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Chang YC, Lan YY, Lin HY, Liu C, Chang SJ. Low-molecular-weight polyphenol promotes cell sensitivity to cisplatin and alleviates cancer-related muscle atrophy via NF-κB suppression in oral squamous cell carcinoma. J Oral Biosci 2025; 67:100595. [PMID: 39709169 DOI: 10.1016/j.job.2024.100595] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2024] [Revised: 12/03/2024] [Accepted: 12/04/2024] [Indexed: 12/23/2024]
Abstract
OBJECTIVE Drug resistance and subsequent adverse effects, such as cancer cachexia, limit the clinical use of cisplatin. Oligonol® (Olg), a low-molecular-weight polyphenol, exhibits NF-κB inhibitory properties. NF-κB activation has been implicated in cisplatin resistance of cancer cells and skeletal muscle wasting. Therefore, we hypothesized that combined cisplatin and Olg could overcome chemoresistance and reduce muscle atrophy. METHODS To investigate the efficiency of Olg, oral squamous cell carcinoma (OSCC) cells were used for chemosensitivity, and human skeletal muscle myoblast (HSkMC) was used for muscle atrophy. HSkMCs treated with OSCC cell-derived conditioned medium were used to examine the role of Olg in muscle atrophy mediated by the tumor inflammatory microenvironment. RESULTS Olg exerted little effect on the viability of OSCC cells by promoting apoptotic cell death. However, it exhibited excellent capability to enhance the sensitivity of OSCC cells to cisplatin and overcome the acquired cisplatin resistance of OSCC. We revealed that NF-κB signaling contributes to cisplatin resistance in OSCC cells, whereas Olg enhances cell sensitivity to cisplatin by NF-κB suppression. Conversely, Olg contributes to a positive protein turnover and alleviates cisplatin-induced muscle atrophy by regulating Akt/mTOR/p70S6K and NF-κB/MuRF1 pathway. Olg represses TNF-α and interleukin 6 driven from OSCC cells and alleviates muscle atrophy mediated by the tumor inflammatory microenvironment. CONCLUSIONS Olg enhanced cisplatin chemosensitivity and reduced its adverse effects on skeletal muscle, suggesting its potential as a chemosensitizing agent for cisplatin. Further animal and clinical studies are required to validate these findings.
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Affiliation(s)
- Yun-Ching Chang
- School of Medicine, College of Medicine, I-Shou University, Kaohsiung, Taiwan.
| | - Yu-Yan Lan
- School of Medicine, College of Medicine, I-Shou University, Kaohsiung, Taiwan
| | - Hung-Yu Lin
- School of Medicine, College of Medicine, I-Shou University, Kaohsiung, Taiwan; Department of Urology, E-Da Cancer Hospital, I-Shou University, Kaohsiung, Taiwan
| | - Cheng Liu
- Department of Physical Therapy, Shu-Zen Junior College of Medicine and Management, Kaohsiung, Taiwan
| | - Sue-Joan Chang
- Department of Life Sciences, National Cheng Kung University, Tainan, Taiwan; Marine Biology and Cetacean Research Center, National Cheng Kung University, Tainan, Taiwan.
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Mokrani M, Saad N, Nardy L, Sifré E, Despres J, Brochot A, Varon C, Urdaci MC. Biombalance™, an Oligomeric Procyanidins-Enriched Grape Seed Extract, Prevents Inflammation and Microbiota Dysbiosis in a Mice Colitis Model. Antioxidants (Basel) 2025; 14:305. [PMID: 40227242 PMCID: PMC11939601 DOI: 10.3390/antiox14030305] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2024] [Revised: 02/21/2025] [Accepted: 02/26/2025] [Indexed: 04/15/2025] Open
Abstract
Inflammatory bowel disease (IBD) results from genetic factors, environmental factors, and intestinal microbiota interactions. This study investigated the effects of Biombalance™ (BB) in dextran sulphate sodium (DSS)-induced colitis in mice. BB extract exhibits high antioxidant activity, as determined by DPPH and ORAC tests. Mice were fed a standard diet, and BB was administered by gavage for ten days, before administration of 2.75% DSS in drinking water. BB significantly protected mice against DSS effects, as assessed by colon length, disease activity index (DAI) scores and colonic pathological damage. In addition, BB inhibited the expression of proinflammatory markers, such as IL-6, IL-17, CXCL1 and TNF-α, and the inflammatory mediators iNOS, TGF-β, FoxP3 and F4/80, while increasing IL-10 expression in the colon. BB modified microbiota composition, attenuating the microbial diversity lost due to DSS, increasing beneficial bacteria like Muribaculum, Lactobacillus, Muscispirillum, Roseburia and Bifidobacterium, and decreasing potentially harmful bacteria such as Proteobacteria and Enterococcus. Interestingly, microbiota-predicted functions using PICRUSt revealed that BB extract increases the antioxidant superpathway of ubiquinol biosynthesis, including ubiquinol-7, 8, 9 and 10 (CoenzymesQ). These findings suggest that Biombalance™ administration may help to reduce gut inflammation and oxidation, at least partly through modifications of the microbiota and its metabolites.
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Affiliation(s)
- Mohamed Mokrani
- University Bordeaux, CNRS, Bordeaux INP, CBMN, UMR 5248, F-33600 Pessac, France; (M.M.); (N.S.); (L.N.)
- Bordeaux Sciences Agro, F-33175 Gradignan, France
- Groupe Berkem, 20 Rue Jean Duvert, F-33290 Blanquefort, France; (J.D.); (A.B.)
| | - Naima Saad
- University Bordeaux, CNRS, Bordeaux INP, CBMN, UMR 5248, F-33600 Pessac, France; (M.M.); (N.S.); (L.N.)
- Univ. Limoges, LABCiS, UR 22722, F-87000 Limoges, France
| | - Ludivine Nardy
- University Bordeaux, CNRS, Bordeaux INP, CBMN, UMR 5248, F-33600 Pessac, France; (M.M.); (N.S.); (L.N.)
- Bordeaux Sciences Agro, F-33175 Gradignan, France
| | - Elodie Sifré
- INSERM U1312 BRIC Bordeaux Institute of Oncology, Université de Bordeaux, F-33077 Bordeaux, France; (E.S.); (C.V.)
| | - Julie Despres
- Groupe Berkem, 20 Rue Jean Duvert, F-33290 Blanquefort, France; (J.D.); (A.B.)
| | - Amandine Brochot
- Groupe Berkem, 20 Rue Jean Duvert, F-33290 Blanquefort, France; (J.D.); (A.B.)
| | - Christine Varon
- INSERM U1312 BRIC Bordeaux Institute of Oncology, Université de Bordeaux, F-33077 Bordeaux, France; (E.S.); (C.V.)
| | - Maria C. Urdaci
- University Bordeaux, CNRS, Bordeaux INP, CBMN, UMR 5248, F-33600 Pessac, France; (M.M.); (N.S.); (L.N.)
- Bordeaux Sciences Agro, F-33175 Gradignan, France
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3
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Song CH, Kim N, Nam RH, Choi SI, Jang JY, Kim EH, Ha S, Shin E, Choi H, Kim KW, Jeon S, Oh GT, Seok YJ. Ninjurin1 deficiency differentially mitigates colorectal cancer induced by azoxymethane and dextran sulfate sodium in male and female mice. Int J Cancer 2025; 156:826-839. [PMID: 39417611 DOI: 10.1002/ijc.35225] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2023] [Revised: 06/07/2024] [Accepted: 06/14/2024] [Indexed: 10/19/2024]
Abstract
This study investigated the role of Ninjurin1 (Ninj1), encoding a small transmembrane protein, in colitis-associated colon tumorigenesis in relation to sex hormones. Male and female wild-type (WT) and Ninj1 knockout (KO) mice were treated with azoxymethane (AOM) and dextran sulfate sodium (DSS), with or without testosterone propionate (TP). At week 2 (acute colitis stage), Ninj1 KO exhibited an alleviation in the colitis symptoms in both male and female mice. The M2 macrophage population increased and CD8+ T cell population decreased only in the female Ninj1 KO than in the female WT AOM/DSS group. In the female AOM/DSS group, TP treatment exacerbated colon shortening in the Ninj1 KO than in the WT. At week 13 (tumorigenesis stage), male Ninj1 KO mice had fewer tumors, but females showed similar tumors. In the WT AOM/DSS group, females had more M2 macrophages and fewer M1 macrophages than males, but this difference was absent in Ninj1 KO mice. In the Ninj1 KO versus WT group, the expression of pro-inflammatory mediators and Ho-1 and CD8+ T cell populations decreased in both female and male Ninj1 KO mice. In the WT group, M2 macrophage populations were increased by AOM/DSS treatment and decreased by TP treatment. However, neither treatment changed the cell populations in the Ninj1 KO group. These results suggest that Ninj1 is involved in colorectal cancer development in a testosterone-dependent manner, which was different in male and female. This highlights the importance of considering sex disparities in understanding Ninj1's role in cancer pathogenesis.
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Affiliation(s)
- Chin-Hee Song
- Department of Internal Medicine and Research Center for Sex- and Gender-Specific Medicine, Seoul National University Bundang Hospital, Seongnam, Gyeonggi-do, South Korea
| | - Nayoung Kim
- Department of Internal Medicine and Research Center for Sex- and Gender-Specific Medicine, Seoul National University Bundang Hospital, Seongnam, Gyeonggi-do, South Korea
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, South Korea
| | - Ryoung Hee Nam
- Department of Internal Medicine and Research Center for Sex- and Gender-Specific Medicine, Seoul National University Bundang Hospital, Seongnam, Gyeonggi-do, South Korea
| | - Soo In Choi
- Department of Internal Medicine and Research Center for Sex- and Gender-Specific Medicine, Seoul National University Bundang Hospital, Seongnam, Gyeonggi-do, South Korea
| | - Jae Young Jang
- Department of Internal Medicine and Research Center for Sex- and Gender-Specific Medicine, Seoul National University Bundang Hospital, Seongnam, Gyeonggi-do, South Korea
| | - Eun Hye Kim
- Department of Internal Medicine and Research Center for Sex- and Gender-Specific Medicine, Seoul National University Bundang Hospital, Seongnam, Gyeonggi-do, South Korea
| | - Sungchan Ha
- Department of Internal Medicine and Research Center for Sex- and Gender-Specific Medicine, Seoul National University Bundang Hospital, Seongnam, Gyeonggi-do, South Korea
| | - Eun Shin
- Department of Pathology, Hallym University Dongtan Sacred Heart Hospital, Hwaseong, Gyeonggi-do, South Korea
| | - Hoon Choi
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, South Korea
| | - Kyu-Won Kim
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, South Korea
| | - Sejin Jeon
- Department of Vaccine Biothechnology, Andong National University, Andong, South Korea
| | - Goo Taeg Oh
- Department of Life Sciences, Heart-Immune-Brain Network Research Center, Ewha Womans University, Seoul, South Korea
| | - Yeong-Jae Seok
- Department of Biological Sciences and Institute of Microbiology, Seoul National University, Seoul, South Korea
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Chen Y, Bao J, Wang Q, Hameed MS, Tang S, Chen Q, Fan H, Yan J, Yang G, Zhang K, Han X. Simultaneous Detection of Hydrogen Sulfide and Peroxynitrite Dysregulation with a Sequentially Activated Fluorescent Probe in Ulcerative Colitis Disease. Anal Chem 2025; 97:721-730. [PMID: 39810341 DOI: 10.1021/acs.analchem.4c05160] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2025]
Abstract
Ulcerative colitis (UC), often referred to as "green cancer", is a chronic inflammatory bowel disease with an unclear etiology, closely associated with the imbalance of hydrogen sulfide (H2S) and peroxynitrite (ONOO-). H2S exhibits anti-inflammatory effects at physiological levels, but excessive concentrations can compromise the intestinal barrier, while ONOO- aggravates inflammation. To facilitate the molecular-level monitoring of these compounds in UC, we developed a novel fluorescent probe, BCH, capable of simultaneously detecting H2S and ONOO- via distinct fluorescent channels in a cascade mode. BCH features rapid response times (H2S: 6 min; ONOO-: 5 min) with well-separated emission peaks (120 nm), minimizing spectral overlap. The probe demonstrates high selectivity and good detection linearity for H2S (0-500 μM) and ONOO- (0-100 μM), with detection limits of 1.6 μM for H2S and 0.05 μM for ONOO-. BCH has been successfully applied for imaging H2S and ONOO- in living cells and zebrafish, enabling the sensitive detection of their fluctuations in a UC mouse model. These findings indicate that BCH is highly promising for studying the roles of H2S and ONOO- in UC and assessing their biological functions.
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Affiliation(s)
- Yiliang Chen
- School of Chemistry and Chemical Engineering, Anhui University of Technology, Ma'anshan 243032, P. R. China
| | - Jiawei Bao
- School of Chemistry and Chemical Engineering, Anhui University of Technology, Ma'anshan 243032, P. R. China
| | - Qi Wang
- School of Chemistry and Chemical Engineering, Anhui University of Technology, Ma'anshan 243032, P. R. China
| | - Muhammad Salman Hameed
- State Key Laboratory of Green Pesticide, College of Chemistry, Central China Normal University, Wuhan 430079, P. R. China
| | - Siyuan Tang
- School of Chemistry and Chemical Engineering, Anhui University of Technology, Ma'anshan 243032, P. R. China
| | - Qian Chen
- School of Chemistry and Chemical Engineering, Anhui University of Technology, Ma'anshan 243032, P. R. China
| | - Hai Fan
- Maanshan People's Hospital, Ma'anshan 243099, P. R. China
| | - Jufen Yan
- School of Chemistry and Chemical Engineering, Anhui University of Technology, Ma'anshan 243032, P. R. China
- Maanshan People's Hospital, Ma'anshan 243099, P. R. China
| | - Ganggang Yang
- School of Chemistry and Chemical Engineering, Anhui University of Technology, Ma'anshan 243032, P. R. China
| | - Kui Zhang
- School of Chemistry and Chemical Engineering, Anhui University of Technology, Ma'anshan 243032, P. R. China
| | - Xinya Han
- School of Chemistry and Chemical Engineering, Anhui University of Technology, Ma'anshan 243032, P. R. China
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Hasibuan PAZ, Simanjuntak Y, Hey-Hawkins E, Lubis MF, Rohani AS, Park MN, Kim B, Syahputra RA. Unlocking the potential of flavonoids: Natural solutions in the fight against colon cancer. Biomed Pharmacother 2024; 176:116827. [PMID: 38850646 DOI: 10.1016/j.biopha.2024.116827] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2024] [Revised: 05/21/2024] [Accepted: 05/26/2024] [Indexed: 06/10/2024] Open
Abstract
Colorectal cancer (CRC) is a major cause of cancer-related deaths worldwide, underscoring the importance of understanding the diverse molecular and genetic underpinnings of CRC to improve its diagnosis, prognosis, and treatment. This review delves into the adenoma-carcinoma-metastasis model, emphasizing the "APC-KRAS-TP53" signature events in CRC development. CRC is categorized into four consensus molecular subtypes, each characterized by unique genetic alterations and responses to therapy, illustrating its complexity and heterogeneity. Furthermore, we explore the role of chronic inflammation and the gut microbiome in CRC progression, emphasizing the potential of targeting these factors for prevention and treatment. This review discusses the impact of dietary carcinogens and lifestyle factors and the critical role of early detection in improving outcomes, and also examines conventional chemotherapy options for CRC and associated challenges. There is significant focus on the therapeutic potential of flavonoids for CRC management, discussing various types of flavonoids, their sources, and mechanisms of action, including their antioxidant properties, modulation of cell signaling pathways, and effects on cell cycle and apoptosis. This article presents evidence of the synergistic effects of flavonoids with conventional cancer therapies and their role in modulating the gut microbiome and immune response, thereby offering new avenues for CRC treatment. We conclude by emphasizing the importance of a multidisciplinary approach to CRC research and treatment, incorporating insights from genetic, molecular, and lifestyle factors. Further research is needed on the preventive and therapeutic potential of natural compounds, such as flavonoids, in CRC, underscoring the need for personalized and targeted treatment strategies.
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Affiliation(s)
| | - Yogi Simanjuntak
- Department of Pharmacology, Faculty of Pharmacy, Universitas Sumatera Utara, Sumatera Utara, Indonesia
| | - Evamarie Hey-Hawkins
- Leipzig University, Faculty of Chemistry and Mineralogy, Centre for Biotechnology and Biomedicine (BBZ), Institute of Bioanalytical Chemistry, Deutscher Platz 5, Leipzig 04103, Germany
| | - Muhammad Fauzan Lubis
- Department of Pharmaceutical Biology, Faculty of Pharmacy, Universitas Sumatera Utara, Sumatera Utara, Indonesia
| | - Ade Sri Rohani
- Department of Pharmacology, Faculty of Pharmacy, Universitas Sumatera Utara, Sumatera Utara, Indonesia
| | - Moon Nyeo Park
- Department of Internal Medicine, College of Korean Medicine, Kyung Hee University, Seoul, 02447, Republic of Korea; College of Korean Medicine, Kyung Hee University, Hoegidong Dongdaemungu, Seoul 05253, Republic of Korea
| | - Bonglee Kim
- Department of Internal Medicine, College of Korean Medicine, Kyung Hee University, Seoul, 02447, Republic of Korea; College of Korean Medicine, Kyung Hee University, Hoegidong Dongdaemungu, Seoul 05253, Republic of Korea
| | - Rony Abdi Syahputra
- Department of Pharmacology, Faculty of Pharmacy, Universitas Sumatera Utara, Sumatera Utara, Indonesia
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Kim J, Lee C, Noh SG, Kim S, Chung HY, Lee H, Moon JO. Integrative Transcriptomic Analysis Reveals Upregulated Apoptotic Signaling in Wound-Healing Pathway in Rat Liver Fibrosis Models. Antioxidants (Basel) 2023; 12:1588. [PMID: 37627582 PMCID: PMC10451232 DOI: 10.3390/antiox12081588] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2023] [Revised: 08/03/2023] [Accepted: 08/07/2023] [Indexed: 08/27/2023] Open
Abstract
Liver fibrosis, defined by the aberrant accumulation of extracellular matrix proteins in liver tissue due to chronic inflammation, represents a pressing global health issue. In this study, we investigated the transcriptomic signatures of three independent liver fibrosis models induced by bile duct ligation, carbon tetrachloride, and dimethylnitrosamine (DMN) to unravel the pathological mechanisms underlying hepatic fibrosis. We observed significant changes in gene expression linked to key characteristics of liver fibrosis, with a distinctive correlation to the burn-wound-healing pathway. Building on these transcriptomic insights, we further probed the p53 signaling pathways within the DMN-induced rat liver fibrosis model, utilizing western blot analysis. We observed a pronounced elevation in p53 protein levels and heightened ratios of BAX/BCL2, cleaved/pro-CASPASE-3, and cleaved/full length-PARP in the livers of DMN-exposed rats. Furthermore, we discovered that orally administering oligonol-a polyphenol, derived from lychee, with anti-oxidative properties-effectively countered the overexpressions of pivotal apoptotic genes within these fibrotic models. In conclusion, our findings offer an in-depth understanding of the molecular alterations contributing to liver fibrosis, spotlighting the essential role of the apoptosis pathway tied to the burn-wound-healing process. Most importantly, our research proposes that regulating this pathway, specifically the balance of apoptosis, could serve as a potential therapeutic approach for treating liver fibrosis.
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Affiliation(s)
- Jihyun Kim
- BIT Convergence-Based Innovative Drug Development Targeting Mate-Inflammation, Pusan National University, Busan 46241, Republic of Korea;
- College of Pharmacy and Research Institute for Drug Development, Pusan National University, Busan 46241, Republic of Korea; (C.L.); (S.G.N.); (S.K.); (H.Y.C.)
| | - Changyong Lee
- College of Pharmacy and Research Institute for Drug Development, Pusan National University, Busan 46241, Republic of Korea; (C.L.); (S.G.N.); (S.K.); (H.Y.C.)
| | - Sang Gyun Noh
- College of Pharmacy and Research Institute for Drug Development, Pusan National University, Busan 46241, Republic of Korea; (C.L.); (S.G.N.); (S.K.); (H.Y.C.)
| | - Seungwoo Kim
- College of Pharmacy and Research Institute for Drug Development, Pusan National University, Busan 46241, Republic of Korea; (C.L.); (S.G.N.); (S.K.); (H.Y.C.)
| | - Hae Young Chung
- College of Pharmacy and Research Institute for Drug Development, Pusan National University, Busan 46241, Republic of Korea; (C.L.); (S.G.N.); (S.K.); (H.Y.C.)
| | - Haeseung Lee
- BIT Convergence-Based Innovative Drug Development Targeting Mate-Inflammation, Pusan National University, Busan 46241, Republic of Korea;
- College of Pharmacy and Research Institute for Drug Development, Pusan National University, Busan 46241, Republic of Korea; (C.L.); (S.G.N.); (S.K.); (H.Y.C.)
| | - Jeon-Ok Moon
- College of Pharmacy and Research Institute for Drug Development, Pusan National University, Busan 46241, Republic of Korea; (C.L.); (S.G.N.); (S.K.); (H.Y.C.)
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Peng LN, Lin MH, Lee HF, Hsu CC, Chang SJ, Chen LK. Clinical efficacy of oligonol® supplementation on metabolism and muscle health in middle-aged and older adults: A double-blinded randomized controlled trial. Arch Gerontol Geriatr 2022; 103:104784. [PMID: 35985196 DOI: 10.1016/j.archger.2022.104784] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2022] [Revised: 07/26/2022] [Accepted: 07/29/2022] [Indexed: 11/19/2022]
Abstract
BACKGROUND Oligonol® is a low-molecular-weight polyphenol that has biological effects on metabolism in animals. However, little is known about its roles in muscle function and muscle quality in middle-aged and older adults. METHODS 120 participants were enrolled for study based on 1:1 randomization. Participants in the intervention group were provided 200 mg oligonol® prepared as capsules, and 200 mg placebo (dextrin) was provided in control group. RESULTS Data from 103 participants (52 in the intervention group and 51 in the control group) were available for analysis. The mean age of all participants was 64.0 ± 8.2 years, and two-thirds of the participants were females. Baseline demographic characteristics, functional assessment, laboratory data and muscle parameters were similar between groups. Hip circumference decreased (p = 0.009) during the study period, and the 6-m walking speed increased (p = 0.001) in women in the intervention group. In contrast, 6-m walking speed, 6-min walking distance and handgrip strength were significantly improved in men in the intervention group, but increased total body fat percentage (p = 0.038) and decreased mid-thigh cross-muscle area (CMA) (p = 0.007) were observed in the control group. Compared to the control group, the 12-week interval change in the percentage of mid-thigh CMA was maintained in men in the intervention group but was significantly decreased in the control group (p = 0.03, 95% CI:0.002-0.05). CONCLUSIONS Oligonol supplementation (200 mg per day) significantly improved physical performance and muscle mass in men. Further studies are needed to confirm the potential favorable effects of oligonol® supplementation.
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Affiliation(s)
- Li-Ning Peng
- Center for Geriatrics and Gerontology, Taipei Veterans General Hospital, No. 201, Sec. 2, Shih-Pai Rd., Taipei 11217, Taiwan; Center for Healthy Longevity and Aging Sciences, National Yang Ming Chiao Tung University, No. 1001, Daxue Rd. East Dist., Hsinchu 300093, Taiwan.
| | - Ming-Hsien Lin
- Center for Geriatrics and Gerontology, Taipei Veterans General Hospital, No. 201, Sec. 2, Shih-Pai Rd., Taipei 11217, Taiwan; Center for Healthy Longevity and Aging Sciences, National Yang Ming Chiao Tung University, No. 1001, Daxue Rd. East Dist., Hsinchu 300093, Taiwan
| | - Huei-Fang Lee
- Center for Healthy Longevity and Aging Sciences, National Yang Ming Chiao Tung University, No. 1001, Daxue Rd. East Dist., Hsinchu 300093, Taiwan
| | - Chia-Chia Hsu
- Center for Geriatrics and Gerontology, Taipei Veterans General Hospital, No. 201, Sec. 2, Shih-Pai Rd., Taipei 11217, Taiwan
| | - Sue-Joan Chang
- Department of Life Sciences, National Cheng Kung University, Tainan, Taiwan
| | - Liang-Kung Chen
- Center for Geriatrics and Gerontology, Taipei Veterans General Hospital, No. 201, Sec. 2, Shih-Pai Rd., Taipei 11217, Taiwan; Center for Healthy Longevity and Aging Sciences, National Yang Ming Chiao Tung University, No. 1001, Daxue Rd. East Dist., Hsinchu 300093, Taiwan; Taipei Municipal Gan-Dau Hospital (Managed by Taipei Veterans General Hospital), Taipei, Taiwan
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Ahsan H, Islam SU, Ahmed MB, Lee YS. Role of Nrf2, STAT3, and Src as Molecular Targets for Cancer Chemoprevention. Pharmaceutics 2022; 14:1775. [PMID: 36145523 PMCID: PMC9505731 DOI: 10.3390/pharmaceutics14091775] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2022] [Revised: 07/23/2022] [Accepted: 08/22/2022] [Indexed: 11/16/2022] Open
Abstract
Cancer is a complex and multistage disease that affects various intracellular pathways, leading to rapid cell proliferation, angiogenesis, cell motility, and migration, supported by antiapoptotic mechanisms. Chemoprevention is a new strategy to counteract cancer; to either prevent its incidence or suppress its progression. In this strategy, chemopreventive agents target molecules involved in multiple pathways of cancer initiation and progression. Nrf2, STAT3, and Src are promising molecular candidates that could be targeted for chemoprevention. Nrf2 is involved in the expression of antioxidant and phase II metabolizing enzymes, which have direct antiproliferative action as well as indirect activities of reducing oxidative stress and eliminating carcinogens. Similarly, its cross-talk with NF-κB has great anti-inflammatory potential, which can be utilized in inflammation-induced/associated cancers. STAT3, on the other hand, is involved in multiple pathways of cancer initiation and progression. Activation, phosphorylation, dimerization, and nuclear translocation are associated with tumor cell proliferation and angiogenesis. Src, being the first oncogene to be discovered, is important due to its convergence with many upstream stimuli, its cross-talk with other potential molecular targets, such as STAT3, and its ability to modify the cell cytoskeleton, making it important in cancer invasion and metastasis. Therefore, the development of natural/synthetic molecules and/or design of a regimen that can reduce oxidative stress and inflammation in the tumor microenvironment and stop multiple cellular targets in cancer to stop its initiation or retard its progression can form newer chemopreventive agents.
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Affiliation(s)
- Haseeb Ahsan
- Department of Pharmacy, Faculty of Life and Environmental Sciences, University of Peshawar, Peshawar 25120, Pakistan
| | - Salman Ul Islam
- Department of Pharmacy, CECOS University, Peshawar 25000, Pakistan
| | - Muhammad Bilal Ahmed
- BK21 FOUR KNU Creative BioResearch Group, School of Life Sciences, Kyungpook National University, Daegu 41566, Korea
| | - Young Sup Lee
- BK21 FOUR KNU Creative BioResearch Group, School of Life Sciences, Kyungpook National University, Daegu 41566, Korea
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Song CH, Kim N, Nam RH, Choi SI, Yu JE, Nho H, Surh YJ. Changes in Microbial Community Composition Related to Sex and Colon Cancer by Nrf2 Knockout. Front Cell Infect Microbiol 2021; 11:636808. [PMID: 34249773 PMCID: PMC8261249 DOI: 10.3389/fcimb.2021.636808] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Accepted: 06/11/2021] [Indexed: 12/12/2022] Open
Abstract
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.
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Affiliation(s)
- Chin-Hee Song
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, South Korea
| | - Nayoung Kim
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, South Korea.,Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, South Korea
| | - Ryoung Hee Nam
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, South Korea
| | - Soo In Choi
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, South Korea
| | - Jeong Eun Yu
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, South Korea
| | - Heewon Nho
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, South Korea
| | - Young-Joon Surh
- Tumor Microenvironment Global Core Research Center, College of Pharmacy, Seoul National University, Seoul, South Korea.,Cancer Research Institute, Seoul National University, Seoul, South Korea
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10
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Song CH, Kim N, Nam RH, Choi SI, Yu JE, Nho H, Shin E, Lee HN, Surh YJ. Testosterone strongly enhances azoxymethane/dextran sulfate sodium-induced colorectal cancer development in C57BL/6 mice. Am J Cancer Res 2021; 11:3145-3162. [PMID: 34249451 PMCID: PMC8263677] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Accepted: 04/25/2021] [Indexed: 06/13/2023] Open
Abstract
Colorectal cancer (CRC) is known to occur more frequently in males than in females, with sex hormones reportedly influencing the development. The purpose of the study was to investigate whether orchiectomy in C57BL/6 male mice reduces colorectal tumorigenesis and whether testosterone administration increases tumorigenesis after orchiectomy in an azoxymethane (AOM)/dextran sulfate sodium (DSS) mouse model. Clinical symptoms, including colitis and tumor incidence, were evaluated in the absence or presence of testosterone in AOM/DSS-treated male, as well as orchiectomized (ORX) male and female mice. The levels of serum testosterone and colonic myeloperoxidase, interleukin (IL)-1β, and IL-6 were measured by ELISA. Target mRNA expression was assessed by quantitative real-time PCR. Orchiectomy significantly diminished the AOM/DSS-induced colitis indices, including disease activity index, colon shortening, and histological severity at week 2, and decreased tumor numbers and incidence rates in the distal part of the colon increased following AOM/DSS administration at week 13; this reduction was reversed by testosterone supplementation. Furthermore, it was confirmed that the ELISA level (MPO and IL-1β) and the mRNA expression of the inflammatory mediators (COX-2 and iNOS) were maintained at high levels in the tumors of the testosterone-treated group compared with AOM/DSS groups. Interestingly, both endogenous and exogenous testosterone administrations were associated with tumor development (> 2 mm in size) and submucosal invasive cancer. Based on multivariate logistic regression analysis, testosterone was identified as a reasonable hazard factor for the progression of submucosal invasive cancer of the distal colon. In conclusion, endogenous and exogenous testosterone presented a stimulating effect on AOM/DSS-induced colitis and carcinogenicity.
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Affiliation(s)
- Chin-Hee Song
- Department of Internal Medicine, Seoul National University Bundang HospitalSeongnam, Gyeonggi-do, South Korea
| | - Nayoung Kim
- Department of Internal Medicine, Seoul National University Bundang HospitalSeongnam, Gyeonggi-do, South Korea
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of MedicineSeoul, South Korea
| | - Ryoung Hee Nam
- Department of Internal Medicine, Seoul National University Bundang HospitalSeongnam, Gyeonggi-do, South Korea
| | - Soo In Choi
- Department of Internal Medicine, Seoul National University Bundang HospitalSeongnam, Gyeonggi-do, South Korea
| | - Jeong Eun Yu
- Department of Internal Medicine, Seoul National University Bundang HospitalSeongnam, Gyeonggi-do, South Korea
| | - Heewon Nho
- Department of Internal Medicine, Seoul National University Bundang HospitalSeongnam, Gyeonggi-do, South Korea
| | - Eun Shin
- Department of Pathology, Hallym University Dongtan Sacred Heart HospitalHwaseong, Gyeonggi-do, South Korea
| | - Ha-Na Lee
- Laboratory of Immunology, Division of Biotechnology Review and Research-III, Office of Biotechnology Products, Center for Drug Evaluation and Research, Food and Drug AdministrationSilver Spring, MD 20993, USA
| | - Young-Joon Surh
- Tumor Microenvironment Global Core Research Center, Seoul National University College of PharmacySeoul, South Korea
- Cancer Research Institute, Seoul National UniversitySeoul, South Korea
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11
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Song CH, Kim N, Nam RH, Choi SI, Kang C, Jang JY, Nho H, Shin E, Lee HN. Nuclear Factor Erythroid 2-related Factor 2 Knockout Suppresses the Development of Aggressive Colorectal Cancer Formation Induced by Azoxymethane/Dextran Sulfate Sodium-Treatment in Female Mice. J Cancer Prev 2021; 26:41-53. [PMID: 33842405 PMCID: PMC8020176 DOI: 10.15430/jcp.2021.26.1.41] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
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.
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Affiliation(s)
- Chin-Hee Song
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Nayoung Kim
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea.,Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Ryoung Hee Nam
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Soo In Choi
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Changhee Kang
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Jae Young Jang
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Heewon Nho
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Eun Shin
- Department of Pathology, Hallym University Dongtan Sacred Heart Hospital, Hwaseong, Korea
| | - Ha-Na Lee
- Laboratory of Immunology, Division of Biotechnology Review and Research-III, Office of Biotechnology Products, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA
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12
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17β-Estradiol strongly inhibits azoxymethane/dextran sulfate sodium-induced colorectal cancer development in Nrf2 knockout male mice. Biochem Pharmacol 2020; 182:114279. [PMID: 33068552 DOI: 10.1016/j.bcp.2020.114279] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2020] [Revised: 09/18/2020] [Accepted: 10/07/2020] [Indexed: 12/11/2022]
Abstract
Nuclear factor erythroid 2-related factor 2 (Nrf2) has dual effects on inflammation and cancer progression depending on the microenvironment. Estrogens have a protective effect on colorectal cancer (CRC) development. The aim of this study was to investigate CRC development in Nrf2 knockout (KO) mice. Azoxymethane (AOM) and dextran sulfate sodium (DSS)-treated wild-type (WT) and Nrf2 KO male mice were sacrificed at weeks 2 and 16 after AOM injection with/without 17β-estradiol (E2) treatment during week 1. Disease activity index and colon tissue damage at week 2 showed strong attenuation following E2 administration in WT mice but to a lesser extent in Nrf2 KO male mice. At week 16, E2 significantly diminished AOM/DSS-induced adenoma/cancer incidence at distal colon in the Nrf2 KO group, but not in the WT. Furthermore, mRNA or protein levels of NF-κB-related mediators (i.e., iNOS, TNF-α, and IL-1β) and Nrf2-related antioxidants (i.e., NQO1 and HO-1) were significantly lower in the Nrf2 KO group regardless of E2 treatment compared to the WT. The expression of estrogen receptor beta (ERβ) was higher in the Nrf2 KO group than in the WT. In conclusion, estrogen further inhibits CRC by upregulating ERβ-related alternate pathways in the absence of Nrf2.
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13
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Arya VS, Kanthlal SK, Linda G. The role of dietary polyphenols in inflammatory bowel disease: A possible clue on the molecular mechanisms involved in the prevention of immune and inflammatory reactions. J Food Biochem 2020; 44:e13369. [PMID: 32885438 DOI: 10.1111/jfbc.13369] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2020] [Revised: 05/08/2020] [Accepted: 06/16/2020] [Indexed: 12/17/2022]
Abstract
Inflammatory bowel disease (IBD) is one of the major complications of the gastrointestinal tract, characterized by chronic inflammation, which disturbs the quality of life of the affected individuals. Genetic predisposition, immune, inflammatory, and enzyme-mediated signaling cascades are the primary mechanisms involved in the pathogenesis of the disease. Currently, the treatment strategy involves the maintenance of remission and induction of inflammation by anti-inflammatory agents and immune suppressants. Polyphenol-containing diets, including fruits and vegetables of regular use, possess anti-inflammatory, and antioxidant potential through the inhibition of major contributing pathways to IBD. This review discusses the role of these dietary polyphenols in downregulating the major signaling cascades in IBD. Our review encourages the development of nutritional strategies to improve the efficiency of current therapies for IBD and reduce the risks of side effects associated with conventional therapy. PRACTICAL APPLICATIONS: At present, almost every third person in society is under stress and having chronic disorders like diabetes, arthritis, allergy, cardiovascular disease, IBD, etc. This insists on the direct/indirect role of changes in the lifestyle for such deterioration in society. This review would emphasize the medicinal value of polyphenols present in fruits and vegetables for chronic inflammatory disorders. This concept portrays the food components which have the potential to promote health, improve general well-being, and reduce the risk of IBD. We propose to add fruits with bioactive polyphenols in the regular diet to help in preventing the immune-mediated intestinal chronic inflammatory syndrome and reduce the risks of colorectal cancer development.
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Affiliation(s)
- V S Arya
- Department of Pharmacology, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Science Campus, Kochi, Kerala, India
| | - S K Kanthlal
- Department of Pharmacology, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Science Campus, Kochi, Kerala, India
| | - Geevarghese Linda
- Department of Pharmacology, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Science Campus, Kochi, Kerala, India
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14
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Song CH, Kim N, Nam RH, Choi SI, Lee HN, Surh YJ. 17β-Estradiol supplementation changes gut microbiota diversity in intact and colorectal cancer-induced ICR male mice. Sci Rep 2020; 10:12283. [PMID: 32704056 PMCID: PMC7378548 DOI: 10.1038/s41598-020-69112-w] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2019] [Accepted: 06/17/2020] [Indexed: 02/07/2023] Open
Abstract
The composition of the gut microbiota is influenced by sex hormones and colorectal cancer (CRC). Previously, we reported that 17β-estradiol (E2) inhibits azoxymethane/dextran sulfate sodium (AOM/DSS)-induced tumorigenesis in male mice. Here, we investigated whether the composition of the gut microbiota is different between male and female, and is regulated by estrogen as a secondary outcome of previous studies. We established four groups of mice based on the sex and estrogen status [ovariectomized (OVX) female and E2-treated male]. Additionally, three groups of males were established by treating them with AOM/DSS, and E2, after subjecting them to AOM/DSS treatment. The mice were sacrificed at 21 weeks old. The composition of the gut microbiota was analyzed using 16S rRNA metagenomics sequencing. We observed a significant increase in the microbial diversity (Chao1 index) in females, males supplemented with E2, and males treated with AOM/DSS/E2 compared with normal males. In normal physiological condition, sex difference and E2 treatment did not affect the ratio of Firmicutes/Bacteroidetes (F/B). However, in AOM/DSS-treated male mice, E2 supplementation showed significantly lower level of the F/B ratio. The ratio of commensal bacteria to opportunistic pathogens was higher in females and E2-treated males compared to normal males and females subjected to OVX. Unexpectedly, this ratio was higher in the AOM/DSS group than that determined in other males and the AOM/DSS/E2 group. Our findings suggest that estrogen alters the gut microbiota in ICR (CrljOri:CD1) mice, particularly AOM/DSS-treated males, by decreasing the F/B ratio and changing Shannon and Simpson index by supply of estrogen. This highlights another possibility that estrogen could cause changes in the gut microbiota, thereby reducing the risk of developing CRC.
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Affiliation(s)
- Chin-Hee Song
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Gyeonggi-do, South Korea
| | - Nayoung Kim
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Gyeonggi-do, South Korea. .,Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, South Korea.
| | - Ryoung Hee Nam
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Gyeonggi-do, South Korea
| | - Soo In Choi
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Gyeonggi-do, South Korea
| | - Ha-Na Lee
- Laboratory of Immunology, Division of Biotechnology Review and Research-III, Office of Biotechnology Products, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD, 20993, USA
| | - Young-Joon Surh
- Tumor Microenvironment Global Core Research Center, Seoul National University College of Pharmacy, Seoul, South Korea
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15
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Kamalian A, Sohrabi Asl M, Dolatshahi M, Afshari K, Shamshiri S, Momeni Roudsari N, Momtaz S, Rahimi R, Abdollahi M, Abdolghaffari AH. Interventions of natural and synthetic agents in inflammatory bowel disease, modulation of nitric oxide pathways. World J Gastroenterol 2020; 26:3365-3400. [PMID: 32655263 PMCID: PMC7327787 DOI: 10.3748/wjg.v26.i24.3365] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2020] [Revised: 05/09/2020] [Accepted: 06/04/2020] [Indexed: 02/06/2023] Open
Abstract
Inflammatory bowel disease (IBD) refers to a group of disorders characterized by chronic inflammation of the gastrointestinal (GI) tract. The elevated levels of nitric oxide (NO) in serum and affected tissues; mainly synthesized by the inducible nitric oxide synthase (iNOS) enzyme; can exacerbate GI inflammation and is one of the major biomarkers of GI inflammation. Various natural and synthetic agents are able to ameliorate GI inflammation and decrease iNOS expression to the extent comparable with some IBD drugs. Thereby, the purpose of this study was to gather a list of natural or synthetic mediators capable of modulating IBD through the NO pathway. Electronic databases including Google Scholar and PubMed were searched from 1980 to May 2018. We found that polyphenols and particularly flavonoids are able to markedly attenuate NO production and iNOS expression through the nuclear factor κB (NF-κB) and JAK/STAT signaling pathways. Prebiotics and probiotics can also alter the GI microbiota and reduce NO expression in IBD models through a broad array of mechanisms. A number of synthetic molecules have been found to suppress NO expression either dependent on the NF-κB signaling pathway (i.e., dexamethasone, pioglitazone, tropisetron) or independent from this pathway (i.e., nicotine, prednisolone, celecoxib, β-adrenoceptor antagonists). Co-administration of natural and synthetic agents can affect the tissue level of NO and may improve IBD symptoms mainly by modulating the Toll like receptor-4 and NF-κB signaling pathways.
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Affiliation(s)
- Aida Kamalian
- Department of Medicine, Tehran University of Medical Sciences, Tehran 1417614411, Iran
| | - Masoud Sohrabi Asl
- Department of Medicine, Tehran University of Medical Sciences, Tehran 1417614411, Iran
| | - Mahsa Dolatshahi
- Department of Medicine, Tehran University of Medical Sciences, Tehran 1417614411, Iran
- Students' Scientific Research Center, Tehran University of Medical Sciences, Tehran 1417614411, Iran
| | - Khashayar Afshari
- Department of Medicine, Tehran University of Medical Sciences, Tehran 1417614411, Iran
| | - Shiva Shamshiri
- Department of Traditional Pharmacy, School of Persian Medicine, Tehran University of Medical Sciences, Tehran 1417614411, Iran
| | - Nazanin Momeni Roudsari
- Department of Toxicology and Pharmacology, Faculty of Pharmacy, Tehran Medical Sciences, Islamic Azad University, Tehran 1941933111, Iran
| | - Saeideh Momtaz
- Medicinal Plants Research Center, Institute of Medicinal Plants, ACECR, Tehran 1417614411, Iran
- Toxicology and Diseases Group (TDG), Pharmaceutical Sciences Research Center (PSRC), The Institute of Pharmaceutical Sciences (TIPS), and Department of Toxicology and Pharmacology, School of Pharmacy, Tehran University of Medical Sciences, Tehran 1417614411, Iran
- Gastrointestinal Pharmacology Interest Group, Universal Scientific Education and Research Network, Tehran 1417614411, Iran
| | - Roja Rahimi
- Department of Traditional Pharmacy, School of Persian Medicine, Tehran University of Medical Sciences, Tehran 1417614411, Iran
| | - Mohammad Abdollahi
- Toxicology and Diseases Group (TDG), Pharmaceutical Sciences Research Center (PSRC), The Institute of Pharmaceutical Sciences (TIPS), and Department of Toxicology and Pharmacology, School of Pharmacy, Tehran University of Medical Sciences, Tehran 1417614411, Iran
| | - Amir Hossein Abdolghaffari
- Department of Toxicology and Pharmacology, Faculty of Pharmacy, Tehran Medical Sciences, Islamic Azad University, Tehran 1941933111, Iran
- Medicinal Plants Research Center, Institute of Medicinal Plants, ACECR, Tehran 1417614411, Iran
- Toxicology and Diseases Group (TDG), Pharmaceutical Sciences Research Center (PSRC), The Institute of Pharmaceutical Sciences (TIPS), and Department of Toxicology and Pharmacology, School of Pharmacy, Tehran University of Medical Sciences, Tehran 1417614411, Iran
- Gastrointestinal Pharmacology Interest Group, Universal Scientific Education and Research Network, Tehran 1417614411, Iran
- Department of Toxicology and Pharmacology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran 1417614411, Iran
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Song CH, Kim N, Lee SM, Nam RH, Choi SI, Kang SR, Shin E, Lee DH, Lee HN, Surh YJ. Effects of 17β-estradiol on colorectal cancer development after azoxymethane/dextran sulfate sodium treatment of ovariectomized mice. Biochem Pharmacol 2019; 164:139-151. [PMID: 30981879 DOI: 10.1016/j.bcp.2019.04.011] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2019] [Accepted: 04/10/2019] [Indexed: 02/07/2023]
Abstract
Estrogen is known to have a protective effect in colorectal cancer (CRC) development. Previously, we reported the anti-inflammatory and antitumorigenic effects of 17β-estradiol (E2) in azoxymethane (AOM)/dextran sulfate sodium (DSS)-treated male mice. The aim of this study was to investigate whether ovariectomy in a female AOM/DSS mouse model increases colorectal tumorigenesis and whether tumorigenesis is reduced by estrogen supplementation after ovariectomy. Clinical symptoms and histological severity of colitis and the levels of inflammatory mediators were evaluated in the colon of AOM/DSS-treated ovariectomized (OVX) mice. The levels of E2, myeloperoxidase (MPO), and NF-κB-dependent cytokines (interleukin (IL)-1β and IL-6) were measured by ELISA. Furthermore, quantitative real-time (qRT) PCR and Western blot analysis were performed. Ovariectomy did not aggravate AOM/DSS-induced colitis at 2 weeks. At weeks 10 and 16, ovariectomy significantly increased tumor number and incidence rate in only the proximal colon after AOM/DSS treatment (F_AOM/DSS vs OVX_AOM/DSS), and these increases were significantly reduced by E2 supplementation (OVX_AOM/DSS vs OVX_AOM/DSS/E2). However, ovariectomy did not affect CRC development in the distal colon (F_AOM/DSS vs OVX_AOM/DSS). At week 2, E2 administration to AOM/DSS-treated OVX mice attenuated the histological severity of colitis by decreasing the protein and/or mRNA levels of estrogen receptor alpha (ERα) and NF-κB-related mediators (i.e., COX-2, TNF-α, and IL-6) and by enhancing estrogen receptor beta (ERβ) and nuclear Nrf2 protein expression and the mRNA expression of related antioxidant enzyme genes (i.e., HO-1, GCLC, GCLM, and NQO1). Endogenous estrogen in females protects against the development of proximal colon cancer, and exogenous E2 replacement in OVX female mice showed protective effects against AOM/DSS-induced colitis and carcinogenesis. The mechanism could involve modulating ERs-, NF-κB- and Nrf2-mediated pathways.
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Affiliation(s)
- Chin-Hee Song
- Departments of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Gyeonggi-do, South Korea
| | - Nayoung Kim
- Departments of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Gyeonggi-do, South Korea; Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, South Korea.
| | - Sun Min Lee
- Departments of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Gyeonggi-do, South Korea
| | - Ryoung Hee Nam
- Departments of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Gyeonggi-do, South Korea
| | - Soo In Choi
- Departments of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Gyeonggi-do, South Korea
| | - So Ra Kang
- Departments of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Gyeonggi-do, South Korea
| | - Eun Shin
- Departments of Pathology, Seoul National University Bundang Hospital, Seongnam, Gyeonggi-do, South Korea
| | - Dong Ho Lee
- Departments of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Gyeonggi-do, South Korea; Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, South Korea
| | - Ha-Na Lee
- Tumor Microenvironment Global Core Research Center, Seoul National University College of Pharmacy, Seoul, South Korea
| | - Young-Joon Surh
- Tumor Microenvironment Global Core Research Center, Seoul National University College of Pharmacy, Seoul, South Korea
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17
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Song CH, Kim N, Sohn SH, Lee SM, Nam RH, Na HY, Lee DH, Surh YJ. Effects of 17β-Estradiol on Colonic Permeability and Inflammation in an Azoxymethane/Dextran Sulfate Sodium-Induced Colitis Mouse Model. Gut Liver 2019; 12:682-693. [PMID: 30400733 PMCID: PMC6254630 DOI: 10.5009/gnl18221] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2018] [Revised: 08/28/2018] [Accepted: 09/12/2018] [Indexed: 12/20/2022] Open
Abstract
Background/Aims 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. Methods 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. Results 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. Conclusions 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.
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Affiliation(s)
- Chin-Hee Song
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Nayoung Kim
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea.,Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Korea
| | - Sung Hwa Sohn
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Sun Min Lee
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Ryoung Hee Nam
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Hee Young Na
- Department of Pathology, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Dong Ho Lee
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea.,Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Korea
| | - Young-Joon Surh
- Tumor Microenvironment Global Core Research Center, Seoul National University College of Pharmacy, Seoul, Korea
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Lee AY, Choi JW, Yokozawa T, Cho EJ. Preventive effect of oligonol on nitric oxide and reactive oxygen species production through regulation of nuclear factor kappa B signaling pathway in RAW 264.7 macrophage cells against sodium nitroprusside. RSC Adv 2019; 9:3987-3993. [PMID: 35518095 PMCID: PMC9060530 DOI: 10.1039/c8ra08867e] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2018] [Accepted: 12/14/2018] [Indexed: 11/21/2022] Open
Abstract
Oligonol attenuated SNP-induced oxidative stress and inflammatory responsesviaregulation of the NF-κB signalling pathway in RAW 264.7 macrophage cells.
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Affiliation(s)
- Ah Young Lee
- Department of Food Science and Nutrition
- Kimchi Research Institute
- Pusan National University
- Busan 46241
- Republic of Korea
| | - Ji Won Choi
- Technology Support Center
- Korea Food Research Institute
- Republic of Korea
| | - Takako Yokozawa
- Graduate School of Science and Engineering for Research
- University of Toyama
- Toyama 930-8555
- Japan
| | - Eun Ju Cho
- Department of Food Science and Nutrition
- Kimchi Research Institute
- Pusan National University
- Busan 46241
- Republic of Korea
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19
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Ji Y, Dai Z, Sun S, Ma X, Yang Y, Tso P, Wu G, Wu Z. Hydroxyproline Attenuates Dextran Sulfate Sodium‐Induced Colitis in Mice: Involvment of the NF‐κB Signaling and Oxidative Stress. Mol Nutr Food Res 2018; 62:e1800494. [DOI: 10.1002/mnfr.201800494] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2018] [Revised: 08/02/2018] [Indexed: 12/21/2022]
Affiliation(s)
- Yun Ji
- State Key Laboratory of Animal Nutrition Department of Animal Nutrition and Feed Science China Agricultural University Beijing China 100193
| | - Zhaolai Dai
- State Key Laboratory of Animal Nutrition Department of Animal Nutrition and Feed Science China Agricultural University Beijing China 100193
| | - Shiqiang Sun
- State Key Laboratory of Animal Nutrition Department of Animal Nutrition and Feed Science China Agricultural University Beijing China 100193
| | - Xiaoshi Ma
- State Key Laboratory of Animal Nutrition Department of Animal Nutrition and Feed Science China Agricultural University Beijing China 100193
| | - Ying Yang
- State Key Laboratory of Animal Nutrition Department of Animal Nutrition and Feed Science China Agricultural University Beijing China 100193
| | - Patrick Tso
- Department of Pathology and Laboratory Medicine Metabolic Diseases Institute University of Cincinnati Cincinnati Ohio USA
| | - Guoyao Wu
- State Key Laboratory of Animal Nutrition Department of Animal Nutrition and Feed Science China Agricultural University Beijing China 100193
- Department of Animal Science Texas A&M University College Station TX 77843 USA
| | - Zhenlong Wu
- State Key Laboratory of Animal Nutrition Department of Animal Nutrition and Feed Science China Agricultural University Beijing China 100193
- State Key Laboratory of Animal Nutrition China Agricultural University Beijing 100193 P. R. China
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20
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Han KH, Park JM, Jeong M, Han YM, Go EJ, Park J, Kim H, Han JG, Kwon O, Hahm KB. Heme Oxygenase-1 Induction and Anti-inflammatory Actions of Atractylodes macrocephala and Taraxacum herba Extracts Prevented Colitis and Was More Effective than Sulfasalazine in Preventing Relapse. Gut Liver 2018. [PMID: 28651306 PMCID: PMC5593328 DOI: 10.5009/gnl16496] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Background/Aims In inflammatory bowel disease (IBD), repeated bouts of remission and relapse occur in patients and can impose a risk of colitis-associated cancer. We hypothesized that plant extracts of Atractylodes macrocephala (AM) or Taraxacum herba (TH) may be better than sulfasalazine for treating this disease because these extracts can promote additional regeneration. Methods Murine intestinal epithelial IEC-6 cells were pretreated with AM or TH before a lipopolysaccharide (LPS)-induced challenge. Acute colitis was induced with 7 days of dextran sulfate sodium (DSS) in male C57BL/6 mice, and extracts of AM and TH were administered for 2 weeks before DSS administration. Results In vitro studies demonstrated that AM or TH treatment reduced LPS-induced COX-2 and tumor necrosis factor-α mRNA levels but increased heme oxygenase-1 (HO-1). Oral preadministration of AM and TH rescued mice from DSS-induced colitis by inhibiting inflammatory mediators via inactivated extracellular signal regulated kinase and repressed nuclear factor κB and signal transducer and activator of transcription 3, but the effect was weaker for sulfasalazine than that for the extracts. Anti-inflammatory activities occurred via the inhibition of macrophage and T lymphocyte infiltrations. Unlike sulfasalazine, which did not induce HO-1, TH extracts afforded significant HO-1 induction. Conclusions Because the AM or TH extracts were far superior in preventing DSS-induced colitis than sulfasalazine, AM or TH extracts can be considered natural agents that can prevent IBD relapse.
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Affiliation(s)
- Kyu-Hyun Han
- Digestive Disease Center, CHA University Bundang Medical Center, Seongnam, Korea
| | - Jong-Min Park
- CHA Cancer Prevention Research Center, CHA Cancer Institute, CHA University, Seongnam, Korea
| | - Migyeong Jeong
- CHA Cancer Prevention Research Center, CHA Cancer Institute, CHA University, Seongnam, Korea
| | - Young-Min Han
- CHA Cancer Prevention Research Center, CHA Cancer Institute, CHA University, Seongnam, Korea
| | - Eun-Jin Go
- CHA Cancer Prevention Research Center, CHA Cancer Institute, CHA University, Seongnam, Korea
| | - Juyeon Park
- Korea Institute of Science and Technology for Eastern Medicine (KISTEM), NeuMed Inc., Seoul, Korea
| | - Hocheol Kim
- Department of Herbal Pharmacology, College of Korean Medicine, Kyung Hee University, Seoul, Korea
| | - Jae Gab Han
- Department of Health Food Research & Development, Daesang Corp., Icheon, Korea
| | - Oran Kwon
- Department of Nutritional Science and Food Management, Ewha Womans University, Seoul, Korea
| | - Ki Baik Hahm
- Digestive Disease Center, CHA University Bundang Medical Center, Seongnam, Korea.,CHA Cancer Prevention Research Center, CHA Cancer Institute, CHA University, Seongnam, Korea
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21
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Dandelion root extract protects NCM460 colonic cells and relieves experimental mouse colitis. J Nat Med 2018; 72:857-866. [PMID: 29740735 DOI: 10.1007/s11418-018-1217-7] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2018] [Accepted: 04/12/2018] [Indexed: 12/21/2022]
Abstract
The protective potential of dandelion on acute hepatitis, lung injury and colorectal cancer has recently been revealed. Importantly, ulcerative colitis (UC), a clinically defined inflammatory bowel disease, accelerates the risk of colorectal cancer. However, studies focusing on the activity of dandelion on UC are extremely limited. In the present study, we found that an aqueous extract of dandelion root increases cell viability and decreases apoptosis in dextran sodium sulfate (DSS)-incubated NCM460 human colonic epithelial cells, probably through removing the production of reaction oxygen species and blocking nuclear factor-kappaB signaling. We then examined the anti-colitis efficacy of this extract in an in vivo study. We detected that dandelion root extract efficiently ameliorates progressive acute injury as demonstrated by a reduction in body weight loss, severity scores of disease index and shortened colon length during DSS treatment, as well as reducing the inflammatory conditions and oxidative stress in the colon of DSS-induced mice. Our study clearly demonstrates that dandelion has a strong cytoprotective effect on NCM460 colonocytes and shows powerful defense on an established experimental mouse model of DSS-induced UC. Therefore, dandelion root extract can be an effective anti-colitis complex mixture and can provide a complementary alternative to currently available therapeutic intervention in UC.
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22
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Choi YJ, Choi YJ, Kim N, Nam RH, Lee S, Lee HS, Lee HN, Surh YJ, Lee DH. Açaí Berries Inhibit Colon Tumorigenesis in Azoxymethane/Dextran Sulfate Sodium-Treated Mice. Gut Liver 2017; 11:243-252. [PMID: 27965474 PMCID: PMC5347649 DOI: 10.5009/gnl16068] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2016] [Revised: 05/25/2016] [Accepted: 06/28/2016] [Indexed: 01/05/2023] Open
Abstract
Background/Aims The aim of this study was to investigate the protective effect of açaí against azoxymethane (AOM)/dextran sulfate sodium (DSS)-induced colorectal cancer development. Methods 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. Results 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. Conclusions 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.
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Affiliation(s)
- Yoon Jin Choi
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Yoon Jeong Choi
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Nayoung Kim
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea.,Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Ryoung Hee Nam
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Seonmin Lee
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Hye Seung Lee
- Department of Pathology, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Ha-Na Lee
- Tumor Microenvironment Global Core Research Center, Seoul National University College of Pharmacy, Seoul, Korea
| | - Young-Joon Surh
- Tumor Microenvironment Global Core Research Center, Seoul National University College of Pharmacy, Seoul, Korea
| | - Dong Ho Lee
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea.,Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
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Liu HW, Chen YJ, Chang YC, Chang SJ. Oligonol, a Low-Molecular Weight Polyphenol Derived from Lychee, Alleviates Muscle Loss in Diabetes by Suppressing Atrogin-1 and MuRF1. Nutrients 2017; 9:nu9091040. [PMID: 28930190 PMCID: PMC5622800 DOI: 10.3390/nu9091040] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2017] [Revised: 09/08/2017] [Accepted: 09/18/2017] [Indexed: 12/19/2022] Open
Abstract
Stimulation of the ubiquitin-proteasome pathway-especially E3 ubiquitin ligases Atrogin-1 and MuRF1-is associated with muscle loss in diabetes. Elevated lipid metabolites impair myogenesis. Oligonol, a low molecular weight polyphenol derived from lychee, exhibited anti-diabetic and anti-obesity properties, suggesting it could be a proper supplement for attenuating muscle loss. Dietary (10 weeks) oligonol supplementation (20 or 200 mg/kg diet) on the skeletal muscle loss was investigated in diabetic db/db mice. Transcription factors NF-κB and FoxO3a involved in regulation of Atrogin-1 and MuRF1 were also investigated. Attenuation of muscle loss by oligonol (both doses) was associated with down-regulation of Atrogin-1 and MuRF1 gene expression. Oligonol supplementation decreased NF-κB expression in the nuclear fraction compared with db/db mice without oligonol supplement. Upregulation of sirtuin1 (SIRT1) expression prevented FoxO3a nuclear localization in db/db mice supplemented with oligonol. Marked increases in AMPKα activity and Ppara mRNA expression leading to lower lipid accumulation by oligonol provided additional benefits for attenuating muscle loss. Oligonol limited palmitate-induced senescent phenotype and cell cycle arrest and suppressed Atrogin-1 and MuRF1 mRNA expression in palmitate-treated C2C12 muscle cells, thus contributing to improving the impaired myotube formation. In conclusion, oligonol-mediated downregulation of Atrogin-1 and MuRF1 gene expression alleviates muscle loss and improves the impaired myotube formation, indicating that oligonol supplementation may be useful for the attenuation of myotube loss.
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Affiliation(s)
- Hung-Wen Liu
- Department of Life Sciences, National Cheng Kung University, No. 1, University Road, Tainan 701, Taiwan.
- Department of Physical Education, National Taiwan Normal University, Taipei 106, Taiwan.
| | - Yen-Ju Chen
- Department of Life Sciences, National Cheng Kung University, No. 1, University Road, Tainan 701, Taiwan.
| | - Yun-Ching Chang
- Department of Life Sciences, National Cheng Kung University, No. 1, University Road, Tainan 701, Taiwan.
| | - Sue-Joan Chang
- Department of Life Sciences, National Cheng Kung University, No. 1, University Road, Tainan 701, Taiwan.
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Emanuele S, Lauricella M, Calvaruso G, D'Anneo A, Giuliano M. Litchi chinensis as a Functional Food and a Source of Antitumor Compounds: An Overview and a Description of Biochemical Pathways. Nutrients 2017; 9:nu9090992. [PMID: 28885570 PMCID: PMC5622752 DOI: 10.3390/nu9090992] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2017] [Revised: 09/01/2017] [Accepted: 09/04/2017] [Indexed: 12/11/2022] Open
Abstract
Litchi is a tasty fruit that is commercially grown for food consumption and nutritional benefits in various parts of the world. Due to its biological activities, the fruit is becoming increasingly known and deserves attention not only for its edible part, the pulp, but also for its peel and seed that contain beneficial substances with antioxidant, cancer preventive, antimicrobial, and anti-inflammatory functions. Although literature demonstrates the biological activity of Litchi components in reducing tumor cell viability in in vitro or in vivo models, data about the biochemical mechanisms responsible for these effects are quite fragmentary. This review specifically describes, in a comprehensive analysis, the antitumor properties of the different parts of Litchi and highlights the main biochemical mechanisms involved.
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Affiliation(s)
- Sonia Emanuele
- Department of Experimental Biomedicine and Clinical Neurosciences, Laboratory of Biochemistry, University of Palermo, 90127 Palermo, Italy.
| | - Marianna Lauricella
- Department of Experimental Biomedicine and Clinical Neurosciences, Laboratory of Biochemistry, University of Palermo, 90127 Palermo, Italy.
| | - Giuseppe Calvaruso
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, Laboratory of Biochemistry, University of Palermo, 90127 Palermo, Italy.
| | - Antonella D'Anneo
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, Laboratory of Biochemistry, University of Palermo, 90127 Palermo, Italy.
| | - Michela Giuliano
- Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, Laboratory of Biochemistry, University of Palermo, 90127 Palermo, Italy.
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25
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Sturm C, Wagner AE. Brassica-Derived Plant Bioactives as Modulators of Chemopreventive and Inflammatory Signaling Pathways. Int J Mol Sci 2017; 18:E1890. [PMID: 28862664 PMCID: PMC5618539 DOI: 10.3390/ijms18091890] [Citation(s) in RCA: 63] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2017] [Revised: 08/22/2017] [Accepted: 08/29/2017] [Indexed: 12/20/2022] Open
Abstract
A high consumption of vegetables belonging to the Brassicaceae family has been related to a lower incidence of chronic diseases including different kinds of cancer. These beneficial effects of, e.g., broccoli, cabbage or rocket (arugula) intake have been mainly dedicated to the sulfur-containing glucosinolates (GLSs)-secondary plant compounds nearly exclusively present in Brassicaceae-and in particular to their bioactive breakdown products including isothiocyanates (ITCs). Overall, the current literature indicate that selected Brassica-derived ITCs exhibit health-promoting effects in vitro, as well as in laboratory mice in vivo. Some studies suggest anti-carcinogenic and anti-inflammatory properties for ITCs which may be communicated through an activation of the redox-sensitive transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) that controls the expression of antioxidant and phase II enzymes. Furthermore, it has been shown that ITCs are able to significantly ameliorate a severe inflammatory phenotype in colitic mice in vivo. As there are studies available suggesting an epigenetic mode of action for Brassica-derived phytochemicals, the conduction of further studies would be recommendable to investigate if the beneficial effects of these compounds also persist during an irregular consumption pattern.
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Affiliation(s)
- Christine Sturm
- Institute of Nutritional Medicine, University of Lübeck, Ratzeburger Allee 160, 23538 Lübeck, Germany.
| | - Anika E Wagner
- Institute of Nutritional Medicine, University of Lübeck, Ratzeburger Allee 160, 23538 Lübeck, Germany.
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26
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Salaritabar A, Darvishi B, Hadjiakhoondi F, Manayi A, Sureda A, Nabavi SF, Fitzpatrick LR, Nabavi SM, Bishayee A. Therapeutic potential of flavonoids in inflammatory bowel disease: A comprehensive review. World J Gastroenterol 2017; 23:5097-5114. [PMID: 28811706 PMCID: PMC5537178 DOI: 10.3748/wjg.v23.i28.5097] [Citation(s) in RCA: 129] [Impact Index Per Article: 16.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2017] [Revised: 05/12/2017] [Accepted: 07/04/2017] [Indexed: 02/06/2023] Open
Abstract
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.
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27
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Kanda Y, Osaki M, Okada F. Chemopreventive Strategies for Inflammation-Related Carcinogenesis: Current Status and Future Direction. Int J Mol Sci 2017; 18:E867. [PMID: 28422073 PMCID: PMC5412448 DOI: 10.3390/ijms18040867] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2017] [Revised: 04/14/2017] [Accepted: 04/17/2017] [Indexed: 02/07/2023] Open
Abstract
A sustained and chronically-inflamed environment is characterized by the presence of heterogeneous inflammatory cellular components, including neutrophils, macrophages, lymphocytes and fibroblasts. These infiltrated cells produce growth stimulating mediators (inflammatory cytokines and growth factors), chemotactic factors (chemokines) and genotoxic substances (reactive oxygen species and nitrogen oxide) and induce DNA damage and methylation. Therefore, chronic inflammation serves as an intrinsic niche for carcinogenesis and tumor progression. In this article, we summarize the up-to-date findings regarding definitive/possible causes and mechanisms of inflammation-related carcinogenesis derived from experimental and clinical studies. We also propose 10 strategies, as well as candidate agents for the prevention of inflammation-related carcinogenesis.
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Affiliation(s)
- Yusuke Kanda
- Division of Pathological Biochemistry, Tottori University Faculty of Medicine, Yonago, Tottori 683-8503, Japan.
| | - Mitsuhiko Osaki
- Division of Pathological Biochemistry, Tottori University Faculty of Medicine, Yonago, Tottori 683-8503, Japan.
- Chromosome Engineering Research Center, Tottori University, Yonago, Tottori 683-8503, Japan.
| | - Futoshi Okada
- Division of Pathological Biochemistry, Tottori University Faculty of Medicine, Yonago, Tottori 683-8503, Japan.
- Chromosome Engineering Research Center, Tottori University, Yonago, Tottori 683-8503, Japan.
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Fan FY, Sang LX, Jiang M. Catechins and Their Therapeutic Benefits to Inflammatory Bowel Disease. Molecules 2017; 22:E484. [PMID: 28335502 PMCID: PMC6155401 DOI: 10.3390/molecules22030484] [Citation(s) in RCA: 194] [Impact Index Per Article: 24.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2017] [Revised: 02/19/2017] [Accepted: 02/28/2017] [Indexed: 02/07/2023] Open
Abstract
Catechins are natural polyphenolic phytochemicals that exist in food and medicinal plants, such as tea, legume and rubiaceae. An increasing number of studies have associated the intake of catechins-rich foods with the prevention and treatment of chronic diseases in humans, such as inflammatory bowel disease (IBD). Some studies have demonstrated that catechins could significantly inhibit the excessive oxidative stress through direct or indirect antioxidant effects and promote the activation of the antioxidative substances such as glutathione peroxidases (GPO) and glutathione (GSH), reducing the oxidative damages to the colon. In addition, catechins can also regulate the infiltration and proliferation of immune related-cells, such as neutrophils, colonic epithelial cells, macrophages, and T lymphocytes, helping reduce the inflammatory relations and provide benefits to IBD. Perhaps catechins can further inhibit the deterioration of intestinal lesions through regulating the cell gap junctions. Furthermore, catechins can exert their significant anti-inflammatory properties by regulating the activation or deactivation of inflammation-related oxidative stress-related cell signaling pathways, such as nuclear factor-kappa B (NF-κB), mitogen activated protein kinases (MAPKs), transcription factor nuclear factor (erythroid-derived 2)-like 2 (Nrf2), signal transducer and the activator of transcription 1/3 (STAT1/3) pathways. Finally, catechins can also stabilize the structure of the gastrointestinal micro-ecological environment via promoting the proliferation of beneficial intestinal bacteria and regulating the balance of intestinal flora, so as to relieve the IBD. Furthermore, catechins may regulate the tight junctions (TJ) in the epithelium. This paper elaborates the currently known possible molecular mechanisms of catechins in favor of IBD.
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Affiliation(s)
- Fei-Yan Fan
- Department of Gastroenterology, First Affiliated Hospital of China Medical University, 155 Nanjing North Street, Heping District, Shenyang 110001, China.
| | - Li-Xuan Sang
- Department of Geriatrics, First Affiliated Hospital of China Medical University, 155 Nanjing North Street, Heping District, Shenyang 110001, China.
| | - Min Jiang
- Department of Gastroenterology, First Affiliated Hospital of China Medical University, 155 Nanjing North Street, Heping District, Shenyang 110001, China.
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Lee SM, Kim N, Son HJ, Park JH, Nam RH, Ham MH, Choi D, Sohn SH, Shin E, Hwang YJ, Sung J, Lee DH, Lee HN. The Effect of Sex on the Azoxymethane/Dextran Sulfate Sodium-treated Mice Model of Colon Cancer. J Cancer Prev 2016; 21:271-278. [PMID: 28053962 PMCID: PMC5207612 DOI: 10.15430/jcp.2016.21.4.271] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2016] [Accepted: 11/26/2016] [Indexed: 12/27/2022] Open
Abstract
Background 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. Methods 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. Results 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). Conclusions 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.
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Affiliation(s)
- Sun Min Lee
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Nayoung Kim
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea; Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Hee Jin Son
- Seoul National University College of Medicine, Seoul, Korea
| | - Ji Hyun Park
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Ryoung Hee Nam
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Min Hee Ham
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Daeun Choi
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Sung Hwa Sohn
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Eun Shin
- Department of Pathology, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Young-Jae Hwang
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Jihee Sung
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Dong Ho Lee
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Ha-Na Lee
- Receptor Cell Biology Section, Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, NIH, Rockville, MD 20852, USA
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30
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Bioactivity of Polyphenols: Preventive and Adjuvant Strategies toward Reducing Inflammatory Bowel Diseases-Promises, Perspectives, and Pitfalls. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2016; 2016:9346470. [PMID: 27478535 PMCID: PMC4958438 DOI: 10.1155/2016/9346470] [Citation(s) in RCA: 99] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/04/2016] [Revised: 04/13/2016] [Accepted: 05/24/2016] [Indexed: 12/13/2022]
Abstract
Inflammatory bowel diseases (IBDs) are characterized by autoimmune and inflammation-related complications of the large intestine (ulcerative colitis) and additional parts of the digestive tract (Crohn's disease). Complications include pain, diarrhoea, chronic inflammation, and cancer. IBD prevalence has increased during the past decades, especially in Westernized countries, being as high as 1%. As prognosis is poor and medication often ineffective or causing side effects, additional preventive/adjuvant strategies are sought. A possible approach is via diets rich in protective constituents. Polyphenols, the most abundant phytochemicals, have been associated with anti-inflammatory, antioxidant, immunomodulatory, and apoptotic properties. Locally reducing oxidative stress, they can further act on cellular targets, altering gene expression related to inflammation, including NF-κB, Nrf-2, Jak/STAT, and MAPKs, suppressing downstream cytokine formation (e.g., IL-8, IL-1β, and TNF-α), and boosting the bodies' own antioxidant status (HO-1, SOD, and GPx). Moreover, they may promote, as prebiotics, healthy microbiota (e.g., Bifidobacteria, Akkermansia), short-chain fatty acid formation, and reduced gut permeability/improved tight junction stability. However, potential adverse effects such as acting as prooxidants, or perturbations of efflux transporters and phase I/II metabolizing enzymes, with increased uptake of undesired xenobiotics, should also be considered. In this review, we summarize current knowledge around preventive and arbitrary actions of polyphenols targeting IBD.
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Liu HW, Wei CC, Chen YJ, Chen YA, Chang SJ. Flavanol-rich lychee fruit extract alleviates diet-induced insulin resistance via suppressing mTOR/SREBP-1 mediated lipogenesis in liver and restoring insulin signaling in skeletal muscle. Mol Nutr Food Res 2016; 60:2288-2296. [DOI: 10.1002/mnfr.201501064] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2015] [Revised: 02/29/2016] [Accepted: 05/04/2016] [Indexed: 12/18/2022]
Affiliation(s)
- Hung-Wen Liu
- Department of Life Sciences; National Cheng Kung University; Tainan Taiwan
| | - Chu-Chun Wei
- Department of Life Sciences; National Cheng Kung University; Tainan Taiwan
| | - Yen-Ju Chen
- Department of Life Sciences; National Cheng Kung University; Tainan Taiwan
| | - Yun-An Chen
- Department of Life Sciences; National Cheng Kung University; Tainan Taiwan
| | - Sue-Joan Chang
- Department of Life Sciences; National Cheng Kung University; Tainan Taiwan
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An inhibitor of the Keap1-Nrf2 protein-protein interaction protects NCM460 colonic cells and alleviates experimental colitis. Sci Rep 2016; 6:26585. [PMID: 27215610 PMCID: PMC4877580 DOI: 10.1038/srep26585] [Citation(s) in RCA: 88] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2015] [Accepted: 05/04/2016] [Indexed: 02/06/2023] Open
Abstract
Ulcerative colitis (UC) is a chronic relapsing-remitting form of inflammatory bowel disease (IBD) that increases the risk of colorectal cancer, the third most common malignancy in humans. Oxidative stress is a risk factor for the development of UC. The Keap1-Nrf2-ARE pathway is one of the most important defensive mechanisms against oxidative and/or electrophilic stresses. In this study, we identified CPUY192018 as a potent small-molecule inhibitor of the Keap1-Nrf2 PPI, investigated the cyto-protective effects of CPUY192018 on the NCM460 colonic cells and evaluated whether treatment with the inhibitor of the Keap1-Nrf2 PPI exerts protection on an established experimental model of UC induced by dextran sodium sulfate (DSS). Our study clearly demonstrated that CPUY192018 had a cytoprotective effect against DSS in both NCM460 cells and mouse colon via the activation of Nrf2 signaling. These results suggested that activation of Nrf2 by directly inhibiting the Keap1-Nrf2 PPI may be beneficial as a treatment for UC.
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Oligonol, a lychee fruit-derived low-molecular form of polyphenol mixture, suppresses inflammatory cytokine production from human monocytes. Hum Immunol 2016; 77:512-5. [PMID: 27079270 DOI: 10.1016/j.humimm.2016.04.011] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2014] [Revised: 02/02/2016] [Accepted: 04/11/2016] [Indexed: 12/21/2022]
Abstract
Monocytes produce high levels of inflammatory cytokines including IL-6 and TNF-α that are involved in autoimmunity, inflammatory diseases, cardiovascular disease and obesity. Therapies targeting IL-6 and TNF-α have been utilized in treating chronic inflammatory diseases. Oligonol is a lychee fruit-derived low-molecular form of polyphenol mixture, typically catechin-type monomers and oligomers of proanthocyanidins, which are produced by an oligomerization process. Although previous studies reported anti-inflammatory properties of Oligonol, it is unknown whether and how Oligonol suppresses IL-6 and TNF-α production in human monocytes. The results of our study demonstrate that Oligonol (25μg/ml) decreases the production of IL-6 and TNF-α from human primary monocytes as measured by flow cytometry and ELISA. Such an anti-cytokine effect was likely mediated by the suppression of NF-κB activation without inducing cell death. Our findings raise the possibility of exploring the benefits of Oligonol in controlling inflammatory conditions, especially those associated with monocytes, in humans.
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Martin DA, Bolling BW. A review of the efficacy of dietary polyphenols in experimental models of inflammatory bowel diseases. Food Funct 2016; 6:1773-86. [PMID: 25986932 DOI: 10.1039/c5fo00202h] [Citation(s) in RCA: 96] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Crohn's disease and ulcerative colitis presently have no cure and are treated with anti-inflammatory drugs or monoclonal antibodies targeting pro-inflammatory cytokines. A variety of rodent models have been used to model chronic and acute colitis. Dietary polyphenols in foods and botanicals are of considerable interest for prevention and treatment of colitis. Many dietary polyphenols have been utilized for prevention of colitis in rodent models. Berries, green tea polyphenols, curcumin, and stilbenes have been the most extensively tested polyphenols in rodent models of colitis. The majority of polyphenols tested have inhibited colitis in rodents, but increasing doses of EGCG and green tea, isoflavones, flaxseed, and α-mangostin have exacerbated colitis. Few studies have examined combination of polyphenols or other bioactives for inhibition of colitis. Translating polyphenol doses used in rodent models of colitis to human equivalent doses reveals that supplemental doses are most likely required to inhibit colitis from a single polyphenol treatment. The ability to translate polyphenol treatments in rodent models is likely to be limited by species differences in xenobiotic metabolism and microbiota. Given these limitations, data from polyphenols in rodent models suggests merit for pursuing additional clinical studies for prevention of colitis.
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Affiliation(s)
- Derek A Martin
- Department of Food Science, University of Wisconsin-Madison, 1605 Linden Dr, Madison, WI 53706, USA.
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Antioxidant therapy for treatment of inflammatory bowel disease: Does it work? Redox Biol 2015; 6:617-639. [PMID: 26520808 PMCID: PMC4637335 DOI: 10.1016/j.redox.2015.10.006] [Citation(s) in RCA: 269] [Impact Index Per Article: 26.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2015] [Revised: 10/18/2015] [Accepted: 10/20/2015] [Indexed: 12/13/2022] Open
Abstract
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. Challenges were identified for the yet poor use of antioxidant therapy in IBD. This review stimulates the investigation of alternative and efficacious antioxidant therapies.
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Ahn JH, Choi JW, Choi JM, Maeda T, Fujii H, Yokozawa T, Cho EJ. Protective role of oligonol from oxidative stress-induced inflammation in C6 glial cell. Nutr Res Pract 2014; 9:123-8. [PMID: 25861417 PMCID: PMC4388942 DOI: 10.4162/nrp.2015.9.2.123] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2014] [Revised: 08/21/2014] [Accepted: 08/27/2014] [Indexed: 01/12/2023] Open
Abstract
BACKGROUND/OBJECTIVES Natural products or active components with a protective effect against oxidative stress have attracted significant attention for prevention and treatment of degenerative disease. Oligonol is a low molecular weight polyphenol containing catechin-type monomers and oligomers derived from Litchi chinensis Sonn. We investigated the protective effect and its related mechanism of oligonol against oxidative stress. MATERIALS/METHODS Oxidative stress in C6 glial cells was induced by hydrogen peroxide (H2O2) and the protective effects of oligonol on cell viability, nitric oxide (NO) and reactive oxygen species (ROS) synthesis, and mRNA expression related to oxidative stress were determined. RESULTS Treatment with oligonol inhibited NO and ROS formation under cellular oxidative stress in C6 glial cells. In addition, it recovered cell viability in a dose dependent-manner. Treatment with oligonol also resulted in down-regulated mRNA expression related to oxidative stress, nuclear factor kappa-B (NF-κB) p65, cyclooxygenase-2 (COX-2), and inducible nitric oxide synthase (iNOS), compared with the control group treated with H2O2. In particular, expression of NF-κB p65, COX-2, and iNOS was effectively reduced to the normal level by treatment with 10 µg/mL and 25 µg/mL of oligonol. CONCLUSIONS These results indicate that oligonol has protective activity against oxidative stress-induced inflammation. Oligonol might be a promising agent for treatment of degenerative diseases through inhibition of ROS formation and NF-κB pathway gene expression.
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Affiliation(s)
- Jae Hyun Ahn
- Department of Food Science and Nutrition, Pusan National University, Busandaehak-ro 63 beon-gil, Geumjeong-gu, Busan 609-735, Korea
| | - Ji Won Choi
- Department of Food Science and Nutrition, Pusan National University, Busandaehak-ro 63 beon-gil, Geumjeong-gu, Busan 609-735, Korea
| | - Ji Myung Choi
- Department of Food Science and Nutrition, Pusan National University, Busandaehak-ro 63 beon-gil, Geumjeong-gu, Busan 609-735, Korea
| | | | - Hajime Fujii
- Amino Up Chemical Co., Ltd, Sapporo 004-0839, Japan
| | - Takako Yokozawa
- Institute of Natural Medicine, University of Toyama, Toyama 930-0194, Japan
| | - Eun Ju Cho
- Department of Food Science and Nutrition, Pusan National University, Busandaehak-ro 63 beon-gil, Geumjeong-gu, Busan 609-735, Korea
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Hartmann RM, Fillmann HS, Martins MIM, Meurer L, Marroni NP. Boswellia serrata has beneficial anti-inflammatory and antioxidant properties in a model of experimental colitis. Phytother Res 2014; 28:1392-8. [PMID: 24619538 DOI: 10.1002/ptr.5142] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2013] [Revised: 02/09/2014] [Accepted: 02/16/2014] [Indexed: 12/14/2022]
Abstract
Ulcerative colitis is an inflammatory disease that involves only the colon and rectum, being characterized by leukocyte infiltrate and superficial ulcers in the intestinal mucosa. To evaluate the anti-inflammatory and antioxidant effects of extract from the Boswellia serrata plant in an experimental rat model of acute ulcerative colitis induced by the administration of acetic acid (AA). An extract of B. serrata (34.2 mg/kg/day) was administered by oral gavage for 2 days before and after the induction of colitis with 4 mL of 4% AA. The anal sphincter pressure in the colitis group showed a significant decrease compared to that of the control groups (p < 0.001). The analysis of the values of lipid peroxidation (LPO) obtained by substances that react with thiobarbituric acid (TBARS) showed a significantly increased LPO in the colitis group compared to the control groups (p < 0.001). The nitric oxide levels and the expression of inducible nitric oxide synthase (iNOS) showed a significant increase in the colitis group compared to control groups (p < 0.01). Both pretreatment and treatment with B. serrata exhibited significantly reduced lipid peroxidation, nitric oxide and iNOS and showed improvements in tissue injury and anal sphincter pressure in animals with ulcerative colitis. The B. serrata extract has protective anti-inflammatory and antioxidant effects that inhibit inflammatory mediators in acute experimental colitis.
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Affiliation(s)
- Renata Minuzzo Hartmann
- Universidade Federal do Rio Grande do Sul-UFRGS, Programa de Pós-Graduação em Medicina: Ciências Médicas, Brasil; Hospital de Clínicas de Porto Alegre-HCPA, Laboratório de Hepatologia e Gastroenterologia Experimental, Brasil
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Ahmad N, Mukhtar H. Antioxidants meet molecular targets for cancer prevention and therapeutics. Antioxid Redox Signal 2013; 19:85-8. [PMID: 23521502 PMCID: PMC3689158 DOI: 10.1089/ars.2013.5299] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Abstract
A fine balance between oxidants and antioxidants is required for the normal functioning of living systems. A deregulation of this balance has been implicated in many adverse effects and diseases, including cancer. Extensive research has been done in the area of cancer prevention and therapeutics by a wide range of antioxidants, especially naturally occurring and diet-based agents. However, additional efforts are still needed toward clinical development of the most promising antioxidant agents. For this purpose, it is important to focus our efforts toward (i) defining/validating new targets; (ii) identifying novel agents followed by assessments of their efficacy, safety/toxicity, metabolism, and bioavailability in appropriate model systems; and (iii) conducting clinical trials in an appropriate population. Although research with specific antioxidants is important, an emerging critical issue that is up for a debate is whether the "whole foods" concept is better for cancer prevention than a single agent. Recent work has suggested that the dietary phytochemicals can enhance the bioavailability of different nutrients and can target multiple molecular pathways to yield a better response. Another critical issue that is often ignored during target-based agent development is a lack of focus on the appropriate population for a specific target. It is possible that a specific target may not be appropriate for certain people. Further, we need to design quick "phase 0" clinical trials to eliminate the agents with little clinical potential. Thus, multidisciplinary efforts of researchers from diverse scientific disciplines are needed in order to take the most promising antioxidant agents from the bench to the bedside.
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Affiliation(s)
- Nihal Ahmad
- Department of Dermatology, University of Wisconsin, Madison, Wisconsin
| | - Hasan Mukhtar
- Department of Dermatology, University of Wisconsin, Madison, Wisconsin
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