Chrysophanol suppresses pro-inflammatory response in microglia<i>via</i>regulation of Drp1-dependent mitochondrial fission

Chae, Unbin; Min, Ju-Sik; Lee, Hanna; Song, Kyung‐Sik; Lee, Hyun‐Shik; Lee, Hong Jun; Lee, Sang-Rae; Lee, Dong‐Seok

doi:10.1080/08923973.2017.1344988

Cited by 23 publications

(11 citation statements)

References 26 publications

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“…At this time point, we did not observe any difference in immune activation between groups. This does not necessarily exclude an immune response as LPS-induced inflammatory effects require more than 1 h to reach a maximal effect in vitro [ 11 ] and experiments generally focus on 24 h post-injection in vivo [ 48 , 58 ] although changes in Iba-1 expression have been observed as early as 2 h [ 48 ]. Given the focus on later time points with the very immunogenic nature of LPS, it is not surprising that an immune response is not observed 1 h post-injection.…”

Section: Discussionmentioning

confidence: 99%

Demonstration of prion-like properties of mutant huntingtin fibrils in both in vitro and in vivo paradigms

et al. 2019

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In recent years, evidence has accumulated to suggest that mutant huntingtin protein (mHTT) can spread into healthy tissue in a prion-like fashion. This theory, however, remains controversial. To fully address this concept and to understand the possible consequences of mHTT spreading to Huntington’s disease pathology, we investigated the effects of exogenous human fibrillar mHTT (Q48) and huntingtin (HTT) (Q25) N-terminal fragments in three cellular models and three distinct animal paradigms. For in vitro experiments, human neuronal cells [induced pluripotent stem cell-derived GABA neurons (iGABA) and (SH-SY5Y)] as well as human THP1-derived macrophages, were incubated with recombinant mHTT fibrils. Recombinant mHTT and HTT fibrils were taken up by all cell types, inducing cell morphology changes and death. Variations in HTT aggregation were further observed following incubation with fibrils in both THP1 and SH-SY5Y cells. For in vivo experiments, adult wild-type (WT) mice received a unilateral intracerebral cortical injection and R6/2 and WT pups were administered fibrils via bilateral intraventricular injections. In both protocols, the injection of Q48 fibrils resulted in cognitive deficits and increased anxiety-like behavior. Post-mortem analysis of adult WT mice indicated that most fibrils had been degraded/cleared from the brain by 14 months post-surgery. Despite the absence of fibrils at these later time points, a change in the staining pattern of endogenous HTT was detected. A similar change was revealed in post-mortem analysis of the R6/2 mice. These effects were specific to central administration of fibrils, as mice receiving intravenous injections were not characterized by behavioral changes. In fact, peripheral administration resulted in an immune response mounting against the fibrils. Together, the in vitro and in vivo data indicate that exogenously administered mHTT is capable of both causing and exacerbating disease pathology. Electronic supplementary material The online version of this article (10.1007/s00401-019-01973-6) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Demonstration of prion-like properties of mutant huntingtin fibrils in both in vitro and in vivo paradigms

et al. 2019

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“…In addition, chrysophanol could significantly reduce the expression of iNOS, TNF‐α and IL‐6 by inhibiting the expression of RIP140 and NF‐κB in LPS‐induced acute liver injury of mice . Chrysophanol protected LPS‐stimulated BV‐2 murein microglial cells by down‐regulating MAPK, NF‐jB and ROS generation and Drp1 (S637) dephosphorylation . Zhang et al .…”

Section: Pharmacologymentioning

confidence: 99%

“…In a mouse model of MCAO, chrysophans attenuated neuronal damage associated with nitric oxide (NO) production by reducing cleaved caspase‐3 expression and enhancing SOD and manganese‐dependent SOD (MnSOD) activity . In the next, Chae et al . found that chrysophanol (10 μ m ) inhibited LPS‐induced BV‐2 murein microglial cell inflammatory response by down‐regulating dynamin‐related protein 1 (Drp1) (S637) dephosphorylation to inhibit the production of pro‐inflammatory mediators and cytokines via regulation of mitogen‐activated protein kinase (MAPK), nuclear factor‐jB (NF‐jB)and reactive oxygen species (ROS) generation.…”

Section: Pharmacologymentioning

confidence: 99%

Chrysophanol: a review of its pharmacology, toxicity and pharmacokinetics

Xie

Tang

Song

et al. 2019

Journal of Pharmacy and Pharmacology

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Objective Chrysophanol is a natural anthraquinone, also known as chrysophanic acid and 1,8‐dihydroxy‐3‐methyl‐anthraquinone. It has been widely used in the food and pharmaceutical fields. This review is intended to provide a comprehensive overview of the pharmacology, toxicity and pharmacokinetic researches of chrysophanol. Key finding Information on chrysophanol was collected from the Internet database PubMed, Elsevier, ResearchGate, Web of Science, Wiley Online Library and Europe PM using a combination of keywords including ‘pharmacology’, ‘toxicology’ and ‘pharmacokinetics’. The literature we collected included from January 2010 to June 2019. Chrysophanol has a wide spectrum of pharmacological effects, including anticancer, antioxidation, neuroprotection, antibacterial and antiviral, and regulating blood lipids. However, chrysophanol has obvious hepatotoxicity and nephrotoxicity, and pharmacokinetics indicate that the use of chrysophanol in combination with other drugs can reduce toxicity and enhance efficacy. Summary Chrysophanol can be used in many diseases. Future research directions include how the concentration of chrysophanol affects pharmacological effects and toxicity; the mechanism of synergy between chrysophanol and other drugs.

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“…However, no study examined the effect of LRRK2 on mitochondrial morphology in microglia. Interestingly, LPS stimulations of microglia also increased mitochondrial fission, Drp1 level, production of pro-inflammatory cytokines and ROS as well as kinase activity of LRRK2 [ 15 16 26 27 28 ]. In addition, phagocytic activity of macrophages is regulated by Drp1-mediated mitochondrial fission [ 29 ].…”

Section: Introductionmentioning

confidence: 99%

LRRK2 Kinase Activity Induces Mitochondrial Fission in Microglia via Drp1 and Modulates Neuroinflammation

Lee

et al. 2018

Exp Neurobiol

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Leucine-rich repeat kinase 2 (LRRK2) mutations are the most common genetic cause of Parkinson's disease (PD). LRRK2 contains a functional kinase domain and G2019S, the most prevalent LRRK2 pathogenic mutation, increases its kinase activity. LRRK2 regulates mitochondria morphology and autophagy in neurons. LPS treatment increases LRRK2 protein level and mitochondrial fission in microglia, and down-regulation of LRRK2 expression or inhibition of its kinase activity attenuates microglia activation. Here, we evaluated the direct role of LRRK2 G2019S in mitochondrial dynamics in microglia. Initial observation of microglia in G2019S transgenic mice revealed a decrease in mitochondrial area and shortage of microglial processes compared with their littermates. Next, we elucidated the molecular mechanisms of these phenotypes. Treatment of BV2 cells and primary microglia with LPS enhanced mitochondrial fission and increased Drp1, a mitochondrial fission marker, as previously reported. Importantly, both phenotypes were rescued by treatment with GSK2578215A, a LRRK2 kinase inhibitor. Finally, the protein levels of CD68, an active microglia marker, Drp1 and TNF-α were significantly higher in brain lysates of G2019S transgenic mice compared with the levels in their littermates. Taken together, our data suggest that LRRK2 could promote microglial mitochondrial alteration via Drp1 in a kinase-dependent manner, resulting in stimulation of pro-inflammatory responses. This mechanism in microglia might be a potential target to develop PD therapy since neuroinflammation by active microglia is a major symptom of PD.

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Chrysophanol suppresses pro-inflammatory response in microgliaviaregulation of Drp1-dependent mitochondrial fission

Cited by 23 publications

References 26 publications

Demonstration of prion-like properties of mutant huntingtin fibrils in both in vitro and in vivo paradigms

Demonstration of prion-like properties of mutant huntingtin fibrils in both in vitro and in vivo paradigms

Chrysophanol: a review of its pharmacology, toxicity and pharmacokinetics

LRRK2 Kinase Activity Induces Mitochondrial Fission in Microglia via Drp1 and Modulates Neuroinflammation

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