Association of Circulating Retinol and α-TOH Levels with Cognitive Function in Aging Subject with Type 2 Diabetes Mellitus

Huang X, Guo Y, Li P, Ma X, Dong S, Hu H, Li Y, Yuan L.

J Nutr Health Aging. 2020;24(3):290-299. doi: 10.1007/s12603-020-1328-1.

Abstract

OBJECTIVES:

Malnutrition of vitamin A (retinol) and vitamin E (α-tocopherol, α-TOH) was observed in type 2 diabetes mellitus (T2DM) or dementia patients. However, how these vitamins affect cognitive function of subjects with T2DM was seldom reported. The objective of this study was to determine the association of circulating retinol and α-TOH with cognition in aging subjects with T2DM.

METHODS:

A total of 448 T2DM subjects and 448 age, gender and education matched control subjects (aged 55-75 years) were included in the study. Demographic characters of the participants were collected. Food frequency questionnaire (FFQ) method was used to collect dietary intake information. To assess the status of cognition, the MoCA test was used. Circulating retinol and α-TOH levels were compared between T2DM and non-T2DM subjects. Correlation of circulating retinol and α-TOH levels with cognitive function was analyzed in T2DM subjects. The effect of serum retinol and α-TOH levels on the risk of MCI in T2DM patients was explored.

RESULTS:

We found that T2DM-MCI subjects demonstrate lower serum retinol level than T2DM-nonMCI subjects (P < 0.01). Serum retinol level was positively correlated to cognitive function in T2DM subject (P < 0.05). T2DM subjects with higher circulating retinol level demonstrate higher cognitive scores in visual and executive, attention, language, memory and delayed recall domains (P < 0.05).

CONCLUSION:

Diminished circulating retinol predicts an increased risk of MCI in T2DM patients. Our findings provide suggestions that optimal retinol nutritional status might benefit cognition and decrease the risk of MCI in aging subjects with T2DM.

Pirhadi-Tavandashti N, Imani H, Ebrahimpour-Koujan S, Samavat S, Hakemi MS

Complement Ther Med. 2020 Mar;49:102357. doi: 10.1016/j.ctim.2020.102357. Epub 2020 Feb 26.

Abstract

OBJECTIVES:

The present study was aimed to investigate the effect of alpha-tocopherol supplementation on biomarkers of endothelial function (Intercellular Adhesion Molecule 1 and Vascular Cell Adhesion Protein 1) and inflammatory markers (Interleukin 6 and high-sensitivity C-reactive protein) among the hemodialysis patients.

METHODS:

To conduct this randomized, double-blinded, and placebo-controlled clinical trial, 49 hemodialysis patients, aged 20-60 years, were recruited and randomly divided into the intervention and control groups. The intervention group (n = 25) received 600 IU alpha-tocopherol soft gels (200 IU three times daily), while the controls (n = 24) consumed the identical placebo soft gels for 10 weeks. At the baseline and end of the study, 7 ml pre-dialysis blood samples were taken from all participants to measure their serum concentrations of ICAM-1, VCAM-1, IL-6, and hs-CRP.

RESULTS:

Alpha-tocopherol supplementation reduced the serum levels of ICAM-1 and VCAM-1 significantly (-140.67 ± 57.25 ng/ml vs. -15.97 ± 79.19 ng/ml, P = 0.001 for ICAM-1 and –6.79 ± 4.76 ng/ml vs. 1.02 ± 3.22 ng/ml, P = 0.019 for VCAM-1). However, no significant difference was observed between the two groups regarding the serum levels of hs-CRP (-0.15 ± 0.19 mg/l vs. 0.02 ± 0.12 mg/l; P = 0.32) and IL-6 (-0.03 ± 0.1 pg/ml vs. – 0.06 ± 0.11 pg/ml; P = 0.65).

CONCLUSIONS:

Our results showed that 10 weeks of supplementation with 600 IU alpha-tocopherol improved ICAM-1 and VCAM-1 levels, but did not have any effect on the serum concentration of IL-6 and hs-CRP in hemodialysis patients. Further studies are required to confirm these findings.

Khuzhakhmetova LK, Teply DL, Bazhanova ED

Adv Gerontol. 2019;32(6):915-922.

Abstract

in English, Russian

As is known, the pineal gland plays an important role in adaptogenesis, and the hypothalamus is one of the main links of the stress-reactive system and is involved in the regulation of the involution of the whole organism. So, the study of changes in these organs during stress and aging is very interesting. The aim of the work is to study the mechanisms of apoptosis of pinealocytes and neurosecretory cells of the suprachiasmatic nucleus of the hypothalamus during aging, stress, and under the conditions of pharmacological correction of involutional processes and stress response (antioxidant alpha-tocopherol acetate, immunomodulator cycloferon). We used Wistar rats as model, young (2-4 months) and old (30 months). Age-related features of the apoptosis dynamics of pinealocytes and neurosecretory cells of the hypothalamic suprachiasmatic nucleus were studied using TUNEL and immunohistochemistry, and the possibilities of pharmacological correction of apoptotic processes are determined. An age-dependent increase of apoptosis level of cells of suprachiasmatic nucleus and epiphysis in rats was revealed. The stress effect (immobilization) led to the intensification of cell death, more significant in older animals. The pineal gland and suprachiasmatic nucleus, traditionally regarded as regulators of circadian rhythms, are at the same time actively involved in general adaptation processes. The studied drugs (α-tocopherol-acetate, cycloferon, and their combination) have a pronounced anti-apoptotic, cytoprotective effect under physiological conditions during aging, as well as during non-specific emotional stress (immobilization) in young and old animals. The regulatory effect is accomplished by activating the expression of the anti-apoptotic protein Bcl-2 in the neurosecretory cells of the suprachiasmatic nucleus and pinealocytes.

Tupal A, Sabzichi M, Bazzaz R, Fathi Maroufi N, Mohammadi M, Pirouzpanah SM, Ramezani F

Nutr Cancer. 2020;72(4):653-661. doi: 10.1080/01635581.2019.1650191. Epub 2019 Aug 8.

Abstract

Tumor-targeted nanoparticle delivery system has been known as a substitute and capable achievement in cancer treatment compared to conventional methods. In this study, we examined potential application of ɑ-tocotrienol-Precirol formulation to enhance efficiency of doxorubicin (DOX) in induction of apoptosis in HUH-7 hepatocarcinoma cells. ɑ-tocotrienol-loaded nanoparticles were characterized at the point of zeta potential, particle size, scanning electron microscope (SEM), and cell internalization. To evaluate antiproliferative effects of formulation, apoptosis, cell cycle procedure, flow cytometry, and MTT assays were employed. Optimum size of the ɑ-tocotrienol formulation revealed narrow size distribution with mean average of 78 ± 3 nm. IC₅₀ values for ɑ-tocotrienol and ɑ-tocotrienol-nano structured lipid carriers after 24 h were 15 ± 0.6 and 10 ± 0.03 µM, respectively. After incubation of cells with ɑ-tocotrienol-loaded careers, the rate of cell proliferation decreased from 53 ± 6.1 to 34 ± 7.1% (P < 0.05). A significant improvement in the apoptosis percentage was revealed after treatment of the HUH-7 cell line with DOX and ɑ-tocotrienol careers (P < 0.05). Gene expression results demonstrated a marked decrease in survivin and increase in Bid and Bax levels. Our findings suggest that ɑ-tocotrienol-loaded nanoparticles elevate DOX efficacy in HUH-7 hepatocarcinoma cell.

Ling L, Ismail M, Shang Z, Hu Y, Li B

Int J Pharm. 2020 Mar 15;577:119049. doi: 10.1016/j.ijpharm.2020.119049. Epub 2020 Jan 23.

Abstract

Irinotecan (Ir) is a potent antitumor chemotherapeutics in clinic and used for the treatment of a various cancers, but the degree of its application is critically limited by toxic side-effects and marked heterogeneities. Nano-formulation of prodrugs, based on “all-in-one” carrier-free self-assemblies offers an effective approach to alter pharmacokinetics and safety profiles of cytotoxic agents. In this study, a novel vitamin E succinate-based formulation of Ir (VES-Ir) combined with nanoscaled characteristics and synergistic combination was constructed through esterification. The conjugation makes amphiphilic VES-Ir prodrug self-assemble into nanoparticles with a fine diameter (VES-Ir NPs, 75.4 nm) of spherical morphology. Furthermore, VES-Ir NPs with a 1:1 drug-to-drug ratio was demonstrated to possess respectable physiological stability within 72 h test, while can react to pH/esterase-sensitive drug release in lysosomes internalized into tumor cells, potentially highlighting their alleviating side effects. Compared with single and mixture drugs administration, the nanoformulated VES-Ir NPs codelivered both VES and Ir with different anticancer mechanisms to induce the highest suppress proliferation of MCF-7 (IC₅₀ 0.18 μM) and A549 (IC₅₀ 0.29 μM) cells in a synergistic way (CI < 1). More importantly, the formulating nanoparticulate Ir is to significantly enhance its bioavailability in vivo with long retention time in bloodstream and thereby, resulting the superior tumor inhibitory rate (TIR) of 85.2% versus controls. This simple nanoformulation of Ir drug deprived from VES conjugation, together with self-delivery and synergistic property, may provide an effective strategy for multiple chemotherapeutics delivery to treat cancers or other diseases.

Nowicka B, Fesenko T, Walczak J, Kruk J

Ecotoxicol Environ Saf. 2020 Mar 15;191:110241. doi: 10.1016/j.ecoenv.2020.110241. Epub 2020 Jan 31.

Abstract

One of the major mechanisms of heavy metal toxicity is the induction of oxidative stress. Redox-active heavy metals, like chromium, can induce it directly, whereas redox-inactive metals, like cadmium, play an indirect role in the generation of reactive oxygen species (ROS). Living organisms defend themselves against oxidative stress taking advantage of low-molecular-weight antioxidants and ROS-detoxifying enzymes. Tocopherols and plastoquinol are important plastid prenyllipid antioxidants, playing a role during acclimation of Chlamydomonas reinhardtii to heavy metal-induced stress. However, partial inhibition of synthesis of these prenyllipids by pyrazolate did not decrease the tolerance of C. reinhardtii to Cr- and Cd-induced stress, suggesting redundancy between antioxidant mechanisms. To verify this hypothesis we have performed comparative analyses of growth, photosynthetic pigments, low-molecular-weight antioxidants (tocopherols, plastoquinol, plastochromanol, ascorbate, soluble thiols, proline), activities of the ascorbate peroxidase (APX), catalase and superoxide dismutase (SOD) and cumulative superoxide production in C. reinhardtii exposed to Cd²⁺ and Cr₂O₇^2- ions in the presence or absence of pyrazolate. The decreased α-tocopherol and plastoquinol content resulted in the increase in superoxide generation and APX activity in pyrazolate-treated algae. The application of heavy metal ions and pyrazolate had a pronounced impact on Asc and total thiol content, as well as SOD and APX activities (the latter only in Cd-exposed cultures), when compared with algae grown in the presence of heavy metal ions or pyrazolate alone. The superoxide production in cultures exposed to heavy metal ions and pyrazolate decreased when compared to the cultures exposed to either heavy metal ions or an inhibitor alone.

Wang M, Wang Q, Du Y, Jiang H, Zhang X

Andrology. 2020 Mar 14. doi: 10.1111/andr.12787. [Epub ahead of print]

Abstract

BACKGROUND:

Male infertility is a tough problem in medicine. This article aims to provide the latest evidence for the efficacy and safety of traditional Chinese medicine (TCM) combined with vitamins in the treatment of male infertility.

METHOD:

All randomized controlled trials (RCTs) that used TCM combined with vitamins for male infertility treatment were included in databases of China National Knowledge Infrastructure (CNKI), Wanfang, VIP Database, China Biology Medicine disc (CBM), MEDLINE, EMBASE, and Cochrane Library. The quality of the included articles was evaluated using the Cochrane Reviewer’s Handbook 5.3, and meta-analysis was performed using Stata 15.

RESULTS:

A total of 14 eligible studies with 1488 patients were included in this meta-analysis. The results suggested that, compared with vitamin E or vitamin E + C alone, combination of TCM with vitamins increased significantly sperm concentration, sperm motility, sperm viability, liquefaction time of semen, the activity of acrosome enzyme, and the pregnancy rate of patients with male infertility. Three kinds of TCM (Shengjing capsule, Huanshao capsule, and compound Xuanju capsule) showed significant improvement for male infertility in terms of pregnancy rate, sperm concentration, or sperm motility. In addition, the results of the publication bias test demonstrated that no significant bias occurred.

CONCLUSION:

Traditional Chinese medicine combined with vitamins has significant efficacy in the treatment of male infertility with no increase in side effects. The specific implementing regulations still need more long-term, multicenter, randomized, and double-blind clinical trials.

Sozen E, Yazgan B, Tok OE, Demirel T, Ercan F, Proto JD, Ozer NK

Metabolism. 2020 Mar 14;106:154205. doi: 10.1016/j.metabol.2020.154205. [Epub ahead of print]

Abstract

BACKGROUND:

Cardiovascular diseases (CVDs), with highest mortality and morbidity rates, are the major cause of death in the world. Due to the limited information on heart tissue changes, mediated by hypercholesterolemia, we planned to investigate molecular mechanisms of endoplasmic reticulum (ER) stress and related cell death in high cholesterol fed rabbit model and possible beneficial effects of α-tocopherol.

METHODS:

Molecular changes in rabbit heart tissue and cultured cardiomyocytes (H9c2 cells) were measured by western blotting, qRT-PCR, immunflouresence and flow cytometry experiments. Histological modifications were assessed by light and electron microscopes, while degradation of mitochondria was quantified through confocal microscope.

RESULTS:

Feeding rabbits 2% cholesterol diet for 8 weeks and treatment of cultured cardiomyocytes with 10 μg/mL cholesterol for 3 h induced excessive autophagic activity via IRE1/JNK pathway. While no change in ER-associated degradation (ERAD) and apoptotic cell death were determined, electron and confocal microscopy analyses in cholesterol supplemented rabbits revealed significant parameters of autophagic cell death, including cytoplasmic autophagosomes, autolysosomes and organelle loss in juxtanuclear area as well as mitochondria engulfment by autophagosome. Either inhibition of ER stress or JNK in cultured cardiomyocytes or α-tocopherol supplementation in rabbits could counteract the effects of cholesterol.

CONCLUSION:

Our findings underline the essential role of hypercholesterolemia in stimulating IRE1/JNK branch of ER stress response which then leads to autophagic cell death in heart tissue. Results also showed α-tocopherol as a promising regulator of autophagic cell death in cardiomyocytes.

Hosny KM, Rizg WY, Khallaf RA

Pharmaceutics. 2020 Mar 13;12(3). pii: E263. doi: 10.3390/pharmaceutics12030263.

Abstract

The objective of this study was to develop an optimized sustained-release nanotransfersomes (NTS) based in situ gel formulation of rosuvastatin (RO) combined with ellagic acid (EA) antioxidant, to enhance cytotoxic and anti-proliferative activity against tongue carcinoma. The concentrations of lecithin, Tween 80, and d-tocopherol polyethylene glycol succinate (TPGS) were considered as independent variables. Particle size, entrapment, and stability were selected as dependent variables. The obtained formulation containing 25% lecithin, 20% Tween 80, and TPGS 15% fulfilled the prerequisites of the optimum formulation. RO-NTS loaded in situ gel was prepared and optimized for concentrations of Poloxamer 407, and Carbopol, using statistical design. Drug release from in situ gel showed a sustained release profile. The RO IC50 was decreased by half for the in situ gel in comparison to plain RO and RO-EA-NTS. A significant amount of caspase-3 was detected in all the formulation treatments. The studies indicated that EA’s synergistic anti-oxidant effect owing to a high affinity to the PGP efflux transporter and higher penetration in the RO-NTS formulation led to a higher inhibition against human chondrosarcome-3 cancer cell lines. RO-EA NTS-loaded in situ gel had a sustained release that could be significant in localized therapy as an alternative to surgery in the treatment of aggressive tongue carcinoma.

Li Y, Ye C, Cai C, Zhao M, Han N, Liu Z, Zhai J, Yin J

Pharm Res. 2020 Mar 12;37(3):66. doi: 10.1007/s11095-020-02789-w.

Abstract

PURPOSE:

TXA9, a novel cardiac glycoside, has a potent anti-proliferative effect against A549 human lung cancer cells, however, possesses a poor water-solubility and a rapid metabolic rate in vivo which limited the further development of TXA9. To overcome the shortcomings of TXA9, four polymer prodrugs of TXA9 were designed and synthesized.

METHODS:

Poly (ethylene glycol) monomethyl ether (mPEG) and α-tocopherol polyethylene glycol succinate (TPGS) were applied to modify TXA9 via carbonate ester and glycine linkers respectively to obtain four polymer prodrugs. The water-solubility and stability of prodrugs were studied in vitro while their pharmacokinetic behaviors and antitumor activity were investigated in vivo.

RESULTS:

The water-solubility of TXA9 was obviously increased and prodrugs with glycine linkers showed a better stability in rat plasma. Their pharmacokinetic investigation found that the t_1/2 and AUC_0-∞ of TPGS-Gly-TXA9 was increased by 80- and 9.6-fold compared with that of TXA9, which was more superior than the other three prodrugs. More importantly, the tumor inhibition rate of TPGS-Gly-TXA9 (43.81%) on A549 xenograft nude mice was significantly increased compared with that of TXA9 (25.26%).

CONCLUSION:

The above results suggested that TPGS-Gly-TXA9 possessed better antitumor efficiency than TXA9 and could be further investigated as an anti-cancer agent.