Inducers of Senescence, Toxic Compounds, and Senolytics: The Multiple Faces of Nrf2-Activating Phytochemicals in Cancer Adjuvant Therapy

Malavolta M, Bracci M, Santarelli L, Sayeed MA, Pierpaoli E, Giacconi R, Costarelli L, Piacenza F, Basso A, Cardelli M, Provinciali M

Mediators Inflamm. 2018 Feb 12;2018:4159013. doi: 10.1155/2018/4159013. eCollection 2018.


The reactivation of senescence in cancer and the subsequent clearance of senescent cells are suggested as therapeutic intervention in the eradication of cancer. Several natural compounds that activate Nrf2 (nuclear factor erythroid-derived 2-related factor 2) pathway, which is involved in complex cytoprotective responses, have been paradoxically shown to induce cell death or senescence in cancer. Promoting the cytoprotective Nrf2 pathway may be desirable for chemoprevention, but it might be detrimental in later stages and advanced cancers. However, senolytic activity shown by some Nrf2-activating compounds could be used to target senescent cancer cells (particularly in aged immune-depressed organisms) that escape immunosurveillance. We herein describe in vitro and in vivo effects of fifteen Nrf2-interacting natural compounds (tocotrienols, curcumin, epigallocatechin gallate, quercetin, genistein, resveratrol, silybin, phenethyl isothiocyanate, sulforaphane, triptolide, allicin, berberine, piperlongumine, fisetin, and phloretin) on cellular senescence and discuss their use in adjuvant cancer therapy. In light of available literature, it can be concluded that the meaning and the potential of adjuvant therapy with natural compounds in humans remain unclear, also taking into account the existence of few clinical trials mostly characterized by uncertain results. Further studies are needed to investigate the therapeutic potential of those compounds that display senolytic activity.

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Protective effects of rosuvastatin and vitamin E against fipronil-mediated oxidative damage and apoptosis in rat liver and kidney.

Abdel-Daim MM, Abdeen A

Food Chem Toxicol. 2018 Feb 9;114:69-77. doi: 10.1016/j.fct.2018.01.055. [Epub ahead of print]


Fipronil (FPN) is a phenylpyrazole insecticide that is extensively used in agriculture and veterinary applications. However, FPN is also a potent environmental toxicant to animals and humans. Therefore, the current study aimed to investigate the protective role of rosuvastatin (ROSU) and vitamin E (Vit E) against FPN-induced hepatorenal toxicity in albino rats. Seven groups with eight rats each were used for this purpose; these groups included the control vehicle group that received corn oil, the Vit E group (1000 mg/kg, orally), the ROSU group (10 mg/kg, orally), the FPN group (20 mg/kg, orally), the FPN-ROSU group, the FPN-Vit E group, and the FPN-Vit E-ROSU group. The results revealed that FPN significantly increased serum levels of alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, lactate dehydrogenase, cholesterol, urea, and creatinine. In addition, there were substantial increases in the liver and kidney contents of malondialdehyde and nitric oxide, along with significant decreases in glutathione, superoxide dismutase, catalase, and glutathione peroxidase. FPN also caused histological changes and increased the expression of caspase-3 in the liver and kidney tissues. However, administration of ROSU and Vit E alone or in combination ameliorated the FPN-induced oxidative damage and apoptosis, possibly through their antioxidant properties.

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δ-Tocopherol inhibits the development of prostate adenocarcinoma in prostate specific Pten-/- mice.

Wang H, Yang X, Liu A, Wang G, Bosland MC, Yang CS

Carcinogenesis. 2018 Feb 9;39(2):158-169. doi: 10.1093/carcin/bgx128.


The PTEN/PI3K/AKT axis plays a critical role in regulating cell growth, differentiation and survival. Activation of this signaling pathway is frequently found in human cancers. Our previous studies demonstrated that δ-tocopherol (δ-T) attenuates the activation of AKT by growth factor in prostate cancer cell lines, leading to inhibition of proliferation and induction of apoptosis. Herein, we investigated whether δ-T inhibits the development of prostate adenocarcinoma in prostate-specific Pten-/- (Ptenp-/-) mice in which the activation of AKT is the major driving force for tumorigenesis. By feeding Ptenp-/- mice with AIN93M or 0.2% δ-T supplemented diet starting at the age of 6 or 12 weeks, we found that δ-T treatment reduced prostate adenocarcinoma multiplicity at the age of 40 weeks by 53.3 and 42.7%, respectively. Immunohistochemical (IHC) analysis demonstrated that the phosphorylation of AKT (T308) was reduced in the prostate of the mice administered the δ-T diet. Consistently, proliferation was reduced and apoptosis was increased in prostate lesions of mice on the δ-T diet. Oxidative stress, as determined by IHC staining of 8-OH-dG, was not altered during prostate tumorigenesis, nor was it affected by administration of δ-T. In contrast, α-tocopherol (α-T) at 0.2% in the diet did not affect prostate adenocarcinoma multiplicity in the Ptenp-/- mice. This finding is consistent with data from our previous study that δ-T, but not α-T, inhibits the activation of AKT and the growth of prostate cancer cells. Together, these results demonstrate that δ-T inhibits the development of prostate adenocarcinoma in Ptenp-/- mice, mainly through inhibition of AKT activation.

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Association of Alpha Tocopherol and Ag Sulfadiazine Chitosan Oleate Nanocarriers in Bioactive Dressings Supporting Platelet Lysate Application to Skin Wounds.

Bonferoni MC, Sandri G, Rossi S, Dellera E, Invernizzi A, Boselli C, Cornaglia AI, Del Fante C, Perotti C, Vigani B, Riva F, Caramella C, Ferrari F

Mar Drugs. 2018 Feb 9;16(2). pii: E56. doi: 10.3390/md16020056.


Chitosan oleate was previously proposed to encapsulate in nanocarriers some poorly soluble molecules aimed to wound therapy, such as the anti-infective silver sulfadiazine, and the antioxidant α tocopherol. Because nanocarriers need a suitable formulation to be administered to wounds, in the present paper, these previously developed nanocarriers were loaded into freeze dried dressings based on chitosan glutamate. These were proposed as bioactive dressings aimed to support the application to wounds of platelet lysate, a hemoderivative rich in growth factors. The dressings were characterized for hydration capacity, morphological aspect, and rheological and mechanical behavior. Although chitosan oleate nanocarriers clearly decreased the mechanical properties of dressings, these remained compatible with handling and application to wounds. Preliminary studies in vitro on fibroblast cell cultures demonstrated good compatibility of platelet lysate with nanocarriers and bioactive dressings. An in vivo study on a murine wound model showed an accelerating wound healing effect for the bioactive dressing and its suitability as support of the platelet lysate application to wounds.

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The antioxidant status of coenzyme Q10 and vitamin E in children with type 1 diabetes.

Alkholy UM, Abdalmonem N, Zaki A, Elkoumi MA, Hashim MIA, Basset MAA, Salah HE

J Pediatr (Rio J). 2018 Feb 7. pii: S0021-7557(17)30834-3. doi: 10.1016/j.jped.2017.12.005. [Epub ahead of print]



The purpose of this study was to evaluate the antioxidant status of plasma vitamin E and plasma and intracellular coenzyme Q10 in children with type 1 diabetes.


This case-control study was conducted on 72 children with type 1 diabetes and compared to 48 healthy children, who were age, sex, and ethnicity-matched. The diabetic children were divided according to their glycosylated hemoglobin (A1c %) into two groups: poor and good glycemic control groups. All children underwent full history taking, clinical examination, and laboratory measurement of complete blood count, A1c %, plasma cholesterol, triglycerides, and vitamin E levels and coenzyme Q10 levels in plasma, erythrocytes, and platelets.


Children with poor glycemic control showed significantly higher plasma vitamin E, coenzyme Q10, triglycerides, low-density lipoproteins, waist circumference/height ratio, cholesterol levels, and lower high-density lipoproteins and platelet coenzyme Q10 redox status in comparison to those with good glycemic control and the control group (p<0.05). Plasma coenzyme Q10 showed a positive correlation with the duration of type 1 diabetes, triglycerides, cholesterol, vitamin E, and A1c %, and negative correlation with the age of the diabetic group (p<0.05). The platelet redox status showed a negative correlation with the A1c % levels (r=-0.31; p=0.022) and the duration of type 1 diabetes (r=-0.35, p=0.012).


Patients with type 1 diabetes, especially poorly controlled, had elevation of plasma vitamin E and coenzyme Q10 levels and decreased platelet redox status of coenzyme Q10, which may be an indicator of increased oxidative stress.

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Tocotrienols Regulate Bone Loss through Suppression on Osteoclast Differentiation and Activity: A Systematic Review.

Radzi NFM, Ismail NAS, Alias E

Curr Drug Targets. 2018 Feb 6. doi: 10.2174/1389450119666180207092539. [Epub ahead of print]


There are accumulating studies reporting vitamin E in general exhibits bone protective effects. This systematic review, however discusses the effects of a group of vitamin E isomers, tocotrienols in preventing bone loss through osteoclast differentiation and activity suppression. This review is aimed to discuss the literature reporting the effects of tocotrienols on osteoclasts, the cells specialized for resorbing bone. Literature search for relevant studies was conducted using SCOPUS and PUBMED MEDLINE. The inclusion criteria were original research articles published that reported the effect of any tocotrienol isomers or treatment with mixture containing tocotrienols on osteoclasts. Out of the total 22 studies from the literature search, only 11 of them were identified as relevant, which comprised of eight animal studies, two in vitro studies and only one combination of both. The in vivo studies indicated that tocotrienols improve the bone health and reduce bone loss via inhibition of osteoclast formation and resorption activity, which could be through regulation of RANKL and OPG expression as seen from their levels in the sera. This is well supported by data from the in vitro studies demonstrating the suppression of osteoclast formation and resorption activity following treatment with tocotrienol isomers. Thus, tocotrienols are suggested to be potential antioxidants for prevention and treatment of bone-related diseases characterized by increased bone loss.

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α-Tocopherol promotes HaCaT keratinocyte wound repair through the regulation of polarity proteins leading to the polarized cell migration.

Horikoshi Y, Kamizaki K, Hanaki T, Morimoto M, Kitagawa Y, Nakaso K, Kusumoto C, Matsura T

Biofactors. 2018 Feb 5. doi: 10.1002/biof.1414. [Epub ahead of print]


In many developed countries including Japan, how to care the bedridden elderly people with chronic wounds such as decubitus becomes one of the most concerned issues. Although antioxidant micronutrients including vitamin E, especially α-tocopherol (α-Toc), are reported to shorten a period of wound closure, the promoting effect of α-Toc on wound healing independent of its antioxidant activity remains to be fully elucidated. The aim of this study was to examine whether α-Toc affects wound-mediated HaCaT keratinocyte polarization process including the recruitment of polarity regulating proteins, leading to wound repair independently of its antioxidant activity. We investigated the effects of α-Toc and other antioxidants such as Trolox, a cell-permeable α-Toc analog on the migration, proliferation, and cell polarization of HaCaT keratinocytes after wounding. We analyzed the localization and complex formation of polarity proteins, partitioning defective 3 (Par3), and atypical protein kinase C (aPKC), and aPKC activity by immunohistochemistry, immunoprecipitation analyses, and in vitro kinase assays, respectively. α-Toc but not other antioxidants enhanced the wound closure and cell polarization in HaCaT keratinocytes after wounding. α-Toc regulated the localization and complex formation of Par3 and aPKC during wound healing. Knockdown of aPKC or Par3 abrogated α-Toc-mediated promotion of the wound closure and cell polarization in HaCaT keratinocytes. Furthermore, aPKC kinase activity was significantly increased in α-Toc-treated cells through activation of phosphatidylinositol 3-kinase/Akt signaling pathway. These results suggest that α-Toc promotes HaCaT keratinocyte wound repair by regulating the aPKC kinase activity and the formation of aPKC-Par3 complex.

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Effect of in vitro vitamin E (alpha-tocopherol) supplementation in human spermatozoon submitted to oxidative stress.

Adami LNG, Belardin LB, Lima BT, Jeremias JT, Antoniassi MP, Okada FK, Bertolla RP

Andrologia. 2018 Feb 2. doi: 10.1111/and.12959. [Epub ahead of print]


The aim of this study was to evaluate the antioxidant effect of in vitro supplementation with vitamin E in human spermatozoon incubated with an oxidative stress inducer. In this study, semen samples from 30 patients were collected and with one aliquot we performed semen analysis according to WHO. The remaining volume was divided into four aliquots: group C: incubated with BWW medium; group I: incubated with 5 mmol 1-1 hydrogen peroxide; group A: incubated with 40 μmol 1-1 vitamin E; and group AI: incubated with both them. After incubations, sperm functional analyses were performed and included: evaluation of oxidative stress, acrosome integrity, mitochondrial activity and DNA fragmentation. Groups were compared using a Friedman test with Bonferroni post hoc (α = 5%). In this study, we observed that in group I there was a decrease in acrosome integrity and mitochondrial activity, and an increase in DNA fragmentation, when compared to group C. Group AI showed an increase in acrosome integrity and mitochondrial activity when compared with group I. Based on our findings, we conclude that the vitamin E supplementation had a positive effect in protecting human spermatozoon from induced oxidative stress.

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Interaction of Vitamin E Intake and Pro12Ala Polymorphism of PPARG with Adiponectin Levels.

Campos-Perez W, Torres-Castillo N, Perez-Robles M, Muñoz-Valle JF, Vizmanos-Lamotte B, Martinez-Lopez E

J Nutrigenet Nutrigenomics. 2018 Feb 2;10(5-6):172-180. doi: 10.1159/000486160. [Epub ahead of print]



One of the beneficial effects associated with vitamin E intake is the enhancement of peroxisome proliferator-activated receptor gamma (PPARγ) activity and the consequent upregulation of adiponectin expression. The aim of this study was to analyze the adiponectin levels in subjects with the Pro12Ala polymorphism of PPARG according to vitamin E intake.


A total of 283 subjects were enrolled. Total vitamin E intake was estimated based on a validated 3-day food consumption record and analyzed using Nutritionist ProTM software. The Pro12Ala polymorphism (rs1801282) was determined by allelic discrimination. The adiponectin levels were measured by an ELISA assay.


Vitamin E intake was deficient in all subjects (1.50 ± 1.78 mg/day). Subjects with higher vitamin E intake levels and the Pro12Ala/Ala12Ala genotype had statistically significant higher levels of serum adiponectin than subjects with the Pro12Pro genotype (4.4 [3.2-5.7] vs. 2.7 [2.0-3.5] μg/mL; p = 0.024).


Our results suggest that increased consumption of vitamin E should be encouraged since it has been reported that vitamin E promotes adiponectin expression via PPARγ activation. Subjects with Pro12Pro genotype had lower serum adiponectin levels than subjects with Pro12Ala/Ala12Ala genotype; therefore, they might be at higher risk of developing metabolic complications.

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Potential roles of vitamin E in age-related changes in skeletal muscle health.

Chung E, Mo H, Wang S, Zu Y, Elfakhani M, Rios SR, Chyu MC, Yang RS, Shen CL

Nutr Res. 2018 Jan;49:23-36. doi: 10.1016/j.nutres.2017.09.005. Epub 2017 Sep 21.


Skeletal muscle disorders including sarcopenia are prevalent during the complex biological process of aging. Loss of muscle mass and strength commonly seen in sarcopenia is induced by impaired neuromuscular innervation, transition of skeletal muscle fiber type, and reduced muscle regenerative capacity, all attributable to chronic inflammation, oxidative stress, and mitochondrial dysfunction. Current literature suggests that vitamin E molecules (α-, β-, γ-, δ-tocopherols and the corresponding tocotrienols) with their antioxidant and anti-inflammatory capabilities may mitigate age-associated skeletal dysfunction and enhance muscle regeneration, thus attenuating sarcopenia. Preclinical and human experimental studies show that vitamin E benefits myoblast proliferation, differentiation, survival, membrane repair, mitochondrial efficiency, muscle mass, muscle contractile properties, and exercise capacity. Limited number of human cross-sectional observational studies reveal positive associations between serum tocopherol level and muscle strength. Several factors, including difficulties in validating vitamin E intake and deficiency, variations in muscle-protective activity and metabolism of diverse forms of vitamin E, and lack of understanding of the mechanisms of action, preclude randomized clinical trials of vitamin E in people with sarcopenia. Future research should consider long-term clinical trials of with adequate sample size, advanced imaging technology and omics approaches to investigate underlying mechanisms and assess clinically meaningful parameters such as muscle strength, physical performance, and muscle mass in sarcopenia prevention and/or treatment.

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