Lactobacillus casei HY2782 and Pueraria lobata Root Extract Complex Ameliorates Particulate Matter-Induced Airway Inflammation in Mice by Inhibiting Th2 and Th17 Immune Responses.

This study aimed to investigate the effects of Lactobacillus casei HY2782 and Pueraria lobata root extract complex (HY2782 complex) in mitigating airway inflammation resulting from exposure to particulate matter ≤2.5 µm in diameter (PM2.5) in an animal model. Chronic inflammatory airway disease is associated with Th2-related cytokines interleukin (IL)-4, IL-5, and IL-13 and Th17-related cytokine IL-17A, which are the major contributors to allergy and asthma. Results indicated that PM2.5 elevates allergen-related airway inflammation and respiratory hyperresponsiveness in C57BL/6 mice. The HY2782 complex significantly reduced Th2/Th17-derived cytokines IL-4, IL5, IL-13, and IL-17A; immunoglobulin E; and leukotriene C4 in bronchoalveolar lavage fluid (BALF) and serum. Furthermore, the HY2782 complex was associated with the modulation of oxidative stress-related genes. Administration of the HY2782 complex resulted in a markedly reduced number of neutrophils and eosinophil infiltration in BALF. Histopathological observation of lung tissue also showed reduced inflammatory cell infiltration into airways and surrounding tissue. The HY2782 complex may be a promising candidate for the preventive therapy of allergic diseases and airway inflammation caused by PM2.5 inhalation.

The Impact of Gut Microbiome on the Pharmacokinetics of Ginsenosides Rd and Rg3 in Mice after Oral Administration of Red Ginseng.

Ginsenosides of orally administered red ginseng (RG) extracts are metabolized and absorbed into blood. Here, we examined the pharmacokinetic profiles of ginsenosides Rd and Rg3 in mice orally gavaged with RG, then investigated the correlations between these and gut microbiota composition. RG water extract (RGw), RG ethanol extract (RGe), or fermented RGe (fRGe) was orally gavaged in mice. The plasma concentrations of the ginsenosides were determined, and the gut microbiota composition was analyzed. RGe and fRGe-treated mice showed higher plasma concentration levels of ginsenoside Rd compared with RGw-treated mice; particularly, ginsenoside Rd absorbed was substantially high in fRGe-treated mice. Oral administration of RG extracts modified the gut microbiota composition; the modified gut microbiota, such as Peptococcaceae, Rikenellaceae, and Hungateiclostridiaceae, were closely correlated with the absorption of ginsenosides, such as Rd and Rg3. These results suggest that oral administration of RG extracts can modify gut microbiome, which may consequently affect the bioavailability of RG ginsenosides.

Fermented Red Ginseng Alleviates Ovalbumin-Induced Inflammation in Mice by Suppressing Interleukin-4 and Immunoglobulin E Expression.

Ginseng (the root of Panax ginseng Meyer) has been reported to have many biologic therapeutic effects, including anti-inflammatory properties, and ginsenosides are considered as one of the factors responsible for these therapeutic effects. To improve their therapeutic action, probiotic bacteria are used to ferment and chemically transform ginsenosides in red ginseng (RG). In this study, we aimed to investigate the beneficial effects of RG fermented by probiotic bacteria (FRG) against ovalbumin (OVA)-induced allergic rhinitis in a mouse model. We induced the mouse model via OVA inhalation; experimental results revealed increased immunoglobulin E (IgE) and interleukin (IL)-4 levels, leading to Th2-type cytokine response. The mice with induced allergy were then orally administered RG and FRG over 2 weeks, as a result of which, IL-4 and IgE levels in bronchoalveolar lavage fluid, nasal fluid, and serum were found to be ameliorated more effectively by FRG than by RG, suggesting that FRG has better immune regulatory effects than RG. FRG also downregulated immune cell levels, such as those of eosinophils and basophils, and significantly decreased the thickness of OVA-induced respiratory epithelium compared to RG. Collectively, the results showed that FRG treatment alleviates inflammation, thereby extending a protective effect to mice with OVA-induced inflammatory allergic rhinitis.

Gastroprotective Effects of Cudrania tricuspidata Leaf Extracts by Suppressing Gastric cAMP and Increasing Gastric Mucins.

Cudrania tricuspidata has been used as an East Asian folk remedy to treat various symptoms. Recently, scientific evidence of the efficacy of C. tricuspidata has emerged. The objective of this study was to elucidate protective role of C. tricuspidata in the gastric mucosa using pylorus-ligated Sprague-Dawley rats and primary parietal cells. C. tricuspidata ethanol extracts attenuated gastric mucosal damage, secretion, and juice acidity in pylorus-ligated rats; however, it did not affect expression of gastric acid-related genes [muscarinic acetylcholine receptor M3 receptor (M3R), histamine H2-receptors (H2R), and cholecystokinin-2/gastrin receptors (CCK2R)] or serum gastrin concentrations. Furthermore, extracts greatly reduced levels of gastric cyclic adenosine monophosphate (cAMP) and significantly increased mRNA levels of gastric-type mucins (MUC5AC and MUC6). To identify the mode of action of C. tricuspidata extract in regulating gastric acid secretion, intracellular cAMP and mRNA for H2R, M3R, and CCK2R were measured in primary parietal cells. mRNA levels of H2R, M3R, and CCK2R did not significantly differ following treatment with C. tricuspidata extract, whereas cAMP induced by the H2R-specific agonist was significantly decreased. C. tricuspidata may therefore reduce gastric acid secretion by inhibiting H2R activity rather than regulating mRNA expression. These finding suggest that ethanol extracts of C. tricuspidata inhibit H2R-related gastric acid secretion and increase gastric mucus to help prevent gastric mucosal damage. Therefore, C. tricuspidata extract has potential to be used in foods and medicines to prevent diseases related to gastric mucosal damage, such as gastritis and functional dyspepsia.

Regulatory effects of Lactobacillus plantarum HY7714 on skin health by improving intestinal condition.

Despite increasing research on the gut-skin axis, there is a lack of comprehensive studies on the improvement of skin health through the regulation of the intestinal condition in humans. In this study, we investigated the benefits of Lactobacillus plantarum HY7714 (HY7714) consumption on skin health through its modulatory effects on the intestine and ensuing immune responses. HY7714 consumption led to differences in bacterial abundances from phylum to genus level, including increases in Actinobacteria followed by Bifidobacterium and a decrease in Proteobacteria. Additionally, HY7714 significantly ameliorated inflammation by reducing matrix metallopeptidases (MMP-2 and MMP-9), zonulin, and calprotectin in plasma, all of which are related to skin and intestinal permeability. Furthermore, RNA-seq analysis revealed its efficacy at restoring the integrity of the gut barrier by regulating gene expression associated with the extracellular matrix and immunity. This was evident by the upregulation of IGFBP5, SERPINE1, EFEMP1, COL6A3, and SEMA3B and downregulation of MT2A, MT1E, MT1X, MT1G, and MT1F between TNF- α and TNF- α plus HY7714 treated Caco-2 cells. These results propose the potential mechanistic role of HY7714 on skin health by the regulation of the gut condition.

Cyclized Oligopeptide Targeting LRP5/6-DKK1 Interaction Reduces the Growth of Tumor Burden in a Multiple Myeloma Mouse Model.

PURPOSE: Dickkopf 1 (DKK1) has been extensively investigated in mouse models of multiple myeloma, which results in osteolytic bone lesions. Elevated DKK1 levels in bone marrow plasma and serum inhibit the differentiation of osteoblast precursors. Present pharmaceutical approaches to target bone lesions are limited to antiresorptive agents. In this study, we developed a cyclized oligopeptide against DKK1-low density lipoprotein receptor-related protein (LRP) 5/6 interaction and tested the effects of the oligopeptide on tumor burden. MATERIALS AND METHODS: A cyclized oligopeptide based on DKK1-LRP5/6 interactions was synthesized chemically, and its nuclear magnetic resonance structure was assessed. Luciferase reporter assay and mRNA expressions of osteoblast markers were evaluated after oligopeptide treatment. MOPC315.BM.Luc cells were injected into the tail vein of mice, after which cyclized oligopeptide was delivered subcutaneously 6 days a week for 4 weeks. RESULTS: The cyclized oligopeptide containing NXI motif bound to the E1 domain of LRP5/6 effectively on surface plasmon resonance analysis. It abrogated the Wnt-ß-catenin signaling inhibited by DKK1, but not by sclerostin, dose dependently. RT-PCR and alkaline phosphatase staining showed increased expressions of osteoblast markers according to the treatment concentrations. Bioluminescence images showed that the treatment of cyclized oligopeptide reduced tumor burden more in oligopeptide treated group than in the vehicle group. CONCLUSION: The cyclized oligopeptide reported here may be another option for the treatment of tumor burden in multiple myeloma.

A Novel Human PTH Analog [Cys25]hPTH(1-34) Restores Bone Mass in Ovariectomized Mice.

CONTEXT: Recently, an arginine-to-cysteine homozygous mutation at position 25 in mature PTH was reported in a Korean patient with hypoparathyroidism. OBJECTIVE: To clarify whether the high bone mass phenotype observed in this patient was related to the hypoparathyroidism itself or to chronic elevation of mutant PTH. METHODS: A series of in vitro and in vivo experiments were performed in MC3T3E1, ROS 17/2.8, and SAOS2 cells treated with human (h)PTH(1-34), Cys25hPTH(1-34), Ala1Cys25hPTH(1-34), and Bpa1Cys25hPTH(1-34). The peptides were then sc delivered to ovariectomized mice as daily single injections. RESULTS: Compared with hPTH(1-34) and Ala1Cys25hPTH(1-34), treatment with Cys25hPTH(1-34) or Bpa1Cys25hPTH(1-34) resulted in decreases in the cAMP response and promoter-cAMP-response element luciferase reporter activity. Although the cAMP response was sustained with hPTH(1-34) in MC3T3E1 cells, such response was not observed with the other mutated peptides. Meanwhile, all PTH analogues exhibited ERK phosphorylation and cytoplasmic Ca++ signals comparable with hPTH(1-34). On microcomputed tomography analyses, trabecular and cortical bone parameters improved after 6 weeks of respective treatments as follows: hPTH(1-34) (80 µg/kg) = Ala1Cys25hPTH(1-34) (80 µg/kg) = Cys25hPTH(1-34) (80 µg/kg) > Bpa1Cys25hPTH(1-34) (80 µg/kg) > hPTH(1-34) (40 µg/kg). The increment of RANKL to OPG mRNA ratio in the MC3T3E1 cells after 6 hours of treatment of Cys25hPTH(1-34), AL1Cys25hPTH(1-34), and Bpa1Cys25hPTH(1-34) was less than that was obtained after hPTH(1-34) treatment. On bone histomorphometric analysis, AL1Cys25hPTH(1-34) increased the bone formation rate in both trabecular and periosteal bones compared with the control group. CONCLUSION: The high bone mass phenotype observed in this patient with hypoparathyrodism caused by a Cys mutation at the 25th residue of hPTH(1-84) may have arisen from both direct and indirect effects exerted by the mutant PTH itself on bone.