The present study investigated the effects of a preparation of a gamma-tocopherol-rich mixture of tocopherols (gamma-TmT) on chemically induced lung tumorigenesis in female A/J mice and the growth of H1299 human lung cancer cell xenograft tumors. In the A/J mouse model, the lung tumors were induced by either 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK; intraperitoneal injections with 100 and 75 mg/kg on Week 1 and 2, respectively) or NNK plus benzo[a]pyrene (B[a]P) (8 weekly gavages of 2 mumole each from Week 1 to 8). The NNK plus B[a]P treatment induced 21 tumors per lung on Week 19; dietary 0.3% gamma-TmT treatment during the entire experimental period significantly lowered tumor multiplicity, tumor volume and tumor burden (by 30, 50 and 55%, respectively; P < 0.05). For three groups of mice treated with NNK alone, the gamma-TmT diet was given during the initiation stage (Week 0 to 3), post-initiation stage (Week 3 to 19) or the entire experimental period, and the tumor multiplicity was reduced by 17.8, 19.7 or 29.3%, respectively (P < 0.05). gamma-TmT treatment during the tumor initiation stage or throughout the entire period of the experiment also significantly reduced tumor burden (by 36 or 43%, respectively). In the xenograft tumor model of human lung cancer H1299 cells in NCr-nu/nu mice, 0.3% dietary gamma-TmT treatment significantly reduced tumor volume and tumor weight by 56 and 47%, respectively (P < 0.05). In both the carcinogenesis and tumor growth models, the inhibitory action of gamma-TmT was associated with enhanced apoptosis and lowered levels of 8-hydroxydeoxyguanine, gamma-H2AX and nitrotyrosine in the tumors of the gamma-TmT-treated mice. In cell culture, the growth of H1299 cells was inhibited by tocopherols with their effectiveness following the order of delta-T > gamma-TmT > gamma-T, whereas alpha-T was not effective. These results demonstrate the inhibitory effect of gamma-TmT against lung tumorigenesis and the growth of xenograft tumors of human lung cancer cells. The inhibitory activity may be due mainly to the actions of delta-T and gamma-T.

2007-05-01·Journal of Lipid Research2区 · 生物学

Identification and quantitation of novel vitamin E metabolites, sulfated long-chain carboxychromanols, in human A549 cells and in rats

2区 · 生物学

Article

作者: Helene Freiser ; Qing Jiang ; Xinmin Yin ; Karl V. Wood

The metabolism of vitamin E involves oxidation of the phytyl chain to generate the terminal metabolite 7,8-dimethyl-2-(beta-carboxyethyl)-6-hydroxychroman (CEHC) via intermediate formation of 13'-hydroxychromanol and long-chain carboxychromanols. Conjugated (including sulfated) metabolites were reported previously but were limited to CEHCs. Here, using electrospray and inductively coupled plasma mass spectrometry, we discovered that gamma-tocopherol (gamma-T) and delta-T were metabolized to sulfated 9'-, 11'-, and 13'-carboxychromanol (9'S, 11'S, and 13'S) in human A549 cells. To further study the metabolites, we developed a HPLC assay with fluorescence detection that simultaneously analyzes sulfated and nonconjugated intermediate metabolites. Using this assay, we found that sulfated metabolites were converted to nonconjugated carboxychromanols by sulfatase digestion. In cultured cells, approximately 45% long-chain carboxychromanols from gamma-T but only 10% from delta-T were sulfated. Upon supplementation with gamma-T, rats had increased tissue levels of 9'S, 11'S, and 13'S, 13'-hydroxychromanol, 13'-carboxychromanol, and gamma-CEHC. The plasma concentrations of combined sulfated long-chain metabolites were comparable to or exceeded those of CEHCs and increased proportionally with the supplement dosages of gamma-T. Our study identifies sulfated long-chain carboxychromanols as novel vitamin E metabolites and provides evidence that sulfation may occur parallel with beta-oxidation. In addition, the HPLC fluorescence assay is a useful tool for the investigation of vitamin E metabolism.

2004-03-01·International Journal of Food Sciences and Nutrition3区 · 工程技术

Inhibitory action of conventional food-grade natural antioxidants and of natural antioxidants of new development on the thermal-induced oxidation of cholesterol

3区 · 工程技术

Article

作者: Susana Nieto ; Julio Sanhueza ; Alfonso Valenzuela ; Pilar Alonso ; Alicia Corbari

Cholesterol is a molecule with an unsaturated bond; therefore, like polyunsaturated fatty acids, it is prone to oxidation. Cholesterol oxidation products (COPs) are found in many common foods and have been shown to be atherogenic, cytotoxic, mutagenic and possibly carcinogenic. Therefore, efforts to prevent or to avoid COPs formation during manufacture and/or processing of foods are of high priority. The effect of natural antioxidants on COPs formation has not been extensively studied. We assayed the effect of some widely applied natural antioxidants, such as tocopherol homologs (alpha-T, gamma-T, and delta-T) and rosemary extract, and of some natural products of newly developed as antioxidants, such as the flavonoids quercetin, catechin, morin, and rutin, and also of an alkaloid-derived product, boldine, to inhibit cholesterol oxidation of soybean oil, added of cholesterol, induced in the Rancimat test conditions (150 degrees C and air bubbling). Formation of six different COPs at the induction period and at the 100 microS conductivity value was monitored by gas chromatography. Under the experimental conditions gamma-T, quercetin, and rosemary extract prove effective to inhibit both soybean oil oxidation and COP formation. alpha-T, catechin, and morin are less efficient to prevent COP formation. delta-T, rutin and boldine are devoid of protective action against COP formation. gamma-T, quercetin and rosemary extract may inhibit COP formation from the nucleus and from the lateral chain of the cholesterol molecule.

项与 Gamma-delta T cell immunotherapy(Incysus Ltd.) 相关的新闻（医药）

2021-11-11

·BioSpace

IN8bio to Present Preclinical Data on the Potential for Gamma-Delta T-cell Therapy Combinations with PARP and Checkpoint Inhibitors in Solid Tumors

NEW YORK, Nov. 11, 2021 (GLOBE NEWSWIRE) -- IN8bio, Inc. (Nasdaq: INAB), a clinical-stage biopharmaceutical company focused on the discovery and development of innovative gamma-delta T-cell therapies utilizing its proprietary DeltEx platform, today announced a poster presentation of preclinical data demonstrating the potential of its cellular therapies in combination with Poly (ADP-ribose) polymerase (PARPi) and checkpoint inhibitors, which may enhance the recognition and killing of cancer cells by its DeltEx drug resistant immunotherapy (DRI) gamma-delta T cells. Kate Rochlin, Ph.D., Vice President, Operations and Innovation at IN8bio, will present on the potential uses of such therapeutic combinations to drive tumor immunogenicity in the solid tumor setting at the 36th Annual Meeting of the Society for Immunotherapy Conference (SITC). “Our DeltEx platform leverages the inherent ability of the gamma-delta T-cell to kill tumor cells through the recognition of stress-induced natural killer group D ligands (NKG2DL),” said Dr. Rochlin. “This work demonstrates that the use of alkylating chemotherapies in combination with PARPi could act synergistically to reduce tumor size and significantly increase expression of NKG2DL. Such combinations could make any residual tumors susceptible to elimination by our DeltEX DRI gamma-delta T-cells, but could also increase checkpoint ligands, suggesting that unique therapeutic combinations may help to reduce and ultimately eradicate solid tumors.” Dr. Rochlin will present work that has been conducted as part of a collaboration with the Hjelmeland Laboratory at the University of Alabama at Birmingham (UAB), which demonstrated that chemotherapy, in this case temozolomide (TMZ) plus PARPi (niraparib) increases expression of stress ligands on solid tumor cell lines in vitro. In some cell lines up to a 29x increase in mRNA expression of NKG2DL was observed. Increases were seen in both classical and proneural human glioblastoma lines as well as in SB28 cells. SB28 is a treatment and checkpoint resistant glioma cell line used in syngeneic mouse models that is thought to closely resemble treatment responses of human tumors. This suggests that gamma-delta T-cell therapy could be enhanced through the use of orthogonal therapeutic combinations that drive increased tumor cell immunogenicity. The poster presentation details are as follows: Event: Society for Immunotherapy of Cancer (SITC) 36th Annual Meeting Presenter: Kate Rochlin, Ph.D., Vice President, Operations and Innovation at IN8bio Presentation: Poster 158: Chemotherapy Resistant Gamma Delta T-cell Immunotherapy can leverage synergistic ligand expression through combinational chemotherapy and PARP-inhibitor use to enhance tumor cell recognition & killing Date: November 13th Time: 7 to 8:30 p.m. EST Location: Walter E. Washington Convention Center, Washington, D.C. About IN8bio IN8bio is a clinical-stage biopharmaceutical company focused on the discovery, development and commercialization of gamma-delta T-cell product candidates for solid and liquid tumors. Gamma-delta T-cells are a specialized population of T-cells that possess unique properties, including the ability to differentiate between healthy and diseased tissue. IN8bio’s DeltEx platform employs allogeneic, autologous and genetically modified approaches to develop cell therapies, designed to effectively identify and eradicate tumor cells. IN8bio is currently conducting two investigator-initiated Phase 1 clinical trials for its lead gamma-delta T-cell product candidates: INB-200 for the treatment of newly diagnosed glioblastoma and INB-100 for the treatment of patients with leukemia undergoing hematopoietic stem cell transplantation. IN8bio also has a broad portfolio of preclinical programs focused on addressing other solid tumor types. For more information about IN8bio and its programs, please visit . Company Contact: IN8bio, Inc. Charles Butler +1 646.600.6GDT (6438) cbutler@IN8bio.com Investors: Solebury Trout David Buck + 1 646.378.2927 dbuck@soleburytrout.com Media: Burns McClellan, Inc. Robert Flamm, Ph.D. / Harrison Wong +1 212.213.0006 - ext. 364 / 316 rflamm@burnsmc.com / hwong@burnsmc.com

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