Melatonin decreases M1 polarization via attenuating mitochondrial oxidative damage depending on UCP2 pathway in prorenin-treated microglia

Hu, Li; Zhang, Shutian; Wen, Haoyu; Liu, Tianfeng; Cai, Jingwen; Du, Dongshu; Zhu, Dawei; Chen, Fuxue; Xia, Chunmei

doi:10.1371/journal.pone.0212138

Cited by 33 publications

(28 citation statements)

References 53 publications

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“…Whilst the decrease in the ATP/ADP ratio and the increase of the NAD + /NADH ratio suggested, respectively, reduced mitochondrial phosphorylating capacity [49] and compensatory increase of the glycolytic rate [50,51], the increase in the NADP + /NADPH ratio seems to be linked to the increase in Nox-2 levels, thus strongly supporting a major role of NADPH-oxidase (Nox-2) as a ROS generator during macrophage activation [52,53].…”

Section: Discussionmentioning

confidence: 96%

Modulation of Pro-Oxidant and Pro-Inflammatory Activities of M1 Macrophages by the Natural Dipeptide Carnosine

Fresta

Fidilio

Lazzarino

et al. 2020

IJMS

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Carnosine is a natural endogenous dipeptide widely distributed in mammalian tissues, existing at particularly high concentrations in the muscles and brain and possesses well-characterized antioxidant and anti-inflammatory activities. In an in vitro model of macrophage activation, induced by lipopolysaccharide + interferon-gamma (LPS + IFN-γ), we here report the ability of carnosine to modulate pro-oxidant and pro-inflammatory activities of macrophages, representing the primary cell type that is activated as a part of the immune response. An ample set of parameters aimed to evaluate cytotoxicity (MTT assay), energy metabolism (HPLC), gene expressions (high-throughput real-time PCR (qRT-PCR)), protein expressions (western blot) and nitric oxide production (qRT-PCR and HPLC), was used to assess the effects of carnosine on activated macrophages challenged with a non cytotoxic LPS (100 ng/mL) + IFN-γ (600 U/mL) concentration. In our experimental model, main carnosine beneficial effects were: (1) the modulation of nitric oxide production and metabolism; (2) the amelioration of the macrophage energy state; (3) the decrease of the expressions of pro-oxidant enzymes (Nox-2, Cox-2) and of the lipid peroxidation product malondialdehyde; (4) the restoration and/or increase of the expressions of antioxidant enzymes (Gpx1, SOD-2 and Cat); (5) the increase of the transforming growth factor-β1 (TGF-β1) and the down-regulation of the expressions of interleukins 1β and 6 (IL-1β and IL-6) and 6) the increase of the expressions of Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and heme oxygenase-1 (HO-1). According to these results carnosine is worth being tested in the treatment of diseases characterized by elevated levels of oxidative stress and inflammation (atherosclerosis, cancer, depression, metabolic syndrome, and neurodegenerative diseases).

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Section: Discussionmentioning

confidence: 96%

Modulation of Pro-Oxidant and Pro-Inflammatory Activities of M1 Macrophages by the Natural Dipeptide Carnosine

Fresta

Fidilio

Lazzarino

et al. 2020

IJMS

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“…Preclinical work suggests that melatonin can reduce microglial alterations in brain regions such as the AMY, hypothalamus, ipsilateral basal cortex, and HIP [139][140][141]. Melatonin can modulate microglia density and morphology as well as phagocytic response to LPS in the HIP both in adulthood [142,143] and in early life [102]. Furthermore, melatonin treatment during gestation has attenuated microglia activation in the HIP as a result of umbilical cord occlusion in early life, and kainic acid administration via intraperitoneal injection in adulthood [144,145].…”

Section: Early Preventative Interventionsmentioning

confidence: 99%

Microglial Function in the Effects of Early-Life Stress on Brain and Behavioral Development

Catale

Gironda

Iacono

et al. 2020

JCM

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The putative effects of early-life stress (ELS) on later behavior and neurobiology have been widely investigated. Recently, microglia have been implicated in mediating some of the effects of ELS on behavior. In this review, findings from preclinical and clinical literature with a specific focus on microglial alterations induced by the exposure to ELS (i.e., exposure to behavioral stressors or environmental agents and infection) are summarized. These studies were utilized to interpret changes in developmental trajectories based on the time at which the stress occurred, as well as the paradigm used. ELS and microglial alterations were found to be associated with a wide array of deficits including cognitive performance, memory, reward processing, and processing of social stimuli. Four general conclusions emerged: (1) ELS interferes with microglial developmental programs, including their proliferation and death and their phagocytic activity; (2) this can affect neuronal and non-neuronal developmental processes, which are dynamic during development and for which microglial activity is instrumental; (3) the effects are extremely dependent on the time point at which the investigation is carried out; and (4) both pre- and postnatal ELS can prime microglial reactivity, indicating a long-lasting alteration, which has been implicated in behavioral abnormalities later in life.

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“…RVLM microglia were isolated as we described previously [13]. Cells were grown in Eagle's minimum essential medium containing 10% heat-inactivated fetal bovine serum (FBS) (Invitrogen, Carlsbad, CA), 100 U/ml of penicillin and 100 μg/ml of streptomycin in a humidified atmosphere of 5% CO2 at 37°C.…”

Section: Microglia Isolations and Ex Vivo Treatmentsmentioning

confidence: 99%

“…Total RNA was isolated from microglia using TRIzol reagent (Invitrogen; Thermo Fisher Scientific, Inc.) according to the manufacturer's instructions. cDNA was transcribed and SYBR-Green-based real time quantitative PCR was performed as we described previously [13].…”

Section: Rna Isolation and Qpcr Analysismentioning

confidence: 99%

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CLOCK-induced upregulated HMGB1 resulting in circadian rhythms disruption of inflammatory microglia contributes to non-dipper hypertension in stressed rats

Zhang

Xia

2020

Preprint

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Increased microglia activation and neuroinflammation within autonomic brain regions have been implicated in stress-induced hypertension (SIH). The circadian clock affects physiological cellular and biological processes, including blood pressure (BP) control, but the mechanisms remain unclear. Microglia possess endogenous timekeeping mechanisms regulate immune responses. Here, we explore whether SIH is associated with disrupted diurnal rhythms in microglia proinflammatory factors (PICs) releasing. We found that SIH exhibit diminished BP circadian rhythms, which showed non-dipper hypertension. Microglia isolated from the rostral ventrolateral medulla (RVLM) of SIH rats had aberrant PICs releasing and CLOCK rhythms, while microglia from control rats exhibited robust rhythms of PICs expression both ex vivo and in vivo. In the RVLM, stress upregulated CLOCK expression which is independent of time of day in comparison with that of control. We further identified that upregulated CLOCK depressed sirt1 expression thereby increased oxidative stress-related HMGB1-PICs releasing in microglia in RVLM of SIH rats. In conclusion, the disrupts intrinsic circadian rhythms of microglia-derived PICs releasing involves in pathogeneses of non-dipper hypertension in stressed rats. Highlights• The aberrant rhythms CLOCK gene induced increased HMGB expression in microglia in the RVLM of stress-induced hypertension rats.• Aberrant CLOCK depressed sirt1 expression, which resulted in oxidative stress initiated inflammatory HMGB1 activation in microglia in RVLM of stress-induced hypertension rats.• The disrupts intrinsic circadian rhythms of microglia-derived inflammatory factor releasing in the RVLM involving in pathogeneses of non-dipper hypertension. Graphical abstractAbnormal CLOCK-sirt1-HMGB1 caused the aberrant circadian rhythms of microglial inflammatory factors releasing contributes to non-dipper hypertension. The disrupted circadian of CLOCK resulted in HMGB1 activation via sirt1-dependent oxidative stress in the RVLM.

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Melatonin decreases M1 polarization via attenuating mitochondrial oxidative damage depending on UCP2 pathway in prorenin-treated microglia

Cited by 33 publications

References 53 publications

Modulation of Pro-Oxidant and Pro-Inflammatory Activities of M1 Macrophages by the Natural Dipeptide Carnosine

Modulation of Pro-Oxidant and Pro-Inflammatory Activities of M1 Macrophages by the Natural Dipeptide Carnosine

Microglial Function in the Effects of Early-Life Stress on Brain and Behavioral Development

CLOCK-induced upregulated HMGB1 resulting in circadian rhythms disruption of inflammatory microglia contributes to non-dipper hypertension in stressed rats

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