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As a minor consideration, one review suggests that direct application may be less effective than microneedling and notes that very dark pigmentation spots may require patience and continued use

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In addition to activation by NAPQI, the Nrf2 signalling pathway is also regulated by protein tyrosine phosphatase 1B (PTP1B) and M1 muscarinic receptors (M1Rs) (Mobasher et al., 2013

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