Search

Aspartame is the most common artificial sweetener and a famous sweet-taste receptor agonist. Macrophages are essential in the antibacterial system to maintain the stability of the intestinal environment. Recently, the sweet taste receptor has been found in macrophages. However, the effects of aspartame on macrophage phagocytosis in the gastrointestinal tract are little known. The current study sought to assess the influence of aspartame intake on the scavenging activity of mice to low-dose Escherichia coli infection and related mechanisms. Firstly, no inflammatory response or pathological injury was observed in the intestines of mice after oral administration of aspartame (25-100 mg/kg, i.g.) for 2 weeks. Subsequently, aspartame intake was found to enhance the scavenging activity of mice to low-dose E. coli infection. Similarly, aspartame dose-dependent strengthened the ability of RAW264.7 cells to phagocytose GFP-E.coli J96. Further mechanism evaluation reflected that aspartame could enhance macrophage phagocytosis, migration, and rearrangement via PLCβ-2/Ca 2+ /PKCβ/Rho A/ROCK1 pathway caused by sweet taste receptor activation. In conclusion, the present study, for the first time, demonstrated that aspartame could enhance the scavenging activity of mice to low-dose E. coli infection via strengthening macrophage phagocytic function through activating sweet taste receptor. It is then suggested that aspartame may affect the antibacterial activity of human gastrointestinal macrophages, and further studies need to validate these effects., (© 2024 Federation of American Societies for Experimental Biology.)

Objective: Excessive consumption of added sugars has been linked to the rise in obesity and associated metabolic abnormalities. Non-nutritive sweeteners (NNSs) offer a potential solution to reduce sugar intake, yet their metabolic safety remains debated. This study aimed to systematically assess the long-term metabolic effects of commonly used NNSs under both normal and obesogenic conditions., Methods: To ensure consistent sweetness level and controlling for the acceptable daily intake (ADI), eight weeks old C57BL/6 male mice were administered with acesulfame K (ace K, 535.25 mg/L), aspartame (411.75 mg/L), sucralose (179.5 mg/L), saccharin (80 mg/L), or steviol glycoside (Reb M, 536.25 mg/L) in the drinking water, on the background of either regular or high-fat diets (in high fat diet 60% of calories from fat). Water or fructose-sweetened water (82.3.gr/L), were used as controls. Anthropometric and metabolic parameters, as well as microbiome composition, were analyzed following 20-weeks of exposure., Results: Under a regular chow diet, chronic NNS consumption did not significantly affect body weight, fat mass, or glucose metabolism as compared to water consumption, with aspartame demonstrating decreased glucose tolerance. In diet-induced obesity, NNS exposure did not increase body weight or alter food intake. Exposure to sucralose and Reb M led to improved insulin sensitivity and decreased weight gain. Reb M specifically was associated with increased prevalence of colonic Lachnospiracea bacteria., Conclusions: Long-term consumption of commonly used NNSs does not induce adverse metabolic effects, with Reb M demonstrating a mild improvement in metabolic abnormalities. These findings provide valuable insights into the metabolic impact of different NNSs, aiding in the development of strategies to combat obesity and related metabolic disorders., Competing Interests: Declaration of competing interest None., (Copyright © 2024 The Authors. Published by Elsevier GmbH.. All rights reserved.)

Background and Objective: Aspartame (L-aspartyl L-phenylalanine methyl ester) is an artificial sweetener widely used as a sugar substitute. There are concerns regarding the effects of high aspartame doses on the kidney owing to oxidative stress; however, whether the maximum allowed dose of aspartame in humans affects the kidneys remains unknown. Therefore, in this study, we investigated whether the maximum allowed dose of aspartame in humans affects the kidneys., Methods: In this study, animals were fed a folate-deficient diet to mimic human aspartame metabolism. Eight-week-old ICR mice were divided into control (CTL), 40 mg/kg/day of aspartame-administered (ASP), folate-deficient diet (FD), and 40 mg/kg/day of aspartame-administered with a folate-deficient diet (FD + ASP) groups. Aspartame was administered orally for eight weeks. Thereafter, we evaluated aspartame's effect on kidneys via histological analysis., Results: There were no differences in serum creatinine and blood urea nitrogen levels between the CTL and ASP groups or between the FD and FD + ASP groups. There was no histological change in the kidneys in any group. The expression of superoxide dismutase and 4-hydroxy-2-nonenal in the kidney did not differ between the CTL and ASP groups or the FD and FD + ASP groups., Conclusion: Our findings indicate that the allowed doses of aspartame in humans may not affect kidney function or oxidative states., (© 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: Artificial sweeteners, used as sugar substitutes have found their ways into almost all the food items due to the notion that they are non-caloric. Aspartame is used in numerous food products throughout the world. The primary users of aspartame include diabetics and calorie conscious people who intend to limit their calorie intake., Methods: Female Swiss albino mice were divided into three groups (12 mice each) for the duration of 30 and 60 days consecutively. The treatment groups received 40 mg/kg b. w. aspartame orally. Hormone assays using ELISA and tissue histopathology have been performed along with the fertility assay to access the treatment outcomeon the fertility of treated mice in comparison to controls., Results: Present study reports that female mice treated with aspartame for 30 and 60 days showed significant reduction in body weight, relative organ weight of (liver and kidney) and gonadosomatic index. These changes were more significantly recorded in 60 days treatment group. Aspartame treated animals for 30 and 60 days showed duration-dependent decrease gonandotropins (follicle stimulating hormone and luteinizing hormone), and steroids (estradiol and progesterone). Moreover, severe histopathological changes, reduction in number of growing follicles, degenerative changes in follicular structure, corona radiata and zonagranulosa were also observed. Besides, histomorphological changes were also observed in the uterine structure including atrophic uterine endometrial glands, contracted endometrial lining, disruption of the endometrial structure and the shapes of blood vessels were also altered., Conclusion: Non-nutritive artificial sweeteners including aspartame negatively impact the function of ovaries and feedback mechanism of reproductive hormones by affecting the hypothalamic-pituitary-gonadal axis. In light of present findings the aspartame negatively impacted the reproductive system of female mice. More studies are required to identify the molecular mechanism and the pathways involved., (© 2023. BioMed Central Ltd., part of Springer Nature.)

The effects of consuming specific types of nonnutritive sweeteners (NNSs) on adiposity changes in children have remained inconsistent. In this study, we aimed to investigate the effects of the intake of different kinds of NNSs on long-term adiposity changes during pubertal growth. Furthermore, we examined the above relationships among different sexes, pubertal stages, and levels of obesity. A total of 1893 6-15-year-old adults were recruited and followed-up every 3 months. The NNS-FFQ (Food Frequency Questionnaire) was conducted and urine samples were collected to investigate the effects of the selected sweeteners, which included acesulfame potassium, aspartame, sucralose, glycyrrhizin, steviol glycosides, and sorbitol. Multivariate linear mixed-effects models were used to examine the relationship between NNS intake and body composition. The consumption of aspartame, sucralose, glycyrrhizin, stevioside, and sorbitol was associated with decreased fat mass and increased fat-free mass. In the highest tertile group, the effects of NNS consumption on fat mass corresponded to values of -1.21 (95% CI: -2.04 to -0.38) for aspartame, -0.62 (95% CI: -1.42 to 0.19) for sucralose, -1.26 (95% CI: -2.05 to -0.47) for glycyrrhizin, -0.90 (95% CI: -2.28 to 0.48) for stevioside, and -0.87 (95% CI: -1.67 to -0.08) for sorbitol, while the effects on fat-free mass corresponded to values of 1.20 (95% CI: 0.36 to -0.38) for aspartame, 0.62 (95% CI: -0.19 to 1.43) for sucralose, 1.27 (95% CI: 0.48 to 2.06) for glycyrrhizin, 0.85 (95% CI: -0.53 to 2.23) for stevioside, and 0.87 (95% CI: 0.08 to 1.67) for sorbitol. Particularly, aspartame and sorbitol revealed a dose-responsiveness effect. The above finding was more prominent among girls than boys. Moreover, fat mass was significantly reduced in normal-weight children who consumed a moderate amount of aspartame and a large amount of glycyrrhizin and sorbitol compared with obese children. In conclusion, the NNS-specific and sex-specific effects of long-term NNS consumption revealed associations of decreasing fat mass and increasing fat-free mass for children undergoing pubertal growth.

Due to a worldwide increase in obesity and metabolic disorders such as type 2 diabetes, synthetic sweeteners such as aspartame are frequently used to substitute sugar in the diet. Possible uncertainties regarding aspartame's ability to induce oxidative stress, amongst others, has led to the recommendation of a daily maximum dose of 40 to 50 mg per kg. To date, little is known about the effects of this non-nutritive sweetener on cellular lipid homeostasis, which, besides elevated oxidative stress, plays an important role in the pathogenesis of various diseases, including neurodegenerative diseases such as Alzheimer's disease. In the present study, treatment of the human neuroblastoma cell line SH-SY5Y with aspartame (271.7 µM) or its three metabolites (aspartic acid, phenylalanine, and methanol (271.7 µM)), generated after digestion of aspartame in the human intestinal tract, resulted in significantly elevated oxidative stress associated with mitochondrial damage, which was illustrated with reduced cardiolipin levels, increased gene expression of SOD1/2, PINK1, and FIS1, and an increase in APF fluorescence. In addition, treatment of SH-SY5Y cells with aspartame or aspartame metabolites led to a significant increase in triacylglycerides and phospholipids, especially phosphatidylcholines and phosphatidylethanolamines, accompanied by an accumulation of lipid droplets inside neuronal cells. Due to these lipid-mediating properties, the use of aspartame as a sugar substitute should be reconsidered and the effects of aspartame on the brain metabolism should be addressed in vivo.

Background: There has been an emerging concern that non-nutritive sweeteners (NNS) can increase the risk of cardiometabolic disease. Much of the attention has focused on acute metabolic and endocrine responses to NNS. To examine whether these mechanisms are operational under real-world scenarios, we conducted a systematic review and network meta-analysis of acute trials comparing the effects of non-nutritive sweetened beverages (NNS beverages) with water and sugar-sweetened beverages (SSBs) in humans. Methods: MEDLINE, EMBASE, and The Cochrane Library were searched through to January 15, 2022. We included acute, single-exposure, randomized, and non-randomized, clinical trials in humans, regardless of health status. Three patterns of intake were examined: (1) uncoupling interventions, where NNS beverages were consumed alone without added energy or nutrients; (2) coupling interventions, where NNS beverages were consumed together with added energy and nutrients as carbohydrates; and (3) delayed coupling interventions, where NNS beverages were consumed as a preload prior to added energy and nutrients as carbohydrates. The primary outcome was a 2 h incremental area under the curve (iAUC) for blood glucose concentration. Secondary outcomes included 2 h iAUC for insulin, glucagon-like peptide 1 (GLP-1), gastric inhibitory polypeptide (GIP), peptide YY (PYY), ghrelin, leptin, and glucagon concentrations. Network meta-analysis and confidence in the network meta-analysis (CINeMA) were conducted in R-studio and CINeMA, respectively. Results: Thirty-six trials involving 472 predominantly healthy participants were included. Trials examined a variety of single NNS (acesulfame potassium, aspartame, cyclamate, saccharin, stevia, and sucralose) and NNS blends (acesulfame potassium + aspartame, acesulfame potassium + sucralose, acesulfame potassium + aspartame + cyclamate, and acesulfame potassium + aspartame + sucralose), along with matched water/unsweetened controls and SSBs sweetened with various caloric sugars (glucose, sucrose, and fructose). In uncoupling interventions, NNS beverages (single or blends) had no effect on postprandial glucose, insulin, GLP-1, GIP, PYY, ghrelin, and glucagon responses similar to water controls (generally, low to moderate confidence), whereas SSBs sweetened with caloric sugars (glucose and sucrose) increased postprandial glucose, insulin, GLP-1, and GIP responses with no differences in postprandial ghrelin and glucagon responses (generally, low to moderate confidence). In coupling and delayed coupling interventions, NNS beverages had no postprandial glucose and endocrine effects similar to controls (generally, low to moderate confidence). Conclusions: The available evidence suggests that NNS beverages sweetened with single or blends of NNS have no acute metabolic and endocrine effects, similar to water. These findings provide support for NNS beverages as an alternative replacement strategy for SSBs in the acute postprandial setting.

Objective: This study aimed to determine changes in saliva secretion and subjective taste intensity during a sustained period with continuous gustatory stimulation., Design: Twenty-two healthy adults participated in this study. The selected taste solutions were aspartame, sucralose, and acesulfame potassium, which are nonnutritive sweeteners. The concentrations of sucralose1 and acesulfame potassium were set to show the same sweetness intensity as aspartame. Sucralose2 was twice the concentration of sucralose1. The solution was continuously fed into the oral cavity at a flow rate of 0.04 mL / min through a neck-worn precise infusion system. The salivary flow rate (g/min) after 10 min of intraoral water supply from the device was used as the baseline. Salivary flow rate, subjective taste intensity evaluated by the visual analog scale (VAS), and salivary flow rate relative to the baseline were recorded at 10, 30, 60, and 120 min after the start of the test., Results: In the aspartame, sucralose1, and sucralose2 groups, the salivary flow rate increased significantly from 10 min to 120 min after the start of the test when compared to the rate at baseline (p < 0.05). The relative salivary flow rate increased and the VAS value decreased significantly over time and were affected by the time factor (p < 0.001, p = 0.013, respectively) but not by the sweetener-group factor and the interaction effects., Conclusions: Continuous gustatory stimulation may maintain increased salivary production for a sustained period., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Objectives: The aim of this study was to determine the effects of regular exposure to certain low- or no-calorie sweeteners (LNCS) on glucose tolerance and glucagon-like peptide 1 (GLP-1) release in healthy individuals., Methods: It was designed as a randomized, single-blinded, controlled study. Healthy and normoglycemic adults who did not have regular consumption of LNCS were recruited. Participants underwent a 75-g oral glucose tolerance test (OGTT) at baseline and were randomly assigned to consume 330 mL water sweetened with saccharine, sucralose, or aspartame + acesulfame-K (Asp+Ace-K), or plain water for the control group, daily for 4 wk. Fasting plasma glucose, insulin, GLP-1, and glycated hemoglobin A 1c (HbA 1c ) levels and 1-h, 2-h, and 3-h plasma glucose and insulin levels during OGTT were obtained at baseline. The change in insulin sensitivity was assessed by both the Homeostatic Model Assessment Insulin Resistance (HOMA-IR) Index and the Matsuda Index. Anthropometric measurements and dietary intakes were determined at baseline. Baseline measurements were repeated at week 4., Results: Of the participants enrolled in the study, 42 (age, 21.24 ± 2.26 y; body mass index, 20.65 ± 2.88 kg/m 2 ) completed the 4-wk intervention period. There were no differences for glucose, insulin, GLP-1, or HbA 1c levels or HOMA-IR scores at baseline or at week 4 when compared with the control group. The area under the curve of mean glucose and insulin values during OGTT were also found to be similar between groups at baseline and week 4. There were also no effects of LNCS intake on body weight, body composition, and waist circumference., Conclusions: These results suggest that regular consumption of LNCS-sweetened water similar to doses consumed in daily life over 4 wk had no significant effect on glycemic response, insulin sensitivity, GLP-1 release, and body weight in healthy individuals. This trial was registered at www., Clinicaltrials: gov as NCT04904133., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Aspartame (Asp) and acesulfame-K (Ace-K) are nonnutritive sweeteners (NNSs) commonly used in combination to replace added sugars in reduced- or low-calorie foods and beverages. Despite Asp/Ace-K blends having negligible calories, their effects on appetite have not been reviewed systematically. We therefore undertook a systematic review and meta-analysis of the metabolic effects of Asp/Ace-K blends on energy intake (EI), subjective appetite scores, blood glucose, and the incretin hormones glucose-dependent insulinotropic peptide and glucagon-like peptide. MEDLINE, Web of Science, and Cochrane CENTRAL databases (Embase, PubMed, and CINAHL) were searched (May 2021) for randomized controlled trials (RCTs). Human RCTs using Asp/Ace-K blends compared with sugar and water controls were included, whereas isolated cell and animal studies were excluded. An overall 4829 publications were identified and 8 studies, including 274 participants, were retrieved for review. The Asp/Ace-K group's EI was significantly reduced compared with sugar [mean difference (MD): -196.56 kcal/meal; 95% CI: -332.01, -61.11 kcal/meal; P = 0.004] and water (MD: -213.42 kcal/meal; 95% CI: -345.4, -81.44 kcal/meal; P = 0.002). Meta-analysis of subjective appetite scores and incretins could not be undertaken due to inconsistencies in data reporting and insufficient data, respectively, but of the 4 studies identified, no differences were observed between Asp/Ace-K blends and controls. The Asp/Ace-K group's blood glucose was nonsignificantly reduced compared with sugar (MD: -1.48 mmol/L; 95% CI: -3.26, 0.3 mmol/L; P = 0.1) and water (MD: -0.08 mmol/L; 95% CI: -0.62, 0.47 mmol/L; P = 0.78). Lower EI in participants who were predominantly healthy and assigned to Asp/Ace-K blends could not be reliably attributed to changes in subjective appetite scores. Blood glucose and incretins were also generally not affected by Asp/Ace-K blends when compared with controls. Additional short- and long-term RCTs using NNSs and sugars at dietarily relevant levels are needed. This trial was registered at the International Prospective Register of Systematic Reviews (PROSPERO: CRD42017061015)., (© The Author(s) 2022. Published by Oxford University Press on behalf of the American Society for Nutrition.)

The main goal of this study was to investigate the molecular changes in pancreatic progenitor cells subject to high glucose, aspartame, and metformin in vitro. This scope of work glucose, aspartame, and metformin were exposed to pancreatic islet derived progenitor cells (PID-PCs) for 10 days. GLUT1's role in beta-cell differentiation was examined by using GLUT1 inhibitor WZB117. Insulin + cell ratio was measured by flow cytometry; the expression of beta-cell differentiation related genes was shown by RT-PCR; mitochondrial mass, mitochondrial ROS level, cytoplasmic Ca2 + , glucose uptake, and metabolite analysis were made fluorometrically and spectrophotometrically; and proteins involved in related molecular pathways were determined by western blotting. Findings showed that glucose or aspartame exposed cells had similar metabolic and gene expression profile to control PID-PCs. Furthermore, relatively few insulin + cells in aspartame treated cells were determined. Aspartame signal is transmitted through PLCβ2, CAMKK2 and LKB1 in PID-PCs. The most obvious finding of this study is that metformin significantly increased beta-cell differentiation. The mechanism involves suppression of the sweet taste signal's molecules T1R3, PLCβ2, cytoplasmic Ca +2 , and AKT in addition to the direct effect of metformin on mitochondria and AMPK, and the energy metabolism of PID-PCs is remodelled in the direction of oxidative phosphorylation. These findings are very important in terms of determining that metformin stimulates the mitochondrial remodeling and the differentiation of PID-PCs to beta-cells and thus it may contribute to the compensation step, which is the first stage of diabetes development., (© 2022. The Author(s) under exclusive licence to University of Navarra.)

Non-nutritive sweeteners (NNS) are commonly integrated into human diet and presumed to be inert; however, animal studies suggest that they may impact the microbiome and downstream glycemic responses. We causally assessed NNS impacts in humans and their microbiomes in a randomized-controlled trial encompassing 120 healthy adults, administered saccharin, sucralose, aspartame, and stevia sachets for 2 weeks in doses lower than the acceptable daily intake, compared with controls receiving sachet-contained vehicle glucose or no supplement. As groups, each administered NNS distinctly altered stool and oral microbiome and plasma metabolome, whereas saccharin and sucralose significantly impaired glycemic responses. Importantly, gnotobiotic mice conventionalized with microbiomes from multiple top and bottom responders of each of the four NNS-supplemented groups featured glycemic responses largely reflecting those noted in respective human donors, which were preempted by distinct microbial signals, as exemplified by sucralose. Collectively, human NNS consumption may induce person-specific, microbiome-dependent glycemic alterations, necessitating future assessment of clinical implications., Competing Interests: Declaration of interests E.S. is a scientific co-founder of DayTwo. E.E. is a scientific co-founder of DayTwo and BiomX, and a paid consultant to Hello Inside and Aposense. E.E. is a member of the Cell scientific advisory board., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Non-caloric artificial sweeteners are being widely used as safe table sugar substitutes with highly intensive sweetness but low calories. Previous studies have suggested that some of the sweeteners can alter the gut microbiota composition and promote horizontal transfer of antibiotic resistance genes across bacterial genera. However, little is known about whether these sweeteners could show antibiotic-like antimicrobial activity against bacteria, especially gut relevant bacteria. Whether they could affect evolutional trajectory of antibiotic resistance or tolerance in bacteria is also not clear yet. Here we investigated four commonly used artificial sweeteners (saccharin, sucralose, aspartame, and acesulfame potassium) against both Gram-negative (Escherichia coli and Klebsiella pneumoniae) and positive (Bacillus subtilis) strains. Results show that all four sweeteners exhibit antimicrobial effects on these strains. The antimicrobial mechanism is due to increased reactive oxygen species (ROS) and cell envelope damage. Compared to sucrose and glucose, the treatment of artificial sweeteners stimulates bacterial efflux pumps and promotes bacterial evolution of antibiotic tolerance. Collectively, our finding provides insights into roles of artificial sweeteners in the emergence of antibiotic tolerance and calls for a re-evaluation of risks due to their intensive usage., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Thirty-two male Wistar albino rats were chosen to test the possible protective role of antioxidants of the edible seaweed Sargassum vulgare as a functional food additive to alleviate oxidative stress and toxicity associated with consumption of the artificial sweetener 'aspartame (ASP)'. Biochemical and spleen histopathological analyses of the orally ASP-administrated rats, at a dose of 500 mg/kg for one week daily, showed different apoptotic and inflammatory patterns. Rats treated with ASP and then supplemented orally with the S. vulgare -MeOH extract, at a dose of 150 mg/kg for three consecutive weeks daily, showed significant positive reactions in all investigated assays related to ASP consumption. The protective and immune-stimulant efficacy of S. vulgare -MeOH extract, inferred from combating oxidative stress-induced lipid peroxidation, modulating the low levels of the endogenous antioxidant enzymes superoxide dismutase (SOD) and catalase (CAT) and of the thyroid hormones T3 and T4, attenuating the elevated levels of apoptotic CASP-3 and inflammatory biomarkers TNF-α and IL-6, as well as heat shock proteins (Hsp70), can be most likely ascribed to the synergistic effect of its potent antioxidant phenolics (mainly gallic, ferulic, salicylic, and chlorogenic, and p -coumaric acids) and flavonoids (rutin, kaempferol, and hesperidin). Mechanism of action of these natural antioxidants was discussed.

Repurposing existing drugs, as well as natural and artificial sweeteners for novel therapeutic indications could speed up the drug discovery process since numerous associated risks and costs for drug development can be surpassed. In this study, natural and artificial sweeteners have been evaluated by in silico and experimental studies for their potency to inhibit lipoxygenase enzyme, an enzyme participating in the inflammation pathway. A variety of different methods pinpointed that aspartame inhibits the lipoxygenase isoform 1 (LOX-1). In particular, "LOX-aspartame" complex, that was predicted by docking studies, was further evaluated by Molecular Dynamics (MD) simulations in order to assess the stability of the complex. The binding energy of the complex has been calculated after MD simulations using Molecular Mechanics/Generalized Born Surface Area (MM/GBSA) method. Furthermore, Quantum Mechanics/Molecular Mechanics (QM/MM) calculations have been applied for geometry optimization of the "enzyme-ligand" complex. After having fully characterized the "LOX-aspartame" complex in silico , followed in vitro biological assays confirmed that aspartame inhibits LOX-1 (IC 50 =50 ± 3.0 μΜ) and blocks its biological response. The atomic details of aspartame's interaction profile with LOX-1 were revealed through Saturation Transfer Difference (STD) NMR (Nuclear Magnetic Resonance). Finally, aspartame was also tested with Molecular Docking and Molecular Dynamics studies for its potent binding to a number of different LOX isoforms of many organisms, including human. The in silico methods indicated that aspartame could serve as a novel starting point for drug design against LOX enzyme. Communicated by Ramaswamy H. Sarma.

Aspartame (ASP) and sucralose (SUC) are non-nutritive sweeteners which are widely consumed worldwide. They are considered safe for human consumption, but their effects on certain physiological aspects, such as the lifespan or health status, of the organism have not yet been studied in depth and only limited data are available in the literature. The objectives of this study were to evaluate the effects of ASP and SUC on the lifespan and health indexes using Caenorhabditis elegans ( C. elegans ) as a model system. Interestingly, it was shown that at the concentrations tested, ASP (0.03-3 mg mL -1 ) showed an increasing trend of the mean lifespan of C. elegans , with a significant increase of 27.6% compared to the control at 3 mg mL -1 . Similarly, SUC (ranging from 0.03 to 10 mg mL -1 ) also significantly increased the mean lifespan by 20.3% and 22.3% at 0.03 and 0.3 mg mL -1 , respectively. However, 10 mg mL -1 SUC had a negative effect on the lifespan, though it did not reach a statistically significant level. In addition, ASP and SUC decreased lipofuscin accumulation and transiently improved motility, indicating improved health status. Nonetheless, they had different effects on food intake and intestinal fat deposition (IFD) at different intervals of time. Taken together, our findings revealed that ASP and SUC can prolong the lifespan and improve the health status of C. elegans .

This study aimed to investigate the molecular effects of the common natural sugar glucose and artificial sweetener aspartame on cancer stem cell (CSC) population and cancer aggressiveness of PANC-1 human pancreas adenocarcinoma cells. According to our findings while aspartame exposure significantly increased the CSC population, high glucose had no effect on it. The epithelial-mesenchymal transition marker N-cadherin increased only in the aspartame group. The findings indicate that a high level of glucose exposure does not effect the invasion and migration of PANC-1 cells, while aspartame increases both of these aggressiveness criteria. The findings also suggest that a high concentration of glucose maintains CSC population through induction of nuclear Oct3/4 and differentiation to parental cells via increasing cytoplasmic c-myc. Aspartame exposure to PANC-1 cells activated AKT and deactivated GSK3β by increasing levels of ROS and cytoplasmic Ca +2 , respectively, through T1R2/T1R3 stimulation. Then p-GSK3β(Ser9) boosted the CSC population by increasing pluripotency factors Oct3/4 and c-myc via NICD, GLI1 and p21. In the aspartame group, T1R1 silencing further increased the CSC population but decreased cell viability and suppressed the p21, NICD and GLI activation. The presence and amount of T1R subunits in the membrane fraction of PANC-1 cells are demonstrated for the first time in this study, as is the regulatory effect of T1R1's on CSC population. In conclusion, the present study demonstrated that long-term aspartame exposure increases CSC population and tumor cell aggressiveness through p21, NICD, GLI1. Moreover, while aspartame had no tumorigenic effect, it could potentially advance an existing tumor., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Artificial sweeteners (AS) are synthetic sugar substitutes that are commonly consumed in the diet. Recent studies have indicated considerable health risks which links the consumption of AS with metabolic derangements and gut microbiota perturbations. Despite these studies, there is still limited data on how AS impacts the commensal microbiota to cause pathogenicity. The present study sought to investigate the role of commonly consumed AS on gut bacterial pathogenicity and gut epithelium-microbiota interactions, using models of microbiota ( Escherichia coli NCTC10418 and Enterococcus faecalis ATCC19433) and the intestinal epithelium (Caco-2 cells). Model gut bacteria were exposed to different concentrations of the AS saccharin, sucralose, and aspartame, and their pathogenicity and changes in interactions with Caco-2 cells were measured using in vitro studies. Findings show that sweeteners differentially increase the ability of bacteria to form a biofilm. Co-culture with human intestinal epithelial cells shows an increase in the ability of model gut bacteria to adhere to, invade and kill the host epithelium. The pan-sweet taste inhibitor, zinc sulphate, effectively blocked these negative impacts. Since AS consumption in the diet continues to increase, understanding how this food additive affects gut microbiota and how these damaging effects can be ameliorated is vital.

Artificial sweeteners (AS) are widely used as sugar substitutes because natural sweetener (sugar) leads to a number of health issues, including diabetes, obesity, and tooth decay. Since natural sugar (sucrose), diabetes and skin are highly interlinked, and also sucrose is known to inhibit the fibrillation of collagen, the major protein of the skin, a study on the impact of AS on collagen is important and essential. Herein, we have studied the influence of commonly used AS such as Sucralose (SUC), Aspartame (APM), and Saccharin (SAC) on the structure, stability, and fibrillation of collagen using various spectroscopic methods. The circular dichroism and turbidity results suggest that the AS does not disrupt the triple helix structure and also the fibrillar property of collagen, respectively. The fibrillar morphology was sustained, although there was a trivial difference in the entanglement of fibrils in the presence of SAC, compared to native collagen fibrils. The thermal stability of collagen is maintained in the presence of AS. Fluorescence and STD-NMR results indicate that the interaction between AS and collagen was weak, which supports the intact structure, stability, and fibrillation property of collagen. The current study thus suggests that the chosen AS does not influence collagen properties., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Aspartame (ASP), an artificial sweetener abundantly consumed in recent years in an array of dietary products, has raised some concerns in terms of toxicity, and it was even suggested a link with the risk of carcinogenesis (colorectal cancer), though the present scientific data are rather inconclusive. This study aims at investigating the potential role of aspartame in colorectal cancer by suggesting two experimental approaches: (i) an in vitro cytotoxicity screening in HT-29 human colorectal carcinoma cells based on cell viability (Alamar blue assay), cell morphology and cell migration (scratch assay) assessment and (ii) an in ovo evaluation in terms of angiogenic and irritant potential by means of the chorioallantoic membrane method (CAM). The in vitro results showed a dose-dependent cytotoxic effect, with a significant decrease of viable cells at the highest concentrations tested (15, 30 and 50 mM) and morphological cellular changes. In ovo, aspartame (15 and 30 mM) proved to have a pro-angiogenic effect and a weak irritant potential at the vascular level. These data suggest new directions of research regarding aspartame's role in colorectal cancer.

Non-nutritive artificial sweeteners (NNSs) may have the ability to change the gut microbiota, which could potentially alter glucose metabolism. This study aimed to determine the effect of sucralose and aspartame consumption on gut microbiota composition using realistic doses of NNSs. Seventeen healthy participants between the ages of 18 and 45 years who had a body mass index (BMI) of 20-25 were selected. They undertook two 14-day treatment periods separated by a four-week washout period. The sweeteners consumed by each participant consisted of a standardized dose of 14% (0.425 g) of the acceptable daily intake (ADI) for aspartame and 20% (0.136 g) of the ADI for sucralose. Faecal samples collected before and after treatments were analysed for microbiome and short-chain fatty acids (SCFAs). There were no differences in the median relative proportions of the most abundant bacterial taxa (family and genus) before and after treatments with both NNSs. The microbiota community structure also did not show any obvious differences. There were no differences in faecal SCFAs following the consumption of the NNSs. These findings suggest that daily repeated consumption of pure aspartame or sucralose in doses reflective of typical high consumption have minimal effect on gut microbiota composition or SCFA production.

Background: Fructose consumption increases risk factors for cardiometabolic disease. It is assumed that the effects of free sugars on risk factors are less potent because they contain less fructose. We compared the effects of consuming fructose, glucose or their combination, high fructose corn syrup (HFCS), on cardiometabolic risk factors., Methods: Adults (18-40 years; BMI 18-35 kg/m 2 ) participated in a parallel, double-blinded dietary intervention during which beverages sweetened with aspartame, glucose (25% of energy requirements (ereq)), fructose or HFCS (25% and 17.5% ereq) were consumed for two weeks. Groups were matched for sex, baseline BMI and plasma lipid/lipoprotein concentrations. 24-h serial blood samples were collected at baseline and at the end of intervention. Primary outcomes were 24-h triglyceride AUC, LDL-cholesterol (C), and apolipoprotein (apo)B. Interactions between fructose and glucose were assessed post hoc., Findings: 145 subjects (26.0 ± 5.8 years; body mass index 25.0 ± 3.7 kg/m 2 ) completed the study. As expected, the increase of 24-h triglycerides compared with aspartame was highest during fructose consumption (25%: 6.66 mmol/Lx24h 95% CI [1.90 to 11.63], P = 0.0013 versus aspartame), intermediate during HFCS consumption (25%: 4.68 mmol/Lx24h 95% CI [-0.18 to 9.55], P = 0.066 versus aspartame) and lowest during glucose consumption. In contrast, the increase of LDL-C was highest during HFCS consumption (25%: 0.46 mmol/L 95% CI [0.16 to 0.77], P = 0.0002 versus aspartame) and intermediate during fructose consumption (25%: 0.33 mmol/L 95% CI [0.03 to 0.63], P = 0.023 versus aspartame), as was the increase of apoB (HFCS-25%: 0.108 g/L 95%CI [0.032 to 0.184], P = 0.001; fructose 25%: 0.072 g/L 95%CI [-0.004 to 0.148], P = 0.074 versus aspartame). The post hoc analyses showed significant interactive effects of fructose*glucose on LDL-C and apoB (both P < 0.01), but not on 24-h triglyceride (P = 0.340)., Conclusion: A significant interaction between fructose and glucose contributed to increases of lipoprotein risk factors when the two monosaccharides were co-ingested as HFCS. Thus, the effects of HFCS on lipoprotein risks factors are not solely mediated by the fructose content and it cannot be assumed that glucose is a benign component of HFCS. Our findings suggest that HFCS may be as harmful as isocaloric amounts of pure fructose and provide further support for the urgency to implement strategies to limit free sugar consumption., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objective: We examined the impact of maternal low-dose aspartame and stevia consumption on adiposity, glucose tolerance, gut microbiota and mesolimbic pathway in obese dams and their offspring., Design: Following obesity induction, female Sprague-Dawley rats were allocated during pregnancy and lactation to: (1) high fat/sucrose diet (HFS) +water (obese-WTR); (2) HFS +aspartame (obese-APM; 5-7 mg/kg/day); (3) HFS +stevia (obese-STV; 2-3 mg/kg/day). Offspring were weaned onto control diet and water and followed until 18 weeks. Gut microbiota and metabolic outcomes were measured in dams and offspring. Cecal matter from offspring at weaning was used for faecal microbiota transplant (FMT) into germ-free (GF) mice., Results: Maternal APM and STV intake with a HFS diet increased body fat in offspring at weaning and body weight long-term with APM. Maternal APM/HFS consumption impaired glucose tolerance in male offspring at age 8 weeks and both APM and STV altered faecal microbiota in dams and offspring. Maternal obesity/HFS diet affected offspring adiposity and glucose tolerance more so than maternal LCS consumption at age 12 and 18 weeks. APM and STV altered expression of genes in the mesolimbic reward system that may promote consumption of a palatable diet. GF mice receiving an FMT from obese-APM and obese-STV offspring had greater weight gain and body fat and impaired glucose tolerance compared with obese-WTR., Conclusion: Maternal low-calorie sweetener consumption alongside HFS may disrupt weight regulation, glucose control and gut microbiota in dams and their offspring most notably in early life despite no direct low-calorie sweetener consumption by offspring., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Non-nutritive sweeteners are thought to be useful replacements for caloric sweeteners in sweet food and beverages, since the reduction in energy and carbohydrate intake may lead to health benefits stemming from weight management and glycemic control. However, the potential effects of non-nutritive sweeteners on glucose metabolism and gut hormones have not been determined definitively. Here, the available evidence of the effects of aspartame and sucralose consumption on glucose metabolism and gut hormones is reviewed. A majority of studies have found that consumption of aspartame or sucralose has no effect on concentrations of blood glucose, insulin, or gut hormones; however, 2 trials have shown that aspartame consumption affects glucose, insulin, and glucagon-like peptide 1 concentrations, while only a few trials have shown that sucralose consumption affects glucose, insulin, and glucagon-like peptide 1 concentrations. One study found higher glucose concentrations after sucralose consumption, while 3 studies found lower concentrations and 33 studies found no change in glucose concentrations. Moreover, only 4 studies reported increased concentrations of glucagon-like peptide 1. Three studies reported decreased insulin sensitivity following sucralose consumption, while 1 trial reported an increase in insulin sensitivity. In summary, the evidence from the clinical trials conducted to date is contradictory because of the different protocols used., (© The Author(s) 2020. Published by Oxford University Press on behalf of the International Life Sciences Institute. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Alterations of transition metal levels have been associated with obesity, hepatic steatosis, and metabolic syndrome in humans. Studies in animals indicate an association between dietary sugars and copper metabolism. Our group has conducted a study in which young adults consumed beverages sweetened with glucose, fructose, high fructose corn syrup (HFCS), or aspartame for two weeks and has reported that consumption of both fructose- and HFCS-sweetened beverages increased cardiovascular disease risk factors. Baseline and intervention serum samples from 107 participants of this study were measured for copper metabolism (copper, ceruloplasmin ferroxidase activity, ceruloplasmin protein), zinc levels, and iron metabolism (iron, ferritin, and transferrin) parameters. Fructose and/or glucose consumption were associated with decreased ceruloplasmin ferroxidase activity and serum copper and zinc concentrations. Ceruloplasmin protein levels did not change in response to intervention. The changes in copper concentrations were correlated with zinc, but not with iron. The decreases in copper, ceruloplasmin ferroxidase activity, ferritin, and transferrin were inversely associated with the increases in metabolic risk factors associated with sugar consumption, specifically, apolipoprotein CIII, triglycerides, or post-meal glucose, insulin, and lactate responses. These findings are the first evidence that consumption of sugar-sweetened beverages can alter clinical parameters of transition metal metabolism in healthy subjects.

Lymphomas and leukaemias involving the lung have in some cases been hard to distinguish from respiratory tract infection in Sprague-Dawley (SD) rats from long-term bioassays. In order to differentiate between tumours and immune cell infiltrates, updated pathological criteria and nomenclature were used and immunohistochemistry (IHC) was applied to haematopoietic and lymphoid tissue tumours (HLTs) in the original prenatal long-term Aspartame (APM) study performed by the Ramazzini Institute (RI). All 78 cases of HLTs from treated and control groups were re-examined based on light microscopic morphological characteristics and subjected to a panel of IHC markers including Ki67, CD3, PAX5, CD20, CD68, TdT, CD45, CD14 and CD33. The analysis confirmed the diagnoses of HLTs in 72 cases, identified 3 cases of preneoplastic lesions (lymphoid hyperplasia), and categorized 3 cases as inflammatory lesions. A statistically significant increase in total HLTs (p = 0.006), total lymphomas (p = 0.032) and total leukaemias (p = 0.031) in treated female rats was confirmed (high dose vs control), and a statistically significant linear trend for each HLT type was also observed. After the HLT cases re-evaluation, the results obtained are consistent with those reported in the previous RI publication and reinforce the hypothesis that APM has a leukaemogenic and lymphomatogenic effect., (Copyright © 2020. Published by Elsevier GmbH.)

This study aimed to determine the effect of pure forms of sucralose and aspartame, in doses reflective of common consumption, on glucose metabolism. Healthy participants consumed pure forms of a non-nutritive sweetener (NNS) that were mixed with water and standardized to doses of 14% (0.425 g) of the acceptable daily intake (ADI) for aspartame and 20% (0.136 g) of the ADI for sucralose every day for 2 weeks. Blood samples were collected and analyzed for glucose, insulin, active glucagon-like peptide-1 (GLP-1), and leptin. Seventeen participants (10 females and 7 males; age, 24 ± 6.8 years; body mass index, 22.9 ± 2.5 kg/m 2 ) participated in the study. The total area under the curve values of glucose, insulin, active GLP-1 and leptin were similar for the aspartame and sucralose treatment groups compared with the baseline values in healthy participants. There was no change in insulin sensitivity after NNS treatment compared with the baseline values. These findings suggest that daily repeated consumption of pure sucralose or aspartame for 2 weeks had no effect on glucose metabolism among normoglycaemic adults. However, these results need to be tested in studies with longer durations. Novelty Daily consumption of pure aspartame or sucralose for 2 weeks had no effect on glucose metabolism. Daily consumption of pure aspartame or sucralose for 2 weeks had no effect on insulin sensitivity among healthy adults.

Sweeteners that are a hundred thousand times sweeter than sucrose are being consumed as sugar substitutes. The effects of sweeteners on gut microbiota composition have not been completely elucidated yet, and numerous gaps related to the effects of nonnutritive sweeteners (NNS) on health still remain. The NNS aspartame and acesulfame-K do not interact with the colonic microbiota, and, as a result, potentially expected shifts in the gut microbiota are relatively limited, although acesulfame-K intake increases Firmicutes and depletes Akkermansia muciniphila populations. On the other hand, saccharin and sucralose provoke changes in the gut microbiota populations, while no health effects, either positive or negative, have been described; hence, further studies are needed to clarify these observations. Steviol glycosides might directly interact with the intestinal microbiota and need bacteria for their metabolization, thus they could potentially alter the bacterial population. Finally, the effects of polyols, which are sugar alcohols that can reach the colonic microbiota, are not completely understood; polyols have some prebiotics properties, with laxative effects, especially in patients with inflammatory bowel syndrome. In this review, we aimed to update the current evidence about sweeteners' effects on and their plausible biological interactions with the gut microbiota.

Irinotecan (CPT-11) is a cytotoxic drug that has wide applicability and usage in cancer treatment. Despite its success, patients suffer dose-dependent diarrhea, limiting the drug's efficacy. No effective therapy is available for this unmet medical need. The bacterial β-glucuronidase (β-GUS) plays pivotal role in CPT-11-induced diarrhea (CID) via activating the non-toxic SN-38G to toxic SN-38 inside intestine. By using structural-based virtual screening, three old drugs (N-Desmethylclozapine, Aspartame, and Gemifloxacin) were firstly identified as selective bacterial β-GUS inhibitors. The IC 50 values of the compounds in the enzyme-based and cell-based assays range from 0.0389 to 3.6040 and 0.0105 to 5.3730 μM, respectively. The compounds also showed good selectivity against mammalian β-GUS and no significant cytotoxicity in bacteria. Molecular docking and molecular dynamics simulations were performed to further investigate the binding modes of compounds with bacterial β-GUS. Binding free energy decomposition revealed that the compounds formed strong interactions with E413 in catalytic trail from primary monomer and F365' on the bacterial loop from the other monomer of bacterial β-GUS, explaining the selectivity against mammalian β-GUS. The old drugs identified here may be used as bacterial β-GUS inhibitors for CID or other bacterial β-GUS-related disorders., (© 2019 John Wiley & Sons A/S.)

Aim: Hyperglycemia status induces endothelial dysfunction, although the underlying pathogenic mechanisms are not fully understood. There are several studies connecting sugar/sweetened beverages to the cardiovascular disease. Currently, many sweeteners have been extensively introduced into lifestyle to normalize blood glucose levels without altering the sweet taste. However, there is growing concern for their impact on metabolic health., Methods: Human endothelial cells were treated with Glucose, Fructose, Aspartame, Rebaudioside A, Stevioside, or Steviol. Morphological characteristics, in vitro angiogenesis and array gene expression were analyzed., Results: High-glucose and fructose concentrations significantly decreased cell features such as angiogenic capability. Interestingly, non-caloric sweeteners did not significantly modified all cell characteristics and they did not compromised cell angiogenic ability. Array gene expression analysis revealed that the chemokine fractalkine (CX3CL1) and the enzyme transferase (HPRT1) were always significantly upregulated and downregulated respectively, after glucose and fructose treatments (P > .05), whereas they were non-differentially expressed with all the other sweeteners. Interestingly, both genes are considered as cardiovascular disease risk biomarkers. Specifically, upregulation of CX3CL1/CX3CR1 occurs in the human placenta and serum levels of the ligand are associated with markers of insulin resistance in GDM., Conclusions: Differently from glucose and fructose, steviol glycosides do not damage endothelial cells. Prospective preclinical studies and clinical trials are warranted to confirm the long-term safety of such compounds., (Copyright © 2019. Published by Elsevier Ltd.)

Substituting sugar-sweetened for artificially sweetened beverages may reduce energy intakes. This study aims to ascertain the acute glycaemic effects of the NNS aspartame and acesulfame-K in UK diet-cola (DC). Ten healthy participants attended the laboratory fasted on three occasions. Individuals drank (1) 25 g glucose in 125 mL water + 236 mL water, (2) 25 g glucose in 125 mL water with 236 mL DC and (3) 236 mL sucrose-sweetened cola with 125 mL water. Blood (glucose) was measured pre-test and every 15 minutes over a 120-minute period using portable glucometers. The glucose-control and glucose + DC elicited similar blood glucose rises above pre-prandial levels. Sucrose-sweetened cola showed a non-significant lower rise in postprandial glycaemia, exhibiting the lowest glycaemic index (GI) (77.0 ± 9.1). GI of glucose (100.0 ± 15.2) and glucose + DC (104.3 ± 8.5) was similar and a one-way repeated-measures ANOVA showed no significant differences in glycaemic response between test drinks ( F (2,29) = 1.68, p  > .05). Results demonstrate the glycaemic inactivity of non-nutritive sweeteners.

The objective of this study was to test the hypothesis that aspartame supplementation in starter diet accelerates small intestinal cell cycle by stimulating secretion and expression of glucagon-like peptide -2 (GLP-2) in pre-weaned lambs using animal and cell culture experiments. In vivo, twelve 14-day-old lambs were selected and allocated randomly to two groups; one was treated with plain starter diet (Con, n = 6) and the other was treated with starter supplemented with 200 mg of aspartame/kg starter (APM, n = 6). Results showed that the lambs received APM treatment for 35 d had higher (p < .05) GLP-2 concentration in the plasma and greater jejunum weight/live body weight (BW) and jejunal crypt depth. Furthermore, APM treatment significantly upregulated (p < .05) the mRNA expression of cyclin D1 in duodenum; and cyclin A2, cyclin D1, cyclin-dependent kinases 6 (CDK6) in jejunum; and cyclin A2, cyclin D1, CDK4 in ileum. Moreover, APM treatment increased (p < .05) the mRNA expression of glucagon (GCG), insulin-like growth factor 1 (IGF-1) in the jejunum and ileum and mRNA expression of GLP-2 receptor (GLP-2R) in the jejunum. In vitro, when jejunal cells were treated with GLP-2 for 2 hr, the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) OD, IGF-1 concentration, and the mRNA expression of IGF-1, cyclin D1 and CDK6 were increased (p < .05). Furthermore, IGF-1 receptor (IGF-1R) inhibitor decreased (p < .05) the mRNA expression of IGF-1, cyclin A2, cyclin D1 and CDK6 in GLP-2 treatment jejunal cells. These results suggest that aspartame supplementation in starter accelerates small intestinal cell cycle that may, in part, be related to stimulate secretion and expression of GLP-2 in pre-weaning lambs. Furthermore, GLP-2 can indirectly promote the proliferation of jejunal cells mainly through the IGF-1 pathway. These findings provide new insights into nutritional interventions that promote the development of small intestines in young ruminants., (© 2019 Blackwell Verlag GmbH.)

Objective: To determine the cytoplasmic fatty change of rat liver due to artificial sweeteners - aspartame and sucralose., Study Design: Experimental study., Place and Duration of Study: Department of Anatomy, King Edward Medical University, Lahore, in collaboration with the University of Veterinary and Animal Sciences Lahore, from May to October 2016., Methodology: Adult Wistar albino rats were randomly divided into five groups. Group I was control group (animals were given drinking water by oral gavage). The animals of group II and III were given low (40 mg/kg body weight) and high dose (1000 mg/kg body weight) of aspartame, respectively. Animals of group IV and V were given low (5 mg/kg body weight) and high dose (1000 mg/kg body weight) of sucralose respectively by oral gavage. Doses were given once daily, six days a week for a total duration of 8 weeks. At the end of experiment, livers of all animal groups were observed for fatty change of cytoplasm., Results: Artificial sweeteners cause cytoplasmic fatty change of varying degrees. This change was more marked in high dose group of aspartame (group III) as compared to low dose group (group II). In sucralose group, this change was seen only in high dose group (group V)., Conclusion: Both artificial sweeteners-induced fatty changes in rat liver; the effect was least pronounced with low dose of sucralose.

Previously, we reported that oral stimulation with Gymnema sylvestre (GS), a plant that selectively suppresses sweet taste sensation in humans, delayed gastric emptying and glycemic response during and after oral glucose ingestion. It is unclear whether these responses are triggered by sweet taste sensing per se. We tested the hypothesis that the effects of sweet taste sensing involving a low-energy sweetener, aspartame, alters gastric emptying, blood glucose, and plasma insulin responses during and after the prandial phase. Nine participants rinsed their mouths with either 25 mL of water (control) or a 2.5% GS solution, and then ingested 200 g (50 g × four times) of either 0.09% aspartame or 15% glucose solution containing 100 mg of 13 C-sodium acetate. Gastric emptying was measured with a 13 C breath test. Blood glucose and plasma insulin were measured at baseline as well as during and after ingestion of the sweet solutions. Decreased subjective sweet taste intensity was observed in the GS group for both the aspartame and glucose trials. In the aspartame trial, no measurements showed significant differences between either group. In the glucose trial, gastric emptying was delayed in the GS group compared to controls. In the initial phase, both during and after glucose ingestion in the glucose trial, blood glucose and plasma insulin responses were lower in the GS group than the controls. The presence or absence of sweet taste-sensing involving glucose had a significant effect on gastric emptying and glycemic metabolism, both during and after the prandial phase, as opposed to the effects involving aspartame., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Purpose of Review: By replacing sugar, nonnutritive sweeteners (NNSs) are thought to aid in weight management and decrease insulin resistance. We reviewed the latest randomized clinical trials (RCTs) investigating the effects NNSs on glycaemic control., Recent Findings: Six RCTs addressed this topic between 2017 and 2018; the majority tested artificial NNS (sucralose or aspartame), with only one testing natural NNS (stevia and monk fruit extract). Most found no effect of NNS on blood glucose, insulin, gastric inhibitory polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) levels; however, two trials showed an effect of sucralose on the acute insulin response., Summary: We are still incapable of reaching a definite judgement on which types of NNS, if any, impact glycaemic control. There is a need for more research to overcome the limitations of recent RCTs, related to sample size, intervention duration, dose, form of NNSs used, and inclusion of males or female participants only. Future studies should also compare different NNS types with each other, and include the increasingly popular 'natural' NNS.

Background: Low-calorie sweeteners (LCSs) provide sweetness with little or no energy. However, each LCS's unique chemical structure has potential to elicit different sensory, physiological, and behavioral responses that affect body weight., Objective: The purpose of this trial was to compare the effects of consumption of 4 LCSs and sucrose on body weight, ingestive behaviors, and glucose tolerance over a 12-wk intervention in adults (18-60 y old) with overweight or obesity (body mass index 25-40 kg/m2)., Methods: In a parallel-arm design, 154 participants were randomly assigned to consume 1.25-1.75 L of beverage sweetened with sucrose (n = 39), aspartame (n = 30), saccharin (n = 29), sucralose (n = 28), or rebaudioside A (rebA) (n = 28) daily for 12 wk. The beverages contained 400-560 kcal/d (sucrose treatments) or <5 kcal/d (LCS treatments). Anthropometric indexes, energy intake, energy expenditure, appetite, and glucose tolerance were measured at baseline. Body weight was measured every 2 wk with energy intake, expenditure, and appetite assessed every 4 wk. Twenty-four-hour urine collections were completed every 4 wk to determine study compliance via para-aminobenzoic acid excretion., Results: Of the participants enrolled in the trial, 123 completed the 12-wk intervention. Sucrose and saccharin consumption led to increased body weight across the 12-wk intervention (Δweight = +1.85 ± 0.36 kg and +1.18 ± 0.36 kg, respectively; P ≤ 0.02) and did not differ from each other. There was no significant change in body weight with consumption of the other LCS treatments compared with baseline, but change in body weight for sucralose was negative and significantly lower compared with all other LCSs at week 12 (weight difference ≥ 1.37 ± 0.52 kg, P ≤ 0.008). Energy intake decreased with sucralose consumption (P = 0.02) and ingestive frequency was lower for sucralose than for saccharin (P = 0.045). Glucose tolerance was not significantly affected by any of the sweetener treatments., Conclusions: Sucrose and saccharin consumption significantly increase body weight compared with aspartame, rebA, and sucralose, whereas weight change was directionally negative and lower for sucralose compared with saccharin, aspartame, and rebA consumption. LCSs should be categorized as distinct entities because of their differing effects on body weight. This trial was registered at clinicaltrials.gov as NCT02928653., (Copyright © American Society for Nutrition 2019.)

The non-caloric sweetener aspartame can be potentially harmful to the developing brain, as some studies suggest an association between aspartame intake and adverse neural effects. This study aimed to evaluate the possible effects of aspartame, with or without associated early nutritional deficiency, on behavioral parameters suggestive of anxiety and electrophysiological features of the excitability-related phenomenon known as cortical spreading depression (CSD). Newborn Wistar rats (n = 80) were suckled under favorable (L 9 ; n = 40) or unfavorable lactation conditions (L 15 ; n = 40), consisting of litters with 9 or 15 pups, respectively. In each lactation condition, animals were divided into 4 groups that received per gavage, from postnatal day 8 to 28, 75 mg/kg/d or 125 mg/kg/d aspartame (groups ASP75 and ASP125), or water (vehicle group), or no treatment (naive group). Behavioral tests (elevated plus-maze [EPM]) were performed at postnatal days 86-95 and CSD was recorded between postnatal days 96-115. Compared to the control groups, aspartame dose-dependently reduced body weight, suggesting a negative impact on animal development; aspartame also caused behavioral changes suggestive of anxiety (shorter stay in the open arms in the EPM) and decelerated CSD (lower propagation speed). Some of these parameters were more affected in L 15 animals, suggesting an interaction among aspartame and lactation condition. We concluded that early consumption of aspartame adversely affects development of the organism (weight loss), with actions on behavioral (anxiety-like) and cerebral electrophysiological (CSD) parameters. The data suggest caution in aspartame consumption by lactating mothers and their infants.

The safety of food additives has been widely concerned. Using single additives in the provisions of scope is safe, but the combination of additives, may induce additive, synergy, antagonism and other joint effects. This study investigated the cytotoxicity of aspartame (AT) together with potassium sorbate (PS). Thiazolyl Blue Tetrazolium Bromide (MTT) assay indicated that AT and PS had IC 50 values of 0.48 g/L and 1.25 g/L at 24 h, respectively. High content analysis (HCA) showed that both AT and PS had a negative effect on mitochondrial membrane potential (MMP), reactive oxygen species (ROS) and DNA damage while the joint group behaved more obviously. The biochemical assays revealed typical cell morphological changes and the activation of cytochrome c and caspase-3 verified apoptosis induced by AT together with PS. With dissipation of MMP and increase of cell membrane permeability (CMP), it indicated AT together with PS-induced apoptosis was mediated by mitochondrial pathway. Meanwhile, p53 were involved in DNA damage, and the ratio of Bax/Bcl-2 was increased. Moreover, excessive ROS induced by AT together with PS is a key initiating factor for apoptosis. All these results proved that p53 was involved in apoptosis via mitochondria-mediated pathway and the process was regulated by ROS.

The human gut is inhabited by several hundred different bacterial species. These bacteria are closely associated with our health and well-being. The composition of these diverse commensals is influenced by our dietary intakes. Non-caloric artificial sweeteners (NAS) have gained global popularity, particularly among diabetic patients, due to their perceived health benefits, such as reduction of body weight and maintenance of blood glucose level compared to caloric sugars. Recent studies have reported that these artificial sweeteners can alter the composition of gut microbiota and, thus, affect our normal physiological state. Here, we investigated the effect of aspartame and acesulfame potassium (ace-K), two popular NAS, in a commercial formulation on the growth and metabolic pathways of omnipresent gut commensal Escherichia coliby analyzing the relative expression levels of the key genes, which control over twenty important metabolic pathways. Treatment with NAS preparation (aspartame and ace-K) modulates the growth of E. colias well as inducing the expression of important metabolic genes associated with glucose (pfkA, sucA, aceE, pfkB, lpdA), nucleotide (tmk, adk, tdk, thyA), and fatty acid (fabI) metabolisms, among others. Several of the affected geneswere previously reported to be important for the colonization of the microbes in the gut. These findings may shed light on the mechanism of alteration of gut microbes and their metabolism by NAS., (© 2019 S. Karger AG, Basel.)

Aspartame (ASP) has been used as an alternative to sucrose for diabetics and obese people worldwide. Co-administration of L-carnitine (LC) with ASP has a protective effect against the liver and kidney toxicity induced of ASP. The goal of the investigation was to assess the enhancement of LC effect on the cardiac toxicity caused of ASP. The rats were divided into 6 groups: control with saline, LC (10 mg/kg), ASP (75 mg/kg), ASP (150 mg/kg), LC with 75 mg/kg of ASP, and LC with 150 mg/kg ASP. The antioxidants were determined by measuring the activities of myeloperoxidase, xanthine oxidase, superoxide dismutase, catalase, and glutathione peroxidase, and by assessing the levels of lipid peroxidation, total thiols, and glutathione. There was a significant elevation in LPO, in conjunction with a significant decline in the enzymatic antioxidants superoxide dismutase, catalase, and glutathione peroxidase and the non-enzymatic antioxidants glutathione and thiols. The cardiac myofibrils were found in a disarrayed pattern in ASP treated-animals as compared to the control rats. The animals treated with ASP-HD showed more than one apoptotic cell with a large tail and a small head, and the relaxed loops of the damaged DNA were extended to form a comet-shaped structure. These effects may be due to the excessive generation of reactive oxygen species by ASP, which reduces cardiac function. Co-administration of LC with ASP improved all of the above-mentioned parameters that were disrupted of ASP alone. This study evidences a sufficient originality in showing how LC plays a positive role against cardiac toxicity of ASP., Competing Interests: The authors have declared that no competing interests exist.

Epidemiological and clinical research studies have provided ample evidence demonstrating that consumption of sugar-sweetened beverages increases risk factors involved in the development of obesity, Type 2 diabetes, and cardiovascular disease (CVD). Our previous study demonstrated that when compared with aspartame (Asp), 2 wk of high-fructose corn syrup (HFCS)-sweetened beverages provided at 25% of daily energy requirement was associated with increased body weight, postprandial (pp) triglycerides (TG), and fasting and pp CVD risk factors in young adults. The fatty acid ethanolamide, anandamide (AEA), and the monoacylglycerol, 2-arachidonoyl- sn-glycerol (2-AG), are two primary endocannabinoids (ECs) that play a role in regulating food intake, increasing adipose storage, and regulating lipid metabolism. Therefore, we measured plasma concentrations of ECs and their analogs, oleoylethanolamide (OEA), docosahexaenoyl ethanolamide (DHEA), and docosahexaenoyl glycerol (DHG), in participants from our previous study who consumed HFCS- or Asp-sweetened beverages to determine associations with weight gain and CVD risk factors. Two-week exposure to either HFCS- or Asp-sweetened beverages resulted in significant differences in the changes in fasting levels of OEA and DHEA between groups after the testing period. Subjects who consumed Asp, but not HFCS, displayed a reduction in AEA, OEA, and DHEA after the testing period. In contrast, there were significant positive relationships between AEA, OEA, and DHEA vs. ppTG, ppApoCIII, and ppApoE in those consuming HFCS, but not in those consuming Asp. Our findings reveal previously unknown associations between circulating ECs and EC-related molecules with markers of lipid metabolism and CVD risk after HFCS consumption.

Background: The effects of the regular intake of beverages containing high-intensity sweeteners on insulin sensitivity in healthy individuals remain controversial., Objective: This trial compared the effects of the consumption of a carbonated beverage containing aspartame and acesulfame K (high-intensity sweeteners beverage-HISB) with those of an unsweetened, no-calorie carbonated beverage (UB) on insulin sensitivity and secretion in nondiabetic adults., Methods: SEDULC was a randomized, double-blind, crossover study. Nondiabetic adults [mean age 31 y, 44% men, body mass index (BMI; kg/m²) 19-29] who did not consume high-intensity sweeteners were randomized 1:1 to drink 1 of the 2 carbonated beverages, 2 cans (330 mL each)/d, for 12 wk. After a 4-wk washout period, participants were switched to the opposite beverage for 12 wk. The primary outcome tested was the change in insulin sensitivity as assessed by the Matsuda Insulin Sensitivity Index (MISI) after an oral glucose load. Secondary outcomes were indexes of insulin secretion., Results: Sixty individuals were enrolled and 50 completed the study (28 nonoverweight and 22 overweight participants). The change in MISI from baseline did not significantly differ between beverages and noninferiority was demonstrated (difference = -0.23; 95% CI: -1.31, 0.85; P < 0.0001). The change in insulinogenic (means ± SEMs: 0.23 ± 0.14 for HISB compared with 0.08 ± 0.1 for UB) and disposition indexes (2.70 ± 0.99 for HISB compared with 1.62 ± 0.90 for UB) did not differ, and no differences in insulin secretion estimates were confirmed by the Stumvoll indexes. Consuming the high-intensity sweeteners did not affect body weight, self-reported dietary consumption, or self-reported physical activity., Conclusions: These findings suggest that the daily consumption of 2 cans of a beverage containing aspartame and acesulfame K over 12 wk has no significant effect on insulin sensitivity and secretion in nondiabetic adults. This trial was registered at clinicaltrials.gov as NCT02031497.

The usefulness of replacement of caloric sugars by low-calorie sweeteners (LCS) for weight management has been questioned on the grounds that the uncoupling of LCS sweet taste and dietary energy may confuse physiological mechanisms, leading potentially to higher energy and sugar intake. The aim of the present study was to determine whether LCS beverages compared to water, when consumed with meals, differ in their effects on energy and food intake in acute trials and after long-term habituation. Ad libitum food intake of 166 (80 women; 86 men) healthy non-obese adults (BMI between 19 and 28 kg/m2), infrequent consumers of LCS was measured in four 2-consecutive-day testing sessions (Day 1 in the laboratory, Day 2 free-living). During the first 3 sessions, held one-week apart, participants were required to drink either water or commercial non-carbonated LCS lemonade (330 ml) with their main meals (randomised cross-over design). On Day 1, motivational ratings were obtained using visual analogue scales and ad libitum food intakes (amounts and types of foods selected) were measured using the plate waste method. On Day 2, participants reported their ad libitum intakes using a food diary. After Session 3, participants were randomly assigned to the LCS habituation group or to the water control group. The habituation (660 ml LCS lemonade daily vs 660 ml water) lasted 5 weeks. The fourth and final test session measured food intakes and motivational ratings after habituation. Water and LCS beverage did not differ in their effects on total energy intake, macronutrient intakes or the selection of sweet foods and on motivational ratings. Similar results were obtained in both LCS-naïve and LCS-habituated individuals.

Background: Low-calorie sweeteners are often used to moderate energy intake and postprandial glycemia, but some evidence indicates that they may exacerbate these aims., Objective: The trial's primary aim was to assess the effect of daily aspartame ingestion for 12 wk on glycemia. Effects on appetite and body weight were secondary aims., Methods: One hundred lean [body mass index (kg/m2): 18-25] adults aged 18-60 y were randomly assigned to consume 0, 350, or 1050 mg aspartame/d (ASP groups) in a beverage for 12 wk in a parallel-arm design. At baseline, body weight and composition were determined, a 240-min oral-glucose-tolerance test (OGTT) was administered, and measurements were made of appetite and selected hormones. Participants also collected a 24-h urine sample. During the intervention, the 0-mg/d ASP group consumed capsules containing 680 mg dextrose and 80 mg para-amino benzoic acid. For the 350-mg/d ASP group, the beverage contained 350 mg aspartame and the 1050-mg/d ASP group consumed the same beverage plus capsules containing 680 mg dextrose and 700 mg aspartame. Body weight, blood pressure, heart rate, and waist circumference were measured weekly. At weeks 4, 8, and 12, participants collected 24-h urine samples and kept appetite logs. Baseline measurements were repeated at week 12., Results: With the exception of the baseline OGTT glucose concentration at 60 min (and resulting area under the curve value), there were no group differences for glucose, insulin, resting leptin, glucagon-like peptide 1, or gastric inhibitory peptide at baseline or week 12. There also were no effects of aspartame ingestion on appetite, body weight, or body composition. Compliance with the beverage intervention was ∼95%., Conclusions: Aspartame ingested at 2 doses for 12 wk had no effect on glycemia, appetite, or body weight among healthy, lean adults. These data do not support the view that aspartame is problematic for the management of glycemia, appetite, or body weight. This trial was registered at www.clinicaltrials.gov as NCT02999321.

Rationale: Aspartame (L-aspartyl phenylalanine methyl ester) is a non-nutritive sweetener (NNS) approved for use in more than 6000 dietary products and pharmaceuticals consumed by the general public including adults and children, pregnant and nursing mothers. However a recent prospective study reported a doubling of the risk of being overweight amongst 1-year old children whose mothers consumed NNS-sweetened beverages daily during pregnancy. We have previously shown that chronic aspartame (ASP) exposure commencing in utero may detrimentally affect adulthood adiposity status, glucose metabolism and aspects of behavior and spatial cognition, and that this can be modulated by developmental N-methyl-D-aspartate receptor (NMDAR) blockade with the competitive antagonist CGP 39551 (CGP). Since glucose homeostasis and certain aspects of behavior and locomotion are regulated in part by the NMDAR-rich hypothalamus, which is part of the hypothalamic-pituitary-adrenal- (HPA) axis, we have elected to examine changes in hypothalamic and adrenal gene expression in response to ASP exposure in the presence or absence of developmental NMDAR antagonism with CGP, using Affymetrix microarray analysis., Results: Using 2-factor ANOVA we identified 189 ASP-responsive differentially expressed genes (DEGs) in the adult male hypothalamus and 2188 in the adrenals, and a further 23 hypothalamic and 232 adrenal genes significantly regulated by developmental treatment with CGP alone. ASP exposure robustly elevated the expression of a network of genes involved in hypothalamic neurosteroidogenesis, together with cell stress and inflammatory genes, consistent with previous reports of aspartame-induced CNS stress and oxidative damage. These genes were not differentially expressed in ASP mice with CGP antagonism. In the adrenal glands of ASP-exposed mice, GABA and Glutamate receptor subunit genes were amongst those most highly upregulated. Developmental NMDAR antagonism alone had less effect on adulthood gene expression and affected mainly hypothalamic neurogenesis and adrenal steroid metabolism. Combined ASP + CGP treatment mainly upregulated genes involved in adrenal drug and cholesterol metabolism., Conclusion: ASP exposure increased the expression of functional networks of genes involved in hypothalamic neurosteroidogenesis and adrenal catecholamine synthesis, patterns of expression which were not present in ASP-exposed mice with developmental NMDAR antagonism.

Aspartame is an artificial sweetener used in about 6000 sugar-free products. Aspartame consumption could be associated with various neurological disorders. This study aimed to evaluate the effect of aspartame onmedial Prefrontal Cortex (mPFC) as well as neuroprotective effects of vitamin E. The rats were divided into seven groups, including distilled water, corn oil, vitamin E (100mg/kg/day), and low (acceptable daily dose) and high doses of aspartame (40 and 200mg/kg/day) respectively, with or without vitamin E consumption, for 8 weeks. Behavioral tests were recorded and the brain was prepared for stereological assessments. Novel objects test and eight-arm radial maze showed impairmentoflong- and short-termmemoriesin aspartame groups. Besides, mPFC volume, infralimbic volume, neurons number, glial cells number, dendrites length per neuron,and number of spines per dendrite length were decreased by 7-61% in the rats treated with aspartame. However, neurons' number, glial cells number, and rats' performance in eight-arm radial mazes were improved by concomitant consumption of vitamin E and aspartame. Yet, the mPFC volume and infralimbic cortex were protected only in the rats receiving the low dose of aspartame+vitamin E. On the other hand, dendrites length, spines number,and novel object recognition were not protected by treatment with vitamin E+aspartame. The acceptable daily dose or higher doses of aspartame could induce memory impairments and cortical cells loss in mPFC. However, vitamin E could ameliorate some of these changes., (Copyright © 2017 Elsevier GmbH. All rights reserved.)

Data about harms or benefits associated with the consumption of aspartame, a nonnutritive sweetener worldwide consumed, are still controversial. This systematic review and meta-analysis of randomized controlled clinical trials aimed to assess the effect of aspartame consumption on metabolic parameters related to diabetes and obesity. The search was performed on Cochrane, LILACS, PubMed, SCOPUS, Web of Science databases, and on a gray literature using Open Grey, Google Scholar, and ProQuest Dissertations & Theses Global. Searches across all databases were conducted from the earliest available date up to April 13, 2016, without date and language restrictions. Pooled mean differences were calculated using a random or fixed-effects model for heterogeneous and homogenous studies, respectively. Twenty-nine articles were included in qualitative synthesis and twelve, presenting numeric results, were used in meta-analysis. Fasting blood glucose (mmol/L), insulin levels (μU/mL), total cholesterol (mmol/L), triglycerides concentrations (mmol/L), high-density lipoprotein cholesterol (mmol/L), body weight (kg), and energy intake (MJ) were considered as the main outcomes in subjects that consumed aspartame, and results were presented as mean difference; % confidence interval, range. Aspartame consumption was not associated with alterations on blood glucose levels compared to control (-0.03 mmol/L; 95% CI, -0.21 to 0.14) or to sucrose (0.31 mmol/L; 95% CI, -0.05 to 0.67) and on insulin levels compared to control (0.13 μU/mL; 95% CI, -0.69 to 0.95) or to sucrose (2.54 μU/mL; 95% CI, -6.29 to 11.37). Total cholesterol was not affected by aspartame consumption compared to control (-0.02 mmol/L; 95% CI, -0.31 to 0.27) or to sucrose (-0.24 mmol/L; 95% CI, -0.89 to 0.42). Triglycerides concentrations were not affected by aspartame consumption compared to control (0.00 mmol/L; 95% CI, -0.04 to 0.05) or to sucrose (0.00 mmol/L; 95% CI, -0.09 to 0.09). High-density lipoprotein cholesterol serum levels were higher on aspartame compared to control (-0.03 mmol/L; 95% CI, -0.06 to -0.01) and lower on aspartame compared to sucrose (0.05 mmol/L; 95% CI, 0.02 to 0.09). Body weight did not change after aspartame consumption compared to control (5.00 kg; 95% CI, -1.56 to 11.56) or to sucrose (3.78 kg; 95% CI, -2.18 to 9.74). Energy intake was not altered by aspartame consumption compared to control (-0.49 MJ; 95% CI, -1.21 to 0.22) or to sucrose (-0.17 MJ; 95% CI, -2.03 to 1.69). Data concerning effects of aspartame on main metabolic variables associated to diabetes and obesity do not support a beneficial related to its consumption.

Replacing nutritive sweetener with non-nutritive sweeteners (NNS) has the potential to improve glycaemic control. The objective of this study was to investigate the effects of consuming artificial NNS (that is, aspartame), natural NNS (that is, monk fruit and stevia), and sucrose-sweetened beverages on 24-h glucose profiles. Ten healthy males took part in this randomised, crossover study with the following four treatments: aspartame-, monk fruit-, stevia-, and sucrose- (65 g) sweetened beverages. Participants were asked to consume the test beverage as a preload mid-morning. Medtronic iPro2 continuous glucose monitoring system was used to measure mean 24-h glucose, incremental area under the curve (iAUC) and total area under the curve (AUC) for glucose, and 24-h glycaemic variability. Overall no significant differences were found in mean 24-h glucose, iAUC and total AUC for glucose, and 24-h glycaemic variability between the four test beverages. Twenty-four-hour glucose profiles did not differ between beverages sweetened with non-nutritive (artificial vs natural) and nutritive sweeteners. The simple exchange of a single serving of sucrose-sweetened beverage with NNS over a day appears to have minimal effect on 24-h glucose profiles in healthy males.

Although several studies on toxic effect of aspartame metabolite have been studied, controversial reports over the use of aspartame owing to the fact that it releases methanol as one of its metabolite during metabolism exist. This present study is proposed to investigate whether aspartame (40 mg kg -1 b.wt) administration for 90 days could induce oxidative stress and alter antioxidant status of epididymal sperm in Wistar strain male albino rats. To mimic the human methanol metabolism, methotrexate (MTX)-treated rats were included to study the effects of aspartame. Oral intubations of FDA approved 40 mg kg -1 b.wt aspartame were given daily for 90 days to Wistar strain male albino rats and studied along with controls and MTX-treated controls. Sperm count, viability, morphology, morphometry and motility were assessed. A significant decrease in sperm function of aspartame treated animals was observed when compared with the control and MTX control. The free radical generation were observed in epididymal sperm by assessing the scavenging enzymes, enzymatic and non-enzymatic antioxidants. Result suggest that there was a significant increase glutathione-s-transferase (GST), with a significant decrease in reduced glutathione (GSH), superoxide dismutase activity (SOD), glutathione peroxidase levels (GPx), catalase activity (CAT) and glutathione reductase concentration. The increase in free radicals generation could have ultimately caused the lipid peroxidation mediated damages on the testis. Aspartame treated animals also revealed the reduced space in seminiferous tubules, which resulted in reduced Leydig cells when compared with control in histopathology. These findings demonstrate that aspartame metabolites could be a contributing factor for development of oxidative stress in the epididymal sperm.