Effects of Co-administration of Vitamin E and Lithium Chloride on Chronic Constriction Injury-induced Neuropathy in Male Wistar Rats: Focus on antioxidant and anti-inflammatory mechanisms

Kingsley Dominic Esu, Ahmed Olalekan Bakare, Bamidele Victor Owoyele

Pain Pract . 2021 Aug 5. doi: 10.1111/papr.13064. Online ahead of print.


Objectives: This study investigated the antinociceptive effects of co-administration of lithium chloride (LiCl) and vitamin E (Vit. E) on chronic constriction injury (CCI)-induced peripheral neuropathy in male Wistar rats. It further explored the anti-inflammatory and neuroprotective properties of LiCl and Vit. E which may be complementary to the antinociceptive effects of the two substances.

Methods: Thirty-six male Wistar rats, 190.00 ± 10.00 g of body weight (b.w) were randomly assigned to six experimental groups and administered with either normal saline, Vit. E, LiCl, or their combination, once daily for twenty-one (21) days. CCI was used to induce NP and mechanical allodynia was assessed using von Frey filaments and pinprick test. Open field maze (OFM) was used to assess the exploratory behaviour. Biochemical parameters were assessed in the dorsal root ganglion (DRG) after twenty-one days of treatment.

Results: Mechanical allodynia was developed in rats following CCI. Co-administration of LiCl and Vit.E. synergistically reduced mechanical hyperalgesia in rats which were significantly different compared with the single administration of either Vit.E. or LiCl. Combined doses of Vit.E. and LiCl significantly increases the explorative behaviour in the OFM. CCI increased malondialdehyde (MDA), tumour necrotic factor-alpha (TNF-α), calcitonin gene-related polypeptide (CGRP), calcium ion (Ca2+ ), and reduced superoxide dismutase (SOD) activities. Co-administration of LiCl and Vit.E. significantly reduced MDA, TNF-α, but increased SOD compared with ligated control.

Discussion: The findings revealed that the synergistic effects of the co-administration of Vit. E and LiCl in ameliorating neuropathic pain are mediated by their anti-inflammatory and antioxidant properties.

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Vitamin E-facilitated carbon monoxide pro-drug nanomedicine for efficient light-responsive combination cancer therapy

Yaw Opoku-Damoah, Run Zhang, Hang T Ta, Zhi Ping Xu

Biomater Sci . 2021 Aug 4. doi: 10.1039/d1bm00941a. Online ahead of print.


The quest to maximize therapeutic efficiency in cancer treatment requires innovative delivery nanoplatforms capable of employing different modules simultaneously. Combination therapy has proven to be one of the best anticancer strategies so far. Herein, we have developed a lipid-encapsulated nanoplatform that combines chemotherapy with photoresponsive gas therapy for colon cancer treatment. Carbon monoxide releasing molecules (CORMs) and vitamin E analogues (pure/pegylated α-tocopheryl succinate; α-TOS) were co-loaded into the lipid layer with core-shell upconversion nanoparticles (UCNPs), which converted 808 nm light to 360 nm photons to trigger CO release at the tumor site. This folic acid (FA)-targeting nanomedicine (Lipid/UCNP/CORM/α-TOS/FA: LUCTF) possessed a cancer-targeting ability and a light-triggered CO release ability for synergistic apoptosis of HCT116 cells via enhanced ROS generation and mitochondrial membrane breaking. In vivo data have confirmed the significantly enhanced therapeutic efficacy of LUCTF without any significant biosafety issues after intravenous administration. Thus, nanomedicine LUCTF represents a novel way for efficient cancer therapy via combining locally released CO and a compatible chemotherapeutic agent (e.g. α-TOS).

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High cholesterol diet activates ER stress mediated apoptosis in testes tissue: Role of α-tocopherol

Erdi Sozen, Tugce Demirel-Yalciner, M Kutay Koroglu, Merve Acikel Elmas, Feriha Ercan, Nesrin Kartal Ozer

IUBMB Life . 2021 Aug 4. doi: 10.1002/iub.2535. Online ahead of print.


The seminiferous tubules where spermatogenesis occurs are enveloped and protected by the Sertoli cells to support germ cells undergoing meiosis to produce haploid gametes. Clearly, induction of apoptosis in seminiferous tubules leads to abnormalities in spermatogenesis and male infertility. Studies demonstrated that increased hyperlipidemia impairs male infertility and spermatogenesis by enhancing seminiferous tubules apoptosis. However, molecular mechanisms underlying high-cholesterol-mediated testicular damage remain poorly elucidated. In this scope, we established a rabbit model and investigated the role of endoplasmic reticulum (ER) stress on high cholesterol diet induced seminiferous tubule apoptosis. Histopatological examinations revealed increased seminifer tubule apoptosis in testes of rabbits fed high cholesterol diet. In addition, phosphorylated forms of IRE1 and PERK, two well-identified markers of ER stress, were significantly induced in accordance with high cholesterol diet. High cholesterol diet also exhibited CHOP induction in testes, indicating increased ER stress related apoptosis. Supplementation of α-tocopherol significantly attenuated cholesterol mediated ER stress, and restored seminiferous tubules apoptosis. Taken together, our findings suggest that α-tocopherol might be capable to reduce testicular damage via ameliorating histopatological features and inhibiting seminiferous tubules apoptosis in hypercholesterolemic rabbits.

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Is the lower serum level of vitamin E associated with pregnant women with allergic rhinitis?

Yiu-Tai Li, Wen-Ling Lee, Peng-Hui Wang

J Chin Med Assoc . 2021 Aug 1;84(8):739-740. doi: 10.1097/JCMA.0000000000000566.


It is well known that adequate maintenance or support of nutrition during pregnancy, including essential and trace elements and calorie intake, is a critical dimension not only to maintain peak health and performance of themselves but also for the lifelong health of the offspring.1–7 Malnutrition often results in inadequate protein intake, fewer calories, and deficiency of certain-type essential trace elements. Intake of enough calorie can be easily monitored by measuring gestational weight gain (GWG) in the entire pregnancy period or more accurately estimated by separating GWG according to the different trimesters3; however, it is hard to define whether these pregnant women have adequate dietary intake or meet recommendations for vitamins D, C, A, B complex, K, and E, as well as folate, choline, iron, calcium, potassium, magnesium, zinc, and other essential trace elements (minerals or essential amino acids and so on), partly because of difficulty to measure and monitor these essential trace elements, and partly because of overlooking its important and critical role on both maternal and offspring’s outcome.1,2,4–6 Additionally, these certain-type essential trace elements sometimes make physicians or healthcares confused, based on the presence of multifaced functions of these elements. It has been reported that continuous supplementation of vitamin E throughout offspring lifespan provides beneficial effects to the offspring, but one meta-analysis using experimental models and observational investigations, which are involved with more than 135 000 participants in 19 trials carried out between 1966 and 2004 did not support the above-mentioned findings, based on a significantly increasing mortality from all causes when high dosage vitamin E supplements are given as a supplement throughout their lifespan.

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Vitamin E Toxicity

Kristen N. Owen, Olga Dewald

In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021 Jan. 2021 Aug 1.


Vitamin E is a major lipid-soluble antioxidant obtained exclusively from the diet. It was discovered in the 1920s as an essential dietary element required by rats for reproduction. There are approximately eight different vitamin E-related molecules, but the dominant molecule in humans is alpha-tocopherol. Tocotrienols are the other molecules that are widely studied for vitamin E supplementation. These two molecules have been studied in various dosages and for many different health purposes. Vitamin E has peroxyl radical scavenger properties. While vitamin E toxicity is associated with an increased risk of bleeding, its deficiency has been associated with neurologic diseases and anemia.

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Reduced infiltration of T-regulatory cells in tumours from mice fed daily with gamma-tocotrienol supplementation

Shonia Subramaniam, Jeya Seela Anandha Rao, Premdass Ramdas, Mei Han Ng, Methil Kannan Kutty, Kanga Rani Selvaduray, Ammu Kutty Radhakrishnan

Clin Exp Immunol . 2021 Jul 31. doi: 10.1111/cei.13650. Online ahead of print.


Gamma-tocotrienol (γT3) is an analogue of vitamin E with beneficial effects on the immune system, including immune-modulatory properties. This study reports the immune-modulatory effects of daily supplementation of γT3 on host T-helper (Th) and T-regulatory (Treg) populations in a syngeneic mouse model of breast cancer. Female BALB/c mice were fed with either γT3 or vehicle (soy oil) for 2-weeks via oral gavage before they were inoculated with syngeneic 4T1 mouse mammary cancer cells (4T1 cells). Supplementation continued until the mice were sacrificed. Mice (n=6) were sacrificed at specified time-points for various analysis (blood leucocyte, cytokine production, and immunohistochemistry). Tumour volume was measured once every seven days. Gene expression studies were carried out on tumour-specific T-lymphocytes isolated from splenic cultures. Supplementation with γT3 increased CD4+ (p<0.05), CD8+ (p<0.05) T-cells and natural killer cells (p<0.05) but suppressed Treg cells (p<0.05) in peripheral blood when compared to animals fed with the vehicle. Higher interferon-gamma (IFNγ) and lower transforming growth factor-beta (TGF-ꞵ) levels were noted in the γT3 fed mice. Immunohistochemistry findings revealed higher infiltration of CD4+ cells, increased expression of interleukin-12 receptor-beta-2 (IL-12ꞵ2R), interleukin-24 (IL-24) and reduced expression of cells that express the forkhead box P3 (FoxP3) in tumours from the γT3 fed animals. Gene expression studies showed the downregulation of seven prominent genes in splenic CD4+ T-cells isolated from γT3-fed mice. Supplementation with γT3 from palm oil-induced T-cell dependent cell-mediated immune responses and suppressed Treg cells in the tumour microenvironment in a syngeneic mouse model of BC.

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Increased α-tocopherol metabolism in horses with equine neuroaxonal dystrophy

Erin N Hales, Hadi Habib, Gianna Favro, Scott Katzman, R Russell Sakai, Sabin Marquardt, Matthew H Bordbari, Brittni Ming-Whitfield, Janel Peterson, Anna R Dahlgren, Victor Rivas, Carolina Alanis Ramirez, Sichong Peng, Callum G Donnelly, Bobbi-Sue Dizmang, Angelica Kallenberg, Robert Grahn, Andrew D Miller, Kevin Woolard, Benjamin Moeller, Birgit Puschner, Carrie J Finno

J Vet Intern Med . 2021 Jul 31. doi: 10.1111/jvim.16233. Online ahead of print.


Background: Equine neuroaxonal dystrophy/equine degenerative myeloencephalopathy (eNAD/EDM) is an inherited neurodegenerative disorder associated with a vitamin E deficiency within the first year of life. Vitamin E consists of 8 isoforms metabolized by the CYP4F2 enzyme. No antemortem diagnostic test currently exists for eNAD/EDM.

Hypothesis/objectives: Based on the association of α-tocopherol deficiency with the development of eNAD/EDM, we hypothesized that the rate of α-tocopherol, but not γ-tocopherol or tocotrienol metabolism, would be increased in eNAD/EDM-affected horses.

Animals: Vitamin E metabolism: Proof of concept (POC) study; eNAD/EDM-affected (n = 5) and control (n = 6) horses. Validation study: eNAD/EDM-affected Quarter Horses (QHs; n = 6), cervical vertebral compressive myelopathy affected (n = 6) horses and control (n = 29) horses. CYP4F2 expression and copy number: eNAD/EDM-affected (n = 12) and age- and sex-matched control (n = 11-12) horses.

Methods: The rates of α-tocopherol/tocotrienol and γ-tocopherol/tocotrienol metabolism were assessed in equine serum (POC and validation) and urine (POC only) using liquid chromatography tandem mass spectrometry (LC-MS/MS). Quantitative reverse-transcriptase PCR (qRT-PCR) and droplet digital (dd)-PCR were used to assay expression and genomic copy number of a CYP4F2 equine ortholog.

Results: Metabolic rate of α-tocopherol was increased in eNAD/EDM horses (POC,P < .0001; validation, P = .03), with no difference in the metabolic rate of γ-tocopherol. Horses with eNAD/EDM had increased expression of the CYP4F2 equine orthologue (P = .02) but no differences in copy number.

Conclusions and clinical importance: Increased α-tocopherol metabolism in eNAD/EDM-affected QHs provides novel insight into alterations in vitamin E processing in eNAD/EDM and highlights the need for high-dose supplementation to prevent the clinical phenotype in genetically susceptible horses.

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A Fast and Efficient Ultrasound-Assisted Extraction of Tocopherols in Cow Milk Followed by HPLC Determination

Archimede Rotondo, Giovanna Loredana La Torre, Teresa Gervasi, Giacomo di Matteo, Mattia Spano, Cinzia Ingallina, Andrea Salvo

Molecules . 2021 Jul 30;26(15):4645. doi: 10.3390/molecules26154645.


A fast HPLC method with fluorescence detector (FD) was developed for the determination of three tocopherols (TOCs) in milk samples from Modicana cattle breed. The ultrasound-assisted procedure was optimized for the extraction of TOCs prior to HPLC/FD analysis, reducing sample preparation time and allowing a fast quantification of α-tocopherol, δ-tocopherol and γ tocopherol. The optimized ultrasonic extraction combines an efficient and simple saponification at room temperature and a rapid HPLC quantification of TOCs in milk. The precision of the full analytical procedure was satisfactory and the recoveries at three spiked levels were between 95.3% and 87.8%. The linear correlations were evaluated (R2 > 0.99) and the relative standard deviation (RSD) values for intra-day and inter-day tests at three spiked levels were below 1% for the retention time and below 5.20% for the area at low level spiking. The proposed procedure, reducing the experimental complexity, allowed accurate extraction and detection of three TOCs in milk samples from Modicana cattle breed.

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Controlled Release of the α-Tocopherol-Derived Metabolite α-13′-Carboxychromanol from Bacterial Nanocellulose Wound Cover Improves Wound Healing

Jessica Hoff, Berit Karl, Jana Gerstmeier, Uwe Beekmann, Lisa Schmölz, Friedemann Börner, Dana Kralisch, Michael Bauer, Oliver Werz, Dagmar Fischer, Stefan Lorkowski, Adrian T Press

Nanomaterials (Basel) . 2021 Jul 28;11(8):1939. doi: 10.3390/nano11081939.


Inflammation is a hallmark of tissue remodeling during wound healing. The inflammatory response to wounds is tightly controlled and well-coordinated; dysregulation compromises wound healing and causes persistent inflammation. Topical application of natural anti-inflammatory products may improve wound healing, in particular under chronic pathological conditions. The long-chain metabolites of vitamin E (LCM) are bioactive molecules that mediate cellular effects via oxidative stress signaling as well as anti-inflammatory pathways. However, the effect of LCM on wound healing has not been investigated. We administered the α-tocopherol-derived LCMs α-13′-hydroxychromanol (α-13′-OH) and α-13′-carboxychromanol (α-13′-COOH) as well as the natural product garcinoic acid, a δ-tocotrienol derivative, in different pharmaceutical formulations directly to wounds using a splinted wound mouse model to investigate their effects on the wounds’ proinflammatory microenvironment and wound healing. Garcinoic acid and, in particular, α-13′-COOH accelerated wound healing and quality of the newly formed tissue. We next loaded bacterial nanocellulose (BNC), a valuable nanomaterial used as a wound dressing with high potential for drug delivery, with α-13′-COOH. The controlled release of α-13′-COOH using BNC promoted wound healing and wound closure, mainly when a diabetic condition was induced before the injury. This study highlights the potential of α-13′-COOH combined with BNC as a potential active wound dressing for the advanced therapy of skin injuries.

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Vitamin E Can Ameliorate Oxidative Damage of Ovine Hepatocytes In Vitro by Regulating Genes Expression Associated with Apoptosis and Pyroptosis, but Not Ferroptosis

Luyang Jian, Ying Xue, Yuefeng Gao, Bo Wang, Yanghua Qu, Shuanghong Li, Heqiong Li, Zhen Li, Bing Wang, Hailing Luo

Molecules . 2021 Jul 27;26(15):4520. doi: 10.3390/molecules26154520.


(1) Background: the current research was conducted to investigate the potential non-antioxidant roles of vitamin E in the protection of hepatocysts from oxidative damage. (2) Methods: primary sheep hepatocytes were cultured and exposed to 200, 400, 600, or 800 μmol/L hydrogen peroxide, while their viability was assessed using a CCK-8 kit. Then, cells were treated with 400 μmol/L hydrogen peroxide following a pretreatment with 50, 100, 200, 400, and 800 μmol/L vitamin E and their intracellular ROS levels were determined by means of the DCF-DA assay. RNA-seq, verified by qRT-PCR, was conducted thereafter: non-treated control (C1); cells treated with 400 μmol/L hydrogen peroxide (C2); and C2 plus a pretreatment with 100 μmol/L vitamin E (T1). (3) Results: the 200-800 μmol/L hydrogen peroxide caused significant cell death, while 50, 100, and 200 μmol/L vitamin E pretreatment significantly improved the survival rate of hepatocytes. ROS content in the cells pretreated with vitamin E was significantly lower than that in the control group and hydrogen-peroxide-treated group, especially in those pretreated with 100 μmol/L vitamin E. The differentially expressed genes (DEGs) concerning cell death involved in apoptosis (RIPK1TLR7CASP8, and CASP8AP2), pyroptosis (NLRP3IL-1β, and IRAK2), and ferroptosis (TFRC and PTGS2). The abundances of IL-1βIRAK2NLRP3CASP8CASP8AP2RIPK1, and TLR7 were significantly increased in the C1 group and decreased in T1 group, while TFRC and PTGS2 were increased in T1 group. (4) Conclusions: oxidative stress induced by hydrogen peroxide caused cellular damage and death in sheep hepatocytes. Pretreatment with vitamin E effectively reduced intracellular ROS levels and protected the hepatocytes from cell death by regulating gene expression associated with apoptosis (RIPK1TLR7CASP8, and CASP8AP2) and pyroptosis (NLRP3IL-1β, and IRAK2), but not ferroptosis (TFRC and PTGS2).

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