Role of gut-derived bacterial lipopolysaccharide and peripheral TLR4 in immobilization stress-induced itch aggravation in a mouse model of atopic dermatitis.

Psychological stress and intestinal leakage are key factors in atopic dermatitis (AD) recurrence and exacerbation. Here, we demonstrate the mechanism underlying bacterial translocation across intestinal epithelial barrier damaged due to stress and further aggravation of trimellitic anhydride (TMA)-induced itch, which remain unclear, in AD mice. Immobilization (IMO) stress exacerbated scratching bouts and colon histological damage, and increased serum corticosterone and lipopolysaccharide (LPS). Orally administered fluorescein isothiocyanate (FITC)-dextran and surgically injected (into the colon) Cy5.5-conjugated LPS were detected in the serum and skin after IMO stress, respectively. The relative abundance of aerobic or facultative anaerobic bacteria was increased in the colon mucus layer, and Lactobacillus murinus, E. coli, Staphylococcus nepalensis, and several strains of Bacillus sp. were isolated from the spleens and mesenteric lymph nodes. Oral antibiotics or intestinal permeability blockers, such as lubiprostone (Lu), 2,4,6-triaminopyrimidine (TAP) and ML-7, inhibited IMO stress-associated itch; however, it was reinduced through intradermal or i.p. injection of LPS without IMO stress. I.p. injection of TAK-242 (resatorvid), a TLR4 inhibitor, abrogated IMO stress-associated itch, which was also confirmed in TLR4-KO mice. IMO stress alone did not cause itch in naïve mice. IMO stress-induced itch aggravation in TMA-treated AD mice might be attributed to the translocation of gut-derived bacterial cells and LPS, which activates peripheral TLR4 signaling.

[The Effects of Stress Vulnerability and Parental Burnout on Mental Health in Women with Early School-Age Children during the COVID-19 Pandemic: Mediating Effect of Spirituality].

PURPOSE: This study examined the effects of stress vulnerability and parental burnout on the mental health of women with early school-aged children, with a focus on the mediating role of spirituality. METHODS: A survey was conducted among 171 women with early school-aged children in Gyeonggi Province, Gangwon Province, and Seoul. Data were collected from September to December 2022 using the Korean-Symptom Check List 95, the Parental Burnout Assessment, and the Spirituality Assessment Scale. The data were analyzed using structural equation modeling with SPSS/WIN 22.0 and AMOS 20.0. RESULTS: The study model demonstrated a good fit, explaining 40.5% of the variance in mental health through stress vulnerability, parental burnout, and spirituality. Spirituality had a significant direct impact on mental health. Additionally, participants' spirituality directly influenced their mental health, while stress vulnerability and parental burnout indirectly affected their mental health and were mediated through spirituality. CONCLUSION: Stress vulnerability and parental burnout are negatively associated with mental health, while spirituality partially mediates these effects. Implementing a program to promote spirituality is suggested to assist mothers in recognizing the value and meaning of parenting activities during nursing interventions for mental health.

Chronic Gut Inflammation and Dysbiosis in IBS: Unraveling Their Contribution to Atopic Dermatitis Progression.

Emerging evidence suggests a link between atopic dermatitis (AD) and gastrointestinal disorders, particularly in relation to gut microbial dysbiosis. This study explored the potential exacerbation of AD by gut inflammation and microbial imbalances using an irritable bowel syndrome (IBS) mouse model. Chronic gut inflammation was induced in the model by intrarectal injection of 2,4,6-trinitrobenzene sulfonic acid (TNBS), followed by a 4-week development period. We noted significant upregulation of proinflammatory cytokines in the colon and evident gut microbial dysbiosis in the IBS mice. Additionally, these mice exhibited impaired gut barrier function, increased permeability, and elevated systemic inflammation markers such as IL-6 and LPS. A subsequent MC903 challenge on the right cheek lasting for 7 days revealed more severe AD symptoms in IBS mice compared to controls. Further, fecal microbial transplantation (FMT) from IBS mice resulted in aggravated AD symptoms, a result similarly observed with FMT from an IBS patient. Notably, an increased abundance of Alistipes in the feces of IBS mice correlated with heightened systemic and localized inflammation in both the gut and skin. These findings collectively indicate that chronic gut inflammation and microbial dysbiosis in IBS are critical factors exacerbating AD, highlighting the integral relationship between gut and skin health.

Impact of Virtual Reality Mental Health Nursing Simulation on Nursing Students' Competence.

Purpose: This study investigates the impact of a Virtual Reality (VR)-based Mental Health Nursing Practice Simulation (MHNPS) on nursing students' competency in caring for individuals with mental disorders. Nursing students often face fear, anxiety, and helplessness during mental health (MH) rotations, impeding the attainment of learning objectives in the MH nursing practicum. Therefore, innovative strategies offering practice opportunities are crucial for their competence development. Methods: Using a one-group pretest-posttest repeated measures experimental design, 50 nursing students, having completed at least one MH theory course but not yet engaged in MH clinical practicum, were enrolled. Data collection occurred from October 30, 2022, to January 6, 2023. The VR simulation included six modules covering delusion, hallucination, mania, geriatric depression, adolescent depression with suicidal ideation, and obsessive-compulsive disorder. Pre-simulation questionnaires and post-simulation surveys were administered through provided links. Data were analyzed using descriptive statistics and paired t-tests to assess changes over time. Results: Immediate and sustained improvements were observed in mental disorder-related nursing knowledge, communication self-efficacy, critical thinking ability, and MH nursing clinical confidence. Attitudes toward mental illness improved significantly post-intervention (t=-2.22, p=0.031), while the problem-solving process exhibited significant enhancement six weeks later (t=3.87, p<0.001). Conclusion: The findings affirm the simulation intervention's effectiveness in enhancing nursing students' knowledge, self-efficacy, critical thinking, and confidence in MH nursing practice, with no compromise to patient safety. Integrating simulation into MH nursing practicum narrows the gap between theory and clinical practice, elevates MH care quality, and instills confidence in nursing students as professionals. Despite potential subject selection bias in this single-group pre-post intervention study, the program's comprehensive impact on knowledge, skills, and attitudes suggests opportunities for expanding psychiatric nursing practice capabilities through subsequent studies. Caution is warranted in interpreting results, but the developed program lays the groundwork for advancing nursing students' capabilities in psychiatric nursing practice.

Correction: Prediction of disease severity using serum biomarkers in patients with mild-moderate Atopic Dermatitis: A pilot study.

[This corrects the article DOI: 10.1371/journal.pone.0293332.].

Prediction of disease severity using serum biomarkers in patients with mild-moderate Atopic Dermatitis: A pilot study.

Atopic dermatitis (AD) is an inflammatory skin condition that relies largely on subjective evaluation of clinical signs and symptoms for diagnosis and severity assessment. Using multivariate data, we attempted to construct prediction models that can diagnose the disease and assess its severity. We combined data from 28 mild-moderate AD patients and 20 healthy controls (HC) to create random forest models for classification (AD vs. HC) and regression analysis to predict symptom severities. The classification model outperformed the random permutation model significantly (area under the curve: 0.85 ± 0.10 vs. 0.50 ± 0.15; balanced accuracy: 0.81 ± 0.15 vs. 0.50 ± 0.15). Correlation analysis revealed a significant positive correlation between measured and predicted total SCORing Atopic Dermatitis score (SCORAD; r = 0.43), objective SCORAD (r = 0.53), eczema area and severity index scores (r = 0.58, each p < 0.001), but not between measured and predicted itch ratings (r = 0.21, p = 0.18). We developed and tested multivariate prediction models and identified important features using a variety of serum biomarkers, implying that discovering the deep-branching relationships between clinical measurements and serum measurements in mild-moderate AD patients may be possible using a multivariate machine learning method. We also suggest future methods for utilizing machine learning algorithms to enhance drug target selection, diagnosis, prognosis, and customized treatment in AD.

Long-term administration of red ginseng non-saponin fraction rescues the loss of skeletal muscle mass and strength associated with aging in mice.

Background: Sarcopenia is a new and emerging risk factor aggravating the quality of life of elderly population. Because Korean Red Ginseng (RG) is known to have a great effect on relieving fatigue and enhancing physical performance, it is invaluable to examine its potential as an anti-sarcopenic drug. Methods: Anti-sarcopenic effect of non-saponin fraction of Korean Red Ginseng (RGNS) was evaluated in C2C12 myoblasts treated with C2-ceramide to induce senescence phenotypes, and 22-month-old mice fed with chow diet containing 2% RGNS (w/w) for 4 further months. Results: The RGNS treatment significantly alleviated cellular senescence indicated by intracellular lipid accumulation, increased amount of lysosomal ß-galactosidase, and reduced proliferative capacity in C2C12 myoblasts. This effect was not observed with saponin fraction. In an aged mouse, the 4-month-RGNS diet significantly improved aging-associated loss of muscle mass and strength, assessed by the weights of hindlimb skeletal muscles such as tibialis anterior (TA), extensor digitorum longus (EDL), gastrocnemius (GN) and soleus (SOL), and the cross-sectional area (CSA) of SOL muscle, and the behaviors in grip strength and hanging wire tests, respectively. During the same period, an aging-associated shift of fast-to slow-twitch muscle in SOL muscle was also retarded by the RGNS treatment. Conclusions: These findings suggested that the long-term diet of RGNS significantly prevented aging-associated muscle atrophy and reduced physical performance, and thus RGNS has a strong potential to be developed as a drug that prevents or improves sarcopenia.

Acupuncture attenuates comorbid anxiety- and depressive-like behaviors of atopic dermatitis through modulating neuroadaptation in the brain reward circuit in mice.

Atopic dermatitis (AD) is highly comorbid with negative emotions such as anxiety and depression. Although acupuncture has demonstrated efficacy in AD, its influence on comorbid anxiety and depression remains unclear. We sought to explore the impact and mechanisms of action of acupuncture on comorbid anxiety and depression of AD. AD-like skin lesions were induced by the topical application of MC903 to the mouse cheek. Acupuncture was performed at Gok-Ji (LI11) acupoints. AD-like phenotypes were quantified by lesion scores, scratching behavior, and histopathological changes. The effects of acupuncture on comorbid anxiety and depression-like behaviors were assessed using the elevated plus-maze (EPM), open-field tests (OFT), and tail-suspension test (TST). In addition, biochemical changes in the brain reward regions were investigated by immunoblotting for the expression of tyrosine hydroxylase (TH), dopamine D1 receptor (D1R), phospho-dopamine and cAMP-regulated phosphoprotein-32 kDa (pDARPP-32), phospho-cAMP response element binding protein (pCREB), ΔFosB, and brain-derived neurotrophic factor (BDNF) in the nucleus accumbens, dorsolateral striatum, and ventral tegmental area. Acupuncture effectively improved the chronic itching and robust AD-like skin lesions with epidermal thickening. Additionally, it considerably reduced comorbid anxiety- and depression-like symptoms, as indicated by more time spent in the open arms of the EPM and in the center of the open field and less time spent immobile in the TST. Higher pCREB, ΔFosB, BDNF, and pDARPP-32 levels, and reduced TH and D1R protein expression in the brain reward regions of AD mice were reversed by acupuncture treatment. The beneficial effects of acupuncture on clinical symptoms (scratching behavior) and comorbid psychological distress in AD strongly correlated with dorsal striatal ΔFosB levels. Collectively, these data indicate that acupuncture had a significant, positive impact on comorbid anxiety- and depression-like behaviors by modulating neuroadaptation in the brain reward circuit in mice with AD, providing a novel perspective for the non-pharmacological management of psychiatric comorbidities of AD.

Menaquinone-7 ameliorates cerebrovascular calcification-associated memory decline in aged mice.

Menaquinone (MK)-7 is a vitamin K2 analog that functions as a cofactor of γ-glutamyl carboxylase involved in the activation of vitamin K (VK)-dependent proteins. The present study aimed to evaluate the effect of MK-7 on memory and cognitive function in aged C57BL/6 mice. Eighteen-month-old mice were raised for a further 4 months, fed on a standard or calcium-rich diet (3 % [w/w]), and were orally given MK-7 (40 and 400 µg/day/mouse) five times per week during the same period. The Morris water maze (MWM) test was performed at 19 and 22 months. The aged mice showed noticeable memory declines in the MWM test at all time points compared with 6-week-old mice, and this memory loss was significantly restored by the daily administration of high-dose MK-7 for 4 months. MK-7 administration also improved micro-computed tomography-based cerebrovascular calcification and aging-associated declines in growth arrest-specific 6, total and carboxylated matrix Gla proteins, and ganglioside levels in the brain of aged mice. It serologically reduced phosphorous levels in the blood, but not the urea, cholesterol, and calcium. Taken together, the long-term administration of MK-7 significantly improved age-related memory and cognitive impairments, possibly through inhibition of cerebrovascular calcification in aged mice, indicating that it can be used to develop new drugs for improving memory and cognitive function in older adults.

Exploring the Differences in the Gut Microbiome in Atopic Dermatitis According to the Presence of Gastrointestinal Symptoms.

(1) Background: Atopic dermatitis (AD) is a multifactorial chronic allergic skin disease. Gastrointestinal (GI) functions have been suggested to be associated with its incidence or severity. As modulators of the gut-skin axis, gut microbes might affect the pathophysiology of AD. (2) Methods: We divided a cohort of patients with AD according to their GI symptoms as follows: AD with epigastric fullness (ADwEF), AD with epigastric rigidity (ADwER), and AD without GI symptoms (ADw/oGI). The gut microbial profiles were analyzed using 16S rRNA amplicon sequencing. (3) Results: The microbiota of the ADwER group showed low diversity indices in richness and evenness and formed a separate cluster to the other groups. In the ADwER group, the proportion of Bacteroides increased, while that of Prevotella decreased; functional pathways related to phosphotransferase systems were not abundant relative to those in the ADw/oGI group. Taken together, patients with AD with GI symptoms have a different microbiome from patients with simple AD. (4) Conclusions: In an exploratory study aimed at evaluating the relationship between AD and GI symptoms, the gut microbiome in patients with AD with GI symptoms differed from that in patients with simple AD, and this result could serve as a basis for further gut-skin axis studies.

Acupuncture attenuates comorbid anxiety- and depressive-like behaviors of atopic dermatitis through modulating neuroadaptation in the brain reward circuit in mice

Atopic dermatitis (AD) is highly comorbid with negative emotions such as anxiety and depression. Although acupuncture has demonstrated efficacy in AD, its influence on comorbid anxiety and depression remains unclear. We sought to explore the impact and mechanisms of action of acupuncture on comorbid anxiety and depression of AD. AD-like skin lesions were induced by the topical application of MC903 to the mouse cheek. Acupuncture was performed at Gok-Ji (LI11) acupoints. AD-like phenotypes were quantified by lesion scores, scratching behavior, and histopathological changes. The effects of acupuncture on comorbid anxiety and depression-like behaviors were assessed using the elevated plus-maze (EPM), open-field tests (OFT), and tail-suspension test (TST). In addition, biochemical changes in the brain reward regions were investigated by immunoblotting for the expression of tyrosine hydroxylase (TH), dopamine D1 receptor (D1R), phospho-dopamine and cAMP-regulated phosphoprotein-32 kDa (pDARPP-32), phospho-cAMP response element binding protein (pCREB), ΔFosB, and brain-derived neurotrophic factor (BDNF) in the nucleus accumbens, dorsolateral striatum, and ventral tegmental area. Acupuncture effectively improved the chronic itching and robust AD-like skin lesions with epidermal thickening. Additionally, it considerably reduced comorbid anxiety- and depression-like symptoms, as indicated by more time spent in the open arms of the EPM and in the center of the open field and less time spent immobile in the TST. Higher pCREB, ΔFosB, BDNF, and pDARPP-32 levels, and reduced TH and D1R protein expression in the brain reward regions of AD mice were reversed by acupuncture treatment. The beneficial effects of acupuncture on clinical symptoms (scratching behavior) and comorbid psychological distress in AD strongly correlated with dorsal striatal ΔFosB levels. Collectively, these data indicate that acupuncture had a significant, positive impact on comorbid anxiety- and depression-like behaviors by modulating neuroadaptation in the brain reward circuit in mice with AD, providing a novel perspective for the non-pharmacological management of psychiatric comorbidities of AD.

Effect of Acupuncture on Gut-Brain Axis Parameters in Patients with Atopic Dermatitis: A Study Protocol for a Randomized, Participant- and Assessor-Blind, Sham-Controlled Trial.

Atopic dermatitis (AD) is a relapsing and remitting chronic inflammatory skin disease for which a variety of etiological factors are involved. Treatment strategies should be multifaceted and have few side effects. In this respect, acupuncture has become increasingly popular as a safe, consistently effective, and drug-free therapy that treats multiple AD symptoms. We aim to not only verify the effectiveness of acupuncture but also suggest patient-specific response determinants and a new underlying mechanism implicating the gut-brain axis. We have designed a randomized, participant-blinded, sham-controlled clinical trial for 60 mild to moderate AD patients. In a previous study, we observed that the clinical skin symptoms of AD were closely associated with gastrointestinal (GI) symptoms. From these findings, we developed an intervention with six acupuncture points: three for AD symptoms and three for GI symptoms. Also, since high responders and low responders to the acupuncture treatment could be identified in the previous study, we now aim to explore response-determining factors, with a particular focus on GI symptoms. Therefore, we will precisely evaluate not only AD symptoms using the SCORAD, EASI, and DLQI tools, but also GI symptoms using the GSRS, TDS, BSFS, and AR tools and abdominal examination. AD develops in association with complicated pathophysiological factors, such as skin barrier function, genetic susceptibility, and immunological factors. Moreover, the underlying mechanism by which acupuncture treatment works has not been clearly elucidated. We, therefore, will conduct a simultaneous cross-sectional study with a sample of 40 healthy individuals, wherein potential indicators, such as fMRI, gut microbiota, and serum TARC and ATX, will be investigated to determine the gut-brain axis-associated mechanism of acupuncture. We expect that the results of this study could provide important clinical evidence for the effects of acupuncture and help elucidate the therapeutic mechanisms that underlie acupuncture's efficacy in AD treatment. This trial is registered with https://clinicaltrials.gov/ct2/show/KCT0005422 (Trial registration: Korean Clinical Trial Registry (http://cris.nih.go.kr; registration number: KCT0005422); date of registration: September 23, 2020).

Bee venom phospholipase A2 alleviates collagen-induced polyarthritis by inducing Foxp3+ regulatory T cell polarization in mice.

The mechanism underlying bee venom (BV) therapy is still controversial, with opinions ranging from constituent-based pharmacological action to homeopathic-like activity. The purpose of this study was to examine whether BV phospholipase A2 (bvPLA2), an enzymatic component of BV, is a novel anti-inflammatory and anti-arthritic mediator capable of stimulating CD25+ Foxp3+ regulatory T cell (Treg) polarization in a mouse model of human rheumatoid arthritis (RA). An experimental model of RA was established in male DBA/1 mouse by 2-week-interval injections of 100 µg type II collagen emulsified in complete (first injection) or incomplete Freund's adjuvant (second injection) at the base of the tail. During arthritis development, bvPLA2 (0.1, 0.5, 1.0 mg/kg) and/or Treg inhibitors such as anti-CD25 antibodies and peptide 60 (P60) were injected intraperitoneally for 5 weeks. Arthritic symptoms and the expansion of Tregs were then assessed by behavioral assessments, histological and micro-CT imaging, and flow cytometry. bvPLA2 injections significantly alleviated arthritic behaviors such as squeaking and joint swelling, consistent with changes seen on both histological and micro-CT images. The anti-arthritic effects of bvPLA2 were blocked by intraperitoneal injections of 0.25 mg/kg anti-CD25 antibody and 10 µg/kg P60, as determined by behavioral assessments. Flow cytometric analysis of dendritic cells, B cells, and major T cell subsets from spleens revealed a significant depletion of Tregs following anti-CD25 antibody, but not P60, treatment. bvPLA2 treatment exerted significant anti-inflammatory and anti-arthritic activities in a mouse model of RA via the induction of Tregs.

Acupuncture ameliorates not only atopic dermatitis-like skin inflammation but also acute and chronic serotonergic itch possibly through blockade of 5-HT2 and 5-HT7 receptors in mice.

Acupuncture has been known to be effective for atopic dermatitis, especially ameliorating itch; however, its mechanisms are still unclear. The aim of this study was to test the anti-itch effects of acupuncture and to investigate its possible mechanisms. Acupuncture was performed at Gok-Ji (LI11) acupoints just before the injection of pruritogens in the mouse cheek model of acute itch and of MC903-induced atopic dermatitis displaying serotonergic chronic itch. Acupuncture significantly reduced acute itch triggered by compound 48/80, chloroquine, or especially serotonin. It also markedly reduced scratching behaviors evoked by the serotonin 5-HT2 receptor agonist α-methylserotonin and selective 5-HT7 receptor agonist LP 44. In addition, acupuncture treatment at LI11 had the preventive and therapeutic effects on persistent itch as well as the robust skin inflammation with epidermal thickening in mice with MC903-induced atopic dermatitis. It also considerably reduced the increased expression of 5-HT2A, 5-HT2B and 5-HT7 receptors in atopic dermatitis-like skin lesions in mice treated with MC903. Taken together, these findings highlight that acupuncture significantly ameliorates not only skin inflammation, but also acute and chronic serotonergic itch, possibly through blockade of serotonin 5-HT2 and 5-HT7 receptors.

Acupuncture inhibits neuroinflammation and gut microbial dysbiosis in a mouse model of Parkinson's disease.

Growing evidences show that gut microbiota is associated with the pathogenesis of Parkinson's disease (PD) and the gut-brain axis can be promising target for the development of the therapeutic strategies for PD. Acupuncture has been used to improve brain functions and inflammation in neurological disorders such as PD, and to recover the gastrointestinal dysfunctions in various gastrointestinal disorders. Thus, we investigated whether acupuncture could improve Parkinsonism and gut microbial dysbiosis induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. First, we observed that acupuncture treatment at acupoints GB34 and ST36 could improve motor functions and comorbid anxiety in PD mice. Next, we found that acupuncture increased the levels of dopaminergic fibers and neurons in the striatum and the substantia nigra, respectively. Acupuncture also restored the overexpression of microglia and astrocyte as well as conversion of Bax and Bcl-2 expression in both the striatum and the substantia nigra, indicating that inflammatory responses and apoptosis were blocked by acupuncture. Additionally, via 16S rRNA sequence analysis, we observed that the relative abundance of 18 genera were changed in acupuncture-treated mice compared to the PD mice. Of them, Butyricimonas, Holdemania, Frisingicoccus, Gracilibacter, Phocea, and Aestuariispira showed significant correlations with anxiety as well as motor functions. Furthermore, the predicted functional analyses showed that acupuncture restored the physiology functions such as glutathione metabolism, methane metabolism, and PD pathway. In conclusion, we suggest that the effects of acupuncture on the enhanced motor function and the protection of the dopaminergic neurons may be associated with the regulation of the gut microbial dysbiosis and thus the inhibition of the neuroinflammation in the PD mice.

Protective Effects of Quercetin on Anxiety-Like Symptoms and Neuroinflammation Induced by Lipopolysaccharide in Rats.

Recently, neuroinflammation is thought to be one of the important causes of many neuropsychiatric diseases. Quercetin (QUER) is a natural flavonoid, and it is well known that QUER has antioxidative, anti-inflammatory, and neuroprotective effects. In our study, lipopolysaccharide (LPS) was injected into the lateral ventricle of rats to induce anxiety-like behaviors and neuroinflammation, and it was confirmed that chronic administration of QUER could improve anxiety-like symptoms. We also investigated the effects of QUER on inflammatory markers and its major mechanisms associated with inflammation in the hippocampus. Daily administration of QUER (10, 50, and 100 mg/kg) daily for 21 days significantly improved anxiety-like behaviors in the elevated plus-maze test and open field test. QUER administration significantly reduced inflammatory markers such as interleukin-6, interleukin-1ß, cyclooxygenase-2, and nuclear factor-kappaB levels in the brain. In addition, QUER significantly increased the brain-derived neurotrophic factor (BDNF) mRNA level and decreased the nitric oxide synthase (iNOS) mRNA level. Therefore, our results have shown that QUER can improve anxiety-like behaviors caused by chronic neuroinflammation. This anxiolytic effect of QUER has been shown to be due to its anti-inflammatory effects and appropriate regulation of BDNF and iNOS expression. Thus, QUER provides the potential as a therapeutic agent to inhibit anxiety-like symptoms in neuropsychiatric diseases, such as anxiety.

Inhibitory effect of carvacrol on lipopolysaccharide-induced memory impairment in rats.

Neuroinflammation is an important process underlying a wide variety of neurodegenerative diseases. Carvacrol (CAR) is a phenolic monoterpene commonly used as a food additive due to its antibacterial properties, but it has also been shown to exhibit strong antioxidative, anti-inflammatory, and neuroprotective effects. Here, we sought to investigate the effects of CAR on inflammation in the hippocampus and prefrontal cortex, as well as the molecular mechanisms underlying these effects. In our study, lipopolysaccharide was injected into the lateral ventricle of rats to induce memory impairment and neuroinflammation. Daily administration of CAR (25, 50, and 100 mg/kg) for 21 days improved recognition, discrimination, and memory impairments relative to untreated controls. CAR administration significantly attenuated expression of several inflammatory factors in the brain, including interleukin-1ß, tumor necrosis factor-α, and cyclooxygenase-2. In addition, CAR significantly increased expression of brain-derived neurotrophic factor (BDNF) mRNA, and decreased expression of Toll-like receptor 4 (TLR4) mRNA. Taken together, these results show that CAR can improve memory impairment caused by neuroinflammation. This cognitive enhancement is due to the anti-inflammatory effects of CAR medicated by its regulation of BDNF and TLR4. Thus, CAR has significant potential as an inhibitor of memory degeneration in neurodegenerative diseases.

Umbelliferone modulates depression-like symptoms by altering monoamines in a rat post-traumatic stress disorder model.

Post-traumatic stress disorder (PTSD) is a debilitating psychological disease that is triggered by traumatic events. It is known to cause various complications, including anxiety and depression. Umbelliferone (UMB) is a natural product of the coumarin family. This substance has been reported to exert antioxidant, anti-inflammatory, neuroprotective, and other biological effects. We used the open field test (OFT) and the forced swimming test (FST) to examine the effects of UMB on depression-like symptoms in rats after exposure to a single prolonged stress (SPS), which led to dysregulated activation of the serotonergic system. Male rats were given UMB (20, 40, or 60 mg/kg, intraperitoneal injection) once daily for 14 days after exposure to an SPS. Daily UMB administration significantly improved depression-like behaviors on the FST, increased the number of lines crossed in the central zone of the OFT, and reduced freezing behavior in both contextual and cued fear conditioning. UMB treatment attenuated the SPS-induced decrease in serotonin (5-HT) concentrations in the hippocampus and amygdala. The increased 5-HT concentration during UMB treatment was partially due to a decrease in the ratio of 5-hydroxyindoleacetic acid/5-HT in the hippocampus of rats with PTSD. According to our results, UMB has an antidepressant effect in rats exposed to an SPS, suggesting that this natural product of the coumarin family can be used to effectively treat PTSD.