ORALS

SESSION: OxidativeThuAM-R5	Intl. Symp. on Oxidative Stress for Sustainable Development of Human Beings
Thu Oct, 24 2019 / Room: Zeus (55/Mezz. F)
Session Chairs: Christian Amatore; HARUHIKO INUFUSA; Session Monitor: TBA

11:45: [OxidativeThuAM02]
Exposome-Induced Oxidative Stress and Protective Effects of Antioxidants in Rats
Yukiko Minamiyama¹ ; Keiko Kobayashi² ; Ririko Kawatani³ ; Hiroshi Ichikawa⁴ ; Shigekazu Takemura⁵ ; Fuhua (fukka) Yang (you)⁶ ; Haruhiko Inufusa⁷ ; Toshikazu Yoshikawa⁸ ; ¹Kyoto Prefectural University, KYoto, Japan; ²Kyoto Prefectural University, Kyoto, Japan; ³Graduate School of Life and Medical Sciences Doshisha University, Kyotanabe, Japan; ⁴Doshisha University, Kyotanabe City, Japan; ⁵Graduate School of Medicine, Osaka City University, Osaka, Japan; ⁶Gifu University Division of Anaerobe Research, Gifu, Japan; ⁷TIMA Japan Corporation, Gifu, Japan; ⁸Louis Pasteur Center for Med. Res., Tohoku, Japan;
Paper Id: 196 [Abstract]

The exposome can be defined as the totality of exposures (diet, lifestyle, occupational, and environmental factors) received by an individual throughout the entire lifetime. It is unclear how these exposures are related to health. There is an increasing trend to intake food additives due to food mileage extension and maintenance of a healthy lifestyle. Therefore, we investigated the effect of aspartame (APM), an artificial sweetener, and ortho-phenyl phenol (OPP), a broad-spectrum fungicide and antibacterial agent, on oxidative stress in rats. APM (250 mg/kg/day; 1/16 NOAEL) or OPP (1 &#u181;g/kg/day; 1/10⁵ NOAEL) were administered to rats for &#~8776;eight weeks, through their mixed diet and drinking water, respectively. Administration of both exposomes for two weeks led to a significant reduction in reactive oxygen specie (ROS)-scavenging ability for hydroxyl radicals in plasma. In epididymis and hippocampus, both exposome treatments increased the 4-hydroxy-2-nonenal (HNE) levels, an index of lipid peroxidation. APM treatment for two weeks increased ROS generation in sperms without motility changes. Moreover, APM treatment for eight weeks slightly decreased sperm motility. Furthermore, amyloid beta (Abeta) levels were significantly increased in both epididymis and hippocampus after two weeks of OPP administration, that may be related to male infertility and dementia. Pretreatment with the antioxidant Twendee X (20 mg/kg/day; TIMA Japan) inhibited the Abeta level increase in both tissues. In conclusion, our data indicate that some exposomes systemically induce oxidative stress and increase Abeta levels in both epididymis and hippocampus. These results suggested that effective antioxidants such as Twendee X can inhibit exposome-induced oxidative stress in male infertility and neurodegenerative diseases.

References:
1. Takemura S, Ichikawa H, Naito Y, Takagi T, Yoshikawa T, Minamiyama Y. S-allyl cysteine ameliorates the quality of sperm and provides protection from age-related sperm dysfunction and oxidative stress in rats.\nJ Clin Biochem Nutr. 2014 Nov;55(3):155-61.\n2. Minamiyama Y, Ichikawa H, Takemura S, Kusunoki H, Naito Y, Yoshikawa T. Generation of reactive oxygen species in sperms of rats as an earlier marker for evaluating the toxicity of endocrine-disrupting chemicals.\nFree Radic Res. 2010 Dec;44(12):1398-406.

SESSION: OxidativeThuAM-R5	Intl. Symp. on Oxidative Stress for Sustainable Development of Human Beings
Thu Oct, 24 2019 / Room: Zeus (55/Mezz. F)
Session Chairs: Christian Amatore; HARUHIKO INUFUSA; Session Monitor: TBA

12:35: [OxidativeThuAM04]
Oxidative Stress: Cancer and Oxidative Stress
Naomi Okada¹ ; Fuhua (fukka) Yang (you)² ; Haruhiko Inufusa³ ; ¹Gifu University, Gifu, Japan; ²Gifu University Division of Anaerobe Research, Gifu, Japan; ³TIMA Japan Corporation, Gifu, Japan;
Paper Id: 230 [Abstract]

Molecular targeting drugs were referred to as a paradigm shift in cancer treatment; it could not be beyond cytotoxic chemotherapy in terms of side effects and drug resistance. Only three treatments, namely surgery, chemotherapy and radiation have been the treatments for cancer for a long time. Because removal of cancer is the essence of these treatments, patients have been forced to carry a heavy burden. Various immunotherapies have been developed based on the theory, but almost all have failed. Immune checkpoint inhibitors (ICIs), however, which were the subjects of the Nobel Prize in Medicine and Physiology in 2018, have changed that aspect. Nivolumab, an immune checkpoint inhibitor, has dramatically improved the prognosis of melanoma which is one of the most refractory and poor-prone tumors. Melanoma is now followed by lung cancer, renal cancer, gastric cancer, and so on. ICIs make immune therapy the 4th cancer treatment. The most important thing is that immune therapy with ICIs is essentially different from the conventional three cancer treatments. ICIs work by adjusting the host side environment whereas the latter are is "artificially" eliminating cancer. ICIs only elicit the ability given by God to eliminate the cancer. As antioxidants also have effects on the environment of the host’s side. These effects have been used in combination with chemotherapy and radiotherapy. Antioxidants have two main effects. One is the prevention from adverse effects of chemotherapy and radiotherapy. Another is the anti-tumor effects. As for the former, the preventing effects from mucinous inflammation and neuropathy caused by chemotherapy and radiotherapy have been reported. The control of these symptoms is important because these adverse effects are the main reason for the discontinuation of the treatments. Many studies have shown that antioxidants have the effects of suppressing the activation of NF-kappaB which leads to cancer growth and apoptosis suppression. According to some reports of chemotherapy, radiotherapy and molecular targeted therapies may have more host-mediated pro-tumorigenic and pro-metastatic effects than anti-tumor effects. Such therapy induced host effects are said to have angiogenesis, metastasis, and tumor-cell repopulation properties which are resistant to therapy. Preliminary in vivo mouse experiments with anti-oxidant composition showed elimination of the pro-metastatic effects of chemotherapy. Tumor growth was observed with short term exposure of 5-FU. Although anti-oxidant composition alone had no anti-tumor effect, tumor growth with 5-FU was completely reversed by anti-oxidant composition. The modulation of host side factors may have the same effects as the treatment itself and antioxidants are considered to be able to become a main player of cancer treatments.

References:
1. Balancing efficacy of and host immune responses to cancer therapy: the yin and yang effects. Shbaked Y, Nat Rev Clin Oncol. 2016 Oct;13(10):611-26.\n2.Systematic Review: Generating Evidence-Based Guidelines on the Concurrent Use of Dietary Antioxidants and Chemotherapy or Radiotherapy. Akiko Nakayama, Karen P, Obianuju Lgbokwe, and Leffrey D. white. Cancer Invest.2011 Dec :29(10 ):655-667.

SESSION: OxidativeThuPM1-R5	Intl. Symp. on Oxidative Stress for Sustainable Development of Human Beings
Thu Oct, 24 2019 / Room: Zeus (55/Mezz. F)
Session Chairs: Toshikazu Yoshikawa; Shigeru Hirano; Session Monitor: TBA

14:25: [OxidativeThuPM106]
Role of Anti-oxidant Twendee X for Maintenance of Voice and Swallow
Shigeru Hirano¹ ; Haruhiko Inufusa² ; Toshikazu Yoshikawa³ ; ¹Kyoto Prefectural University of Medicine, Kyoto, Japan; ²TIMA Japan Corporation, Gifu, Japan; ³Louis Pasteur Center for Med. Res., Tohoku, Japan;
Paper Id: 266 [Abstract]

The larynx and pharynx have important roles in maintaining voice and swallowing functions. Age-related deterioration of vocal and swallowing functions has become a significant problem for the elderly which can lead to aspiration pneumonia in the worst cases. Age-related histological and functional deficit of the pharyngolaryngeal system is the main issue. The vocal fold, the producer of the voice, becomes atrophied and weak which causes glottic insufficiency with reduced mucosal vibration. The voice becomes harsh and weak. Glottic insufficiency also causes mis-swallowing. Laryngeal elevation and pharyngeal constriction are weakened with age which can lead to aspiration. We have confirmed that oxidative stress increases with age in the vocal fold mucosa and muscle, as well as the pharyngeal muscles. Reactive oxygen species (ROS) damage the tissue and hamper function. In the case of singers or other professional voice users, overuse of the vocal fold also causes damage to the function of the vocal fold via ROS. Anti-oxidants are the promising material that can maintain or improve the voice and the swallowing ability. We have revealed that anti-oxidants can maintain the vocal fold during excessive vocal loading tasks, avoiding inflammation or exhaustion of the vocal fold. Twendee X (TWX) has proven the strongest anti-oxidant, and our preliminary study demonstrated that an opera singer's voice was well maintained with the 1-month use of TWX. Another aspect of TWX is its capability to reduce allergic inflammation in the upper airway which is also important for protection of the pharyngolarynx. Anti-oxidants should be effective, useful, and promising for maintaining the pharyngolarynx which secures voicing and swallowing functions.

References:
[1]Inufusa H. Characterization of cell protection effects of Twendee X by oxidative stress. J World Mitochondria Soc 2016;2:42.
[2]Kaneko M, Kishimoto Y, Suzuki R, et al. Protective Effect of Astaxanthin on Vocal Fold Injury and Inflammation Due to Vocal Loading: A Clinical Trial. J Voice. 2017;31(3):352-358.

SESSION: OxidativeThuPM1-R5	Intl. Symp. on Oxidative Stress for Sustainable Development of Human Beings
Thu Oct, 24 2019 / Room: Zeus (55/Mezz. F)
Session Chairs: Toshikazu Yoshikawa; Shigeru Hirano; Session Monitor: TBA

14:50: [OxidativeThuPM107]
Oxidative Stress: Does Continuous Oxidative Stress Reduction Prevent and Ameliorate Diseases through Species Diversity of Intestinal Bacteria?
Fuhua (fukka) Yang (you)¹ ; Kaori Tanaka² ; Haruhiko Inufusa³ ; ¹Gifu University Division of Anaerobe Research, Gifu, Japan; ²1) Division of Anaerobe Research, Life Science Research Center, Gifu University, Gifu, Japan; ³TIMA Japan Corporation, Gifu, Japan;
Paper Id: 226 [Abstract]

Intestines are said to be involved in 60% of human immunity. More than 100 species, or 100 trillions of bacteria (intestinal bacteria) inhabit in the intestines and those bacteria can be divided into bad bacteria that trigger diseases, good bacteria that are considered to benefit health, and opportunistic bacteria. Regarding 20% of good, 10% of bad, and 70% of opportunistic bacteria as an ideal balance of gut bacteria, this balance can be disturbed by diarrhea, constipation and various diseases. In other words, oxidative stress can reduce diversity of gut bacteria. In that case, how does reducing oxidative stress alter gut microflora, and how does reducing oxidative stress affect daily defecation? Although administering antiseptic agent OPP to rats for 2 weeks increased their blood oxidative stress by 5%, there were no significant changes of bacterial gut diversity. Rats, however, were given a strong antioxidant composition, Twendee X(TWX), from 1 week before OPP decreased their oxidative stress by 13.3% against control, and increased bacterial diversity by 1.5 times. Also, observation of the defecating condition and gut microflora of 57 healthy persons showed increased diversity index and improvement of the defecating condition after TWX administration. These results suggest that, even if exposed to toxic substances which results in oxidative stress, daily effort of decreasing oxidative stress can improve/prevent their host's diseases by increasing gut bacterial diversity.

References:
1. Novel compositions and uses thereof WO 2008071790 A3\n2. Antioxidant composition and its use in diabetes EP 1932542 A1\n3. Composition for accelerating alcohol metabolism and for reducing the risk of alcohol induced diseases WO 2012095509 A8\n4. Composition for moderating triglyceride and cholesterol levels WO 2009062910 A1

SESSION: OxidativeThuPM1-R5	Intl. Symp. on Oxidative Stress for Sustainable Development of Human Beings
Thu Oct, 24 2019 / Room: Zeus (55/Mezz. F)
Session Chairs: Toshikazu Yoshikawa; Shigeru Hirano; Session Monitor: TBA

15:15: [OxidativeThuPM108]
Brain Disease and Oxidative Stress: Ischemia and Dementia
Haruhiko Inufusa¹ ; Koji Abe² ; Isao Tadokoro² ; Fuhua (fukka) Yang (you)³ ; Toshikazu Yoshikawa⁴ ; ¹TIMA Japan Corporation, Gifu, Japan; ²Department of Neurology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan; ³Gifu University Division of Anaerobe Research, Gifu, Japan; ⁴Louis Pasteur Center for Med. Res., Tohoku, Japan;
Paper Id: 229 [Abstract]

Reactive Oxygen Species (ROS) are closely related to various diseases of the brain. Twendee X (TWX) is an antioxidant composition consisting of Vitamin C, L-Glutamine, L-Cystine or L-Cysteine, Riboflavin, Succinic acid, Fumaric acid, Coenzyme Q10, and Niacin. TWX was invented from the basic experiments of alcohol, glucose, and fat metabolisms (1-4). TWX strongly reduces ROS (Patent: WIPO WO2013/072441 A1, COMPOSITION FOR PROTECTION AGAINST CELL-DAMAGING EFFECTS). Lysozyme radiation experiments showed that the antioxidant effects of TWX are 6-7 times higher than Vitamin C (Data from Dr. Helmut Durschschlarg, Regensburg Univ. Germany). Oxidative stress and mitochondrial expert ICDD (France) experiments using hepatic cancer cell line HepG2 showed TWX decrease of 63% of mitochondrial ROS and an increase of 147% mitochondrial SOD. ICDD confirmed that TWX is safe and has most strong anti-ROS and protection effects from ROS. TWX increase Neogenesis nerves cell numbers of the hippocampal dentate gyrus of the 56 weeks mouse. The same occurs within 6 weeks by TWX administration. The mitochondrial metabolism of the mouse’s hippocampal dentate gyrus was activated by TWX administration by the metabolome analysis. The model of the brain of the mouse for ischemia and Alzheimer's disease were used to evaluate the effects of TWX. The double blind clinical trial of the Japanese Association for Prevention of Dementia from autumn 2017 to March 2019 for mild cognitive impairment was performed to analyze TWX prevention effects on Alzheimer's disease. TWX decreased volume of brain ischemia to 2/3, and inflammation and oxidative stress in the brain was also reduced in the mouse ischemia model. TWX inhibited deposition of amyloid beta. Inflammation and oxidative stress in the brain was also reduced in the mouse model of Alzheimer. Double blind clinical research resulted in the TWX group significantly increasing the score of the Mini Mental State Examination compared to the placebo group at 6 months after the start of TWX administration. Thus, TWX is effective to prevent Alzheimer's disease and vascular dementia.

References:
1. Novel compositions and uses thereof WO 2008071790 A3\n2. Antioxidant composition and its use in diabetes EP 1932542 A1\n3. Pretreatment Twendee X reduced acute ischemic brain damage. Kusaki M, Inufusa H, Abe K, JSCVD 2017; 26: 1191-1196\n4. Clinical and Pathological Benefit of Twendee X in Alzheimer's Disease Transgenic Mice with Chronic Cerebral Hypoperfusion. XiaLiu, Abe K https://doi.org/10.1016/j.jstrokecerebrovasdis.2019.03.029