Effects of Betaine on LPS-Stimulated Activation of Microglial M1/M2 Phenotypes by Suppressing TLR4/NF-κB Pathways in N9 Cells

Shi, Hui; Wang, Xiaolong; Quan, Hongfeng; Yang, Lin; Pei, Xiuying; Wang, Rui; Peng, Xiao-Dong

doi:10.3390/molecules24020367

Cited by 87 publications

(62 citation statements)

References 50 publications

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“…We found that VX765 treatment significantly inhibited microglial activation and recruitment and altered polarization by inhibiting and promoting M1 and M2 activation, respectively. This may be associated with the decrease of proinflammatory cytokines and the increase of anti-inflammatory cytokines [65]. In conclusion, we demonstrated that VX765 regulated the polarization direction of microglia and the severity of pyroptosis by changing the expression of pro-and anti-inflammatory cytokines.…”

Section: Discussionmentioning

confidence: 51%

VX765 Attenuates Pyroptosis and HMGB1/TLR4/NF-κB Pathways to Improve Functional Outcomes in TBI Mice

Sun

Nyanzu

Yang

et al. 2020

Oxidative Medicine and Cellular Longevity

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Background. Traumatic brain injury (TBI) refers to temporary or permanent damage to brain function caused by penetrating objects or blunt force trauma. TBI activates inflammasome-mediated pathways and other cell death pathways to remove inactive and damaged cells, however, they are also harmful to the central nervous system. The newly discovered cell death pattern termed pyroptosis has become an area of interest. It mainly relies on caspase-1-mediated pathways, leading to cell death. Methods. Our research focus is VX765, a known caspase-1 inhibitor which may offer neuroprotection after the process of TBI. We established a controlled cortical impact (CCI) mouse model and then controlled the degree of pyroptosis in TBI with VX765. The effects of caspase-1 inhibition on inflammatory response, pyroptosis, blood-brain barrier (BBB), apoptosis, and microglia activation, in addition to neurological deficits, were investigated. Results. We found that TBI led to NOD-like receptors (NLRs) as well as absent in melanoma 2 (AIM2) inflammasome-mediated pyroptosis in the damaged cerebral cortex. VX765 curbed the expressions of indispensable inflammatory subunits (caspase-1 as well as key downstream proinflammatory cytokines such as interleukin- (IL-) 1β and IL-18). It also inhibited gasdermin D (GSDMD) cleavage and apoptosis-associated spot-like protein (ASC) oligomerization in the injured cortex. In addition to the above, VX765 also inhibited the inflammatory activity of the high-mobility cassette -1/Toll-like receptor 4/nuclear factor-kappa B (HMGB1/TLR4/NF-kappa B) pathway. By inhibiting pyroptosis and inflammatory mediator expression, we demonstrated that VX765 can decrease blood-brain barrier (BBB) leakage, apoptosis, and microglia polarization to exhibit its neuroprotective effects. Conclusion. In conclusion, VX765 can counteract neurological damage after TBI by reducing pyroptosis and HMGB1/TLR4/NF-κB pathway activities. VX765 may have a good therapeutic effect on TBI.

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Section: Discussionmentioning

confidence: 51%

VX765 Attenuates Pyroptosis and HMGB1/TLR4/NF-κB Pathways to Improve Functional Outcomes in TBI Mice

Sun

Nyanzu

Yang

et al. 2020

Oxidative Medicine and Cellular Longevity

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“…Furthermore, TLR4 could activate the downstream IκB kinase (IKK) complex, and then phosphorylate IκB, an NF-κB inhibitor that could prevent nuclear translocation of NF-κB. Upon phosphorylation, IκB was degraded and released NF-κB, which then entered nucleus and mediated the expression of in ammatory cytokines [32,33]. In the present study, we found that the expression of TLR4, MyD88, p-NF-κB p65, p-IκBα and p-IKKα/β in breast cancer cells was signi cantly down-regulated after AT-I treatment.…”

Section: Discussionmentioning

confidence: 99%

Atractylenolide-I suppresses tumorigenesis of breast cancer by inhibiting toll-like receptor 4 (TLR4)-mediated NF-κB signaling pathway

Long

Lin

Zhang

et al. 2020

Preprint

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Background: Toll-like receptor 4 (TLR4) is an essential sensor related to tumorigenesis, and overexpression of TLR4 in human tumors often correlates with poor prognosis. Atractylenolide I (AT-I) is a major bioactive component from Rhizoma Atractylodes Macrocephalae. Emerging evidence suggests that AT-I exerts anti-tumor effects on various cancers such as colorectal cancer, bladder cancer and melanoma. Nevertheless, the effects of AT-I on mammary tumorigenesis remain unclear.Methods: In order to ascertain the correlation of TLR4/NF-κB pathway with breast cancer, the expression of TLR4 and NF-κB in normal breast tissues and cancer tissues with different TNM-stages was detected by human tissue microarray (TMA) and immunohistochemistry technology. The effects of AT-I on tumorigenesis were investigated by cell viability, colony formation, apoptosis, migration and invasion assays in two breast cancer cells (MCF-7 and MDA-MB-231), and N-Nitroso-N-methylurea (NMU) induced rat breast cancer models were developed to evaluate the anti-tumor effects of AT-I in vivo. The possible underlying mechanisms were further explored by western blot and ELISA assays after a series of LPS treatment and TLR4 knockdown experiments.Results：We found that TLR4 and NF-κB were significantly up-regulated in breast cancer tissues, and was correlated with advanced TNM-stages. AT-I could inhibit TLR4 mediated NF-κB signaling pathway and decrease NF-κB-regulated cytokines in breast cancer cells, thus inhibiting cell proliferation, migration and invasion, and inducing apoptosis of breast cancer cells. Furthermore, AT-I could inhibit NMU-induced rat mammary tumor progression through TLR4/NF-κB pathway.Conclusions: Our findings demonstrated that TLR4 and NF-κB were over expressed in breast cancer, and AT-I could suppress tumorigenesis of breast cancer via inhibiting TLR4-mediated NF-κB signaling pathway.

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“…So far, there is still a lack of effective treatment for NP [3,4]. Microglia, the resident macrophage cells of the central nervous system, has been shown to mediate neuroinflammation [5]. Microglia activation and subsequent pro-inflammatory responses play an important role in the development of NP [6].…”

Section: Introductionmentioning

confidence: 99%

“…The M1 phenotype is characterized by increased expression of several proteins including inducible NO synthase (iNOS) and CD68, as well as increased secretion of several proinflammatory factors such as interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α [7,8]. The M2 phenotype is characterized by increased expression of several proteins such as arginase-1 (Arg-1) and mannose receptor (MR/CD206), as well as increased production of antiinflammatory cytokines such as IL-4 and IL-10 [5,9]. The microglial polarization toward the pro-inflammatory M1 phenotype often occurs during NP.…”

Section: Introductionmentioning

confidence: 99%

Botulinum toxin type A promotes microglial M2 polarization and suppresses chronic constriction injury-induced neuropathic pain through the P2X7 receptor

Gui

Wang

et al. 2020

Cell Biosci

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Background: Switching microglial polarization from the pro-inflammatory M1 phenotype to the anti-inflammatory M2 phenotype represents a novel therapeutic strategy for neuropathic pain (NP). This study aims to investigate whether botulinum toxin type A (BTX-A) regulates microglial M1/M2 polarization by inhibiting P2X7 expression in a rat model of NP. Results: The BTX-A administration elevated pain threshold, induced microglial polarization toward the M2 phenotype, and decreased P2X7 protein level in a rat model of NP induced by chronic compression injury (CCI). Lipopolysaccharide (LPS) was used to activate HAPI rat microglial cells as an in vitro inflammatory model and we demonstrated that BTX-A promoted microglial M2 polarization in LPS-stimulated HAPI microglial cells through suppressing P2X7. Conclusions: Our results indicate that BTX-A promotes microglial M2 polarization and suppresses CCI-induced NP through inhibiting P2X7 receptor. These findings provide new insights into the mechanism of BTX-A in relieving NP.

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Effects of Betaine on LPS-Stimulated Activation of Microglial M1/M2 Phenotypes by Suppressing TLR4/NF-κB Pathways in N9 Cells

Cited by 87 publications

References 50 publications

VX765 Attenuates Pyroptosis and HMGB1/TLR4/NF-κB Pathways to Improve Functional Outcomes in TBI Mice

VX765 Attenuates Pyroptosis and HMGB1/TLR4/NF-κB Pathways to Improve Functional Outcomes in TBI Mice

Atractylenolide-I suppresses tumorigenesis of breast cancer by inhibiting toll-like receptor 4 (TLR4)-mediated NF-κB signaling pathway

Botulinum toxin type A promotes microglial M2 polarization and suppresses chronic constriction injury-induced neuropathic pain through the P2X7 receptor

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