Effects of Pear Extracts on Microbiome and Immunocytokines to Alleviate Air Pollution-Related Respiratory Hypersensitivity.

Pears are ancient functional foods for modern times. Particularly, Korean pears (Pyrus pyrifolia cv.) have been used as folk medicine for respiratory diseases and have strong potential for the treatment of hazardous aerosol-related diseases. Thus, the effects of pear ethanol extracts on air pollution-related respiratory hypersensitivity were studied by toxicokinetics, pro-inflammatory cytokines, and microbiomics in preclinical and randomized double-blind clinical studies. The mild-asthma subjects, who lived in the same city, Seoul, Korea, were separated into the placebo and the treatment (pear extracts, as brix 55; arbutin 5.01 mg and chlorogenic acid 0.18 mg/3 mL per day) groups for 4 weeks (n = 20). As results, there were positive associations between urinary 2-naphthol (NT) or 1-hydroxypyrene (OHP), exposure biomarkers for polyaromatic hydrocarbons in PM2.5, and pro-inflammatory cytokines, interleukin (IL)-4 or IgE, respectively, in the human subjects. The pear extracts somewhat reduced 2-NT and 1-OHP levels. The proportions of fiber-degrading bacteria that stimulate growth of beneficial microflora for immune defense, that is, Bifidobacterium and Eubacterium, were significantly higher in the pear consuming group than in the placebo group. Moreover, pro-inflammatory cytokines, including IgE, IL-4, IL-5, and IL-13, were significantly suppressed by the pear extracts in the preclinical tests of the ovalbumin-induced asthma mice. Thus, we suggest that air pollution-related respiratory hypersensitivity can be alleviated by Korean pear extracts by modulation of microbiome and immunocytokines.

A review of pears (Pyrus spp.), ancient functional food for modern times.

BACKGROUND: Pears have been world-widely used as a sweet and nutritious food and a folk medicine for more than two millennia. METHODS: We conducted a review from ancient literatures to current reports to extract evidence-based functions of pears. RESULTS: We found that pears have many active compounds, e.g., flavonoids, triterpenoids, and phenolic acids including arbutin, chlorogenic acid, malaxinic acid, etc. Most of researchers agree that the beneficial compounds are concentrated in the peels. From various in vitro, in vivo, and human studies, the medicinal functions of pears can be summarized as anti-diabetic,-obese, -hyperlipidemic, -inflammatory, -mutagenic, and -carcinogenic effects, detoxification of xenobiotics, respiratory and cardio-protective effects, and skin whitening effects. Therefore, pears seem to be even effective for prevention from Covid-19 or PM2.5 among high susceptible people with multiple underlying diseases. CONCLUSION: For the current or post Covid-19 era, pears have potential for functional food or medicine for both of communicable and non-communicable disease.

Epigenetic modulation of Chlorella (Chlorella vulgaris) on exposure to polycyclic aromatic hydrocarbons.

DNA methylation in promoter region can be a new chemopreventive marker against polycyclic aromatic hydrocarbons (PAHs). We performed a randomized, double blind and cross-over trial (N=12 healthy females) to evaluate chlorella (Chlorella vulgaris)-induced epigenetic modulation on exposure to PAHs. The subjects consumed 4 tablets of placebo or chlorella supplement (total chlorophyll ≈ 8.3mg/tablet) three times a day before meals for 2 weeks. When the subjects consumed chlorella, status of global hypermethylation (5-methylcytosine) was reduced, compared to placebo (p=0.04). However, DNA methylation at the DNMT1 or NQO1 was not modified by chlorella. We observed the reduced levels of urinary 1-hydroxypyrene (1-OHP), a typical metabolite of PAHs, by chlorella intake (p<0.1) and a positive association between chlorella-induced changes in global hypermethylation and urinary 1-OHP (p<0.01). Therefore, our study suggests chlorella works for PAH-detoxification through the epigenetic modulation, the interference of ADME of PAHs and the interaction of mechanisms.

Habitual coffee intake, genetic polymorphisms, and type 2 diabetes.

BACKGROUND: The association between coffee intake and type 2 diabetes may be modulated by common genetic variation. OBJECTIVE: The purpose of this study was to examine the association between habitual coffee intake and the risk of type 2 diabetes and to determine whether this association varied by genetic polymorphisms related to type 2 diabetes in Korean adults. DESIGN AND METHODS: A population-based cohort study over a follow-up of 4 years was conducted. A total of 4077 Korean men and women aged 40-69 years with a normal glucose level at baseline were included. Coffee intake was assessed using a validated food frequency questionnaire, and incident type 2 diabetes or prediabetes was defined by oral glucose tolerance test or fasting blood glucose test. The genomic DNA samples were genotyped with the Affymetrix Genome-Wide Human SNP Array 5.0, and nine single-nucleotide polymorphisms related to type 2 diabetes in East Asian populations were extracted. RESULTS: A total of 120 cases of type 2 diabetes and 1128 cases of prediabetes were identified. After adjustment for potential confounding factors, we observed an inverse association, but without any clear linear trend, between coffee intake and the combined risk of type 2 diabetes and prediabetes. We found that inverse associations between habitual coffee intake and the combined risk of type 2 diabetes and prediabetes were limited to those with the T-allele (GT/TT) of rs4402960 in IGF2BP2, those with the G-allele (GG/GC) of rs7754840 in CDKAL1, or those with CC of rs5215 in KCNJ11. CONCLUSION: We found a lower risk of prediabetes and type 2 diabetes combined with coffee intake among individuals with the GT/TT of IGF2BP2 rs4402960, GG/GC of CDKAL1 rs7754840, or CC of KCNJ11 rs5215, which are known to be related to type 2 diabetes in East Asians.

Detoxification of chlorella supplement on heterocyclic amines in Korean young adults.

Heterocyclic amines (HCAs) and polycyclic aromatic hydrocarbons (PAHs) have been established as carcinogenic chemicals in Western diet. This study was performed to estimate HCA exposure levels in Korean daily life and to assess the ability of Chlorella vulgaris to detoxify carcinogenic HCAs in a randomized, double blind, placebo-controlled crossover study with chlorella supplement (N=6, all females, age: 27.17±7.73yr) for 2 weeks. We analyzed HCAs in hydrolyzed urine specimens using LC/TOF-MS. As results, urinary levels of MeIQx, PhIP, and IQx-8-COOH were 323.36±220.11ng/L, 351.59±254.93ng/L, and 130.85±83.22ng/L, respectively. Effects of chlorella to reduce urinary MeIQx were marginally significant (before, 430±226.86pg/mL vs. after, 174.45±101.65pg/mL: 0.05

Effects of Korean red ginseng (Panax Ginseng Meyer) on bisphenol A exposure and gynecologic complaints: single blind, randomized clinical trial of efficacy and safety.

BACKGROUND: Korean red ginseng (KRG) is a processed ginseng from raw ginseng to enhance safety, preservation and efficacy, known having beneficial effects on women's health due to its estrogen like function. While estrogen supplementation showed some modulation of endocrine disrupting chemicals, bisphenol A (BPA) has been focused as a potential endocrine disrupting chemical. In this study, we examined the efficacy and safety outcomes of KRG against BPA, focusing on female quality of life (QOL). Individual variations in susceptibility to KRG were also investigated with the Sasang Typology, the personalized medicine used for hundred years in Korea. METHODS: We performed a single-blind randomized clinical trial. Study subjects were young women (N = 22), consumed 2.7 g of KRG or placebo per day for 2 weeks and filled up questionnaires regarding gynecologic complaints at the 4 time spots. We analyzed urinary total BPA and malondialdehyde (MDA), an oxidative stress biomarker, with GC/MS and HPLC/UVD respectively, and diagnosed their Sasang Typology with the questionnaire for the Sasang constitution Classification (QSCC II). RESULTS: KRG consumption decreased urinary BPA and MDA levels (ps < 0.05) and alleviated 'menstrual irregularity', 'menstrual pain', and 'constipation' (ps < 0.05). SoEum type (Lesser Yin person) among the Sasang types showed significant alleviation in insomnia, flushing, perspiration and appetite by KRG consumption, rather than other Sasang types. During the intervention, no one experienced any aggravated side effects. CONCLUSION: We suggest KRG is efficient for protection for female QOL and BPA- exposure and - related oxidative stress. However, individual variation in susceptibility to KRG should be further considered for identifying ideal therapy. TRIAL REGISTRATION: KCT0000920.

Eicosapentaenoic acid and docosahexaenoic acid suppress Th2 cytokine expression in RBL-2H3 basophilic leukemia cells.

It is known that the intake of omega-3 fatty acids, such as eicosapentaenoic (EPA) and docosahexaenoic acid (DHA), is beneficial for preventing and/or treating allergic diseases. The pathogenesis of allergic diseases is associated with overactivation of Th2-skewed immunity. Basophils generate large amounts of Th2 cytokines such as interleukin (IL)-4 and IL-13, which are critically involved in allergic inflammation. We investigated how EPA and DHA affect Th2 cytokine expression in phorbol 12-myristate 13-acetate- and ionomycin (PI)-activated RBL-2H3 basophilic leukemia cells. EPA and DHA induced a dramatic decrease in the production of IL-4 and IL-13 and their transcription in a dose-dependent manner. Luciferase assays of RBL-2H3 cells stably expressing Il4 and Il13 promoter-reporter plasmids demonstrated a significant suppression of PI-induced promoter activation. Analysis of certain transcription factors revealed that nuclear expression of c-Fos and the mRNA expression were suppressed by EPA and DHA. Furthermore, they significantly inhibited the nuclear expression and translocation of nuclear factor of activated T cells (NF-AT)1. In contrast, the expression levels of nuclear factor kappa-B (NF-κB), GATA-binding proteins (GATAs), and CCAAT/enhancer binding protein alpha (C/EBPα) were not significantly affected by EPA and DHA. Phosphorylation of extracellular signal-related kinase was inhibited by EPA and DHA, and phosphorylation of p38 mitogen-activated protein kinase was decreased by DHA, but not by EPA. Taken together, our data suggest that EPA and DHA may suppress Th2-skewed allergic immune responses by inhibiting the expression of basophilic IL-4 and IL-13.

Pheophytin a and chlorophyll a identified from environmentally friendly cultivation of green pepper enhance interleukin-2 and interferon-γ in Peyer's patches ex vivo.

The oral consumption of capsicum has been reported to increase interleukin (IL)-2 and interferon (IFN)-γ production in Peyer's patches (PP); however, the active components responsible for these effects have not been completely identified. The beneficial biological effects of green peppers cultivated under environmentally friendly farming conditions (ECP), without the use of chemical pesticides, have rarely been compared with those of green peppers cultivated under conventional farming conditions (CCP). Oral administration of ECP extract significantly induced the production of IL-2 and IFN-γ in concanavalin A-treated cells from PP ex vivo; their levels were much higher than those in the CCP extract-treated group. A comparative analysis of the HPLC profiles indicated a 1.7-fold increase of a peak, named EF-1, at 415 nm in the ECP extract. The major component of EF-1 was identified as pheophytin a, which is a chlorophyll a molecule lacking a central Mg(2+) ion, as determined from NMR data. Intake of pheophytin a and chlorophyll a significantly increased IL-2 and IFN-γ production, and the percentage of IL-2- and IFN-γ-producing CD4+ T-cells in PP. Taken together, our data suggest that ECPs produce a higher content of pheophytin a than CCPs, and pheophytin a and chlorophyll a are immune-modulating components in green vegetables.

Suppressive effects of fructus of Magnolia denudata on IL-4 and IL-13 expression in T cells.

Magnolia species have been used for the treatment of allergic diseases in Asia as folk medicine; however, the cellular and molecular mechanisms of its anti-allergic effects have rarely been investigated. In this study, we demonstrated that a methanolic extract of the fructus of Magnolia denudata has suppressive effects on Th2 cytokine production such as IL-4 and IL-13, but not IFN-γ and IL-17, produced by both phorbol 12-myristate 13-acetate/ionomycin (PI)- and CD3/CD28-stimulated EL-4 T cells. Moreover, the mRNA expression of Th2 cytokines was significantly inhibited, and luciferase activity in cells transiently transfected with IL-4 or IL-13 promoter reporter plasmids was suppressed by M. denudata, indicating that M. denudata may regulate these expression at the transcriptional level. Western blot analysis for transcription factors involved in the cytokine gene expression indicated that the activation of c-Jun was significantly downregulated in the nucleus of cells, while the activations of nuclear factor of activated T cells, nuclear factor kappa B and c-Fos, were not affected. Furthermore, the mRNA expression and nuclear translocation of GATA-binding protein 3, a key transcriptional factor for Th2 commitment and Th2 cytokine expression, but not T-bet and RORγt, were dramatically downregulated by M. denudata. Treatment with M. denudata suppressed the phosphorylation of p38 mitogen-activated protein kinase; however, the PI-induced phosphorylation of extracellular signal-related kinase and c-Jun N-terminal kinase was unaffected. Taken together, our study indicated that M. denudata inhibited IL-4 and IL-13 expression, possibly through regulation of p38 mitogen-activated protein kinase phosphorylation and selective transcription factors, such as GATA-3 and c-Jun, in EL-4 T cells.

Effects and action mechanisms of Korean pear (Pyrus pyrifolia cv. Shingo) on alcohol detoxification.

Korean pear (Pyrus pyrifolia cv. Shingo) has been used as a traditional medicine for alleviating alcohol hangover. However, scientific evidence for its effectiveness or mechanism is not clearly established. To investigate its mechanism of alcohol detoxification, both in vitro and in vivo studies were performed with an aldehyde dehydrogenase 2 (ALDH2) alternated animal model. The pear extract (10 mL/kg bw) was administered to Aldh2 normal (C57BL/6) and deficient (Aldh2 -/-) male mice. After 30 min, ethanol (1 g or 2 g/kg bw) was administered to the mice via gavage. Levels of alcohol and acetaldehyde in blood were quantified by GC/MS. First, it was observed that the pears stimulated both alcohol dehydrogenase (ADH) and ALDH activities by 2∼3- and 1.3-fold in in vitro studies, respectively. Second, mouse PK data (AUC(∞) and C(max) ) showed that the pear extract decreased the alcohol level in blood regardless of ALDH2 genotype. Third, the pear increased the acetaldehyde level in blood in Aldh2 deficient mice but not in Aldh2 normal mice. Therefore, the consistent in vitro and in vivo data suggest that Korean pears stimulate the two key alcohol-metabolizing enzymes. These stimulations could be the main mechanism of the Korean pear for alcohol detoxification. Finally, the results suggest that polymorphisms of human ALDH2 could bring out individual variations in the effects of Korean pear on alcohol detoxification.

Inhibition by wheat sprout (Triticum aestivum) juice of bisphenol A-induced oxidative stress in young women.

For health of future generation, fertile young women should be monitored for exposure of endocrine disrupting chemicals (EDCs). Among EDCs, bisphenol A (BPA) is suggested to induce reactive oxygen species (ROS) which play an important role in pathologies of female diseases such as endometriosis. On the other hand, previous studies suggested that sprouts of wheat (Triticum aestivum) have antimutagenicity and antioxidant activity. We performed the 2 weeks intervention of wheat sprout juice (100ml/day) to investigate its effects on BPA-exposure and -oxidative toxicity in young women (N=14, age=24.4±4.0). Geometrical mean of urinary BPA levels was 1.81 (GSTD, 4.34)µg/g creatinine. We observed that irregular meals significantly increased levels of urinary BPA approximate 3 times (p=0.03). In addition, we found BPA-induced oxidative stress is correlated with levels of 8-hydroxydeoxyguanosine (8-OHdG) or malondialdehyde (MDA) levels (p=0.18 or 0.03, respectively). We also observed a continuous reduction of urinary BPA during the wheat sprout intervention (p=0.02). In summary, our data suggested potential detoxification of wheat sprouts on BPA-toxicity via antioxidative and interference of absorption, distribution, metabolism and excretion (ADME)-mediated mechanisms in young women.

Garlic (Allium sativum) extract inhibits lipopolysaccharide-induced Toll-like receptor 4 dimerization.

Garlic has long been used as a folk medicine. Numerous studies have demonstrated that a garlic extract and its sulfur-containing compounds inhibited nuclear factor kappa B (NF-kappaB) activation induced by various receptor agonists including lipopolysaccharide (LPS). Toll-like receptors (TLRs) play a key role in sensing diverse microbial products and inducing innate immune responses. The dimerization of TLR4 is required for the activation of downstream signaling pathways, including NF-kappaB. Therefore, TLR4 dimerization may be one of the first lines of regulation in activating LPS-induced signaling pathways. We report here biochemical evidence that the ethyl acetate fraction of garlic inhibited the LPS-induced dimerization of TLR4, resulting in the inhibition of NF-kappaB activation and the expression of cyclooxygenase 2 and inducible nitric oxide synthase. Our results demonstrate for the first time that a garlic extract can directly inhibit the TLRs-mediated signaling pathway at the receptor level. These results shed a new insight into understanding how garlic modulates the immune responses that could modify the risk of many chronic diseases.