Anti-inflammatory and anti-oxidant mechanisms of an MMP-8 inhibitor in lipoteichoic acid-stimulated rat primary astrocytes: involvement of NF-κB, Nrf2, and PPAR-γ signaling pathways

Lee, Eun Jung; Park, Jin-Sun; Lee, Yu Young; Kim, Do Yeon; Kang, Jihee Lee; Kim, Hee Sun

doi:10.1186/s12974-018-1363-6

Cited by 36 publications

(33 citation statements)

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“…Age-up genes in astrocytes, C4b, involved in synapse elimination [48]; Snca and Sncg, 2 genes related to Parkinson's disease pathogenesis [49] that also play several roles in synaptic activity, such as regulation of synaptic-vesicle trafficking and subsequent neurotransmitter release [50,51], suggesting that astrocytes play a critical role in synapse elimination and synaptic transmission. Spock3 and Timp4, encode proteins that participate in inhibiting matrix metalloproteinases (MMPs) involved in the degradation of the extracellular matrix [52], and the other genes encode proteins that inhibit lipoteichoic acid-induced NF-κB, MAP kinase, and Akt activities [53] and decrease the invasion and metastasis of tumor cells in the brain [54]. Pcsk1n, an inhibitor of prohormone convertase 1 that regulates the proteolytic cleavage of neuroendocrine peptide precursors [55].…”

Section: Discussionmentioning

confidence: 99%

Transcriptomic profiling of microglia and astrocytes throughout aging

Pan

et al. 2020

J Neuroinflammation

120

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Background: Activation of microglia and astrocytes, a prominent hallmark of both aging and Alzheimer's disease (AD), has been suggested to contribute to aging and AD progression, but the underlying cellular and molecular mechanisms are largely unknown. Methods:We performed RNA-seq analyses on microglia and astrocytes freshly isolated from wild-type and APP-PS1 (AD) mouse brains at five time points to elucidate their age-related gene-expression profiles.Results: Our results showed that from 4 months onward, a set of age-related genes in microglia and astrocytes exhibited consistent upregulation or downregulation (termed "age-up"/"age-down" genes) relative to their expression at the young-adult stage (2 months). And most age-up genes were more highly expressed in AD mice at the same time points. Bioinformatic analyses revealed that the age-up genes in microglia were associated with the inflammatory response, whereas these genes in astrocytes included widely recognized AD risk genes, genes associated with synaptic transmission or elimination, and peptidase-inhibitor genes.Conclusions: Overall, our RNA-seq data provide a valuable resource for future investigations into the roles of microglia and astrocytes in aging-and amyloid-β-induced AD pathologies.

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Section: Discussionmentioning

confidence: 99%

Transcriptomic profiling of microglia and astrocytes throughout aging

Pan

et al. 2020

J Neuroinflammation

120

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Section: The Therapeutic Impact: a Glial Avenue For Nigrostriatal Resmentioning

confidence: 99%

“…Tert-butylhydroquinone (tBHQ) enhanced angiogenesis and astrocyte activation through Nrf2 pathway in mice with permanent distal middle cerebral artery occlusion (dMCAO) [ 312 ]. tBHQ significantly reduced the infarct volume, enhanced post-stroke angiogenesis and astrocytic endfeet covered ratio in the peri-infarct area [ 312 ]. The Nrf2/HO-1/VEGF pathway was activated by tBHQ in the angiogenesis process, but not in Nrf2 −/− mice, where the Nrf2 deficiency blocked the effects of tBHQ on angiogenesis process and neurological recovery indicating a beneficial effect of activating Nrf2 pathway after cerebral ischemia [ 312 ].…”

Section: The Therapeutic Impact: a Glial Avenue For Nigrostriatal Resmentioning

confidence: 99%

“…Matrix metalloproteinase (MMP)-8 inhibitor , M8I, can control neuroinflammation in lipoteichoic acid (LTA)-stimulated rat primary astrocytes [ 312 ]. Here, treatment with LTA, a major cell wall component of Gram-positive bacteria, led to astrocyte activation and induced the expression of inflammatory molecules such as iNOS, COX-2, and pro-inflammatory cytokines, as well as MMP-1, MMP-3, MMP-8, MMP-9, and MMP-13 in rat primary astrocytes [ 312 ]. M8I inhibited LTA-induced NF-κB, MAP kinase, and Akt activities, while it increased the anti-inflammatory PPAR-γ activities.…”

Section: The Therapeutic Impact: a Glial Avenue For Nigrostriatal Resmentioning

confidence: 99%

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Nrf2/Wnt resilience orchestrates rejuvenation of glia-neuron dialogue in Parkinson's disease

Marchetti

2020

Redox Biology

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Oxidative stress and inflammation have long been recognized to contribute to Parkinson's disease (PD), a common movement disorder characterized by the selective loss of midbrain dopaminergic neurons (mDAn) of the substantia nigra pars compacta (SNpc). The causes and mechanisms still remain elusive, but a complex interplay between several genes and a number of interconnected environmental factors, are chiefly involved in mDAn demise, as they intersect the key cellular functions affected in PD, such as the inflammatory response, mitochondrial, lysosomal, proteosomal and autophagic functions. Nuclear factor erythroid 2 -like 2 ( NFE2L2/Nrf2 ), the master regulator of cellular defense against oxidative stress and inflammation, and Wingless ( Wnt ) /β-catenin signaling cascade, a vital pathway for mDAn neurogenesis and neuroprotection, emerge as critical intertwinned actors in mDAn physiopathology, as a decline of an Nrf2/Wnt/β-catenin prosurvival axis with age underlying PD mutations and a variety of noxious environmental exposures drive PD neurodegeneration. Unexpectedly, astrocytes, the so-called “ star-shaped ” cells, harbouring an arsenal of “beneficial” and “harmful” molecules represent the turning point in the physiopathological and therapeutical scenario of PD. Fascinatingly, “ astrocyte's fil rouge” brings back to Nrf2/Wnt resilience, as boosting the Nrf2/Wnt resilience program rejuvenates astrocytes, in turn (i) mitigating nigrostriatal degeneration of aged mice, (ii) reactivating neural stem progenitor cell proliferation and neuron differentiation in the brain and (iii) promoting a beneficial immunomodulation via bidirectional communication with mDAns. Then, through resilience of Nrf2/Wnt/β-catenin anti-ageing, prosurvival and proregenerative molecular programs, it seems possible to boost the inherent endogenous self-repair mechanisms. Here, the cellular and molecular aspects as well as the therapeutical options for rejuvenating glia-neuron dialogue will be discussed together with major glial-derived mechanisms and therapies that will be fundamental to the identification of novel diagnostic tools and treatments for neurodegenerative diseases (NDs), to fight ageing and nigrostriatal DAergic degeneration and promote functional recovery.

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“…Further, individual gene expression analysis suggested that certain genes involved in PD inflammation were upregulated in DJ-1 −/− mice. The Poly(ADP-ribose) polymerase family, member 1 (Parp1) (p = 0.03) and Matrix metallopeptidase-8 (Mmp-8) (p = 0.01) genes which are involved in microglia and astroycytes inflammation [65][66][67] were significantly upregulated in DJ-1 −/− mice in the mid brain regions (Fig. 6d).…”

Section: Increased Inflammatory Genes Related To Pd In Dj-1 −/− Mice mentioning

confidence: 99%

DJ-1 (Park7) affects the gut microbiome, metabolites and the development of innate lymphoid cells (ILCs)

Singh

Trautwein

Dhariwal

et al. 2020

Sci Rep

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The proper communication between gut and brain is pivotal for the maintenance of health and, dysregulation of the gut-brain axis can lead to several clinical disorders. In Parkinson’s disease (PD) 85% of all patients experienced constipation many years before showing any signs of motor phenotypes. For differential diagnosis and preventive treatment, there is an urgent need for the identification of biomarkers indicating early disease stages long before the disease phenotype manifests. DJ-1 is a chaperone protein involved in the protection against PD and genetic mutations in this protein have been shown to cause familial PD. However, how the deficiency of DJ-1 influences the risk of PD remains incompletely understood. In the present study, we provide evidence that DJ-1 is implicated in shaping the gut microbiome including; their metabolite production, inflammation and innate immune cells (ILCs) development. We revealed that deficiency of DJ-1 leads to a significant increase in two specific genera/species, namely Alistipes and Rikenella. In DJ-1 knock-out (DJ-1-/-) mice the production of fecal calprotectin and MCP-1 inflammatory proteins were elevated. Fecal and serum metabolic profile showed that malonate which influences the immune system was significantly more abundant in DJ-1−/− mice. DJ-1 appeared also to be involved in ILCs development. Further, inflammatory genes related to PD were augmented in the midbrain of DJ-1−/− mice. Our data suggest that metabolites and inflammation produced in the gut could be used as biomarkers for PD detection. Perhaps, these metabolites and inflammatory mediators could be involved in triggering inflammation resulting in PD pathology.

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Anti-inflammatory and anti-oxidant mechanisms of an MMP-8 inhibitor in lipoteichoic acid-stimulated rat primary astrocytes: involvement of NF-κB, Nrf2, and PPAR-γ signaling pathways

Cited by 36 publications

References 50 publications

Transcriptomic profiling of microglia and astrocytes throughout aging

Transcriptomic profiling of microglia and astrocytes throughout aging

Nrf2/Wnt resilience orchestrates rejuvenation of glia-neuron dialogue in Parkinson's disease

DJ-1 (Park7) affects the gut microbiome, metabolites and the development of innate lymphoid cells (ILCs)

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