Effects of antibiotics on degradation and bioavailability of different vitamin E forms in mice

Ran L, Liu AB, Lee MJ, Xie P, Lin Y, Yang CS

Biofactors. 2019 Jan 29. doi: 10.1002/biof.1492. [Epub ahead of print]

Abstract

Tocopherols (T) and tocotrienols (T3), all existing in α, β, γ, and δ-forms, are the eight forms of vitamin E (VE). In this study, we investigated the effects of gut microbiota on the degradation and tissue levels of different VE forms by treating mice with antibiotics in drinking water for 12 days. The mice also received an intragastric (i.g.) dose of VE mixture (mVE; α-T, γ-T, δ-T, γ-T3, and δ-T3, each at a dose of 75 mg/kg) every morning. Antibiotic treatment significantly increased the blood levels of all VE forms in mice that received an i.g. dose of mVE in the morning, 3 h before sacrifice. Without this morning dose, the blood levels of α-T were at the normal physiological levels, but those of the other VE forms were much lower; and the levels of all VE forms were not significantly affected by antibiotics. The liver levels of these VE forms were generally higher and followed the same pattern as the serum. On the contrary, the levels of most side-chain degradation metabolites of VE forms in the serum, liver, kidney, urine, and fecal samples were significantly decreased by antibiotics. The increased bioavailability of VE by antibiotics is probably due to increased absorption of VE or its decreased degradation by gut microbes. The results demonstrate the important roles of gut microbiota in the degradation of VE and in decreasing the bioavailabilities of VE forms.

Afzali H, Jafari Kashi AH, Momen-Heravi M, Razzaghi R, Amirani E, Bahmani F, Gilasi HR, Asemi Z

Wound Repair Regen. 2019 Jan 28. doi: 10.1111/wrr.12701. [Epub ahead of print]

Abstract

This study was carried out to determine the effects of magnesium and vitamin E co-supplementation on wound healing and metabolic status in patients with diabetic foot ulcer (DFU). The current randomized, double-blind, placebo-controlled trial was conducted among 57 patients with grade 3 DFU. Participants were randomly divided into two groups to take either 250 mg magnesium oxide plus 400 IU vitamin E (n = 29) or placebo per day (n = 28) for 12 weeks. Compared with the placebo, taking magnesium plus vitamin E supplements reduced ulcer length (β [difference in the mean of outcomes measures between treatment groups] -0.56 cm; 95% CI, -0.92, -0.20; p = 0.003), width (β -0.35 cm; 95% CI, -0.64, -0.05; p = 0.02) and depth (β -0.18 cm; 95% CI, -0.33, -0.02; p = 0.02). In addition, co-supplementation led to a significant reduction in fasting plasma glucose (β -13.41 mg/dL; 95% CI, -20.96, -5.86; p = 0.001), insulin (β -1.45 μIU/ml; 95% CI, -2.37, -0.52; p = 0.003), insulin resistance (β -0.60; 95% CI, -0.99, -0.20; p = 0.003) and HbA1c (β -0.32%; 95% CI, -0.48, -0.16; p < 0.003), and a significant elevation in insulin sensitivity (β 0.007; 95% CI, 0.003, 0.01; p < 0.001) compared with the placebo. Additionally, compared with the placebo, taking magnesium plus vitamin E supplements decreased triglycerides (β -10.08 mg/dL; 95% CI, -19.70, -0.46; p = 0.04), LDL-cholesterol (β -5.88 mg/dL; 95% CI, -11.42, -0.34; p = 0.03), high sensitivity C-reactive protein (hs-CRP) (β -3.42 mg/L; 95% CI, -4.44, -2.41; p < 0.001) and malondialdehyde (MDA) (β -0.30 μmol/L; 95% CI, -0.45, -0.15; p < 0.001), and increased HDL-cholesterol (β 2.62 mg/dL; 95% CI, 0.60, 4.63; p = 0.01) and total antioxidant capacity (TAC) levels (β 53.61 mmol/L; 95% CI, 4.65, 102.57; p = 0.03). Overall, magnesium and vitamin E co-supplementation for 12 weeks to patients with DFU had beneficial effects on ulcer size, glycemic control, triglycerides, LDL- and HDL-cholesterol, hs-CRP, TAC, and MDA levels.

Ambrogini P, Torquato P, Bartolini D, Albertini MC, Lattanzi D, Di Palma M, Marinelli R, Betti M, Minelli A, Cuppini R, Galli F

Biochim Biophys Acta Mol Basis Dis. 2019 Jan 28. pii: S0925-4439(19)30032-8. doi: 10.1016/j.bbadis.2019.01.026. [Epub ahead of print]

Abstract

Glutamate-mediated excitotoxicity, neuroinflammation, and oxidative stress are common underlying events in neurodegeneration. This pathogenic “triad” characterizes the neurobiology of epilepsy, leading to seizure-induced cell death, increased susceptibility to neuronal synchronization and network alterations. Along with other maladaptive changes, these events pave the way to spontaneous recurrent seizures and progressive degeneration of the interested brain areas. In vivo models of epilepsy are available to explore such epileptogenic mechanisms, also assessing the efficacy of chemoprevention and therapy strategies at the pre-clinical level. The kainic acid model of pharmacological excitotoxicity and epileptogenesis is one of the most investigated mimicking the chronicization profile of temporal lobe epilepsy in humans. Its pathogenic cues include inflammatory and neuronal death pathway activation, mitochondrial disturbances and lipid peroxidation of several regions of the brain, the most vulnerable being the hippocampus. The importance of neuroinflammation and lipid peroxidation as underlying molecular events of brain damage was demonstrated in this model by the possibility to counteract the related maladaptive morphological and functional changes of this organ with vitamin E, the main fat-soluble cellular antioxidant and “conditional” co-factor of enzymatic pathways involved in polyunsaturated lipid metabolism and inflammatory signaling. The present review paper provides an overview of the literature supporting the potential for a timely intervention with vitamin E therapy in clinical management of seizures and epileptogenic processes associated with excitotoxicity, neuroinflammation and lipid peroxidation, i.e. the pathogenic “triad”.

Miyazawa T, Burdeos GC, Itaya M, Nakagawa K, Miyazawa T

IUBMB Life. 2019 Jan 25. doi: 10.1002/iub.2008. [Epub ahead of print]

Abstract

Vitamin E is an essential nutrient that was discovered in the 1920s. Many of the physiological functions of vitamin E, including its antioxidative effects, have been studied for nearly 100 years. Changes in redox balance induced by both endogenously and exogenously generated reactive oxygen species (ROS) are involved in various diseases, and are also a phenomenon that is considered essential for survival. Vitamin E is known to regulate redox balance in the body due to its high concentration among the lipid soluble vitamin groups, and exists ubiquitously in the whole body, including cell membranes and lipoproteins. However, it has been reported that the beneficial properties of vitamin E, including its antioxidative effects, are only displayed in vitro, and not in vivo. Therefore, there exists an ongoing debate regarding the biological functions of vitamin E and its relationship with redox balance. In this review, we introduce the relationship between vitamin Eand redox interactions with (i) absorption, distribution, metabolism, and excretion of vitamin E, (ii) oxidative stress and ROS in the body, (iii) mechanism of antioxidative effects, (iv) non-antioxidant functions of vitamin E, and (v) recent recognition of the field of oxidative stress research. Understanding the recent findings of the redox interaction of vitamin E may help to elucidate the different antioxidative phenomena observed for vitamin E in vitro and in vivo.

Dobrzyński M, Kuropka P, Leśków A, Herman K, Tarnowska M, Wiglusz RJ

Adv Clin Exp Med. 2019 Jan 24. doi: 10.17219/acem/99613. [Epub ahead of print]

Abstract

BACKGROUND:

Exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) can cause adverse effects in many organs. Toxic effects are caused due to the formation of a TCDD complex with the cytoplasmatic aryl hydrocarbon receptor (AhR), whose mechanism of action is similar to that of the estrogen receptor (ER). Some substances, including α-tocopherol (E) and acetylsalicylic acid (ASA), can reduce the toxic effects of TCDD in offspring.

OBJECTIVES:

The objective of this study was to evaluate the co-expression of AhR and ER in the incisors of rat offspring whose mothers were exposed to TCDD, using immunohistochemical and histological techniques. Moreover, the possible protective role of E and ASA was investigated.

MATERIAL AND METHODS:

Four groups of 2-day-old rat offspring, whose mothers were intoxicated by TCDD before mating, were established: control group (C), TCDD group, TCDD+E group and TCDD+ASA group.

RESULTS:

In the TCDD group, there was an increase in ER expression and a decrease in AhR expression in comparison with the C group. In the TCDD+E and TCDD+ASA groups, there was a weak or negative ER expression and slightly stronger expression of AhR than in the TCDD group.

CONCLUSIONS:

The co-expression of AhR and ER during tooth development suggests the role of AhR and ER in the control of this process. Both receptors are also involved in the process of detoxification of TCDD. The increase in AhR in TCDD+E and TCDD+ASA groups indicate a preventive action of antioxidant and antiinflammatory pharmaceutics, which may limit negative effects of TCDD.

Zhao Y, Zhang W, Jia Q, Feng Z, Guo J, Han X, Liu Y, Shang H, Wang Y, Liu WJ

Front Physiol. 2019 Jan 21;9:1939. doi: 10.3389/fphys.2018.01939. eCollection 2018.

Abstract

It has been reported that autophagic stress, which is involved in many diseases, plays a key role in the development of diabetic nephropathy (DN). In this study, we investigated the effects of high dose vitamin E on renal tubular epithelial cells and autophagic stress-related mechanisms in diabetes condition. In diabetic rats, high dose vitamin E treatment significantly decreased the serum creatinine, urea nitrogen, urinary albumin and urinary protein, reduced the levels of LCN2, HAVCR1, LDH and 8-OHdG in urine, and attenuated the cellular apoptosis and interstitial fibrosis in renal cortex. In vitro, vitamin E could reduce the release of LCN2 and HAVCR1 and the protein levels of caspase 3 and TGF-β1, as well as improve the growth inhibition in cultured HK-2 cells after exposure to advanced glycation end products (AGEs). Also, LC3-II and SQSTM1-positive dots were significantly increased in the renal tubular epithelial cells of DN patients and diabetic rats, and in HK-2 cells after exposure to AGEs, which were markedly declined by vitamin E. In addition, we found that the autophagosome formation was not affected by AGEs, as assessed by the mRNA levels of LC3B, Beclin-1, and ATG7. However, AGEs blocked the lysosomal degradation of autophagosome, which was characterized by a decrease in the enzymatic activity of cathepsin B/cathepsin L and DQ-ovalbumin degradation in HK-2 cells, indicating that AGEs-induced accumulation of autophagic vacuoles was a sign of autophagic stress. Interestingly, vitamin Eexerted a protective effect on lysosomes to reduce the autophagic stress. Taken together, we conclude that autophagic stress may play an important part in the progression of DN, and alleviation of autophagic stress though improvement of lysosomal function provides a promising novel approach for treating DN.

Sood AK, Burbank AJ, Duran CG, Enders K, Zhou H, Peden DB, Hernandez ML

J Allergy Clin Immunol. 2019 Jan 17. pii: S0091-6749(19)30031-4. doi: 10.1016/j.jaci.2018.12.1009. [Epub ahead of print]

Abstract

In an era of personalized and precision medicine, efficacy data of therapeutic agents targeting airway inflammation are increasingly taking into account effect modifiers to optimize treatment strategies. Neutrophilic airway inflammation is often less responsive to corticosteroid treatment,¹ and there is a great unmet need for nonsteroidal therapies to target this specific type of inflammation. Obesity is a well-known risk factor for specific asthma phenotypes and negatively affects asthma severity and control, partially as a result of increased airway neutrophilic inflammation.

Tham SY, Loh HS, Mai CW, Fu JY

Int J Mol Sci. 2019 Jan 16;20(2). pii: E372. doi: 10.3390/ijms20020372.

Abstract

Malignancy often arises from sophisticated defects in the intricate molecular mechanisms of cells, rendering a complicated molecular ground to effectively target cancers. Resistance toward cell death and enhancement of cell survival are the common adaptations in cancer due to its infinite proliferative capacity. Existing cancer treatment strategies that target a single molecular pathway or cancer hallmark fail to fully resolve the problem. Hence, multitargeted anticancer agents that can concurrently target cell death and survival pathways are seen as a promising alternative to treat cancer. Tocotrienols, a minor constituent of the vitamin E family that have previously been reported to induce various cell death mechanisms and target several key survival pathways, could be an effective anticancer agent. This review puts forward the potential application of tocotrienols as an anticancer treatment from a perspective of influencing the life or death decision of cancer cells. The cell death mechanisms elicited by tocotrienols, particularly apoptosis and autophagy, are highlighted. The influences of several cell survival signaling pathways in shaping cancer cell death, particularly NF-κB, PI3K/Akt, MAPK, and Wnt, are also reviewed. This review may stimulate further mechanistic researches and foster clinical applications of tocotrienols via rational drug designs.

Figueroa D, Asaduzzaman M, Young F

Biomed Res Int. 2019 Jan 15;2019:6146972. doi: 10.1155/2019/6146972. eCollection 2019.

Abstract

The combination of doxorubicin and cyclophosphamide commonly used to treat breast cancer can cause premature ovarian failure and infertility. α–Tocopherol is a potent antioxidant whereas γ–tocopherol causes apoptosis in a variety of cancer models in vitro including breast cancer. We hypothesised that the combination of doxorubicin (Dox) and 4-hydroperoxycyclophosphamide (4-Cyc) would be more cytotoxic in vitro than each agent alone, and that α–tocopherol would reduce and γ–tocopherol would augment the cytotoxicity of the combined chemotherapeutics. Human MCF-7 breast cancer and KGN ovarian cells were exposed to Dox, 4-Cyc, combined Dox and 4-Cyc, α–tocopherol, γ–tocopherol, or a combination of Dox and 4-Cyc with α–tocopherol or γ–tocopherol. Cell viability was assessed using a crystal violet assay according to four schedules: 24h exposure, 24h exposure + 24h culture in medium, 24h exposure + 48h culture in medium, or 72h continuous exposure. Supernatants from each separate KGN culture experiment (n=3) were examined using an estradiol ELISA. Dox was cytotoxic to both MCF-7 and KGN cells, but 4-Cyc only killed MCF-7 cells. γ–Tocopherol significantly decreased MCF-7 but not KGN cell viability. The combined chemotherapeutics and γ–tocopherol were more cytotoxic to MCF-7 than KGN cells, and α–tocopherol reduced the cytotoxicity of the combined chemotherapeutics towards KGN ovarian cells, but not MCF-7 cells. The addition of both γ–tocopherol and α–tocopherol to the chemotherapeutic combination of Dox and cyclophosphamide has the potential to increase in vitro chemotherapeutic efficacy against breast cancer cells whilst decreasing cytotoxicity towards ovarian granulosa cells.

Luan S, Muhayimana S, Xu J, Zhang X, Xiao C, Huang Q

Ecotoxicol Environ Saf. 2019 Jan 15;167:114-121. doi: 10.1016/j.ecoenv.2018.09.125. Epub 2018 Oct 10.

Abstract

Emamectin benzoate (EMB) toxicity contributes a potential risk to environment and human health. To investigate the effect of α-tocopherol(VitE) and dithiothreitol (DTT) in ameliorating EMB-induced cytotoxicity in human K562 cells, in vitro cultured human K562 cells were incubated with different concentrations of EMB in supplement with VitE and DTT when the cells were in the logarithmic phase. Next, the cell growth inhibition was evaluated using the MTT assay and cellular morphology observation. Reactive oxygen species (ROS) production was monitored using DCFH-DA probe and NF-κB signaling was determined using Western blotting. The results demonstrated that treatment with EMB (time- and concentration-dependent) showed significantly greater inhibition on K562 cell viability, heavier chromatin condensation and DNA fragmentation, and stronger suppression of NF-κB/p105 and p65/RelA expression of K562 cells than the control group (p < 0.01). The supplementation of VitE or DTT could help protect K562 cells against EMB-induced cytotoxicity by improving cell viability, preventing ROS accumulation and up-regulating NF-κB signaling through their ameliorating effects against oxidative stress induced by EMB. VitE had a stronger synergistic effect in limiting EMB cytotoxicity than DTT. Our findings indicate that VitE and DTT are potent antioxidants for human K562 cells, offering a promising means of ameliorating EMB cytotoxicity.