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      Administration of Metabiotics Extracted From Probiotic Lactobacillus rhamnosus MD 14 Inhibit Experimental Colorectal Carcinogenesis by Targeting Wnt/β-Catenin Pathway

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          Abstract

          Background and Objective: The cellular microenvironment, diet, and lifestyle play a key role in the occurrence of colorectal cancer. Due to its rising trend, attempts are being made to devise novel biointerventions as adjunct to conventional therapies to prevent this deadly disease. “Metabiotics,” the beneficial metabolic signatures of probiotics are emerging as potential anticancer agent due to their ability to alter metabolic processes in the gut lumen and reduce the severity of colon carcinogenesis. Although beneficial attributes of metabiotics have been elucidated in vitro, yet their anticancer mechanism in vivo needs to be explored. Thus, the present study was performed to envisage anticancer potential of metabiotic extract obtained from indigenous probiotic, Lactobacillus rhamnosus MD 14, in early experimental colon carcinogenesis.

          Materials and Methods: Sprague–Dawley rats were daily administered with low, medium, and high dose of metabiotic extract orally along with a single dose of weekly intraperitoneal injection of 1,2-dimethylhydrazine up to 6 weeks and monitored for the markers of early colon carcinogenesis.

          Results: It was observed that the medium dose of metabiotic extract attenuated early colon carcinogenesis by reducing fecal procarcinogenic enzymes, oxidants, aberrant crypt foci, vis-à-vis downregulating oncogenes [K-ras, β-catenin, Cox-2, nuclear factor kappa B (NF-κB)] and upregulating tumor suppressor p53 gene leading to almost normal colon histology.

          Conclusions: It can be suggested that metabiotics modulate experimental colorectal cancer and could be used as a promising alternative of probiotics, particularly in immunocompromised individuals.

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          Most cited references55

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          Mechanisms of lipid peroxide formation in animal tissues.

          E D WILLS (1966)
          1. Homogenates of rat liver, spleen, heart and kidney form lipid peroxides when incubated in vitro and actively catalyse peroxide formation in emulsions of linoleic acid or linolenic acid. 2. In liver, catalytic activity is distributed throughout the nuclear, mitochondrial and microsomal fractions and is present in the 100000g supernatant. Activity is weak in the nuclear fraction. 3. Dilute (0.5%, w/v) homogenates catalyse peroxidation over the range pH5.0-8.0 but concentrated (5%, w/v) homogenates inhibit peroxidation and destroy peroxide if the solution is more alkaline than pH7.0. 4. Ascorbic acid increases the rate of peroxidation of unsaturated fatty acids catalysed by whole homogenates of liver, heart, kidney and spleen at pH6.0 but not at pH7.4. 5. Catalysis of peroxidation of unsaturated fatty acids by the mitochondrial and microsomal fractions of liver is inhibited by ascorbic acid at pH7.4 but the activity of the supernatant fraction is enhanced. 6. Inorganic iron or ferritin are active catalysts in the presence of ascorbic acid. 7. Lipid peroxide formation in linoleic acid or linolenic acid emulsions catalysed by tissue homogenates is partially inhibited by EDTA but stimulated by o-phenanthroline. 8. Cysteine or glutathione (1mm) inhibits peroxide formation catalysed by whole homogenates, mitochondria or haemoprotein. Inhibition increases with increase of pH.
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            Phospholipid Remodeling and Cholesterol Availability Regulate Intestinal Stemness and Tumorigenesis

            Adequate availability of cellular building blocks, including lipids, is a prerequisite for cellular proliferation, but excess dietary lipids are linked to increased cancer risk. Despite these connections, specific regulatory relationships between membrane composition, intestinal stem cell (ISC) proliferation and tumorigenesis are unclear. We reveal an unexpected link between membrane phospholipid remodeling and cholesterol biosynthesis and demonstrate that cholesterol itself acts as a mitogen for ISCs. Inhibition of the phospholipid-remodeling enzyme Lpcat3 increases membrane saturation and stimulates cholesterol biosynthesis, thereby driving ISC proliferation. Pharmacologic inhibition of cholesterol synthesis normalizes crypt hyperproliferation in Lpcat3-deficient organoids and mice. Conversely, increasing cellular cholesterol content stimulates crypt organoid growth, and providing excess dietary cholesterol or driving endogenous cholesterol synthesis through SREBP-2 expression promotes ISC proliferation in vivo . Finally, disruption of Lpcat3-dependent phospholipid and cholesterol homeostasis dramatically enhances tumor formation in Apc min mice. These findings identify a critical dietary-responsive phospholipid-cholesterol axis regulating ISC proliferation and tumorigenesis. Tontonoz and colleagues show that the phospholipid remodeling enzyme Lpcat3 regulates intestinal stem cell and progenitor cells by stimulating cholesterol biosynthesis. Furthermore, enhancing cholesterol availability, either by providing it in the diet or through genetic manipulation, promotes tumorigenesis in Apc min/+ mice.
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              Dysbiosis of gut microbiota in promoting the development of colorectal cancer

              Abstract Gastrointestinal microbiome, containing at least 100 trillion bacteria, resides in the mucosal surface of human intestine. Recent studies show that perturbations in the microbiota may influence physiology and link to a number of diseases, including colon tumorigenesis. Colorectal cancer (CRC), the third most common cancer, is the disease resulting from multi-genes and multi-factors, but the mechanistic details between gut microenvironment and CRC remain poorly characterized. Thanks to new technologies such as metagenome sequencing, progress in large-scale analysis of the genetic and metabolic profile of gut microbial has been possible, which has facilitated studies about microbiota composition, taxonomic alterations and host interactions. Different bacterial species and their metabolites play critical roles in the development of CRC. Also, microbiota is important in the inflammatory response and immune processes deregulation during the development and progression of CRC. This review summarizes current studies regarding the association between gastrointestinal microbiota and the development of CRC, which provides insights into the therapeutic strategy of CRC.
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                Author and article information

                Contributors
                Journal
                Front Oncol
                Front Oncol
                Front. Oncol.
                Frontiers in Oncology
                Frontiers Media S.A.
                2234-943X
                02 June 2020
                2020
                : 10
                : 746
                Affiliations
                Department of Microbiology, Panjab University , Chandigarh, India
                Author notes

                Edited by: Simona Gurzu, University of Medicine and Pharmacy of Târgu Mureş, Romania

                Reviewed by: Brian M. Olson, Emory University, United States; Maozhen Han, Anhui Medical University, China; Lin Wang, New York University, United States

                *Correspondence: Geeta Shukla geeta_shukla@ 123456pu.ac.in

                This article was submitted to Gastrointestinal Cancers, a section of the journal Frontiers in Oncology

                Article
                10.3389/fonc.2020.00746
                7326139
                32670864
                3c3231b5-0283-4f13-b6ee-060553abf0d0
                Copyright © 2020 Sharma and Shukla.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 02 October 2019
                : 20 April 2020
                Page count
                Figures: 7, Tables: 1, Equations: 0, References: 64, Pages: 14, Words: 7839
                Funding
                Funded by: Indian Council of Medical Research 10.13039/501100001411
                Award ID: 3/1/3 JRF-2013/HRD-060
                Categories
                Oncology
                Original Research

                Oncology & Radiotherapy
                metabiotics,bioactive substances,probiotics,colon cancer,aberrant crypt foci

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