LCE3E inhibitors are a set of chemical compounds that contribute to reducing the functional activity of the LCE3E protein through various mechanisms that affect the differentiation of keratinocytes and the formation of the skin barrier. Palmitic acid and tunicamycin exert their inhibitory effects by inducing endoplasmic reticulum stress and activating the unfolded protein response, which leads to an overall reduction in protein synthesis, including the downregulation of LCE3E. Similarly, thapsigargin triggers ER stress by depleting ER calcium stores, contributing to a decrease in LCE3E levels in response to stress attenuation. Phorbol 12-myristate 13-acetate (PMA) and lithium chloride alter the proliferation and differentiation of keratinocytes and may decrease LCE3E expression through hyperproliferation and GSK-3 inhibition, respectively. The calcium ionophore A23187 and retinoic acid also modulate LCE3E inhibition by activating calcium-dependent proteases that can degrade LCE3E and by altering the transcriptional program of differentiating keratinocytes, thus reducing LCE3E expression.
U0126 and staurosporine reduce LCE3E activity by inhibiting MEK in the MAPK/ERK pathway and a variety of kinases, respectively, which are critical for keratinocyte differentiation and survival. Rapamycin suppresses the mTOR pathway, which is vital for the epidermal differentiation program that includes LCE3E. The active form of vitamin D3, Calcitriol, modulates keratinocyte differentiation and can suppress LCE3E expression by regulating calcium-binding proteins. The widespread inhibition of protein synthesis by cycloheximide directly reduces the availability of LCE3E for skin barrier formation. Collectively, these inhibitors exert specific effects on cell signaling and biochemical pathways that lead to the reduced functional activity of LCE3E, which is essential for the integrity of the epidermal barrier.
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