Development of a Novel Pharmaceutical Formula of Nanoparticle Lipid Carriers of Gentamicin/α-Tocopherol and In Vivo Assessment of the Antioxidant Protective Effect of α-Tocopherol in Gentamicin-Induced Nephrotoxicity

Elfaky MA, Thabit AK, Sirwi A, Fahmy UA, Bahabri RM, Al-Awad EA, Basaeed LF

Antibiotics (Basel). 2019 Nov 25;8(4). pii: E234. doi: 10.3390/antibiotics8040234.

Abstract

Gentamicin is a potent antibiotic with a nephrotoxicity drawback which limits its use. D-α-tocopherol polyethylene glycol succinate (α-tocopherol) is widely used as a surfactant and have potent antioxidant properties. This study aimed to assess the protective effect of α-tocopherol on gentamicin-induced nephrotoxicity by loading gentamicin on nanostructured lipid carriers (NLC). In vivo, the product was administered intravenously to three groups of rabbits (control, gentamicin and gentamicin/α-tocopherol NLC) for 10 consecutive days. Blood was collected on days 1, 5 and 10 to assess renal function. A significant difference in all plasma parameters related to kidney function were observed in the gentamicin group compared to the control by day 5 and 10, confirming the nephrotoxicity effect. On the other hand, the same parameter levels of the NLC group were significantly different compared to the gentamicin group, confirming the protective effect on kidney function. Gentamicin also caused significant decreases in plasma levels of glutathione sulfhydryl (GSH) and superoxide dismutase (SOD) activity. However, gentamicin-α-tocopherol NLC significantly elevates both plasma levels of GSH as well as SOD activity. The present work indicates that, loading of gentamicin on NLC by using α-tocopherol, is an innovative strategy to protect against aminoglycoside-induced nephrotoxicity due to its antioxidant activity.

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Single-Cell RNA-seq Reveals Profound Alterations in Mechanosensitive Dorsal Root Ganglion Neurons with Vitamin E Deficiency

Finno CJ, Peterson J, Kang M, Park S, Bordbari MH, Durbin-Johnson B, Settles M, Perez-Flores MC, Lee JH, Yamoah EN

iScience. 2019 Nov 22;21:720-735. doi: 10.1016/j.isci.2019.10.064.

Abstract

Ninety percent of Americans consume less than the estimated average requirements of dietary vitamin E (vitE). Severe vitE deficiency due to genetic mutations in the tocopherol transfer protein (TTPA) in humans results in ataxia with vitE deficiency (AVED), with proprioceptive deficits and somatosensory degeneration arising from dorsal root ganglia neurons (DRGNs). Single-cell RNA-sequencing of DRGNs was performed in Ttpa-/- mice, an established model of AVED. In stark contrast to expected changes in proprioceptive neurons, Ttpa-/- DRGNs showed marked upregulation of voltage-gated Ca2+ and K+ channels in mechanosensitive, tyrosine-hydroxylase positive (TH+) DRGNs. The ensuing significant conductance changes resulted in reduced excitability in mechanosensitive Ttpa-/- DRGNs. A highly supplemented vitE diet (600 mg dl-α-tocopheryl acetate/kg diet) prevented the cellular and molecular alterations and improved mechanosensation. VitE deficiency profoundly alters the molecular signature and functional properties of mechanosensitive TH+ DRGN, representing an intriguing shift of the prevailing paradigm from proprioception to mechanical sensation.

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Bioactive Compounds: Natural Defense Against Cancer?

Subramaniam S, Selvaduray KR, Radhakrishnan AK

Biomolecules. 2019 Nov 21;9(12). pii: E758. doi: 10.3390/biom9120758.

Abstract

Cancer is a devastating disease that has claimed many lives. Natural bioactive agents from plants are gaining wide attention for their anticancer activities. Several studies have found that natural plant-based bioactive compounds can enhance the efficacy of chemotherapy, and in some cases ameliorate some of the side-effects of drugs used as chemotherapeutic agents. In this paper, we have reviewed the literature on the anticancer effects of four plant-based bioactive compounds namely, curcumin, myricetin, geraniin and tocotrienols (T3) to provide an overview on some of the key findings that are related to this effect. The molecular mechanisms through which the active compounds may exert their anticancer properties in cell and animal-based studies also discussed.

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Tocotrienol-rich fraction from annatto ameliorates expression of lysyl oxidase in human osteoblastic MG-63 cells

Kohno K, Yamada W, Ishitsuka A, Sekine M, Virgona N, Ota M, Yano T

Biosci Biotechnol Biochem. 2019 Nov 19:1-10. doi: 10.1080/09168451.2019.1693252.

Abstract

Lysyl oxidase (LOX) is required for the formation of bone collagen cross-links. Inactivation of the LOX gene in osteoblasts by DNA methylation and JAK signaling has been reported to cause loss of cross-links and an increased risk of fractures. Tocotrienols (T3s) have proven benefits on bone strength, but their potential effects on LOX remain largely unknown. Thus, the present study investigates the in vitro effects of T3s on LOX expression in human osteoblastic MG-63 cells. Results indicated that Tocotrienol-Rich Fraction (TRF), the δ-T3 rich oil extracted from Annatto was the most effective and significantly increased LOX expression. TRF treatment decreased de-novo methyltransferases (DNMTs), DNMT3A and DNMT3B levels. In addition, TRF significantly inhibited JAK2 activation and decreased expression of Fli1, a transcription factor of DNMTs. We conclude that TRF induced an increase in LOX expression via inhibition of de-novo methylation and reduction of Fli1 expression by the inactivation of JAK2.

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Plasma versus Erythrocyte Vitamin E in Renal Transplant Recipients, and Duality of Tocopherol Species

Sotomayor CG, Rodrigo R, Gomes-Neto AW, Gormaz JG, Pol RA, Minović I, Eggersdorfer ML, Vos M, Riphagen IJ, de Borst MH, Nolte IM, Berger SP, Navis GJ, Bakker SJL

Nutrients. 2019 Nov 19;11(11). pii: E2821. doi: 10.3390/nu11112821.

Abstract

Redox imbalance is an adverse on-going phenomenon in renal transplant recipients (RTR). Vitamin E has important antioxidant properties that counterbalance its deleterious effects. However, plasma vitamin E affinity with lipids challenges interpretation of its levels. To test the hypothesis that erythrocyte membranes represent a lipids-independent specimen to estimate vitamin E status, we performed a cross-sectional study in a cohort of adult RTR (n = 113) recruited in a university setting (2015-2018). We compared crude and total lipids-standardized linear regression-derived coefficients of plasma and erythrocyte tocopherol species in relation to clinical and laboratory parameters. Strongly positive associations of fasting lipids with plasma tocopherol became inverse, rather than absent, in total lipids-standardized analyses, indicating potential overadjustment. Whilst, no variables from the lipids domain were associated with the tocopherol species measured from erythrocyte specimens. In relation to inflammatory status and clinical parameters with antioxidant activity, we found associations in directions that are consistent with either beneficial or adverse effects concerning α- or γ-tocopherol, respectively. In conclusion, erythrocytes offer a lipids-independent alternative to estimate vitamin E status and investigate its relationship with parameters over other biological domains. In RTR, α- and γ-tocopherol may serve as biomarkers of relatively lower or higher vulnerability to oxidative stress and inflammation, noticeably in opposite directions.

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The Vitamin E Derivative Gamma Tocotrienol Promotes Anti-Tumor Effects in Acute Myeloid Leukemia Cell Lines

Ghanem P, Zouein A, Mohamad M, Hodroj MH, Haykal T, Abou Najem S, Naim HY, Rizk S

Nutrients. 2019 Nov 17;11(11). pii: E2808. doi: 10.3390/nu11112808.

Abstract

Acute myeloid leukemia (AML) is a blood cancer characterized by the formation of faulty defective myelogenous cells with morphological heterogeneity and cytogenic aberrations leading to a loss of their function. In an attempt to find an effective and safe AML treatment, vitamin E derivatives, including tocopherols were considered as potential anti-tumor compounds. Recently, other isoforms of vitamin E, namely tocotrienols have been proposed as potential potent anti-cancerous agents, displaying promising therapeutic effects in different cancer types. In this study we evaluated the anti-cancerous effects of γ-tocotrienol, on AML cell lines in vitro. For this purpose, AML cell lines incubated with γ-tocotrienol were examined for their viability, cell cycle status, apoptotic cell death, DNA fragmentation, production of reactive oxygen species and expression of proapoptotic proteins. Our results showed that γ-tocotrienol exhibits time and dose-dependent anti-proliferative, pro-apoptotic and antioxidant effects on U937 and KG-1 cell lines, through the upregulation of proteins involved in the intrinsic apoptotic pathway.

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Vitamin E prevents the cognitive impairments in post-traumatic stress disorder rat model: behavioral and molecular study

Ahmed M, Alzoubi KH, Khabour OF

Psychopharmacology (Berl). 2019 Nov 16. doi: 10.1007/s00213-019-05395-w.

Abstract

RATIONALE:

Post-traumatic stress disorder (PTSD) is a psychiatric disorder developed after an exposure to severe traumatic events. Patients with PTSD suffer from different symptoms including memory impairment. In addition, PTSD is associated with oxidative stress. Vitamin E, a fat-soluble vitamin, possesses cognition protective effects via its antioxidative properties.

OBJECTIVES:

To investigate the impact of vitamin E on memory impairment induced by PTSD in animals.

METHODS:

A rat model of PTSD-like behavior and the radial arm water maze (RAWM) for testing of learning and memory paradigm were used. Rats were divided into 4 groups: control, vitamin E, PTSD, and vitamin E + PTSD.

RESULTS:

In the learning phase, results showed no significant differences among experimental groups, indicating that PTSD-like behavior did not impair learning ability in rats. However, memory tests in the RAWM showed that PTSD-like animals had impairment in both short-term and long-term memories. Vitamin E, on the other hand, prevented this impairment of memory. With respect to oxidative stress, significant decreases were detected in reduced glutathione/oxidized glutathione (GSH/GSSG) ratio, glutathione peroxidase (GPx) and catalase enzyme activities, global histone 3 acetylation, and brain derived neurotrophic factor (BDNF) levels in the PTSD-like animals group compared with other groups (P < 0.05). Vitamin E protected the reduction of these oxidative stress biomarkers, global histone 3 acetylation, and BDNF levels.

CONCLUSIONS:

Vitamin E prevented memory impairment associated with PTSD-like behavior in animals, probably via its antioxidative properties, and preservation of epigenetic changes induced in PTSD-like animals.

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Vitamin e-loaded membrane dialyzers reduce hemodialysis inflammaging

Sepe V, Gregorini M, Rampino T, Esposito P, Coppo R, Galli F, Libetta C

BMC Nephrol. 2019 Nov 15;20(1):412. doi: 10.1186/s12882-019-1585-6.

Abstract

BACKGROUND:

Inflammaging is a persistent, low-grade, sterile, nonresolving inflammatory state, associated with the senescence of the immune system. Such condition downregulates both innate and adaptive immune responses during chronic disorders as type II diabetes, cancer and hemodialysis, accounting for their susceptibility to infections, malignancy and resistance to vaccination. Aim of this study was to investigate hemodialysis inflammaging, by evaluating changes of several hemodialysis treatments on indoleamine 2,3-dioxygenase-1 activity and nitric oxide formation.

METHODS:

We conducted a randomized controlled observational crossover trial. Eighteen hemodialysis patients were treated with 3 different hemodialysis procedures respectively: 1) Low-flux bicarbonate hemodialysis, 2) Low-flux bicarbonate hemodialysis with vitamin E - loaded dialyzers, and 3) Hemodialfitration. The control group consisted of 14 hospital staff healthy volunteers. Blood samples were collected from all 18 hemodialysis patients just after the long interdialytic interval, at the end of each hemodialysis treatment period.

RESULTS:

Hemodialysis kynurenine and kynurenine/L - tryptophan blood ratio levels were significantly higher, when compared to the control group, indicating an increased indoleamine 2,3-dioxygenase-1 activity in hemodialysis patients. At the end of the low-flux bicarbonate hemodialysis with vitamin E - loaded dialyzers period, L - tryptophan serum levels remained unchanged vs both low-flux bicarbonate hemodialysis and hemodialfitration. Kynurenine levels instead decreased, resulting in a significant reduction of kynurenine/L - tryptophan blood ratio and indoleamine 2,3-dioxygenase-1 activity, when matched to both low-flux bicarbonate hemodialysis and HDF respectively. Serum nitric oxide control group levels, were significantly lower when compared to all hemodialysis patient groups. Interestingly, low-flux bicarbonate hemodialysis with vitamin E - loaded dialyzers nitric oxide serum levels from venous line blood samples taken 60 min after starting the hemodialysis session were significantly lower vs serum taken simultaneously from the arterial blood line.

CONCLUSIONS:

The treatment with more biocompatible hemodialysis procedure as low-flux bicarbonate hemodialysis with vitamin E - loaded dialyzers, reduced indoleamine 2,3-dioxygenase-1 activity and nitric oxide formation when compared to both low-flux bicarbonate hemodialysis and hemodialfitration. These data suggest that low-flux bicarbonate hemodialysis with vitamin E - loaded dialyzers lowering hemodialysis inflammaging, could be associated to changes of proinflammatory signalling a regulated molecular level.

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Comparative study on the plasma lipid oxidation induced by peroxynitrite and peroxyl radicals and its inhibition by antioxidants

Morita M, Naito Y, Itoh Y, Niki E

Free Radic Res. 2019 Nov 14:1-13. doi: 10.1080/10715762.2019.1688799.

Abstract

The unregulated oxidative modification of biological molecules has been implicated in the pathogenesis of various diseases, and the beneficial effects of antioxidants against detrimental oxidation have received much attention. Among the multiple oxidants, peroxyl radical and peroxynitrite play an important role as chain-carrying species in lipid peroxidation and one of the major oxidants produced in vivo, respectively. This study was performed to elucidate the prominent features of these two oxidants by comparing their reactivity and selectivity and also the effects of antioxidants against plasma lipid oxidation induced by the two oxidants. It was shown that despite peroxyl radical and peroxynitrite gave similar pattern of lipid peroxidation products of plasma, and these two oxidants exert different selectivity and reactivity towards probes and antioxidants. The capacity of antioxidants to scavenge peroxynitrite and peroxyl radical decreased in the order BSA > glutathione > α-tocopherol ∼ bilirubin ∼ α – tocotrienol > γ-tocotrienol ∼ γ – tocopherol > uric acid and α-tocopherol ∼ α – tocotrienol > bilirubin > γ-tocotrienol ∼ γ – tocopherol > BSA > glutathione > uric acid, respectively. α-Tocopherol localised within plasma lipoproteins was six times less effective than trolox in aqueous phase for scavenging peroxynitrite and the derived oxidants, despite the same chemical reactivity of the two chromanols. BSA was relatively more effective as antioxidant against peroxynitrite than peroxyl radical, whereas TEMPO did not act as efficient antioxidant against both oxidants. It was suggested that thiols act as more potent antioxidant against peroxynitrite than phenolic antioxidants, while phenolic antioxidants are potent inhibitor of lipid peroxidation induced by free radicals including those derived from peroxynitrite. Abbreviations: AAPH: 2,2′-azobis(2-amidinopropane) dihydrochloride; C11-BODIPY: 4,4-difluoro-5-(4-phenyl-1,3-butadienyl)-4-bora-3a,4a-diaza-s-indacene-3-undecanoic acid; BSA: bovine serum albumin; DPPP: diphenyl-1-pyrenylphosphine; H(p)ODE: hydro(pero)xyoctadecadienoates; PGR: pyrogallol red; PUFA: polyunsaturated fatty acid; SIN-1: 3-morpholinosydnonimine; TEMPO: 2,2-6,6 tetramethylpiperidine-1-oxyl; Trolox: 2-carboxy-2,5,7,8-tetramethyl-6-hydroxychroman.

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Investigation of the curative effects of palm vitamin E tocotrienols on autoimmune arthritis disease in vivo

Zainal Z, Rahim AA, Radhakrishnan AK, Chang SK, Khaza'ai H

Sci Rep. 2019 Nov 14;9(1):16793. doi: 10.1038/s41598-019-53424-7.

Abstract

The tocotrienol-rich fraction (TRF) from palm oil contains vitamin E, which possesses potent antioxidant and anti-inflammatory activities. Rheumatoid arthritis (RA) is a chronic joint inflammatory disease characterised by severe joint pain, cartilage destruction, and bone erosion owing to the effects of various pro-inflammatory mediators and cytokines. Here, we investigated the therapeutic effects of TRF in a rat model of collagen-induced arthritis (CIA). Arthritis was induced by a single intradermal injection of collagen type II in Dark Agouti (DA) rats. Rats were then treated with or without TRF by oral gavage from day 28 after the first collagen injection. Arthritic rats supplemented with TRF showed decreased articular index scores, ankle circumferences, paw volumes, and radiographic scores when compared with untreated rats. The untreated arthritic rats showed higher plasma C-reactive protein levels (p < 0.05) and production of pro-inflammatory cytokines than arthritic rats fed TRF. Moreover, there was a marked reduction in the severity of histopathological changes observed in arthritic rats treated with TRF compared with that in untreated arthritic rats. Overall, the results show that TRF had beneficial effects in this rat model of RA.

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