Search Results (323)

Cerebral small vessel disease (CSVD) is a leading cause of stroke, cognitive impairment, and vascular dementia, yet disease-modifying therapeutic strategies remain limited. Emerging evidence suggests that sleep fragmentation (SF), a common and often under-recognized feature of aging and cardiometabolic disorders, plays a pivotal role in CSVD pathogenesis by disrupting the glymphatic system, the brain’s primary waste clearance pathway. Sleep-dependent glymphatic function facilitates the removal of neurotoxic metabolites and maintains neurovascular homeostasis. In contrast, SF impairs cerebrospinal fluid (CSF)–interstitial fluid (ISF) exchange, promotes perivascular space enlargement, endothelial dysfunction, blood–brain barrier (BBB) breakdown, and chronic neuroinflammation, hallmarks of CSVD. This review synthesizes current mechanistic, preclinical, and clinical evidence linking SF to glymphatic dysfunction and small vessel pathology, framing these interactions as a sleep–glymphatic–vascular continuum underlying CSVD progression and cognitive decline. We further explore the emerging therapeutic potential of tocotrienols (T3), vitamin E isoforms with potent antioxidant, anti-inflammatory, and vasculoprotective properties, as modulators of neurovascular integrity within this continuum. Although direct evidence linking T3 to glymphatic regulation remains limited, converging data support their capacity to preserve endothelial function, attenuate oxidative stress, and stabilize astrocytic and BBB dynamics, mechanisms highly relevant to glymphatic and microvascular health. By integrating sleep biology, glymphatic neuroscience, and nutritional vascular protection, this review highlights hypothesis-generating preventive and therapeutic avenues for CSVD and delineates key knowledge gaps, including the need for longitudinal human studies, standardized glymphatic imaging, objective sleep phenotyping, and interventional trials to establish causal and translational relevance. Full article

Current industrial sources of tocotrienols are almost entirely composed of tropical monocots. However, recent reports have observed significant tocotrienol (T3) contents in eudicot families, including Passifloraceae. While passion fruits are also tropical, their cultivation is not strictly limited to rainforests, and seeds are often a by-product of fruit processing. To elucidate tocochromanol production in the Passifloraceae family, seeds (54 samples representing 18 species) were gathered from botanical gardens worldwide. Ultrasound-assisted extraction in ethanol (UAEE) was compared with the standard saponification protocol as a greener alternative. Tocotrienols constituted a major percentage (48–91%) of Passifloraceae species’ seed tocochromanols, and γ-T3 (12–53%) and δ-T3 (8–68%) were major contributors. Although a higher δ-T3 content was observed in some Passiflora species, it was less consistent than the γ-T3 content between and within species. The highest total tocochromanol content was observed in P. subpeltata (28.98 ± 5.83 mg 100 g⁻¹ dry weight). The UAEE protocol recovered tocotrienols and tocopherols at degrees similar to those of saponification (100% and 93%, respectively). Therefore, UAEE could also be proposed for the effective recovery of these valuable phytochemicals from by-products of Passiflora fruits. Full article

Inspired by the lack of wide-scale family level screenings, the profile of tocochromanols in Berberidaceae family species belonging to the Berberis, Mahonia, Caulophyllum, Jeffersonia and Podophyllum genera was studied. Seeds were acquired from botanical gardens around the world and tocopherol and tocotrienol content was tested using ultrasound-assisted extraction in ethanol (UAEE) and compared to saponification protocol and analyzed by an RP-HPLC-FLD system. The UAEE protocol produced 93% average tocochromanol recovery compared to the saponification protocol. All investigated samples were tocotrienol-dominated, the lowest proportions being in B. regeliana, B. thunbergii and B. aristata at means of 55%, 56% and 58%, respectively. The main tocochromanol constituents were α-tocotrienol and γ-tocotrienol. The highest α-tocotrienol content was observed in B. tchonskyana at 9.14 mg 100 g⁻¹ dw, and the highest γ-tocotrienol and sum of free tocochromanol content was observed in J. diphylla at 18.00 and 23.76 mg 100 g⁻¹ dw, respectively. Principal component analysis and k-means cluster analysis based on a free tocochromanol profile indicated γ-tocotrienol and α-tocotrienol content as the main differentiators. However, a comprehensive sample set could only be collected for the Berberis genus, warranting further research into Berberidaceae seed tocochromanols. Full article

Background: Food rich in tocopherols (T) and tocotrienols (T3) are considered functional due to their ability to reduce oxidative stress and modulate anti-viability and pro-apoptotic pathways with anticancer potential; however, their efficacy differs between T and T3 and among isoforms (α and γ) likely due to differences in intracellular uptake and, consequently, in the activation of anticancer signaling pathways. To address these isoform-dependent differences, HeLa and MCF7 cancer cell lines were used to assess the antiproliferative activity of α-tocopherol (αT), γ-tocopherol (γT) and tocotrienols (Tocomin) as well as their pharmacological interactions according to Loewe and Chou–Talalay models. Methods: The tocol profile of the commercial mixture of T3 (Tocomin) was quantified by normal-phase HPLC. HeLa, MCF7, and ARPE-19 cells were cultured in DMEM supplemented with 10% FBS and exposed to αT, γT, or Tocomin (50–800 µg/mL; DMSO vehicle) for 48 h; viability was measured by the MTT assay and EC50 values were obtained from log(dose)–response fits (n = 3). Fixed-ratio (1:1) combinations were evaluated in HeLa and MCF7, and interactions were quantified using Loewe additivity and Chou–Talalay combination indices, supported by isobologram analysis. Results: Tocomin showed greater potency with αT and γT, and synergy with αT/γT; however, the combination of αT + γT showed antagonism in both cell lines. Conclusions: The higher potency of Tocomin and its synergistic interactions with αT or γT suggest that tocotrienol-rich mixtures may enhance the antiproliferative response, whereas combining αT and γT together may reduce efficacy under the tested conditions. Full article

Oral administration of tocotrienol has poor systemic distribution due to poor selectivity by the α-tocopherol transfer protein at the liver. Local injection of tocotrienols with appropriate drug delivery systems is significant to ensure that the drug is delivered directly to the site of injury or fracture. This paper presents a tocotrienol-loaded gelatin hydrogel crosslinked with genipin for bone regeneration. This innovative method improves the incorporation and sustained delivery of tocotrienol while overcoming its incompatibility with hydrophilic biomaterials. It establishes a novel platform for targeted therapeutic applications in bone treatment. The cytotoxicity and physicochemical properties of tocotrienol were examined using the genipin-crosslinked gelatin hydrogel. A 10% tocotrienol nanoemulsion (TTE) was prepared using a sonicator and characterized with a zeta sizer and FTIR. A dose–response analysis was conducted to determine the appropriate tocotrienol concentration for hydrogel integration with gelatin (7% or 10% w/v) and crosslinked with genipin (0.1% or 0.3% w/v). The dose–response study’s tocotrienol nanoemulsion was added to gelatin before polymerization. With 141.9 nm particles and 0.150 PDI, the nanoemulsion was homogeneous and stable. The 1% tocotrienol nanoemulsion was chosen due to its viability. Formulations 1% TTE_0.1% GNP_7% GEL and 1%TTE_0.3% GNP_7% GEL had superior physicochemical properties compared to other groups. The 1% TTE_0.3% GNP_7% GEL had outstanding hydrophilicity, low weight loss, and a suitable swelling ratio for bone application. SEM scans of the surface and cross-section showed that 1% TTE_0. 3% GNP_7% GEL had interconnected pores with an optimal average pore size of 292 ± 37 μm. Adding tocotrienol to the gelatin hydrogel matrix did not affect FTIR, XRD, or EDX. In vitro cytotoxicity studies indicated >90% cell viability of hFOB 1.19 cells cultured on 1% TTE_0.1% GNP_7% GEL and 1% TTE_0.3% GNP_7% GEL (105 ± 4.36% and 95.36 ± 9.78%). Combining tocotrienol with a genipin-crosslinked gelatin hydrogel demonstrated superior physicochemical properties and no in vitro toxicity. Full article

A novel optimized bioactive lipid (OBL) rich in long-chain polyunsaturated omega-3 fatty acids (n-3 LCPUFA) was synthesized through enzymatic acidolysis using concentrated belly oil from rainbow trout (Oncorhynchus mykiss) (CB) and tocopherols obtained from cold-pressed maqui seed oil (Aristotelia chilensis (Mol.) Stuntz) (MSO) under supercritical CO₂ conditions. The reaction was catalyzed by Candida antarctica lipase B (CALB) and optimized using a 3² response surface design with 12 experimental runs and three central points, considering pressure (100–300 bar) and temperature (50–80 °C) as independent variables. The response variables included the concentrations of EPA, DHA, α-, β-, γ-, and δ-tocopherols, as well as β- and γ-tocotrienols. MSO contained 10.63, 25.62, and 53.55 g·100 g⁻¹ total fatty acids (TFAs) of α-linolenic, oleic, and linoleic acids, respectively, together with 280.95 mg α-tocopherol·kg⁻¹ and 89.75 mg β-tocotrienol·kg⁻¹. The CB contained 49.57 g EPA + DHA·100 g⁻¹ TFAs. Optimal conditions (72.7 °C and 248.9 bar), experimentally validated at the RSM-predicted point, yielded an OBL containing 41.28 g EPA + DHA·100 g⁻¹ TFAs, 0.39 mg α-tocopherol·kg⁻¹, 3.54 mg β-tocopherol·kg⁻¹, 18.48 mg β-tocotrienol·kg⁻¹, 6.92 mg γ-tocopherol·kg⁻¹, and 16.36 mg γ-tocotrienol·kg⁻¹. Oil quality evaluation using official AOCS methods showed that the OBL exhibited an acceptable oxidative status within international regulatory limits while retaining a measurable phenolic content and intermediate antioxidant capacity derived from MSO. This study demonstrates the successful synthesis of a stable OBL from agro-industrial by-products as a sustainable source of functional ingredients for food, nutraceutical, and cosmetic applications. Full article

Plants from the eudicot Celastraceae family are primarily cultivated for ornamental use due to their colourful autumn foliage, and, as such, their chemical composition is rarely investigated. In total, 125 samples from, altogether, 40 shrub, vine and tree species (Catha, Celastrus, Euonymus, Gymnosporia, Maytenus, Parnassia, and Tripterygium) were investigated to confirm tocotrienol dominance in the family, which was observed in the initial screenings. The tocochromanol–tocopherol (T) and tocotrienol (T3) contents ranged from 3.04 to 66.22 mg 100 g⁻¹ dw. Almost all the samples were tocotrienol-dominated (50.1–98.5% of total tocochromanols), except for Parnassia. The two most prevalent compounds were γ-T3 and α-T3. Most Euonymus species’ seeds contained primarily α-T3 (16.2–86.0% of total tocochromanols) and tocopherol (up to 35.0%), while the other species had higher γ-T3 (36.0–87.2%) and tocopherol (up to 29.9%) contents, except the Parnassia samples, which contained primarily γ-T and δ-T. The highest total tocochromanol content was observed in E. scandens, but it was highly variable. The content of α-T3 was less variable than γ-T3 (coefficients of variation of 0.74 and 1.46, respectively). This study shows that tocotrienols are predominant in the Celastraceae family. A streamlined ethanolic extraction protocol was evaluated and deemed suitable for routine screening and, potentially, bioactive extraction. Full article

Although not major crops, Cornaceae species, the dogwood family, are common in most continents and used primarily as ornamental crops, though some are used for food as well. In the present study, tocochromanol–tocopherol (T) and tocotrienol (T3)–contents were analyzed in the seeds of twenty-four Cornus species belonging to six Cornus subgenera. Given the substantial number of samples included in this study, we applied a fast extraction protocol using an ethanol and ultrasound treatment and systematically compared its performance with that of a conventional alkaline saponification method. Total tocochromanol content ranged from 0.78 to 21.63 mg 100 g⁻¹ dry weight (dw) seeds in C. kousa and C. controversa, respectively. The highest mean total tocochromanol content was (16.70 ± 5.28 mg 100 g⁻¹ dw), followed by C. nuttallii (12.96 mg 100 g⁻¹ dw) and C. sanguinea (9.10 ± 2.47 mg 100 g⁻¹ dw). The major tocochromanols in the seeds were γ-T3 (up to 93% in C. rugosa), α-T (up to 98% in C. mas) and γ-T (up to 60% in C. controversa). Tocochromanol composition was strongly subgenus-dependent. The applied sustainable solvent–ethanol and ultrasound-treatment approach for the extraction of tocochromanols demonstrated the suitability of this method for screening daily Cornus species seed samples and potential extraction. Full article

Most research on tocochromanols suggests that tocotrienols (T3) are rarely found in nature, especially in dicotyledonous species. The present study investigates species from the Ilex (holly) genus, the sole surviving genus in the Aquifoliaceae family. The study tested 29 species or hybrids from botanical gardens across Eurasia and the US. A direct ultrasound-assisted extraction in ethanol (UAEE) protocol was validated and used to extract tocochromanols. Tocochromanol recovery from seeds via UAEE ranged between 96–100%, compared to saponification. α-T3 and γ-T3 accounted for an average of 91% of all tocochromanols determined in Ilex species. The highest tocochromanol content was found in I. crenata and I. serrata (8.11 and 6.66 mg 100 g⁻¹ dry weight, respectively). A total of 19 of 29 species in the Aquifoliaceae family were dominated by α-T3. Differences between plant type (shrub/tree) and seasonality (deciduous/evergreen) were not statistically significant, and appear to be mainly influenced by other factors. Linear discriminant analysis identified I. crenata, I. asprella, I. × meserveae, I. vomitoria, and I. geniculata (all shrubby) as divergent. Full article

Several members of the Rutaceae (citrus) family are widely cultivated and processed. Tocopherol (T) synthesis and composition are well-documented, while tocotrienols (T3) in most plant families remain underreported. To amend this, mass screening of Rutaceae species’ seed tocochromanols were analysed. Of the 53 analysed species, seed tocochromanols were tocotrienol-dominated in 22 species, including a majority of species Zanthoxyloideae (Choisya, Dictamnus, Melicope, Ptelea, Skimmia, Tetradium, Zanthoxylum) and the Cneoroideae (Cneorum) subfamily. Total tocochromanol content ranged from 0.20–25.98 mg 100 g⁻¹ dry weight (dw) seeds. The highest tocochromanol content was observed in Murraya paniculata, Ruta graveolens seeds, the highest tocotrienol (T3) content was observed in Skimmia anquetilia and Dictamnus albus—19.80 and 19.70 mg 100 g⁻¹ dw, respectively. The major tocochromanols in the seeds were γ-T and γ-T3, while others were present in low concentration or absent. Linear discriminant analysis (LDA), principal component analysis (PCA) and non-hierarchal cluster analysis (N-HCA) identified similar tocochromanol content trends in the Rutoideae subfamily species and the Bergera and Murraya genus, while the Zanthoxyloideae subfamily species’ seed tocochromanol composition was highly variable. The efficient extractability of tocochromanols using sustainable solvent–ethanol is demonstrating suitability of this approach for daily samples screening and bioactive extraction. Full article

Background: Vitamin E has been studied for its role in reducing the growth of colorectal cancer (CRC). CRC is a worldwide health concern. A meta-analysis reported that CRC patients have a lower concentration of serum vitamin E, suggesting it to be a risk factor. Although rodent models are widely used in disease research, their application in studying vitamin E as a preventive or therapeutic agent in CRC is not well characterized. To address this gap, we conducted a scoping review to examine the available evidence, adhering to the PRISMA-ScR checklist. Methods: We searched PubMed, Google Scholar, Scopus, and Web of Science (WoS) for full-text English original articles published before May 2024, using Medical Subject Headings (MeSH) terms and free text. The following search string strategy was applied: (Vitamin E OR tocopherol$ OR tocotrienol$) AND (Colo$ cancer OR colo$ carcinoma) AND (Rodentia OR mouse OR Rodent$ OR mice OR murine OR rats OR guinea OR rabbit OR hamsters OR Animal model OR Animal testing OR animals) AND (neoplasm$ OR “tumor mass” OR tumor volume OR tumor weight OR tumor burden). Data were charted into five categories using a standardized, pretested form. The charted data were synthesized using descriptive and narrative methods. Conclusions: This study highlights that γ- and δ-tocopherols, as well as δ-tocotrienol and its metabolites, were reported to reduce tumor volume and formation in various rodent models. While these results are promising, this scoping review identifies a need for further research to address translational barriers such as dosing, bioavailability, and long-term safety before clinical application. Full article

Rice bran oil (RBO) is increasingly valued for its bioactive constituents and associated health benefits. This study presents a comprehensive comparative analysis of RBOs derived from purple (PRBO), red (RRBO), and white (WRBO) rice bran, focusing on their physicochemical properties, fatty-acid profiles, bioactive components, antioxidant activity, oxidative stability, and lipidomics. Our results demonstrate that PRBO consistently exhibited a more favorable fatty-acid composition, characterized by a higher proportion of unsaturated fatty acids and significantly greater concentrations of bioactive compounds (including tocopherols/tocotrienols, γ-oryzanol, phytosterols, and squalene). Accordingly, PRBO showed the highest radical-scavenging activity and storage oxidative stability, followed by RRBO and WRBO. Additionally, untargeted lipidomics using UPLC–MS–MS identified 2908 lipid species spanning 57 subclasses and revealed distinct variety-specific lipid signatures. PRBO was uniquely enriched in lipid species such as ceramide phosphate (CerP) and monogalactosyldiacylglycerol (MGDG). RRBO was characterized by a distinct abundance of sitosteryl esters (SiE), phosphatidic acid (PA), and cardiolipin (CL), while WRBO was distinguished by phosphatidylethanol (PEt), lysodimethylphosphatidylethanolamine (LdMePE), and sphingomyelin (SM). Overall, PRBO possessed not only a broader repertoire of lipid species but also higher relative abundances of nutritionally significant lipids. These results enable quality evaluation and varietal authentication of colored RBOs and guide their targeted use in health-oriented foods and nutritional interventions. Full article

A rapid and robust analytical method was validated for the simultaneous extraction and quantification of carotenoids and other lipophilic antioxidants (tocopherols, tocotrienols, retinol and coenzyme Q10) in human and animal tissues using a tandem RRLC-DAD-FLD system. Thirty-eight compounds were identified, with limits of quantification as low as 0.001 µg for astaxanthin, retinol, and coenzyme Q10. Most analytes exhibited high recoveries (85–94%) and good precision (coefficient of variation < 10%), except for Co-Q10, which showed moderate variability. The method was applied to seven human tissue types and their corresponding animal tissues, demonstrating high versatility and analytical reliability. Several isomers of colourless carotenoids were identified in human tissues for the first time, reinforcing their emerging relevance in photoprotection and health. This method provides a valuable analytical tool for investigating the tissue distribution, bioavailability, functionality and nutritional significance of lipophilic antioxidants, thereby supporting future research on antioxidant status and health-related actions. Full article

Persistent and chronic hyperglycaemia in Type II diabetic mellitus (DM) is known to cause oxidative stress, which exacerbates underlying metabolic disorders, contributing to the progression of complications such as diabetic peripheral neuropathy (DPN). Palm tocotrienol-rich fraction (TRF) is renowned for its potent antioxidative and neuroprotective properties and might have the potential to halt or mitigate the severity of DPN. This study aimed to investigate the effects of palm TRF on diabetic rats with peripheral neuropathy and to identify the correlation between plasma metabolomic alterations and DPN parameters. Male Sprague Dawley (SD) rats were randomly divided into normal control and DM groups in which Type II DM was induced using a high-fat diet and a low-dose streptozotocin (STZ) (35 mg/kg). Successful diabetic rats were randomly divided and received daily oral treatments of palm olein (vehicle), metformin (70 mg/kg), TRF (60 mg/kg), or a combination of TRF and metformin for 12 weeks. Behavioural parameters, serum biomarkers, and plasma metabolomic profiling were assessed at 0 (baseline) and 12 weeks of intervention. From the behavioural parameters, improvement in the symptoms of thermal hyperalgesia and mechanical allodynia was seen with TRF interventions, either alone or in combination with metformin. A significant reduction in the neurofilament light (NEFL) chain, accompanied by a notable increase in nerve growth factor (NGF) levels in the serum of treatment groups, was also observed. From the plasma samples, findings reveal that TRF increases metabolites related to neurotransmitter pathways (acetylcholine, choline, phenylalanine, tryptophan) and decreases inflammatory metabolites (kynurenine, prostaglandin) compared to untreated diabetic rats. These metabolites, except for prostaglandin, showed positive correlations with pain sensitivity. In contrast, prostaglandin showed opposite correlations with pain and nerve damage markers, suggesting its potential role in inflammation and axonal injury. Full article

Red palm oil (RPO) is a rich source of bioactive compounds, including carotenoids, tocopherols, tocotrienols, and polyphenols, which contribute to its potent antioxidant and anti-inflammatory properties. This review summarizes the current understanding of RPO composition, bioactivity, and potential applications in health and cosmetics. Current preclinical and small-scale clinical studies suggest that RPO bioactives can mitigate oxidative stress, modulate inflammatory pathways, and improve skin barrier function. Strategies to enhance stability and bioavailability, such as microencapsulation and formulation into emulsions or liposomes, are also discussed. The manuscript highlights the potential of RPO as a natural functional ingredient in dietary, nutraceutical, and cosmetic products. Comprehensive evaluation of these bioactive compounds provides insights for future research and practical applications in promoting human health. Full article