Depression is a prevalent and debilitating condition that has a severe negative impact on a person's life. Chronic stress exposure plays a substantial role in the development of depression. In the present study, rats were exposed to chronic unpredictable mild stress (CUMS) for four weeks. Empagliflozin (EMPA), a Sodium-Glucose Cotransporter-2 (SGLT-2) inhibitor, is an oral antidiabetic agent exhibiting antioxidant, anti-inflammatory, and antiapoptotic effects. This study aimed to examine the antidepressant effect of EMPA in an experimental animal model of depression induced by CUMS in rats and explore the probable underlying mechanisms. Rats were treated with EMPA, per-orally, at a dose of 10 mg/kg/day for four weeks. EMPA treatment counteracted CUMS-induced histopathological, biochemical and behavioral alterations. EMPA suppressed the CUMS-induced increase in the oxidative stress, inflammatory, and apoptotic markers, where levels of MDA, IL-1β, TNF-α, NF-κB, NLRP3 and active caspase 3 were reduced by 29.6 %, 24.8 %, 17.9 %, 36.6 %, 24.5 % and 41.5 %, respectively, compared to the disease group. Furthermore, EMPA decreased the level of the microglial activation marker, iba-1 by 24 % in comparison to the disease group. In addition, EMPA treatment decreased blood glucose levels by 39 %, decreased serum insulin levels by 60.6 %, decreased HOMA-IR by 76.5 % and increased GLUT 4 expression, compared to the CUMS group, all which proves that EMPA has an effect insulin signaling and alleviates insulin resistance. Our results conclude that modulating key factors involved in depression, such as inflammation, oxidative stress, and NLRP3 inflammasome pathway, accounts for the anti-depressant effect of EMPA.

The potential link between metabolic syndrome (MetS) and the risk of dementia or cognitive impairment remains uncertain. This study aimed to assess the association between MetS and cognitive decline through a comprehensive review and meta-analysis of the existing literature.

A systematic search was conducted in Medline (PubMed), Web of Science, Scopus and Embase up to January 2023. Eligible studies included cohort and case-control designs. Statistical analyses were performed using STATA version 17.

A total of 20 studies comprising 5,727,594 participants were included. The pooled relative risk (RR) of cognitive impairment among individuals with MetS was 1.34 (95% CI: 1.25-1.43), indicating a significant association. Subgroup analyses revealed that the NCEP-ATP III criteria more effectively identified this relationship compared to other diagnostic methods. The association appeared strongest in Asian populations, followed by European and American groups.

This meta-analysis supports a significant association between MetS and cognitive impairment. Geographic variation in the strength of this relationship may be influenced by differences in diagnostic criteria and lifestyle factors. The findings underscore the importance of early screening and the development of region-specific public health interventions to mitigate cognitive decline in individuals with MetS.

Alzheimer's disease (AD)is an age-related neurodegenerative disease characterized by memory decline and cognitive impairment .AD is common in people aged > 65 years, though most of AD cases are sporadic, which accounts for 95%, and 1-5% of AD is caused by familial causes . The causes of AD are aging, environmental toxins, and cardiometabolic factors that induce the degeneration of cholinergic neurons. It has been shown that the metabolic syndrome which is a clustering of dissimilar constituents including insulin resistance (IR), glucose intolerance, visceral obesity, hypertension, and dyslipidemia is implicated in the pathogenesis of AD. Metabolic syndrome disapprovingly affects cognitive function and the development in AD by inducing the development of oxidative stress, neuroinflammation, and brain IR. These changes, together with brain IR, impair cerebrovascular reactivity causing cognitive impairment and dementia. Nevertheless, the fundamental mechanism by which metabolic syndrome persuades AD risk is not entirely explicated. Accordingly, this review aims to discuss the connotation between metabolic syndrome and AD. In conclusion, metabolic syndrome is regarded as a possible risk factor for the initiation of AD neuropathology by diverse signaling pathways such as brain IR, activation of inflammatory signaling pathways, neuroinflammation, defective proteostasis, and dysregulation of lipid mediators.

Synaptotagmin-7 (Syt7) KO mice show diurnal fluctuations of mania- and depression-like behavioral abnormalities. Although GluN2B-NMDAR hypoactivity has been shown to be involved in the induction of mania-like behaviors of the Syt7 KO mice in the dark phase, the reasons for the depression-like behaviors in the light phase and behavioral fluctuation remain unknown. Here, we show that bipolar I disorder (BDI)-patient-induced pluripotent stem cell (iPSC)-derived islet-like organoids exhibited Syt7-dependent insulin secretion defects; moreover, Syt7-deficiency-induced insulin hyposecretion generated depression-like behaviors in Syt7 KO mice in the light phase. Furthermore, pancreatic insulin secretion and neuronal activity showed opposite diurnal patterns, in which the Syt7-deficiency-induced disequilibrium induced periodic antagonistic shifts in the mania- and depression-like behaviors. Finally, using RNA sequencing (RNA-seq) analysis, we explored downstream pathways that might underlie the diurnal fluctuation of behaviors. Therefore, Syt7-deficiency-induced insulin hypoactivity contributed to light-phase depression-like behaviors and diurnal behavioral fluctuations in the mice.

Diabetic neuropathy (DN) is a prevalent and debilitating complication of diabetes mellitus, significantly impacting patient quality of life and contributing to morbidity and mortality. Affecting approximately 50% of patients with diabetes, DN is predominantly characterized by distal symmetric polyneuropathy, leading to sensory loss, pain, and motor dysfunction, often resulting in diabetic foot ulcers and lower-limb amputations. The pathogenesis of DN is multifaceted, involving hyperglycemia, dyslipidemia, oxidative stress, mitochondrial dysfunction, and inflammation, which collectively damage peripheral nerves. Despite extensive research, disease-modifying treatments remain elusive, with current management primarily focusing on symptom control. This review explores the complex mechanisms underlying DN and highlights recent advances in diagnostic and therapeutic strategies. Emerging insights into the molecular and cellular pathways have unveiled potential targets for intervention, including neuroprotective agents, gene and stem cell therapies, and innovative pharmacological approaches. Additionally, novel diagnostic tools, such as corneal confocal microscopy and biomarker-based tests, have improved early detection and intervention. Lifestyle modifications and multidisciplinary care strategies can enhance patient outcomes. While significant progress has been made, further research is required to develop therapies that can effectively halt or reverse disease progression, ultimately improving the lives of individuals with DN. This review provides a comprehensive overview of current understanding and future directions in DN research and management.

At present, there lacks a definitive pharmaceutical intervention or therapeutic approach for diabetes-associated cognitive impairment. Herein, we delved into the impact of electroacupuncture on cognitive function in high-fat diet/streptozocin (HFD/STZ)-induced type 2 diabetes mellitus (T2DM) mice and underlying mechanisms. Hippocampal insulin resistance was determined by western blot analysis. Cognitive function was evaluated by Morris water maze test. The morphology of the hippocampal neurons was observed through hematoxylin & eosin staining and Nissl staining. Synaptic plasticity was assessed by western blot analysis. Immunofluorescence, immunohistochemistry, western blot and real-time PCR were employed to detect the levels of ferroptosis markers, autophagy markers, and netrin-1. Electroacupuncture treatment exhibited ameliorative outcomes on hippocampal insulin resistance, spatial learning, memory function, neuronal damage, and synaptic plasticity in T2DM mice. Furthermore, it effectively suppressed neuronal ferroptosis in the hippocampus by upregulating GPX4 and SLC7A11 expression, and reducing 4-HNE expression. Meanwhile, electroacupuncture intervention increased the levels of Beclin1 and LC3II/LC3I, as well as decreased the levels of p62 and phosphorylated-mTOR in the hippocampus of T2DM mice, suggesting that electroacupuncture facilitated autophagy activation by inhibiting mTOR activity. 3-MA-mediated autophagy inhibition undermined the beneficial effects of electroacupuncture on neuronal ferroptosis and cognitive deficits in T2DM mice. Additionally, the beneficial effects of electroacupuncture on autophagy and ferroptosis was achieved by upregulation of netrin-1 in the hippocampus. Our study revealed that electroacupuncture therapy inhibited neuronal ferroptosis via the activation of autophagy, thereby ameliorating cognitive deficits in T2DM mice.

This study aims to investigate the association of global cognitive with chronic conditions, physical impairment, olfactory function, socio-demographics and other factors among older adults in the urban community, West Jakarta.

The cross-sectional study involved 334 older adults aged 60 years and older who resided in urban community Jakarta, Indonesia. Trained interviewers visited and evaluated the respondents in the sub-district office. Cognitive function is examined using Montreal Cognitive Assessment-Indonesian Version (MoCA-INA). Respondents were clinically examined using a standardized protocol, which included medical history, general physical examination, cognitive assessment, and blood test for diabetes.

Global cognitive impairment was significantly associated with being female (adjusted odd ratio [AOR]: 1.99, 95% CI: 1.14-3.50) and low education (AOR: 4.79, 95% CI: 2.80-8.18). Moreover diabetes, impaired balance, and olfactory dysfunction have AOR:3.23 (95% CI: 1.39-7.51), 2.55% (95% CI: 1.07-6.07), and 2.26 (95% CI: 1.32-3.85) respectively.

This paper highlights that cognitively impaired and diabetic as well as low education subject in urban community, West Jakarta, Indonesia. Global cognitive impairment was associated with being female, having obtained low levels of education, having diabetes, impaired balance and olfactory dysfunction.

Metabolic syndrome (MetS) and mild cognitive impairment (MCI) are interconnected conditions sharing common pathological pathways, such as inflammation and oxidative stress, leading to the concept of "metabolic-cognitive syndrome." This highlights their mutual influence and potential overlapping therapeutic strategies. Although lifestyle modifications remain essential, nutraceutical supplementation has emerged as a promising adjunct for the prevention and management of these preclinical conditions. This review examines clinical and translational evidence on commonly used nutraceuticals targeting shared pathophysiological mechanisms of MetS and MCI. By addressing inflammation, oxidative stress, and metabolic dysfunction, these supplements may offer a valuable approach to mitigating the progression and consequences of both conditions. Understanding their efficacy could provide practical tools to complement lifestyle changes, offering a more comprehensive strategy for managing metabolic-cognitive syndrome.

Highly reactive metabolic intermediates and other small molecules frequently react with amino acid side chains, leading to non-enzymatic posttranslational modifications (nPTMs) of proteins. The abundance of these modifications increases under high metabolic activity or stress conditions and can dramatically impact protein structure and function. Although protein quality control mechanisms typically mitigate the effects of these impaired proteins, in long-lived and degradation-resistant proteins, nPTMs accumulate. In some cases, such as cataract development and diabetes, clear links between nPTMs, aging, and disease progression have been established. In neurodegenerative diseases such as Alzheimer's and Parkinson's disease, a key question is whether accumulation of nPTMs is a cause or consequence of protein aggregation. This review focuses on major nPTMs found on proteins with central roles in neurodegenerative diseases such as α-synuclein, β-amyloid, and tau. We summarize current knowledge on the formation of these modifications and discuss their potential impact on disease onset and progression. Additionally, we examine what is known to date about how nPTMs impair cellular detoxification, repair, and degradation systems. Finally, we critically discuss the available methodologies to systematically investigate nPTMs at the molecular level and outline suitable approaches to study their effects on protein aggregation. We aim to foster more research into the role of nPTMs in neurodegeneration by adapting methodologies that have proven successful in studying enzymatic posttranslational modifications. Specifically, we advocate for site-specific incorporation of these modifications into target proteins using advanced chemical and molecular biology techniques.

The prevalence of Alzheimer's disease or dementia in the elderly population has been increasing both nationally and globally. Males and females are impacted differently when it comes to cognitive health, and this can be influenced by various risk factors.

This study highlights the sociodemographic, chronic disease, and genetic biomarker risk factors associated with gender differences and cognitive impairments in the elderly population living in Cochran, Parmer, and Bailey counties of rural West Texas.

Cross tabulation, Pearson's chi-squared, two sample proportions, binary logistic regression, and multinomial logistic regression were utilized to analyze data. SPSS software was used to detect significant risk factors.

Using a bivariate logistic regression, the age group 70 and above of males and females for the Cochran and Parmer counties was found significantly associated with cognitive impairment. Anxiety, depression, diabetes, and cardiovascular disease were found to be significantly associated with an increased risk of cognitive impairment in females in Parmer County. Gender differences were observed in Cochran County for smoking but females in Bailey County were found to be more tobacco-dependent compared to other counties. However, in Cochran County the prevalence of cognitive impairment with rates of 66% for males and 70% for females was observed to be significantly lower in hypertensive group who consumed modified diet.

Gender-based disparities in cognitive impairment are essential for gaining more insights into Alzheimer's disease or dementia prevention and advancement of healthcare and medical approaches in the underserved rural communities of West Texas.

Our systematic review and meta-analysis aimed to uncover the relationship between UPFs intake and neurodegenerative disorders, including multiple sclerosis (MS), Parkinson's disease (PD), Alzheimer's disease (AD), cognitive impairment, and dementia.

A systematic search was conducted using the Scopus, PubMed/MEDLINE, and ISI Web of Science databases without any limitation until June 24, 2023. Relative risk (RR) and 95% confidence interval (CI) were pooled by using a random-effects model, while validated methods examined quality and publication bias via Newcastle-Ottawa Scale, Egger's regression asymmetry, and Begg's rank correlation tests, respectively.

Analysis from 28 studies indicated that a higher UPFs intake was significantly related to an enhanced risk of MS (RR = 1.15; 95% CI: 1.00, 1.33; I2 = 37.5%; p = 0.050; n = 14), PD (RR = 1.56; 95% CI: 1.21, 2.02; I2 = 64.1%; p = 0.001; n = 15), and cognitive impairment (RR = 1.17; 95% CI: 1.06, 1.30; I2 = 74.1%; p = 0.003; n = 17), although not AD or dementia. We observed that a 25 g increment in UPFs intake was related to a 4% higher risk of MS (RR = 1.04; 95% CI: 1.01, 1.06; I2 = 0.0%; p = 0.013; n = 7), but not PD. The non-linear dose-response relationship indicated a positive non-linear association between UPF intake and the risk of MS (Pnonlinearity = 0.031, Pdose-response = 0.002). This association was not observed for the risk of PD (Pnonlinearity = 0.431, Pdose-response = 0.231).

These findings indicate that persistent overconsumption of UPFs may have an adverse impact on neurodegenerative conditions, potentially leading to a decline in quality of life and reduced independence as individuals age.

Although pesticides have been a constant concern for decades, in the last ten years, public discussions and scientific research have emphasized their impact on human health and the environment, drawing increased attention to the problems associated with their use. The association of environmental stressors such as pesticides with a sugar-rich diet can contribute to the growing global metabolic disease epidemic through overlapping mechanisms of insulin resistance, inflammation, and metabolic dysregulation. The main aim of this study was to evaluate the behavioral effects of the exposure of Silver crucian carp (Carassius auratus gibelio) to a commercial insecticide formulation containing fipronil, pyriproxyfen, and other additives, as well as sucrose and their mixtures. The behavioral responses in the T-test showed significant abnormalities in the exploratory activity evocative of memory deficits and an increased degree of anxiety in the groups of fish treated with the insecticide formulation and the mixture of the insecticide with sucrose. Aggression, quantified in the mirror-biting test, as biting and the frequency of approaches to the mirror contact zone, was significantly decreased only in the insecticide and sucrose group. All three groups showed behavioral changes reflective of toxicity, but only the combination of the two stress factors, environmental (insecticide) and metabolic (sucrose intake), resulted in pronounced memory alterations.

Degenerative diseases and injuries of central nervous system (CNS) often cause nerve cell apoptosis and neural dysfunction. Protection of surviving cells or inducing the differentiation of stem cells into functional cells is considered to be an important way of neurorepair. In addition, transdifferentiation technology emerged recently is expected to provide new solutions for nerve regeneration. Cell surface receptors are transmembrane proteins embedded in cytoplasmic membrane, and play crucial roles in maintaining communication between extracellular signals and intracellular signaling processes. The extracellular microenvironment changed dramatically upon neural lesion, exploring the biological function of signals mediated by cell surface receptors will help to develop molecular strategies for nerve regeneration. An increasing number of studies have reported that cell surface receptor-mediated signaling affects the survival, differentiation, and functioning of neural cells, and even regulate their trans-lineage reprogramming. Here, we provide a review on the roles of cell surface receptors in CNS regeneration, thus providing new cues for better treatment of neurodegenerative diseases or nerve injury.

Metabolic syndrome (MetS) is usually associated with cognitive impairment, neuropathic pain, and reduced brain-derived neurotrophic factor (BDNF) levels. BDNF via tropomyosin receptor kinase B (TrkB) exerts neuroprotection by activating protein kinase B (Akt) to inhibit glycogen synthase kinase-3β (GSK3β). Although Vitamin D3 (VitD3) has demonstrated favorable metabolic and neuronal outcomes in MetS, the precise molecular mechanisms underlying its neuroprotective effects remain poorly elucidated. We aimed to test the hypothesis that VitD3 mitigates MetS-induced cognition deficits and neuropathic pain via modulating the BDNF/TRKB/Akt/GS3Kβ signaling pathway. MetS was induced in male rats by 10% fructose-supplemented water and 3% salt-enriched diet. After 6 weeks, normal and MetS rats received either vehicle or VitD3 (10 µg/kg/day) for an additional 6 weeks. Glycemic status, lipid profile, and behavioral changes were assessed. The advanced glycation end products (AGEs), and markers of inflammation (TNF-α and NF-κB), oxidative stress (malondialdehyde), and apoptosis (caspase3), as well as BDNF, TrkB, PI3K, Akt, GSK3β, phosphorylated tau, and amyloid beta (Aβ) were assessed in the cerebral cortex. MetS rats had deteriorated glycemic and lipid profiles, higher AGEs, reduced levels of BDNF, TrkB, PI3K, and active Akt, along with increased GSK3β levels, inflammation, oxidative stress, and apoptosis. These changes were associated with higher levels of cognitive impairment markers phosphorylated tau and Aβ, as well as behavioral changes indicative of cognitive impairment and neuropathic pain. VitD3 improved the cognitive and behavioral alterations, while mitigating the associated molecular derangements. Our results indicate that VitD3 may exert neuroprotective effects by modulating the BDNF/TrkB/PI3K/Akt/GSK3β signaling pathway.

Diabetes is a major risk factor for Alzheimer's disease (AD). Amino acid compound 2 (AAC2) improves glycemic and cognitive functions in diabetic mouse models through mechanisms distinct from insulin. Our goal was to compare the effects of AAC2, insulin, and their nanofiber-forming combination on early asymptomatic AD pathogenesis in APP/PS1 mice. Insulin, but not AAC2 or the combination treatment (administered intraperitoneally every 48 h for 120 days), increased seizure-related mortality, altered the brain fat-to-lean mass ratio, and improved specific cognitive functions in APP/PS1 mice. NanoString and pathway analysis of cerebral gene expression revealed dysregulated synaptic mechanisms, with upregulation of Bdnf and downregulation of Slc1a6 in insulin-treated mice, correlating with insulin-induced seizures. In contrast, AAC2 promoted the expression of Syn2 and Syp synaptic genes, preserved brain composition, and improved survival. The combination of AAC2 and insulin counteracted free insulin's effects. None of the treatments influenced canonical amyloidogenic pathways. This study highlights AAC2's potential in regulating synaptic gene expression in AD and insulin-induced contexts related to seizure activity.

Golden tomato (GT), harvested at the veraison stage, has gained attention due to its rich content of bioactive compounds and potential health benefits. Previous studies have highlighted GT's antioxidant properties and its positive effects on metabolic syndrome (MetS), a condition characterized by obesity, dyslipidemia, and oxidative stress. This study investigates for the first time a derivative from GT, i.e., the juice (GTJ), which could be a potential candidate for development as a functional food. We first characterized GT juice, identifying 9-oxo-10(E),12(E)-octadecadienoic (9-oxo-10(E),12(E)-ODA) fatty acid, a known peroxisome proliferator-activated receptor alpha (PPAR-α) agonist, using High-Performance Liquid Chromatography (HPLC)-mass spectrometry. Then, using a high-fat-diet (HFD) rat model, we assessed the impact of daily GT juice supplementation in addressing MetS. We outlined that GTJ improved body weight and leptin-mediated food intake. Moreover, it ameliorated glucose tolerance, lipid profile, systemic redox homeostasis, hepatic oxidative stress, and steatosis in HFD rats. Furthermore, GT juice enhances the hepatic transcription of PPAR-α, thus putatively promoting fatty acid oxidation and lipid metabolism. These findings suggest that GT juice mitigates lipidic accumulation and putatively halters oxidative species at the hepatic level through PPAR-α activation. Our study underscores the protective effects of GT juice against MetS, highlighting its future potential as a nutraceutical for improving dysmetabolism and associated alterations.

Peroxisome proliferator-activated receptors (PPARs) have emerged as a promising target for the treatment of various neurodegenerative disorders. Studies have shown that both PPAR α & γ individually modulate various pathophysiological events like neuroinflammation and insulin resistance, which are known to variedly affect neurogenesis. Our study aimed to evaluate the effect of saroglitazar (SGZR), a dual PPAR agonist, on adult neurogenesis and spatial learning and memory, in intracerebroventricular streptozotocin (ICV STZ)-induced dementia in rats. We have found that SGZR at the dose of 4 mg/kg per oral showed significant improvement in learning and memory compared to ICV STZ-treated rats. A substantial increase in neurogenesis was observed in the subventricular zone (SVZ) and the dentate gyrus (DG), as indicated by an increase in the number of 5-bromo-2'-deoxyuridine (BrdU)+ cells, BrdU+ nestin+ cells, and doublecortin (DCX)+cells. Treatment with SGZR also decreased the active form of glycogen synthase kinase 3β (GSK3β) and hence enhanced the nuclear translocation of the β-catenin. Enhanced expression of Wnt transcription factors and target genes indicates that the up-regulation of Wnt signaling might be involved in the observed increase in neurogenesis. Hence, it can be concluded that the SGZR enhances memory functions and adult neurogenesis via the upregulation of Wnt β-catenin signaling in ICV STZ-treated rats.

Insulin resistance, induced by high fructose consumption, affects cognitive function negatively. Nifedipine may be suggested for neurological disorders. This study aimed to assess the effect of nifedipine with either a normal diet (ND) or a ketogenic diet (KD) in cognitive dysfunction. Male Wistar rats received 10% fructose in drinking water for 8 weeks to induce insulin resistance. Rats received nifedipine (5.2 mg/kg/day; p.o.) later with ND or KD for an additional five weeks. One and two-way ANOVAs were used in analyzing the data. Reversion to the ND improved insulin resistance and lipid profile, besides brain-derived neurotrophic factor (BDNF), glycogen synthase kinase-3 beta (GSK3β), and insulin-degrading enzyme (IDE) levels. Rats fed KD alone and those that received nifedipine with KD did not show similar improvement in the previously mentioned parameters as the ND group. However, nifedipine-ND rats showed improvement in cognitive behavior and insulin resistance. Treatment with nifedipine-KD ameliorated GSK3β, amyloid β (Aβ), and tau protein levels. As the nifedipine-KD combination succeeded in diminishing the accumulated Aβ and tau protein, KD may be used for a while due to its side effects, then nifedipine treatment could be continued with an ND. This conclusion is based on the finding that this combination mitigated insulin resistance with the associated improved behavior.

A wealth of evidence underscores the bioactive properties of nutraceuticals and functional foods in addressing oxyinflammatory-based diseases with implications at both peripheral and central levels. Opuntia ficus-indica (OFI) is well-documented for its health-promoting attributes, though its fruit (OFIF) remains relatively understudied. Not only poses Metabolic Syndrome (MetS) cardiometabolic risks but also contributes significantly to cognitive impairment, especially in crucial brain areas such as hippocampus and hypothalamus.

Following 8 weeks of HFD to induce MetS, rats received OFIF oral supplementation for 4 weeks to evaluate cognitive and affective modifications using behavioural paradigms, i.e. open field, burrowing, white-dark box, novelty-suppressed feeding, and object recognition tests. Our investigation extended to biochemical evaluations of lipid homeostasis, central and peripheral oxidative stress and neurotrophic pathways, correlating these measures together with circulating leptin levels.

Our data revealed that OFIF modulation of leptin positively correlates with systemic and brain oxidative stress, with markers of increased anxiety-like behaviour and impaired lipid homeostasis. On the other hand, leptin levels reduced by OFIF are associated with improved antioxidant barriers, declarative memory and neurotrophic signalling.

This study underscores OFIF neuroactive potential in the context of MetS-associated cognitive impairment, offering insights into its mechanisms and implications for future therapeutic strategies.

Alzheimer's disease (AD) is a progressive central neurodegenerative disorder with an insidious onset. With global aging, the incidence and mortality of AD have been steadily increasing, yet effective treatments remain elusive. Obesity, characterized by excessive or abnormal fat accumulation, is a complex metabolic disorder and a confirmed risk factor for numerous diseases. Both obesity and AD have become major public health concerns, posing significant threats to human health and economic development. Studies have revealed a strong correlation between obesity and AD, with multiple contributing factors, including metabolic abnormalities of endocrine factors, inflammatory responses, and genetic interactions. Exploring the correlation and mechanisms between obesity and AD provides important insights and new strategies for the prevention and treatment of AD.

The Mediterranean diet (MedDiet) has demonstrated efficacy in preventing age-related cognitive decline and modulating plasma concentrations of endocannabinoids (eCBs) and N-acylethanolamines (NAEs, or eCB-like compounds), which are lipid mediators involved in multiple neurological disorders and metabolic processes. Hypothesizing that eCBs and NAEs will be biomarkers of a MedDiet intervention and will be related to the cognitive response, we investigated this relationship according to sex and apolipoprotein E (APOE) genotype, which may affect eCBs and cognitive performance.

This was a prospective cohort study of 102 participants (53.9% women, 18.8% APOE-ɛ4 carriers, aged 65.6 ± 4.5 years) from the PREDIMED-Plus-Cognition substudy, who were recruited at the Hospital del Mar Research Institute (Barcelona). All of them presented metabolic syndrome plus overweight/obesity (inclusion criteria of the PREDIMED-Plus) and normal cognitive performance at baseline (inclusion criteria of this substudy). A comprehensive battery of neuropsychological tests was administered at baseline and after 1 and 3 years. Plasma concentrations of eCBs and NAEs, including 2-arachidonoylglycerol (2-AG), anandamide (AEA), oleoylethanolamide (OEA), palmitoylethanolamide (PEA), and N-docosahexaenoylethanolamine (DHEA), were also monitored. Baseline cognition, cognitive changes, and the association between eCBs/NAEs and cognition were evaluated according to gender (crude models), sex (adjusted models), and APOE genotype.

At baseline, men had better executive function and global cognition than women (the effect size of gender differences was - 0.49, p = 0.015; and - 0.42, p = 0.036); however, these differences became nonsignificant in models of sex differences. After 3 years of MedDiet intervention, participants exhibited modest improvements in memory and global cognition. However, greater memory changes were observed in men than in women (Cohen's d of 0.40 vs. 0.25; p = 0.017). In men and APOE-ε4 carriers, 2-AG concentrations were inversely associated with baseline cognition and cognitive changes, while in women, cognitive changes were positively linked to changes in DHEA and the DHEA/AEA ratio. In men, changes in the OEA/AEA and OEA/PEA ratios were positively associated with cognitive changes.

The MedDiet improved participants' cognitive performance but the effect size was small and negatively influenced by female sex. Changes in 2-AG, DHEA, the OEA/AEA, the OEA/PEA and the DHEA/AEA ratios were associated with cognitive changes in a sex- and APOE-dependent fashion. These results support the modulation of the endocannabinoid system as a potential therapeutic approach to prevent cognitive decline in at-risk populations.

ISRCTN89898870.

This study aimed to assess the relationship between A Body Shape Index (ABSI) and cognitive impairment among older adults in the United States.

This cross-sectional study analyzed cognitive function in 2,752 individuals aged 60 and older using data from the 2011-2014 National Health and Nutrition Examination Survey (NHANES). Cognitive assessments were conducted using the Immediate Recall Test (IRT), Delayed Recall Test (DRT), Animal Fluency Test (AFT), and Digit Symbol Substitution Test (DSST). A Body Shape Index (ABSI) was calculated from waist circumference (WC), weight, and height. The relationship between ABSI and cognitive outcomes was examined through multifactorial linear regression, smooth curve fitting, and subgroup and interaction analyses.

With complete data, 2752 persons 60 and older participated in the study. After adjusting for covariables, these results showed statistically significant negative relationships between ABSI, IRT, and DSST scores. The negative correlation between DSST and ABSI is more substantial in males than females. There is less of a negative link between ABSI, AFT, and DSST among drinkers who consume 12 or more drinks annually compared to those who consume less. Furthermore, compared to individuals without high blood pressure(HBP), those who suffered HBP showed a more significant negative connection between ABSI and AFT.

Lower cognitive function was linked to higher ABSI.

Diabetic encephalopathy (DE), characterized by cognitive impairment, currently lacks targeted treatment. Previous studies have shown that Sarcandra glabra extracted residue polysaccharide (SERP) exhibited hypoglycemic effects either in vitro or in streptozotocin-induced diabetes mice. However, the therapeutic effect of SERP on DE was not elucidated. This study investigated the therapeutic effect of SERP on DE and its underlying mechanism. Our results revealed that SERP regulates glucose and lipid metabolism, improves cognitive function, and exhibits diminished activity post-antibiotic intervention. Importantly, we discovered a novel mechanism by which SERP modulates the gut microbiota, specifically enriching Bacteroidales S24-7, resulting in elevated levels of butyric acid in the intestine. This regulation modulates the intestinal endocrine cell lipid metabolism level, restores damaged intestinal barriers and neural epithelial circuits, thus exhibiting cure effects. Our findings suggest that SERP could become a candidate for treating DE, potentially involving the regulation mechanism of the "microbiota-gut-brain axis". This study underscores the unique therapeutic efficacy of SERP in managing DE, offering fresh drug candidates and innovative treatment strategies for this challenging condition.

Dihydroquercetin (DHQ) is commonly used as a dietary additive, but its activity in improving brain injury with metabolic syndrome (MS) remains known. In present study, the MS rat model was induced using 10 % fructose water. The apoptosis rate of primary brain cells was detected. The HIF-1α/AKT/NR2B signalling pathway, levels of KEAP1/NRF2, HO-1 and NQO-1 were detected. In vitro experiments were performed using H2O2-stimulated PC-12 cells. The effect of DHQ on rates of cell survival and apoptosis were detected. After silencing HIF-1α, we further elucidate the mechanism of action of DHQ. The results indicated that DHQ reduced the hyperactivity and inhibited oxidative stress via increasing the levels of HIF-1α/AKT/NR2B signalling pathway, whereas regulated KEAP1/NRF2 pathway. In vitro experiments showed that the HIF-1α plays an important role in this process. Overall, DHQ may improve impaired brain function in rats with metabolic syndrome by regulating the HIF-1α/AKT/NR2B signalling pathway.

Clinical and epidemiological research shows that people with diabetes mellitus frequently experience diabetic cognitive impairment. Schisandrin A (SchA), one of the lignans found in the dried fruit of Schisandra chinensis, has a variety of pharmacological effects on immune system control, apoptosis suppression, anti-oxidation and anti-inflammation. The goal of the current investigation was to clarify the probable neuro-protective effects of SchA against streptozotocin-induced diabetes deficiencies of the spatial learning and memory in rats. The outcomes show that SchA therapy effectively improved impaired glucose tolerance, fasting blood glucose level and serum insulin level in diabetic rats. Additionally, in the Morris water maze test, diabetic rats showed deficits in spatial learning and memory that were ameliorated by SchA treatment. Moreover, giving diabetic rats SchA reduced damage to the hippocampus structure and increased the production of synaptic proteins. Further research revealed that SchA therapy reduced diabetic-induced hippocampus neuron damage and the generation of Aβ, as demonstrated by the upregulated phosphorylation levels of insulin signaling pathway connected proteins and by the decreased expression levels of inflammatory-related factors. Collectively, these results suggested that SchA could improve diabetes-related impairments in spatial learning and memory, presumably by reducing inflammatory responses and regulating the insulin signaling system.

Neurodegenerative diseases (NDDs) have been increasing in incidence in recent years and are now widespread worldwide. Neuronal death is defined as the progressive loss of neuronal structure or function which is closely associated with NDDs and represents the intrinsic features of such disorders. Amyotrophic lateral sclerosis, frontotemporal dementia, Alzheimer's, Parkinson's, and Huntington's diseases (AD, PD, and HD, respectively) are considered neurodegenerative diseases that affect a large number of people worldwide. Despite the testing of various drugs, there is currently no available therapy that can remedy or effectively slow the progression of these diseases. Nanomedicine has the potential to revolutionize drug delivery for the management of NDDs. The use of nanoparticles (NPs) has recently been developed to improve drug delivery efficiency and is currently subjected to extensive studies. Nanoengineered particles, known as nanodrugs, can cross the blood-brain barrier while also being less invasive compared to the most treatment strategies in use. Polymeric, magnetic, carbonic, and inorganic NPs are examples of NPs that have been developed to improve drug delivery efficiency. Primary research studies using NPs to cure AD are promising, but thorough research is needed to introduce these approaches to clinical use. In the present review, we discussed the role of metal-based NPs, polymeric nanogels, nanocarrier systems such as liposomes, solid lipid NPs, polymeric NPs, exosomes, quantum dots, dendrimers, polymersomes, carbon nanotubes, and nanofibers and surfactant-based systems for the therapy of neurodegenerative diseases. In addition, we highlighted nanoformulations such as N-butyl cyanoacrylate, poly(butyl cyanoacrylate), D-penicillamine, citrate-coated peptide, magnetic iron oxide, chitosan (CS), lipoprotein, ceria, silica, metallic nanoparticles, cholinesterase inhibitors, an acetylcholinesterase inhibitors, metal chelators, anti-amyloid, protein, and peptide-loaded NPs for the treatment of AD.

Early-onset dementia (EOD, onset age < 65) and late-onset dementia (LOD, onset age ≥ 65) exhibit distinct features. Understanding the risk factors for dementia development and mortality in EOD and LOD respectively is crucial for personalized care. While risk factors are known for LOD development and mortality, their impact on EOD remains unclear. We aimed to investigate how hypertension, diabetes mellitus, hyperlipidemia, atrial fibrillation, and osteoporosis influence the development and mortality of EOD and LOD, respectively.

Using the Korean National Health Insurance Service (NHIS) database, we collected 546,709 dementia-free individuals and followed up for 11 years. In the two study groups, the Younger group (< 65 years old) and the Older group (≥ 65 years old), we applied Cox proportional hazard models to assess risk factors for development of EOD and LOD, respectively. Then, we assessed risk factors for mortality among EOD and LOD.

Diabetes mellitus and osteoporosis increased the risk of EOD and LOD development. Hypertension increased the risk of EOD, while atrial fibrillation increased the risk of LOD. Conversely, hyperlipidemia exhibited a protective effect against LOD development. Additionally, diabetes mellitus increased mortality in EOD and LOD. Hypertension and atrial fibrillation increased mortality in LOD, while hyperlipidemia decreased mortality in EOD and LOD.

Risk factors influencing dementia development and mortality differed in EOD and LOD. Targeted public health interventions addressing age-related risk factors may reduce dementia incidence and mortality.

While insulin sensitivity plays an important role in maintaining glucose metabolic homeostasis and cognitive function, its impact on postoperative delirium (POD) remains unclear. This study aimed to investigate the association between POD and indicators of insulin sensitivity, including insulin resistance and osteocalcin.

A total of 120 elderly patients undergoing joint replacement were recruited and divided into delirium and non-delirium groups. Plasma and cerebrospinal fluid (CSF) samples were collected for the analysis of biomarkers, including insulin, uncarboxylated osteocalcin (ucOC), total osteocalcin (tOC), and glucose. Insulin resistance was assessed through the homeostatic model assessment of insulin resistance (HOMA-IR).

Out of the total, 28 patients (23.3%) experienced POD within 5 days after surgery. Patients with delirium exhibited higher levels of preoperative HOMA-IR and ucOC in CSF and plasma, and of tOC in CSF (P = 0.028, P < 0.001, P = 0.005, P = 0.019). After adjusting for variables, including age, Mini-Mental State Examination score, surgical site and preoperative fracture, only preoperative ucOC in CSF and HOMA-IR were significantly linked to the incidence of delirium (OR = 5.940, P = 0.008; OR = 1.208, P = 0.046, respectively), both of which also correlated with the severity of delirium (P = 0.007, P < 0.001). Receiver operating curve analysis indicated that preoperative HOMA-IR and ucOC in CSF might partly predict POD (area under the curve [AUC] = 0.697, 95% confidence interval [CI] = 0.501-0.775, AUC = 0.745, 95% CI = 0.659-0.860).

We observed that preoperative elevated HOMA-IR and ucOC in CSF were associated with the incidence and severity of POD. While these preliminary results need confirmation, they suggest a potential involvement of insulin resistance and osteocalcin in the pathological mechanism of POD. Geriatr Gerontol Int 2024; 24: 421-429.

Dementia has been faced with significant public health challenges and economic burdens that urges the need to develop safe and effective interventions. In recent years, an increasing number of studies have focused on the relationship between dementia and liver and pancreatic metabolic disorders that result in diseases such as diabetes, obesity, hypertension and dyslipidemia. Previous reports have shown that there is a plausible correlation between pathologies caused by hepatopancreatic dysfunctions and dementia. Glucose, insulin and IGF-1 metabolized in the liver and pancreas probably have an important influence on the pathophysiology of the most common dementias: Alzheimer's and vascular dementia. This current review highlights recent studies aimed at identifying convergent mechanisms, such as insulin resistance and other diseases, linked to altered hepatic and pancreatic metabolism, which are capable of causing brain changes that ultimately lead to dementia.

Cognitive impairment poses a considerable health challenge in the context of type 2 diabetes mellitus (T2DM), emphasizing the need for effective interventions. This study delves into the therapeutic efficacy of quercetin, a natural flavonoid, in mitigating cognitive impairment induced by T2DM in murine models.

Serum exosome samples were obtained from both T2DM-related and healthy mice for transcriptome sequencing, enabling the identification of differentially expressed mRNAs and long noncoding RNAs (lncRNAs). Subsequent experiments were conducted to ascertain the binding affinity between mmu-miR-129-5p, NEAT1 and BDNF. The structural characteristics and dimensions of isolated exosomes were scrutinized, and the expression levels of exosome-associated proteins were quantified. Primary mouse hippocampal neurons were cultured for in vitro validation, assessing the expression of pertinent genes as well as neuronal vitality, proliferation, and apoptosis capabilities. For in vivo validation, a T2DM mouse model was established, and quercetin treatment was administered. Changes in various parameters, cognitive ability, and the expression of insulin-related proteins, along with pivotal signaling pathways, were monitored.

Analysis of serum exosomes from T2DM mice revealed dysregulation of NEAT1, mmu-miR-129-5p, and BDNF. In vitro investigations demonstrated that NEAT1 upregulated BDNF expression by inhibiting mmu-miR-129-5p. Overexpression of mmu-miR-129-5p or silencing NEAT1 resulted in the downregulation of insulin-related protein expression, enhanced apoptosis, and suppressed neuronal proliferation. In vivo studies validated that quercetin treatment significantly ameliorated T2DM-related cognitive impairment in mice.

These findings suggest that quercetin holds promise in inhibiting hippocampal neuron apoptosis and improving T2DM-related cognitive impairment by modulating the NEAT1/miR-129-5p/BDNF pathway within serum exosomes.

Systemic chronic inflammation is recognized as a significant contributor to the development of obesity-related insulin resistance. Previous studies have revealed the physiological benefits of resistant dextrin (RD), including obesity reduction, lower fasting glucose levels, and anti-inflammation. The present study investigated the effects of RD intervention on insulin resistance (IR) in Kunming mice, expounding the mechanisms through the gut microbiome and transcriptome of white adipose. In this eight-week study, we investigated changes in tissue weight, glucose-lipid metabolism levels, serum inflammation levels, and lesions of epididymal white adipose tissue (eWAT) evaluated via Hematoxylin and Eosin (H&E) staining. Moreover, we analyzed the gut microbiota composition and transcriptome of eWAT to assess the potential protective effects of RD intervention. Compared with a high-fat, high-sugar diet (HFHSD) group, the RD intervention significantly enhanced glucose homeostasis (e.g., AUC-OGTT, HOMA-IR, p < 0.001), and reduced lipid metabolism (e.g., TG, LDL-C, p < 0.001) and serum inflammation levels (e.g., IL-1β, IL-6, p < 0.001). The RD intervention also led to changes in the gut microbiota composition, with an increase in the abundance of probiotics (e.g., Parabacteroides, Faecalibaculum, and Muribaculum, p < 0.05) and a decrease in harmful bacteria (Colidextribacter, p < 0.05). Moreover, the RD intervention had a noticeable effect on the gene transcription profile of eWAT, and KEGG enrichment analysis revealed that differential genes were enriched in PI3K/AKT, AMPK, in glucose-lipid metabolism, and in the regulation of lipolysis in adipocytes signaling pathways. The findings demonstrated that RD not only ameliorated IR, but also remodeled the gut microbiota and modified the transcriptome profile of eWAT.

The discovery of new biomarkers that can distinguish Alzheimer's disease (AD) from mild cognitive impairment (MCI) in the early stages will help to provide new diagnostic and therapeutic strategies and slow the transition from MCI to AD. Patients with AD may present with a concomitant metabolic disorder, such as diabetes, obesity, and dyslipidemia, as a risk factor for AD that may be involved in the onset of both AD pathology and cognitive impairment. Therefore, metabolite profiling, or metabolomics, can be very useful in diagnosing AD, developing new therapeutic targets, and evaluating both the course of treatment and the clinical course of the disease. In addition, studying the relationship between nutritional behavior and AD requires investigation of the role of conditions such as obesity, hypertension, dyslipidemia, and elevated glucose level. Based on this literature review, nutritional recommendations, including weight loss by reducing calorie and cholesterol intake and omega-3 fatty acid supplementation can prevent cognitive decline and dementia in the elderly. The underlying metabolic causes of the pathology and cognitive decline caused by AD and MCI are not well understood. In this review article, metabolomics biomarkers for diagnosis of AD and MCI and metabolic risk factors for cognitive decline in AD were evaluated.

Cognitive deficit is one of the challenging complications of type 2 diabetes. Sphingosine 1- phosphate receptors (S1PRs) have been implicated in various neurodegenerative and metabolic disorders. The association of S1PRs and cognition in type 2 diabetes remains elusive. Microglia-mediated neuronal damage could be the thread propagating cognitive deficit. The effects of S1PR2 inhibition on cognition in high-fat diet and streptozotocin-induced diabetic mice were examined in this work. We further assessed microglial activation and putative microglial polarisation routes. Cognitive function loss was observed after four months of diabetes induction in Type 2 diabetes animal model. JTE013, an S1PR2 inhibitor, was used to assess neuroprotection against cognitive decline and neuroinflammation in vitro and in vivo diabetes model. JTE013 (10 mg/kg) improved synaptic plasticity by upregulating psd95 and synaptophysin while reducing cognitive decline and neuroinflammation. It further enhanced anti-inflammatory microglia in the hippocampus and prefrontal cortex (PFC), as evidenced by increased Arg-1, CD206, and YM-1 levels and decreased iNOS, CD16, and MHCII levels. TIGAR, TP53-induced glycolysis and apoptosis regulator, might facilitate the anti-inflammatory microglial phenotype by promoting oxidative phosphorylation and decreasing apoptosis. However, since p53 is a TIGAR suppressor, inhibiting p53 could be beneficial. S1PR2 inhibition increased p-Akt and TIGAR levels and reduced the levels of p53 in the PFC and hippocampus of type 2 diabetic mice, thereby decreasing apoptosis. In vitro, palmitate was used to imitate sphingolipid dysregulation in BV2 cells, followed by conditioned media exposure to Neuro2A cells. JTE013 rescued the palmitate-induced neuronal apoptosis by promoting the anti-inflammatory microglia. In the present study, we demonstrate that the inhibition of S1PR2 improves cognitive function and skews microglia toward anti-inflammatory phenotype in type 2 diabetic mice, thereby promising to be a potential therapy for neuroinflammation.

Insulin resistance and glucose metabolism have been associated with neurodevelopmental disorders. However, in the metabolically more susceptible Asian populations, it is not clear whether the genetic burden of glycaemic dysregulation influences early-life neurodevelopment. In a multi-ethnic Asian prospective cohort study in Singapore (Growing Up in Singapore Towards healthy Outcomes (GUSTO)), we constructed child and parental polygenic risk scores (PRS) for glycaemic dysregulation based on the largest genome-wide association studies of type 2 diabetes and fasting glucose among Asians. We found that child PRS for HOMA-IR was associated with a lower perceptual reasoning score at ~7 years (β = -0. 141, p-value = 0.024, 95% CI -0. 264 to -0. 018) and a lower WIAT-III mean score at ~9 years (β = -0.222, p-value = 0.001, 95% CI -0.357 to -0.087). This association were consistent in direction among boys and girls. These inverse associations were not influenced by parental PRS and were likely mediated via insulin resistance rather than mediators such as birth weight and childhood body mass index. Higher paternal PRS for HOMA-IR was suggestively associated with lower child perceptual reasoning at ~7 years (β = -0.172, p-value = 0.002, 95% CI -0.280 to -0.064). Replication analysis in a European cohort, the Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort, showed that higher child PRS for fasting glucose was associated with lower verbal IQ score while higher maternal PRS for insulin resistance was associated with lower performance IQ score in their children at ~8.5 years. In summary, our findings suggest that higher child PRS for HOMA-IR was associated with lower cognitive scores in both Asian and European replication cohorts. Differential findings between cohorts may be attributed to genetic and environmental factors. Further investigation of the functions of the genetic structure and ancestry-specific PRS and a more comprehensive investigation of behavioural mediators may help to understand these findings better.

Patients with diabetes are at higher risk of cognitive impairment and memory loss than the normal population. Thus, using hypoglycemic agents to improve brain function is important for diabetic patients. Sodium-glucose cotransporters-2 inhibitors (SGLT2i) are a class of therapeutic agents used in the management of diabetes that has some pharmacologic effects enabling them to fight against the onset and progress of memory deficits. Although the exact mediating pathways are not well understood, emerging evidence suggests that SGLT2 inhibition is associated with improved brain function. This study reviewed the possible mechanisms and provided evidence suggesting SGLT2 inhibitors could ameliorate cognitive deficits.

Metabolic syndrome (MetS) is a cluster of metabolic abnormalities that has a high prevalence worldwide. Apigenin is a flavonoid present in several vegetables and fruits and has anti-inflammatory, anti-oxidant, and anti-MetS properties. This study aims to systematically review the effects of apigenin against MetS and the relevant molecular and cellular mechanisms of action, pharmacokinetics features, and potential structure-activity relationship. Electronic databases including Scopus, PubMed, Science Direct and Cochrane Library were searched for in vivo, and in vitro, and human studies with the following keywords: "apigenin" and "metabolic syndrome or insulin resistance syndrome", "fatty liver", "hypertension or blood pressure", "diabetes or blood glucose", "dyslipidemia", "heart or cardiovascular " and "obesity" in title/abstract. Data were collected from 2000 until 2021 (up to April). Only papers published in the English language were included. Forty-six full-text articles out of 1016 retrieved papers were reviewed and underwent quality assessment by investigators. Anti-obesity activity of apigenin is mainly through attenuating adipocyte differentiation by suppressing the mitotic clonal expansion and the adipogenesis-related factors. Its anti-diabetic effects can be exerted through inhibition of protein tyrosine phosphatase1B expression, maintaining the activity of anti-oxidant enzymes, reducing intracellular ROS production, cellular DNA damage, protein carbonylation, and attenuating β-cell apoptosis. Moreover, apigenin could attenuate dyslipidemia and subsequent atherosclerotic conditions through down-regulating sterol regulatory element-binding proteins (SREBP)-1c, SREBP-2, stearyl-CoA desaturase-1, and 3-hydroxy-3-methyl-glutaryl-CoA reductase. Apigenin as a dietary bioactive compound would be a promising candidate for improving MetS and its components.