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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.

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.

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.

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.

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).

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 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-HT

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.

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-1β, 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.

Aims Acupuncture, particularly electroacupuncture (EA) has been shown to have the lipid-lowering effects, but not completely investigated. The present study was aimed to examine whether EA could attenuate poloxamer-407 (P-407)-induced hyperlipidemia in the rats and to investigate its potential mechanisms. Main methods Rats received P-407 (0.4 g/kg, i.p.) to induce hyperlipidemia. EA was performed at ST36 and ST40 acupoints a total of three times with 12 h-interval starting 1 h before the P-407 injection at 0.6 mA intensity and 2 Hz frequency for 10 min. Key findings In P-407-induced hyperlipidemic rats, EA stimulation at ST36 and ST40 acupoints significantly lowered the serum levels of triglycerides, total cholesterol, LDL-cholesterol and atherogenic index, while markedly increasing the serum HDL-cholesterol levels. Meanwhile, hyperlipidemic rats had significantly higher expression of sterol regulatory element-binding protein (SREBP)-2, without any difference in SREBP-1 expression in the liver, as compared with normal ones. EA significantly attenuated the expression of SREBP-2 with a subsequent decrease in 3-hydroxy-3-methylglutaryl coenzyme A reductase and an increase in low-density lipoprotein receptor at both mRNA and protein levels in the liver of hyperlipidemic rats. These changes did not occur after electrical stimulation at a non-acupoint. Significance Taken together, our findings indicate that EA stimulation to P-407-induced hyperlipidemic rats improves the lipid abnormalities, which may be associated with regulation of the expression of key enzymes of cholesterol synthesis in the liver through modulation of SREBP-2.

Ethnopharmacological relevance Schisandra chinensis (Turcz.) Baill (SC), Lycium chinense Mill (LC) and Eucommia ulmoides Oliv (EU) are representative tonic herbal medicines that help to strengthen body muscles and bones making them stronger according to the Donguibogam, a tradition medical book of the Joseon Dynasty in Korea. Aim of the study To evaluate effects of an herbal formula consisting of SC, LC and EU on muscle atrophy in C2C12 myotubes and in a rat model of immobilization-induced muscle atrophy. Materials and methods Muscle atrophy was developed by cast immobilization of unilateral hindlimb on rats for 3 weeks. Treatments were administered orally 14 times over 3 weeks. After treatments, we compared the change of body weight, muscle weight, grip strength, muscle fiber size, muscle fiber type shift by Grip strength meter, H&E stain and ATPase stain. And western blot was used for evaluating molecular mechanism in muscle atrophy on C2C12 cells. Results When taken individually, SC was the most effective of the three in inhibiting tumor necrosis factor alpha (TNF-α)-induced degeneration of C2C12 myogenesis. The formulation with a mass ratio of 2:1:1 SC: LC: EU (SSLE) was more effective against TNF-α-induced muscle atrophy than was a 1:1:1 SC: LC: EU (SLE) formula or any of the single herbal extracts. In a rat model of disuse muscle atrophy, the SSLE formula significantly inhibited reductions in muscle weight, grip strength and muscle fiber size induced by hindlimb immobilization, in a dose-dependent manner. The formula also inhibited immobilization-induced shifting of the muscle fiber type in soleus muscle. Treatment with SSLE inhibited TNF-α-induced expression of the atrogenes atrogin-1 and muscle RING-finger protein 1 in C2C12 cells. The SSLE formula also increased myoblast differentiation markers (myoD and myogenin) and activation of the Akt and mammalian target of rapamycin (mTOR) signaling pathway. Conclusion These findings suggest that the SSLE formula prevents muscle atrophy through inhibition of the ubiquitin-proteasome system as well as upregulation of myoblast differentiation and muscle protein synthesis in C2C12 cells. Taken together, we conclude that the SSLE formula is invaluable for the development of therapeutic medicines to prevent disuse muscle atrophy and its accompanying muscle weakness.

Background Blocking the formation and invasive growth of pannus and its secretion of inflammatory cytokines and MMPs is important for treating rheumatoid arthritis. Hypothesis/Purpose Anti-arthritic activity of Aralia continentalis Kitag., an oriental herbal medicine, and the underlying mechanisms involved were investigated. Study Design Anti-inflammatory and anti-nocicpetive activities of the ethanolic extract (50% v/v) of Aralia continentalis Kitag. harvested from Imsil, Korea (ACI) were investigated in IL-1β-stimulated human fibroblast-like synoviocyte (FLS) cells and rodent models of collagen-induced polyarthritis and carrageenan-induced acute paw pain. Methods In IL-1β-stimulated FLS cells derived from rheumatoid arthritis patients, the anti-inflammatory activity of ACI was examined by analyzing the expression levels of inflammatory mediators such as TNF-α, IL-6, IL-8, MMP-1, MMP-3, MMP-13, PGE2, and COX-2 using ELISA and RT-PCR analysis. The anti-arthritic activity of ACI was investigated by measuring body weight, squeaking score, paw volume, and arthritis index in collagen-induced polyarthritis mice. The anti-nociceptive activity of ACI was examined in the paw-pressure test and Tail-flick latency test in rats. Results The ethanolic extract (50% v/v) of ACI reduced the levels of TNF-α, IL-6, IL-8, MMP-1, and MMP-13 secreted by IL-1β-stimulated FLS cells, whereas MMP-3, COX-2, and PGE2 were not significantly affected. ACI inhibited the migration of NF-κB into the nucleus through the inhibition of ERK- and JNK-dependent MAP kinase pathways in IL-1β-stimulated FLS cells. In collagen-induced polyarthritis mice, oral administration of ACI extract (200 mg/kg) significantly alleviated arthritic behaviors. Histological observations of arthritic mouse knees were consistent with their behaviors. The anti-arthritic and anti-inflammatory activities of 200 mg/kg ACI extract were comparable to those of 10 mg/kg prednisolone when administered to mice. However, ACI administration did not significantly affect carrageenan-induced hyperalgesia or thermal nociception in rats. Conclusion These results suggest that the ethanolic extract of ACI have significant anti-inflammatory and anti-arthritic effects in a rodent arthritis model and in IL-1β-stimulated FLS cells. Thus, ACI may be a useful candidate for developing pharmaceuticals or dietary supplements for the treatment of inflammatory arthritis.

The aim of this study was to identify the active compound responsible for the pharmacological activities of Manchurian spikenard (Aralia continentalis Kitag.). Interleukin (IL)-1&beta, stimulated human chondrocytes and monoiodoacetate (MIA)-induced osteoarthritic rats were treated with the 50% ethanolic extract of spikenard or its major components, such as continentalic acid (ent-pimara-8(14),15-diene-19-oic acid) and kaurenoic acid (ent-kaura-16-en-19-oic acid). The spikenard extract significantly inhibited IL-1&beta, stimulated production of IL-6, IL-8, metalloproteinase (MMP)-1, MMP-13, cyclooxygenase (COX)-2, inducible nitric oxide synthase (iNOS) and prostaglandin(PG)E2 in a dose-dependent manner but not MMP-3 production. The extract also inhibited the IL-1&beta, induced translocation of NF-&kappa, B/p65 into the nucleus and dose-dependent phosphorylation levels of extracellular signal-regulated kinase (ERK), Jun amino-terminal kinase (JNK) and p38 mitogen-activated protein (MAP) kinase. Continentalic acid exhibited significant anti-arthritic activity corresponding exactly to that of the extract containing an equivalent amount of continentalic acid. On the other hand, kaurenoic acid exhibited a compatible activity at about a 10-times higher molar concentration than that of continentalic acid. In vitro anti-arthritic activities of the spikenard extract and continentalic acid were also confirmed in MIA-induced osteoarthritic rats. The 50% ethanolic extract of Manchurian spikenard exhibited promising anti-arthritic activities in the in vitro and in vivo osteoarthritis models, and continentalic acid, not kaurenoic acid, was most probably responsible for those activities.

Background Cnidii Rhizoma is the dried root stem of Cnidium officinale Makino. Cnidii Rhizoma (CR) has been used to treat menstrual irregularity, menstrual pain, and menopause in Korea. However, the effects and mechanisms of CR on RANKL-induced osteoclastogenesis pathway remain to be elucidated. In this study, we investigated the effects of CR on the inhibition of bone resorption of osteoclast and its mechanism RANK signaling pathway. Methods The anti-osteoclastogenesis of water extract of CR was measured using RAW 264.7 cell. Tartrate-resistant acid phosphatase (TRAP) assay, pit assay, reverse transcription polymerase chain reaction (RT-PCR) and western blot were performed. Moreover, the effects of CR were determined with an in vivo model using ovariectomized (OVX) rats. Results CR extract suppressed osteoclastogenesis, its activity and bone resorption activity through decreasing gene of osteoclast-related such as nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1), c-Fos, etc. Moreover, CR extract prevented the bone loss in OVX rats. Conclusion These results show that CR has a positive effect on menopausal osteoporosis by suppressing osteoclastogenesis. Electronic supplementary material The online version of this article (10.1186/s12906-019-2611-8) contains supplementary material, which is available to authorized users.

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-1β, 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.

Background Post-traumatic stress disorder (PTSD) is a disease associated with that the experience of traumatic stress. The traumatic experience results in the development of a prolonged stress response that causes impaired memory function and increased inflammation in the hippocampus. Currently, antidepressants are the only approved therapy for PTSD. However, the efficacy of antidepressants in the treatment of PTSD is marginal. The ethanol extract of Aralia continentalis (AC) is traditionally used in oriental medicine, and has been showed to possess pharmacological properties, including anti-inflammatory, anti-cancer, anti-atherosclerotic, and anti-diabetic effects. Nevertheless, the effects of AC on cognitive memory and its mechanism of action in PTSD remain unclear. Given the necessity of further treatment options for PTSD, we investigated the effect of AC on the spatial cognitive impairment caused by single prolonged stress (SPS) in a rat model of PTSD. Methods Male rats were treated with various intraperitoneal (i.p.) doses of AC for 21 consecutive days after inducing chronic stress with the SPS procedure. Results Cognitive impairment caused by SPS were inhibited after treatment with 100 mg/kg AC, as measured by the Morris water maze test and an object recognition test. Additionally, AC treatment significantly alleviated memory-related decreases in brain-derived neurotrophic factor (BDNF) mRNA and protein levels in the hippocampus. Our results suggest that AC significantly inhibited the cognitive deficits caused by SPS via increased expression of pro-inflammatory cytokines, including tumor necrosis factor-α and interleukin-6, in the rat brain. Conclusions AC reversed the behavioral impairments and inflammation triggered by SPS-derived traumatic stress and should be further evaluated as a potential therapeutic drug for PTSD.

Purpose: This study aimed to develop and test a model of the happiness of mothers with young children based on the stress-coping-adaptation model of Lazarus and Folkman. Methods: The data collection period was from May to July 2016. A self-report questionnaire was used to collect data from 210 mothers with children under 5 years of age living in Seoul, Gyeonggi, and Gangwon provinces. The exogenous variable was parenting stress, and the endogenous variables were parenting alliance, depression, optimism, ways of coping, and happiness. Data from 201 questionnaires were analyzed using the SPSS 22.0 and AMOS 20.0 programs. Data analyses included descriptive statistics, factor analysis, and structural equation modeling. Results: The final modified model showed a reasonable fit to the data, and out of 25 paths, 13 were statistically significant. This model explained 78.4% of the variance in the happiness of mothers with young children and confirmed that depression, optimism, parenting alliance, and social support-focused coping have a direct effect on the subject’s happiness. Parenting stress also influenced happiness through parenting alliance, depression, and optimism. Conclusion: In order to bolster the happiness of mothers with young children, positive psychological interventions that can minimize psychological vulnerabilities, such as depression, and that can enhance their strengths, such as optimism, may serve as effective ways of coping with and adapting to stress.

Exposure to severe stress can lead to the development of neuropsychiatric disorders such as depression and post-traumatic stress disorder (PTSD) in at-risk individuals. Gastrodin (GAS), a primary constituent of an Oriental herbal medicine, has been shown to effectively treat various mood disorders. Thus, the present study aimed to determine whether GAS would ameliorate stress-associated depression-like behaviors in a rat model of single prolonged stress (SPS)-induced PTSD. Following the SPS procedure, rats received intraperitoneal administration of GAS (20, 50, or 100 mg/kg) once daily for 2 weeks. Subsequently, the rats performed the forced swimming test, and norepinephrine (NE) levels in the hippocampus were measured. Daily GAS (100 mg/kg) significantly reversed depression-like behaviors and restored SPS-induced increases in hippocampal NE concentrations as well as tyrosine hydroxylase expression in the locus coeruleus. Furthermore, the administration of GAS attenuated SPS-induced decreases in the hypothalamic expression of neuropeptide Y and the hippocampal mRNA expression of brain-derived neurotrophic factor. These findings indicate that GAS possesses antidepressant effects in the PTSD and may be an effective herbal preparation for the treatment of PTSD.

We examined whether wogonin (WO) improved hippocampal neuronal activity, behavioral alterations and cognitive impairment, in rats induced by administration of trimethyltin (TMT), an organotin compound that is neurotoxic to these animals. The ability of WO to improve cognitive efficacy in the TMT-induced neurodegenerative rats was investigated using a passive avoidance test, and the Morris water maze test, and using immunohistochemistry to detect components of the acetylcholinergic system, brain-derived neurotrophic factor (BDNF), and cAMP-response element-binding protein (CREB) expression. Rats injected with TMT showed impairments in learning and memory and daily administration of WO improved memory function, and reduced aggressive behavior. Administration of WO significantly alleviated the TMT-induced loss of cholinergic immunoreactivity and restored the hippocampal expression levels of BDNF and CREB proteins and their encoding mRNAs to normal levels. These findings suggest that WO might be useful as a new therapy for treatment of various neurodegenerative diseases.

Ethnopharmacological relevance Xanthii fructus (XF) has long been used to treat a variety of inflammatory conditions in Korean traditional medicine, but the underlying mechanisms that could explain the anti-inflammatory actions of XF remain largely unknown. Aim of the study This study aimed to elucidate the anti-inflammatory effects of X. fructus (XF) and to examine its underlying molecular mechanisms in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages. Materials and methods The effect of XF on LPS-induced mRNA and protein expressions of inflammatory mediators and cytokines were determined. Moreover, the activation of the nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways and the expression of heme oxygenase-1 (HO-1) were explored to elucidate the anti-inflammatory mechanisms. Results XF significantly inhibited LPS-induced production of inflammatory mediators, interleukin-6 (IL-6), nitric oxide (NO), and prostaglandin E 2 (PGE 2 ), without any cytotoxicity. However, it did not affect tissue necrosis factor (TNF)-α or IL-1β production in LPS-stimulated RAW 264.7 cells. Expression levels of inducible nitric oxide synthase (iNOS) mRNA and protein were inhibited dose-dependently by XF in LPS-stimulated RAW 264.7 cells, but there were no changes in cyclooxygenase-2 (COX-2) mRNA and protein. XF significantly attenuated LPS-induced phosphorylation and degradation of inhibitory kappa Bα (IκBα) and consequently reduced the nuclear translocation of p65 NF-κB. Pretreatment with XF also strongly inhibited the LPS-induced phosphorylation of p38 kinase and JNK, whereas the phosphorylation of ERK1/2 was not affected. In addition, XF led to an increase in HO-1 expression. Conclusion Taken together, our findings support that XF inhibits LPS-induced inflammatory responses by blocking NF-κB activation, inhibiting JNK/p38 MAPK phosphorylation, and enhancing HO-1 expression in macrophages, suggesting that it could be an attractive therapeutic candidate for various inflammatory diseases.

Single prolonged stress (SPS), a rat model of post-traumatic stress disorder (PTSD), induces alterations in the hypothalamic-pituitary-adrenal axis. Korean red ginseng, whose major active component is ginsenoside Rb1 (GRb1), is one of the widely used traditional anxiolytics. However, the efficacy of GRb1 in alleviating PTSD-associated anxiety-like abnormalities has not been investigated. The present study used several behavioral tests to examine the effects of GRb1 on symptoms of anxiety in rats after SPS exposure and on the central noradrenergic system. Male Sprague-Dawley rats received GRb1 (10 or 30 mg/kg, i.p., once daily) during 14 days of SPS. Daily GRb1 (30 mg/kg) administration significantly increased the number and duration of open-arm visits in the elevated plus maze (EPM) test, reduced the anxiety index, increased the risk assessment, reduced grooming behaviors in the EPM test, and increased the total number of line crossings of an open field after SPS. The higher dose of GRb1 also blocked SPS-induced decreases in hypothalamic neuropeptide Y expression, increases in locus coeruleus tyrosine hydroxylase expression, and decreases in hippocampal mRNA expression of brain-derived neurotrophic factor. These findings suggest that GRb1 has anxiolytic-like effects on both behavioral and biochemical symptoms similar to those observed in patients with PTSD.

β-asarone (BAS) is an active component of Acori graminei rhizoma, a traditional medicine used clinically in treating dementia and chronic stress in Korea. However, the cognitive effects of BAS and its mechanism of action have remained elusive. The purpose of this study was to examine whether BAS improved spatial cognitive impairment induced in rats following chronic corticosterone (CORT) administration. CORT administration (40 mg/kg, i.p., 21 days) resulted in cognitive impairment in the avoidance conditioning test (AAT) and the Morris water maze (MWM) test that was reversed by BAS (200 mg/kg, i.p). Additionally, as assessed by immunohistochemistry and RT-PCR analysis, the administration of BAS significantly alleviated memory-associated decreases in the expression levels of brain-derived neurotrophic factor (BDNF) and cAMP-response element-binding protein (CREB) proteins and mRNAs in the hippocampus. Also, BAS administration significantly restored the expression of Bax and Bcl-2 mRNAs in the hippocampus. Thus, BAS may be an effective therapeutic for learning and memory disturbances, and its neuroprotective effect was mediated, in part, by normalizing the CORT response, resulting in regulation of BDNF and CREB functions and anti-apoptosis in rats.

Clinically, it has been reported that atopic dermatitis (AD) has been linked with negative emotional problems such as depression and anxiety, thereby reducing the quality of life, but little is known about the molecular mechanism that underlies AD-associated emotional impairments. We sought to determine whether AD could induce anxiety- and depressive-like symptoms in mice and to identify pertinent signaling changes in brain reward circuitry. AD-like lesions were induced by the repeated intradermal application of MC903 into the cheek of the mouse. We assessed dermatitis severity with scratching behavior, histopathological changes, anxiety- and depressive-like behaviors using the elevated plus maze, open field and tail suspension tests, and serum corticosterone levels. In the nucleus accumbens (NAc), dorsal striatum (DS) and ventral tegmental area (VTA), protein levels of dopamine- and plasticity-related signaling molecules were determined by Western immunoblotting assay. Intradermal administration of MC903 into mouse cheek provoked a strong hind limb scratching behavior as well as the robust skin inflammation with epidermal thickening. MC903-treated mice also displayed markedly increased anxiety- and depressive-like behaviors, along with elevated serum corticosterone levels. Under these conditions, enhanced cAMP response element binding protein (CREB) and dopamine and cAMP-regulated phosphoprotein, 32 kDa (DARPP32) phosphorylation, significantly higher brain-derived neurotrophic factor (BDNF) and ΔFosB, but reduced tyrosine hydroxylase (TH) and dopamine D1 receptor (D1R) protein expression were found in the NAc, DS and VTA. Striatal BDNF, phospho-DARPP32 and phospho-CREB levels were significantly associated with the levels of depressive-like behavior in these mice. Taken together, these findings demonstrate that AD-like skin lesion elicits anxiety- and depressive-like phenotypes that are associated with neuroplasticity-related changes in reward circuitry, providing a better understanding of AD-associated emotional impairments.

Background and Objective: Bupleurum falcatum (BF) extract, a natural product with anti-inflammatory properties, has been traditionally used to treat menopausal symptoms, but its role in osteoporosis, another serious health concern of menopausal women, remains unknown. Here we investigated whether and how BF prevents estrogen deficiency-induced bone loss using both in vitro and in vivo models. Methods: Female Sprague-Dawley rats were ovariectomized (OVX) and subjected to oral BF treatment daily for 8 weeks. Additionally, pre-osteoclastic RAW 264.7 cells were employed to evaluate the effects of BF and its underlying mechanism on receptor activator of nuclear factor kappa-B ligand (RANKL)-induced osteoclast formation in vitro. Results: A high dose of BF partially prevented ovariectomy (OVX)-induced bone loss and reduced the levels of tartrate-resistant acid phosphatase (TRAP) in serum and osteoclast numbers in femurs of OVX rats. Furthermore, BF clearly inhibited RANKL-induced osteoclast differentiation and bone resorption activity in RAW 264.7 cells. BF also inhibited the osteoclastogenic transcription factors c-Fos and nuclear factor of activated T cells c1 (NFATc1) and, consequently, downregulated the expression of osteoclast marker genes. Moreover, BF upregulated interferon-β (IFN-β)/inducible nitric oxide synthase (iNOS)/nitric oxide (NO) signaling, even though it had no impact on mitogen-activated protein kinases (MAPK) or NF-κB. The inhibition of osteoclast formation by BF was abrogated by iNOS-specific inhibitors. Consistent with cellular studies, BF upregulated iNOS protein expression in femurs from OVX rats. Conclusion: Taken together, our results indicate that BF partially prevented estrogen deficiency-induced bone loss with anti-osteoclastogenic activity potentially due to enhanced iNOS/NO signaling.

Objectives To assess the feasibility of a definitive trial investigating the effects of acupuncture on atopic dermatitis symptoms including itching. Design A randomized, sham-controlled preliminary trial with three arms with a 4-week intervention period and a 4-week follow-up. Interventions Thirty participants were allocated to three arms (the verum acupuncture group 1 [VA1, 3 times weekly for 4 weeks], the verum acupuncture group 2 [VA2, twice weekly for 4 weeks], and the sham acupuncture group [SA, twice weekly for 4 weeks]) at a 1:1:1 ratio. Main outcome measures We determined the visual analogue scale (VAS) for itching and insomnia, SCORing Atopic Dermatitis (SCORAD), Eczema Area and Severity Index (EASI), Patient Oriented Eczema Measure (POEM), and Dermatology Life Quality Index (DLQI) scores over the course of the study. Baseline index score (BIS) comparison according to general symptom was performed. Results The SCORAD, VAS (Pruritus), VAS (Insomnia), POEM, DLQI, and EASI were significantly improved in the VA groups. Significant BIS mean differences were observed most predominantly in epigastric tenderness and dyspepsia. There was no significant difference between VA1 and VA2 groups in all the main evaluation indices. Conclusions For the following research, the authors suggest SCORAD (Total) as primary outcome and SCORAD (objective), VAS (Itch), VAS (insomnia), EASI, POEM, and DLQI as secondary outcomes. Thirty six participants should be conducted a 4-week acupuncture period (twice weekly) and a 4-week follow-up. It is necessary to compare the differences of general symptoms according to presence of epigastric tenderness or dyspepsia at the screening level.

This study aims to test the feasibility of a randomised clinical trial to evaluate how acupuncture affects atopic dermatitis (AD) symptoms and quality of life and to explore potential biomarkers that may be associated with AD. It is a sham-controlled trial in which 30 eligible patients will be randomly allocated in a 1 : 1 : 1 ratio to one of three groups: verum acupuncture (VA) group 1 (3 times weekly for 4 weeks); VA group 2 (twice weekly for 4 weeks); or sham acupuncture group (SA; twice weekly for 4 weeks). SA will consist of nonpenetrating acupuncture. Outcome measures will include the Visual Analogue Scale for itch, SCORing Atopic Dermatitis, and Eczema Area and Severity Index to evaluate AD symptoms improvement along with the Patient Oriented Eczema Measure and Dermatology Life Quality Index to assess quality of life. Measures will be collected at baseline, once weekly during the treatment period, and after a 4-week follow-up period. Blood collection will be at baseline and 4 and 8 weeks after treatment and compared with healthy controls. Illumina sequencing will be used to profile microRNA expression in each group to explore candidate microRNA biomarkers for specific effects of acupuncture in patients with AD. This trial is registered via US National Institutes of Health Clinical Trials registry (ClinicalTrials.gov) on 15 July 2016, identifier: NCT02844452.

Aims The purpose of this study was to investigate the effect of Lactobacillus casei variety rhamnosus (LCR35) on Atopic dermatitis (AD)-like symptoms in mice. Methods and Results AD-like skin lesions in BALB/C mice were induced by sensitization and subsequent repeated challenges with trimellitic anhydride (TMA) for 10 days. LCR35 was orally administered to the mice once daily throughout the study. In the TMA-induced AD model, orally administered LCR35 suppressed significantly irritant-related scratching behaviour and skin dehydration as well as apparent severity of AD. LCR35 also significantly decreased serum levels of IgE and IL-4, but not IFN-γ, implying the restoration of TMA-induced disruption of Th1/Th2 balance. Quantitative real-time PCR targeting hypervariable regions of 16S rDNA gene of faecal microbiota indicated that the LCR35 treatment increased the population of Bifidobacterium, Lactobacilli, Enterococcus and Bacteroides fragilis group, but decreased those of Clostridium coccoides group. Conclusions LCR35 has the ability to suppress the development of AD in mice, possibly through the modulation of Th1/Th2 balance and gut microbiota. Significance and Impact of the Study LCR35 has a strong potential as a probiotic for preventing AD.

The positive effect of glucosylceramide (GlcCer) on skin conditions is well known. Recently, there has been increasing interest in the potential antiinflammatory effects of GlcCer due to its efficacy in relieving atopic skin symptoms. However, the role of GlcCer in inflammation has not been investigated completely. Thus, we hypothesized that GlcCer might exhibit the antiinflammatory effects through the inhibition of nuclear factor κB (NF-κB) and mitogen-activated protein kinase (MAPK) signaling. To test this hypothesis, the antiinflammatory effects and signaling mechanisms of GlcCer were investigated in lipopolysaccharide (LPS)-induced RAW 264.7 cells. We report that GlcCer inhibited messenger RNA and protein expression of tissue necrosis factor α and interleukin 1β without cytotoxicity. However, it did not affect interleukin 6 production in LPS-stimulated RAW 264.7 macrophages. Glucosylceramide also suppressed prostaglandin E2 but not nitric oxide production, consistent with its inhibition of cyclooxygenase 2 but not of inducible nitric oxide synthase expression. The molecular mechanism of GlcCer-mediated inhibition of LPS-induced inflammation in RAW 264.7 cells is closely related to suppression of NF-κB p65 subunit nuclear translocation as well as to phosphorylation of extracellular signal-regulated kinase and, in particular, p38 MAPK. In addition, GlcCer did not affect c-Jun N-terminal kinase phosphorylation. In conclusion, GlcCer inhibits LPS-induced inflammation by blocking the nuclear translocation of NF-κB and inhibiting the phosphorylation of extracellular signal-regulated kinase/p38 MAPK pathways in macrophages, suggesting that it might be a promising potential drug candidate for various inflammatory diseases.

Background Not many studies have investigated individual sensitivity to acupuncture. To explore the intrinsic factors related to individual responses to acupuncture, we reviewed published pre-clinical studies using responder analysis on pain. Methods We searched the PubMed and EMBASE databases to June 2015. We included pre-clinical reports describing responders and non-responders to anti-nociceptive and analgesic effects of acupuncture in animal study. We identified the potential intrinsic factors which might be related with the response to acupuncture. Results Totally, 216 potentially relevant articles were retrieved and 14 studies met our inclusion criteria. Rat (n = 1348) and rabbit (n = 56) were used, and only electroacupuncture (EA) was applied as an intervention. Results showed that high levels of cholecystokinin-8 and receptors were associated with poor responsiveness to EA. Endogenous opioids including β-endorphin and met-enkephalin, descending inhibitory norepinephrine and serotonin system, and hypothalamic 5′-AMP-activated protein kinase seemed to be associated with high-level responses. Spinal levels of neurotransmitters and pro-inflammatory cytokines were also differentially expressed depending on the EA sensitiveness. In the central nervous system, hypothalamus, periaqueductal grey, pituitary gland, and spinal cord were suggested to be involved in the EA responsiveness. Identified individual variations did not seem to be accidental, as the responsiveness to EA was replicated over time. However, methodological issues such as reproducibility, cut-off criteria, and clinical relevance need to be further elaborated. Conclusion Our study suggests that the identification of the biological factors differentiating responders from non-responders is necessary and it may aid in understanding how acupuncture modulates pain. Electronic supplementary material The online version of this article (doi:10.1186/s12906-017-1792-2) contains supplementary material, which is available to authorized users.

Abnormal adaptation of the stress-response system following traumatic stress can lead to alterations in the hypothalamic-pituitary-adrenal (HPA) axis that may contribute to the development of post-traumatic stress disorder (PTSD). The present study used several behavioral tests to investigate the anxiolytic-like and antidepressant activity of L-tetrahydropalmatine (L-THP) in an experimental rat model of anxiety and depression induced by single prolonged stress (SPS), an animal model of PTSD. Male rats were treated intraperitoneally (i.p.) with vehicle or varied doses of THP 30 min prior to SPS for 8 consecutive days. Daily THP (50 mg/kg) administration significantly increased the number and duration of open arm visits in the elevated plus maze (EPM) test, reduced the anxiety index, increased the risk assessment, and increased the number of head dips over the borders of the open arms after SPS. THP was also associated with increased time spent at the center of the open field, reduced grooming behaviors in the EPM test, and reduced time spent immobile in the forced swimming test (FST). It also blocked the decrease in neuropeptide Y (NPY) and the increase in corticotrophin-releasing factor (CRF) expression in the hypothalamus. This is the first study to determine that THP exerts pronounced anxiolytic-like and antidepressant effects on the development of the behavioral and biochemical symptoms associated with PTSD, indicating its prophylactic potential. Thus, THP reversed several behavioral impairments triggered by the traumatic stress of SPS and is a potential non-invasive therapeutic intervention for PTSD.

Ethnopharmacological relevance Cyperus Rotundus L. (CyR) has been widely used for the treatment of gynecologic disorder. Recent studies have reported that CyR can prevent the formation of cystic follicles and ovarian malfunction. However, the effects of CyR on osteoclastogenesis and postmenopausal osteoporosis remain unknown. Aim of the study This study was aimed to investigate the preventive effects of CyR on RANKL-induced osteoclast formation and ovariectomy (OVX)-induced bone loss. Materials and methods In this in vitro study, we investigate the anti-osteoporotic effect of CyR on receptor activator of nuclear factor kappa-B ligand (RANKL)-induced osteoclastogenesis, the formation of tartrate-resistant acid phosphatase (TRAP) multinucleated cells, pit formation, transcription factors such as NFATc1 and c-Fos, and mRNA expression of osteoclast-associated genes were investigated. Forty 12-weeks female Sprague-Dawley rats for in vivo effect of CyR were used and OVX rat model was determined. The rats were randomly assigned into sham group and four OVX groups, i.e. OVX with D.W; OVX with estradiol (E2, 100 μg/kg/day), OVX with CyR-L (16 mg/kg/day), OVX with CyR-H (160 mg/kg/day). The treatment lasted for 8weeks. Results CyR inhibited osteoclast differentiation and pit formation in the RANKL-induced osteoclastogenesis of RAW 264.7 cells. Reverse transcription polymerase chain reaction analysis also showed that CyR reduced the mRNA expression of osteoclast-associated genes such as carbonic anhydrase II, TRAP, RANK, cathepsin K, matrix metalloproteinase 9, nuclear factor of activated T cells cytoplasmic 1 (NFATc1), and c-Fos. In addition, CyR decreased protein levels of NFATc1 and c-Fos. CyR inhibited trabecular bone loss in the femur caused by OVX. Conclusion The results of this study indicate that CyR inhibits the RANKL-induced osteoclast differentiation in RAW 264.7 cells and trabecular bone loss in OVX rats.