Search Results (347)

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

Choline has been recognized as an essential nutrient involved in various physiological functions critical to human health. Adequate daily intake of choline has been established by the US National Academy of Medicine in 1998, considering choline requirements for different ages, sex differences and physiological states (e.g., pregnancy). By serving as a precursor for acetylcholine and phospholipids, choline is important for cholinergic transmission and the structural integrity of cell membranes. In addition, choline is involved in lipid and cholesterol transport and serves as a methyl donor after oxidation to betaine. Extracellular choline is transported across the cell membrane via various transport systems (high-affinity and low-affinity choline transporters) with distinct features and roles. An adequate dietary intake of choline during pregnancy supports proper fetal development, and throughout life supports brain, liver, and muscle functions, while choline deficiency is linked to disease states like fatty liver. Choline has important roles in neurodevelopment, cognition, liver function, lipid metabolism, and cardiovascular health. While its signaling role has been considered mostly indirect via acetylcholine and phosphatidylcholine which are synthesized from choline, emerging evidence supports a role for choline as an intracellular messenger acting on Sigma-1R, a non-opioid intracellular receptor. These new findings expand the cell signaling repertoire and increase the current understanding of the role of choline while warranting more research to uncover the molecular mechanisms and significance in the context of GPCR signaling, the relevance for physiology and disease states. Full article

Background: Exposure to per- and polyfluoroalkyl substances (PFAS, including 7H-Perfluoro-4-methyl-3,6-dioxaoctanesulfonic acid (PFESA-BP2), perfluorooctanoic acid (PFOA), and hexafluoropropylene oxide (GenX), has been associated with liver dysfunction. While previous research has characterized PFAS-induced hepatic lipid alterations, their downstream effects on energy metabolism remain unclear. This study investigates metabolic alterations in the liver following PFAS exposure to identify mechanisms leading to hepatoxicity. Methods: We analyzed RNA sequencing datasets of mouse liver tissues exposed to PFAS to identify metabolic pathways influenced by the chemical toxicant. We integrated the transcriptome data with a mouse genome-scale metabolic model to perform in silico flux analysis and investigated reactions and genes associated with lipid and energy metabolism. Results: PFESA-BP2 exposure caused dose- and sex-dependent changes, including upregulation of fatty acid metabolism, β-oxidation, and cholesterol biosynthesis. On the contrary, triglycerides, sphingolipids, and glycerophospholipids metabolism were suppressed. Simulations from the integrated genome-scale metabolic models confirmed increased flux for mevalonate and lanosterol metabolism, supporting potential cholesterol accumulation. GenX and PFOA triggered strong PPARα-dependent responses, especially in β-oxidation and lipolysis, which were attenuated in PPARα^−/− mice. Mitochondrial fatty acid transport and acylcarnitine turnover were also disrupted, suggesting impaired mitochondrial dysfunction. Additional PFAS effects included perturbations in the tricarboxylic acid (TCA) cycle, oxidative phosphorylation, and blood–brain barrier (BBB) function, pointing to broader systemic toxicity. Conclusions: Our findings highlight key metabolic signatures and suggest PFAS-mediated disruption of hepatic and possibly neurological functions. This study underscores the utility of genome-scale metabolic modeling as a powerful tool to interpret transcriptomic data and predict systemic metabolic outcomes of toxicant exposure. Full article

Blood–brain barrier (BBB) dysfunction is a hallmark of cerebral small vessel disease (cSVD). This study aimed to identify a mouse model that replicates BBB impairment and shares key cSVD risk factors. Transgenic db/db and LDLr^−/−.Leiden mice, both prone to obesity and hypertension, were compared to C57BL/6J controls. BBB leakage was assessed using DCE-MRI and sodium fluorescein (NaFl); cerebral blood flow (CBF) by MRI. Dyslipidemia and vascular inflammation were measured by plasma tests. Tight junction integrity, endothelial dysfunction (glucose transporter 1, GLUT-1) and neuroinflammation were evaluated with immunohistochemistry and PCR. Both transgenic models developed an obese phenotype with hyperinsulinemia, but only LDLr^−/−.Leiden mice showed human-like dyslipidemia. When fed a high-fat diet (HFD) or HFD plus cholesterol, LDLr^−/−.Leiden mice showed reduced CBF, endothelial dysfunction (lowered GLUT-1), elevated vascular inflammation (ICAM-1, VCAM-1, S-selectin), and BBB leakage, as evidenced by DCE-MRI and NaFl, together with reduced ZO-1 and claudin-5 expression. Contrastingly, db/db mice showed endothelial dysfunction without BBB leakage. Neuroinflammation (IBA-1, GFAP) was observed only in LDLr^−/−.Leiden groups, consistent with BBB disruption. These findings indicate that LDLr^−/−.Leiden mice, but not db/db mice, are a promising translational model for studying BBB dysfunction in cSVD, offering insights into disease mechanisms and a platform for therapeutic development. Full article

Cholesterol homeostasis is necessary for normal vertebrate development. The disruption of cholesterol homeostasis can cause abnormal body and nervous system development and lead to dysfunctional behavior and increased mortality. Commonly prescribed psychopharmaceuticals can alter cholesterol synthesis and may disrupt early vertebrate development. A high-throughput vertebrate zebrafish model system was used to test the hypothesis that exposure to psychopharmaceutical medications alters cholesterol biosynthesis and disrupts gene transcription, early whole-body and brain development, and nervous system function, resulting in abnormal behavior. Exposure to cariprazine, aripiprazole, trazodone, and AY9944 increased 7-dehydrocholesterol levels compared to vehicle-treated zebrafish. Significant differences in disease-associated gene expression, brain structure, and functional behaviors were observed in psychopharmaceutical and AY9944-treated zebrafish compared to controls. These data reveal that the high-throughput zebrafish model system can discern psychopharmaceutical effects on cholesterol synthesis, gene transcription, and key features of early vertebrate development that influences behavior. Full article

Background/Objectives: Nutritional support in neurosurgical patients is challenging due to severe brain injury, neurological disease, or post-surgical complications. This study aimed to assess outcomes of long-term enteral nutrition via endoscopic gastrostomy (PEG) in these patients over a 22-year period. Methods: A single-center retrospective (2001–2023) study was conducted on patients referred for PEG. Included patients presented severe traumatic brain injury (TBI), stroke, brain tumor, or other neurosurgical conditions. Demographic, anthropometric, and clinical data were collected. Results: A total of 196 patients were included (105 men); 57% were under 65 years. The main diagnoses were stroke (41.8%), TBI (35.2%), and brain tumors (19.9%). The median time from diagnosis to PEG was 94 days. At the time of PEG, only 38.5% were underweight. Outcomes: A total of 132 deaths (75.4%) occurred, while 21 patients resumed oral feeding (10.7%), 22 patients remained PEG-fed (12.6%), and 21 patients were lost to follow-up (10.7%). Most surviving PEG-fed patients had experienced stroke (77%). Median post-PEG survival was 11.5 months and 88% survived >1 month. Higher albumin, transferrin, and cholesterol levels at the time of PEG were associated with longer survival. Albumin (p < 0.001) and transferrin (p < 0.01) were significantly associated with reduced short-term mortality. Conclusions: Despite limited overall survival, reflecting the clinical severity of the diseases, most patients were adequate survivors, and PEG-feeding proved to be appropriate and useful for neurosurgical patients. While most patients had normal-to-high BMI, low serum biomarkers reflected acute illness. Higher serum albumin level was associated with better outcomes, supporting its potential prognostic value. Full article

Mitochondrial transplantation (MTx) has emerged as a potential therapeutic approach for diseases associated with mitochondrial dysfunction, yet its scalability and cross-species feasibility remain underexplored. This study aimed to evaluate the dose-dependent uptake and molecular effects of xenogeneic mitochondrial transplantation (xeno-MTx) using rat-derived mitochondria in mouse neuronal systems. HT-22 hippocampal neuronal cells and a murine model of cardiac arrest-induced global cerebral ischemia were used to assess mitochondrial uptake, gene expression, and mitochondrial DNA presence. Donor mitochondria were isolated from rat pectoralis muscle and labeled with MitoTracker dyes. Flow cytometry and confocal microscopy revealed a dose-dependent increase in donor mitochondrial uptake in vitro. Quantitative PCR demonstrated a corresponding increase in rat-specific mitochondrial DNA and upregulation of Mfn2 and Bak1, with no changes in other fusion, fission, or apoptotic genes. Inhibitor studies indicated that mitochondrial internalization may involve actin-dependent macropinocytosis and cholesterol-sensitive endocytic pathways. In vivo, rat mitochondrial DNA was detected in mouse brains post–xeno-MTx, confirming donor mitochondrial delivery to ischemic tissue. These findings support the feasibility of xeno-MTx and its dose-responsive biological effects in neuronal systems while underscoring the need for further research to determine long-term functional outcomes and clinical applicability. Full article

Background: This study aimed to evaluate the impact of physical activity levels on selected biochemical markers (glucose, insulin, cholesterol, triglycerides, interleukin-6 [IL-6]), brain-derived neurotrophic factor (BDNF), cognitive functions, and additional macronutrient intake in postmenopausal women. Method: A total of 72 generally healthy women aged 55–73 from western Poland participated in the study. Physical activity levels were assessed using the International Physical Activity Questionnaire (IPAQ), resulting in two distinct groups: 56 women in the lower activity level group and 16 in the higher activity level group. We calculated body mass index (BMI), measured body composition and blood pressure, and conducted cognitive assessments, including the Mini-Mental State Examination (MMSE), motor and psychomotor skills tests, the Clock Drawing Test, and the Geriatric Depression Scale (GDS). Nutritional intake was evaluated using a detailed 3-day food record to analyze macronutrient consumption and total caloric intake. Results: A statistically significant difference in total blood cholesterol levels (p = 0.0277) was observed between the two groups, with the higher physical activity group showing elevated cholesterol levels. Although no other biochemical markers showed statistically significant differences, variations in BDNF, glucose, triglycerides, IL-6, and insulin levels were noted between groups. Moreover, correlations between these markers and cognitive performance, like motor and psychomotor speeds, varied depending on physical activity level. The analyzed dietary pattern of the studied group shows slight deviations from current nutritional recommendations. Conclusions: The findings suggest that physical activity level may influence certain biochemical markers and cognitive functions in postmenopausal women. While these results highlight the potential benefits of physical activity, further research is needed to clarify underlying mechanisms and to validate physical activity as an effective strategy for improving postmenopausal health. Full article

This study investigates the biochemical and physiological responses of the economically important fish Barbonymus gonionotus to acute temperature fluctuations. Focusing on malondialdehyde (MDA) levels in serum and visceral organs, serum biochemical indices, hematological parameters, cortisol levels, and operculum movement, this research assessed the impacts of thermal stress. Experimental conditions involved two thermal regimes: heat shock at 25–29 °C and 25–37 °C; as well as cold shock at 25–21 °C and 25–13 °C sustained over 24 (D1), 48 (D2), and 72 (D3) h. Serum MDA levels increased significantly. Notably, MDA in the gills, brain, and liver fluctuated under cold stress, particularly at 13 °C. Serum parameters showed significant alterations except for AST, total protein, and cholesterol, which remained unaffected by heat shock. Red blood cell (RBC) counts dropped to their lowest at 13 °C, while white blood cell (WBC) counts diminished significantly when temperatures dropped to 21 °C and then stabilized. Cortisol surged with temperature changes, peaking at 13 °C and 29 °C for cold and heat shock, respectively. Operculum movement was inversely affected by thermal changes, decreasing with cold and increasing with heat. These findings underscore the sensitivity of silver barb to thermal extremes, providing insights for optimized aquaculture management and enhanced resilience to environmental stressors. Full article

Background: This study aimed to explore the therapeutic potential of a dietary regimen of banaba leaf extract (BNB), policosanol (PCO, Raydel^®), and their combination (BNB+PCO), to mitigate high cholesterol (HC) and high galactose (HG) diet-induced dyslipidemia, hyperglycemia, oxidative stress, senescence, and organ damage in zebrafish (Danio rerio). Methodology: Zebrafish (n = 28/group) were fed with HC (4% w/w)+HG (30% w/w) or HC+HG supplemented either with BNB (0.1% w/w) or PCO (0.1% w/w) or BNB+PCO (0.1% w/w each). Following 6 weeks of dietary intervention, biochemical and histopathological examinations across the groups were performed. Results: Post 6 weeks of consumption, the BNB+PCO group exhibited a significant 40% decrease in body weight (BW) relative to the BW of the HC+HG group, while the BNB or PCO groups displayed nonsignificant changes in BW. Both BNB and PCO reduced HC+HG-induced dyslipidemia and hyperglycemia; however, co-administration (BNB+PCO) demonstrated a significantly greater therapeutic effect in countering these conditions compared to either BNB or PCO alone. A similar effect of the BNB+PCO combination was observed on the elevation of plasma sulfhydryl content, paraoxonase (PON), and ferric ion reduction activity (FRA), with notably ~1.2-times (p < 0.01) higher levels compared to their corresponding values observed in the BNB or PCO groups. Significantly diminished plasma AST, ALT, hepatic interleukin 6 (IL-6) levels, and fatty liver changes were observed in response to BNB+PCO, compared to either BNB or PCO alone. Also, BNB+PCO displayed a higher curative effect against HC+HG-induced impairment of tissue regeneration than BNB or PCO alone. A notable effect of BNB+PCO was perceived in protecting kidneys, testis, and ovary damage. Consistently, BNB+PCO showed a profound impact on mitigating HC+HG elevated reactive oxygen species (ROS) generation, apoptosis, cellular senescence, and accumulation of brain-binding lipid proteins (BLBPs) and 4-hydroxynoneal (4-HNE) in the brain. Conclusions: The findings highlight the synergistic effects of the BNB and PCO combination to mitigate the adversity posed by the consumption of the HC+HG diet. Full article

The development of nanocarriers for drug delivery has drawn a lot of attention due to the possibility for tailored delivery to the ill region while preserving the neighboring healthy tissue. In medicine, delivering drugs safely and effectively has never been easy; therefore, the creation of surfactant-based vesicles (niosomes) to enhance medication delivery has gained attention in the past years. Niosomes (NIOs) are versatile drug delivery systems that facilitate applications varying from transdermal transport to targeted brain delivery. These self-assembling vesicular nano-carriers are formed by hydrating cholesterol, non-ionic surfactants, and other amphiphilic substances. The focus of the review is to report on the latest NIO-type formulations which also include biopolymers from the polysaccharide class, highlighting their role in the development of these drug delivery systems (DDSs). The NIO and polysaccharide types, together with the recent pharmaceutical applications such as ocular, oral, nose-to brain, pulmonary, cardiac, and transdermal drug delivery, are all thoroughly summarized in this review, which offers a comprehensive compendium of polysaccharide-based niosomal research to date. Lastly, this delivery system’s limits and prospects are also examined. Full article

N-acetylaspartate (NAA) is the second most abundant metabolite in the human brain. Quantifiable amounts of NAA are also present in the blood, but its role in the peripheral tissues is largely unknown. First, we determined the acute effects of insulin administration on NAA concentrations; second, we assessed whether circulating NAA levels associate with markers of central and peripheral insulin sensitivity. A total of 24 persons living with obesity and 19 healthy, lean controls, without neurological disorders, underwent a euglycemic hyperinsulinemic clamp combined with fluorodeoxyglucose positron emission tomography ([¹⁸F]FDG-PET) imaging of the brain, abdomen, and femoral area. Plasma concentrations of NAA were measured at baseline and ~2 h into the clamp using high-performance liquid chromatography coupled with tandem mass spectrometry (HPLC-MS-MS). Glucose uptake (GU) rates were analysed using a fractional uptake rate. Serum acetate levels were also assessed using nuclear magnetic resonance (NMR) metabolomics. From baseline to steady-state, insulin levels increased from a mean level of 66 to 447 pmol/L (p < 0.0001). Over this period, circulating NAA concentrations decreased by 5% (p = 0.01), similarly in both groups. The change in NAA was inversely related with the change in plasma acetate (r = −0.36, p = 0.048). Circulating NAA was associated with waist–hip ratio (rho = −0.54, p = 0.0002), steady-state free fatty acids (rho = −0.44, p = 0.003), and directly with HDL cholesterol (rho = 0.54, p = 0.0002), adiponectin (rho = 0.48, p = 0.003), and whole-body insulin sensitivity (rho = 0.34, p = 0.03). Circulating NAA was directly related with skeletal muscle (rho = 0.42, p = 0.01) and visceral adipose tissue GU (rho = 0.41, p = 0.02). Insulin administration leads to a small decrease in circulating NAA levels, and NAA associates consistently with markers of insulin sensitivity. While plasma NAA may be relevant to aspects of whole-body homeostasis, mechanistic insights are needed. Full article

Lipid metabolism disorders represent a significant risk factor for the pathogenesis of Alzheimer’s disease (AD). Apolipoprotein E (APOE) has been regarded as a pivotal regulator of lipid homeostasis in the central nervous system (CNS), with polymorphic alleles identified as genetic risk factors for late-onset AD. Despite advances in APOE research and the development of numerous pharmaceutical approaches targeting distinct APOE isoforms, there remain limited treatment approaches for AD that focus on lipid metabolic homeostasis. Consequently, it is necessary to reevaluate the lipid metabolic process in the CNS. Apolipoprotein A1 (APOA-I), a major component of high-density lipoprotein (HDL), plays a crucial role in reverse cholesterol transport from tissues to the liver to maintain lipid homeostasis. Over the past few decades, numerous studies have suggested a connection between reduced APOA-I levels and a higher risk of AD. APOA-I is synthesized exclusively in the liver and intestines, and there is a lack of conclusive evidence supporting its functional significance within the central nervous system, in contrast to APOE, which is produced locally by glial cells and neurons within the CNS. Moreover, APOA-I’s ability to penetrate the blood-brain barrier (BBB) is still poorly understood, which causes its significance in central lipid metabolism and AD pathophysiology to be mainly disregarded. Recent advancements in tracing methodologies have underscored the essential role of APOA-I in regulating lipid metabolism in the CNS. This review aims to elucidate the physiological functions and metabolic pathways of APOA-I, integrating its associations with AD-related pathologies, risk factors, and potential therapeutic targets. Through this discourse, we aim to provide novel insights into the intricate relationship between AD and APOA-I, paving the way for future research in this field. Full article

The efficacy of Cuban sugarcane-extracted policosanol (Raydel^®), a purified blend of eight long-chain aliphatic alcohols, was compared to copycat sugarcane-extract powder (SCEP) to assess their effects on dyslipidemia, oxidative stress, and vital organs of zebrafish under the influence of a high-cholesterol diet (HCD). Zebrafish were fed with HCD (final 4%, w/w) or HCD infused with policosanol (PCO, final 1%, w/w) or SCEP (final 1%, w/w). Post 14-week consumption, blood and organs were harvested and processed for various biochemical, histological, and immunohistochemical (IHC) examinations, and fluorescent staining. Following 14-week consumption, the PCO-supplemented group exhibited higher zebrafish survival probability than the SCEP-supplemented group. Both PCO and SCEP substantially impacted the HCD-disrupted plasma lipid profile; however, PCO supplementation exhibited a significantly better effect than SCEP. Similarly, PCO supplementation significantly improved the blood glucose level, hepatic function biomarkers, and oxidative-antioxidant balance disturbed by HCD. PCO supplementation displayed a substantial inhibitory effect against HCD-induced fatty liver changes, nephromegaly, and cellular senescence. Likewise, PCO effectively protected the brain against HCD-induced apoptosis and accumulation of 4-hydroxynonenal (4-HNE); in contrast, SCEP supplementation showed almost no effect in reducing such adverse changes. The comparative findings between PCO and SCEP highlight the protective effects of PCO against HCD-induced oxidative stress and dyslipidemia via the enhancement of antioxidant markers, leading to protection of the liver, kidney, and brain, while SCEP failed to achieve similar outcomes. Full article

Background. Microglia, accounting for 5–15% of total brain cells, represent an essential population of glial cells in the cultures used for modeling neuroinflammation in vitro. However, microglia proliferation is poor in neuron–glial cultures. Here, we studied the population composition of rat hippocampal neuron–glial cell cultures prepared utilizing papain (PAP cultures) and trypsin (TRY cultures) as proteolytic enzymes for cell isolation. Methods. To evaluate the percentage and morphology of microglia in TRY and PAP cultures and cultures incubated in the presence of TGFβ+MCSF+cholesterol, which should enhance microglia proliferation, we used an immunostaining and calcium imaging approach in combination with staining using the recently developed vital microglia fluorescent probe CDr20. Results. We have shown that the microglia percentage in PAP cultures was higher than in TRY cultures. Microglia in PAP cultures are predominantly polarized, while bushy morphology was more characteristic of TRY cultures. We have also demonstrated that the TGFβ+MCSF+cholesterol combination increases the microglia number both in PAP and TRY cultures (up to 25–30%) and promotes the appearance of ameboid microglia characterized by high mobility. However, the significant appearance of ameboid microglia was observed already at the early stages of cultivation (2 DIV) in TRY cultures, while in PAP cultures, the described transformation was observed at 7 DIV. Based on the absence of the ATP-induced Ca²⁺ response, round shape, significant proliferation, and high mobility, we have suggested that ameboid microglia are reactive. Conclusions. Thus, our results demonstrate that papain is a more suitable proteolytic enzyme for preparing mixed hippocampal neuron–glial cultures with a higher percentage of heterogeneous microglia and functional neurons and astrocytes (tricultures). Full article