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Background: The intake of high-fructose corn syrup (HFCS) may increase the risk of colorectal cancer (CRC). This study aimed to explore the potential effects and mechanisms of resistant starch (RS) in HFCS-induced colon tumorigenesis., Methods: The azoxymethane/dextran sodium sulfate (AOM/DSS) and Apc Min/+ mice models were used to investigate the roles of HFCS and RS in CRC in vivo. An immunohistochemistry (IHC) staining analysis was used to detect the expression of proliferation-related proteins in tissues. 16S rRNA sequencing for microbial community, gas chromatography for short-chain fatty acids (SCFAs), and mass spectrometry analysis for glycolysis products in the intestines were performed. Furthermore, lactic acid assay kit was used to detect the glycolysis levels in vitro., Results: RS suppressed HFCS-induced colon tumorigenesis through reshaping the microbial community. Mechanistically, the alteration of the microbial community after RS supplement increased the levels of intestinal SCFAs, especially butyrate, leading to the suppression of glycolysis and CRC cell proliferation by downregulating HK2., Conclusions: Our study identified RS as a candidate of protective factors in CRC and may provide a potential target for HFCS-related CRC treatment., (© 2024. The Author(s).)

High-fructose corn syrup (HFCS) has been a subject of intense debate due to its association with cardiovascular risks. This study investigates the potential protective effects of selenium (Se) supplementation against cardiac damage induced by HFCS. Thirty-two male Wistar albino rats were divided into four equal groups: control, CS (20%-HFCS), CS with Se (20%-HFCS, 0.3 mg/kg-Se), and Se (0.3 mg/kg-Se) only. After a 6-week period, heart and aorta tissues were collected for histopathological, immunohistochemical, biochemical, and genetic analyses. HFCS consumption led to severe cardiac pathologies, increased oxidative stress, and altered gene expressions associated with inflammation, apoptosis, and antioxidant defenses. In the CS group, pronounced oxidative stress within the cardiac tissue was concomitant with elevated Bcl-2-associated X protein (Bax) expression and diminished expressions of B-cell-lymphoma-2 (Bcl-2), nuclear factor erythroid 2-related factor 2 (Nrf2), peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1-α), and silenced information regulator 1 (SIRT1). Se supplementation mitigated these effects, showing protective properties. Immunohistochemical analysis supported these findings, demonstrating decreased expressions of caspase-3, tumor necrosis factor-alpha (TNF-α), IL-1β, and vascular endothelial growth factor (VEGF) in the CS + Se group compared to the CS group. The study suggests that Se supplementation exerts anti-inflammatory, antioxidant, and antiapoptotic effects, potentially attenuating HFCS-induced cardiovascular toxicity. These findings highlight the importance of dietary considerations and selenium supplementation in mitigating cardiovascular risks associated with HFCS consumption., (© 2024. The Author(s).)

Background: The black/white heart disease mortality disparity began increasing in the early 1980's, coincident with the switch from sucrose to high-fructose-corn-syrup/(HFCS) in the US food supply. There has been more fructose in HFCS than generally-recognized-as-safe/GRAS, which has contributed to unprecedented excess-free-fructose/(unpaired-fructose) in foods/beverages. Average- per-capita excess-free-fructose, from HFCS, began exceeding dosages/(5-10 g) that trigger fructose-malabsorption in the early 1980's. Fructose malabsorption contributes to gut-dysbiosis and gut-in-situ-fructosylation of dietary peptides/incretins/(GLP-1/GIP) which forms atherosclerotic advanced-glycation-end-products. Both dysregulate gut endocrine function and are risk factors for cardiovascular disease/(CVD). Limited research shows that African Americans have higher fructose malabsorption prevalence than others. CVD risk begins early in life., Methods: Coronary-Artery-Risk-Development-in-Adults/(CARDIA) study data beginning in 1985-86 with 2186 Black and 2277 White participants, aged 18-30 y, were used to test the hypothesis that HFCS sweetened beverage intake increases CVD risk/incidence, more among Black than White young adults, and at lower intakes; while orange juice-a low excess-free-fructose juice with comparable total sugars and total fructose, but a 1:1 fructose-to-glucose-ratio, i.e., low excess-free-fructose, does not. Cox proportional hazards models were used to calculate hazard ratios., Results: HFCS sweetened beverage intake was associated with higher CVD risk (HR = 1.7) than smoking (HR = 1.6). CVD risk was higher at lower HFCS sweetened beverage intake among Black than White participants. Intake, as low as 3 times/wk, was associated with twice the CVD risk vs. less frequent/never, among Black participants only (HR 2.1, 95% CI 1.2-3.7; P = 0.013). Probability of an ordered relationship approached significance. Among Black participants, CVD incidence jumped 62% from 59.8/1000, among ≤ 2-times/wk, to 96.9/1000 among 3-6 times/wk consumers. Among White participants, CVD incidence increased from 37.6/1000, among ≤ 1.5-times/wk, to 41.1/1000, among 2 times/wk-once/d - a 9% increase. Hypertension was highest among Black daily HFCS sweetened beverage consumers., Conclusion: The ubiquitous presence of HFCS over-the-past-40 years, at higher fructose-to-glucose ratios than generally-recognized-as-safe, may have contributed to CVD racial disparities, due to higher fructose-malabsorption prevalence among Black individuals, unpaired/excess-free-fructose induced gut dysbiosis and gut fructosylation of dietary peptides/incretins (GLP-1/GIP). These disturbances contribute to atherosclerotic plaque; promote incretin insufficiency/dysregulation/altered satiety/dysglycemia; decrease protective microbiota metabolites; and increase hypertension, CVD morbidity and mortality., (© 2024. The Author(s).)

High Fructose Corn Syrup (HFCS) and Fructose (FR) are widely used sweeteners in many foods and beverages. This study aimed at investigating the cytotoxic effects of HFCS (5%-30%) and FR (62.5-2000 μg/mL) using MTT assay in Human Hepatocellular Carcinoma (HepG 2 ) cells, and genotoxic effects of using Chromosome Aberrations (CAs), Sister Chromatid Exchanges (SCEs), Micronuclei (MN) and comet assays in human lymphocytes. HFCS significantly reduced the cell viability in HepG 2 cells at between 7.5% and 30% for 24 and 48 h. 30% HFCS caused a very significant toxic effect. FR had a cytotoxic effect in HepG 2 cells at all treatments. However, as fructose concentration decreased, the cell viability decreased. HFCS (10%-20%) and FR (250-2000 μg/mL) decreased the mitotic index at higher concentrations. IC 50 value was found to be a 15% for 48 h. IC 50 value of FR was detected as 62.5 μg/mL for 24 h and 48 h. HFCS significantly increased CAs frequency at 15% and 20%. FR significantly increased the frequency of CAs at 250, 1000, and 2000 μg/mL for 48 h. Both sweeteners increased the frequency of SCEs at all concentrations. HFCS (15% and 20%) and FR (250, 1000, and 2000 μg/mL) induced MN frequency at higher concentrations. HFCS caused DNA damage in comet assay at 10% -30%. FR increased tail intensity and moment at 125-2000 μg/mL and tail length at 62.5, 250 and 500 μg/mL. Therefore, HFCS and FR are clearly seen to be cytotoxic and genotoxic, especially at higher concentrations.

Introduction: Cigarettes containing nicotine (Nic) are a risk factor for the development of cardiovascular and metabolic diseases. We reported that Nic delivered via injections or e-cigarette vapor led to hepatic steatosis in mice fed with a high-fat diet. High-fructose corn syrup (HFCS) is the main sweetener in sugar-sweetened beverages (SSBs) in the US. Increased consumption of SSBs with HFCS is associated with increased risks of non-alcoholic fatty liver disease (NAFLD). Nicotinamide riboside (NR) increases mitochondrial nicotinamide adenine dinucleotide (NAD + ) and protects mice against hepatic steatosis. This study evaluated if Nic plus Coca-Cola ™ (Coke) with HFCS can cause hepatic steatosis and that can be protected by NR., Methods: C57BL/6J mice received twice daily intraperitoneal (IP) injections of Nic or saline and were given Coke (HFCS), or Coke with sugar, and NR supplementation for 10 weeks., Results: Our results show that Nic+Coke caused increased caloric intake and induced hepatic steatosis, and the addition of NR prevented these changes. Western blot analysis showed lipogenesis markers were activated (increased cleavage of the sterol regulatory element-binding protein 1 [SREBP1c] and reduction of phospho-Acetyl-CoA Carboxylase [p-ACC]) in the Nic+Coke compared to the Sal+Water group. The hepatic detrimental effects of Nic+Coke were mediated by decreased NAD + signaling, increased oxidative stress, and mitochondrial damage. NR reduced oxidative stress and prevented mitochondrial damage by restoring protein levels of Sirtuin1 (Sirt1) and peroxisome proliferator-activated receptor coactivator 1-alpha (PGC1) signaling., Conclusion: We conclude that Nic+Coke has an additive effect on producing hepatic steatosis, and NR is protective. This study suggests concern for the development of NAFLD in subjects who consume nicotine and drink SSBs with HFCS., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Rivera, Espinoza-Derout, Hasan, Molina-Mancio, Martínez, Lao, Lee, Lee, Wilson, Sinha-Hikim and Friedman.)

Background/aim: The global prevalence of type 2 diabetes (T2D) continues to increase, necessitating the need for understanding the causes of its development. The widespread use of high-fructose corn syrup (HFCS) in drinks and diets is suspected to play a role in metabolic disorders. Although many studies have reported on the effects of excessive HFCS and excessive energy intakes in middle-aged individuals, few have focused on energy restriction. This study aimed to investigate the effects of excessive HFCS drink intake under energy restriction on developing T2D in early middle-aged mice., Materials and Methods: Early middle-aged mice were divided in HFCS and control groups; they were provided either 10% HFCS water or deionized water ad libitum for 12 weeks, respectively. Total energy intake was controlled using a standard rodent diet. Oral glucose tolerance test (OGTT), insulin tolerance test (ITT), tissue weight measurements, serum parameter analyses, and mRNA expression assessments were performed., Results: No increase in body and adipose tissue weight was observed with excessive HFCS intake under energy restriction. Moreover, serum lipid parameters did not differ from those of controls. However, in the OGTT and ITT, the HFCS group showed higher blood glucose levels than the control group. Moreover, the pancreatic weight and insulin II mRNA expression were reduced., Conclusion: The excessive HFCS drink intake under energy restriction did not induce obesity; however, it induced impaired glucose tolerance, indicating its negative effects on the pancreas in early middle-aged mice. When translated in human physiology, our results show that even if one does not become obese, excessive HFCS may affect the overall metabolic mechanism; these effects may vary depending on age., (Copyright © 2024, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

In our study, we aimed to investigate the negative effects of the prefrontal cortex (PFC)-associated impairment of cholinergic activity on memory and learning caused by high fructose corn syrup (HFCS) and the protective role of vitamin D in adolescent rats. Twenty-four animals were divided into three groups as control, HFCS group (11 % HFCS-55 solution, ad libitum) and HFCS+ Vit D (42 μg/kg/day). Elevated Plus Maze (EPM), Forced Swim Test (FST), and Morris Water Maze (MWM, performed from day 23) tests were applied to all animals. Fluid intake consumption of the rats was measured daily, weight gain and blood glucose were measured weekly. After 31 days of treatment, the rats were sacrificed and PFC tissue was removed for biochemical, histopathological and immunohistochemical analyses. In HFCS group, fluid consumption, blood glucose, malondialdehyde (MDA) levels, degenerative neuron count and choline acetyltransferase (ChAT) expression were significantly increased; superoxide dismutase (SOD), catalase (CAT) enzyme activity and brain-derived neurotrophic factor (BDNF) expression were significantly decreased. In addition, the time spent in the enclosed arm in EPM was increased, the immobility time in FST was, and the time spent in the target quadrant in MWM was significantly decreased. Vitamin D treatment reversed all these parameters. In conclusion, HFCS caused an increase in the number of degenerative neurons in the PFC, disrupted cholinergic activity and negatively affected learning-memory functions. Vitamin D, decreased the number of degenerative neurons, increased cholinergic activity and positively affected learning and memory performance. BRIEF SYNOPSIS: In this study, prefrontal cortex damage was investigated in adolescent rats fed high fructose corn syrup. The effect of vitamin D on prefrontal cortex damage was evaluated., Competing Interests: Competing interests The authors declare there are no competing interests., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Labels do not disclose the excess-free-fructose/unpaired-fructose content in foods/beverages. Objective was to estimate excess-free-fructose intake using USDA loss-adjusted-food-availability (LAFA) data (1970-2019) for high fructose corn syrup (HFCS) and apple juice, major sources of excess-free-fructose, for comparison with malabsorption dosages (~ 5 g-children/ ~ 10 g-adults). Unlike sucrose and equimolar fructose/glucose, unpaired-fructose triggers fructose malabsorption and its health consequences. Daily intakes were calculated for HFCS that is generally-recognized-as-safe/ (55% fructose/45% glucose), and variants (65/35, 60/40) with higher fructose-to-glucose ratios (1.9:1, 1.5:1), as measured by independent laboratories. Estimations include consumer-level-loss (CLL) allowances used before (20%), and after, subjective, retroactively-applied increases (34%), as recommended by corn-refiners (~ 2012). No contributions from crystalline-fructose or agave syrup were included due to lack of LAFA data. High-excess-free-fructose-fruits (apples/pears/watermelons/mangoes) were not included. Eaten in moderation they are less likely to trigger malabsorption. Another objective was to identify potential parallel trends between excess-free-fructose intake and the "unexplained" US asthma epidemic. The fructose/gut-dysbiosis/lung axis is well documented, case-study evidence and epidemiological research link HFCS/apple juice intake with asthma, and unlike gut-dysbiosis/gut-fructosylation, childhood asthma prevalence data spans > 40 years. Results Excess-free-fructose daily intake for individuals consuming HFCS with an average 1.5:1 fructose-to-glucose ratio, ranged from 0.10 g/d in 1970, to 11.3 g/d in 1999, to 6.5 g/d in 2019, and for those consuming HFCS with an average 1.9:1 ratio, intakes ranged from 0.13 g/d to 16.9 g/d (1999), to 9.7 g/d in 2019, based upon estimates with a 20% CLL allowance. Intake exceeded dosages that trigger malabsorption (~ 5 g) around ~ 1980. By the early 1980's, tripled apple juice intake had added ~ 0.5 g to average-per-capita excess-free-fructose intake. Contributions were higher (~ 3.8 g /4-oz.) for individuals consuming apple juice consistent with a healthy eating pattern (4-oz. children, 8-oz. adults). The "unexplained" childhood asthma epidemic (1980-present) parallels increasing average-per-capita HFCS/apple juice intake trends and reflects epidemiological research findings. Conclusion Displacement of sucrose with HFCS, its ubiquitous presence in the US food-supply, the industry practice of adding more fructose to HFCS than generally-recognized-as-safe, and increased use of apple juice/crystalline fructose/agave syrup in foods/beverages has contributed to unprecedented excess-free-fructose intake levels, fructose malabsorption, gut-dysbiosis and gut-fructosylation (immunogen burden)-gateways to chronic disease., (© 2024. The Author(s).)

(1) Background: Clinical results on the effects of excess sugar consumption on insulin sensitivity are conflicting, possibly due to differences in sugar type and the insulin sensitivity index (ISI) assessed. Therefore, we compared the effects of consuming four different sugars on insulin sensitivity indices derived from oral glucose tolerance tests (OGTT). (2) Methods: Young adults consumed fructose-, glucose-, high-fructose corn syrup (HFCS)-, sucrose-, or aspartame-sweetened beverages (SB) for 2 weeks. Participants underwent OGTT before and at the end of the intervention. Fasting glucose and insulin, Homeostatic Model Assessment-Insulin Resistance (HOMA-IR), glucose and insulin area under the curve, Surrogate Hepatic Insulin Resistance Index, Matsuda ISI, Predicted M ISI, and Stumvoll Index were assessed. Outcomes were analyzed to determine: (1) effects of the five SB; (2) effects of the proportions of fructose and glucose in all SB. (3) Results: Fructose-SB and the fructose component in mixed sugars negatively affected outcomes that assess hepatic insulin sensitivity, while glucose did not. The effects of glucose-SB and the glucose component in mixed sugar on muscle insulin sensitivity were more negative than those of fructose. (4) Conclusion: the effects of consuming sugar-SB on insulin sensitivity varied depending on type of sugar and ISI index because outcomes assessing hepatic insulin sensitivity were negatively affected by fructose, and outcomes assessing muscle insulin sensitivity were more negatively affected by glucose.

Background: High-Fructose Corn Syrup (HFCS), a sweetener rich in glucose and fructose, is nowadays widely used in beverages and processed foods; its consumption has been correlated to the emergence and progression of Non-Alcoholic Fatty Liver Disease (NAFLD). Nevertheless, the molecular mechanisms by which HFCS impacts hepatic metabolism remain scarce, especially in the context of obesity. Besides, the majority of current studies focuses either on the detrimental role of fructose in hepatic steatosis or compare separately the additive impact of fructose versus glucose in high fat diet-induced NAFLD., Aim: By engaging combined omics approaches, we sought to characterize the role of HFCS in obesity-associated NAFLD and reveal molecular processes, which mediate the exaggeration of steatosis under these conditions., Methods: Herein, C57BL/6 mice were fed a normal-fat-diet (ND), a high-fat-diet (HFD) or a HFD supplemented with HFCS (HFD-HFCS) and upon examination of their metabolic and NAFLD phenotype, proteomic, lipidomic and metabolomic analyses were conducted to identify HFCS-related molecular alterations of the hepatic metabolic landscape in obesity., Results: Although HFD and HFD-HFCS mice displayed comparable obesity, HFD-HFCS mice showed aggravation of hepatic steatosis, as analysis of the lipid droplet area in liver sections revealed (12,15 % of total section area in HFD vs 22,35 % in HFD-HFCS), increased NAFLD activity score (3,29 in HFD vs 4,86 in HFD-HFCS) and deteriorated hepatic insulin resistance, as compared to the HFD mice. Besides, the hepatic proteome of HFD-HFCS mice was characterized by a marked upregulation of 5 core proteins implicated in de novo lipogenesis (DNL), while an increased phosphatidyl-cholines(PC)/phosphatidyl-ethanolamines(PE) ratio (2.01 in HFD vs 3.04 in HFD-HFCS) was observed in the livers of HFD-HFCS versus HFD mice. Integrated analysis of the omics datasets indicated that Tricarboxylic Acid (TCA) cycle overactivation is likely contributing towards the intensification of steatosis during HFD-HFCS-induced NAFLD., Conclusion: Our results imply that HFCS significantly contributes to steatosis aggravation during obesity-related NAFLD, likely deriving from DNL upregulation, accompanied by TCA cycle overactivation and deteriorated hepatic insulin resistance., Competing Interests: Declaration of competing interest ‘Declarations of interest: none’. The authors declare no conflict of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Metformin, a frontline therapy for type 2 diabetes and related metabolic diseases, results in variable outcomes. This study aimed to investigate whether sweetened beverages (caloric or non-caloric) affect the therapeutic benefits of metformin on glucose, food intake, and weight loss in diet-induced obesity. Mice were given a high-fat diet and sweetened water for 8 weeks to induce obesity and glucose intolerance. Then, mice were randomized to receive metformin in either water, high-fructose corn syrup (HFCS), or the non-nutritive sweetener saccharin for 6 weeks. After 6 weeks of metformin treatment, all groups had improved glucose tolerance compared to pretreatment. However, saccharin resulted in worse glucose tolerance and weight gain outcomes than the water or HFCS groups and correlated with lower plasma growth differentiation factor 15 levels. In conclusion, reducing non-nutritive sweetener consumption during metformin therapy is recommended to avoid impairing the therapeutic effects of metformin on body weight and glucose homeostasis.

The presence of obesity and metabolic syndrome is strongly linked with chronic kidney disease (CKD), but the mechanisms responsible for the association are poorly understood. Here, we tested the hypothesis that mice with obesity and metabolic syndrome might have increased susceptibility to CKD from liquid high fructose corn syrup (HFCS) by favoring the absorption and utilization of fructose. We evaluated the pound mouse model of metabolic syndrome to determine if it showed baseline differences in fructose transport and metabolism and whether it was more susceptible to chronic kidney disease when administered HFCS. Pound mice have increased expression of fructose transporter (Glut5) and fructokinase (the limiting enzyme driving fructose metabolism) associated with enhanced fructose absorption. Pound mice receiving HFCS rapidly develop CKD with increased mortality rates associated with intrarenal mitochondria loss and oxidative stress. In pound mice lacking fructokinase, the effect of HFCS to cause CKD and early mortality was aborted, associated with reductions in oxidative stress and fewer mitochondria loss. Obesity and metabolic syndrome show increased susceptibility to fructose-containing sugars and increased risk for CKD and mortality. Lowering added sugar intake may be beneficial in reducing the risk for CKD in subjects with metabolic syndrome.

We previously reported that maternal fructose consumption increases blood corticosterone levels in rat offspring. However, the underlying mechanism of action remains unclear. In the present study, we aimed to elucidate the molecular mechanism by which maternal high-fructose corn syrup (HFCS) intake increases circulating GC levels in rat offspring (GC; corticosterone in rodents and cortisol in humans). Female Sprague Dawley rats received HFCS solution during gestation and lactation. The male offspring were fed distilled water from weaning to 60 days of age. We investigated the activities of GC-metabolizing enzymes (11β-Hsd1 and 11β-Hsd2) in various tissues (i.e., liver, kidney, adrenal glands, muscle, and white adipose tissue) and epigenetic modification. 11β-Hsd2 activity decreased in the kidney of the HFCS-fed dams. Moreover, the epigenetic analysis suggested that miR-27a reduced Hsd11b2 mRNA expression in the kidney of offspring. Maternal HFCS-induced elevation of circulating GC levels in offspring may be explained by a decrease in 11β-Hsd2 activity via renal miR-27a expression. The present study may allow us to determine one of the mechanisms of GC elevation in rat offspring that is often observed in the developmental origins of the health and disease (DOHaD) phenomenon.

Excessive high fructose corn syrup (HFCS) consumption is known to cause oxidative stress, which induces transient receptor potential melastatin type 2 (TRPM2) channel gating. Oxidative stress-induced TRPM2 gating is suggested to play an important role in neurons, indicating a role for the TRPM2 channel in a variety of neuropsychiatric disorders including depression and anxiety. We investigated the effects of HFCS and chronic immobilization stress (CIS) on TRPM2 channel immunoreactivity, anxiety, and depressive-like behaviors in adult male rats. The male rats (n=8/group) were divided into 4 groups: Control, 20% HFCS (F20), 40% HFCS (F40), and stress. The control group received tap water, and F20 and F40 groups were exposed to HFCS 20% and 40% respectively for 14 consecutive days. Rats in the stress group were subjected to immobilization stress for 3 or 6 hours daily in the first and second weeks to induce CIS. Then, light/dark tests, open field tests (OFT), and tail suspension tests (TST) were performed, respectively. In the light/dark test, the time spent in the dark chamber significantly increased in all groups vs the control group (P<0.01). In support of this result, time spent in the light chamber significantly decreased in all groups vs the control group (P<0.01). Besides, CIS significantly increased depressive-like behavior in the stress group vs the control group (P<0.05). In serum hormone levels, corticosterone (CORT) levels significantly increased in the F40 and stress groups vs the control group (P<0.01). TRPM2 immunoreactivity significantly increased in the hippocampus, prefrontal cortex (PFC), nucleus accumbens (NaC), and amygdala regions by HFCS and CIS treatments. For the first time in the present study,  showed that f increased immunoreactivity of the TRPM2 cation channels may be linked to the anxiety-like behavior induced by HFCS.

High-fructose corn syrup (HFCS) is consumed worldwide. However, it has been demonstrated that an increased intake of sweetened beverages, including those sweetened using fructose, is associated with the development of childhood obesity. It is unknown why the negative effects of fructose are stronger in young persons than in elderly individuals. In recent years, mitochondria have been identified as 1 of the targets of the negative effects of fructose; they possess their own genome called mitochondrial DNA (mtDNA), which encodes genes involved in metabolic functions. We hypothesized that HFCS intake affects mtDNA in the livers of rats, and that the intensity of these effects is age-dependent. The experimental period was divided into 3 parts: childhood and adolescence (postnatal day [PD] 21-60), young adulthood (PD61-100), and adulthood (PD101-140). Rats in the different age groups were assigned to receive either water (control group [CONT]) or a 20% HFCS solution (HFCS). The hepatic mtDNA copy number of the HFCS group was higher than that of the CONT group in childhood and adolescence. In addition, the mtDNA methylation level was increased in the HFCS group in the same experimental period. No significant differences were observed between the CONT and HFCS groups during the other experimental periods. We demonstrated that HFCS has the strongest effect on mtDNA during childhood and adolescence, suggesting a need to analyze the HFCS intake of young people., Competing Interests: Declaration of Competing Interest The authors declare that there are no conflicts of interest., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Concerns about the negative intergenerational effects of excessive fructose intake are being raised, with evidence suggesting that prenatal fructose intake increases susceptibility to metabolic and cognitive dysfunction later in life. In the present study, we hypothesized that prenatal and postnatal fructose intake acts synergistically to impact on hippocampus of adult offspring. Female Sprague-Dawley rats received distilled water or 20% high-fructose corn syrup (HFCS) solution in addition to standard chow throughout gestation and lactation. Male offspring were weaned at postnatal day 21 (PD21) and were randomized to receive distilled water or 20% HFCS solution until PD60. The following experimental groups were: CC: distilled water dams and post-weaning distilled water, CH: distilled water dams and post-weaning HFCS solution, HC: HFCS solution dams and post-weaning distilled water and HH: HFCS solution dams and post-weaning HFCS solution. The synergistic effect of maternal and post-weaning HFCS intake on the hippocampus was investigated by studying the expression of pro-inflammatory cytokine genes (Tnfa, Il1b, and Il6). At weaning, expression levels of pro-inflammatory cytokines between the offspring of the distilled water and HFCS solution fed dams were not significantly different. At PD60, Tnfa expression was significantly higher in the HH group than in the CC, HC and CH groups, whereas no significant differences were found between the CC, HC, and CH groups. These results suggest that postnatal fructose intake negatively impacts the hippocampus by acting synergistically with prenatal fructose intake.

Background: Consumption of high fructose corn syrup sweetened drinks and diet soft drinks has increased in the United States. However, the relationship between the intake of high fructose corn syrup sweetened drinks and diet soft drinks, and serum sodium has been scarcely studied. Our objective is to evaluate the relation between intake of high fructose corn syrup sweetened drinks and diet soft drinks, and serum sodium, and explore the possible effect modifiers in a nationally representative sample of adults from the United States., Methods: We conducted a cross-sectional study using data from the National Health and Nutrition Examination Survey 2003-2006. The study participants included 6989 adults aged ≥18 years. Using survey-weighted generalized linear regression analyses, we investigated the relationship between high fructose corn syrup sweetened drink, diet soft drink consumption, and serum sodium. Consumption of high fructose corn syrup sweetened drinks and diet soft drinks was evaluated through a food-frequency questionnaire., Results: Serum sodium levels increased as high fructose corn syrup sweetened drink intake increased. Serum sodium levels were higher in participants in the highest high fructose corn syrup sweetened drink consumption quantile, compared with those in the lowest high fructose corn syrup sweetened drink intake quantile (p = 0.020). The multivariate betas for serum sodium, according to the corresponding high fructose corn syrup sweetened drink intake quantiles, were 0.16, 0.19, and 0.21, respectively (P for trend = 0.051). We found no relationship between diet soft drink consumption and serum sodium after adjustment of confounding. (multivariate P > 0.05)., Conclusion: There was a a step-wise increase in serum sodium concentration with increasing consumption of HFCS sweetened beverages. Even moderate HFCS sweetened soft drink intake was associated with an elevated serum sodium level - a risk factor for hypertension., (© 2022. The Author(s).)

The consumption of high-fructose corn syrup (HFCS) has been increasing in recent decades, especially among children. Some reports suggest that children and adolescents are more sensitive to the adverse effects of fructose intake than adults. However, the underlying mechanism of the difference in vulnerability between adolescence and adulthood have not yet been elucidated. In this study, we attempted to elucidate the different effects of HFCS intake at different growth stages in rats: childhood and adolescence (postnatal day (PD) 21-60), young adulthood (PD60-100), and adulthood (PD100-140). Since alterations in hepatic glucocorticoid (GC) metabolism can cause diseases including insulin resistance, we focused on GC metabolizing enzymes such as 11 beta-hydroxysteroid dehydrogenase 1 and 2 (Hsd11b1 and Hsd11b2) and steroid 5 alpha-reductase 1 (Srd5a1). Western blotting showed an increase in Hsd11b1 expression and a decrease in Hsd11b2 expression in childhood and adolescence but not in adulthood. We also observed changes in Hsd11b1 and Hsd11b2 activities only in childhood and adolescence, consistent with the results of mRNA and protein expression analysis. The effect of high-fructose intake with regards to GC metabolism may therefore vary with developmental stage. This study provides insight into the adverse effects of fructose on GC metabolism in children in the context of increasing rates of HFCS consumption., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

The consumption of fructose as sugar and high-fructose corn syrup has markedly increased during the past several decades. This trend coincides with the exponential rise of metabolic diseases, including obesity, nonalcoholic fatty liver disease, cardiovascular disease, and diabetes. While the biochemical pathways of fructose metabolism were elucidated in the early 1990s, organismal-level fructose metabolism and its whole-body pathophysiological impacts have been only recently investigated. In this review, we discuss the history of fructose consumption, biochemical and molecular pathways involved in fructose metabolism in different organs and gut microbiota, the role of fructose in the pathogenesis of metabolic diseases, and the remaining questions to treat such diseases.

The dramatically increasing incidence and prevalence of inflammatory bowel disease (IBD) are reportedly related to a Western diet, which is characterized by high sugar consumption. Dietary simple sugars aggravate IBD in animal models. However, the mechanisms underlying this effect remain unclear. Given that high-fructose corn syrup (HFCS) is a major added sugar in food and beverages, we focus on HFCS and investigated the effects of HFCS on a dextran sulfate sodium (DSS)-induced murine colitis model and in RAW264.7 macrophages. Our data demonstrate that short-term consumption of HFCS aggravates colitis and upregulates the proportion of macrophages in IBD mice but not in healthy mice. We find that HFCS promotes proinflammatory cytokine production through reactive oxygen species (ROS)-mediated nuclear factor-κB (NF-κB) signaling in RAW264.7 macrophages. Furthermore, N-acetylcysteine (NAC), an ROS scavenger, alleviates HFCS-aggravated colitis in mice and inhibits the ROS-mediated NF-κB signaling pathway in RAW264.7 macrophages. Our work unveils the important role of macrophages in HFCS-induced exacerbation of colitis and reveals the mechanism of how HFCS immunologically aggravates IBD., (Copyright © 2022. Published by Elsevier B.V.)

Aims: This study aimed to analyze differences in sensitivity to hepatic lipid metabolism at different ages, through DNA methylation, using an experimental rat model of high-fructose corn syrup (HFCS) intake., Main Methods: The experimental was divided into three periods: childhood and adolescence (postnatal day (PD) 21-60), young adulthood (PD61-100), and adulthood (PD101-140). Rats in the different age groups were assigned to receive either water (C: control group) or 20% HFCS solution (H: HFCS-fed group). We measured hepatic mRNA levels of peroxisome proliferator-activated receptor alpha (Ppara), carnitine palmitoyltransferase 1A (Cpt1a), fatty acid synthase (Fasn), and peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (Pgc1a) using real-time PCR. Additionally, we examined the DNA methylation levels of Ppara, Cpt1a, Fasn, and Pgc1a using pyrosequencing., Key Findings: Gene expressions of Cpt1a and Ppara in childhood and adolescence were significantly lower in the H group than in the C group. Conversely, Fasn and Pgc1a expressions were significantly higher in the H group than in the C group. Additionally, there was hypermethylation of Cpt1a and Ppara and hypomethylation of Fasn and Pgc1a in the H groups of childhood and adolescence. However, only one gene expression and methylation change was observed in young adulthood and adulthood groups. We found that HFCS intake in rats had stronger lipid metabolic effects in childhood and adolescence than in other generations, and that its mechanism involved epigenetic regulation., Significance: We anticipate that these research findings will be a breakthrough for elucidating the varying effects of growth stage in the future., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Consumption of fructose-containing beverages such as high-fructose corn syrup (HFCS) is increasing, raising concerns about the negative effects of excessive fructose intake. A recent report indicated that excess HFCS intake impairs hippocampal function. In this study, we focused on neurotrophic factors (NFs) in the hippocampus from the viewpoint of epigenetics to clarify the adverse effects of fructose. We analyzed the effects of HFCS intake on hippocampal function in three age categories: childhood and adolescence (postnatal day (PD) 21-60), young adulthood (PD60-100), and late adulthood (PD100-140). For the experiments, male Sprague-Dawley rats were divided into three age categories, the control group was received distilled water and the HFCS group was received 20% HFCS solution for 40 days in each period. We analyzed mRNA and protein levels for qPCR and western blotting, respectively, of a hippocampal NF, brain-derived neurotrophic factor (Bdnf). HFCS consumption reduced hippocampal Bdnf mRNA and protein expressions in childhood and adolescence. Moreover, pyrosequencing assays revealed increased DNA methylation at the Bdnf promoter in childhood and adolescence. This Bdnf levels reduction may be due to hypermethylation of the promoter regions. It should be noted that this phenomenon was observed only in childhood and adolescence fructose consumption. Our results indicate that the sensitivity of the hippocampus to fructose may vary with age. This study provides insight into the adverse effects of excessive HFCS consumption on the hippocampus in children., Competing Interests: The authors have declared that no competing interests exist.

There are concerns about the negative effects of fructose intake during pregnancy on the next generation. We have previously reported that offspring from dams fed with fructose during gestation and lactation demonstrate abnormal lipid metabolism in the liver. In this study, we aimed to elucidate the molecular mechanism of the effects of maternal high-fructose corn syrup (HFCS) consumption on offspring. Pregnant Sprague-Dawley rats were fed with 20% HFCS water solution during gestation and lactation. Offspring were put on a normal diet after weaning, and the serum parameters and gene expression patterns were studied at predetermined intervals. Offsprings from pregnant rats fed with 20% HFCS (HFCS group) developed insulin resistance and hyperlipidemia at 60 d of age. RNA-seq analysis demonstrated that peroxisome proliferator-activated receptor α (PPARα) expression is downregulated by maternal HFCS intake. Hepatic Pparα expression in the HFCS group appeared to be suppressed by the enhanced DNA methylation of its promoter region. It is suggested that the development of insulin resistance and hyperlipidemia in the HFCS group may be attributable to aberrant Pparα methylation in the offspring liver. Pparα hypermethylation may be one of molecular mechanism underlying the toxicity of maternal fructose intake., (Copyright © 2022. Published by Elsevier Inc.)

Increased hepatic lipid content and decreased insulin sensitivity have critical roles in the development of cardiometabolic diseases. Therefore, our objective was to investigate the dose-response effects of consuming high fructose corn syrup (HFCS)-sweetened beverages for two weeks on hepatic lipid content and insulin sensitivity in young (18-40 years) adults (BMI 18-35 kg/m 2 ). In a parallel, double-blinded study, participants consumed three beverages/day providing 0% (aspartame: n = 23), 10% ( n = 18), 17.5% ( n = 16), or 25% ( n = 28) daily energy requirements from HFCS. Magnetic resonance imaging for hepatic lipid content and oral glucose tolerance tests (OGTT) were conducted during 3.5-day inpatient visits at baseline and again at the end of a 15-day intervention. During the 12 intervening outpatient days participants consumed their usual diets with their assigned beverages. Significant linear dose-response effects were observed for increases of hepatic lipid content ( p = 0.015) and glucose and insulin AUCs during OGTT (both p = 0.0004), and for decreases in the Matsuda ( p = 0.0087) and Predicted M ( p = 0.0027) indices of insulin sensitivity. These dose-response effects strengthen the mechanistic evidence implicating consumption of HFCS-sweetened beverages as a contributor to the metabolic dysregulation that increases risk for nonalcoholic fatty liver disease and type 2 diabetes.

The aim of the study was to evaluate whether high-fructose corn syrup (HFCS) intake (20% beverages) impacts antioxidative structures and inflammation in the gingival tissue and masseter muscle of rats. Kefir was tested for its potential utility on changes induced by HFCS. Animals were randomly divided into four groups as control, kefir, HFCS, and HFCS plus kefir. HFCS was given as 20% solutions in drinking water while kefir supplementations were given by gastric gavage for 8 weeks. It has been clearly determined that the HFCS diet increased expressions of interleukin (IL)-6, IL-1β, and tumor necrosis factor-α proinflammatory structures via lymphocyte infiltration by suppressing antioxidant enzymes such as catalase, superoxide dismutase, and glutathione peroxidase in both tissues. Kefir improved these undesirable changes in rats fed with HFCS. The results of this current study, the first investigation to examine the effects of kefir on masseter muscle and gingival tissue, may provide new access to the restorative effects of kefir consumption on oral health disorders caused by high fructose in the diet. PRACTICAL APPLICATIONS: In this study, at an early age, the effects of kefir on improving inflammation via antioxidation in the masseter muscle and gingival tissue were investigated for the first time. We showed that kefir feeding ameliorates lymphocyte infiltration on the high-fructose corn syrup (HFCS)-induced masseter muscle and gingival tissue inflammation in rats. The mRNA expressions of inflammatory parameters measured in the study were supported by protein measurements via ELISA or immunohistochemistry. In the present study, kefir may play an important role in the antioxidation and inflammation process on the masseter muscle and gingival tissue against HFCS., (© 2021 Wiley Periodicals LLC.)

The metabolic syndrome (MetS) has become a global public health burden due to its link to cardiovascular disease and diabetes mellitus. The present study was designed to characterize the metabolic and cardiovascular disturbances, as well as changes in gut microbiota associated with high-fructose high-fat diet (HFFD)-induced MetS in Watanabe heritable hyperlipidemic (WHHL) rabbits. Twenty-one Watanabe rabbits were assigned to a control (n = 9) and HFFD (n = 12) groups, receiving a chow diet and a HFFD, respectively. During a 12-weeks protocol, morphological parameters were monitored; plasma fasting levels of lipids, glucose and insulin were measured and a glucose tolerance test (GTT) was performed. HOMA-IR was calculated. Cardiac function and vascular reactivity were evaluated using the Langendorff isolated heart and isolated carotid arteries methods, respectively. 16S rRNA sequencing of stool samples was used to determine gut microbial composition and abundance. HFFD-fed Watanabe rabbits exhibited increased fasting insulin (p < 0.03, 12th week vs. Baseline), HOMA-IR (p < 0.03 vs. Control), area under the curve of the GTT (p < 0.02 vs. Control), triglycerides (p < 0.05, 12th week vs. Baseline), TC (p < 0.01 vs. Control), LDL-C (p < 0.001 vs. Control). The HFFD group also displayed a significant decrease in intestinal microbial richness, evenness and diversity (FDR < 0.001, FDR < 0.0001, FDR < 0.01, respectively vs. Control group) and an increase in its Firmicutes/Bacteroidetes ratio (R = 3.39 in control vs. R = 28.24 in the HFFD group) indicating a shift in intestinal microbial composition and diversity. Our results suggest that HFFD induces insulin resistance and gut microbiota dysbiosis and accentuates dyslipidemia; and that, when subjected to HFFD, Watanabe rabbits might become a potential diet-induced MetS animal models with two main features, dyslipidemia and insulin resistance., Competing Interests: The authors have declared that no competing interests exist.

Fructose ingestion elicits a diversity of brain alterations, but it is unknown how it affects N-methyl-D-Aspartate receptors (NMDAr). Here, we analyzed the expression of NMDAr subunits and protein kinases after the long-term dietary fructose intake. Since NMDAr are related to epileptogenesis, we also examined whether fructose increases the susceptibility to seizures after the microinjection of kainic acid (KA) in the rat hippocampus. Wistar rats were randomly divided into water (control) and fructose groups. For twelve weeks, groups had ad libitum access to water or fructose solution (10% w/v). After treatment, hippocampal protein expression of NMDAr subunits and protein kinases involved in NMDAr regulation were analyzed. Additionally, electroencephalographic and behavioral changes related to seizures were evaluated after the microinjection of a sub-convulsive dose of KA in the hippocampus. Fructose induced the decrease of NR1 and, conversely, the increase of NR2A subunits expression in the hippocampus. Also, the phosphorylation of protein kinase C alpha (PKCα) and c-Src increased significantly. No electroencephalographic or behavioral patterns related to convulsive motor seizures were observed in the control group. However, all the rats that ingested fructose showed stage 3 seizures (forelimb clonus) and a significant increase in the number of wet-dog shakes. Moreover, electroencephalographic recordings revealed pronounced epileptiform activity and increased total spectral power at 30 and 60 min after the microinjection of KA. This study shows for the first time that fructose intake exacerbates the seizures induced by KA. Therefore, we propose that this proconvulsant effect could be mediated by changes in NMDAr subunits expression and increased activation of kinases modulating NMDAr function., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Adolescence is a critical period of development, during which the brain undergoes rapid maturation. Problematically, adolescents are the top consumers of high fructose corn syrup (HFCS) sweetened beverages and snacks, which may have neurodevelopmental consequences. While HFCS consumption has been linked to an increased likelihood of obesity and other physical health impairments, the link between HFCS and persistent behavioral changes is not yet fully established. The present study aimed to assess whether adolescent HFCS consumption could lead to alterations in adult behaviors and protein expression, following cessation. Adolescent HFCS-exposure contributed to deficits in learning and motivation on an effort-related T-Maze procedure, as well as increased immobility time in the forced swim paradigm during adulthood. Molecularly, protracted decreases in accumbal dopamine D1 and D2 receptors and protein kinase G (PKG), as well as increases in tyrosine hydroxylase and GluA2 receptor subunits, were observed following HFCS-exposure. Taken together, these data suggest that adolescent HFCS-consumption leads to protracted dysfunction in affective behaviors and alterations in accumbal proteins which persist following cessation of HFCS-consumption., (Copyright © 2021 Elsevier B.V. All rights reserved.)

The consumption of fructose has increased in children and adolescents and is partially responsible for the high incidence of metabolic diseases. The lifestyle during postnatal development can result in altered metabolic programming, thereby impairing the reproductive system and fertility during adulthood. Therefore, the aim of this study was to evaluate the effect of a high-fructose diet in the male reproductive system of pubertal and adult rats. Male Wistar rats (30 d old) were assigned to four different groups: Fr30, which received fructose (20%) in water for 30 d and were euthanized at postnatal day (PND) 60; Re-Fr30, which received fructose (20%) for 30 d and were euthanized at PND 120; and two control groups C30 and Re-C30, which received water ad libitum and were euthanized at PND 60 and 120, respectively. Fructose induced an increase in abnormal seminiferous tubules with epithelial vacuoles, degeneration, and immature cells in the lumen. Moreover, Fr30 rats showed altered spermatogenesis and daily sperm production (DSP), as well as increased serum testosterone concentrations. After discontinuing high-fructose consumption, DSP and sperm number decreased significantly. We observed tissue remodeling in the epididymis, with a reduction in stromal and epithelial compartments that might have influenced sperm motility. Therefore, we concluded that fructose intake in peripubertal rats led to changes in the reproductive system observed both during puberty and adulthood.

Aims: This study was designed to reveal the effect of probiotics and omega-3 fatty acids in a fatty liver model in rats induced by high-fructose corn syrup (HFCS)., Methods: In the study, 40 male Wistar Albino rats were used, and these rats were divided into five groups. HFCS was added to the drinking water (30% solution) of four groups (Groups 2, 3, 4, and 5) for three weeks, and the animals were fed ad libitum. At the end of three weeks, the rats in Groups 3, 4, and 5 were administered omega-3 fatty acids (400 mg/kg) and probiotics (1.5 × 10 9  cfu/mL/day) with the gavage method for four weeks. The body weights of rats were weighed and recorded before starting the experiment, at the end of the third week, and before the animals were sacrificed at the last week, all at the same hour. By subtracting the remaining amount of food and water from the daily food and water amount, the amount of food and water consumed was calculated. These values were recorded for seven weeks. At the end of the seven weeks, the rats were sacrificed after blood specimens and tissues were taken., Results: Analyzing the changes in the food intake of each group within itself throughout the experiment, it was observed that there was an increase in the food intake in the control group; from the starting week to the last week, the food intake amount of the HFCS group began to decrease particularly after the second week; and it began to decrease after the third week in the groups that were administered probiotics and omega-3 fatty acids. The changes in the sacrifice weights in the HFCS + omega-3 fatty acid, HFCS + probiotic, and HFCS + probiotic + omega-3 fatty acid groups were found to be lower than that in the HFCS group. The maximum levels of glucose, ALT, ALP, serum cholesterol, triglyceride and AST were found to be in the HFCS group. It was determined that the minimum mean steatosis level was in the control group, while the maximum steatosis level was in the HFCS group., Conclusions: As a result, there was a protective effect of probiotic and omega-3 fatty acid., Competing Interests: The authors declare no conflicts of interest regarding this study., (Copyright © 2022 Nildem Kizilaslan et al.)

Introduction: Dietary high fructose corn syrup (HFCS) is involved in the pathogenesis of oral diseases as well as metabolic diseases. The aim of this study was to investigate the effects of HFCS-feeding on the craniomandibular bone development at an early age and also the potential of milk kefir for preventive treatment., Materials and Methods: In this study, Control, Kefir, HFCS, and HFCS plus Kefir groups were formed; kefir was given by gastric gavage, while HFCS (20% beverages) was given in drinking water; for 8 weeks., Results: Based on morphological evaluations, immunohistochemical, and gene expression results, it was clearly determined that excess dose of HFCS consumption decreased osteoblastic activity in craniomandibular bones while increasing osteoclastic activity. However, it has been determined that the intake of kefir with the HFCS-feeding greatly suppresses the effects of HFCS on bone tissues., Conclusion: In conclusion, dietary the excess dose of HFCS at an early age has been observed to pose a risk for cranial and mandible bone development. The healing effects of kefir may be a new approach to the treatment via kefir consumption in young's., (© 2021. The Japanese Society Bone and Mineral Research.)

Glucose and fructose are closely related simple sugars, but fructose has been associated more closely with metabolic disease. Until the 1960s, the major dietary source of fructose was fruit, but subsequently, high-fructose corn syrup (HFCS) became a dominant component of the Western diet. The exponential increase in HFCS consumption correlates with the increased incidence of obesity and type 2 diabetes mellitus, but the mechanistic link between these metabolic diseases and fructose remains tenuous. Although dietary fructose was thought to be metabolized exclusively in the liver, evidence has emerged that it is also metabolized in the small intestine and leads to intestinal epithelial barrier deterioration. Along with the clinical manifestations of hereditary fructose intolerance, these findings suggest that, along with the direct effect of fructose on liver metabolism, the gut-liver axis plays a key role in fructose metabolism and pathology. Here, we summarize recent studies on fructose biology and pathology and discuss new opportunities for prevention and treatment of diseases associated with high-fructose consumption., Competing Interests: Declaration of interests M.K. holds US Patent No. 10034462 B2 on the use of MUP-uPA mice for the study of NASH and NASH-driven HCC. M.A.F. is a co-inventor of IC7Fc and hold patents for this molecule (US 60/920,822; WO/2008/119110 A1)., (Published by Elsevier Inc.)

Context: Studies in rodents and humans suggest that high-fructose corn syrup (HFCS)-sweetened diets promote greater metabolic dysfunction than sucrose-sweetened diets., Objective: To compare the effects of consuming sucrose-sweetened beverage (SB), HFCS-SB, or a control beverage sweetened with aspartame on metabolic outcomes in humans., Methods: A parallel, double-blinded, NIH-funded study. Experimental procedures were conducted during 3.5 days of inpatient residence with controlled feeding at a research clinic before (baseline) and after a 12-day outpatient intervention period. Seventy-five adults (18-40 years) were assigned to beverage groups matched for sex, body mass index (18-35 kg/m2), and fasting triglyceride, lipoprotein and insulin concentrations. The intervention was 3 servings/day of sucrose- or HFCS-SB providing 25% of energy requirement or aspartame-SB, consumed for 16 days. Main outcome measures were %hepatic lipid, Matsuda insulin sensitivity index (ISI), and Predicted M ISI., Results: Sucrose-SB increased %hepatic lipid (absolute change: 0.6 ± 0.2%) compared with aspartame-SB (-0.2 ± 0.2%, P < 0.05) and compared with baseline (P < 0.001). HFCS-SB increased %hepatic lipid compared with baseline (0.4 ± 0.2%, P < 0.05). Compared with aspartame-SB, Matsuda ISI decreased after consumption of HFCS- (P < 0.01) and sucrose-SB (P < 0.01), and Predicted M ISI decreased after consumption of HFCS-SB (P < 0.05). Sucrose- and HFCS-SB increased plasma concentrations of lipids, lipoproteins, and uric acid compared with aspartame-SB. No outcomes were differentially affected by sucrose- compared with HFCS-SB. Beverage group effects remained significant when analyses were adjusted for changes in body weight., Conclusion: Consumption of both sucrose- and HFCS-SB induced detrimental changes in hepatic lipid, insulin sensitivity, and circulating lipids, lipoproteins and uric acid in 2 weeks., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society.)

This study tested the hypotheses that compared to drinking water, consumption of a caffeinated soft drink sweetened with high-fructose corn syrup (HFCS) attenuates the cutaneous vasodilatory response to local skin heating without (Protocol 1) and following ischemia-reperfusion injury (Protocol 2). In a randomized, counterbalanced crossover design, 14 healthy adults (25 ± 3 year, 6 women) consumed 500 ml of water (water) or a caffeinated soft drink sweetened with HFCS (Mtn. Dew, DEW). Thirty minutes following beverage consumption local skin heating commenced on the right forearm (Protocol 1), while on the left forearm ischemia-reperfusion commenced with 20 min of ischemia followed by 20 min of reperfusion and then local skin heating (Protocol 2). Local skin heating involved 40 min of heating to 39℃ followed by 20 min of heating to 44℃. Skin blood flow (SkBf, laser Doppler) data were normalized to mean arterial pressure and are presented as a cutaneous vascular conductance (CVC) and as percentage of the CVC response during heating to 44℃ (%CVC max ). Protocol 1: During local heating at 39℃, no differences were observed in CVC (water: 2.0 ± 0.6 PU/mmHg; DEW: 2.0 ± 0.8 PU/mmHg, p = 0.83) or %CVC max (water: 59 ± 14%; DEW 60 ± 15%, p = 0.84) between trials. Protocol 2: During local skin heating at 39℃, no differences were observed in CVC (water: 1.7 ± 0.5 PU/mmHg; DEW: 1.5 ± 0.5 PU/mmHg, p = 0.33) or %CVC max (water: 64 ± 15%; DEW 61 ± 15% p = 0.62) between trials. The cutaneous microvascular vasodilator response to local heating with or without prior ischemia-reperfusion injury is not affected by acute consumption of a caffeinated soft drink sweetened with HFCS., (© 2021 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

High-fructose syrups are used as sugar substitutes due to their physical and functional properties. High fructose corn syrup (HFCS) is used in bakery products, dairy products, breakfast cereals and beverages, but it has been reported that there might be a direct relationship between high fructose intake and adverse health effects such as obesity and the metabolic syndrome. Thus, fructose has recently received much attention, most of which was negative. Although studies have indicated that there might be a correlation between high fructose-rich diet and several adverse effects, however, the results of these studies cannot be certainly generalised to the effects of HFCS; because they have investigated pure fructose at very high concentrations in measurement of metabolic upsets. This review critically considered the advantages and possible disadvantages of HFCS application and consumption in food industry, as a current challenging issue between nutritionists and food technologists.

Background: Fructose consumption has been linked to nonalcoholic fatty liver disease (NAFLD) in children. However, the effect of high-fructose corn syrup (HFCS) compared with sucrose in pediatric NAFLD has not been investigated., Objectives: We tested whether the isocaloric substitution of dietary sucrose by HFCS would increase the severity of NAFLD in juvenile pigs, and whether this effect would be associated with changes in gut histology, SCFA production, and microbial diversity., Methods: Iberian pigs, 53-d-old and pair-housed in pens balanced for weight and sex, were randomly assigned to receive a mash diet top-dressed with increasing amounts of sucrose (SUC; n = 3 pens; 281.6-486.8 g/kg diet) or HFCS (n = 4; 444.3-724.8 g/kg diet) during 16 wk. Diets exceeded the animal's energy requirements by providing sugars in excess, but met the requirements for all other nutrients. Animals were killed at 165 d of age after blood sampling, and liver, muscle, and gut were collected for histology, metabolome, and microbiome analyses. Data were analyzed by multivariate and univariate statistics., Results: Compared with SUC, HFCS increased subcutaneous fat, triacylglycerides in plasma, and butyrate in colon (P ≤ 0.05). In addition, HFCS decreased UMP and short-chain acyl carnitines in liver, and urea nitrogen and creatinine in serum (P ≤ 0.05). Microbiome analysis showed a 24.8% average dissimilarity between HFCS and SUC associated with changes in SCFA-producing bacteria. Body weight gain, intramuscular fat, histological and serum markers of liver injury, and circulating hormones, glucose, and proinflammatory cytokines did not differ between diets., Conclusions: Fructose consumption derived from HFCS promoted butyrate synthesis, triglyceridemia, and subcutaneous lipid deposition in juvenile Iberian pigs, but did not increase serum and histological markers of NAFLD compared with a sucrose-enriched diet. Longer studies could be needed to observe differences in liver injury among sugar types., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Society for Nutrition.)

In healthy humans, fructose-sweetened water consumption increases blood pressure variability (BPV) and decreases spontaneous cardiovagal baroreflex sensitivity (cBRS) and heart rate variability (HRV). However, whether consuming commercially available soft drinks containing high levels of fructose elicits similar responses is unknown. We hypothesized that high-fructose corn syrup (HFCS)-sweetened soft drink consumption increases BPV and decreases cBRS and HRV to a greater extent compared with artificially sweetened (diet) and sucrose-sweetened (sucrose) soft drinks and water. Twelve subjects completed four randomized, double-blinded trials in which they drank 500 mL of water or commercially available soft drinks matched for taste and caffeine content. We continuously measured beat-to-beat blood pressure (photoplethysmography) and R-R interval (ECG) before and 30 min after drink consumption during supine rest for 5 min during spontaneous and paced breathing. BPV was evaluated using standard deviation (SD), average real variability (ARV), and successive variation (SV) methods for systolic and diastolic blood pressure. cBRS was assessed using the sequence method. HRV was evaluated using the root mean square of successive differences (RMSSD) in R-R interval. There were no differences between conditions in the magnitude of change from baseline in SD, ARV, and SV ( P ≥ 0.07). There were greater reductions in cBRS during spontaneous breathing in the HFCS (-3 ± 5 ms/mmHg) and sucrose (-3 ± 5 ms/mmHg) trials compared with the water trial (+1 ± 5 ms/mmHg, P < 0.03). During paced breathing, HFCS evoked greater reductions in RMSSD compared with water (-26 ± 34 vs. +2 ± 26 ms, P < 0.01). These findings suggest that sugar-sweetened soft drink consumption alters cBRS and HRV but not BPV.

Key Points: The prevalence of obesity and non-alcoholic fatty liver disease in children is dramatically increasing at the same time as consumption of foods with a high sugar content. Intake of high fructose corn syrup (HFCS) is a possible aetiology as it is thought to be more lipogenic than glucose. In a mouse model, HFCS intake during adolescence increased fat mass and hepatic lipid levels in male and female mice. However, only males showed impaired glucose tolerance. Multiple metabolites including lipids, bile acids, carbohydrates and amino acids were altered in liver in a sex-specific manner at 6 weeks of age. Some of these changes were also present in adulthood even though HFCS exposure ended at 6 weeks. HFCS significantly altered the gut microbiome, which was associated with changes in key microbial metabolites. These results suggest that HFCS intake during adolescence has profound metabolic changes that are linked to changes in the microbiome and these changes are sex-specific., Abstract: The rapid increase in obesity, diabetes and fatty liver disease in children over the past 20 years has been linked to increased consumption of high fructose corn syrup (HFCS), making it essential to determine the short- and long-term effects of HFCS during this vulnerable developmental window. We hypothesized that HFCS exposure during adolescence significantly impairs hepatic metabolic signalling pathways and alters gut microbial composition, contributing to changes in energy metabolism with sex-specific effects. C57bl/6J mice with free access to HFCS during adolescence (3-6 weeks of age) underwent glucose tolerance and body composition testing and hepatic metabolomics, gene expression and triglyceride content analysis at 6 and 30 weeks of age (n = 6-8 per sex). At 6 weeks HFCS-exposed mice had significant increases in fat mass, glucose intolerance, hepatic triglycerides (females) and de novo lipogenesis gene expression (ACC, DGAT, FAS, ChREBP, SCD, SREBP, CPT and PPARα) with sex-specific effects. At 30 weeks, HFCS-exposed mice also had abnormalities in glucose tolerance (males) and fat mass (females). HFCS exposure enriched carbohydrate, amino acid, long chain fatty acid and secondary bile acid metabolism at 6 weeks with changes in secondary bile metabolism at 6 and 30 weeks. Microbiome studies performed immediately before and after HFCS exposure identified profound shifts of microbial species in male mice only. In summary, short-term HFCS exposure during adolescence induces fatty liver, alters important metabolic pathways, some of which continue to be altered in adulthood, and changes the microbiome in a sex-specific manner., (© 2021 The Authors. The Journal of Physiology © 2021 The Physiological Society.)

It is known that dietary habits have a strong influence on body metabolism. In the last decades, the dietary habits have changed worldwide, and the consumption of fructose, especially in sugar-sweetened beverages, increased significantly. In this perspective, the present review aimed to summarize the effects of fructose on different cardiometabolic conditions. Clinical, experimental, and epidemiological studies evidenced that fructose can exert several deleterious effects when its consumption is above the recommended amounts. The increased fructose consumption decreases satiety, favoring a positive energy balance, increases adipogenesis, leading to visceral fat accumulation, induces ectopic fat accumulation, especially in the skeletal muscle and liver, leading to insulin resistance, inflammation, and lipid metabolism impairment, increases arterial blood pressure and causes vascular damage. Therefore, increased fructose consumption is linked to the development of alarming cardiometabolic conditions, such as obesity, insulin resistance, type 2 diabetes, non-alcoholic fatty liver disease, and cardiovascular diseases, through several different mechanisms. Further clinical and experimental studies are still necessary to elucidate additional signaling pathways and mechanisms by which fructose is involved in all the mentioned cardiometabolic disorders. Also, the reported findings raise the need for the creation of public health policies aimed to prevent diet-associated cardiometabolic disorders, thus improving the population quality of life., Competing Interests: Declaration of competing interest None., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Excessive sugar intake including high-fructose corn syrup (HFCS) is implicated in the rise of obesity, insulin resistance and non-alcoholic fatty liver disease. Liver glycogen synthesis is influenced by both fructose and insulin signaling. Therefore, the effect of HFCS on hepatic glycogenesis was evaluated in mice feeding ad-libitum. Using deuterated water: the fraction of glycogen derived from triose-P sources, Krebs cycle substrates, and direct pathway + cycling, was measured in 9 normal-chow fed mice (NC) and 12 mice fed normal chow plus a 55% fructose/45% glucose mix in the drinking water at 30% w/v (HFCS-55). This was enriched with [U- 13 C]fructose or [U- 13 C]glucose to determine the contribution of each to glycogenesis. For NC, direct pathway + cycling, Krebs cycle, and triose-P sources accounted for 66 ± 0.7%, 23 ± 0.8% and 11 ± 0.4% of glycogen synthesis, respectively. HFCS-55 mice had similar direct pathway + cycling (64 ± 1%) but lower Krebs cycle (12 ± 1%, p < 0.001) and higher triose-P contributions (24 ± 1%, p < 0.001). HFCS-55-fructose contributed 17 ± 1% via triose-P and 2 ± 0% via Krebs cycle. HFCS-55-glucose contributed 16 ± 3% via direct pathway and 1 ± 0% via Krebs cycle. In conclusion, HFCS-55 supplementation resulted in similar hepatic glycogen deposition rates. Indirect pathway contributions shifted from Krebs cycle to Triose-P sources reflecting HFCS-55-fructose utilization, while HFCS-55-glucose was incorporated almost exclusively by the direct pathway.

Background: Recent research provides consistent evidence that the unexplained doubling of childhood asthma prevalence (1980-1995), its continued climb and 2013 plateau, may be associated with the proliferation of high-fructose-corn-syrup (HFCS) in the US food supply. The HFCS used in soft drinks has been shown to contain a higher fructose-to-glucose ratio than previously thought. This coincides with a preference shift from orange to apple juice among young children. Apple juice naturally contains a high (≥2:1) fructose-to-glucose ratio. Thus, children have received high excess-free-fructose doses, the fructose type associated with fructose malabsorption. Unabsorbed excess-free-fructose in the gut may react with dietary proteins to form immunogens that bind asthma mediating receptors, and/or alter the microbiota towards a profile linked to lung disorders. Studies with longitudinal childhood data are lacking. Therefore, we tested the hypothesis that excess-free-fructose intake is associated with childhood asthma risk., Methods: Cox regression models were used to analyze prospective early childhood data (12-30 months of age) from the National Children's Study. Intake frequencies for soda/sports/fruit drinks, and 100% juices were used for analyses., Results: Greater consumption of 100% juice, soda/sports/fruit drinks, and any combination, was associated with ~two (P = 0.001), ~ 2.5 (P = 0.001), and ~ 3.5 times (P < 0.0001) higher asthma incidence., Conclusions: Given these results, prior research and case-study evidence, it is reasonable to suggest that the two-fold higher asthma risk associated with 100% juice consumption is due to apple juice's high fructose-to-glucose ratio, and that the ~ 2.5/~ 3.5 times higher risk associated with soda/sports/fruit drinks intake is with the excess-free-fructose in HFCS.

The incidence of metabolic diseases, such as type 2 diabetes, has increased steadily worldwide. Diet, beverages, and food texture can all markedly influence these metabolic disorders. However, the combined effects of food texture and beverages on energy metabolism remains unclear. In the present study, we examined the effect of food texture on energy metabolism in mice administered high-fructose corn syrup (HFCS). Mice were fed a soft or hard diet along with 4.2% HFCS or tap water. Body weight and total caloric intake were not affected by food texture irrespective of HFCS consumption. However, caloric intake from HFCS (i.e., drinking volume) and diet were higher and lower, respectively, in the hard food group than in the soft food group. The hard food group's preference for HFCS was absent in case of mice treated with the μ-opioid receptor antagonist naltrexone. Despite increased HFCS consumption, blood glucose levels were lower in the hard-diet group than in the soft-diet group. In HFCS-fed mice, insulin levels after glucose stimulation and insulin content in the pancreas were higher in the hard food group than the soft food group, whereas insulin tolerance did not differ between the groups. These food texture-induced differences in glucose tolerance were not observed in mice fed tap water. Thus, food texture appears to affect glucose tolerance by influencing pancreatic β-cell function in HFCS-fed mice. These data shed light on the combined effects of eating habits and food texture on human health., Competing Interests: The authors declare no competing financial interests.

Skin health is vital for a healthy body. Herbal remedies have long been used for skin care, and their global use has tremendously increased over the past three decades. Although cellulite is seen as a normal condition by the medical community, it is considered a serious cosmetic concern for most affected women. Many topical anti-cellulite creams are available on the market, but unfortunately, their efficacy has not been proven scientifically. Microneedles (MNs) represent a new approach to enhance the permeation of loaded medication through the skin. In this study, the anti-cellulite effects of Vitex agnus-castus and Tamarindus indica extracts were compared using safe and effective polymeric MNs. This delivery system offers a painless alternative to the combined treatment strategy of microneedling devices and anti-cellulite products. The selected standardized extracts were evaluated for their mineral, phenolic and flavonoid contents, which are correlated to a promising antioxidant effect, as demonstrated by an in vitro radical scavenging activity assay. 3D-printing techniques were chosen for fabrication of a micromold, which is inexpensive for mass production. To ensure that MNs were sufficiently strong to perforate the skin without breaking, axial failure force was measured using a micro-mechanical test machine. The anticellulite effects of MNs were assessed using an in vivo diet-induced obesity guinea pig model. Skin properties, histopathology and inflammatory markers were examined. MNs loaded with plant extracts were statistically comparable in normalizing the oxidative state and reducing inflammation, while myeloperoxidase levels were more significantly reduced by T. indica than by V. agnus-castus. This novel delivery system opens the door for new transdermal strategies for cellulite management.

We first tested the hypothesis that consuming a high-fructose corn syrup (HFCS)-sweetened soft drink augments kidney vasoconstriction to sympathetic stimulation compared with water ( study 1 ). In a second study, we examined the mechanisms underlying these observations ( study 2 ). In study 1 , 13 healthy adults completed a cold pressor test, a sympathoexcitatory maneuver, before (preconsumption) and 30 min after drinking 500 mL of decarbonated HFCS-sweetened soft drink or water (postconsumption). In study 2 , venous blood samples were obtained in 12 healthy adults before and 30 min after consumption of 500 mL water or soft drinks matched for caffeine content and taste, which were either artificially sweetened (Diet trial), sucrose-sweetened (Sucrose trial), or sweetened with HFCS (HFCS trial). In both study 1 and study 2 , vascular resistance was calculated as mean arterial pressure divided by blood velocity, which was measured via Doppler ultrasound in renal and segmental arteries. In study 1 , HFCS consumption increased vascular resistance in the segmental artery at rest (by 0.5 ± 0.6 mmHg·cm -1 ·s -1 , P = 0.01) and during the cold pressor test (average change: 0.5 ± 1.0 mmHg·cm -1 ·s -1 , main effect: P = 0.05). In study 2 , segmental artery vascular resistance increased in the HFCS trial (by 0.8 ± 0.7 mmHg·cm -1 ·s -1 , P = 0.02) but not in the other trials. Increases in serum uric acid were greater in the HFCS trial (0.3 ± 0.4 mg/dL, P ≤ 0.04) compared with the Water and Diet trials, and serum copeptin increased in the HFCS trial (by 0.8 ± 1.0 pmol/L, P = 0.06). These findings indicate that HFCS acutely increases vascular resistance in the kidneys, independent of caffeine content and beverage osmolality, which likely occurs via simultaneous elevations in circulating uric acid and vasopressin.

Metabolic syndrome (MetS) is a combination of risk factors that include insulin resistance, obesity, dyslipidemia, and hypertension. The consumption of high-fructose diets contributes to the development of MetS. β -sitosterol a naturally occurring phytosterol possesses antiobesogenic and antidiabetic effects. This study evaluated the potential protective effect of β -sitosterol against the development of metabolic dysfunction in growing female rats fed a high-fructose diet, mimicking children fed obesogenic diets. Thirty-five 21-day-old female Sprague Dawley rat pups were randomly allocated to and administered the following treatments: group 1-standard rat chow (SRC) + plain drinking water (PW) + plain gelatine cube (PC); group 2-SRC + 20% w/w fructose solution (FS) as drinking fluid + PC; group 3-SRC + FS + 100 mg/kg fenofibrate in gelatine cubes; group 4-SRC + FS + 20 mg/kg β -sitosterol gelatine cube (Bst); and group 5-SRC + PW + Bst. Following 12 weeks of feeding, the rats were fasted overnight, weighed, and then euthanized. Plasma cholesterol, insulin, glucose, triglyceride, and adiponectin concentrations were determined. Visceral fat was dissected out and weighed. The high-fructose diet increased ( P  < .05) visceral adiposity and plasma triglyceride concentration but decreased ( P  < .05) plasma adiponectin concentration. β -sitosterol prevented the high-fructose diet-induced visceral obesity, hypertriglyceridemia, and hypoadiponectinemia. β -sitosterol alone increased plasma adiponectin concentration and reduced plasma insulin concentration and homeostatic model assessment index. In conclusion, β -sitosterol could be potentially used to prevent high-fructose diet-induced metabolic dysfunction.

Background: The health of honeybee colonies is critical for bee products and agricultural production, and colony health is closely associated with the bacteria in the guts of honeybees. Although colony loss in winter is now the primary restriction in beekeeping, the effects of different sugars as winter food on the health of honeybee colonies are not well understood. Therefore, in this study, the influence of different sugar diets on honeybee gut bacteria during overwintering was examined., Results: The bacterial communities in honeybee midguts and hindguts before winter and after bees were fed honey, sucrose, and high-fructose syrup as winter-food were determined by targeting the V3-V4 region of 16S rDNA using the Illumina MiSeq platform. The dominant microbiota in honeybee guts were the phyla Proteobacteria (63.17%), Firmicutes (17.61%; Lactobacillus, 15.91%), Actinobacteria (4.06%; Bifidobacterium, 3.34%), and Bacteroidetes (1.72%). The dominant taxa were conserved and not affected by season, type of overwintering sugar, or spatial position in the gut. However, the relative abundance of the dominant taxa was affected by those factors. In the midgut, microbial diversity of the sucrose group was higher than that of the honey and high-fructose syrup groups, but in the hindgut, microbial diversity of the honey and high-fructose groups was higher than that in the sucrose group. Sucrose increased the relative abundance of Actinobacteria (Bifidobacteriales Bifidobacteriaceae) and Alphaproteobacteria (Rhizobiales and Mitochondria) of honeybee midgut, and honey enriched the Bacteroidetes and Gammaproteobacteria (Pasteurellales) in honeybee hindgut. High-fructose syrup increased the relative abundance of Betaproteobacteria (Neisseriales: Neisseriaceae) of the midgut., Conclusion: The type of sugar used as winter food affected the relative abundance of the dominant bacterial communities in honeybee guts, not the taxa, which could affect the health and safety of honeybee colonies during overwintering. The presence of the supernal Alphaproteobacteria, Bifidobacteriales, and Lactobacillaceae in the gut of honeybees fed sucrose and cheaper than honey both indicate that sucrose is very suitable as the overwintering food for honeybees.

There is compelling evidence that a hypercaloric, high-fructose diet can cause metabolic syndrome (MetS) and a whole range of other metabolic changes. In the context of androgen deficiency, MetS in boys merits special attention, but the effects of fructose-rich diet in youth on future male reproductive function are still poorly evidenced. The aim of this study was to address this issue and analyse the effects of high-fructose intake starting from weaning to puberty (postnatal day 23 up to 83) on the reproductive function of male rats. For this purpose juvenile male Wistar rats were divided in two groups: control and the group receiving 10 % fructose solution instead of drinking water. Reproductive function was evaluated in terms of fertility, sperm count, testes/epididymis morphology, and serum sex hormones. The fructose-treated group showed a decrease in testosterone and twofold increase in luteinising and follicle-stimulating hormone levels in the serum. This was accompanied with lower testis/epididymis weights, sperm count, and changed testis/epididymis morphology. Their fertility remained unchanged, but the fertility of females mating with these males diminished. In addition, pre-implantation and post-implantation embryonic death rate rose in these females. Our results have confirmed that high fructose consumption from early age until puberty can impair the reproductive function of male rats, and call for further animal and epidemiological investigation.

Nuclear factor-erythroid 2 related factor 2 (Nrf2)-mediated signaling plays a central role in maintaining cellular redox homeostasis of hepatic cells. Carbon monoxide releasing molecule-A1 (CORM-A1) has been reported to stimulate up-regulation and nuclear translocation of Nrf2 in hepatocytes. However, the role of CORM-A1 in improving lipid metabolism, antioxidant signaling and mitochondrial functions in nonalcoholic steatohepatitis (NASH) is unknown. In this study, we report that CORM-A1 prevents hepatic steatosis in high fat high fructose (HFHF) diet fed C57BL/6J mice, used as model of NASH. The beneficial effects of CORM-A1 in HFHF fed mice was associated with improved lipid homeostasis, Nrf2 activation, upregulation of antioxidant responsive (ARE) genes and increased ATP production. As, mitochondria are intracellular source of reactive oxygen species (ROS) and important sites of lipid metabolism, we further investigated the mechanisms of action of CORM-A1-mediated improvement in mitochondrial function in palmitic acid (PA) treated HepG2 cells. Cellular oxidative stress and cell viability were found to be improved in PA + CORM-A1 treated cells via Nrf2 translocation and activation of cytoprotective genes. Furthermore, in PA treated cells, CORM-A1 improved mitochondrial oxidative stress, membrane potential and rescued mitochondrial biogenesis thru upregulation of Drp1, TFAM, PGC-1α and NRF-1 genes. CORM-A1 treatment improved cellular status by lowering glycolytic respiration and maximizing OCR. Improvement in mitochondrial respiration and increment in ATP production in PA + CORM-A1 treated cells further corroborate our findings. In summary, our data demonstrate for the first time that CORM-A1 ameliorates tissue damage in steatotic liver via Nrf2 activation and improved mitochondrial function, thus, suggesting the anti-NASH potential of CORM-A1., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)