MOO demonstrating a greater ability to inhibit the brain senescence process compared to MOE.

Whey protein supplementation reduced the liver damage scores of rats fed with a high fat-high fructose diet.

Different functional foods with bioactive nutrients are being explored for the management of NAFLD. Whey proteins are rich in bioactive peptides and are suggested to show antioxidant and anti-inflammatory effects. We aim to test the hypothesis that the whey protein supplementation following a high fat-high fructose (HFHF) diet would protect against liver damage, inflammation, endotoxemia and steatosis in male Wistar rats. 36 rats were randomized into four groups for 8 weeks as the HFHF diet group, HFHF diet and whey protein isolate (WPI-200mg/kg/day) group (HFHF+WPI), control (C) group, and C+WPI (200mg/kg/day) group. Rats fed with a HFHF diet had higher final body weight compared to C and C+WPI groups (p = 0.002). Thus, WPI showed no significant effects for the body weight of rats with a HFHF diet. On the other hand, the HFHF+WPI group had significantly lower abdominal circumference when compared with the HFHF group (p<0,001). Higher serum CRP levels were observed in the groups with a HFHF diet (p<0,001) and WPI supplementation showed no effects on CRP levels. Whey protein supplementation resulted with lower total liver damage score in HFHF+WPI group compared with the HFHF diet group (p<0,001). Conversely, higher liver damage scores were observed with the C+WPI group compared to C group (p<0,001). HFHF diet resulted with higher expression of TLR-4 in the liver meanwhile WPI supplementation showed no effects on liver TLR-4 expression. We observed higher colon Occludin expression in HFHF+WPI and C+WPI groups compared with HFHF and C groups (p<0,001). Our results showed that, whey protein supplementation might help improve liver damage associated with a high fat-high fructose diet and increase the expression of Occludin in the small intestine and colon.