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TICs maintain lower intracellular ROS levels than other cancer cells within the tumor, primarily through the accumulation of ROS scavengers like glutathione and the overexpression of Gclm and glutathione synthetase, the enzymes necessary for its synthesis, as shown in breast and liver cancer stem cells [18, 20]

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Furthermore , these receptors play a role in stimulating melanin production, which is responsible for skin pigmentation

Multiple other causes should be considered including peripheral vascular disease, neuropathy, medication effects from other drugs (particularly diuretics, beta-agonists, and statins), hypothyroidism, pregnancy, and musculoskeletal conditions

doi: 10.1056/NEJMra1510030 14 MenconiFMarcocciCMarinM

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