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Liang Z, Gao X, Jing C, Yuan T, Zhang L, Yin Y, Ou J, Li X, Qi W, Zhao D, Su H, Zhang H. Protective effect of ginseng extract and total ginsenosides on hematopoietic stem cell damage by inhibiting cell apoptosis and regulating the intestinal microflora. Int J Mol Med 2025; 55:14. [PMID: 39513620 PMCID: PMC11573321 DOI: 10.3892/ijmm.2024.5455] [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: 04/19/2024] [Accepted: 10/07/2024] [Indexed: 11/15/2024] Open
Abstract
Ginseng may improve the myelosuppression and intestinal microbiota disorder induced by cyclophosphamide (CY); however, the effect of ginseng components on hematopoietic stem cell (HSC) damage remains largely unexplored. The present study aimed to assess the protective effect of ginseng extract (GE), total ginsenosides (TG) and total polysaccharides (TP) from ginseng on the intestinal microflora and HSCs of model mice. In the present study, a mouse model of HSC damage induced by CY was constructed, intestinal microflora of fecal samples were sequenced using the 16S ribosomal RNA (rRNA) sequencing techniques, the differentially expressed genes (DEGs) of HSCs were analyzed using high‑throughput RNA‑sequencing, cell apoptosis and erythroid differentiation were detected using flow cytometry and the blood cell parameters were analyzed using a hematology analyzer. Analysis of the 16S rRNA in fecal samples showed that GE, TG and TP improved an imbalanced intestinal microflora, where the relative abundance of Lactobacillus intestinalis had a positive correlation with ginsenosides content. Specifically, TP significantly increased the expression of low‑abundance microflora. Transcriptomic analysis results revealed 2,250, 3,432 and 261 DEGs in the GE, TG and TP groups compared with those in the Model group, respectively. In the expression analysis of DEGs, both TG and GE were found to markedly increase the expression levels of Klf4, Hhex, Pbx1, Kmt2a, Mecom, Zc3h12a, Zbtb16, Lilr4b, Flt3 and Klf13. Furthermore, TG inhibited the apoptosis of HSCs by increasing the expression levels of Bcl2 and Mcl1, whilst decreasing the expression of Bax. By contrast, GE inhibited the apoptosis of HSCs by reducing the expression of Bax and Bad. Regarding erythroid differentiation and blood cell parameters, GE was found to significantly increase the expression of TER‑119. In addition, GE and TG improved all blood cell parameters, including the count of white blood cells, neutrophils (NEUT), lymphocytes (LYMPH), red blood cells (RBC), hemoglobin (HGB) and reticulocyte and platelets (PLT), whereas TP could only improve the counts of LYMPH, RBC, HGB and PLT. The improvement effect of GE and TG on WBC, NEUT and Ret was superior to TP. In conclusion, TG may protect the hematopoiesis function of HSCs in a CY‑induced mouse model of HSC damage, followed by GE. However, TP did not appear to improve HSC damage. Ginsenosides may therefore be considered essential ingredients in GE when protecting HSCs against damage. GE and TG exerted their protective effects on HSCs by inhibiting the apoptosis of HSCs whilst improving the imbalance of intestinal microflora.
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Affiliation(s)
- Zuguo Liang
- Research Center of Traditional Chinese Medicine, The Affiliated Hospital to Changchun University of Chinese Medicine, Changchun, Jilin 130021, P.R. China
- College of Pharmacy, Changchun University of Chinese Medicine, Changchun, Jilin 130117, P.R. China
| | - Xiang Gao
- Research Center of Traditional Chinese Medicine, The Affiliated Hospital to Changchun University of Chinese Medicine, Changchun, Jilin 130021, P.R. China
- College of Pharmacy, Changchun University of Chinese Medicine, Changchun, Jilin 130117, P.R. China
| | - Chenxu Jing
- Research Center of Traditional Chinese Medicine, The Affiliated Hospital to Changchun University of Chinese Medicine, Changchun, Jilin 130021, P.R. China
| | - Tongyi Yuan
- Research Center of Traditional Chinese Medicine, The Affiliated Hospital to Changchun University of Chinese Medicine, Changchun, Jilin 130021, P.R. China
- College of Pharmacy, Changchun University of Chinese Medicine, Changchun, Jilin 130117, P.R. China
| | - Lancao Zhang
- Northeast Asia Research Institute of Traditional Chinese Medicine, Changchun University of Chinese Medicine, Changchun, Jilin 130117, P.R. China
| | - Yifei Yin
- Research Center of Traditional Chinese Medicine, The Affiliated Hospital to Changchun University of Chinese Medicine, Changchun, Jilin 130021, P.R. China
- College of Pharmacy, Changchun University of Chinese Medicine, Changchun, Jilin 130117, P.R. China
| | - Jianze Ou
- Research Center of Traditional Chinese Medicine, The Affiliated Hospital to Changchun University of Chinese Medicine, Changchun, Jilin 130021, P.R. China
- College of Pharmacy, Changchun University of Chinese Medicine, Changchun, Jilin 130117, P.R. China
| | - Xiangyan Li
- Northeast Asia Research Institute of Traditional Chinese Medicine, Changchun University of Chinese Medicine, Changchun, Jilin 130117, P.R. China
| | - Wenxiu Qi
- Northeast Asia Research Institute of Traditional Chinese Medicine, Changchun University of Chinese Medicine, Changchun, Jilin 130117, P.R. China
| | - Daqing Zhao
- Northeast Asia Research Institute of Traditional Chinese Medicine, Changchun University of Chinese Medicine, Changchun, Jilin 130117, P.R. China
| | - Hang Su
- Northeast Asia Research Institute of Traditional Chinese Medicine, Changchun University of Chinese Medicine, Changchun, Jilin 130117, P.R. China
| | - He Zhang
- Research Center of Traditional Chinese Medicine, The Affiliated Hospital to Changchun University of Chinese Medicine, Changchun, Jilin 130021, P.R. China
- College of Pharmacy, Changchun University of Chinese Medicine, Changchun, Jilin 130117, P.R. China
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Kulmambetova G, Kurentay B, Gusmaulemova A, Utupov T, Auganova D, Tarlykov P, Mamlin M, Khamzina S, Shalekenov S, Kozhakhmetov A. Association of Fusobacterium nucleatum infection with colorectal cancer in Kazakhstani patients. Front Oncol 2024; 14:1473575. [PMID: 39726700 PMCID: PMC11669545 DOI: 10.3389/fonc.2024.1473575] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2024] [Accepted: 11/27/2024] [Indexed: 12/28/2024] Open
Abstract
Objectives Fusobacterium nucleatum is a gram-negative anaerobic bacillus associated with colorectal cancer (CRC). We aimed to determine the abundance of F. nucleatum and other CRC-associated bacteria using quantitative real-time polymerase chain reaction (qPCR) analysis to detect the possible correlations between tumor and normal tissues and the relationships between patients' clinical characteristics, diet, and CRC-associated bacteria. Methods A total of 249 biopsy samples of tumor and paired normal tissues were collected from patients with CRC. Biopsy samples were screened for detection of F. nucleatum using qPCR targeting nusG gene. Bacteroides fragilis, Escherichia coli, and Streptococcus gallolyticus were also detected in the samples using species-specific genes. Results The frequencies of detection of F. nucleatum in the tumor and normal tissues of patients with CRC were 43.37 and 24.1%, respectively (P < 0.05). Statistical analysis using cycle threshold (Ct) values from qPCR data and clinical characteristics showed that tumor size, tumor location, and processed meat consumption were significantly correlated with the abundance of F. nucleatum (P < 0.05). The significance of the prevalence of B. fragilis and E. coli in tumor tissues was marginally higher than that in normal tissues (P < 0.1), and the consumption of processed/red meat affected the prevalence of these bacteria (P < 0.05). Conclusions Our results showed an association between the presence of F. nucleatum in tumor tissues and CRC, indicating that F. nucleatum may be a potential marker for CRC diagnosis. F. nucleatum is enriched in CRC tissues and is associated with CRC development.
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Affiliation(s)
| | - Botakoz Kurentay
- Department of Genomics, National Center for Biotechnology, Astana, Kazakhstan
| | - Alua Gusmaulemova
- Department of Genomics, National Center for Biotechnology, Astana, Kazakhstan
| | - Talgat Utupov
- Department of Genomics, National Center for Biotechnology, Astana, Kazakhstan
| | - Dana Auganova
- Department of Genomics, National Center for Biotechnology, Astana, Kazakhstan
| | - Pavel Tarlykov
- Department of Genomics, National Center for Biotechnology, Astana, Kazakhstan
| | - Meiram Mamlin
- Multidisciplinary Surgery Center, National Research Oncology Center, Astana, Kazakhstan
| | - Saule Khamzina
- Multidisciplinary Surgery Center, National Research Oncology Center, Astana, Kazakhstan
| | - Sanzhar Shalekenov
- Multidisciplinary Surgery Center, National Research Oncology Center, Astana, Kazakhstan
| | - Arman Kozhakhmetov
- Department of Surgery, Nazarbayev University School of Medicine, Astana, Kazakhstan
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Carson TL, Byrd DA, Smith KS, Carter D, Gomez M, Abaskaron M, Little RB, Holmes ST, van Der Pol WJ, Lefkowitz EJ, Morrow CD, Fruge AD. A case-control study of the association between the gut microbiota and colorectal cancer: exploring the roles of diet, stress, and race. Gut Pathog 2024; 16:13. [PMID: 38468325 PMCID: PMC10929127 DOI: 10.1186/s13099-024-00608-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/14/2023] [Accepted: 02/29/2024] [Indexed: 03/13/2024] Open
Abstract
BACKGROUND The gut microbiota is associated with risk for colorectal cancer (CRC), a chronic disease for which racial disparities persist with Black Americans having a higher risk of CRC incidence and mortality compared to other groups. Given documented racial differences, the gut microbiota may offer some insight into previously unexplained racial disparities in CRC incidence and mortality. A case-control analysis comparing 11 women newly diagnosed with CRC with 22 cancer-free women matched on age, BMI, and race in a 1:2 ratio was conducted. Information about participants' diet and perceived stress levels were obtained via 24-h Dietary Recall and Perceived Stress Scale-10 survey, respectively. Participants provided stool samples from which microbial genomic DNA was extracted to reveal the abundance of 26 genera chosen a priori based on their previously observed relevance to CRC, anxiety symptoms, and diet. RESULTS Significantly lower alpha diversity was observed among cancer-free Black women compared to all other race-cancer status combinations. No group differences were observed when comparing beta diversity. Non-Hispanic White CRC cases tended to have higher relative abundance of Fusobacteria, Gemellaceae, and Peptostreptococcus compared to all other race-cancer combination groups. Perceived stress was inversely associated with alpha diversity and was associated with additional genera. CONCLUSIONS Our findings suggest that microbiome-CRC associations may differ by racial group. Additional large, racially diverse population-based studies are needed to determine if previously identified associations between characteristics of the gut microbiome and CRC are generalizable to Black women and other racial, ethnic, and gender groups.
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Affiliation(s)
- Tiffany L Carson
- Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL, 33612, USA.
| | - Doratha A Byrd
- Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL, 33612, USA
| | - Kristen S Smith
- Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL, 33612, USA
| | - Daniel Carter
- Auburn University, 1161 W. Samford Avenue, Auburn, AL, 36849, USA
| | - Maria Gomez
- Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL, 33612, USA
| | | | - Rebecca B Little
- University of Alabama at Birmingham, 1720 2nd Avenue South, Birmingham, AL, 35294, USA
| | | | - William J van Der Pol
- University of Alabama at Birmingham, 1720 2nd Avenue South, Birmingham, AL, 35294, USA
| | - Elliot J Lefkowitz
- University of Alabama at Birmingham, 1720 2nd Avenue South, Birmingham, AL, 35294, USA
| | - Casey D Morrow
- University of Alabama at Birmingham, 1720 2nd Avenue South, Birmingham, AL, 35294, USA
| | - Andrew D Fruge
- Auburn University, 1161 W. Samford Avenue, Auburn, AL, 36849, USA
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Carson TL, Byrd DA, Smith KS, Carter D, Abaskaron M, Little RB, Holmes ST, van Der Pol WJ, Lefkowitz EJ, Morrow CD, Fruge AD, Gomez M. A case-control study of the association between the gut microbiota and colorectal cancer: exploring the roles of diet, stress, and race. RESEARCH SQUARE 2023:rs.3.rs-2475944. [PMID: 36711747 PMCID: PMC9882682 DOI: 10.21203/rs.3.rs-2475944/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
Background The gut microbiota is associated with risk for colorectal cancer (CRC), a chronic disease for which racial disparities persist with Black Americans having a higher risk of CRC incidence and mortality compared to other groups. Given documented racial differences, the gut microbiota may offer some insight into previously unexplained racial disparities in CRC incidence and mortality. A case-control analysis comparing 11 women newly diagnosed with CRC with 22 cancer-free women matched on age, BMI, and race in a 1:2 ratio was conducted. Information about participants' diet and perceived stress levels were obtained via 24-hour Dietary Recall and Perceived Stress Scale-10 survey, respectively. Participants provided stool samples from which microbial genomic DNA was extracted to reveal the abundance of 26 genera chosen a priori based on their previously observed relevance to CRC, anxiety symptoms, and diet. Results Significantly lower alpha diversity was observed among cancer-free Black women compared to all other race-cancer status combinations. No group differences were observed when comparing beta diversity. Non-Hispanic White CRC cases tended to have higher relative abundance of Fusobacteria, Gemellaceae, and Peptostreptococcus compared to all other race-cancer combination groups. Perceived stress was inversely associated with alpha diversity and was associated with additional genera. Conclusions Our findings suggest that microbiome-CRC associations may differ by racial group. Additional large, racially diverse population-based studies are needed to determine if previously identified associations between characteristics of the gut microbiome and CRC are generalizable to Black women and other racial, ethnic, and gender groups.
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Kim YK, Yum KS. Effects of red ginseng extract on gut microbial distribution. J Ginseng Res 2022; 46:91-103. [PMID: 35035242 PMCID: PMC8753433 DOI: 10.1016/j.jgr.2021.04.005] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2020] [Revised: 03/10/2021] [Accepted: 04/16/2021] [Indexed: 12/20/2022] Open
Abstract
Background Red ginseng extract boosts immunity against inflammation and cancer in the human body. However, studies on the effects of red ginseng extract on the gut microbiome remain unexplored. Methods In 2019, the positive effects and changes in the gut microbiome after administering 1 pack (3 g) of red ginseng extract per day to 53 adults aged 40 to 75 for 24 weeks were investigated. The gut microbial environment changes were qualitatively and quantitatively analyzed using next-generation sequencing and real-time polymerase chain reaction technology. Results On comparing and analyzing alpha diversity and beta diversity, the microbial pattern showed significant differences (OTUs p = 0.003, chao1 p < 0.001, Bray-Curtis p = 0.001) before and after ingestion of red ginseng extract, indicating that gut microbial richness increased after ingestion. Moreover, after comparing and analyzing the gut microbiome's differences after red ginseng extract intake, significant differences were noted between three strains at the phylum level and among 57 strains at the genus level. Conclusion This study proposes the potential use of red ginseng extract as a prebiotic after confirming its positive effects, including increasing gut microbiome richness, reducing harm to the gut microbiome, and increasing the number of some strains in the gut microbiome.
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Affiliation(s)
| | - Keun-Sang Yum
- Corresponding author. Department of Family Medicine, The Catholic University of Korea, Uijeongbu St. Mary's Hospital, Seoul, 11765, Republic of Korea.
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Kurt M, Yumuk Z. Diagnostic accuracy of Fusobacterium nucleatum IgA and IgG ELISA test in colorectal cancer. Sci Rep 2021; 11:1608. [PMID: 33452405 PMCID: PMC7811007 DOI: 10.1038/s41598-021-81171-1] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2020] [Accepted: 12/24/2020] [Indexed: 12/13/2022] Open
Abstract
The colorectal cancer is a serious health problem. The diagnosis of the disease mostly relies on an invasive procedure. A non-invasive diagnostic test such as an immunoassay, may facilitate diagnosis of colorectal cancer. The purpose of the study was to evaluate the use of antibodies against Fusobacterium nucleatum in the diagnosis of colorectal cancer (CRC). Totally 78 patients in three groups were included in the study. F. nucleatum in the tissues was detected using quantitative polymerase chain reaction assay. F. nucleatum IgA and IgG were measured using enzyme linked immunosorbent assay. F. nucleatum was detected in 86.7% and 73.1% cases of CRC and precancerous-benign colon disease (P-BCD), respectively. The OD values from F. nucleatum IgA and IgG ELISA tests were higher in CRC group compared with healthy individuals. The sensitivity of IgA ELISA test varied between 31.8 and 95.5% depending on the chosen cut-off values. The positivity rate of antibodies in patients with high amount of F. nucleatum in tissue was significantly greater than in the negative group. The F. nucleatum IgA and IgG antibodies in CRC were higher than the ones in healthy controls but the discriminative ability of the ELISA test was not adequate to be considered as a diagnostic tool.
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Affiliation(s)
- Melike Kurt
- Department of Medical Microbiology, Kocaeli University Faculty of Medicine, 41380, Kocaeli, Turkey
| | - Zeki Yumuk
- Department of Medical Microbiology, Kocaeli University Faculty of Medicine, 41380, Kocaeli, Turkey.
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Choudhry H. The Microbiome and Its Implications in Cancer Immunotherapy. Molecules 2021; 26:E206. [PMID: 33401586 PMCID: PMC7795182 DOI: 10.3390/molecules26010206] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2020] [Revised: 12/22/2020] [Accepted: 12/30/2020] [Indexed: 02/06/2023] Open
Abstract
Cancer is responsible for ~18 million deaths globally each year, representing a major cause of death. Several types of therapy strategies such as radiotherapy, chemotherapy and more recently immunotherapy, have been implemented in treating various types of cancer. Microbes have recently been found to be both directly and indirectly involved in cancer progression and regulation, and studies have provided novel and clear insights into the microbiome-mediated emergence of cancers. Scientists around the globe are striving hard to identify and characterize these microbes and the underlying mechanisms by which they promote or suppress various kinds of cancer. Microbes may influence immunotherapy by blocking various cell cycle checkpoints and the production of certain metabolites. Hence, there is an urgent need to better understand the role of these microbes in the promotion and suppression of cancer. The identification of microbes may help in the development of future diagnostic tools to cure cancers possibly associated with the microbiome. This review mainly focuses on various microbes and their association with different types of cancer, responses to immunotherapeutic modulation, physiological responses, and prebiotic and postbiotic effects.
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Affiliation(s)
- Hani Choudhry
- Department of Biochemistry, Faculty of Sciences, Cancer and Mutagenesis Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah 21589, Saudi Arabia
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Liu K, Yang X, Zeng M, Yuan Y, Sun J, He P, Sun J, Xie Q, Chang X, Zhang S, Chen X, Cai L, Xie Y, Jiao X. The Role of Fecal Fusobacterium nucleatum and pks+ Escherichia coli as Early Diagnostic Markers of Colorectal Cancer. DISEASE MARKERS 2021; 2021:1171239. [PMID: 34853619 PMCID: PMC8629656 DOI: 10.1155/2021/1171239] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Revised: 10/21/2021] [Accepted: 11/02/2021] [Indexed: 02/05/2023]
Abstract
BACKGROUND Accurate analysis of intestinal microbiota will facilitate establishment of an evaluating system for assessing colorectal cancer (CRC) risk and prognosis. This study evaluates the potential role of Fusobacterium nucleatum (F. nucleatum) and Escherichia coli with a pks gene (pks+ E. coli) in early CRC diagnosis. METHODS We recruited 139 patients, including CRC (n = 60), colorectal adenomatous polyposis (CAP) (n = 37), and healthy individuals (n = 42) based on their colonoscopy examinations. We collected stool and serum samples from the participants and measured the relative abundance of F. nucleatum and pks+ E. coli in fecal samples by quantitative PCR. Receiver operating characteristic curve (ROC) analyses were used to analyze the diagnostic value of single or combined biomarkers. RESULTS Fecal F. nucleatum and pks+ E. coli levels were higher in the CRC group in either the CAP group or healthy controls (P = 0.02; 0.01). There was no statistical difference in the distribution of F. nucleatum and pks+ E. coli in patients with different tumor sites (P > 0.05). The combination of F. nucleatum+pks+ E. coli+CEA+CA19-9+FOBT was chosen as the optimal panel in differentiating both CRC and CAP from the controls. The combination of F. nucleatum, pks+ E. coli, and FOBT improved diagnostic efficiency. However, there was difficulty in differentiating CRC from CAP. CONCLUSION Our results suggested that combining bacterial markers with conventional tumor markers improves the diagnostic efficiency for noninvasive diagnosis of CRC.
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Affiliation(s)
- Kaixi Liu
- Departments of Clinical Laboratory, Shantou Central Hospital, Shantou, China
| | - Xinran Yang
- Departments of Clinical Laboratory, The First Affiliated Hospital of Shantou University Medical College, China
| | - Mi Zeng
- Medical College of Shantou University, Shantou, China
| | - Yumeng Yuan
- Medical College of Shantou University, Shantou, China
| | - Jianhong Sun
- Departments of Clinical Pathology, Shantou Central Hospital, Shantou, China
| | - Ping He
- Medical College of Shantou University, Shantou, China
| | - Jiayu Sun
- Medical College of Shantou University, Shantou, China
| | - Qingdong Xie
- Medical College of Shantou University, Shantou, China
| | - Xiaolan Chang
- Medical College of Shantou University, Shantou, China
| | - Suwei Zhang
- Departments of Clinical Laboratory, Shantou Central Hospital, Shantou, China
| | - Xiang Chen
- Departments of Health Care Center, The First Affiliated Hospital of Shantou University Medical College, China
| | - Leshan Cai
- Departments of Clinical Laboratory, The First Affiliated Hospital of Shantou University Medical College, China
| | - Yanxuan Xie
- Departments of Clinical Laboratory, The First Affiliated Hospital of Shantou University Medical College, China
| | - Xiaoyang Jiao
- Medical College of Shantou University, Shantou, China
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Guo P, Tian Z, Kong X, Yang L, Shan X, Dong B, Ding X, Jing X, Jiang C, Jiang N, Yu Y. FadA promotes DNA damage and progression of Fusobacterium nucleatum-induced colorectal cancer through up-regulation of chk2. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2020; 39:202. [PMID: 32993749 PMCID: PMC7523382 DOI: 10.1186/s13046-020-01677-w] [Citation(s) in RCA: 97] [Impact Index Per Article: 19.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/07/2020] [Accepted: 08/17/2020] [Indexed: 12/14/2022]
Abstract
Background Globally, colorectal cancer (CRC) affects more than 1 million people each year. In addition to non-modifiable and other environmental risk factors, Fusobacterium nucleatum infection has been linked to CRC recently. In this study, we explored mechanisms underlying the role of Fusobacterium nucleatum infection in the progression of CRC in a mouse model. Methods C57BL/6 J-Adenomatous polyposis coli (APC) Min/J mice [APC (Min/+)] were treated with Fusobacterium nucleatum (109 cfu/mL, 0.2 mL/time/day, i.g., 12 weeks), saline, or FadA knockout (FadA−/−) Fusobacterium nucleatum. The number, size, and weight of CRC tumors were determined in isolated tumor masses. The human CRC cell lines HCT29 and HT116 were treated with lentiviral vectors overexpressing chk2 or silencing β-catenin. DNA damage was determined by Comet assay and γH2AX immunofluorescence assay and flow cytometry. The mRNA expression of chk2 was determined by RT-qPCR. Protein expression of FadA, E-cadherin, β-catenin, and chk2 were determined by Western blot analysis. Results Fusobacterium nucleatum treatment promoted DNA damage in CRC in APC (Min/+) mice. Fusobacterium nucleatum also increased the number of CRC cells that were in the S phase of the cell cycle. FadA−/− reduced tumor number, size, and burden in vivo. FadA−/− also reduced DNA damage, cell proliferation, expression of E-cadherin and chk2, and cells in the S phase. Chk2 overexpression elevated DNA damage and tumor growth in APC (Min/+) mice. Conclusions In conclusion, this study provided evidence that Fusobacterium nucleatum induced DNA damage and cell growth in CRC through FadA-dependent activation of the E-cadherin/β-catenin pathway, leading to up-regulation of chk2.
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Affiliation(s)
- Pin Guo
- Department of Neurosurgery, The Affiliated Hospital of Qingdao University, Qingdao, 266003, People's Republic of China
| | - Zibin Tian
- Department of Gastroenterology, The Affiliated Hospital of Qingdao University, No. 16, Jiangsu Road, Qingdao, 266003, Shandong Province, People's Republic of China
| | - Xinjuan Kong
- Department of Gastroenterology, The Affiliated Hospital of Qingdao University, No. 16, Jiangsu Road, Qingdao, 266003, Shandong Province, People's Republic of China
| | - Lin Yang
- Department of Gastroenterology, The Affiliated Hospital of Qingdao University, No. 16, Jiangsu Road, Qingdao, 266003, Shandong Province, People's Republic of China
| | - Xinzhi Shan
- Department of Gastroenterology, The Affiliated Hospital of Qingdao University, No. 16, Jiangsu Road, Qingdao, 266003, Shandong Province, People's Republic of China
| | - Bingzi Dong
- Department of Endocrinology and Metabolism, The Affiliated Hospital of Qingdao University, Qingdao, 266003, People's Republic of China
| | - Xueli Ding
- Department of Gastroenterology, The Affiliated Hospital of Qingdao University, No. 16, Jiangsu Road, Qingdao, 266003, Shandong Province, People's Republic of China
| | - Xue Jing
- Department of Gastroenterology, The Affiliated Hospital of Qingdao University, No. 16, Jiangsu Road, Qingdao, 266003, Shandong Province, People's Republic of China
| | - Chen Jiang
- Department of Gastroenterology, The Affiliated Hospital of Qingdao University, No. 16, Jiangsu Road, Qingdao, 266003, Shandong Province, People's Republic of China
| | - Na Jiang
- Department of Gastroenterology, The Affiliated Hospital of Qingdao University, No. 16, Jiangsu Road, Qingdao, 266003, Shandong Province, People's Republic of China
| | - Yanan Yu
- Department of Gastroenterology, The Affiliated Hospital of Qingdao University, No. 16, Jiangsu Road, Qingdao, 266003, Shandong Province, People's Republic of China.
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Yu MR, Kim HJ, Park HR. Fusobacterium nucleatum Accelerates the Progression of Colitis-Associated Colorectal Cancer by Promoting EMT. Cancers (Basel) 2020; 12:cancers12102728. [PMID: 32977534 PMCID: PMC7598280 DOI: 10.3390/cancers12102728] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2020] [Revised: 09/16/2020] [Accepted: 09/20/2020] [Indexed: 12/16/2022] Open
Abstract
Simple Summary Colitis-associated cancer (CAC) are associated with the development and progression of colorectal cancer (CRC). And Fusobacterium nucleatum (F. nucleatum), a major pathogen involved in chronic periodontitis, may play an important role in CRC progression. Though the importance of F. nucleatum in CRC has attracted attention, its exact role and related mechanism in CAC progression remain unclear. We investigated the effects of F. nucleatum in both in vitro and in vivo colitis models induced with dextran sodium sulfate (DSS), a well-known colitis-inducing chemical, on the aggressiveness of CAC and its related mechanism. This study showed that F. nucleatum accelerates the progression of CAC cancer by promoting epithelial–mesenchymal transition (EMT). This study provides a novel mechanism involved F. nucleatum in the development of colitis-associated CRC. Abstract Recently, it has been reported that Fusobacterium nucleatum, a major pathogen involved in chronic periodontitis, may play an important role in colorectal cancer (CRC) progression. In addition, inflammatory bowel diseases such as ulcerative colitis and Crohn’s disease represent major predisposing conditions for the development of CRC, and this subtype of cancer is called colitis-associated cancer (CAC). Although the importance of F. nucleatum in CRC has attracted attention, its exact role and related mechanism in CAC progression remain unclear. In this study, we investigated the effects of F. nucleatum in experimental colitis induced with dextran sodium sulfate (DSS), which is a well-known colitis-inducing chemical, on the aggressiveness of CAC and its related mechanism in both in vitro and in vivo models. F. nucleatum synergistically increased the aggressiveness and epithelial–mesenchymal transition (EMT) characteristics of CRC cells that were treated with DSS compared to those in non-treated CRC cells. The role of F. nucleatum in CAC progression was further confirmed in mouse models, as F. nucleatum was found to significantly increase the malignancy of azoxymethane (AOM)/DSS-induced colon cancer. This promoting effect of F. nucleatum was based on activation of the EGFR signaling pathways, including protein kinase B (AKT) and extracellular signal-regulated kinase (ERK), and epidermal growth factor receptor (EGFR) inhibition significantly reduced the F. nucleatum-induced EMT alteration. In conclusion, F. nucleatum accelerates the progression of CAC by promoting EMT through the EGFR signaling pathway.
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Affiliation(s)
- Mi Ra Yu
- Department of Oral Pathology, BK21 PLUS Project, School of Dentistry, Pusan National University, Yangsan 50612, Korea
- Periodontal Disease Signaling Network Research Center (MRC), School of Dentistry, Pusan National University, Yangsan 50612, Korea
| | - Hye Jung Kim
- Periodontal Disease Signaling Network Research Center (MRC), School of Dentistry, Pusan National University, Yangsan 50612, Korea
| | - Hae Ryoun Park
- Department of Oral Pathology, BK21 PLUS Project, School of Dentistry, Pusan National University, Yangsan 50612, Korea
- Periodontal Disease Signaling Network Research Center (MRC), School of Dentistry, Pusan National University, Yangsan 50612, Korea
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Ahmed N, Kamarul Bahrin MH, Agha A, Deshmukh A. Sporadic Fusobacterium Bacteremia as an Atypical Cause of Acute Hepatitis in a Young Caucasian Woman. Cureus 2020; 12:e10590. [PMID: 33110726 PMCID: PMC7581212 DOI: 10.7759/cureus.10590] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Fusobacterium species are gram-negative anaerobic non-spore-forming bacteria, which colonize mucous membranes in humans. Over the recent decade, the significance of these organisms has been increasingly recognized. We describe a rare case of acute hepatitis, which was found to be likely due to Fusobacterium nucleatum, grown on blood culture. In our case, the hepatitis caused by this microorganism resolved completely without any long-term sequelae to the liver, through conservative management namely intravenous antibiotics and supportive therapy only. This case highlights that early detection and prompt treatment in a case of acute hepatitis resulted in a good outcome. In addition, this case also illustrates that the differential diagnosis can be varied in cases of acute hepatitis.
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12
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Sánchez-Alcoholado L, Ordóñez R, Otero A, Plaza-Andrade I, Laborda-Illanes A, Medina JA, Ramos-Molina B, Gómez-Millán J, Queipo-Ortuño MI. Gut Microbiota-Mediated Inflammation and Gut Permeability in Patients with Obesity and Colorectal Cancer. Int J Mol Sci 2020; 21:ijms21186782. [PMID: 32947866 PMCID: PMC7555154 DOI: 10.3390/ijms21186782] [Citation(s) in RCA: 65] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2020] [Revised: 09/11/2020] [Accepted: 09/14/2020] [Indexed: 12/14/2022] Open
Abstract
Obesity is considered an important factor that increases the risk of colorectal cancer (CRC). So far, the association of gut microbiota with both obesity and cancer has been described independently. Nevertheless, a specific obesity-related microbial profile linked to CRC development has not been identified. The aim of this study was to determine the gut microbiota composition in fecal samples from CRC patients with (OB-CRC) and without obesity (L-CRC) compared to the microbiota profile present in non-obese healthy controls (L-HC), in order to unravel the possible relationship between gut microbiota and microbial-derived metabolite trimethylamine N-oxide (TMAO), the inflammatory status, and the intestinal permeability in the context of obesity-associated CRC. The presence of obesity does not induce significant changes in the diversity and richness of intestinal bacteria of CRC patients. Nevertheless, OB-CRC patients display a specific gut microbiota profile characterized by a reduction in butyrate-producing bacteria and an overabundance of opportunistic pathogens, which in turn could be responsible, at least in part, for the higher levels of proinflammatory cytokine IL-1β, the deleterious bacterial metabolite TMAO, and gut permeability found in these patients. These results suggest a possible role of obesity-related gut microbiota in the development of CRC, which could give new clues for the design of new diagnostic tools for CRC prevention.
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Affiliation(s)
- Lidia Sánchez-Alcoholado
- Unidad de Gestión Clínica Intercentros de Oncología Médica, Hospitales Universitarios Regional y Virgen de la Victoria, Instituto de Investigación Biomédica de Málaga (IBIMA)-CIMES-UMA, 29010 Málaga, Spain; (L.S.-A.); (I.P.-A.); (A.L.-I.)
- Facultad de Medicina, Universidad de Málaga, Campus de Teatinos s/n, 29071 Málaga, Spain
| | - Rafael Ordóñez
- Unidad de Gestión Clínica de Oncología Radioterápica, Hospital Universitario Virgen de la Victoria, Instituto de Investigación Biomédica de Málaga (IBIMA), 29010 Málaga, Spain; (R.O.); (A.O.); (J.A.M.)
| | - Ana Otero
- Unidad de Gestión Clínica de Oncología Radioterápica, Hospital Universitario Virgen de la Victoria, Instituto de Investigación Biomédica de Málaga (IBIMA), 29010 Málaga, Spain; (R.O.); (A.O.); (J.A.M.)
| | - Isaac Plaza-Andrade
- Unidad de Gestión Clínica Intercentros de Oncología Médica, Hospitales Universitarios Regional y Virgen de la Victoria, Instituto de Investigación Biomédica de Málaga (IBIMA)-CIMES-UMA, 29010 Málaga, Spain; (L.S.-A.); (I.P.-A.); (A.L.-I.)
| | - Aurora Laborda-Illanes
- Unidad de Gestión Clínica Intercentros de Oncología Médica, Hospitales Universitarios Regional y Virgen de la Victoria, Instituto de Investigación Biomédica de Málaga (IBIMA)-CIMES-UMA, 29010 Málaga, Spain; (L.S.-A.); (I.P.-A.); (A.L.-I.)
- Facultad de Medicina, Universidad de Málaga, Campus de Teatinos s/n, 29071 Málaga, Spain
| | - José Antonio Medina
- Unidad de Gestión Clínica de Oncología Radioterápica, Hospital Universitario Virgen de la Victoria, Instituto de Investigación Biomédica de Málaga (IBIMA), 29010 Málaga, Spain; (R.O.); (A.O.); (J.A.M.)
| | - Bruno Ramos-Molina
- Grupo de Cirugía Digestiva, Endocrina y Transplante de Órganos Abdominales, Instituto Murciano de Investigación Biosanitaria (IMIB-Arrixaca), 30120 Murcia, Spain;
| | - Jaime Gómez-Millán
- Unidad de Gestión Clínica de Oncología Radioterápica, Hospital Universitario Virgen de la Victoria, Instituto de Investigación Biomédica de Málaga (IBIMA), 29010 Málaga, Spain; (R.O.); (A.O.); (J.A.M.)
- Correspondence: (J.G.-M.); (M.I.Q.-O.)
| | - María Isabel Queipo-Ortuño
- Unidad de Gestión Clínica Intercentros de Oncología Médica, Hospitales Universitarios Regional y Virgen de la Victoria, Instituto de Investigación Biomédica de Málaga (IBIMA)-CIMES-UMA, 29010 Málaga, Spain; (L.S.-A.); (I.P.-A.); (A.L.-I.)
- Correspondence: (J.G.-M.); (M.I.Q.-O.)
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Oehmcke-Hecht S, Mandl V, Naatz LT, Dühring L, Köhler J, Kreikemeyer B, Maletzki C. Streptococcus gallolyticus abrogates anti-carcinogenic properties of tannic acid on low-passage colorectal carcinomas. Sci Rep 2020; 10:4714. [PMID: 32170212 PMCID: PMC7070001 DOI: 10.1038/s41598-020-61458-5] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2019] [Accepted: 02/16/2020] [Indexed: 12/16/2022] Open
Abstract
The tannase-producing Gram-positive bacterial species Streptococcus gallolyticus subsp. gallolyticus (Sgg) is an opportunistic pathogen of the human gut and strongly associated with colorectal cancer (CRC). A unique feature of Sgg is its ability to degrade tannic acids (TA). TA constitute an important part of the human diet with known anti-tumorigenic properties. Here, we examined whether Sgg is able to protect tumor cells from the toxic effect of TA and thus drive tumorigenesis indirectly. Human CRC cell lines (n = 8) were treated with increasing concentrations of TA. We confirmed the cytotoxic activity of TA in a dose-dependent manner. In virtually all cell lines, viability decreased significantly (>60% inhibition). Moreover, pyrogallol, the degradation product of TA, had no effect on the tested cell lines. This suggests a specific effect of TA. Cytotoxicity was due to necrosis and induction of senescence in residual cells. Finally, when TA was degraded by Sgg, the cytotoxic effect could be abolished. Tumor cells even responded with boosted cell proliferation, highlighting the impact of Sgg on CRC progression. We here provide another piece of evidence for the active interplay between Sgg and cancer preventive components. These data will help to move forward in designing concepts for therapeutic and eventually also prophylactic approaches to combat gastrointestinal malignancies.
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Affiliation(s)
- Sonja Oehmcke-Hecht
- Institute of Medical Microbiology, Virology and Hygiene, Rostock University Medical Center, Rostock, Germany.
| | - Vanessa Mandl
- Institute of Medical Microbiology, Virology and Hygiene, Rostock University Medical Center, Rostock, Germany.,Department of Internal Medicine, Medical Clinic III - Hematology, Oncology, Palliative Care, Rostock University Medical Center, Rostock, Germany
| | - Lukas Tim Naatz
- Institute of Medical Microbiology, Virology and Hygiene, Rostock University Medical Center, Rostock, Germany.,Department of Internal Medicine, Medical Clinic III - Hematology, Oncology, Palliative Care, Rostock University Medical Center, Rostock, Germany
| | - Lara Dühring
- Institute of Medical Microbiology, Virology and Hygiene, Rostock University Medical Center, Rostock, Germany.,Department of Internal Medicine, Medical Clinic III - Hematology, Oncology, Palliative Care, Rostock University Medical Center, Rostock, Germany
| | - Juliane Köhler
- Institute of Medical Microbiology, Virology and Hygiene, Rostock University Medical Center, Rostock, Germany
| | - Bernd Kreikemeyer
- Institute of Medical Microbiology, Virology and Hygiene, Rostock University Medical Center, Rostock, Germany
| | - Claudia Maletzki
- Department of Internal Medicine, Medical Clinic III - Hematology, Oncology, Palliative Care, Rostock University Medical Center, Rostock, Germany.
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14
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Wang ST, Cui WQ, Pan D, Jiang M, Chang B, Sang LX. Tea polyphenols and their chemopreventive and therapeutic effects on colorectal cancer. World J Gastroenterol 2020; 26:562-597. [PMID: 32103869 PMCID: PMC7029350 DOI: 10.3748/wjg.v26.i6.562] [Citation(s) in RCA: 70] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2019] [Revised: 12/30/2019] [Accepted: 01/11/2020] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer (CRC), a multifactorial disease, is usually induced and developed through complex mechanisms, including impact of diet and lifestyle, genomic abnormalities, change of signaling pathways, inflammatory response, oxidation stress, dysbiosis, and so on. As natural polyphenolic phytochemicals that exist primarily in tea, tea polyphenols (TPs) have been shown to have many clinical applications, especially as anticancer agents. Most animal studies and epidemiological studies have demonstrated that TPs can prevent and treat CRC. TPs can inhibit the growth and metastasis of CRC by exerting the anti-inflammatory, anti-oxidative or pro-oxidative, and pro-apoptotic effects, which are achieved by modulations at multiple levels. Many experiments have demonstrated that TPs can modulate several signaling pathways in cancer cells, including the mitogen-activated protein kinase pathway, phosphatidylinositol-3 kinase/Akt pathway, Wnt/β-catenin pathway, and 67 kDa laminin receptor pathway, to inhibit proliferation and promote cell apoptosis. In addition, novel studies have also suggested that TPs can prevent the growth and metastasis of CRC by modulating the composition of gut microbiota to improve immune system and decrease inflammatory responses. Molecular pathological epidemiology, a novel multidisciplinary investigation, has made great progress on CRC, and the further molecular pathological epidemiology research should be developed in the field of TPs and CRC. This review summarizes the existing in vitro and in vivo animal and human studies and potential mechanisms to examine the effects of tea polyphenols on CRC.
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Affiliation(s)
- Shi-Tong Wang
- Department of Cardiovascular Ultrasound, First Affiliated Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
| | - Wen-Qi Cui
- Department of Neurology, Shengjing Hospital, Affiliated Hospital of China Medical University, Shenyang 110004, Liaoning Province, China
| | - Dan Pan
- Department of Geriatrics, First Affiliated Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
| | - Min Jiang
- Department of Gastroenterology, First Affiliated Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
| | - Bing Chang
- Department of Gastroenterology, First Affiliated Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
| | - Li-Xuan Sang
- Department of Geriatrics, First Affiliated Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
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