Neferine reduces cisplatin-induced nephrotoxicity by enhancing autophagy via the AMPK/mTOR signaling pathway

Li, Hui; Tang, Yuling; Wen, Lin; Kong, Xianglong; Chen, Xuelian; Liu, Ping; Zhou, Zhong; Chen, Wenhang; Xiao, Chenggen; Xiao, Ping; Xiao, Xiangcheng

doi:10.1016/j.bbrc.2017.01.180

Cited by 34 publications

(23 citation statements)

References 27 publications

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“…The cell invasion assay was studied by using the BioCoat Matrigel One of the hallmarks of cancer cells are autonomous growth advantage and resistance to death signals, thus most of the commercial cancer chemotherapeutic agents were designed to kill these rapid growing cancer cells through various mechanism of action. [31,32] Hence, the possible cytotoxic effects of PTZ toward normal cells was cell death on cancerous cells, which is consistent with our previous findings. [19]…”

Section: Cell Invasion Assaysupporting

confidence: 90%

10H‐3,6‐Diazaphenothiazines triggered the mitochondrial‐dependent and cell death receptor‐dependent apoptosis pathways and further increased the chemosensitivity of MCF‐7 breast cancer cells via inhibition of AKT1 pathways

Ren

Hao

Yang

et al. 2020

J Biochem & Molecular Tox

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Breast cancer is one of the leading causes of death in cancer categories, followed by lung, colorectal, and ovarian among the female gender across the world. 10H‐3,6‐diazaphenothiazine (PTZ) is a thiazine derivative compound that exhibits many pharmacological activities. Herein, we proceed to investigate the pharmacological activities of PTZ toward breast cancer MCF‐7 cells as a representative in vitro breast cancer cell model. The PTZ exhibited a proliferation inhibition (IC50 = 0.895 µM) toward MCF‐7 cells. Further, cell cycle analysis illustrated that the S‐phase checkpoint was activated to achieve proliferation inhibition. In vitro cytotoxicity test on three normal cell lines (HEK293 normal kidney cells, MCF‐10A normal breast cells, and H9C2 normal heart cells) demonstrated that PTZ was more potent toward cancer cells. Increase in the levels of reactive oxygen species results in polarization of mitochondrial membrane potential (ΔΨm), together with suppression of mitochondrial thioredoxin reductase enzymatic activity suggested that PTZ induced oxidative damages toward mitochondria and contributed to improved drug efficacy toward treatment. The RT2 PCR Profiler Array (human apoptosis pathways) proved that PTZ induced cell death via mitochondria‐dependent and cell death receptor‐dependent pathways, through a series of modulation of caspases, and the respective morphology of apoptosis was observed. Mechanistic studies of apoptosis suggested that PTZ inhibited AKT1 pathways resulting in enhanced drug efficacy despite it preventing invasion of cancer cells. These results showed the effectiveness of PTZ in initiation of apoptosis, programmed cell death, toward highly chemoresistant MCF‐7 cells, thus suggesting its potential as a chemotherapeutic drug.

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Section: Cell Invasion Assaysupporting

confidence: 90%

10H‐3,6‐Diazaphenothiazines triggered the mitochondrial‐dependent and cell death receptor‐dependent apoptosis pathways and further increased the chemosensitivity of MCF‐7 breast cancer cells via inhibition of AKT1 pathways

Ren

Hao

Yang

et al. 2020

J Biochem & Molecular Tox

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“…Autophagy is constitutively activated in most cells for development, differentiation, survival, and homeostasis . A lot of evidence shows that autophagy is relevant to several liver diseases, including toxin‐ and drug‐induced liver injury, viral hepatitis, non‐alcoholic liver cirrhosis, alcoholic liver cirrhosis, and hepatocellular carcinoma . Recent publications, as well as our study, indicate that autophagy also acts as a protective mechanism, allowing cells to cope with nutrient starvation and anoxia, and ameliorate liver I/R injury …”

Section: Introductionsupporting

confidence: 71%

Inhibition of glycogen synthase kinase 3β protects liver against ischemia/reperfusion injury by activating 5′ adenosine monophosphate‐activated protein kinase‐mediated autophagy

Kong

Hua

Qin

et al. 2018

Hepatology Research

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Aim: Autophagy has been found to play an important role in hepatic ischemia/reperfusion (I/R) injury. Our previous study has also clarified that rictor deficiency aggravated hepatic I/R injury by suppressing autophagy. Here, we explore whether autophagy participates in glycogen synthase kinase 3β (GSK3β)mediated cytoprotection in liver I/R. Methods:Mice were treated with SB216763 to inhibit GSK3β before being subjected to hepatic I/R. Liver injury was evaluated by liver and blood samples. Autophagy was measured by detecting expression of microtubule-associated protein 1 light chain-3B (LC3B) II and autophagy protein 5 (ATG-5), as well as the number of autophagosomes by transmission electron microscope. Primary hepatocytes pretreated with SB216763 for 2 h were subjected to hypoxia/reoxygenation to induce autophagy. The lactate dehydrogenase level was used to evaluate cell death and survival. Autophagy inhibitors and 5 0 adenosine monophosphate-activated protein kinase (AMPK) inhibitor were given in vivo or in vitro. Results: SB216763 significantly increased the number of autophagosomes and the protein levels of LC3B II and ATG-5 in liver I/R models, which was accompanied by a decline of hepatic necrosis and apoptosis. Consistent with the in vivo study, autophagy and cytoprotection were induced by the inhibition of GSK3β in the in vitro study. Moreover, pretreatment with autophagy inhibitors attenuated the cytoprotective role of autophagy in the GSK3β-treated liver I/R models. Further analysis showed that pretreatment with an AMPK inhibitor increased mammalian target of rapamycin (mTOR) activity, decreased autophagy, and abrogated GSK3β-mediated liver protection.Conclusion: Autophagy was induced by GSK3β inhibition through the AMPK/mTOR pathway and could substantially ameliorate liver I/R injury. Therefore, our findings strongly renew the therapeutic value of the GSK3β/autophagy axis in hepatic I/R injury.

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“…Enhancing autophagy through the AMPK/mTOR-mediated pathway also provided protection against cisplatin-induced nephrotoxicity. Furthermore, metformin [98] and neferine [99], which enhance autophagy via the AMPK/mTOR pathway, ameliorate cisplatin nephrotoxicity. In a sepsis model of cecal ligation and puncture, nicotinamide adenine dinucleotide NAD-dependent protein deacetylase SIRT3, a member of the mammalian sirtuin family of proteins, provided protection from sepsis-induced AKI through AMPK/mTOR-regulated autophagy [100].…”

Section: Ampk-mtorc1/ulk1-mediated Autophagy In Renal Injurymentioning

confidence: 99%

Autophagy Function and Regulation in Kidney Disease

et al. 2020

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Autophagy is a dynamic process by which intracellular damaged macromolecules and organelles are degraded and recycled for the synthesis of new cellular components. Basal autophagy in the kidney acts as a quality control system and is vital for cellular metabolic and organelle homeostasis. Under pathological conditions, autophagy facilitates cellular adaptation; however, activation of autophagy in response to renal injury may be insufficient to provide protection, especially under dysregulated conditions. Kidney-specific deletion of Atg genes in mice has consistently demonstrated worsened acute kidney injury (AKI) outcomes supporting the notion of a pro-survival role of autophagy. Recent studies have also begun to unfold the role of autophagy in progressive renal disease and subsequent fibrosis. Autophagy also influences tubular cell death in renal injury. In this review, we reported the current understanding of autophagy regulation and its role in the pathogenesis of renal injury. In particular, the classic mammalian target of rapamycin (mTOR)-dependent signaling pathway and other mTOR-independent alternative signaling pathways of autophagy regulation were described. Finally, we summarized the impact of autophagy activation on different forms of cell death, including apoptosis and regulated necrosis, associated with the pathophysiology of renal injury. Understanding the regulatory mechanisms of autophagy would identify important targets for therapeutic approaches.

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Neferine reduces cisplatin-induced nephrotoxicity by enhancing autophagy via the AMPK/mTOR signaling pathway

Cited by 34 publications

References 27 publications

10H‐3,6‐Diazaphenothiazines triggered the mitochondrial‐dependent and cell death receptor‐dependent apoptosis pathways and further increased the chemosensitivity of MCF‐7 breast cancer cells via inhibition of AKT1 pathways

10H‐3,6‐Diazaphenothiazines triggered the mitochondrial‐dependent and cell death receptor‐dependent apoptosis pathways and further increased the chemosensitivity of MCF‐7 breast cancer cells via inhibition of AKT1 pathways

Inhibition of glycogen synthase kinase 3β protects liver against ischemia/reperfusion injury by activating 5′ adenosine monophosphate‐activated protein kinase‐mediated autophagy

Autophagy Function and Regulation in Kidney Disease

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