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An increase in ambient temperature leads to an increase in sleep. However, the mechanisms behind this phenomenon remain unknown. This study aimed to investigate the role of microglia in the increase of sleep caused by high ambient temperature. We confirmed that at 35 °C, slow-wave sleep was significantly increased relative to those observed at 25 °C. Notably, this effect was abolished upon treatment with PLX3397, a CSF1R inhibitor that can deplete microglia, while sleep amount at 25 °C was unaffected. These observations suggest that microglia play a pivotal role in modulating the homeostatic regulation of sleep in response to the fluctuations in ambient temperature., (© 2024. The Author(s).)

Microglia are the residential immune cells in the central nervous system. Their roles as innate immune cells and regulators of synaptic remodeling are critical to the development and the maintenance of the brain. Numerous studies have depleted microglia to elucidate their involvement in healthy and pathological conditions. PLX3397, a blocker of colony stimulating factor 1 receptor (CSF1R), is widely used to deplete mouse microglia due to its non-invasiveness and convenience. Recently, other small rodents, including Syrian hamsters (Mesocricetus auratus) and Mongolian gerbils (Meriones unguiculatus), have been recognized as valuable animal models for studying brain functions and diseases. However, whether microglia depletion via PLX3397 is feasible in these species remains unclear. Here, we administered PLX3397 orally via food pellets to hamsters and gerbils. PLX3397 successfully depleted gerbil microglia but had no effect on microglial density in hamsters. Comparative analysis of the CSF1R amino acid sequence in different species hints that amino acid substitutions in the juxtamembrane domain may potentially contribute to the inefficacy of PLX3397 in hamsters., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest associated with this manuscript., (Copyright © 2024 The Authors. Production and hosting by Elsevier B.V. All rights reserved.)

Although diurnal animals displaying monophasic sleep patterns exhibit periodic cycles of alternating slow-wave sleep (SWS) and rapid eye movement sleep (REMS), the regulatory mechanisms underlying these regular sleep cycles remain unclear. Here, we report that in the Australian dragon Pogona vitticeps exposed to constant darkness (DD), sleep behavior and sleep-related neuronal activity emerged over a 24-h cycle. However, the regularity of the REMS/SWS alternation was disrupted under these conditions. Notably, when the lizards were then exposed to 12 h of light after DD, the regularity of the sleep stages was restored. These results suggest that sleep-related neuronal activity in lizards is regulated by circadian rhythms and that the regularity of REMS and SWS cycling is influenced by daytime light exposure., (© The Author(s) 2023. Published by Oxford University Press on behalf of National Academy of Sciences.)

An efficient strategy for the identification of potential nephroprotective substances in Zhu-Ling decoction has been established with the integration of absorbed components characterization, pharmacokinetics, and activity evaluation. A qualitative method was developed to characterize the chemical constituents absorbed components in vivo of Zhu-Ling decoction by using ultra-performance liquid chromatography-quadrupole-time-of-flight mass spectrometry. A quantitative method was established and validated for the simultaneous determination of eight compounds in rat plasma by using ultra-performance liquid chromatography-triple quadruple tandem mass spectrometry. Finally, the nephroprotective activities of absorbed components with high exposure were assessed by cell survival rate, superoxide dismutase, and malondialdehyde activities in hydrogen peroxide-induced Vero cells. As a result, 111 compounds in Zhu-Ling decoction and 36 absorbed components were identified in rat plasma and urine, and poricoic acid A, poricoic acid B, alisol A, 16-oxo-alisol A, and dehydro-tumulosic acid had high exposure levels in rat plasma. Finally, poricoic acid B, poricoic acid A, 16-oxo-alisol A, and dehydro-tumulosic acid showed remarkable nephroprotective activity against Vero cells damage induced by hydrogen peroxide. Besides, superoxide dismutase and malondialdehyde activities were obviously regulated in hydrogen peroxide-induced Vero cells by treatment with the four compounds mentioned above. Therefore, these four compounds were considered to be effective substances of Zhu-Ling decoction due to their relatively high exposure in vivo and biological activity. This study provided a chemical basis for the action mechanism of Zhu-Ling decoction in the treatment of chronic kidney diseases., (© 2023 Wiley-VCH GmbH.)

Memory is a fundamental brain function that can be affected by a variety of external factors including environmental pollutants. One of these pollutants is methyl vinyl ketone (MVK), a hazardous substance found in cigarettes, industrial wastes, and car exhaust. Humans can be exposed to MVK under many circumstances; however, it is unclear whether MVK affects higher-order brain functions such as memory. Here, we examined the memory performances of mice receiving systemic MVK administration. We found that 1 mg/kg of MVK impaired spatial memory. We also showed that 1 mg/kg MVK activated glial cells and altered glial functions in several subregions of the hippocampus, a brain region involved in learning and memory. These results suggest that MVK induces memory deficits and activates glial cells in hippocampal subregions., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Sato et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Patients with metastatic esophageal squamous cell carcinoma (ESCC) have a grave prognosis with limited life expectancy. Here, a phase II clinical trial was conducted to investigate the effect of Andrographis paniculata (AP) on the palliative care of patients with metastatic ESCC. Patients with metastatic or locally advanced ESCC deemed unfit for surgery, and who have already completed palliative chemotherapy or chemoradiotherapy or are not fit for these treatments, were recruited. These patients were prescribed AP concentrated granules for 4 months. They also received clinical and quality of life assessments for clinical response, as well as positron emission tomography-computed tomography at 3 and 6 months after AP treatment for the assessment of tumor volume. Furthermore, the change in gut microbiota composition after AP treatment was studied. From the results, among the 30 recruited patients, 10 completed the entire course of AP treatment, while 20 received partial AP treatment. Patients who completed the AP treatment achieved significantly longer overall survival periods with the maintenance of the quality of life during the survival period when compared to those who could not complete AP treatment. The treatment effect of AP also contributed to the shift of the overall structure of gut microbiota for ESCC patients towards those of healthy individuals. The significance of this study is the establishment of AP as a safe and effective palliative treatment for patients with squamous cell carcinoma of the esophagus. To the best of our knowledge, this is the first clinical trial of AP water extract in esophageal cancer patients demonstrating its new medicinal use., (© 2023 The Authors. Phytotherapy Research published by John Wiley & Sons Ltd.)

Microglia, as macrophages in the brain, are responsible for immune responses and synaptic remodeling. Although the function of microglia is regulated by circadian rhythms, it is still unclear whether microglia are involved in the generation and light entrainment of circadian rhythms of behavior. Here, we report that microglial depletion does not alter behavioral circadian rhythms. We depleted ~ 95% of microglia in the mouse brain by PLX3397, a CSF1R inhibitor, and analyzed the effect on the spontaneous behaviors of mice. We found that neither the free-running period under constant darkness nor light entrainment under jet-lag circumstances were influenced by the ablation of microglia. Our results demonstrate that the circadian rhythms of locomotor activity, an important output of the circadian clock in the brain, are likely a phenomenon not produced by microglia., (© 2023. The Author(s).)

Memory is one of the fundamental cognitive functions of brain. The formation and consolidation of memory depend on the hippocampus and sleep. Sharp wave ripple (SWR) is an electrophysiological event which is most frequently observed in the hippocampus during sleep. It represents a highly synchronized neuronal activity pattern which modulates numerous brain regions including the neocortex, subcortical areas, and the hippocampus itself. In this review, we discuss how SWRs link experiences to memories and what happens in the hippocampus and other brain regions during sleep by focusing on synaptic plasticity., (Copyright © 2023 Elsevier Ltd and Japan Neuroscience Society. All rights reserved.)

Background: Polysaccharide peptide (PSP) extract of Coriolus versicolor (L.) Quél. (1886) ( Trametes ; Polyporaceae) is increasingly used in cancer to support the immune system. However, its interaction with tamoxifen is unknown. Aim of the study: To investigate the effect of a PSP extract on the pharmacokinetics, biochemical parameters, and depletion of tamoxifen. Methods: The pharmacokinetic and biochemical parameters of tamoxifen (20 mg/mL oral single dose and repeated dosing for 12 days) was investigated in female Sprague Dawley rats with or without PSP (340 mg/kg orally for 7 days) ( n = 5 per group). Tamoxifen (5 µM) depletion rate with PSP (10-100 μg/mL) was measured in female rat hepatic microsomes in vitro . Results: Compared to tamoxifen alone, the time to reach maximum concentration (T max ) significantly increased by 228% (4.15 ± 1.15 versus 13.6 ± 2.71 h) in the single tamoxifen dose with PSP and 93% (6 ± 2.17 versus 11.6 ± 0.4 h) in the repeated tamoxifen dosing with PSP ( p < 0.05). No significant changes in the area-under-curve and maximum concentration were observed in the single dose and repeated tamoxifen dosing plus PSP compared to tamoxifen alone. Pharmacodynamically, the repeated tamoxifen dosing with PSP maintained 19 out of 23 hepatic, renal and cardiac biochemical serum parameters in rats compared to untreated rats ( p > 0.05). PSP extract did not significantly alter in vitro intrinsic clearance of tamoxifen compared to tamoxifen control. Conclusion: With the increased use of PSP as an adjunct therapy, this study highlights the importance of clinician's knowledge of its interaction with tamoxifen to avoid compromising clinical actions and enhancing clinical therapy., Competing Interests: HN is the R&D Manager at PuraPharm Corp. Ltd. Hong Kong. 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. This study received funding from Western Sydney University Research Partnerships Program (in partnership with PuraPharm International (H. K.) Ltd.) (Grant ID: 22058). The funder (PuraPharm) provided the extract and endorsed the preparation and publication of the manuscript., (Copyright © 2022 Razmovski-Naumovski, Kimble, Laurenti, Nammi, Norimoto and Chan.)

Methyl vinyl ketone (MVK) is an environmental hazardous substrate which is mainly present in cigarette smoke, industrial waste, and exhaust gas. Despite many chances to be exposed to MVK, the cellular toxicity of MVK is largely unknown. Neurons are the main component of the brain, which is one the most vital organs to human beings. Nevertheless, the influence of MVK to neurons has not been investigated. Here, we determined whether MVK treatment negatively affects neuronal survival and axonal morphogenesis using primary hippocampal neuronal cultures. We treated hippocampal neurons with 0.1 μM to 3.0 μM MVK and observed a concentration-dependent increase of neuronal death rate. We also demonstrated that the treatment with a low concentration of MVK 0.1 μM or 0.3 μM inhibited axonal branching specifically without affecting axon outgrowth. Our results suggest that MVK is highly toxic to neurons.

Background: Diarrhea is a major gastrointestinal complication in cancer patients receiving chemotherapy. Prognosis and treatment of chemotherapy-induced diarrhea (CID) remain unsatisfactory. This study aims to explore the potential of an ancient Chinese Medicine herbal formula Huanglian Jiedu Decoction (HLJDD) as an adjuvant treatment on CID., Method: HLJDD extract was prepared by GMP manufacturing standard with quality and stability being checked. 5-fluorouracil (5-Fu) and irinotecan (CPT-11)-induced diarrhea model in mice was established and pre-, co- and post-treatment of HLJDD was implemented. Mechanism of action was explored by detecting related protein expression. In addition, the effect of HLJDD on diarrhea and tumor response induced by clinical regimens FOLFOX and FOLFIRI was measured in murine orthotopic colorectal cancer model., Results: HLJDD exhibited consistency in quality and stability after 24-month storage. Pre-treatment of HLJDD, but not co-treatment or post-treatment, could significantly improve the diarrhea score, body weight loss and intestinal damage in 5-Fu- and CPT-11-treated mice. Pre-treatment of HLJDD reduced cell apoptosis in the intestine of chemotherapy-treated mice, and promoted renewal of intestinal cell wall. CD44 was predicted as the potential target of HLJDD-containing compounds in CID. HLJDD pre-treatment induced presentation of CD44-postive cells in the intestine of chemotherapy-treated mice, and initiated expression of stemness-associated genes. Transcriptional products of the downstream Wnt signaling of CD44 were elevated. Furthermore, pre-treatment of HLJDD could significantly improve the tumor response of clinical chemotherapy regimens FOLFOX and FOLFIRI in orthotopic colorectal cancer, and reduce diarrhea and intestinal damage. Conclusion: Our study suggests the potential of HLJDD as a neoadjuvant treatment of chemotherapy by reducing diarrhea and improving tumor response., (Copyright © 2020 Chan, Cheung, Zhang, Fu, Tan, Norimoto, Wang and Feng.)

The mammalian claustrum, owing to its widespread connectivity with other forebrain structures, has been hypothesized to mediate functions that range from decision-making to consciousness 1 . Here we report that a homologue of the claustrum, identified by single-cell transcriptomics and viral tracing of connectivity, also exists in a reptile-the Australian bearded dragon Pogona vitticeps. In Pogona, the claustrum underlies the generation of sharp waves during slow-wave sleep. The sharp waves, together with superimposed high-frequency ripples 2 , propagate to the entire neighbouring pallial dorsal ventricular ridge (DVR). Unilateral or bilateral lesions of the claustrum suppress the production of sharp-wave ripples during slow-wave sleep in a unilateral or bilateral manner, respectively, but do not affect the regular and rapidly alternating sleep rhythm that is characteristic of sleep in this species 3 . The claustrum is thus not involved in the generation of the sleep rhythm itself. Tract tracing revealed that the reptilian claustrum projects widely to a variety of forebrain areas, including the cortex, and that it receives converging inputs from, among others, areas of the mid- and hindbrain that are known to be involved in wake-sleep control in mammals 4-6 . Periodically modulating the concentration of serotonin in the claustrum, for example, caused a matching modulation of sharp-wave production there and in the neighbouring DVR. Using transcriptomic approaches, we also identified a claustrum in the turtle Trachemys scripta, a distant reptilian relative of lizards. The claustrum is therefore an ancient structure that was probably already present in the brain of the common vertebrate ancestor of reptiles and mammals. It may have an important role in the control of brain states owing to the ascending input it receives from the mid- and hindbrain, its widespread projections to the forebrain and its role in sharp-wave generation during slow-wave sleep.

Bletilla Tuber (dried tuber of Bletilla striata) is used as an astringent hemostatic medicine for the treatment of ulcers, bleeding, and burns in traditional Chinese medicine (TCM). The Chinese Pharmacopoeia describes the heat processing methods used on raw tubers of Bletilla striata to produce the herbal medicine "Bletilla Tuber". In this study, we compared the chemical constituents of well-processed Bletilla Tuber (BT1) and normally processed Bletilla Tuber (BT2) derived from the same origin. In addition, as an indicator of the hemostatic activity of Bletilla Tuber, the NO inhibitory activities of extracts obtained from BT1 and BT2 and the isolated compounds were examined. As a result of LC-MS analysis, three types of compounds, glucosyloxybenzyl 2-isobutylmalates, bibenzyl derivatives and phenanthrene derivatives, were detected. Comparison of the chemical profiles of the extracts indicated that the relative contents of glucosyloxybenzyl 2-isobutylmalates had changed by heat processing, whereas the relative contents of bibenzyls and phenanthrenes had not changed. The extracts of BT1 and BT2 showed similar IC 50 values on NO production suppressing activity. Furthermore, phenanthrenes and bibenzyls were identified as the compounds responsible for suppressing the NO activity. These results suggest that the biological activities, such as the anti-inflammatory and hemostatic activities, of Bletilla Tuber are not affected by heat processing.

Hippocampal neurons play a crucial role in memory formation. Accumulating evidence raises the possibility that hippocampal sharp-wave ripples (SW-Rs) are involved in memory consolidation. Here, we examined in an animal model of diabetes and found the amplitude of SW-Rs in diabetic mice were smaller than control group and were rescued by acute application of l-lactate, a major neural energy source. The cognitive impairment in diabetic mice was alleviated by intracerebroventricular l-lactate treatment. Our results suggested that l-lactate is important for hippocampal dysfunction in diabetes., (Copyright © 2019 The Authors. Production and hosting by Elsevier B.V. All rights reserved.)

Background: A method that promotes the retrieval of lost long-term memories has not been well established. Histamine in the central nervous system is implicated in learning and memory, and treatment with antihistamines impairs learning and memory. Because histamine H 3 receptor inverse agonists upregulate histamine release, the inverse agonists may enhance learning and memory. However, whether the inverse agonists promote the retrieval of forgotten long-term memory has not yet been determined., Methods: Here, we employed multidisciplinary methods, including mouse behavior, calcium imaging, and chemogenetic manipulation, to examine whether and how the histamine H 3 receptor inverse agonists, thioperamide and betahistine, promote the retrieval of a forgotten long-term object memory in mice. In addition, we conducted a randomized double-blind, placebo-controlled crossover trial in healthy adult participants to investigate whether betahistine treatment promotes memory retrieval in humans., Results: The treatment of H 3 receptor inverse agonists induced the recall of forgotten memories even 1 week and 1 month after training in mice. The memory recovery was mediated by the disinhibition of histamine release in the perirhinal cortex, which activated the histamine H 2 receptor. Histamine depolarized perirhinal cortex neurons, enhanced their spontaneous activity, and facilitated the reactivation of behaviorally activated neuronal ensembles. A human clinical trial revealed that treatment of H 3 receptor inverse agonists is specifically more effective for items that are more difficult to remember and subjects with poorer performance., Conclusions: These results highlight a novel interaction between the central histamine signaling and memory engrams., (Copyright © 2018 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

The specific effects of sleep on synaptic plasticity remain unclear. We report that mouse hippocampal sharp-wave ripple oscillations serve as intrinsic events that trigger long-lasting synaptic depression. Silencing of sharp-wave ripples during slow-wave states prevented the spontaneous down-regulation of net synaptic weights and impaired the learning of new memories. The synaptic down-regulation was dependent on the N -methyl-d-aspartate receptor and selective for a specific input pathway. Thus, our findings are consistent with the role of slow-wave states in refining memory engrams by reducing recent memory-irrelevant neuronal activity and suggest a previously unrecognized function for sharp-wave ripples., (Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Our group has recently reported that in the immortal human HepG2 liver cell line, sphingosine 1‑phosphate (S1P) increases transcription of plasminogen activator inhibitor type‑1 (PAI‑1), the major physiological inhibitor of fibrinolysis, within 4 h. The present study aimed to elucidate the molecular mechanisms underlying this effect. PAI‑1 expression was measured by reverse transcription‑quantitative polymerase chain reaction and immunoblotting. It was demonstrated that S1P increased PAI‑1 promoter activity but did not increase the activity of promoters lacking the hypoxia responsive element (HRE) 2. In addition, S1P transiently increased the concentration of hypoxia inducible factor (HIF)‑1α, a transcription factor capable of binding to HRE. When HIF‑1α was knocked down, the induction of transcription of PAI‑1 by S1P was no longer observed. Sphingosine kinase (SPHK) activity is increased by hypoxia. It was demonstrated that increases in the concentration of the HIF‑1α protein induced by hypoxia were prevented by treatment with SPHK inhibitor or S1P receptor antagonists. Thus, modification of the induction of HIF‑1α by S1P, leading to increased transcription of PAI‑1, may be an attractive therapeutic target for thrombosis and consequent inhibition of fibrinolysis associated with hypoxia.

The rhizomes of many Atractylodes species, including Atractylodes chinensis Koidzumi, Atractylodes macrocephala Koidzumi, and Atractylodes japonica Koidzumi, are collectively termed Atractylodis Rhizoma. We prepared n-hexane extracts of the three species and evaluated their anti-inflammatory effects on lipopolysaccharide (LPS)-induced RAW 264.7 cells. Among all n-hexane extracts, those of A. japonica most strongly inhibited nitric oxide (NO) production in LPS-induced RAW 264.7 cells; five sesquiterpenes, atractylon, atractylenolide I, atractylenolide II, atractylenolide III, and 8-epiasterolid, were isolated from A. japonica. The phytochemical content of A. japonica was similar to those of A. chinensis and A. macrocephala. Moreover, the atractylon concentration was higher in A. japonica than in A. chinensis and A. macrocephala. Atractylon significantly inhibited NO and prostaglandin E2 production as well as inducible NO synthase and cyclooxygenase-2 expression in LPS-induced RAW 264.7 cells. Atractylon (40 mg/kg) also significantly reduced the acetic-acid-induced writhing response, carrageenan-induced paw edema, and hot-plate latent pain response in mice. According to the results, A. japonica has anti-inflammatory and antinociceptive effects and atractylon is the major active component of A. japonica. Therefore, atractylon can be used as a bioactivity marker in A. japonica.

Background: Calcium imaging has become a fundamental modality for studying neuronal circuit dynamics both in vitro and in vivo. However, identifying calcium events (CEs) from spectral data remains laborious and difficult, especially since the signal-to-noise ratio (SNR) often falls below 2. Existing automated signal detection methods are generally applied at high SNRs, leaving a large need for an automated algorithm that can accurately extract CEs from fluorescence intensity data of SNR 2 and below., New Method: In this work we develop a Matched filter for Multi-unit Calcium Event (MMiCE) detection to extract CEs from fluorescence intensity traces of simulated and experimentally recorded neuronal calcium imaging data., Results: MMiCE reached perfect performance on simulated data with SNR ≥ 2 and a true positive (TP) rate of 98.27% (± 1.38% with a 95% confidence interval), and a false positive(FP) rate of 6.59% (± 2.56%) on simulated data with SNR 0.2. On real data, verified by patch-clamp recording, MMiCE performed with a TP rate of 100.00% (± 0.00) and a FP rate of 2.04% (± 4.10)., Comparison With Existing Method(s): This high level of performance exceeds existing methods at SNRs as low as 0.2, which are well below those used in previous studies (SNR ≃ 5-10)., Conclusion: Overall, the MMiCE detector performed exceptionally well on both simulated data, and experimentally recorded neuronal calcium imaging data. The MMiCE detector is accurate, reliable, well suited for wide-spread use, and freely available at sites.uci.edu/aggies or from the corresponding author., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Chronic pruritus is a major and distressing symptom of many cutaneous diseases, however, the treatment remains a challenge in the clinic. The traditional Chinese-Japanese medicine (Kampo medicine) is a conservative and increasingly popular approach to treat chronic pruritus for both patients and medical providers. Yokukansankachimpihange (YKH), a Kampo formula has been demonstrated to be effective in the treatment of itching of atopic dermatitis in Japan although its pharmacological mechanism is unknown clearly. In an attempt to clarify its pharmacological actions, in this study, we focused on the inhibitory activity of YKH against neurite growth induced with nerve growth factor (NGF) in cultured rat dorsal root ganglion (DRG) neurons because epidermal hyperinnervation is deeply related to itch sensitization. YKH showed approximately 200-fold inhibitory activity against NGF-induced neurite growth than that of neurotropin (positive control), a drug used clinically for treatment of chronic pruritus. Moreover, it also found that Uncaria hook, Bupleurum root and their chemical constituents rhynchophylline, hirsutine, and saikosaponin a, d showed inhibitory activities against NGF-induced neurite growth, suggesting they should mainly contribute to the inhibitory activity of YKH. Further study on the effects of YKH against epidermal nerve density in "itch-scratch" animal models is under investigation.

Allocentric sense is one of the major components that underlie spatial navigation. In blind patients, the difficulty in spatial exploration is attributed, at least partly, to the deficit of absolute direction perception. In support of this notion, we announce that blind adult rats can perform spatial tasks normally when externally provided with real-time feedback of their head directions. Head-mountable microstimulators coupled with a digital geomagnetic compass were bilaterally implanted in the primary visual cortex of adult rats whose eyelids had been sutured. These "blind" rats were trained to seek food pellets in a T-shaped maze or a more complicated maze. Within tens of trials, they learned to manage the geomagnetic information source to solve the mazes. Their performance levels and navigation strategies were similar to those of normal sighted, intact rats. Thus, blind rats can recognize self-location through extrinsically provided stereotactic cues., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

The EtOAc-soluble portion of the 80 % (v/v) EtOH extract from the twigs of Garcinia esculenta exhibited strong xanthine oxidase inhibition in vitro. Bioassay-guided purification led to the isolation of 1,3,6,7-tetrahydroxyxanthone (3) and griffipavixanthone (8) as the main xanthine oxidase inhibitors, along with six additional compounds (1, 2, 4-7), including two new compounds (1 and 2). This enzyme inhibition was dose dependent with an IC50 value of approximately 1.2 µM for 3 and 6.3 µM for 8. The inhibitory activity of 3 was stronger than the control allopurinol (IC50 value: 5.3 µM). To our knowledge, compound 8 is the first bixanthone that demonstrated potent XO inhibitory activity in vitro. The structures of the new compounds were established by spectroscopic analysis, and the optical properties and absolute stereochemistry of racemic (±) esculentin A (2) were further determined by the calculation of the DP4 probability and analysis of its MTPA ester derivatives., (Georg Thieme Verlag KG Stuttgart · New York.)

Spontaneous neuronal activity is present in virtually all brain regions, but neither its function nor spatiotemporal patterns are fully understood. Ex vivo organotypic slice cultures may offer an opportunity to investigate some aspects of spontaneous activity, because they self-restore their networks that collapsed during slicing procedures. In hippocampal networks, we compared the levels and patterns of in vivo spontaneous activity to those in acute and cultured slices. We found that the firing rates and excitatory synaptic activity in the in vivo hippocampus are more similar to those in slice cultures compared to acute slices. The soft confidence-weighted algorithm, a machine learning technique without human bias, also revealed that hippocampal slice cultures resemble the in vivo hippocampus in terms of the overall tendency of the parameters of spontaneous activity.

Hallucinations are a common non-motor symptom of Parkinson's disease and various forms of dementias. Yokukansan and Yokukansankachimpihange have attracted attention due to their effectiveness in the treatment of hallucinations of dementia. To clarify which component in these formulas contribute to the effects, at first, we focused on their differences in compositions to examine the pharmacological effects on the selective 5-HT2A/2C agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI)-induced head-twitch response (HTR) in mice that has been used as animal hallucination model. Results indicated that water extract of Byaku-jutsu (Atractylodes japonica) showed a stronger inhibitory effect on DOI-induced HTR than that of So-jutsu (A. lancea) corresponding to their major constituents of atractylenolide III and β-eudesmol, and suggested that the major constituents should be active constituents contributing to the antihallucination effects of Byaku- and So-jutsu. Besides, the part B-C ring (butenolide) in atractylenolide III was found to be similar to the structure of serotonin and suggested that the B-C ring may partially play role in antagonistic activity against serotonin receptors. Thus, a novel, rational design of butenolide-related compounds may as potential lead compounds for new drug development. Analysis of the chemical components of Byaku- and So-jutsu and further study on their structure-activity relationships are currently in progress.

Purpose: Hachimijiogan (HJG, Rehmannia Eight Formula), a kidney-replenishing Kampo formula, is clinically known to be effective in the treatment of male infertility with oligozoospermia. The purpose of this study was to evaluate the effect of HJG on the epididymal sperm characteristics and related serum hormone changes in rats in an attempt to determine its mechanism., Methods: Male Wistar-Imamichi rats (233.4 ± 5.2 g, nine weeks old) were assigned randomly to four groups ( n = 6 for each group). Apart from one control group treated with distilled water, the other groups were administered HJG consecutively for 9-11 days with doses of 250, 500 and 1,000 mg/kg. After the last administration the caude epididymides were quickly removed under anesthesia for assessing sperm characteristics. Additionally, the testes, seminal vesicles, prostate and adrenal glands were removed surgically and their wet weights measured., Results: Results showed that HJG increased sperm numbers and motility as well as the weights of seminal vesicles and adrenal glands at lower doses. Moreover, HJG decreased serum levels of testosterone and luteinizing hormone while increasing follicle-stimulating hormone levels., Conclusions: Our findings may support the conclusion that a lower dosage of HJG has an effect on improving local spermatogenous environments by activating adrenal functions and/or promoting local androgen activity., Competing Interests: Toru R. Saito has received research grants from Kracie Pharma, Ltd. Yuying Wang, Chiaki Murayama, Seiwa Michihara and Hisayoshi Norimoto declare that they have no conflict of interest.

Hippocampal sharp wave (SW)/ripple complexes are thought to contribute to memory consolidation. Previous studies suggest that behavioral rewards facilitate SW occurrence in vivo. However, little is known about the precise mechanism underlying this enhancement. Here, we examined the effect of dopaminergic neuromodulation on spontaneously occurring SWs in acute hippocampal slices. Local field potentials were recorded from the CA1 region. A brief (1 min) treatment with dopamine led to a persistent increase in the event frequency and the magnitude of SWs. This effect lasted at least for our recording period of 45 min and did not occur in the presence of a dopamine D1/D5 receptor antagonist. Functional multineuron calcium imaging revealed that dopamine-induced SW augmentation was associated with an enriched repertoire of the firing patterns in SW events, whereas the overall tendency of individual neurons to participate in SWs and the mean number of cells participating in a single SW were maintained. Therefore, dopaminergic activation is likely to reorganize cell assemblies during SWs.

In previous studies we found that anionic surfactants such as sodium laurate (SL) and/or sodium dodecylsulfate (SDS) exert actions on epidermal keratinocytes rather than mast cells to give rise of histamine production and skin itching through increasing the expression of the 53-kDa active form of L-histidine decarboxylase (HDC). In addition, with treatment of SL in a three-dimensional human keratinocyte culture, increases in both the 53-kDa HDC and histamine production are detected and thus this culture assay is applied to screen anti-itching materials from natural resources. In this study, the inhibitory activity of "Kin-gin-ka" (flower buds of Lonicera japonica Thunb., FLJ) against histamine production and expression of the active form of HDC were examined in this culture assay. FLJ is a well-known traditional Chinese medicine, being used to treat fevers, coughs and some infectious diseases. The result showed both FLJ and chlorogenic acid had inhibitory activities against the expression of 53-kDa HDC and histamine production. However, chlorogenic acid showed a weaker effect on histamine production than that of FLJ, suggesting that other chemical constituents besides chlorogenic acid could contribute to the inhibitory activities. Thus, a further chemical study of FLJ is now under investigation.

Hippocampal sharp waves (SWs)/ripples represent the reactivation of neurons involved in recently acquired memory and are crucial for memory consolidation. By labeling active cells with fluorescent protein under the control of an immediate-early gene promoter, we found that neurons that had been activated while mice explored a novel environment were preferentially reactivated during spontaneous SWs in hippocampal slices in vitro. During SWs, the reactivated neurons received strong excitatory synaptic inputs as opposed to a globally tuned network balance between excitation and inhibition.

Dried citrus peels (Chimpi) is one of the most common natural medicines with qi (energy flow) rectifying and shi (dampness) drying actions, which originates from Citrus unshiu, and/or C. reticulata according to the definition of the pharmacopoeiae of Japan and China. In this study, the pharmacological effects of their extracts and major chemical constituents hesperidin and its aglycone hesperetin on anxiety were examined with an anxiety model of elevated open-platform test using ICR male mice (6-week-old) and total duration of freezing was decreased in fluoxetine-treated mice, which is a simple and highly sensitive to the effects of serotonergic anxiolytics. Moreover, yokukansankachimpihange (YKH), a combination of yokukansan with Chimpi and Hange (Pinellia) was also examined because Chimpi is considered to play a crucial part in this formula against anxious symptoms in dementia patients. The results showed that Chimpi and YKH possess a significant anxiolytic-like effect similar to that of fluoxetine, suggesting that they might be similar to fluoxetine in their pharmacological actions through the serotonergic neurotransmission pathway. Moreover, it also suggested that the major chemical constituent, hesperidin could be an active principle attributed to the antianxiety-like effects with a direct and indirect role via its aglycone hesperetin.

The term "late-onset hypogonadism (LOH)" is recommended to express the symptoms in middle-aged males with decreased testosterone. Although androgen replacement therapy (ART) might be an effective way to manage LOH, the risk of testosterone supplementation in elderly men is still concerned. On the other hand, to avoid adverse effects of ART, Kampo medicine (traditional Chinese-Japanese medicine) is often a first choice to treat LOH in Japan. However, their pharmacological studies are few. In this study, castrated mice was used as an LOH animal model for examining the pharmacological effects of a Kampo formula, saikokaryukotsuboreito (shortly SKRBT) on serum testosterone levels and seminal vesicles weights. Furthermore, an attempt to elucidate its pharmacological mechanism, inhibition of SKRBT and its components against aromatase were also examined with the enzyme-based assay. As a result, SKRBT improved significantly both the decline of serum testosterone levels and decrease of seminal vesicles weight of castrated mice at a dose of 125 mg/kg with a non dose-dependent manner. SKRBT and two components Scutellariae radix and Rhei rhizoma exhibited inhibitory activities with the IC(50) values of 145, 29.2 and 29.7 µg/ml, respectively. These results suggested that the aromatase inhibitory activity of SKRBT may contribute, to a different extent, to the improvement of serum testosterone levels.

Sharp wave-ripple complexes (SW-Rs), a transient form of high-frequency field oscillations observed in the hippocampus, are thought to mediate memory consolidation. They are initiated mainly in hippocampal CA3 area and propagate to the entorhinal cortex through the subiculum; however, little is known about how SW-Rs are initiated and propagate. Here, we used functional multineuronal calcium imaging to monitor SW-R-relevant neuronal activity from the subiculum at single-cell resolution. An unexpected finding was that a subset of subicular neurons was activated immediately before hippocampal SW-Rs. The SW-R-preceding activity was not abolished by surgical lesion of the CA1-to-subiculum projection, and thus, it probably arose from entorhinal inputs. Therefore, SW-Rs are likely to be triggered by entorhinal-to-CA3/CA1 inputs. Moreover, the subiculum is not merely a passive intermediate region that SW-Rs pass through, but rather, it seems to contribute to an active modification of neural information related to SW-Rs.

Cholinergic muscarinic innervations to the hippocampus play a role in learning and memory. Here we report that pharmacological activation of muscarinic receptors eliminates sharp wave-ripple events in the mouse hippocampal CA1 region in vivo and in vitro. This effect was associated with a decorrelation of excitatory synaptic inputs and a net increase in inhibitory conductances in pyramidal neurons. Multineuron calcium imaging revealed that muscarinic activation altered the spatiotemporal pattern of network activities. Thus, cholinergic input is likely to contribute to a neuromodulatory switch of hippocampal network states, as proposed in the "two-stage" model of learning processes., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Cannabinoid agonists impair hippocampus-dependent learning and memory. Using mouse hippocampal slice preparations, we examined the effect of anandamide, an endogenous cannabinoid, on sharp wave-ripple (SW-R) complexes, which are believed to mediate memory consolidation during slow-wave sleep or behavioral immobility. Anandamide reduced the frequency of SW-Rs recorded from the CA3 region, and this effect was abolished by AM251, a cannabinoid CB1-receptor antagonist. We further addressed the action of anandamide using a functional multineuron calcium imaging technique. Anandamide reduced the firing rate of hippocampal neurons as well as disrupted the temporal coordination of their firings during SW-R.

The production of melanin is not only activated by external factors such as sunlight or UV-exposure, but is also considered to be triggered by hormonal factors, particularly sex hormones such as ovarian hormones. Previously, keishibukuryoganryokayokuinin (KBY) was reported to increase the pigmentation and moisture content of dermis in women during the luteal phase of the menstrual cycle, thus suggesting that progesterone could play a critical role in the development of skin pigmentation. In the present study, female DBA/2 mice, a dilute brown strain, were used to examine the effects of KBY on the increase in epidermal pigment cells in mice exposed to ultraviolet B (UVB) radiation or progesterone in an attempt to elucidate its mechanism. An increase in epidermal pigment cells was observed in mice exposed to progesterone. To the best of our knowledge, this is the first study to demonstrate that progesterone causes pigmentation in vivo. Furthermore, administration of KBY to progesterone-exposed mice significantly reduced the number of epidermal pigment cells. However, KBY had no such effects on UVB-induced pigmentation. Another important finding was the gain in body weight in progesterone-exposed mice, while body weight gain was reduced by KBY. The body weight gain was believed to be due to sodium and fluid retention, a kind of adverse effect of progesterone, which may further affect the intracellular pH of melanosomes, which synthesize melanin, in turn, leading to melanin production because tyrosinase activity is linked to the intracellular pH environment. This may help explain the mechanism of the role of KBY in pigmentation.