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Haynes J, Manogaran P. Mechanisms and Strategies to Overcome Drug Resistance in Colorectal Cancer. Int J Mol Sci 2025; 26:1988. [PMID: 40076613 PMCID: PMC11901061 DOI: 10.3390/ijms26051988] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2025] [Revised: 02/22/2025] [Accepted: 02/24/2025] [Indexed: 03/14/2025] Open
Abstract
Colorectal cancer (CRC) is a major cause of cancer-related mortality worldwide, with a significant impact on public health. Current treatment options include surgery, chemotherapy, radiotherapy, molecular-targeted therapy, and immunotherapy. Despite advancements in these therapeutic modalities, resistance remains a significant challenge, often leading to treatment failure, poor progression-free survival, and cancer recurrence. Mechanisms of resistance in CRC are multifaceted, involving genetic mutations, epigenetic alterations, tumor heterogeneity, and the tumor microenvironment. Understanding these mechanisms at the molecular level is crucial for identifying novel therapeutic targets and developing strategies to overcome resistance. This review provides an overview of the diverse mechanisms driving drug resistance in sporadic CRC and discusses strategies currently under investigation to counteract this resistance. Several promising strategies are being explored, including targeting drug transport, key signaling pathways, DNA damage response, cell death pathways, epigenetic modifications, cancer stem cells, and the tumor microenvironment. The integration of emerging therapeutic approaches that target resistance mechanisms aims to enhance the efficacy of current CRC treatments and improve patient outcomes.
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Affiliation(s)
- Jennifer Haynes
- Department of Clinical and Translational Sciences, Joan C. Edwards School of Medicine, Marshall University, 1600 Medical Center Drive, Huntington, WV 25701, USA;
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Becht JM, Kohlleppel H, Schins RPF, Kämpfer AAM. Effect of Butyrate on Food-Grade Titanium Dioxide Toxicity in Different Intestinal In Vitro Models. Chem Res Toxicol 2024; 37:1501-1514. [PMID: 39213652 PMCID: PMC11409378 DOI: 10.1021/acs.chemrestox.4c00086] [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: 09/04/2024]
Abstract
Short-chain fatty acids (SCFA) are an important energy source for colonocytes and crucial messenger molecules both locally in the intestine and systemically. Butyrate, one of the most prominent and best-studied SCFA, was demonstrated to exert anti-inflammatory effects, improve barrier integrity, enhance mucus synthesis in the intestine, and promote cell differentiation of intestinal epithelial cells in vitro. While the physiological relevance is undisputed, it remains unclear if and to what extent butyrate can influence the effects of xenobiotics, such as food-grade titanium dioxide (E171, fgTiO2), in the intestine. TiO2 has been controversially discussed for its DNA-damaging potential and banned as a food additive within the European Union (EU) since 2022. First, we used enterocyte Caco-2 monocultures to test if butyrate affects the cytotoxicity and inflammatory potential of fgTiO2 in a pristine state or following pretreatment under simulated gastric and intestinal pH conditions. We then investigated pretreated fgTiO2 in intestinal triple cultures of Caco-2, HT29-MTX-E12, and THP-1 cells in homeostatic and inflamed-like state for cytotoxicity, barrier integrity, cytokine release as well as gene expression of mucins, oxidative stress markers, and DNA repair. In Caco-2 monocultures, butyrate had an ambivalent role: pretreated but not pristine fgTiO2 induced cytotoxicity in Caco-2 cells, which was not observed in the presence of butyrate. Conversely, fgTiO2 induced the release of interleukin 8 in the presence but not in the absence of butyrate. In the advanced in vitro models, butyrate did not affect the characteristics of the healthy or inflamed states and caused negligible effects in the investigated end points following fgTiO2 exposure. Taken together, the effects of fgTiO2 strongly depend on the applied testing approach. Our findings underline the importance of the experimental setup, including the choice of in vitro model and the physiological relevance of the exposure scenario, for the hazard testing of food-grade pigments like TiO2.
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Affiliation(s)
- Janine M Becht
- IUF─Leibniz Research Institute for Environmental Medicine, Düsseldorf 40225, Germany
| | - Hendrik Kohlleppel
- IUF─Leibniz Research Institute for Environmental Medicine, Düsseldorf 40225, Germany
| | - Roel P F Schins
- IUF─Leibniz Research Institute for Environmental Medicine, Düsseldorf 40225, Germany
| | - Angela A M Kämpfer
- IUF─Leibniz Research Institute for Environmental Medicine, Düsseldorf 40225, Germany
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Guan T, Fu S, Wu X, Yu H, Liu Y. Bioturbation effect of artificial inoculation on the flavor metabolites and bacterial communities in the Chinese Mao-tofu fermentation. Food Chem X 2024; 21:101133. [PMID: 38304046 PMCID: PMC10832485 DOI: 10.1016/j.fochx.2024.101133] [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: 11/01/2023] [Revised: 01/07/2024] [Accepted: 01/08/2024] [Indexed: 02/03/2024] Open
Abstract
A comparison between artificially inoculated Mao-tofu (CC) and naturally fermented Mao-tofu (MM) indicated that artificially adding Mucor plasmaticus to Mao-tofu dramatically enhanced the essential amino acid (EAA) content, as well as umami and sweet amino acids. Gas chromatography-tandem mass spectrometry (GC-MS/MS) analysis revealed that phenol (3.226 μg/g), 1-octen-3-ol (5.031 μg/g), ethyl heptanoate (1.646 μg/g), and indole (3.422 μg/g) were the key flavor components in Mao-tofu. Unlike MM, CC displayed a substantial increase in esters and a considerable decrease in foul odor substances, including sulfur-containing compounds and indole. Lactococcus raffinolactis, Enterobacter sp. 638, and Streptococcus parauberis KCTC 11537 represented the key bacterial species altering the amino acids and flavor of Mao-tofu according to PacBio single-molecule real-time (SMRT) sequencing and correlation analysis. This study presents the technical feasibility of artificially inoculating Mao-tofu to regulate the core bacterial communities and control the quality of fermented soybean products.
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Affiliation(s)
- Tongwei Guan
- College of Food and Biological Engineering, Xihua University, Chengdu 610039, China
| | - Shiyu Fu
- College of Food and Biological Engineering, Xihua University, Chengdu 610039, China
| | - Xiaotian Wu
- College of Food and Biological Engineering, Xihua University, Chengdu 610039, China
| | - Hao Yu
- Hanyuan County Xige Mao-tofu Products Factory, Hanyuan 625300, China
| | - Ying Liu
- College of Food and Biological Engineering, Xihua University, Chengdu 610039, China
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Cheng J, Zhang G, Liu L, Luo J, Peng X. Anti-inflammatory activity of β-glucans from different sources before and after fermentation by fecal bacteria in vitro. JOURNAL OF THE SCIENCE OF FOOD AND AGRICULTURE 2024; 104:1116-1131. [PMID: 37740718 DOI: 10.1002/jsfa.12997] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/27/2022] [Revised: 04/17/2023] [Accepted: 09/23/2023] [Indexed: 09/25/2023]
Abstract
BACKGROUND β-Glucans are widely sourced and have various physiological effects, including anti-inflammatory effects. However, the strength of the anti-inflammatory activity of β-glucans from different sources remains unknown due to the lack of rapid and effective biomarkers. This study therefore aimed to screen out the β-glucans with strong anti-inflammatory activity from five different sources and to further screen out possible biomarkers in metabolites after fermenting the β-glucans with gut microorganisms. RESULTS The results showed that all five β-glucans inhibited the production of lipopolysaccharide (LPS)-induced pro-inflammatory mediators and suppressed the mRNA expression level of TLR4/MyD88. Their anti-inflammatory mechanisms involved the inhibition of intracellular reactive oxygen species (ROS) production and suppression of mRNA expression of the NF-κB pathway and JNK pathway. Among them, barley β-glucan exhibited the strongest anti-inflammatory effect, followed by Ganoderma lucidum β-glucan. Enhanced anti-inflammatory activity of β-glucan was found after fermentation and may be related to the increased abundance of metabolites such as vanillin, dihydroxyphenylacetic acid, caffeic acid, acetic acid, butyric acid, and lactic acid. They were strongly positively correlated to the abundance of beneficial bacteria such as Blautia, suggesting that the production of those metabolites may be responsible for the flourishing of the beneficial bacteria. CONCLUSION In conclusion, barley was a preferred raw material for the preparation of β-glucans with strong anti-inflammatory activity. Vanillin, dihydroxyphenylacetic acid, caffeic acid, acetic acid, butyric acid, and lactic acid were the possible biomarkers that could be utilized to evaluate the anti-inflammatory effect of β-glucans. © 2023 Society of Chemical Industry.
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Affiliation(s)
- Jing Cheng
- Department of Food Science and Engineering, Jinan University, Guangzhou, China
| | - Guangwen Zhang
- Department of Food Science and Engineering, Jinan University, Guangzhou, China
| | - Liu Liu
- Department of Food Science and Engineering, Jinan University, Guangzhou, China
| | - Jianming Luo
- Department of Food Science and Engineering, Jinan University, Guangzhou, China
| | - Xichun Peng
- Department of Food Science and Engineering, Jinan University, Guangzhou, China
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Tewari AB, Saini A, Sharma D. Extirpating the cancer stem cell hydra: Differentiation therapy and Hyperthermia therapy for targeting the cancer stem cell hierarchy. Clin Exp Med 2023; 23:3125-3145. [PMID: 37093450 DOI: 10.1007/s10238-023-01066-5] [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: 12/09/2022] [Accepted: 04/02/2023] [Indexed: 04/25/2023]
Abstract
Ever since the discovery of cancer stem cells (CSCs), they have progressively attracted more attention as a therapeutic target. Like the mythical hydra, this subpopulation of cells seems to contribute to cancer immortality, spawning more cells each time that some components of the cancer cell hierarchy are destroyed. Traditional modalities focusing on cancer treatment have emphasized apoptosis as a route to eliminate the tumor burden. A major problem is that cancer cells are often in varying degrees of dedifferentiation contributing to what is known as the CSCs hierarchy and cells which are known to be resistant to conventional therapy. Differentiation therapy is an experimental therapeutic modality aimed at the conversion of malignant phenotype to a more benign one. Hyperthermia therapy (HT) is a modality exploiting the changes induced in cells by the application of heat produced to aid in cancer therapy. While differentiation therapy has been successfully employed in the treatment of acute myeloid leukemia, it has not been hugely successful for other cancer types. Mounting evidence suggests that hyperthermia therapy may greatly augment the effects of differentiation therapy while simultaneously overcoming many of the hard-to-treat facets of recurrent tumors. This review summarizes the progress made so far in integrating hyperthermia therapy with existing modules of differentiation therapy. The focus is on studies related to the successful application of both hyperthermia and differentiation therapy when used alone or in conjunction for hard-to-treat cancer cell niche with emphasis on combined approaches to target the CSCs hierarchy.
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Affiliation(s)
- Amit B Tewari
- Institute of Nano Science and Technology (INST), Knowledge City, Sector 81, Mohali, Punjab, 140306, India
| | - Anamika Saini
- Institute of Nano Science and Technology (INST), Knowledge City, Sector 81, Mohali, Punjab, 140306, India
| | - Deepika Sharma
- Institute of Nano Science and Technology (INST), Knowledge City, Sector 81, Mohali, Punjab, 140306, India.
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Stein RA, Riber L. Epigenetic effects of short-chain fatty acids from the large intestine on host cells. MICROLIFE 2023; 4:uqad032. [PMID: 37441522 PMCID: PMC10335734 DOI: 10.1093/femsml/uqad032] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Revised: 06/04/2023] [Accepted: 06/14/2023] [Indexed: 07/15/2023]
Abstract
Adult humans harbor at least as many microbial cells as eukaryotic ones. The largest compartment of this diverse microbial population, the gut microbiota, encompasses the collection of bacteria, archaea, viruses, and eukaryotic organisms that populate the gastrointestinal tract, and represents a complex and dynamic ecosystem that has been increasingly implicated in health and disease. The gut microbiota carries ∼100-to-150-times more genes than the human genome and is intimately involved in development, homeostasis, and disease. Of the several microbial metabolites that have been studied, short-chain fatty acids emerge as a group of molecules that shape gene expression in several types of eukaryotic cells by multiple mechanisms, which include DNA methylation changes, histone post-translational modifications, and microRNA-mediated gene silencing. Butyric acid, one of the most extensively studied short-chain fatty acids, reaches higher concentrations in the colonic lumen, where it provides a source of energy for healthy colonocytes, and its concentrations decrease towards the bottom of the colonic crypts, where stem cells reside. The lower butyric acid concentration in the colonic crypts allows undifferentiated cells, such as stem cells, to progress through the cell cycle, pointing towards the importance of the crypts in providing them with a protective niche. In cancerous colonocytes, which metabolize relatively little butyric acid and mostly rely on glycolysis, butyric acid preferentially acts as a histone deacetylase inhibitor, leading to decreased cell proliferation and increased apoptosis. A better understanding of the interface between the gut microbiota metabolites and epigenetic changes in eukaryotic cells promises to unravel in more detail processes that occur physiologically and as part of disease, help develop novel biomarkers, and identify new therapeutic modalities.
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Affiliation(s)
- Richard A Stein
- Corresponding author. Department of Chemical and Biomolecular Engineering, NYU Tandon School of Engineering, 6 MetroTech Center, Brooklyn, NY 11201, USA. Tel: +1-917-684-9438; E-mail: ;
| | - Leise Riber
- Department of Plant & Environmental Sciences, University of Copenhagen, Thorvaldsensvej 40, DK-1871 Frederiksberg, Denmark
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Bruno L, Evariste L, Houdeau E. Dysregulation along the gut microbiota-immune system axis after oral exposure to titanium dioxide nanoparticles: A possible environmental factor promoting obesity-related metabolic disorders. ENVIRONMENTAL POLLUTION (BARKING, ESSEX : 1987) 2023; 330:121795. [PMID: 37187281 DOI: 10.1016/j.envpol.2023.121795] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Revised: 04/24/2023] [Accepted: 05/07/2023] [Indexed: 05/17/2023]
Abstract
Food additives are one major hallmark of ultra-processed food in the Western-diet, a food habit often associated with metabolic disorders. Among these additives, the whitener and opacifying agent titanium dioxide (TiO2) raises public health issues due to the ability of TiO2 nanoparticles (NPs) to cross biological barriers and accumulate in different systemic organs like spleen, liver and pancreas. However before their systemic passage, the biocidal properties of TiO2 NPs may alter the composition and activity of the gut microbiota, which play a crucial role for the development and maintenance of immune functions. Once absorbed, TiO2 NPs may further interact with immune intestinal cells involved in gut microbiota regulation. Since obesity-related metabolic diseases such as diabetes are associated with alterations in the microbiota-immune system axis, this raises questions about the possible involvement of long-term exposure to food-grade TiO2 in the development or worsening of these diseases. The current purpose is to review the dysregulations along the gut microbiota-immune system axis after oral TiO2 exposure compared to those reported in obese or diabetic patients, and to highlight potential mechanisms by which foodborne TiO2 NPs may increase the susceptibility to develop obesity-related metabolic disorders.
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Affiliation(s)
- Lamas Bruno
- Toxalim (Research Centre in Food Toxicology), Team Endocrinology and Toxicology of Intestinal Barrier, Université de Toulouse, INRAE, ENVT, INP-Purpan, UPS, Toulouse, France.
| | - Lauris Evariste
- Toxalim (Research Centre in Food Toxicology), Team Endocrinology and Toxicology of Intestinal Barrier, Université de Toulouse, INRAE, ENVT, INP-Purpan, UPS, Toulouse, France
| | - Eric Houdeau
- Toxalim (Research Centre in Food Toxicology), Team Endocrinology and Toxicology of Intestinal Barrier, Université de Toulouse, INRAE, ENVT, INP-Purpan, UPS, Toulouse, France
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Lamas B, Evariste L, Houdeau E. Interactions du dioxyde de titane alimentaire avec l’axe microbiote-système immunitaire : un nouvel acteur dans le développement de désordres métaboliques ? CAHIERS DE NUTRITION ET DE DIÉTÉTIQUE 2022. [DOI: 10.1016/j.cnd.2022.09.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
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Li Y, Huang X, Tong D, Jiang C, Zhu X, Wei Z, Gong T, Jin C. Relationships among microbiota, gastric cancer, and immunotherapy. Front Microbiol 2022; 13:987763. [PMID: 36171746 PMCID: PMC9511979 DOI: 10.3389/fmicb.2022.987763] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2022] [Accepted: 08/03/2022] [Indexed: 12/07/2022] Open
Abstract
Currently, conventional neoadjuvant therapy or postoperative adjuvant therapy, such as chemotherapy and radiation therapy, can only bring limited survival benefits to gastric cancer (GC). Median survival after palliative chemotherapy is also low, at about 8-10 months. Immunotargeting is a new option for the treatment of GC, but has not been widely replicated. The highly immunosuppressed tumor microenvironment (TME) discounts the efficacy of immunotherapy for GC. Therefore, new strategies are needed to enhance the immune response of the TME. This paper reviewed the relationship between microorganisms and GC, potential links between microorganisms and immunotherapy and research of microorganisms combined immunotherapy.
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Affiliation(s)
- Yuzhen Li
- Department of Oncology, Wuxi Hospital Affiliated to Nanjing University of Chinese Medicine, Wuxi, China
| | - Xiaona Huang
- Department of Oncology, Wuxi Hospital Affiliated to Nanjing University of Chinese Medicine, Wuxi, China
| | - Desheng Tong
- Key Laboratory of National Health and Family Planning Commission on Parasitic Disease Control and Prevention, Jiangsu Provincial Key Laboratory on Parasite and Vector Control Technology, Jiangsu Institute of Parasitic Diseases, Wuxi, China
| | - Chenyu Jiang
- Department of Oncology, Wuxi Hospital Affiliated to Nanjing University of Chinese Medicine, Wuxi, China
| | - Xiaodan Zhu
- Department of Oncology, Wuxi Hospital Affiliated to Nanjing University of Chinese Medicine, Wuxi, China
| | - Zhipeng Wei
- Department of Oncology, Wuxi Hospital Affiliated to Nanjing University of Chinese Medicine, Wuxi, China
| | - Tingjie Gong
- Department of Oncology, Wuxi Hospital Affiliated to Nanjing University of Chinese Medicine, Wuxi, China
| | - Chunhui Jin
- Department of Oncology, Wuxi Hospital Affiliated to Nanjing University of Chinese Medicine, Wuxi, China
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8-Hydroxyquinoline a natural chelating agent from Streptomyces spp. inhibits A549 lung cancer cell lines via BCL2/STAT3 regulating pathways. World J Microbiol Biotechnol 2022; 38:182. [PMID: 35953631 DOI: 10.1007/s11274-022-03368-4] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Accepted: 07/28/2022] [Indexed: 10/15/2022]
Abstract
Biomolecules from Streptomyces spp. are emerging sources of natural drugs and have been focused on over the decade. The discovery of bioactive chemotherapeutic molecules from soil Streptomyces spp. has opened the medium for the search for natural drugs. In the current study, 8-HOQ was extracted and purified from soil Streptomyces spp. and was evaluated on A549 and BEAS cell lines. The apoptotic and caspase mediated pathways were evaluated using cell proliferation, dual fluorescent staining, migration, invasion and mRNA as well as protein quantification of apoptotic markers. In vitro cytotoxicity test revealed that 8-HOQ possesses potent cytotoxicity activities with IC50 values of 26 µM, 5 µM, 7.2 µM at 24 h, 48 h, and 72 h respectively against A549 lung cancer cell lines. The result also demonstrated that 8-HOQ from Streptomyces spp significantly inhibited the A549 lung cancer cell lines and activated the intrinsic pathways of apoptosis. The caspase-3 and caspase-8 activities were potentially elevated in 8-HOQ treated A549 cell lines and confirmed that 8-HOQ mediated A549 cancer cell death through the intrinsic pathway. The results explored caspase-mediated apoptosis as a mechanism underlying the inhibition of cancer cell viability in a dose-dependent manner. The expression of P53, BCL2 and STAT3 were inhibited in A549 cell lines and confirmed the metastasis inhibitory potential of 8-HOQ by blocking migration and invasion in A549 cell lines. These results indicated that 8-HOQ from Streptomyces spp. potentially inhibited growth and migration of A549 lung cancer cell lines.
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Kaźmierczak-Siedlecka K, Daca A, Roviello G, Catalano M, Połom K. Interdisciplinary insights into the link between gut microbiome and gastric carcinogenesis-what is currently known? Gastric Cancer 2022; 25:1-10. [PMID: 34741681 PMCID: PMC8732854 DOI: 10.1007/s10120-021-01260-y] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/06/2021] [Accepted: 10/20/2021] [Indexed: 02/07/2023]
Abstract
Currently, gastric cancer is one of the leading death-related cancer globally. The etiopathogenesis of gastric cancer is multifactorial and includes among others dysbiotic alterations of gastric microbiota. Molecular techniques revealed that stomach is not a sterile organ and it is resides with ecosystem of microbes. Due to the fact that the role of Helicobacter pylori infection in development of gastric cancer is established and well-studied, this paper is mainly focused on the role of other bacterial as well as viral and fungal gut microbiota imbalance in gastric carcinogenesis. Notably, not only the composition of gastric microbiota may play an important role in development of gastric cancer, but also its activity. Microbial metabolites, such as short-chain fatty acids, polyamines, N-nitroso compounds, and lactate, may significantly affect gastric carcinogenesis. Therefore, this paper discussed aforementioned aspects with the interdisciplinary insights (regarding also immunological point of view) into the association between gut microbiome and gastric carcinogenesis based on up-to-date studies.
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Affiliation(s)
| | - Agnieszka Daca
- Department of Pathology and Experimental Rheumatology, Medical University of Gdansk, Gdańsk, Poland
| | - Giandomenico Roviello
- Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Viale Pieraccini, 6, 50139, Florence, Italy
| | - Martina Catalano
- Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Viale Pieraccini, 6, 50139, Florence, Italy
| | - Karol Połom
- Department of Surgical Oncology, Medical University of Gdansk, ul. Smoluchowskiego 17, 80-214, Gdańsk, Poland
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Cytotoxic effects of butyric acid derivatives through GPR109A receptor in Colorectal Carcinoma cells by in silico and in vitro methods. J Mol Struct 2021. [DOI: 10.1016/j.molstruc.2021.130832] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
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Czerwińska ME, Bobińska A, Cichocka K, Buchholz T, Woliński K, Melzig MF. Cornus mas and Cornus officinalis-A Comparison of Antioxidant and Immunomodulatory Activities of Standardized Fruit Extracts in Human Neutrophils and Caco-2 Models. PLANTS (BASEL, SWITZERLAND) 2021; 10:plants10112347. [PMID: 34834710 PMCID: PMC8618406 DOI: 10.3390/plants10112347] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Revised: 10/24/2021] [Accepted: 10/27/2021] [Indexed: 05/06/2023]
Abstract
Fruits of Cornus mas and Cornus officinalis are representative plant materials traditionally used in Europe and Asia, respectively, in the treatment of diabetes and diabetes-related complications, which are often mediated by pathogenic inflammatory agents. Additionally, due to the fact of mutual infiltration of Asian and European medicines, the differentiation as well as standardization of traditional prescriptions seem to be crucial for ensuring the quality of traditional products. The objective of this study was a comparison of biological activity of extracts from fruits of C. mas and C. officinalis by an assessment of their effect on reactive oxygen species (ROS) generation in human neutrophils as well as cytokines secretion both in neutrophils (tumor necrosis factor α, TNF- α; interleukin 8, IL-8; interleukin 1β, IL-1β) and in human colon adenocarcinoma cell line Caco-2 (IL-8). To evaluate the phytochemical differences between the studied extracts as well as to provide a method for standardization procedures, a quantitative analysis of iridoids, such as loganin, sweroside, and loganic acid, found in extracts of Cornus fruits was performed with HPLC-DAD. All standardized extracts significantly inhibited ROS production, whereas the aqueous-alcoholic extracts were particularly active inhibitors of IL-8 secretion by neutrophils. The aqueous-methanolic extract of C. officinalis fruit, decreased IL-8 secretion by neutrophils to 54.64 ± 7.67%, 49.68 ± 6.55%, 50.29 ± 5.87% at concentrations of 5, 50, and 100 µg/mL, respectively, compared to LPS-stimulated control (100%). The aqueous extract of C. officinalis fruit significantly inhibited TNF-α release by neutrophils at concentrations of 50 and 100 µg/mL. On the other hand, the aqueous-ethanolic extract of C. mas fruit showed the propensity to increase TNF-α and IL-1β secretion. The modulatory activity of the Cornus extracts was noted in the case of secretion of IL-8 in Caco-2 cells. The effect was comparable with dexamethasone. The content of loganin in aqueous and aqueous-methanolic extract of C. officinalis fruit was higher than in the aqueous-ethanolic extract of C. mas fruit, which was characterized by a significant quantity of loganic acid. In conclusion, the immunomodulatory effect observed in vitro may partially confirm the traditional use of Cornus fruits through alleviation of the development of diabetes-derived inflammatory complications. Loganin and loganic acid are significant markers for standardization of C. mas and C. officinalis fruit extracts, respectively.
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Affiliation(s)
- Monika E. Czerwińska
- Department of Biochemistry and Pharmacogenomics, Faculty of Pharmacy, Medical University of Warsaw, Banacha 1, 02-097 Warsaw, Poland
- Centre for Preclinical Research, Medical University of Warsaw, Banacha 1B, 02-097 Warsaw, Poland
- Correspondence: ; Tel.: +48-221-166-185
| | - Agata Bobińska
- Student Scientific Association “Farmakon”, Department of Biochemistry and Pharmacogenomics, Medical University of Warsaw, Banacha 1, 02-097 Warsaw, Poland; (A.B.); (K.C.)
| | - Katarzyna Cichocka
- Student Scientific Association “Farmakon”, Department of Biochemistry and Pharmacogenomics, Medical University of Warsaw, Banacha 1, 02-097 Warsaw, Poland; (A.B.); (K.C.)
| | - Tina Buchholz
- Institute of Pharmacy, Freie Universitaet Berlin, Königin-Luise-Str. 2+4, D-14195 Berlin, Germany; (T.B.); (M.F.M.)
| | - Konrad Woliński
- Polish Academy of Sciences Botanical Garden, Center for Biological Diversity Conservation in Powsin, Prawdziwka 2, 02-973 Warsaw, Poland;
| | - Matthias F. Melzig
- Institute of Pharmacy, Freie Universitaet Berlin, Königin-Luise-Str. 2+4, D-14195 Berlin, Germany; (T.B.); (M.F.M.)
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Suzuki K, Masuike Y, Mizuno R, Sachdeva UM, Chatterji P, Andres SF, Sun W, Klein-Szanto AJ, Besharati S, Remotti HE, Verzi MP, Rustgi AK. LIN28B induces a differentiation program through CDX2 in colon cancer. JCI Insight 2021; 6:140382. [PMID: 33755595 PMCID: PMC8262288 DOI: 10.1172/jci.insight.140382] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2020] [Accepted: 03/18/2021] [Indexed: 12/03/2022] Open
Abstract
Most colorectal cancers (CRCs) are moderately differentiated or well differentiated, a status that is preserved even in metastatic tumors. However, the molecular mechanisms underlying CRC differentiation remain to be elucidated. Herein, we unravel a potentially novel posttranscriptional regulatory mechanism via a LIN28B/CDX2 signaling axis that plays a critical role in mediating CRC differentiation. Owing to a large number of mRNA targets, the mRNA-binding protein LIN28B has diverse functions in development, metabolism, tissue regeneration, and tumorigenesis. Our RNA-binding protein IP (RIP) assay revealed that LIN28B directly binds CDX2 mRNA, which is a pivotal homeobox transcription factor in normal intestinal epithelial cell identity and differentiation. Furthermore, LIN28B overexpression resulted in enhanced CDX2 expression to promote differentiation in subcutaneous xenograft tumors generated from CRC cells and metastatic tumor colonization through mesenchymal-epithelial transition in CRC liver metastasis mouse models. A ChIP sequence for CDX2 identified α-methylacyl-CoA racemase (AMACR) as a potentially novel transcriptional target of CDX2 in the context of LIN28B overexpression. We also found that AMACR enhanced intestinal alkaline phosphatase activity, which is known as a key component of intestinal differentiation, through the upregulation of butyric acid. Overall, we demonstrated that LIN28B promotes CRC differentiation through the CDX2/AMACR axis.
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Affiliation(s)
- Kensuke Suzuki
- Herbert Irving Comprehensive Cancer Center, Division of Digestive and Liver Disease, Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, New York, USA
| | - Yasunori Masuike
- Herbert Irving Comprehensive Cancer Center, Division of Digestive and Liver Disease, Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, New York, USA
| | - Rei Mizuno
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Uma M Sachdeva
- Division of Thoracic Surgery, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Priya Chatterji
- Broad Institute of MIT and Harvard University, Cambridge, Massachusetts, USA
| | - Sarah F Andres
- Papé Family Pediatric Research Institute, Oregon Health & Science University, Portland, Oregon, USA
| | - Wenping Sun
- Institute for Biomedical informatics, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Andres J Klein-Szanto
- Histopathology Facility and Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA
| | - Sepideh Besharati
- Department of Pathology and Cell Biology, Columbia University Medical Center, New York, New York, USA
| | - Helen E Remotti
- Department of Pathology and Cell Biology, Columbia University Medical Center, New York, New York, USA
| | - Michael P Verzi
- Department of Genetics, Human Genetics Institute of New Jersey, Rutgers University, Piscataway, New Jersey, USA
| | - Anil K Rustgi
- Herbert Irving Comprehensive Cancer Center, Division of Digestive and Liver Disease, Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, New York, USA
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15
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Lamas B, Martins Breyner N, Houdeau E. Impacts of foodborne inorganic nanoparticles on the gut microbiota-immune axis: potential consequences for host health. Part Fibre Toxicol 2020; 17:19. [PMID: 32487227 PMCID: PMC7268708 DOI: 10.1186/s12989-020-00349-z] [Citation(s) in RCA: 96] [Impact Index Per Article: 19.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2019] [Accepted: 05/11/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND In food toxicology, there is growing interest in studying the impacts of foodborne nanoparticles (NPs, originating from food additives, food supplements or food packaging) on the intestinal microbiome due to the important and complex physiological roles of these microbial communities in host health. Biocidal activities, as described over recent years for most inorganic and metal NPs, could favour chronic changes in the composition and/or metabolic activities of commensal bacteria (namely, intestinal dysbiosis) with consequences on immune functions. Reciprocally, direct interactions of NPs with the immune system (e.g., inflammatory responses, adjuvant or immunosuppressive properties) may in turn have effects on the gut microbiota. Many chronic diseases in humans are associated with alterations along the microbiota-immune system axis, such as inflammatory bowel diseases (IBD) (Crohn's disease and ulcerative colitis), metabolic disorders (e.g., obesity) or colorectal cancer (CRC). This raises the question of whether chronic dietary exposure to inorganic NPs may be viewed as a risk factor facilitating disease onset and/or progression. Deciphering the variety of effects along the microbiota-immune axis may aid the understanding of how daily exposure to inorganic NPs through various foodstuffs may potentially disturb the intricate dialogue between gut commensals and immunity, hence increasing the vulnerability of the host. In animal studies, dose levels and durations of oral treatment are key factors for mimicking exposure conditions to which humans are or may be exposed through the diet on a daily basis, and are needed for hazard identification and risk assessment of foodborne NPs. This review summarizes relevant studies to support the development of predictive toxicological models that account for the gut microbiota-immune axis. CONCLUSIONS The literature indicates that, in addition to evoking immune dysfunctions in the gut, inorganic NPs exhibit a moderate to extensive impact on intestinal microbiota composition and activity, highlighting a recurrent signature that favours colonization of the intestine by pathobionts at the expense of beneficial bacterial strains, as observed in IBD, CRC and obesity. Considering the long-term exposure via food, the effects of NPs on the gut microbiome should be considered in human health risk assessment, especially when a nanomaterial exhibits antimicrobial properties.
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Affiliation(s)
- Bruno Lamas
- INRAE Toxalim UMR 1331 (Research Center in Food Toxicology), Team Endocrinology and Toxicology of the Intestinal Barrier, INRAE, Toulouse University, ENVT, INP-Purpan, UPS, 180 Chemin de Tournefeuille, 31027, Toulouse cedex 3, France.
| | - Natalia Martins Breyner
- INRAE Toxalim UMR 1331 (Research Center in Food Toxicology), Team Endocrinology and Toxicology of the Intestinal Barrier, INRAE, Toulouse University, ENVT, INP-Purpan, UPS, 180 Chemin de Tournefeuille, 31027, Toulouse cedex 3, France
| | - Eric Houdeau
- INRAE Toxalim UMR 1331 (Research Center in Food Toxicology), Team Endocrinology and Toxicology of the Intestinal Barrier, INRAE, Toulouse University, ENVT, INP-Purpan, UPS, 180 Chemin de Tournefeuille, 31027, Toulouse cedex 3, France.
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16
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Tsvetikova SA, Koshel EI. Microbiota and cancer: host cellular mechanisms activated by gut microbial metabolites. Int J Med Microbiol 2020; 310:151425. [PMID: 32423739 DOI: 10.1016/j.ijmm.2020.151425] [Citation(s) in RCA: 51] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2019] [Revised: 03/25/2020] [Accepted: 04/13/2020] [Indexed: 12/13/2022] Open
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17
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Chaturvedi LS, Wang Q, More SK, Vomhof-DeKrey EE, Basson MD. Schlafen 12 mediates the effects of butyrate and repetitive mechanical deformation on intestinal epithelial differentiation in human Caco-2 intestinal epithelial cells. Hum Cell 2019; 32:240-250. [PMID: 30875077 PMCID: PMC6571040 DOI: 10.1007/s13577-019-00247-3] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2018] [Accepted: 03/02/2019] [Indexed: 12/12/2022]
Abstract
Intestinal epithelial differentiation may be stimulated by diverse pathways including luminal short-chain fatty acids and repetitive mechanical deformation engendered by villous motility and peristalsis. Schlafen 12 (SLFN12) is a cytosolic protein that stimulates sucrase-isomaltase (SI) expression. We hypothesized that two disparate differentiating stimuli, butyrate and repetitive deformation, would each stimulate SLFN12 expression in human Caco-2 intestinal epithelial cells and that increased SLFN12 expression would contribute to the differentiating activity of the human Caco-2 intestinal epithelial cells. We stimulated Caco-2 cells with 1-2 mM butyrate or repetitive mechanical deformation at 10 cycles/min at an average 10% strain, and measured SLFN12 and SI expression by qRT-PCR. Sodium butyrate enhanced SLFN12 expression at both 1 mM and 2 mM although SI expression was only significantly increased at 2 mM. Repetitive deformation induced by cyclic mechanical strain also significantly increased both SLFN12 and SI gene expression. Reducing SLFN12 by siRNA decreased basal, deformation-stimulated, and butyrate-stimulated SLFN12 levels, compared to control cells treated with non-targeting siRNA, although both deformation and butyrate were still able to stimulate SLFN12 expression in siRNA-treated cells compared to control cells treated with the same siRNA. This attenuation of the increase in SLFN12 expression in response to mechanical strain or butyrate was accompanied by parallel attenuation of SI expression. Butyrate stimulated SI-promoter activity, and reducing SLFN12 by siRNA attenuated butyrate-induced SI-promoter activity. These data suggest that SLFN12 mediates at least in part the stimulation by both butyrate and repetitive mechanical deformation of sucrase-isomaltase, a late stage differentiation marker in human intestinal epithelial cells.
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Affiliation(s)
- Lakshmi S Chaturvedi
- Departments of Surgery, Pathology, and Biomedical Sciences, School of Medicine and the Health Sciences, University of North Dakota, 1301 North Columbia Road, Stop 9037, Grand Forks, ND, 58202, USA
- Currently at Departments of Pharmaceutical Sciences and Biomedical Sciences-College of Pharmacy, Departments of Basic Sciences and Surgery-College of Medicine, California Northstate University, Elk Grove, CA, 95757, USA
| | - Qinggang Wang
- Departments of Surgery, Pathology, and Biomedical Sciences, School of Medicine and the Health Sciences, University of North Dakota, 1301 North Columbia Road, Stop 9037, Grand Forks, ND, 58202, USA
| | - Shyam K More
- Departments of Surgery, Pathology, and Biomedical Sciences, School of Medicine and the Health Sciences, University of North Dakota, 1301 North Columbia Road, Stop 9037, Grand Forks, ND, 58202, USA
| | - Emilie E Vomhof-DeKrey
- Departments of Surgery, Pathology, and Biomedical Sciences, School of Medicine and the Health Sciences, University of North Dakota, 1301 North Columbia Road, Stop 9037, Grand Forks, ND, 58202, USA
| | - Marc D Basson
- Departments of Surgery, Pathology, and Biomedical Sciences, School of Medicine and the Health Sciences, University of North Dakota, 1301 North Columbia Road, Stop 9037, Grand Forks, ND, 58202, USA.
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18
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Effects of Intestinal Microbial⁻Elaborated Butyrate on Oncogenic Signaling Pathways. Nutrients 2019; 11:nu11051026. [PMID: 31067776 PMCID: PMC6566851 DOI: 10.3390/nu11051026] [Citation(s) in RCA: 115] [Impact Index Per Article: 19.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2019] [Revised: 04/29/2019] [Accepted: 05/05/2019] [Indexed: 12/12/2022] Open
Abstract
The intestinal microbiota is well known to have multiple benefits on human health, including cancer prevention and treatment. The effects are partially mediated by microbiota-produced short chain fatty acids (SCFAs) such as butyrate, propionate and acetate. The anti-cancer effect of butyrate has been demonstrated in cancer cell cultures and animal models of cancer. Butyrate, as a signaling molecule, has effects on multiple signaling pathways. The most studied effect is its inhibition on histone deacetylase (HDAC), which leads to alterations of several important oncogenic signaling pathways such as JAK2/STAT3, VEGF. Butyrate can interfere with both mitochondrial apoptotic and extrinsic apoptotic pathways. In addition, butyrate also reduces gut inflammation by promoting T-regulatory cell differentiation with decreased activities of the NF-κB and STAT3 pathways. Through PKC and Wnt pathways, butyrate increases cancer cell differentiation. Furthermore, butyrate regulates oncogenic signaling molecules through microRNAs and methylation. Therefore, butyrate has the potential to be incorporated into cancer prevention and treatment regimens. In this review we summarize recent progress in butyrate research and discuss the future development of butyrate as an anti-cancer agent with emphasis on its effects on oncogenic signaling pathways. The low bioavailability of butyrate is a problem, which precludes clinical application. The disadvantage of butyrate for medicinal applications may be overcome by several approaches including nano-delivery, analogue development and combination use with other anti-cancer agents or phytochemicals.
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19
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Sun X, Zhu MJ. Butyrate Inhibits Indices of Colorectal Carcinogenesis via Enhancing α-Ketoglutarate-Dependent DNA Demethylation of Mismatch Repair Genes. Mol Nutr Food Res 2018; 62:e1700932. [PMID: 29577594 DOI: 10.1002/mnfr.201700932] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2017] [Revised: 02/28/2018] [Indexed: 12/16/2022]
Abstract
SCOPE Butyrate, the fermentation end product of gut microbiota in the colon, is known for its antitumor effects, but the mechanisms remained to be defined. α-ketoglutarate (α-KG) mediates DNA demethylation and aberrant epigenetic modifications are associated with carcinogenesis. The objectives of this study are to evaluate the effects of butyrate on α-KG mediated epigenetic modification in colorectal adenocarcinoma HT-29 and Caco-2 cells. METHODS AND RESULTS Butyrate suppressed proliferation, potentiated differentiation, and induced apoptosis in both HT-29 and Caco-2 cells, associated with enhanced expression of isocitrate dehydrogenase 1 (IDH1) and pyruvate dehydrogenase. Furthermore, butyrate upregulated acetyl-CoA and α-KG, concomitant with enhanced histone acetylation and DNA demethylation in the promoter of DNA mismatch repair (MMR) gene. Knocking down IDH1 abolished the positive effects of butyrate on CRC apoptosis and MMR protein expression, in conjunction with reduced α-KG content. Importantly, α-KG supplementation recovered the beneficial effects of butyrate in IDH1-deficient cells. CONCLUSION In summary, butyrate inhibits indices of colorectal carcinogenesis in an α-KG-dependent manner.
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Affiliation(s)
- Xiaofei Sun
- School of Food Science, Washington State University, Pullman, WA, 99164, USA
| | - Mei-Jun Zhu
- School of Food Science, Washington State University, Pullman, WA, 99164, USA
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20
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Leccioli V, Oliveri M, Romeo M, Berretta M, Rossi P. A New Proposal for the Pathogenic Mechanism of Non-Coeliac/Non-Allergic Gluten/Wheat Sensitivity: Piecing Together the Puzzle of Recent Scientific Evidence. Nutrients 2017; 9:nu9111203. [PMID: 29099090 PMCID: PMC5707675 DOI: 10.3390/nu9111203] [Citation(s) in RCA: 28] [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: 09/18/2017] [Revised: 10/27/2017] [Accepted: 10/31/2017] [Indexed: 12/12/2022] Open
Abstract
Non-coeliac/non-allergic gluten/wheat sensitivity (NCG/WS) is a gluten-related disorder, the pathogenesis of which remains unclear. Recently, the involvement of an increased intestinal permeability has been recognized in the onset of this clinical condition. However, mechanisms through which it takes place are still unclear. In this review, we attempt to uncover these mechanisms by providing, for the first time, an integrated vision of recent scientific literature, resulting in a new hypothesis about the pathogenic mechanisms involved in NCG/WS. According to this, the root cause of NCG/WS is a particular dysbiotic profile characterized by decreased butyrate-producing-Firmicutes and/or Bifidobacteria, leading to low levels of intestinal butyrate. Beyond a critical threshold of the latter, a chain reaction of events and vicious circles occurs, involving other protagonists such as microbial lipopolysaccharide (LPS), intestinal alkaline phosphatase (IAP) and wheat α-amylase trypsin inhibitors (ATIs). NCG/WS is likely to be a multi-factor-onset disorder, probably transient and preventable, related to quality and balance of the diet, and not to the presence of gluten in itself. If future studies confirm our proposal, this would have important implications both for the definition of the disease, as well as for the prevention and therapeutic-nutritional management of individuals with NCG/WS.
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Affiliation(s)
- Valentina Leccioli
- Department of Biology and Biotechnology "L. Spallanzani", University of Pavia, via Ferrata 1, 27100 Pavia, Italy.
| | - Mara Oliveri
- Department of Biology and Biotechnology "L. Spallanzani", University of Pavia, via Ferrata 1, 27100 Pavia, Italy.
| | - Marcello Romeo
- C.E.R.H.M. Center for Experimental Research for Human Microbiome Ludes H.E.I., Pietro Stiges Palace, Strait Street, 1436 Valletta, Malta.
| | - Massimiliano Berretta
- Department of Medical Oncology, CRO-Aviano, National Cancer Institute, Via Franco Gallini 2, 33081 Aviano, Italy.
| | - Paola Rossi
- Department of Biology and Biotechnology "L. Spallanzani", University of Pavia, via Ferrata 1, 27100 Pavia, Italy.
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21
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Dai LN, Yan JK, Xiao YT, Wen J, Zhang T, Zhou KJ, Wang Y, Cai W. Butyrate stimulates the growth of human intestinal smooth muscle cells by activation of yes-associated protein. J Cell Physiol 2017; 233:3119-3128. [PMID: 28834539 DOI: 10.1002/jcp.26149] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2017] [Accepted: 08/11/2017] [Indexed: 01/15/2023]
Abstract
Intestinal smooth muscle cells play a critical role in the remodeling of intestinal structure and functional adaptation after bowel resection. Recent studies have shown that supplementation of butyrate (Bu) contributes to the compensatory expansion of a muscular layer of the residual intestine in a rodent model of short-bowel syndrome (SBS). However, the underlying mechanism remains elusive. In this study, we found that the growth of human intestinal smooth muscle cells (HISMCs) was significantly stimulated by Bu via activation of Yes-Associated Protein (YAP). Incubation with 0.5 mM Bu induced a distinct proliferative effect on HISMCs, as indicated by the promotion of cell cycle progression and increased DNA replication. Notably, YAP silencing by RNA interference or its specific inhibitor significantly abolished the proliferative effect of Bu on HISMCs. Furthermore, Bu induced YAP expression and enhanced the translocation of YAP from the cytoplasm to the nucleus, which led to changes in the expression of mitogenesis genes, including TEAD1, TEAD4, CTGF, and Cyr61. These results provide evidence that Bu stimulates the growth of human intestinal muscle cells by activation of YAP, which may be a potential treatment for improving intestinal adaptation.
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Affiliation(s)
- Li-Na Dai
- Department of Pediatric Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Kongjiang Road, Shanghai, P.R. China
| | - Jun-Kai Yan
- Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai Institute for Pediatric Research, Shanghai, P.R. China
| | - Yong-Tao Xiao
- Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai Institute for Pediatric Research, Shanghai, P.R. China
| | - Jie Wen
- Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai Institute for Pediatric Research, Shanghai, P.R. China
| | - Tian Zhang
- Department of Pediatric Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Kongjiang Road, Shanghai, P.R. China
| | - Ke-Jun Zhou
- Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai Institute for Pediatric Research, Shanghai, P.R. China
| | - Yang Wang
- Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai Institute for Pediatric Research, Shanghai, P.R. China
| | - Wei Cai
- Department of Pediatric Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Kongjiang Road, Shanghai, P.R. China.,Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai Institute for Pediatric Research, Shanghai, P.R. China
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22
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Panasevich MR, Peppler WT, Oerther DB, Wright DC, Rector RS. Microbiome and NAFLD: potential influence of aerobic fitness and lifestyle modification. Physiol Genomics 2017; 49:385-399. [PMID: 28600319 DOI: 10.1152/physiolgenomics.00012.2017] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a chronic liver disease with prevalence rates that are on the rise in the US and worldwide. NAFLD encompasses a spectrum of liver pathologies including simple steatosis to nonalcoholic steatohepatitis (NASH) with inflammation and fibrosis. The gut microbiome has emerged as a potential therapeutic target in combating metabolic diseases including obesity, Type 2 diabetes, and NAFLD/NASH. Diet-induced obesity/Western style diet feeding causes severe microbial dysbiosis initiating a microbiome signature that promotes metabolite production that directly impacts hepatic metabolism. Changes in lifestyle (i.e., diet, exercise, and aerobic fitness) improve NAFLD outcomes and can significantly influence the microbiome. However, directly linking lifestyle-induced remodeling of the microbiome to NAFLD pathogenesis is not well understood. Understanding the reshaping of the microbiome and the metabolites produced and their subsequent actions on hepatic metabolism are vital in understanding the gut-liver axis. In this review, we 1) discuss microbiome-derived metabolites that significantly contribute to the gut-liver axis and are directly linked to NAFLD/NASH and 2) present evidence on lifestyle modifications reshaping the microbiome and the potential therapeutic aspects in combating the disease.
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Affiliation(s)
- Matthew R Panasevich
- Research Service, Harry S Truman Memorial Veterans Medical Center, Columbia, Missouri.,Department of Medicine, Division of Gastroenterology and Hepatology, University of Missouri, Columbia, Missouri.,Department of Nutrition and Exercise Physiology; University of Missouri, Columbia, Missouri
| | - Willem T Peppler
- Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, Ontario, Canada
| | - Daniel B Oerther
- Department of Civil, Architectural, and Environmental Engineering, Missouri University of Science and Technology, Rolla, Missouri; and
| | - David C Wright
- Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, Ontario, Canada
| | - R Scott Rector
- Research Service, Harry S Truman Memorial Veterans Medical Center, Columbia, Missouri; .,Department of Medicine, Division of Gastroenterology and Hepatology, University of Missouri, Columbia, Missouri.,Department of Nutrition and Exercise Physiology; University of Missouri, Columbia, Missouri
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23
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Nurdin SU, Le Leu RK, Young GP, Stangoulis JCR, Christophersen CT, Abbott CA. Analysis of the Anti-Cancer Effects of Cincau Extract (Premna oblongifolia Merr) and Other Types of Non-Digestible Fibre Using Faecal Fermentation Supernatants and Caco-2 Cells as a Model of the Human Colon. Nutrients 2017; 9:nu9040355. [PMID: 28368356 PMCID: PMC5409694 DOI: 10.3390/nu9040355] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2016] [Revised: 03/16/2017] [Accepted: 03/29/2017] [Indexed: 02/04/2023] Open
Abstract
Green cincau (Premna oblongifolia Merr) is an Indonesian food plant with a high dietary fibre content. Research has shown that dietary fibre mixtures may be more beneficial for colorectal cancer prevention than a single dietary fibre type. The aim of this study was to investigate the effects of green cincau extract on short chain fatty acid (SCFA) production in anaerobic batch cultures inoculated with human faecal slurries and to compare these to results obtained using different dietary fibre types (pectin, inulin, and cellulose), singly and in combination. Furthermore, fermentation supernatants (FSs) were evaluated in Caco-2 cells for their effect on cell viability, differentiation, and apoptosis. Cincau increased total SCFA concentration by increasing acetate and propionate, but not butyrate concentration. FSs from all dietary fibre sources, including cincau, reduced Caco-2 cell viability. However, the effects of all FSs on cell viability, cell differentiation, and apoptosis were not simply explainable by their butyrate content. In conclusion, products of fermentation of cincau extracts induced cell death, but further work is required to understand the mechanism of action. This study demonstrates for the first time that this Indonesian traditional source of dietary fibre may be protective against colorectal cancer.
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Affiliation(s)
- Samsu U Nurdin
- School of Biological Sciences, Flinders University, Adelaide, SA 5042, Australia.
- Department of Agricultural Product Technology, Lampung University, Bandar Lampung 35145, Indonesia.
- Flinders Centre for Innovation in Cancer, Adelaide, SA 5042, Australia.
| | - Richard K Le Leu
- Flinders Centre for Innovation in Cancer, Adelaide, SA 5042, Australia.
- CSIRO Food and Nutrition, Adelaide, SA 5000, Australia.
| | - Graeme P Young
- Flinders Centre for Innovation in Cancer, Adelaide, SA 5042, Australia.
| | - James C R Stangoulis
- School of Biological Sciences, Flinders University, Adelaide, SA 5042, Australia.
| | - Claus T Christophersen
- CSIRO Food and Nutrition, Adelaide, SA 5000, Australia.
- School of Medical and Health Sciences, Edith Cowan University, Joondalup, WA 6027, Australia.
| | - Catherine A Abbott
- School of Biological Sciences, Flinders University, Adelaide, SA 5042, Australia.
- Flinders Centre for Innovation in Cancer, Adelaide, SA 5042, Australia.
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24
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Uchiyama K, Sakiyama T, Hasebe T, Musch MW, Miyoshi H, Nakagawa Y, He TC, Lichtenstein L, Naito Y, Itoh Y, Yoshikawa T, Jabri B, Stappenbeck T, Chang EB. Butyrate and bioactive proteolytic form of Wnt-5a regulate colonic epithelial proliferation and spatial development. Sci Rep 2016; 6:32094. [PMID: 27561676 PMCID: PMC4999796 DOI: 10.1038/srep32094] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2016] [Accepted: 08/01/2016] [Indexed: 12/13/2022] Open
Abstract
Proliferation and spatial development of colonic epithelial cells are highly regulated along the crypt vertical axis, which, when perturbed, can result in aberrant growth and carcinogenesis. In this study, two key factors were identified that have important and counterbalancing roles regulating these processes: pericrypt myofibroblast-derived Wnt-5a and the microbial metabolite butyrate. Cultured YAMC cell proliferation and heat shock protein induction were analzyed after butryate, conditioned medium with Wnt5a activity, and FrzB containing conditioned medium. In vivo studies to modulate Hsp25 employed intra-colonic wall Hsp25 encoding lentivirus. To silence Wnt-5a in vivo, intra-colonic wall Wnt-5a silencing RNA was used. Wnt-5a, secreted by stromal myofibroblasts of the lower crypt, promotes proliferation through canonical β-catenin activation. Essential to this are two key requirements: (1) proteolytic conversion of the highly insoluble ~40 kD Wnt-5a protein to a soluble 36 mer amino acid peptide that activates epithelial β-catenin and cellular proliferation, and (2) the simultaneous inhibition of butyrate-induced Hsp25 by Wnt-5a which is necessary to arrest the proliferative process in the upper colonic crypt. The interplay and spatial gradients of these factors insures that crypt epithelial cell proliferation and development proceed in an orderly fashion, but with sufficient plasticity to adapt to physiological perturbations including inflammation.
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Affiliation(s)
- Kazuhiko Uchiyama
- Department of Medicine, University of Chicago, Chicago, IL 60637; USA.,Department of Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto 6028566; Japan
| | - Toshio Sakiyama
- Department of Medicine, University of Chicago, Chicago, IL 60637; USA.,Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima 8908520; Japan
| | - Takumu Hasebe
- Department of Medicine, University of Chicago, Chicago, IL 60637; USA
| | - Mark W Musch
- Department of Medicine, University of Chicago, Chicago, IL 60637; USA
| | - Hiroyuki Miyoshi
- Department of Pathology, Washington University at St. Louis, St. Louis, MO, USA
| | - Yasushi Nakagawa
- Department of Medicine, University of Chicago, Chicago, IL 60637; USA
| | - Tong-Chuan He
- Department of Surgery, University of Chicago; Chicago, IL 60637; USA
| | - Lev Lichtenstein
- Department of Medicine, University of Chicago, Chicago, IL 60637; USA.,Department of Gastroenterology, Soroka University Medical Center, Beer-Sheva 84101; Israel
| | - Yuji Naito
- Department of Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto 6028566; Japan
| | - Yoshito Itoh
- Department of Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto 6028566; Japan
| | - Toshikazu Yoshikawa
- Department of Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto 6028566; Japan
| | - Bana Jabri
- Department of Medicine, University of Chicago, Chicago, IL 60637; USA
| | | | - Eugene B Chang
- Department of Medicine, University of Chicago, Chicago, IL 60637; USA
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25
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Abstract
Highlights Fermentation of the dietary fiber by intestinal microflora results in production of butyrate.Butyrate possesses anticarcinogenic effect at the colonic level.Three transporters (MCT1, SMCT1 and BCRP) regulate the intracellular concentration of BT in colonic epithelial cells.Changes in the expression of these transporters occur in colorectal cancer. Abstract Colorectal cancer (CRC) is one of the most common solid tumors worldwide. Consumption of dietary fiber is associated with a low risk of developing CRC. The fermentation of the dietary fiber by intestinal microflora results in production of butyrate (BT). This short-chain fatty acid is an important metabolic substrate in normal colonic epithelial cells and has important homeostatic functions at the colonic level. Because the cellular effects of BT (e.g. inhibition of histone deacetylases) are dependent on its intracellular concentration, knowledge on the mechanisms involved in BT membrane transport and its regulation seems particularly relevant. In this review, we will present the carrier-mediated mechanisms involved in BT membrane transport at the colonic epithelial level and their regulation, with an emphasis on CRC. Several xenobiotics known to modulate the risk for developing CRC are able to interfere with BT transport at the intestinal level. Thus, interference with BT transport certainly contributes to the anticarcinogenic or procarcinogenic effect of these compounds and these compounds may interfere with the anticarcinogenic effect of BT. Finally, we suggest that differences in BT transport between normal colonocytes and tumoral cells contribute to the "BT paradox" (the apparent opposing effect of BT in CRC cells and normal colonocytes).
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Dasgupta N, Thakur BK, Ta A, Dutta P, Das S. Suppression of Spleen Tyrosine Kinase (Syk) by Histone Deacetylation Promotes, Whereas BAY61-3606, a Synthetic Syk Inhibitor Abrogates Colonocyte Apoptosis by ERK Activation. J Cell Biochem 2016; 118:191-203. [PMID: 27293079 DOI: 10.1002/jcb.25625] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2015] [Accepted: 06/10/2016] [Indexed: 01/10/2023]
Abstract
Spleen tyrosine kinase (Syk), a non-receptor tyrosine kinase, regulates tumor progression, either negatively or positively, depending on the tissue lineage. Information about the role of Syk in colorectal cancers (CRC) is limited, and conflicting reports have been published. We studied Syk expression and its role in differentiation and apoptosis of the colonocytes. Here, we reported for the first time that expression of two transcript variants of Syk is suppressed in colonocytes during butyrate-induced differentiation, which mediates apoptosis of HT-29 cells. Despite being a known HDAC inhibitor, butyrate deacetylates histone3/4 around the transcription start site (TSS) of Syk. Histone deacetylation precludes the binding of RNA Polymerase II to the promoter and inhibits transcription. Since butyrate is a colonic metabolite derived from undigested fibers, our study offers a plausible explanation of the underlying mechanisms of the protective role of butyrate as well as the dietary fibers against CRC through the regulation of Syk. We also report that combined use of butyrate and highly specific Syk inhibitor BAY61-3606 does not enhance differentiation and apoptosis of colonocytes. Instead, BAY completely abolishes butyrate-induced differentiation and apoptosis in a Syk- and ERK1/2-dependent manner. While butyrate dephosphorylates ERK1/2 in HT-29 cells, BAY re-phosphorylates it, leading to its activation. This study describes a novel mechanism of butyrate action in CRC and explores the role of Syk in butyrate-induced differentiation and apoptosis. In addition, our study highlights those commercial small molecule inhibitors, although attractive drug candidates should be used with concern because of their frequent off-target effects. J. Cell. Biochem. 118: 191-203, 2017. © 2016 Wiley Periodicals, Inc.
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Affiliation(s)
- Nirmalya Dasgupta
- Department of Clinical Medicine, National Institute of Cholera and Enteric Diseases, P-33, C.I.T. Road, Scheme XM, Beliaghata, Kolkata 700010, India
| | - Bhupesh Kumar Thakur
- Department of Clinical Medicine, National Institute of Cholera and Enteric Diseases, P-33, C.I.T. Road, Scheme XM, Beliaghata, Kolkata 700010, India
| | - Atri Ta
- Department of Clinical Medicine, National Institute of Cholera and Enteric Diseases, P-33, C.I.T. Road, Scheme XM, Beliaghata, Kolkata 700010, India
| | - Pujarini Dutta
- Department of Clinical Medicine, National Institute of Cholera and Enteric Diseases, P-33, C.I.T. Road, Scheme XM, Beliaghata, Kolkata 700010, India
| | - Santasabuj Das
- Department of Clinical Medicine, National Institute of Cholera and Enteric Diseases, P-33, C.I.T. Road, Scheme XM, Beliaghata, Kolkata 700010, India
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SHI XINPENG, LUO XIAOYONG, YAN QINGQING, ZHANG WENJING, WU YAO, ZHANG MENGNAN, ZHAO JINJUN, PENG YING, CHEN YE, ZHANG YALI, CHEN CUNLONG, CHENG TIANMING, CHEN CHUDI, LIU SIDE, BAI YANG, WANG JIDE. Suppression of KLF8 induces cell differentiation and sensitizes colorectal cancer to 5-fluorouracil. Oncol Rep 2015; 34:1221-30. [PMID: 26133391 DOI: 10.3892/or.2015.4094] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2015] [Accepted: 05/20/2015] [Indexed: 11/05/2022] Open
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A novel class I HDAC inhibitor, MPT0G030, induces cell apoptosis and differentiation in human colorectal cancer cells via HDAC1/PKCδ and E-cadherin. Oncotarget 2015; 5:5651-62. [PMID: 25015091 PMCID: PMC4170623 DOI: 10.18632/oncotarget.2155] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
Abstract
Accumulation of genetic and epigenetic changes contributes to cancer development and progression. Compared with gene mutations or deletions, epigenetic changes are reversible, which alter the chromatin structure remodeling instead of changes in DNA sequence, and therefore become a promising strategy for chemotherapy. Histone deacetylases (HDACs) are a class of enzymes that responsible for the epigenetic regulation of gene expression. MPT0G030 is a potent and selective class I HDAC inhibitor which showed broad-spectrum cytotoxicity against various human cancer cell lines. in vitro fluorometric HDAC activity assay showed that MPT0G030 effectively inhibited Class I HDACs (HDAC1~3), which were overexpressed in many malignant neoplasms. Interestingly, MPT0G030 not only induced histone acetylation and tumor suppressor p21 transcription, but also redistributed E-cadherin and activated Protein Kinase C δ (PKCδ), which was linked to cell apoptosis and differentiation. Further, activation of PKCδ was demonstrated to be modulated through HDAC1. The in vivo anticancer activity of MPT0G030 and the importance of PKCδ were confirmed in the HT-29 tumor xenograft models. Taken together, those results indicate that MPT0G030, a class I HDAC inhibitor, has great potential as a new drug candidate for cancer therapy.
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Dasgupta N, Kumar Thakur B, Ta A, Das S. Caveolin-1 is transcribed from a hypermethylated promoter to mediate colonocyte differentiation and apoptosis. Exp Cell Res 2015; 334:323-36. [DOI: 10.1016/j.yexcr.2015.03.020] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2015] [Revised: 03/23/2015] [Accepted: 03/24/2015] [Indexed: 11/28/2022]
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Chernet BT, Levin M. Transmembrane voltage potential of somatic cells controls oncogene-mediated tumorigenesis at long-range. Oncotarget 2015; 5:3287-306. [PMID: 24830454 PMCID: PMC4102810 DOI: 10.18632/oncotarget.1935] [Citation(s) in RCA: 89] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
The microenvironment is increasingly recognized as a crucial aspect of cancer. In contrast and complement to the field's focus on biochemical factors and extracellular matrix, we characterize a novel aspect of host:tumor interaction - endogenous bioelectric signals among non-excitable somatic cells. Extending prior work focused on the bioelectric state of cancer cells themselves, we show for the first time that the resting potentials of distant cells are critical for oncogene-dependent tumorigenesis. In the Xenopus laevis tadpole model, we used human oncogenes such as mutant KRAS to drive formation of tumor-like structures that exhibited overproliferation, increased nuclear size, hypoxia, acidity, and leukocyte attraction. Remarkably, misexpression of hyperpolarizing ion channels at distant sites within the tadpole significantly reduced the incidence of these tumors. The suppression of tumorigenesis could also be achieved by hyperpolarization using native CLIC1 chloride channels, suggesting a treatment modality not requiring gene therapy. Using a dominant negative approach, we implicate HDAC1 as the mechanism by which resting potential changes affect downstream cell behaviors. Based on published data on the voltage-mediated changes of butyrate flux through the SLC5A8 transporter, we present a model linking resting potentials of host cells to the ability of oncogenes to initiate tumorigenesis. Antibiotic data suggest that the relevant butyrate is generated by a native bacterial species, identifying a novel link between the microbiome and cancer that is mediated by alterations in bioelectric signaling.
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Affiliation(s)
- Brook T Chernet
- Center for Regenerative and Developmental Biology and Department of Biology Tufts University 200 Boston Avenue,Suite 4600 Medford, MA 02155 U.S.A
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Paula AV, Nunes GFM, Osório NM, Santos JC, de Castro HF, Ferreira-Dias S. Continuous enzymatic interesterification of milkfat with soybean oil produces a highly spreadable product rich in polyunsaturated fatty acids. EUR J LIPID SCI TECH 2014. [DOI: 10.1002/ejlt.201400316] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Affiliation(s)
- Ariela V. Paula
- Faculty of Pharmaceutical Sciences; UNESP - State University “Júlio de Mesquita Filho”; Departament of Bioprocess and Biotechnology; Araraquara SP Brazil
| | - Gisele F. M. Nunes
- Engineering School of Lorena; University of São Paulo; Biotechnology Department; Lorena São Paulo Brazil
| | - Natália M. Osório
- Instituto Superior de Agronomia; University of Lisbon; CEER; Biosystems Engineering; Lisbon Portugal
| | - Júlio C. Santos
- Engineering School of Lorena; University of São Paulo; Biotechnology Department; Lorena São Paulo Brazil
| | - Heizir F. de Castro
- Engineering School of Lorena; University of São Paulo; Chemical Engineering Department; Lorena São Paulo Brazil
| | - Suzana Ferreira-Dias
- Instituto Superior de Agronomia; University of Lisbon; CEER; Biosystems Engineering; Lisbon Portugal
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Wang N, Chen Y, Yang X, Jiang Y. Selenium-binding protein 1 is associated with the degree of colorectal cancer differentiation and is regulated by histone modification. Oncol Rep 2014; 31:2506-14. [PMID: 24737289 DOI: 10.3892/or.2014.3141] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2013] [Accepted: 02/24/2014] [Indexed: 01/05/2023] Open
Abstract
The aim of the present study was to examine the regulation of selenium binding protein 1 (SELENBP1) expression in colorectal cancer (CRC). Samples of cancer tissue and adjacent normal mucosa were collected from 83 CRC patients, and analyzed for SELENBP1 expression by 2D-DIGE, immunoblotting, RT-PCR and immunostaining. Expression levels of SELENBP1, carcinoembryonic antigen (CEA) and alkaline phosphatase (AKP) were determined in cultures of human colon cancer cell lines (SW480, SW620 and HT29) folllowing treatment with i) sodium butyrate (NaB, 2 mM), a differentiation inducer; ii) Trichostatin A (TSA, 0.3 µM), a histone deacetylase inhibitor; or iii) 5'-aza-2'-deoxycytidine (5-Aza-dC, 5 µM), a DNA methylation inhibitor. SELENBP1 expression was found to be downregulated (2.54-fold) in the CRC samples as determined by 2D-DIGE and confirmed by immunoblotting and RT-PCR. SELENBP1 expression was correlated with the degree of differentiation, but not with TNM stage or lymph node metastasis, and was higher in benign polyps (1.97±0.57) than in CRC tissues (0.96±0.59). In the CRC cell lines, NaB treatment led to the upregulation of SELENBP1, CEA and AKP when compared with the untreated cells (2.24- to 4.82-fold). SELENBP1 was also upregulated in cells treated with TSA alone (1.25- to 3.64-fold), or in combination with 5-Aza-dC (1.32- to 4.13-fold). In CRC, the downregulated SELENBP1 expression was reactivated by inducing differentiation. Therefore, SELENBP1 is a potential pharmacological target for individualized CRC treatment.
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Affiliation(s)
- Ning Wang
- Department of General Surgery, The First Hospital, China Medical University, Shenyang, Liaoning 110001, P.R. China
| | - Yang Chen
- Central Experimental Laboratory, The First Hospital, China Medical University, Shenyang, Liaoning 110001, P.R. China
| | - Xinghua Yang
- Department of General Surgery, The First Hospital, China Medical University, Shenyang, Liaoning 110001, P.R. China
| | - Yi Jiang
- Central Experimental Laboratory, The First Hospital, China Medical University, Shenyang, Liaoning 110001, P.R. China
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Kato R, Matsui-Yuasa I, Azuma H, Kojima-Yuasa A. The synergistic effect of 1′-acetoxychavicol acetate and sodium butyrate on the death of human hepatocellular carcinoma cells. Chem Biol Interact 2014; 212:1-10. [DOI: 10.1016/j.cbi.2014.01.010] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2013] [Revised: 12/24/2013] [Accepted: 01/17/2014] [Indexed: 12/30/2022]
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Cancer cell sensitization and improved treatment efficacy by combined sodium butyrate and paclitaxel formulations is cancer-type specific. Int J Pharm 2013; 461:437-47. [PMID: 24370842 DOI: 10.1016/j.ijpharm.2013.12.021] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2013] [Accepted: 12/14/2013] [Indexed: 11/22/2022]
Abstract
We queried whether cancer treatment by combinations of paclitaxel and butyrate - free or formulated in drug delivery systems - can improve therapeutic responses compared to each drug alone. Combination treatments were conducted with HT-29 and HeLa cells, as representatives of differentiation-induced and cell-death-induced cancer lines, respectively. Pre-treatment of the HT-29 cells with butyrate (at doses inducing differentiation), followed by butyrate+paclitaxel generated changes in cell cycle profile, increased the level of dead cells beyond that of each drug alone, and allowed reduction in paclitaxel doses. A similar combination treatment of HeLa cells was detrimental, indicating that whether the combination is beneficial or not is cancer-type specific. We hypothesize that while butyrate-treated HT-29 cells became sensitive to paclitaxel-induced Fas-mediated apoptosis, butyrate-adapted HeLa cells became apoptosis-resistant. We next tested the same drug combination on HT-29 cells, but each drug in a specific tumor-targeted carrier. The combination of drug carriers outperformed an equidose combination of the free drugs, showing potential to achieve high therapeutic responses (even in drug-resistant cells) at significantly lower and detergent-free paclitaxel doses, which should allow for reduction in adverse effects and risks of toxicity.
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35
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Rawłuszko AA, Antoniucci M, Horbacka K, Lianeri M, Krokowicz P, Jagodziński PP. Reduced expression of steroid sulfatase in primary colorectal cancer. Biomed Pharmacother 2013; 67:577-82. [PMID: 23916543 DOI: 10.1016/j.biopha.2013.04.007] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2013] [Accepted: 04/19/2013] [Indexed: 02/07/2023] Open
Abstract
Colorectal cancer (CRC) is considered an estrogen-dependent malignancy, and intratissue estrogen concentration can be controlled by steroid sulfatase (STS). Little is known about changes in the expression of STS during the development of CRC. Therefore, we analysed the STS mRNA levels in primary colonic adenocarcinoma tissues and adjacent histopathologically unchanged colonic mucosa from patients who underwent radical colon resection (n=90). We found a statistically significant decrease in STS transcript levels in CRC (P=0.0453). Moreover, we found that sodium butyrate (NaBu) significantly upregulated STS transcript levels in DLD-1 and HCT116 CRC cells. Our results suggest that STS expression can be decreased in the process of large intestinal carcinogenesis. Moreover, we observed that NaBu might increase STS expression in CRC cells.
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Affiliation(s)
- Agnieszka Anna Rawłuszko
- Department of Biochemistry and Molecular Biology, Poznań University of Medical Sciences, Poznań, Poland
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36
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Xu Y, Zou ST, Zhu R, Li W, Gu CW, Wei SH, Xie JM, Wu HR. Inhibition of proliferation of estrogen receptor‑positive MCF‑7 human breast cancer cells by tamoxifen through c‑Jun transcription factors. Mol Med Rep 2013; 7:1283-7. [PMID: 23404426 DOI: 10.3892/mmr.2013.1306] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2012] [Accepted: 01/21/2013] [Indexed: 11/06/2022] Open
Abstract
Activator of protein 1 (AP-1) is a heterodimeric transcription factor composed of various members of the Jun and Fos families and binds to DNA at specific AP-1 binding sites. AP-1 transcriptional activity is increased by phosphorylation at serine residues in the c‑Jun component of AP-1. In the present study, the proliferation of MCF-7 breast cancer cells was found to be suppressed by tamoxifen (TAM)-activated c-Jun through the protein kinase C (PKC) pathway. The molecular mechanism by which c‑Jun activation induces antiproliferative signals in estrogen receptor (ER)-positive MCF-7 human breast cancer cells remains unknown. TAM inhibited the proliferation of ER-positive MCF-7 human breast cancer cells and ER-negative MDA-MB-435 human breast cancer cells and 48 h incubation with 10 µM TAM led to inhibition of 80% of proliferation. In addition, no significant difference in c-Jun mRNA and protein levels was detected in MCF-7 and MDA-MB-435 cells stimulated by TAM for 48 h. TAM treatment of MCF-7 cells activated the transcriptional activity of AP-1, which responds specifically to phorbol ester. To determine the role of c-Jun in the antiproliferation of MCF-7 cells stimulated by TAM, the inhibition rates of MCF‑7 cells were correlated with c‑Jun expression and stimulation of TAM. Results showed that the inhibition rate of TAM-stimulated MCF-7 cells was positively regulated by overexpression of c-Jun and negatively regulated by underexpression of c-Jun. Overall, these results indicate that the TAM-stimulated antiproliferation of MCF-7 cells is positively regulated by c-Jun through activation of the PKC pathway.
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Affiliation(s)
- Yan Xu
- Department of General Surgery, Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215004, P.R China
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Adnan H, Quach H, MacIntosh K, Antenos M, Kirby GM. Low levels of GSTA1 expression are required for Caco-2 cell proliferation. PLoS One 2012; 7:e51739. [PMID: 23251616 PMCID: PMC3519693 DOI: 10.1371/journal.pone.0051739] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2012] [Accepted: 11/09/2012] [Indexed: 01/16/2023] Open
Abstract
The colonic epithelium continuously regenerates with transitions through various cellular phases including proliferation, differentiation and cell death via apoptosis. Human colonic adenocarcinoma (Caco-2) cells in culture undergo spontaneous differentiation into mature enterocytes in association with progressive increases in expression of glutathione S-transferase alpha-1 (GSTA1). We hypothesize that GSTA1 plays a functional role in controlling proliferation, differentiation and apoptosis in Caco-2 cells. We demonstrate increased GSTA1 levels associated with decreased proliferation and increased expression of differentiation markers alkaline phosphatase, villin, dipeptidyl peptidase-4 and E-cadherin in postconfluent Caco-2 cells. Results of MTS assays, BrdU incorporation and flow cytometry indicate that forced expression of GSTA1 significantly reduces cellular proliferation and siRNA-mediated down-regulation of GSTA1 significantly increases cells in S-phase and associated cell proliferation. Sodium butyrate (NaB) at a concentration of 1 mM reduces Caco-2 cell proliferation, increases differentiation and increases GSTA1 activity 4-fold by 72 hours. In contrast, 10 mM NaB causes significant toxicity in preconfluent cells via apoptosis through caspase-3 activation with reduced GSTA1 activity. However, GSTA1 down-regulation by siRNA does not alter NaB-induced differentiation or apoptosis in Caco-2 cells. While 10 mM NaB causes GSTA1-JNK complex dissociation, phosphorylation of JNK is not altered. These findings suggest that GSTA1 levels may play a role in modulating enterocyte proliferation but do not influence differentiation or apoptosis.
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Affiliation(s)
- Humaira Adnan
- Department of Biomedical Sciences, University of Guelph, Ontario, Canada
| | - Holly Quach
- Department of Biomedical Sciences, University of Guelph, Ontario, Canada
| | | | - Monica Antenos
- Department of Biomedical Sciences, University of Guelph, Ontario, Canada
| | - Gordon M. Kirby
- Department of Biomedical Sciences, University of Guelph, Ontario, Canada
- * E-mail:
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Yu LCH, Wang JT, Wei SC, Ni YH. Host-microbial interactions and regulation of intestinal epithelial barrier function: From physiology to pathology. World J Gastrointest Pathophysiol 2012; 3:27-43. [PMID: 22368784 PMCID: PMC3284523 DOI: 10.4291/wjgp.v3.i1.27] [Citation(s) in RCA: 176] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/11/2011] [Revised: 10/04/2011] [Accepted: 02/08/2012] [Indexed: 02/06/2023] Open
Abstract
The gastrointestinal tract is the largest reservoir of commensal bacteria in the human body, providing nutrients and space for the survival of microbes while concurrently operating mucosal barriers to confine the microbial population. The epithelial cells linked by tight junctions not only physically separate the microbiota from the lamina propria, but also secrete proinflammatory cytokines and reactive oxygen species in response to pathogen invasion and metabolic stress and serve as a sentinel to the underlying immune cells. Accumulating evidence indicates that commensal bacteria are involved in various physiological functions in the gut and microbial imbalances (dysbiosis) may cause pathology. Commensal bacteria are involved in the regulation of intestinal epithelial cell turnover, promotion of epithelial restitution and reorganization of tight junctions, all of which are pivotal for fortifying barrier function. Recent studies indicate that aberrant bacterial lipopolysaccharide-mediated signaling in gut mucosa may be involved in the pathogenesis of chronic inflammation and carcinogenesis. Our perception of enteric commensals has now changed from one of opportunistic pathogens to active participants in maintaining intestinal homeostasis. This review attempts to explain the dynamic interaction between the intestinal epithelium and commensal bacteria in disease and health status.
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Effect of butyrate on aromatase cytochrome P450 levels in HT29, DLD-1 and LoVo colon cancer cells. Biomed Pharmacother 2012; 66:77-82. [PMID: 22386365 DOI: 10.1016/j.biopha.2011.12.001] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2011] [Accepted: 12/15/2011] [Indexed: 02/07/2023] Open
Abstract
Epidemiological studies suggest that colonic production of butyrate and estrogen may be involved in human susceptibility to colorectal cancer (CRC). Estrone (E1) can be produced by the aromatase pathway during the conversion of androstenedione (A) to E1. Therefore, we studied the effect of sodium butyrate (NaBu) on the CYP19A1 transcript and protein levels and on the conversion of A to E1 in HT29, DLD-1 and LoVo CRC cells. We found that NaBu significantly downregulated CYP19A1 transcript and protein levels, a phenomenon that was associated with reduced conversion of A to E1 in HT29, DLD-1 and LoVo cells. Our studies demonstrated that, although butyrate exhibited a protective role in CRC development, this compound may reduce aromatase activity and the production of E1 in colon cancer cells.
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40
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Jiang W, Guo Q, Wu J, Guo B, Wang Y, Zhao S, Lou H, Yu X, Mei X, Wu C, Qiao S, Wu Y. Dual effects of sodium butyrate on hepatocellular carcinoma cells. Mol Biol Rep 2012; 39:6235-42. [PMID: 22228088 DOI: 10.1007/s11033-011-1443-5] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2011] [Accepted: 12/27/2011] [Indexed: 01/09/2023]
Abstract
Sodium butyrate (NaBu), a histone deacetylase inhibitor, has been shown to inhibit cell growth, induce cell differentiation and apoptosis in multiple cell lines. In present study, we revealed the dual effects of NaBu in regulating hepatocellular carcinoma (HCC) cells. In two different HCC cell lines, SK-Hep1 and SMMC-7721, low concentrations of NaBu induced a significant increase in cell growth ratio and S-phase cell percentage, accompanied by a reduced p21 Cip1 expression at both mRNA and protein levels, while dissimilarly, high concentrations of NaBu inhibited cell growth and induced G1 arrest through up-regulation of p21 Cip1 and p27 Kip1 protein expression. The reduction of p45 Skp2 expression further indicated that the ubiquitin-mediated protein degradation might play a role in NaBu-induced up-regulation of p21 Cip1 and p27 Kip1. Moreover, the high concentration of NaBu was also able to trigger HCC cell apoptosis. Taken together, these results demonstrate the distinct effects of NaBu at different dosages. This finding may contribute to develop more effective tumor therapeutic protocols of NaBu in HCC.
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Affiliation(s)
- Wenjun Jiang
- State Key Laboratory of Genetic Engineering, Institute of Genetics, Fudan University, 220 Handan Road, Shanghai, 200433, People's Republic of China
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Cerbone A, Toaldo C, Pizzimenti S, Pettazzoni P, Dianzani C, Minelli R, Ciamporcero E, Roma G, Dianzani MU, Canaparo R, Ferretti C, Barrera G. AS601245, an Anti-Inflammatory JNK Inhibitor, and Clofibrate Have a Synergistic Effect in Inducing Cell Responses and in Affecting the Gene Expression Profile in CaCo-2 Colon Cancer Cells. PPAR Res 2012; 2012:269751. [PMID: 22619672 PMCID: PMC3349252 DOI: 10.1155/2012/269751] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2011] [Revised: 10/29/2011] [Accepted: 11/01/2011] [Indexed: 12/13/2022] Open
Abstract
PPARαs are nuclear receptors highly expressed in colon cells. They can be activated by the fibrates (clofibrate, ciprofibrate etc.) used to treat hyperlipidemia. Since PPARα transcriptional activity can be negatively regulated by JNK, the inhibition of JNK activity could increase the effectiveness of PPARα ligands. We analysed the effects of AS601245 (a JNK inhibitor) and clofibrate alone or in association, on proliferation, apoptosis, differentiation and the gene expression profile of CaCo-2 human colon cancer cells. Proliferation was inhibited in a dose-dependent way by clofibrate and AS601245. Combined treatment synergistically reduced cell proliferation, cyclin D1 and PCNA expression and induced apoptosis and differentiation. Reduction of cell proliferation, accompanied by the modulation of p21 expression was observed in HepG2 cells, also. Gene expression analysis revealed that some genes were highly modulated by the combined treatment and 28 genes containing PPRE were up-regulated, while clofibrate alone was ineffective. Moreover, STAT3 signalling was strongly reduced by combined treatment. After combined treatment, the binding of PPARα to PPRE increased and paralleled with the expression of the PPAR coactivator MED1. Results demonstrate that combined treatment increases the effectiveness of both compounds and suggest a positive interaction between PPARα ligands and anti-inflammatory agents in humans.
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Affiliation(s)
- Angelo Cerbone
- 1MerckSerono Ivrea, Istituto di Ricerche Biomediche “A. Marxer”, RBM S.p.A., 10010 Colleretto Giacosa, Italy
| | - Cristina Toaldo
- 2Department of Medicine and Experimental Oncology, Section of General Pathology, University of Turin, 10125 Turin, Italy
- *Cristina Toaldo:
| | - Stefania Pizzimenti
- 2Department of Medicine and Experimental Oncology, Section of General Pathology, University of Turin, 10125 Turin, Italy
| | - Piergiorgio Pettazzoni
- 2Department of Medicine and Experimental Oncology, Section of General Pathology, University of Turin, 10125 Turin, Italy
| | - Chiara Dianzani
- 3Department of Anatomy, Pharmacology and Forensic Medicine, Section of Pharmacology and Pharmacognosy, University of Turin,10125 Turin, Italy
| | - Rosalba Minelli
- 3Department of Anatomy, Pharmacology and Forensic Medicine, Section of Pharmacology and Pharmacognosy, University of Turin,10125 Turin, Italy
| | - Eric Ciamporcero
- 2Department of Medicine and Experimental Oncology, Section of General Pathology, University of Turin, 10125 Turin, Italy
| | - Guglielmo Roma
- 1MerckSerono Ivrea, Istituto di Ricerche Biomediche “A. Marxer”, RBM S.p.A., 10010 Colleretto Giacosa, Italy
| | - Mario Umberto Dianzani
- 2Department of Medicine and Experimental Oncology, Section of General Pathology, University of Turin, 10125 Turin, Italy
| | - Roberto Canaparo
- 4Department of Anatomy, Pharmacology, and Forensic Medicine, Section of Pharmacology and Experimental Therapy, University of Turin, 10125 Turin, Italy
| | - Carlo Ferretti
- 4Department of Anatomy, Pharmacology, and Forensic Medicine, Section of Pharmacology and Experimental Therapy, University of Turin, 10125 Turin, Italy
| | - Giuseppina Barrera
- 2Department of Medicine and Experimental Oncology, Section of General Pathology, University of Turin, 10125 Turin, Italy
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Schlörmann W, Hiller B, Jahns F, Zöger R, Hennemeier I, Wilhelm A, Lindhauer MG, Glei M. Chemopreventive effects of in vitro digested and fermented bread in human colon cells. Eur J Nutr 2011; 51:827-39. [PMID: 22033853 DOI: 10.1007/s00394-011-0262-8] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2011] [Accepted: 10/07/2011] [Indexed: 12/19/2022]
Abstract
PURPOSE Bread as a staple food product represents an important source for dietary fibre consumption. Effects of wheat bread, wholemeal wheat bread and wholemeal rye bread on mechanisms which could have impact on chemoprevention were analysed in colon cells after in vitro fermentation. METHODS Effects of fermented bread samples on gene expression, glutathione S-transferase activity and glutathione content, differentiation, growth and apoptosis were investigated using the human colon adenoma cell line LT97. Additionally, apoptosis was studied in normal and tumour colon tissue by determination of caspase activities. RESULTS The expression of 76 genes (biotransformation, differentiation, apoptosis) was significantly upregulated (1.5-fold) in LT97 cells. The fermented bread samples were able to significantly increase glutathione S-transferase activity (1.8-fold) and glutathione content (1.4-fold) of the cells. Alkaline phosphatase activity as a marker of differentiation was also significantly enhanced (1.7-fold). The fermented bread samples significantly inhibited LT97 cell growth and increased the level of apoptotic cells (1.8-fold). Only marginal effects on apoptosis in tumour compared to normal tissue were observed. CONCLUSIONS This is the first study which presents chemopreventive effects of different breads after in vitro fermentation. In spite of differences in composition, the results were comparable between the bread types. Nevertheless, they indicate a potential involvement of this staple food product regarding the prevention of colon cancer.
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Affiliation(s)
- Wiebke Schlörmann
- Department of Nutritional Toxicology, Institute of Nutrition, Friedrich-Schiller-University Jena, Dornburger Strasse 24, 07743, Jena, Germany.
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Azcárate-Peril MA, Sikes M, Bruno-Bárcena JM. The intestinal microbiota, gastrointestinal environment and colorectal cancer: a putative role for probiotics in prevention of colorectal cancer? Am J Physiol Gastrointest Liver Physiol 2011; 301:G401-24. [PMID: 21700901 PMCID: PMC3774253 DOI: 10.1152/ajpgi.00110.2011] [Citation(s) in RCA: 171] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Colorectal cancer (CRC) is the third most commonly diagnosed cancer in the United States, and, even though 5-15% of the total CRC cases can be attributed to individual genetic predisposition, environmental factors could be considered major factors in susceptibility to CRC. Lifestyle factors increasing the risks of CRC include elevated body mass index, obesity, and reduced physical activity. Additionally, a number of dietary elements have been associated with higher or lower incidence of CRC. In this context, it has been suggested that diets high in fruit and low in meat might have a protective effect, reducing the incidence of colorectal adenomas by modulating the composition of the normal nonpathogenic commensal microbiota. In addition, it has been demonstrated that changes in abundance of taxonomic groups have a profound impact on the gastrointestinal physiology, and an increasing number of studies are proposing that the microbiota mediates the generation of dietary factors triggering colon cancer. High-throughput sequencing and molecular taxonomic technologies are rapidly filling the knowledge gaps left by conventional microbiology techniques to obtain a comprehensive catalog of the human intestinal microbiota and their associated metabolic repertoire. The information provided by these studies will be essential to identify agents capable of modulating the massive amount of gut bacteria in safe noninvasive manners to prevent CRC. Probiotics, defined as "live microorganisms which, when administered in adequate amounts, confer a health benefit on the host" (219), are capable of transient modulation of the microbiota, and their beneficial effects include reinforcement of the natural defense mechanisms and protection against gastrointestinal disorders. Probiotics have been successfully used to manage infant diarrhea, food allergies, and inflammatory bowel disease; hence, the purpose of this review was to examine probiotic metabolic activities that may have an effect on the prevention of CRC by scavenging toxic compounds or preventing their generation in situ. Additionally, a brief consideration is given to safety evaluation and production methods in the context of probiotics efficacy.
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Affiliation(s)
- M. Andrea Azcárate-Peril
- 1Department of Cell and Molecular Physiology, University of North Carolina School of Medicine, Chapel Hill;
| | - Michael Sikes
- 2Department of Microbiology, North Carolina State University, Raleigh, North Carolina
| | - José M. Bruno-Bárcena
- 2Department of Microbiology, North Carolina State University, Raleigh, North Carolina
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Rawłuszko AA, Krokowicz P, Jagodziński PP. Butyrate induces expression of 17β-hydroxysteroid dehydrogenase type 1 in HT29 and SW707 colorectal cancer cells. DNA Cell Biol 2011; 30:661-9. [PMID: 21563966 DOI: 10.1089/dna.2010.1192] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Epidemiological studies have revealed that butyrate and 17β-estradiol (E2) may decrease the incidence of colorectal cancer (CRC). In peripheral tissue, E2 can be produced locally by 17β-hydroxysteroid dehydrogenase 1 (HSD17B1) estrone (E1) reduction. Using quantitative real-time polymerase chain reaction and western blotting analysis, we found that sodium butyrate significantly upregulates HSD17B1 long and short transcripts and protein levels in HT29 and SW707 CRC cells. Chromatin immunoprecipitation analysis showed that upregulation of these transcript levels correlated with an increase in binding of Polymerase II to proximal and distal promoters of HSD17B1. Moreover, we observed that upregulation of HSD17B1 protein levels was associated with increased conversion of E1 to E2 in HT29 and SW707 CRC cells. Since sodium butyrate increases the conversion of E1 to E2, our findings may support the validity of butyrate in the prophylaxis of CRC incidence.
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Affiliation(s)
- Agnieszka Anna Rawłuszko
- Department of Biochemistry and Molecular Biology, Poznań University of Medical Sciences, Poznań, Poland
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Valproic acid antagonizes the capacity of other histone deacetylase inhibitors to activate the Epstein-barr virus lytic cycle. J Virol 2011; 85:5628-43. [PMID: 21411522 DOI: 10.1128/jvi.02659-10] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Diverse stimuli reactivate the Epstein-Barr virus (EBV) lytic cycle in Burkitt lymphoma (BL) cells. In HH514-16 BL cells, two histone deacetylase (HDAC) inhibitors, sodium butyrate (NaB) and trichostatin A (TSA), and the DNA methyltransferase inhibitor azacytidine (AzaCdR) promote lytic reactivation. Valproic acid (VPA), which, like NaB, belongs to the short-chain fatty acid class of HDAC inhibitors, fails to induce the EBV lytic cycle in these cells. Nonetheless, VPA behaves as an HDAC inhibitor; it causes hyperacetylation of histone H3 (J. K. Countryman, L. Gradoville, and G. Miller, J. Virol. 82:4706-4719, 2008). Here we show that VPA blocked the induction of EBV early lytic proteins ZEBRA and EA-D in response to NaB, TSA, or AzaCdR. The block in lytic activation occurred prior to the accumulation of BZLF1 transcripts. Reactivation of EBV in Akata cells, in response to anti-IgG, and in Raji cells, in response to tetradecanoyl phorbol acetate (TPA), was also inhibited by VPA. MS-275 and apicidin, representing two additional classes of HDAC inhibitors, and suberoylanilide hydroxamic acid (SAHA) reactivated EBV in HH514-16 cells; this activity was also inhibited by VPA. Although VPA potently blocked the expression of viral lytic-cycle transcripts, it did not generally block the transcription of cellular genes and was not toxic. The levels and kinetics of specific cellular transcripts, such as Stat3, Frmd6, Mad1, Sepp1, c-fos, c-jun, and egr1, which were activated by NaB and TSA, were similar in HH514-16 cells treated with VPA. When combined with NaB or TSA, VPA did not inhibit the activation of these cellular genes. Changes in cellular gene expression in response to VPA, NaB, or TSA were globally similar as assessed by human genome arrays; however, VPA selectively stimulated the expression of some cellular genes, such as MEF2D, YY1, and ZEB1, that could repress the EBV lytic cycle. We describe a novel example of functional antagonism between HDAC inhibitors.
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Goto K, Zako K, Komizu Y, Ueoka R. Inhibitory Effects of Hybrid Liposomes Composed of Phosphatidylcholine and Docosahexaenoic Acid on the Growth of Colon Cancer Cells along with Apoptosis and Differentiation. CHEM LETT 2011. [DOI: 10.1246/cl.2011.90] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
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Lea MA. Recently identified and potential targets for colon cancer treatment. Future Oncol 2010; 6:993-1002. [PMID: 20528236 DOI: 10.2217/fon.10.53] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
The systemic therapy for colorectal cancer has advanced from essentially a single, partially effective agent, 5-fluorouracil, to a combination of cytotoxics and antibodies offering increased survival. In addition to damage of DNA through agents, such as oxaliplatin and irinotecan, and inhibition of DNA replication, a promising approach involves modifying the control of gene expression, including epigenetic control. Modulation of invasion and metastasis should become increasingly important. Inhibition of growth-factor signaling with small-molecule drugs and antibodies can be a part of this effort. Further progress in the control of gene expression in colon cancer may be achieved with miRNAs and RNA interference if technical problems can be overcome. A number of genetic changes in colorectal cancer progression have been identified and offer targets for future therapy.
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Affiliation(s)
- Michael A Lea
- Department of Biochemistry & Molecular Biology, UMDNJ-New Jersey Medical School, 185 South Orange Avenue, Newark, NJ 07103, USA.
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Unveiling an abundant core microbiota in the human adult colon by a phylogroup-independent searching approach. ISME JOURNAL 2010; 5:519-31. [PMID: 20740026 DOI: 10.1038/ismej.2010.129] [Citation(s) in RCA: 67] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
The potential presence of widespread and stable bacterial core phylogroups in the human colon has promoted considerable attention. Despite major efforts, no such phylogroups have yet been identified. Therefore, using a novel phylogroup- and tree-independent approach, we present a reanalysis of 1,114,722 V2 region and 71,550 near full-length 16S rRNA sequences from a total of 210 human beings, with widespread geographic origin, ethnic background and diet, in addition to a wide range of other mammals. We found two highly prevalent core phylogroups (cores 1 and 2), belonging to the clostridial family Lachnospiraceae. These core phylogroups showed a log-normal distribution among human individuals, while non-core phylogroups showed more skewed distributions towards individuals with low levels compared with the log-normal distribution. Molecular clock analyses suggest that core 2 co-evolved with the radiation of vertebrates, while core 1 co-evolved with the mammals. Taken together, the stability, prevalence and potential functionality support the fact that the identified core phylogroups are pivotal in maintaining gut homeostasis and health.
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Campos-Vega R, Guevara-Gonzalez R, Guevara-Olvera B, Dave Oomah B, Loarca-Piña G. Bean (Phaseolus vulgaris L.) polysaccharides modulate gene expression in human colon cancer cells (HT-29). Food Res Int 2010. [DOI: 10.1016/j.foodres.2010.01.017] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
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Butyrate-induced cell death and differentiation are associated with distinct patterns of ROS in HT29-derived human colon cancer cells. Dig Dis Sci 2010; 55:920-30. [PMID: 19434493 DOI: 10.1007/s10620-009-0820-6] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2009] [Accepted: 04/12/2009] [Indexed: 01/28/2023]
Abstract
To investigate the role of reactive oxygen species (ROS) induced by butyrate in tumor cells, we compared HT29R, an HT29-derived human colon cancer cell line refractory to butyrate-induced cell differentiation but highly sensitive to cell death, with the differentiation-positive HT29-12 and HT29-21 cell lines (exhibiting low sensitivity to butyrate-induced cell death), with respect to levels of butyrate-induced free radicals (FRs), ROS, and H(2)O(2). Dose-dependent increase of FRs (as determined by electron spin resonance spectroscopy) and ROS (dichlorofluorescein assay) was induced in HT29R, but not in HT29-12 and HT29-21 cells, where, in contrast to HT29R, a dose-dependent increase of H(2)O(2) release (phenol red assay) was induced by butyrate. The mode of butyrate-induced cell death in HT29R cells was of a mixed type with necrosis predominating, which, however, switched to apoptosis as the major type of cell death in the presence of the drugs 1,5-dihydroxyisoquinoline, resveratrol, or cyclosporine A. The results suggest that FRs and ROS induced by butyrate in HT29R cells are products of cell death, while H(2)O(2) induced in HT29-12 and HT29-21 cells is functionally related to cell differentiation.
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