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  • Our results showed suppressed autophagy

    2024-07-10

    Our results showed suppressed autophagy in GECs under HAGG stimulation. Recently, people have paid more attentions on the roles of autophagy in lupus and tried to use autophagy regulators for therapy. Rapamycin could prevent the development of nephritis [49] and attenuate the established nephritis [50] in lupus-prone NZB/W F1 mice. Rapamycin also reduced disease activities in lupus patients [51]. Glucocorticoid, the current first-line medicine for lupus therapy, is demonstrated to induce autophagy in different cell kinds, including osteocytes [52] and lymphocytes [53], through mTOR-dependent pathways. The altered autophagy in LN by ICs may be part of the reasons for organ damage and may provide new targets for therapy.
    Introduction Cholesterol oxidation products have been shown to modulate several signaling pathways, thus biochemical effects of these compounds are varied from their strong pro-inflammatory, pro-apoptotic and pro-fibrogenic properties [1]. Among them, scientist are increasingly drawing attention to oxysterols, a family of 27-carbon molecules originated from cholesterol oxidation, that appear significantly involved in the progression of inflammatory-based chronic pathologies, such as atherosclerosis, neurodegenerative diseases, Tubastatin A and cancer [2], [3], [4], [5]. The oxysterol 27-hydroxycholesterol (27-OH), one of the most represented oxysterols in the peripheral blood of healthy individuals, is enzymatically produced by 27-hydroxylase (CYP27A1) [6]. Nowadays, 27-OH has been shown to act as a competitive ligand for liver X receptor [7], [8] and a selective estrogen receptor [9], thus it appears to modulate intracellular signals related to cancer cell growth and atherosclerosis progression [10], [11]. It is now well accepted that certain oxysterols, including 27-OH, modulate not only the pro-apoptotic and pro-inflammatory response but also cell survival pathways in various cell types [12], [13]. In particular, they trigger signaling transduction pathways either pro-apoptotic or anti-apoptotic, depending on cell types, oxysterol concentration and exposure time [14], [15]. Moreover, this dual effect exerted by oxysterols appeared to be modulated via a mechanism involving reactive oxygen species (ROS) [16], [17], [18]. Very recently, our group provided a clear evidence of modulation of survival signaling with a low micromolar concentration (10 µM) of 27-OH in U937 human promonocytic cells through extracellular signal-regulated kinase (ERK) and the phosphoinositide 3-kinase (PI3K)/Akt pathways [19]. Moreover, the marked up-regulation of the ERK/Akt axis was, in turn, able to quench the oxidative imbalance exerted by the oxysterol itself through the induction of nuclear factor erythroid 2 p45-related factor 2 (Nrf2) antioxidant defense system.[20]. Namely, a significant induction of Nrf2 and synthesis of Nrf2 target enzymes, including heme oxygenase-1 (HO-1) and NAD(P)H:quinone oxireductase, appeared to be dependent on the activation of ERK and Akt pathways and fundamentally responsible for the observed oxysterol-induced pro-survival response, at low concentration (10 µM), in promonocytic cells. However, relatively high concentration of 27-OH (100 µM) did not exert any survival effect in U937 cells while a constant pro-oxidant effect induced by the oxysterol was demonstrated. Macroautophagy (generally referred to as autophagy) breaks down protein aggregates and damaged organelles in order to maintenance cellular recycling during stress conditions. Autophagy is a multi-step physiological process that starts with sequestration of the cell material to be eliminated within double-membrane vesicles, known as autophagosomes; then, these autophagosomes fuse with lysosomes for subsequent degradation [21]. It is generally accepted that even if autophagy serves as a cell survival mechanism, under certain stress conditions its excessive enhancement may lead to cell death [22]. Accumulating data point to a critical role for autophagy at intersection of life and death of cancer cells, while a cross-talk exists between autophagy and classical apoptosis. It is now well established that autophagy appears regulated by ROS [23]. Hence, the redox regulation of autophagy has been observed in various pathological conditions but how autophagy induction affects these processes remains incompletely understood. Recent studies have highlighted the important role of oxidized lipids, including 4-hydroxy-trans-2-nonenal (HNE) and oxysterols, in the regulation of autophagy in atherosclerosis. Additional work is needed to elucidate the up-stream signal transduction pathways responsible for the effects of oxysterols on autophagy modulation [24], [25].