Evaluating perioperative stresses in children by noninvasive modalities using salivary cortisol and autonomic reactivity.

PURPOSE: Salivary cortisol (SalC) and low to high pulse ratio (LHR) were used for evaluating perioperative stresses in children. METHODS: Children aged 6 months-16 years having elective general (thoracic/abdominal) or minor (open/minimally invasive: MI) procedures underwent pulse monitoring during AM (08:00-12:00) and PM (17:00-21:00) saliva collections from the day before surgery (S-1) to 3 days after surgery (S + 3). SalC/LHR were correlated with age, sex, caregiver attendance, operative time, and surgical site/approach using mixed model analysis and face/numeric pain rating scales (FRS/NRS). RESULTS: Mean ages (years): minor-open (n = 31) 4.7 ± 2.0, thoracic-open (n = 2) 8.7 ± 4.9, thoracic-MI (n = 6) 9.6 ± 6.1, abdominal-open (n = 14) 4.3 ± 4.1, and abdominal-MI (n = 32) 8.0 ± 5.0. Postoperative SalC increased rapidly and decreased to preoperative levels by S + 3 (p < 0.001). LHR increased slightly without decreasing (p = 0.038). SalC correlated positively with operative time (p = 0.036) and open surgery (p = 0.0057), and negatively with age (p < 0.0001) and caregiver attendance (p < 0.001). SalC correlated positively with FRS (n = 51) at S + 2(PM) (p = 0.023), S + 3(AM) (p < 0.001), S + 3(PM) (p = 0.012) and NRS (n = 34) at S + 1(AM) (p = 0.031), S + 3(AM) (p < 0.044). LHR positively correlated with age (p = 0.0072), female sex (p = 0.0047), and caregiver attendance (p = 0.0026). Postoperative SalC after robotic-assisted MI was significantly lower than after open surgery at S + 2(AM) (p = 0.020). CONCLUSIONS: SalC correlated with pain. Caregiver attendance effectively alleviated stress.

The Impact of 5-Aminolevulinic Acid Supplementation on Redox Balance and Aerobic Capacity.

We examined the impact of 5-aminolevulinic acid (5-ALA) and sodium-ferrous-citrate supplementation on aerobic capacity and redox balance through a placebo-controlled, double-blind trial. Fourteen healthy volunteers were randomly assigned to Pla + ALA (4-week placebo followed by 4-week 5-ALA supplementation) or ALA + Pla (4-week 5-ALA supplement followed by a 4-week placebo) group and administered 5-ALA (25 mg/day) or placebo once daily. The participants underwent submaximal incremental cycling tests at weeks 0, 2, 4, 6, and 8. In the cycling test at week 0, individual load-intensity stages required for blood lactate levels >2 mmol/L (lactate threshold, LT) and 4 mmol/L (onset of blood lactate accumulation, OBLA) were determined. The heart rate (HR), blood lactate (La), and oxidative stress markers (diacron reactive oxygen metabolite, d-ROMs; biological antioxidant potential, BAP) were measured at resting, LT, and OBLA states in each cycling test. Marker values were not significantly different between the groups. HR, La, and d-ROMs at resting, LT, and OBLA states were not significantly different among the conditions. BAP and BAP/d-ROMs ratios were significantly different in the OBLA state at week 4 of the 5-ALA group compared with that of the placebo group (p < 0.05). In conclusion, 5-ALA supplementation might improve redox balance during high-intensity aerobic exercise.

Oral Administration of the Japanese Traditional Medicine Keishibukuryogan-ka-yokuinin Decreases Reactive Oxygen Metabolites in Rat Plasma: Identification of Chemical Constituents Contributing to Antioxidant Activity.

Insufficient detoxification and/or overproduction of reactive oxygen species (ROS) induce cellular and tissue damage, and generated reactive oxygen metabolites become exacerbating factors of dermatitis. Keishibukuryogan-ka-yokuinin (KBGY) is a traditional Japanese medicine prescribed to treat dermatitis such as acne vulgaris. Our aim was to verify the antioxidant properties of KBGY, and identify its active constituents by blood pharmacokinetic techniques. Chemical constituents were quantified in extracts of KBGY, crude components, and the plasma of rats treated with a single oral administration of KBGY. Twenty-three KBGY compounds were detected in plasma, including gallic acid, prunasin, paeoniflorin, and azelaic acid, which have been reported to be effective for inflammation. KBGY decreased level of the diacron-reactive oxygen metabolites (d-ROMs) in plasma. ROS-scavenging and lipid hydroperoxide (LPO) generation assays revealed that gallic acid, 3-O-methylgallic acid, (+)-catechin, and lariciresinol possess strong antioxidant activities. Gallic acid was active at a similar concentration to the maximum plasma concentration, therefore, our findings indicate that gallic acid is an important active constituent contributing to the antioxidant effects of KBGY. KBGY and its active constituents may improve redox imbalances induced by oxidative stress as an optional treatment for skin diseases.

Suppressive effect of Yokukansan on glutamate released from canine keratinocytes.

Background: Canine atopic dermatitis (CAD) is caused by skin barrier dysfunction due to allergen exposure. Excessive glutamate release in the skin is associated with delayed skin barrier function recovery and epidermal thickening and lichenification. Treatment with Yokukansan (YKS), a traditional Japanese medicine, reduces dermatitis severity and scratching behavior in NC/Nga mice by decreasing epidermal glutamate levels. However, the association between canine keratinocytes and glutamate and the mechanism by which YKS inhibits glutamate release from keratinocytes remains unknown. Aim: We aimed to investigate glutamate release from canine progenitor epidermal keratinocytes (CPEKs) and the inhibitory effect of YKS on this release. We also explored the underlying mechanism of YKS to enable its application in CAD treatment. Methods: Glutamate produced from CPEKs in the medium at 24 hours was measured. The measurement conditions varied in terms of cell density and YKS concentration. CPEKs were treated with a glutamate receptor antagonist (MK-801), a glutamate transporter antagonist (THA), and a glutamate dehydrogenase inhibitor (epigallocatechin gallate; EGCG), and the inhibitory effect of YKS, YKS + THA, MK-801, and EGCG on this release was determined. MK-801 and glutamate dehydrogenase inhibitor were tested alone, and THA was tested in combination with YKS. Finally, glutamine incorporated into CPEKs at 24 hours was measured using radioisotope labeling. Results: CPEKs released glutamate in a cell density-dependent manner, inhibited by YKS in a concentration-dependent manner. Moreover, YKS reduced the intracellular uptake of radioisotope-labeled glutamine in a concentration-dependent manner. No involvement of glutamate receptor antagonism or activation of glutamate transporters was found, as suggested by previous studies. In addition, EGCG could inhibit glutamate release from CPEKs. Conclusion: Our findings indicated that glutamate release from CPEKs could be effectively inhibited by YKS, suggesting the utility of YKS in maintaining skin barrier function during CAD. In addition, CPEKs are appropriate for analyzing the mechanism of YKS. However, we found that the mechanism of action of YKS differs from that reported in previous studies, suggesting that it may have had a similar effect to EGCG in this study. Further research is warranted to understand the exact mechanism and clinical efficacy in treating CAD.

Does tomato juice consumption have a positive effect on the physical and psychological states of individuals in the Coronavirus era?

OBJECTIVES: This preliminary study aims to examine the effects of tomato juice, which can be easily consumed regularly, on the physical and psychological states of healthy adults in the Coronavirus era. DESIGN: Prospective observational study. MATERIALS AND METHODS: Ten healthy adults (mean age, 39.7±4.2 years) who consumed 180 mL of tomato juice twice daily for 4 weeks were enrolled. Measurements were taken before and after 4 weeks of consumption for the items below. Five salivary stress biomarkers (cortisol, α-amylase, secretory immunoglobulin A, chromogranin A, and oxytocin) were measured using approximately 1ml of passively pooled saliva samples, which were stored at -20°C until measurement. Autonomic nervous system (ANS) activity was evaluated using an acceleration pulse wave meter. Skin moisture content and transepidermal water loss (TEWL) were measured using Multi Display devices® MDD4 with specific probes. Subjective psychological states were assessed using Profile of Mood Status (POMS2®) and a survey on skin condition was conducted. RESULTS: As for salivary stress biomarkers, tomato juice intake reduced cortisol and significantly increased oxytocin levels (p = 0.0427). No significant changes were observed in ANS activity. POMS2® results showed a significant decrease in confusion and bewilderment (p = 0.0207). Skin moisture content increased significantly (p = 0.0011), whereas TEWL decreased. The skin condition survey revealed significant changes in 10 parameters. CONCLUSIONS: Tomato juice, which can be easily consumed regularly, may alleviate the stress of healthy adults in the Coronavirus era, supported by positive changes in salivary stress biomarker levels, skin moisture content, TEWL, and POMS2® results of this preliminary study.

Shoseiryuto Promotes the Formation of a Tight-Junction Barrier in Cultured Human Bronchial Epithelial Cells.

Shoseiryuto (SST) (Xiao-Qing-Long-Tang in Chinese) is an effective treatment for respiratory diseases, such as bronchial asthma and allergic rhinitis, but its effects on the bronchial tight-junction (TJ) barrier have not been clarified. This study aimed to evaluate the effect of SST on TJ-barrier function in human bronchial epithelial (16HBE) cells. The 16HBE cells were cultured in a culture medium without (control) and with SST in the absence and presence of bacterial endotoxin lipopolysaccharide (LPS) in transwell chambers. Transepithelial electrical resistance (TEER) and sodium fluorescein (Na-F) permeability of the cultured-cell monolayer were measured as TJ integrity markers. In addition, immunofluorescence staining and quantitative real-time polymerase chain reaction analysis were used to measure the expression of the TJ protein, occludin. SST increased TEER and decreased Na-F permeability of the 16HBE cell monolayers. Furthermore, SST increased both occludin mRNA and immunostained protein expressions, suggesting that SST has the effect of directly promoting epithelial TJ-barrier function. LPS decreased TEER, increased Na-F permeability, and decreased both occludin mRNA and protein expression. LPS-induced barrier dysfunction was completely blocked by pre/co- and posttreatment with SST. These results suggest that SST has protective and therapeutic effects against LPS-induced TJ-barrier damage. To our knowledge, these are the first results to demonstrate the protective and therapeutic effects conferred by TJ-barrier promoting, which may be a novel mechanism contributing to the efficacy of SST for respiratory diseases.

Differences in the diurnal variation of salivary stress biomarkers during the coronavirus (COVID-19) pandemic between telecommuters and office workers.

OBJECTIVES: It is necessary to objectively assess the stress state of workers, from the standpoint of holistic palliative care, in order to determine how the rapid change in work styles in the "live with coronavirus era"-in which people will coexist and live with the coronavirus (COVID-19)-will affect their physical and mental health. The aim of this study is to assess the impact of rapid changes in work patterns during the COVID-19 pandemic on the neuroendocrine stress response of workers. DESIGN AND METHODS: A total of sixteen subjects, 9 telecommuters (2 males, 7 females; age, 37.1±2.6 years) and 7 office workers (3 males, 4 females; age, 37.3±3.0 years) who provided their informed consent were enrolled in this prospective observational study. Saliva was collected four times a day (after waking, noon, evening, and before bedtime) and three times a week (Monday, Wednesday, and Friday) during May and June 2020. The saliva samples were stored at -20°C until measurement. Saliva components were analyzed by ELISA for cortisol, melatonin, s-IgA, and oxytocin. RESULTS: The diurnal variation of salivary components between telecommuting and office work groups was investigated. Cortisol showed diurnal variation with higher secretion during waking hours and lower secretion toward nighttime in both groups, and no modulation was observed. In the office work group Melatonin showed diurnal variation, with increased secretion at night. In contrast, the telecommuting group showed modulation, with higher secretion at waking and lower secretion at night. s-IgA showed diurnal variation with a high level at waking and a low level thereafter in both groups, and no modulation was observed. The telecommuting group showed higher oxytocin levels in comparison to the office work group. CONCLUSIONS: These results suggest that the absence of commuting in the telecommuting group reduces anxiety due to infection, and that the diurnal variation of melatonin may be due to the alteration of circadian rhythm caused by being at home all day.

A network pharmacology-based investigation of emodin against pancreatic adenocarcinoma.

Pancreatic adenocarcinoma (PAAD) is one of the most common malignancies worldwide with an increasing incidence and poor outcome due to the lack of effective diagnostic and treatment methods. Emerging evidence implicates that emodin displays extensive spectrum anticancer properties. Differential expression genes in PAAD patients were analyzed by Gene Expression Profiling Interactive Analysis (GEPIA) website, and the targets of emodin were obtained via Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform. Subsequently, enrichment analyses were performed using R software. A protein-protein interaction (PPI) network was constructed by STRING database and Cytoscape software was used to identify the hub genes. Prognostic value and immune infiltration landscapes were explored through Kaplan-Meier plotter (KM plotter) website and the Single-Sample Gene Set Enrichment Analysis package of R. Finally, molecular docking was used to computationally verify the interaction of ligand and receptor proteins. A total of 9191 genes were significantly differentially expressed in PAAD patients and 34 potential targets of emodin were obtained. Intersections of the 2 groups were considered as potential targets of emodin against PAAD. Functional enrichment analyses illustrated that these potential targets were linked to numerous pathological processes. Hub genes identified through PPI networks were correlated with poor prognosis and infiltration level of different immune cells in PAAD patients. Perhaps emodin interacted with the key molecules and regulate the activity of them. We revealed the inherent mechanism of emodin against PAAD with the aid of network pharmacology, which provided reliable evidence and a novel guideline for clinical treatment.

Hochuekkito (TJ-41), a Kampo Formula, Ameliorates Cachexia Induced by Colon 26 Adenocarcinoma in Mice.

Cachexia, a major cause of cancer-related death, is characterized by depletion of muscle and fat tissues, anorexia, asthenia, and hypoglycemia. Recent studies indicate that secretions of proinflammatory cytokines such as interleukin-6 (IL-6) play a crucial role in cachexia development, and that these cytokines are secreted from not only cancer cells but also host cells such as macrophages. In this study, we investigated the therapeutic effects of hochuekkito, a Kampo formula, on cachexia induced by colon 26 adenocarcinoma in mice. Hochuekkito treatment did not inhibit tumor growth, but significantly attenuated the reduction in carcass weight, food and water intake, weight of the gastrocnemius muscle and fat tissue around the testes, and decrease of serum triglyceride level compared with controls. Furthermore, hochuekkito treatment significantly reduced serum IL-6 level and IL-6 expression level in macrophages in tissues surrounding the tumor. In vitro studies showed that hochuekkito suppressed the production of IL-6 by THP-1 or RAW264.7 macrophage cells, although it did not affect IL-6 production by colon 26 carcinoma cells. These results suggest that hochuekkito inhibits the production of proinflammatory cytokines, particularly IL-6, by host cells such as macrophages. Therefore, hochuekkito may be a promising anticachectic agent for the treatment of patients with cancer.

Inchinkoto, the Traditional Japanese Kampo Medicine, Enhances Intestinal Epithelial Barrier Function In Vitro.

Inchinkoto (ICKT), a traditional herbal medicine that is often used as a hepatoprotective drug in Japan, has pharmacological properties that include antioxidant, anti-inflammatory, and choleretic actions. Genipin is a metabolite of geniposide and the most abundant ingredient of ICKT; furthermore, it is considered to be the active substance responsible for its pharmacological properties in the liver. Drugs with such pharmacological characteristics are expected to prevent intestinal barrier dysfunction, which causes inflammatory bowel diseases (IBDs). However, no studies have investigated the effects of ICKT on the intestinal epithelial barrier. Therefore, we investigated the activity of ICKT in intestinal tight junctions by using cultured Caco-2 cell monolayers. The action of the compound on tight junctions was examined by measuring transepithelial electrical resistance (TEER) and sodium fluorescein (Na-F) permeability in the presence or absence of lipopolysaccharide (LPS). Moreover, the expression of the tight junction protein claudin-1 was assessed by using immunofluorescent staining. ICKT and genipin increased TEER and decreased Na-F permeability, which was suggestive of enhanced intestinal epithelial barrier function. Moreover, they prevented the LPS-induced destruction of the barrier, i.e., a decrease in TEER and an increase in Na-F permeability. Immunofluorescence staining revealed a high claudin-1 expression level on the cell surface, whereas exposure to LPS downregulated claudin-1. In turn, ICKT and genipin prevented the LPS-mediated reduction of claudin-1. These results suggest that ICKT enhances intestinal epithelial barrier function by upregulating claudin-1. Furthermore, genipin contributed to these effects. ICKT may be a promising medicine for the prevention and treatment of diseases associated with intestinal barrier disruption, such as IBD, obesity, and metabolic disorders.

The blood-brain barrier permeability of geissoschizine methyl ether in Uncaria hook, a galenical constituent of the traditional Japanese medicine yokukansan.

Geissoschizine methyl ether (GM) in Uncaria hook, a galenical constituent of yokukansan is thought to be one of active components in the psychotropic effect of yokukansan, a traditional Japanese medicine (kampo medicine). However, there is no data on the blood-brain barrier (BBB) permeability of Uncaria hook-derived alkaloids containing GM. In this study, we investigated the BBB permeability of seven Uncaria hook alkaloids (GM, isocorynoxeine, isorhynchophylline, hirsuteine, hirsutine, rhynchophylline, and corynoxeine) using in vivo and in vitro methods. In the in vivo experiment, seven alkaloids in the plasma and brain of rats orally administered with yokukansan were measured by liquid chromatography-mass spectroscopy/mass spectrometric multiple reaction monitoring assay. In the in vitro experiment, the BBB permeability of seven alkaloids were examined using the BBB model composed of co-culture of endothelial cells, pericytes, and astrocytes. In the in vivo study, six components containing GM but not isocorynoxeine were detected in the plasma, and three (GM, hirsuteine, and corynoxeine) of components were detected in the brain. The in vitro BBB permeability data indicated that seven alkaloids were able to cross brain endothelial cells in culture conditions and that the BBB permeability of GM was higher than those of the other six alkaloids. These results suggest that target ingredient GM in yokukansan administered orally is absorbed into the blood and then reaches the brain through the BBB. This evidence further supports the possibility that GM is an active component in the psychotropic effect of yokukansan.

Effects of yokukansan and donepezil on learning disturbance and aggressiveness induced by intracerebroventricular injection of amyloid ß protein in mice.

The effects of yokukansan and donepezil on learning disturbance and aggressiveness were examined in amyloid ß protein (Aß)-injected mice. Intellicage tests showed that both yokukansan and donepezil ameliorated Aß-induced learning disturbance, but the ameliorating effect of donepezil was not enhanced by concomitant administration of yokukansan. On the other hand, a social interaction test showed that Aß-induced aggressiveness was ameliorated by yokukansan, but not by donepezil. Co-administration of both drugs also ameliorated aggressiveness, as did yokukansan alone. In vitro binding assays revealed that yokukansan did not bind to choline receptors or transporters. In vitro enzyme assays revealed that yokukansan did not affect choline acetyltransferase activity or inhibit acetylcholinesterase activity, as did donepezil. These results suggest that yokukansan might ameliorate aggressiveness without interfering with the pharmacological efficacy (antidementia effect) of donepezil and also that concomitant administration of yokukansan might be useful for amelioration of aggressiveness, which was not lessened by donepezil. The difference in the efficacies of both drugs may be due to a difference in their pharmacological mechanisms.

Comprehensive assessment of the impact of horticultural activities on salivary stress biomarkers, psychological status, and the autonomic nervous system response visualized using a wearable biosensor.

OBJECTIVES: This study aims to comprehensively investigate the changes of salivary stress biomarkers, psychological status, and autonomic nervous system (ANS) response due to horticultural activities (HAs). DESIGN AND METHODS: A prospective observational study was conducted in twenty Japanese healthy adults (mean age, 58.4 years). Flower appreciation, flower arrangement, and farm work experience were performed as three HAs with different working concepts. Five salivary stress biomarkers (cortisol, α-amylase, S-IgA, chromogranin A, and oxytocin) were measured to quantify the stress levels before and after each HA. The Profile of Mood Status 2nd edition (POMS2) was used as a subjective psychological evaluation. Wearable biosensors were used to visualize the continuous ANS response throughout the process. RESULTS: In the POMS2 investigation, the negative factors, which included Anger-Hostility, Confusion-Bewilderment, Depression-Dejection, Tension-Anxiety, and Total Mood Disturbance, were significantly decreased (p=0.0135, p=0.0004, p=0.0024, p=0.0015, p=0.0063, respectively). In the measurement of salivary stress biomarkers, flower appreciation decreased cortisol (p=0.0134), and farm work experience not only decreased cortisol but also increased oxytocin (p=0.0041, p=0.0128 respectively). In the visualization results of the ANS response, a graph demonstrated that the difference in activity between the sympathetic nerve and the parasympathetic nerve was narrowed by a series of HAs. CONCLUSIONS: In healthy adults, HAs had a stress-reducing effect, which was evidenced by neuroendocrinological and psychological evaluations, a study of POMS2, salivary stress biomarkers, and visualization of the ANS response.

Electron-microscopic examination of effects of yokukansan, a traditional Japanese medicine, on degeneration of cerebral cells in thiamine-deficient rats.

We previously demonstrated that yokukansan ameliorated not only learning disturbance but also behavioral and psychological symptoms of dementia-like behaviors (anxiety, aggressiveness) and neurological symptoms (opisthotonus) induced in rats by dietary thiamine deficiency (TD). In the present study, the effects of yokukansan on degeneration of cerebral cells were further examined electron-microscopically during pre-symptomatic and symptomatic stages in TD rats. In the pre-symptomatic TD stage, which appeared as increase in aggressive behaviors on the 21st and 28th days of TD diet-feeding, severe edematous degeneration of astrocytes was detected by electron microscopy, although the changes were not observed by light microscopy. In the symptomatic TD stage (the 34th day) characterized by development of neurological symptoms, severe sponge-like degeneration and multiple hemorrhages in the parenchyma were obvious by light microscopy. The electron-microscopic examination showed degeneration in neurons, oligodendroglias, and myelin sheaths in addition to astrocytes. TD rats, which exhibited multiple hemorrhages light microscopically, showed severe edematous changes and hypertrophy of the foot processes of astrocytes surrounding blood vessels. Administration of yokukansan ameliorated not only the TD-induced aggressive behavior and neurological symptoms but also degeneration of the cerebral cells. These results suggest that the inhibitory effect of yokukansan on degeneration in various brain cells might be closely related to the amelioration of aggression and neurological symptoms in TD rats.

A traditional medicinal herb Paeonia suffruticosa and its active constituent 1,2,3,4,6-penta-O-galloyl-beta-D-glucopyranose have potent anti-aggregation effects on Alzheimer's amyloid beta proteins in vitro and in vivo.

The deposition of amyloid beta (Abeta) protein is a consistent pathological hallmark of Alzheimer's disease (AD) brains; therefore, inhibition of Abeta fibril formation and destabilization of pre-formed Abeta fibrils is an attractive therapeutic and preventive strategy in the development of disease-modifying drugs for AD. This study demonstrated that Paeonia suffruticosa, a traditional medicinal herb, not only inhibited fibril formation of both Abeta(1-40) and Abeta(1-42) but it also destabilized pre-formed Abeta fibrils in a concentration-dependent manner. Memory function was examined using the passive-avoidance task followed by measurement of Abeta burden in the brains of Tg2576 transgenic mice. The herb improved long-term memory impairment in the transgenic mice and inhibited the accumulation of Abeta in the brain. Three-dimensional HPLC analysis revealed that a water extract of the herb contained several different chemical compounds including 1,2,3,4,6-penta-O-galloyl-beta-D-glucopyranose (PGG). No obvious adverse/toxic were found following treatment with PGG. As was observed with Paeonia suffruticosa, PGG alone inhibited Abeta fibril formation and destabilized pre-formed Abeta fibrils in vitro and in vivo. Our results suggest that both Paeonia suffruticosa and its active constituent PGG have strong inhibitory effects on formation of Abeta fibrils in vitro and in vivo. PGG is likely to be a safe and promising lead compound in the development of disease-modifying drugs to prevent and/or cure AD.

Effects of yokukansan, a traditional Japanese medicine, on memory disturbance and behavioral and psychological symptoms of dementia in thiamine-deficient rats.

Effects of yokukansan (TJ-54) on memory disturbance and behavioral and psychological symptoms of dementia (BPSD) were investigated in thiamine-deficient (TD) rats which were produced by feeding a TD diet for 37 d. Daily oral administration of TJ-54 (0.5, 1.0 g/kg) ameliorated the memory disturbance, anxiety-like behavior, the increase in aggressive behaviors, the decrease in social behaviors, and several neurological symptoms including opisthotonus observed in TD rats, in a dose-dependent manner. In addition, histopathological examinations showed that TJ-54 inhibited the degeneration of neuronal and astroglial cells in the brain stem, hippocampus and cortex in TD rats. Microdialysis experiments showed that TJ-54 inhibited extracellular glutamate rise in the ventral posterior medial thalamus in TD rats. These results suggest that TJ-54 possesses the preventive or progress inhibitive effect against the development of memory disturbance and BPSD-like behaviors induced by the degeneration of neuronal and astroglial cells resulting from TD. TJ-54 may inhibit glutamate-mediated excitotoxicity as one of mechanisms.

Effect of yokukansan, a traditional Japanese medicine, on social and aggressive behaviour of para-chloroamphetamine-injected rats.

OBJECTIVES: Yokukansan, a traditional Japanese medicine, has been approved by the Ministry of Health, Labour, and Welfare of Japan as a remedy for neurosis, insomnia or night crying and irritability in children. It has recently been reported to improve behavioural and psychological symptoms of dementia, such as hallucinations, agitation, and aggressiveness in patients with some forms of senile dementia. Little is known about the mechanism underlying the effectiveness of yokukansan. Our aim was to clarify the involvement of yokukansan in serotonergic function in para-chloroamphetamine (PCA)-induced aggressive behaviour in rats. METHODS: The effect of yokukansan on social interactions, including social and aggressive behaviour, was examined in PCA-injected rats. Concentration and release level of serotonin (5-HT) in the hypothalamus were measured. KEY FINDINGS: PCA reduced not only the 5-HT concentration but also the high K(+)-induced 5-HT release in the rat hypothalamus. Social interaction tests showed a significant decrease in social behaviour and a significant increase in aggressive behaviour in the PCA-treated rats. The decrease in social behaviour was ameliorated by the 5-HT1A agonist buspirone and further decreased by a 5-HT1A antagonist, N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)cyclo-hexanecarboxamide trihydrochloride (WAY-100635), whereas it was further decreased by the 5-HT2A agonist, 2,5-dimethoxy-4-iodoamphetamine (DOI), and ameliorated by the 5-HT2A antagonist ketanserin. On the other hand, the increase in aggressive behaviour was ameliorated by buspirone but not affected by WAY-100635, whereas it was enhanced by DOI and ameliorated by ketanserin. A single injection of yokukansan ameliorated the PCA-induced decrease in social behaviour but not aggressive behaviour. Chronic treatment for 14 days with yokukansan ameliorated PCA-induced abnormal behaviour, decreased social behaviour and increased aggressive behaviour, but it did not ameliorate PCA-induced decreases in the cerebral 5-HT concentration and 5-HT release. The ameliorative effects of chronic yokukansan on behaviour were counteracted by co-administration of WAY-100635. CONCLUSIONS: These results suggest that yokukansan might have two different effects: an acute effect on social behaviour and a chronic effect on aggressive behaviour. One of the mechanisms of these effects of yokukansan may be related to the agonistic effect on 5-HT1A receptors.

Effects of yokukansan, a traditional Japanese medicine, on aggressiveness induced by intracerebroventricular injection of amyloid beta protein into mice.

The effects of yokukansan, a traditional Japanese medicine, on aggressiveness and motor activities were examined in mice after injection of amyloid beta protein (Abeta) into the lateral ventricle of the brain. The results were compared with those of conventional (haloperidol) and atypical (risperidone) antipsychotic medicines. A significant increase in aggressiveness was observed on day 7 after injection of Abeta, and it lasted until day 28. A single oral administration of yokukansan (1.0 g/kg) did not ameliorate the aggressiveness observed on day 7. However, a tendency toward amelioration of the aggressiveness was observed after the administration of yokukansan (0.5 and 1.0 g/kg) for 1 week (days 7-14). The 3 week administration (days 7-28) of yokukansan significantly ameliorated the aggressiveness in a dose-dependent manner without inhibition of motor activity. In contrast, a single administration of intraperitoneal haloperidol (0.03-0.1 mg/kg) or oral risperidone (0.1-0.3 mg/kg) on day 28 significantly reduced aggressiveness in a dose-dependent manner. However, motor activities were significantly suppressed. These results suggest yokukansan reduces aggressiveness without suppressing physical activity.

Bioinformatic evidences and analysis of putative biomarkers in pancreatic ductal adenocarcinoma.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal human cancers. Aberrant expression of genes plays important role in the procession of PDAC. The analysis of gene expression profile will contribute to the research of carcinoma mechanism. OBJECTIVE: This present study is focused to investigate the differentially expressed genes (DEGs) from 3 PDAC microarray datasets, which would provide candidate genes for putative biomarkers to understand the mechanism of PDAC and potential targets of treatment. METHOD: Based on the overlap genes obtained from 3 GEO datasets, the hub genes were identified using STRING and Cytoscape plugin MCODE. The enrichment and function analysis were applied using DAVID. The protein-protein interaction network was performed using cBioPortal and UCSC Xena. The Oncomine was finally used to determine the candidate gene by analyzing their expression between pancreas sample and PDAC sample. RESULTS: 25 hub genes were selected from a total of 1006 DEGs from 3 GEO datasets, consisting of 14 upregulated genes and 11 downregulated genes. The overall decline of hub gene expression enriched in G1 phase of cell cycle in other subtypes of pancreatic cancer. Oncomine database was ultimately performed to determine the 8 candidate genes, including CXCL5, CCL20, NMU, F2R, ANXA1, EDNRA, LPAR6, and GNA15. CONCLUSIONS: Conclusively, 8 candidate genes would become the potential PDAC combined biomarkers for diagnosis and therapeutic strategies.

Hydrogen water ameliorates the severity of atopic dermatitis-like lesions and decreases interleukin-1ß, interleukin-33, and mast cell infiltration in NC/Nga mice.

OBJECTIVES: To examine the effect of hydrogen water (HW) on the severity of atopic dermatitis (AD) and elucidate the underlying pathophysiological mechanisms. METHODS: For this experimental study between March 2015 and December 2015, NC/Nga mice characterized by mild AD severity were given either HW (n=11) or purified water (PW) (n=9) ad libitum; specific-pathogen-free mice (n=9) were used as AD-free control. Atopic dermatitis severity score and transepidermal water loss (TEWL) were examined at baseline (0 week), and after 4 weeks of HW/PW treatment. Levels of serum thymus and activation-regulated chemokine (TARC) and cytokines in the AD lesion were measured by ELISA; and mRNA expression of TARC  and aquaporin (AQP-3) genes in the skin was examined by real-time polymerase chain reaction. Results: Mice treated with HW for 4 weeks demonstrated a significant decrease in the AD severity score compared with PW-treated mice (p less than 0.01). Hydrogen water administration also significantly reduced TEWL and serum TARC levels (p less than 0.01), infiltration of mast cells (p less than 0.05), and secretion of the proinflammatory cytokines interleukin (IL)-1ß and IL-33 (p less than 0.05) in skin lesions compared with PW. However, no difference was observed between PW and HW groups in interferon-γ secretion and expression of AQP-3 and TARC genes. Conclusion: Hydrogen water suppressed inflammation in AD mice, leading to amelioration of disease severity, which suggests the therapeutic potential of HW in AD treatment.