Nutritive/non-nutritive sweeteners and high fat diet contribute to dysregulation of sweet taste receptors and metabolic derangements in oral, intestinal and central nervous tissues.

OBJECTIVES: Overconsumption of non-nutritive sweeteners is associated with obesity, whereas the underlying mechanisms remain controversial. This study aimed to investigate the effects of long-term consumption of nutritive or non-nutritive sweeteners with or without high fat diet on sweet taste receptor expression in nutrient-sensing tissues and energy regulation dependent on sweet-sensing. METHODS: 50 Male Sprague-Dawley rats (140-160 g) were assigned to 10 groups (n = 5/group). All received fructose at 2.5% or 10%, sucralose at 0.01% or 0.015% or water with a normal chow diet or high fat diet for 12 weeks. Food and drink intake were monitored daily. Oral glucose tolerance test and intraperitoneal glucose tolerance test were performed at week 10 and 11 respectively. Serum was obtained for measurement of biochemical parameters. Tongue, duodenum, jejunum, ileum, colon and hypothalamus were rapidly removed to assess gene expression. RESULTS: Long-term consumption of sweeteners impaired glucose tolerance, increased calorie intake and body weight. A significant upregulation of sweet taste receptor expression was observed in all the four intestinal segments in groups fed 0.01% sucralose or 0.015% sucralose, most strikingly in the ileum, accompanied by elevated serum glucagon-like peptide-1 levels and up-regulated expression of sodium-dependent glucose cotransporter 1 and glucose transporter 2. A significant down-regulation in the tongue and hypothalamus was observed in groups fed 10% fructose or 0.015% sucralose, with alterations in hypothalamic appetite signals. The presence of high fat diet differentially modulates sweet taste perception in nutrient-sensing tissues. CONCLUSIONS: Long-term consumption of whether nutritive sweeteners or non-nutritive sweeteners combined with high fat diet contribute to dysregulation of sweet taste receptor expression in oral, intestinal and central nervous tissues.

Propionate ameliorates diabetes-induced neurological dysfunction through regulating the PI3K/Akt/eNOS signaling pathway.

A large body of research has established diabetes-related cognitive deterioration, sometimes known as "diabetic encephalopathy". Current evidence supports that oxidative stress, neuronal apoptosis, and cerebral microcirculation weakness are associated with cognition deficits induced by diabetes. The present study explores the effect of propionate on neurological deficits, cerebral blood flow, and oxidative stress in diabetic mice. Propionate in different doses (37.5, 75 and 150 mg/kg) was orally administrated daily. Here, we show that propionate can markedly improve neurological function, which is correlated with its capabilities of stimulating nitrogen monoxide (NO) production, increasing cerebral microcirculation, suppressing oxidative stress, and reducing neuron loss in the hippocampus. In addition, the results of Western Blotting indicated that the brain-protective function of propionate in streptozocin (STZ)-induced type 1 diabetes mellitus (T1DM) mice is related to phosphoinositide 3-kinase (PI3K)/serine-threonine protein kinase (Akt)/endothelial nitrogen monoxide synthase (eNOS) signaling pathway. In a diabetic mouse model, propionate reduces cerebral microcirculation, hippocampus apoptosis, and neurological impairment. Thus, propionate, now employed as a food preservative, may also help slow diabetes-induced cognitive loss.

18ß-Glycyrrhetinic acid alleviates demyelination by modulating the microglial M1/M2 phenotype in a mouse model of cuprizone-induced demyelination.

This research aimed to examine the nutritious supplementary function of 18ß-Glycyrrhetinic acid (18ß-GA) in moderating the myelin sheath destruction and behavioral impairments observed in the cuprizone model of demyelination. Mice were fed daily on food containing cuprizone (0.3 %) and given doses of 18ß-GA (5 or 1 mg/kg) for a period of five weeks. The groups treated with 18ß-GA exhibited improvements in exploratory behavior, locomotive activity, and weight. As assessed using luxol-fast blue and myelin basic protein (MBP) staining, which were used to detect demyelination in the brain, 18ß-GA both reduced and prevented instances of cuprizone-induced demyelinating lesions; treatment with 18ß-GA also caused the MBP level in the corpus callosum to increase. Furthermore, alongside these positive results following 18ß-GA treatment, microglial polarisation was also observed to shift towards the beneficial M2 phenotype. The results of this research thus indicate the potential clinical application of 18ß-GA for the prevention of myelin damage and behavioral dysfunction.

Insulin injections inhibits PTZ-induced mitochondrial dysfunction, oxidative stress and neurological deficits via the SIRT1/PGC-1α/SIRT3 pathway.

With an associated 20% death risk, epilepsy mainly involves seizures of an unpredictable and recurrent nature. This study was designed to evaluate the neuroprotective effects and underlying mechanisms of insulin on mitochondrial disruption, oxidative stress, cell apoptosis and neurological deficits after epilepsy seizures. Mice were exposed to repetitive injections of pentylenetetrazol at a dose of 37 mg per kg. The influence of insulin was assessed by many biochemical assays, histopathological studies and neurobehavioral experiments. The administration of insulin was proven to increase the latency of seizures while also decreasing their intensity. It also caused a reversal of mitochondrial dysfunction and ameliorated oxidative stress. Additionally, insulin pretreatment upregulated Bcl-2, downregulated Bax, and then played a neuroprotective role against hippocampal neuron apoptosis. Furthermore, when insulin was administered, SIRT1/PGC-1α/SIRT3 signals were activated, possibly due to the fact that insulin's neuroprotective and anti-mitochondrial damage characteristics added to its observed antiepileptic functions. Finally, insulin treatment is thus extremely valuable for effecting improvements in neurological functions, as has been estimated in a series of functional tests. In conclude, the results of this study consequently demonstrate insulin to have significant potential for future application in epilepsy management.

Butyrate alleviates PTZ-induced mitochondrial dysfunction, oxidative stress and neuron apoptosis in mice via Keap1/Nrf2/HO-1 pathway.

This study aims to evaluate the neuroprotective effect of sodium butyrate against the pentylenetetrazol (PTZ)-induced kindling epilepsy. Sodium butyrate (SB) (5, 10 and 20 mg/kg) and sodium valproate for 40 days and PTZ (37 mg/kg) injection every day were conducted for Kunming mice, to investigate seizure intensity and latency, oxidative stress parameters, mitochondrial structure and function, histopathology, and Keap1/Nrf2/HO-1 expressions. It is shown that seizure latency was effectively increased and the intensity of seizures decreased by treatment with sodium butyrate. It was also found to reverse the structural disruption of the mitochondria, reduce the ROS level and improve the levels of NAD + and ATP in the brains of epileptic mice. Furthermore, pretreatment with SB led to an increase in antioxidant enzyme activity (CAT, SOD and GSH-PX) in the brain as well as conferred a neuroprotective effect against neuron loss and apoptosis. The activation of Keap1/Nrf2/HO-1 signals was also identified, in which the antiepileptic effect of SB may be partially due to its anti-mitochondrial injury and neuroprotective activities. Accordingly, the results of a series of functional tests indicate a significant improvement of neurological function following SB treatment. In a mouse model of seizures, brain injury and neurological deficits can be attenuated by treatment with butyrate through the activation of Nrf2 pathway and the improvement of mitochondrial function.