The expression of HO-1 by kaempferol inhibits cisplatin-induced apoptosis in HEI-OC1 cells, and the mechanism of protective effect is also associated with its inductive effect of GCLC expression.
Luteolin has been shown to possess antitumorigenic, antioxidant, and anti-inflammatory properties. In the present study, we investigated the protective mechanism of luteolin against cisplatin-induced apoptosis in auditory (House Ear Institute-Organ of Corti 1 [HEI-OC1]) cells. Luteolin was found to induce the expression of heme oxygenase-1 (HO-1) in a dose- and time-dependent manner. Luteolin also activated the extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase pathway, which plays an important role in the expression of HO-1. Luteolin protected the cells against cisplatin-induced apoptotic cell death. The protective effect of luteolin was abrogated by zinc protoporphyrin IX (ZnPP IX), an HO inhibitor, and antisense oligodeoxynucleotides against the HO-1 gene. Furthermore, pretreatment with luteolin inhibited the activation of caspase-3 and the mitochondrial dysfunction, and the effect of luteolin on the activation of caspase-3 disappeared in the presence of ZnPP IX or PD098059. These results demonstrate that the expression of HO-1 by luteolin is mediated by the ERK pathway, and also that the activating of HO-1 inhibits cisplatin-induced apoptosis in HEI-OC1 1 cells.
Activation of the proinflammatory-associated cytokine, tumor necrosis factor-α (TNF-α), in nucleus pulposus (NP) cells is essential for the pathogenesis of intervertebral disc degeneration (IDD). Restoring autophagic flux has been shown to effectively protect against IDD and is a potential target for treatment. The goal of this study was to explore particular autophagic signalings responsible for the protective effects of naringin, a known autophagy activator, on human NP cells. The results showed that significantly increased autophagic flux was observed in NP cells treated with naringin, with pronounced decreases in the inflammatory response and oxidative stress, which rescued the disturbed cellular homeostasis induced by TNF-α activation. Autophagic flux inhibition was detectable in NP cells cotreated with 3-methyladenine (3-MA, an autophagy inhibitor), partially offsetting naringin-induced beneficial effects. Naringin promoted the expressions of autophagy-associated markers via SIRT1 (silent information regulator-1) activation by AMPK (AMP-activated protein kinase) phosphorylation. Either AMPK inhibition by BML-275 or SIRT1 silencing partially counteracted naringin-induced autophagic flux enhancement. These findings indicate that naringin boosts autophagic flux through SIRT1 upregulation via AMPK activation, thus protecting NP cells against inflammatory response, oxidative stress, and impaired cellular homeostasis. Naringin can be a promising inducer of restoration autophagic flux restoration for IDD.
In this study, we examined the protective effects of Caesalpinia sappan L. and its major component, brazilin, against tert-butylhydroperoxide (t-BHP)-induced cell death in House Ear Institute-Organ of Corti 1 (HEI-OC1) cells. We found that the extract of C. sappan L. and brazilin induced antioxidant response element (ARE)-luciferase activity and heme oxygenase-1 (HO-1) expression in a concentration-dependent manner. The inductive effect of brazilin was more potent than the extract of C. sappan L. and the expression of HO-1 reached a peak at 12 h after brazilin treatment. The extract and brazilin protected the cells against t-BHP-induced cell death. Their protective effects were abrogated by zinc protoporphyrin IX (ZnPP IX), a HO inhibitor. These results demonstrate that the extract of C. sappan L. and brazilin induce the expression of HO-1 and the enzyme diminishes t-BHP-induced cell death in HEI-OC1 cells.
Cisplatin is a highly effective chemotherapeutic agent, but it has significant ototoxic side effects. Apoptosis is an important mechanism of cochlear hair cell loss following exposure to cisplatin. The present study examined the effects of phloretin, a natural polyphenolic compound found in apples and pears, on cisplatin-induced apoptosis. We found that phloretin induced the expression of heme oxygenase-1 (HO-1) protein in a concentration- and time-dependent manner. Phloretin induced nuclear factor-E2-related factor 2 (Nrf2) nuclear translocation, and dominant-negative Nrf2 attenuated phloretin-induced expression of HO-1. Phloretin activated the JNK, ERK and p38 mitogen-activated protein kinase (MAPK) pathways, and the JNK pathway played an important role in phloretin-induced HO-1 expression. Phloretin protected the cells against cisplatin-induced apoptosis. The protective effect of phloretin was abrogated by zinc protoporphyrin IX (ZnPP IX), a HO inhibitor. Furthermore, phloretin pretreatment inhibited mitochondrial dysfunction and the activation of caspases. These results demonstrate that the expression of HO-1 induced by phloretin is mediated by both the JNK pathway and Nrf2; the expression inhibits cisplatin-induced apoptosis in HEI-OC1 cells.
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