Cosmetics Ingredient EUK-134(81065-76-1) What Effects It is-APICDMO

1. Cosmetics Ingredient EUK-134(81065-76-1): What Effects It is? 1. EUK-134................................................................................................................................2 2. What Is EUK-134?...............................................................................................................2 3. How Does EUK-134 Work?................................................................................................2 4. Therapeutic Effects Of EUK-134.......................................................................................3 5. Who Should Avoid EUK-134?............................................................................................7 6. Where To Buy EUK-134?....................................................................................................7 Sources From www.apicdmo.com Time: 26th,Oct. 2021 www.apicdmo.com JINAN APICDMO BIOTECHNOLOGY CO., LIMITED Tel: +8613682461609 Email: emily@apicdmo.com

2. 1. EUK-134 EUK -134, chemically known as Ethylbisiminomethylguaiacol manganese chloride is a manganese-salen complex. It is a synthetic superoxide dismutase (SOD) and catalase mimic compound that has potent antioxidant properties. 2. What Is EUK-134? EUK-134 is a manganese-salen derivative that has dual antioxidant function i.e. superoxide dismutase and catalase mimetic activities. Its therapeutic use and studies conducted are based on its property to reduce reactive oxygen species (ROS) induced cellular injury in the body. It is a low-molecular-weight synthetic complex that has better potency, stability, and bioavailability than endogenous antioxidant enzymes. 3. How Does EUK-134 Work? EUK-134 has superoxide dismutase, SOD, and catalase mimic activity. SOD converts the superoxide radical into ordinary molecular oxygen and hydrogen peroxide and Catalase decomposes hydrogen peroxidase into water and oxygen. This property of EUK-143 helps neutralize the oxidative stress caused by superoxide radicals and hydrogen peroxide which are reactive oxygen species (ROS) and reduce cellular injury. At the cellular level during normal biochemical reactions to produce energy in the form of ATP by oxygen metabolism in the mitochondria, a process called oxidative phosphorylation takes place during which ROS are produced as partially reduced byproducts which when present in low amount help in cell signaling and homeostasis. The formation of ROS can also be stimulated by a variety of agents such as UV, pollutants, heavy metals, tobacco, smoke, drugs, xenobiotics, or radiation which are exogenous sources. These ROS are highly reactive and are immediately neutralized by a group of antioxidant enzymes such as superoxide dismutase (SOD), catalase (CAT), www.apicdmo.com JINAN APICDMO BIOTECHNOLOGY CO., LIMITED Tel: +8613682461609 Email: emily@apicdmo.com

3. and non-enzymatic antioxidants. When there is an imbalance in this neutralization, the concentration of ROS is increased, and they cause oxidative stress leading to oxidative damage of nucleic acids, proteins, and lipids which can lead to cellular death and tissue injury. glutathione peroxidases (GPxs), thioredoxin (Trx) as well as These potentially harmful effects of ROS under oxidative stress have been viewed as an underlying mechanism of aging and a number of diseases, such as ischemia-reperfusion disorders, cardiovascular conditions, cancer, and diabetes. neurodegenerative disorders, 4. Therapeutic Effects Of EUK-134 ♦ Skin Many inflammatory and non-inflammatory diseases, UV rays, pollutants, smoke, and radiation exposure can cause oxidative damage to the skin. Research done to study the effect of UVB exposure on pre-treated human skin cells with EUK-134, confirmed that pre-treated cells were protected from UVB-induced oxidative stress and their survival was also increased. [1] www.apicdmo.com JINAN APICDMO BIOTECHNOLOGY CO., LIMITED Tel: +8613682461609 Email: emily@apicdmo.com

4. Another study with the human volunteers, EUK-134 (0.01–0.1%) reduced the level of skin surface lipid peroxidation in UVA-exposed skin. The reduction of squalene hydroperoxide levels at the skin surface was found even when applying the antioxidant after UVA exposure. This data supports the concept that the synthetic SOD/catalase mimetic EUK-134 might be able to compensate for seasonal deficiencies in antioxidant defense capacity at the skin surface, damage. The levels of catalase in the skin decrease on continuous exposure to the sun, so antioxidant levels are low during summer [2] protecting the skin against oxidative As a consequence of this study, EUK-134 is now commercially available as an antioxidant for the protection of dry or irritated skin. It is available as EUK-134, 0.1% with propanidiol as a solubilizer. It must not be used immediately with strong acids such as suspensions of Ascorbic Acid. Strong acids will completely destroy EUK-134 which is based on manganese. ♦ Cardiovascular Diseases Oxidative stress and ROS injury have been implicated as underlying pathophysiology in cardiovascular events [3]. A study focused on EUK-134 as a greater catalase and cytoprotective agent was conducted in a rat focal ischemia model involving middle cerebral artery occlusion concluded that there was a significant reduction in brain infarct size, with the highest dose apparently preventing further infarct growth. Overall, this study suggests that synthetic SOD/catalase mimetics might serve as novel, multifunctional therapeutic agents for stroke. [4] In another study conducted on monocrotaline-induced pulmonary hypertension in rats, EUK-134 was administered intraperitoneally daily. reported that EUK-134 prevented the force decrease and the actin modifications in pulmonary hypertension diaphragm bundles. Thus, antioxidant treatment can be a promising strategy for PH patients with inspiratory failure.[5] ♦ Neurodegenerative diseases The brain is prone to oxidative stress as a result of the high levels of oxygen it consumes for energy. Also, neural membranes have high concentrations of polyunsaturated fatty acids which auto-oxidizable neurotransmitters that can cause ROS-mediated damage. generate lipid hydroperoxides and www.apicdmo.com JINAN APICDMO BIOTECHNOLOGY CO., LIMITED Tel: +8613682461609 Email: emily@apicdmo.com

5. Excessive ROS levels have been associated with neurodegenerative disorders like Alzheimer’s Disease, Parkinson’s Disease, amyotrophic lateral sclerosis, and Huntington’s Disease.[6] Many animal studies have been conducted that have shown EUK-134 helps reduce neuronal injury. EUK-134 had been found to protect from neuronal injury by ROS induced by pre-treatment of rats with kainic acid excitotoxicity. [7] A study focused on EUK-134 as a greater catalase and cytoprotective agent was conducted in a rat focal ischemia model involving middle cerebral artery occlusion concluded that there was a significant reduction in brain infarct size, with the highest dose apparently preventing further infarct growth. Overall, this study suggests that synthetic SOD/catalase mimetics might serve as novel, multifunctional therapeutic agents for stroke. [4] ♦ Ionizing Radiation Exposure Studies have shown that EUK-134 suppresses the effects of ionizing radiation on mitochondrial function in rat astrocyte cultures. [8] Manganese-salen complexes could be useful to decrease delayed radiation injury to normal tissues following radiation exposure accidental exposure, or radiological terrorism. (x-rays, microwaves from oven), ♦ Inflammation EUK-134 can decrease inflammation-induced oxidative stress. A study was conducted to evaluate the effects of EUK-134 in Duchene muscular dystrophy mice model. EUK-134 reduced 4-hydroxynonenal and total hydroperoxides, markers of oxidative stress, and decreased markers of muscle damage [9]. During inflammatory conditions, excessive ROS are produced from the vascular endothelium. Delivery of antioxidants to endothelium will help manage and limit inflammatory injury. A study was conducted to develop a new translational antioxidant intervention targeted to the vascular endothelium using PEG-liposomes loaded with EUK-134. [10] ♦ Ischemia-Reperfusion Induced Damage Ischemia-reperfusion-induced damage occurs when the tissue gets oxygen after a period of hypoxia. This leads to sudden activation of aerobic metabolism and increased production of ROS. The antioxidant system cannot balance the ROS production leading to tissue injury. www.apicdmo.com JINAN APICDMO BIOTECHNOLOGY CO., LIMITED Tel: +8613682461609 Email: emily@apicdmo.com

6. EUK-134, was tested in un-nephrectomized rats that underwent a left renal artery clamping. After a 75-min left renal artery clamping, a single intravenous injection of EUK-134 at 0.2 mg/kg, just before unclamping, provided significantly better renal function recovery during the week after the ischemic insult compared with the recovery of untreated animals [11]. ♦ Fetus Protective The anti-teratogenic potential of a potent synthetic superoxide dismutase plus catalase mimetic, EUK-134 was tested in mice that concluded that antioxidants can significantly improve the adverse developmental outcome that results from ethanol exposure in utero, decreasing the incidence and severity of major malformations that result from exposure to this important human teratogen [12] ♦ Liver A study was conducted to evaluate the role of EUK-134 in the progression of induced Non-alcoholic steatohepatitis (NASH) to non-alcoholic fatty liver disease, which is induced by oxidative stress. Antioxidant (EUK-8, EUK-134, and vitamin C) supplementation reduces NASH-induced biochemical and histological abnormalities, pointing out that antioxidant strategy could be beneficial in the treatment of NASH. [13] ♦ Renal EUK-134 prevented renal dysfunction and tubulointerstitial injury by reducing oxidative and nitrosative stress in renal Ischemia-Reperfusion injury [11], hence showing renoprotective function. ♦ Extending Lifespan The injury caused by oxidative stress causing cell death can decrease the life expectancy of an organism. The life expectancy of animal models subjected to oxidative stress or with pathologies associated with this stress is increased with treatment with manganese-salen complexes. However, the use of these synthetic antioxidants in normal and healthy individuals probably does not have any advantageous effect on lifespan extension. [14] [15] www.apicdmo.com JINAN APICDMO BIOTECHNOLOGY CO., LIMITED Tel: +8613682461609 Email: emily@apicdmo.com

7. All these above-mentioned therapeutic uses have only been tested in animal models. These study results help provide insight into future possible use in humans that can help in preventing and treating many diseases. The only human-tested study is the cosmetic use of EUK-134 on the skin as a keratocyte protective agent. It is available in liquid form of strength 0.1%. It helps reduce oxidative stress by UV rays and other exogenous stimulants and prevents cellular injury. 5. Who Should Avoid EUK-134? You should avoid EUK-134 if you have known hypersensitivity to manganese. Always do a patch test on the upper forearm with the product, to test for possible allergic reaction 6. Where To Buy EUK-134? You can buy EUK-134 solution for cosmetic use from any authorized cosmetic retail store or you can buy them online. APICDMO can provide the best quality raw materials for EUK-134 in China. We are designed to operate and provide raw materials in large quantities, and our production capacity is 500 kg per month. Our company is SO9001 & ISO14001 certified and has a complete production management system. References Cited: [1] Decraene, D., Smaers, K., Gan, D., Mammone, T., Matsui, M., Maes, D., ... & Garmyn, M. (2004). A synthetic superoxide dismutase/catalase mimetic (EUK-134) inhibits membrane-damage-induced activation of mitogen-activated protein kinase pathways and reduces p53 accumulation in ultraviolet B-exposed primary human keratinocytes. Journal of investigative dermatology, 122(2), 484-491. [2] Declercq, L., Sente, I., Hellemans, L., Corstjens, H., & Maes, D. (2004). Use of the synthetic superoxide dismutase/catalase mimetic EUK‐134 to compensate for seasonal antioxidant deficiency by reducing pre‐existing lipid www.apicdmo.com JINAN APICDMO BIOTECHNOLOGY CO., LIMITED Tel: +8613682461609 Email: emily@apicdmo.com

8. peroxides at the human skin surface. International journal of cosmetic science, 26(5), 255-263. [3] Moris, D., Spartalis, M., Spartalis, E., Karachaliou, G. S., Karaolanis, G. I., Tsourouflis, G., ... & Theocharis, S. (2017). The role of reactive oxygen species in the pathophysiology of cardiovascular diseases and the clinical significance of myocardial redox. Annals of translational medicine, 5(16). [4] Baker, K., Marcus, C. B., Huffman, K., Kruk, H., Malfroy, B., & Doctrow, S. R. (1998). Synthetic combined superoxide dismutase/catalase mimetics are protective as a delayed treatment in a rat stroke model: a key role for reactive oxygen species in ischemic brain injury. Journal of Pharmacology and Experimental Therapeutics, 284(1), 215-221. [5] Himori, K., Abe, M., Tatebayashi, D., Lee, J., Westerblad, H., Lanner, J. T., & Yamada, T. (2017). Superoxide dismutase/catalase mimetic EUK-134 prevents diaphragm muscle weakness in monocrotalin-induced pulmonary hypertension. PloS one, 12(2), e0169146. [6] Li, J., Li, W., Jiang, Z. G., & Ghanbari, H. A. (2013). Oxidative stress and neurodegenerative disorders. International journal of molecular sciences, 14(12), 24438-24475. [7] Rong, Y., Doctrow, S. R., Tocco, G., & Baudry, M. (1999). EUK-134, a synthetic superoxide dismutase and catalase mimetic, prevents oxidative stress and attenuates kainate-induced neuropathology. Proceedings of the National Academy of Sciences, 96(17), 9897-9902. [8] A Rosenthal, R., Fish, B., P Hill, R., D Huffman, K., Lazarova, Z., Mahmood, J., ... & R Doctrow, S. (2011). Salen Mn complexes mitigate radiation injury in normal tissues. Anti-Cancer Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry-Anti-Cancer Agents), 11(4), 359-372. [9] Kim, J. H., & Lawler, J. M. (2012). Amplification of proinflammatory phenotype, damage, and weakness by oxidative stress in the diaphragm muscle of mdx mice. Free Radical Biology and Medicine, 52(9), 1597-1606. [10] Howard, M. D., Greineder, C. F., Hood, E. D., & Muzykantov, V. R. (2014). Endothelial targeting of liposomes encapsulating SOD/catalase mimetic EUK-134 alleviates acute pulmonary inflammation. Journal of controlled release, 177, 34-41. www.apicdmo.com JINAN APICDMO BIOTECHNOLOGY CO., LIMITED Tel: +8613682461609 Email: emily@apicdmo.com

9. [11] Gianello, P., Saliez, A., Bufkens, X., Pettinger, R., Misseleyn, D., Hori, S., & Malfroy, B. (1996). EUK-134, a synthetic superoxide dismutase and catalase mimetic, protects rat kidneys from ischemia-reperfusion-induced damage. Transplantation, 62(11), 1664-1666. [12] Chen, S. Y., Dehart, D. B., & Sulik, K. K. (2004). Protection from ethanol‐induced limb malformations by the superoxide dismutase/catalase mimetic, EUK‐134. The FASEB journal, 18(11), 1234-1236. [13] Rezazadeh, A., Yazdanparast, R., & Molaei, M. (2012). Amelioration of diet-induced nonalcoholic steatohepatitis in rats by Mn-salen complexes via reduction of oxidative stress. Journal of biomedical science, 19(1), 1-8. [14] Sadowska-Bartosz, I., & Bartosz, G. (2014). Effect of antioxidants supplementation on aging and longevity. BioMed research international, 2014. [15] Pham, T. T. H., Huang, W. Y., Chen, C. S., Chiu, W. T., & Chuang, H. S. (2021). Effects of electrotactic exercise and antioxidant EUK-134 on oxidative stress relief in Caenorhabditis elegans. Plos one, 16(1), e0245474. www.apicdmo.com JINAN APICDMO BIOTECHNOLOGY CO., LIMITED Tel: +8613682461609 Email: emily@apicdmo.com