Co-delivery of doxorubicin, docosahexaenoic acid, and α-tocopherol succinate by nanostructured lipid carriers has a synergistic effect to enhance antitumor activity and reduce toxicity

Eduardo Burgarelli Lages, Renata Salgado Fernandes, Juliana de Oliveira Silva, Ângelo Malachias de Souza, Geovanni Dantas Cassali, André Luís Branco de Barros, Lucas Antônio Miranda Ferreira

Biomed Pharmacother . 2020 Oct 24;132:110876. doi: 10.1016/j.biopha.2020.110876. Online ahead of print.

Abstract

Doxorubicin (DOX) is widely used in cancer treatment, however, its use is often limited due to its side effects. To avoid these shortcomings, the encapsulation of DOX into nanocarriers has been suggested. Herein, we proposed a novel nanostructured lipid carrier (NLC) formulation loading DOX, docosahexaenoic acid (DHA), and α-tocopherol succinate (TS) for cancer treatment. DHA is an omega-3 fatty acid and TS is a vitamin E derivative. It has been proposed that these compounds can enhance the antitumor activity of chemotherapeutics. Thus, we hypothesized that the combination of DOX, DHA, and TS in NLC (NLC-DHA-DOX-TS) could increase antitumor efficacy and also reduce toxicity. NLC-DHA-DOX-TS was prepared using emulsification-ultrasound. DOX was incorporated after preparing the NLC, which prevented its degradation during manufacture. High DOX encapsulation efficiency was obtained due to the ion-pairing with TS. This ion-pairing increases lipophilicity of DOX and reduces its crystallinity, contributing to its encapsulation in the lipid matrix. Controlled DOX release from the NLC was observed in vitro, with increased drug release at the acidic environment. In vitro cell studies indicated that DOX, DHA, and TS have synergistic effects against 4T1 tumor cells. The in vivo study showed that NLC-DHA-DOX-TS exhibited the greatest antitumor efficacy by reducing tumor growth in 4T1 tumor-bearing mice. In addition, this formulation reduced mice mortality, prevented lung metastasis, and decreased DOX-induced toxicity to the heart and liver, which was demonstrated by hematologic, biochemical, and histologic analyses. These results indicate that NLC-DHA-DOX-TS may be a promising carrier for breast cancer treatment.

Mónica De la Fuente, Carmen Sánchez, Carmen Vellejo, Estefanía Díaz-Del Cerro, Francisco Arnalich, Ángel Hernanz

Exp Gerontol . 2020 Oct 19;111118. doi: 10.1016/j.exger.2020.111118. Online ahead of print.

Abstract

With aging the immune response is impaired. This immunosenescence, in which an alteration of the redox state of the immune cells appears, is involved in the rate of aging. Since leukocyte function is a good marker of health and predictor of longevity, the effects of daily oral administration of the antioxidant vitamin C (500 mg), or both vitamin C (500 mg) and vitamin E (200 mg) on several blood neutrophil (adherence, chemotaxis, phagocytosis, and superoxide anion levels) and lymphocyte (adherence, chemotaxis, proliferation, interleukin-2 secretion and natural killer activity) functions were studied in healthy elderly men and women. These parameters were analysed before supplementation, after 3 months of supplementation, and 6 months after the end of supplementation. The results showed that vitamin C, in elderly participants, improved the immune functions studied which achieved values close to those of young adults. These effects were maintained in several functions after 6 months without supplementation. Similar effects were found in the elderly supplemented with both vitamin C and E. Thus, a short period of vitamin C or vitamin C and E ingestion, with the doses used, improves the immune function in elderly men and women and could contribute to a healthy longevity.

Cheryl Wei Ling Teo, Shawn Han Yueh Tay, Hong Liang Tey, Yee Wei Ung, Wei Ney Yap

Dermatology . 2020 Oct 16;1-12. doi: 10.1159/000510653. Online ahead of print.

Abstract

Background: Oxidative stress and inflammation are some of the proposed mechanisms involved in the pathogenesis of atopic dermatitis (AD). Current pharmacotherapeutic approaches are effective yet they are not without adverse effects. Vitamin E has great potential as an adjunctive treatment for AD owing to its antioxidant and anti-inflammatory bioactivities.

Summary: This review article summarizes the current available evidence from cellular, animal and clinical studies on the relationship between vitamin E and AD. The future prospects of vitamin E are also discussed. Vitamin E in practice does not show any toxicity to humans within a range of reasonable dosage. Albeit rarely, vitamin E as a contact allergen should be considered. Collectively, this review envisaged vitamin E as an adjunctive treatment for AD patients. Future research on the distinct effects of different vitamin E isoforms as well as their delivery system in skin disorders is needed.

Aliah R Alshanwani, Laila M Faddah, Hanan Hagar, Ahlam M Alhusaini, Sameerah Shaheen, Raeesa A Mohammad, Fatima M B Alharbi, Alaa AlHarthii, Amira M Badr

Drug Chem Toxicol . 2020 Oct 15;1-9. doi: 10.1080/01480545.2020.1831012. Online ahead of print.

Abstract

The purpose of this research was to evaluate the efficacy of carsil (CAR) either alone or in combination with α-tocopherol (α-TOCO) and/or turmeric (TUMR) against tetrachloromethane (TCM)-induced cardiomyocyte injury in rats. Administration of CAR either alone or in combination with α-TOCO and/or TUMR post-TCM injection, significantly mitigated the increases in serum troponin T, creatine kinase-MB (CK-MB) as well as interleukin-6 (IL-6), interferon γ (IFN-γ), tumor necrosis factor-α (TNF-α), C-reactive protein (CRP). They also decline the elevation of caspase-3, vascular endothelial growth factor (VEGF) protein expression as well as DNA damage in cardiac tissues induced by TCM. The biochemical results were confirmed by histopathological investigation. Conclusion: The combination of the three antioxidants showed greater cardioprotective potential, compared to individual drugs. Therefore, this combination may be recommended as a complementary therapy to antagonize cardiac injury induced by different insults.

Raúl Francisco Pastor, Marisa Gabriela Repetto, Fabiana Lairion, Alberto Lazarowski, Amalia Merelli, Zulma Manfredi Carabetti, Isabel Pastor, Elena Pastor, Laura Valeria Iermoli, Carlos Amadeo Bavasso, Roberto Héctor Iermoli

Nutrients . 2020 Oct 15;12(10):E3149. doi: 10.3390/nu12103149.

Abstract

Metabolic Syndrome (MetS) is increasing worldwide regardless of culture, genetic, gender, and geographic differences. While multiple individual risk factors, such as obesity, hypertension, diabetes, and hyperlipidemia, can cause cardiovascular disease (CVD), it is the intercurrence of these risk factors that defines MetS as a cluster that creates an environment for atherosclerosis and other manifestations of CVD. Despite the advances in the knowledge and management of each of the components of MetS, there are two molecular biology processes, chronic inflammation and oxidative stress, which are still underdiagnosed and undertreated. In order to assess the effect of a dietary supplement on chronic inflammation in MetS, we conducted a clinical trial with volunteers receiving a formula composed of resveratrol, piperine and alpha tocopherol (FRAMINTROL^®), together with their habitual treatment, for three months. The inflammatory state was evaluated by ultrasensitive C reactive protein (US CRP) and ferritin in plasma, and oxygen consumption and chemiluminescence in neutrophils. The results showed that ferritin decreased by 10% (p < 0.05), US-CRP by 33% (p < 0.0001), oxygen consumption by 55% (p < 0.0001), and spontaneous chemiluminiscence was by 25% (p < 0.005) after treatment. As far as we know, this is the first study showing a chronic inflammation decrease in MetS patients due to the administration of a biopower Resveratrol-piperine and alpha tocopherol dietary supplement together with conventional therapy.

Masoud Hosseinzadeh, Amir Alizadeh, Parnian Heydari, Marzieh Kafami, Mahmoud Hosseini, Farimah Beheshti, Narges Marefati, Moustafa Ghanbarabadi

Acta Neuropsychiatr . 2020 Oct 15;1-16. doi: 10.1017/neu.2020.34. Online ahead of print.

Abstract

Objective: Neurotoxicity is an adverse effect caused by cisplatin due to inflammation and oxidative stress in the central nervous system. The present study aimed to assess the effects of vitamin E injection on the learning and memory of rats with cisplatin-induced cognitive impairment.

Methods: Male rats were administered with cisplatin (2 mg/kg/7day ; i.p.) and/or vitamin E (200 mg/kg/7 day; i.p.) for one week, and the control group received saline solution. Spatial memory was evaluated using Morris water maze (MWM). In addition, the hippocampal concentrations of malondialdehyde (MDA), thiol, and superoxide dismutase (SOD) were measured using biochemical methods.

Results: According to the findings, cisplatin significantly increased the escape latency, while decreasing the time spent and traveled pathway in the target quadrant on the final trial day compared to the control group. Furthermore, pretreatment with vitamin E significantly reversed all the results in the spatial memory test. The biochemical data indicated that vitamin E could decrease MDA activity and increase thiol and SOD activity compared to the control group.

Conclusion: According to the results, vitamin E could improve cisplatin-induced memory impairment possibly through affecting the hippocampal oxidative status.

Omid Asbaghi, Mehdi Sadeghian, Behzad Nazarian, Mehrnoosh Sarreshtedari, Hassan Mozaffari-Khosravi, Vahid Maleki, Mohammad Alizadeh, Azad Shokri, Omid Sadeghi

Sci Rep . 2020 Oct 14;10(1):17234. doi: 10.1038/s41598-020-73741-6.

Abstract

The previous meta-analysis of clinical trials revealed a beneficial effect of vitamin E supplementation on serum C-reactive protein (CRP) concentrations; however, it is unknown whether this vitamin has the same influence on other inflammatory biomarkers. Also, several clinical trials have been published since the release of earlier meta-analysis. Therefore, we aimed to conduct a comprehensive meta-analysis to summarize current evidence on the effects of vitamin E supplementation on inflammatory biomarkers in adults. We searched the online databases using relevant keywords up to November 2019. Randomized clinical trials (RCTs) investigating the effect of vitamin E, compared with the placebo, on serum concentrations of inflammatory cytokines were included. Overall, we included 33 trials with a total sample size of 2102 individuals, aged from 20 to 70 years. Based on 36 effect sizes from 26 RCTs on serum concentrations of CRP, we found a significant reduction following supplementation with vitamin E (- 0.52, 95% CI – 0.80, – 0.23 mg/L, P < 0.001). Although the overall effect of vitamin E supplementation on serum concentrations of interleukin-6 (IL-6) was not significant, a significant reduction in this cytokine was seen in studies that used α-tocopherol and those trials that included patients with disorders related to insulin resistance. Moreover, we found a significant reducing effect of vitamin E supplementation on tumor necrosis factor-α (TNF-α) concentrations at high dosages of vitamin E; such that based on dose-response analysis, serum TNF-α concentrations were reduced significantly at the dosages of ≥ 700 mg/day vitamin E (P_{non-linearity} = 0.001). Considering different chemical forms of vitamin E, α-tocopherol, unlike other forms, had a reducing effect on serum levels of CRP and IL-6. In conclusion, our findings revealed a beneficial effect of vitamin E supplementation, particularly in the form of α-tocopherol, on subclinical inflammation in adults. Future high-quality RCTs should be conducted to translate this anti-inflammatory effect of vitamin E to the clinical setting.

Radosław Motkowski, Mateusz Maciejczyk, Marta Hryniewicka, Joanna Karpińska, Bożena Mikołuć

Cardiovasc Drugs Ther . 2020 Oct 14. doi: 10.1007/s10557-020-07091-w. Online ahead of print.

Abstract

Purpose: Familial hypercholesterolemia (FH) requires early treatment. However, statins, which are regarded the first-line therapy, have an influence on redox balance. Antioxidant vitamins are important for many metabolic processes in the developing body. There are few data available on the long-term safety of statin use in children. The aim of this study was to evaluate the influence of statin treatment in children with FH on plasma concentrations of antioxidant vitamins: retinol, alpha-tocopherol and coenzyme Q10.

Methods: The first study group consisted of 13 children aged 10-18 years treated with simvastatin for at least 6 months, and the second group comprised 13 age- and sex-matched children with hypercholesterolemia, in whom pharmacological treatment had not been applied yet. Analyses were performed using a high-performance liquid chromatograph coupled with a MS detector.

Results: The analysis did not reveal significant differences in the concentration of retinol, alpha-tocopherol or coenzyme Q10 between the studied groups. The adjustment of the concentrations of the vitamins to the cholesterol level also indicated no significant differences. We found no deficits in antioxidant vitamins in patients treated with statins, or any risk of adverse effects associated with an increase in their concentration.

Conclusion: There is no rationale for additional supplementation using antioxidant vitamins or modification of low-fat and low-cholesterol diet in pediatric patients treated with statins.

Bin Shen, Pingping Zhou, Xue Jiao, Zhen Yao, Lidan Ye, Hongwei Yu

Nat Commun . 2020 Oct 14;11(1):5155. doi: 10.1038/s41467-020-18958-9.

Abstract

The diverse physiological functions of tocotrienols have listed them as valuable supplementations to α-tocopherol-dominated Vitamin E products. To make tocotrienols more readily available, tocotrienols-producing S. cerevisiae has been constructed by combining the heterologous genes from photosynthetic organisms with the endogenous shikimate pathway and mevalonate pathway. After identification and elimination of metabolic bottlenecks and enhancement of precursors supply, the engineered yeast can produce tocotrienols at yield of up to 7.6 mg/g dry cell weight (DCW). In particular, proper truncation of the N-terminal transit peptide from the plant-sourced enzymes is crucial. To further solve the conflict between cell growth and tocotrienols accumulation so as to enable high-density fermentation, a cold-shock-triggered temperature control system is designed for efficient control of two-stage fermentation, leading to production of 320 mg/L tocotrienols. The success in high-density fermentation of tocotrienols by engineered yeast sheds light on the potential of fermentative production of vitamin E tocochromanols.

Antonella Mosca, Annalisa Crudele, Antonella Smeriglio, Maria Rita Braghini, Nadia Panera, Donatella Comparcola, Arianna Alterio, Maria Rita Sartorelli, Giulia Tozzi, Massimiliano Raponi, Domenico Trombetta, Anna Alisi

Dig Liver Dis . 2020 Oct 12;S1590-8658(20)30920-8. doi: 10.1016/j.dld.2020.09.021. Online ahead of print.

Abstract

Background: 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.

Aim: Here, we investigated if HXT+VitE may reduce systemic inflammation in the above-mentioned patients.

Methods: 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).

Results: 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.

Conclusion: 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.