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Abstract:Osteoarthritis is a progressive disease characterized by cartilage destruction in the joints. Matrix metalloproteinases (MMPs) and a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTSs) play key roles in osteoarthritis progression. In this study, we screened a chemical compound library to identify new drug candidates that target MMP and ADAMTS using a cytokine-stimulated OUMS-27 chondrosarcoma cells. By screening PCR-based mRNA expression, we selected 2-(8-methoxy-2-methyl-4-oxoquinolin-1(4H)-yl)-N-(3-methoxyphenyl) acetamide as a potential candidate. We found that 2-(8-methoxy-2-methyl-4-oxoquinolin-1(4H)-yl)-N-(3-methoxyphenyl) acetamide attenuated IL-1β-induced MMP13 mRNA expression in a dose-dependent manner, without causing serious cytotoxicity. Signaling pathway analysis revealed that 2-(8-methoxy-2-methyl-4-oxoquinolin-1(4H)-yl)-N-(3-methoxyphenyl) acetamide attenuated ERK- and p-38-phosphorylation as well as JNK phosphorylation. We then examined the additive effect of 2-(8-methoxy-2-methyl-4-oxoquinolin-1(4H)-yl)-N-(3-methoxyphenyl) acetamide in combination with low-dose betamethasone on IL-1β-stimulated cells. Combined treatment with 2-(8-methoxy-2-methyl-4-oxoquinolin-1(4H)-yl)-N-(3-methoxyphenyl) acetamide and betamethasone significantly attenuated MMP13 and ADAMTS9 mRNA expression. In conclusion, we identified a potential compound of interest that may help attenuate matrix-degrading enzymes in the early osteoarthritis-affected joints.Keywords: osteoarthritis; matrix metalloproteinase; MMP13; ADAMTS9; expression screening; chondrocytes

Evaluates the carcinogenic risk to humans posed by the consumption of chlorinated drinking-water, by two chemicals used in the chlorination of drinking-water, by a number of halogenated by-products formed when chlorine interacts with organic matter in water, and by a selection of other halogenated compounds found in drinking-water. Chlorination was selected for evaluation because of its widespread use and because potentially carcinogenic by-products have been measured in chlorinated water. The book also includes a separate monograph on cobalt and cobalt compounds. The volume opens with a discussion of the many methodological problems that complicate efforts to assess the carcinogenicity of chlorinated water. Against this background, the book evaluates the design and findings of all studies relevant to the carcinogenicity assessment of chlorinated drinking-water, two chemicals (sodium chlorite and hypochlorite salts) used in the chlorination of water, eight of the by-products most frequently measured in drinking-water, and three additional halogenated chemicals detected in drinking-water. Because of the formidable methodological obstacles faced by all investigations, only one of these substances could be classified: bromodichloromethane was classified as possibly carcinogenic to humans. The final monograph considers data on metallic cobalt, cobalt alloys, including cobalt-containing surgical implants and dental devices, and cobalt compounds. In view of the strength of evidence linking cobalt metal powder and cobalt[II] oxide to cancer in experimental animals, cobalt and cobalt compounds were classified as possibly carcinogenic to humans.

The theory of oxygen-free radicals has been known about fifty years ago (4). However, only within the last two decades, has there been an explosive discovery of their roles in the development of diseases, and also of the health protective effects of antioxidants.

Free radicals can be produced from non-enzymatic reactions of oxygen with organic compounds as well as those initiated by ionizing radiations. The nonenzymatic process can also occur during oxidative phosphorylation (i.e. aerobic respiration) in the mitochondria (4, 5, 8).

Vitamin E. Vitamin E is a fat-soluble vitamin with high antioxidant potency. Vitamin E is a chiral compound with eight stereoisomers: α, β, γ, δ tocopherol and α, β, γ, δ tocotrienol. Only α-tocopherol is the most bioactive form in humans. Studies in both animals and humans indicate that natural dextrorotary d-α-tocopherol is nearly twice as effective as synthetic racemic dl-α-tocopherol (39). Because it is fat-soluble, α-tocopherol safeguards cell membranes from damage by free radicals. Its antioxidant function mainly resides in the protection against lipid peroxidation. Vitamin E has been proposed for the prevention against colon, prostate and breast cancers, some cardiovascular diseases, ischemia, cataract, arthritis and certain neurological disorders. (40). However, a recent trial revealed that daily α-tocopherol doses of 400 IU or more can increase the risk of death and should be avoided. In contrast, there is no increased risk of death with a dose of 200 IU per day or less, and there may even be some benefit (41). Although controversial, the use of long-term vitamin E supplementation in high dose should be approached cautiously until further evidence for its safety is available. The dietary sources of vitamin E are vegetable oils, wheat germ oil, whole grains, nuts, cereals, fruits, eggs, poultry, meat (6, 40). Cooking and storage may destroy natural d-α-tocopherol in foods (40).

Vitamin C. Vitamin C also known as ascorbic acid, is a water-soluble vitamin. It is essential for collagen, carnitine and neurotransmitters biosynthesis (42). Health benefits of vitamin C are antioxidant, anti-atherogenic, anti-carcinogenic, immunomodulator. The positive effect of vitamin C resides in reducing the incidence of stomach cancer, and in preventing lung and colorectal cancer. Vitamin C works synergistically with vitamin E to quench free radicals and also regenerates the reduced form of vitamin E. However, the intake of high doses of vitamin C (2000mg or more/day) has been the subject of debate for its eventual pro-oxidant or carcinogen property (42-43). Natural sources of vitamin C are acid fruits, green vegetables, tomatoes. Ascorbic acid is a labile molecule, therefore it may be lost from during cooking (43).

Free flowing plastics are those small objects that fill a box or a subdivision within the box without restraint. The theory is that during a fire. The objects will freely fall out of the box and either smother the fire or fall away from it, removing themselves as fuel. Since the burning rate is reduced and fuel load has been lessened, free-flowing plastics are permitted to be treated as a Class IV commodity. 2b1af7f3a8