Deuteration of the Farnesyl Terminal Methyl Groups of δ-Tocotrienol and Its Effects on the Metabolic Stability and Ability of Inducing G-CSF Production

Xingui Liu, Zhengya Gao, Qiang Fu, Lin Song, Peiyi Zhang, Xuan Zhang, Howard Hendrickson, Peter A Crooks, Daohong Zhou, Guangrong Zheng

Bioorg Med Chem . 2020 Jun 1;28(11):115498. doi: 10.1016/j.bmc.2020.115498. Epub 2020 Apr 8.

Abstract

δ-tocotrienol (DT3), a member of vitamin E family, has been shown to have a potent radio-protective effect. However, its application as a radioprotectant is limited, at least in part, by its short plasma elimination half-life and low bioavailability. In an effort to increase the metabolic stability of DT3, a deuterium substituted DT3 derivative, d₆-DT3, was designed and synthesized. d₆-DT3 showed improved in vitro and in vivo metabolic stability compared to DT3. The unexpected lower potency of d₆-DT3 in inducing granulocyte-colony stimulating factor (G-CSF) production in mouse revealed that the metabolite(s) of DT3 might play a major role in inducing G-CSF induction.

Shogo Kitasaka, Mikio Yagi, Azusa Kikuchi

Photochem Photobiol Sci . 2020 Jun 2. doi: 10.1039/d0pp00023j. Online ahead of print.

Abstract

Menthyl anthranilate (MA, tradename meradimate) is a UV-A absorber. The interactions of ground-state molecular oxygen with the long-lived triplet state of MA produce singlet oxygen through energy transfer. The quantum yield of singlet oxygen generation is 0.12 in air-saturated ethanol. Kinetic traces of the near-IR phosphorescence of singlet oxygen generated by MA-photosensitization have been measured in the absence and presence of Trolox (a water-soluble analogue of vitamin E and a quencher of singlet oxygen) and α-tocopherol (vitamin E, a natural antioxidant) in ethanol. Fluorescence and transient absorption measurements suggest that Trolox and α-tocopherol quench the lowest excited singlet and triplet states of MA. As a result, Trolox and α-tocopherol suppress MA-photosensitized singlet oxygen generation. Not only the quenching of singlet oxygen but also the suppression of singlet oxygen generation is the mechanism of antioxidant properties of Trolox and α-tocopherol for MA. The ability of α-tocopherol to suppress the MA-photosensitized singlet oxygen generation in isododecane, used as a solvent for an oil-soluble UV absorber, is close to that in ethanol. Suppression of sunscreen-photosensitized singlet oxygen generation is an important method for the formulation of safe cosmetic sunscreens.

Delanian SE, Lenglet T, Maisonobe T, Resche-Rigon M, Pradat PF

Int J Radiat Oncol Biol Phys. 2020 May 1;107(1):154-162. doi: 10.1016/j.ijrobp.2020.01.002. Epub 2020 Jan 24.

Abstract

PURPOSE:

Radiation-induced (RI) plexopathy is a rare peripheral nerve injury after radiation therapy for cancer. No treatment has been shown to slow its progression. A pentoxifylline-vitamin E combination significantly reduced RI fibrosis, and its association with clodronate (PENTOCLO) allowed healing of osteoradionecrosis and reduction of neurologic symptoms in phase 2 trials.

METHODS AND MATERIALS:

A placebo-controlled, double-blind trial conducted in adults with RI limb plexopathy without cancer recurrence, randomized in 2 arms to PENTOCLO (pentoxifylline 800 mg, tocopherol 1000 mg, clodronate 1600 mg 5 days per week) or triple placebo. The primary outcome measure after 18 months of treatment was the neurologic Subjective Objective Management Analytic (SOMA) score evaluating pain, paresthesia, and motor disability.

RESULTS:

Between 2011 and 2015, 59 patients were included: 1 false inclusion (neoplastic plexopathy), 29 treated with placebo (group P), and 29 treated with the active drugs (group A); 46 patients presented an upper-limb and 12 a lower-limb plexopathy. The mean delay after irradiation was 26 ± 8 years, for patients with neurologic symptoms for 5 ± 5 years. The median global SOMA scores in the P and A groups, respectively, were 9 (range, 6-11) versus 9 (range, 8-11) at M₀ and 9 (range, 5-12) versus 10 (range, 6-11) at M₁₈ without any significant difference. Analysis of the secondary outcomes showed that SOMA score subdomains for pain and paresthesia were more affected in group A (not significant). The frequency of adverse events was similar in the 2 groups (81% of patients): slight expected vascular-gastrointestinal symptoms in A, but a large excess of RI complications (arterial stenosis).

CONCLUSIONS:

This first randomized drug trial in RI plexopathy failed to show a beneficial effect. More studies are needed in patients with less advanced disease and fewer confounding comorbidities and with a more sensitive measure to detect a therapeutic effect.

Rosen E, Fatanmi OO, Wise SY, Rao VA, Singh VK

Health Phys. 2020 Mar 20. doi: 10.1097/HP.0000000000001221. [Epub ahead of print]

Abstract

The aim of this study was to analyze the changes in mouse jejunum protein expression in response to prophylactic administration of two promising tocols, γ-tocotrienol (GT3) and α-tocopherol succinate (TS), as radiation countermeasures before irradiation to elucidate the molecular mechanism(s) of their radioprotective efficacy. Mice were administered GT3 or TS (200 mg kg) subcutaneously 24 h prior to exposure to 11 Gy Co γ-radiation, a supralethal dose for mice. Jejunum was harvested 24 h post-irradiation. Results of the two-dimensional differential in-gel electrophoresis (2D-DIGE), coupled with mass spectrometry, and advanced bioinformatics tools suggest that the tocols have a corresponding impact on expression of 13 proteins as identified by mass spectrometry. Ingenuity Pathway Analysis (IPA) reveals a network of associated proteins involved in inflammatory response, organismal injury and abnormalities, and cellular development. Relevant signaling pathways including actin cytoskeleton signaling, RhoA signaling, and Rho family GTPase were identified. This study reveals the major proteins, pathways, and networks involved in preventing the radiation-induced injury in gut that may be contributing to enhanced survival.

Yumusak N, Sadic M, Akbulut A, Aydinbelge FN, Koca G, Korkmaz M

Bratisl Lek Listy. 2019;120(4):263-269. doi: 10.4149/BLL_2019_048.

Abstract

OBJECTIVES:

The aim of the present study was to investigate the radioprotective effect of vitamin E in the prevention of radioiodine (RAI) induced gastrointestinal damage.

METHOD:

Twenty-four rats were randomly divided into three groups as follows: Group-1 was untreated control group, Group-2 was orally administered single dose of 111 MBq RAI, and Group-3 was orally administered 111 MBq RAI and 1 mL of oral vitamin E. Vitamin E was started two days before RAI administration and was continued for five days once daily after RAI. Pathomorphological parameters of gastrointestinal tissues (stomach, small intestines and bowels) were measured using Hematoxylin-Eosin and Masson’s trichrome staining.

RESULTS:

Varying degrees of inflammation, edema, ulcer, mucosal degeneration, necrosis and fibrosis were seen in the stomach, small intestine and bowel tissues of the rats in both study groups and not in the control group. The differences were statistically significant between these groups for all parameters (p < 0.05). The histopathological damage in the vitamin E treated group was significantly less than the damage in the RAI only group (p < 0.05 for all pathomorphological parameters).

CONCLUSION:

The results of this study showed that vitamin E has a radioprotective property with antiinflammatory and antifibrotic effects protecting against gastrointestinal damage caused by radioiodine.

Nasef SM, Khozemy EE, Kamoun EA, El-Gendi H

Int J Biol Macromol. 2019 Jul 5;137:878-885. doi: 10.1016/j.ijbiomac.2019.07.033. [Epub ahead of print]

Abstract

Crosslinked hydrogel composite membranes based on polyvinyl alcohol (PVA) and chitosan-loaded AgNO₃ and vitamin E were prepared using gamma irradiation. Chitosan has been used as antimicrobial blend materials to provide further biocompatibility for the prepared composite hydrogel membranes. The crosslinking reaction between PVA and chitosan owing to gamma irradiation was verified and characterized by FTIR analysis, while the morphology of hydrogel composite membranes was investigated by SEM. Important parameters affecting on hydrogel membranes formation, such as copolymer concentration, irradiation dose, AgNO₃ concentration, plasticizer, and vitamin E of PVA/chitosan membranes were evaluated and discussed in details. In addition, the mechanical and thermal properties of hydrogel composite membranes were examined to evaluate the possibility of its application for wound dressings. The results revealed that the gelation (%) of hydrogel membranes increased dramatically with PVA composition, irradiation dose and glycerol content up to 20%; however, it decreased with AgNP incorporation due to the viscosity of copolymer composition is hyper-increased. The swelling ratio of composed hydrogel membranes decreased notably with increasing the radiation dose and incorporation of AgNP, due to reducing of the crosslinking degree of formed hydrogel membranes. PVA-Cs-Ag composed hydrogel membranes showed significant antimicrobial activity in particular against Streptococcus mutans due to the presence of AgNP in membranes, compared to other bacteria and fungi microbes. Thus, the PVA/chitosan/AgNO₃-Vit.E hydrogel composite membranes showed satisfactory properties for use as wound dressing materials.

Yumusak N, Sadic M, Akbulut A, Aydinbelge FN, Koca G, Korkmaz M

Bratisl Lek Listy. 2019;120(4):263-269. doi: 10.4149/BLL_2019_048.

Abstract

OBJECTIVES:

The aim of the present study was to investigate the radioprotective effect of vitamin E in the prevention of radioiodine (RAI) induced gastrointestinal damage.

METHOD:

RESULTS:

CONCLUSION:

The results of this study showed that vitamin E has a radioprotective property with antiinflammatory and antifibrotic effects protecting against gastrointestinal damage caused by radioiodine.

Garg S, Sadhukhan R, Banerjee S, Savenka AV, Basnakian AG, McHargue V, Wang J, Pawar SA, Ghosh SP, Ware J, Hauer-Jensen M, Pathak R

Antioxidants (Basel). 2019 Mar 6;8(3). pii: E57. doi: 10.3390/antiox8030057.

Abstract

Natural antioxidant gamma-tocotrienol (GT3), a vitamin E family member, provides intestinal radiation protection. We seek to understand whether this protection is mediated via mucosal epithelial stem cells or sub-mucosal mesenchymal immune cells. Vehicle- or GT3-treated male CD2F1 mice were exposed to total body irradiation (TBI). Cell death was determined by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. Villus height and crypt depth were measured with computer-assisted software in tissue sections. Functional activity was determined with an intestinal permeability assay. Immune cell recovery was measured with immunohistochemistry and Western blot, and the regeneration of intestinal crypts was assessed with ex vivo organoid culture. A single dose of GT3 (200 mg/kg body weight (bwt)) administered 24 h before TBI suppressed cell death, prevented a decrease in villus height, increased crypt depth, attenuated intestinal permeability, and upregulated occludin level in the intestine compared to the vehicle treated group. GT3 accelerated mesenchymal immune cell recovery after irradiation, but it did not promote ex vivo organoid formation and failed to enhance the expression of stem cell markers. Finally, GT3 significantly upregulated protein kinase B or AKT phosphorylation after TBI. Pretreatment with GT3 attenuates TBI-induced structural and functional damage to the intestine, potentially by facilitating intestinal immune cell recovery. Thus, GT3 could be used as an intestinal radioprotector.

Pathak R, Kumar VP, Hauer-Jensen M, Ghosh SP

Mil Med. 2019 Mar 1;184(Supplement_1):644-651. doi: 10.1093/milmed/usy408.

Abstract

Ionizing radiation exposure is a major concern for active military service members, as well as civilian population. Considering that the exposure is not predictable, it is imperative that strategies to counteract radiation damage must be discovered. Recent in vitro studies performed in our laboratory demonstrated that the vitamin E analog gamma-tocotrienol (GT3) in combination with cholesterol-lowering drugs (Statins), synergistically induced endothelial thrombomodulin, an anticoagulant with radio-protective efficacy. It was hypothesized that the combination of treatment with both GT3 along with Statins would provide better radiation protection in vivo than each drug individually. CD2F1 mice were injected subcutaneously with either vehicle or single dose of GT3 (200 mg/kg body weight) 24 hours before irradiation followed by oral or subcutaneous administration of various doses of simvastatin (25, 50, and 100 mg/kg body weight) before exposure to lethal doses (11.5 and 12 Gy) of Cobalt-60 (60Co) gamma-irradiation. The combined treatment group exhibited enhanced radiation lethality protection substantially, accelerated white blood cell recovery, and augmented restoration of bone marrow cellularity when compared to the animals treated with either drug exclusively. This information clearly suggests that combined treatment could be used as a safeguard for military personnel from exposure to harmful ionizing radiation.

Aykin-Burns N, Pathak R, Boerma M, Kim T, Hauer-Jensen M

Semin Radiat Oncol. 2019 Jan;29(1):55-61. doi: 10.1016/j.semradonc.2018.10.008.

Abstract

Despite advances in radiation delivery techniques, side effects of radiation therapy due to radiation exposure of normal tissues are common and can limit the deliverable dose to tumors. Significant interests lie in pharmacologic modifiers that may protect against normal tissue toxicity from cancer treatment while simultaneously enhancing the tumor response to therapy. While no such treatments are available in the clinic, this is an area of active preclinical and clinical research. This review summarizes research studies that provide evidence to indicate that tocotrienols, natural forms of vitamin E, are potent radiation protectors and may also have antitumor effects. Hence, several current clinical trials test tocotrienols as concomitant treatment in cancer therapies.