Melatonin protects against ischemic stroke by modulating microglia/macrophage polarization toward anti‐inflammatory phenotype through STAT3 pathway

Liu, Zongjian; Ran, Yuanyuan; Qie, Shuyan; Gong, Wenrong; Gao, Fuhai; Ding, Zitong; Xi, Jianing

doi:10.1111/cns.13261

Cited by 130 publications

(94 citation statements)

References 43 publications

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“…To further confirm whether candesartan may protect against neuronal death through the regulation of microglial polarization, the neuron-microglia co-culture system was performed as we showed previously. 22 LPS + IFN-γ could stimulate microglia toward M1 polarization. When M1 microglia co-cultured with post-OGD neurons, they significantly exacerbated neuronal death and enhanced LDH release.…”

Section: Candesartan Reduces the Neurotoxic Effect Of M1 Microglia Onmentioning

confidence: 96%

Candesartan modulates microglia activation and polarization via NF-κB signaling pathway

Qie

Ran

et al. 2020

Int J Immunopathol Pharmacol

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Microglia are diverse cells that acquire different functional phenotypes in response to microenvironment in which they reside. Several transcriptional regulators have been identified that regulate different microglia phenotypes. They are mainly stimulated into two opposing phenotypes, classically (M1) and alternatively (M2) phenotype. Regulating microglia polarization from M1 to M2 state has been suggested as a potential therapeutic approach in treatment of CNS disorders. Candesartan, an angiotensin II type I receptors antagonist, exerts beneficial effects for antioxidant, anti-inflammation, neurotrophic, and anti-apoptotic function. However, the effect of candesartan on microglia polarization and underlying mechanisms remain unknown. In this study, the resting microglia were stimulated to M1 microglia with lipopolysaccharide (LPS) and interferon-γ (IFN-γ), and then treated with vehicle or candesartan for 24 h. RT-PCR was utilized to detect the mRNA expression of microglia phenotype markers and inflammatory cytokines. Microglia phenotype markers and toll-like receptor 4 (TLR4)/nuclear factor kappa B (NF-κB) pathway were determined by western blot. A neuron-microglia co-culture system was used to determine whether candesartan could ameliorate the neurotoxic effect of M1 microglia to oxygen-glucose deprivation (OGD) neuron. Candesartan treatment reduced the expression of M1 markers, and increased M2 markers. Meanwhile, candesartan reduced fluorescence intensity and protein level of M1 marker and enhanced M2 marker. Candesartan also regulated the neuroinflammatory response via reducing the release of pro-inflammatory cytokines and increasing anti-inflammatory cytokines in LPS + IFN-γ stimulated BV2 cells. Candesartan markedly inhibited the protein level of TLR4, the phosphorylation of IKBα and p65, and suppressed nuclear translocation of NF-κB p65. BAY 11-7085, a NF-κB inhibitor, remarkably enlarged the inhibitory effect of candesartan on NF-κB pathway. In addition, M1 phenotype microglia exacerbated post-OGD N2a cells death and LDH release, whereas candesartan reversed such neurotoxic effect. Candesartan treatment may ameliorate stroke-induced neuronal damage through shifting microglia to M2 phenotype in a TLR4/NF-κB-dependent manner.

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Section: Candesartan Reduces the Neurotoxic Effect Of M1 Microglia Onmentioning

confidence: 96%

Candesartan modulates microglia activation and polarization via NF-κB signaling pathway

Qie

Ran

et al. 2020

Int J Immunopathol Pharmacol

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“…Once produced, PGH2 is transformed into prostaglandin E2 (PGE2), which is an important neuroinflammatory mediator [116]. Signal transducer and activator of transcription 3 (STAT3) is an important transcription factor in the immune system, participating in many inflammatory responses in CNS [117][118][119]. In this sense, the induction of COX2 would activate the COX2/PGE2/STAT3 pathway, thus contributing to LPS-induced IL-6 production [120].…”

Section: Tlr4 Transcriptional Targetsmentioning

confidence: 99%

Microglia: Agents of the CNS Pro-Inflammatory Response

Rodríguez‐Gómez

Kavanagh

Engskog-Vlachos

et al. 2020

Cells

191

136

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The pro-inflammatory immune response driven by microglia is a key contributor to the pathogenesis of several neurodegenerative diseases. Though the research of microglia spans over a century, the last two decades have increased our understanding exponentially. Here, we discuss the phenotypic transformation from homeostatic microglia towards reactive microglia, initiated by specific ligand binding to pattern recognition receptors including toll-like receptor-4 (TLR4) or triggering receptors expressed on myeloid cells-2 (TREM2), as well as pro-inflammatory signaling pathways triggered such as the caspase-mediated immune response. Additionally, new research disciplines such as epigenetics and immunometabolism have provided us with a more holistic view of how changes in DNA methylation, microRNAs, and the metabolome may influence the pro-inflammatory response. This review aimed to discuss our current knowledge of pro-inflammatory microglia from different angles, including recent research highlights such as the role of exosomes in spreading neuroinflammation and emerging techniques in microglia research including positron emission tomography (PET) scanning and the use of human microglia generated from induced pluripotent stem cells (iPSCs). Finally, we also discuss current thoughts on the impact of pro-inflammatory microglia in neurodegenerative diseases.

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“…On the other hand, melatonin, through the suppression of estrogen receptor alpha [55] regulates the expression of UBC9 [56], another key protein of set 1 that interacts with SARS-CoV N protein [57]. It has also been described that melatonin can lead to the activation of STAT3 in some cell types [58,59], and it could be useful to counteract the STAT3 dephosphorylation induced by SARS-CoV [60].…”

Section: Plos Onementioning

confidence: 99%

In-silico drug repurposing study predicts the combination of pirfenidone and melatonin as a promising candidate therapy to reduce SARS-CoV-2 infection progression and respiratory distress caused by cytokine storm

et al. 2020

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From January 2020, COVID-19 is spreading around the world producing serious respiratory symptoms in infected patients that in some cases can be complicated by the severe acute respiratory syndrome, sepsis and septic shock, multiorgan failure, including acute kidney injury and cardiac injury. Cost and time efficient approaches to reduce the burthen of the disease are needed. To find potential COVID-19 treatments among the whole arsenal of existing drugs, we combined system biology and artificial intelligence-based approaches. The drug combination of pirfenidone and melatonin has been identified as a candidate treatment that may contribute to reduce the virus infection. Starting from different drug targets the effect of the drugs converges on human proteins with a known role in SARS-CoV-2 infection cycle. Simultaneously, GUILDify v2.0 web server has been used as an alternative method to corroborate the effect of pirfenidone and melatonin against the infection of SARS-CoV-2. We have also predicted a potential therapeutic effect of the drug combination over the respiratory associated pathology, thus tackling at the same time two important issues in COVID-19. These evidences, together with the fact that from a medical point of view both drugs are considered safe and can be combined with the current standard of care treatments for COVID-19 makes this combination very attractive for treating patients at stage II, nonsevere symptomatic patients with the presence of virus and those patients who are at risk of developing severe pulmonary complications.

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Melatonin protects against ischemic stroke by modulating microglia/macrophage polarization toward anti‐inflammatory phenotype through STAT3 pathway

Cited by 130 publications

References 43 publications

Candesartan modulates microglia activation and polarization via NF-κB signaling pathway

Candesartan modulates microglia activation and polarization via NF-κB signaling pathway

Microglia: Agents of the CNS Pro-Inflammatory Response

In-silico drug repurposing study predicts the combination of pirfenidone and melatonin as a promising candidate therapy to reduce SARS-CoV-2 infection progression and respiratory distress caused by cytokine storm

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