PPARγ agonist pioglitazone inhibits microglia inflammation by blocking p38 mitogen-activated protein kinase signaling pathways

Ji, Huoyan; Wang, Huimin; Zhang, Fupeng; Li, Xiaohong; Lü, Xiang; Shen, Aiguo

doi:10.1007/s00011-010-0203-7

Cited by 65 publications

(47 citation statements)

References 20 publications

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“…Of interest is also that minocycline was ineffective in protecting neurons against this conditioned medium, but protected neurons against the toxicity of DEP in a co-culture system, indicating that the target for minocycline neuroprotection is microglia. Indeed, another reported inhibitor of microglia activation, the PPAR-γ agonist pioglitazone (Ji et al 2010; Drew et al 2015), also protected neurons from DEP-induced, microglia-mediated neurotoxicity.…”

Section: Discussionmentioning

confidence: 98%

Microglia mediate diesel exhaust particle-induced cerebellar neuronal toxicity through neuroinflammatory mechanisms

2016

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In addition to the well-established effects of air pollution on the cardiovascular and respiratory systems, emerging evidence has implicated it in inducing negative effects on the central nervous system. Diesel exhaust particulate matter (DEP), a major component of air pollution, is a complex mixture of numerous toxicants. Limited studies have shown that DEP-induced dopaminergic neuron dysfunction is mediated by microglia, the resident immune cells of the brain. Here we show that mouse microglia similarly mediate primary cerebellar granule neuron (CGN) death in vitro. While DEP (0, 25, 50, 100 µg/2 cm2) had no effect on CGN viability after 24 h of treatment, in the presence of primary cortical microglia neuronal cell death increased by 2–3-fold after co-treatment with DEP, suggesting that microglia are important contributors to DEP-induced CGN neurotoxicity. DEP (50 µg/2 cm2) treatment of primary microglia for 24 h resulted in morphological changes indicative of microglia activation, suggesting that DEP may induce the release of cytotoxic factors. Microglia-conditioned medium after 24 h treatment with DEP, was also toxic to CGNs. DEP caused a significant increase in reactive oxygen species in microglia, however, antioxidants failed to protect neurons from DEP/microglia-induced toxicity. DEP increased mRNA levels of the pro-inflammatory cytokines IL-6 and IL1-β, and the release of IL-6. The antibiotic minocycline (50 µM) and the peroxisome proliferator-activated receptor-γ agonist pioglitazone (50 µM) attenuated DEP-induced CGN death in the co-culture system. Microglia and CGNs from male mice appeared to be somewhat more susceptible to DEP neurotoxicity than cells from female mice possibly because of lower paraoxonase-2 expression. Together, these results suggest that microglia-induced neuroinflammation may play a critical role in modulating the effect of DEP on neuronal viability.

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Section: Discussionmentioning

confidence: 98%

Microglia mediate diesel exhaust particle-induced cerebellar neuronal toxicity through neuroinflammatory mechanisms

2016

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“…Also, it has been reported that ERK or JNK inhibitors had no effect on PPARγ expression and loss by LPS stimulation. (41) Therefore, our results may show that sargaquinoic acid can inhibit the iNOS expression through the control of other signals, like NF-κB and JNK pathway, activated by LPS as well as PPARγ activation. Thus, we are currently investigating the effect of sargaquinoic acid on the PPARs activation, as well as the NF-κB DNA-binding activity and the PI3K/Akt signaling pathway in RAW264.7 macrophages.…”

Section: Discussionmentioning

confidence: 72%

Sargaquinoic acid isolated fromSargassum siliquastruminhibits lipopolysaccharide-induced nitric oxide production in macrophagesviamodulation of nuclear factor-κB and c-JunN-terminal kinase pathways

Kang

Han

Yoon

et al. 2012

Immunopharmacology and Immunotoxicology

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Nitric oxide (NO) is a crucial molecule in inflammatory diseases and is synthesized from L-arginine by a specific enzyme, NO synthase (NOS). The expression of inducible NOS (iNOS) is activated in macrophages by various stimuli, such as lipopolysaccharide (LPS), a wall component of gram-negative bacteria. LPS binds to toll-like receptor 4 (TLR4) on the macrophage surface and activates several downstream signaling pathways, including mitogen-activated protein kinase (MAPK) and nuclear factor (NF)-κB pathways. This study investigated whether sargaquinoic acid isolated from Sargassum siliquastrum might have anti-inflammatory activity and interfere with NO production in macrophages by disrupting LPS-induced signaling. This study was conducted in vitro using RAW264.7 murine macrophages. LPS-stimulated cells were treated with sargaquinoic acid, and the effects on NO production, iNOS expression, and involvement of the NF-κB signaling pathway were investigated by Griess assay, western blotting, and confocal microscopy. The results demonstrated that sargaquinoic acid inhibited the production of NO and the expression of the iNOS protein in LPS-stimulated RAW264.7 macrophages. Moreover, sargaquinoic acid inhibited the degradation of inhibitory-κB protein (IκB)-α and the nuclear translocation of NF-κB, a key transcription factor for the regulation of iNOS expression. Also, sargaquinoic acid influenced the phosphorylation of JNK1/2 MAPK, except ERK1/2 and p38 MAPKs, stimulated by LPS. These results suggest that sargaquinoic acid specifically prevents NO production in macrophages via the blockade of NF-κB activation and may thus have therapeutic applications in various inflammatory diseases.

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“…iNOS and COX-2 were inhibited by rosiglitazone in rats (Cuzzocrea et al 2004). Studies also showed that pioglitazone inhibit lipopolysaccharide-induced inflammation block p38 phosphorylation (Ji et al 2010). So does rosiglitazone .…”

Section: Discussionmentioning

confidence: 94%

The role of ribosylated-BSA in regulating PC12 cell viability

et al. 2012

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Glycation, one of the post-translational modifications, is known to influence protein structure and biological function. Advanced glycation end products (AGEs) have been shown to cause pathologies of diabetes. Glycation levels in patients with Alzheimer's disease (AD) are higher than in normal people. However, whether the glycation of susceptible proteins is a triggering event for cell damage or simply a result remains to be elucidated. In this study, we demonstrated that ribose-conjugated BSA (Rib-BSA) directly induces PC12 cell death in a dose- and time-dependent manner. The IC(50) is 4.6 μM. Unlike glucose-incubated BSA, Rib-BSA rapidly forms cytotoxic AGEs. PC12 is vulnerable to Rib-BSA. However, fructose can induce AGE formation, although no effect on cell survival was observed. This effect of Rib-BSA is reversed by pretreatment of pioglitazone and rosiglitazone, which belongs to thiazolidinediones (TZDs) and are peroxisome proliferator-activated receptor (PPAR-γ) ligands. Moreover, Rib-BSA upregulates inducible nitric oxide synthase (iNOS), cycloxygenase 2 (COX-2) expression, and p-38 phosphorylation and leaves extracellular regulated protein1/2 (ERK1/2) phosphorylation unchanged. The Rib-BSA-induced signaling changes are blocked by rosiglitazone and confirmed by PPAR-γ small-interfering RNA transfection. The reduction of cell survival by Rib-BSA is blocked by the iNOS inhibitor and p38 inhibitor. No effect on cell survival was observed using the COX-2 inhibitor. Consequently, these results show that Rib-BSA directly inducing PC12 cell death is a triggering event and TZDs protect PC12 cell from Rib-BSA damage. Signaling molecules, such as PPAR-γ, P38, and iNOS, are involved in Rib-BSA-mediated cytotoxicity.

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PPARγ agonist pioglitazone inhibits microglia inflammation by blocking p38 mitogen-activated protein kinase signaling pathways

Abstract: The results show that pioglitazone can inhibit LPS-stimulated microglia inflammation by blocking p38 MAPK signaling pathway.

Cited by 65 publications

References 20 publications

Microglia mediate diesel exhaust particle-induced cerebellar neuronal toxicity through neuroinflammatory mechanisms

Microglia mediate diesel exhaust particle-induced cerebellar neuronal toxicity through neuroinflammatory mechanisms

Sargaquinoic acid isolated fromSargassum siliquastruminhibits lipopolysaccharide-induced nitric oxide production in macrophagesviamodulation of nuclear factor-κB and c-JunN-terminal kinase pathways

The role of ribosylated-BSA in regulating PC12 cell viability

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