Genotoxicity of nedaplatin in cultured lymphocytes: modulation by vitamin E

Muntaha S Al-Khdour, Omar F Khabour, Laith N Al-Eitan, Karem H Alzoubi

Drug Chem Toxicol . 2021 Dec 29;1-5. doi: 10.1080/01480545.2021.2015369. Online ahead of print.

Abstract

Nedaplatin is a chemotherapeutic agent used widely in cancer therapy. Nedaplatin has been shown to cause DNA damage to cells via the induction of oxidative stress. Vitamin E (Vit E) has an anti-mutagenic activity that can protect cells from DNA damaging agents. The objective of this study is to examine the genotoxic and cytotoxic effects of nedaplatin in human cultured lymphocytes. In addition, modulation of such effects by Vit E was also examined. The frequencies of sister chromatid exchange (SCE) and chromosomal aberrations (CAs) were used as an indicator for genotoxicity. The mitotic and proliferative indices were used to examine the cytotoxic effects of nedaplatin. The results showed that nedaplatin significantly elevated SCE and CA frequencies in human lymphocytes (p ˂ 0.01). The increases in the frequencies of SCE and CA caused by nedaplatin were lowered by pretreatment treatment with Vit E (p < 0.05). Nedaplatin significantly lowered mitotic index but Vit E pretreatment did not modulate this effect. These results suggest that Vit E has the potential to ameliorate the genotoxicity of nedaplatin in cultured lymphocytes.

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γ-Tocotrienol Protects against Mitochondrial Dysfunction, Energy Deficits, Morphological Damage, and Decreases in Renal Functions after Renal Ischemia

Grazyna Nowak, Judit Megyesi

Int J Mol Sci . 2021 Nov 24;22(23):12674. doi: 10.3390/ijms222312674.

Abstract

Ischemia-induced mitochondrial dysfunction and ATP depletion in the kidney result in disruption of primary functions and acute injury of the kidney. This study tested whether γ-tocotrienol (GTT), a member of the vitamin E family, protects mitochondrial function, reduces ATP deficits, and improves renal functions and survival after ischemia/reperfusion injury. Vehicle or GTT (200 mg/kg) were administered to mice 12 h before bilateral kidney ischemia, and endpoints were assessed at different timepoints of reperfusion. GTT treatment reduced decreases in state 3 respiration and accelerated recovery of this function after ischemia. GTT prevented decreases in activities of complexes I and III of the respiratory chain, and blocked ischemia-induced decreases in F0F1-ATPase activity and ATP content in renal cortical tissue. GTT improved renal morphology at 72 h after ischemia, reduced numbers of necrotic proximal tubular and inflammatory cells, and enhanced tubular regeneration. GTT treatment ameliorated increases in plasma creatinine levels and accelerated recovery of creatinine levels after ischemia. Lastly, 89% of mice receiving GTT and 70% of those receiving vehicle survived ischemia. Conclusions: Our data show novel observations that GTT administration improves mitochondrial respiration, prevents ATP deficits, promotes tubular regeneration, ameliorates decreases in renal functions, and increases survival after acute kidney injury in mice.

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Paclitaxel-loaded polymeric nanoparticles based on α-tocopheryl succinate for the treatment of head and neck squamous cell carcinoma: in vivo murine model

Juan Riestra-Ayora, Carolina Sánchez-Rodríguez, Raquel Palao-Suay, Joaquín Yanes-Díaz, Ana Martín-Hita, María Rosa Aguilar, Ricardo Sanz-Fernández

Drug Deliv . 2021 Dec;28(1):1376-1388. doi: 10.1080/10717544.2021.1923863.

Abstract

The prognosis of patients with recurrent or metastatic head and neck squamous cell cancer (HNSCC) is generally poor. New treatments are required to supplement the current standard of care. Paclitaxel (PTX), an effective chemotherapeutic for HNSCC, has serious side effects. A polymeric nanocarrier system was developed for the delivery of PTX to improve HNSCC treatment. This study aimed to evaluate the antitumor efficacy of PTX-loaded polymeric nanoparticles based on α-TOS (PTX-NPs) administered by direct intratumoral injection into a Hypopharynx carcinoma squamous cells (FaDu) tumor xenograft mouse model. The nanocarrier system based on block copolymers of polyethylene glycol (PEG) and a methacrylic derivative of α-TOS was synthesized and PTX was loaded into the delivery system. Tumor volume was measured to evaluate the antitumor effect of the PTX-NPs. The relative mechanisms of apoptosis, cell proliferation, growth, angiogenesis, and oxidative and nitrosative stress were detected by Western blotting, fluorescent probes, and immunohistochemical analysis. The antitumor activity results showed that compared to free PTX, PTX-NPs exhibited much higher antitumor efficacy and apoptosis-inducing in a FaDu mouse xenograft model and demonstrated an improved safety profile. Ki-67, EGFR, and angiogenesis markers (Factor VIII, CD31, and CD34) expression were significantly lower in the PTX-NPs group compared with other groups (p < .05). Also, PTX-NPs induced oxidative and nitrosative stress in tumor tissue. Direct administration of PTX-loaded polymeric nanoparticles based on α-Tocopheryl Succinate at the tumor sites, proved to be promising for HNSCC therapy.

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Delta-tocotrienol enhances the antitumor effects of interferon alpha through ROS and Erk/MAPK signaling pathways in hepatocellular carcinoma cells

Alvaro Lucci, Marina C Vera, Carla G Comanzo, Florencia Lorenzetti, Anabela C Ferretti, María Paula Ceballos, Ariel D Quiroga, Maria de Lujan Alvarez, María Cristina Carrillo

Can J Physiol Pharmacol . 2021 Dec 21. doi: 10.1139/cjpp-2021-0606. Online ahead of print.

Abstract

The complexity of hepatocellular carcinoma (HCC) signaling and the failure of pharmacological therapeutics reveal the significance of establishing new anti-cancer strategies. Interferon alpha (IFN α) has been used as adjuvant therapy for reducing HCC recurrence and improving survival. Delta-tocotrienol (δ-tocotrienol), a natural unsaturated isoform of vitamin E, is a promising candidate for cancer treatment. In this study, we evaluated whether the combination of δ-tocotrienol with IFN α displays significant advantages in the treatment of HCC cells. Results showed that the combination significantly decreased cell viability, migration and invasion of HCC cells compared to single therapies. Combining δ-tocotrienol and IFN α enhanced the decrease in proliferating cell nuclear antigen (PCNA) and matrix metalloproteinases MMP-7 and MMP-9. The combination also produced an enhancement of apoptosis together with increased Bax/Bcl-xL ratio and ROS generation. δ-tocotrienol induced Notch1 activation and changes in Erk and p38 MAPK signaling status. Blocking experiments confirmed that ROS and Erk are involved, at least in part, in the anticancer effects of the combined treatment. In conclusion, the combination of δ-tocotrienol with IFN α therapy showed promising results for HCC cells treatment, which makes the combination of cytokine-based immunotherapy with natural products a potential strategy against liver cancer.

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δ-tocotrienol suppresses the migration and angiogenesis of trophoblasts in preeclampsia and promotes their apoptosis via miR-429/ ZEB1 axis

Mei Shi, Xiuyun Chen, Hui Li, Lixia Zheng

Bioengineered . 2021 Dec;12(1):1861-1873. doi: 10.1080/21655979.2021.1923238.

Abstract

Preeclampsia (PE) is a severe medical disorder during pregnancy and there has been controversy about the effects of vitamin E on PE. This research intended to explore if δ-tocotrienol (δ-TT), an isomer of vitamin E, could impact PE. Preeclamptic and normal placentas were obtained and total RNA was extracted. The expression of different genes was analyzed through quantitative real-time polymerase chain reaction (qRT-PCR) and Pearson correlation analysis was conducted. After that, HTR-8/SVneo cells (human trophoblasts) were chosen and they were subjected to δ-tocotrienol treatment and then Cell Counting Kit-8 was used to test cell viability. To assess the effects of δ-TT on trophoblasts, wound healing assay and Transwell invasion assay were performed. How miR-429 interacts with ZEB1 was examined via dual luciferase reporter assay. Also, protein expression was evaluated via Western blotting. Our results have shown that δ-TT can impair the viability of trophoblasts and induce their apoptosis. Additionally, it can repress the growth, migration, epithelial-mesenchymal transition (EMT), invasion and angiogenesis in trophoblasts. Mechanistically, δ-TT exerts these effects on trophoblasts via downregulating miR-429 and upregulating ZEB1. Furthermore, miR-429 can bind ZEB1 directly. Clinical sample analysis has revealed that miR-429 expression in preeclamptic placenta is higher than that in normal placenta, but ZEB1 expression in preeclamptic placenta is downregulated. Also, there is a negative association between miR-429 and ZEB1 expression in preeclamptic placentas. These discoveries imply that δ-TT may be hazardous to pregnancy and should not be used in preeclamptic patients. In addition, targeting miR-429 might treat PE.

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The Vitamin E Isoform α-Tocopherol is Not Effective as a Complementary Treatment in Cancer Treatment: A Systematic Review

Dorothee Retzlaff, Jennifer Dörfler, Sabine Kutschan, Maren Freuding, Jens Büntzel, Jutta Hübner

Nutr Cancer . 2021 Dec 17;1-24. doi: 10.1080/01635581.2021.2014905. Online ahead of print

Abstract

The term vitamin E describes tocopherols and tocotrienols, whose chemical variations result in different biological activities including antioxidants. Neuroprotective effects of alpha-tocopherol against different toxins are assumed, therefore, it is discussed as a possible protective factor for adverse effects in cancer treatment. In July 2020, a systematic search was conducted searching five databases (Embase, Cochrane, PsychInfo, Cinahl, Medline) to find studies concerning the impact of α-tocopherol application and its potential harm on cancer patients. From 7546 search results, 22 publications referring to 20 studies with 1941 patients were included. Included patients were diagnosed with various cancer types and stages. Outcome variables were overall survival of cancer, symptom management of mucositis and chemotherapy-induced peripheral neuropathy (CIPN). The studies had different methodological qualities (mainly acceptable) and reported heterogeneous results: some reported significant improvement of mucositis and CIPN while others did not find changes concerning these endpoints. Due to heterogeneous results and methodical limitations of the included studies, a clear statement regarding the effectiveness of α-tocopherol as complementary treatment for cancer patients is not possible. Despite findings regarding reduction of oral side effects, usage of α-tocopherol during therapy must be discouraged because of potential negative influence on survival rates.

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Attenuating Effect of Vitamin E against Silver Nano Particles Toxicity in Submandibular Salivary Glands

Mahmoud M Bakr, Mahmoud M Al-Ankily, Sara M Shogaa, Mohamed Shamel

Bioengineering (Basel) . 2021 Dec 16;8(12):219. doi: 10.3390/bioengineering8120219.

Abstract

Silver nanoparticles (AgNPs) are extensively used in many industries due to their superior antimicrobial properties. However, it is evident from many studies that AgNPs has cytotoxic potential through its effect on excessive formation of reactive oxygen species (ROS). The aim of this study was to examine the toxic effect of AgNPs on the submandibular salivary glands and the attenuating effect of vitamin E, as a natural antioxidant, against this toxicity. Thirty Albino rats were divided into 3 groups (n = 10): control group, AgNPs group receiving 2 mg/kg daily for 28 days, and AgNPs and vitamin E group receiving AgNPs the same as the previous group in addition to vitamin E at a dose of 100 mg/kg. Microscopic, ultrastructural, and cytokeratin immune-reactivity examination of the glands were performed. The AgNPs group showed noticeable degeneration in all structures of the gland as evident in the histological and ultrastructural examination. The AgNPs and vitamin E group revealed an improvement of the glandular elements. A significant increase in cytokeratin immune expression was found after comparison of both groups (p = 0.01). This current study shows that vitamin E has powerful antioxidant properties, which can combat the cytotoxic effect caused by AgNPs. Further studies are deemed necessary to confirm this finding using other immunohistochemical markers, such as myosin and E-cadherin.

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γ-Tocotrienol induced the proliferation and differentiation of MC3T3-E1 cells through the stimulation of the Wnt/β-catenin signaling pathway

Weili Xu, Yutong Li, Rennan Feng, Pan He, Yuqi Zhang

Food Funct . 2021 Dec 15. doi: 10.1039/d1fo02583j. Online ahead of print.

Abstract

γ-Tocotrienol (γ-T3), an isoprenoid phytochemical, has shown the promotion of osteoblast proliferation and differentiation in our previous study. In this study, its underlying mechanism was investigated through regulating the Wnt/β-catenin signaling pathway in MC3T3-E1 cells. Comparative experiment results showed that γ-T3, not α-tocopherol (α-TOC) increased more significantly the viability and differentiation in MC3T3-E1 cells. After that, the cells were incubated with 10 mM LiCl, or 4 μM γ-T3 with or without 1 μM XAV-939. γ-T3 at 4 μM stimulated the Wnt/β-catenin signaling pathway by increasing the expression and nuclear accumulation of β-catenin, and the expressions of their downstream factors, such as cyclin-D1, c-Myc, BMP2 and BMP-4 in MC3T3-E1 cells. γ-T3 not only upregulated the viability, induced G0/G1 to the S phase, and promoted the expressions of PCNA (Proliferating Cell Nuclear Antigen) and Ki-67, but also increased ALP activity and the expressions of ON, OPN and OCN. Moreover, the effects of γ-T3 on the MC3T3-E1 cells resembled the actions of LiCl, an activator of the Wnt/β-catenin signaling pathway. Notably, all these effects of γ-T3 on the MC3T3-E1 cells were completely blocked by the Wnt/β-catenin signaling pathway inhibitor XAV-939. Our data demonstrated that γ-T3 can target β-catenin to enhance the Wnt/β-catenin signaling pathway, which led to increased expressions of the downstream cell proliferation and cell cycle-associated (cyclin D1 and c-myc), and cell differentiation-associated (BMP-2 and BMP-4) target genes, and ultimately promoted MC3T3-E1 cell proliferation and differentiation. Therefore, γ-T3 may be a potential agent to prevent and reverse osteoporosis due to its safety and powerful abilities of osteogenesis.

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Tocotrienols-rich naringenin nanoemulgel for the management of diabetic wound: Fabrication, characterization and comparative in vitro evaluations

Eileen Yeo, Clement Jia Yew Chieng, Hira Choudhury, Manisha Pandey, Bapi Gorain

Curr Res Pharmacol Drug Discov . 2021 Mar 14;2:100019. doi: 10.1016/j.crphar.2021.100019. eCollection 2021.

Abstract

The present research had been attempted to formulate and characterize tocotrienols-rich naringenin nanoemulgel for topical application in chronic wound conditions associated with diabetes. In due course, different phases of the nanoemulsion were chosen based on the solubility study, where combination of Capryol 90 and tocotrienols, Solutol HS15, and Transcutol P were selected as oil, surfactant, and cosurfactant, respectively. The nanoemulsions were formulated using the spontaneous emulsification method. Subsequently, Carbopols were incorporated to develop corresponding nanoemulgels of the optimized nanoemulsions. Thermodynamically stable optimized nanoemulgels were evaluated for their globule size, polydispersity index (PDI), surface charge, viscosity, mucoadhesive property, spreadability, in vitro release and release mechanism. Further, increasing polymer concentration in the nanoemulgels was reflected with the increased mucoadhesive property with corresponding decrease in the release rate of the drug. The optimized nanoemulgel (NG1) consisted of uniform dispersion (PDI, 0.452 ​± ​0.03) of the nanometric globules (145.58 ​± ​12.5) of the dispersed phase, and negative surface charge (-21.1 ​± ​3.32 ​mV) with viscosity 297,600 ​cP and good spreadability. In vitro release of naringenin in phosphate buffer saline revealed a sustained release profile up to a maximum of 74.62 ​± ​4.54% from the formulated nanoemulgel (NG1) within the time-frame of 24 ​h. Alternatively, the release from the nanoemulsion was much higher (89.17 ​± ​2.87%), which might be due to lack of polymer coating on the dispersed oil droplets. Moreover, the in vitro release kinetics from the nanoemulgel followed the first-order release and Higuchi model with non-Fickian diffusion. Therefore, encouraging results in this research is evident in bringing a promising future in wound management, particularly associated with diabetes complications.

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