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Chronic stress is a major risk factor for various psychiatric diseases, including depression; it triggers various cellular and structural changes, resulting in the alteration of neurocircuitry and subsequent development of depression. Accumulating evidence suggests that microglial cells orchestrate stress-induced depression. Preclinical studies of stress-induced depression revealed microglial inflammatory activation in regions of the brain that regulate mood. Although studies have identified several molecules that trigger inflammatory responses in microglia, the pathways that regulate stress-induced microglial activation remain unclear. Understanding the exact triggers that induce microglial inflammatory activation can help find therapeutic targets in order to treat depression. In the current review, we summarize the recent literature on possible sources of microglial inflammatory activation in animal models of chronic stress-induced depression. In addition, we describe how microglial inflammatory signaling affects neuronal health and causes depressive-like behavior in animal models. Finally, we propose ways to target the microglial inflammatory cascade to treat depressive disorders. [ABSTRACT FROM AUTHOR]

Objectives: This study evaluated the plasma concentration of prolylcarboxypeptidase (PRCP) and its clinical relevance in patients with idiopathic acute optic neuritis (ON). Methods: We investigated the expression of PRCP in the optic nerves of experimental autoimmune optic neuritis (EAON)-induced mice. Peripheral blood samples were collected from ON patients (n = 20) and healthy controls (n = 20). ELISA was used to measure the plasma PRCP levels. We performed measurements of visual acuity and the mean thicknesses of the macular ganglion cell layer plus inner plexiform layer (GCL+IPL) at diagnosis and 6 months after diagnosis. Results: The PRCP mRNA expression in EAON-induced mice was markedly higher than that in naïve mice. The mean plasma PRCP level was significantly higher in patients with ON than in controls. Plasma PRCP levels were negatively correlated with logMAR visual acuity at 6 months after diagnosis and differences in macular GCL+IPL thickness during an ON attack. A plasma PRCP level of 49.98 (pg/mL) predicted the recurrence of ON with a 75% sensitivity and 87.5% specificity. Conclusions: Patients with idiopathic acute ON had higher plasma PRCP levels, and this was positively correlated with final visual outcome and well-preserved macular GCL+IPL thickness during an ON attack. The increase in plasma PRCP level may reflect its compensatory secretion to counteract neuroinflammation in ON patients. [ABSTRACT FROM AUTHOR]

Background and Objective: Long noncoding RNAs (lncRNAs) are crucial in regulating various physiological and pathological processes, including immune responses. LINC01686 is a lncRNA with previously uncharacterized functions in immune regulation. This study aims to investigate the function of LINC01686 in lipopolysaccharide (LPS)‐induced inflammatory responses in the human monocytic leukemia cell line THP‐1 and its potential regulatory mechanisms involving miR‐18a‐5p and the anti‐inflammatory protein A20. Method: THP‐1 cells were stimulated with LPS to induce inflammatory responses, followed by analysis of LINC01686 expression levels. The role of LINC01686 in regulating the expression of interleukin (IL)‐6, IL‐8, A20, and signal transducer and activator of transcription 1 (STAT1) was examined using small interfering RNA‐mediated knockdown. Additionally, the involvement of miR‐18a‐5p in LINC01686‐mediated regulatory pathways was assessed by transfection with decoy RNAs mimicking the miR‐18a‐5p binding sites of LINC01686 or A20 messenger RNA. Results: LINC01686 expression was upregulated in THP‐1 cells following LPS stimulation. Suppression of LINC01686 enhanced LPS‐induced expression of IL‐6 and IL‐8, mediated through increased production of reactive oxygen species. Moreover, LINC01686 knockdown upregulated the expression and activation of IκB‐ζ, STAT1, and downregulated A20 expression. Transfection with decoy RNAs reversed the effects of LINC01686 suppression on A20, STAT1, IL‐6, and IL‐8 expression, highlighting the role of LINC01686 in sponging miR‐18a‐5p and regulating A20 expression. Conclusion: This study provides the first evidence that LINC01686 plays a critical role in modulating LPS‐induced inflammatory responses in THP‐1 cells by sponging miR‐18a‐5p, thereby regulating the expression and activation of A20 and STAT1. These findings shed light on the complex regulatory mechanisms involving lncRNAs in immune responses and offer potential therapeutic targets for inflammatory diseases. [ABSTRACT FROM AUTHOR]

Neuroinflammation is mediated by resident central nervous system glia, neurons, peripherally derived immune cells, blood-brain barrier, and inflammatory mediators secreted from these cells. Neuroinflammation has been implicated in stroke and neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, and amyotrophic lateral sclerosis. Protein kinases have been one of the most exploited therapeutic targets in the current pharmacological research, especially in studies on cancer and inflammation. To date, 32 small-molecule protein kinase inhibitors have been approved by the United States Food and Drug Administration for the treatment of cancer and inflammation. However, there is no drug effectively targeting neuroinflammation and/or neurodegenerative diseases. Recent studies have advanced several protein kinases as important drug targets in neuroinflammation and/or neurodegenerative diseases. Here, we review emerging protein kinases potentially involved in neuroinflammation and subsequent neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

Lipocalin-2 (LCN2) is a member of the secreted lipocalin protein family. LCN2 is also a representative gliocalin that is primarily released by glial cells, as well as acts upon them. Astrocytes are one of the major cellular sources of LCN2 under brain injury conditions. Astrocytes secrete LCN2 to promote neuroinflammation. Studies using Lcn2 knockout animals and cultured neural cells suggest an important role of LCN2 in regulating the development of hemorrhagic and ischemic stroke as well as other brain injuries. The clinical relevance of LCN2 is supported by studies on patients with stroke. Mechanistic studies have revealed that LCN2 is a molecular switch for determining the phenotypic fate of astrocytes under inflammatory conditions. LCN2 gene expression is regulated at the multiple levels; mostly at the transcription level, post-transcription level by microRNAs, and protein level by minor post-translational modification. Recent advances in LCN2 research strongly indicate that astrocytic LCN2 is a promising drug target for the injured brain. Future research should focus on its translational aspects, such as developing small-molecule inhibitors or neutralizing antibodies to target LCN2 for the treatment of brain injury. However, spatiotemporally complex roles of LCN2, which are either beneficial or deleterious, should be considered when targeting LCN2. The potential use of LCN2 as a biomarker for the diagnosis and prognosis of various brain disorders is also discussed. [ABSTRACT FROM AUTHOR]

MARCKS, a substrate of protein kinase C, is involved in various processes associated with cytoskeletal movement. Although the expression of MARCKS is highly induced in macrophages, its role in macrophage function has not been studied in detail. Notably, the suppression of MARCKS expression in macrophage cell lines blocked LPS-induced expression of TNF-α at the transcriptional level. Treatment of macrophages with MARCKS N-terminus sequence (MANS) and effector domain (ED) peptides, which mimic functional domains and block the phosphorylation of MARCKS, suppressed the LPS-induced expression of TNF-α through suppression of p38 and JNK MAPKs and NF-κB. Treatment of mice with MANS peptide reduced serum TNF-α and IL-6 levels and resulted in 40% survival of mice after the administration of a lethal dose of LPS. These data demonstrate that MARCKS is involved in the regulation of proinflammatory cytokine expression in macrophages and that MARCKS-derived peptides can be used to suppress inflammatory responses. [ABSTRACT FROM AUTHOR]

Highlights: [•] LIGHT-mediated signaling was analyzed in human macrophage cell line THP-1. [•] LIGHT triggering induced expression of MMP-9 and IL-8. [•] LIGHT triggering suppressed phagocytic activity of THP-1 cells. [•] ERK/PI3K/NF-κB mediated in the signaling induced by LIGHT. [Copyright &y& Elsevier]

Background: Src homology 2 domain-containing protein tyrosine phosphatase substrate (SHPS)-1 is known to have regulatory effects on myeloid cells. However, its role in macrophage activation is not clearly understood. Methods and results: In order to investigate the role of SHPS-1 in Toll-like receptor (TLR)-mediated activation, human monocytic cell lines were treated with anti-SHPS-1 monoclonal antibody. The triggering of SHPS-1 blocked the expression of IL-8 and TNF-α in cells treated with a TLR4 ligand that induces a signaling pathway involving myeloid differentiation factor 88 (MyD88) and Toll-interleukin-1 receptor (TIR)-domain-containing adapter-inducing interferon-β (TRIF). Interestingly, SHPS-1 inhibited TLR9/MyD88-mediated, but not TLR3/TRIF-mediated, expression of IL-8. Accordingly, a synthetic peptide representing the immunoreceptor tyrosine-based inhibition motif (ITIM) of SHPS-1 suppressed only the MyD88 pathway. Utilization of specific inhibitors and Western blot analysis indicated that the inhibitory effects were mediated by Src homology 2 domain-containing phosphatases (SHPs) and phosphoinositide 3-kinase (PI3K). Conclusion: SHPS-1 negatively regulates the MyD88-dependent TLR signaling pathway through the inhibition of NF-κB activation. [ABSTRACT FROM AUTHOR]

Abstract: Lysosome-associated membrane proteins (LAMPs), a family of highly glycosylated transmembrane proteins, are well known lysosomal markers. Recent investigations revealed the cell surface expression of LAMPs, especially after activation in various cell types. Although their role in lysosome function is under intense investigation, little is known about the function of this cell surface form of LAMPs. To investigate the role of cell surface LAMPs in macrophage activities, the human macrophage-like cell line THP-1 was stimulated with monoclonal antibodies specific to CD107a (LAMP-1) or CD107b (LAMP-2). Stimulation of CD107 enhanced LPS-induced IL-8 secretion and induced adhesion of THP-1 cells to culture plates coated with extracellular matrix proteins such as collagen, fibronectin, and laminin. Utilization of specific inhibitors of signaling adapters and Western blot analysis revealed that extracellular signal-regulated kinase (ERK) mediates the regulatory action of CD107. These results suggest that stimulation of THP-1 cells through CD107 affects macrophage-associated functions such as cytokine secretion and cellular adhesion through activation of ERK. [Copyright &y& Elsevier]

Chemical genetics is a new field of study that employs diverse small-molecule compounds to interrogate specific biological functions. The chemical genetics approach has been recently applied to microglial biology. Microglial cells are the primary immune cells of the brain, and are believed to play a major role in both host defense and tissue repair in the central nervous system. However, excessive microglial activation with overexpression of proinflammatory cytokines and oxidative stress products is linked to the progression of several neurodegenerative diseases. Therefore, suppression of microglial activation and subsequent neuroinflammation may be a potential therapeutic approach against these diseases. From microglia cell-based assays, the natural compound obovatol and several synthetic compounds were identified as inhibitors of microglial activation. They showed strong anti-neuroinflammatory activities in various in vitro and in vivo studies. Nuclear factor-κB and mitogen-activated protein kinase pathways were found to be related to the effects of these compounds on microglia. In particular, based on the affinity purification approach, peroxiredoxin 2 was identified as a microglial target of obovatol. Thus, natural and synthetic compounds are not only important biological tools for the study of microglial physiology and pathology, but they are also attractive candidates for the development of therapeutic drugs against neuroinflammatory and neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

Abstract: Activated monocytes/macrophages are known to release toxic materials. Identification of these materials is important for developing more effective treatments for inflammatory disorders where self attack occurs. We stimulated human monocytes and THP-1 cells with LPS/IFNγ and measured the toxic effects of their conditioned media against differentiated human NT-2 cells. Their cytotoxicity, as measured by LDH release, was reduced by half when their conditioned media was passed through a 3kDa cutoff filter, indicating an equal division between high and low molecular weight materials. When the high molecular weight components tumor necrosis factor-α (TNFα), interleukin-1β (IL-1β), and IL-6 were removed from the conditioned medium by specific antibodies, the toxicity was reduced by 37–38%. When prostaglandin production was blocked by treatment with the COX inhibitors acetylsalicylic acid and ibuprofen, toxicity was reduced by 15–16%. When oxygen free radical production was blocked by the NADPH inhibitor diphenylene iodonium (DPI) the toxicity was reduced by 17–18%. Treatment with the nitric oxide scavenger carboxy-phenyl-tetramethylimidazolineoxyl-oxide, or the NOS inhibitor NG-monomethylene-l-arginine, attenuated the toxicity by about 20%. Removal of released glutamate by glutamate decarboxylase also attenuated the toxicity by 12–13%. In combination, these treatments reduced the toxicity by approximately 50% accounting for the low molecular weight component toxicity. About 10% of the overall toxicity, which was associated with the high molecular weight component, was not identified. Optimal antiinflammatory therapy may require combined suppression of these identified toxin-generating pathways as well as relatively minor pathways yet to be identified. [Copyright &y& Elsevier]

Objectives Neurodegenerative diseases have a prominent inflammatory component. Several synthetic fluorovinyloxyacetamide derivatives were screened by microglia cell-based assay in order to identify novel compounds that inhibit the inflammatory activation of microglia. Methods Microglia cell-based nitric oxide assay was employed to screen the compounds. RT-PCR and ELISA were conducted to evaluate the expression of inflammatory gene expression. Molecular mechanisms were determined by western blot analysis, immunocytochemistry, EMSA, and microglia/neuroblastoma cocultures. Key findings A fluorovinyloxyacetamide compound KT-14480 significantly suppressed nitric oxide production in lipopolysaccharide-stimulated microglia cells. KT-14480 also suppressed the secretion and expression of several inflammatory mediators such as tumour necrosis factor-α, interleukin-1β and inducible nitric oxide synthase. Additional studies showed that these inhibitory effects were accompanied by the suppression of nuclear factor-κB and neuroprotection in the microglia/neuroblastoma coculture. Conclusions Our results indicate that the anti-inflammatory compound KT-14480 may be a novel therapeutic drug candidate against neuroinflammatory diseases. [ABSTRACT FROM AUTHOR]

Abstract: Microglia are brain-resident immune cells playing a pivotal role in the neuroinflammation. Previously, it has been shown that immunostimulation protects microglial cells against nitric oxide toxicity. Herein, we report that heme oxygenase-1 (HO-1) mediates the protective effects of immunostimulation. Pro-inflammatory activation of BV-2 microglial cells with endotoxin lipopolysaccharide (LPS) conferred a protection against various cytotoxic stimuli, whereas anti-inflammatory cytokines such as IL-4 and IL-10 were without effects. The LPS-induced cytoprotection was accompanied by HO-1 induction. The cytoprotective effect of LPS treatment was significantly attenuated by co-treatment with a HO-1 inhibitor, zinc protoporphyrin. Adenoviral expression of HO-1 in microglial cells was similarly cytoprotective, indicating that HO-1 mediates the cytoprotective effects of pro-inflammatory stimulation. Additional experiments revealed the involvement of carbon monoxide (CO) and iron, products of HO-1-mediated heme degradation, in the cytoprotective effect of LPS. Taken together, our results suggest that immunostimulation of microglia with LPS provides cytoprotective effects via HO-1 induction followed by the generation of CO and iron. [Copyright &y& Elsevier]

Hypoxia is one of the important physiological stimuli that are often associated with a variety of pathological states such as ischemia, respiratory diseases, and tumorigenesis. In the central nervous system, hypoxia that is accompanied by cerebral ischemia not only causes neuronal cell injury, but may also induce pathological microglial activation. We have previously shown that hypoxia induces inflammatory activation of cultured microglia and their inducible nitric oxide synthase induction via p38 mitogen-activated protein kinase (MAPK) pathway, and a neuropeptide PACAP selectively inhibits microglial signal transduction. Based on these findings, we hypothesized that the neuropeptide may inhibit the hypoxic activation of microglia, and this may provide a neuroprotection against inflammation-induced neuronal injury. When this possibility was tested using cultured microglia and PC12 cells, we found that PACAP attenuates inflammatory activation of microglia under hypoxic condition, and protects cocultured PC12 cells from microglial neurotoxicity. In addition, the neuropeptide reduced the hypoxia-induced activation of p38 MAPK, indicating that the p38 MAPK is a molecular target of the PACAP action in microglia. The neuroprotective effects of PACAP in animal models of cerebral hypoxia/ischemia may be partly due to its direct actions on brain microglia and neurotoxic inflammation. [Copyright &y& Elsevier]

Hypoxia is one of the important physiological stimuli that are often associated with a variety of pathological states such as ischemia, respiratory diseases, and tumorigenesis. In the central nervous system, hypoxia that is accompanied by cerebral ischemia not only causes neuronal cell injury, but may also induce pathological microglial activation. We have previously shown that hypoxia induces inflammatory activation of cultured microglia, and the hypoxic induction of nitric oxide production in microglia is mediated through p38 mitogen-activated protein kinase pathway. Now, we present evidence that minocycline, a tetracycline derivative, suppresses the hypoxic activation of cultured microglia by inhibiting p38 mitogen-activated protein kinase pathway. The drug markedly inhibited hypoxia-induced production of inflammatory mediators such as nitric oxide, TNFα, and IL-1β as well as iNOS protein expression. The signal transduction pathway that leads to the activation of p38 mitogen-activated protein kinase was the molecular target of minocycline. Thus, the known neuroprotective effects of minocycline in animal models of cerebral ischemia may be partly due to its direct actions on brain microglia. [Copyright &y& Elsevier]

In traditional Oriental medicine, Uncaria rhynchophylla has been used to lower blood pressure and to relieve various neurological symptoms. However, scientific evidence related to its effectiveness or precise modes of action has not been available. Thus, in the current study, we evaluated neuroprotective effects of U. rhynchophylla after transient global ischemia using 4-vessel occlusion model in rats. Methanol extract of U. rhynchophylla administered intraperitoneally (100–1000 mg/kg at 0 and 90 min after reperfusion) significantly protected hippocampal CA1 neurons against 10 min transient forebrain ischemia. Measurement of neuronal cell density in CA1 region at 7 days after ischemia by Nissl staining revealed more than 70% protection in U. rhynchophylla-treated rats compared to saline-treated animals. In U. rhynchophylla-treated animals, induction of cyclooxygenase-2 in hippocampus at 24 hr after ischemia was significantly inhibited at both mRNA and protein levels. Furthermore, U. rhynchophylla extract inhibited TNF-α and nitric oxide production in BV-2 mouse microglial cells in vitro. These anti-inflammatory actions of U. rhynchophylla extract may contribute to its neuroprotective effects. [Copyright &y& Elsevier]

We have previously shown that rat astrocytes undergo apoptosis upon inflammatory activation. Nitric oxide (NO) produced by activated astrocytes was the major cytotoxic mediator in this type of autoregulatory apoptosis. However, an inhibitor of nitric oxide synthase did not completely block the apoptosis of activated astrocytes, suggesting the presence of other apoptotic pathways. Here, we present evidence that caspase-11 is an essential molecule in NO-independent apoptotic pathway of activated astrocytes. Inflammatory activation (lipopolysaccharide, interferon-γ, and tumor necrosis factor-α treatment) of rat astrocyte cultures and C6 glioma cells led to the induction of caspase-11 followed by activation of caspases-11, -1, and -3. In contrast, NO donors induced activation of caspase-3 only. Inactivation of caspase-11 by the transfection of dominant negative mutant or treatment with the caspase inhibitors rendered the astrocytes partially resistant to the apoptosis following inflammatory activation, but not NO donor exposure. These results indicate that inflammatory stimuli not only induce the production of cytotoxic NO, but also␣initiate NO-independent apoptotic pathway through the induction of caspase-11 expression. [ABSTRACT FROM AUTHOR]

The study by Kim and colleagues (in press) demonstrated that the expression of nuclear isoform of clusterin is induced by ethanol (EtOH) to participate in apoptotic cell death of neurons in developing rodent brain. EtOH-induced nuclear clusterin interacts with BclXL, thereby liberating proapoptotic Bax. This study indicates the proapoptotic role of nuclear clusterin in EtOH-exposed neurons, linking specific nuclear events to alcohol neurotoxicity. The study provides novel insights into the molecular mechanisms underlying fetal alcohol spectrum disorders. [ABSTRACT FROM AUTHOR]

Over the past century, molecular biology's focus has transitioned from proteins to DNA, and now to RNA. Once considered merely a genetic information carrier, RNA is now recognized as both a vital element in early cellular life and a regulator in complex organisms. Long noncoding RNAs (lncRNAs), which are over 200 bases long but do not code for proteins, play roles in gene expression regulation and signal transduction by inducing epigenetic changes or interacting with various proteins and RNAs. These interactions exhibit a range of functions in various cell types, including macrophages. Notably, some macrophage lncRNAs influence the activation of NF-κB, a crucial transcription factor governing immune and inflammatory responses. Macrophage NF-κB is instrumental in the progression of various pathological conditions including sepsis, atherosclerosis, cancer, autoimmune disorders, and hypersensitivity. It orchestrates gene expression related to immune responses, inflammation, cell survival, and proliferation. Consequently, its malfunction is a key contributor to the onset and development of these diseases. This review aims to summarize the function of lncRNAs in regulating NF-κB activity in macrophage activation and inflammation, with a particular emphasis on their relevance to human diseases and their potential as therapeutic targets. The insights gained from studies on macrophage lncRNAs, as discussed in this review, could provide valuable knowledge for the development of treatments for various pathological conditions involving macrophages. [ABSTRACT FROM AUTHOR]

Mitochondria affect cellular functions alone or in cooperation with other cellular organelles. Recent research has demonstrated the close relationship of mitochondria with the endoplasmic reticulum (ER), both at the physical and the functional level. In an effort to define the combined effect of mitochondrial dysfunction (MD) and ER stress in the proinflammatory activities of macrophages, the human macrophage-like monocytic leukemia cell line THP-1 was treated with mitochondrial electron transport chain (ETC) blockers, and changes in the cellular responses upon stimulation by interferon (IFN)-γ were analyzed. Inducing mitochondrial dysfunction (MD) with ETC blockers resulted in suppression of IFN-induced activation of JAK1 and STAT1/3, as well as the expression of STAT1-regulated genes. In addition, experiments utilizing pharmacological modulators of adenosine 5′-monophosphate (AMP)-activated protein kinase (AMPK) and liver kinase B1 (LKB1)-deficient HeLa cells demonstrated that these suppressive effects are mediated by the LKB1–AMPK pathway. Treatment with pharmacological inhibitors of ER stress sensors failed to affect these processes, thus indicating that involvement of ER stress is not required. These results indicate that MD, induced by blocking the ETC, affects IFN-induced activation of JAK–STAT and associated inflammatory changes in THP-1 cells through the LKB1–AMPK pathway independently of ER stress. [ABSTRACT FROM AUTHOR]

Objective To evaluate the combined effects of a decompressive craniectomy and prolonged selective brain hypothermia on large hemispheric infarction in a rat model. Methods Permanent middle cerebral artery infarction using an endovascular occlusion technique was created in rats assigned to 4 groups. Normothermia was maintained without a craniectomy in group A (n = 20) as the control, prolonged (>44 hours), selective brain hypothermic treatment was performed on group B (n = 20), a craniectomy was performed on group C (n = 18), and prolonged, selective brain hypothermic treatment using a cooling coil implanted in the craniectomy site was combined with a craniectomy for group D (n = 18). Results Group B and C exhibited a significantly reduced infarct volume when compared with the control. Furthermore, group D showed a significantly reduced infarct volume when compared with group C, plus a significantly improved neurologic score. These results for group D were associated with an increased neuronal cell count and reduced hyperactive microglia and hypertrophic astrocytes in the cortical penumbra (P < 0.01). Moreover, a greater preservation of normal-appearing axonal bundles and the blood–brain barrier was observed in the core infarct region at the caudoputamen. Conclusions A decompressive craniectomy reduced the infarct volume and improved the neurologic outcomes in a rat model of middle cerebral artery infarction. Furthermore, when combined with prolonged selective brain hypothermia, significant additional benefits were observed for the neurologic outcomes, infarct volume, and degree of neuroinflammation. Highlights • Selective brain hypothermia was combined with a craniectomy in a rat model of pMCAO. • The combined treatment reduced the infarct volume. • The combined treatment also improved the neurologic outcomes. • It was associated with the survival of at-risk neurons in the ischemic penumbra. • Neuroinflammation was reduced in the ischemic penumbra. [ABSTRACT FROM AUTHOR]

Preclinical studies have suggested that chronic inflammation in the brain might be associated with multiple metabolic disorders, including obesity and diabetes. In particular, hypothalamic inflammation interferes with the endocrine system and modulates nutritional homeostasis, leading to metabolic alterations and consequent pathologies. With regard to the mechanisms underlying molecular and cellular pathogenesis, neurons, non-neuronal cells, and the crosstalk between them have gained particular attention. Specifically, malfunctioning glia have recently been implicated as an important component of pathological hypothalamic inflammation. Hypothalamic inflammation modulates food intake, energy expenditure, insulin secretion, hepatic glucose production, and glucose and fatty acid metabolism. Moreover, growing evidence suggests that hypothalamic inflammation is intrinsically associated with the pathogenesis of obesity, diabetes, and their dysfunctional consequences. However, the translational significance of hypothalamic inflammation has not yet been fully explored. In this review, we cover recent advances suggesting that hypothalamic inflammation and glia play a central role in the ontology of obesity, diabetes, and their complications. Finally, we explore the possibilities and challenges of targeting hypothalamic inflammation as a potential therapeutic strategy. [ABSTRACT FROM AUTHOR]

This study investigated the therapeutic effects of transplanting human mesenchymal stem cells (hMSCs) into wild-type mice that were intraperitoneally administered cytosine arabinoside (Ara-C) to develop cerebellar ataxia (CA) during the first three postnatal days. hMSCs were intrathecally injected into 10-week-old mice once or thrice at 4-week intervals. Compared to the nontreated mice, the hMSC-treated mice showed improved motor and balance coordination, as measured using the rotarod, open-field, and ataxic scoring assessments, and increased protein levels in Purkinje and cerebellar granule cells, as measured using calbindin and NeuN protein markers. Multiple hMSC injections preserved Ara-C-induced cerebellar neuronal loss and improved cerebellar weight. Furthermore, the hMSC implantation significantly elevated the levels of neurotrophic factors, including brain-derived and glial cell line-derived neurotrophic factors, and suppressed TNF-α-, IL-1β-, and iNOS-mediated proinflammatory responses. Collectively, our results demonstrate that hMSCs exhibit therapeutic potential for Ara-C-induced CA by protecting neurons through the stimulation of neurotrophic factors and inhibition of cerebellar inflammatory responses, which can improve motor behavior and alleviate ataxia-related neuropathology. In summary, this study suggests that hMSC administration, particularly multiple treatments, can effectively treat ataxia-related symptoms with cerebellar toxicity. [ABSTRACT FROM AUTHOR]

Sodium azide (NaN 3 ) is a chemical compound with multiple toxic effects on vascular and neuronal systems, causing hypotension and neurotoxicity, respectively. In order to test its effects on the immune system, human and mouse macrophage-like cell lines were treated with nontoxic doses of NaN 3 and the changes in LPS-induced inflammatory activation was measured. Interestingly, the LPS-induced expression of monocyte chemoattractant protein (MCP)-1 was suppressed by NaN 3 without affecting the expression of IL-8 and TNF-α. Further analysis of cellular signaling mediators involved in the expression of these cytokines revealed that NaN 3 suppressed the LPS-induced activation of signal transducers and activator of transcription (STAT)1 and inhibitor of κB (IκB) ς, which are involved in the LPS-induced expression of MCP-1, while the LPS-induced activation of nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) was not affected. The LPS-induced expression of MCP-2 and CXCL10, which are also regulated by STAT1, was suppressed by NaN 3 . Similarly, the LPS-induced expression of IL-6, which is regulated by IκBζ, was suppressed by NaN 3 . These results demonstrate that NaN 3 selectively suppresses the LPS-induced expression of pro-inflammatory mediators through the suppression of STAT1 and IκBζ activation. These new findings about the activity of NaN 3 may contribute to the development of specific regulators of macrophage activity during acute and chronic inflammation. [ABSTRACT FROM AUTHOR]

Emerging evidence indicates that there is a complex interplay between metabolism and chronic disorders in the nervous system. In particular, the pyruvate dehydrogenase (PDH) kinase (PDK)–lactic acid axis is a critical link that connects metabolic reprogramming and the pathophysiology of neurological disorders. PDKs, via regulation of PDH complex activity, orchestrate the conversion of pyruvate either aerobically to acetyl-CoA, or anaerobically to lactate. The kinases are also involved in neurometabolic dysregulation under pathological conditions. Lactate, an energy substrate for neurons, is also a recently acknowledged signaling molecule involved in neuronal plasticity, neuron–glia interactions, neuroimmune communication, and nociception. More recently, the PDK–lactic acid axis has been recognized to modulate neuronal and glial phenotypes and activities, contributing to the pathophysiologies of diverse neurological disorders. This review covers the recent advances that implicate the PDK–lactic acid axis as a novel linker of metabolism and diverse neuropathophysiologies. We finally explore the possibilities of employing the PDK–lactic acid axis and its downstream mediators as putative future therapeutic strategies aimed at prevention or treatment of neurological disorders. [ABSTRACT FROM AUTHOR]

Glial cells are the most abundant cells of the brain, outnumbering neurons. These multifunctional cells are crucial for maintaining brain homeostasis by providing trophic and nutritional support to neurons, sculpting synapses, and providing an immune defense. Glia are highly plastic and undergo both structural and functional alterations in response to changes in the brain microenvironment. Glial phenotypes are intimately regulated by underlying metabolic machinery, which dictates the effector functions of these cells. Altered brain energy metabolism and chronic neuroinflammation are common features of several neurodegenerative diseases. Microglia and astrocytes are the major glial cells fueling the ongoing neuroinflammatory process, exacerbating neurodegeneration. Distinct metabolic perturbations in microglia and astrocytes, including altered carbohydrate, lipid, and amino acid metabolism have been documented in neurodegenerative diseases. These disturbances aggravate the neurodegenerative process by potentiating the inflammatory activation of glial cells. This review covers the recent advances in the molecular aspects of glial metabolic changes in the pathophysiology of neurodegenerative diseases. Finally, we discuss studies exploiting glial metabolism as a potential therapeutic avenue in neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

Recent studies have suggested that mouse cathelicidin-related antimicrobial peptide (CRAMP) and its human homologue leucine leucine-37 (LL-37) play critical roles in innate immune responses. Here, we studied the role of mouse CRAMP in bacterial endotoxin lipopolysaccharide (LPS)-induced neuroinflammation. CRAMP peptide treatment significantly inhibited LPS-mediated inflammatory activation of glial cells in culture. In the animal model of LPS-induced neuroinflammation, CRAMP expression was highly induced in multiple cell types, such as astrocytes, microglia, and neurons. Injection of exogenous CRAMP peptide significantly inhibited inflammatory cytokine expression and the reactivity of glial cells in the mouse brain following intraperitoneal or intracerebroventricular LPS administration. Altogether, results of the study suggest that CRAMP plays an important part in containment of LPS-induced neuroinflammatory responses, and that CRAMP can be exploited for the development of targeted therapies for neuroinflammatory conditions associated with bacterial infection. [ABSTRACT FROM AUTHOR]

Targeting kinases, such as receptor-interacting serine/threonine-protein kinase 1 (RIPK1), with small-molecule inhibitors is a promising strategy for treating neuroinflammatory diseases [[7]]. The study also showed that RIPK1 inhibition exerted anti-inflammatory effects primarily by modulating the AMPK, PI3K/Akt, MAPKs, and NF- B pathways in LPS-stimulated BV-2 mouse microglia cells. It is now well established that glial cells play an equal, if not greater, role in regulating intricate functions of the central nervous system (CNS) compared with neurons [[1]]. The review presents a comprehensive analysis of current research on the potential relationship between microglia-mediated neuroinflammation and stress-induced depression. [Extracted from the article]

Purpose: Hydrogen sulfide (H2S) plays important roles in brain pathophysiology. However, nuclear imaging probes for the in vivo detection of brain H2S in living animals have not been developed. Here, we report the first nuclear imaging probe that enables in vivo imaging of endogenous H2S in the brain of live mice. Methods: Utilizing a bis(thiosemicarbazone) backbone, a fluorescent ATSM-FITC conjugate was synthesized. Its copper complex, Cu(ATSM-FITC) was thoroughly tested as a biosensor for H2S. The same ATSM-FITC ligand was quantitatively labeled with [64Cu]CuCl2 to obtain a radioactive [64Cu][Cu(ATSM-FITC)] imaging probe. Biodistribution and positron emission tomography (PET) imaging studies were performed in healthy mice and neuroinflammation models. Results: The Cu(ATSM-FITC) complex reacts instantly with H2S to release CuS and becomes fluorescent. It showed excellent reactivity, sensitivity, and selectivity to H2S. Endogenous H2S levels in living cells were successfully detected by fluorescence microscopy. Exceptionally high brain uptake of [64Cu][Cu(ATSM-FITC)] (> 9% ID/g) was observed in biodistribution and PET imaging studies. Subtle changes in brain H2S concentrations in live mice were accurately detected by quantitative PET imaging. Due to its dual modality feature, increased H2S levels in neuroinflammation models were characterized at the subcellular level by fluorescence imaging and at the whole-body scale by PET imaging. Conclusion: Our biosensor can be readily utilized to study brain H2S function in live animal models and shows great potential as a novel imaging agent for diagnosing brain diseases. [ABSTRACT FROM AUTHOR]

This study investigated the potential immunomodulatory effects of fermented soybean extract (FSE) in RAW264.7 cells and BALB/c mice. The expression of proinflammatory cytokines in RAW264.7 cells was measured after LPS stimulation in the presence or absence of FSE. Mice were orally administered 125, 250, and 500 mg/kg FSE for 21 days, and their immune response was analyzed. In RAW264.7 cells, FSE significantly reduced the expression of proinflammatory cytokines. In vivo experiments revealed significantly elevated splenocyte proliferation; neutrophil migration; phagocytic activities; expression of CD18+, CD4+, and CD8+ T cells; and expression of IL-2, IL-4, and IFN-γ. The major compounds in FSE were identified by GC–MS and by LC–MS/MS. Molecular docking analysis showed that daidzin, genistin and daidzein could potentially bind to the human high-affinity FcγRI–IgG complex to be involved in immunological responses. Taken together, FSE can be a candidate ingredient for health functional food with enhanced immunomodulating ability. [ABSTRACT FROM AUTHOR]

Recent neuroscience research has established the adult brain as a dynamic organ having a unique ability to undergo changes with time. Neuroglia, especially microglia and astrocytes, provide dynamicity to the brain. Activation of these glial cells is a major component of the neuroinflammatory responses underlying brain injury and neurodegeneration. Glial cells execute functional reaction programs in response to diverse microenvironmental signals manifested by neuropathological conditions. Activated microglia exist along a continuum of two functional states of polarization namely M1-type (classical/proinflammatory activation) and M2-type (alternative/anti-inflammatory activation) as in macrophages. The balance between classically and alternatively activated microglial phenotypes influences disease progression in the CNS. The classically activated state of microglia drives the neuroinflammatory response and mediates the detrimental effects on neurons, whereas in their alternative activation state, which is apparently a beneficial activation state, the microglia play a crucial role in tissue maintenance and repair. Likewise, in response to immune or inflammatory microenvironments astrocytes also adopt neurotoxic or neuroprotective phenotypes. Reactive astrocytes exhibit two distinctive functional phenotypes defined by pro- or anti-inflammatory gene expression profile. In this review, we have thoroughly covered recent advances in the understanding of the functional polarization of brain and peripheral glia and its implications in neuroinflammation and neurological disorders. The identifiable phenotypes adopted by neuroglia in response to specific insult or injury can be exploited as promising diagnostic markers of neuroinflammatory diseases. Furthermore, harnessing the beneficial effects of the polarized glia could undoubtedly pave the way for the formulation of novel glia-based therapeutic strategies for diverse neurological disorders. [ABSTRACT FROM AUTHOR]

Long intergenic non-coding RNA 346 (LINC00346) has been reported to be involved in the development of atherosclerosis and specific cancers by affecting signaling pathways. However, its function in inflammation has not been thoroughly studied. Therefore, its expression pattern and function were determined in the human macrophage-like cell line THP-1. Lipopolysaccharide (LPS) treatment induced the expression of LINC00346. LPS-induced NF-κB activation and proinflammatory cytokine expression were suppressed or enhanced by the overexpression or knockdown of LINC00346, respectively. Analyses using dual luciferase assay and decoy RNAs that could block RNA–RNA interactions indicated that LINC00346 improves phosphatase and tensin homolog (PTEN) expression by sponging miR-25–3p. Subsequently, PTEN suppresses phosphoinositide-3 kinase (PI3K)-mediated conversion of phosphatidylinositol-4,5-bisphosphate (PIP 2) into phosphatidylinositol-3,4,5-trisphosphate (PIP 3) as well as consequent activation of protein kinase B (AKT) and NF-κB. Interestingly, database analysis revealed that the expression levels of LINC00346 and PTEN were simultaneously decreased in breast cancer tissues. Further analyses conducted using a breast cancer cell line, MDA-MB-231, confirmed the functional relationship among LINC00346, miR-25–3p, and PTEN in LPS-induced activation of NF-κB. These results indicate that miR-25-3p-sponging activity of LINC00346 affects the balance between PTEN and PI3K as well as the downstream activation of AKT/NF-κB pathway in inflammatory conditions. LINC00346 governs NF-κB activation and cytokine expression induced by LPS in THP-1 cells.Serving as a miR-25–3p decoy, LINC00346 fosters PTEN and suppresses the PI3K/AKT/NF-κB pathway.The LINC00346/miR-25–3p/PTEN axis finds validation in breast cancer database analysis and breast cancer cell lines. [Display omitted] • The role of LINC00346 in inflammation was tested in THP-1 cells. • LINC00346, as an miR-25–3p sponge, regulate PTEN/PI3K/AKT/NF-κB pathway. • LINC00346 activity was confirmed in breast cancer tissues through database analysis. • LINC00346 activity was also confirmed in the MDA-MB-231 breast cancer cell line. [ABSTRACT FROM AUTHOR]

This study aimed to evaluate the correlation between plasma lipocalin-2 (LCN2) levels and myelin oligodendrocyte glycoprotein (MOG)-immunoglobulin G (IgG) seropositivity in patients with optic neuritis. Peripheral blood samples were collected from 19 patients with optic neuritis and 20 healthy controls. Plasma LCN2 and MOG-IgG levels were measured using enzyme-linked immunosorbent assay and a cell-based assay, respectively. The correlation between plasma LCN2 levels and MOG-IgG titers in patients with optic neuritis was analyzed. Receiver operating characteristic (ROC) curves were constructed to assess and compare the ability of plasma LCN2 and MOG-IgG levels for predicting optic neuritis recurrence. Patients with MOG-IgG–positive optic neuritis had significantly higher mean plasma LCN2 levels than controls and patients with MOG-IgG–negative optic neuritis (p = 0.037). Plasma LCN2 and MOG-IgG levels were significantly correlated in patients with optic neuritis (r = 0.553, p = 0.0141). There were no significant differences in the areas under the ROC curve (AUC) of plasma LCN2 (0.693, 95% confidence interval [CI] 0.443–0.880, p = 0.133) and MOG-IgG (0.641, 95% CI, 0.400–0.840, p = 0.298) levels (95% CI, −0.266–0.448, p = 0.618). Plasma LCN2 levels may aid differentiation of MOG-IgG–positive optic neuritis from MOG-IgG–negative optic neuritis. [ABSTRACT FROM AUTHOR]

Lymphotoxin-beta receptor (LTβR), a receptor for LIGHT and LTα 1 β 2 , is expressed on the epithelial, stromal, and myeloid cells. LTβR is known to affect the lymphoid organ development and immune homeostasis. However, its role in macrophage function has not been sufficiently elucidated. The effect of LTβR stimulation in the inflammatory activation of macrophages was investigated by treating the human macrophage-like cell line THP-1 with LTβR-specific monoclonal antibody. Interestingly, combined treatment with anti-LTβR antibody and LPS caused the synergistic induction of IL-8 expression at the transcriptional level. Analysis indicated that nuclear factor (NF)-κB activity was enhanced via the mitogen-activated protein kinase (MAPK) and glycogen synthase kinase (GSK)-3β/cAMP response element binding protein (CREB) pathways. In addition, LTβR stimulation induced the expression of interferon regulatory factor (IRF)-1, one of the major transcription factors of IL-8 gene. Down-regulation of IRF-1 expression reduced the enhancing effect caused by LTβR stimulation. This indicates that the LTβR stimulation enhances the LPS-induced expression of IL-8 via the combined action of NF-κB and IRF-1. [ABSTRACT FROM AUTHOR]

Fascin is a well-known cytoskeletal regulatory protein that, as a substrate of protein kinase C (PKC), is involved in PKC-mediated translational regulation of TNF-α in macrophages stimulated with lipopolysaccharide (LPS). The regulatory effects of fascin targeted the 3′-untraslated region (UTR) of the TNF-α mRNA, and suppression of PKC activity or fascin expression resulted in specific blockage of the LPS-induced translational activation of the mRNA. In an effort to identify the molecular mechanism of this fascin-mediated translational regulation, the expression levels of micro-RNA (miRNA) after stimulation of the toll-like receptor 4 (TLR4) signaling pathways were analyzed in cells with down-regulation of fascin. The LPS-induced translation of TNF-α is known to be regulated by miR-155 and miR-125b, which have positive and negative effects, respectively. Interestingly, suppression of fascin expression reversed LPS-induced down-regulation of miR-125b and abolished the LPS-induced increase in miR-155. Furthermore, introduction of miR-155 precursor, blocking of miR-125b activity, or introduction of a mutation into the miR-125b binding site of the TNF-α 3′-UTR restored translational activation in cells with suppressed fascin expression. These data indicate that fascin regulates translation through miR-155 and miR-125b, which target 3′ UTR in TNF-α mRNA. [ABSTRACT FROM AUTHOR]

The hypothalamus is a critical brain region for the regulation of energy homeostasis. Over the years, studies on energy metabolism primarily focused on the neuronal component of the hypothalamus. Studies have recently uncovered the vital role of glial cells as an additional player in energy balance regulation. However, their inflammatory activation under metabolic stress condition contributes to various metabolic diseases. The recruitment of monocytes and macrophages in the hypothalamus helps sustain such inflammation and worsens the disease state. Neurons were found to actively participate in hypothalamic inflammatory response by transmitting signals to the surrounding non-neuronal cells. This activation of different cell types in the hypothalamus leads to chronic, low-grade inflammation, impairing energy balance and contributing to defective feeding habits, thermogenesis, and insulin and leptin signaling, eventually leading to metabolic disorders (i.e., diabetes, obesity, and hypertension). The hypothalamus is also responsible for the causation of systemic aging under metabolic stress. A better understanding of the multiple factors contributing to hypothalamic inflammation, the role of the different hypothalamic cells, and their crosstalks may help identify new therapeutic targets. In this review, we focus on the role of glial cells in establishing a cause–effect relationship between hypothalamic inflammation and the development of metabolic diseases. We also cover the role of other cell types and discuss the possibilities and challenges of targeting hypothalamic inflammation as a valid therapeutic approach. [ABSTRACT FROM AUTHOR]

Increasing evidence supports that inflammation is closely associated with the development of cancer. In an effort to develop synthetic peptides that can suppress the inflammatory activation of cancer cells, decapeptides representing immunoreceptor tyrosine-based inhibitory motif (ITIM)-like sequences of immune receptor expressed on myeloid cells-1 (IREM-1) were tested for their anti-inflammatory effects in cancer cell lines. One (named TAT-YADL) out of the five synthetic peptides tested exhibited inhibitory effects on the expression of inflammatory mediators as well as invasion and migration. The inhibitory activities of the synthetic peptides required activation of SH2-containing protein tyrosine phosphatase-1 (SHP-1) and phosphoinositide 3-kinase (PI3K). [ABSTRACT FROM AUTHOR]

Summary CD300a, a membrane protein expressed on myeloid lineages and specific subsets of CD4+ T cells, has been reported to have inhibitory activities in cellular activation. However, the role of CD300a in Toll-like receptor (TLR) -mediated macrophage activation has not been investigated. The human monocytic cell lines THP-1 and U937 were stimulated with various TLR ligands after triggering of CD300a with specific monoclonal antibody. Interestingly, CD300a blocked TLR4-mediated and TLR9-mediated expression of pro-inflammatory mediators without affecting TLR3-mediated events. In contrast, CD300f, another member of the CD300 family, blocked the activation of cells induced by all TLR ligands. A transient transfection assay using luciferase reporter gene under the regulation of nuclear factor-κB binding sites indicated that co-transfection of CD300f blocked reporter expression induced by over-expression of both myeloid differentiation factor 88 (MyD88) and toll-interleukin 1 receptor-domain-containing adapter-inducing interferon-β (TRIF), whereas CD300a blocked only MyD88-induced events. Synthetic peptides representing immunoreceptor tyrosine-based inhibitory motifs of CD300a or CD300f mimicked the differential inhibition patterns of their original molecules. The use of various signalling inhibitors and Western blotting analysis revealed that TLR9/MyD88-mediated signalling was regulated mainly by SH2-containing tyrosine phosphatase 1 (SHP-1), which could be activated by CD300a or CD300f. In contrast, regulation of the TLR3/TRIF-mediated pathway required the combined action of SHP-1 and SHP-2, which could be accomplished by CD300f but not CD300a. These data indicate that CD300a and CD300f regulate the MyD88 and TRIF-mediated TLR signalling pathways through differential activation of SHP-1 and SHP-2. [ABSTRACT FROM AUTHOR]

FasL is a member of the tumor necrosis factor (TNF) superfamily involved in the various immune reactions such as activation-induced cell death, cytotoxic effector function, and establishment of immune privileged sites through its interaction with Fas. On the other hand, FasL is known to transmit a reverse signal that serves as a T cell co-stimulatory signal. However, the role of FasL-mediated reverse signaling in macrophage function has not been investigated. In order to investigate the presence of FasL-mediated signaling in macrophages, the human macrophage-like cell line THP-1 was analyzed after treatment with FasL ligating agents such as recombinant Fas:Fc fusion protein or anti-FasL monoclonal antibody. Stimulation of FasL induced the expression of proinflammatory mediators such as matrix metalloproteinase-9, TNF-α, and IL-8. The specificity of the reaction was confirmed by the transfection of the FasL-specific siRNAs, which suppressed FasL expression as well as the production of proinflammatory mediators. Utilization of various inhibitors of signaling adaptors and ELISA-base nuclear factor (NF)-κB binding assay demonstrated that the signaling initiated from FasL is mediated by mitogen-activated protein kinases including extracellular signal-regulated kinase, p38, and c-Jun N-terminal kinase which induce subsequent activation of NF-κB. These data indicate that membrane expression of FasL and its interaction with its counterpart may contribute to the inflammatory activation of macrophages during immune reactions or pathogenesis of chronic inflammatory diseases. [ABSTRACT FROM AUTHOR]

Previous studies indicate that astrocytes are the brain cells that express acidic fibroblast growth factor (aFGF) and that the expression is increased upon activation. However, there has been no study investigating the significance of this phenomenon. Here we report that aFGF treatment of IFN?-stimulated human astrocytes, and LPS/IFN?-stimulated human microglia, enhances their secretion of inflammatory cytokines and other materials toxic to human neuroblastoma SH-SY5Y cells. The mechanism of aFGF enhancement involves stimulation of the receptor FGFR2 IIIb. We show by RT-PCR that this receptor, but not other FGF receptors, is robustly expressed by astrocytes and microglia. We establish by Western blotting, and immunohistochemistry on postmortem human brain tissue that the FGFR2 IIIb protein is expressed by both of these glial cell types. We blocked the inflammatory stimulant action of aFGF by transfecting microglia and astrocytes with a small inhibitory RNA (siRNA) to FGFR2 IIIb as well as by removal of aFGF using an anti-aFGF antibody. Treatment with bFGF in combination with the stimulants was without effect, but together with aFGF, it partially counteracted the action of aFGF, indicating that it may be a weak antagonist of FGFR2 IIIb. The inflammatory effect was also attenuated by treatment with inhibitors of protein kinase C, Src tyrosine kinase, and MEK-1/2 indicating the involvement of these intracellular pathways. Our data suggest that inhibition of expression or release of aFGF could have therapeutic potential by inhibiting inflammation in neurodegenerative diseases such as Alzheimer disease where many neuroinflammatory molecules are prominently expressed. [ABSTRACT FROM AUTHOR]

Previously, chitinase 3-like 1 (CHI3L1) protein level was increased in various inflammatory conditions and cancers. This study was aimed to evaluate the plasma CHI3L1 level as a potential prognostic biomarker for Alzheimer's disease (AD). Forty-nine patients with mild cognitive impairment (MCI), 61 patients with mild to severe AD, and 35 healthy elderly controls were recruited for this study. They were given a comprehensive neuropsychological test battery including a mini-mental status examination (MMSE), clinical dementia rating (CDR), and neuropsychiatric inventory (NPI). The CHI3L1 levels were measured using a specific enzyme-linked immunosorbent assay in the plasma and cerebrospinal fluid (CSF). A significant increase in the mean plasma level of CHI3L1 was found in early AD patients compared to control subjects and MCI patients. No significant difference was found between MCI patients and controls. There was a significant positive correlation between CHI3L1 levels and neuropsychological test scores such as CDR and NPI in MCI and early AD patients. Our results demonstrate that CHI3L1 plasma levels are elevated in early AD compared to control or MCI patients. Thus, CHI3L1 plasma levels may be useful as a biomarker, reflecting disease severity in AD patients. [ABSTRACT FROM AUTHOR]

Pentraxin 3 is a prototypic long pentraxin. Pentraxin 3 is a soluble recognition receptor that is involved in innate immunity and the inflammatory response. Its expression is induced by proinflammatory signals. The aim of this study was to compare the plasma levels of pentraxin 3 in healthy subjects and patients with neurodegenerative disorders such as mild cognitive impairment, Alzheimer's disease, and Parkinson's disease (PD). Thirty-nine patients with mild cognitive impairment, 75 patients with Alzheimer's disease, 66 patients with PD, and 41 healthy elderly controls were recruited for this study. We performed an extensive battery of neuropsychological tests, including a Mini-Mental Status Examination, clinical dementia rating, and the Unified Parkinson's Disease Rating Scale. A variety of clinical information was collected from the administered semistructured questionnaire. Plasma pentraxin 3 levels were measured using a specific enzyme-linked immunosorbent assay. Plasma pentraxin 3 levels were significantly higher in the PD patients than in the patients with mild cognitive impairment and Alzheimer's disease and in the control subjects. Plasma pentraxin 3 levels in the PD patients were correlated with activities of daily living ( r = 0.368; P = .003) and motor function ( r = 0.358; P = .004). Plasma pentraxin 3 levels could be a new biochemical marker for PD, and they may be associated with the severity of motor dysfunction and other clinical symptoms in PD patients. © 2011 Movement Disorder Society [ABSTRACT FROM AUTHOR]

Abstract: Although Fas is known to be an apoptosis triggering molecule, accumulating studies indicate that Fas has non-apoptotic functions in certain cases. In an effort to identify the role of Fas in macrophage function, the human macrophage-like cell line THP-1 was analyzed after treatment with agonistic anti-Fas monoclonal antibody or co-incubation with FasL-expressing cells. Stimulation of Fas induced the expression of pro-inflammatory mediators such as matrix metalloproteinase (MMP)-9 and IL-8. The specificity of the reaction was confirmed by the transfection of Fas-specific siRNAs which resulted in a suppression of Fas expression as well as the responsiveness to the agonistic antibody. Utilization of various signaling inhibitors and ELISA-based NF-κB DNA binding assay demonstrated that the signaling initiated from Fas is mediated by mitogen activated protein kinases (MAPKs) including extracellular-signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) which induce subsequent activation of NF-κB. Furthermore, mixed cell culture experiment demonstrated that Fas can be activated through interaction with membrane-bound form of FasL during cell-to-cell interaction. These data indicate that Fas plays a role as an activation inducing molecule through interaction with its counterpart and Fas-mediate events are mediated by ERK/JNK MAPKs which subsequently activate NF-κB for the transcriptional activation of pro-inflammatory mediators. [Copyright &y& Elsevier]

Summary B-cell activation factor of the tumour necrosis factor family (BAFF), an important regulator of B-cell survival, has recently been found to be expressed on the surface of murine and human macrophages and engagement with its receptor was shown to trigger induction of pro-inflammatory mediators and block phagocytic activity. In an effort to generate immunomodulatory agents that can regulate BAFF-mediated signal, decapeptides representing the intracellular immunoreceptor tyrosine-based inhibitory motifs (ITIMs) of immune receptor expressed on myeloid cells (IREM)-1, an inhibitory transmembrane protein expressed on myeloid cells, were synthesized in conjugation with HIV-transactivator of transcription (TAT)48-57, which facilitates the internalization of peptides into cells. Interestingly, all five of these synthetic peptides, representing the five ITIM-like sequences present in the cytoplasmic tail of IREM-1, exhibited inhibitory action against BAFF-mediated induction of matrix metalloproteinase-9 and interleukin-8 expression. Inhibitor assay and immunoprecipitation assay followed by Western blotting demonstrated that the inhibitory action was mediated by Src homology 2 (SH2)-containing tyrosine phosphatase (SHP)-1 and/or phosphoinositide 3-kinase (PI3K). ELISA-based nuclear factor-κB DNA binding assay observed that the synthetic peptides blocked the activation of nuclear factor-κB in an SHP-1 and phosphoinositide 3-kinase-dependent manner. Three of these synthetic peptides exhibited varying degrees of inhibitory action against BAFF-mediated blockage of phagocytosis in a SHP-1 and PI3K-dependent manner. These data indicate that the synthetic peptides are capable of blocking BAFF-mediated regulation of macrophage activities through the activation of SHP-1 and PI3K as well as inhibition of nuclear factor-κB activation. [ABSTRACT FROM AUTHOR]

Background: BAFF and APRIL, as closely related members of the TNF superfamily, are important regulators of B-cell survival. They share two receptors, TACI and BCMA, and BAFF can stimulate an additional receptor, BAFF-R. Although these molecules have been under intense investigation in order to identify their role in immune reactions, the effect of BAFF and APRIL on macrophage function has not been tested. Methods: The human macrophage-like cell line THP-1, which expresses BAFF/APRIL and all three of their receptors, was stimulated with recombinant human BAFF or APRIL or monoclonal antibodies against the receptors and the resulting cellular responses were investigated. Treatment of the cells with these agents induced the expression of pro-inflammatory mediators such as matrix metalloproteinase (MMP)-9 and IL-8. Suppression of the expression of these receptors using specific siRNAs resulted in the blocking of the response, confirming that these responses require specific interaction between BAFF/APRIL and their receptors. Inhibitors of MAPK and NF-κB blocked the expression of IL-8. Furthermore, inhibitors of MAPK blocked the BAFF-induced specific DNA binding activity of NF-κB. Conclusion: These data indicate that BAFF and APRIL can induce inflammatory activation of THP-1 cells through the activation of MAPK, which leads to the subsequent activation of NF-κB. [ABSTRACT FROM AUTHOR]

Abstract: Background: Alzheimer''s disease (AD) is a progressive neurodegenerative disorder characterized by an irreversible cognitive decline and neuronal loss associated with neurofibrillary tangles and senile plaques. Mild cognitive impairment (MCI) is a prodromal stage of AD and is associated with memory loss and a high risk of developing AD. Lipocalin 2 (LCN2) is an acute phase protein. Our previous studies have shown that exposure to inflammatory stimuli resulted in elevated LCN2 levels in brain microglia and astrocytes implicating LCN2 in brain inflammation. Therefore, we hypothesize that there may be a significant change in the plasma LCN2 levels in patients with MCI and AD when compared to healthy control subjects. Methods: Forty-one patients with MCI, 62 patients with AD and 38 healthy elderly control subjects were recruited for this study. They were given a comprehensive battery of neuropsychological tests including a mini-mental status examination (MMSE) and clinical dementia rating (CDR). A variety of clinical information was collected from the semi-structured questionnaire administered. The LCN2 levels were measured using a specific enzyme-linked immunosorbent assay in the plasma, which had been collected early in the morning after overnight fasting. Results: The LCN2 levels were significantly higher in MCI patients compared to the healthy control subjects and AD patients [control vs. MCI (p=0.005); MCI vs. AD (p=0.009)]. There was a significant negative correlation between the LCN2 levels and CDR scores (r=−0.245, p=0.014), and there was a positive correlation between the LCN2 levels and MMSE scores (r=0.317, p=0.001) among all of the MCI and AD patients. Conclusion: MCI represents a prodromal stage of AD, and inflammation occurs as one of the earliest pathological events in AD. Thus, increased plasma LCN2 levels during MCI could be helpful in predicting the progression from MCI to AD. [Copyright &y& Elsevier]

Abstract: βig-h3, an extracellular matrix protein involved in various biological processes including cellular growth, differentiation, adhesion, migration, and angiogenesis, has been shown to be elevated in various inflammatory processes. Death receptor 3 (DR3), a member of the TNF-receptor superfamily that is expressed on T cells and macrophages, is involved in the regulation of inflammatory processes through interaction with its cognate ligand, TNF-like ligand 1A (TL1A). In order to find out whether the TL1A-induced inflammatory activation of macrophages is associated with the up-regulation of βig-h3 expression, the human acute monocytic leukemia cell line (THP-1) was stimulated with either recombinant human TL1A- or DR3-specific monoclonal antibodies. Stimulation of DR3 up-regulated the intracellular levels as well as the secretion of βig-h3. Utilization of various inhibitors and Western blot analysis revealed that activation of protein kinase C (PKC), extracellular signal-regulated kinase (ERK), phosphoinositide kinase-3 (PI3K), and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is required for TL1A-induced βig-h3 expression. PKC appears to be the upstream regulator of PI3K since the presence of PKC inhibitor blocked the phosphorylation of AKT without affecting ERK phosphorylation. On the other hand, suppression of either PI3K or ERK activity resulted in the suppression of IκB phosphorylation. These findings indicate that TL1A can regulate the inflammatory processes through modulation of the βig-h3 expression through two separate pathways, one through PKC and PI3K and the other through ERK, which culminates at NF-κB activation. [ABSTRACT FROM AUTHOR]