Artepillin C, a major component of Brazilian green propolis, inhibits endoplasmic reticulum stress and protein aggregation

Hirata, Yoko; Motoyama, Masanari; Kimura, Shige; Takashima, Madoka; Ikawa, Takanori; Oh‐hashi, Kentaro; Kamatari, Yuji O.

doi:10.1016/j.ejphar.2021.174572

Cited by 13 publications

(13 citation statements)

References 29 publications

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“…Upon ER stress, aggresomes commonly increase. Aggresomes were stained using Proteostat ® Aggresome Detection dye (Enzo Life Sciences) [ 61 ], and the degree of aggresome accumulation was determined by flow cytometry. Briefly, cells were prefixed with 4% paraformaldehyde for 30 min and permeabilized by 0.5% Triton X-100 for 30 min at 4 °C.…”

Section: Methodsmentioning

confidence: 99%

Oxidative-Stress-Mediated ER Stress Is Involved in Regulating Manoalide-Induced Antiproliferation in Oral Cancer Cells

Peng

Tang

Lan

et al. 2023

IJMS

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Manoalide provides preferential antiproliferation of oral cancer but is non-cytotoxic to normal cells by modulating reactive oxygen species (ROS) and apoptosis. Although ROS interplays with endoplasmic reticulum (ER) stress and apoptosis, the influence of ER stress on manoalide-triggered apoptosis has not been reported. The role of ER stress in manoalide-induced preferential antiproliferation and apoptosis was assessed in this study. Manoalide induces a higher ER expansion and aggresome accumulation of oral cancer than normal cells. Generally, manoalide differentially influences higher mRNA and protein expressions of ER-stress-associated genes (PERK, IRE1α, ATF6, and BIP) in oral cancer cells than in normal cells. Subsequently, the contribution of ER stress on manoalide-treated oral cancer cells was further examined. ER stress inducer, thapsigargin, enhances the manoalide-induced antiproliferation, caspase 3/7 activation, and autophagy of oral cancer cells rather than normal cells. Moreover, N-acetylcysteine, an ROS inhibitor, reverses the responses of ER stress, aggresome formation, and the antiproliferation of oral cancer cells. Consequently, the preferential ER stress of manoalide-treated oral cancer cells is crucial for its antiproliferative effect.

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Section: Methodsmentioning

confidence: 99%

Oxidative-Stress-Mediated ER Stress Is Involved in Regulating Manoalide-Induced Antiproliferation in Oral Cancer Cells

Peng

Tang

Lan

et al. 2023

IJMS

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“…The aggregated protein was detected in cells using the ProteoStat aggresome detection kit (Enzo Life Sciences) under a fluorescence digital microscope (BZ-X800, Keyence Corporation, Osaka, Japan) as previously described. 35 Fluorescence intensity was quantified using the Keyence image measurement and analysis software (BZ-X analyzer, Keyence Corporation).…”

Section: ■ Methodsmentioning

confidence: 99%

Identification of Novel Oxindole Compounds That Suppress ER Stress-Induced Cell Death as Chemical Chaperones

Hasegawa

Motoyama

Hamamoto

et al. 2022

ACS Chem. Neurosci.

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Endoplasmic reticulum (ER) stress and oxidative stress lead to protein misfolding, and the resulting accumulation of protein aggregates is often associated with the pathogenesis of neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and prion disease. Small molecules preventing these pathogenic processes may be effective interventions for such neurodegenerative disorders. In this paper, we identify several novel oxindole compounds that can prevent ER stress-and oxidative stress-induced cell death. Among them, derivatives of the lead compound GIF-0726-r in which a hydrogen atom at the oxindole ring 5 position is substituted with a methyl (GIF-0852-r), bromine (GIF-0854-r), or nitro (GIF-0856-r) group potently suppressed global ER stress. Furthermore, GIF-0854-r and -0856-r prevented protein aggregate accumulation in vitro and in cultured hippocampal HT22 neuronal cells, indicating that these two compounds function effectively as chemical chaperones. In addition, GIF-0852-r, -0854-r, and -0856-r prevented glutamateinduced oxytosis and erastin-induced ferroptosis. Collectively, these results suggest that the novel oxindole compounds GIF-0854-r and -0856-r may be useful therapeutics against protein-misfolding diseases as well as valuable research tools for studying the molecular mechanisms of ER and oxidative stress.

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“…Artepillin C (APC) is a major component of Brazilian green propolis with a wide range of pharmacological benefits, including antioxidant [ 1 , 2 ], anti−inflammatory [ 3 , 4 ], anticancer [ 5 , 6 ], and immunomodulatory effects [ 6 , 7 ]. Our previous report demonstrated that APC could ameliorate metabolic syndrome by suppressing CREB/CRTC2− mediated gluconeogenesis and the transcription of sterol regulatory element−binding protein (SREBP) in obese mice [ 8 ].…”

Section: Introductionmentioning

confidence: 99%

Artepillin C Time−Dependently Alleviates Metabolic Syndrome in Obese Mice by Regulating CREB/CRTC2−BMAL1 Signaling

et al. 2023

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Artepillin C (APC), a cAMP-response element−binding (CREB)/CREB regulated transcription coactivator 2 (CRTC2) inhibitor isolated from Brazilian green propolis, can ameliorate metabolic syndrome in obese mice. Because the sensitivity and responsiveness of the body to the drug depend on the time of day and the circadian clock alignment, the optimal administration time of APC for desired efficacy in treating metabolic syndrome remains unclear. In this study, APC (20 mg/kg) or the vehicle was intraperitoneally injected into obese mice once daily for one or three weeks. The results of the insulin tolerance test, pyruvate tolerance test, and histological and biochemical assays showed that APC could improve whole−body glucose homeostasis and decrease hepatic lipid synthesis following a circadian rhythm. Further exploration of the underlying mechanism revealed that APC may disturb the diurnal oscillations of the expression of brain and muscle ARNT−like protein (BMAL1) in primary hepatocytes and the livers of the study subjects. Moreover, APC could inhibit hepatic BMAL1 expression by blocking the CREB/CRTC2 transcription complex. BMAL1 overexpression in primary hepatocytes or the livers of db/db mice antagonized the inhibitory effect of APC on hepatic lipid metabolism. In conclusion, the chronotherapy of APC may relieve metabolic syndrome in obese mice, and the mechanism behind APC−mediated time−of−day effects on metabolic syndrome were unveiled, thereby providing a foundation for optimized APC treatment from a mechanistic perspective.

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Artepillin C, a major component of Brazilian green propolis, inhibits endoplasmic reticulum stress and protein aggregation

Cited by 13 publications

References 29 publications

Oxidative-Stress-Mediated ER Stress Is Involved in Regulating Manoalide-Induced Antiproliferation in Oral Cancer Cells

Oxidative-Stress-Mediated ER Stress Is Involved in Regulating Manoalide-Induced Antiproliferation in Oral Cancer Cells

Identification of Novel Oxindole Compounds That Suppress ER Stress-Induced Cell Death as Chemical Chaperones

Artepillin C Time−Dependently Alleviates Metabolic Syndrome in Obese Mice by Regulating CREB/CRTC2−BMAL1 Signaling

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