Immune-enhancement effects of Angelica gigas Nakai extracts via MAPK/NF-ƙB signaling pathways in cyclophosphamide-induced immunosuppressed mice.

This study investigated the immune-enhancement effects of Angelica gigas Nakai extract (ANE) and its yeast-fermented extract (FAN) in cyclophosphamide (CPP)-induced immunosuppressed mice. Angelica gigas Nakai (AGN) increased the protein level of inducible nitric oxide synthase (iNOS) and the production of nitric oxide (NO) and immune-related cytokines in mouse splenocytes. AGN also restored CPP-induced suppression of NK cell activity and splenocyte proliferation. Furthermore, AGN activated the ERK and p38 MAPK/NF-κB signaling pathways in mouse splenocytes via phosphorylation of signaling molecules. These findings indicate that upregulation of cytokines and enzymes may be closely associated with the MAPK/NF-κB signaling pathways. In conclusion, AGN can restore CPP-induced immunosuppression in mice, although there was no significant difference in the immune-enhancing effect between ANE and FAN. It is suggested that AGN might have the potential to enhance immunity as an immunostimulant under immunosuppressed conditions. Therefore, it could be used as an effective agent or a dietary supplement for improving immunity. Supplementary Information: The online version contains supplementary material available at 10.1007/s10068-023-01281-6.

Extract of Aster glehni ameliorates potassium oxonate-induced hyperuricemia by modulating renal urate transporters and renal inflammation by suppressing TLR4/MyD88 signaling.

Recent studies suggest that Aster glehni extract (AGE) reduces hyperuricemia by preventing xanthine oxidase activity. However, its effect on renal urate transporters responsible for modulating urate excretion has not been examined. This study investigated whether AGE affects gene expressions of urate transporters using potassium oxonate (PO)-induced hyperuricemia rats. Furthermore, the underlying mechanisms of AGE were explored to ameliorate renal inflammation and injury by PO. AGE effectively restored PO-induced dysregulation of renal urate transporter 1 (URAT1), glucose transporter 9 (GLUT9), ATP-binding cassette transporter subfamily G member 2 (ABCG2), organic anion transporter 1 (OAT1), and organic cation transporter 1 (OCT1), resulting in increasing urate excretion. Additionally, AGE suppressed toll-like receptor 4/myeloid differentiation factor 88 (TLR4/MyD88) signaling, phosphorylation of nuclear factor kappa B (NF-κB), and renal production of IFN-γ, IL-1ß, TNF-α, and IL-6. These results suggest that AGE may ameliorate PO-induced hyperuricemia by modulating renal transporters, and further renal inflammation via inhibiting the TLR4/MyD88/NF-κB signaling pathway. Supplementary Information: The online version contains supplementary material available at 10.1007/s10068-022-01153-5.

Evaluation of Subchronic Toxicity and Genotoxicity of Ethanolic Extract of Aster glehni Leaves and Stems.

Aster glehni, a traditional plant on Ulleung Island in the Republic of Korea, has been recognized for its multiple medicinal properties. However, potential toxicity and safety analyses of A. glehni have not been previously investigated. Therefore, this study aimed to evaluate the safety profile of ethanolic extract of A. glehni leaves and stems (EAG) in terms of genotoxicity and subchronic oral animal toxicity under OECD guidelines and GLP conditions. Toxicological assessments were performed at doses of 1,250, 2,500, and 5,000 mg/kg/day in a 13-week oral repeated-dose toxicity study of EAG in male and female SD rats. In addition, an Ames test, an in vitro mammalian chromosomal aberration test, and a micronucleus test were performed. No toxicological changes in clinical signs, body weights, water and food consumption, urinalysis, hematology, clinical biochemistry, gross findings, and histopathological examinations were observed in subchronic oral animal toxicity. In addition, EAG gave negative results when evaluated using in vitro and in vivo genotoxicity tests. In conclusion, the no-observed-adverse-effect level (NOAEL) of EAG was considered to be 5,000 mg/kg/day, and no target organs were identified in both sexes of rats. EAG was also classified as nonmutagenic and nonclastogenic in genotoxicity testing. Collectively, these results show a lack of general toxicity and genotoxicity for EAG that supports clinical work for development as a herbal medicine.

Efficacy of Ethanolic Extract of Opuntia ficus-indica var. saboten Stems for Improving Cognitive Function in Elderly Subjects 55-85 Years of Age: A Randomized, Double-Blind, Placebo-Controlled Study.

Many natural compounds have been reported to improve cognitive function in cell- and animal-based studies. In this clinical trial, we evaluated the efficacy of ethanolic extract of Opuntia ficus-indica var. saboten stem for improving cognitive function using a randomized, double-blind, placebo-controlled trial (n = 81) in aged people. After 12 weeks of administration of OFE (a mixture of ethanolic extract of O. ficus-indica var. Saboten stem and dextrin) or placebo, the effect on cognitive function was assessed. Overall, OFE did not show a significant difference from the placebo in terms of efficacy. However, the cognitive function significantly improved in the OFE group compared with the placebo group in the subgroup ≤70 years of age, which means that the effect of OFE administration exhibits an age-dependent effect. In addition, the safety of OFE was confirmed by analyzing blood test results, vital signs, and electrocardiograms. In conclusion, OFE administration in participants ≤70 years of age shows a positive effect on overall cognitive function. The trial was registered on CRIS (the Clinical Research Information Service), administered by the Korea Centers for Disease Control & Prevention (Registration Number: KCT0003766; URL: https://cris.nih.go.kr/cris/en/search/search_result_st01.jsp?seq=12957).

Fermented Platycodon grandiflorum Extracts Relieve Airway Inflammation and Cough Reflex Sensitivity In Vivo.

Platycodon grandiflorum (PG) has been extensively utilized as an herb to relieve phlegm. In this study, the effects of PG root extracts on airway inflammation and cough reflex were investigated, especially using fermented PG extracts (FPE) to increase an active compound, platycodin D by fermentation. FPE significantly reduced the numbers of eosinophils and total cells in the bronchoalveolar lavage fluid (BALF) obtained from lipopolysaccharide/ovalbumin (LPS/OVA)-induced asthma mice versus those of vehicle control. Moreover, in the BALF and the serum, FPE significantly reduced the concentration of IL-17E, a proinflammatory cytokine that causes TH2 immunity, including eosinophil amplification. It was also demonstrated that FPE might relieve inflammations through histological analysis of the lung separated from each mouse. Furthermore, in cough reflex guinea pigs induced by citric acid treatment, FPE treatment significantly reduced the number of coughs versus that of vehicle control, and consequently decreased cough reflex sensitivity. In addition, the total cell number and eosinophils significantly decreased in the BALF obtained from each guinea pig versus that of vehicle control. In in vitro study, pretreatment with FPE in LPS-stimulated RAW264.7 cells significantly reduced the levels of proinflammatory cytokines such as TNF-α, IL-6, and IL-1ß, and inducible nitric oxide synthases (iNOS). Therefore, we demonstrated that FPE relieved airway inflammation and cough reflex sensitivity in vivo, and exhibited anti-inflammatory effects through suppression of iNOS and several proinflammatory cytokines. These findings suggest that FPE might have a beneficial effect on respiratory health, and may be useful as a functional food to prevent respiratory diseases.

Effects of Aster glehni Extract on Serum Uric Acid in Subjects with Mild Hyperuricemia: A Randomized, Placebo-Controlled Trial.

Aster glehni extracts (AGE) reduced serum uric acid levels in hyperuricemia rats in several previous studies. However, its efficacy in human has not been yet explored. This study aimed at investigating the efficacy and safety of AGE on the anti-hyperuricemia effect in subjects with slightly high serum uric acid. A randomized, double-blinded, placebo-controlled clinical trial was conducted for 12 weeks. Eligible subjects were randomly assigned to either AGE (480 mg/day) or placebo. The primary endpoint was the change in serum uric acid concentrations from baseline to follow-up time points. The secondary endpoints were the change of serum xanthine oxidase activity, and the levels of C-reactive protein (CRP) and tumor necrosis factor alpha (TNF-α) in the blood from baseline to follow-up time points. Safety was assessed by clinical laboratory parameters and adverse events reported by subjects. Six weeks of AGE supplementation significantly reduced serum uric acid level from baseline (P = .0468) but at the end of the intervention the participants did not show the beneficial effect of AGE supplementation. Also, the serum uric acid level in the AGE group was not significantly different at the follow-up time points, when compared with placebo. The mean changes of secondary endpoints from baseline to each time point did not show significant differences within and between the two groups. There were no adverse events reported by subjects or changes in safety parameters after intervention. In conclusion, AGE supplementation for 12 weeks did not show significant benefits for reducing serum uric acid concentrations in subjects with mild hyperuricemia.

Aster glehni Extract Ameliorates Scopolamine-Induced Cognitive Impairment in Mice.

The leaves of Aster glehni Fr. Schm. (Asteraceae) have been used to treat insomnia in Korea. Insomnia is a common adverse effect of therapeutic agents for Alzheimer's disease (AD), and the control of sleep disturbance may prevent dementia. We hypothesized that the leaves of A. glehni can attenuate cognitive dysfunctions observed in AD. We observed the ameliorating effects of the ethanolic extract of leaves of A. glehni (AG-D) on memory dysfunction through the Morris water maze test, the passive avoidance test, and the Y-maze test. We performed acetylcholinesterase (AChE) activity assay and Western blotting to determine the mechanism of action of AG-D. AG-D significantly attenuated memory dysfunction observed in the above behavior studies and inhibited the activity of AChE. AG-D also increased the levels of phosphorylation extracellular signal-regulated kinase (ERK), cAMP response element-binding protein (CREB), phosphatidylinositol 3-kinase (PI3K), protein kinase B (Akt), and glycogen synthase kinase 3ß (GSK-3ß) and the expression levels of brain-derived neurotrophic factor (BDNF) in the hippocampi. These results suggest that AG-D ameliorates memory impairments by AChE inhibition and activation of ERK-CREB-BDNF and PI3K-Akt-GSK-3ß signaling pathways. Taken together, this study suggests that AG-D could be used as a potential treatment for cognitive dysfunction.

An oral toxicity test in rats and a genotoxicity study of extracts from the stems of Opuntia ficus-indica var. saboten.

BACKGROUND: Opuntia ficus-indica var. saboten (OFIS) is used widely in Korea to treat constipation due to its diuretic effects and its enhancement of bowel function and appetite. However, its safety has not yet been established. The aim of this study was to evaluate the repeated oral toxicity and genotoxicity of OFIS extract (OE). METHODS: White female and male Sprague Dawley rats (n = 6) were divided into 4 groups, and OE was administered to them orally (0, 500, 1000, and 2000 mg/kg/day, respectively) for one week. The Ames test, the chromosomal aberration assay, and the mammalian micronucleus test were performed to determine the OE genotoxicity. The Ames test was conducted using Salmonella typhimurium (S. typhimurium) strains TA100, TA1535, TA98, and TA153 and Escherichia coli (E. coli) WP2 urvA, and Chinese hamster lung (CHL) cells were used for the chromosomal aberration assay. The mammalian micronucleus test was performed using mouse bone marrow cells. RESULTS: This study revealed that OE administration did not alter the normal rat behavior, body weight gain, and food and water consumption with respect to the normal controls. In addition, there were no toxic effects observed during the ophthalmological test. The biochemical hematological and serum values as well as urinalysis parameters and organ weights were all similar to those of the normal control group. In addition, no mutagenicity effects from the OE were found in S. typhimurium or E. coli with or without S9 activation according to the Ames test. The OE did not significantly alter the number of structural aberrations in the CHL cells in the presence or absence of S9 activation. The oral administration of OE also caused no significant increase in the number of micronucleated polychromatic erythrocytes or in the mean ratio of polychromatic to total erythrocytes. CONCLUSIONS: In conclusion, OE could be considered as a reliable and safe herbal medicine or functional food since no toxicity was found under the conditions of this study.

Synergic effect in the reduction of serum uric acid level between ethanol extract of Aster glehni and vitamin B6.

In this study, synergistic hypoudpricemic activities between ethanol extract of Aster glehni (AG) and vitamin B6 were investigated in vitro and in vivo. Xanthine oxidase inhibitory activities in the different parts, leaf, stem, and flower, during spring and autumn were compared. In addition, to improve hypouricemic activity, two chemicals (AG extract and vitamins) were mixed and measured inhibitory activity of xanthine oxidase. As a result, autumn leaf AG extracts showed the most effective xanthine oxidase inhibitory activity and we named autumn leaf AG extracts as AG-D006. In synergistic study, AG-D006 with vitamin B6 showed significantly increased inhibitory activity on xanthine oxidase. AG-D006 with vitamin B6 also showed significantly reduced uric acid level in hyperuricemic rats in vivo. In conclusion, AG-D006 with vitamin B6 might be used functional foods in reducing serum uric acid level in gout.

Ethanolic Extract of Opuntia ficus-indica var. saboten Ameliorates Cognitive Dysfunction Induced by Cholinergic Blockade in Mice.

The stem of Opuntia ficus-indica var. saboten is edible and has been used as a medicinal herb on Jeju Island in Korea. We previously reported that the butanolic extract of O. ficus-indica var. saboten exerts the enhancement of long-term memory in mice. However, the antiamnesic effects of O. ficus-indica var. saboten and its mode of action has not been clearly elucidated. In the present study, we explored the effects of the ethanolic extract of stems of O. ficus-indica var. saboten (EOFS) on cognitive performance in mouse and attempted to delineate its mechanism of action. We used the passive avoidance, Y-maze, and novel object recognition tests to assess its effects on cognitive functions in scopolamine-induced memory-impaired mice. We observed that EOFS (100, 200, and 400 mg/kg) ameliorated scopolamine-induced cognitive dysfunction. We also explored its mechanism of action by conducting an acetylcholinesterase (AChE) activity assay using the mouse whole brain and Western blot using the mouse hippocampal tissue. Western blot analysis and the ex vivo study revealed that EOFS increased the levels of phosphorylated extracellular signal-regulated kinase and cAMP response element-binding protein (CREB) and the levels of brain-derived neurotrophic factor (BDNF) expression in the hippocampus. It also inhibited AChE activity in the brain. Our findings suggest that EOFS would be useful for the treatment of cholinergic blockade-induced cognitive dysfunction.

Hypouricemic Effect of Ethanol Extract of Aster glehni Leaves in Potassium Oxonate-Induced Hyperuricemic Rats.

The prevalence of gout is increasing worldwide, and control of serum uric acid level has been regarded as one of the therapeutic methods for gout. Inhibition of xanthine oxidase (XO) activity which can oxidize hypoxanthine to uric acid has been commonly proposed to decrease serum uric acid level. The aim of this study was to demonstrate the hypouricemic effect of ethanol extract of Aster glehni leaves (EAG) by in vitro and in vivo study in potassium oxonate (PO)-induced hyperuricemic rats. EAG possessed 132.5 ± 6.8 mg QE/g of total flavonoid and showed antioxidant activity. EAG showed in vitro and in vivo inhibitory activity against XO and significantly decreased serum uric acid level in PO-induced hyperuricemic rats without liver toxicity. These results show that EAG significantly attenuates hyperuricemia by inhibiting XO activity, which resulted in the decrease of serum uric acid level. Therefore, EAG might possess a potential therapeutic ability for improving gout.

Bee Venom Promotes Hair Growth in Association with Inhibiting 5α-Reductase Expression.

Alopecia is an important issue that can occur in people of all ages. Recent studies show that bee venom can be used to treat certain diseases including rheumatoid arthritis, neuralgia, and multiple sclerosis. In this study, we investigated the preventive effect of bee venom on alopecia, which was measured by applying bee venom (0.001, 0.005, 0.01%) or minoxidil (2%) as a positive control to the dorsal skin of female C57BL/6 mice for 19 d. Growth factors responsible for hair growth were analyzed by quantitative real-time PCR and Western blot analysis using mice skins and human dermal papilla cells (hDPCs). Bee venom promoted hair growth and inhibited transition from the anagen to catagen phase. In both anagen phase mice and dexamethasone-induced catagen phase mice, hair growth was increased dose dependently compared with controls. Bee venom inhibited the expression of SRD5A2, which encodes a type II 5α-reductase that plays a major role in the conversion of testosterone into dihydrotestosterone. Moreover, bee venom stimulated proliferation of hDPCs and several growth factors (insulin-like growth factor 1 receptor (IGF-1R), vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF)2 and 7) in bee venom-treated hDPCs dose dependently compared with the control group. In conclusion, bee venom is a potentially potent 5α-reductase inhibitor and hair growth promoter.

Identification of differentially expressed genes by gabapentin in cultured dorsal root ganglion in a rat neuropathic pain model.

Neuropathic pain is a chronic pain disorder caused by nervous system lesions as a direct consequence of a lesion or by disease of the portions of the nervous system that normally signal pain. The spinal nerve ligation (SNL) model in rats that reflect some components of clinical pain have played a crucial role in the understanding of neuropathic pain. To investigate the direct effects of gabapentin on differential gene expression in cultured dorsal root ganglion (DRG) cells of SNL model rats, we performed a differential display reverse transcription-polymerase chain reaction analysis with random priming approach using annealing control primer. Genes encoding metallothionein 1a, transforming growth factor-ß1 and palmitoyl-protein thioesterase-2 were up-regulated in gabapentin-treated DRG cells of SNL model rats. The functional roles of these differentially expressed genes were previously suggested as neuroprotective genes. Further study of these genes is expected to reveal potential targets of gabapentin.