Brain tocopherol levels are associated with lower activated microglia density in elderly human cortex

Francisca A de Leeuw, Julie A Schneider, Sonal Agrawal, Sue E Leurgans, Martha Clare Morris

Alzheimers Dement (N Y) . 2020 Aug 24;6(1):e12021. doi: 10.1002/trc2.12021. eCollection 2020.

Abstract

Introduction: Higher brain tocopherol levels have been associated with lower levels of Alzheimer’s disease (AD) neuropathology; however, the underlying mechanisms are unclear.

Methods: We studied the relations of α- and γ-tocopherol brain levels to microglia density in 113 deceased participants from the Memory and Aging Project. We used linear regression analyses to examine associations between tocopherol levels and microglia densities in a basic model adjusted for age, sex, education, apolipoprotein E (APOE)ε4 genotype (any ε4 allele vs. none) , and post-mortem time interval, and a second model additionally adjusted for total amyloid load and neurofibrillary tangle severity.

Results: Higher α- and γ-tocopherol levels were associated with lower total and activated microglia density in cortical but not in subcortical brain regions. The association between cortical α-tocopherol and total microglia density remained statistically significant after adjusting for AD neuropathology.

Discussion: These results suggest that the relation between tocopherols and AD might be partly explained by the alleviating effects of tocopherols on microglia activation.

Julie R A Massier, Joost H J Van Erp, Thom E Snijders, Arthur DE Gast

Acta Orthop . 2020 Aug 24;1-6. doi: 10.1080/17453674.2020.1807220. Online ahead of print.

Abstract

Background and purpose – Survivorship of total hip arthroplasty (THA) with the ultra-high molecular weight polyethylene (UHMWPE) monoblock cup has been limited due to periprosthetic osteolysis and aseptic loosening, secondary to wear of the UHMWPE. In response, a vitamin E blended highly cross-linked polyethylene (HXLPE) cup was developed. This study set out to compare the wear and clinical 6-year outcomes of vitamin E blended HXLPE with UHMWPE in an isoelastic monoblock cup in patients with hip osteoarthritis who underwent uncemented THA. The 2-year results have been reported previously.Patients and methods – For this randomized controlled trial 199 patients were included. 102 patients received the vitamin E blended HXLPE uncemented acetabular cup and 97 patients the uncemented UHMWPE monoblock cup. Clinical and radiographic parameters were obtained preoperatively, directly postoperatively, and at 3, 12, 24, and 72 months. Wear rates were compared using the femoral head penetration (FHP) rate.Results – 173 patients (87%) completed the 6-year follow-up. The mean NRS scores for rest pain, load pain, and patient satisfaction were 0.3 (SD 1), 0.6 (SD 1), and 8.6 (SD 1) respectively. The mean Harris Hip Score was 93 (SD 12). The FHP rate was lower in the vitamin E blended HXLPE cup (0.028 mm/year) compared with the UHMWPE cup (0.035 mm/year) (p = 0.002). No adverse reactions associated with the clinical application of vitamin E blended HXLPE were observed. 15 complications occurred, equally distributed between the two cups. The 6-year survival to revision rate was 98% for both cups. There was no aseptic loosening.Interpretation – This study shows the superior performance of the HXLPE blended with vitamin E acetabular cup with clinical and radiographic results similar to the UHMWPE acetabular cup.

Shotaro Matsumoto, Xiaohui Fang , Maret G Traber, Kirk D Jones, Charles Langelier, Paula Hayakawa Serpa, Carolyn S Calfee, Michael A Matthay, Jeffrey E Gotts

Am J Respir Cell Mol Biol . 2020 Aug 21. doi: 10.1165/rcmb.2020-0209OC. Online ahead of print.

Abstract

E-cigarette, or vaping, product use-associated lung injury (EVALI) is a syndrome of acute respiratory failure characterized by monocytic and neutrophilic alveolar inflammation. Epidemiological and clinical evidence suggests a role of Vitamin E acetate (VEA) in the development of EVALI, yet it remains unclear whether VEA has direct pulmonary toxicity. To test the hypotheses that aerosolized VEA causes lung injury in mice and directly injures human alveolar epithelial cells, we exposed adult mice and primary human alveolar epithelial type II (AT II) cells to an aerosol of VEA generated by a device designed for vaping oils. Outcome measures in mice included lung edema, bronchoalveolar lavage (BAL) analysis, histology, and inflammatory cytokines; in vitro outcomes included cell death, cytokine release, cellular uptake of VEA, and gene expression analysis. Comparison exposures in both models included the popular nicotine-containing JUUL aerosol. We discovered that VEA caused dose-dependent increases in lung water and BAL protein compared to control and JUUL-exposed mice in association with increased BAL neutrophils, oil-laden macrophages, multinucleated giant cells, and inflammatory cytokines. VEA aerosol was also toxic to AT II cells, causing increased cell death and the release of monocyte and neutrophil chemokines. VEA was directly absorbed by AT II cells, resulting in the differential gene expression of several inflammatory biological pathways. Given the epidemiological and clinical characteristics of the EVALI outbreak, these results suggest that VEA plays an important causal role.

Sang-Gyu Lee, Teja Muralidhar Kalidindi, Hanzhi Lou, Kishore Gangangari, Blesida Punzalan, Ariana Bitton 2, Casey Lee, Soobin Park, Lisa Bodei, Michael Kharas, Vijay K Singh, NagaVaraKishore Pillarsetty, Steven M Larson

J Nucl Med . 2020 Aug 21;jnumed.120.244681. doi: 10.2967/jnumed.120.244681. Online ahead of print.

Abstract

Rationale: With the successful development and increased use of targeted radionuclide therapy for treating cancer comes the increased risk of radiation injury to bone marrow-both direct suppression and stochastic effects, leading to neoplasia. Herein, we report a novel radioprotector drug, a liposomal formulation of gamma-tocotrienol (GT3), or GT3-Nano for short, to mitigate bone marrow radiation damage during targeted radionuclide therapy (TRT). Methods: GT3 was loaded into liposomes using passive loading. [⁶⁴Cu]-GT3-Nano and ³H-GT3-Nano were synthesized to study the in vivo biodistribution profile of the liposome and GT3 individually. Radioprotection efficacy of GT3-Nano was assessed after acute ¹³⁷Cs whole-body irradiation at sublethal (4 Gy), lethal (9 Gy), or single high-dose [¹⁵³Sm]-EDTMP administration. Flow cytometry was used to analyze hematopoietic cell population dynamics and fluorescence microscopy was used to assess the cellular site of GT3-Nano localization in the spleen and bone marrow. Results: Bone marrow uptake and retention of [⁶⁴Cu]-GT3-Nano was 6.98 ± 2.34 %ID/g, while [³H]-GT3-Nano uptake and retention was 7.44 ± 2.52 %ID/g at 24 h, respectively. GT3-Nano administered 24 hours before or after 4 Gy TBI promoted rapid and complete hematopoietic recovery while recovery of controls stalled at 60%. GT3-Nano demonstrated dose-dependent radioprotection, achieving 90% survival at 50 mg/kg against lethal 9 Gy TBI. Flow cytometry of bone marrow indicated progenitor bone marrow cells MPP2 and CMP cells were upregulated in GT3-Nano-treated mice. Immunohistochemistry showed that GT3-Nano accumulates in CD105-positive sinusoid epithelial cells. Conclusion: GT3-Nano is highly effective in mitigating marrow suppressive effects of sub-lethal and lethal TBI in mice. GT3-Nano can aid in rapid recovery of hematopoietic components in mice treated with the endoradiotherapeutic agent [¹⁵³Sm]-EDTMP.

Xuejun Bo, Ping Wang, Yan Nie, Rongfen Li, Jiru Lu, Haiying Wang

Exp Ther Med . 2020 Aug;20(2):796-801. doi: 10.3892/etm.2020.8800. Epub 2020 May 27.

Abstract

This study was designed to investigate the protective effect of hypothermia and vitamin E on spermatogenic function after reduction of testicular torsion in rats. Ninety-six pure inbred male SD rats were divided into group A, B, C and D according to the principle of body weight and birth similarity, with 24 rats in each group. Four groups of rats were respectively twisted on the left testis to establish unilateral testicular torsion rats. Rats in groups A, B, C, D were respectively given normal saline, hypothermia therapy, vitamin E therapy, and hypothermia and vitamin E therapy. The superoxide dismutase (SOD) activity and malondialdehyde (MDA) content of the four groups were detected, and the correlation levels of inflammatory factors IL-1β, hs-CRP and related sex hormones luteinizing hormone (LH), follicle-stimulating hormone (FSH), total testosterone (T) were detected by ELISA. Apoptosis of spermatogenic cells of testis in the four groups was detected by flow cytometry. SOD activity and MDA content in groups B, C and D were significantly higher than those in group A, MDA content was significantly lower than that in group A (P<0.05), SOD activity in group D was higher than that in groups B and C, while MDA content was lower than that in groups B and C (P<0.05). The levels of IL-1β and hs-CRP in group A were much higher than those in groups B, C and D (P<0.05). LH and FSH levels in group A were significantly higher than those in groups B, C and D (P<0.05), and in group D were significantly lower than those in groups B and C (P<0.05). Apoptosis rate of spermatogenic cells in group A was significantly higher than that in groups B, C and D (P<0.05). Hypothermia combined with vitamin E can reverse testicular injury in rats and reduce the apoptosis rate of spermatogenic cells.

Andreas Vadarlis, Christina Antza, Dimitra Rafailia Bakaloudi, Ioannis Doundoulakis, Georgios Kalopitas, Myrto Samara, Theodoros Dardavessis, Theofanis Maris, Michael Chourdakis

J Gastroenterol Hepatol . 2020 Aug 18. doi: 10.1111/jgh.15221. Online ahead of print.

Abstract

Background: Νon-alcoholic fatty liver disease (NAFLD) is estimated to be the most common cause of end-stage liver disease in the next years. Vitamin E has shown beneficial effects as a possible “scavenger” of oxidative stress products, which play a major role in pathogenesis of the disease.

Aims: The purpose of the present meta-analysis is to investigate the effects of vitamin E supplementation in biochemical and histological parameters in adult patients with NAFLD.

Methods: Literature search was performed in major electronic databases (MEDLINE, CENTRAL and EMBASE) up to June 2020 for randomized clinical trials, which examined vitamin E versus placebo treatment in adults with NAFLD. Changes in liver enzymes were considered as primary outcomes, while changes in histology, biochemical and metabolic parameters as secondary. Quality of evidence was assessed through risk of bias according to the Cochrane risk of bias tool.

Results: Eight studies were included in qualitative analysis and seven in quantitative analysis. Vitamin E reduced the values of liver enzymes compared to placebo (-7.37 IU/L, 95% CI: -10.11 to -4.64 for ALT and -5.71 IU/L, 95% CI: -9.49 to -1.93 for AST) Additionally, vitamin E improved statistically significantly liver pathology in every individual histologic parameter as well LDL, FBG and serum leptin values.

Conclusions: Vitamin E can improve biochemical and histological characteristics of NAFLD patients, especially of NASH patients. The results indicate that vitamin E could be a promising choice and be considered as a treatment option in patients with NAFLD.

Darren Chan, Maureen L Meister, Chappell R Madhani, Manal Elfakhani, Sophie T Yount, Xiangming Ji, Rafaela G Feresin, Desiree Wanders, Huanbiao Mo

Nutr Cancer . 2020 Aug 18;1-12. doi: 10.1080/01635581.2020.1807573. Online ahead of print

Abstract

Isoprenoids suppress the mevalonate pathway that provides prenyl groups for the posttranslational modification of growth-regulating proteins. We hypothesize that xanthorrhizol and d-δ-tocotrienol synergistically suppress the growth of murine B16 melanoma and human DU145 prostate carcinoma cells. Xanthorrhizol (0-200 µmol/L; half maximal inhibitory concentration [IC₅₀] = 65 µmol/L) and d-δ-tocotrienol (0-40 µmol/L; IC₅₀ = 20 µmol/L) each induced a concentration-dependent suppression of the proliferation of B16 cells and concurrent cell cycle arrest at the G1 phase. A blend of 16.25 µmol/L xanthorrhizol and 10 µmol/L d-δ-tocotrienol suppressed B16 cell proliferation by 69%, an impact greater than the sum of those induced by xanthorrhizol (15%) and d-δ-tocotrienol (12%) individually. The blend cumulatively reduced the levels of cyclin-dependent kinase four and cyclin D1, key regulators of cell cycle progression at the G1 phase. The expression of RAS and extracellular signal-regulated kinase (ERK1/2) in the proliferation-stimulating RAS-RAF-MEK-ERK pathway was downregulated by the blend. Xanthorrhizol also induced a concentration-dependent suppression of the proliferation of DU145 cells with concomitant morphological changes. Isobologram confirmed the synergistic effect of xanthorrhizol and d-δ-tocotrienol on DU145 cell proliferation with combination index values ranging 0.61-0.94. Novel combinations of isoprenoids with synergistic actions may offer effective approaches in cancer prevention and therapy.

M Di Foggia, S Affatato, P Taddei

Braz J Med Biol Res . 2020;53(10):e9930. doi: 10.1590/1414-431x20209930. Epub 2020 Aug 17.

Abstract

In knee replacements, vitamin E-doped ultra-high molecular weight polyethylene (UHMWPE) shows a better wear behavior than standard UHMWPE. Therefore, different sets of polyethylene (PE) acetabular cups, i.e. standard UHMWPE and cross-linked polyethylene irradiated with 50 kGy and 75 kGy, were compared, at a molecular level, with vitamin E-doped UHMWPE to evaluate their wear performance after being tested on a hip joint simulator for five million cycles. Unworn control and worn acetabular cups were analyzed by micro-Raman spectroscopy to gain insight into the effects of wear on the microstructure and phase composition of PE. Macroscopic wear was evaluated through mass loss measurements. The data showed that the samples could be divided into two groups: 1) standard and vitamin E-doped cups (mass loss of about 100 mg) and 2) the cross-linked cups (mass loss of about 30-40 mg). Micro-Raman spectroscopy disclosed different wear mechanisms in the four sets of acetabular cups, which were related to surface topography data. The vitamin E-doped samples did not show a better wear behavior than the cross-linked ones in terms of either mass loss or morphology changes. However, they showed lower variation at the morphological level (lower changes in phase composition) than the UHMWPE cups, thus confirming a certain protecting role of vitamin E against microstructural changes induced by wear testing.

Mohammad Samare-Najaf, Fatemeh Zal, Solmaz Safari

Reprod Toxicol . 2020 Aug 15;96:316-326. doi: 10.1016/j.reprotox.2020.07.015. Online ahead of print.

Abstract

The incidence of cancer has recently risen among the women at the reproductive age. Therefore, exposure to doxorubicin (DOX) chemotherapy has become a cause of reproductive toxicity followed by secondary destructive effects. The present study aimed to evaluate the effects of quercetin (QCT) and vitamin.E (Vit.E) on doxorubicin-induced toxicity in the ovary and uterus, and the secondary bone-related effects in a rat model. Animals were divided into six groups including control normal saline/corn oil (CON), QCT at 20 mg/Kg, Vit.E at 200 mg/Kg, DOX at accumulative 15 mg/Kg, DOX/QCT, and DOX/Vit.E. After 21 days of treatment, the alterations were analyzed in histoarchitecture, apoptosis, hormones secretion, the gene expression of aromatase and estrogen α-receptor (ER-α) in the uterine and ovarian tissues, and serum levels of bone-related factors. The results demonstrated the ameliorative effects of QCT and Vit.E on doxorubicin caused altered ovarian histology, increased apoptosis, decreased ovarian aromatase and ER-α gene expression (p-value<0.05), decreased estrogen and progesterone levels, decreased ALP (p-value<0.001), and increased osteocalcin (p-value<0.05). The findings suggested that the studied antioxidants administration could be a promising fertility preservation strategy in DOX-treated females.

Nora Sovira, Munar Lubis, Pustika Amalia Wahidiyat, Franciscus D Suyatna, Djajadiman Gatot, Saptawati Bardosono, Mohammad Sadikin

Clin Exp Pediatr . 2020 Aug;63(8):314-320. doi: 10.3345/cep.2019.00542. Epub 2020 Aug 15.

Abstract

Background: The accumulation of unpaired α-globin chains in patients with β-thalassemia major may clinically create ineffective erythropoiesis, hemolysis, and chronic anemia. Multiple blood transfusions and iron overload cause cellular oxidative damage. However, α-tocopherol, an antioxidant, is a potent scavenger of lipid radicals in the membranes of red blood cells (RBCs) of patients with β-thalassemia major.

Purpose: To evaluate the effects of α-tocopherol on hemolysis and oxidative stress markers on the RBC membranes of patients with β-thalassemia major.

Methods: Forty subjects included in this randomized controlled trial were allocated to the placebo and α-tocopherol groups. Doses of α-tocopherol were based on Institute of Medicine recommendations: 4-8 years old, 200 mg/day; 9-13 years old, 400 mg/day; 14-18 years old, 600 mg/day. Hemolysis, oxidative stress, and antioxidant variables were evaluated before and after 4-week α-tocopherol or placebo treatment, performed before blood transfusions.

Results: Significant enhancements in plasma haptoglobin were noted in the α-tocopherol group (3.01 mg/dL; range, 0.60-42.42 mg/dL; P=0.021). However, there was no significant intergroup difference in osmotic fragility test results; hemopexin, malondialdehyde, reduced glutathione (GSH), or oxidized glutathione (GSSG) levels; or GSH/GSSG ratio.

Conclusion: Use of α-tocopherol could indirectly improve hemolysis and haptoglobin levels. However, it played no significant role in oxidative stress or as an endogen antioxidant marker in β-thalassemia major.