• Cisplatin resistance
• Low-molecular-weight polyphenol
• Muscle atrophy
• NF-κB signaling
• Tumor inflammatory microenvironment

• Cisplatin/pharmacology
• Humans
• NF-kappa B/antagonists & inhibitors
• NF-kappa B/metabolism
• Muscular Atrophy/drug therapy
• Muscular Atrophy/etiology
• Muscular Atrophy/prevention & control
• Mouth Neoplasms/drug therapy
• Mouth Neoplasms/pathology
• Carcinoma, Squamous Cell/drug therapy
• Carcinoma, Squamous Cell/pathology
• Cell Line, Tumor
• Drug Resistance, Neoplasm/drug effects
• Antineoplastic Agents/pharmacology
• Polyphenols/pharmacology
• Tumor Microenvironment/drug effects
• Apoptosis/drug effects
• Signal Transduction/drug effects
• Cell Survival/drug effects
• Interleukin-6/metabolism

• DSS
• OPC
• anti-inflammatory
• antioxidant
• grape seed extract
• microbiota
• prebiotic

• NINJ1 protein
• colitis‐associated neoplasms
• sex characteristics
• testosterone propionate

• Animals
• Female
• Azoxymethane/toxicity
• Male
• Cell Adhesion Molecules, Neuronal/genetics
• Cell Adhesion Molecules, Neuronal/metabolism
• Dextran Sulfate/toxicity
• Mice
• Mice, Knockout
• Colorectal Neoplasms/pathology
• Colorectal Neoplasms/chemically induced
• Colorectal Neoplasms/genetics
• Colorectal Neoplasms/metabolism
• Colorectal Neoplasms/etiology
• Macrophages/metabolism
• Colitis/chemically induced
• Colitis/metabolism
• Colitis/pathology
• Colitis/genetics
• Mice, Inbred C57BL
• CD8-Positive T-Lymphocytes/metabolism
• CD8-Positive T-Lymphocytes/immunology
• Sex Factors
• Testosterone/metabolism
• Nerve Growth Factors

• 02-2020-041 Seoul National University Bundang Hospital
• 06-2021-0018 Seoul National University Bundang Hospital
• 2019R1A2C2085149 National Research Foundation of Korea

• Hydrogen Sulfide/analysis
• Hydrogen Sulfide/metabolism
• Peroxynitrous Acid/analysis
• Peroxynitrous Acid/metabolism
• Animals
• Fluorescent Dyes/chemistry
• Fluorescent Dyes/chemical synthesis
• Colitis, Ulcerative/metabolism
• Colitis, Ulcerative/diagnostic imaging
• Zebrafish
• Mice
• Humans
• Optical Imaging
• Limit of Detection

• Chemoprevention
• Colon cancer
• Flavonoids
• Inflammation
• Xenograft, Genetically engineered mouse models (GEMMs)

• Humans
• Flavonoids/pharmacology
• Flavonoids/therapeutic use
• Animals
• Colonic Neoplasms/drug therapy
• Colonic Neoplasms/pathology
• Colonic Neoplasms/prevention & control
• Gastrointestinal Microbiome/drug effects

• apoptosis
• burn-wound healing
• hepatoprotective
• liver fibrosis
• oligonol
• transcriptomic analysis

• 2-Year Research Grant Pusan National University

• Metabolism
• Muscle health
• Older adults
• Oligonol®

• NF κB
• Nrf2
• STAT3
• Src
• chemoprevention
• inflammation

The frequency of azoxymethane/dextran sulfate sodium (AOM/DSS)-induced carcinogenesis in male mice is higher than that in female mice. Previous studies have reported that 17β-estradiol inhibits tumorigenesis in males by modulating nuclear factor-erythroid 2-related factor 2 (Nrf2). This study aimed to investigate the changes in mouse gut microbiome composition based on sex, AOM/DSS-induced colorectal cancer (CRC), and Nrf2 genotype. The gut microbiome composition was determined by 16S rRNA gene sequencing fecal samples obtained at week 16 post-AOM administration. In terms of sex differences, our results showed that the wild-type (WT) male control mice had higher alpha diversity (i.e. Chao1, Shannon, and Simpson) than the WT female control mice. The linear discriminant analysis effect size (LEfSe) results revealed that the abundances of Akkermansia muciniphila and Lactobacillus murinus were higher in WT male control mice than in WT female controls. In terms of colon tumorigenesis, the alpha diversity of the male CRC group was lower than that of the male controls in both WT and Nrf2 KO, but did not show such changes in females. Furthermore, the abundance of A. muciniphila was higher in male CRC groups than in male controls in both WT and Nrf2 KO. The abundance of Bacteroides vulgatus was higher in WT CRC groups than in WT controls in both males and females. However, the abundance of L. murinus was lower in WT female CRC and Nrf2 KO male CRC groups than in its controls. The abundance of A. muciniphila was not altered by Nrf2 KO. In contrast, the abundances of L. murinus and B. vulgatus were changed differently by Nrf2 KO depending on sex and CRC. Interestingly, L. murinus showed negative correlation with tumor numbers in the whole colon. In addition, B. vulgatus showed positive correlation with inflammatory markers (i.e. myeloperoxidase and IL-1β levels), tumor numbers, and high-grade adenoma, especially, developed mucosal and submucosal invasive adenocarcinoma at the distal part of the colon. In conclusion, Nrf2 differentially alters the gut microbiota composition depending on sex and CRC induction.

• AOM/DSS mouse model
• Nrf2 knockout
• colorectal cancer
• gut microbiota
• sex difference

• AOM/DSS mouse model
• Colorectal cancer
• colitis
• orchiectomy
• sex difference
• sex hormone
• testosterone propionate

Colon tumors develop more frequently in male than in female. Nuclear factor erythroid 2-related factor 2 (Nrf2) plays differential roles in the stage of tumorigenesis. The purpose of this study was to investigate the role of Nrf2 on colitis-associated tumorigenesis using Nrf2 knockout (KO) female mice. Azoxymethane (AOM) and dextran sulfate sodium (DSS)-treated wild-type (WT) and Nrf2 KO female mice were sacrificed at week 2 and 16 after AOM injection. Severity of colitis, tumor incidence, and levels of inflammatory mediators were evaluated in AOM/DSS-treated WT and Nrf2 KO mice. Furthermore, qRT-PCR, Western blot abnalysis, and ELISA were performed in colon tissues. At week 2, AOM/DSS-induced colon tissue damages were significantly greater in Nrf2 KO than in WT mice. At week 16, tumor numbers (> 2 mm size) were significantly lower in both the proximal and distal colon in Nrf2 KO compared to WT. The overall incidences of adenoma/cancer of the proximal colon and submucosal invasive cancer of the distal colon were reduced by Nrf2 KO. The mRNA and protein expression levels of NF-κB-related mediators (i.e., iNOS and COX-2) and Nrf2-related antioxidants (i.e., heme oxygenase-1 and glutamate-cysteine ligase catalytic subunit) were significantly lower in the Nrf2 KO than in WT mice. Interestingly, the protein level of 15-hydroxyprostaglandin dehydrogenase (15-PGDH) was higher in AOM/DSS-treated Nrf2 KO than in WT mice. Our results support the oncogenic effect of Nrf2 in the later stage of carcinogenesis and upregulation of tumor suppressor 15-PGDH might contribute to the repression of colitis-associated tumorigenesis in Nrf2 KO female mice.

• 15-PGDH
• AOM/DSS mouse model
• Colitis-associated carcinogenesis
• Colon cancer
• Nrf2 knockout

• 17β-Estradiol
• AOM/DSS mouse model
• Colitis
• Colitis-associated colon cancer
• Nrf2 knockout

• IBD
• dietary polyphenols
• immune reaction
• inflammation

• Crohn’s disease
• Inflammatory bowel disease
• Natural or synthetic mediators
• Nitric oxide
• Nuclear factor-κB
• Ulcerative colitis

• Colitis
• Humans
• Inflammatory Bowel Diseases/drug therapy
• NF-kappa B/metabolism
• Nitric Oxide
• Nitric Oxide Synthase Type II
• Signal Transduction

• AOM/DSS mouse model
• Colorectal cancer
• Estrogen
• Inflammation
• Ovariectomy

Intestinal barrier dysfunction is a hallmark of inflammatory bowel diseases (IBDs) such as ulcerative colitis. This dysfunction is caused by increased permeability and the loss of tight junctions in intestinal epithelial cells. The aim of this study was to investigate whether estradiol treatment reduces colonic permeability, tight junction disruption, and inflammation in an azoxymethane (AOM)/dextran sodium sulfate (DSS) colon cancer mouse model.

The effects of 17β-estradiol (E2) were evaluated in ICR male mice 4 weeks after AOM/DSS treatment. Histological damage was scored by hematoxylin and eosin staining and the levels of the colonic mucosal cytokine myeloperoxidase (MPO) were assessed by enzyme-linked immunosorbent assay (ELISA). To evaluate the effects of E2 on intestinal permeability, tight junctions, and inflammation, we performed quantitative real-time polymerase chain reaction and Western blot analysis. Furthermore, the expression levels of mucin 2 (MUC2) and mucin 4 (MUC4) were measured as target genes for intestinal permeability, whereas zonula occludens 1 (ZO-1), occludin (OCLN), and claudin 4 (CLDN4) served as target genes for the tight junctions.

The colitis-mediated induced damage score and MPO activity were reduced by E2 treatment (p<0.05). In addition, the mRNA expression levels of intestinal barrier-related molecules (i.e., MUC2, ZO-1, OCLN, and CLDN4) were decreased by AOM/DSS-treatment; furthermore, this inhibition was rescued by E2 supplementation. The mRNA and protein expression of inflammation-related genes (i.e., KLF4, NF-κB, iNOS, and COX-2) was increased by AOM/DSS-treatment and ameliorated by E2.

E2 acts through the estrogen receptor β signaling pathway to elicit anti-inflammatory effects on intestinal barrier by inducing the expression of MUC2 and tight junction molecules and inhibiting pro-inflammatory cytokines.

• AOM/DSS colitis mouse model
• Estrogen
• Inflammation
• Permeability
• Tight junction

Oligonol attenuated SNP-induced oxidative stress and inflammatory responsesviaregulation of the NF-κB signalling pathway in RAW 264.7 macrophage cells.

• Atractylodes macrocephala
• Inflammation
• Inflammatory bowel disease
• Regeneration
• Taraxacum herba

• Dandelion
• Dextran sodium sulfate
• Mouse
• NCM460 cell
• Ulcerative colitis

The aim of this study was to investigate the protective effect of açaí against azoxymethane (AOM)/dextran sulfate sodium (DSS)-induced colorectal cancer development.

The effect of açaí on tumorigenesis was assessed by evaluating tumor incidence, multiplicity and invasiveness in the mouse colon. The levels of myeloperoxidase (MPO) and proinflammatory cytokines (tumor necrosis factor α [TNF-α], interleukin [IL]-1β, and IL-6) were measured via enzyme-linked immunosorbent assay. Protein levels of cyclooxygenase 2 (COX-2), proliferating cell nuclear antigen (PCNA), B-cell lymphoma 2 (Bcl-2), Bcl-2-associated death promoter (Bad) and cleaved-caspase-3 were assessed by immunoblotting.

Administration of pellets containing 5% açaí powder reduced the incidences of both colonic adenoma and cancer (adenoma, 23.1% vs 76.9%, respectively, p=0.006; cancer, 15.4% vs 76.9%, respectively, p=0.002). In the açaí-treated mice, the MPO, TNF-α, IL-1β and IL-6 levels in the colon were significantly down-regulated. Açaí inhibited PCNA and Bcl-2 expression and increased Bad and cleaved-caspase-3 expression. In vitro studies demonstrated that açaí treatment reduced lipopolysaccharide-induced expression of TNF-α, IL-1β, IL-6 and COX-2 in murine macrophage RAW 264.7 cells.

Açaí demonstrated protective effects against AOM/DSS-induced colon carcinogenesis, which suggests that the intake of açaí may be beneficial for the prevention of human colon cancer.

• Anti-inflammatory
• Açaí berry
• Colorectal neoplasms
• Proapoptotic

• Atrogin-1 and MuRF1
• NF-κB
• diabetes
• flavanol-rich lychee fruit extract
• muscle loss

• Animals
• Catechin/analogs & derivatives
• Catechin/pharmacology
• Cell Differentiation/drug effects
• Cells, Cultured
• Diabetes Mellitus, Experimental/physiopathology
• Disease Models, Animal
• Forkhead Box Protein O3/genetics
• Forkhead Box Protein O3/metabolism
• Fruit/chemistry
• Gene Expression Regulation
• Litchi/chemistry
• Male
• Mice
• Mice, Inbred C57BL
• Molecular Weight
• Muscle Proteins/antagonists & inhibitors
• Muscle Proteins/genetics
• Muscle, Skeletal/drug effects
• Muscle, Skeletal/metabolism
• NF-kappa B/genetics
• NF-kappa B/metabolism
• Phenols/pharmacology
• Polyphenols/pharmacology
• RNA, Messenger/genetics
• RNA, Messenger/metabolism
• SKP Cullin F-Box Protein Ligases/antagonists & inhibitors
• SKP Cullin F-Box Protein Ligases/genetics
• Sarcopenia/drug therapy
• Sirtuin 1/genetics
• Sirtuin 1/metabolism
• Tripartite Motif Proteins/antagonists & inhibitors
• Tripartite Motif Proteins/genetics
• Ubiquitin-Protein Ligases/antagonists & inhibitors
• Ubiquitin-Protein Ligases/genetics

• Litchi chinensis fruit extracts
• antitumor activity
• nutraceutical properties

• Animals
• Antineoplastic Agents, Phytogenic/chemistry
• Antineoplastic Agents, Phytogenic/pharmacology
• Fruit/chemistry
• Functional Food
• Humans
• Litchi/chemistry
• Plant Extracts

• Brassicaceae
• NFκB
• Nrf2
• epigenetics
• isothiocyanates
• sulforaphane

• Animals
• Anti-Inflammatory Agents/chemistry
• Anti-Inflammatory Agents/therapeutic use
• Anticarcinogenic Agents/chemistry
• Anticarcinogenic Agents/therapeutic use
• Antioxidants/chemistry
• Antioxidants/therapeutic use
• Brassica/chemistry
• Humans
• Inflammation/diet therapy
• Isothiocyanates/chemistry
• Isothiocyanates/therapeutic use
• Mice
• Neoplasms/diet therapy
• Phytochemicals/therapeutic use
• Signal Transduction/drug effects
• Vegetables

The inflammatory process plays a central role in the development and progression of numerous pathological situations, such as inflammatory bowel disease (IBD), autoimmune and neurodegenerative diseases, metabolic syndrome, and cardiovascular disorders. IBDs involve inflammation of the gastrointestinal area and mainly comprise Crohn’s disease (CD) and ulcerative colitis (UC). Both pathological situations usually involve recurring or bloody diarrhea, pain, fatigue and weight loss. There is at present no pharmacological cure for CD or UC. However, surgery may be curative for UC patients. The prescribed treatment aims to ameliorate the symptoms and prevent and/or delay new painful episodes. Flavonoid compounds are a large family of hydroxylated polyphenolic molecules abundant in plants, including vegetables and fruits which are the major dietary sources of these compounds for humans, together with wine and tea. Flavonoids are becoming very popular because they have many health-promoting and disease-preventive effects. Most interest has been directed towards the antioxidant activity of flavonoids, evidencing a remarkable free-radical scavenging capacity. However, accumulating evidence suggests that flavonoids have many other biological properties, including anti-inflammatory, antiviral, anticancer, and neuroprotective activities through different mechanisms of action. The present review analyzes the available data about the different types of flavonoids and their potential effectiveness as adjuvant therapy of IBDs.

• Antioxidant
• Inflammation
• Gastrointestinal tract
• Flavonoids
• Polyphenols

• Animals
• Anti-Inflammatory Agents/therapeutic use
• Clinical Trials as Topic
• Colitis, Ulcerative/drug therapy
• Colitis, Ulcerative/pathology
• Colon/drug effects
• Colon/pathology
• Crohn Disease/drug therapy
• Crohn Disease/pathology
• Disease Models, Animal
• Flavonoids/pharmacology
• Flavonoids/therapeutic use
• Intestinal Mucosa/drug effects
• Intestinal Mucosa/pathology
• Treatment Outcome

• chemoprevention
• chronic inflammation
• inflammation-related carcinogenesis

• Animals
• Carcinogenesis/drug effects
• Chemoprevention/methods
• Chronic Disease
• Cytokines/metabolism
• DNA Damage
• Disease Models, Animal
• Humans
• Inflammation/complications
• Inflammation/drug therapy
• Inflammation/metabolism
• Inflammation Mediators/metabolism
• Neoplasms/etiology
• Neoplasms/prevention & control
• Reactive Nitrogen Species
• Reactive Oxygen Species

• catechins
• inflammatory bowel disease
• mechanisms
• oxidative stress
• tight junction functionality

• Catechin/chemistry
• Catechin/pharmacology
• Catechin/therapeutic use
• Cell Proliferation/drug effects
• Gastrointestinal Microbiome/drug effects
• Gene Expression Regulation/drug effects
• Humans
• Inflammatory Bowel Diseases/drug therapy
• Inflammatory Bowel Diseases/immunology
• Inflammatory Bowel Diseases/prevention & control
• Intercellular Junctions/drug effects
• Neutrophil Infiltration/drug effects
• Oxidative Stress/drug effects

The colitis-associated cancer exhibits different characteristics according to sex in the initiation and progression of the tumors. The aim of this study was to investigate the sex-associated difference in the azoxymethane/dextran sulfate sodium (AOM/DSS)-induced colitis-associated cancer model.

The AOM/DSS ICR mouse model was established to compare male with female, and then the severity of colitis-associated carcinogenesis was examined macroscopically and histologically regarding the number, size, and location of tumors. Subsequently, levels of colonic mucosal cytokine, interleukin (IL)-1β and myeloperoxidase (MPO) were assessed.

At the 16th week, the tumor multiplicity and the pro-inflammatory factors differed according to sex. The total tumor number was significantly higher in male (P = 0.020) and the number of large tumors (diameter > 2 mm) was higher in male (P = 0.026). In male, the tumors located more in distal colon (P = 0.001). MPO was significantly higher in AOM/DSS-treated male mice compared to the control group (P = 0.003), whereas the corresponding female group showed no significant change (P = 0.086). Colonic IL-1β level significantly increased in AOM/DSS groups compared to control groups both in male and female (male, P = 0.014; female, P = 0.005). It was higher in male group; however, there was no statistical significance (P = 0.226).

In AOM/DSS murine model, colitis-associated colon tumorigenesis are induced more severely in male mice than female probably by way of inflammatory mediators such as IL-1β and MPO. The sex-related differences at the animal model of colon cancer suggest the importance of approach to disease with sex-specific medicine in human.

• Colitis
• Colonic neoplasms
• Disease models
• Sex
• animal

• Cytokines
• Human
• Monocytes
• Oligonol
• Polyphenols

Oxidative stress (OS) is considered as one of the etiologic factors involved in several signals and symptoms of inflammatory bowel diseases (IBD) that include diarrhea, toxic megacolon and abdominal pain. This systematic review discusses approaches, challenges and perspectives into the use of nontraditional antioxidant therapy on IBD, including natural and synthetic compounds in both human and animal models. One hundred and thirty four papers were identified, of which only four were evaluated in humans. Some of the challenges identified in this review can shed light on this fact: lack of standardization of OS biomarkers, absence of safety data and clinical trials for the chemicals and biological molecules, as well as the fact that most of the compounds were not repeatedly tested in several situations, including acute and chronic colitis. This review hopes to stimulate researchers to become more involved in this fruitful area, to warrant investigation of novel, alternative and efficacious antioxidant-based therapies.

•

Major biomarkers used for evaluation of antioxidant therapy were MPO, TBARS/MDA and glutathione levels.

• Antioxidant therapy
• Biomarkers
• Complementary and alternative medicine
• Crohn's disease
• Inflammatory bowel diseases
• Nutraceuticals
• Oxidative stress
• Ulcerative colitis

• C6cell
• Oligonol
• inflammation
• nitric oxide
• oxidative stress

• Boswellia serrata
• inflammation
• nitric oxide
• oxidative stress
• ulcerative colitis