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Abstract: The purpose of this present study was to explore the therapeutic potential of prostaglandins E1 and E2 on the systemic inflammatory response evoked by endotoxin. Since interleukin-18, a monocyte-derived cytokine, is increased during sepsis, decreasing the production of interleukin-18 is important in treating this condition. Prostaglandin E1 and E2 inhibited interleukin-18 production in human monocytes treated with lipopolysaccharide and prostanoid IP-, EP2- and EP4-receptor agonists mimicked the effects of prostaglandins E1 and E2. Therefore, prostanoid IP, EP2- and EP4-receptors might be involved in the decrease in interleukin-18 production during sepsis. [Copyright &y& Elsevier]

Endogenous catecholamine, epinephrine and norepinephrine, and isoproterenol concentration-dependently induced the production of interleukin (IL)-18, tumor necrosis factor (TNF)-α and interferon (IFN)-γ, and inhibited that of IL-10 in human peripheral blood mononuclear cells (PBMC). All responses by these stimulations were antagonized by the selective β2-adrenergic receptor (AR) antagonist, butoxamine, but not by α1-, α2- and β1-AR antagonists. The selective β2-AR agonists, salbutamol and terbutaline, induced a similar pattern of cytokine production, indicating that the effect of these AR agonists on cytokine production was through β2-AR stimulation. Anti-IL-18 Ab or caspase-1 inhibitor prevented all increase/decrease effects, suggesting that IL-18 might affect the production of all other cytokines. While endogenous IL-18 produced by salbutamol and terbutaline reached a sufficient concentration to induce IL-12 production, these β2-AR agonists did not induce the production of IL-12 at all. Epinephrine/norepinephrine/isoproterenol/β2-AR agonists increased the production of IL-18 in monocytes, but had no effect on IL-12, TNF-α, IFN-γ and IL-10 production. The lack of β2-AR-induced effect on IL-12 production was due to a β2-AR-induced inhibition of an IL-18-elicited upregulation of both CD40 and CD40 ligand (CD40L/CD154) expressions on monocytes. The sympathetic innervating lymphoid organs may be under the control of β2-AR stimulation, maintaining the basal cytokine environment in the tissues. [Copyright &y& Elsevier]

Systemic administration of kainic acid induces repeated convulsive seizures (KA convulsions) that result in neuropathological changes similar to temporal lobe epilepsy and the appearance of spontaneous recurrent seizures (SRS). The appearance of SRS is considered a result of the remodeling of neuronal networks following neuronal degeneration. We investigated the changes in chondroitin sulfate proteoglycans (CSPGs) in the limbic structures after KA convulsions in the rat using monoclonal antibodies 1G2, which recognizes full-length neurocan and the C-terminal half of neurocan, neurocan C, and 6B4, which recognize phosphacan and protein tyrosine phosphatase ζ. After KA convulsions, full-length neurocan appeared by 24 h and reached a peak by 48 to 72 h, whereas phosphacan decreased within 24 h in the hippocampus. In immunohistochemistry, neurocan increased in the limbic structures coincident with the appearance of reactive astrocytes. Phosphacan decreased coincident with pyramidal cell loss in the hippocampus, and the number of phosphacan-positive perineuronal nets around parvalbumin neurons decreased, whereas parvalbumin neurons were relatively conserved. In contrast, phosphacan increased in the entorhinal and piriform cortices in correlation with the severity of neuronal loss. Both neurocan and phosphacan recovered to the control level by 8 weeks after KA convulsions in some rats, but the changes in neurocan and phosphacan described above still persisted in more than half the rats. The results indicate that KA convulsions induce prolonged changes in neurocan and phosphacan similar to those in the developing rat brain and suggest a role of these CSPGs in the remodeling of neuronal networks related to the establishment or enhancement of epileptogenesis. [Copyright &y& Elsevier]

To elucidate the temporal characteristics of information processing for motor action differing in complexity in relation to both perceptual and cognitive information processing, we investigated whether the reaction times (RTs) to a visual target would be affected by task complexity (finger lifting or manual aiming), pre-cueing (with a pre-cue or without a pre-cue), or target location (five horizontal positions). Using the right hand, seven right-handed subjects performed two tasks, finger lifting and manual aiming at a target, with or without a pre-cue. The pre-cue announced the location of the target to be presented. An ANOVA showed significant interactions between task and location and between pre-cue and location with no significant interaction between task and pre-cue, indicating that the task–location interaction does not depend on whether or not a pre-cue is given. The manual-aiming RTs were longer than the finger-lifting RTs, and the effects of the target location on the RTs differed for finger lifting and manual aiming. It can be assumed that the longer RTs of manual aiming reflect the time for information processing that is needed when preparing for the aiming action per se, which is an extra movement performed in addition to the simple initiation of finger lifting. Differential RTs (DRTs) calculated by subtracting the finger-lifting RTs from the aiming RTs were therefore examined. The DRTs significantly differed for target locations (i.e., a lateralized effect), with the DRTs for an ipsilateral target appearing to be significantly shorter than those for contralateral and central targets. The lateralized effect appearing on the DRTs may be mediated by the processing of visual-spatial information about visual targets as motor preparations are made for manual aiming. [Copyright &y& Elsevier]

Various biomarkers have been proposed for sepsis; however, only a few become the standard. We previously reported that plasma histidine-rich glycoprotein (HRG) levels decreased in septic mice, and supplemental infusion of HRG improved survival in mice model of sepsis. Moreover, our previous clinical study demonstrated that HRG levels in septic patients were lower than those in noninfective systemic inflammatory response syndrome patients, and it could be a biomarker for sepsis. In this study, we focused on septic patients and assessed the differences in HRG levels between the non-survivors and survivors. We studied ICU patients newly diagnosed with sepsis. Blood samples were collected within 24 h of ICU admission, and HRG levels were determined using an enzyme-linked immunosorbent assay. Ninety-nine septic patients from 11 institutes in Japan were included. HRG levels were significantly lower in non-survivors (n = 16) than in survivors (n = 83) (median, 15.1 [interquartile ranges, 12.7–16.6] vs. 30.6 [22.1–39.6] µg/ml; p < 0.01). Survival analysis revealed that HRG levels were associated with mortality (hazard ratio 0.79, p < 0.01), and the Harrell C-index (predictive power) for HRG was 0.90. These results suggested that HRG could be a novel prognostic biomarker for sepsis. [ABSTRACT FROM AUTHOR]

Hyperglycaemia provides a suitable environment for infections and the mechanisms of glucose toxicity include the formation of advanced glycation end-products (AGEs), which comprise non-enzymatically glycosylated proteins, lipids, and nucleic acid amino groups. Among AGE-associated phenotypes, glycolaldehyde-derived toxic AGE (AGE-3) is involved in the pathogenesis of diabetic complications. Internalisation of endotoxin by various cell types contributes to innate immune responses against bacterial infection. An endotoxin derived from Gram-negative bacteria, lipopolysaccharide (LPS), was reported to enhance its own uptake by RAW264.7 mouse macrophage-like cells, and an LPS binding protein, CD14, was involved in the LPS uptake. The LPS uptake induced the activation of RAW264.7 leading to the production of chemokine CXC motif ligand (CXCL) 10, which promotes T helper cell type 1 responses. Previously, we reported that AGE-3 was internalised into RAW264.7 cells through scavenger receptor-1 Class A. We hypothesized that AGEs uptake interrupt LPS uptake and impair innate immune response to LPS in RAW264.7 cells. In the present study, we found that AGE-3 attenuated CD14 expression, LPS uptake, and CXCL10 production, which was concentration-dependent, whereas LPS did not affect AGE uptake. AGEs were reported to stimulate the receptor for AGEs and Toll-like receptor 4, which cause inflammatory reactions. We found that inhibitors for RAGE, but not Toll-like receptor 4, restored the AGE-induced suppression of CD14 expression, LPS uptake, and CXCL10 production. These results indicate that the receptor for the AGE-initiated pathway partially impairs the immune response in diabetes patients. [ABSTRACT FROM AUTHOR]

Sepsis is caused by infections associated with life-threatening multiple organ failure (MOF). Septic MOF appears to be closely related to circulatory failure due to immunothrombosis. This process involves the production of reactive oxygen spices (ROS) in inflammatory sites. Therefore, the detoxification of the systemic excess ROS is important for the improvement of the process in septic pathogenesis. Histidine-rich glycoprotein (HRG), a plasma glycoprotein, ameliorates a septic condition through the suppression of both excess ROS production from neutrophils and immunothrombosis. Hydroxyl radical is known as the most important species among ROS in pathogenesis; however, the direct influence of HRG on hydroxyl radical formation and ROS activity is poorly understood. In this study, we showed that HRG, in a concentration-dependent manner, efficiently inhibited the production of hydroxyl radical induced by the Fenton's reaction through chelation of the divalent iron. HRG also exhibited antioxidant activity against peroxyl radical by oxidation of HRG itself as a substrate; however, it did not show superoxide dismutase and catalase-like activities. Additionally, HRG enhanced glutathione peroxidase, a well-known antioxidant enzyme, activity. These results suggest that HRG may play a unique role in suppression of the production of hydroxyl radicals and subsequent tissue damage at inflammatory sites. Marked reduction in plasma HRG in sepsis might lose such an important protective mechanism. Thus, the present study provides evidence that inhibition of ROS and ROS-production systems by HRG may contribute to antiseptic effects in vivo and that HRG could be potential therapy for ROS-related diseases. [ABSTRACT FROM AUTHOR]

Background: Cerebral small vessel disease (CSVD) is associated with future stroke. Although pathological alteration in small vessels of patients with CSVD can be detected by neuroimaging, diagnosis of CSVD is delayed because it is an asymptomatic disease. The stroke-prone spontaneously hypertensive rat (SHRSP) show similar pathological features to human CSVD and develop stroke-related symptoms with advancing age. Objective: We investigated the time course of haematological parameters in Wistar rats and SHRSP. Material and Methods: Blood cells were analysed using an automated haematological analyser. Results: SHRSP develop stroke-related symptoms including onset of neurological symptoms, decreased body weight and blood brain barrier leakage between 12 and 14 weeks of age. Lymphocyte counts were gradually decreased at 3 weeks before development of stoke-related symptoms and then were further decreased after the development of stroke-related symptoms. The both mean platelet volume and large platelet ratio gradually increased at 3 weeks before the development of stoke-related symptoms. However, although SHRSP showed more microcytic red cells than Wistar rats, the trajectories of change in erythrocyte-related parameters were similar between Wistar rats and SHRSP. Conclusion: Our pilot study suggests that alterations of lymphocyte count and platelet volume predictive indicators for asymptomatic CSVD and symptomatic stroke in SHRSP. [ABSTRACT FROM AUTHOR]

Advanced glycation end products (AGEs) are considered to be related to the pathogenesis of some inflammatory diseases. AGEs were reported to stimulate the receptor for AGEs (RAGE), which causes inflammatory reactions. However, recently, toll‐like receptors (TLRs), in addition to RAGE, have been reported to be related to AGE‐mediated cellular responses, and it remains unclear which receptor is responsible for AGE recognition. To reveal the role of pattern‐recognition receptors, including TLRs and/or RAGE, in AGE‐mediated cellular responses, we generated macrophage‐like RAW264.7 knockout (KO) cells lacking these receptors by genome editing using the CRISPR/Cas9 system and assessed AGE‐stimulated changes in these cells. Comparison of the established clones suggested that RAGE partially affects the expression of TLRs. In the KO clone lacking TLR4 and TLR2, AGE‐stimulated tumor necrosis factor alpha (TNF‐α) expression and phosphorylation of IκBα, p38, and extracellular signal‐regulated kinase (ERK) were significantly attenuated, suggesting that AGE‐mediated responses are largely dependent on TLRs. On the other hand, on comparison of the AGE‐stimulated responses between the KO clone lacking TLR4 and TLR2, and the clone lacking TLR4, TLR2, and RAGE, RAGE played little role in AGE‐stimulated TNF‐α transcription and ERK phosphorylation. Taken together, this study suggested that AGE‐stimulated inflammatory responses occur mainly through TLRs rather than RAGE. [ABSTRACT FROM AUTHOR]

Advanced glycation end products (AGEs) are a heterogeneous group of compounds that are non-enzymatically produced by reactions between carbonyl compounds and proteins. Many types of AGEs are produced according to the type or concentration of the reacting carbonyl compound. We have previously demonstrated that a glycolaldehyde-derived AGE suppresses stimulator of interferon gene (STING)/TANK-binding kinase 1 (TBK1)/interferon regulatory transcription factor 3 (IRF3), which is a component of the innate immune system. In this report, we investigated the effects of AGEs prepared by several carbonyl compounds on STING/TBK1/IRF3 signaling. AGEs used in the present study were numbered based on the carbonyl compound type: AGE1, derived from glucose; AGE2, derived from glyceraldehyde; AGE3, derived from glycolaldehyde; AGE4, derived from methylglyoxal; and AGE5, derived from glyoxal. AGEs derived from aldehyde (AGE2 and AGE3) and dicarbonyl compounds (AGE4 and AGE5) suppressed cyclic GMP-AMP (cGAMP)-induced activation of STING/TBK1/IRF3 signaling, with different suppression efficiencies observed. Lysine modification by carbonyl compounds was related to the efficiency of the suppressive effect on STING/TBK1/IRF3 signaling. Among the AGEs used, only AGE1 enhanced cGAMP-induced activation of STING/TBK1/IRF3 signaling. Enhancing the modulation of STING/TBK1/IRF3 signaling by AGE1 was mediated by toll-like receptor 4. These results indicated that modulation of STING/TBK1/IRF3 signaling by prepared AGEs is dependent on the type and concentration of the carbonyl compound present. Modulating STING/TBK1/IRF3 signaling by AGEs may involve modification of lysine residues in proteins. [Display omitted] • AGEs are prepared by incubation of protein with carbonyl compound. • Effects of AGEs on STING/TBK1/IRF3 signaling depend on types of the carbonyl compound. • AGEs derived from aldehyde and dicarbonyl compounds exerts suppressive effect. • Lysine modification by carbonyl compounds is related to the efficiency of the suppressive effect. • Glucose-derived AGE enhance cGAMP-induced activation of STING/TBK1/IRF3 signaling. [ABSTRACT FROM AUTHOR]

There is ample evidence that motor learning changes the function of perceptual systems. Previous studies examining the interactions between speech production and perception have shown that the discrimination of phonetic contrasts characterized by the difference in articulatory place features is altered following their production changes caused by the perturbation of auditory feedback. The present study focused on a voiced–voiceless contrast in stop consonants, which is characterized by a temporal articulatory parameter, voice-onset time (VOT). In the experiment, we manipulated the participants' motor functions concerning VOT using a cross-categorical auditory feedback (CAF) paradigm (Mitsuya et al. in J Acoust Soc Am 135:2986–2994, 2014), in which a pre-recorded syllable sound starting with a voiced stop consonant (/da/) was fed back simultaneously with the participant's utterance of a voiceless stop consonant (/ta/), and vice versa. The VOT difference between /da/ and /ta/ productions was increased by the CAF, which is consistent with the result of Mitsuya's study. In addition, we conducted perceptual identification tasks of /da/-/ta/ continuum stimuli varying in VOT before and after the CAF task, and found that the identification function became sharper after as compared to before the CAF task. A significant positive correlation between such production and perception changes was also found. On the basis of these results, we consider that the change in motor function concerning VOT affected voiced–voiceless perceptual processing. The present study is the first to show the involvement of the speech production system in the perception of phonetic contrasts characterized by articulatory temporal features. [ABSTRACT FROM AUTHOR]

Background High mobility group box 1 (HMGB1) protein plays a key role in triggering inflammatory responses in many diseases. Our previous study showed that HMGB1 is found upstream of secondary damage in traumatic brain injury (TBI). We found that anti-HMGB1 monoclonal antibody (mAb) effectively decreased acute brain damage, including the disruption of the blood-brain barrier, brain edema, and neurologic dysfunction. This effect of anti-HMGB1 mAb lasts for at least 1 week. In this study, we explored subacute effects of anti-HMGB1 mAb after TBI. Methods TBI was induced in rats by fluid percussion. Anti-HMGB1 mAb or control mAb was given intravenously after TBI. Histochemical staining, plasma levels of HMGB1, motor activity and memory, and video electroencephalography monitoring were evaluated 2 weeks after fluid percussion injury. Results Anti-HMGB1 mAb remarkably attenuated accumulation of activated microglia in the rat cortex in the ipsilateral hemisphere after TBI. Anti-HMGB1 mAb also prevented neuronal death in the hippocampus in the ipsilateral hemisphere after TBI. Treatment of rats with anti-HMGB1 mAb inhibited HMGB1 translocation and suppressed impairment of motor function. The beneficial effects of anti-HMGB1 mAb on motor and cognitive function persisted for 14 days after injury. Treatment with anti-HMGB1 mAb also had positive effects on electroencephalography activity. Conclusions The beneficial effects of anti-HMGB1 mAb continued during the subacute postinjury phase, suggesting that anti-HMGB1 mAb may prevent cognitive dysfunction after TBI. [ABSTRACT FROM AUTHOR]

4-hydroxy-2-nonenal (4-HNE) is a lipid peroxidation product that is known to be elevated during oxidative stress. During systemic inflammation and endotoxemia, plasma levels of 4-HNE are elevated in response to lipopolysaccharide (LPS) stimulation. 4-HNE is a highly reactive molecule due to its generation of both Schiff bases and Michael adducts with proteins, which may result in modulation of inflammatory signaling pathways. In this study, we report the production of a 4-HNE adduct-specific monoclonal antibody (mAb) and the effectiveness of the intravenous injection of this mAb (1 mg/kg) in ameliorating LPS (10 mg/kg, i.v.)-induced endotoxemia and liver injury in mice. Endotoxic lethality in control mAb-treated group was suppressed by the administration of anti-4-HNE mAb (75 vs. 27%). After LPS injection, we observed a significant increase in the plasma levels of AST, ALT, IL-6, TNF-α and MCP-1, and elevated expressions of IL-6, IL-10 and TNF-α in the liver. All these elevations were inhibited by anti-4-HNE mAb treatment. As to the underlining mechanism, anti-4-HNE mAb inhibited the elevation of plasma high mobility group box-1 (HMGB1) levels, the translocation and release of HMGB1 in the liver and the formation of 4-HNE adducts themselves, suggesting a functional role of extracellular 4-HNE adducts in hypercytokinemia and liver injury associated with HMGB1 mobilization. In summary, this study reveals a novel therapeutic application of anti-4-HNE mAb for endotoxemia. [ABSTRACT FROM AUTHOR]

We have previously reported that advanced glycation end products derived from incubation of albumin with glycolaldehyde (glycol-AGE), lead to suppression of the toll-like receptor 4 (TLR4) signaling response to lipopolysaccharide. Glycol-AGE-induced suppression of TLR4 signaling is involved in the downregulation of CD14, which is an adaptor protein necessary for transferring lipopolysaccharide to TLR4. Therefore, glycol-AGEs impair the innate immune response through suppression of the upstream process in TLR4 signaling. However, the effect of glycol-AGEs on intracellular signaling related to the innate immune response remains unclear. This study aimed to examined the effect of glycol-AGEs on stimulator of interferon gene (STING) signaling in macrophages. In differentiated THP-1 cells, which are a human monocytic leukemia cell line, cyclic GMP-AMP (cGAMP) transfection was used to activate STING signaling. The phosphorylation levels of TANK-binding kinase 1 (TBK1)/interferon regulatory transcription factor 3 (IRF3) were evaluated by western blot analysis. Downstream cytokine levels were evaluated by quantitative real-time polymerase chain reaction and enzyme-linked immunosorbent assays. Glycol-AGEs suppressed cGAMP-induced phosphorylation of TBK1 and IRF3, as well as the production of cytokines regulated by IRF3. There was no effect of glycol-AGEs on the efficacy of cGAMP transfection. Treatment of a neutralizing antibody against CD36 prevented cGAMP-induced phosphorylation of TBK1 and IRF3, and also upregulation of interferon-β and C-X-C motif chemokine ligand 10 in glycol-AGE-treated cells. Glycol-AGEs negatively regulate cGAMP-induced activation of STING/TBK1/IRF3 signaling via CD36. Our findings suggest that glycol-AGEs lead to impairment of the innate immune response by suppressing intracellular signaling. [Display omitted] • Cyclic GMP-AMP (cGAMP) transfection activates STING signaling. • Glycolaldehyde-derived advanced glycation end products (glycol-AGEs) suppress STING signaling. • CD36 contributes to the suppression of STING signaling by glycol-AGEs. • There is no effect of glycol-AGEs on the efficacy of cGAMP transfection. • There is no binding interaction between glycol-AGEs and STING or cGAMP. [ABSTRACT FROM AUTHOR]

In the adult hypothalamus and ependymal lining of the third ventricle, tanycytes function as multipotential progenitor cells that enable continuous neurogenesis, suggesting that tanycytes may be able to mediate the restoration of homeostatic function after stroke. Voluntary wheel running has been shown to alter neurochemistry and neuronal function and to increase neurogenesis in rodents. In the present study, we found that voluntary exercise improved the survival rate and energy balance of stroke-prone spontaneously hypertensive rats (SHRSP/Kpo). We also investigated the effect of exercise on the proliferation and differentiation of hypothalamic cells using immunoreactivity for tanycytes and neural markers. The proliferation of elongated cells, which may be the tanycytes, was enhanced in exercising SHRSP compared to sedentary rats before and after stroke. In addition, the proliferation of cells was correlated with the induction of fibroblast growth factor-2 in the subependymal cells of the third ventricle and in the cerebrospinal fluid. Some of the newborn cells of exercising SHRSP showed differentiation into mature neurons after stroke. Our results suggest that voluntary exercise correlates with hypothalamic neurogenesis, leading to recovery of homeostatic functions in the adult brain after stroke. [ABSTRACT FROM AUTHOR]

Abstract: Cell–cell interaction through binding of adhesion molecules on monocytes to their ligands on T-cells plays roles in cytokine production and lymphocyte proliferation. High mobility group box 1 (HMGB1), an abundant and conserved nuclear protein, acts in the extracellular environment as a primary pro-inflammatory signal. HMGB1 induces expression of intercellular adhesion molecule (ICAM), B7.1, B7.2 and CD40 on monocytes, resulting in production of interferon (IFN)-γ and tumor necrosis factor (TNF)-α production and lymphocyte proliferation in human peripheral blood mononuclear cells (PBMCs). Histamine inhibits pro-inflammatory cytokine production via histamine H2-receptors; however, it is not known whether histamine inhibits HMGB1 activity. This study was designed to study the inhibitory effect of histamine on HMGB1 activity. We examined the effect of histamine on HMGB1-induced expression of ICAM-1, B7.1, B7.2 and CD40 on monocytes, production of IFN-γ and TNF-α and lymphocyte proliferation in PBMCs. Histamine inhibited HMGB1 activity in a concentration-dependent manner. The effects of histamine were partially ablated by the H2-receptor antagonist, famotidine, and mimicked by the H2/H4-receptor agonists, dimaprit and 4-methylhistamine. Histamine induced cyclic adenosine monophosphate (cAMP) production in the presence and absence of HMGB1. The effects of histamine were reversed by the protein kinase A (PKA) inhibitor, H89, and mimicked by the membrane-permeable cAMP analog, dibutyryl cAMP (dbcAMP), and the adenylate cyclase activator, forskolin. These results together indicated that histamine inhibited HMGB1 activity [Copyright &y& Elsevier]

Abstract: Cell–cell interaction through binding of intercellular adhesion molecule (ICAM), B7.1, B7.2 and CD40 on monocytes to their ligands on T-cells plays a number of roles in cytokine . High mobility group box 1 (HMGB1), an abundant and conserved nuclproduction and lymphocyte proliferationear protein, acts in the extracellular environment as a primary pro-inflammatory signal. The receptor for advanced glycation end products (RAGE), toll-like receptor (TLR)-2 and TLR-4 are receptors for HMGB1. HMGB1 induces pro-inflammatory cytokine production in monocytes and T-cells. This study was designed to study the cellular mechanism of cytokine production. HMGB1 concentration-dependently induced ICAM-1, B7.1, B7.2 and CD40 expression on monocytes, and interferon (IFN)-γ and tumor necrosis factor (TNF)-α production and lymphocyte proliferation in human peripheral blood mononuclear cells (PBMCs). These HMGB1 activities depended on the stimulation of RAGE on monocytes. HMGB1 also up-regulated RAGE, but not TLR-2 or TLR-4, expression on monocytes, which was inhibited by antibodies (Abs) against ICAM-1, B7.1, B7.2 and CD40. These results together indicated that HMGB1 could induce an intimate cellular interplay between monocytes and T-cells in PBMCs through the stimulation and up-regulation of RAGE and other adhesive molecules on monocytes. [Copyright &y& Elsevier]

Abstract: Interleukin (IL)-18, which is elevated in the plasma during acute rejection after organ transplantation, is known to induce the expression of intercellular adhesion molecule (ICAM)-1, B7.1, B7.2, CD40 and CD40 ligand (CD40L) on monocytes, the production of interferon (IFN)-γ and IL-12 and the proliferation of lymphocytes during the human mixed lymphocyte reaction (MLR). Ciprofloxacin (CIP), which is useful for the clinical treatment of infections due to its antibacterial properties after transplantation, was shown to suppress the IFN-γ and IL-12 production, the lymphocyte proliferation and the ICAM-1, B7.1, B7.2 and CD40 expression on monocytes during MLR in the presence of IL-18. CIP also induced the production of prostaglandin (PG) E2. In order to determine whether the effects of CIP on the expression of the activation markers were due to CIP-dependent production of PGE2, we examined the effect of cyclooxygenase (COX)-2 and protein kinase A (PKA) inhibitors on the actions of CIP. Thereby, the inhibitors were found to abolish the actions of CIP. These results therefore suggest that CIP might exert its immune modulatory effects via the production of PGE2. [Copyright &y& Elsevier]

Abstract: The effect of prostaglandins E1 and E2 on the 1 ng/ml lipopolysaccharide-induced expression of intercellular adhesion molecule (ICAM)-1, B7.1, B7.2, CD40 and CD40 ligand (CD40L) on monocytes was examined. Prostaglandin E1 suppressed B7.1 and CD40 expression, but prostaglandin E2 did not effect on any type of adhesion molecule expression. Both prostaglandins inhibited tumor necrosis factor (TNF)-α production and T-cell proliferation of lipopolysaccharide-treated human peripheral blood mononuclear cells (PBMC). Among prostaglandin E1 receptors (IP/EP1/EP2/EP3/EP4) agonists, ONO-1301, a prostanoid IP-receptor agonist, prevented B7.1 and CD40 expression. ONO-AE1-259-01 a prostanoid EP2-receptor agonist, ONO-AE1-329, a prostanoid EP4-receptor agonist, and ONO-1301 inhibited TNF-α production and T-cell proliferation. Moreover, anti-B7.1 and anti-CD40 Abs prevented lipopolysaccharide-induced TNF-α production and T-cell proliferation. Therefore, the effect of prostaglandin E1 on TNF-α production and T-cell proliferation might depend on the inhibition of B7.1 and CD40 expression, but that of prostaglandin E2 might be independent of adhesion molecules expression. In conclusion, the mechanism responsible for the effect of prostaglandin E1 on lipopolysaccharide-induced responses is distinct from that of prostaglandin E2. [Copyright &y& Elsevier]

Protease-activated receptor-2 (PAR-2) has been demonstrated to be highly expressed in the gastrointestinal tract. In the present study, we investigated the effects of PAR-2 stimulation on the cell signaling and proliferation of DLD-1, a human colon carcinoma cell line, in comparison with the PAR-1 stimulation. PAR-2 stimulation by agonist peptide SLIGKV concentration–dependently induced the increase in [Ca2+]i and the proliferation of DLD-1 whereas the inverse peptide LSIGKV did not. Trypin (10−9 M), an agonist protease for PAR-2, also enhanced the proliferation of DLD-1. The proliferative response of DLD-1 to PAR-2 stimulation was associated with the transient phosphorylation of MEK and MAP kinase, but not p38 MAP kinase and JNK. Inhibition of MEK by PD98059 (50 μM) completely inhibited the proliferation-stimulating effects as well as the phosphorylation of MAP kinase induced by PAR-2 agonist peptide (100 μM) and trypsin (10−9 M). The prolonged treatment with PAR-2 agonist peptide for more than one hour was required for the enhanced proliferative response, suggesting the existence of unknown long-lasting cooperative signaling with MAP kinase cascade. PAR-1 stimulation by the agonist peptide SFLLRN (100 μM) or thrombin (10−8 M) produced Ca2+ signaling, however, the stimulation neither produced the cell proliferative response nor the activation of MEK-MAP kinase cascade. These results indicated that Ca2+ signaling induced by PARs activation was not enough for inducing the cell proliferation in DLD-1 cells and that stimulation of PAR-2 can induce the activation of MEK-MAP kinase cascade, leading to the growth promoting response. [Copyright &y& Elsevier]

Lipopolysaccharide (LPS) binds to LPS-binding protein (LBP) in plasma and is delivered to the cell surface receptor CD14 on human monocyte. LPS is transferred to the transmembrane signaling receptor toll-like receptor (TLR) 4. In the present study, the effect of histamine on the expression of CD14 on human monocytes was investigated. Histamine concentration- and time-dependently decreased the expression of cell surface CD14, whereas histamine did not decrease mRNA for CD14 nor increase soluble CD14 (sCD14). The inhibitory effects of histamine on CD14 expression were antagonized by H2-receptor antagonist, but not by H1 and H3/H4 antagonist. The effects of selective H2-receptor agonists, 4-methylhistamine and dimaprit, on CD14 expression mimicked that of histamine indicating that histamine regulated CD14 expression through the stimulation of H2-receptors. The pretreatment with histamine partially inhibited the LPS-induced TNF-α production in human peripheral blood mononuclear cells (PBMC). Such inhibition might be due to the down-regulation of CD14 expression on monocytes by histamine. [Copyright &y& Elsevier]

Toxic advanced glycation end products (toxic AGEs) derived from glycolaldehyde (AGE3) have been implicated in the development of diabetic vascular complications such as retinopathy characterised by excessive angiogenesis. Different receptor types, such as receptor for AGEs (RAGE), Toll like receptor-4 and scavenger receptors, are expressed in endothelial cells and contribute to AGE-elicited alteration of cell function. In the present study, we examined the involvement of AGE-related receptors on AGE-induced angiogenesis in endothelial cells. The effects of pharmacological inhibitors or receptor neutralizing antibodies on AGE3-induced tube formation were investigated using the in vitro Matrigel tube formation assay in b.End5 cells (mouse endothelial cells). AGE3-induced signalling pathways and receptor expression changes were analysed by Western blot analysis and flow cytometry, respectively. Both FPS-ZM1, a RAGE inhibitor, and fucoidan, a ligand for scavenger receptors, suppressed AGE3-induced tube formation. Cocktails of neutralizing antibodies against the scavenger receptors CD36, CD163 and LOX-1 prevented AGE3-induced tube formation. AGE3 activated mTOR signalling, resulting in facilitation of tube formation. Activation of the AGE-RAGE pathway also led to the upregulation of scavenger receptors. Taken together, our findings suggest that the scavenger receptors CD36, CD163 and LOX-1 in conjunction with the RAGE receptor work together to mediate toxic AGE-induced facilitation of angiogenesis. [Display omitted] • Multiple scavenger receptors contribute to AGE-induced angiogenesis. • RAGE contributes to AGE-induced angiogenesis by upregulation of scavenger receptors. • AGE activates mTOR signaling. [ABSTRACT FROM AUTHOR]

In an attempt to develop tests of auditory temporal resolution using gap detection, we conducted computer simulations of Zippy Estimation by Sequential Testing (ZEST), an adaptive Bayesian threshold estimation procedure, for measuring gap detection thresholds. The results showed that the measures of efficiency and precision of ZEST changed with the mean and standard deviation (SD) of the initial probability density function implemented in ZEST. Appropriate combinations of mean and SD values led to efficient ZEST performance; i.e., the threshold estimates converged to their true values after 10 to 15 trials., (© 2024 Author(s). All article content, except where otherwise noted, is licensed under a Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).)

Decision-making is an important component in the perception-action coupling required for athletes to achieve fine performance. Signal detection theory (SDT) provides a means of quantifying athletes' decision-making processes, based on their ability to discriminate between different types of stimuli (sensitivity) and the locations of their response criteria along a decision axis in a given situation. Studies have shown differences in these two indices between athletes and less-experienced counterparts, although these studies were limited to unidimensional decision-making problems. In the present study, SDT analysis was applied to two-dimensional decision-making by volleyball players regarding their opponents' attacks, using a four-alternative forced-choice task combining judgments of the type (spike or tip) and direction (cross-court or down-the-line) of attacks. Furthermore, a temporal occlusion task was used to reveal the timecourses of changes in sensitivity and the location of response criteria relating to judgments of attack type and direction. There were three groups of participants, eight top-league players, ten collegiate players, and ten novices. The results showed clear effects of expertise and distinct timecourses for the two types of judgment. For the attack type judgments, the sensitivities of the top-league players were relatively low at the early occlusion points, and their response criteria were biased toward judging attacking actions as spikes. At the late occlusion points, their sensitivity peaked, and there was no bias in their response criteria. For the directional judgments, the sensitivity of the three groups improved as the occlusion point advanced, while their response criteria tended to become more similar, which was not the case for the attack type judgments. These results are discussed together with previous studies of volleyball players' decision-making and judgments regarding deceptive actions in sports., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Introduction: Although auditory temporal processing plays an important role in speech comprehension, it cannot be measured by pure tone audiometry. Auditory temporal resolution is often assessed by behavioral gaps-in-noise test. To evaluate whether auditory temporal resolution could be objectively assessed, we measured the auditory steady state response (ASSR) elicited by silent gaps embedded within broadband noises at 80 Hz., Methods: We prepared six sound types as test stimuli. One was a continuous broadband noise without a silent interval as a control stimulus and the others were broadband noises with 80 Hz silent intervals of 0.4, 0.8, 1.6, 3.1, and 6.3 ms., Results: Significant ASSRs were recorded only when the gap length was longer than the behavioral thresholds and the ASSR amplitude increased as the gap length increased., Conclusion: Eighty Hertz gap-evoked ASSR appears to reflect the neural activity related to the auditory gap processing and may be used as an objective measure of auditory temporal resolution in humans., Competing Interests: TM was employed by RION Co., Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Kadowaki, Morimoto, Pijanowska, Mori and Okamoto.)

Auditory temporal resolution plays a critical role in the everyday experience of listening to complex acoustic patterns. Amplitude modulation detection thresholds are widely used to measure auditory temporal resolution. In an attempt to develop a standardized clinical test of auditory temporal resolution, we used ZEST (Zippy Estimation by Sequential Testing, a Bayesian threshold estimation procedure, to measure amplitude modulation detection thresholds. ZEST utilizes prior knowledge about a listener's thresholds, as represented by a probability density function of the thresholds, and psychometric functions of the listener's responses. This paper reports a preliminary study in which ZEST parameters that could be used for measurements of amplitude modulation detection thresholds were sought. For this purpose, we created histograms of the detection thresholds for a wide range of modulation frequencies, measured the psychometric functions of amplitude modulation detection, and performed computer simulations of ZEST threshold estimation. The results suggested that, with appropriately-set parameters, ZEST allows for the accurate estimation of amplitude modulation detection thresholds within 20 trials., Competing Interests: TM was employed by RION Co., Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Mori, Morimoto, Murata, Okamoto and Kanzaki.)

Background: Advanced glycation end products (AGEs) are heterogeneous proinflammatory molecules produced by a non-enzymatic glycation reaction between reducing sugars (and their metabolites) and biomolecules with amino groups, such as proteins. Although increases in and the accumulation of AGEs have been implicated in the onset and exacerbation of lifestyle- or age-related diseases, including diabetes, their physiological functions have not yet been elucidated in detail., Methods and Results: The present study investigated the cellular responses of the macrophage cell line RAW264.7 stimulated by glycolaldehyde-derived AGEs (Glycol-AGEs) known as representative toxic AGEs. The results obtained showed that Glycol-AGEs significantly promoted the proliferation of RAW264.7 cells at a low concentration range (1-10 µg/mL) in a concentration-dependent manner. On the other hand, neither TNF-α production nor cytotoxicity were induced by the same concentrations of Glycol-AGEs. The increases observed in cell proliferation by low concentrations of Glycol-AGEs were also detected in receptor triple knockout (RAGE-TLR4-TLR2 KO) cells as well as in wild-type cells. Increases in cell proliferation were not affected by various kinase inhibitors, including MAP kinase inhibitors, but were significantly suppressed by JAK2 and STAT5 inhibitors. In addition, the expression of some cell cycle-related genes was up-regulated by the stimulation with Glycol-AGEs., Conclusions: These results suggest a novel physiological role for AGEs in the promotion of cell proliferation via the JAK-STAT pathway., (© 2023. The Author(s), under exclusive licence to Springer Nature B.V.)

Histamine is a well-known inflammatory mediator, but how histamine induces angiogenesis remains poorly understood. In the present study, we demonstrated a dose-dependent dynamic tube formation in the human endothelial cell line EA.hy926 in the presence of histamine that was completely blocked by histamine H1 receptor (H1R) and protein kinase C (PKC) inhibitors. However, histamine H2, H3, and H4 receptor inhibitors did not inhibit tube formation, suggesting that H1R-PKC signaling is involved in histamine-induced tube formation. Moreover, we found an H1-specific induction of vascular endothelial growth factor (VEGF) expression. Inhibition of VEGF receptor 2 (VEGFR2) suppressed the histamine-induced tube formation, indicating that VEGF is downstream of histamine signaling. Additionally, we demonstrated that histamine stimulation induces the expression of critical regulators of angiogenesis such as matrix metalloproteinase (MMP)-9 and MMP-14 metalloproteases, as histamine-induced tube formation is blocked by MMP inhibitors. In summary, our study indicates that histamine can activate the H1R in human endothelial cells and thereby promote tube formation through the PKC, MMP, and VEGF signaling pathways., Competing Interests: Declaration of competing interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 The Authors. Production and hosting by Elsevier B.V. All rights reserved.)

The coronavirus disease 2019 (COVID-19) pandemic has considerably affected several social services. The Ministry of Health, Labour, and Welfare has partially revised the Pharmaceuticals and Medical Devices Law and established legislations on permanent online medication instructions. Based on these social needs, the development of human resources to provide online medication instructions is vital. Therefore, we developed a training program for providing online medication instructions in preparatory clinical education. Pharmacy students who had conducted medical interviews with standardized patients participated in the training. Educational outcomes were evaluated using an objective multiple-choice test and free description before and after practical training. The median number of correct answers on objective tests on the legislation on online medication instructions increased significantly. Based on the free description analysis, students were able to comprehend the influence of communication environment on the quality of medication instructions. Based on the results of the direct evaluation using objective testing and indirect evaluation by analyzing the free descriptions, they also acquired the skills necessary for providing online medication instructions. Therefore, this training program can contribute to mastering the provision of online medication instructions.

Background: Methylglyoxal (MGO) is a known toxic byproduct of glycolysis, with MGO-induced cytotoxicity believed to contribute to the pathogenesis of several diseases. Glyoxalase I (GLO1) is a key enzyme for eliminating MGO in mammalian cells, therefore, compounds affecting GLO1 activity are potential therapeutic agents for MGO-induced disorders. Previously, we found nordihydroguaiaretic acid (NDGA) as a potent GLO1 inhibitor., Methods: The inhibitory characteristics of NDGA were determined spectrophotometrically with recombinant GLO1. NDGA-induced growth-inhibition and accumulation of MGO-derived advanced glycation end products (AGEs) were examined in EA.hy926 cells., Results: NDGA showed significant inhibition of GLO1 enzymatic activity in a dose-dependent manner. Its K i value was estimated to be 146-fold lower than that of myricetin, a known GLO1 inhibitor. The co-addition of MGO with NDGA to the cells resulted in significant growth inhibition, suggesting that MGO accumulation, sufficient to affect cell growth, was caused by NDGA inhibiting GLO1. These findings were supported by the observations that the addition of aminoguanidine, a typical MGO scavenger, significantly reversed cell-growth inhibition by co-addition of MGO with NDGA, and that an increase in intracellular MGO-derived AGEs was observed during incubation with the co-addition of MGO with NDGA., Conclusion: NDGA was found to be a novel and potent inhibitor of GLO1. The co-addition of NDGA with MGO to the cells resulted in increased intracellular MGO accumulation followed by enhanced cell-growth inhibition., (© 2022. The Author(s), under exclusive licence to Springer Nature B.V.)

Introduction: Past studies have provided evidence that the effects of tactile stimulation on binocular rivalry are mediated by primitive features (orientation and spatial frequency) common in vision and touch. In this study, we examined whether such effects on binocular rivalry can be obtained through the roughness of naturalistic objects. In three experiments, the total dominant time of visual percepts of two objects was measured under binocular rivalry when participants touched one of the objects., Result: In Experiment 1, the total dominant time for the image of artificial turf and bathmat was prolonged by congruent tactile stimulation and shortened by incongruent tactile stimulation. In Experiment 2, we used the same stimuli but rotated their visual images in opposite directions. The dominant time for either image was prolonged by congruent tactile stimulation. In Experiment 3, we used different types of stimuli, smooth marble and rough fabric, and noted significant effects of the congruent and incongruent tactile stimulation on the dominant time of visual percepts., Conclusion: These three experiments demonstrated that visuo-tactile interaction on binocular rivalry can be mediated by roughness., (© 2022. The Author(s).)

Background: We previously reported that advanced glycation endproducts (AGEs) increase the proinflammatory activity of high mobility group box-1 (HMGB1), a representative damage-associated molecular pattern molecule (DAMP), through their direct interaction. This suggested that AGEs activate other DAMPs and led us to search for novel DAMPs capable of interacting with AGEs., Methods and Results: The chromatographic analysis using AGE-immobilized gel revealed the ribosomal protein family to be a factor with binding activity to AGEs. Ribosomal protein L9 (RPL9), a member of the ribosomal protein family, was found in the centrifugal supernatant of ruptured cells and in the serum of lipopolysaccharide (LPS)-stimulated sepsis model mice, exhibiting similar characteristic properties to HMGB1. Although HMGB1 potentiated LPS-stimulated TNF-α expression in macrophage-like RAW264.7 cells, RPL9 hardly exhibited this activity. Of note, RPL9 significantly suppressed the potentiated mRNA expression and protein production of TNF-α by HMGB1 plus LPS stimulation, suggesting its regulatory roles in DAMP-induced proinflammatory activity. Based on the differential scanning fluorimetric analysis, the direct interaction between RPL9 and HMGB1 may play a role in the suppressive effects of RPL9., Conclusions: This study suggested that RPL9 is a novel type of DAMP with a regulatory role in the proinflammatory response and provided insight into the pathophysiology of inflammatory diseases., (© 2021. The Author(s), under exclusive licence to Springer Nature B.V.)

Advanced Glycation End Products (AGEs) are produced through a non-enzymatic reaction between reducing sugar and biomolecules. These molecules are suggested to stimulate several receptors and activate inflammatory reactions. Because the accumulation of AGEs was found to be associated with hyperglycemia and/or aging, these molecules should be contributed to the pathogenesis of inflammatory diseases related to these conditions. Interestingly, possible receptors to engage AGEs are common to endogenous proinflammatory factors called damage-associated molecular pattern molecules (DAMPs). This raised the possibility that the action mechanism of AGEs and DAMPs is closely correlated. Previously, we found that AGEs interacted with high mobility group box-1 (HMGB1), a representative DAMP, and that this interaction activated the proinflammatory activity of HMGB1. These findings suggested that exacerbation of inflammation induced by HMGB1 was caused by the condition accumulating AGEs. In addition, AGEs were found to change the action of tumor necrosis factor-like weak inducer of apoptosis (TWEAK) through their direct interaction. TWEAK is called a multifunctional cytokine, and is suggested to regulate tumor necrosis factor-α (TNF-α) induced inflammatory reactions. We found that coexistence of AGEs and TWEAK inhibited this action of TWEAK, suggesting that accumulation of AGEs induces exacerbation of inflammation induced by TNF-α. Furthermore, we found ribosomal protein L9 (RPL9) as a novel AGE-binding protein. RPL9 inhibited HMGB1-induced inflammatory reaction, suggesting that RPL9 is the endogenous regulator for DAMPs. These findings suggested that there is a novel mechanism to regulate inflammatory reactions through the interaction among AGEs, DAMPs, and/or cytokines.

Nagata, A, Doma, K, Yamashita, D, Hasegawa, H, and Mori, S. The effect of augmented feedback type and frequency on velocity-based training-induced adaptation and retention. J Strength Cond Res 34(11): 3110-3117, 2020-The purpose of this study was to compare the benefits of 4 weeks of velocity-based training (VBT) using different augmented feedback (AugFb) types and the frequency of AugFb, and whether adaptations are retained 10 days post-training. Thirty-seven collegiate male rugby players were divided into groups that received immediate feedback (ImFb; n = 9), visual feedback (ViFb; n = 10), average feedback (AvgFb; n = 10) and no feedback (NoFb; n = 8) during each VBT session consisting of 3 sets of 5 repetitions of loaded jump squats. The ImFb group received AugFb regarding lifting velocity under loaded jump squats (LV-JS) after every jump, whereas LV-JS measures were averaged after each set of jumps and presented to the AvgFb group. The LV-JS were video-recorded and displayed as kinematic feedback for the ViFb group after each set, although NoFb was provided for the NoFb group. Loaded jump squats measures were reported at baseline, during each training session and 10 days post-training. Loaded jump squats measures were significantly greater for the ImFb Group compared with the other groups during a number of post-baseline time points (p ≤ 0.05). Furthermore, at 4 weeks of VBT and 10 days post-retention, effect size (ES) calculations showed that LV-JS measures were greater with moderate to large effects for the ImFb group compared with the NoFb (ES = 1.02-1.25), AvgFb (ES = 0.78-0.82) and ViFb (ES = 0.74-1.60), respectively. However, LV-JS measures were reduced with moderate to large effects 10 days post-retention for the ViFb (ES = -0.60) and NoFb (ES = -0.85) groups. Providing LV-JS feedback after each jump appears to optimize performance and should be considered as a training tool during VBT.

Previously, we found that advanced glycation endproducts (AGEs) directly interact with tumor necrosis factor (TNF)-like weak inducer of apoptosis, a cytokine that controls inflammation, and that this interaction inhibited its action. This finding raised the novel possibility that AGEs alter the function of other cytokines through direct interaction. To investigate this possibility, we performed comprehensive screening for candidates that interacted with AGEs using protein array analysis. The array analysis revealed that high mobility group box-1 (HMGB1) had a markedly high affinity for AGEs. HMGB1 is a representative proinflammatory damage-associated molecular pattern molecule, and is reported to interact with lipopolysaccharide (LPS) directly to exert its inflammatory function. When LPS, HMGB1, and AGEs were mixed, the mobility of HMGB1 had shifted significantly in native PAGE, suggesting that these three molecules formed a triplet complex. The addition of AGEs to the LPS-HMGB1 mixture synergistically potentiated LPS-HMGB1-stimulated TNF-α mRNA expression in macrophage-like RAW264.7 cells. In addition, using receptor knockout clones, the increased proinflammatory response by LPS-HMGB1-AGEs complex was demonstrated to be mediated via Toll-like receptor 4 and receptor for AGEs. Taken together, this study suggested that AGEs carry out their pathophysiological roles by potentiating the LPS-HMGB1-stimulated proinflammatory response through direct interactions.

High-mobility group box-1 (HMGB1) protein has been postulated to play a pathogenic role in severe sepsis. Histidine-rich glycoprotein (HRG), a 75 kDa plasma protein, was demonstrated to improve the survival rate of septic mice through the regulation of neutrophils and endothelium barrier function. As the relationship of HRG and HMGB1 remains poorly understood, we investigated the effects of HRG on HMGB1-mediated pathway in endothelial cells, focusing on the involvement of specific receptors for HRG. HRG potently inhibited the HMGB1 mobilization and effectively suppressed rHMGB1-induced inflammatory responses and expression of all three HMGB1 receptors in endothelial cells. Moreover, we first clarified that these protective effects of HRG on endothelial cells were mediated through C-type lectin domain family 1 member A (CLEC-1A) receptor. Thus, current study elucidates protective effects of HRG on vascular endothelial cells through inhibition of HMGB1-mediated pathways may contribute to the therapeutic effects of HRG on severe sepsis., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Advanced glycation end-products, especially toxic advanced glycation end-products derived from glyceraldehyde (advanced glycation end-product-2) and glycolaldehyde (advanced glycation end-product-3), are biologically reactive compounds associated with diabetic complications. We previously demonstrated that toxic advanced glycation end-products were internalised into macrophage-like RAW264.7 cells through scavenger receptor-1 class A (CD204). Toxic advanced glycation end-product uptake was inhibited by fucoidan, a sulphated polysaccharide and antagonistic ligand for scavenger receptors, suggesting that sulphated polysaccharides are emerging candidates for treatment of advanced glycation end-product-related diseases. In this study, we compared the effects of six types of sulphated and non-sulphated polysaccharides on toxic advanced glycation end-product uptake in RAW264.7 cells. Fucoidan, carrageenan and dextran sulphate attenuated toxic advanced glycation end-product uptake. Fucoidan and carrageenan inhibited advanced glycation end-product-2-induced upregulation of SR-A, while advanced glycation end-product-3-induced upregulation of scavenger receptor-1 class A was only suppressed by fucoidan. Dextran sulphate did not affect scavenger receptor-1 class A levels in toxic advanced glycation end-product-treated cells. Chondroitin sulphate, heparin and hyaluronic acid failed to attenuate toxic advanced glycation end-product uptake. Heparin and hyaluronic acid had no effect on scavenger receptor-1 class A levels, while chondroitin sulphate inhibited advanced glycation end-product-3-induced upregulation of scavenger receptor-1 class A. Taken together, fucoidan and carrageenan, but not the other sulphated polysaccharides examined, had inhibitory activities on toxic advanced glycation end-product uptake and toxic advanced glycation end-product-induced upregulation of scavenger receptor-1 class A, possibly because of structural differences among sulphated polysaccharides.

High mobility group box-1 (HMGB1), a representative damage associated-molecular pattern (DAMP), has been reported to be involved in many inflammatory diseases. Several drugs are thought to have potential to control the translocation and secretion of HMGB1, or to neutralize extracellular HMGB1 by binding to it. One of these drugs, anti-HMGB1 monoclonal antibody (mAb), is highly specific for HMGB1 and has been shown to be effective for the treatment of a wide range of CNS diseases when modeled in animals, including stroke, traumatic brain injury, Parkinson's disease, epilepsy and Alzheimer's disease. Thus, anti-HMGB1 mAb not only is useful for target validation but also has extensive potential for the treatment of the above-mentioned diseases. In this review, we summarize existing knowledge on the effects of anti-HMGB1 mAb on CNS and PNS diseases, the common features of translocation and secretion of HMGB1 and the functional roles of HMGB1 in these diseases. The existing literature suggests that anti-HMGB1 mAb therapy would be effective for a wide range of CNS and PNS diseases., (Copyright © 2019 The Authors. Production and hosting by Elsevier B.V. All rights reserved.)

Purpose The purpose of this study was to investigate whether speech perception would reflect small latency changes in subcortical speech representation. Method Twelve native Japanese listeners participated in the experiment. Those listeners participated in speech identification task and auditory brainstem response (ABR) measurement using /d/-/t/ continuum stimuli varying in voice onset time (VOT) with manipulation of the amplitude of initial noise (consonant) portion, the duration of which corresponded to VOT. Results Increasing the noise portion amplitude lengthened subcortical representation of VOT, which is the latency difference between ABRs synchronizing to the onsets of initial noise and following periodic (vowel) portions (VOT ABR ) and made listeners likely to perceive the stimuli with ambiguous VOT as a voiceless stop /t/. In addition, the amount of VOT ABR lengthening was close to that of the VOT boundary shortening. Conclusion A few milliseconds of difference in subcortical speech representation are important for the perception of speech sounds with ambiguous acoustic cues. Supplemental Material https://doi.org/10.23641/asha.7728695.

The detection of a silent interval or gap provides important insight into temporal processing by the auditory system. Previous research has uncovered a multitude of empirical findings leaving the mechanism of gap detection poorly understood and key issues unresolved. Here, we expand the findings by measuring psychometric functions for a number of conditions including both across-frequency and across-intensity gap detection as a first study of its kind. A model is presented which not only accounts for our findings in a quantitative manner, but also helps frame the body of work on auditory gap research. The model is based on the peripheral response and postulates that the identification of gap requires the detection of activity associated with silence.

Objectives: Severe acute pancreatitis is a highly lethal disease caused by systemic inflammatory response syndrome, leading to multiple organ failure. We recently showed that histidine-rich glycoprotein (HRG) supplemental therapy ameliorated septic acute respiratory distress syndrome due to unnecessary neutrophil activation and immunothrombosis formation. Here, we evaluated the effect of HRG on lung inflammation followed by pancreatitis in a severe acute pancreatitis mouse model., Methods: Mice received intraperitoneal injections of cerulein 7 times (100 μg/kg each) at 1-hour intervals to induce acute pancreatitis. Immediately after the first cerulein injection, phosphate-buffered saline, human serum albumin (20 mg/kg), or HRG (20 mg/kg) was intravenously injected. One hour after the last cerulein injection, phosphate-buffered saline or lipopolysaccharide (5 mg/kg) was intravenously injected into the tail vein. We evaluated lung inflammatory level after pancreatitis., Results: We observed significantly decreased plasma HRG levels in an acute pancreatitis mouse model. Histidine-rich glycoprotein treatment inhibited lung edema and the accumulation of neutrophil in severe acute pancreatitis, but HRG did not directly affect pancreatitis. Moreover, HRG suppressed tumor necrosis factor α, inducible nitric oxide synthase, interleukin 6, and neutrophil elastase mRNA expression and myeloperoxidase activity in the lung., Conclusions: These data suggested that HRG ameliorated lung inflammation secondary to pancreatitis.

Together with residual host neurons, transplanted neural stem cell (NSC)-derived neurons play a critical role in reconstructing disrupted neural circuits after spinal cord injury (SCI). Since a large number of tracts are disrupted and the majority of host neurons die around the lesion site as the damage spreads, minimizing this spreading and preserving the lesion site are important for attaining further improvements in reconstruction. High mobility group box-1 (HMGB1) is a damage-associated molecular pattern protein that triggers sterile inflammation after tissue injury. In the ischemic and injured brain, neutralization of HMGB1 with a specific antibody reportedly stabilizes the blood-brain barrier, suppresses inflammatory cytokine expression, and improves functional recovery. Using a SCI model mouse, we here developed a combinatorial treatment for SCI: administering anti-HMGB1 antibody prior to transplantation of NSCs derived from human induced pluripotent stem cells (hiPSC-NSCs) yielded a dramatic improvement in locomotion recovery after SCI. Even anti-HMGB1 antibody treatment alone alleviated blood-spinal cord barrier disruption and edema formation, and increased the number of neurites from spared axons and the survival of host neurons, resulting in functional recovery. However, this recovery was greatly enhanced by the subsequent hiPSC-NSC transplantation, reaching an extent that has never before been reported. We also found that this improved recovery was directly associated with connections established between surviving host neurons and transplant-derived neurons. Taken together, our results highlight combinatorial treatment with anti-HMGB1 antibody and hiPSC-NSC transplantation as a promising novel therapy for SCI. Stem Cells 2018;36:737-750., (© 2018 The Authors Stem Cells published by Wiley Periodicals, Inc. on behalf of AlphaMed Press.)

Advanced glycation end-products (AGEs), which comprise non-enzymatically glycosylated proteins, lipids, and nucleic acid amino groups, play an important role in several diseases and aging processes including angiopathy, renal failure, diabetic complications, and neurodegenerative diseases. Among AGE-associated phenotypes, toxic AGEs, glyceraldehyde-derived AGE-2, and glycolaldehyde-derived AGE-3 are involved in the pathogenesis of diabetic complications. In addition, macrophages are reported to remove extracellular AGEs from tissues via scavenger receptors, leading to the progression of atherosclerosis. In the present study, we found that AGE-2 and AGE-3 enhanced their own endocytic uptake by RAW264.7 mouse macrophage-like cells in a concentration-dependent manner. Furthermore, we demonstrated, for the first time, the morphology of phagocytic macrophages and the endocytosis of AGE particles. The toxic AGEs induced the expression of a scavenger receptor, CD204/scavenger receptors-1 class A (SR-A). Notably, an antibody against CD204 significantly prevented toxic AGE uptake. Moreover, an SR-A antagonistic ligand, fucoidan, also attenuated the AGE-2- and AGE-3-evoked uptake in a concentration-dependent manner. These results indicated that SR-A stimulation, at least in part, plays a role in AGE uptake.

Objectives: Many biomarkers for sepsis are used in clinical practice; however, few have become the standard. We measured plasma histidine-rich glycoprotein levels in patients with systemic inflammatory response syndrome. We compared histidine-rich glycoprotein, procalcitonin, and presepsin levels to assess their significance as biomarkers., Design: Single-center, prospective, observational cohort study., Setting: ICU at an university-affiliated hospital., Patients: Seventy-nine ICU patients (70 with systemic inflammatory response syndrome and 9 without systemic inflammatory response syndrome) and 16 healthy volunteers., Interventions: None., Measurements and Main Results: We collected blood samples from patients within 24 hours of ICU admission. Histidine-rich glycoprotein levels were determined using enzyme-linked immunosorbent assay. The median histidine-rich glycoprotein level in healthy volunteers (n = 16) was 63.00 µg/mL (interquartile range, 51.53-66.21 µg/mL). Histidine-rich glycoprotein levels in systemic inflammatory response syndrome patients (n = 70; 28.72 µg/mL [15.74-41.46 µg/mL]) were lower than those in nonsystemic inflammatory response syndrome patients (n = 9; 38.64 µg/mL [30.26-51.81 µg/mL]; p = 0.049). Of 70 patients with systemic inflammatory response syndrome, 20 had sepsis. Histidine-rich glycoprotein levels were lower in septic patients than in noninfective systemic inflammatory response syndrome patients (8.71 µg/mL [6.72-15.74 µg/mL] vs 33.27 µg/mL [26.57-44.99 µg/mL]; p < 0.001) and were lower in nonsurvivors (n = 8) than in survivors (n = 62) of systemic inflammatory response syndrome (9.06 µg/mL [4.49-15.70 µg/mL] vs 31.78 µg/mL [18.57-42.11 µg/mL]; p < 0.001). Histidine-rich glycoprotein showed a high sensitivity and specificity for diagnosing sepsis. Receiver operating characteristic curve analysis for detecting sepsis within systemic inflammatory response syndrome patients showed that the area under the curve for histidine-rich glycoprotein, procalcitonin, and presepsin was 0.97, 0.82, and 0.77, respectively. In addition, survival analysis in systemic inflammatory response syndrome patients revealed that the Harrell C-index for histidine-rich glycoprotein, procalcitonin, and presepsin was 0.85, 0.65, and 0.87, respectively., Conclusions: Histidine-rich glycoprotein levels were low in patients with sepsis and were significantly related to mortality in systemic inflammatory response syndrome population. Furthermore, as a biomarker, histidine-rich glycoprotein may be superior to procalcitonin and presepsin.

Purpose: The purpose of this study was to investigate the psychophysical boundary used for categorization of voiced-voiceless stop consonants in native Japanese speakers., Method: Twelve native Japanese speakers participated in the experiment. The stimuli were synthetic stop consonant-vowel stimuli varying in voice onset time (VOT) with manipulation of the amplitude of the initial noise portion and the first formant (F1) frequency of the periodic portion. There were 3 tasks, namely, speech identification to either /d/ or /t/, detection of the noise portion, and simultaneity judgment of onsets of the noise and periodic portions., Results: The VOT boundaries of /d/-/t/ were close to the shortest VOT values that allowed for detection of the noise portion but not to those for perceived nonsimultaneity of the noise and periodic portions. The slopes of noise detection functions along VOT were as sharp as those of voiced-voiceless identification functions. In addition, the effects of manipulating the amplitude of the noise portion and the F1 frequency of the periodic portion on the detection of the noise portion were similar to those on voiced-voiceless identification., Conclusion: The psychophysical boundary of perception of the initial noise portion masked by the following periodic portion may be used for voiced-voiceless categorization by Japanese speakers.

M2 macrophage (Mφ) promotes pathologic angiogenesis through a release of pro-angiogenic mediators or the direct cell-cell interaction with endothelium in the micromilieu of several chronic inflammatory diseases, including rheumatoid arthritis and cancer, where interleukin (IL)-18 also contributes to excessive angiogenesis. However, the detailed mechanism remains unclear. The aim of this study is to investigate the mechanism by which M2 Mφs in the micromilieu containing IL-18 induce excessive angiogenesis in the in vitro experimental model using mouse Mφ-like cell line, RAW264.7 cells, and mouse endothelial cell line, b.End5 cells. We discovered that IL-18 acts synergistically with IL-10 to amplify the production of Mφ-derived mediators like osteopontin (OPN) and thrombin, yielding thrombin-cleaved form of OPN generation, which acts through integrins α4/α9, thereby augmenting M2 polarization of Mφ with characteristics of increasing surface CD163 expression in association with morphological alteration. Furthermore, the results of visualizing temporal behavior and morphological alteration of Mφs during angiogenesis demonstrated that M2-like Mφs induced excessive angiogenesis through the direct cell-cell interaction with endothelial cells, possibly mediated by CD163.

The apoptotic process of erythrocytes is known as eryptosis, and is characterized by phosphatidylserine (PS) expression on the outer membrane. PS-positive erythrocytes are increased in sepsis, and PS is believed to facilitate coagulation of erythrocytes and activate macrophages. However, the relationship between eryptosis and abnormal coagulation in sepsis is still not fully understood. Histidine-rich glycoprotein (HRG) inhibits immunothrombus formation by regulating neutrophils and vascular endothelial cells. In the present study, we subjected isolated erythrocytes to Zn 2+ stimulation, which activated their aggregation and PS expression. We then determined the Zn 2+ contents in septic lung and kidney tissues, and found that they were elevated, suggesting that eryptosis was enhanced in these tissues. Erythrocyte adhesion to endothelial cells was also significantly increased after Zn 2+ stimulation, and this effect was inhibited by HRG. Finally, we examined HRG treatment in septic model mice, and found that HRG decreased hemolysis, possibly due to its ability to bind heme. Our study demonstrated a novel Zn 2+ -initiated aggregation/thrombus formation pathway. We also showed the regulatory role of HRG in this pathway, together with the ability of HRG to inhibit hemolysis under septic conditions. HRG supplementation might be a novel therapeutic strategy for inflammatory disorders, especially sepsis., (Copyright © 2018 The Authors. Production and hosting by Elsevier B.V. All rights reserved.)

Advanced glycation end products (AGEs) are formed from the non-enzymatic glycation reaction of reducing sugars or their metabolites with the free amino groups of several biomolecules and are known to play pathophysiological roles in various inflammatory diseases. In an earlier study, it was suggested that tumor necrosis factor-like weak inducer of apoptosis (TWEAK) has a unique role to regulate the tumor necrosis factor α (TNFα)-induced inflammatory response. In this study, we investigated the effect of the AGEs-TWEAK interaction on proinflammatory signaling responses in endothelial cells and the influence of AGEs on the cellular function of TWEAK in the inflammatory process. The effect of AGEs on the TWEAK/TNFα-induced gene expression of interleukin-8 (IL-8) was determined by real-time RT-PCR in endothelial-like EA.hy.926 cells. The pull-down assay was performed using recombinant His-tagged TWEAK and AGEs. The NF-κB activation was analyzed by Western blotting with canonical and non-canonical pathway-specific antibodies. AGEs dose-dependently inhibited TWEAK-induced IL-8 gene expression, whereas AGEs themselves had almost no effect on IL-8 expression. AGEs were found to bind directly to TWEAK in the pull-down assay. TNFα-induced IL-8 production and canonical NF-κB activation were suppressed by TWEAK pretreatment, whereas TWEAK-induced non-canonical NF-κB activation was enhanced by pretreatment. These effects induced by TWEAK pretreatment were abolished by the co-addition of AGEs. Our findings suggest that AGEs attenuate the function of TWEAK to regulate the TNFα-induced inflammatory responses, which provide important clues for understanding the significance of the AGEs-TWEAK interaction in inflammatory processes.