Long-Term Ingestion of Sicilian Black Bee Chestnut Honey and/or D-Limonene Counteracts Brain Damage Induced by High Fat-Diet in Obese Mice.

Obesity is linked to neurodegeneration, which is mainly caused by inflammation and oxidative stress. We analyzed whether the long-term intake of honey and/or D-limonene, which are known for their antioxidant and anti-inflammatory actions, when ingested separately or in combination, can counteract the neurodegeneration occurring in high fat diet (HFD)-induced obesity. After 10 weeks of HFD, mice were divided into: HFD-, HFD + honey (HFD-H)-, HFD + D-limonene (HFD-L)-, HFD + honey + D-limonene (HFD-H + L)-fed groups, for another 10 weeks. Another group was fed a standard diet (STD). We analyzed the brain neurodegeneration, inflammation, oxidative stress, and gene expression of Alzheimer's disease (AD) markers. The HFD animals showed higher neuronal apoptosis, upregulation of pro-apoptotic genes Fas-L, Bim P27 and downregulation of anti-apoptotic factors BDNF and BCL2; increased gene expression of the pro-inflammatory IL-1ß, IL-6 and TNF-α and elevated oxidative stress markers COX-2, iNOS, ROS and nitrite. The honey and D-limonene intake counteracted these alterations; however, they did so in a stronger manner when in combination. Genes involved in amyloid plaque processing (APP and TAU), synaptic function (Ache) and AD-related hyperphosphorylation were higher in HFD brains, and significantly downregulated in HFD-H, HFD-L and HFD-H + L. These results suggest that honey and limonene ingestion counteract obesity-related neurodegeneration and that joint consumption is more efficacious than a single administration.

Aphanizomenon flos-aquae (AFA) Extract Prevents Neurodegeneration in the HFD Mouse Model by Modulating Astrocytes and Microglia Activation.

Obesity and related metabolic dysfunctions are associated with neurodegenerative diseases, such as Alzheimer's disease. Aphanizomenon flos-aquae (AFA) is a cyanobacterium considered a suitable supplement for its nutritional profile and beneficial properties. The potential neuroprotective effect of an AFA extract, commercialized as KlamExtra®, including the two AFA extracts Klamin® and AphaMax®, in High-Fat Diet (HFD)-fed mice was explored. Three groups of mice were provided with a standard diet (Lean), HFD or HFD supplemented with AFA extract (HFD + AFA) for 28 weeks. Metabolic parameters, brain insulin resistance, expression of apoptosis biomarkers, modulation of astrocytes and microglia activation markers, and Aß deposition were analyzed and compared in the brains of different groups. AFA extract treatment attenuated HFD-induced neurodegeneration by reducing insulin resistance and loss of neurons. AFA supplementation improved the expression of synaptic proteins and reduced the HFD-induced astrocytes and microglia activation, and Aß plaques accumulation. Together, these outcomes indicate that regular intake of AFA extract could benefit the metabolic and neuronal dysfunction caused by HFD, decreasing neuroinflammation and promoting Aß plaques clearance.

TRPM8 Channel Activation Reduces the Spontaneous Contractions in Human Distal Colon.

The transient receptor potential-melastatin 8 (TRPM8) is a non-selective Ca2+-permeable channel, activated by cold, membrane depolarization, and different cooling compounds. TRPM8 expression has been found in gut mucosal, submucosal, and muscular nerve endings. Although TRPM8 plays a role in pathological conditions, being involved in visceral pain and inflammation, the physiological functions in the digestive system remain unclear as yet. The aims of the present study were: (i) to verify the TRPM8 expression in human distal colon; (ii) to examine the effects of TRPM8 activation on colonic contractility; (iii) to characterize the mechanism of action. Reverse transcriptase-polymerase chain reaction (RT-PCR) and western blotting were used to analyze TRPM8 expression. The responses of human colon circular strips to different TRPM8 agonists [1-[Dialkyl-phosphinoyl]-alkane (DAPA) 2-5, 1-[Diisopropyl-phosphinoyl]-alkane (DIPA) 1-7, DIPA 1-8, DIPA 1-9, DIPA 1-10, and DIPA 1-12) were recorded using a vertical organ bath. The biomolecular analysis revealed gene and protein expression of TRPM8 in both mucosal and smooth muscle layers. All the agonists tested, except-DIPA 1-12, produced a concentration-dependent decrease in spontaneous contraction amplitude. The effect was significantly antagonized by 5-benzyloxytryptamine, a TRPM8 antagonist. The DIPA 1-8 agonist resulted in the most efficacious and potent activation among the tested molecules. The DIPA 1-8 effects were not affected by tetrodotoxin, a neural blocker, but they were significantly reduced by tetraethylammonium chloride, a non-selective blocker of K+ channels. Moreover, iberiotoxin, a blocker of the large-conductance Ca2+-dependent K+-channels, but not apamin, a blocker of small-conductance Ca2+-dependent K+ channels, significantly reduced the inhibitory DIPA 1-8 actions. The results of the present study demonstrated that TRPM8 receptors are also expressed in human distal colon in healthy conditions and that ligand-dependent TRPM8 activation is able to reduce the colonic spontaneous motility, probably by the opening of the large-conductance Ca2+-dependent K+-channels.

Pistachio Consumption Alleviates Inflammation and Improves Gut Microbiota Composition in Mice Fed a High-Fat Diet.

High-fat diet (HFD) induces inflammation and microbial dysbiosis, which are components of the metabolic syndrome. Nutritional strategies can be a valid tool to prevent metabolic and inflammatory diseases. The aim of the present study was to evaluate if the chronic intake of pistachio prevents obesity-associated inflammation and dysbiosis in HFD-fed mice. Three groups of male mice (four weeks old; n = 8 per group) were fed for 16 weeks with a standard diet (STD), HFD, or HFD supplemented with pistachios (HFD-P; 180 g/kg of HFD). Serum, hepatic and adipose tissue inflammation markers were analyzed in HFD-P animals and compared to HFD and STD groups. Measures of inflammation, obesity, and intestinal integrity were assessed. Fecal samples were collected for gut microbiota analysis. Serum TNF-α and IL-1ß levels were significantly reduced in HFD-P compared to HFD. Number and area of adipocytes, crown-like structure density, IL-1ß, TNF-α, F4-80, and CCL-2 mRNA expression levels were significantly reduced in HFD-P subcutaneous and visceral adipose tissues, compared to HFD. A significant reduction in the number of inflammatory foci and IL-1ß and CCL-2 gene expression was observed in the liver of HFD-P mice compared with HFD. Firmicutes/Bacteroidetes ratio was reduced in HFD-P mice in comparison to the HFD group. A pistachio diet significantly increased abundance of healthy bacteria genera such as Parabacteroides, Dorea, Allobaculum, Turicibacter, Lactobacillus, and Anaeroplasma, and greatly reduced bacteria associated with inflammation, such as Oscillospira, Desulfovibrio, Coprobacillus, and Bilophila. The intestinal conductance was lower in HFD-P mice than in the HFD mice, suggesting an improvement in the gut barrier function. The results of the present study showed that regular pistachio consumption improved inflammation in obese mice. The positive effects could be related to positive modulation of the microbiota composition.

Betalains: colours for human health.

In the last years, the use of natural phytochemical compounds as protective agents in the prevention and treatment of obesity and the related-metabolic syndrome has gained much attention worldwide. Different studies have shown health benefits for many vegetables such Opuntia ficus-indica and Beta vulgaris and their pigments collectively referred as betalains. Betalains exert antioxidative, anti-inflammation, lipid lowering, antidiabetic and anti-obesity effects. This review summarizes findings in the literature and highlights the therapeutic potential of betalains and their natural source as valid alternative for supplementation in obesity-related disorders treatment. Further research is needed to establish the mechanisms through which these natural pigments exert their beneficial effects and to translate the promising findings from animal models to humans.

Positive Impacts of Aphanizomenon Flos Aquae Extract on Obesity-Related Dysmetabolism in Mice with Diet-Induced Obesity.

The present study evaluated the ability of KlamExtra®, an Aphanizomenon flos aquae (AFA) extract, to counteract metabolic dysfunctions due to a high fat diet (HFD) or to accelerate their reversion induced by switching an HFD to a normocaloric diet in mice with diet-induced obesity. A group of HFD mice was fed with an HFD supplemented with AFA (HFD-AFA) and another one was fed with regular chow (standard diet-STD) alone or supplemented with AFA (STD-AFA). AFA was able to significantly reduce body weight, hypertriglyceridemia, liver fat accumulation and adipocyte size in HFD mice. AFA also reduced hyperglycaemia, insulinaemia, HOMA-IR and ameliorated the glucose tolerance and the insulin response of obese mice. Furthermore, in obese mice AFA normalised the gene and the protein expression of factors involved in lipid metabolism (FAS, PPAR-γ, SREBP-1c and FAT-P mRNA), inflammation (TNF-α and IL-6 mRNA, NFkB and IL-10 proteins) and oxidative stress (ROS levels and SOD activity). Interestingly, AFA accelerated the STD-induced reversion of glucose dysmetabolism, hepatic and VAT inflammation and oxidative stress. In conclusion, AFA supplementation prevents HFD-induced dysmetabolism and accelerates the STD-dependent recovery of glucose dysmetabolism by positively modulating oxidative stress, inflammation and the expression of the genes linked to lipid metabolism.

A Nutraceutical Containing Chlorogenic Acid and Luteolin Improves Cardiometabolic Parameters in Subjects with Pre-Obesity: A 6-Month Randomized, Double-Blind, Placebo-Controlled Study.

Pre-obesity is a condition that predisposes to the risk of developing obesity, cardiovascular diseases (CVD), and diabetes. Our previous study demonstrated that a Cynara cardunculus (L.) based nutraceutical named Altilix® (Bionap, Italy), containing chlorogenic acid and luteolin extracts, was able to improve several hepatic and cardio-metabolic parameters. Given this background, we conducted a post-hoc analysis of the Altilix® study in order to analyze the supplement's effects in the subgroup of pre-obesity subjects on anthropometry (weight and waist circumference), glucose metabolism (HbA1C, HOMA-IR, and HOMA-ß), lipid profile (total cholesterol, triglycerides, LDL-cholesterol and HDL-cholesterol), hepatic functionality (FLI, AST, ALT and AST/ALT), carotid-media thickness (CIMT) and endothelial function (FMD). Fifty subjects from the original study cohort (which consisted of 100 subjects) were chosen with BMI ≥ 25 and < 30 kg/m2. All subjects received the Altilix® supplement (150 mg/day) or placebo using a computer-based random allocation system. After six months of treatment Altilix® significantly reduced body weight, glycemic, and lipid parameters (total cholesterol, triglycerides, LDL-cholesterol) and improved hepatic functionality, CIMT, and FMD. In conclusion, these results confirm that Altilix® supplementation has a significant effect on cardiometabolic parameters not only in obese subjects but also in pre-obesity subjects.

Preventive Impact of Long-Term Ingestion of Chestnut Honey on Glucose Disorders and Neurodegeneration in Obese Mice.

The purpose of the present study was to evaluate the impact of long-term honey ingestion on metabolic disorders and neurodegeneration in mice fed a high-fat diet (HFD). Three groups of mice were fed with a standard diet (STD), HFD or HFD supplemented with honey (HFD-H) for 16 weeks. Biochemical, histological, Western blotting, RT-PCR and Profiler PCR array were performed to assess metabolic parameters, peripheral and central insulin resistance and neurodegeneration. Daily honey intake prevented the HFD-induced glucose dysmetabolism. In fact, it reduced plasma fasting glucose, insulin and leptin concentrations and increased adiponectin levels. It improved glucose tolerance, insulin sensitivity and HOMA index without affecting plasma lipid concentration. HFD mice showed a significantly higher number of apoptotic nuclei in the superficial and deep cerebral cortex, upregulation of Fas-L, Bim and P27 (neuronal pro-apoptotic markers) and downregulation of Bcl-2 and BDNF (anti-apoptotic factors) in comparison with STD- and HFD-H mice, providing evidence for honey neuroprotective effects. PCR-array analysis showed that long-term honey intake increased the expression of genes involved in insulin sensitivity and decreased genes involved in neuroinflammation or lipogenesis, suggesting improvement of central insulin resistance. The expressions of p-AKT and p-GSK3 in HFD-H mice, which were decreased and increased, respectively, in HFD mouse brain, index of central insulin resistance, were similar to STD animals supporting the ability of regular honey intake to protect brain neurons from insulin resistance. In conclusion, the present results provide evidence for the beneficial preventative impact of regular honey ingestion on neuronal damage caused by HFD.

From obesity to Alzheimer's disease through insulin resistance.

Alzheimer's disease is one of the most frequent forms of dementia. It is a progressive neurodegenerative disease, characterized by presence of amyloid plaques and neurofibrillary tangles in the brain. Obesity is regarded as abnormal fat accumulation with deleterious impact on human health. There is full scientific evidence that obesity and the metabolic comorbidities (e.g., insulin resistance, hyperglycaemia, and type 2 diabetes) are related to Alzheimer's disease and likely in the causative pathway. Numerous studies have identified several overlapping neurodegenerative mechanisms, including oxidative stress, mitochondrial dysfunction, and inflammation. In this review, we present how obesity and the associated lipotoxicity as well as chronic inflammation initiate a state of insulin resistance that in turn, may have a role in causing the characteristic cerebral alterations of AD. In particular, we focus on the molecular mechanisms linking the obesity-induced impairment in insulin signalling to the upregulation of Aß aggregation, tau hyper-phosphorylation, inflammation, oxidative stress and mitochondrial dysfunction.

Spasmolytic Effects of Aphanizomenon Flos Aquae (AFA) Extract on the Human Colon Contractility.

The blue-green algae Aphanizomenon flos aquae (AFA), rich in beneficial nutrients, exerts various beneficial effects, acting in different organs including the gut. Klamin® is an AFA extract particularly rich in ß-PEA, a trace-amine considered a neuromodulator in the central nervous system. To date, it is not clear if ß-PEA exerts a role in the enteric nervous system. The aims of the present study were to investigate the effects induced by Klamin® on the human distal colon mechanical activity, to analyze the mechanism of action, and to verify a ß-PEA involvement. The organ bath technique, RT-PCR, and immunohistochemistry (IHC) were used. Klamin® reduced, in a concentration-dependent manner, the amplitude of the spontaneous contractions. EPPTB, a trace-amine receptor (TAAR1) antagonist, significantly antagonized the inhibitory effects of both Klamin® and exogenous ß-PEA, suggesting a trace-amine involvement in the Klamin® effects. Accordingly, AphaMax®, an AFA extract containing lesser amount of ß-PEA, failed to modify colon contractility. Moreover, the Klamin® effects were abolished by tetrodotoxin, a neural blocker, but not by L-NAME, a nitric oxide-synthase inhibitor. On the contrary methysergide, a serotonin receptor antagonist, significantly antagonized the Klamin® effects, as well as the contractility reduction induced by 5-HT. The RT-PCR analysis revealed TAAR1 gene expression in the colon and the IHC experiments showed that 5-HT-positive neurons are co-expressed with TAAR1 positive neurons. In conclusion, the results of this study suggest that Klamin® exerts spasmolytic effects in human colon contractility through ß-PEA, that, by activating neural TAAR1, induce serotonin release from serotoninergic neurons of the myenteric plexus.

Indicaxanthin from Opuntia ficus-indica Fruit Ameliorates Glucose Dysmetabolism and Counteracts Insulin Resistance in High-Fat-Diet-Fed Mice.

Obesity-related dysmetabolic conditions are amongst the most common causes of death globally. Indicaxanthin, a bioavailable betalain pigment from Opuntia ficus-indica fruit, has been demonstrated to modulate redox-dependent signalling pathways, exerting significant anti-oxidative and anti-inflammatory effects in vitro and in vivo. In light of the strict interconnections between inflammation, oxidative stress and insulin resistance (IR), a nutritionally relevant dose of indicaxanthin has been evaluated in a high-fat diet (HFD) model of obesity-related IR. To this end, biochemical and histological analysis, oxidative stress and inflammation evaluations in liver and adipose tissue were carried out. Our results showed that indicaxanthin treatment significantly reduced body weight, daily food intake and visceral fat mass. Moreover, indicaxanthin administration induced remarkable, beneficial effects on HFD-induced glucose dysmetabolism, reducing fasting glycaemia and insulinaemia, improving glucose and insulin tolerance and restoring the HOMA index to physiological values. These effects were associated with a reduction in hepatic and adipose tissue oxidative stress and inflammation. A decrease in RONS, malondialdehyde and NO levels, in TNF-α, CCL-2 and F4-80 gene expression, in p65, p-JNK, COX-2 and i-NOS protein levels, in crown-like structures and hepatic inflammatory foci was, indeed, observed. The current findings encourage further clinical studies to confirm the effectiveness of indicaxanthin to prevent and treat obesity-related dysmetabolic conditions.

Altered insulin pathway compromises mitochondrial function and quality control both in in vitro and in vivo model systems.

Altered insulin signaling and insulin resistance are considered the link between Alzheimer's disease (AD) and metabolic syndrome. Here, by using an in vitro and an in vivo model, we investigated the relationship between these disorders focusing on neuronal mitochondrial dysfunction and mitophagy. In vitro Aß insult induced the opening of mitochondrial permeability transition pore (mPTP), mitochondrial membrane potential (ΔΨm) loss, and apoptosis while insulin addition ameliorated these dysfunctions. The same alterations were detected in a 16 weeks of age mouse model of diet-induced obesity and insulin resistance. In addition, we detected an increase of fission related proteins and activation of mitophagy, proved by the rise of PINK1 and Parkin proteins. Nevertheless, in vitro, the increase of p62 and LC3 indicated an alteration in autophagy, while, in vivo decreased expression of p62 and increase of LC3 suggested removing of damaged mitochondria. Finally, in aged mice (28 and 48 weeks), the data indicated impairment of mitophagy and suggested the accumulation of damaged mitochondria. Taken together these outcomes indicate that alteration of the insulin pathway affects mitochondrial integrity, and effective mitophagy is age-dependent.

Honey and obesity-related dysfunctions: a summary on health benefits.

Honey is a natural product, containing flavonoids and phenolic acids, appreciated for its therapeutic abilities since ancient times. Although the bioactive potential is linked to the composition, that is variable depending on mainly the botanical origin, honey has antioxidant and anti-inflammatory properties. Therefore, honey, administered alone or in combination with conventional therapy, might result useful in the management of chronic diseases that are commonly associated with oxidative stress and inflammation state. Obesity is a metabolic disorder characterized by visceral adiposity. The adipose tissue becomes hypertrophic and undergoes hyperplasia, resulting in a hypoxic environment, oxidative stress and production of pro-inflammatory mediators that can be responsible for other disorders, such as metabolic syndrome and neurodegeneration. Experimental evidence from animals have shown that honey improves glycemic control and lipid profile with consequent protection from endothelial dysfunction and neurodegeneration. The purpose of the present review is to summarize the current literature concerning the beneficial effects of honey in the management of the obesity-related dysfunctions, including neurodegeneration. Based on the key constituents of honey, the paper also highlights polyphenols to be potentially responsible for the health benefits of honey. Further well-designed and controlled studies are necessary to validate these benefits in humans.

Regular Intake of Pistachio Mitigates the Deleterious Effects of a High Fat-Diet in the Brain of Obese Mice.

：Obesity has been associated with neurodegeneration and cognitive dysfunctions. Recent data showed that pistachio consumption is able to prevent and ameliorate dyslipidemia, hepatic steatosis, systemic and adipose tissue inflammation in mice fed a high-fat diet (HFD). The present study investigated the neuroprotective effects of pistachio intake in HFD mice. Three groups of mice were fed a standard diet (STD), HFD, or HFD supplemented with pistachio (HFD-P) for 16 weeks. Metabolic parameters (oxidative stress, apoptosis, and mitochondrial dysfunction) were analyzed by using specific assays and biomarkers. The pistachio diet significantly reduced the serum levels of triglycerides and cholesterol in the HFD model. No difference was observed in the index of insulin resistance between HFD and HFD-P. A higher number of fragmented nuclei were found in HFD cerebral cortex compared to STD and HFD-P. A decrease in reactive oxygen species, singlet oxygen and phosphorylated extracellular signal-regulated kinase, and an increase of superoxide dismutase 2 and heme oxygenase expression were found in the brains of the HFD-P samples compared to HFD. Furthermore, the impaired mitochondrial function found in HFD brain was partially recovered in HFD-P mice. These results suggest that the regular intake of pistachio may be useful in preventing obesity-related neurodegeneration, being able to reduce both metabolic and cellular dysfunctions.

Natural Compounds as Beneficial Antioxidant Agents in Neurodegenerative Disorders: A Focus on Alzheimer's Disease.

The positive role of nutrition in chronic neurodegenerative diseases (NDs) suggests that dietary interventions represent helpful tools for preventing NDs. In particular, diets enriched with natural compounds have become an increasingly attractive, non-invasive, and inexpensive option to support a healthy brain and to potentially treat NDs. Bioactive compounds found in vegetables or microalgae possess special properties able to counteract oxidative stress, which is involved as a triggering factor in neurodegeneration. Here, we briefly review the relevant experimental data on curcuminoids, silymarin, chlorogenic acid, and compounds derived from the microalga Aphanizomenon flos aquae (AFA) which have been demonstrated to possess encouraging beneficial effects on neurodegeneration, in particular on Alzheimer's disease models.

Health benefits of pistachios consumption.

The health benefits of nuts, mainly in relation to the improvement of dysmetabolic conditions such as obesity, type 2 diabetes mellitus and the related cardiovascular diseases, have been widely demonstrated. Compared to other nuts, pistachios have a lower fat and caloric content, and contain the highest levels of unsaturated fatty acids, potassium, γ-tocopherol, phytosterols and xanthophyll carotenoids, all substances that are well known for their antioxidant and anti-inflammatory actions. This variety of nutrients contributes to the growing body of evidence that the consumption of pistachios improves health, leading to a greater potential of healthy antioxidant and anti-inflammatory activity, glycemic control, and endothelial function. The present review examines the nutrients and phytochemicals present in pistachios as well as the potential health benefits of including pistachios in a diet.

Pistachio Consumption Prevents and Improves Lipid Dysmetabolism by Reducing the Lipid Metabolizing Gene Expression in Diet-Induced Obese Mice.

Pistachios contain beneficial substances such as unsaturated fatty acids, phytosterols, and polyphenols. In the present study, we investigated if pistachio consumption is able to prevent or to revert hyperglycemia, dyslipidemia, hepatic steatosis, and adipose tissue morphological alterations caused by high fat diet (HFD) in the mouse. Moreover, the impact of pistachio intake on the mRNA expression of peroxisome proliferator-activated receptor γ (PPAR-γ), fatty acid transport proteins (FAT-P), fatty acid synthase (FAS), stearoyl-CoA desaturase (SCD1), and sterol regulatory element-binding transcription factor-1c (SREBP-1c) in liver and adipose tissue was also analyzed. No change in body weight, food intake, and hyperglycemia was observed between mice consuming pistachios (HFD-P) and HFD mice. Pistachio intake was able to prevent but not to reverse HFD-induced hypertriglyceridemia. Cholesterol plasma levels, steatosis grading, body fat mass, and adipocyte size were significantly lower in HFD-P group compared to HFD in both prevention and reversal protocol. Pistachio-diet was able to prevent HFD-induced overexpression of PPAR-γ, FAS, and SCD1 in the liver and SREBP-1c, PPAR-γ, and FAT-P in adipose tissue. Similarly, HFD-P significantly ameliorated the expression levels of FAT-P and SCD1 in the liver and SREBP-1c, FAS, and SCD1 in adipose tissue of obese mice. The present study shows that pistachio consumption is able to prevent and to ameliorate obesity-related dysfunctions by positively modulating the expression of genes linked to lipid metabolism.

A Natural Dietary Supplement with a Combination of Nutrients Prevents Neurodegeneration Induced by a High Fat Diet in Mice.

Obesity and metabolic disorders can be risk factors for the onset and development of neurodegenerative diseases. The aim of the present study was to investigate the protective effects of a natural dietary supplement (NDS), containing Curcuma longa, silymarin, guggul, chlorogenic acid and inulin, on dysmetabolism and neurodegeneration in the brains of high fat diet (HFD)-fed mice. Decrease in the expression of FACL-4, CerS-1, CerS-4, cholesterol concentration and increase in the insulin receptor expression and insulin signaling activation, were found in brains of NDS-treated HFD brains in comparison with HFD untreated-mice, suggesting that NDS is able to prevent brain lipid accumulation and central insulin resistance. In the brains of NDS-treated HFD mice, the levels of RNS, ROS and lipid peroxidation, the expression of p-ERK, H-Oxy, i-NOS, HSP60, NF-kB, GFAP, IL-1ß, IL-6 and CD4 positive cell infiltration were lower than in untreated HFD mice, suggesting antioxidant and anti-inflammatory effects of NDS. The decreased expression of p-ERK and GFAP in NDS-treated HFD mice was confirmed by immunofluorescence. Lastly, a lower number of apoptotic nuclei was found in cortical sections of NDS-treated HFD mice. The present data indicate that NDS exerts neuroprotective effects in HFD mice by reducing brain fat accumulation, oxidative stress and inflammation and improving brain insulin resistance.