Preventive effects of Korean red ginseng on experimentally induced colitis and colon carcinogenesis

© 2020 Center for Food and Biomolecules, National Taiwan UniversityKorean Red Ginseng (KRG) exerts chemopreventive effects on experimentally induced carcinogenesis through multiple mechanisms. In this study, we investigated effects of KRG on dextran sulfate sodium (DSS)-induced colitis and azoxymethane (AOM) plus DSS-induced colon carcinogenesis in mice. Male C57BL/6J mice were fed diet containing 1% KRG or a standard diet throughout the experiment. The mouse colitis was induced by administration of 3% DSS in drinking water for 1 week. DSS caused body weight loss, diarrhea, rectal bleeding and colon length shortening, and all these symptoms were ameliorated by KRG treatment. KRG inhibited DSS-induced expression of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) by suppressing activation of nuclear factor-kappa B (NF-κB) and signal transducer and activation of transcription 3 (STAT3). In another experiment, colon carcinogenesis was initiated by single intraperitoneal injection of AOM (10 mg/kg) and promoted by 2% DSS in drinking water. KRG administration relieved the symptoms of colitis and reduced the incidence, the multiplicity and the size of colon tumor. The up-regulation of COX-2, iNOS, c-Myc and Cyclin D1 by AOM plus DSS was attenuated in KRG fed mice which was associated with suppression of NF-κB and STAT3 activation. These results suggest that KRG is a potential candidate for chemoprevention of inflammation-associated cancer in the colon.

17-Oxo-docosahexaenoic acid induces Nrf2-mediated expression of heme oxygenase-1 in mouse skin in vivo and in cultured murine epidermal cells

Recently, growing attention has been given to new classes of bioactive lipid mediators derived from omega-3 polyunsaturated fatty acids, such as docosahexaenoic acid (DHA), especially in the context of their role as endogenous signal modulators. One such molecule is 17-oxo-DHA, generated from DHA by the action of COX2 and a dehydrogenase. The redox-sensitive transcription factor, Nrf2 plays a key role in cellular stress responses. In the present study, the effects of 17-oxo-DHA on Nrf2-mediated expression of cytoprotective enzymes were examined in mouse skin in vivo and cultured murine epidermal JB6 cells. Topical application of 17-oxo-DHA markedly elevated the nuclear localization of Nrf2 and expression of heme oxygenase-1 (HO-1) and NAD(P) H:quinone oxidoreductase-1 in hairless mouse skin. In contrast to 17-oxo-DHA, the non-electrophilic metabolic precursor 17-hydroxy-DHA was a much weaker inducer of Nrf2 activation and its target protein expression. Likewise, 17-oxo-DHA significantly enhanced nuclear translocation and transcriptional activity of Nrf2 with concomitant upregulation of HO-1 expression in cultured JB6 cells. 17-Oxo-DHA was a much stronger inducer of Nrf2-mediated antioxidant response than its parent molecule, DHA. HO-1 expression was abolished in Nrf2 knockdown JB6 cells or embryo fibroblasts from Nrf2 knock out mice. 17-Oxo-DHA also markedly reduced the level of Keap1 protein by inducing ubiquitination. Mutation of Cys151 and Cys273 in Keap1 abrogated 17-oxo-DHA-induced ubiquitination and proteasome-mediated degradation of Keap1 as well as HO-1 expression, suggesting that these cysteine residues are putative sites for 17-oxo-DHA binding. Further, Keap1 degradation stimulated by 17-oxo-DHA coincided with accumulation of the autophagy substrate, p62/SQSTM1.

Prevalence and comorbidity of allergic diseases in preschool children

PurposeAllergic disease and its comorbidities significantly influence the quality of life. Although the comorbidities of allergic diseases are well described in adult populations, little is known about them in preschool children. In the present study, we aimed to assess the prevalence and comorbidity of allergic diseases in Korean preschool children.MethodsWe conducted a cross-sectional study comprising 615 Korean children (age, 3 to 6 years). Symptoms of allergic diseases were assessed using the Korean version of the International Study of Asthma and Allergies in Childhood (ISAAC) questionnaire that was modified for preschool children. Comorbidities of allergic diseases were assessed by 'In the last 12 months, has your child had symptoms?'.ResultsThe prevalence of symptoms of asthma, allergic rhinitis, and atopic dermatitis as recorded using the ISAAC questionnaire, within the last 12 months was 13.8%, 40.7%, and 20.8%, respectively. The symptom rates of allergic conjunctivitis, food allergy, and drug allergy were 14.8%, 10.4%, and 0.8%, respectively. The prevalence of allergic rhinitis in children with asthma was 64.3% and that of asthma in children with allergic rhinitis was 21.6%. The prevalence of rhinitis in children with conjunctivitis was 64.8% and that of conjunctivitis in children with rhinitis was 23.6%.ConclusionThe prevalence of current rhinitis in our preschool children is shown to be higher than that previously reported. Allergic conjunctivitis is closely associated with asthma and allergic rhinitis. However, further studies are warranted to determine the prevalence and effects of these comorbidities on health outcomes in preschool children

Food allergen sensitization in young children with typical signs and symptoms of immediate-type food allergies: a comparison between monosensitized and polysensitized children

PurposeThe clinical interpretation of children sensitized to allergens is challenging, particularly in children with food allergies. We aimed to examine clinical differences between children with monosensitization and those with polysensitization to common food allergens and to determine risk factors for polysensitization in young children <10 years of age with immediate-type food allergies.MethodsThe study included children <10 years of age with signs and symptoms indicative of immediate-type food allergies. Serum total IgE level was measured, and ImmunoCAP analysis for food allergens was performed.ResultsThe mean age of the study subjects was 1.6±1.6 years (75 boys and 51 girls). Thirty-eight children (30.2%) were monosensitized and 88 children (69.8%) were polysensitized. Multivariate logistic regression analysis showed that the development of polysensitization to common food allergens was positively associated with a parental history of allergic rhinitis (adjusted odds ratio [aOR], 6.28; 95% confidence interval [CI], 1.78-22.13; P=0.004), season of birth (summer/fall) (aOR, 3.10; 95% CI, 1.10-8.79; P=0.033), and exclusive breastfeeding in the first 6 months of age (aOR, 3.51; 95% CI, 1.20-10.25; P=0.022).ConclusionWe found significant clinical differences between children with monosensitization and those with polysensitization to common food allergens and identified risk factors for the development of polysensitization in young children with immediate-type food allergies. Clinicians should consider these clinical risk factors when evaluating, counseling, treating, and monitoring young children with food allergies

Reference values for respiratory system impedance using impulse oscillometry in healthy preschool children

PurposeThe normal values for lung resistance and lung capacity of children, as determined by impulse oscillometry (IOS), are different for children of different ethnicities. However, reference values there is no available reference value for Korean preschool children have yet to be determined. The aim of the present study was to determine the normal ranges of IOS parameters in Korean preschool children.MethodsA total of 133 healthy Korean preschool children were selected from 639 children (aged 3 to 6 years) who attended kindergarten in Seongnam, Gyeonggi province, Korea. Healthy children were defined according to the European Respiratory Society (ERS) criteria. All subjects underwent lung function tests using IOS. The relationships between IOS value (respiratory resistance (Rrs) and reactance (Xrs) at 5 and 10 Hz and resonance frequency (RF)) and age, height, and weight were analyzed by simple linear and multiple linear regression analyses.ResultsThe IOS success rate was 89.5%, yielding data on 119 children. Linear regression identified height as the best predictor of Rrs and Xrs. Using stepwise multiple linear regressions based on age, height, and weight, we determined regression equations and coefficients of determination (R2) for boys (Rrs5=1.934-0.009×Height, R2=12.1%; Xrs5=0.774+0.006×Height-0.002×Age, R2=20.2% and for girls (Rrs5=2.201-0.012×Height, R2=18.2%; Xrs5=-0.674+0.004×Height, R2=10.5%).ConclusionThis study provides reference values for IOS measurements of normal Korean preschool children. These provide a basis for the diagnosis and monitoring of preschool children with a variety of respiratory diseases

Oral food challenges in children

Many patients assume that allergic reactions against foods are responsible for triggering or worsening their allergic symptoms. Therefore, it is important to identify patients who would benefit from an elimination diet, while avoiding unnecessary dietary restrictions. The diagnosis of food allergy depends on the thorough review of the patients's medical history, results of supplemented trials of dietary elimination, and in vivo and in vitro tests for measuring specific IgE levels. However, in some cases the reliability of such procedures is suboptimal. Oral food challenges are procedures employed for making an accurate diagnosis of immediate and occasionally delayed adverse reactions to foods. The timing and type of the challenge, preparation of patients, foods to be tested, and dosing schedule should be determined on the basis of the patient's history, age, and experience. Although double-blind, placebo-controlled food challenges(DBPCFC) are used to establish definitively if a food is the cause of adverse reactions, they are time-consuming, expensive and troublesome for physician and patients. In practice, An open challenge controlled by trained personnel is sufficient especially in infants and young children. The interpretation of the results and follow-up after a challenge are also important. Since theses challenges are relatively safe and informative, controlled oral food challenges could become the measure of choice in children

Perilla frutescens Extracts Protects against Dextran Sulfate Sodium-Induced Murine Colitis: NF-κB, STAT3, and Nrf2 as Putative Targets

Perilla frutescens is a culinary and medicinal herb which has a strong anti-inflammatory and antioxidative effects. In the present study, we investigated the effects of Perilla frutescens extract (PE) against dextran sulfate sodium (DSS)-induced mouse colitis, an animal model that mimics human inflammatory bowel disease (IBD). Five-week-old male ICR mice were treated with a daily dose of PE (20 or 100 mg/kg, p.o.) for 1 week, followed by administration of 3% DSS in double distilled drinking water and PE by gavage for another week. DSS-induced colitis was characterized by body weight loss, colon length shortening, diarrhea and bloody stool, and these symptoms were significantly ameliorated by PE treatment. PE administration suppressed DSS-induced expression of proinflammatory enzymes, including cyclooxygenase-2 and inducible nitric oxide synthase as well as cyclin D1, in a dose-dependent fashion. Nuclear factor-kappa B (NF-κB) and signal transducer and activator of transcription 3 (STAT3) are major transcriptional regulators of inflammatory signaling. PE administration significantly inhibited the activation of both NF-κB and STAT3 induced by DSS, while it elevated the accumulation of Nrf2 and heme oxygenase-1 in the colon. In another experiment, treatment of CCD841CoN human normal colon epithelial cells with PE (10 mg/ml) resulted in the attenuation of the tumor necrosis factor-α-induced expression/activation of mediators of proinflammatory signaling. The above results indicate that PE has a preventive potential for use in the management of IBD

Anti-inflammatory effects of docosahexaenoic acid: Implications for its cancer chemopreventive potential

The implication of inflammatory tissue damage in pathophysiology of human cancer as well as some metabolic disorders has been under intense investigation. Numerous studies have identified a series of critical signaling molecules involved in cellular responses to inflammatory stimuli. These include nuclear factor kappa B, peroxisome proliferator-activated receptor gamma, nuclear factor erythroid 2 p45-related factor 2 and sterol regulatory element-binding protein 1. The proper regulation of these transcription factors mediating pro- and anti-inflammatory signaling hence provides an important strategy for the chemo-prevention of inflammation-associated cancer. There is compelling evidence supporting that dietary supplementation with fish oil-derived omega-3 polyunsaturated fatty acids including docosahexaenoic acid (DHA) ameliorates symptomatic inflammation associated with cancer as well as other divergent human disorders. Acute or physiologic inflammation is an essential body's first line of defence to microbial infection and tissue injuries, but it must be properly completed by a process termed 'resolution'. Failure of resolution mechanisms can result in persistence of inflammation, leading to chronic inflammatory conditions and related malignancies. The phagocytic engulfment of apoptotic neutrophils and clearance of their potentially histotoxic contents by macrophages, called efferocytosis is an essential component in resolving inflammation. Of note, DHA is a precursor of endogenous proresolving lipid mediators which regulate the leukocyte trafficking and recruitment and thereby facilitate efferocytosis. Therefore, DHA and its metabolites may have a preventive potential in the management of human cancer which arises as a consequence of impaired resolution of inflammation as well as chronic inflammation. (C) 2016 Elsevier Ltd. All rights reserved

ANTI-INFLAMMATORY, PRORESOLVING AND CANCER CHEMOPREVENTIVE EFFECTS OF DOCOSAHEXAENOIC ACID AND ITS METABOLITES

Docosahexaenoic acid (DHA), a representative ω-3 polyunsaturated fatty acid derived from fish oil, has been reported to possess a wide spectrum of health beneficial effects. We have previously reported that topical application of DHA prior to UVB irradiation attenuated the expression of cyclooxygenase-2 and NAD(P)H:oxidase-4 in hairless mouse skin. DHA pretreatment also attenuated UVB-induced DNA binding of nuclear factor-kappaB (NF-κB) through inhibition of phosphorylation of IκB kinase-α/β, phosphorylation and degradation of IκBα and phosphorylation and nuclear translocation of p65, a functionally active subunit of NF-κB. When topically applied to mouse skin or treating mouse epidermal cells with it, DHA induced the activation of Nrf2 that plays a pivotal role in cellular defence against oxidative stress and inflammatory damage. DHA also inhibited experimentally induced colitis in mice. Timely resolution of inflammation at the early stage is important in preventing further progression to chronic inflammation and related disorders including cancer. Resolution of inflammation is an active coordinated process regulated by distinct endogenous lipid mediators, such as resolvins and lipoxins that have anti-inflammatory and pro-resolving effects. Our recent studies have revealed that DHA enhances the efferocytic activity of macrophages, an essential event in the resolution of inflammation. Moreover, DHA induced M2 macrophage polarization through peroxisome proliferator-activated receptor γ activation. DHA undergoes oxidation to produce 17-hydroxy-DHA that is converted to an electrophilic 17-oxo metabolite. The 17-oxo-DHA induced activation of Nrf2 and upregulation of its target proteins, such as heme oxygenase-1 with anti-inflammatory activity. Further, transgenic mice harbouring fat-1 gene capable of generating spontaneously n-3 polyunsaturated fatty acids including DHA were found to be less susceptible to experimentally induced colitis and skin carcinogenesis

The azoxymethane plus dextran sulfate sodium-induced mouse colon cancer model for the study of dietary chemoprevention of inflammation-associated carcinogenesis

The azoxymethane (AOM) plus dextran sulfate sodium (DSS)-induced mouse colon carcinogenesis model is a fascinating tool for investigating the pathogenesis and chemoprevention of colitis-associated colorectal cancer. In this two-stage mouse colon cancer model, tumorigenesis is initiated by a single intraperitoneal administration of the carcinogen AOM and promoted by DSS-induced inflammation. The successful induction of AOM plus DSS-induced colorectal cancer relies on several critical factors, such as the molecular weight and the dosage of DSS, the strain, age, and sex of animals, and other experimental conditions. Here, we provide the optimized protocol for effective induction of colon tumors in mice by treatment with AOM plus DSS. Inflammation-induced colon carcinogenesis is accompanied by a series of histopathological and molecular changes. In this chapter, we also describe the step-by-step protocols for macroscopic examination, hematoxylin and eosin (H & E) staining, immunohistochemical analysis, immunoblot analysis, and the electrophoretic mobility shift assay, all of which are used for investigating the inflammation-associated colon carcinogenesis and the chemopreventive effect of dietary phytochemicals. © 2014 Springer Science+Business Media New York