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Recently, there have been studies that examined the relationship between neuroinflammation and anxiety disorder. Herein, we investigated the anxiolytic effect of a well-studied medicinal plant with anti-inflammatory properties, Magnolia obovata, by conducting cellular and animal studies. At the cellular level, the ethanol extract of M. obovata leaves demonstrated inhibitory effects on the production of nitric oxide and inflammatory cytokines and proteins in cultured BV-2 cells. The extract also enhanced GABA-benzodiazepine receptor activity by increasing chloride ion influx in primary cultured neuronal cells. We also examined the anxiolytic effect of the extract in imprinting control region male mice by conducting several behavioral tests. The mice were administered daily oral dose of M. obovata extract (25 mg/kg and 50 mg/kg) for 2 weeks. The extract increased the number of entries and time spent in open arms in the elevated plus maze test and decreased locomotor activity in the spontaneous locomotor activity test, thus implying that the extract ameliorated anxiety levels in mice. Furthermore, we found that the extract inhibited the expression of inflammatory proteins and cytokines and enhanced the expression of GABA-benzodiazepine receptor. These results suggest that the ethanol extract of M. obovata leaves may have an anxiolytic effect through enhancement of the GABAergic system and anti-neuroinflammatory mechanisms., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests., (Copyright © 2020. Published by Elsevier B.V.)

Chitinase 3-like 1 (Chi3L1) plays a major role in the pathogenesis of inflammatory diseases. We investigated the effect of Chi3L1 knockout on stroke development. Ischemia/reperfusion was induced by middle cerebral artery occlusion (MCAO) in Chi3L1 knockout and wildtype mice. Significantly increased infarct volume and decreased neurological deficit scores at 24 h after ischemia/reperfusion were found in Chi3L1 knockout mice compared to wildtype mice. Moreover, ischemic neuronal cell death was increased in Chi3L1 knockout mice through increased oxidative stress and release of IL-6 and IL-1β but IL-10 and IL-4 were reduced. Furthermore, expression of inflammation-related proteins (iNOS, COX-2, Iba-1, and GFAP) was significantly increased in Chi3L1 knockout mice compared to wildtype. In microglia isolated from MCAO-injured Chi3L1 knockout mice, expression of M1 markers (iNOS, CD86, IL-1β, and IL-6) was increased and M2 markers (Arg1, Mrc1, IL-10, and IL-4Ra) was decreased. In BV-2 cells, knockdown of Chi3L1 increased TNF-α- and INF-γ-induced expression of iNOS, COX-2, and Iba-1, but decreased the expression of Arg1, MRC1, and IL-4 receptor-alpha (IL-4Rα). Expression of IL-4Rα, an important factor of M2 polarization, and its downstream signals p-JAK1, p-JAK3, and p-STAT6, was much reduced in the knockout mice. Additionally, in BV-2 cells, knockdown of Chi3L1 by siRNA Chi3L1 decreased rhTNF-α- and INF-γ-induced expression of IL-4Rα, p-JAK1, p-JAK3, and p-STAT6. Furthermore, treatment with AS1517499 abolished Chi3L1 knockdown-induced reduced IL-4Rα and Arg1 but not CD86 expression. Our results indicate that deletion of Chi3L1 accelerates stroke development through enhancement of neuroinflammation by markedly decreasing STAT6-dependent M2 macrophage polarization., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Chitinase 3-like 1 (CHI3L1) is a secreted glycoprotein that mediates inflammation, macrophage polarization, apoptosis, and carcinogenesis. The expression of CHI3L1 is strongly increased by various inflammatory and immunological conditions, including rheumatoid arthritis, multiple sclerosis, Alzheimer's disease, and several cancers. However, its physiological and pathophysiological roles in the development of cancer and neurodegenerative and inflammatory diseases remain unclear. Several studies have reported that CHI3L1 promotes cancer proliferation, inflammatory cytokine production, and microglial activation, and that multiple receptors, such as advanced glycation end product, syndecan-1/αVβ3, and IL-13Rα2, are involved. In addition, the pro-inflammatory action of CHI3L1 may be mediated via the protein kinase B and phosphoinositide-3 signaling pathways and responses to various pro-inflammatory cytokines, including tumor necrosis factor-α, interleukin-1β, interleukin-6, and interferon-γ. Therefore, CHI3L1 could contribute to a vast array of inflammatory diseases. In this article, we review recent findings regarding the roles of CHI3L1 and suggest therapeutic approaches targeting CHI3L1 in the development of cancers, neurodegenerative diseases, and inflammatory diseases., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Multiple sclerosis (MS), also known as disseminated sclerosis or encephalomyelitis disseminate, is an inflammatory disease in which myelin in the spinal cord and brain are damaged. IL-32α is known as a critical molecule in the pathophysiology of immune-mediated chronic inflammatory disease such as rheumatoid arthritis, chronic pulmonary disease, and cancers. However, the role of IL-32α on spinal cord injuries and demyelination is poorly understood. Recently, we reported that the release of proinflammatory cytokines were reduced in IL-32α-overexpressing transgenic mice. In this study, we investigated whether IL-32α plays a role on MS using experimental autoimmune encephalomyelitis (EAE), an experimental mouse model of MS, in human IL-32α Tg mice. The Tg mice were immunized with MOG35-55 suspended in CFA emulsion followed by pertussis toxin, and then EAE paralysis of mice was scored. We observed that the paralytic severity and neuropathology of EAE in IL-32α Tg mice were significantly decreased compared with that of non-Tg mice. The immune cells infiltration, astrocytes/microglials activation, and pro-inflammatory cytokines (IL-1β and IL-6) levels in spinal cord were suppressed in IL-32α Tg mice. Furthermore, NG2 and O4 were decreased in IL-32α Tg mice, indicating that spinal cord damaging was suppressed. In addition, in vitro assay also revealed that IL-32α has a preventive role against Con A stimulation which is evidenced by decrease in T cell proliferation and inflammatory cytokine levels in IL-32α overexpressed Jurkat cell. Taken together, our findings suggested that IL-32α may play a protective role in EAE by suppressing neuroinflammation in spinal cord.

Chronic stress is thought to be a major contributor to the onset of mental disorders such as anxiety disorders. Several studies have demonstrated a correlation between anxiety state and neuroinflammation, but the detailed mechanism is unclear. Chitinase-3-like 1 (CHI3L1) is expressed in several chronic inflammatorily damaged tissues and is well known to play a major role in mediating inflammatory responses. In the present study, we investigated the anxiolytic-like effect of N-Allyl-2-[(6-butyl-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidin-5-yl)sulfanyl]acetamide (G721-0282), an inhibitor of CHI3L1, on mice treated with chronic unpredictable mild stress (CUMS), as well as the mechanism of its action. We examined the anxiolytic-like effect of G721-0282 by conducting several behavioral tests with oral administration of G721-0282 to CUMS-treated BALB/c male mice. We found that administration of G721-0282 relieves CUMS-induced anxiety. Anxiolytic-like effects of G721-0282 have been shown to be associated with decreased expressions of CUMS-induced inflammatory proteins and cytokines in the hippocampus. The CUMS-elevated levels of CHI3L1 and IGFBP3 were inhibited by treatment with G721-0282 in vivo and in vitro. However, CHI3L1 deficiency abolished the anti-inflammatory effects of G721-0282 in microglial BV-2 cells. These results suggest that G721-0282 could lower CUMS-induced anxiety like behaviors by regulating IGFBP3-mediated neuroinflammation via inhibition of CHI3L1. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD) is one of the most prevalent neurodegenerative disorders characterized by gradual memory loss and neuropsychiatric symptoms. We have previously demonstrated that the 2-({3-[2-(1-cyclohexene-1-yl)ethyl]-6,7-dimethoxy-4-oxo-3,4-dihydro-2-quinazolinyl}sulfanyl)-N-(4-ethylphenyl)butanamide (K284-6111), the inhibitor of CHI3L1, has the inhibitory effect on memory impairment in Αβ infusion mouse model and on LPS-induced neuroinflammation in the murine BV-2 microglia and primary cultured astrocyte.Methods: In the present study, we investigated the inhibitory effect of K284-6111 on memory dysfunction and neuroinflammation in Tg2576 transgenic mice, and a more detailed correlation of CHI3L1 and AD. To investigate the effects of K284-6111 on memory dysfunction, we administered K284-6111 (3 mg/kg, p.o.) daily for 4 weeks to Tg2576 mice, followed by behavioral tests of water maze test, probe test, and passive avoidance test.Results: Administration of K284-6111 alleviated memory impairment in Tg2576 mice and had the effect of reducing the accumulation of Aβ and neuroinflammatory responses in the mouse brain. K284-6111 treatment also selectively inactivated ERK and NF-κB pathways, which were activated when CHI3L1 was overexpressed, in the mouse brain and in BV-2 cells. Web-based gene network analysis and our results of gene expression level in BV-2 cells showed that CHI3L1 is closely correlated with PTX3. Our result revealed that knockdown of PTX3 has an inhibitory effect on the production of inflammatory proteins and cytokines, and on the phosphorylation of ERK and IκBα.Conclusion: These results suggest that K284-6111 could improve memory dysfunction by alleviating neuroinflammation through inhibiting CHI3L1 enhancing ERK-dependent PTX3 pathway. [ABSTRACT FROM AUTHOR]

Neuroinflammation is important in the pathogenesis and development of Alzheimer's disease (AD). In the AD brain, microglial activation and upregulation of pro-inflammatory mediators both induce amyloid beta (Aβ) accumulation. Regulatory T cells (Tregs) and nuclear factor-kappa B (NF-κB) signaling have been implicated in AD development through their effects on neuroinflammation and microglial activation. The bee venom soluble phospholipase A2 (bv-sPLA2) enzyme is known to exert anti-inflammatory and anti-immune effects. Here, we investigated the inhibitory effects of bv-sPLA2 on memory deficiency in a lipopolysaccharide (LPS)-induced mouse model of AD. We examined whether bv-sPLA2 (0.02, 0.2, and 2 mg/kg by i.p. injection three times for 1 week) could inhibit neuroinflammation and memory impairment in LPS-treated mice (250 μg/kg by i.p. injection daily for 1 week). We also assessed the effects of bv-sPLA2 administration (0.01, 0.1, and 1 μg/ml) on LPS (1 μg/ml)-treated microglial BV-2 cells. In the LPS-injected mouse brain, sPLA2 treatment rescued memory dysfunction and decreased Aβ levels, through the downregulation of amyloidogenic proteins, and decreased the expression of inflammatory proteins and pro-inflammatory cytokines. Moreover, the LPS-mediated increase in inflammatory protein expression was attenuated bv-sPLA2 treatment in BV-2 cells. Treatment with bv-sPLA2 also downregulated signaling by NF-κB, which is considered to be an important factor in the regulation of neuroinflammatory and amyloidogenic responses, both in vivo and in vitro. Additionally, co-treatment with NF-κB (5 μM) and bv-sPLA2 (0.1 μg/ml) exerted more marked anti-inflammatory effects, compared to bv-sPLA2 treatment alone. These results indicate that bv-sPLA2 inhibits LPS-induced neuroinflammation and amyloidogenesis via inhibition of NF-κB. [ABSTRACT FROM AUTHOR]

Highlights • Aβ infusion induced memory deficit and neuroinflammation in ovariectomized mice. • β-Estradiol treatment prevented Aβ-induced neuroinflammation. • Aβ-induced NF-ĸB activation was inhibited by estrogen treatment. • Estrogen deficiency promoted Alzheimer’s disease pathology via NF-ĸB. Abstract Estrogen is well known to have a preventative effect in Alzheimer’s disease (AD) pathology. Several studies have demonstrated that nuclear factor kappa-B (NF-ĸB) can contribute to the effects of estrogen on the development of AD. We investigated whether NF-ĸB affects amyloid-beta (Aβ)-induced memory impairment in an estrogen-lacking condition. In the present study, nine-week-old Institute cancer research (ICR) mice were ovariectomized to block estrogen stimulation. Ten weeks after the ovariectomization, mice were administered with Aβ (300 pmol) via intracerebroventricular (ICV) infusion for 2 weeks. Memory impairment, neuroinflammatory protein expression, and amyloidogenic pathways were then measured. Ovariectomized mice demonstrated severe memory impairment, Aβ accumulation, neprilysin downregulation, and activation of NF-ĸB signaling compared to sham-control mice. In vitro experiments demonstrated that β-estradiol (10 μM) inhibited Aβ (1 μM)-induced neuroinflammation in microglial BV-2 cells and prevented Aβ-induced cell death in primary cultured neuronal cells. As in in vivo experiments, NF-ĸB activation was significantly upregulated in in vitro experiments. Furthermore β-estradiol treatment inhibited NF-ĸB activation in both of microglial BV-2 cells and cultured neuronal cells. These findings suggest that estrogen may protect against memory impairment through the regulation of Aβ accumulation and neurogenic inflammation by inhibiting NF-κB activity. [ABSTRACT FROM AUTHOR]

Background: Neuroinflammation and accumulation of β-amyloid (Aβ) play a significant role in the onset and progression of Alzheimer's disease (AD). Our previous study demonstrated that signal transducer and activator of transcription-3 (STAT3) plays a major role in neuroinflammation and amyloidogenesis. Methods: In the present study, we investigated the inhibitory effect of bee venom phospholipase A2 (bvPLA2) on memory deficiency in Tg2576 mice, which demonstrate genetic characteristics of AD and the mechanism of its action at the cellular and animal level. For in vivo study, we examined the effect of bvPLA2 on improving memory by conducting several behavioral tests with the administration of bvPLA2 (1 mg/kg) to Tg2576 mice. For in vitro study, we examined the effect of bvPLA2 on amyloidogenesis and neuroinflammation by treating bvPLA2 on LPS-activated BV2 cells. Results: We found that bvPLA2 alleviated memory impairment in Tg2576 mice, as demonstrated in the behavioral tests assessing memory. In the bvPLA2-treated group, Aβ, amyloid precursor protein (APP), and β-secretase 1 (BACE1) levels and β-secretase activity were significantly decreased. Expression of pro-inflammatory cytokines and inflammation-related proteins decreased in the brain of bvPLA2-treated group, whereas anti-inflammatory cytokines increased. In addition, bvPLA2 reduced STAT3 phosphorylation in the brains of the bvPLA2-treated group. At the cellular level, bvPLA2 inhibits production of nitric oxide, pro-inflammatory cytokines, and inflammation-related proteins including p-STAT3. Additionally, bvPLA2 inhibits the production of Aβ in cultured BV-2 cells. Results from the docking experiment, pull-down assay, and the luciferase assay show that bvPLA2 directly binds STAT3 and, thus, regulates gene expression levels. Moreover, when the STAT3 inhibitor and bvPLA2 were administered together, the anti-amyloidogenic and anti-inflammatory effects were further enhanced than when they were administered alone. Conclusion: These results suggest that bvPLA2 could restore memory by inhibiting the accumulation of Aβ and inflammatory responses via blockage of STAT3 activity. [ABSTRACT FROM AUTHOR]

• MMPP enhances the survival rate of LPS-induced liver sepsis mice model. • MMPP reduces the expression of iNOS, COX-2, and secretion of inflammatory cytokines. • MMPP prevents LPS-induced STAT3 phosphorylation. • MMPP alleviates liver sepsis through STAT3 inhibition. Sepsis is a life-threatening disease with limited treatment options, and the inflammatory process represents an important factor affecting its progression. Many studies have demonstrated the critical roles of signal transducer and activator of transcription 3 (STAT3) in sepsis pathophysiology and pro-inflammatory responses. Inhibition of STAT3 activity may therefore represent a promising treatment option for sepsis. We here used a mouse model to demonstrate that (E)-2-methoxy-4-(3-(4-methoxyphenyl)prop-1-en-1-yl)phenol (MMPP) treatment prevented the liver sepsis-related mortality induced by 30 mg/kg lipopolysaccharide (LPS) treatment and reduced LPS-induced increase in alanine transaminase, aspartate transaminase, and lactate dehydrogenase levels, all of which are markers of liver sepsis progression. These recovery effects were associated with decreased LPS-induced STAT3, p65, and JAK1 phosphorylation and proinflammatory cytokine (interleukin 1 beta, interleukin 6, and tumor necrosis factor alpha) level; expression of cyclooxygenase-2 and induced nitric oxide synthase were also reduced by MMPP. In an in vitro study using the normal liver cell line THLE-2, MMPP treatment prevented the LPS-induced increase of STAT3, p65, and JAK1 phosphorylation and inflammatory protein expression in a dose-dependent manner, and this effect was enhanced by combination treatment with MMPP and STAT3 inhibitor. The results clearly indicate that MMPP treatment prevents LPS-induced mortality by inhibiting the inflammatory response via STAT3 activity inhibition. Thus, MMPP represents a novel agent for alleviating LPS-induced liver sepsis. [ABSTRACT FROM AUTHOR]