Abstract
Conessine, a steroidal alkaloid isolated from Holarrhena floribunda, has anti-malarial activity and interacts with the histamine H3 receptor. However, the cellular effects of conessine are poorly understood. Accordingly, we evaluated the involvement of conessine in the regulation of autophagy. We searched natural compounds that modulate autophagy, and conessine was identified as an inhibitor of autophagic flux. Conessine treatment induced the formation of autophagosomes, and p62, an autophagic adapter, accumulated in the autophagosomes. Reactive oxygen species such as hydrogen peroxide (H2O2) result in muscle cell death by inducing excessive autophagic flux. Treatment with conessine inhibited H2O2-induced autophagic flux in C2C12 myoblast cells and also interfered with cell death. Our results indicate that conessine has the potential effect to inhibit muscle cell death by interfering with autophagic flux.
Highlights
Autophagy, a catabolic pathway responsible for degrading protein aggregates and organelles [1], can be induced by extracellular stress [2, 3]
Cytoplasmic punctuates were evident at a concentration of 10 μM conessine (Fig 1C), providing confirmation that conessine is likely involved in autophagy regulation
Autophagy is involved in various diseases including cancer and neurodegenerative diseases, making autophagy modulators potentially useful for treatment
Summary
Autophagy (macroautophagy), a catabolic pathway responsible for degrading protein aggregates and organelles [1], can be induced by extracellular stress (e.g., nutrient starvation, hypoxia, high temperature, and microgravity) [2, 3]. The relationship between autophagy and diseases is not clear, excessive autophagic flux or lack of autophagy can contribute to various diseases such as cancer and neurodegenerative diseases [5,6,7]. Reactive oxygen species are produced in the mitochondria, and several antioxidant enzymes such as catalase and hydrogen peroxidase are responsible for their removal. Treatment with hydrogen peroxide (H2O2) can cause oxidative damage and induce autophagy and autophagic cell death under certain conditions [8]. Silencing experiments on autophagy-related genes show that autophagy is involved in ROS-induced cell death [9, 10]
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