Search Results (540)

Neuromuscular electrical stimulation (NMES) has been shown to improve motor activities and daily living. Prior studies indicated extracellular vesicles (EVs) play a role in cellular communication. Here, we evaluated transcriptomic profiles of tibialis muscle, brain, and plasma-derived EVs following NMES in wild type (WT) and Klotho heterozygous (Kl^HET) mice. Muscle RNA-seq data demonstrated that, in both genotypes, the most upregulated functional categories were related to glucose metabolism and response to insulin, with pathways uniquely affected in each genotype. There was a similarity of the non-coding RNA transcriptome of plasma EVs, with functional patterns suggesting response to oxygen and insulin and long-term synaptic potentiation. The brain transcriptome showed little functional overlap between WT and Kl^HET mice. In WT, brain upregulation of genes was related to blood flow and cell adhesion processes, while Kl^HET showed upregulation of immune function. The results indicate that similar metabolic function is impacted in the location of stimulation, but the distal impact of stimulation on the brain is associated with Klotho deficiency. Full article

Prediabetes and early type 2 diabetes mellitus (T2D) are increasingly recognized as states of both metabolic and neurochemical dysregulation. This narrative review synthesizes emerging evidence of alterations in key neurotransmitter systems—dopamine, serotonin, norepinephrine, gamma-aminobutyric acid, and glutamate—in individuals with prediabetes and diabetes. Beyond peripheral insulin resistance and β-cell dysfunction, disturbances in the central nervous system, especially related to neurotransmitter signaling, may play a role in disease onset and progression. Neuroimaging studies reveal early imbalances in excitatory and inhibitory neurotransmitters, while biochemical and histological findings demonstrate altered receptor expression in both the brain and pancreatic islets. These changes affect metabolic control and are implicated in mood, cognition, and feeding behavior. We investigate the mechanistic links between neurotransmitter dysfunction and glucose metabolism, including the roles of brain insulin resistance, inflammation, mitochondrial stress, and gut–brain axis signaling. Finally, we discuss therapeutic strategies that target neurochemical pathways and highlight the need for longitudinal, sex-aware, and multi-omics studies to refine early interventions. Understanding the neurobiological roots of early T2D could revolutionize risk assessment and open doors for new neuro-metabolic treatments. Full article

The efficacy of Lagerstroemia speciosa (banaba) leaf extract (BLE), policosanol (POL), and their combination (BLE+POL) was evaluated in zebrafish (Danio rerio) against high cholesterol (HC)- and galactose (HG)-induced metabolic stress and organ toxicity. After 12 weeks of dietary intervention, BLE+POL significantly reduced HC+HG-augmented weight gain and improved hepatic and nephromegaly. Compared with BLE or POL alone, the combined intake of BLE+POL more effectively alleviated dyslipidemia and blood glucose levels. Likewise, BLE+POL effectively reduced blood malondialdehyde (MDA), aspartate aminotransferase (AST), and alanine aminotransferase (ALT) levels and boosted plasma sulfhydryl content, ferric ion reduction ability (FRA), and paraoxonase (PON) activity. Histological outcomes suggest that BLE+POL has higher efficacy than either BLE or POL in mitigating HC+HG-induced fatty liver changes, hepatic inflammation, kidney senescence, and reactive oxygen species (ROS) production. Consistently, BLE+POL augmented the spermatozoa counts in the testes, enhanced mature vitellogenic oocytes in ovaries, and protected them from the HC+HG-induced oxidative stress. Compared with either BLE or POL, a combined intake of BLE+POL displayed a superior effect in inhibiting the apoptosis and accumulation of lipid peroxidation species 4-hyrdoxynonenal (4-HNE) in the brain. A combined intake of BLE+POL exhibited a pronounced impact than the BLE and POL alone and can be utilized as an effective formulation to counteract the HC+HG-induced events. Full article

Cardiovascular disease (CVD) and dementia may share common pathogenic factors such as atherosclerosis and hyperlipoproteinemia. Dyslipidemia-induced oxidative stress contributes to dementia comorbidity in CVD. Abelmoschus esculentus (AE, okra) potentiates in alleviating hyperlipidemia and diabetes-related cognitive impairment. This study evaluated the effects of AE in hyperlipidemic ApoE^−/− mice treated with streptozotocin (50 mg/kg) and fed a high-fat diet (17% lard oil, 1.2% cholesterol). AE fractions F1 or F2 (0.65 mg/kg) were administered for 8 weeks. AE significantly reduced serum LDL-C, HDL-C, triglycerides, and glucose, improved cognitive and memory function, and protected hippocampal neurons. AE also lowered oxidative stress markers (8-hydroxy-2′-deoxyguanosine, 8-OHdG) and modulated neuronal nuclei (NeuN) and doublecortin (DCX) expression. In vitro, AE promoted neurite outgrowth and neuronal differentiation in retinoic acid (RA)-differentiated human SH-SY5Y cells under metabolic stress (glucose and palmitate), alongside the upregulation of heme oxygenase-1 (HO-1), Nuclear factor-erythroid 2-related factor 2 (Nrf2), and brain-derived neurotrophic factor (BDNF). These findings suggest AE may counter cognitive decline via oxidative stress regulation and the enhancement of neuronal differentiation. Full article

Brain ischemia is a severe condition caused by reduced cerebral blood flow, leading to the disruption of ion gradients in brain tissue. This imbalance triggers spreading depolarizations, which are waves of neuronal and glial depolarization propagating through the gray matter. Microelectrode arrays (MEAs) are essential for real-time monitoring of these electrophysiological processes both in vivo and in vitro, but their sensitivity and signal quality are critical for accurate detection of extracellular brain activity. In this study, we evaluate the performance of a flexible microelectrode array based on gold-coated zinc oxide nanorods (ZnO NRs), referred to as nano-fMEA, specifically for high-fidelity electrophysiological recording under pathological conditions. Acute mouse brain slices were tested under two ischemic models: oxygen–glucose deprivation (OGD) and hyperkalemia. The nano-fMEA demonstrated significant improvements in event detection rates and in capturing subtle fluctuations in neural signals compared to flat fMEAs. This enhanced performance is primarily attributed to an optimized electrode–tissue interface that reduces impedance and improves charge transfer. These features enabled the nano-fMEA to detect weak or transient electrophysiological events more effectively, making it a valuable platform for investigating neural dynamics during metabolic stress. Overall, the results underscore the promise of ZnO NRs in advancing electrophysiological tools for neuroscience research. Full article

Central nervous system (CNS) insulin signaling is involved in a broad array of cardiometabolic physiology, including glucose and lipid metabolism, feeding, energy expenditure, and blood pressure regulation. A key role for hypothalamic neuroendocrine and autonomic centers in regulating insulin-associated cardiovascular and metabolic physiology has been highlighted. However, it is still unclear which CNS site(s) initiate insulin-dependent neural cascades. While some investigations have suggested that circulating insulin can access hypothalamic regions by crossing the blood-brain barrier, other studies point to a necessity of other brain areas upstream of the hypothalamus to initiate central insulin actions. In this context, accumulating evidence points to a possible involvement of the sensory circumventricular organs (CVOs), unique areas located outside of the blood-brain barrier, in insulin-dependent cardiometabolic homeostasis. Here, the multifaceted roles for the sensory CVOs in cardiovascular and metabolic regulation, with a special emphasis on insulin receptor pathways, are discussed. Full article

Due to their clinical heterogeneity, nonspecific symptoms, and the limitations of existing biomarkers and imaging modalities, metabolic brain diseases (MBDs), such as mitochondrial encephalopathies, lysosomal storage disorders, and glucose metabolism syndromes, pose significant diagnostic challenges. This review examines the growing potential of cell-free DNA (cfDNA) derived from cerebrospinal fluid (CSF) epigenetic profiling as a dynamic, cell-type-specific, minimally invasive biomarker approach for MBD diagnosis and monitoring. We review important technological platforms and their use in identifying CNS-specific DNA methylation patterns indicative of neuronal injury, neuroinflammation, and metabolic reprogramming, including cfMeDIP-seq, enzymatic methyl sequencing (EM-seq), and targeted bisulfite sequencing. By synthesizing current findings across disorders such as MELAS, Niemann–Pick disease, Gaucher disease, GLUT1 deficiency syndrome, and diabetes-associated cognitive decline, we highlight the superior diagnostic and prognostic resolution offered by CSF cfDNA methylation signatures relative to conventional CSF markers or neuroimaging. We also address technical limitations, interpretive challenges, and translational barriers to clinical implementation. Ultimately, this review explores CSF cfDNA epigenetic analysis as a liquid biopsy modality. The central objective is to assess whether epigenetic profiling of CSF-derived cfDNA can serve as a reliable and clinically actionable biomarker for improving the diagnosis and longitudinal monitoring of metabolic brain diseases. Full article

The insulin-like growth factor binding protein, acid-labile subunit (IGFALS), plays a crucial role in glucose metabolism and immune regulation, key processes in recovery from surgery. Here, we studied the perioperative serum IGFALS dynamics and explored potential clinical implications. A total of 79 patients undergoing elective cardiac surgery with implementation of cardiopulmonary bypass had their serum isolated at baseline, 24 h, seven days, and three months postoperatively to assess serum concentrations of IGFALS and insulin growth factor 1 (IGF-1). Markers of perioperative injury included troponin I (TnI), high-mobility group box 1 (HMGB-1), and heat shock protein 60 (Hsp-60). Inflammatory status was assessed via interleukin-6 (IL-6) and interleukin-8 (IL-8). Additionally, we measured in vitro cytokine production to viral stimulation of whole blood and monocytes. Surrogates of neuronal distress included neurofilament light chain (NF-L), total tau (τ), phosphorylated tau at threonine 181 (τp181), and amyloid β40 and β42. Renal impairment was defined by RIFLE criteria. Cardiac dysfunction was denoted by serum N-terminal pro-brain natriuretic peptide (NT-proBNP) levels. Serum IGFALS levels declined significantly after surgery and remained depressed even at 3 months. Administration of acetaminophen and acetylsalicylic acid differentiated IGFALS levels at the 24 h postoperatively. Serum IGFALS 24 h post-operatively correlated with production of cytokines by leukocytes after in vitro viral stimulation. Serum amyloid-β1-42 was significantly associated with IGFALS at baseline and 24 h post-surgery Patients discharged home had higher IGFALS levels at 28 days and 3 months than those discharged to healthcare facilities or who died. These findings suggest that IGFALS may serve as a prognostic biomarker for recovery trajectory and postoperative outcomes in cardiac surgery patients. Full article

Brain muscle ARNT-like1 (Bmal1) is a transcriptional factor, consisting of basic helix–loop–helix (bHLH) and PER-ARNT-SIM (PAS) domains, that plays a central role in circadian clock activity. However, the precise roles of the BMAL1-PAS domain, a circadian rhythm-regulating structure, remain unexplored in monocytes. Here, we highlight the BMAL1-PAS domain as a key structure in monocyte pleiotropic functions by using human monocytic cell line THP-1. THP-1 cells lacking the BMAL1-PAS-B domain (THP-1#207) abrogated the circadian expression of core clock genes. THP-1#207 cells exhibited less proliferation, glycolysis and oxidative phosphorylation activity, and LPS-induced IL-1β production, but exhibited more production of LPS-induced IL-10 than THP-1 cells. A quantitative proteomics analysis revealed significant expression changes in ~10% metabolic enzymes in THP-1#207 cells compared to THP-1 cells, including reduction in a rate-limiting enzyme hexokinase2 (HK2) in the glycolytic pathway. Importantly, treatment of THP-1 with 2-deoxy-D-glucose (2-DG), an HK2 inhibitor, largely recapitulated the phenotypes of THP-1#207 cells. These findings suggest that the BMAL1-PAS-B domain is an important structure for the regulation of proliferation, cellular energetics, and inflammatory response in THP-1 cells, at least in part, via the control of glycolytic activity. Thus, the BMAL1-PAS-B domain may become a promising pharmacological target to control inflammation. Full article

Background: Brain injuries, including stroke and traumatic brain injury (TBI), pose a major healthcare challenge due to their severe consequences and complex recovery. While ischemic strokes are more common, hemorrhagic strokes have a worse prognosis. TBI often affects young adults and leads to long-term disability. A critical concern in these patients is the frequent development of chronic critical illness, compounded by metabolic disturbances and malnutrition that hinder recovery. Objective: This study aimed to compare changes in nutritional status parameters under standard enteral nutrition protocols and clinical outcomes in prolonged/chronic critically ill patients with TBI or stroke versus such a population of patients without TBI or stroke. Methods: This matched prospective–retrospective cohort study included intensive care unit (ICU) patients with TBI or stroke from the Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology and patients without these conditions from the eICU-CRD database. Inclusion criteria comprised age 18–74 years, ICU stay >5 days, and enteral nutrition. Patients with re-hospitalization, diabetes, acute organ failure, or incomplete data were excluded. Laboratory values and clinical outcomes were compared between the two groups. Propensity score matching (PSM) was used to balance baseline characteristics (age, sex, and body mass index). Results: After PSM, 29 patients with TBI or stroke and 121 without were included. Univariate analysis showed significant differences in 21 laboratory parameters and three hospitalization outcomes. On day 1, the TBI/stroke group had higher hemoglobin, hematocrit, lymphocytes, total protein, and albumin, but lower blood urea nitrogen (BUN), creatinine, and glucose. By day 20, they had statistically significantly lower calcium, BUN, creatinine, and glucose. This group also showed less change in lymphocytes, calcium, and direct bilirubin. Hospitalization outcomes showed longer mechanical ventilation duration (p = 0.030) and fewer cases of acute kidney injury (p = 0.0220) in the TBI/stroke group. Conclusions: TBI and stroke patients exhibit unique metabolic patterns during prolonged/chronic critical illness, differing significantly from other ICU populations in protein/glucose metabolism and complication rates. These findings underscore the necessity for specialized nutritional strategies in neurocritical care and warrant further investigation into targeted metabolic interventions. Full article

Cognitive decline is a common complication of diabetes mellitus, driven in part by oxidative stress and impaired glucose–insulin homeostasis. This study examined the neuroprotective effects of agmatine (200 mg/kg intraperitoneally) in female BALB/c diabetic mice. Several receptor pathways were examined using commercially available antagonists. Behavioral performance was evaluated using the novel object recognition test. Metabolic parameters, such as glucose and insulin levels, as well as antioxidants, including catalase (CAT), superoxide dismutase (SOD), and glutathione (GSH), were measured in blood and brain tissue. The diabetic mice exhibited impaired recognition memory (discrimination index = 0.08), hyperglycemia (24.3 mmol/L), decreased insulin levels (38.4 µU/mL), and diminished antioxidant defenses (CAT: 75.4 U/g tissue, SOD: 32.6 U/g tissue, and GSH: 8.3 mmol/g tissue). Agmatine treatment improved cognitive function and reversed the biochemical alterations. However, these effects were reduced when agmatine was co-administered with imidazoline I₂/I₃ receptor antagonists. Correlation analysis revealed that cognitive performance positively correlated with antioxidant enzyme levels and insulin levels and negatively correlated with glucose concentrations. Strong intercorrelations among CAT, SOD, and GSH levels suggest a coordinated antioxidant response. Overall, these results imply that agmatine’s neuroprotective effects are partially mediated by modulation of the oxidative balance and glucose–insulin regulation via imidazoline receptors. Full article

Background/Objectives: Type 2 diabetes mellitus (T2DM) is frequently associated with depressive disorder (DD), which negatively impacts glycemic control and overall metabolic outcomes. Recent evidence suggests that glucagon-like peptide-1 receptor agonists (GLP-1 RAs) may exert neuroprotective effects and modulate mood. Likewise, it is unknown whether the presence of a DD, due to increased brain inflammation, could lead to a poorer response to GLP-1 RAs in terms of weight loss. This study evaluates the impact of DD on metabolic outcomes in individuals treated with GLP-1 RAs. Methods: We conducted a retrospective longitudinal study including 115 patients with T2DM treated with GLP-1 RAs for at least six months. DD was identified based on a documented clinical diagnosis, chronic antidepressant use, or a Beck Depression Inventory (BDI) score ≥16. Metabolic parameters, including glycated hemoglobin (HbA1c), fasting glucose, the body mass index (BMI), the waist circumference, and triglycerides, were compared between patients with and without DD. Results: Patients with DD had significantly higher baseline HbA1c (7.5% vs. 6.9%, p = 0.01), fasting glucose, and triglyceride levels. The waist circumference was also higher in the DD group (p = 0.001). However, no significant differences were observed in weight loss or BMI reductions following the GLP-1 RA treatment. Final HbA1c levels remained higher in the DD group (7.2% vs. 7.0%, p = 0.01). Conclusions: While DD is associated with a poorer baseline metabolic control in T2DM, it does not appear to impair the weight loss efficacy with GLP-1 RAs. However, patients with DD maintain higher post-treatment HbA1c levels, underscoring the need for integrated metabolic and psychiatric care in diabetes management. Full article

Sweet sensing is a fundamental sensory experience that plays a critical role not only in food preference, reward and dietary behaviour but also in glucose metabolism. Sweet taste receptors (STRs), composed of a heterodimer of taste receptor type 1 member 2 (T1R2) and member 3 (T1R3), are now recognised as being widely distributed throughout the body, including the gastrointestinal tract. Preclinical studies suggest these receptors are central to nutrient and glucose sensing, detecting energy availability and triggering metabolic and behavioural responses to maintain energy balance. Both internal and external factors tightly regulate their signalling pathways, and dysfunction within these systems may contribute to the development of metabolic disorders such as obesity and type 2 diabetes (T2D). Functional magnetic resonance imaging (fMRI) has provided valuable insights into the neural mechanisms underlying sweet sensing by mapping brain responses to both lingual/oral and gastrointestinal sweet stimuli. This review highlights key findings from fMRI studies and explores how these neural responses are modulated by metabolic state and individual characteristics such as body mass index, habitual intake and metabolic health. By integrating current evidence, this review advances our understanding of the complex interplay between sweet sensing, brain responses, and health and identifies key gaps and directions for future research in nutritional neuroscience. Full article

Background: Elevated levels of methylmalonic acid (MMA) are observed in the bodily fluids and tissues of patients with methylmalonic aciduria, a metabolic disorder characterized by manifestations such as vomiting, lethargy, muscle weakness, seizures, and coma. Objectives and Methods: To better understand the neuropathological mechanisms underlying this condition, we investigated the effects of intraperitoneal (i.p.) and intracerebroventricular (i.c.v.) administration of MMA on antioxidant defenses, citric acid cycle functioning, and glial reactivity in the cerebral cortex and striatum of Wistar rats. Amino acid levels were also quantified. Results: i.p. and i.c.v. administration of MMA decreased reduced glutathione levels and altered the activities of different antioxidant enzymes in the cortex and striatum. The activity of the citric acid cycle enzyme succinate dehydrogenase was diminished in both brain regions by i.p. and i.c.v. administration. Citrate synthase, isocitrate dehydrogenase, and malate dehydrogenase activities were further inhibited in the striatum. Furthermore, the i.p. administration increased glial fibrillary acidic protein (GFAP) and glucose transporter 1 (GLUT1) levels, whereas i.c.v. administration elevated GFAP and ionized calcium-binding adaptor molecule 1 (IBA1) levels in the striatum, suggesting glial activation. In contrast, no significant changes in glial markers were detected in the cortex. Moreover, synaptophysin levels remained unaltered in both regions. Finally, i.p. administration increased glutamate, glycine, and serine levels and reduced tyrosine concentrations in the striatum. Conclusions: Our findings indicate that oxidative stress, bioenergetic dysfunction, and glial reactivity induced by MMA may contribute to the neurological deficits observed in methylmalonic aciduria. Full article

Brain-derived neurotrophic factor (BDNF) is a neurotrophin involved in the regulation of synaptic plasticity and metabolic processes, including glucose metabolism and insulin sensitivity. In patients with obstructive sleep apnea (OSA), recurrent episodes of intermittent hypoxia may stimulate BDNF expression as a compensatory neuroprotective response. OSA is associated with metabolic disturbances, such as increased insulin resistance and a higher risk of type 2 diabetes. Continuous positive airway pressure (CPAP) therapy may influence both BDNF levels and metabolic outcomes. The aim of this study was to evaluate changes in BDNF concentration and glucose metabolism in patients with OSA, with particular emphasis on the effect of long-term CPAP therapy. Sixty-six adult patients with OSA confirmed by polysomnography were enrolled and divided into severe (s-OSA) and non-severe (ns-OSA) groups. Fasting blood samples were collected to measure glucose, insulin, and BDNF concentrations. Patients with s-OSA were re-evaluated after 12 months of CPAP therapy and further classified as compliant (sc-OSA) or non-compliant (snc-OSA) based on recorded device usage. The same biochemical parameters were assessed after the 12-month follow-up. Baseline BDNF levels were significantly higher in the s-OSA group compared to the ns-OSA group (20.1 ng/mL vs. 8.1 ng/mL, p = 0.02) and correlated with the apnea–hypopnea index (AHI, r = 0.38, p = 0.02). In the nsc-OSA group, BDNF concentrations increased significantly after 12 months (16.2 ng/mL vs. 35.5 ng/mL, p < 0.001), while no significant change was observed in the sc-OSA group (24.4 ng/mL vs. 27.4 ng/mL, p = 0.33). Among sc-OSA patients, a significant improvement in insulin resistance was noted, although no significant changes were observed in fasting glucose or insulin levels. Increased BDNF levels were observed in patients with s-OSA compared to ns-OSA. Compliant CPAP therapy was associated with reduced insulin resistance and no further BDNF increase, in contrast to non-compliance, suggesting a beneficial effect of CPAP on glucose metabolism and BDNF regulation. These findings support the hypothesis that both neurotrophic and metabolic responses in OSA may be modulated by disease severity and therapy adherence. Full article