Dataset Information

2?Hydroxypropyl???cyclodextrin blocks autophagy flux and triggers caspase?8?mediated apoptotic cascades in HepG2 cells.

ABSTRACT: The cyclodextrin derivative, 2?Hydroxypropyl-??cyclodextrin (HP?CD), from the cyclodextrin family is widely used as a drug carrier and offers promising strategies for treating neurodegenerative diseases and atherosclerosis regression. However, its side effects are not fully understood. Therefore, the aim of the present study was to investigate the possible adverse effects of relatively high concentrations of HP?CD on hepatocytes. It was found that a high dose (20 mM) of HP?CD treatment significantly inhibited the AKT/mTOR pathway and disrupted infusion of autophagosomes and lysosomes, which rapidly led to massive autophagosome accumulation in HepG2 cells. The autophagosomal membrane serves as a platform for caspase?8 oligomerization, which is considered as the key step for its self?activation. Using flow cytometry and TUNEL assay, increased apoptosis of HepG2 cells treated with a high dose HP?CD (20 mM) for 48 h was observed. In addition, western blotting results demonstrated that the expression of cleaved?caspase?8 was positively associated with microtubule?associated protein 1 light chain 3 BII expression, which is an indicator of autophagosome level in the cytoplasm. Therefore, the present study provided novel evidence that HP?CD might be a potential risk contributing to the pathophysiological process of hepatic diseases, especially in an autophagy?deficient state.

SUBMITTER: Sun H

PROVIDER: S-EPMC7413020 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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2‑Hydroxypropyl‑β‑cyclodextrin blocks autophagy flux and triggers caspase‑8‑mediated apoptotic cascades in HepG2 cells.

Sun Haidong H Zong Huajie H Wu Gang G

Molecular medicine reports 20200626 3

The cyclodextrin derivative, 2‑Hydroxypropyl-β‑cyclodextrin (HPβCD), from the cyclodextrin family is widely used as a drug carrier and offers promising strategies for treating neurodegenerative diseases and atherosclerosis regression. However, its side effects are not fully understood. Therefore, the aim of the present study was to investigate the possible adverse effects of relatively high concentrations of HPβCD on hepatocytes. It was found that a high dose (20 mM) of HPβCD treatment significa ...[more]

PMID: 32705246

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Project description:Lifestyle- and genetically induced disorders related to disturbances in cholesterol metabolism have shown the detrimental impact of excessive cholesterol levels on a plethora of pathological processes such as inflammation. In this context, two-hydroxypropyl-β-cyclodextrin (CD) is increasingly considered as a novel pharmacological compound to decrease cellular cholesterol levels due to its ability to increase cholesterol solubility. However, recent findings have reported contra-indicating events after the use of CD questioning the clinical applicability of this compound. Given its potential as a therapeutic compound in metabolic inflammatory diseases, in this study, we evaluated the inflammatory effects of CD administration in the context of cholesterol-induced metabolic inflammation in vivo and in vitro. The inflammatory and cholesterol-depleting effects of CD were first investigated in low-density lipoprotein receptor knockout (Ldlr-/ ) mice that were transplanted with Npc1nih or Npc1wt bone marrow and were fed either regular chow or a high-fat, high-cholesterol (HFC) diet for 12 weeks, thereby creating an extreme model of lysosomal cholesterol-induced metabolic inflammation. In the final three weeks, these mice received daily injections of either control (saline) or CD subcutaneously. Subsequently, the inflammatory properties of CD were investigated in vitro in two macrophage cell lines and in murine bone marrow-derived macrophages (BMDMs). While CD administration improved cholesterol mobilization outside lysosomes in BMDMs, an overall pro-inflammatory profile was observed after CD treatment, evidenced by increased hepatic inflammation in vivo and a strong increase in cytokine release and inflammatory gene expression in vitro in murine BMDMs and macrophages cell lines. Nevertheless, this CD-induced pro-inflammatory profile was time-dependent, as short term exposure to CD did not result in a pro-inflammatory response in BMDM. While CD exerts desired cholesterol-depleting effects, its inflammatory effect is dependent on the exposure time. As such, using CD in the clinic, especially in a metabolic inflammatory context, should be closely monitored as it may lead to undesired, pro-inflammatory side effects.

Dataset Information

2?Hydroxypropyl???cyclodextrin blocks autophagy flux and triggers caspase?8?mediated apoptotic cascades in HepG2 cells.

Publications

2‑Hydroxypropyl‑β‑cyclodextrin blocks autophagy flux and triggers caspase‑8‑mediated apoptotic cascades in HepG2 cells.

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