Scope
Tocomonoenols (T1) are little‐known vitamin E derivatives naturally occurring in foods. Limited knowledge exists regarding the cellular uptake and metabolism of α‐tocomonoenol (αT1) and none ...about that of γ‐tocomonoenol (γT1).
Methods and results
The study investigates the cytotoxicity, uptake, and metabolism of αT1 and γT1 in HepG2 cells compared to the α‐ and γ‐tocopherols (T) and ‐tocotrienols (T3). None of the studied tocochromanols are cytotoxic up to 100 µmol L−1. The uptake of the γ‐congeners is significantly higher than that of the corresponding α‐forms, whereas no significant differences are observed based on the degree of saturation of the sidechain. Carboxymethylbutyl‐hydroxychromans (CMBHC) are the predominant short‐chain metabolites of all tocochromanols and conversion is higher for γT1 than αT1 as well as for the γ‐congeners of T and T3. The rate of metabolism increases with the number of double bonds in the sidechain. The rate of metabolic conversion of the T1 is more similar to tocopherols than to that of the tocotrienols.
Conclusion
This is the first evidence that both αT1 and γT1 follow the same sidechain degradation pathway and exert similar rates of metabolism than tocopherols. Therefore, investigation into the biological activities of tocomonoenols is warranted.
Metabolism of α‐ and γ‐tocomonoenols (T1), tocopherols (T) and tocotrienols (T3) in liver cells shows that their metabolism increases with increasing number of double bonds in sidechain (T < T1 ≪ T3) and with the methylation of the chromanol ring (α ≪ γ). The main product of T1 metabolism is carboxymethylbutyl‐hydroxychroman (CMBHC) and αT1 metabolism closely resembles that of α‐tocopherol.
d-α-Tocopheryl polyethylene glycol 1000 succinate (simply TPGS or Vitamin E TPGS) is formed by the esterification of Vitamin E succinate with polyethylene glycol 1000. As novel nonionic surfactant, ...it exhibits amphipathic properties and can form stable micelles in aqueous vehicles at concentration as low as 0.02wt%. It has been widely investigated for its emulsifying, dispersing, gelling, and solubilizing effects on poorly water-soluble drugs. It can also act as a P-glycoprotein (P-gp) inhibitor and has been served as an excipient for overcoming multidrug resistance (MDR) and for increasing the oral bioavailability of many anticancer drugs. Since TPGS has been approved by FDA as a safe pharmaceutic adjuvant, many TPGS-based drug delivery systems (DDS) have been developed. In this review, we discuss TPGS properties as a P-gp inhibitor, solubilizer/absorption and permeation enhancer in drug delivery and TPGS-related formulations such as nanocrystals, nanosuspensions, tablets/solid dispersions, adjuvant in vaccine systems, nutrition supplement, plasticizer of film, anticancer reagent and so on. This review will greatly impact and bring out new insights in the use of TPGS in DDS.
•VE regulates tumor cell physiological activity through MAPK pathway.•VE regulate ERK inducing apoptosis, differentiation, cell cycle arrest.•VE regulates JNK inducing apoptosis and inhibiting the ...expression of AR.•VE regulates p38MAPK inducing apoptosis and autophagy.
In tumour cells, vitamin E and its derivatives play a critical role in the regulation of multiple signalling pathways through their oxidative and nonoxidative functions. To date, there are 8 known natural vitamin E forms and many kinds of derivatives, among which VES and α-TEA have excellent anticancer activities. The MAPK pathway consists of a complex cascade of proteins that control the proliferation, differentiation and apoptosis of tumour cells. The MAPK pathway includes four subfamilies, ERK1/2, JNK1/2, p38 MAPK, and ERK5. Most of the proteins in these subfamilies interact with each other in a complex manner. The anticancer function of vitamin E and its derivatives is closely related to the MAPK cascade. Studies have shown that in tumour cells, α-T/γ-T/γ-T3/δ-T3/VES/α-TEA regulated ERK1/2, prevent tumorigenesis, inhibit tumour cell growth and metastasis and induce cell differentiation, apoptosis, and cell cycle arrest; γ-T3/δ-T3/VES/α-TEA regulates JNK1/2, induce apoptosis, reduce ceramide synthesis and inhibit proliferation; and γ-T3/δ-T3/VES regulate p38 MAPK and induce apoptosis. This paper reviews the role of vitamin E and its derivatives in the MAPK cascade, and tumour cells are used as a model in an attempt to explore the mechanism of their interactions.
Vitamin E was proposed as treatment for Alzheimer's disease many years ago. However, the effectiveness of the drug is not clear. Vitamin E is an antioxidant and neuroprotector and it has ...anti-inflammatory and hypocholesterolemic properties, driving to its importance for brain health. Moreover, the levels of vitamin E in Alzheimer's disease patients are lower than in non-demented controls. Thus, vitamin E could be a good candidate to have beneficial effects against Alzheimer's. However, evidence is consistent with a limited effectiveness of vitamin E in slowing progression of dementia; the information is mixed and inconclusive. The question is why does vitamin E fail to treat Alzheimer's disease? In this paper we review the studies with and without positive results in Alzheimer's disease and we discuss the reasons why vitamin E as treatment sometimes has positive results on cognition but at others, it does not.
•A number of nutrients have been associated with improved outcomes for patients with COVID-19.•Vitamin D is associated with both decreased rates of infection and improved outcomes for ...patients.•Vitamin C may shorten the course of the disease and decrease the severity of the symptoms.•Vitamin E, zinc and selenium are known to assist with recovery from viral infection, and may have efficacy in COVID-19.•There are a number of trials underway evaluating the use of high-dose supplements in COVID-19.
The world is currently in the grips of the coronavirus disease (COVID-19) pandemic, caused by the SARS-CoV-2 virus, which has mutated to allow human-to-human spread. Infection can cause fever, dry cough, fatigue, severe pneumonia, respiratory distress syndrome and in some instances death. COVID-19 affects the immune system by producing a systemic inflammatory response, or cytokine release syndrome. Patients with COVID-19 have shown a high level of pro-inflammatory cytokines and chemokines. There are currently no effective anti-SARS-CoV-2 viral drugs or vaccines. COVID-19 disproportionately affects the elderly, both directly, and through a number of significant age-related comorbidities. Undoubtedly, nutrition is a key determinant of maintaining good health. Key dietary components such as vitamins C, D, E, zinc, selenium and the omega 3 fatty acids have well-established immunomodulatory effects, with benefits in infectious disease. Some of these nutrients have also been shown to have a potential role in the management of COVID-19. In this paper, evidence surrounding the role of these dietary components in immunity as well as their specific effect in COVID-19 patients are discussed. In addition, how supplementation of these nutrients may be used as therapeutic modalities potentially to decrease the morbidity and mortality rates of patients with COVID-19 is discussed.
The rise in paediatric non-alcoholic fatty liver disease (NAFLD) is particularly alarming. We recently reported that Hydroxytyrosol (HXT) and Vitamin E (VitE) may improve oxidative stress, insulin ...resistance, and steatosis in children with biopsy-proven NAFLD.
Here, we investigated if HXT+VitE may reduce systemic inflammation in the above-mentioned patients.
This study analysed the plasma levels of IL (interleukin)-6, IL-1β, IL-10, tumour necrosis factor (TNF)-α, 4‑hydroxy-2-nonenal (4-HNE) and 8-hydroxy-2′deoxyguanosine (8-OHdG) in children enrolled in the HXT+VitE trial (ClinicalTrials.gov, NCT02842567).
Changes in markers of systemic inflammation were found in both placebo (Pla) and HXT+VitE. In particular, after four months, the levels of IL-1β and TNF-α were reduced in both groups, while IL-6 decreased, and IL-10 increased significantly only in the group treated with HXT+VitE. Children treated with HXT+VitE showed a significant decrease of 4-HNE and 8-OHdG that correlated with the improvement of triglyceride levels. Noticeably, only the 8-OHdG decrease correlated with steatosis amelioration and with the increase of IL-10 levels.
The treatment with HXT and VitE reduced the NAFLD-related systemic inflammation in children, mainly by an increase of IL-10 circulating levels that occurred in response to DNA damage recovery, ultimately improving steatosis and hypertriglyceridemia.
Vitamin E is the last of all vitamins whose essentiality is not yet understood. Its widely accepted role as a lipophilic antioxidant has been questioned, since proof of its in vivo relevance remained ...scarce. The influence of vitamin E on biomarkers of oxidative stress in vivo is inconsistent and metabolites of vitamin E having reacted as an antioxidant are hardly detectable. Novel functions of vitamin E include the regulation of enzymes, most of which are membrane bound or activated by membrane recruitment. Also, expression of genes responds to vitamin E. The search for a transcription factor common to all regulated genes failed so far and a receptor that specifically binds vitamin E has not yet been identified. According to microarray data, pathways preferentially affected by the vitamin E status are the inflammatory response and cellular traffic. A role of vitamin E in cellular trafficking could best explain the neurological symptoms seen in vitamin E deficiency. Emerging knowledge on vitamin E is compiled here with the perspective to unravel the molecular mechanisms that could more likely explain the essentiality of the vitamin than its ability to scavenge free radicals.
The synthesis of complex organic compounds usually relies on controlling the reactions of the functional groups. In recent years, it has become possible to carry out reactions directly on the C-H ...bonds, previously considered to be unreactive. One of the major challenges is to control the site-selectivity because most organic compounds have many similar C-H bonds. The most well developed procedures so far rely on the use of substrate control, in which the substrate has one inherently more reactive C-H bond or contains a directing group or the reaction is conducted intramolecularly so that a specific C-H bond is favoured. A more versatile but more challenging approach is to use catalysts to control which site in the substrate is functionalized. p450 enzymes exhibit C-H oxidation site-selectivity, in which the enzyme scaffold causes a specific C-H bond to be functionalized by placing it close to the iron-oxo haem complex. Several studies have aimed to emulate this enzymatic site-selectivity with designed transition-metal catalysts but it is difficult to achieve exceptionally high levels of site-selectivity. Recently, we reported a dirhodium catalyst for the site-selective functionalization of the most accessible non-activated (that is, not next to a functional group) secondary C-H bonds by means of rhodium-carbene-induced C-H insertion. Here we describe another dirhodium catalyst that has a very different reactivity profile. Instead of the secondary C-H bond, the new catalyst is capable of precise site-selectivity at the most accessible tertiary C-H bonds. Using this catalyst, we modify several natural products, including steroids and a vitamin E derivative, indicating the applicability of this method of synthesis to the late-stage functionalization of complex molecules. These studies show it is possible to achieve site-selectivity at different positions within a substrate simply by selecting the appropriate catalyst. We hope that this work will inspire the design of even more sophisticated catalysts, such that catalyst-controlled C-H functionalization becomes a broadly applied strategy for the synthesis of complex molecules.
Berberine (Brb) is an active alkaloid occurring in various common plant species, with well-recognized potential for cancer therapy. Brb not only augments the efficacy of antineoplastic chemotherapy ...and radiotherapy but also exhibits direct antimitotic and proapoptotic actions, along with distinct antiangiogenic and antimetastatic activities in a variety of tumors. Despite its low systemic toxicity, several pharmaceutical challenges limit the application of Brb in cancer therapy (ie, extremely low solubility and permeability, very poor pharmacokinetics (PKs), and oral bioavailability). Among lipid-based nanocarriers investigated recently for Brb, stealth amphiphilic micelles of polymeric phospholipid conjugates were studied here as a promising strategy to improve Brb delivery to tumors. Specifically, physicochemically stable micelles made of 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-methoxy(polyethyleneglycol)-2000 (PEG-PE) mixed with d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) (PEG-succinate ester of vitamin E), in a 3:1 M ratio, increased Brb solubilization by 300%. Our PEG-PE/TPGS-mixed micelles firmly retained the incorporated Brb, displaying extended-release profile in simulated media, with up to 30-fold projected improvement in simulated PKs of Brb. Owing to the markedly better uptake of Brb-containing mixed micelles in vitro, our Brb-mixed micelles nanoformulation significantly amplified apoptosis and overall cytotoxic effectiveness against monolayer and spheroid cultures of human prostate carcinomas (16- to 18-fold lower half-maximal inhibitory concentration values in PC3 and LNPaC, respectively), compared to free Brb. Mixed PEG-PE/TPGS micelles represent a promising delivery platform for the sparingly soluble anticancer agent, Brb, encouraging further pharmaceutical development of this drug for cancer therapy.
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